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 S e i z u r e - p r o t e c t i n g _ J J   e f f e c t s _ N N 2   o f _ I O   k y o t o r p h i n _ N N 1   a n d _ C C   r e l a t e d _ J J   p e p t i d e s _ N N 2   i n _ I I   a n _ A T 1   a n i m a l _ N N 1   m o d e l _ N N 1   o f _ I O   e p i l e p s y _ N N 1   . _ .   
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 I n _ I I   o n e _ M C 1   l o n g - t e r m _ J J   f o l l o w - u p _ J J   s t u d y _ N N 1   , _ ,   g r e a t e r _ J J R   t h a n _ C S N   9 5 % _ N N U   o f _ I O   p a t i e n t s _ N N 2   w i t h _ I W   p r o s t a t e _ N N 1   c a n c e r _ N N 1   w h o _ P N Q S   u n d e r w e n t _ V V D   s u r g e r y _ N N 1   o r _ C C   r e c e i v e d _ V V D   r a d i a t i o n _ N N 1   e x p e r i e n c e d _ V V D   s o m e _ D D   s e x u a l _ J J   d y s f u n c t i o n _ N N 1   , _ ,   a n d _ C C   a b o u t _ R G   5 0 % _ N N U   r e p o r t e d _ J J   u r i n a r y _ N N 1   o r _ C C   b o w e l _ N N 1   d y s f u n c t i o n . 1 0 2 _ F O   P a t i e n t s _ N N 2   r e c e i v i n g _ V V G   h o r m o n a l _ J J   t r e a t m e n t _ N N 1   m a y _ V M   e x p e r i e n c e _ V V I   l o s s _ N N 1   o f _ I O   l i b i d o _ N N 1   , _ ,   h o t _ J J   f l a s h e s _ N N 2   , _ ,   n i g h t _ N N T 1   s w e a t s _ N N 2   , _ ,   i r r i t a b i l i t y _ N N 1   , _ ,   a n d _ C C   b r e a s t _ N N 1   d e v e l o p m e n t _ N N 1   . _ .   
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 A l t h o u g h _ C S   t h e _ A T   c e r v i x _ N N 1   m a y _ V M   h a v e _ V H I   a p p e a r e d _ V V N   ' _ N U L L   n o r m a l _ J J   ' _ N U L L   i n _ I I   t h e s e _ D D 2   w o m e n _ N N 2   , _ ,   a _ A T 1   s h o r t e n e d _ J J   c e r v i c a l _ J J   l e n g t h _ N N 1   m a y _ V M   h a v e _ V H I   b e e n _ V B N   p r e s e n t _ J J   . _ .   
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 D a t a _ N N   a r e _ V B R   p r e s e n t e d _ V V N   a s _ C S A   m e a n _ N N 1   p l u s _ N N 1   a n d _ C C   m i n u s _ N N 1   S D _ N N 1   a n d _ C C   a _ A T 1   P - v a l u e _ N N 1   o f _ I O   l e s s _ D A R   t h a n _ C S N   a n d _ C C   e q u a l _ J J   t o _ I I   0 . 0 5 _ M C   w a s _ V B D Z   c o n s i d e r e d _ V V N   s t a t i s t i c a l l y _ R R   s i g n i f i c a n t _ J J   . _ .   
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 T h i s _ D D 1   d e p e n d e n t _ J J   p r o c e s s i n g _ N N 1   e f f e c t _ N N 1   o f _ I O   a r o u s a l _ N N 1   o n _ I I   v a l e n c e _ N N 1   o f _ I O   s t i m u l i _ N N 2   m i g h t _ V M   e x p l a i n _ V V I   t h e _ A T   l a c k _ N N 1   o f _ I O   e f f e c t _ N N 1   s e e n _ V V N   w h e n _ C S   e x a m i n i n g _ V V G   t h e _ A T   d i m e n s i o n _ N N 1   o f _ I O   a r o u s a l _ N N 1   a l o n e _ R R   ( _ (   a s s u m i n g _ V V G   v a l e n c e _ N N 1   l e v e l s _ N N 2   w e r e _ V B D R   s i m i l a r _ J J   f o r _ I F   t h e _ A T   t h r e e _ M C   l e v e l s _ N N 2   o f _ I O   a r o u s a l _ N N 1   ) _ )   . _ .   
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 I n _ I I 3 1   a d d i t i o n _ I I 3 2   t o _ I I 3 3   t h e _ A T   C T _ N N 1   s c a n s _ N N 2   , _ ,   o t h e r _ J J   c l i n i c a l _ J J   f e a t u r e s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   c e r e b r o s p i n a l _ J J   f l u i d _ N N 1   l e a k s _ N N 2   a n d _ C C   c r a n i a l _ J J   n e r v e _ N N 1   i n j u r y _ N N 1   w e r e _ V B D R   a l s o _ R R   c o n s i d e r e d _ V V N   i n d i c a t i v e _ J J   f o r _ I F   a _ A T 1   b a s a l _ J J   s k u l l _ N N 1   f r a c t u r e _ N N 1   . _ .   
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 R e c o n s t r u c t i v e _ J J   t e c h n i q u e s _ N N 2   , _ ,   e s p e c i a l l y _ R R   f l a p s _ V V Z   r e p l a c i n g _ V V G   t h e _ A T   p o s t e r i o r _ J J   t o n g u e _ N N 1   , _ ,   c a n _ V M   c o m p r o m i s e _ V V I   t h e _ A T   a i r w a y _ N N 1   e v e n _ R R   a f t e r _ I I   a _ A T 1   t r a c h e o s t o m y _ N N 1   i s _ V B Z   a l l o w e d _ V V N   t o _ T O   c l o s e _ V V I   . _ .   
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 T h e _ A T   l e v e l s _ N N 2   o f _ I O   F A - e x t r a c t a b l e _ J J   A m i u x 4 0 _ F O   a n d _ C C   A m i u x 4 2 _ F O   w e r e _ V B D R   q u a n t i f i e d _ V V N   b y _ I I   C - t e r m i n a l _ J J   s p e c i f i c _ J J   s a n d w i c h _ N N 1   E L I S A s _ N P 2   a s _ C S A   d e s c r i b e d _ V V N   a b o v e _ R L   . _ .   
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 W e _ P P I S 2   r a n k e d _ V V D   t h e _ A T   c l i n i c a l _ J J   d i a g n o s i s _ N N 1   i n _ I I   o r d e r _ N N 1   o f _ I O   d e c r e a s i n g _ J J   s e v e r i t y _ N N 1   a c c o r d i n g _ I I 2 1   t o _ I I 2 2   T a b l e _ N N 1   1 _ M C 1   . _ .   
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 T h e _ A T   r e g i o n s _ N N 2   o f _ I O   h o m o z y g o s i t y _ N N 1   a r e _ V B R   g i v e n _ V V N   i n _ I I   t h e _ A T   a p p e n d i x _ N N 1   ( _ (   p _ Z Z 1   1 1 _ M C   ) _ )   . _ .   
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 C E U S _ N P 1   w a s _ V B D Z   p e r f o r m e d _ V V N   u s i n g _ V V G   S o n o - V u e _ N P 1   a s _ C S A   c o n t r a s t _ N N 1   a g e n t _ N N 1   ( _ (   B r a c c o _ N P 1   S p A _ N N 1   , _ ,   M i l a n _ N P 1   , _ ,   I t a l y _ N P 1   ) _ )   , _ ,   a _ A T 1   s u s p e n s i o n _ N N 1   o f _ I O   h e x a f l u o r i d e _ N N 1   g a s _ N N 1   f o r m i n g _ V V G   m i c r o b u b b l e s _ N N 2   w i t h _ I W   a _ A T 1   d i a m e t e r _ N N 1   f r o m _ I I   0 . 5 _ M C   u p _ R G 2 1   t o _ R G 2 2   1 . 5 _ M C   m i c r o m e t e r _ N N 1   . _ .   
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 S t a t i s t i c a l _ J J   A n a l y s i s _ N N 1   S t u d y _ N N 1   d a t a _ N N   w e r e _ V B D R   a n a l y z e d _ V V N   u s i n g _ V V G   b o t h _ R R   p e r - p r o t o c o l _ J J   ( _ (   o n l y _ R R   c o m p l e t e _ J J   s u b j e c t _ N N 1   d a t a _ N N   a n a l y z e d _ V V D   ) _ )   a n d _ C C   i n t e n t i o n - t o - t r e a t _ N N 1   ( _ (   I T T _ N P 1   ) _ )   a n a l y s e s _ N N 2   ( _ (   a l l _ D B   s u b j e c t _ J J   d a t a _ N N   a n a l y z e d _ V V D   w i t h _ I W   m i s s i n g _ J J   d a t a _ N N   p o i n t s _ N N 2   c a l c u l a t e d _ V V D   u s i n g _ V V G   m u l t i p l e _ J J   i m p u t a t i o n _ N N 1   ) _ )   . _ .   
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 L o n g i t u d i n a l _ J J   r e s e a r c h _ N N 1   o n _ I I   w a r - a f f e c t e d _ J J   y o u t h _ N N 1   i n _ I I   t h e _ A T   r e g i o n _ N N 1   d e m o n s t r a t e s _ V V Z   h i g h _ J J   l e v e l s _ N N 2   o f _ I O   c o m o r b i d _ J J   m e n t a l _ J J   h e a l t h _ N N 1   p r o b l e m s _ N N 2   , _ ,   s u g g e s t i n g _ V V G   a _ A T 1   n e e d _ N N 1   f o r _ I F   t r a u m a - i n f o r m e d _ N N 1   , _ ,   b r o a d - b a s e d _ J J   i n t e r v e n t i o n s _ N N 2   . _ .   
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 F u r t h e r m o r e _ R R   , _ ,   o n l y _ R R   t h e s e _ D D 2   n i n e _ M C   c o u n t r i e s _ N N 2   r e p r e s e n t i n g _ V V G   t h r e e _ M C   c o n t i n e n t s _ N N 2   h a d _ V H D   d a t a _ N N   n e c e s s a r y _ J J   f o r _ I F   t h i s _ D D 1   a n a l y s i s _ N N 1   a n d _ C C   t h e r e _ E X   a r e _ V B R   l a r g e _ J J   d i f f e r e n c e s _ N N 2   i n _ I I   p l a c e _ N N 1   a n d _ C C   a t t e n d a n c e _ N N 1   a t _ I I   b i r t h _ N N 1   a m o n g _ I I   t h e s e _ D D 2   c o u n t r i e s _ N N 2   . _ .   
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 I n _ I I   c o n t r a s t _ N N 1   , _ ,   t h e _ A T   B R U M S _ N P 2   p r o v i d e s _ V V Z   a _ A T 1   s c o r e _ N N 1   r a n g e _ N N 1   f r o m _ I I   0 _ M C   t o _ I I   1 6 _ M C   A U _ F O   , _ ,   b a s e d _ V V N   o n _ I I   s u b j e c t i v e _ J J   f e e l i n g s _ N N 2   o f _ I O   t i r e d n e s s _ N N 1   ( _ (   f o u r _ M C   s y n o n y m o u s _ J J   w o r d s _ N N 2   s c o r e d _ V V N   f r o m _ I I   0 _ M C   t o _ I I   4 _ M C   A U _ F O   e a c h _ D D 1   ) _ )   . _ .   
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 T h e _ A T   a u t h o r s _ N N 2   d e c l a r e _ V V 0   t h a t _ C S T   t h e y _ P P H S 2   h a v e _ V H 0   n o _ A T   c o n f l i c t _ N N 1   o f _ I O   i n t e r e s t _ N N 1   . _ .   
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 T o g e t h e r _ R L   w i t h _ I W   a _ A T 1   m o t o r _ N N 1   e x a m i n a t i o n _ N N 1   t h e _ A T   l e v e l _ N N 1   o f _ I O   c o m p l e t e n e s s _ N N 1   i s _ V B Z   t h e n _ R T   c l a s s i f i e d _ V V N   w i t h _ I W   t h e _ A T   A S I A _ N P 1   I m p a i r m e n t _ N N 1   S c a l e _ N N 1   . _ .   
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 C o n f l r m a t i o n _ N N 1   o f _ I O   d i a g n o s i s _ N N 1   H e a l t h y _ J J   p a n c r e a s _ N N 1   w a s _ V B D Z   a s s u m e d _ V V N   d u e _ J J   t o _ T O   l a c k _ V V I   o f _ I O   e p i g a s t r i c _ J J   s y m p t o m s _ N N 2   o r _ C C   d i a r r h e a _ N N 1   , _ ,   n o r m a l _ J J   l e v e l s _ N N 2   o f _ I O   l i p a s e _ N N 1   a n d _ C C   n o r m a l _ J J   t r a n s a b d o m i n a l _ J J   u l t r a s o u n d _ N N 1   . _ .   
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 O n c o l o g y _ N N 1   p r a c t i t i o n e r s _ N N 2   l i k e l y _ R R   w i l l _ V M   h a v e _ V H I   t o _ T O   c o n s i d e r _ V V I   f i n a n c i a l _ J J   i m p l i c a t i o n s _ N N 2   w h e n _ C S   f o r m u l a t i n g _ V V G   t r e a t m e n t _ N N 1   p l a n s _ N N 2   . _ .   
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 W i t h i n _ I I   d a y s _ N N T 2   f o l l o w i n g _ R A   i n t r a v i t r e a l _ J J   i n j e c t i o n _ N N 1   ' _ N U L L   f u n d u s _ N N 1   p h o t o g r a p h y _ N N 1   s h o w s _ V V Z   p r o g r e s s i v e _ J J   m e d i a _ N N   h a z e _ N N 1   . _ .   
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 A s _ C S A   n o t e d _ V V N   a b o v e _ R L   , _ ,   4 _ M C   p a t i e n t s _ N N 2   w e r e _ V B D R   c l a s s i f i e d _ V V N   d u e _ I I 2 1   t o _ I I 2 2   u n a u t h o r i z e d _ J J   d o s e _ N N 1   e s c a l a t i o n _ N N 1   ; _ ;   4 _ M C   p a t i e n t s _ N N 2   h a d _ V H D   n o n p r e s c r i b e d _ V V N   c o n t r o l l e d _ V V N   o r _ C C   i l l i c i t _ J J   s u b s t a n c e s _ N N 2   o n _ I I   U D T _ N P 1   t e s t i n g _ N N 1   ( _ (   B _ Z Z 1   , _ ,   C _ N P 1   : _ :   o p i o i d s _ N N 2   ; _ ;   D _ N P 1   : _ :   c o c a i n e _ N N 1   a n d _ C C   a l c o h o l _ N N 1   m e t a b o l i t e s _ N N 2   ; _ ;   E _ N P 1   : _ :   t e t r a h y d r o c a n n a b i n o l _ N N 1   ) _ )   , _ ,   a n d _ C C   1 _ M C 1   p a t i e n t _ N N 1   ( _ (   S u b j e c t _ N N 1   I _ Z Z 1   ) _ )   r e p o r t e d _ V V D   c o n t i n u e d _ J J   o p i o i d _ J J   u s e _ N N 1   d e s p i t e _ I I   a d v e r s e _ J J   c o n s e q u e n c e s _ N N 2   . _ .   
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 N a m e _ N N 1   : _ :   J a n _ N P 1   V a n _ N P 1   H e m e l r i j c k _ N P 1   , _ ,   M D _ N N A   , _ ,   P h D _ N N 1   . _ .   
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 U l t r a s o u n d _ V V 0   t i s s u e _ N N 1   c h a r a c t e r i s a t i o n _ N N 1   , _ ,   a _ A T 1   n o v e l _ J J   f o r m _ N N 1   o f _ I O   u l t r a s o u n d _ N N 1   , _ ,   c a n _ V M   q u a n t i f y _ V V I   t h e _ A T   d e g r e e _ N N 1   o f _ I O   d i s o r g a n i s a t i o n _ N N 1   w i t h i n _ I I   a _ A T 1   t e n d o n _ N N 1   a n d _ C C   m a y _ V M   e n h a n c e _ V V I   c l i n i c a l _ J J   i n f o r m a t i o n _ N N 1   f r o m _ I I   i m a g i n g _ N N 1   ( _ (   F i g u r e s _ V V Z   3 _ M C   a n d _ C C   4 _ M C   ) _ )   . _ .   
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 C h r o n i c _ J J   p a i n _ N N 1   o f _ I O   a n y _ D D   k i n d _ N N 1   i s _ V B Z   d e b i l i t a t i n g _ J J   w i t h _ I W   f a r _ R R   r e a c h i n g _ V V G   c o n s e q u e n c e s _ N N 2   o n _ I I   t h e _ A T   p a t i e n t _ N N 1   ' _ N U L L   s _ Z Z 1   l i f e _ N N 1   . _ .   
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 I n _ I I   s o m a t i c _ J J   t i s s u e s _ N N 2   , _ ,   c a l c i n e u r i n _ N N 1   i s _ V B Z   c o m p o s e d _ V V N   o f _ I O   a _ A T 1   c a t a l y t i c _ J J   s u b u n i t _ N N 1   , _ ,   e n c o d e d _ V V N   b y _ I I   t w o _ M C   d i s t i n c t _ J J   g e n e s _ N N 2   ( _ (   P P P 3 C A _ F O   a n d _ C C   P P P 3 C B _ F O   ) _ )   , _ ,   a n d _ C C   a _ A T 1   r e g u l a t o r y _ J J   s u b u n i t _ N N 1   , _ ,   e n c o d e d _ V V N   b y _ I I   P P P 3 R 1 _ F O   . _ .   
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 T h e _ A T   c a l c u l a t i o n _ N N 1   o f _ I O   t h e _ A T   a r t e r i a l _ J J   e n h a n c e m e n t _ N N 1   f r a c t i o n _ N N 1   ( _ (   A E F _ N P 1   ) _ )   , _ ,   a s _ C S A   i n t r o d u c e d _ V V N   b y _ I I   K i m _ N P 1   e t _ R A 2 1   a l _ R A 2 2   , _ ,   1 2 _ M C   a l l o w s _ V V Z   t h e _ A T   c a l c u l a t i o n _ N N 1   o f _ I O   a _ A T 1   q u a n t i t a t i v e _ J J   c o l o r e d _ J J   l i v e r _ N N 1   m a p _ N N 1   u s i n g _ V V G   t h e _ A T   r a w _ J J   d a t a _ N N   o f _ I O   a _ A T 1   s t a n d a r d _ J J   C T _ N N 1   s c a n _ N N 1   w i t h _ I W   t r i p h a s i c _ J J   a c q u i s i t i o n _ N N 1   ( _ (   u n e n h a n c e d _ J J   , _ ,   a r t e r i a l _ J J   , _ ,   a n d _ C C   p o r t a l _ N N 1   v e n o u s _ J J   p h a s e _ N N 1   ) _ )   . _ .   
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 T h e _ A T   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   t h e r a p y _ N N 1   g r o u p _ N N 1   r e c e i v e d _ V V D   o r a l _ J J   d o x y c y c l i n e _ N N 1   a t _ I I   a _ A T 1   d o s e _ N N 1   o f _ I O   1 0 0 _ M C   m g _ N N U   p e r _ I I   d a y _ N N T 1   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   a _ A T 1   c a t e g o r i c a l _ J J   i r r i t a b i l i t y _ N N 1   o u t c o m e _ N N 1   w a s _ V B D Z   g e n e r a t e d _ V V N   u s i n g _ V V G   a _ A T 1   m e d i a n _ J J   s p l i t _ N N 1   i n t o _ I I   h i g h _ J J   a n d _ C C   l o w _ J J   i r r i t a b i l i t y _ N N 1   a n d _ C C   w a s _ V B D Z   u s e d _ V V N   f o r _ I F   p u r p o s e s _ N N 2   o f _ I O   i l l u s t r a t i o n _ N N 1   i n _ I I   s e v e r a l _ D A 2   f i g u r e s _ N N 2   . _ .   
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 I m a g i n e _ V V 0   u s i n g _ V V G   b e d s i d e _ N N 1   u l t r a s o u n d _ N N 1   t o _ T O   d i a g n o s e _ V V I   p n e u m o n i a _ N N 1   i n _ I I   a _ A T 1   s c r e a m i n g _ J J   1 - y e a r - o l d _ J J   o r _ C C   t o _ T O   r u l e _ V V I   o u t _ R P   a n _ A T 1   e l b o w _ N N 1   f r a c t u r e _ N N 1   i n _ I I   a _ A T 1   k i n d e r g a r t e n e r _ N N 1   w h o _ P N Q S   f e l l _ V V D   o f f _ I I   t h e _ A T   m o n k e y _ N N 1   b a r s _ N N 2   , _ ,   p o t e n t i a l l y _ R R   s p a r i n g _ V V G   t h e s e _ D D 2   c h i l d r e n _ N N 2   a _ A T 1   r a d i o g r a p h _ N N 1   ( _ (   a n d _ C C   s p a r i n g _ V V G   t h e i r _ A P P G E   p a r e n t s _ N N 2   t h e _ A T   c o s t _ N N 1   a n d _ C C   t i m e _ N N T 1   i t _ P P H 1   w o u l d _ V M   t a k e _ V V I   t o _ T O   g e t _ V V I   o n e _ M C 1   ) _ )   . _ .   
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 M o r e o v e r _ R R   , _ ,   i n f a r c t s _ N N 2   w e r e _ V B D R   v i s u a l l y _ R R   i d e n t i f i e d _ V V N   a n d _ C C   e x c l u d e d _ V V N   f r o m _ I I   t h e _ A T   W M H s _ N P 1   . _ .   
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 M e t h o d s _ N N 2   ' _ N U L L   U s i n g _ V V G   C H O _ N P 1   A P P 7 5 i S W _ F O   c e l l s _ N N 2   w e _ P P I S 2   i d e n t i f i e d _ V V D   a n d _ C C   c h a r a c t e r i z e d _ V V D   e f f e c t s _ N N 2   o f _ I O   2 - & l s q b ; _ (   ( _ (   p y r i d i n e - 2 - y l m e t h y l _ N N 1   ) _ )   - a m i n o _ N N 1   & r s q b ; _ )   - p h e n o l _ N N 1   ( _ (   2 - P M A P _ N P 1   ) _ )   o n _ I I   A P P _ N P 1   s t e a d y - s t a t e _ J J   l e v e l _ N N 1   a n d _ C C   A P _ N P 1   p r o d u c t i o n _ N N 1   . _ .   
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 A _ A T 1   t r a u m a - i n f o r m e d _ J J   a p p r o a c h _ N N 1   a l l o w s _ V V Z   c a r e _ N N 1   p r o v i d e r s _ N N 2   t o _ T O   u n d e r s t a n d _ V V I   t h a t _ C S T   m a n y _ D A 2   p a t i e n t s _ N N 2   a n d _ C C   t h e i r _ A P P G E   p a r e n t s _ N N 2   m a y _ V M   h a v e _ V H I   e x p e r i e n c e d _ V V N   p r i o r _ J J   P T E s _ N N 2   a n d _ C C   t h a t _ C S T   t h e s e _ D D 2   e x p e r i e n c e s _ N N 2   i m p a c t _ N N 1   h o w _ R R Q   t h e y _ P P H S 2   e x p e r i e n c e _ V V 0   m e d i c a l _ J J   c a r e _ N N 1   . _ .   
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 O n e _ M C 1   r a t e r _ N N 1   w a s _ V B D Z   t h e _ A T   n u r s e _ N N 1   i n _ I I 3 1   c h a r g e _ I I 3 2   o f _ I I 3 3   t h e _ A T   i n f a n t _ N N 1   ' _ N U L L   s _ Z Z 1   c a r e _ N N 1   w h i l e _ C S   t h e _ A T   s e c o n d _ M D   r a t e r _ N N 1   w a s _ V B D Z   d r a w n _ V V N   f r o m _ I I   t h e _ A T   p o o l _ N N 1   o f _ I O   r e c r u i t e d _ J J   n u r s e s _ N N 2   . _ .   
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 U s i n g _ V V G   t h e _ A T   p o s t - E D _ J J   R R T _ N P 1   a s _ I I   a _ A T 1   t r i g g e r _ N N 1   i n c r e a s e d _ V V D   t h e _ A T   c a s e s _ N N 2   r e v i e w e d _ V V N   b y _ I I   3 6 . 5 % _ F O   . _ .   
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 I n _ I I   t h e _ A T   p r e s e n t _ J J   s t u d y _ N N 1   , _ ,   w e _ P P I S 2   i n v e s t i g a t e d _ V V D   a g e - r e l a t e d _ J J   d e c l i n e _ N N 1   i n _ I I   d u r a t i o n _ N N 1   c o m p a r i s o n _ N N 1   o n _ I I   a _ A T 1   m i l l i s e c o n d _ N N T 1   l e v e l _ N N 1   u s i n g _ V V G   t h e _ A T   p a s s i v e _ J J   o d d b a l l _ N N 1   t a s k _ N N 1   t o _ T O   e l i c i t _ V V I   t h e _ A T   m i s m a t c h _ N N 1   n e g a t i v i t y _ N N 1   c o m p o n e n t _ N N 1   ( _ (   M M N _ N P 1   ; _ ;   N a a t a n e n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 9 7 8 _ M C   ) _ )   . _ .   
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 I n _ I I   d o i n g _ V D G   s o _ R R   , _ ,   w e _ P P I S 2   c r e a t e d _ V V D   a _ A T 1   m o d e l _ N N 1   i n _ I I   w h i c h _ D D Q   d o n o r _ N N 1   D C s _ N N 2   , _ ,   p r e s e n t i n g _ V V G   M H C - c l a s s _ J J   I _ Z Z 1   m o l e c u l e s _ N N 2   a n d _ C C   O V A _ N N 2   p e p t i d e _ N N 1   , _ ,   c o u l d _ V M   b e _ V B I   r e m o v e d _ V V N   b y _ I I   u s i n g _ V V G   D T _ N P 1   , _ ,   f o l l o w i n g _ V V G   A c t - m O V A x D T R / G F P _ N N 1   s k i n _ N N 1   t r a n s p l a n t a t i o n _ N N 1   ( _ (   F i g u r e _ N N 1   2 A _ F O   ) _ )   . _ .   
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 ( _ (   2 8 _ M C   ) _ )   c o m p a r e d _ V V D   c o h o r t s _ N N 2   o f _ I O   p a t i e n t s _ N N 2   w h o _ P N Q S   h a d _ V H D   r e c e i v e d _ V V N   S o C _ N P 1   ( _ (   n _ Z Z 1   = _ F O   1 1 _ M C   ) _ )   , _ ,   R E T _ N P 1   ( _ (   n _ Z Z 1   = _ F O   1 7 _ M C   ) _ )   , _ ,   l o n g - t e r m _ J J   o x a n d r o l o n e _ N N 1   t r e a t m e n t _ N N 1   ( _ (   n _ Z Z 1   = _ F O   9 _ M C   ) _ )   , _ ,   o r _ C C   b o t h _ D B 2   R E T _ V V 0   a n d _ C C   l o n g - t e r m _ J J   o x a n d r o l o n e _ N N 1   ( _ (   n _ Z Z 1   = _ F O   1 4 _ M C   ) _ )   . _ .   
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 H e r e _ R L   w e _ P P I S 2   r e c o r d _ V V 0   , _ ,   f o r _ I F   t h e _ A T   f i r s t _ M D   t i m e _ N N T 1   , _ ,   s p o n t a n e o u s _ J J   s e i z u r e s _ N N 2   i n _ I I   a _ A T 1   r a t _ N N 1   m o d e l _ N N 1   o f _ I O   v a s c u l a r _ J J   i n j u r y _ N N 1   a n d _ C C   B B B _ N P 1   b r e a k d o w n _ N N 1   , _ ,   a n d _ C C   s h o w _ V V 0   t h a t _ C S T   l o c a l _ J J   e x p o s u r e _ N N 1   o f _ I O   t h e _ A T   c o r t e x _ N N 1   t o _ I I   a l b u m i n _ N N 1   i s _ V B Z   s u f f i c i e n t _ J J   t o _ T O   i n d u c e _ V V I   s e i z u r e s _ N N 2   . _ .   
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 V i d e o _ N N 1   c a s s e t t e _ N N 1   r e c o r d e r s _ N N 2   h a d _ V H D   b e e n _ V B N   a d o p t e d _ V V N   b y _ I I   t h e _ A T   m a j o r i t y _ N N 1   o f _ I O   h o u s e h o l d s _ N N 2   w i t h i n _ I I   a _ A T 1   d e c a d e _ N N T 1   a f t e r _ I I   t h e _ A T   f i r s t _ M D   V H S _ N P 1   f o r m a t _ N N 1   p l a y e r _ N N 1   w a s _ V B D Z   i n t r o d u c e d _ V V N   i n _ I I   1 9 7 6 _ M C   . _ .   
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 T o _ I I   o u r _ A P P G E   k n o w l e d g e _ N N 1   , _ ,   t h e r e _ E X   a r e _ V B R   n o _ A T   h e a d - t o - h e a d _ J J   p r o s p e c t i v e _ J J   c l i n i c a l _ J J   t r i a l s _ N N 2   c o m p a r i n g _ V V G   t h e s e _ D D 2   t w o _ M C   a b l a t i v e _ J J   l o c a l _ J J   t r e a t m e n t _ N N 1   s t r a t e g i e s _ N N 2   . _ .   
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 T h e _ A T   r e c o v e r y _ N N 1   r a t e _ N N 1   f o r _ I F   i n t r a t y m p a n i c _ J J   s t e r o i d _ J J   i n j e c t i o n _ N N 1   h a s _ V H Z   b e e n _ V B N   r e p o r t e d _ V V N   t o _ T O   b e _ V B I   6 1 . 5 - 7 7 . 3 % _ F O   . _ .   
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 I n t r a t y m p a n i c _ J J   s t e r o i d _ J J   i n j e c t i o n _ N N 1   h a s _ V H Z   a d v a n t a g e s _ N N 2   i n _ C S 2 1   t h a t _ C S 2 2   t h e _ A T   c o n c e n t r a t i o n _ N N 1   w i t h i n _ I I   t h e _ A T   p e r i l y m p h _ N N 1   i s _ V B Z   h i g h e r _ J J R   t h a n _ C S N   t h e _ A T   a d m i n i s t e r e d _ J J   d o s e _ N N 1   , _ ,   a n d _ C C   s i d e - e f f e c t s _ N N 2   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   c o m p l i c a t i o n s _ N N 2   o f _ I O   s y s t e m i c _ J J   a d m i n i s t r a t i o n _ N N 1   s u c h _ I I 2 1   a s _ I I 2 2   a d r e n a l _ J J   s u p p r e s s i o n _ N N 1   o r _ C C   l i v e r _ N N 1   d y s f u n c t i o n _ N N 1   r a r e l y _ R R   d e v e l o p _ V V 0   . _ .   
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 F u r t h e r m o r e _ R R   ' _ N U L L   L V s _ N P 1   a r e _ V B R   p r o m i s i n g _ J J   v e h i c l e s _ N N 2   t o _ T O   t r a n s f e r _ V V I   g e n e s _ N N 2   i n t o _ I I   i P S C s _ N N 2   b e c a u s e _ I I 2 1   o f _ I I 2 2   t h e i r _ A P P G E   s t a b l e _ N N 1   i n t e g r a t i n g _ V V G   c a p a b i l i t y _ N N 1   . _ .   
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 I n _ I I 3 1   a c c o r d a n c e _ I I 3 2   w i t h _ I I 3 3   t h e _ A T   i n i t i a l _ J J   a n a l y s i s _ N N 1   , _ ,   a _ A T 1   s h i f t _ N N 1   t o _ I I   s l o w e r _ J J R   p r o c e s s _ N N 1   s p e e d s _ V V Z   w i t h _ I W   a g i n g _ N N 1   w a s _ V B D Z   a g a i n _ R T   f o u n d _ V V N   ( _ (   F i g . _ N N 1   3 D - F _ N P 1   ) _ )   . _ .   
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 P a t i e n t s _ N N 2   i n _ I I   t h e _ A T   l G B C A _ N N 1   i n t e r v a l _ N N 1   r e c e i v e d _ V V D   a _ A T 1   s t a n d a r d i z e d _ J J   a p p l i c a t i o n _ N N 1   o f _ I O   1 5 _ M C   o r _ C C   2 0 _ M C   m L _ N N U   ( _ (   0 . 5 _ M C   m m o l / m L _ F U   ) _ )   p e r _ I I   M R I _ N P 1   . _ .   
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 O t h e r _ J J   p r o m i s i n g _ J J   t r e a t m e n t _ N N 1   a p p r o a c h e s _ V V Z   f o r _ I F   B A C E 1 _ F O   i n h i b i t i o n _ N N 1   , _ ,   s u c h _ I I 2 1   a s _ I I 2 2   a n t i - B A C E 1 _ J J   a n t i b o d i e s _ N N 2   , _ ,   6 4 , 6 5 _ M C   a r e _ V B R   i n _ I I   p r e c l i n i c a l _ J J   p h a s e s _ N N 2   a n d _ C C   w i l l _ V M   n o t _ X X   b e _ V B I   d e s c r i b e d _ V V N   i n _ I I   t h e _ A T   i n t e r e s t _ N N 1   o f _ I O   b r e v i t y _ N N 1   . _ .   
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 W h i t e _ J J   c e l l _ N N 1   c o u n t s _ N N 2   a n d _ C C   n e u t r o p h i l _ V V 0   n u m b e r s _ N N 2   a f t e r _ I I   a d j u s t m e n t _ N N 1   f o r _ I F   t h e _ A T   m o s t _ R G T   c o m m o n _ J J   c o n f o u n d e r s _ N N 2   a r e _ V B R   r a i s e d _ V V N   i n _ I I   p o p u l a t i o n s _ N N 2   o f _ I O   f r a i l _ J J   o l d e r _ J J R   p e o p l e _ N N   ( _ (   L e n g _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 7 _ M C   ; _ ;   L e n g _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 9 _ M C   ; _ ;   C o l l e r t o n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 2 _ M C   ) _ )   . _ .   
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 C o n c l u s i o n s _ N N 2   : _ :   T h e s e _ D D 2   r e s u l t s _ N N 2   h i g h l i g h t _ V V 0   t h e _ A T   c h a l l e n g e s _ N N 2   o f _ I O   i d e n t i f y i n g _ V V G   n o n a d h e r e n c e _ N N 1   t o _ I I   a _ A T 1   p r e s c r i p t i o n _ N N 1   r e g i m e n _ N N 1   a m o n g _ I I   a d o l e s c e n t s _ N N 2   w i t h _ I W   c h r o n i c _ J J   p a i n _ N N 1   . _ .   
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 A b s e n c e _ N N 1   o f _ I O   N r f 2 _ F O   i n _ I I   A P P / P 1 _ N P 1   m o u s e _ N N 1   l e a d s _ V V Z   t o _ I I   a u t o p h a g y _ J J   i n h i b i t i o n _ N N 1   M a m m a l i a n _ J J   t a r g e t _ N N 1   o f _ I O   r a p a m y c i n _ N N 1   ( _ (   m T O R _ N N 1   ) _ )   i s _ V B Z   a _ A T 1   s e r i n e / t h r e o n i n e _ J J   k i n a s e _ N N 1   t h a t _ C S T   r e g u l a t e s _ V V Z   s e v e r a l _ D A 2   c e l l u l a r _ J J   f u n c t i o n s _ N N 2   i n c l u d i n g _ V V G   , _ ,   b u t _ C C B   n o t _ X X   l i m i t e d _ V V N   , _ ,   t o _ I I   a u t o p h a g y _ N N 1   . _ .   
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 O r a l _ J J   g l u c o s e _ N N 1   t o l e r a n c e _ N N 1   t e s t s _ N N 2   T e n _ M C   c h i l d r e n _ N N 2   w i t h _ I W   m u l t i p l e _ J J   C M N _ N P 1   u n d e r w e n t _ V V D   a n _ A T 1   o r a l _ J J   g l u c o s e _ N N 1   t o l e r a n c e _ N N 1   t e s t _ N N 1   ( _ (   O G T T _ N P 1   ) _ )   f o l l o w i n g _ V V G   t h e _ A T   s t a n d a r d _ J J   h o s p i t a l _ N N 1   p r o t o c o l _ N N 1   . _ .   
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 I n _ I I   G J B 2 p a t i e n t s _ F O   a n _ A T 1   a b n o r m a l _ J J   v e s t i b u l a r _ J J   p h e n o t y p e _ N N 1   i s _ V B Z   s o m e t i m e s _ R T   f o u n d _ V V N   ( _ (   D o d s o n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 1 _ M C   ; _ ;   E p p s t e i n e r _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 1 _ M C   ; _ ;   K a s a i _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 0 _ M C   ; _ ;   T o d t _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 5 _ M C   ; _ ;   Z a g o l s k i _ N P 1   , _ ,   2 0 0 7 _ M C   ) _ )   b u t _ C C B   i n _ I I   m o s t _ D A T   c a s e s _ N N 2   i t _ P P H 1   i s _ V B Z   a b s e n t _ J J   ( _ (   C o h n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 9 9 9 _ M C   ; _ ;   D e n o y e l l e _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 9 9 9 _ M C   ; _ ;   S h i n j o _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 7 _ M C   ) _ )   . _ .   
 
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 T h e _ A T   f o l l o w i n g _ J J   m e a s u r e m e n t s _ N N 2   w e r e _ V B D R   d o n e _ V D N   : _ :   3 - p o i n t - D i x o n _ N P 1   f a t - f r a c t i o n _ J J   q u a n t i f i c a t i o n _ N N 1   r e s u l t i n g _ V V G   i n _ I I   f a t - f r a c t i o n _ J J   m a p s _ N N 2   e x p r e s s e d _ V V N   a s _ C S A   p e r c e n t a g e _ N N 1   f a t _ N N 1   ( _ (   0 - 1 0 0 % _ F O   ) _ )   , _ ,   n o n - f a t - s u p p r e s s e d _ N N 1   T 2 _ F O   m e a s u r e m e n t _ N N 1   b y _ I I   d u a l - c o n t r a s t _ J J   t u r b o - s p i n - e c h o _ J J   i m a g i n g _ N N 1   , _ ,   a n d _ C C   M T R _ N P 1   i m a g i n g _ N N 1   r e q u i r i n g _ V V G   t w o _ M C   3 D - F L A S H _ J J   i m a g e s _ N N 2   w i t h _ I W   a n d _ C C   w i t h o u t _ I W   a _ A T 1   m a g n e t i s a t i o n _ N N 1   t r a n s f e r _ N N 1   p r e - p u l s e _ N N 1   w i t h _ I W   r a d i o f r e q u e n c y _ N N 1   f i e l d _ N N 1   ( _ (   B 1 _ F O   ) _ )   n o n - u n i f o r m i t y _ J J   c o r r e c t i o n _ N N 1   r e s u l t i n g _ V V G   i n _ I I   M T R _ N P 1   m a p s _ N N 2   w i t h _ I W   v a l u e s _ N N 2   e x p r e s s e d _ V V N   b y _ I I   c o n v e n t i o n _ N N 1   i n _ I I   p e r c e n t a g e _ N N 1   u n i t s _ N N 2   ( _ (   0 - 1 0 0 _ M C M C   p u _ F O   ) _ )   . 2 2 _ M C   S e q u e n c e _ N N 1   d e t a i l s _ N N 2   a n d _ C C   v a r i a b l e s _ N N 2   a r e _ V B R   l i s t e d _ V V N   i n _ I I   t h e _ A T   a p p e n d i x _ N N 1   ; _ ;   t h e _ A T   t o t a l _ J J   a c q u i s i t i o n _ N N 1   t i m e _ N N T 1   p e r _ I I   p a r t i c i p a n t _ N N 1   p e r _ I I   v i s i t _ N N 1   w a s _ V B D Z   a b o u t _ R G   3 5 _ M C   m i n _ N N U   . _ .   
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 A c t i v a t e d _ J J   R A S _ N P 2   b i n d s t o _ N N 1   R A F _ N P 1   a n d _ C C   p r o m o t e s _ V V Z   i t s _ A P P G E   a c t i v a t i o n _ N N 1   . _ .   
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 A f t e r _ I I   s e e k i n g _ V V G   p a r e n t a l _ J J   p e r m i s s i o n _ N N 1   , _ ,   t h e y _ P P H S 2   o b t a i n e d _ V V D   a c c e s s _ N N 1   t o _ I I   r e s u l t s _ N N 2   o f _ I O   s t a n d a r d i z e d _ J J   a c h i e v e m e n t _ N N 1   t e s t i n g _ N N 1   a n d _ C C   d i s c o v e r e d _ V V D   2 _ M C   f i n d i n g s _ N N 2   o f _ I O   p a r t i c u l a r _ J J   c o n c e r n _ N N 1   . _ .   
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 H R s _ N N U 2   w e r e _ V B D R   c o m b i n e d _ V V N   u s i n g _ V V G   t h e _ A T   f i x e d - e f f e c t _ J J   m o d e l _ N N 1   ( _ (   M a n t e l - H a e n z s e l _ N P 1   ) _ )   . _ .   
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 T h e _ A T   n a t u r e _ N N 1   o f _ I O   c o g n i t i v e / a t t e n t i o n a l _ J J   i m p a i r m e n t _ N N 1   r e q u i r e s _ V V Z   d i s c u s s i o n _ N N 1   . _ .   
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 E a c h _ D D 1   p h y s i c i a n _ N N 1   w a s _ V B D Z   p r o v i d e d _ V V N   a _ A T 1   s e t _ N N 1   o f _ I O   S o n y _ N P 1   M D R - E X 3 8 i P _ N P 1   i n - e a r _ J J   s t e r e o _ N N 1   h e a d p h o n e s _ N N 2   ( _ (   S o n y _ N P 1   , _ ,   N e w Y o r k _ N P 1   , _ ,   N e w _ N P 1   Y o r k _ N P 1   ) _ )   a n d _ C C   w a s _ V B D Z   r e q u e s t e d _ V V N   t o _ T O   s e t _ V V I   t h e _ A T   a u d i o _ J J   p l a y b a c k _ N N 1   v o l u m e _ N N 1   i n _ I I   a _ A T 1   r a n g e _ N N 1   s i m i l a r _ J J   t o _ I I   a c t u a l _ J J   p h y s i c a l _ J J   a u s c u l t a t i o n _ N N 1   . _ .   
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 A c k n o w l e d g m e n t s _ N N 2   T h i s _ D D 1   p a p e r _ N N 1   i s _ V B Z   d e d i c a t e d _ V V N   t o _ I I   t h e _ A T   m e m o r y _ N N 1   o f _ I O   G a r y _ N P 1   W h i t l o c k _ N P 1   , _ ,   w h o _ P N Q S   c o n t r i b u t e d _ V V D   m u c h _ R R   t o _ I I   d e v e l o p i n g _ V V G   t h e _ A T   c o l l a b o r a t i o n _ N N 1   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   r e f e r e n c e _ N N 1   l i s t s _ N N 2   o f _ I O   t h e _ A T   s e l e c t e d _ J J   s t u d i e s _ N N 2   w e r e _ V B D R   c h e c k e d _ V V N   f o r _ I F   a r t i c l e s _ N N 2   m i s s e d _ V V N   i n _ I I   t h e _ A T   i n i t i a l _ J J   s e a r c h _ N N 1   . _ .   
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 T o _ I I   o u r _ A P P G E   k n o w l e d g e _ N N 1   , _ ,   t h i s _ D D 1   i s _ V B Z   t h e _ A T   f i r s t _ M D   s t u d y _ N N 1   e x a m i n i n g _ V V G   o b j e c t i v e l y _ R R   m e a s u r e d _ V V N   P A _ N N 1   c h a n g e _ N N 1   i n _ I I   t h i s _ D D 1   m u c h _ D A 1   d e t a i l _ N N 1   o v e r _ R G   4 _ M C   y e a r s _ N N T 2   i n _ I I   B r i t i s h _ J J   a d o l e s c e n t s _ N N 2   . _ .   
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 A c k n o w l e d g e m e n t s _ N N 2   T h e _ A T   w o r k _ N N 1   w a s _ V B D Z   s u p p o r t e d _ V V N   b y _ I I   t h e _ A T   M e d i c a l _ J J   R e s e a r c h _ N N 1   C o u n c i l _ N N 1   ( _ (   P a u l _ N P 1   P o t t e r _ N P 1   , _ ,   I a n _ N P 1   . _ .   
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 B o t h _ D B 2   a c c e l e r a t i o n _ N N 1   f o r c e s _ N N 2   m u s t _ V M   b e _ V B I   m a n a g e d _ V V N   w i t h i n _ I I   t h e _ A T   s a m e _ D A   p a d d i n g _ N N 1   s y s t e m _ N N 1   . _ .   
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 S U M M A R Y _ N N 1   R E M A R K S _ V V Z   M a j o r _ J J   b u r n _ N N 1   t r a u m a _ N N 1   i s _ V B Z   u n i q u e _ J J   i n _ I I 3 1   t e r m s _ I I 3 2   o f _ I I 3 3   t h e _ A T   l o n g - t e r m _ J J   d e l e t e r i o u s _ J J   e f f e c t s _ N N 2   i t _ P P H 1   i n f l i c t s _ V V Z   o n _ I I   n u m e r o u s _ J J   p h y s i o l o g i c a l _ J J   s y s t e m s _ N N 2   w i t h i n _ I I   t h e _ A T   b o d y _ N N 1   . _ .   
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 I n _ I I   s e p a r a t e _ J J   e n c o u n t e r s _ N N 2   , _ ,   e a c h _ D D 1   p h y s i c i a n _ N N 1   d e s c r i b e d _ V V D   b o t h _ R R   t h e _ A T   e p i d u r a l _ N N 1   a n d _ C C   b r a c h i a l _ J J   p l e x u s _ N N 1   b l o c k _ N N 1   p r o c e d u r e s _ N N 2   , _ ,   a n d _ C C   e a c h _ D D 1   p a t i e n t - p a r t i c i p a n t _ N N 1   h e a r d _ V V D   b o t h _ D B 2   p r o c e d u r e s _ N N 2   d e s c r i b e d _ V V N   . _ .   
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 F o l l o w i n g _ V V G   t h e s e _ D D 2   g u i d e l i n e s _ N N 2   f r o m _ I I   t h e _ A T   N C A A _ N N 1   , _ ,   t h e r e _ E X   i s _ V B Z   s o m e _ D D   a m b i g u i t y _ N N 1   a s _ I I 2 1   t o _ I I 2 2   w h e t h e r _ C S W   a _ A T 1   s t u d e n t - a t h l e t e _ N N 1   c a n _ V M   b e g i n _ V V I   h i s / h e r _ A P P G E   a c a d e m i c _ J J   r e t u r n _ N N 1   w h e n _ C S   h e / s h e _ P P H S 1   t o l e r a t e s _ V V Z   c o g n i t i v e _ J J   a c t i v i t y _ N N 1   w i t h o u t _ I W   a n y _ D D   i n c r e a s e _ N N 1   i n _ I I   c o n c u s s i v e _ J J   s y m p t o m s _ N N 2   , _ ,   o r _ C C   i f _ C S   h e / s h e _ P P H S 1   m u s t _ V M   b e _ V B I   c o m p l e t e l y _ R R   s y m p t o m _ N N 1   f r e e _ J J   . _ .   
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 A d d i t i o n a l l y _ R R   , _ ,   n e w l y _ R R   d e v e l o p e d _ J J   i n h i b i t o r s _ N N 2   o f _ I O   t h e _ A T   H C V _ N P 1   e n z y m e _ N N 1   m a y _ V M   s h o w _ V V I   d i f f e r e n t _ J J   r e s i s t a n c e _ N N 1   p r o f i l e s _ N N 2   f o r _ I F   t h e _ A T   v a r i o u s _ J J   s u b t y p e s _ N N 2   , _ ,   e v e n _ R R   w i t h i n _ I I   o n e _ M C 1   H C V _ N P 1   g e n o t y p e _ N N 1   & l s q b ; _ (   1 8 2 0 _ M C   & r s q b ; _ )   . _ .   
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 I n t e r e s t i n g l y _ R R   , _ ,   a n d _ C C   i n _ I I 3 1   s u p p o r t _ I I 3 2   o f _ I I 3 3   t h i s _ D D 1   p r i m a r i l y _ R R   b e i n g _ V B G   a _ A T 1   p r e n a t a l _ J J   d e v e l o p m e n t a l _ J J   a b n o r m a l i t y _ N N 1   , _ ,   t h e _ A T   t r a n s p l a n t e d _ J J   f a t _ N N 1   d o e s _ V D Z   n o t _ X X   a p p e a r _ V V I   t o _ T O   b e _ V B I   a f f e c t e d _ V V N   b y _ I I   t h e _ A T   n a e v u s _ N N 1   . _ .   
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 U l t r a s o u n d - g u i d e d _ J J   F N A _ N N 1   h a s _ V H Z   p r o v e n _ V V N   t o _ T O   b e _ V B I   m o r e _ R G R   e f f i c i e n t _ J J   t h a n _ C S N   c o n v e n t i o n a l _ J J   F N A _ N N 1   , _ ,   p a r t i c u l a r l y _ R R   f o r _ I F   n o d u l e s _ N N 2   l o c a t e d _ V V D   d e e p _ R R   i n _ I I   t h e _ A T   t h y r o i d _ J J   l o b e s _ N N 2   , _ ,   h a v e _ V H 0   a _ A T 1   s m a l l _ J J   v o l u m e _ N N 1   , _ ,   o r _ C C   f e a t u r e _ V V 0   a _ A T 1   m i x e d _ J J   s o l i d _ J J   c y s t i c _ J J   c o n t e n t _ N N 1   . _ .   
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 T h e _ A T   t P A _ N N 1   u t i l i z a t i o n _ N N 1   r a t e _ N N 1   i n _ I I   P S C s _ N P 2   i s _ V B Z   n e a r l y _ R R   3 _ M C   t i m e s _ N N T 2   t h e _ A T   n a t i o n a l _ J J   r a t e . 6 _ F O   H o w e v e r _ R R   , _ ,   t h e _ A T   P S C _ N P 1   c e r t i f i c a t i o n _ N N 1   p r o g r a m _ N N 1   c u r r e n t l y _ R R   d o e s _ V D Z   n o t _ X X   i n c l u d e _ V V I   a _ A T 1   s p e c i f i c _ J J   s t r a t e g y _ N N 1   f o r _ I F   t h e _ A T   2 0 % _ N N U   o f _ I O   t h e _ A T   U S _ N P 1   p o p u l a t i o n _ N N 1   t h a t _ C S T   l i v e s _ V V Z   i n _ I I   r u r a l _ J J   a r e a s _ N N 2   . _ .   
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 W e _ P P I S 2   i n t e n t i o n a l l y _ R R   a n a l y z e d _ V V D   m e a s u r e s _ N N 2   o f _ I O   a c c u r a c y _ N N 1   a n d _ C C   a g r e e m e n t _ N N 1   e x c l u s i v e l y _ R R   b a s e d _ V V N   o n _ I I   s u b g r o u p s _ N N 2   o f _ I O   n u t r i t i o n a l _ J J   s t a t u s _ N N 1   , _ ,   r a t h e r _ I I 2 1   t h a n _ I I 2 2   t h e _ A T   p o p u l a t i o n _ N N 1   a s _ I I   a _ A T 1   w h o l e _ N N 1   , _ ,   a s _ C S A   o u r _ A P P G E   s t u d y _ N N 1   p o p u l a t i o n _ N N 1   w a s _ V B D Z   l a r g e l y _ R R   m a l n o u r i s h e d _ J J   a n d _ C C   n o t _ X X   i n t e n d e d _ V V N   r e f l e c t _ V V 0   t h e _ A T   g e n e r a l _ J J   p e d i a t r i c _ J J   p o p u l a t i o n _ N N 1   . _ .   
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 T o _ T O   c o n f i r m _ V V I   t h a t _ C S T   t h e s e _ D D 2   p h a r m a c o k i n e t i c _ J J   m e a s u r e s _ N N 2   w e r e _ V B D R   a c h i e v e d _ V V N   d u r i n g _ I I   t h e _ A T   s t u d y _ N N 1   , _ ,   w e _ P P I S 2   m e a s u r e d _ V V D   p l a s m a _ N N 1   c o n c e n t r a t i o n s _ N N 2   o f _ I O   d r u g _ N N 1   a n d _ C C   i t s _ A P P G E   a c t i v e _ J J   m e t a b o l i t e _ N N 1   i n _ I I   t h e _ A T   f i r s t _ M D   c o h o r t _ N N 1   o f _ I O   e i g h t _ M C   m o n k e y s _ N N 2   . _ .   
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 T h e y _ P P H S 2   h a d _ V H D   l o w e r _ J J R   c a s e _ N N 1   m i x _ N N 1   i n d e x _ N N 1   a n d _ C C   c o m p a r a b l e _ J J   E m e r g e n c y _ N N 1   S e v e r i t y _ N N 1   I n d e x _ N N 1   s c o r e s _ N N 2   . _ .   
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 O v e r - e x p r e s s i o n _ N N 1   o f _ I O   m i R - 2 1 7 _ M C   i n _ I I   y o u n g e r _ J J R   H U V E C s _ N N 2   l e a d s _ V V Z   t o _ I I   a n _ A T 1   a g e i n g p h e n o t y p e _ N N 1   a s _ C S A   s e e n _ V V N   b y _ I I   i n c r e a s e d _ J J   S A - _ J J   - G a l _ J J   a c t i v i t y _ N N 1   , _ ,   d e c r e a s e d _ V V D   t e l - o m e r a s e _ J J   a c t i v i t y _ N N 1   a n d _ C C   i m p a i r e d _ V V D   a n _ A T 1   g i o g e n i c _ J J   f u n c t i o n _ N N 1   , _ ,   i l l u s t r a t i n g _ V V G   i t _ P P H 1   a s _ C S A   p r o a g e i n g _ V V G   m i c r o R N A _ N N 1   ( _ (   M e n g h i n i _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 9 _ M C   ) _ )   . _ .   
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 W e _ P P I S 2   h y p o t h e s i z e d _ V V D   t h a t _ C S T   e l e v a t e d _ J J   v a l u e s _ N N 2   o f _ I O   N P Y _ N P 1   m e a s u r e d _ V V D   i n _ I I   p e r i p h e r a l _ J J   b l o o d _ N N 1   w o u l d _ V M   b e _ V B I   c o r r e l a t e d _ V V N   t o _ I I   t h e _ A T   d e g r e e _ N N 1   o f _ I O   a n g i o g r a p h i c _ J J   v a s o s p a s m _ N N 1   a n d _ C C   t o _ T O   d e c r e a s e _ V V I   i n _ I I   g l o b a l _ J J   C B F _ N P 1   a n d _ C C   t h a t _ D D 1   e l e v a t e d _ J J   l e v e l s _ N N 2   w o u l d _ V M   b e _ V B I   f o u n d _ V V N   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   c l i n i c a l _ J J   m a n i f e s t a t i o n s _ N N 2   o f _ I O   D C I _ M C   . _ .   
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 I n _ I I   t h i s _ D D 1   r e a c t i o n _ N N 1   , _ ,   a d e n o s i n e _ V V 0   m o n o p h o s p h a t e _ N N 1   ( _ (   A M P _ N N 1   ) _ )   i s _ V B Z   p r o d u c e d _ V V N   a n d _ C C   r e m o v e d _ V V N   b y _ I I   A M P _ N N 1   d e a m i n a s e _ N N 1   1 _ M C 1   , _ ,   r e s u l t i n g _ V V G   i n _ I I   t h e _ A T   p r o d u c t i o n _ N N 1   o f _ I O   N H 3 + _ F O   a n d _ C C   i n o s i n e _ V V 0   m o n o p h o s p h a t e _ N N 1   ( _ (   I M P _ N P 1   ) _ )   , _ ,   t h e _ A T   l a t t e r _ D A   b e i n g _ N N 1   m e t a b o l i z e d _ V V D   t o _ T O   i n o s i n e _ V V I   a n d _ C C   t h e n _ R T   t o _ T O   h y p o x a n t h i n e _ V V I   , _ ,   x a n t h i n e _ V V I   , _ ,   a n d _ C C   u r i c _ J J   a c i d _ N N 1   v i a _ I I   x a n t h i n e _ N N 1   o x i d a s e _ N N 1   , _ ,   w h i c h _ D D Q   g e n e r a t e s _ V V Z   r e a c t i v e _ J J   o x y g e n _ N N 1   s p e c i e s _ N N   ( _ (   R O S _ N P 1   ) _ )   . _ .   
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 M i c r o b l e e d s _ N N 2   t h u s _ R R   a p p e a r _ V V 0   b e s t _ R R T   s u i t e d _ V V N   t o _ T O   s e r v e _ V V I   a s _ I I   a n _ A T 1   e a r l y _ J J   p h a s e _ N N 1   m a r k e r _ N N 1   o f _ I O   t h e r a p i e s _ N N 2   a i m e d _ V V N   a t _ I I   r e d u c i n g _ V V G   C A A - r e l a t e d _ J J   h e m o r r h a g i c _ J J   e v e n t s _ N N 2   , _ ,   b u t _ C C B   r e q u i r e _ V V 0   c a r e f u l _ J J   m e t h o d s _ N N 2   f o r _ I F   s t a n d a r d i z e d _ J J   d e t e c t i o n _ N N 1   a n d _ C C   i n t e r p r e t a t i o n _ N N 1   . _ .   
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 2 0 1 6 _ M C   ) _ )   ' _ N U L L   t h e r e _ E X   a r e _ V B R   n o w _ R T   u n i q u e _ J J   o p p o r t u n i t i e s _ N N 2   t o _ T O   s t u d y _ V V I   c e l l - s p e c i f i c _ J J   c a v e o l i n / c a v e o l a e _ F U   f u n c t i o n s _ V V Z   ' _ N U L L   i n _ R R 2 1   v i v o _ R R 2 2   . _ .   
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 A l t h o u g h _ C S   c a s e s _ N N 2   o f _ I O   r e c o n s t r u c t i o n _ N N 1   o f _ I O   t h e _ A T   h a r d _ J J   p a l a t e _ N N 1   a n d _ C C   m a x i l l a _ N N 1   b y _ I I   a n _ A T 1   o s t e o m y o c u t a n e o u s _ J J   s u b m e n t a l _ J J   f l a p _ N N 1   h a v e _ V H 0   b e e n _ V B N   d e s c r i b e d _ V V N   , _ ,   t h i s _ D D 1   i s _ V B Z   t h e _ A T   f i r s t _ M D   c a s e _ N N 1   d e m o n s t r a t i n g _ V V G   t h e _ A T   r e c o n s t r u c t i o n _ N N 1   o f _ I O   t h e _ A T   i n f e r i o r _ J J   o r b i t a l _ J J   r i m _ N N 1   b y _ I I   a n _ A T 1   o s t e o m y o c u t a n e o u s _ J J   s u b m e n t a l _ J J   f l a p _ N N 1   . _ .   
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 P a r a l l e l _ J J   i m a g i n g _ N N 1   , _ ,   a s _ C S A   d e s c r i b e d _ V V N   i n _ I I   t h e _ A T   p r e v i o u s _ J J   p a r a g r a p h _ N N 1   , _ ,   t h u s _ R R   a l l o w s _ V V Z   i n c r e a s e d _ J J   i m a g i n g _ N N 1   s p e e d _ N N 1   , _ ,   a _ A T 1   m a j o r _ J J   r e a s o n _ N N 1   f o r _ I F   i t s _ A P P G E   d e v e l o p m e n t _ N N 1   . _ .   
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 D e t a i l s _ N N 2   a r e _ V B R   i n c l u d e d _ V V N   i n _ I I   t h e _ A T   S u p p l e m e n t a l _ J J   E x p e r i m e n t a l _ J J   P r o c e d u r e s _ N N 2   . _ .   
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 F u r t h e r m o r e _ R R   , _ ,   p o t e n t i a l _ J J   g r o u p _ N N 1   d i f f e r e n c e s _ N N 2   i n _ I I   g l o b a l _ J J   s o c i a l _ J J   f u n c t i o n i n g _ N N 1   a n d _ C C   c o m m u n i c a t i o n _ N N 1   a t _ I I   b a s e l i n e _ N N 1   a r e _ V B R   u n k n o w n _ J J   b e c a u s e _ C S   t h e _ A T   S C Q _ N P 1   : _ :   C _ N P 1   w a s _ V B D Z   a d m i n i s t e r e d _ V V N   o n l y _ R R   a t _ I I   1 2 - m o n t h _ J J   f o l l o w - u p _ N N 1   . _ .   
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 F o r _ I F   m e m b r a n e _ N N 1   p r o t e i n s _ N N 2   a f f i n i t y _ N N 1   c h r o m a t o g r a p h y _ N N 1   i s _ V B Z   t h e _ A T   p r e f e r r e d _ J J   m o d e _ N N 1   o f _ I O   p u r i f i c a t i o n _ N N 1   . _ .   
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 F o r t y - t h r e e _ M C   p a p e r s _ N N 2   h a d _ V H D   a _ A T 1   r e s p o n s e _ N N 1   r a t e _ N N 1   o f _ I O   g r e a t e r _ J J R   t h a n _ C S N   5 0 % _ N N U   a n d _ C C   g a v e _ V V D   s u f f i c i e n t _ J J   G l a s g o w _ N P 1   B e n e f i t _ N N 1   I n v e n t o r y _ N N 1   t o t a l _ N N 1   a n d _ C C   s u b s c a l e s _ N N 2   f o r _ I F   m e t a - a n a l y s i s _ N N 1   . _ .   
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 B e n z o d i a z e p i n e s _ N N 2   s h o u l d _ V M   b e _ V B I   a v o i d e d _ V V N   b e c a u s e _ I I 2 1   o f _ I I 2 2   t h e i r _ A P P G E   a d v e r s e _ J J   e f f e c t s _ N N 2   . _ .   
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 I n _ I I   c o n c l u s i o n _ N N 1   , _ ,   w e _ P P I S 2   h a v e _ V H 0   d o c u m e n t e d _ V V N   a _ A T 1   t e m p o r a l _ J J   i n c r e a s e _ N N 1   i n _ I I   p r e e c l a m p s i a _ N N 1   i n _ I I   W a s h i n g t o n _ N P 1   S t a t e _ N N 1   b e t w e e n _ I I   2 0 0 0 _ M C   a n d _ C C   2 0 0 8 _ M C   t h a t _ C S T   o c c u r r e d _ V V D   p r e d o m i n a n t l y _ R R   b e c a u s e _ I I 2 1   o f _ I I 2 2   a n _ A T 1   i n c r e a s e _ N N 1   i n _ I I   e a r l y - o n s e t _ J J   d i s e a s e _ N N 1   . _ .   
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 H i g h _ J J   r e s o l u t i o n _ N N 1   m i c r o p e r i m e t r i c _ J J   a s s e s s m e n t _ N N 1   u s i n g _ V V G   a d a p t i v e _ J J   o p t i c s _ N N 1   t e c h n o l o g y _ N N 1   h a s _ V H Z   b e e n _ V B N   d e s c r i b e d _ V V N   . _ .   
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 T h i s _ D D 1   e f f e c t _ N N 1   w a s _ V B D Z   s t r o n g e s t _ J J T   w h e n _ C S   o n l y _ R R   o n e _ M C 1   a n x i e t y _ N N 1   d i s o r d e r _ N N 1   w a s _ V B D Z   p r e s e n t _ J J   ( _ (   e . g . _ R E X   , _ ,   a n _ A T 1   8 4 % _ N N U   r e s p o n s e _ N N 1   r a t e _ N N 1   c o m p a r e d _ V V N   w i t h _ I W   a _ A T 1   5 3 % _ N N U   r e s p o n s e _ N N 1   r a t e _ N N 1   f o r _ I F   i n t e n s i v e _ J J   p s y c h o t h e r a p y _ N N 1   v e r s u s _ I I   c o l l a b o r a t i v e _ J J   c a r e _ N N 1   ) _ )   ; _ ;   w i t h _ I W   t w o _ M C   o r _ C C   m o r e _ D A R   a n x i e t y _ N N 1   d i s o r d e r s _ N N 2   , _ ,   t h e _ A T   a d v a n t a g e _ N N 1   o f _ I O   i n t e n s i v e _ J J   p s y c h o t h e r a p y _ N N 1   w a s _ V B D Z   a t t e n u a t e d _ V V N   t o _ I I   a _ A T 1   v e r y _ R G   s m a l l _ J J   e f f e c t _ N N 1   s i z e _ N N 1   ( _ (   i . e . _ R E X   , _ ,   n u m b e r _ N N 1   n e e d e d _ V V N   t o _ I I   t r e a t = 1 2 . 5 _ F O   ) _ )   . _ .   
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 A n _ A T 1   i n d e x _ N N 1   v i s i t _ N N 1   w a s _ V B D Z   d e f i n e d _ V V N   a s _ I I   t h e _ A T   f i r s t _ M D   E D _ N N 1   v i s i t _ N N 1   ( _ (   r e g a r d l e s s _ R R   o f _ I O   d i s p o s i t i o n _ N N 1   ) _ )   f o r _ I F   a _ A T 1   u n i q u e _ J J   p a t i e n t _ N N 1   o r _ C C   a n y _ D D   s u c c e s s i v e _ J J   v i s i t s _ N N 2   i n _ I I   w h i c h _ D D Q   t h e _ A T   p a t i e n t _ N N 1   h a d _ V H D   n o _ A T   p r i o r _ J J   v i s i t _ N N 1   o r _ C C   h o s p i t a l i z a t i o n _ N N 1   d u r i n g _ I I   t h e _ A T   p r e c e d i n g _ J J   3 0 _ M C   d a y s _ N N T 2   . _ .   
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 B y _ I I   r e f l e c t i n g _ V V G   a _ A T 1   l a r g e r _ J J R   p r o p o r t i o n _ N N 1   o f _ I O   t h e _ A T   i n c i d e n t _ N N 1   U S _ N P 1   b e a m _ N N 1   , _ ,   e c h o g e n i c _ J J   n e e d l e s _ N N 2   h a v e _ V H 0   b e e n _ V B N   s h o w n _ V V N   t o _ T O   i m p r o v e _ V V I   n e e d l e _ N N 1   v i s i b i l i t y _ N N 1   i n _ I I   p h a n t o m s _ N N 2   a n d _ C C   c a d a v e r s _ N N 2   , _ ,   p a r t i c u l a r l y _ R R   i n _ I I   d e e p e r _ J J R   b l o c k s _ N N 2   r e q u i r i n g _ V V G   s t e e p e r _ J J R   n e e d l e _ N N 1   t r a j e c t o r i e s _ N N 2   , _ ,   a l t h o u g h _ C S   e v i d e n c e _ N N 1   o f _ I O   a _ A T 1   c l i n i c a l _ J J   b e n e f i t _ N N 1   i s _ V B Z   s c a n t _ J J   a t _ R R 2 1   p r e s e n t _ R R 2 2   . _ .   
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 E x t e r n a l _ J J   g e n i t a l _ J J   e x a m i n a t i o n _ N N 1   A t _ I I   t h e _ A T   l e a s t _ R R T   , _ ,   t h e _ A T   p h y s i c a l _ J J   e x a m i n a t i o n _ N N 1   i n c l u d e s _ V V Z   t h e _ A T   s t e p s _ N N 2   o f _ I O   c o m p r e h e n s i v e _ J J   i n t e r n a l _ J J   a n d _ C C   e x t e r n a l _ J J   g e n i t a l _ J J   e x a m i n a t i o n _ N N 1   u s e d _ V V N   i n _ I I   a d u l t _ N N 1   a n d _ C C   a d o l e s c e n t / p e d i a t r i c _ J J   g y n e c o l o g i c _ J J   p r a c - t i c e 1 2 0 - 1 2 2 _ M C   ; _ ;   t h e r e f o r e _ R R   , _ ,   i t _ P P H 1   r e q u i r e s _ V V Z   a n _ A T 1   e x a m i n e r _ N N 1   s k i l l e d _ J J   i n _ I I   g e n i t o p e l v i c _ J J   e x a m i n a t i o n _ N N 1   a n d _ C C   p r o c e d u r e s _ N N 2   . _ .   
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 A d d i t i o n a l l y _ R R   , _ ,   t h e _ A T   I n t e r g r o u p _ J J   M e l a n o m a _ N P 1   S u r g i c a l _ J J   T r i a l 4 _ F O   o f _ I O   p a t i e n t s _ N N 2   r a n d o m l y _ R R   a s s i g n e d _ V V N   t o _ I I   e i t h e r _ R R   a _ A T 1   2 _ M C   c m _ N N U   o r _ C C   4 _ M C   c m _ N N U   e x c i s i o n _ N N 1   m a r g i n _ N N 1   f o r _ I F   t r u n k _ N N 1   a n d _ C C   e x t r e m i t y _ N N 1   m e l a n o m a s _ N N 2   w i t h _ I W   B r e s l o w _ N P 1   t h i c k n e s s _ N N 1   1 - 4 _ M C M C   m m _ N N U   ( _ (   m e d i a n _ N N 1   1 . 9 6 _ M C   m m _ N N U   ) _ )   s h o w e d _ V V D   a _ A T 1   n o n - s i g n i f i c a n t _ J J   d i f f e r e n c e _ N N 1   ( _ (   p = 0 . 0 7 _ F O   ) _ )   i n _ I I   1 0 - y e a r _ J J   d i s e a s e - s p e c i f i c _ J J   s u r v i v a l _ N N 1   b e t w e e n _ I I   g r o u p s _ N N 2   ( _ (   7 0 % _ N N U   f o r _ I F   t h e _ A T   2 _ M C   c m _ N N U   g r o u p _ N N 1   a n d _ C C   7 7 % _ N N U   f o r _ I F   t h e _ A T   4 _ M C   c m _ N N U   g r o u p _ N N 1   ) _ )   . _ .   
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 T h e _ A T   m i u _ N N 1   r a t e _ N N 1   c o n s t a n t s _ N N 2   w e r e _ V B D R   0 . 1 0 7 _ M C   h o u r - 1 _ M C 1   f o r _ I F   g a d o t e r a t e _ J J   m e g l u m i n e _ N N 1   a t _ I I   0 . 1 _ M C   m m o l / k g _ F U   , _ ,   0 . 0 0 7 _ M C   a n d _ C C   0 . 0 2 0 _ M C   h o u r _ N N T 1   ' _ N U L L   1 _ M C 1   f o r _ I F   g a d o d i a m i d e _ N N 1   a t _ I I   0 . 1 _ M C   a n d _ C C   0 . 3 _ M C   m m o l / k g _ F U   , _ ,   0 . 0 2 9 _ M C   a n d _ C C   0 . 0 2 7 _ M C   h o u r _ N N T 1   ' _ N U L L   1 _ M C 1   f o r _ I F   g a d o x e t a t e _ N N 1   d i s o d i u m _ N N 1   a t _ I I   0 . 2 _ M C   a n d _ C C   0 . 5 _ M C   m m o l / k g _ F U   , _ ,   a n d _ C C   0 . 0 1 8 _ M C   a n d _ C C   0 . 0 1 7 _ M C   h o u r _ N N T 1   ' _ N U L L   1 _ M C 1   f o r _ I F   D y - E O B - D T P A _ N P 1   a t _ I I   0 . 2 5 _ M C   a n d _ C C   0 . 5 _ M C   m m o l / k g _ F U   . _ .   
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 M a n y _ D A 2   o f _ I O   t h e _ A T   m e c h a n i s m s _ N N 2   u n d e r l y i n g _ V V G   t h e _ A T   r e l a t i o n s h i p s _ N N 2   b e t w e e n _ I I   e x e r c i s e _ N N 1   a n d _ C C   h e a l t h _ N N 1   a r e _ V B R   w e l l _ R R   c h a r a c t e r i z e d _ V V N   , _ ,   a n d _ C C   t h e r e _ E X   a r e _ V B R   r e a s o n a b l y _ R R   c l e a r _ J J   e x e r c i s e _ N N 1   t a r g e t s _ N N 2   a n d _ C C   e x p e c t e d _ J J   d o s e _ N N 1   r e s p o n s e _ N N 1   r e l a t i o n s h i p s _ N N 2   . _ .   
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 M e a n w h i l e _ R R   , _ ,   C x 3 6 - m e d i a t e d _ J J   n e u r o n a l _ J J   o s c i l l a t i o n s _ N N 2   i n _ I I   t h e _ A T   g a m m a _ N N 1   f r e q u e n c y _ N N 1   r a n g e _ N N 1   ( _ (   3 0 _ M C   t o _ I I   8 0 _ M C   H z _ N N U   ) _ )   ( _ (   n _ Z Z 1   = _ F O   7 _ M C   t o _ I I   8 _ M C   ) _ )   a n d _ C C   t h e _ A T   n e u r o n a l _ J J   s y n a p t i c _ J J   t r a n s m i s s i o n _ N N 1   ( _ (   n _ Z Z 1   = _ F O   1 3 _ M C   t o _ I I   1 9 _ M C   ) _ )   w e r e _ V B D R   a l s o _ R R   e n h a n c e d _ V V N   . _ .   
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 G l o b a l _ J J   F C I _ N N 1   r e f e r s _ V V Z   t o _ I I   t h e _ A T   a v e r a g e _ J J   F C I _ J J   a b s o l u t e _ J J   v a l u e s _ N N 2   a c r o s s _ I I   a l l _ D B   v a l u e s _ N N 2   i n _ I I   t h e _ A T   m a t r i x _ N N 1   ( _ (   m a t r i x _ N N 1   d i a g o n a l _ J J   e x c l u d e d _ J J   ) _ )   , _ ,   a n d _ C C   a l l o w s _ V V Z   u s _ P P I O 2   t o _ T O   q u a n t i f y _ V V I   v a r i a t i o n _ N N 1   i n _ I I   F C I _ N P 1   a t _ I I   t h e _ A T   g l o b a l _ J J   l e v e l _ N N 1   w i t h i n _ I I   t h e _ A T   e n t i r e _ J J   b i l a t e r a l _ J J   l a n g u a g e _ N N 1   t e m p l a t e _ N N 1   . _ .   
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 W e _ P P I S 2   u s e d _ V V D   3 _ M C   d a t a _ N N   f i l e s _ N N 2   : _ :   t h e _ A T   r e g i s t r y _ N N 1   o f _ I O   b e n e f i c i a r i e s _ N N 2   , _ ,   t h e _ A T   r e g i s t r y _ N N 1   o f _ I O   C a t a s t r o p h i c _ J J   I l l n e s s _ N N 1   P a t i e n t _ N N 1   D a t a b a s e _ N N 1   ( _ (   C I P D _ N P 1   ) _ )   , _ ,   a n d _ C C   a l l _ D B   i n p a t i e n t _ N N 1   a n d _ C C   a m b u l a t o r y _ J J   c a r e _ N N 1   r e c o r d s _ N N 2   f o r _ I F   c a n c e r _ N N 1   c a r e _ N N 1   . _ .   
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 A _ A T 1   f u l l _ J J   d e s c r i p t i o n _ N N 1   o f _ I O   w h i c h _ D D Q   s o u r c e s _ N N 2   c o n t r i b u t e d _ V V N   t o _ I I   e a c h _ D D 1   o f _ I O   t h e _ A T   1 5 _ M C   C N V s _ N P 1   a n a l y s e d _ V V D   i s _ V B Z   p r o v i d e d _ V V N   i n _ I I   t h e _ A T   S u p p l e m e n t a r y _ J J   M a t e r i a l _ N N 1   ; _ ;   S u p p l e m e n t a r y _ J J   T a b l e _ N N 1   S 3 _ F O   . _ .   
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 T h i s _ D D 1   r e v e a l e d _ V V D   t h a t _ D D 1   m u t a n t _ N N 1   c o l l a g e n _ N N 1   d i r e c t l y _ R R   r e d u c e d _ V V N   r e p l i c a t i v e _ J J   l i f e s p a n _ N N 1   a n d _ C C   i n c r e a s e d _ J J   s t r e s s - i n d u c e d _ J J   S A - B G a l _ J J   a c t i v i t y _ N N 1   , _ ,   p 1 6 _ F O   I N K 4 A _ F O   e x p r e s s i o n _ N N 1   , _ ,   a n d _ C C   p 2 1 _ F O   C I P 1 _ F O   e x p r e s s i o n _ N N 1   . _ .   
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 A n o t h e r _ D D 1   f a c t o r _ N N 1   a f f e c t i n g _ V V G   t h e _ A T   q u a l i t y _ N N 1   o f _ I O   d a t a _ N N   m a y _ V M   b e _ V B I   t h e _ A T   p o o r _ J J   5 - y e a r _ J J   s u r v i v a l _ N N 1   r a t e s _ N N 2   f o r _ I F   p a t i e n t s _ N N 2   w h o _ P N Q S   d e v e l o p _ V V 0   h y p o p h a r y n g e a l _ J J   c a n c e r _ N N 1   : _ :   l o n g - t e r m _ J J   o u t c o m e s _ N N 2   c a n _ V M   n o t _ X X   b e _ V B I   a s c e r t a i n e d _ V V N   f o r _ I F   a _ A T 1   l a r g e _ J J   p r o p o r t i o n _ N N 1   o f _ I O   p a t i e n t s _ N N 2   w h o _ P N Q S   r e q u i r e _ V V 0   P L _ N N 1   . _ .   
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 T h e _ A T   A N O V A _ N P 1   r e v e a l e d _ V V D   s i g n i f i c a n t _ J J   m a i n _ J J   e f f e c t s _ N N 2   o f _ I O   s k i n _ N N 1   t y p e _ N N 1   ( _ (   s i m u l t a n e o u s _ J J   2 P D _ F O   , _ ,   F 1 1 4 _ F O   = _ F O   4 6 . 3 _ M C   , _ ,   p _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 0 0 1 _ M C   ; _ ;   s u c c e s s i v e _ J J   2 P D _ F O   , _ ,   F 1 9 _ F O   = _ F O   1 4 6 . 9 8 _ M C   , _ ,   p _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 0 0 1 _ M C   ) _ )   a n d _ C C   m o d a l i t y _ N N 1   ( _ (   s i m u l t a n e o u s _ J J   2 P D _ F O   , _ ,   F 1 1 4 _ F O   = _ F O   8 . 3 _ M C   , _ ,   p _ Z Z 1   = _ F O   0 . 0 1 2 _ M C   ; _ ;   s u c c e s s i v e _ J J   2 P D _ F O   , _ ,   F 1 9 _ F O   = _ F O   2 1 . 6 1 _ M C   , _ ,   p _ Z Z 1   = _ F O   0 . 0 0 1 _ M C   ) _ )   . _ .   
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 W e _ P P I S 2   d i d _ V D D   n o t _ X X   f i n d _ V V I   a _ A T 1   d i s p r o p o r t i o n a t e _ J J   n u m b e r _ N N 1   o f _ I O   i n p a t i e n t _ N N 1   d i a g n o s e s _ V V Z   t h a t _ C S T   w o u l d _ V M   a b s o l u t e l y _ R R   p r o h i b i t _ V V I   t P A _ N N 1   u s e _ N N 1   ; _ ;   h o w e v e r _ R R   , _ ,   c o m o r b i d _ J J   d i s e a s e _ N N 1   s e v e r i t y _ N N 1   , _ ,   p r e s t r o k e _ V V 0   d i s a b i l i t y _ N N 1   , _ ,   l i f e _ N N 1   e x p e c t a n c y _ N N 1   , _ ,   o r _ C C   o t h e r _ J J   f a c t o r s _ N N 2   t h a t _ C S T   r e s u l t _ V V 0   i n _ I I   a p p r o p r i a t e _ J J   t P A _ N N 1   c o n t r a i n d i c a t i o n _ N N 1   m a y _ V M   v a r y _ V V I   i n _ I I   r u r a l _ J J   v s _ I I   u r b a n _ J J   p o p u l a t i o n s _ N N 2   , _ ,   e v e n _ R R   a f t e r _ I I   a c c o u n t i n g _ V V G   f o r _ I F   b a s e l i n e _ N N 1   s o c i o d e m o g r a p h i c _ J J   d i f f e r e n c e s _ N N 2   a n d _ C C   s t a n d a r d _ J J   c o m o r b i d i t y _ N N 1   s c o r i n g _ V V G   i n _ I I   o u r _ A P P G E   s t u d y _ N N 1   . _ .   
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 S p e c i f i c a l l y _ R R   , _ ,   t h e _ A T   m e a n _ J J   d e v i a t i o n s _ N N 2   f r o m _ I I   t h e _ A T   s p i r a l _ J J   g a n g l i o n _ N N 1   e s t i m a t e _ N N 1   w e r e _ V B D R   2 9 . 0 4 _ M C   s e m i t o n e s _ N N 2   ( _ (   S E _ N P 1   : _ :   8 . 5 _ M C   ) _ )   i n _ I I   t h e _ A T   b a s a l _ J J   r e g i o n _ N N 1   , _ ,   1 6 . 3 2 _ M C   s e m i t o n e s _ N N 2   ( _ (   S E _ N P 1   : _ :   2 . 5 4 _ M C   ) _ )   i n _ I I   t h e _ A T   m i d d l e _ J J   r e g i o n _ N N 1   , _ ,   a n d _ C C   4 . 9 9 _ M C   s e m i t o n e s _ N N 2   ( _ (   S E _ N P 1   : _ :   6 . 4 7 _ M C   ) _ )   i n _ I I   t h e _ A T   a p i c a l _ J J   r e g i o n _ N N 1   . _ .   
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 I t _ P P H 1   c o u l d _ V M   b e _ V B I   s p e c u l a t e d _ V V N   t h a t _ C S T   t h e _ A T   d e f i c i t _ N N 1   i n _ I I   d o p a m i n e r g i c _ J J   D 1 / D 5 _ J J   r e c e p t o r - m e d i a t e d _ J J   s i g n a l i n g _ N N 1   i n _ I I   a g i n g _ N N 1   c o u l d _ V M   a f f e c t _ V V I   t r a n s c r i p t i o n _ N N 1   a n d _ C C   t r a n s l a t i o n _ N N 1   o f _ I O   B D N F _ N P 1   c a u s i n g _ V V G   t h e _ A T   m e m o r y _ N N 1   d e f i c i t s _ N N 2   . _ .   
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 I n _ I I   c o n c l u s i o n _ N N 1   , _ ,   t h e _ A T   l i t e r a t u r e _ N N 1   d o e s _ V D Z   n o t _ X X   s u p p o r t _ V V I   t h e _ A T   h y p o t h e s i s _ N N 1   t h a t _ C S T   t r a i n i n g _ N N 1   f o r _ I F   m u s c l e _ N N 1   h y p e r t r o p h y _ N N 1   r e q u i r e s _ V V Z   s h o r t e r _ J J R   r e s t _ N N 1   i n t e r v a l s _ N N 2   t h a n _ C S N   t r a i n i n g _ N N 1   f o r _ I F   s t r e n g t h _ N N 1   d e v e l o p m e n t _ N N 1   o r _ C C   t h a t _ D D 1   p r e d e t e r m i n e d _ J J   r e s t _ N N 1   i n t e r v a l s _ N N 2   a r e _ V B R   p r e f e r a b l e _ J J   t o _ I I   a u t o - r e g u l a t e d _ J J   r e s t _ N N 1   p e r i o d s _ N N 2   i n _ I I   t h i s _ D D 1   r e g a r d _ N N 1   . _ .   
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 E t h i c s _ N N   c o m m i t t e e s _ N N 2   a t _ I I   e a c h _ D D 1   c e n t e r _ N N 1   a p p r o v e d _ V V D   t h e _ A T   s t u d y _ N N 1   a n d _ C C   p a r t i c i p a n t s _ N N 2   p r o v i d e d _ C S   w r i t t e n _ V V N   i n f o r m e d _ J J   c o n s e n t _ N N 1   . _ .   
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 C o m p e t i n g _ J J   i n t e r e s t s _ N N 2   : _ :   T h e _ A T   f u n d i n g _ N N 1   o r g a n i z a t i o n ( s ) _ N N 2   p l a y e d _ V V D   n o _ A T   r o l e _ N N 1   i n _ I I   t h e _ A T   s t u d y _ N N 1   d e s i g n _ N N 1   ; _ ;   i n _ I I   t h e _ A T   c o l l e c t i o n _ N N 1   , _ ,   a n a l y s i s _ N N 1   , _ ,   a n d _ C C   i n t e r p r e t a t i o n _ N N 1   o f _ I O   d a t a _ N N   ; _ ;   i n _ I I   t h e _ A T   w r i t i n g _ N N 1   o f _ I O   t h e _ A T   r e p o r t _ N N 1   ; _ ;   o r _ C C   i n _ I I   t h e _ A T   d e c i s i o n _ N N 1   t o _ T O   s u b m i t _ V V I   t h e _ A T   r e p o r t _ N N 1   f o r _ I F   p u b l i c a t i o n _ N N 1   . _ .   
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 I . _ N P 1   A . _ N P 1   i s _ V B Z   a _ A T 1   H o w a r d _ N P 1   H u g h e s _ N P 1   M e d i c a l _ J J   I n s t i t u t e _ N N 1   E a r l y _ J J   C a r e e r _ N N 1   S c i e n t i s t _ N N 1   . _ .   
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 A d d i t i o n a l l y _ R R   , _ ,   w h e n _ C S   n e u r o n a l _ J J   d e a t h _ N N 1   o c c u r s _ V V Z   i t _ P P H 1   m a y _ V M   i n _ I I   t u r n _ V V I   c a u s e _ V V 0   a _ A T 1   d e c r e a s e d _ J J   l e v e l _ N N 1   o f _ I O   e n d o g e n o u s _ J J   K T P _ N P 1   i n _ I I   b r a i n _ N N 1   w h i c h _ D D Q   f u r t h e r _ J J R   i m p a c t s _ N N 2   o n _ I I   c h r o n i c _ J J   p a i n _ N N 1   a n d _ C C   i m p a i r m e n t _ N N 1   o f _ I O   N O _ A T   p r o d u c t i o n _ N N 1   . _ .   
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 W e _ P P I S 2   e x c l u d e d _ V V D   s t u d i e s _ N N 2   o f _ I O   r e a l - t i m e _ J J   u l t r a s o u n d - g u i d e d _ J J   n e u r a x i a l _ J J   b l o c k s _ N N 2   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   t h o s e _ D D 2   r e l a t e d _ V V N   t o _ I I   i n t e r v e n t i o n a l _ J J   p a i n _ N N 1   p r o c e d u r e s _ N N 2   o n _ I I   t h e _ A T   s p i n e _ N N 1   . _ .   
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 T h e _ A T   a t t a c h e d _ J J   F i g u r e _ N N 1   1 _ M C 1   d e s c r i b e s _ V V Z   s i x _ M C   h y p o t h e t i c a l _ J J   p a t i e n t s _ N N 2   a n d _ C C   a p p l i e s _ V V Z   t o _ I I   a l l _ D B   c a n c e r s _ N N 2   o f _ I O   d i f f e r e n t _ J J   d i s e a s e _ N N 1   b i o l o g y _ N N 1   a n d _ C C   d y n a m i c s _ N N   . _ .   
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 T h e y _ P P H S 2   h a v e _ V H 0   h y p o t h e s i z e d _ V V N   t h a t _ C S T   h s - c T n _ J J   u s e _ N N 1   c o u l d _ V M   d e c r e a s e _ V V I   s p e c i f i c i t y _ N N 1   a n d _ C C   l e a d _ V V I   t o _ I I   m o r e _ D A R   p a t i e n t s _ N N 2   w i t h _ I W   d i a g n o s t i c _ J J   a n d _ C C   t h e r a p e u t i c _ J J   d i l e m m a s _ N N 2   . _ .   
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 B o t h _ D B 2   g r o u p s _ N N 2   u s e d _ V V D   K R _ N P 1   s i m i l a r l y _ R R   a s _ C S A   i n d i c a t e d _ V V N   b y _ I I   t h e _ A T   o v e r a l l _ J J   i n c r e a s e _ N N 1   i n _ I I   v e l o c i t y _ N N 1   ( _ (   F i g u r e s _ V V Z   3 A _ F O   a n d _ C C   3 C _ F O   ) _ )   . _ .   
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 H o w e v e r _ R R   , _ ,   C o l l a l _ N P 1   r / r _ Z Z 1   m i c e _ N N 2   d i s p l a y e d _ V V D   s e v e r a l _ D A 2   f e a t u r e s _ N N 2   o f _ I O   p r e m a t u r e _ J J   a g i n g _ N N 1   . _ .   
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 T h e _ A T   m e c h a n i s m s _ N N 2   u n d e r l y i n g _ V V G   t h e _ A T   h e p a t i c _ J J   5 a l p h a - r e d u c t a s e _ J J   d e f i c i e n c y _ N N 1   a m o n g _ I I   A I P _ N P 1   p a t i e n t s _ N N 2   r e m a i n _ V V 0   o b s c u r e _ J J   . _ .   
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 I n _ I I   n e w l y _ R R   d i a g n o s e d _ V V D   M M _ N N U   a n d _ C C   i n _ I I   p a t i e n t s _ N N 2   r e l a p s i n g _ V V G   f o l l o w i n g _ J J   t r e a t m e n t _ N N 1   d i s c o n t i n u a t i o n _ N N 1   , _ ,   t h e _ A T   p r e d o m i n a t i n g _ J J   t u m o r _ N N 1   c e l l s _ N N 2   a r e _ V B R   X b p 1 s + _ F O   p l a s m a _ N N 1   c e l l s _ N N 2   o r _ C C   p l a s m a b l a s t s _ N N 2   ( _ (   F i g u r e s _ V V Z   6 _ M C   , _ ,   7 A _ F O   , _ ,   a n d _ C C   7 D _ N N U   ) _ )   , _ ,   a l t h o u g h _ C S   p r o g e n i t o r _ N N 1   s u b p o p u l a t i o n s _ N N 2   i n c l u d i n g _ I I   C D 2 0 _ F O   . _ .   
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 A l t h o u g h _ C S   o p i u m _ N N 1   h a d _ V H D   b e e n _ V B N   k n o w n _ V V N   f o r _ I F   c e n t u r i e s _ N N T 2   t o _ T O   r e l i e v e _ V V I   p a i n _ N N 1   a n d _ C C   p r o v i d e _ V V I   s o m e _ D D   s u r g i c a l _ J J   a n a l g e s i a _ N N 1   , _ ,   B o y l e _ N P 1   f o c u s e d _ V V D   o n _ I I   i t _ P P H 1   a s _ C S A   p o i s o n _ N N 1   , _ ,   p e r h a p s _ R R   b e c a u s e _ C S   h i s _ A P P G E   i n t e r e s t _ N N 1   w a s _ V B D Z   m o r e _ R G R   c h e m i c a l _ J J   t h a n _ C S N   m e d i c a l _ J J   , _ ,   a n d _ C C   b e c a u s e _ C S   o p i u m _ N N 1   w a s _ V B D Z   k n o w n _ V V N   t o _ T O   k i l l _ V V I   : _ :   ' _ N U L L   w e _ P P I S 2   h a v e _ V H 0   m o r e _ D A R   t h a n _ C S N   o n c e _ R R   g i v e n _ V V N   t o _ I I   a _ A T 1   D o g _ N N 1   , _ ,   w i t h o u t _ I W   m u c h _ R R   h a r m i n g _ V V G   h i m _ P P H O 1   , _ ,   s u c h _ D A   a _ A T 1   q u a n t i t y _ N N 1   o f _ I O   O p i u m _ N N 1   , _ ,   a s _ C S A   w o u l d _ V M   p r o b a b l y _ R R   h a v e _ V H I   s u f f i c _ J J   ' _ N U L L   d _ Z Z 1   t o _ T O   h a v e _ V H I   k i l l J d _ N N 1   s e v e r a l _ D A 2   M e n _ N N 2   , _ ,   S e v e r a l _ D A 2   p a g e s _ N N 2   o f _ I O   h i s _ A P P G E   e s s a y _ N N 1   w e r e _ V B D R   d e d i c a t e d _ V V N   t o _ I I   t h e _ A T   q u e s t i o n _ N N 1   o f _ I O   h o w _ R R Q   o p i u m _ N N 1   m i g h t _ V M   b e s t _ R R T   b e _ V B I   f o r m u l a t e d _ V V N   a n d _ C C   p r e p a r e d _ V V N   w i t h _ I W   a l c o h o l _ N N 1   t o _ T O   f o r m _ V V I   v a r i o u s _ J J   k i n d s _ N N 2   o f _ I O   l a u d e n u m _ N N 1   , _ ,   s o m e _ D D   i n c l u d i n g _ I I   s a f f r o n _ N N 1   a n d _ C C   v i n e g a r _ N N 1   . _ .   
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 C o n c l u s i o n _ N N 1   : _ :   N o _ A T   c o n n e c t i o n _ N N 1   b e t w e e n _ I I   a l l e r g y _ N N 1   t o _ T O   p r o p o f o l _ V V I   a n d _ C C   a l l e r g y _ N N 1   t o _ I I   e g g _ N N 1   , _ ,   s o y _ J J   o r _ C C   p e a n u t _ N N 1   w a s _ V B D Z   f o u n d _ V V N   . _ .   
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 I n _ B C L 2 1   o r d e r _ B C L 2 2   t o _ T O   p r o v i d e _ V V I   m u l t i p l e _ J J   m e t h o d s _ N N 2   f o r _ I F   c o m p a r i s o n _ N N 1   a c r o s s _ I I   s t u d i e s _ N N 2   , _ ,   s e v e r a l _ D A 2   s t a t i s t i c s _ N N   w e r e _ V B D R   c o m p u t e d _ V V N   t o _ T O   d e s c r i b e _ V V I   a n a l y t e _ N N 1   v a r i a t i o n _ N N 1   . _ .   
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 B y _ I I   a s s u m i n g _ V V G   l e a d e r s h i p _ N N 1   a n d _ C C   r e s p o n s i b i l i t y _ N N 1   f o r _ I F   t h e _ A T   s t e w a r d s h i p _ N N 1   o f _ I O   o u r _ A P P G E   h e a l t h _ N N 1   c a r e _ N N 1   r e s o u r c e s _ N N 2   , _ ,   t h e y _ P P H S 2   h a v e _ V H 0   a n _ A T 1   o p p o r t u n i t y _ N N 1   t o _ T O   p r e s e r v e _ V V I   t h e i r _ A P P G E   a u t o n o m y _ N N 1   a n d _ C C   e n s u r e _ V V I   t h a t _ C S T   h o s p i t a l i z e d _ V V D   c h i l d r e n _ N N 2   r e c e i v e _ V V 0   t h e _ A T   h i g h e s t _ J J T   q u a l i t y _ N N 1   c a r e _ N N 1   . _ .   
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 T o _ T O   a s s e s s _ V V I   f i d e l i t y _ N N 1   , _ ,   g r o u p _ N N 1   l e a d e r s _ N N 2   d o c u m e n t e d _ V V D   s e s s i o n _ N N T 1   a c t i v i t i e s _ N N 2   ( _ (   e g _ R E X   , _ ,   r e v i e w _ N N 1   o f _ I O   h o m e w o r k _ N N 1   a n d _ C C   v i d e o _ N N 1   v i g n e t t e s _ N N 2   d i s c u s s e d _ V V N   ) _ )   a f t e r _ C S   e a c h _ D D 1   s e s s i o n _ N N T 1   u s i n g _ V V G   t h e _ A T   I Y _ N P 1   p r o g r a m _ N N 1   ' _ N U L L   s _ Z Z 1   L e a d e r _ N N 1   ' _ N U L L   s _ Z Z 1   P r o c e s s _ V V 0   C h e c k l i s t _ N N 1   . _ .   
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 A f t e r _ C S   t h e _ A T   r a d i c a l _ J J   m a x i l l e c t o m y _ N N 1   , _ ,   t h e _ A T   u p p e r _ J J   b o r d e r _ N N 1   o f _ I O   t h e _ A T   s u b m e n t a l _ J J   f l a p _ N N 1   w a s _ V B D Z   m a r k e d _ V V N   a t _ I I   t h e _ A T   i n f e r i o r _ J J   b o r d e r _ N N 1   o f _ I O   t h e _ A T   m a n d i b u l a r _ J J   a r c h _ N N 1   . _ .   
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 T w o _ M C   o t h e r _ J J   m a j o r _ J J   s i g n s _ N N 2   t o _ T O   a f f i r m _ V V I   t h e _ A T   d i a g n o s i s _ N N 1   o f _ I O   H C C _ N P 1   b e n e a t h _ I I   t h e _ A T   p e r f u s i o n _ N N 1   c h a r a c t e r i s t i c s _ N N 2   a r e _ V B R   t h e _ A T   p r e s e n c e _ N N 1   o f _ I O   a _ A T 1   c a p s u l e _ N N 1   a n d _ C C   t h r e s h o l d _ N N 1   g r o w t h _ N N 1   b e t w e e n _ I I   2 _ M C   i m a g i n g _ J J   s t u d i e s _ N N 2   . _ .   
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 J e f f r e y _ N P 1   S a p y t a _ N P 1   , _ ,   P h D _ N N A   , _ ,   D u k e _ N N 1   U n i v e r s i t y _ N N 1   M e d i c a l _ J J   C e n t e r _ N N 1   , _ ,   D u r h a m _ N P 1   , _ ,   N C _ N P 1   . _ .   
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 T h e _ A T   p r e v a l e n c e _ N N 1   o f _ I O   m i g r a i n e _ N N 1   w a s _ V B D Z   h i g h e r _ J J R   a m o n g _ I I   p e o p l e _ N N   w i t h _ I W   b i p o l a r _ J J   d i s o r d e r _ N N 1   t y p e _ N N 1   I I _ M C   ( _ (   5 4 . 1 7 % _ F O   , _ ,   9 5 % _ N N U   C I _ F O   3 1 . 5 2 _ M C   t o _ I I   7 5 . 9 5 _ M C   ) _ )   c o m p a r e d _ V V N   w i t h _ I W   b i p o l a r _ J J   d i s o r d e r _ N N 1   t y p e _ N N 1   I _ Z Z 1   ( _ (   3 2 . 7 % _ F O   , _ ,   9 5 % _ N N U   C I _ F O   1 8 . 1 6 _ M C   t o _ I I   4 9 . 1 9 _ M C   ) _ )   . 1 7 _ M C   B i p o l a r _ J J   d i s o r d e r _ N N 1   c o m o r b i d i t y _ N N 1   w i t h _ I W   m i g r a i n e _ N N 1   s e e m s _ V V Z   t o _ T O   b e _ V B I   a _ A T 1   s u b t y p e _ N N 1   o f _ I O   b i p o l a r _ J J   d i s o r d e r _ N N 1   w i t h _ I W   a n _ A T 1   u n s t a b l e _ J J   r a p i d _ J J   c y c l i n g _ N N 1   c o u r s e _ N N 1   , _ ,   a n _ A T 1   i n c r e a s e d _ J J   p r e v a l e n c e _ N N 1   o f _ I O   c o m o r b i d _ J J   p a n i c _ N N 1   a t t a c k s _ N N 2   , _ ,   a n _ A T 1   e a r l i e r _ J J R   a g e _ N N 1   o f _ I O   o n s e t _ N N 1   a n d _ C C   i n c r e a s e d _ J J   p r e v a l e n c e _ N N 1   i n _ I I   w o m e n . 1 8 _ F O   , _ ,   1 9 _ M C   B i p o l a r _ J J   d i s o r d e r _ N N 1   a n d _ C C   m i g r a i n e _ V V 0   s h a r e _ V V 0   s i m i l a r _ J J   f e a t u r e s _ N N 2   . _ .   
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 B e c a u s e _ C S   s t a n d a r d i z e d _ J J   s t r o k e _ N N 1   p r o t o c o l s _ N N 2   a r e _ V B R   g e n e r a l l y _ R R   n o t _ X X   t a i l o r e d _ V V N   t o _ I I   t h e _ A T   d e m o n s t r a t i o n _ N N 1   o f _ I O   v e n o u s _ J J   v e s s e l s _ N N 2   , _ ,   t h e _ A T   c o n f i r m a t i o n _ N N 1   o r _ C C   e x c l u s i o n _ N N 1   o f _ I O   C V S T _ N P 1   i s _ V B Z   f r e q u e n t l y _ R R   n o t _ X X   p o s s i b l e _ J J   i n _ I I   t h e s e _ D D 2   e x a m i n a t i o n s _ N N 2   . _ .   
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 R e p r e s e n t a t i v e _ J J   M R I _ J J   i m a g e s _ N N 2   ( _ (   a x i a l _ J J   r e s o l u t i o n _ N N 1   2 3 . 4 _ M C   m m _ N N U   ) _ )   o f _ I O   t h r e e _ M C   c _ Z Z 1   r a t o r y _ J J   m o d e l s _ N N 2   a c q u i r e d _ V V D   u s i n g _ V V G   e s t a b l i s h e d _ J J   p r o t o c o l s _ N N 2   ( _ (   B e r k o w i t z _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 4 _ M C   ; _ ;   B i s s i g _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 3 _ M C   ) _ )   ; _ ;   t h e _ A T   i m a g e s _ N N 2   a r e _ V B R   p r o p o r t i o n a t e l y _ R R   s i z e d _ V V N   b a s e d _ V V N   o n _ I I   o c u l a r _ J J   a n a t o m y . 2 0 0 9 a _ F O   , _ ,   2 0 1 0 _ M C   , _ ,   2 0 1 2 a _ F O   , _ ,   2 0 0 6 _ M C   , _ ,   2 0 0 7 d _ N N U   ; _ ;   B i s s i g _ N P 1   a n d _ C C   B e r k o w i t z _ N P 1   , _ ,   2 0 1 1 _ M C   ) _ )   . _ .   
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 T h o u g h _ C S   t h e _ A T   p a r e n t s _ N N 2   l o v e _ V V 0   t h e i r _ A P P G E   c h i l d _ N N 1   , _ ,   t h e y _ P P H S 2   g r a d u a l l y _ R R   l a c k _ V V 0   p a t i e n c e _ N N 1   , _ ,   a c c e p t a n c e _ N N 1   , _ ,   u n d e r s t a n d i n g _ V V G   , _ ,   r e s i s t a n c e _ N N 1   a n d _ C C   w i l l i n g n e s s _ N N 1   t o _ T O   s p e n d _ V V I   t i m e _ N N T 1   t o g e t h e r _ R L   ( _ (   F a r n i k _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 0 _ M C   ; _ ;   M i l l e r _ N P 1   , _ ,   2 0 0 9 _ M C   ) _ )   . _ .   
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 P r o v e n a n c e _ N N 1   a n d _ C C   p e e r _ V V 0   r e v i e w _ V V 0   N o t _ X X   c o m m i s s i o n e d _ V V N   ; _ ;   e x t e r n a l l y _ R R   p e e r _ V V 0   r e v i e w e d _ V V N   . _ .   
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 T h e _ A T   s e r u m _ N N 1   p o t a s s i u m _ N N 1   r e p o r t _ N N 1   w a s _ V B D Z   2 . 0 _ M C   m m o l / L _ F U   . _ .   
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 W i t h _ I W   a d m i n i s t r a t i o n _ N N 1   p o t a s s i u m _ N N 1   ( _ (   1 6 0 _ M C   m e q _ J J   i n t r a v e n o u s _ J J   o v e r _ R G   2 4 _ M C   h _ Z Z 1   f o l l o w e d _ V V N   b y _ I I   6 0 _ M C   m e q _ J J   p e r _ I I   d a y _ N N T 1   i n _ I I   t h r e e _ M C   d i v i d e d _ J J   d o s e s _ N N 2   o r a l l y _ R R   i n _ I I   f o r m _ N N 1   o f _ I O   p o t a s s i u m _ N N 1   c h l o r i d e _ N N 1   ) _ )   , _ ,   t h e _ A T   p a t i e n t _ N N 1   s h o w e d _ V V D   d r a m a t i c _ J J   c l i n i c a l _ J J   i m p r o v e m e n t _ N N 1   . _ .   
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 ( _ (   2 0 1 3 _ M C   ) _ )   , _ ,   T h e _ A T   N e w _ J J   V i s u a l _ J J   N e u r o s c i e n c e s _ N P 2   , _ ,   i n _ I I   p r e s s _ N N 1   , _ ,   b y _ I I   p e r m i s s i o n _ N N 1   o f _ I O   t h e _ A T   a u t h o r s _ N N 2   . _ .   
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 W e _ P P I S 2   f i r s t l y _ R R   u s e d _ V V D   t h e _ A T   G e n e v a r _ N N 1   e x p r e s s i o n _ N N 1   d a t a b a s e _ N N 1   , _ ,   c o n s i s t i n g _ V V G   o f _ I O   7 5 _ M C   l y m p h o b l a s t o i d _ J J   c e l l _ N N 1   l i n e s _ N N 2   f r o m _ I I   h e a l t h y _ J J   E u r o p e a n _ J J   i n d i v i d u a l s _ N N 2   , _ ,   4 0 _ M C   a n d _ C C   f o u n d _ V V N   r s 2 7 0 9 3 7 3 _ F O   a n d _ C C   r s 2 5 5 1 9 4 9 _ F O   w e r e _ V B D R   s i g n i f i c a n t l y _ R R   a s s o c i a t e d _ V V N   w i t h _ I W   C R E B 1 _ F O   e x p r e s s i o n _ N N 1   ( _ (   r s 2 7 0 9 3 7 3 _ F O   , _ ,   P _ Z Z 1   = _ F O   2 . 4 _ M C   x _ Z Z 1   1 0 - 3 _ M C M C   ; _ ;   r s 2 5 5 1 9 4 9 _ F O   , _ ,   P _ Z Z 1   = _ F O   5 . 0 _ M C   x _ Z Z 1   1 0 - 4 _ M C M C   , _ ,   p r o b e _ V V 0   I D _ N N 1   : _ :   I L M N 2 3 3 4 2 4 2 _ F O   ; _ ;   F i g u r e _ N N 1   3 a _ F O   ) _ )   , _ ,   w i t h _ I W   t h e _ A T   r i s k _ N N 1   a l l e l e s _ N N 2   h a v i n g _ V H G   h i g h e r _ J J R   e x p r e s s i o n _ N N 1   . _ .   
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 A _ A T 1   d e c r e a s e _ N N 1   i n _ I I   e n d o t o x i n _ N N 1   c o u l d _ V M   t h e o r e t i c a l l y _ R R   r e d u c e _ V V I   t h e _ A T   a c t i v a t i o n _ N N 1   o f _ I O   s y s t e m i c _ J J   p r o i n f l a m m a t o r y _ J J   m e d i a t o r s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   T N F - a _ N P 1   a n d _ C C   N F - k B _ N N 1   r e s u l t i n g _ V V G   i n _ I I   a n _ A T 1   o v e r a l l _ J J   d e c r e a s e _ N N 1   i n _ I I   a d i p o s e _ V V 0   t i s s u e _ N N 1   a n d _ C C   s y s t e m i c _ J J   i n f l a m m a t i o n _ N N 1   . _ .   
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 I m p a i r e d _ J J   m a t u r a t i o n _ N N 1   o f _ I O   p r o N G F _ N N 1   c a u s e d _ V V N   b y _ I I   t h e _ A T   o x i d a t i v e _ J J   m i l i e u _ N N 1   o f _ I O   t h e _ A T   d i a b e t i c _ J J   r e t i n a _ N N 1   r e s u l t s _ N N 2   i n _ I I   i n c r e a s e d _ J J   e x p r e s s i o n _ N N 1   o f _ I O   p r o N G F _ N N 1   , _ ,   w i t h _ I W   a _ A T 1   c o r r e s p o n d i n g _ J J   d e c r e a s e _ N N 1   i n _ I I   N G F _ N P 1   ( _ (   M y s o n a _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 4 _ M C   ) _ )   . _ .   
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 O B J E C T I V E _ J J   T o _ T O   t e s t _ V V I   w h e t h e r _ C S W   C S F _ N P 1   N F L _ N P 1   c o n c e n t r a t i o n _ N N 1   i s _ V B Z   a s s o c i a t e d _ V V N   w i t h _ I W   c o g n i t i v e _ J J   d e c l i n e _ N N 1   a n d _ C C   i m a g i n g _ V V G   e v i d e n c e _ N N 1   o f _ I O   n e u r o d e g e n e r a t i o n _ N N 1   a n d _ C C   w h i t e _ J J   m a t t e r _ N N 1   c h a n g e _ N N 1   i n _ I I   A D . D E S I G N _ N P 1   , _ ,   S E T T I N G _ V V G   , _ ,   A N D _ C C   P A R T I C I P A N T S _ N N 2   A _ Z Z 1   c o m m e r c i a l l y _ R R   a v a i l a b l e _ J J   i m m u n o a s s a y _ N N 1   w a s _ V B D Z   u s e d _ V V N   t o _ T O   a n a l y z e _ V V I   C S F _ N P 1   N F L _ N P 1   c o n c e n t r a t i o n _ N N 1   i n _ I I   a _ A T 1   c o h o r t _ N N 1   o f _ I O   p a t i e n t s _ N N 2   w i t h _ I W   A D _ R A   ( _ (   n _ Z Z 1   = _ F O   9 5 _ M C   ) _ )   o r _ C C   m i l d _ J J   c o g n i t i v e _ J J   i m p a i r m e n t _ N N 1   ( _ (   M C I _ M C   ) _ )   ( _ (   n _ Z Z 1   = _ F O   1 9 2 _ M C   ) _ )   a n d _ C C   i n _ I I   c o g n i t i v e l y _ R R   n o r m a l _ J J   i n d i v i d u a l s _ N N 2   ( _ (   n _ Z Z 1   = _ F O   1 1 0 _ M C   ) _ )   f r o m _ I I   t h e _ A T   A l z h e i m e r _ N P 1   ' _ N U L L   s _ Z Z 1   D i s e a s e _ N N 1   N e u r o i m a g i n g _ V V G   I n i t i a t i v e _ N N 1   . _ .   
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 F o c u s _ V V 0   o n _ I I   B r M _ N P 1   p r o v e d _ V V D   f r u i t f u l _ J J   , _ ,   b e c a u s e _ C S   i t _ P P H 1   i s _ V B Z   t h e _ A T   c o m p a r t m e n t _ N N 1   f o r _ I F   A M D - s p e c i f i c _ J J   l e s i o n s _ N N 2   ( _ (   d r u s e n _ N N 1   a n d _ C C   B L i n D _ J J   ) _ )   , _ ,   t h u s _ R R   i m p a r t i n g _ V V G   g r e a t _ J J   p o t e n t i a l _ N N 1   f o r _ I F   d i r e c t _ J J   i n v o l v e m e n t _ N N 1   i n _ I I   l e s i o n _ N N 1   b i o g e n e s i s _ N N 1   . _ .   
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 W o m e n _ N N 2   w e r e _ V B D R   i n i t i a l l y _ R R   c l a s s i f i e d _ V V N   u s i n g _ V V G   i n f o r m a t i o n _ N N 1   p r o v i d e d _ V V N   a t _ I I   r e c r u i t m e n t _ N N 1   , _ ,   a n d _ C C   t h o s e _ D D 2   w h o _ P N Q S   p r o v i d e d _ V V D   u p d a t e d _ J J   i n f o r m a t i o n _ N N 1   o n _ I I   H T _ N N 1   u s e _ N N 1   o n _ I I   t h e _ A T   s e c o n d _ M D   s t u d y _ N N 1   q u e s t i o n n a i r e _ N N 1   ( _ (   o n _ I I   a v e r a g e _ N N 1   3 _ M C   y e a r s _ N N T 2   a f t e r _ I I   r e c r u i t m e n t _ N N 1   ) _ )   w e r e _ V B D R   t h e n _ R T   r e c l a s s i f i e d _ V V N   u s i n g _ V V G   t h i s _ D D 1   u p d a t e d _ J J   i n f o r m a t i o n _ N N 1   . _ .   
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 C a r o t i d _ J J   i m a g i n g _ N N 1   a t _ I I   7 _ M C   T _ Z Z 1   h a s _ V H Z   a t t r a c t e d _ V V N   s u b s t a n t i a l _ J J   a t t e n t i o n _ N N 1   , _ ,   g i v e n _ V V N   t h e _ A T   i m p o r t a n c e _ N N 1   o f s p a t i a l _ J J   r e s o l u t i o n _ N N 1   i n _ I I   e v a l u a t i n g _ V V G   t h e _ A T   c a r o t i d _ J J   w a l l _ N N 1   a n d _ C C   a t h e r o s c l e r o t i c _ J J   d i s e a s e . 4 3 5 _ F O   O t h e r _ J J   s p e c i a l t y _ N N 1   a r e a s _ N N 2   w i t h i n _ I I   t h e _ A T   C N S _ N P 1   w h e r e _ C S   u l t r a - h i g h _ J J   f i e l d _ N N 1   M R _ N N B   c o u l d _ V M   e a s i l y _ R R   s u r p a s s _ V V I   3 _ M C   T _ Z Z 1   i n _ I I 3 1   t e r m s _ I I 3 2   o f _ I I 3 3   d i a g n o s t i c _ J J   e f f i c a c y _ N N 1   i n c l u d e _ V V 0   t h e _ A T   o r b i t _ N N 1   , _ ,   s e l l a _ N N 1   , _ ,   a n d _ C C   i n t e r n a l _ J J   a u d i t o r y _ J J   c a n a l _ N N 1   . _ .   
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 A _ A T 1   p r e p l a n n e d _ J J   s u b g r o u p _ N N 1   a n a l y s i s _ N N 1   t h a t _ C S T   e x a m i n e d _ V V D   v i s u a l _ J J   o u t c o m e s _ N N 2   a s _ I I   a _ A T 1   f u n c t i o n _ N N 1   o f _ I O   d u r a t i o n _ N N 1   o f _ I O   D M E _ N N 1   a t _ I I   r a n d o m i z a t i o n _ N N 1   ( _ (   a b o v e _ R L   o r _ C C   b e l o w _ I I   t h e _ A T   m e d i a n _ J J   d u r a t i o n _ N N 1   ) _ )   r e v e a l e d _ V V D   t h a t _ C S T   t h e _ A T   t r e a t m e n t _ N N 1   e f f e c t _ N N 1   r e s i d e d _ V V D   p r i m a r i l y _ R R   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   c h r o n i c _ J J   D M E _ N N 1   . _ .   
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 C a r o l i n a s _ N P 2   M e d i c a l _ J J   C e n t e r _ N N 1   , _ ,   C h a r l o t t e _ N P 1   , _ ,   N o r t h _ N D 1   C a r o l i n a _ N P 1   : _ :   J . _ N P 1   B e r n a r d _ N P 1   , _ ,   S . _ N P 1   D i b e r t _ N P 1   , _ ,   J . _ N P 1   S t o r y _ N N 1   , _ ,   J . _ N P 1   M a r t i n _ N P 1   , _ ,   a n d _ C C   M . P r i c e _ N P 1   . _ .   
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 T o _ T O   d e m o n s t r a t e _ V V I   t h e _ A T   u t i l i t y _ N N 1   a n d _ C C   s e n s i t i v i t y _ N N 1   o f _ I O   t h i s _ D D 1   a s s a y _ N N 1   , _ ,   w e _ P P I S 2   a n a l y z e d _ V V D   d e l e t i o n _ N N 1   l o a d s _ N N 2   w i t h i n _ I I   t h e _ A T   m i t o c h o n d r i a l _ J J   g e n o m e _ N N 1   o f _ I O   h u m a n _ J J   b r a i n _ N N 1   s a m p l e s _ N N 2   . _ .   
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 A _ A T 1   n e u r a l _ J J   n e t w o r k _ N N 1   c a n _ V M   b e _ V B I   t h o u g h t _ V V N   o f _ I O   a s _ I I   a _ A T 1   s m a l l _ J J   m a c h i n e _ N N 1   c a p a b l e _ J J   o f _ I O   l e a r n i n g _ N N 1   . _ .   
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 W e _ P P I S 2   r e v i e w _ V V 0   a _ A T 1   r a n g e _ N N 1   o f _ I O   p o t e n t i a l _ J J   o u t c o m e _ N N 1   m a r k e r s _ N N 2   f o r _ I F   C A A _ N P 1   a g a i n s t _ I I   t h e _ A T   i d e a l _ J J   c r i t e r i a _ N N 2   o f _ I O   b e i n g _ V B G   c l i n i c a l l y _ R R   m e a n i n g f u l _ J J   , _ ,   c l o s e l y _ R R   r e f l e c t i v e _ J J   o f _ I O   b i o l o g i c a l _ J J   p r o g r e s s i o n _ N N 1   , _ ,   e f f i c i e n t _ J J   f o r _ I F   s m a l l e r / s h o r t e r _ J J R   t r i a l s _ N N 2   , _ ,   r e l i a b l y _ R R   m e a s u r a b l e _ J J   , _ ,   a n d _ C C   c o s t _ V V 0   e f f e c t i v e _ J J   . _ .   
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 T h e _ A T   a n i m a l _ N N 1   w a s _ V B D Z   t h e n _ R T   r e t u r n e d _ V V N   t o _ I I   i t s _ A P P G E   h o m e _ N N 1   c a g e _ N N 1   f o r _ I F   s e v e n _ M C   d a y s _ N N T 2   s u r v i v a l _ N N 1   t i m e _ N N T 1   . _ .   
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 T w o - b y - t w o _ M C   t a b l e s _ N N 2   w e r e _ V B D R   u s e d _ V V N   t o _ T O   d e t e r m i n e _ V V I   s e n s i t i v i t y _ N N 1   , _ ,   s p e c i f i c i t i e s _ N N 2   , _ ,   p o s i t i v e _ J J   a n d _ C C   n e g a t i v e _ J J   l i k e l i h o o d _ N N 1   r a t i o s _ N N 2   , _ ,   a n d _ C C   a g r e e m e n t _ N N 1   b e t w e e n _ I I   O t t a w a _ N P 1   3 D Y _ F O   S c a l e _ N N 1   s c o r e s _ N N 2   a n d _ C C   A n i m a l _ N N 1   F l u e n c y _ N N 1   T e s t _ N N 1   s c o r e s _ N N 2   a n d _ C C   M i n i M e n t a l _ J J   S t a t e _ N N 1   E x a m i n a t i o n _ N N 1   r e s u l t s _ N N 2   a t _ I I   p r e d e t e r m i n e d _ J J   c u t o f f s _ N N 2   . _ .   
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 F i r s t _ M D   , _ ,   i t _ P P H 1   i s _ V B Z   d i f f i c u l t _ J J   t o _ T O   d r a w _ V V I   c o n c l u s i o n s _ N N 2   r e g a r d i n g _ I I   d e v i c e _ N N 1   p e r f o r m a n c e _ N N 1   i n _ I I   i n d i v i d u a l _ J J   p a t i e n t s _ N N 2   u s i n g _ V V G   t h e _ A T   g e o m e t r i c _ J J   m e a n _ N N 1   o f _ I O   3 7 _ M C   p a t i e n t s _ N N 2   w h o s e _ D D Q G E   u r i n a r y _ J J   h C G _ N N U   c o n c e n t r a t i o n s _ N N 2   d e m o n s t r a t e d _ V V N   s u c h _ D A   a _ A T 1   l a r g e _ J J   s t a n d a r d _ J J   d e v i a t i o n _ N N 1   . _ .   
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 T h e _ A T   C - a r m _ N N 1   ( _ (   M u l t i D i a g n o s t _ N P 1   E l e v a _ N P 1   ; _ ;   P h i l i p s _ N P 1   M e d i c a l _ J J   S y s t e m s _ N N 2   , _ ,   N e d e r l a n d _ N P 1   B . V . _ N P 1   , _ ,   H o l l a n d _ N P 1   ) _ )   w a s _ V B D Z   r o t a t e d _ V V N   u n t i l _ C S   t h e _ A T   s u p e r i o r _ J J   a n d _ C C   i n f e r i o r _ J J   v e r t e b r a l _ J J   p l a t e _ N N 1   w e r e _ V B D R   a l i g n e d _ V V N   a n d _ C C   a n g l e d _ V V N   a t _ I I   a p p r o x i m a t e l y _ R R   4 5 _ M C   d e g r e e s _ N N 2   i n _ I I   t h e _ A T   o b l i q u e _ J J   v i e w _ N N 1   , _ ,   o r _ C C   u n t i l _ C S   t h e _ A T   u p p e r _ J J   t i p _ N N 1   o f _ I O   t h e _ A T   t a r g e t _ N N 1   s u p e r i o r _ J J   a r t i c u l a r _ J J   p r o c e s s _ N N 1   w a s _ V B D Z   l o c a t e d _ V V N   a t _ I I   t h e _ A T   m i d p o i n t _ N N 1   o f _ I O   t h e _ A T   v e r t e b r a l _ J J   b o d y _ N N 1   . _ .   
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 T h e _ A T   s u p p r e s s i o n _ N N 1   o f _ I O   v a r i o u s _ J J   a c t i v i t y - a s s o c i a t e d _ J J   g e n e s _ N N 2   c o u l d _ V M   s t a b i l i z e _ V V I   t h e _ A T   n e u r o m u s c u l a r _ J J   j u n c t i o n _ N N 1   a n d _ C C   i n h i b i t _ V V I   r e i n n e r v a t i o n _ N N 1   i n _ I I   t h e _ A T   M u R F 1 _ F O   K O _ N N 1   m i c e _ N N 2   d u r i n g _ I I   t h i s _ D D 1   t i m e _ N N T 1   o f _ I O   m o t o n e u r o n _ N N 1   l o s s _ N N 1   a n d _ C C   s y n a p s e _ V V 0   r e m o d e l i n g _ V V G   . _ .   
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 D a t a _ N N   A n a l y s e s _ V V Z   P r e v i o u s _ J J   s t u d i e s _ N N 2   t e s t i n g _ V V G   t h e _ A T   c o n c u r r e n t _ J J   v a l i d i t y _ N N 1   o f _ I O   n e o n a t a l _ J J   p a i n _ N N 1   s c a l e s _ N N 2   h a v e _ V H 0   e v i d e n c e d _ V V N   l a r g e _ J J   e f f e c t _ N N 1   s i z e s _ N N 2   . _ .   
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 A s _ I I   a _ A T 1   p r o x y _ N N 1   f o r _ I F   m e a s u r i n g _ V V G   s w i t c h i n g _ N N 1   t o _ I I   l e s s _ R G R   e x p e n s i v e _ J J   c l i n i c i a n s _ N N 2   , _ ,   H O P D _ N P 1   u t i l i z a t i o n _ N N 1   w a s _ V B D Z   e x a m i n e d _ V V N   . _ .   
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 V e n t r i c l e _ N N 1   r e d u c t i o n _ N N 1   w a s _ V B D Z   c o u n t e d _ V V N   a s _ C S A   a g r e e m e n t _ N N 1   b e c a u s e _ C S   e n l a r g e m e n t _ N N 1   o f _ I O   v e n t r i c l e s _ N N 2   c a n _ V M   o f t e n _ R R   r e s o l v e _ V V I   s p o n t a n e o u s l y _ R R   d u r i n g _ I I   p r e g n a n c y _ N N 1   . _ .   
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 H y p o t e n s i o n _ N N 1   n e c e s s i t a t i n g _ V V G   c h a n g e s _ N N 2   i n _ I I   a n a l g e s i c _ N N 1   t h e r a p y _ N N 1   ( _ (   e i t h e r _ R R   h o l d i n g _ V V G   o r _ C C   d o s e _ N N 1   a d j u s t m e n t _ N N 1   ) _ )   o c c u r r e d _ V V D   i n _ R P   a p p r o x i m a t e l y _ R R   2 5 % _ N N U   o f _ I O   p a t i e n t s _ N N 2   o n _ I I   P O D 1 _ F O   a n d _ C C   a p p r o x i m a t e l y _ R R   1 0 % _ N N U   o f _ I O   p a t i e n t s _ N N 2   o n _ I I   P O D 2 _ F O   i n _ I I   t h e _ A T   e p i d u r a l _ J J   a n a l g e s i a _ N N 1   c o h o r t _ N N 1   ; _ ;   i t _ P P H 1   w a s _ V B D Z   v i r t u a l l y _ R R   e l i m i n a t e d _ V V N   i n _ I I   t h e _ A T   i n t r a v e n o u s _ J J   l i d o c a i n e _ N N 1   g r o u p _ N N 1   . _ .   
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 S e v e r a l _ D A 2   c l i n i c a l _ J J   s t u d i e s _ N N 2   h a v e _ V H 0   s h o w n _ V V N   D E X _ V V 0   t o _ T O   b e _ V B I   a _ A T 1   u s e f u l _ J J   s e d a t i v e _ J J   d r u g _ N N 1   f o r _ I F   c o n s c i o u s _ J J   s e d a t i o n _ N N 1   d u r i n g _ I I   a w a k e _ J J   c r a n i o t o m y _ N N 1   , _ ,   b u t _ C C B   t h e _ A T   s e d a t i v e _ N N 1   a n d _ C C   a n a l g e s i c _ N N 1   e f f e c t s _ N N 2   o f _ I O   a n _ A T 1   i n t r a o p e r a t i v e _ J J   i n f u s i o n _ N N 1   o f _ I O   D E X _ N N 1   a f t e r _ I I   c r a n i o t o m y _ N N 1   h a v e _ V H 0   n o t _ X X   b e e n _ V B N   r e p o r t e d _ V V N   . _ .   
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 A _ A T 1   r e v i e w _ N N 1   t e a m _ N N 1   , _ ,   i n c l u d i n g _ I I   c o - c o o r d i n a t o r s _ N N 2   a n d _ C C   s t a f f _ N N   s p e c i f i c a l l y _ R R   t r a i n e d _ V V N   i n _ I I   t h e _ A T   A - 6 _ M C   M e t h o d _ N N 1   a p p l i c a t i o n _ N N 1   , _ ,   c o n d u c t e d _ V V D   t h e _ A T   s y s t e m a t i c _ J J   r e v i e w _ N N 1   . _ .   
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 N o _ N N 1   I S _ V B Z   i n _ I I 3 1   a c c o r d a n c e _ I I 3 2   w i t h _ I I 3 3   t h e _ A T   I n t e r n a t i o n a l _ J J   F e d e r a t i o n _ N N 1   o f _ I O   C l i n i c a l _ J J   C h e m i s t r y _ N N 1   i s _ V B Z   c u r r e n t l y _ R R   a v a i l a b l e _ J J   . _ .   
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 V e r y _ R G   r e c e n t l y _ R R   , _ ,   t w o _ M C   r e v e r s e _ J J   e n d o p h e n o t y p e _ N N 1   s t u d i e s _ N N 2   h a v e _ V H 0   e x a m i n e d _ V V N   t h e _ A T   a b i l i t y _ N N 1   o f _ I O   s c h i z o p h r e n i a _ N N 1   p o l y g e n i c _ J J   r i s k _ N N 1   s c o r e s _ N N 2   t o _ T O   p r e d i c t _ V V I   c o g n i t i v e _ J J   a b i l i t i e s _ N N 2   i n _ I I   i n d e p e n d e n t _ J J   c o h o r t s . 1 1 , 1 2 _ F O   B o t h _ D B 2   s t u d i e s _ N N 2   d r a w _ V V 0   f r o m _ I I   t h e _ A T   w o r k _ N N 1   o f _ I O   t h e _ A T   P s y c h i a t r i c _ J J   G W A S _ N N 2   C o n s o r t i u m _ N N 1   o n _ I I   S c h i z o p h r e n i a _ N N 1   ( _ (   P G C - S C Z _ N P 1   ) _ )   , _ ,   a _ A T 1   l a r g e - s c a l e _ J J   m e g a - a n a l y t i c _ J J   G W A S _ N N 2   o f _ I O   1 7 _ M C   C a u c a s i a n _ J J   c o h o r t s _ N N 2   e n c o m p a s s i n g _ V V G   g r e a t e r _ J J R   t h a n _ C S N   9 0 0 0 _ M C   S C Z _ N P 1   c a s e s _ N N 2   a n d _ C C   g r e a t e r _ J J R   t h a n _ C S N   1 2 , 0 0 0 _ M C   c o n t r o l s . 1 3 _ F O   I n _ I I   o n e _ M C 1   s t u d y 1 2 _ F O   , _ ,   p o l y g e n i c _ J J   r i s k _ N N 1   s c o r e s _ N N 2   f o r _ I F   S C Z _ N P 1   w e r e _ V B D R   s i g n i f i c a n t l y _ R R   a s s o c i a t e d _ V V N   w i t h _ I W   I Q _ N N 1   i n _ I I   a _ A T 1   c o h o r t _ N N 1   o f _ I O   p a t i e n t s _ N N 2   w i t h _ I W   S C Z _ N P 1   a n d _ C C   c o n t r o l s _ N N 2   , _ ,   b u t _ C C B   t h e s e _ D D 2   a s s o c i a t i o n s _ N N 2   w e r e _ V B D R   n o t _ X X   o b s e r v e d _ V V N   i n _ I I   t h e _ A T   s m a l l e r _ J J R   ( _ (   n = 3 2 2 _ F O   ) _ )   h e a l t h y _ J J   c o h o r t _ N N 1   a l o n e _ R R   . _ .   
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 I t _ P P H 1   m a y _ V M   b e _ V B I   t h a t _ D D 1   , _ ,   w i t h _ I W   s u f f i c i e n t _ J J   s a m p l e s _ N N 2   s i z e s _ N N 2   , _ ,   a s s o c i a t i o n s _ N N 2   o f _ I O   S C N 2 A _ F O   S N P s _ N P 2   w i t h _ I W   t h e _ A T   s c h i z o p h r e n i a _ N N 1   d i a g n o s i s _ N N 1   w i l l _ V M   e m e r g e _ V V I   . _ .   
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 T h e _ A T   m e d i a n _ J J   c r e a t i n i n e _ N N 1   f o r _ I F   t h e _ A T   C N D R _ N P 1   m a c h i n e _ N N 1   w a s _ V B D Z   0 . 7 2 _ M C   m g / d L _ F U   w i t h _ I W   a n _ A T 1   i n t e r q u a r t i l e _ J J   r a n g e _ N N 1   o f _ I O   0 . 6 1 _ M C   t o _ I I   0 . 9 0 _ M C   m g / d L _ F U   . _ .   
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 M e d i a n _ J J   i n t r a - i n d i v i d u a l _ J J   c r e a t i n i n e _ N N 1   r e s u l t s _ N N 2   o b t a i n e d _ V V N   w i t h _ I W   t h e _ A T   S t a t S e n s o r _ N P 1   X p r e s s _ N P 1   d e v i c e _ N N 1   w e r e _ V B D R   o n _ I I   t h e _ A T   a v e r a g e _ N N 1   0 . 3 2 _ M C   m g / d L _ F U   h i g h e r _ J J R   t h a n _ C S N   t h e _ A T   C N D R _ N P 1   r e s u l t s _ N N 2   w i t h _ I W   t h e _ A T   m a g n i t u d e _ N N 1   o f _ I O   d i f f e r e n c e _ N N 1   g r e a t e r _ J J R   f o r _ I F   h i g h e r _ J J R   c r e a t i n i n e _ N N 1   c o n c e n t r a t i o n s _ N N 2   . _ .   
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 F u n c t i o n a l _ J J   t e s t s _ N N 2   a r e _ V B R   r e c o m m e n d e d _ V V N   t o _ T O   a s s e s s _ V V I   m o r e _ R G R   c o m p l e x _ J J   a c t i v i t i e s _ N N 2   o f _ I O   d a i l y _ J J   l i v i n g _ N N 1   a n d _ C C   s p o r t _ N N 1   i n _ I I   t h o s e _ D D 2   w i t h _ I W   o r _ C C   a t _ I I   r i s k _ N N 1   o f _ I O   d e g e n e r a t i v e _ J J   k n e e _ N N 1   d i s e a s e _ N N 1   ( _ (   1 1 , 2 1 _ M C   ) _ )   . _ .   
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 T w o _ M C   d i f f e r e n t _ J J   k i n d s _ N N 2   o f _ I O   t o u r n i q u e t _ N N 1   c u f f _ N N 1   w e r e _ V B D R   u s e d _ V V N   i n _ I I   t h e _ A T   s t u d y _ N N 1   . _ .   
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 A l t h o u g h _ C S   l i n e a r _ J J   r a d i o l a b e l e d _ J J   A c - & l s q b ; N l e 4 _ N N 1   , _ ,   D - P h e 7 _ N N 1   & r s q b ; _ )   - a - M S H _ N P 1   ( _ (   N D P _ N P 1   ) _ )   p e p t i d e _ N N 1   a n a l o g u e s _ N N 2   w e r e _ V B D R   e n g i n e e r e d _ V V N   f o r _ I F   i n c r e a s e d _ J J   s t a b i l i t y _ N N 1   i n _ R R 2 1   v i v o _ R R 2 2   , _ ,   t h e y _ P P H S 2   h a v e _ V H 0   s u f f e r e d _ V V N   f r o m _ I I   m o d e r a t e _ J J   t u m o r _ N N 1   u p t a k e _ N N 1   a n d _ C C   p o o r _ J J   t u m o r _ N N 1   r e t e n t i o n _ N N 1   . _ .   
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 T h e s e _ D D 2   a s s u m p t i o n s _ N N 2   h a v e _ V H 0   b e e n _ V B N   t e s t e d _ V V N   a n d _ C C   w i l l _ V M   b e _ V B I   d i s c u s s e d _ V V N   u n d e r _ I I   t h e _ A T   f o l l o w i n g _ J J   3 _ M C   h e a d i n g s : 1 . D i r e c t _ F O   E l e c t r o d e _ N N 1   S t i m u l a t i o n _ N N 1   S t u d i e s _ N N 2   ; _ ;   2 _ M C   . _ .   
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 T w o - D i m e n s i o n a l _ J J   S c r e e n - b a s e d _ J J   S t u d i e s _ N N 2   ; _ ;   a n d 3 . T h r e e - D i m e n s i o n a l _ J J   O b j e c t _ N N 1   R e c o g n i t i o n _ N N 1   S t u d y . 3 . 2 . 1 . 1 _ F O   . _ .   
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 P r e n a t a l _ N P 1   , _ ,   i n f a n t _ N N 1   , _ ,   c h i l d h o o d _ N N 1   p r e d i c t o r s _ N N 2   o f _ I O   a d u l t _ N N 1   o b e s i t y _ N N 1   P r e n a t a l _ J J   r i s k _ N N 1   f a c t o r s _ N N 2   a r e _ V B R   a s s o c i a t e d _ V V N   w i t h _ I W   i n c r e a s e d _ J J   r i s k _ N N 1   f o r _ I F   o b e s i t y _ N N 1   l a t e r _ R R R   i n _ I I   l i f e _ N N 1   ( _ (   F i g . _ N N 1   1 _ M C 1   ) _ )   . _ .   
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 L a u f s _ N N 2   a n d _ C C   c o l l e a g u e s _ N N 2   r e p o r t e d _ V V D   i n c r e a s e d _ J J   c i r c u l a t i n g _ N N 1   E P C _ N P 1   l e v e l s _ N N 2   a f t e r _ I I   t r a i n i n g _ N N 1   w i t h _ I W   3 0 _ M C   m i n _ N N U   o f _ I O   m o d e r a t e _ J J   e x e r c i s e _ N N 1   ( _ (   8 0 _ M C   - _ -   1 0 0 % _ N N U   v e l o c i t y _ N N 1   o f _ I O   t h e _ A T   i n d i v i d u a l s _ N N 2   ' _ N U L L   A T _ I I   ) _ )   b u t _ C C B   n o t _ X X   a f t e r _ I I   s h o r t _ J J   t e r m _ N N 1   ( _ (   1 0 _ M C   m i n _ N N U   ) _ )   o f _ I O   r u n n i n g _ V V G   i n _ I I   h e a l t h y _ J J   s u b j e c t s _ N N 2   . _ .   
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 F a c t o r s _ N N 2   c o n s t r a i n i n g _ V V G   t h e _ A T   b e n e f i t _ N N 1   t o _ I I   s p e e c h _ N N 1   u n d e r s t a n d i n g _ N N 1   o f _ I O   c o m b i n i n g _ V V G   i n f o r m a t i o n _ N N 1   f r o m _ I I   l o w - f r e q u e n c y _ J J   h e a r i n g _ N N 1   a n d _ C C   a _ A T 1   c o c h l e a r _ J J   i m p l a n t _ N N 1   M i c h a e l _ N P 1   F . _ N P 1   D o r m a n _ N P 1   , _ ,   S a r a h _ N P 1   C o o k _ N P 1   , _ ,   T o n y _ N P 1   S p a h r _ N P 1   , _ ,   T i n g _ N N 1   Z h a n g _ N N 1   , _ ,   L o u i s e _ N P 1   L o i s e l l e _ N P 1   , _ ,   D a v i d _ N P 1   S c h r a m m _ N P 1   , _ ,   J o A n n e _ N P 1   W h i t t i n g h a m _ N P 1   , _ ,   a n d _ C C   R e n e _ N P 1   G i f f o r d _ N P 1   A r i z o n a _ N P 1   S t a t e _ N N 1   U n i v e r s i t y _ N N 1   D e p a r t m e n t _ N N 1   o f _ I O   S p e e c h _ N N 1   a n d _ C C   H e a r i n g _ V V G   S c i e n c e _ N N 1   T e m p e _ N P 1   , _ ,   A Z _ N P 1   . _ .   
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 E q u a l l y _ R R   i m p o r t a n t _ J J   ' _ N U L L   s c i e n t i s t s _ N N 2   ' _ N U L L   e n g i n e e r s _ N N 2   a n d _ C C   d e v i c e _ N N 1   m a n u f a c t u r e r s _ N N 2   m u s t _ V M   i m p l e m e n t _ V V I   d e v i c e _ N N 1   p a r a m e t e r s _ N N 2   t h a t _ C S T   p r o v i d e _ V V 0   a _ A T 1   f a i r _ J J   b a l a n c e _ N N 1   o f _ I O   s u b j e c t i v i t y _ N N 1   a n d _ C C   o b j e c t i v i t y _ N N 1   f o r _ I F   t h e _ A T   c l i n i c i a n _ N N 1   t o _ T O   m a k e _ V V I   a n _ A T 1   e d u c a t e d _ J J   d i a g n o s i s _ N N 1   . _ .   
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 B e t w e e n - g r o u p _ J J   d e m o g r a p h i c _ J J   i m b a l a n c e s _ N N 2   i n _ I I   t h e _ A T   f o l l o w - u p _ J J   s a m p l e _ N N 1   w e r e _ V B D R   a d j u s t e d _ V V N   f o r _ I F   i n _ I I   t h e _ A T   a n a l y s i s _ N N 1   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   F C _ N P 1   d i e t _ N N 1   t r e a t m e n t _ N N 1   f o r _ I F   6 _ M C   w e e k s _ N N T 2   s i g n i f i c a n t l y _ R R   i n c r e a s e d _ V V D   t h e _ A T   l e v e l s _ N N 2   o f _ I O   c h o l i n e _ N N 1   a c e t y l t r a n s f e r a s e _ N N 1   ( _ (   C h A T _ N N 1   ) _ )   a n d _ C C   t h e _ A T   p r e s y n a p t i c _ J J   a n d _ C C   p o s t s y n a p t i c _ J J   m a r k e r s _ N N 2   S y n a p s i n - 1 _ M C 1   a n d _ C C   P S D - 9 5 _ M C   , _ ,   r e s p e c t i v e l y _ R R   , _ ,   w h i l e _ C S   d e c r e a s i n g _ J J   l e v e l s _ N N 2   o f _ I O   N o g o - A _ N P 1   , _ ,   a _ A T 1   n e u r i t e _ N N 1   o u t g r o w t h _ N N 1   i n h i b i t o r _ N N 1   . _ .   
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 E f f e c t s _ N N 2   o f _ I O   2 _ M C   d i f f e r e n t _ J J   s w a l l o w i n g _ J J   e x e r c i s e _ N N 1   r e g i m e n s _ N N 2   d u r i n g _ I I   o r g a n - p r e s e r v a t i o n _ J J   t h e r a p i e s _ N N 2   f o r _ I F   h e a d _ N N 1   a n d _ C C   n e c k _ N N 1   c a n c e r s _ N N 2   o n _ I I   s w a l l o w i n g _ V V G   f u n c t i o n _ N N 1   A n e e s h a _ N P 1   V i r a n i _ N P 1   , _ ,   P h D _ N N A   , _ ,   C C C - S L P _ N P 1   , _ ,   M e l d a _ N P 1   K u n d u k _ N P 1   , _ ,   P h D _ N N A   , _ ,   C C C - S L P _ N P 1   , _ ,   D a n i e l _ N P 1   S . _ N P 1   F i n k _ N P 1   , _ ,   M D _ N N A   , _ ,   A n d r e w _ N P 1   J . _ N P 1   M c W h o r t e r _ N P 1   , _ ,   M I D _ J J   D e p a r t m e n t _ N N 1   o f _ I O   C o m m u n i c a t i o n _ N N 1   S c i e n c e s _ N N 2   a n d _ C C   D i s o r d e r s _ N N 2   , _ ,   L o u i s i a n a _ N P 1   S t a t e _ N N 1   U n i v e r s i t y _ N N 1   , _ ,   B a t o n _ N P 1   R o u g e _ N P 1   , _ ,   L o u i s i a n a _ N P 1   , _ ,   0 u r _ F O   L a d y _ N N 1   o f _ I O   t h e _ A T   L a k e _ N N L 1   V o i c e _ N P 1   C e n t e r _ N N 1   , _ ,   B a t o n _ N P 1   R o u g e _ N P 1   , _ ,   L o u i s i a n a _ N P 1   , _ ,   D e p a r t m e n t _ N N 1   o f _ I O   O t o l a r y n g o l o g y - H e a d _ N N 1   a n d _ C C   N e c k _ N N 1   S u r g e r y _ N N 1   , _ ,   L o u i s i a n a _ N P 1   S t a t e _ N N 1   U n i v e r s i t y _ N N 1   H e a l t h _ N N 1   S c i e n c e s _ N N 2   C e n t e r _ N N 1   , _ ,   N e w _ N P 1   O r l e a n s _ N P 1   , _ ,   L o u i s i a n a _ N P 1   C o r r e s p o n d i n g _ J J   a u t h o r _ N N 1   : _ :   M . _ N N 1   K u n d u k _ N N 1   , _ ,   D e p a r t m e n t _ N N 1   o f _ I O   C o m m u n i c a t i o n _ N N 1   S c i e n c e s _ N N 2   a n d _ C C   D i s o r d e r s _ N N 2   , _ ,   L o u i s i a n a _ N P 1   S t a t e _ N N 1   U n i v e r s i t y _ N N 1   , _ ,   6 4 _ M C   H a t c h e r _ N P 1   H a l l _ N N 1   , _ ,   B a t o n _ N P 1   R o u g e _ N P 1   , _ ,   L A _ N P 1   7 0 8 0 3 _ M C   . _ .   
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 D i s c u s s i o n _ N N 1   : _ :   R e s u l t s _ N N 2   o f _ I O   t h i s _ D D 1   s t u d y _ N N 1   p r o v i d e d _ C S   i n i t i a l _ J J   s u p p o r t _ N N 1   f o r _ I F   t h e _ A T   n e w _ J J   F I T _ J J   T e e n s _ N N 2   p r o g r a m _ N N 1   . _ .   
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 D e p r e s s i o n _ N N 1   w a s _ V B D Z   f o u n d _ V V N   t o _ T O   b e _ V B I   s i g n i f i c a n t l y _ R R   c o r r e l a t e d _ V V N   w i t h _ I W   m e n t a l _ J J   h e a l t h _ N N 1   s e r v i c e s _ N N 2   u s e _ V V 0   ( _ (   r = 0 . 2 9 _ F O   , _ ,   p = 0 . 0 0 1 _ F O   ) _ )   , _ ,   s e l f - a d m i n i s t r a t i o n _ N N 1   o f _ I O   p s y c h o t r o p i c _ J J   m e d i c a t i o n _ N N 1   ( _ (   r = 0 . 4 5 _ F O   , _ ,   p _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 0 1 _ M C   ) _ )   , _ ,   a n x i e t y _ N N 1   ( _ (   r = _ F O   0 . 4 3 _ M C   , _ ,   p _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 0 1 _ M C   ) _ )   , _ ,   b u r n o u t _ N N 1   ( _ (   r = 0 . 7 2 _ F O   , _ ,   p _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 0 1 _ M C   ) _ )   , _ ,   a n d _ C C   d r u g _ N N 1   a b u s e _ N N 1   ( _ (   r = 0 . 2 5 _ F O   , _ ,   p = 0 . 0 0 7 _ F O   ) _ )   . _ .   
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 T h e _ A T   s a f e t y _ N N 1   p r o f i l e _ N N 1   o f _ I O   t h e _ A T   D E X _ N N 1   i m p l a n t _ N N 1   i n _ I I   t h i s _ D D 1   s t u d y _ N N 1   w a s _ V B D Z   b e t t e r _ R R R   t h a n _ C S N   t h e _ A T   r e p o r t e d _ J J   s a f e t y _ N N 1   p r o f i l e _ N N 1   o f _ I O   o t h e r _ J J   i n t r a o c u l a r _ J J   c o r t i c o s t e r o i d s _ N N 2   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   D M E _ N P 1   . _ .   
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 T h i s _ D D 1   r i s k _ N N 1   , _ ,   h o w e v e r _ R R   , _ ,   i s _ V B Z   e x t r e m e l y _ R R   s m a l l _ J J   , _ ,   p r o j e c t e d _ V V N   a s _ C S A   o n e _ M C 1   a d d i t i o n a l _ J J   m i s s e d _ J J   c i T B I _ N N 2   f o r _ I F   e v e r y _ A T 1   4 0 0 0 _ M C   c h i l d r e n _ N N 2   e v a l u a t e d _ V V N   f o r _ I F   m i n o r _ J J   h e a d _ N N 1   t r a u m a _ N N 1   . _ .   
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 T h e _ A T   s t u d i e s _ N N 2   w e r e _ V B D R   c o m p l i a n t _ J J   w i t h _ I W   t h e _ A T   r u l e s _ N N 2   a n d _ C C   r e g u l a t i o n s _ N N 2   u n d e r _ I I   t h e _ A T   H e a l t h _ N N 1   I n s u r a n c e _ N N 1   P o r t a b i l i t y _ N N 1   a n d _ C C   A c c o u n t a b i l i t y _ N N 1   A c t _ N N 1   o f _ I O   1 9 9 6 _ M C   . _ .   
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 F o r _ I F   t h e _ A T   s p e c i f i c _ J J   o u t c o m e _ N N 1   o f _ I O   p e r f o r m a n c e _ N N 1   t i m e _ N N T 1   , _ ,   t h e _ A T   s t u d y _ N N 1   w a s _ V B D Z   c l a s s i f i e d _ V V N   a s _ C S A   s u p p o r t i v e _ J J   f o r _ I F   U S _ P P I O 2   o n l y _ R R   i f _ C S   i t _ P P H 1   w a s _ V B D Z   d i r e c t l y _ R R   s t a t e d _ V V N   t h a t _ C S T   U S _ N P 1   s c a n _ N N 1   t i m e _ N N T 1   w a s _ V B D Z   i n c l u d e d _ V V N   i n _ I I   b l o c k _ N N 1   p e r f o r m a n c e _ N N 1   t i m e _ N N T 1   . _ .   
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 B _ Z Z 1   c e l l _ N N 1   d e p l e t i o n _ N N 1   b y _ I I   r i t u x i m a b _ N N 1   i s _ V B Z   t h o u g h t _ V V N   t o _ T O   o c c u r _ V V I   t h r o u g h _ I I   s e v e r a l _ D A 2   p o t e n t i a l _ J J   m e c h a n i s m s _ N N 2   . _ .   
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 T h e r e f o r e _ R R   , _ ,   t h e _ A T   W a r b u r g _ N P 1   e f f e c t _ N N 1   f u n c t i o n s _ N N 2   a s _ I I   t h e _ A T   m e t a b o l i c _ J J   f o u n d a t i o n _ N N 1   o f _ I O   o n c o g e n i c _ J J   g r o w t h _ N N 1   , _ ,   t u m o r _ N N 1   p r o g r e s s i o n _ N N 1   , _ ,   a n d _ C C   t u m o r _ N N 1   r e s i s t a n c e _ N N 1   t o _ I I   t r e a t m e n t _ N N 1   . _ .   
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 N o t e _ V V 0   t h a t _ C S T   f i t t e d _ J J   r e s p o n s e s _ N N 2   w e r e _ V B D R   n e c e s s a r y _ J J   f o r _ I F   c r o s s - c o n d i t i o n _ J J   c o m p a r i s o n s _ N N 2   , _ ,   g i v e n _ C S 2 1   t h a t _ C S 2 2   t h e _ A T   s a m p l e d _ J J   t i m e _ N N T 1   p o i n t s _ N N 2   w e r e _ V B D R   n o t _ X X   i d e n t i c a l _ J J   a c r o s s _ I I   t h e _ A T   d i f f e r e n t _ J J   s t i m u l i _ N N 2   ( _ (   s e e _ V V 0   T a b l e _ N N 1   1 _ M C 1   ) _ )   . _ .   
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 I n _ I I   c o n c l u s i o n _ N N 1   , _ ,   i n _ I I   o u r _ A P P G E   c o h o r t _ N N 1   o f _ I O   o v e r a l l _ J J   h e a l t h y _ J J   s u b j e c t s _ N N 2   , _ ,   s e l f - r e p o r t e d _ N N 1   s n o r i n g _ V V G   a n d _ C C   s l e e p _ V V 0   a p n o e a _ N N 1   a r e _ V B R   i n d e p e n d e n t l y _ R R   a s s o c i a t e d _ V V N   w i t h _ I W   a _ A T 1   h i g h e r _ J J R   P V W _ N P 1   , _ ,   a n d _ C C   A I x _ N P 1   i s _ V B Z   s t a t i s t i c a l l y _ R R   s i g n i f i c a n t l y _ R R   h i g h e r _ J J R   i n _ I I   s n o r e r s _ N N 2   w i t h _ I W   o r _ C C   w i t h o u t _ I W   s l e e p _ N N 1   a p n o e a _ N N 1   t h a n _ C S N   i n _ I I   n o n - s n o r e r s _ N N 2   . _ .   
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 T h e r e f o r e _ R R   , _ ,   t h e _ A T   5 - 5 ( 2 s ) p i n g _ N N 1   a n d _ C C   5 - 5 ( 4 s ) p i n g _ J J   a H D R s _ N N 2   w e r e _ V B D R   a u g m e n t e d _ V V N   b y _ I I   a p p e n d i n g _ V V G   t h e _ A T   i n i t i a l _ J J   p o r t i o n _ N N 1   o f _ I O   a H D R _ N N 1   o f _ I O   t h e _ A T   5 p i n g _ F O   p r i o r _ I I 2 1   t o _ I I 2 2   t h e _ A T   f i r s t _ M D   a c q u i r e d _ J J   d a t a _ N N   p o i n t _ N N 1   ( _ (   i . _ M C   e . _ Z Z 1   , _ ,   4 _ M C   o r _ C C   6 s _ M C 2   p o s t - o n s e t _ N N 1   ) _ )   , _ ,   w i t h _ I W   a _ A T 1   s m o o t h _ J J   c o m b i n a t i o n _ N N 1   a c h i e v e d _ V V N   u s i n g _ V V G   a _ A T 1   3 r d _ M D   o r d e r _ N N 1   p o l y n o m i a l _ N N 1   f i t _ N N 1   . _ .   
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 W h e n _ C S   a n a l y z i n g _ V V G   t h e _ A T   n e e d _ N N 1   f o r _ I F   t r a n s p l a n t a t i o n _ N N 1   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   k e r a t i t i s _ N N 1   o f _ I O   v i r a l _ J J   o r i g i n _ N N 1   a n d _ C C   w i t h _ I W   c e n t r a l _ J J   n e o v a s c u l a r i z a t i o n _ N N 1   , _ ,   r e s u l t s _ N N 2   s h o w e d _ V V D   t h a t _ D D 1   a g a n i r s e n _ N N 1   t r e a t m e n t _ N N 1   s i g n i f i c a n t l y _ R R   d e c r e a s e d _ V V D   t h e _ A T   n e e d _ N N 1   f o r _ I F   t r a n s p l a n t a t i o n _ N N 1   a t _ I I   b o t h _ R R   d a y _ N N T 1   9 0 _ M C   ( _ (   n o m i n a l _ J J   P _ Z Z 1   v a l u e _ N N 1   = 0 . 0 4 8 _ F O   , _ ,   d a t a _ N N   n o t _ X X   s h o w n _ V V N   ) _ )   a n d _ C C   d a y _ N N T 1   1 8 0 _ M C   ( _ (   n o m i n a l _ J J   P _ Z Z 1   v a l u e _ N N 1   = 0 . 0 4 8 _ F O   , _ ,   F i s h e r _ N P 1   e x a c t _ J J   t e s t _ N N 1   ) _ )   ( _ (   T a b l e _ N N 1   6 _ M C   ) _ )   . _ .   
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 T h e r e _ E X   i s _ V B Z   i n d e e d _ R R   e v i d e n c e _ N N 1   o f _ I O   i n c r e a s e d _ J J   l e v e l s _ N N 2   o f _ I O   m u s c l e _ N N 1   A D P _ N N 1   a n d _ C C   p l a s m a _ N N 1   N H 3 + a n d _ F O   h y p o x a n t h i n e _ V V 0   d u r i n g _ I I   e x e r c i s e _ N N 1   i n _ I I   M c A r d l e _ N P 1   d i s e a s e _ N N 1   p a t i e n t s _ N N 2   c o m p a r e d _ V V N   w i t h _ I W   n o n - p a t i e n t s _ N N 2   , _ ,   s u g g e s t i n g _ V V G   h i g h _ J J   o x i d a t i v e _ J J   s t r e s s _ N N 1   i n _ I I   t h e i r _ A P P G E   s k e l e t a l _ J J   m u s c l e s _ N N 2   . _ .   
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 S e v e n t e e n _ M C   H C C _ N P 1   l e s i o n s _ N N 2   l a r g e r _ J J R   t h a n _ C S N   2 _ M C   c m _ N N U   w e r e _ V B D R   t r e a t e d _ V V N   w i t h _ I W   T A C E _ N P 1   b e f o r e _ I I   t h e _ A T   C T _ N N 1   a c q u i s i t i o n s _ N N 2   , _ ,   w h e r e a s _ C S   1 0 _ M C   o f _ I O   t h e _ A T   l e s i o n s _ N N 2   l a r g e r _ J J R   t h a n _ C S N   2 _ M C   c m _ N N U   w e r e _ V B D R   n o t _ X X   t r e a t e d _ V V N   w i t h _ I W   T A C E _ N P 1   b e f o r e _ I I   t h e _ A T   C T _ N N 1   a c q u i s i t i o n _ N N 1   a n d _ C C   t h e _ A T   l i v e r _ N N 1   t r a n s p l a n t a t i o n _ N N 1   . _ .   
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 F u r t h e r _ J J R   a c c u m u l a t i o n _ N N 1   o f _ I O   c a s e s _ N N 2   a n d _ C C   l o n g e r _ J J R   f o l l o w - u p _ N N 1   a r e _ V B R   w a r r a n t e d _ V V N   t o _ T O   e l u c i d a t e _ V V I   t h e _ A T   a b i l i t y _ N N 1   o f _ I O   t h i s _ D D 1   m e t h o d _ N N 1   t o _ T O   p r e d i c t _ V V I   p r o g n o s i s _ N N 1   . _ .   
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 I n d e e d _ R R   , _ ,   a s _ C S A   R i s k i n _ N P 1   e t _ R A 2 1   a l _ R A 2 2   p o i n t e d _ V V D   o u t _ R P   , _ ,   " _ "   m o s t _ D A T   s u r g e o n s _ N N 2   i n n o v a t e _ V V 0   o n _ I I   a _ A T 1   d a i l y _ J J   b a s i s _ N N 1   , _ ,   t a i l o r i n g _ V V G   t h e r a p i e s _ N N 2   a n d _ C C   o p e r a t i o n s _ N N 2   t o _ I I   t h e _ A T   i n t r i n s i c _ J J   u n i q u e n e s s _ N N 1   o f _ I O   e v e r y _ A T 1   p a t i e n t _ N N 1   a n d _ C C   t h e i r _ A P P G E   d i s e a s e _ N N 1   . _ .   " _ "   
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 A l l _ D B   e x p e r i m e n t s _ N N 2   u s e d _ V V D   t h e _ A T   u t e r u s _ N N 1   a s _ I I   a _ A T 1   p o s i t i v e _ J J   c o n t r o l _ N N 1   . _ .   
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 C a n c e r _ N N 1   d i a g n o s e s _ N N 2   a r e _ V B R   r e p o r t e d _ V V N   t o _ I I   l o c a l _ J J   c a n c e r _ N N 1   r e g i s t r i e s _ N N 2   f r o m _ I I   m u l t i p l e _ J J   s o u r c e s _ N N 2   , _ ,   i n c l u d i n g _ I I   l o c a l _ J J   h o s p i t a l s _ N N 2   a n d _ C C   c o m m u n i t y _ N N 1   h e a l t h _ N N 1   c e n t e r s _ N N 2   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   t h e _ A T   U r b a n _ J J   R e s i d e n t _ J J   B a s i c _ J J   M e d i c a l _ J J   I n s u r a n c e _ N N 1   p r o g r a m _ N N 1   a n d _ C C   t h e _ A T   N e w _ J J   R u r a l _ J J   C o o p e r a t i v e _ J J   M e d i c a l _ J J   S c h e m e _ N N 1   . _ .   
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 A s _ C S A   r e s p i r a t o r y _ J J   m o t i o n _ N N 1   a r t i f a c t s _ N N 2   a r e _ V B R   p r o b l e m a t i c _ J J   w h e n _ C S   g e n e r a t i n g _ V V G   p i x e l w i s e _ J J   p a r a m e t e r _ N N 1   m a p s _ N N 2   , _ ,   t h e _ A T   m o t i o n _ N N 1   i n s e n s i t i v e _ J J   t e c h n i q u e _ N N 1   u s e d _ V V N   i n _ I I   t h i s _ D D 1   s t u d y _ N N 1   m i g h t _ V M   b e _ V B I   a _ A T 1   v a l u a b l e _ J J   t o o l _ N N 1   t o _ T O   a c h i e v e _ V V I   v a l i d _ J J   a n d _ C C   r e p r o d u c i b l e _ J J   p a r a m e t e r _ N N 1   m a p s _ N N 2   . _ .   
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 T h e s e _ D D 2   s t u d i e s _ N N 2   w e r e _ V B D R   s h a m _ N N 1   c o n t r o l l e d _ V V N   f o r _ I F   t h e _ A T   f i r s t _ M D   2 _ M C   y e a r s _ N N T 2   ; _ ;   i n _ I I   t h e _ A T   t h i r d _ M D   y e a r _ N N T 1   , _ ,   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   s h a m _ N N 1   g r o u p _ N N 1   c o u l d _ V M   c r o s s _ V V I   o v e r _ R P   t o _ T O   r e c e i v e _ V V I   r a n i b i z u m a b _ N N 1   0 _ M C   . _ .   
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 T h e _ A T   p u r p o s e _ N N 1   o f _ I O   t h i s _ D D 1   s t a t e m e n t _ N N 1   i s _ V B Z   t o _ T O   f u r t h e r _ R R R   d e f i n e _ V V I   a n d _ C C   d i s c u s s _ V V I   t h e _ A T   s t a t u s _ N N 1   o f _ I O   o f f - l a b e l _ J J   u s e _ N N 1   o f _ I O   m e d i c a t i o n s _ N N 2   i n _ I I   c h i l d r e n _ N N 2   . _ .   
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 A l t h o u g h _ C S   i t _ P P H 1   i s _ V B Z   n o t _ X X   c l e a r _ R R   w h y _ R R Q   t h i s _ D D 1   s i d e _ N N 1   e f f e c t _ N N 1   o c c u r r e d _ V V D   , _ ,   t h e _ A T   r a p i d _ J J   d e v e l o p m e n t _ N N 1   o f _ I O   b e h a v i o r a l _ J J   c h a n g e s _ N N 2   i n _ I I   t h e s e _ D D 2   c h i l d r e n _ N N 2   s u g g e s t s _ V V Z   t h a t _ C S T   i t _ P P H 1   m a y _ V M   h a v e _ V H I   b e e n _ V B N   d u e _ I I 2 1   t o _ I I 2 2   a n _ A T 1   i n c r e a s e _ N N 1   i n _ I I   C N S _ N P 1   d o p a m i n e _ N N 1   s e c o n d a r y _ N N 1   t o _ I I   i n c r e a s e d _ J J   5 M T H F _ F O   o r _ C C   t e t r a h y d r o b i o p t e r i n _ N N 1   i n _ I I   t h e _ A T   C N S _ N P 1   , _ ,   w h i c h _ D D Q   t h e n _ R T   m a y _ V M   h a v e _ V H I   r e d u c e d _ V V N   t h e _ A T   d o p a m i n e _ N N 1   r e c e p t o r - b l o c k i n g _ N N 1   e f f e c t _ N N 1   o f _ I O   r i s p e r i d o n e _ N N 1   . _ .   
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 M e t h o d s _ N N 2   : _ :   I n _ I I   t h i s _ D D 1   p o p u l a t i o n - b a s e d _ N N 1   , _ ,   r e t r o s p e c t i v e _ J J   , _ ,   c o h o r t _ N N 1   s t u d y _ N N 1   , _ ,   w e _ P P I S 2   i d e n t i f i e d _ V V D   a l l _ D B   a d u l t _ J J   p a t i e n t s _ N N 2   w h o _ P N Q S   w e r e _ V B D R   d i s c h a r g e d _ V V N   f r o m _ I I   a n _ A T 1   e m e r g e n c y _ N N 1   d e p a r t m e n t _ N N 1   i n _ I I   O n t a r i o _ N P 1   , _ ,   C a n a d a _ N P 1   , _ ,   b e t w e e n _ I I   2 0 0 6 _ M C   a n d _ C C   2 0 1 1 _ M C   , _ ,   w i t h _ I W   a _ A T 1   p r i m a r y _ J J   d i a g n o s i s _ N N 1   o f _ I O   a _ A T 1   p e r i p h e r a l _ J J   v e s t i b u l a r _ J J   d i s o r d e r _ N N 1   . _ .   
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 A _ A T 1   s c h e m a t i c _ J J   o v e r v i e w _ N N 1   i s _ V B Z   s h o w n _ V V N   i n _ I I   F i g u r e _ N N 1   1 _ M C 1   . _ .   
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 C A F _ N P 1   w a s _ V B D Z   t h e _ A T   o n l y _ J J   p a r a m e t e r _ N N 1   s i g n i f i c a n t l y _ R R   p r e d i c t i n g _ V V G   d P r _ N N U   ( _ (   H R = 1 . 0 0 5 _ N P 1   ; _ ;   T a b l e _ N N 1   3 _ M C   ) _ )   , _ ,   w h e r e a s _ C S   c r e a t i n i n e _ N N 1   , _ ,   B U N _ N N 1   a n d _ C C   e G F R _ N N 1   f a i l e d _ V V D   t o _ T O   p r e d i c t _ V V I   t h i s _ D D 1   e n d p o i n t _ N N 1   . _ .   
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 M a t e r i a l s _ N N 2   a n d _ C C   m e t h o d s _ N N 2   T h e _ A T   a n a l y z e r _ N N 1   a n d _ C C   t h e _ A T   r e a g e n t s _ N N 2   u s e d _ V V N   f o r _ I F   t h i s _ D D 1   e v a l u a t i o n _ N N 1   h a v e _ V H 0   b e e n _ V B N   p r o v i d e d _ V V N   b y _ I I   B i o - R a d _ N P 1   L a b o r a t o r i e s _ N N 2   ( _ (   H e r c u l e s _ N P 1   , _ ,   C A _ N P 1   , _ ,   U S A _ N P 1   ) _ )   a n d _ C C   h a v e _ V H 0   b e e n _ V B N   u s e d _ V V N   a c c o r d i n g _ I I 2 1   t o _ I I 2 2   m a n u f a c t u r e r _ N N 1   ' _ N U L L   s _ Z Z 1   i n s t r u c t i o n s _ N N 2   . _ .   
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 T h e s e _ D D 2   f i b r o b l a s t i c _ J J   c e l l s _ N N 2   s e c r e t e _ V V 0   n u m e r o u s _ J J   c y t o k i n e s _ N N 2   a n d _ C C   g r o w t h _ N N 1   f a c t o r s _ N N 2   , _ ,   i n c l u d i n g _ I I   i n s u l i n - l i k e _ J J   g r o w t h _ N N 1   f a c t o r _ N N 1   1 _ M C 1   ( _ (   I G F - 1 _ M C 1   ) _ )   , _ ,   i n t e r l e u k i n - 6 _ M C   ( _ (   I L - 6 _ M C   ) _ )   , _ ,   p r o s t a g l a n d i n _ N N 1   E 2 _ F O   ( _ (   P G E 2 _ F O   ) _ )   , _ ,   a n d _ C C   t r a n s f o r m i n g _ V V G   g r o w t h _ N N 1   f a c t o r - & l s q b ; b e t a & r s q b ; _ N N 1   ( _ (   T G F - & l s q b ; b e t a & r s q b ; _ N N 1   ) _ )   . _ .   
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 F i g u r e _ V V 0   1 _ M C 1   i s _ V B Z   f r o m _ I I   a _ A T 1   c h i l d _ N N 1   w h o _ P N Q S   a t _ I I   1 0 _ M C   y e a r s _ N N T 2   o f _ I O   a g e _ N N 1   s u s t a i n e d _ V V D   a _ A T 1   m T B I _ N N 2   ( _ (   G C S = 1 5 _ F O   ) _ )   w i t h o u t _ I W   d o c u m e n t e d _ J J   l o s s _ N N 1   o f _ I O   c o n s c i o u s n e s s _ N N 1   ( _ (   L O C _ N P 1   ) _ )   a s _ I I   t h e _ A T   r e s u l t _ N N 1   o f _ I O   a _ A T 1   b i c y c l e _ N N 1   a c c i d e n t _ N N 1   . _ .   
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 I n _ I I   c o n c l u s i o n _ N N 1   , _ ,   o u r _ A P P G E   s t u d y _ N N 1   s h o w e d _ V V D   g r o u p _ N N 1   d i f f e r e n c e s _ N N 2   i n _ I I   c e n t r a l _ J J   s p e e c h - s o u n d _ N N 1   d i s c r i m i n a t i o n _ N N 1   b e t w e e n _ I I   C W S _ N P 1   a n d _ C C   T D C _ N P 1   u s i n g _ V V G   t h e _ A T   m u l t i - f e a t u r e _ J J   M M N _ N P 1   p a r a d i g m _ N N 1   i n v o l v i n g _ V V G   s e v e r a l _ D A 2   d i f f e r e n t _ J J   d e v i a n t _ J J   t y p e s _ N N 2   . _ .   
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 A l t h o u g h _ C S   t h e _ A T   p a t h o g e n i c _ J J   m e c h a n i s m s _ N N 2   a n d _ C C   d a t a _ N N   r e v i e w e d _ V V D   h e r e _ R L   f o c u s _ V V 0   s p e c i f i c a l l y _ R R   o n _ I I   C A A _ N P 1   , _ ,   m a n y _ D A 2   o f _ I O   t h e _ A T   c o n s i d e r a t i o n s _ N N 2   a n d _ C C   f i n d i n g s _ N N 2   c a n _ V M   b e _ V B I   g e n e r a l i z e d _ V V N   t o _ I I   a l l _ D B   f o r m s _ N N 2   o f _ I O   c e r e b r a l _ J J   s m a l l _ J J   v e s s e l _ N N 1   d i s e a s e _ N N 1   a s s o c i a t e d _ V V N   w i t h _ I W   v a s c u l a r _ J J   c o g n i t i v e _ J J   i m p a i r m e n t _ N N 1   ( _ (   V C I _ N P 1   ) _ )   . _ .   
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 H o w e v e r _ R R   , _ ,   r e c e n t _ J J   s t u d i e s _ N N 2   i n _ I I   b o t h _ R R   a d u l t s _ N N 2   a n d _ C C   c h i l d r e n _ N N 2   r e p o r t _ V V 0   p o o r _ J J   U S _ N P 1   a c c u r a c y _ N N 1   f o r _ I F   d i f f e r e n t i a t i n g _ V V G   p e r f o r a t e d _ J J   f r o m _ I I   n o n p e r f o r a t e d _ J J   a p p e n d i c i t i s _ N N 1   , _ ,   w i t h _ I W   p u b l i s h e d _ J J   s e n s i t i v i t i e s _ N N 2   r a n g i n g _ V V G   f r o m _ I I   2 3 % _ N N U   t o _ I I   4 8 % _ N N U   a n d _ C C   s p e c i f i c i t i e s _ N N 2   r a n g i n g _ V V G   f r o m _ I I   9 3 % _ N N U   t o _ I I   1 0 0 % _ N N U   . _ .   
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 H o w e v e r _ R R   , _ ,   w h e r e _ C S   a _ A T 1   f i n a n c i a l _ J J   p e n a l t y _ N N 1   w a s _ V B D Z   r e n d e r e d _ V V N   , _ ,   t h e _ A T   f i n d i n g s _ N N 2   w e r e _ V B D R   q u i t e _ R G   s i m i l a r _ J J   , _ ,   a v e r a g i n g _ V V G   1 . 5 _ M C   t o _ I I   2 . 5 _ M C   m i l l i o n _ N N O   d o l l a r s _ N N U 2   p e r _ I I   c a s e _ N N 1   w i t h _ I W   t h e _ A T   h i g h e s t _ J J T   p e n a l t i e s _ N N 2   a s s o c i a t e d _ V V N   w i t h _ I W   c a s e s _ N N 2   i n v o l v i n g _ V V G   a n o x i c _ J J   b r a i n _ N N 1   i n j u r y _ N N 1   . _ .   
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 A _ A T 1   p a t h o l o g i s t _ N N 1   h a s _ V H Z   a _ A T 1   l i m i t e d _ J J   a b i l i t y _ N N 1   t o _ T O   d i s t i n g u i s h _ V V I   a m o n g _ I I   t h e s e _ D D 2   d i a g n o s e s _ N N 2   ' _ N U L L   b u t _ C C B   t r a n s c r i p t o m i c s _ N N 2   c a n _ V M   p o t e n t i a l l y _ R R   p r o v i d e _ V V I   a _ A T 1   m o r e _ R G R   p r e c i s e _ J J   d i f f e r e n t i a l _ N N 1   ( _ (   Y e r e m e n k o _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   ' _ N U L L   
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 O n e _ M C 1   m e m b e r _ N N 1   o f _ I O   t h e _ A T   p a n e l _ N N 1   h a s _ V H Z   s e r v e d _ V V N   i n _ I I   g u i d e l i n e _ N N 1   d e v e l o p m e n t _ N N 1   a n d _ C C   a s _ I I   a _ A T 1   m e m b e r _ N N 1   o f _ I O   t h e _ A T   N a t i o n a l _ J J   Q u a l i t y _ N N 1   F o r u m _ N N 1   N e u r o l o g y _ N N 1   m e a s u r e s _ N N 2   g r o u p _ N N 1   ( _ (   W . G . B . _ N P 1   ) _ )   , _ ,   a n d _ C C   a n o t h e r _ D D 1   m e m b e r _ N N 1   h a s _ V H Z   b e e n _ V B N   i n v o l v e d _ J J   i n _ I I   n a t i o n a l _ J J   s t r o k e _ N N 1   q u a l i t y _ N N 1   i m p r o v e m e n t _ N N 1   e f f o r t s _ N N 2   t h r o u g h _ I I   t h e _ A T   A H A _ U H   , _ ,   i n c l u d i n g _ V V G   G e t _ V V 0   W i t h _ I W   t h e _ A T   G u i d e l i n e s _ N N 2   - _ -   S t r o k e _ V V 0   ( _ (   M . J . R . _ N P 1   ) _ )   . _ .   
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 S a m p l e _ N N 1   s i z e _ N N 1   f o r _ I F   t h e _ A T   E P C _ N P 1   a n a l y s i s _ N N 1   w a s _ V B D Z   c a l c u l a t e d _ V V N   u s i n g _ V V G   t h e _ A T   s h o r t - t e r m _ J J   e f f e c t _ N N 1   o f _ I O   e x e r c i s e _ N N 1   o n _ I I   E P C _ N P 1   r e l e a s e _ N N 1   1 0 _ M C   m i n _ N N U   a f t e r _ I I   a _ A T 1   s y m p t o m - l i m i t e d _ J J   d y n a m i c _ J J   e x e r c i s e _ N N 1   t e s t _ N N 1   i n _ I I   v o l u n t e e r s _ N N 2   . _ .   
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 H o w e v e r _ R R   , _ ,   i n _ I I   p a t i e n t s _ N N 2   p r e s e n t i n g _ V V G   w i t h _ I W   e x p i r a t o r y _ J J   f l o w _ N N 1   l i m i t a t i o n _ N N 1   , _ ,   e x t e r n a l _ J J   P E E P _ N N 1   w i l l _ V M   n o t _ X X   l o w e r _ V V I   t h e _ A T   e x p i r a t o r y _ J J   d r i v i n g _ J J   p r e s s u r e _ N N 1   u n t i l _ C S   t h e _ A T   l e v e l _ N N 1   o f _ I O   e x t e r n a l _ J J   P E E P _ N N 1   e x c e e d s _ V V Z   t h e _ A T   l e v e l _ N N 1   o f _ I O   a u t o - P E E P _ N N 1   b y _ I I   a _ A T 1   r a t i o _ N N 1   o f _ I O   5 0 _ M C   t o _ I I   7 5 % _ N N U   . _ .   
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 T h e r e _ E X   w e r e _ V B D R   s o m e _ D D   o l d e r _ J J R   m i c e _ N N 2   t h a t _ C S T   d i d _ V D D   n o t _ X X   p e r f o r m _ V V I   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   m o s t _ D A T   o f _ I O   t h e _ A T   y o u n g e r _ J J R   m i c e _ N N 2   , _ ,   b u t _ C C B   t h i s _ D D 1   a l s o _ R R   d i d _ V D D   n o t _ X X   d i f f e r _ V V I   b e t w e e n _ I I   g e n o t y p e s _ N N 2   ( _ (   1 / 3 _ M F   f o r _ I F   e a c h _ D D 1   ) _ )   . _ .   
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 A _ A T 1   s c l e r a l _ J J   t r i a n g u l a r _ J J   f l a p _ N N 1   w a s _ V B D Z   m a d e _ V V N   b e h i n d _ I I   t h e _ A T   l i m b u s _ N N 1   c o r r e s p o n d i n g _ V V G   t o _ I I   t h e _ A T   s u p e r i o r _ J J   h a p t i c _ J J   l o c a t i o n _ N N 1   ' _ N U L L   f o l l o w e d _ V V N   b y _ I I   a _ A T 1   l i m b a l _ J J   i n c i s i o n _ N N 1   a p p r o x i m a t e l y _ R R   1 8 0 _ M C   a p a r t _ R L   . _ .   
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 S o _ R G   f a r _ R R   , _ ,   G R A S P _ N N 1   h a s _ V H Z   b e e n _ V B N   s u c c e s s f u l l y _ R R   a p p l i e d _ V V N   i n _ I I   t h e _ A T   l i v e r _ N N 1   a n d _ C C   t h e _ A T   p r o s t a t e _ N N 1   . _ .   
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 L e s i o n s _ N N 2   w e r e _ V B D R   o n l y _ R R   c o n s i d e r e d _ V V N   t o _ T O   b e _ V B I   e l i g i b l e _ J J   t o _ T O   b e _ V B I   u p g r a d e d _ V V N   b y _ I I   t h e _ A T   g i v e n _ J J   p r o p o s e d _ J J   a d j u s t m e n t _ N N 1   w h e n _ R R Q   n o t _ X X   a l r e a d y _ R R   b e i n g _ V B G   u p g r a d e d _ V V N   b y _ I I   t h e _ A T   e x i s t i n g _ J J   d e c i s i o n _ N N 1   r u l e s _ N N 2   ( _ (   e g _ R E X   , _ ,   a _ A T 1   P Z _ N P 1   l e s i o n _ N N 1   b e i n g _ V B G   u p g r a d e d _ V V N   f r o m _ I I   c a t e g o r y _ N N 1   3 _ M C   t o _ I I   4 _ M C   d u e _ I I 2 1   t o _ I I 2 2   D C E _ N P 1   s c o r e _ N N 1   o f _ I O   p o s i t i v e _ J J   o r _ C C   a _ A T 1   l e s i o n _ N N 1   i n _ I I   e i t h e r _ D D 1   z o n e _ N N 1   b e i n g _ V B G   u p g r a d e d _ V V N   f r o m _ I I   c a t e g o r y _ N N 1   4 _ M C   t o _ I I   5 _ M C   d u e _ I I 2 1   t o _ I I 2 2   d e f i n i t e _ J J   e x t r a - p r o s t a t i c _ J J   e x t e n s i o n _ N N 1   w a s _ V B D Z   n o t _ X X   c o n s i d e r e d _ V V N   t o _ T O   b e _ V B I   e l i g i b l e _ J J   t o _ T O   b e _ V B I   u p g r a d e d _ V V N   o n _ I I   t h e _ A T   b a s i s _ N N 1   o f _ I O   p r o p o s e d _ J J   a d j u s t m e n t s _ N N 2   t o _ I I   t h e _ A T   d e c i s i o n _ N N 1   r u l e s _ N N 2   ) _ )   . _ .   
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 A n o t h e r _ D D 1   p o s s i b i l i t y _ N N 1   i s _ V B Z   t h a t _ C S T   t h e _ A T   s e v e r i t y _ N N 1   o f _ I O   d i v e r t i c u l i t i s _ N N 1   h a s _ V H Z   b e e n _ V B N   i n c r e a s i n g _ V V G   , _ ,   a n d _ C C   s u r g e o n s _ N N 2   m a y _ V M   b e _ V B I   p e r f o r m i n g _ V V G   m o r e _ R G R   e l e c t i v e _ J J   p r o c e d u r e s _ N N 2   o n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   m o r e _ R G R   c o m p l i c a t e d _ J J   d i s e a s e _ N N 1   . _ .   
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 T h e _ A T   F A F _ N N 1   i m a g e s _ N N 2   s h o w _ V V 0   a _ A T 1   p r o g r e s s i v e _ J J   l o s s _ N N 1   o f _ I O   R P E _ N P 1   e v e n _ R R   a f t e r _ I I   t h e _ A T   d r u g _ N N 1   i s _ V B Z   s t o p p e d _ V V N   , _ ,   a n d _ C C   t h i s _ D D 1   l o s s _ N N 1   c a n _ V M   s p r e a d _ V V I   t o w a r d _ I I   t h e _ A T   o u t e r _ J J   r e a c h e s _ N N 2   o f _ I O   t h e _ A T   m a c u l a _ N N 1   . _ .   
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 T h e s e _ D D 2   c o n s i d e r a t i o n s _ N N 2   p r o v i d e _ V V 0   a _ A T 1   r a t i o n a l e _ N N 1   f o r _ I F   f o c u s i n g _ V V G   o n _ I I   t h e _ A T   e v a l u a t i o n _ N N 1   o f _ I O   a n t i - o x i d a n t _ J J   t h e r a p y _ N N 1   o n _ I I   r o d _ N N 1   c e l l s _ N N 2   i n _ R R 2 1   v i v o _ R R 2 2   . _ .   
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 T r a n s c r a n i a l _ J J   m a g n e t i c _ J J   s t i m u l a t i o n _ N N 1   ( _ (   T M S _ N P 1   ) _ )   h a s _ V H Z   b e e n _ V B N   s u c c e s s f u l l y _ R R   u s e d _ V V N   t o _ T O   d e m o n s t r a t e _ V V I   t h e _ A T   p r e s e n c e _ N N 1   o f _ I O   s u p r a s p i n a l _ J J   f a t i g u e _ N N 1   a c r o s s _ I I   a _ A T 1   r a n g e _ N N 1   o f _ I O   e x e r c i s e _ N N 1   p a r a d i g m s _ N N 2   . _ .   
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 P r e v i o u s _ J J   w o r k _ N N 1   s u g g e s t s _ V V Z   t h a t _ C S T   t h e r e _ E X   a r e _ V B R   t w o _ M C   k i n d s _ N N 2   o f _ I O   g a p _ N N 1   j u n c t i o n _ N N 1   h e x a m e r s _ N N 2   ( _ (   t w o _ M C   h e x a m e r s _ N N 2   f r o m _ I I   e a c h _ D D 1   c e l l _ N N 1   d o c k _ N N 1   t o _ T O   f o r m _ V V I   a _ A T 1   g a p _ N N 1   j u n c t i o n _ N N 1   ) _ )   , _ ,   h o m o m e r i c _ J J   ( _ (   c o m p o s e d _ V V N   o f _ I O   s a m e _ D A   c o n n e x i n _ N N 1   s u b t y p e s _ V V Z   i n _ I I   t h e _ A T   s a m e _ D A   j u n c t i o n a l _ J J   p l a q u e _ N N 1   ) _ )   a n d _ C C   h e t e r o m e r i c _ J J   ( _ (   c o m p o s e d _ V V N   o f _ I O   d i f f e r e n t _ J J   c o n n e x i n _ N N 1   s u b t y p e s _ V V Z   i n _ I I   t h e _ A T   s a m e _ D A   p l a q u e _ N N 1   ) _ )   ( _ (   K o v a l _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 4 _ M C   ) _ )   . _ .   
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 T h e _ A T   m e d i a n _ N N 1   ( _ (   I Q R _ N P 1   ) _ )   d u r a t i o n _ N N 1   o f _ I O   t h e _ A T   e p i d u r a l _ J J   a d m i n i s t r a t i o n _ N N 1   w a s _ V B D Z   1 9 _ M C   h o u r s _ N N T 2   ( _ (   1 8 _ M C   ' _ N U L L   2 0 _ M C   h o u r s _ N N T 2   ) _ )   a n d _ C C   w a s _ V B D Z   n o t _ X X   d i f f e r e n t _ J J   b e t w e e n _ I I   h i g h _ J J   a n d _ C C   l o w _ J J   s p r e a d _ N N 1   g r o u p s _ N N 2   ( _ (   P _ Z Z 1   = _ F O   0 . 5 0 _ M C   ) _ )   . _ .   
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 T h e _ A T   p r e s e n t _ J J   s t u d y _ N N 1   d e m o n s t r a t e s _ V V Z   t h a t _ C S T   t h i s _ D D 1   t e c h n i q u e _ N N 1   i s _ V B Z   f e a s i b l e _ J J   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   e s t a b l i s h e d _ J J   c i r r h o s i s _ N N 1   a n d _ C C   p r o v i d e s _ V V Z   a _ A T 1   p r a c t i c a l _ J J   a l t e r n a t i v e _ N N 1   t o _ I I   t h e _ A T   c h a l l e n g e s _ N N 2   o f _ I O   m e a s u r i n g _ V V G   p r o p e r _ J J   H A _ U H   f l o w _ N N 1   a n d _ C C   T L B F _ N P 1   u s i n g _ V V G   d i r e c t _ J J   P C M R I _ N N 2   . _ .   
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 I n _ I I 3 1   a d d i t i o n _ I I 3 2   t o _ I I 3 3   s u b t l e _ J J   s t r u c t u r a l _ J J   a b n o r m a l i t i e s _ N N 2   , _ ,   a p p l i c a t i o n _ N N 1   o f _ I O   f u n c t i o n a l _ J J   M R I _ J J   m e t h o d s _ N N 2   h a v e _ V H 0   s h o w n _ V V N   d i f f e r e n c e s _ N N 2   i n _ I I   f u n c t i o n a l _ J J   c o n n e c t i v i t y _ N N 1   w i t h _ I W   t h e _ A T   b a s a l _ J J   g a n g l i a _ N N 2   n e t w o r k _ N N 1   , _ ,   t h e _ A T   d e f a u l t - m o d e _ J J   n e t w o r k _ N N 1   a n d _ C C   t h e _ A T   s e n s o r i m o t o r _ N N 1   r e s t i n g _ N N 1   s t a t e _ N N 1   n e t w o r k _ N N 1   , _ ,   b e t w e e n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   P D _ N P 1   a n d _ C C   h e a l t h y _ J J   c o n t r o l s _ N N 2   , _ ,   s o m e _ D D   o f _ I O   w h i c h _ D D Q   a r e _ V B R   i n f l u e n c e d _ V V N   b y _ I I   d o p a m i n e r g i c _ J J   m e d i c a t i o n _ N N 1   ( _ (   s e e _ V V 0   o n l i n e _ R R   s u p p l e m e n t a r y _ J J   m a t e r i a l _ N N 1   f o r _ I F   e x a m p l e s _ N N 2   o f _ I O   s t u d i e s _ N N 2   ) _ )   . _ .   
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 O w i n g _ I I 2 1   t o _ I I 2 2   t h e _ A T   s m a l l _ J J   s a m p l e _ N N 1   s i z e s _ N N 2   , _ ,   s t r a t i f i c a t i o n _ N N 1   w i t h _ I W   a _ A T 1   p r o p e n s i t y _ N N 1   s c o r e _ N N 1   i s _ V B Z   n o t _ X X   p o s s i b l e _ J J   i n _ I I   t h i s _ D D 1   a n a l y s i s _ N N 1   a n d _ C C   h e n c e _ R R   n o _ A T   a d j u s t m e n t _ N N 1   f o r _ I F   c o v a r i a t e s _ N N 2   w a s _ V B D Z   p e r f o r m e d _ V V N   . _ .   
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 T h e _ A T   l a y o u t _ N N 1   o f _ I O   t h i s _ D D 1   d e s i g n _ N N 1   i s _ V B Z   s h o w n _ V V N   i n _ I I   F i g u r e _ N N 1   1 _ M C 1   . _ .   
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 E x p r e s s i o n _ N N 1   o f _ I O   t h e _ A T   f u l l _ J J   l e n g t h _ N N 1   A P P _ N N 1   w a s _ V B D Z   d e n s i t o m e t r i c a l l y _ R R   q u a n t i f i e d _ V V N   o n _ I I   W e s t e r n _ J J   i m m u n o b l o t s _ N N 2   d e v e l o p e d _ V V D   u s i n g _ V V G   6 E 1 0 _ F O   m A b _ N N 1   w h i l e _ C S   e x p r e s s i o n _ N N 1   o f _ I O   A P P _ N P 1   C T F s _ N P 1   o n _ I I   t h o s e _ D D 2   d e v e l o p e d _ V V N   u s i n g _ V V G   A 1 6 3 _ F O   p A b _ N N 1   . _ .   
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 I t _ P P H 1   i s _ V B Z   s p o r a d i c _ J J   i n _ I I   9 5 % _ N N U   o f _ I O   c a s e s _ N N 2   a n d _ C C   m a i n l y _ R R   a s s o c i a t e d _ V V N   n o t _ X X   o n l y _ R R   w i t h _ I W   a u t o i m m u n e _ N N 1   t h y r o t o x i c o s i s _ N N 1   ( _ (   G r a v e s _ N N 2   d i s e a s e _ N N 1   ) _ )   b u t _ C C B   a l s o _ R R   w i t h _ I W   t h y r o i d _ J J   s t i m u l a t i n g _ J J   h o r m o n e - s e c r e t i n g _ J J   p i t u i t a r y _ J J   t u m o r s _ N N 2   , _ ,   a m i o d a r o n e - i n d u c e d _ J J   t h y r o t o x i c o s i s _ N N 1   , _ ,   l y m p h o c y t i c _ J J   t h y r o i d i t i s _ N N 1   , _ ,   e t c _ R A   . _ .   
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 R e s u l t s _ N N 2   B e t w e e n _ I I   O c t _ N P M 1   2 0 _ M C   , _ ,   2 0 0 3 _ M C   , _ ,   a n d _ C C   A u g _ N P M 1   1 5 _ M C   , _ ,   2 0 0 7 _ M C   , _ ,   2 2 7 3 _ M C   m e n _ N N 2   w e r e _ V B D R   s c r e e n e d _ V V N   f o r _ I F   t h e _ A T   s t u d y _ N N 1   , _ ,   a n d _ C C   1 0 7 1 _ M C   w e r e _ V B D R   r a n d o m l y _ R R   a l l o c a t e d _ V V N   t o _ I I   o n e _ M C 1   o f _ I O   t h e _ A T   f o u r _ M C   t r e a t m e n t _ N N 1   g r o u p s _ N N 2   ( _ (   f i g u r e _ N N 1   1 _ M C 1   ) _ )   . _ .   
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 W e _ P P I S 2   r e p o r t _ V V 0   h a z a r d _ N N 1   r a t i o s _ N N 2   ( _ (   H R s _ N N U 2   ) _ )   a n d _ C C   9 5 % _ N N U   C I s _ N N 2   a s _ I I   a _ A T 1   m e a s u r e _ N N 1   o f _ I O   a s s o c i a t i o n _ N N 1   f o r _ I F   t i m e _ N N T 1   t o _ I I   e v e n t _ N N 1   d a t a _ N N   a n d _ C C   C - S t a - t i s t i c s _ N P 1   ( _ (   a r e a _ N N 1   u n d e r _ I I   t h e _ A T   c u r v e _ N N 1   & l s q b ; _ (   A U C _ N P 1   & r s q b ; _ )   ) _ )   a s _ I I   a _ A T 1   m e a s u r e _ N N 1   o f _ I O   d i s c r i m i n a t i o n _ N N 1   . _ .   
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 W e _ P P I S 2   p e r f o r m e d _ V V D   a d d i t i o n a l _ J J   p o s t h o c _ N N 1   a n a l y s e s _ V V Z   o n _ I I   t h e _ A T   M M S E _ N N 1   a n d _ C C   I M C T _ V V 0   c o g n i t i v e _ J J   f u n c t i o n a l _ J J   t e s t s _ N N 2   . _ .   
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 W e _ P P I S 2   e s t i m a t e d _ V V D   t h e _ A T   c r u d e _ J J   O R _ C C   a n d _ C C   9 5 % _ N N U   C I _ N N 1   f o r _ I F   t h e _ A T   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   m i c r o c e p h a l y _ N N 1   a n d _ C C   l a b o r a t o r y _ N N 1   c o n f i r m a t i o n _ N N 1   o f _ I O   Z i k a _ N P 1   v i r u s _ N N 1   i n f e c t i o n _ N N 1   , _ ,   c o n s i d e r i n g _ C S   t h e _ A T   r e s u l t s _ N N 2   i n _ I I   s e r u m _ N N 1   o r _ C C   c e r e b r o s p i n a l _ J J   f l u i d _ N N 1   a n d _ C C   t h e _ A T   r e s u l t s _ N N 2   i n _ I I   s e r u m _ N N 1   a l o n e _ R R   , _ ,   o v e r a l l _ J J   a n d _ C C   s e p a r a t e l y _ R R   f o r _ I F   c a s e s _ N N 2   w i t h _ I W   a n d _ C C   w i t h o u t _ I W   r a d i o l o g i c a l _ J J   e v i d e n c e _ N N 1   o f _ I O   b r a i n _ N N 1   a b n o r m a l i t i e s _ N N 2   . _ .   
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 I d e a l l y _ R R   , _ ,   e s p e c i a l l y _ R R   i n _ I I   a _ A T 1   c o l l e g i a t e _ J J   s e t t i n g _ N N 1   , _ ,   a _ A T 1   c e r t i f i e d _ J J   a t h l e t i c _ J J   t r a i n e r _ N N 1   w i l l _ V M   b e _ V B I   a v a i l a b l e _ J J   t o _ T O   o v e r s e e _ V V I   e a c h _ D D 1   s t e p _ N N 1   o f _ I O   t h e _ A T   R T P _ N P 1   p r o c e s s _ N N 1   . _ .   
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 A l t h o u g h _ C S   w i d e l y _ R R   e m p l o y e d _ V V N   i n _ I I   c l i n i c a l _ J J   p r a c t i c e _ N N 1   , _ ,   t h e _ A T   c u r r e n t _ J J   p h y s i o t h e r a p e u t i c _ J J   a p p r o a c h _ N N 1   f o r _ I F   p a t i e n t s _ N N 2   w i t h _ I W   c o m m u n i t y - a c q u i r e d _ J J   p n e u m o n i a _ N N 1   , _ ,   w h i c h _ D D Q   f o c u s e s _ V V Z   o n _ I I   a i r w a y _ N N 1   c l e a r a n c e _ N N 1   , _ ,   i s _ V B Z   n o t _ X X   s u p p o r t e d _ V V N   b y _ I I   e v i d e n c e _ N N 1   a n d _ C C   t h e _ A T   m a i n _ J J   g u i d e l i n e s _ N N 2   f o r _ I F   t h e _ A T   m a n a g e m e n t _ N N 1   o f _ I O   t h i s _ D D 1   c o n d i t i o n _ N N 1   d o _ V D 0   n o t _ X X   r e c o m m e n d _ V V I   i t _ P P H 1   . _ .   
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 N o n p a r s i m o n i o u s _ J J   l o g i s t i c _ J J   r e g r e s s i o n _ N N 1   m o d e l s _ N N 2   w e r e _ V B D R   c r e a t e d _ V V N   b y _ I I   f o r c i n g _ V V G   a n d / o r _ C C   e x c h a n g i n g _ V V G   a d d i t i o n a l _ J J   v a r i a b l e s _ N N 2   i n t o _ I I   t h e _ A T   m o d e l s _ N N 2   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   b y _ I I   a l t e r i n g _ V V G   t h e _ A T   v a r i a b l e _ J J   s t r u c t u r e s _ N N 2   f o r _ I F   b l o o d _ N N 1   l o s s _ N N 1   a n d _ C C   o p e r a t i v e _ J J   d u r a t i o n _ N N 1   , _ ,   i n _ I I   a n _ A T 1   a t t e m p t _ N N 1   t o _ T O   d i m i n i s h _ V V I   a s s o c i a t i o n s _ N N 2   b e t w e e n _ I I   a n e s t h e s i a _ N N 1   p r o v i d e r s _ N N 2   a n d _ C C   m a j o r _ J J   c o m p l i c a t i o n _ N N 1   w i t h _ I W   a l t e r n a t i v e _ J J   a d j u s t m e n t _ N N 1   . _ .   
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 T h e _ A T   " _ "   n o t _ X X   m i s s i n g _ V V G   c o m p l e t e l y _ R R   a t _ R R 2 1   r a n d o m _ R R 2 2   " _ "   ( _ (   N O M C A R _ N P 1   ) _ )   o p t i o n _ N N 1   i n _ I I   S A S _ N P 1   w a s _ V B D Z   u s e d _ V V N   f o r _ I F   v a r i a n c e _ N N 1   e s t i m a t i o n _ N N 1   . _ .   
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 D u e _ I I 2 1   t o _ I I 2 2   t h e s e _ D D 2   c h a l l e n g e s _ N N 2   o f _ I O   p e r f o r m i n g _ V V G   c l i n i c a l _ J J   t r i a l s _ N N 2   i n _ I I   i n f a n t s _ N N 2   , _ ,   f e w _ D A 2   l a b e l i n g _ J J   c h a n g e s _ N N 2   h a v e _ V H 0   i n c l u d e d _ V V N   i n f a n t - s p e c i f i c _ J J   i n f o r m a t i o n _ N N 1   . _ .   
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 T h i s _ D D 1   a r t i c l e _ N N 1   m a k e s _ V V Z   a n _ A T 1   i m p o r t a n t _ J J   c o n t r i b u t i o n _ N N 1   t o _ I I   t r a u m a _ N N 1   r e s e a r c h _ N N 1   a n d _ C C   h e a l t h _ N N 1   p o l i c y _ N N 1   b y _ I I   a d d r e s s i n g _ V V G   t h e _ A T   q u e s t i o n _ N N 1   , _ ,   C a n _ V M   w e _ P P I S 2   p o t e n t i a l l y _ R R   s a v e _ V V I   m o n e y _ N N 1   i n _ I I   t r a u m a _ N N 1   s y s t e m s _ N N 2   w i t h o u t _ I W   c o m p r o m i s i n g _ V V G   o u t c o m e s _ N N 2   b y _ I I   r e d i r e c t i n g _ V V G   p a t i e n t s _ N N 2   w i t h _ I W   m i n o r _ J J   t o _ T O   m o d e r a t e _ V V I   i n j u r i e s _ N N 2   a w a y _ I I 2 1   f r o m _ I I 2 2   m a j o r _ J J   t r a u m a _ N N 1   c e n t e r s _ N N 2   ? _ ?   
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 M u l t i s i t e _ N N 1   c o m p l i a n c e _ N N 1   a n d _ C C   l o g i s t i c s _ N N 1   w e r e _ V B D R   r e g u l a t e d _ V V N   i n _ I I   t h e _ A T   D e p a r t m e n t _ N N 1   o f _ I O   A n e s t h e s i o l o g y _ N N 1   a t _ I I   V a n d e r b i l t _ N P 1   U n i v e r s i t y _ N N 1   . _ .   
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 T h i s _ D D 1   m e t a - a n a l y s i s _ N N 1   r e p o r t s _ V V Z   t h a t _ C S T   t h e _ A T   s u p e r i o r _ J J   f r o n t a l _ J J   g y r u s _ N N 1   s h o w s _ V V Z   i n c r e a s e d _ J J   a c t i v a t i o n _ N N 1   i n _ I I   d e p r e s s e d _ J J   p a t i e n t s _ N N 2   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   e n h a n c e d _ J J   a c t i v a t i o n _ N N 1   i n _ I I 3 1   r e s p o n s e _ I I 3 2   t o _ I I 3 3   p o s i t i v e _ J J   e m o t i o n a l _ J J   s t i m u l i _ N N 2   a n d _ C C   d e c r e a s e d _ J J   a c t i v a t i o n _ N N 1   i n _ I I 3 1   r e s p o n s e _ I I 3 2   t o _ I I 3 3   n e g a t i v e _ J J   e m o t i o n a l _ J J   s t i m u l i _ N N 2   . _ .   
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 T h e _ A T   m o u s e _ N N 1   m e l a n o p s i n _ N N 1   o p e n _ J J   r e a d i n g _ N N 1   f r a m e _ N N 1   w a s _ V B D Z   c l o n e d _ V V N   i n t o _ I I   a _ A T 1   b i c i s t r o n i c _ J J   e x p r e s s i o n _ N N 1   v e c t o r _ N N 1   ( _ (   p I R E S 2 - E G F P _ N P 1   ) _ )   . _ .   
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 H o w e v e r _ R R   , _ ,   g i v e n _ V V N   t h e _ A T   i n c r e a s e d _ J J   r i s k _ N N 1   o f _ I O   b o d y _ N N 1   f l u i d _ N N 1   e x p o s u r e _ N N 1   , _ ,   o b s t e t r i c _ J J   u n i t s _ N N 2   c a r i n g _ V V G   f o r _ I F   p a t i e n t s _ N N 2   w i t h _ I W   E b o l a _ N P 1   v i r u s _ N N 1   d i s e a s e _ N N 1   s h o u l d _ V M   e m p l o y _ V V I   a d d i t i o n a l _ J J   p e r s o n a l _ J J   p r o t e c t i v e _ J J   e q u i p m e n t _ N N 1   , _ ,   s u c h _ I I 2 1   a s _ I I 2 2   s h o e _ N N 1   c o v e r s _ N N 2   , _ ,   d o u b l e _ J J   g l o v e s _ N N 2   , _ ,   a n d _ C C   l e g _ N N 1   c o v e r s _ N N 2   . _ .   
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 A n a l y z i n g _ V V G   t h e s e _ D D 2   l e s i o n s _ N N 2   w i t h _ I W   s p e c t r a l _ J J   d o m a i n _ N N 1   o p t i c a l _ J J   c o h e r e n c e _ N N 1   t o m o g r a p h y _ N N 1   ( _ (   S D - O C T _ N P M 1   ) _ )   , _ ,   Z w e i f e l _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 ( _ (   2 0 1 0 _ M C   ) _ )   f o u n d _ V V D   t h a t _ C S T   t h e y _ P P H S 2   a r e _ V B R   l o c a l i z e d _ V V N   b e t w e e n _ I I   t h e _ A T   R P E _ N N 1   a n d _ C C   t h e _ A T   i n n e r _ J J   s e g m e n t / o u t e r _ F U   s e g m e n t _ N N 1   b o u n d a r y _ N N 1   ( _ (   n o w _ R T   r e f e r r e d _ V V N   t o _ I I   a s _ I I   t h e _ A T   " _ "   i n n e r _ J J   s e g m e n t _ N N 1   e l l i p s o i d _ N N 1   ( _ (   I S e _ N P 1   ) _ )   b a n d _ N N 1   " _ "   ) _ )   a n d _ C C   r e f e r r e d _ V V N   t o _ I I   r e t i c u l a r _ J J   l e s i o n s _ N N 2   a s _ C S A   " _ "   s u b r e t i n a l _ J J   d r u s e n o i d _ J J   d e p o s i t s _ N N 2   " _ "   ( _ (   S D D _ N P 1   ) _ )   . _ .   
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 T h e _ A T   H 1 _ F O   h a p l o t y p e _ N N 1   h a s _ V H Z   c o n s i s t e n t l y _ R R   b e e n _ V B N   a s s o c i a t e d _ V V N   w i t h _ I W   4 - r e p e a t _ J J   t a u o p a t h i e s _ N N 2   i n c l u d i n g _ I I   P S P _ N P 1   ( _ (   B a k e r _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 9 9 9 _ M C   ) _ )   a n d _ C C   C B D _ N N 1   ( _ (   D i _ N P 1   M a r i a _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 0 _ M C   ) _ )   r e l a t i v e _ I I 2 1   t o _ I I 2 2   c o n t r o l s _ N N 2   , _ ,   t h o u g h _ C S   w e _ P P I S 2   a r e _ V B R   u n a w a r e _ J J   o f _ I O   a _ A T 1   d i r e c t _ J J   c o m p a r i s o n _ N N 1   b e t w e e n _ I I   F T L D - t a u _ N N 1   a n d _ C C   F T L D - T D P _ N N 1   t h a t _ C S T   e v a l u a t e d _ V V D   t h e _ A T   s p e c i f i c i t y _ N N 1   o f _ I O   t h i s _ D D 1   h a p l o t y p e _ N N 1   . _ .   
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 T h e _ A T   H o u s t o n _ N P 1   C A R E S _ V V Z   r e g i s t r y _ N N 1   h a s _ V H Z   b e e n _ V B N   i n d e p e n d e n t l y _ R R   e v a l u a t e d _ V V N   a n d _ C C   w a s _ V B D Z   s h o w n _ V V N   t o _ T O   h a v e _ V H I   c a p t u r e d _ V V N   e v e r y _ A T 1   9 - 1 - 1 _ M C M C   O H C A _ N N 1   e v e n t _ N N 1   b e t w e e n _ I I   2 0 0 7 _ M C   a n d _ C C   2 0 0 9 . 1 4 _ M C   H o w e v e r _ R R   , _ ,   t h e _ A T   a c c u r a c y _ N N 1   o f _ I O   d a t a _ N N   e n t r y _ N N 1   h a s _ V H Z   n o t _ X X   b e e n _ V B N   a s s e s s e d _ V V N   o r _ C C   v e r i f i e d _ V V D   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   e x e r c i s e _ V V 0   t o l e r a n c e _ N N 1   d u r i n g _ I I   M - > S _ F O   w a s _ V B D Z   e x t e n d e d _ V V N   b y _ I I   2 2 % _ N N U   a f t e r _ I I   N O 3 - _ N N 1   c o m p a r e d _ V V N   w i t h _ I W   p l a c e b o _ N N 1   i n g e s t i o n _ N N 1   . _ .   
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 T h e s e _ D D 2   d a t a _ N N   a r e _ V B R   t h e _ A T   f i r s t _ M D   t o _ T O   s h o w _ V V I   t h a t _ D D 1   t r a n s m e t a l l a t i o n _ N N 1   m a y _ V M   o c c u r _ V V I   i n _ I I   p a t i e n t s _ N N 2   w i t h o u t _ I W   r e n a l _ J J   i n s u f f i c i e n c y _ N N 1   , _ ,   b u t _ C C B   i n _ I I   a _ A T 1   n o n p l a s m a _ N N 1   s l o w l y _ R R   e q u i l i b r a t i n g _ V V G   c o m p a r t m e n t _ N N 1   . _ .   
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 W e _ P P I S 2   h a v e _ V H 0   b e e n _ V B N   w r i t i n g _ V V G   s e n t e n c e s _ N N 2   l i k e _ I I   t h i s _ D D 1   f o r _ I F   y e a r s _ N N T 2   , _ ,   t h u s _ R R   s u g g e s t i n g _ V V G   t h a t _ C S T   t h e _ A T   a d v a n c e s _ N N 2   i n _ I I   t h i s _ D D 1   f i e l d _ N N 1   h a v e _ V H 0   n o t _ X X   b e e n _ V B N   s u f f i c i e n t _ J J   t o _ T O   a c h i e v e _ V V I   a _ A T 1   s i g n i f i c a n t _ J J   c l i n i c a l _ J J   i m p a c t _ N N 1   o n _ I I   t h e _ A T   d i s e a s e _ N N 1   . _ .   
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 I n _ I I   s u m m a r y _ N N 1   , _ ,   1 4 , 5 4 1 _ M C   w o m e n _ N N 2   w e r e _ V B D R   e n r o l l e d _ V V N   , _ ,   p r o v i d e d _ C S 2 1   t h a t _ C S 2 2   t h e y _ P P H S 2   w e r e _ V B D R   r e s i d e n t _ J J   i n _ I I   A v o n _ N P 1   w h i l e _ C S   p r e g n a n t _ J J   a n d _ C C   h a d _ V H D   a n _ A T 1   e x p e c t e d _ J J   d e l i v e r y _ N N 1   d a t e _ N N 1   b e t w e e n _ I I   A p r i l _ N P M 1   1 _ M C 1   , _ ,   1 9 9 1 _ M C   a n d _ C C   D e c e m b e r _ N P M 1   3 1 _ M C   , _ ,   1 9 9 2 _ M C   . _ .   
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 T h e _ A T   i n t e r v i e w s _ N N 2   w e r e _ V B D R   c o n d u c t e d _ V V N   b y _ I I   2 _ M C   a u t h o r s _ N N 2   ( _ (   M a n i s h a _ N P 1   V e r m a _ N P 1   a n d _ C C   M o n a _ N P 1   S a r f a t y _ N P 1   ) _ )   a n d _ C C   w e r e _ V B D R   t a i l o r e d _ V V N   t o _ I I   i n d i v i d u a l _ J J   p r o g r a m s _ N N 2   t o _ T O   c o l l e c t _ V V I   i n f o r m a t i o n _ N N 1   t h a t _ C S T   w a s _ V B D Z   n o t _ X X   f o u n d _ V V N   i n _ I I   t h e _ A T   a v a i l a b l e _ J J   p u b l i c a t i o n s _ N N 2   . _ .   
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 A _ A T 1   g r a d e _ N N 1   2 _ M C   a n t r u m _ N N 1   c o r r e l a t e s _ V V Z   w i t h _ I W   h i g h e r _ J J R   t h a n _ C S N   b a s e l i n e _ N N 1   g a s t r i c _ J J   v o l u m e _ N N 1   a n d _ C C   i s _ V B Z   u n c o m m o n _ J J   i n _ I I   f a s t e d _ J J   s u b j e c t s _ N N 2   0 _ M C   . _ .   
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 M u s c l e _ N N 1   R I N G _ N N 1   F i n g e r _ N N 1   1 _ M C 1   ( _ (   M u R F 1 _ F O   ) _ )   , _ ,   a _ A T 1   m u s c l e - s p e c i f i c _ J J   E 3 _ F O   u b i q u i t i n _ N N 1   l i g a s e _ N N 1   , _ ,   i s _ V B Z   b e l i e v e d _ V V N   t o _ T O   m e d i a t e _ V V I   m u s c l e _ N N 1   a t r o p h y _ N N 1   t h r o u g h _ I I   t h e _ A T   u b i q u i t i n _ N N 1   p r o t e a s o m e _ J J   s y s t e m _ N N 1   ( _ (   U P S _ N N 2   ) _ )   . _ .   
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 P a r t i c i p a n t s _ N N 2   w o r e _ V V D   a n _ A T 1   A B P _ N N 1   c u f f _ N N 1   f r o m _ I I   0 8 0 0 _ M C   h _ Z Z 1   u n t i l _ C S   2 2 0 0 _ M C   h _ Z Z 1   o n _ I I   a l l _ D B   c o n d i t i o n s _ N N 2   . _ .   
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 A l l _ D B   w o m e n _ N N 2   w h o _ P N Q S   t e s t e d _ V V D   p o s i t i v e _ J J   f o r _ I F   f F N _ N N U   i n _ I I   t h e _ A T   s t u d y _ N N 1   ( _ (   n _ Z Z 1   = _ F O   1 1 _ M C   ) _ )   r e c e i v e d _ V V D   t o c o l y t i c _ J J   t h e r a p y _ N N 1   w i t h _ I W   o r a l _ J J   n i f e d i p i n e _ N N 1   . _ .   
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 I t _ P P H 1   h a s _ V H Z   b e e n _ V B N   w e l l - d o c u m e n t e d _ J J   t h a t _ C S T   c o m p a r a b l e _ J J   v o i c e _ N N 1   o u t c o m e s _ N N 2   c a n _ V M   b e _ V B I   a c h i e v e d _ V V N   i n _ I I   t h e s e _ D D 2   p a t i e n t s _ N N 2   w h o _ P N Q S   t h e n _ R T   u n d e r w e n t _ V V D   e i t h e r _ R R   p r i m a r y _ J J   o r _ C C   s e c o n d a r y _ J J   T E P . A s _ N P 1   a v a i l a b l e _ J J   t e c h n o l o g y _ N N 1   h a s _ V H Z   i m p r o v e d _ V V N   , _ ,   s e c o n d a r y _ J J   T E P _ N N 1   p l a c e m e n t _ N N 1   i n _ I I   t h e _ A T   o f f i c e _ N N 1   h a s _ V H Z   b e c o m e _ V V N   a n _ A T 1   a c c e p t e d _ J J   t e c h n i q u e _ N N 1   w i t h _ I W   o u t c o m e s _ N N 2   c o m p a r a b l e _ J J   t o _ I I   p r i m a r y _ J J   T E P _ N N 1   o r _ C C   t r a d i t i o n a l _ J J   s e c o n d a r y _ J J   T E P _ N N 1   u n d e r _ I I   r i g i d _ J J   e n d o s c o p i c _ J J   g u i d a n c e _ N N 1   . _ .   
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 T h e _ A T   s e x _ N N 1   d i f f e r e n c e s _ N N 2   i n _ I I   b o t h _ D B 2   t h e _ A T   t i m i n g _ N N 1   a n d _ C C   t h e _ A T   m a g n i t u d e _ N N 1   o f _ I O   d e c l i n e s _ V V Z   i n _ I I   l u n g _ N N 1   c a n c e r _ N N 1   m o r t a l i t y _ N N 1   a r e _ V B R   b e c a u s e _ I I 2 1   o f _ I I 2 2   s e x _ N N 1   d i f f e r e n c e s _ N N 2   i n _ I I   t h e _ A T   t i m e _ N N T 1   c o u r s e _ N N 1   o f _ I O   c i g a r e t t e _ N N 1   m a r k e t i n g _ N N 1   , _ ,   u s e _ V V 0   , _ ,   a n d _ C C   c e s s a t i o n . 1 1 _ F O   T o b a c c o _ N N 1   u s e _ N N 1   h a s _ V H Z   b e e n _ V B N   o n _ I I   t h e _ A T   d e c l i n e _ N N 1   i n _ I I   t h e _ A T   U n i t e d _ N P 1   S t a t e s _ N P 1   s i n c e _ C S   t h e _ A T   1 9 6 0 s _ M C 2   , _ ,   b u t _ C C B   t h e _ A T   t r a j e c t o r y _ N N 1   o f _ I O   d o w n w a r d _ J J   t r e n d s _ N N 2   i n _ I I   c i g a r e t t e _ N N 1   s m o k i n g _ N N 1   s l o w e d _ V V N   i n _ I I   t h e _ A T   1 9 9 0 s _ M C 2   , _ ,   n o w _ R T   l e a v i n g _ V V G   a b o u t _ I I   1 _ M C 1   o f _ I O   e v e r y _ A T 1   6 _ M C   A m e r i c a n _ J J   a d u l t s _ N N 2   a s _ C S A   r e g u l a r _ J J   c i g a r e t t e _ N N 1   s m o k e r s _ N N 2   . _ .   
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 T h e _ A T   5 5 _ M C   0 0 3 _ M C   r e g i o n s _ N N 2   c a n _ V M   b e _ V B I   i d e n t i f i e d _ V V N   o n _ I I   t h e _ A T   a r r a y _ N N 1   f o r m _ V V 0   t h e _ A T   b a c k g r o u n d _ N N 1   l i s t _ N N 1   f r o m _ I I   w h i c h _ D D Q   D M R s _ N P 1   w e r e _ V B D R   g e n e r a t e d _ V V N   . _ .   
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 S e p a r a t i o n _ N N 1   o f _ I O   t h e _ A T   d i s c s _ N N 2   f r o m _ I I   t h e _ A T   p l a s m a _ N N 1   m e m b r a n e _ N N 1   c o m b i n e d _ V V N   w i t h _ I W   i m m u n o g o l d _ N N 1   e l e c t r o n _ N N 1   m i c r o s c o p y _ N N 1   ( _ (   E M _ F U   ) _ )   s h o w e d _ V V D   t h a t _ C S T   t h i s _ D D 1   p r o t e i n _ N N 1   l o c a l i z e d _ V V D   t o _ I I   t h e _ A T   r i m s _ N N 2   a n d _ C C   i n c i s u r e s _ N N 2   o f _ I O   t h e _ A T   f l a t t e n e d _ J J   O S _ N P 2   d i s c s _ N N 2   ( _ (   M o l d a y _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 9 8 7 _ M C   ) _ )   . _ .   
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 M a i n t a i n i n g _ V V G   t h e _ A T   t r u n k _ N N 1   u p r i g h t _ R L   e n h a n c e s _ V V Z   t h e _ A T   v a l i d i t y _ N N 1   o f _ I O   V V _ N P 1   o r i e n t a t i o n _ N N 1   , _ ,   a n d _ C C   m a i n t a i n i n g _ V V G   t h e _ A T   h e a d _ N N 1   u p r i g h t _ R L   e n h a n c e s _ V V Z   t h e _ A T   v a l i d i t y _ N N 1   o f _ I O   w i t h i n - s u b j e c t _ N N 1   v a r i a b i l i t y _ N N 1   . _ .   
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 A l t h o u g h _ C S   t h e _ A T   s t a n d a r d _ N N 1   o f _ I O   c a r e _ N N 1   m a y _ V M   h a v e _ V H I   c h a n g e d _ V V N   d u r i n g _ I I   t h e _ A T   l a s t _ M D   1 3 _ M C   y e a r s _ N N T 2   , _ ,   b a r r i n g _ V V G   d i r e c t _ J J   c o m p a r i s o n _ N N 1   , _ ,   a l l _ D B   s u b j e c t s _ N N 2   i n _ I I   b o t h _ D B 2   e x p e r i m e n t a l _ J J   a n d _ C C   c o n t r o l _ N N 1   g r o u p s _ N N 2   f o r _ I F   a l l _ D B   3 _ M C   r e c e n t _ J J   t r i a l s _ N N 2   r e c e i v e d _ V V D   e a r l y _ R R   i n t r a v e n o u s _ J J   f l u i d _ N N 1   a n d _ C C   a n t i b i o t i c s _ N N 2   . _ .   
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 B e c a u s e _ I I 2 1   o f _ I I 2 2   t h e _ A T   r a r i t y _ N N 1   o f _ I O   t h e _ A T   t u m o r _ N N 1   , _ ,   t h e r e _ E X   i s _ V B Z   n o _ A T   c o n s e n s u s _ N N 1   f o r _ I F   i t s _ A P P G E   p r o p e r _ J J   d i a g n o s i s _ N N 1   a n d _ C C   t r e a t m e n t _ N N 1   . _ .   
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 O f _ I O   t h e _ A T   9 4 0 _ M C   p a t i e n t s _ N N 2   , _ ,   2 4 9 _ M C   w e r e _ V B D R   e x c l u d e d _ V V N   f o r _ I F   s u b g r o u p _ N N 1   a n a l y s i s _ N N 1   : _ :   2 4 1 _ M C   p a t i e n t s _ N N 2   d i d _ V D D   n o t _ X X   a t t e n d _ V V I   a l l _ D B   t u m o u r _ N N 1   a s s e s s m e n t s _ N N 2   , _ ,   o r _ C C   h a d _ V H D   r e s u l t s _ N N 2   w h e r e _ C S   i t _ P P H 1   w a s _ V B D Z   n o t _ X X   p o s s i b l e _ J J   t o _ T O   d e t e r m i n e _ V V I   r e s p o n s e _ N N 1   s t a t u s _ N N 1   , _ ,   a n d _ C C   e i g h t _ M C   p a t i e n t s _ N N 2   h a d _ V H D   s a l v a g e _ N N 1   t r e a t m e n t _ N N 1   b e f o r e _ I I   t h e _ A T   t h i r d _ M D   a s s e s s m e n t _ N N 1   . _ .   
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 T h e _ A T   p a t i e n t _ J J   s a t i s f a c t i o n _ N N 1   s c o r e _ N N 1   w a s _ V B D Z   r e c o r d e d _ V V N   i n _ I I   o n l y _ R R   5 9 _ M C   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   p l a c e b o _ N N 1   g r o u p _ N N 1   a n d _ C C   5 2 _ M C   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   r o p i v a c a i n e _ N N 1   g r o u p _ N N 1   : _ :   t h e r e _ E X   w a s _ V B D Z   n o _ A T   s i g n i f i c a n t _ J J   d i f f e r e n c e _ N N 1   i n _ I I   t h e _ A T   p a t i e n t _ J J   s a t i s f a c t i o n _ N N 1   s c o r e _ N N 1   b e t w e e n _ I I   t h e _ A T   2 _ M C   g r o u p s _ N N 2   ( _ (   9 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   1 _ M C 1   v s _ I I   9 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   1 _ M C 1   ; _ ;   P _ Z Z 1   = _ F O   0 . 7 0 _ M C   ) _ )   . _ .   
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 T h e s e _ D D 2   m o l e c u l e s _ N N 2   w e r e _ V B D R   s e l e c t e d _ V V N   b e c a u s e _ C S   t h e y _ P P H S 2   a r e _ V B R   i n v o l v e d _ J J   i n _ I I   i n f l a m m a t i o n _ N N 1   a n d _ C C   h a v e _ V H 0   b e e n _ V B N   a s s o c i a t e d _ V V N   w i t h _ I W   d e c r e a s e d _ J J   s u r v i v a l _ N N 1   a n d _ C C   r e c o v e r y _ N N 1   i n _ I I   p r i o r _ J J   s t u d i e s _ N N 2   . _ .   
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 S t u d y _ N N 1   o b j e c t i v e s _ N N 2   a r e _ V B R   t o _ T O   e v a l u a t e _ V V I   t h e _ A T   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   O S A _ N P 1   a n d _ C C   b i o m a r k e r s _ N N 2   , _ ,   a n d _ C C   t o _ T O   t e s t _ V V I   t h e _ A T   h y p o t h e s i s _ N N 1   t h a t _ C S T   a _ A T 1   c o m b i n a t i o n _ N N 1   o f _ I O   m a r k e r s _ N N 2   m a y _ V M   b e _ V B I   u s e f u l _ J J   i n _ I I   s c r e e n i n g _ V V G   f o r _ I F   O S A _ N N 1   . _ .   
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 M a t e r i a l s _ N N 2   a n d _ C C   M e t h o d s _ N N 2   S u b j e c t s _ N N 2   S i x t e e n _ M C   m a l e _ J J   , _ ,   4 - w e e k _ J J   o l d _ J J   a l b i n o _ N N 1   D u n k i n - H a r t l e y _ N P 1   g u i n e a _ N N 1   p i g s _ N N 2   w e r e _ V B D R   p u r c h a s e d _ V V N   f r o m _ I I   C h a r l e s _ N P 1   R i v e r _ N N L 1   L a b o r a t o r i e s _ N N 2   ( _ (   W i l m i n g t o n _ N P 1   , _ ,   M A _ N N A   ) _ )   . _ .   
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 M a r y _ N P 1   T . _ N P 1   R o t h _ N P 1   , _ ,   P h a r m . D . _ N P 1   , _ ,   M . H . S . F r o m _ N P 1   t h e _ A T   D e p a r t m e n t _ N N 1   o f _ I O   P s y c h i a t r y _ N P 1   ( _ (   L C W _ N P 1   ) _ )   , _ ,   U N C _ N P 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   N o r t h _ N D 1   C a r o l i n a _ N P 1   a t _ I I   C h a p e l _ N P 1   H i l l _ N N L 1   , _ ,   C h a p e l _ N P 1   H i l l _ N N L 1   , _ ,   N C _ N P 1   ; _ ;   D i v i s i o n _ N N 1   o f _ I O   G e n e r a l _ J J   M e d i c i n e _ N N 1   a n d _ C C   C l i n i c a l _ J J   E p i d e m i o l o g y _ N N 1   , _ ,   U N C _ N P 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   , _ ,   a n d _ C C   D e p a r t m e n t _ N N 1   o f _ I O   B i o s t a t i s t i c s _ N P 1   ( _ (   D A E _ N P 1   ) _ )   , _ ,   U N C _ N P 1   G i l l i n g s _ N P 1   S c h o o l _ N N 1   o f _ I O   P u b l i c _ J J   H e a l t h _ N N 1   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   N o r t h _ N D 1   C a r o l i n a _ N P 1   a t _ I I   C h a p e l _ N P 1   H i l l _ N N L 1   , _ ,   C h a p e l _ N P 1   H i l l _ N N L 1   , _ ,   N C _ N P 1   ; _ ;   D i v i s i o n _ N N 1   o f _ I O   P h a r m a c y _ N P 1   P r a c t i c e _ N N 1   a n d _ C C   E x p e r i e n t i a l _ J J   E d u c a t i o n _ N N 1   ( _ (   J L I _ N P 1   ) _ )   , _ ,   U N C _ N P 1   E s h e l m a n _ N P 1   S c h o o l _ N N 1   o f _ I O   P h a r m a c y _ N P 1   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   N o r t h _ N D 1   C a r o l i n a _ N P 1   a t _ I I   C h a p e l _ N P 1   H i l l _ N N L 1   , _ ,   C h a p e l _ N P 1   H i l l _ N N L 1   , _ ,   N C _ N P 1   ; _ ;   D i v i s i o n _ N N 1   o f _ I O   G e n e r a l _ J J   M e d i c i n e _ N N 1   a n d _ C C   C l i n i c a l _ J J   E p i d e m i o l o g y _ N N 1   ( _ (   C L L _ N P 1   ) _ )   , _ ,   U N C _ N P 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   N o r t h _ N D 1   C a r o l i n a _ N P 1   a t _ I I   C h a p e l _ N P 1   H i l l _ N N L 1   , _ ,   C h a p e l _ N P 1   H i l l _ N N L 1   , _ ,   N C _ N P 1   ; _ ;   D e p a r t m e n t _ N N 1   o f _ I O   P h a r m a c y _ N P 1   C a r e _ N N 1   S y s t e m s _ N N 2   ( _ (   R H _ F O   ) _ )   , _ ,   H a r r i s o n _ N P 1   S c h o o l _ N N 1   o f _ I O   P h a r m a c y _ N P 1   , _ ,   A u b u r n _ J J   U n i v e r s i t y _ N N 1   , _ ,   A u b u r n _ J J   , _ ,   A L _ F W   ; _ ;   D e p a r t m e n t _ N N 1   o f _ I O   H e a l t h _ N N 1   P o l i c y _ N N 1   a n d _ C C   M a n a g e m e n t _ N N 1   , _ ,   U N C _ N P 1   G i l l i n g s _ N P 1   S c h o o l _ N N 1   o f _ I O   G l o b a l _ J J   P u b l i c _ J J   H e a l t h _ N N 1   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   N o r t h _ N D 1   C a r o l i n a _ N P 1   a t _ I I   C h a p e l _ N P 1   H i l l _ N N L 1   S c h o o l _ N N 1   , _ ,   C h a p e l _ N P 1   H i l l _ N N L 1   , _ ,   N C _ N P 1   ; _ ;   C e n t e r _ N N 1   f o r _ I F   H e a l t h _ N N 1   S e r v i c e s _ N N 2   R e s e a r c h _ N N 1   ( _ (   M W _ N N U   ) _ )   , _ ,   D u r h a m _ N P 1   V e t e r a n s _ N N 2   A f f a i r s _ N N 2   M e d i c a l _ J J   C e n t e r _ N N 1   , _ ,   D u r h a m _ N P 1   , _ ,   N C _ N P 1   ; _ ;   a n d _ C C   D i v i s i o n _ N N 1   o f _ I O   P h a r m a c e u t i c a l _ J J   O u t c o m e s _ N N 2   a n d _ C C   P o l i c y _ N N 1   ( _ (   M T R _ N P 1   ) _ )   , _ ,   U N C _ N P 1   E s h e l m a n _ N P 1   S c h o o l _ N N 1   o f _ I O   P h a r m a c y _ N P 1   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   N o r t h _ N D 1   C a r o l i n a _ N P 1   a t _ I I   C h a p e l _ N P 1   H i l l _ N N L 1   , _ ,   C h a p e l _ N P 1   H i l l _ N N L 1   , _ ,   N C _ N P 1   . _ .   
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 A _ A T 1   s m a l l _ J J   s t u d y _ N N 1   o f _ I O   1 1 _ M C   p a r t i c i p a n t s _ N N 2   w i t h _ I W   C A A - r e l a t e d _ J J   I C H _ F W   a n d _ C C   1 3 _ M C   m a t c h e d _ J J   h e a l t h y _ J J   c o n t r o l s _ N N 2   f o u n d _ V V N   r e d u c e d _ V V D   F A _ N P 1   i n _ I I   t h e _ A T   t e m p o r a l _ J J   w h i t e _ J J   m a t t e r _ N N 1   ( _ (   i n f e r i o r _ J J   l o n g i t u d i n a l _ J J   a n d _ C C   o c c i p i t a l _ J J   f a s c i c u l i _ N N 2   , _ ,   1 7 % _ N N U   r e d u c t i o n _ N N 1   ) _ )   a n d _ C C   s p l e n i u m _ N N 1   o f _ I O   t h e _ A T   c o r p u s _ N N 1   c a l l o s u m _ N N 1   ( _ (   1 5 % _ N N U   r e d u c t i o n _ N N 1   ) _ )   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   i n c r e a s e d _ J J   F A _ N P 1   o f _ I O   l o w e r _ J J R   m a g n i t u d e _ N N 1   i n _ I I   d e e p _ J J   g r e y _ J J   m a t t e r _ N N 1   s t r u c t u r e s _ N N 2   . _ .   
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 A c t u a l l y _ R R   , _ ,   t h e r e _ E X   a r e _ V B R   n o _ A T   v a l i d a t e d _ J J   r e f e r e n c e _ N N 1   c o n t r o l s _ V V Z   f o r _ I F   t h e _ A T   a n a l y s i s _ N N 1   o f _ I O   t h e _ A T   e x p r e s s i o n _ N N 1   o f _ I O   m i R N A s _ N N 2   i n _ I I   P C a _ N P 1   , _ ,   s h o w i n g _ V V G   t h e _ A T   p u b l i s h e d _ J J   s t u d i e s _ N N 2   c o n t r a d i c t o r y _ J J   r e s u l t s _ N N 2   . _ .   
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 A f t e r _ I I   w a s h i n g _ V V G   t h e _ A T   s t r i p s _ N N 2   , _ ,   ( _ (   B C I P _ N P 1   ) _ )   - n i t r o b l u e _ J J   t e t r a z o l i u m _ N N 1   c h r o m o g e n _ N N 1   ( _ (   s u b s t r a t e _ N N 1   ) _ )   r e a c t e d _ V V D   w i t h _ I W   t h e _ A T   c o n j u g a t e _ N N 1   , _ ,   f o r m i n g _ V V G   t h e _ A T   p u r p l e / b r o w n _ J J   v i s i b l e _ J J   l i n e _ N N 1   p a t t e r n s _ N N 2   . _ .   
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 S a r c o p e n i a _ N N 1   i s _ V B Z   a _ A T 1   c o m p o n e n t _ N N 1   o f _ I O   f r a i l t y _ N N 1   , _ ,   w h i c h _ D D Q   i s _ V B Z   t h e _ A T   s t a t u s _ N N 1   o f _ I O   d e c r e a s e d _ J J   p h y s i c a l _ J J   a n d _ C C   c o g n i t i v e _ J J   r e s e r v e _ N N 1   l e a d i n g _ V V G   t o _ I I   a n _ A T 1   i n c r e a s e d _ J J   v u l n e r a b i l i t y _ N N 1   t o _ I I   s t r e s s o r s _ N N 2   . _ .   
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 W h i l e _ N N T 1   o f _ I O   i n t e r e s t _ N N 1   t o _ I I   c l i n i c i a n s _ N N 2   t o _ T O   g u i d e _ V V I   t h e _ A T   t r e a t m e n t _ N N 1   r e q u i r e d _ V V N   , _ ,   t h e _ A T   n e e d _ N N 1   f o r _ I F   f u r t h e r _ J J R   t r e a t m e n t _ N N 1   o f _ I O   i n f e c t e d _ J J   s k i n _ N N 1   r e q u i r i n g _ V V G   m o r e _ D A R   h o s p i t a l _ N N 1   v i s i t s _ N N 2   a n d _ C C   t i m e _ N N T 1   o f f _ I I   w o r k _ N N 1   o r _ C C   r e v i s i o n _ N N 1   s u r g e r y _ N N 1   i s _ V B Z   o f _ I O   g r e a t e r _ J J R   i m p o r t a n c e _ N N 1   t o _ I I   p a t i e n t s _ N N 2   . _ .   
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 T h e _ A T   g r a f t s _ N N 2   w e r e _ V B D R   o b s e r v e d _ V V N   e v e r y _ A T 1   d a y _ N N T 1   a f t e r w a r d s _ R T   a n d _ C C   c o n s i d e r e d _ V V N   r e j e c t e d _ V V N   w h e n _ C S   n o _ A T   v i a b l e _ J J   s k i n _ N N 1   r e m a i n e d _ V V D   . _ .   
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 T h e _ A T   c o n s e r v a t i v e _ J J   v a r i a n c e _ N N 1   a n a l y s i s _ N N 1   a l l o w e d _ V V N   f o r _ I F   c o r r e l a t i o n _ N N 1   o f _ I O   i n d i v i d u a l s _ N N 2   w i t h i n _ I I   r a n d o m i s a t i o n _ N N 1   c l u s t e r s _ N N 2   b u t _ C C B   n o t _ X X   b e t w e e n _ I I   c l u s t e r s _ N N 2   , _ ,   a n d _ C C   u s e d _ V V D   t h e _ A T   H u b e r - W h i t e _ J J   i n f o r m a t i o n _ N N 1   s a n d w i c h _ N N 1   m e t h o d _ N N 1   t o _ T O   e s t i m a t e _ V V I   v a r i a n c e _ N N 1   . _ .   
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 T h e _ A T   p u r p o s e _ N N 1   o f _ I O   t h i s _ D D 1   s t u d y _ N N 1   w a s _ V B D Z   t o _ T O   d e t e r m i n e _ V V I   w h e t h e r _ C S W   a _ A T 1   l o c o m o t o r _ N N 1   a d a p t a t i o n _ N N 1   t h a t _ C S T   r e q u i r e s _ V V Z   o v e r c o m i n g _ V V G   a _ A T 1   n o v e l _ J J   s w i n g - p h a s e _ J J   r e s i s t a n c e _ N N 1   i s _ V B Z   i m p a i r e d _ V V N   i n _ I I   p e r s o n s _ N N 2   w i t h _ I W   c h r o n i c _ J J   s t r o k e _ N N 1   a n d _ C C   h e m i p a r e s i s _ N N 1   . _ .   
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 W h i l e _ C S   c o n f i r m a t i o n _ N N 1   i n _ I I   a _ A T 1   l a r g e r _ J J R   c o h o r t _ N N 1   i s _ V B Z   n e e d e d _ V V N   , _ ,   o u r _ A P P G E   d a t a _ N N   s u g g e s t s _ V V Z   t h a t _ C S T   t h e _ A T   H E A R T _ N N 1   P a t h w a y _ N N 1   m a y _ V M   b e _ V B I   u t i l i z e d _ V V N   w i t h o u t _ I W   m o d i f i c a t i o n _ N N 1   i n _ I I   p l a c e s _ N N 2   w h e r e _ R R Q   h s - c T n I _ N N 2   a s s a y s _ N N 2   a r e _ V B R   a l r e a d y _ R R   a v a i l a b l e _ J J   a n d _ C C   w h e n _ C S   t h e y _ P P H S 2   b e c o m e _ V V 0   a v a i l a b l e _ J J   i n _ I I   t h e _ A T   U . S . _ N P 1   A b s t r a c t _ J J   I M P O R T A N C E - E x e c u t i v e _ N N 1   d y s f u n c t i o n _ N N 1   a f t e r _ I I   t r a u m a t i c _ J J   b r a i n _ N N 1   i n j u r y _ N N 1   ( _ (   T B I _ N P 1   ) _ )   i n _ I I   c h i l d r e n _ N N 2   i s _ V B Z   c o m m o n _ J J   a n d _ C C   l e a d s _ V V Z   t o _ I I   s i g n i f i c a n t _ J J   s h o r t - _ J J   a n d _ C C   l o n g - t e r m _ J J   p r o b l e m s _ N N 2   i n _ I I   f u n c t i o n i n g _ V V G   a c r o s s _ R P   m u l t i p l e _ J J   s e t t i n g s _ N N 2   . _ .   
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 P l a n t a r _ N N 1   f l e x o r _ N N 1   m u s c l e s _ N N 2   o f _ I O   r a t s _ N N 2   i n _ I I   a _ A T 1   s u p i n e _ J J   p o s i t i o n _ N N 1   w e r e _ V B D R   s t i m u l a t e d _ V V N   ( _ (   3 _ M C   H z _ N N U   ; _ ;   p u l s e _ N N 1   d u r a t i o n _ N N 1   : _ :   2 2 0 _ M C   l s _ N N U 2   ) _ )   d i r e c t l y _ R R   w i t h _ I W   t r a n s c u t a n e o u s _ J J   s u r f a c e _ N N 1   e l e c t r o d e s _ N N 2   l o c a t e d _ V V N   a t _ I I   t h e _ A T   k n e e _ N N 1   a n d _ C C   h e e l _ N N 1   l e v e l s _ N N 2   ( _ (   A r s a c _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 8 _ M C   ) _ )   . _ .   
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 I n d i v i d u a l s _ N N 2   w i t h _ I W   o t h e r _ J J   r i s k s _ N N 2   f o r _ I F   n e u r o p a t h y _ N N 1   ( _ (   e g _ R E X   , _ ,   a l c o h o l i s m _ N N 1   , _ ,   v i t a m i n _ N N 1   B 1 2 _ F O   d e f i c i e n c y _ N N 1   , _ ,   c h e m o t h e r a p y _ N N 1   ) _ )   w e r e _ V B D R   e x c l u d e d _ V V N   . _ .   
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 T h e r e _ E X   w a s _ V B D Z   a _ A T 1   s i g n i f i c a n t _ J J   d e c l i n e _ N N 1   w i t h _ I W   a g e _ N N 1   i n _ I I   t h e _ A T   i n t e n s i t y _ N N 1   o f _ I O   O t x 2 _ F O   m R N A _ N N 1   e x p r e s s i o n _ N N 1   a c r o s s _ I I   a l l _ D B   r e g i o n s _ N N 2   e x a m i n e d _ V V D   , _ ,   a n d _ C C   i n _ I I   t h e _ A T   S N C _ N P 1   a n d _ C C   V T A _ N P 1   e x p r e s s i o n _ N N 1   w a s _ V B D Z   r e d u c e d _ V V N   t o _ I I   b e l o w _ I I   a v e r a g e _ N N 1   b y _ I I   e a r l y _ J J   m i d d l e _ J J   a g e _ N N 1   . _ .   
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 S t a t i s t i c a l _ J J   a n a l y s i s _ N N 1   A l l _ D B   a n a l y s e s _ N N 2   w e r e _ V B D R   b y _ I I   i n t e n t i o n _ N N 1   t o _ T O   t r e a t _ V V I   b a s e d _ V V N   o n _ I I   t h e _ A T   r a n d o m i s e d _ J J   t r e a t m e n t _ N N 1   a l l o c a t i o n _ N N 1   . _ .   
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 T h e _ A T   g o l d _ N N 1   s t a n d a r d _ N N 1   f o r _ I F   d i a g n o s i s _ N N 1   i s _ V B Z   c u r r e n t l y _ R R   b a s e d _ V V N   u p o n _ I I   o v e r n i g h t _ J J   p o l y s o m n o g r a p h y _ N N 1   ( _ (   s l e e p _ V V 0   s t u d y _ N N 1   ) _ )   , _ ,   a n d _ C C   p a t i e n t s _ N N 2   a r e _ V B R   o f t e n _ R R   n o t _ X X   r e f e r r e d _ V V N   f o r _ I F   t h i s _ D D 1   d e f i n i t i v e _ J J   t e s t i n g _ N N 1   . _ .   
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 T h e _ A T   c a s e - c o n t r o l _ J J   s t u d y _ N N 1   w i l l _ V M   c o n t i n u e _ V V I   t o _ T O   i n v e s t i g a t e _ V V I   t h e _ A T   c u r r e n t _ J J   a n d _ C C   a l t e r n a t i v e _ J J   h y p o t h e s e s _ N N 2   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   t h e _ A T   r o l e _ N N 1   o f _ I O   c o f a c t o r s _ N N 2   , _ ,   a n d _ C C   p r o v i d e _ V V 0   f i n a l _ J J   e s t i m a t e s _ N N 2   . _ .   
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 C _ N P 1   i n _ I I   a n _ A T 1   E D T A _ N N 1   b u f f e r _ N N 1   ( _ (   p H _ N N 1   8 . 0 _ M C   ; _ ;   S h a n g h a i _ N P 1   S u n _ N N 1   B i o T e c h _ N P 1   C o _ N P 1   , _ ,   S h a n g h a i _ N P 1   , _ ,   C h i n a _ N P 1   ) _ )   f o r _ I F   a _ A T 1   t o t a l _ N N 1   o f _ I O   2 0 _ M C   m i n u t e s _ N N T 2   f o r _ I F   s t a i n i n g _ V V G   f o r _ I F   C D 3 1 _ F O   , _ ,   A D R B 2 _ F O   , _ ,   p - C R E B _ N P 1   , _ ,   A D R A 1 _ F O   , _ ,   a n d _ C C   A D R A 2 _ F O   , _ ,   o r _ C C   c i t r a t e _ J J   b u f f e r _ N N 1   ( _ (   p H 6 . 0 _ F O   ) _ )   f o r _ I F   a _ A T 1   t o t a l _ N N 1   o f _ I O   3 0 _ M C   m i n u t e s _ N N T 2   f o r _ I F   s t a i n i n g _ V V G   f o r _ I F   P C N A _ N P 1   , _ ,   V E G F _ N P 1   , _ ,   A D R B 1 _ F O   , _ ,   a n d _ C C   A D R B 3 _ F O   a n d _ C C   t h e n _ R T   c o o l e d _ V V D   n a t u r a l l y _ R R   t o _ I I   t h e _ A T   r o o m _ N N 1   t e m p e r a t u r e _ N N 1   . _ .   
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 I n _ I I 3 1   l i g h t _ I I 3 2   o f _ I I 3 3   t h e _ A T   s u p p o s e d _ J J   f a i l u r e s _ N N 2   o f _ I O   c o r t e c t o m i e s _ N N 2   o r _ C C   t h a l a - m o t o m i e s _ N N 2   t o _ T O   r e l i e v e _ V V I   p h a n t o m _ J J   p e r c e p t s _ N N 2   a n d _ C C   p a i n _ N N 1   , _ ,   M e l z a c k _ N P 1   p r o p o s e d _ V V D   t h a t _ C S T   t h e _ A T   a n a t o m i c a l _ J J   s u b s t r a t e _ N N 1   o f _ I O   t h e _ A T   p h y s i c a l _ J J   s e l f _ N N 1   i s _ V B Z   a _ A T 1   n e t w o r k _ N N 1   o f _ I O   n e u r o n s _ N N 2   t h a t _ C S T   e x t e n d s _ V V Z   t h r o u g h o u t _ I I   w i d e s p r e a d _ J J   a r e a s _ N N 2   o f _ I O   t h e _ A T   b r a i n _ N N 1   ( _ (   N e u r o m a t r i x _ N P 1   ) _ )   . _ .   
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 W h e n _ C S   w e _ P P I S 2   u s e d _ V V D   m o r e _ D A R   t h a n _ C S N   4 0 0 _ M C   d a t a p o i n t s _ V V Z   t o _ T O   e s t i m a t e _ V V I   t h e _ A T   r e g r e s s i o n _ N N 1   c o e f f i c i e n t s _ N N 2   , _ ,   t h e _ A T   r e g r e s s i o n s _ N N 2   a l s o _ R R   i n c l u d e d _ V V N   r e g i o n a l _ J J   r a n d o m _ J J   e f f e c t s _ N N 2   . _ .   
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 S p e c i f i c _ J J   c o n d i t i o n a l _ N N 1   S o x 2 _ F O   d e l e t i o n _ N N 1   i n d u c e s _ V V Z   a _ A T 1   r a p i d _ J J   l o s s _ N N 1   o f _ I O   N e s t i n + _ F O   N P C s _ N P 1   a n d _ C C   a _ A T 1   d e c l i n e _ N N 1   i n _ I I   d e n t a t e _ N N 1   c e l l _ N N 1   p r o l i f e r a t i o n _ N N 1   , _ ,   s u b s t a n t i a t i n g _ V V G   t h e _ A T   c r u c i a l _ J J   r o l e _ N N 1   o f _ I O   S o x 2 _ F O   i n _ I I   m a i n t a i n i n g _ V V G   u n d i f f e r e n t i a t e d _ J J   N P C s _ N P 1   a n d _ C C   h e n c e _ R R   n e u r o g e n e s i s _ N N 1   i n _ I I   t h e _ A T   a d u l t _ N N 1   h i p p o c a m p u s _ N N 1   ( _ (   F a v a r o _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 9 _ M C   ; _ ;   F e r r i _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 4 _ M C   ) _ )   . _ .   
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 I n _ I I   p l a c e s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   K e n y a _ N P 1   o r _ C C   P a k i s t a n _ N P 1   , _ ,   f o o d _ N N 1   e x p e n d i t u r e s _ N N 2   c o n s u m e _ V V 0   o n _ I I   a v e r a g e _ N N 1   a l m o s t _ R R   o n e - h a l f _ M F   o f _ I O   t h e _ A T   d i s p o s a b l e _ J J   i n c o m e _ N N 1   . _ .   
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 P r o s t a t e _ N N 1   m p M R I _ N N 2   i s _ V B Z   b e i n g _ V B G   u s e d _ V V N   n o t _ X X   o n l y _ R R   t o _ T O   l o c a l i z e _ V V I   a n d _ C C   s t a g e _ N N 1   p r o s t a t e _ N N 1   c a n c e r _ N N 1   b u t _ C C B   a l s o _ R R   t o _ T O   e s t a b l i s h _ V V I   c a n d i d a t e s _ N N 2   f o r _ I F   A S _ I I   . _ .   
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 T h r e e _ M C   p a t i e n t s _ N N 2   , _ ,   a l l _ D B   o f _ I O   w h o m _ P N Q O   h a d _ V H D   h a d _ V H N   s e i z u r e _ N N 1   a c t i v i t y _ N N 1   i n _ I I   t h e _ A T   I C U _ N N 1   b e f o r e _ I I   e n r o l l m e n t _ N N 1   i n _ I I   t h e _ A T   t r i a l _ N N 1   , _ ,   h a d _ V H D   s e i z u r e s _ N N 2   d u r i n g _ I I   a n _ A T 1   e p i s o d e _ N N 1   o f _ I O   h y p o g l y c e m i a _ N N 1   . _ .   
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 O n _ I I   t h e _ A T   b a s i s _ N N 1   o f _ I O   f o r m a l _ J J   r e v i e w _ N N 1   o f _ I O   t h e _ A T   e m e r g i n g _ J J   l i t e r a t u r e _ N N 1   , _ ,   t h e _ A T   A C S _ N N 2   w i l l _ V M   d e t e r m i n e _ V V I   t h e _ A T   n e e d _ N N 1   t o _ T O   u p d a t e _ V V I   o n _ I I   a _ A T 1   r e g u l a r _ J J   b a s i s _ N N 1   . _ .   
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 W h i l e _ C S   t h e _ A T   r e s u l t i n g _ J J   i n c r e a s e _ N N 1   i n _ I I   E r k _ N P 1   a c t i v i t y _ N N 1   w a s _ V B D Z   m i n o r _ J J   , _ ,   i t _ P P H 1   w a s _ V B D Z   s u f f i c i e n t _ J J   t o _ T O   s i g n i f i c a n t l y _ R R   r e d u c e _ V V I   c o l o n y _ N N 1   f o r m i n g _ V V G   c a p a c i t y _ N N 1   o f _ I O   t h e _ A T   t w o _ M C   p r e - B _ J J   A L L _ D B   c a s e s _ N N 2   ( _ (   F i g u r e s _ V V Z   3 G _ N N U   a n d _ C C   3 H _ F O   ) _ )   . _ .   
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 T w o _ M C   a u t h o r s _ N N 2   ( _ (   J . R . I . _ N P 1   a n d _ C C   A . C . K . _ N P 1   ) _ )   i n d e p e n d e n t l y _ R R   u n d e r t o o k _ V V D   s t u d y _ N N 1   s e l e c t i o n _ N N 1   a n d _ C C   n o _ A T   l a n g u a g e _ N N 1   r e s t r i c t i o n s _ N N 2   w e r e _ V B D R   a p p l i e d _ V V N   . _ .   
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 N e s t e d _ J J   n e t w o r k s _ N N 2   : _ :   I n _ I I   a n y _ D D   n e t w o r k _ N N 1   a r c h i t e c t u r e _ N N 1   , _ ,   t h e r e _ E X   a r e _ V B R   t w o _ M C   k i n d s _ N N 2   o f _ I O   n e s t i n g _ N N 1   : _ :   h i e r a r c h i c a l _ J J   a n d _ C C   s i m p l e _ J J   . _ .   
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 N e u r o p a t h i c _ J J   a n i m a l s _ N N 2   r e c e i v e d _ V V N   D r p 1 _ F O   A S _ C S A   o r _ C C   M M - O D N _ N N 1   a t _ I I   d a y _ N N T 1   1 2 _ M C   t o _ I I   1 4 _ M C   a f t e r _ C S   g p 1 2 0 _ F O   . _ .   
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 T h e _ A T   r e o p e r a t i o n _ N N 1   r a t e _ N N 1   w a s _ V B D Z   s i g n i f i c a n t l y _ R R   l o w e r _ J J R   i n _ I I   b o t h _ D B 2   u n i v a r i a t e _ V V 0   a n d _ C C   m u l t i v a r i a b l e _ J J   a n a l y s i s _ N N 1   w i t h _ I W   a d j u s t a b l e _ J J   s u t u r e s _ N N 2   ( _ (   m u l t i v a r i a b l e _ J J   o d d s _ N N 2   r a t i o _ N N 1   , _ ,   O R _ C C   0 . 6 9 _ M C   , _ ,   9 5 % _ N N U   c o n f i d e n c e _ N N 1   i n t e r v a l _ N N 1   , _ ,   C I _ N P 1   , _ ,   0 . 5 2 _ M C   t o _ I I   0 . 9 1 _ M C   , _ ,   p = 0 . 0 2 _ F O   ) _ )   , _ ,   i n _ I I   y o u n g e r _ J J R   p a t i e n t s _ N N 2   ( _ (   a g e _ N N 1   1 8 _ M C   t o _ I I   3 9 _ M C   ) _ )   , _ ,   w i t h _ I W   m o n o c u l a r _ J J   d e v i a t i o n s _ N N 2   , _ ,   w i t h _ I W   u n i l a t e r a l _ J J   s u r g e r y _ N N 1   o n _ I I   t w o _ M C   h o r i z o n t a l _ J J   m u s c l e s _ N N 2   , _ ,   a n d _ C C   w i t h _ I W   s u r g e r y _ N N 1   n o t _ X X   d e f i n e d _ V V N   a s _ C S A   c o m p l e x _ J J   ( _ (   T a b l e s _ N N 2   2 _ M C   a n d _ C C   3 _ M C   ) _ )   . _ .   
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 I n _ I I   a _ A T 1   s e c o n d a r y _ J J   a n a l y s i s _ N N 1   w h i c h _ D D Q   c o u n t e d _ V V D   o n l y _ R R   h o r i z o n t a l _ J J   m u s c l e _ N N 1   s u r g e r i e s _ N N 2   a s _ C S A   r e o p e r a t i o n s _ N N 2   , _ ,   2 8 0 _ M C   p a t i e n t s _ N N 2   ( _ (   6 . 4 % _ F O   ) _ )   h a d _ V H D   a _ A T 1   r e o p e r a t i o n _ N N 1   b y _ I I   o n e _ M C 1   y e a r _ N N T 1   . _ .   
 
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 O c c l u d i n s _ N N 2   a r e _ V B R   i n t e g r a l _ J J   m e m b r a n e _ N N 1   p r o t e i n s _ N N 2   c r u c i a l _ J J   f o r _ I F   t i g h t _ J J   j u n c t i o n s _ N N 2   , _ ,   a n d _ C C   t h e _ A T   c a d h e r i n s _ N N 2   a r e _ V B R   i n v o l v e d _ J J   i n _ I I   c e l l - t o - c e l l _ J J   a d h e s i o n _ N N 1   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   c o m m u n i c a t i o n _ N N 1   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   t h e _ A T   n e e d _ N N 1   f o r _ I F   E B P _ N P 1   w a s _ V B D Z   s i g n i f i c a n t l y _ R R   r e d u c e d _ V V N   f r o m _ I I   5 2 % _ N N U   t o _ I I   2 0 % _ N N U   a n d _ C C   e v e n _ R R   m o r e _ R R R   w h e n _ C S   i n t r a t h e c a l _ J J   s a l i n e _ J J   i n f u s i o n _ N N 1   w a s _ V B D Z   a d d e d _ V V N   t o _ I I   t h e _ A T   i n t r a t h e c a l _ J J   c a t h e t e r _ N N 1   ( _ (   5 2 % - 8 % _ F O   ) _ )   . _ .   
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 C o n c l u s i o n _ N N 1   I n _ I I   c o m m u n i t y - d w e l l i n g _ J J   p e r s o n s _ N N 2   a g e d _ V V N   a t _ R R 2 1   l e a s t _ R R 2 2   7 5 _ M C   y e a r s _ N N T 2   w i t h _ I W   n o _ A T   c o m o r b i d _ J J   d e p r e s s i v e _ N N 1   s y m p t o m s _ N N 2   o r _ C C   c o g n i t i v e _ J J   i m p a i r m e n t _ N N 1   , _ ,   a p a t h y _ N N 1   a s _ I I   a _ A T 1   s y n d r o m e _ N N 1   i n _ I I   i t s _ A P P G E   o w n _ D A   r i g h t _ N N 1   f r e q u e n t l y _ R R   o c c u r r e d _ V V D   i n _ R P   o v e r _ R G   7 % _ N N U   . _ .   
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 T h e _ A T   m a t r i x _ N N 1   s i z e _ N N 1   w a s _ V B D Z   1 0 4 _ M C   x _ Z Z 1   1 0 6 _ M C   a f t e r _ I I   z e r o - f i l l i n g _ N N 1   a n d _ C C   S E N S E _ N N 1   r e c o n s t r u c t i o n _ N N 1   , _ ,   r e s u l t i n g _ V V G   i n _ I I   r e c o n s t r u c t e d _ J J   i m a g e _ N N 1   s i z e _ N N 1   o f _ I O   2 2 4 _ M C   x _ Z Z 1   2 2 4 _ M C   p i x e l s _ N N 2   w i t h _ I W   p i x e l _ N N 1   s i z e _ N N 1   o f _ I O   1 . 6 5 _ M C   x _ Z Z 1   1 . 6 5 _ M C   m m 2 _ F O   . _ .   
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 T o _ T O   i n v e s t i g a t e _ V V I   t h e _ A T   m e c h a n i s m _ N N 1   o f _ I O   a c t i o n _ N N 1   , _ ,   C D 4 + _ F O   T _ Z Z 1   c e l l s _ N N 2   w e r e _ V B D R   c o i n c u b a t e d _ V V N   w i t h _ I W   C D 1 9 + - C D 2 4 h i C D 3 8 h i _ F O   B _ Z Z 1   c e l l s _ N N 2   , _ ,   i n _ I I   t h e _ A T   p r e s e n c e _ N N 1   o f _ I O   h u m a n _ N N 1   I L - 1 0 _ M C   n e u t r a l i z i n g _ N N 1   a n t i b o d y _ N N 1   ( _ (   I L - 1 0 _ M C   m A b _ N N 1   ) _ )   o r _ C C   i s o t y p e _ V V 0   c o n t r o l _ N N 1   ( _ (   F i g . _ N N 1   4 a _ F O   ) _ )   . _ .   
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 E x a c t _ J J   n u m b e r s _ N N 2   a r e _ V B R   9 7 1 _ M C   p r e - r a d i o t h e r a p y _ J J   p l u s _ I I   8 5 _ M C   b a s e l i n e _ N N 1   f o r _ I F   o v e r a l l _ J J   b o w e l _ N N 1   b o t h e r _ V V 0   ; _ ;   9 6 9 _ M C   p l u s _ I I   8 4 _ M C   f o r _ I F   o v e r a l l _ J J   u r i n a r y _ J J   b o t h e r _ N N 1   ( _ (   p e r _ I I   t r e a t m e n t _ N N 1   g r o u p _ N N 1   s h o w n _ V V N   i n _ I I   a p p e n d i x _ N N 1   p _ Z Z 1   1 4 _ M C   ) _ )   . _ .   
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 O u r _ A P P G E   r e s u l t s _ N N 2   a d d _ V V 0   t o _ I I   t h e _ A T   g r o w i n g _ J J   b o d y _ N N 1   o f _ I O   e v i d e n c e _ N N 1   t h a t _ C S T   a c u t e _ J J   i n j u r i e s _ N N 2   i n _ I I   o l d e r _ J J R   a d u l t s _ N N 2   c a n _ V M   h a v e _ V H I   a _ A T 1   s u b s t a n t i a l _ J J   n e g a t i v e _ J J   e f f e c t _ N N 1   o n _ I I   i m p o r t a n t _ J J   l o n g t e r m _ J J   p a i n _ N N 1   a n d _ C C   h e a l t h _ N N 1   o u t c o m e s _ N N 2   a n d _ C C   e x t e n d _ V V 0   t h e s e _ D D 2   f i n d i n g s _ N N 2   t o _ I I   a _ A T 1   p o p u l a t i o n _ N N 1   o f _ I O   i n d e p e n d e n t l y _ R R   l i v i n g _ V V G   o l d e r _ J J R   a d u l t s _ N N 2   w h o m _ P N Q O   m o s t _ D A T   c l i n i c i a n s _ N N 2   w o u l d _ V M   r e g a r d _ V V I   a s _ C S A   l a c k i n g _ V V G   i n j u r i e s _ N N 2   l i k e l y _ J J   t o _ T O   h a v e _ V H I   l o n g - t e r m _ J J   c o n s e q u e n c e s _ N N 2   . _ .   
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 I n _ I I 3 1   t e r m s _ I I 3 2   o f _ I I 3 3   s u p e r v i s i o n _ N N 1   a n d _ C C   a u t o n o m y _ N N 1   , _ ,   w e _ P P I S 2   e x c l u d e d _ V V D   r e s p o n d e n t s _ N N 2   w h o _ P N Q S   g r a d u a t e d _ V V D   m o r e _ D A R   t h a n _ C S N   1 0 _ M C   y e a r s _ N N T 2   a g o _ R A   ( _ (   w h e n _ C S   m o s t _ D A T   p r o g r a m s _ N N 2   w e r e _ V B D R   n o t _ X X   a c c r e d i t e d _ V V N   a n d _ C C   t r a i n i n g _ N N 1   w a s _ V B D Z   i n h e r e n t l y _ R R   d i f f e r e n t _ J J   ) _ )   . _ .   
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 H E K _ V V 0   c e l l s _ N N 2   w e r e _ V B D R   t h e n _ R T   i m m u n o l a b e l e d _ V V N   w i t h _ I W   a n _ A T 1   A l e x a _ N P 1   F l u o r _ N P 1   5 9 4 _ M C   s e c o n d a r y _ J J   a n t i b o d y _ N N 1   a g a i n s t _ I I   h u m a n _ J J   I g G _ N N 1   ( _ (   1 : 1 , 0 0 0 _ M C   ) _ )   . _ .   
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 T h e _ A T   m e t h o d _ N N 1   r o b u s t n e s s _ N N 1   a n d _ C C   s p e c i f i c i t y _ N N 1   w a s _ V B D Z   t e s t e d _ V V N   i n _ I I   m o r e _ D A R   t h a n _ C S N   t h r e e - h u n d r e d _ M C   s a m p l e s _ N N 2   o v e r _ R G   t w o _ M C   y e a r s _ N N T 2   : _ :   i n v a l i d _ J J   I R _ N N 1   o r _ C C   a l t e r e d _ J J   p e a k _ N N 1   s h a p e _ N N 1   w e r e _ V B D R   o b s e r v e d _ V V N   i n _ I I   l e s s _ D A R   t h a n _ C S N   5 % _ N N U   o f _ I O   t h e _ A T   s a m p l e s _ N N 2   . _ .   
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 I n c r e a s i n g _ J J   u r g e _ N N 1   w a s _ V B D Z   a s s o c i a t e d _ V V N   w i t h _ I W   g r e a t e r _ J J R   u r g e n c y _ N N 1   i n c o n t i n e n t _ J J   p a r t i c i p a n t _ N N 1   t h a n _ C S N   c o n t r o l _ N N 1   a c t i v a t i o n _ N N 1   o f _ I O   t h e _ A T   i n t e r o c e p t i v e _ J J   n e t w o r k _ N N 1   a n d _ C C   a c t i v a t i o n _ N N 1   i n _ I I   n e t w o r k s _ N N 2   t h a t _ C S T   a r e _ V B R   d e t e r m i n a n t s _ N N 2   o f _ I O   s e l f - a w a r e n e s s _ N N 1   ( _ (   d e f a u l t _ N N 1   m o d e _ N N 1   n e t w o r k _ N N 1   ) _ )   a n d _ C C   o f _ I O   r e s p o n s e _ N N 1   t o _ I I   u n e x p e c t e d _ J J   e x t e r n a l _ J J   s t i m u l i _ N N 2   ( _ (   v e n t r a l _ J J   a t t e n t i o n _ N N 1   n e t w o r k _ N N 1   ) _ )   . _ .   
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 A _ A T 1   c o n c e r n _ N N 1   w i t h _ I W   p r o v i d i n g _ V V G   R F N _ N P 1   t h e r a p y _ N N 1   t o _ I I   p a t i e n t s _ N N 2   w i t h _ I W   p e d i c l e _ N N 1   s c r e w _ N N 1   h a r d w a r e _ N N 1   i s _ V B Z   t h e _ A T   p o t e n t i a l _ N N 1   f o r _ I F   h e a t _ N N 1   t r a n s m i s s i o n _ N N 1   f r o m _ I I   t h e _ A T   r a d i o f r e q u e n c y _ N N 1   ( _ (   R F _ N P 1   ) _ )   p r o b e _ V V 0   t h r o u g h _ I I   t h e _ A T   p e d i c l e _ N N 1   s c r e w _ N N 1   t o _ I I   t h e _ A T   s u r r o u n d i n g _ J J   b o n y _ J J   o r _ C C   s o f t _ J J   t i s s u e s _ N N 2   . _ .   
 
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 F o r _ R E X 2 1   e x a m p l e _ R E X 2 2   , _ ,   i f _ C S   a n _ A T 1   e l e c t i v e _ J J   s u r g i c a l _ J J   p r o c e d u r e _ N N 1   i s _ V B Z   p l a n n e d _ V V N   ( _ (   e . g . _ R E X   d i a g n o s t i c _ J J   k n e e _ N N 1   a r t h r o s c o p y _ N N 1   ) _ )   , _ ,   t h e _ A T   p r e s e n c e _ N N 1   o f _ I O   s o l i d _ J J   f o o d _ N N 1   i n _ I I   t h e _ A T   s t o m a c h _ N N 1   w i l l _ V M   l i k e l y _ R R   r e s u l t _ V V I   i n _ I I   d e f e r r a l _ N N 1   o f _ I O   t h e _ A T   s u r g i c a l _ J J   t i m i n g _ N N 1   . _ .   
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 O n _ I I   t h e _ A T   o t h e r _ J J   h a n d _ N N 1   , _ ,   a n _ A T 1   u n h e a l t h y _ J J   a g i n g _ J J   c o u r s e _ N N 1   i s _ V B Z   a s s o c i a t e d _ V V N   w i t h _ I W   s e v e r a l _ D A 2   c o m o r b i d _ J J   d i s e a s e s _ N N 2   , _ ,   d i m i n i s h e d _ V V D   q u a l i t y _ N N 1   o f _ I O   l i f e _ N N 1   , _ ,   a n d _ C C   i n c r e a s e d _ J J   m o r t a l i t y _ N N 1   r i s k _ N N 1   ( _ (   S o d e r g r e n _ N P 1   , _ ,   2 0 1 3 _ M C   ) _ )   . _ .   
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 H e _ P P H S 1   p r e s e n t e d _ V V D   t o _ I I   d e r m a t o l o g i s t s _ N N 2   a t _ I I   1 _ M C 1   y e a r _ N N T 1   o f _ I O   a g e _ N N 1   w i t h _ I W   u l c e r a t i n g _ V V G   l e s i o n s _ N N 2   o f _ I O   t h e _ A T   e a r _ N N 1   h e l i c e s _ N N 2   , _ ,   w h i c h _ D D Q   w e r e _ V B D R   e x a c e r b a t e d _ V V N   b y _ I I   c o l d _ J J   a n d _ C C   h e a l e d _ V V N   w i t h _ I W   s c a r r i n g _ V V G   . _ .   
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 T h u s _ R R   , _ ,   i n v e s t i g a t o r s _ N N 2   h a v e _ V H 0   b e e n _ V B N   s e e k i n g _ V V G   a l t e r n a t i v e s _ N N 2   f o r _ I F   t h e _ A T   n o n - i n v a s i v e _ J J   p r e n a t a l _ J J   d e t e c t i o n _ N N 1   o f _ I O   a n e u p l o i d y _ N N 1   . _ .   
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 H y p o x i a _ N P 1   o c c u r r e d _ V V D   i n _ I I   4 0 . 2 _ M C   p e r _ I I   1 , 0 0 0 _ M C   s e d a t i o n s _ N N 2   ( _ (   9 5 % _ N N U   C I _ F O   = _ F O   3 2 . 5 _ M C   t o _ I I   4 7 . 9 _ M C   ) _ )   ; _ ;   v o m i t i n g _ V V G   , _ ,   1 6 . 4 _ M C   p e r _ I I   1 , 0 0 0 _ M C   s e d a t i o n s _ N N 2   ( _ (   9 5 % _ N N U   C I _ F O   = _ F O   9 . 7 _ M C   t o _ I I   2 3 . 0 _ M C   ) _ )   ; _ ;   h y p o t e n s i o n _ N N 1   , _ ,   1 5 . 2 _ M C   p e r _ I I   1 , 0 0 0 _ M C   s e d a t i o n s _ N N 2   ( _ (   9 5 % _ N N U   C I _ F O   = _ F O   1 0 . 7 _ M C   t o _ I I   1 9 . 7 _ M C   ) _ )   ; _ ;   a n d _ C C   a p n e a _ N N 1   1 2 . 4 _ M C   p e r _ I I   1 , 0 0 0 _ M C   ( _ (   9 5 % _ N N U   C I _ F O   = _ F O   7 . 9 _ M C   t o _ I I   1 6 . 9 _ M C   ) _ )   . _ .   
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 M e t h y l a t i o n _ N N 1   o f _ I O   l y s i n e _ N N 1   2 7 _ M C   o n _ I I   h i s t o n e _ N N 1   H 3 _ F O   ( _ (   H 3 K 2 7 m e 3 _ F O   ) _ )   b y _ I I   E Z H 2 _ F O   i m p o s e s _ V V Z   g e n e _ N N 1   s i l e n c i n g _ V V G   i n _ R R 2 1   p a r t _ R R 2 2   b y _ I I   t r i g g e r i n g _ V V G   r e c r u i t m e n t _ N N 1   o f _ I O   P R C 1 _ N P 1   ( _ (   C a o _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 2 _ M C   ; _ ;   M i n _ N N U   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 3 _ M C   ) _ )   a n d _ C C   h i s t o n e _ N N 1   d e a c e t y l a s e s _ N N 2   ( _ (   H D A C s _ N P 2   ) _ )   . _ .   
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 B a s e d _ V V N   o n _ I I   t h e _ A T   a b s e n c e _ N N 1   i n _ I I   c o n t r o l s _ N N 2   , _ ,   t h e _ A T   c o n s e r v a t i o n _ N N 1   o f _ I O   H 5 0 _ F O   , _ ,   a n d _ C C   t h e _ A T   p r e d i c t e d _ J J   a n d _ C C   o b s e r v e d _ V V D   f u n c t i o n a l _ J J   e f f e c t s _ N N 2   a f f e c t i n g _ V V G   c o p p e r _ N N 1   c o o r d i n a t i o n _ N N 1   , _ ,   p . H 5 0 Q _ F O   w a s _ V B D Z   r e g a r d e d _ V V N   a s _ I I   a _ A T 1   p a t h o g e n i c _ J J   m u t a t i o n _ N N 1   . _ .   
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 D a t a _ N N   w e r e _ V B D R   e x p r e s s e d _ V V N   a s _ C S A   m e a n s _ V V Z   p l u s _ I I   a n d _ C C   m i n u s _ I I   S D _ N P 1   u n l e s s _ C S   o t h e r w i s e _ R R   s p e c i f i e d _ V V N   . _ .   
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 I n _ I I   t h e s e _ D D 2   p a t i e n t s _ N N 2   , _ ,   a l t h o u g h _ C S   o v e r a l l _ J J   i m p r o v e m e n t _ N N 1   i n _ I I   B C V A _ N P 1   w a s _ V B D Z   o b s e r v e d _ V V N   a t _ I I   m o n t h _ N N T 1   1 2 _ M C   , _ ,   t h e _ A T   g a i n _ N N 1   w a s _ V B D Z   s i g n i f i c a n t l y _ R R   l o w e r _ J J R   t h a n _ C S N   t h a t _ D D 1   o b s e r v e d _ V V D   i n _ I I   p a t i e n t s _ N N 2   r e c e i v i n g _ V V G   r a n i - b i z u m a b _ N N 1   t h r o u g h o u t _ I I   t h e _ A T   s t u d y . 1 0 _ F O   A _ Z Z 1   V A _ F W   l o s s _ N N 1   o f _ I O   1 5 _ M C   l e t t e r s _ N N 2   o r _ C C   m o r e _ R R R   a t _ I I   m o n t h _ N N T 1   1 2 _ M C   w a s _ V B D Z   r e p o r t e d _ V V N   i n _ I I   a _ A T 1   h i g h e r _ J J R   p e r c e n t a g e _ N N 1   ( _ (   5 . 9 % _ F O   ) _ )   o f _ I O   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   C R Y S T A L _ N N 1   s t u d y _ N N 1   t h a n _ C S N   i n _ I I   t h e _ A T   C R U I S E _ N N 1   s t u d y _ N N 1   ( _ (   2 . 3 % _ F O   ) _ )   , _ ,   1 0 _ M C   p o s s i b l y _ R R   r e l a t e d _ V V N   t o _ I I   t h e _ A T   d i f f e r e n c e s _ N N 2   i n _ I I   t h e _ A T   p a t i e n t _ J J   p o p u l a t i o n _ N N 1   . _ .   
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 D a t a _ N N   A n a l y s i s _ N N 1   D a t a _ N N   w e r e _ V B D R   c o l l e c t e d _ V V N   b y _ I I   a _ A T 1   t r a i n e d _ J J   r e s e a r c h _ N N 1   a s s o c i a t e _ N N 1   a n d _ C C   t h e n _ R T   e n t e r e d _ V V N   i n t o _ I I   a _ A T 1   M i c r o s o f t _ N P 1   E x c e l _ V V 0   d a t a b a s e _ N N 1   . _ .   
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 K e y _ J J   W o r d s _ N N 2   : _ :   E c o l o g i c a l _ J J   M o m e n t a r y _ J J   A s s e s s m e n t _ N N 1   , _ ,   p h y s i c a l _ J J   a c t i v i t y _ N N 1   , _ ,   s e d e n t a r y _ J J   b e h a v i o r _ N N 1   , _ ,   m e t h o d s _ N N 2   , _ ,   h e a l t h _ N N 1   b e h a v i o r _ N N 1   t h e o r y _ N N 1   , _ ,   i n t r a i n d i v i d u a l _ J J   v a r i a b i l i t y _ N N 1   , _ ,   m u l t i l e v e l _ V V 0   m o d e l i n g _ V V G   I N T R O D U C T I O N _ N N 1   P h y s i c a l _ J J   a c t i v i t y _ N N 1   r e d u c e s _ V V Z   r i s k s _ N N 2   o f _ I O   m a n y _ D A 2   s e r i o u s _ J J   h e a l t h _ N N 1   c o n d i t i o n s _ N N 2   , _ ,   i n c l u d i n g _ I I   c o r o n a r y _ J J   h e a r t _ N N 1   d i s e a s e _ N N 1   , _ ,   t y p e _ N N 1   2 _ M C   d i a b e t e s _ N N 1   , _ ,   a n d _ C C   b r e a s t _ N N 1   a n d _ C C   c o l o n _ N N 1   c a n c e r s _ N N 2   ( _ (   2 0 _ M C   ) _ )   . _ .   
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 T h e _ A T   e f f i c i e n t _ J J   t r a n s f e r _ N N 1   o f _ I O   t h e s e _ D D 2   t h r e e _ M C   i t e m s _ N N 2   r e p r e s e n t s _ V V Z   o n e _ M C 1   o f _ I O   t h e _ A T   m a j o r _ J J   h u r d l e s _ N N 2   t o _ T O   o v e r c o m e _ V V I   i n _ R P   i n _ R R 2 1   v i v o _ R R 2 2   r e t i n a l _ J J   g e n o m e _ N N 1   e d i t i n g _ N N 1   ' _ N U L L   a n d _ C C   t h e _ A T   c h o i c e _ N N 1   o f _ I O   a n _ A T 1   o p t i m a l _ J J   v e c t o r _ N N 1   s y s t e m _ N N 1   i s _ V B Z   c r u c i a l _ J J   . _ .   
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 T h e _ A T   e t h n i c _ J J   d i s p a r i t y _ N N 1   i n _ I I   g a s t r i c _ J J   c a n c e r _ N N 1   i s _ V B Z   d r i v e n _ V V N   w h o l l y _ R R   b y _ I I   d i s t a l _ J J   t u m o r s _ N N 2   , _ ,   f o r _ I F   w h i c h _ D D Q   t h e _ A T   i n c i d e n c e _ N N 1   r a t e _ N N 1   i s _ V B Z   6 . 2 _ M C   ( _ (   p e r _ I I   1 0 0 , 0 0 0 _ M C   p o p u l a t i o n _ N N 1   ) _ )   i n _ I I   H i s - p a n i c s _ N N 2   c o m p a r e d _ V V N   w i t h _ I W   2 . 2 _ M C   i n _ I I   N H W s . 1 0 _ F O   I n d e e d _ R R   , _ ,   t h e _ A T   r a t e _ N N 1   f o r _ I F   p r o x i m a l _ J J   t u m o r s _ N N 2   i s _ V B Z   l o w e r _ J J R   i n _ I I   H i s p a n i c s _ N P 1   ( _ (   1 . 5 _ M C   p e r _ I I   1 0 0 , 0 0 0 _ M C   p o p u l a t i o n _ N N 1   ) _ )   t h a n _ C S N   i n _ I I   N H W s _ N P 1   ( _ (   2 . 2 _ M C   ) _ )   . _ .   
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 I n t e r e s t i n g l y _ R R   , _ ,   c o n d i t i o n a l _ J J   k n o c k o u t _ N N 1   s t u d i e s _ N N 2   s u g g e s t _ V V 0   t h a t _ C S T   V E G F R 2 _ F O   s i g n a l l i n g _ V V G   i n _ I I   R G C s _ N P 1   i s _ V B Z   n o t _ X X   r e q u i r e d _ V V N   f o r _ I F   r e t i n a l _ J J   m o r p h o g e n e s i s _ N N 1   ( _ (   O k a b e _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 4 _ M C   ) _ )   , _ ,   w h i l e _ C S   V E G F R 2 _ F O   i s _ V B Z   i n s t e a d _ R R   r e q u i r e d _ V V N   f o r _ I F   t h e _ A T   s u r v i v a l _ N N 1   o f _ I O   M u l l e r _ N P 1   g l i a _ N N 1   , _ ,   w h i c h _ D D Q   a r e _ V B R   i n _ I I   t u r n _ N N 1   e s s e n t i a l _ J J   f o r _ I F   t h e _ A T   v i a b i l i t y _ N N 1   o f _ I O   a d u l t _ J J   r e t i n a l _ J J   n e u r o n s _ N N 2   i n _ I I   a _ A T 1   m o d e l _ N N 1   o f _ I O   d i a b e t i c _ J J   r e t i n o p a t h y _ N N 1   ( _ (   F u _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 T h e _ A T   d i s t r i b u t i o n _ N N 1   o f _ I O   t h e _ A T   a s s i g n e d _ J J   P I - R A D S _ N N 2   V 2 _ F O   c a t e g o r i e s _ N N 2   w a s _ V B D Z   c o m p u t e d _ V V N   , _ ,   a s _ C S A   w e r e _ V B D R   t h e _ A T   f r e q u e n c y _ N N 1   o f _ I O   t u m o r s _ N N 2   a n d _ C C   o f _ I O   G S _ N P 1   g r e a t e r _ J J R   t h a n _ C S N   a n d _ C C   e q u a l _ J J   t o _ I I   7 _ M C   t u m o r s _ N N 2   f o r _ I F   e a c h _ D D 1   c a t e g o r y _ N N 1   , _ ,   o v e r a l l _ J J   a n d _ C C   s e p a r a t e l y _ R R   i n _ I I   t h e _ A T   P Z _ N P 1   a n d _ C C   T Z _ N P 1   . _ .   
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 M o r e o v e r _ R R   , _ ,   s i r o l i m u s _ N N 1   a p p e a r s _ V V Z   t o _ T O   e n h a n c e _ V V I   T _ Z Z 1   r e g u l a t o r y _ J J   c e l l _ N N 1   f u n c t i o n _ N N 1   i n _ I I   h u m a n s _ N N 2   , _ ,   w h i c h _ D D Q   m a y _ V M   h a v e _ V H I   b o t h _ D B 2   b e n e f i c i a l _ J J   a n d _ C C   h a r m f u l _ J J   e f f e c t s _ N N 2   o n _ I I   i m m u n e _ J J   f u n c t i o n _ N N 1   . _ .   
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 D e s p i t e _ I I   s u b s t a n t i a l _ J J   i m p r o v e m e n t _ N N 1   o f _ I O   i m m u n o s u p p r e s s i v e _ J J   t h e r a p y _ N N 1   , _ ,   d e l a y e d _ V V D   g r a f t _ N N 1   f u n c t i o n _ N N 1   a n d _ C C   a l l o g r a f t _ V V 0   r e j e c t i o n _ N N 1   r e m a i n _ V V 0   m a j o r _ J J   p r o b l e m s _ N N 2   l i m i t i n g _ V V G   l o n g - t e r m _ J J   g r a f t _ N N 1   f u n c t i o n _ N N 1   a n d _ C C   g r a f t _ V V 0   s u r v i v a l _ N N 1   . _ .   
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 D i s c u s s i o n _ N N 1   I n _ I I   t h e _ A T   A R T e m i s _ N P 1   s t u d y _ N N 1   , _ ,   t h e _ A T   a d d i t i o n _ N N 1   o f _ I O   s h o r t _ J J   c o u r s e _ N N 1   b e v a c i z u m a b _ N N 1   t o _ I I   s t a n d a r d _ J J   n e o a d j u v a n t _ J J   a n t h r a c y c l i n e _ N N 1   a n d _ C C   t a x a n e - b a s e d _ J J   c h e m o t h e r a p y _ N N 1   i n _ I I   H E R 2 - n e g a t i v e _ J J   , _ ,   e a r l y _ J J   b r e a s t _ N N 1   c a n c e r _ N N 1   , _ ,   w a s _ V B D Z   a s s o c i a t e d _ V V N   w i t h _ I W   a _ A T 1   s i g n i f i c a n t _ J J   i m p r o v e m e n t _ N N 1   i n _ I I   t h e _ A T   p r o p o r t i o n _ N N 1   o f _ I O   p a t i e n t s _ N N 2   a c h i e v i n g _ V V G   a _ A T 1   p a t h o l o g i c a l _ J J   c o m p l e t e _ J J   r e s p o n s e _ N N 1   . _ .   
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 T o _ I I   o u r _ A P P G E   k n o w l e d g e _ N N 1   t h e _ A T   i m p a c t _ N N 1   o f _ I O   E M _ F U   r e s i d e n t s _ N N 2   o n _ I I   a t t e n d i n g _ V V G   p h y s i c i a n s _ N N 2   ' _ N U L L   a b i l i t y _ N N 1   t o _ T O   p r o d u c e _ V V I   a n d _ C C   b i l l _ N N 1   f o r _ I F   R V U s _ N P 1   h a s _ V H Z   n o t _ X X   y e t _ R R   b e e n _ V B N   s t u d i e d _ V V N   . _ .   
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 P o s t o p e r a t i v e _ J J   r a d i o t h e r a p y _ N N 1   s e e m s _ V V Z   t o _ T O   s i g n i f i c a n t l y _ R R   i m p r o v e _ V V I   l o c a l _ J J   c o n t r o l _ N N 1   . _ .   
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 N o _ A T   d i f f e r e n c e s _ N N 2   b e t w e e n _ I I   t h e _ A T   t w o _ M C   m a r g i n _ N N 1   w i d t h s _ N N 2   w e r e _ V B D R   n o t e d _ V V N   r e g a r d i n g _ I I   t h e _ A T   c u m u l a t i v e _ J J   i n c i d e n c e _ N N 1   o f _ I O   d e a t h _ N N 1   d u e _ I I 2 1   t o _ I I 2 2   o t h e r _ J J   c a u s e s _ N N 2   ( _ (   f i g u r e _ N N 1   4 _ M C   ; _ ;   p o i n t _ N N 1   e s t i m a t e s _ N N 2   o f _ I O   c u m u l a t i v e _ J J   i n c i d e n c e _ N N 1   a t _ I I   8 . 8 _ M C   y e a r s _ N N T 2   w e r e _ V B D R   1 4 . 5 % _ F O   & l s q b ; _ (   9 5 % _ N N U   C I _ N N 1   1 0 . 1 - 2 0 . 6 _ M C M C   & r s q b ; _ )   i n _ I I   t h e _ A T   1 _ M C 1   c m _ N N U   m a r g i n _ N N 1   g r o u p _ N N 1   , _ ,   1 8 . 2 % _ F O   & l s q b ; _ (   1 3 . 6 - 2 4 . 0 _ M C M C   & r s q b ; _ )   i n _ I I   t h e _ A T   3 _ M C   c m _ N N U   g r o u p _ N N 1   ) _ )   . _ .   
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 I n _ I I   u n a d j u s t e d _ J J   a n a l y s i s _ N N 1   , _ ,   R R S _ N P 2   i m p l e m e n t a t i o n _ N N 1   w a s _ V B D Z   a s s o c i a t e d _ V V N   w i t h _ I W   a _ A T 1   r e d u c t i o n _ N N 1   i n _ I I   t h e _ A T   p r o p o r t i o n _ N N 1   o f _ I O   u n p l a n n e d _ J J   t r a n s f e r s _ N N 2   r e q u i r i n g _ V V G   v a s o p r e s s o r s _ N N 2   i n _ I I   t h e _ A T   f i r s t _ M D   1 _ M C 1   h o u r _ N N T 1   f o l l o w i n g _ V V G   t r a n s f e r _ N N 1   b u t _ C C B   n o t _ X X   i n _ I I   t h e _ A T   f i r s t _ M D   1 2 _ M C   h o u r s _ N N T 2   ( _ (   T a b l e _ N N 1   2 _ M C   ) _ )   . _ .   
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 T h e _ A T   D N A _ N N 1   h y p o m e t h y l a t i o n _ N N 1   o f _ I O   t h e _ A T   s i g n a t u r e _ N N 1   s e t _ N N 1   i d e n t i f i e d _ V V N   i n _ I I   S C L C _ N P 1   l i n e s _ N N 2   c o r r e c t l y _ R R   p r e d i c t e d _ V V N   s e n s i t i v i t y _ N N 1   t o _ I I   L S D 1 _ F O   i n h i b i t i o n _ N N 1   i n _ I I   p r i m a r y _ J J   S C L C _ N P 1   , _ ,   f u r t h e r _ R R R   s t r e n g t h e n i n g _ V V G   t h e _ A T   r a t i o n a l e _ N N 1   f o r _ I F   c l i n i c a l _ J J   a p p l i c a t i o n _ N N 1   t o _ T O   i d e n t i f y _ V V I   S C L C _ N P 1   p a t i e n t s _ N N 2   m o s t _ R G T   l i k e l y _ J J   t o _ T O   r e s p o n d _ V V I   t o _ I I   G S K 2 8 7 9 5 5 2 _ F O   t r e a t m e n t _ N N 1   . _ .   
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 e p i n e p h r i n e _ N N 1   i n _ I I   t h e _ A T   d o s e _ N N 1   r a n g e _ N N 1   u s e d _ V V N   i n _ I I   t h e _ A T   p r e s e n t _ J J   i n v e s t i g a t i o n _ N N 1   a u g m e n t s _ V V Z   C O _ F O   d u r i n g _ I I   H E A _ N P 1   . _ .   
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 I n _ I I   t h i s _ D D 1   i n s t a n c e _ N N 1   ' _ N U L L   d i r e c t _ J J   a c t i v a t i o n _ N N 1   o f _ I O   t h e _ A T   g p 1 3 0 _ F O   r e c e p t o r _ N N 1   s u b u n i t _ N N 1   w o u l d _ V M   b e _ V B I   f a v o u r a b l e _ J J   a n d _ C C   t h e _ A T   d e s i g n e r _ N N 1   h I L - 6 _ M C   ' _ N U L L   t h a t _ C S T   c o n s i s t s _ V V Z   o f _ I O   t h e _ A T   c o v a l e n t l y _ R R   l i n k e d _ V V N   b i o a c t i v e _ J J   p a r t s _ N N 2   o f _ I O   I L - 6 _ M C   a n d _ C C   s o l u b l e _ J J   I L - 6 a _ F O   ' _ N U L L   d o e s _ V D Z   e x a c t l y _ R R   t h i s _ D D 1   ( _ (   P e t e r s _ V V Z   e t _ R A 2 1   a l _ R A 2 2   . _ .   ' _ N U L L   
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 S i m i l a r _ J J   t o _ I I   t h e _ A T   g e n e t i c _ J J   s t u d y _ N N 1   , _ ,   w e _ P P I S 2   o b s e r v e d _ V V D   t h a t _ C S T   3 x T g _ F O   m i c e _ N N 2   r e c e i v i n g _ V V G   t h e _ A T   a c t i v e _ J J   d r u g _ N N 1   h a d _ V H D   a _ A T 1   s i g n i f i c a n t _ J J   a m e l i o r a t i o n _ N N 1   o f _ I O   t h e i r _ A P P G E   w o r k i n g _ J J   m e m o r y _ N N 1   a n d _ C C   c o n d i t i o n i n g _ J J   l e a r n i n g _ N N 1   . _ .   
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 A p p l i c a t i o n _ N N 1   o f _ I O   A M H _ N P 1   m e a s u r e m e n t _ N N 1   o n t o _ I I   a n _ A T 1   a u t o m a t e d _ J J   i m m u n o a s s a y _ N N 1   p l a t f o r m _ N N 1   i s _ V B Z   a _ A T 1   m a j o r _ J J   s t e p _ N N 1   f o r w a r d _ R L   t o _ T O   a l l o w _ V V I   r a p i d _ J J   a c c e s s _ N N 1   o f _ I O   a n _ A T 1   A M H _ N N 1   a s s a y _ N N 1   t o _ I I   h e a l t h _ N N 1   c a r e _ N N 1   p r o v i d e r s _ N N 2   a n d _ C C   a d o p t i n g _ V V G   i t s _ A P P G E   m e a s u r e m e n t _ N N 1   i n t o _ I I   d a i l y _ J J   c l i n i c a l _ J J   p r a c t i c e _ N N 1   . _ .   
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 S t e p h e n _ N P 1   C _ N P 1   P f l u g f e l d e r _ N P 1   h a s _ V H Z   t h e _ A T   f o l l o w i n g _ J J   f i n a n c i a l _ J J   d i s c l o s u r e s _ N N 2   : _ :   C o n s u l t i n g _ J J   a n d _ C C   r e s e a r c h _ N N 1   f u n d i n g _ N N 1   f r o m _ I I   A l l e r g a n _ N P 1   , _ ,   a n d _ C C   r e s e a r c h _ N N 1   f u n d i n g _ N N 1   f r o m _ I I   B a u s c h _ N P 1   a n d _ C C   L o m b _ N P 1   . _ .   
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 A f t e r _ C S   e m e r g e n c e _ N N 1   , _ ,   1 9 % _ N N U   o f _ I O   t h e _ A T   p a t i e n t s _ N N 2   ( _ (   1 0 / 5 3 _ M F   ) _ )   c o m p l a i n e d _ V V D   o f _ I O   m o d e r a t e _ J J   p a i n _ N N 1   a t _ I I   t h e _ A T   s i t e _ N N 1   o f _ I O   s k i n _ N N 1   i n c i s i o n _ N N 1   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   t h e _ A T   a v e r a g e _ J J   c e l l _ N N 1   d i a m e t e r _ N N 1   i n _ I I   t h e _ A T   c o n t r o l _ N N 1   o b t a i n e d _ V V N   i n _ I I   o u r _ A P P G E   s t u d y _ N N 1   , _ ,   1 1 . 8 _ M C   p m _ R A   , _ ,   i s _ V B Z   w i t h i n _ I I   t h e _ A T   r e p o r t e d _ J J   r a n g e _ N N 1   o f _ I O   1 0 - 1 2 _ M C M C   p m _ R A   , _ ,   1 8 - 2 1 _ M C M C   a n d _ C C   t h e _ A T   b a s a l _ J J   c e l l _ N N 1   d e n s i t y _ N N 1   o f _ I O   t h e _ A T   l i m b u s _ N N 1   i n _ I I   o u r _ A P P G E   n o r m a l _ J J   c o n t r o l _ N N 1   i s _ V B Z   a l s o _ R R   c o m p a r a b l e _ J J   t o _ I I   t h o s e _ D D 2   p r e v i o u s l y _ R R   p u b l i s h e d _ V V N   . _ .   
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 T w o _ M C   m a i n _ J J   D E C T _ N N 1   i m p l e m e n t a t i o n s _ N N 2   a r e _ V B R   c u r r e n t l y _ R R   a v a i l a b l e _ J J   c o m m e r c i a l l y _ R R   , _ ,   r a p i d _ J J   k V p - s w i t c h i n g _ J J   C T _ N N 1   ( _ (   R S C T _ N P 1   ) _ )   , _ ,   w h e r e _ C S   a _ A T 1   s i n g l e _ J J   x - r a y _ J J   s o u r c e _ N N 1   a l t e r n a t e l y _ R R   p u l s e s _ N N 2   b e t w e e n _ I I   l o w _ J J   a n d _ C C   h i g h _ J J   t u b e _ N N 1   p o t e n t i a l s _ N N 2   d u r i n g _ I I   a _ A T 1   s i n g l e _ J J   g a n t r y _ N N 1   r o t a t i o n _ N N 1   , _ ,   a n d _ C C   d u a l - s o u r c e _ J J   C T _ N N 1   ( _ (   D S C T _ N P 1   ) _ )   w h e r e _ R R Q   t w o _ M C   x - r a y _ J J   s o u r c e s _ N N 2   o f f s e t _ V V N   b y _ I I   9 0 _ M C   d e g r e e s _ N N 2   o p e r a t e _ V V 0   a t _ I I   d i f f e r e n t _ J J   t u b e _ N N 1   p o t e n t i a l s _ N N 2   . _ .   
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 T h e _ A T   m e t h o d _ N N 1   p r e d i c t e d _ V V D   s o m e _ D D   g e n e s _ N N 2   t h a t _ C S T   h a v e _ V H 0   b e e n _ V B N   a l r e a d y _ R R   s t u d i e d _ V V N   a n d _ C C   o t h e r s _ N N 2   l e s s _ R R R   k n o w n _ V V N   i n _ I I 3 1   r e l a t i o n _ I I 3 2   t o _ I I 3 3   P C a _ N P 1   . _ .   
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 A _ A T 1   b e n e f i c i a l _ J J   i n t e r v e n t i o n _ N N 1   f o r _ I F   a l l e v i a t i n g _ V V G   e x e r c i s e _ N N 1   i n t o l e r a n c e _ N N 1   s y m p t o m s _ N N 2   a n d _ C C   ' _ N U L L   p r o t e c t i n g _ V V G   ' _ N U L L   t h e _ A T   m u s c l e _ N N 1   f r o m _ I I   r h a b d o - m y o l y s i s _ J J   r i s k _ N N 1   c o n s i s t s _ V V Z   o f _ I O   e n s u r i n g _ V V G   t h a t _ D D 1   s u f f i c i e n t _ J J   b l o o d _ N N 1   g l u c o s e _ N N 1   ( _ (   d e r i v e d _ V V N   f r o m _ I I   h i g h _ J J   h e p a t i c _ J J   g l y c o g e n _ N N 1   s t o r e s _ N N 2   ) _ )   i s _ V B Z   c o n s t a n t l y _ R R   m a d e _ V V N   a v a i l a b l e _ J J   t o _ I I   p a t i e n t s _ N N 2   ' _ N U L L   m u s c l e s _ N N 2   d u r i n g _ I I   t h e _ A T   d a y t i m e _ N N T 1   . _ .   
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 D u r i n g _ I I   h i s _ A P P G E   i n a u g u r a l _ J J   s p e e c h _ N N 1   " _ "   M i n d _ V V 0   t h e _ A T   G a p _ N N 1   , _ ,   " _ "   D r _ N N B   S t a p l e t o n _ N P 1   s e t _ V V D   t h e _ A T   s t a g e _ N N 1   f o r _ I F   w h y _ R R Q   t h e s e _ D D 2   e f f o r t s _ N N 2   a r e _ V B R   i m p o r t a n t _ J J   a n d _ C C   t i e d _ V V N   t o _ I I   a c h i e v i n g _ V V G   e x c e l l e n c e _ N N 1   i n _ I I   a _ A T 1   c h a n g i n g _ J J   w o r l d _ N N 1   . _ .   
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 P a t i e n t s _ N N 2   w i t h _ I W   i m p a i r e d _ J J   a b i l i t y _ N N 1   t o _ T O   p e r f o r m _ V V I   a c t i v i t i e s _ N N 2   o f _ I O   d a i l y _ J J   l i v i n g _ N N 1   s h o u l d _ V M   b e _ V B I   r e f e r r e d _ V V N   t o _ I I   a _ A T 1   r e h a b i l i t a t i o n _ N N 1   s p e c i a l i s t _ N N 1   . _ .   
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 G e s t a t i o n a l _ J J   t i m i n g _ N N 1   o f _ I O   i n f e c t i o n _ N N 1   w a s _ V B D Z   u n k n o w n _ J J   f o r _ I F   2 _ M C   o f _ I O   t h e _ A T   2 6 _ M C   f e t u s e s _ N N 2   o r _ C C   i n f a n t s _ N N 2   w i t h _ I W   b i r t h _ N N 1   d e f e c t s _ N N 2   a n d _ C C   2 7 _ M C   o f _ I O   t h e _ A T   t o t a l _ J J   c o m p l e t e d _ J J   p r e g n a n c i e s _ N N 2   . _ .   
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 R e g a r d i n g _ I I   i n t r a o p e r a t i v e _ J J   d e t a i l s _ N N 2   , _ ,   d e g r e e _ N N 1   o f _ I O   w o u n d _ N N 1   c o n t a m i n a t i o n _ N N 1   a n d _ C C   l e n g t h _ N N 1   o f _ I O   f a s c i a l _ J J   i n c i s i o n _ N N 1   a r e _ V B R   t y p i c a l l y _ R R   k n o w n _ V V N   b e f o r e _ I I   s u r g e r y _ N N 1   a n d _ C C   t h e i r _ A P P G E   i n c l u s i o n _ N N 1   w o u l d _ V M   e n h a n c e _ V V I   t h e _ A T   r i s k _ N N 1   m o d e l _ N N 1   . _ .   
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 T h e _ A T   i n c r e a s e _ N N 1   w a s _ V B D Z   s t a t i s t i c a l l y _ R R   s i g n i f i c a n t l y _ R R   u n t i l _ C S   6 _ M C   m o n t h s _ N N T 2   b u t _ C C B   n o _ A T   f u r t h e r _ J J R   i n c r e a s e _ N N 1   w a s _ V B D Z   o b s e r v e d _ V V N   f r o m _ I I   6 _ M C   t o _ I I   1 2 _ M C   m o n t h s _ N N T 2   . _ .   
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 I n _ I I 3 1   l i n e _ I I 3 2   w i t h _ I I 3 3   t h i s _ D D 1   e v i d e n c e _ N N 1   , _ ,   t h e _ A T   E a s t e r n _ J J   A s s o c i a t i o n _ N N 1   f o r _ I F   t h e _ A T   S u r g e r y _ N N 1   o f _ I O   T r a u m a _ N N 1   ( _ (   E A S T _ N D 1   ) _ )   p r a c t i c e _ N N 1   m a n a g e m e n t _ N N 1   g u i d e l i n e s _ N N 2   a d v o c a t e _ V V 0   l i m i t e d _ J J   p r e h o s p i t a l _ J J   I V F _ N N 1   r e s u s c i t a t i o n . 3 2 _ F O   I n _ I I   t h e _ A T   a b s e n c e _ N N 1   o f _ I O   c o n c l u s i v e _ J J   p a t i e n t - s p e c i f i c _ J J   g u i d e l i n e s _ N N 2   , _ ,   p r e h o s p i t a l _ J J   I V F _ N N 1   a d m i n i s t r a t i o n _ N N 1   s h o u l d _ V M   n o t _ X X   b e _ V B I   a _ A T 1   j u s t i f i c a t i o n _ N N 1   f o r _ I F   d e l a y i n g _ V V G   t r a n s p o r t _ N N 1   o f _ I O   t h e _ A T   i n j u r e d _ J J   p a t i e n t _ N N 1   t o _ I I   a _ A T 1   d e f i n i t i v e _ J J   c a r e _ N N 1   f a c i l i t y _ N N 1   . _ .   
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 I n _ I I   t h e _ A T   U n i t e d _ N P 1   S t a t e s _ N P 1   a l o n e _ R R   t h e _ A T   p o p u l a t i o n _ N N 1   g r o w t h _ N N 1   o f _ I O   p e o p l e _ N N   a g e d _ V V N   a b o v e _ I I   6 5 _ M C   y e a r s _ N N T 2   w a s _ V B D Z   1 5 . 1 % _ F O   b e t w e e n _ I I   2 0 0 0 _ M C   a n d _ C C   2 0 1 0 _ M C   , _ ,   a l t h o u g h _ C S   t h e _ A T   g e n e r a l _ J J   p o p u l a t i o n _ N N 1   g r e w _ V V D   o n l y _ R R   b y _ I I   9 . 7 % _ F O   d u r i n g _ I I   t h e _ A T   s a m e _ D A   t i m e _ N N T 1   i n t e r v a l _ N N 1   ( _ (   V i g e n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 2 _ M C   ) _ )   . _ .   
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 N o t _ X X   a d j u s t i n g _ V V G   f o r _ I F   o b s t e t r i c _ J J   c o m p l i c a t i o n s _ N N 2   a m o n g _ I I   w o m e n _ N N 2   g i v i n g _ V V G   b i r t h _ N N 1   i n _ I I   f a c i l i t i e s _ N N 2   c o u l d _ V M   t h e r e f o r e _ R R   l e a d _ V V I   t o _ I I   i n c o r r e c t _ J J   c o n c l u s i o n s _ N N 2   o n _ I I   t h e _ A T   e f f e c t s _ N N 2   o f _ I O   f a c i l i t y _ N N 1   b i r t h _ N N 1   o n _ I I   n e w b o r n _ J J   m o r t a l i t y _ N N 1   . _ .   
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 F u n d i n g _ N N 1   : _ :   T h i s _ D D 1   s t u d y _ N N 1   w a s _ V B D Z   f i n a n c i a l l y _ R R   s u p p o r t e d _ V V N   b y _ I I   N a t i o n a l _ J J   H e a l t h _ N N 1   a n d _ C C   M e d i c a l _ J J   R e s e a r c h _ N N 1   C o u n c i l _ N N 1   ( _ (   p r a c t i t i o n e r _ N N 1   f e l l o w s h i p _ N N 1   1 0 8 0 5 1 8 _ M C   , _ ,   p r o j e c t _ N N 1   g r a n t s _ V V Z   1 0 8 3 5 3 9 _ M C   a n d _ C C   1 0 3 2 4 8 4 _ M C   a n d _ C C   c e n t r e _ N N 1   f o r _ I F   r e s e a r c h _ N N 1   e x c e l l e n c e _ N N 1   1 0 0 1 2 1 6 _ M C   ) _ )   , _ ,   a n d _ C C   U n i v e r s i t y _ N N 1   o f _ I O   M e l b o u r n e _ N P 1   R e s e a r c h _ N N 1   F e l l o w s h i p _ N N 1   . _ .   
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 A n o t h e r _ D D 1   s t u d y _ N N 1   , _ ,   h o w e v e r _ R R   , _ ,   u s i n g _ V V G   a _ A T 1   s l i g h t l y _ R R   y o u n g e r _ J J R   c o h o r t _ N N 1   w i t h _ I W   m e a n _ J J   a g e _ N N 1   o f _ I O   5 4 . 2 _ M C   y e a r s _ N N T 2   ( _ (   c o m p a r e d _ V V N   w i t h _ I W   6 1 _ M C   y e a r s _ N N T 2   i n _ I I   t h e _ A T   p r e v i o u s _ J J   s t u d y _ N N 1   ) _ )   f a i l e d _ V V D   t o _ T O   s h o w _ V V I   s i g n i f i c a n t _ J J   e v i d e n c e _ N N 1   f o r _ I F   a n _ A T 1   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   d u r a t i o n _ N N 1   o f _ I O   d e l i r i u m _ N N 1   a n d _ C C   c o g n i t i v e _ J J   d e c l i n e _ N N 1   . _ .   
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 T h e _ A T   m a j o r i t y _ N N 1   o f _ I O   p a t i e n t s _ N N 2   w a s _ V B D Z   t r a n s f u s e d _ V V N   i n t r a o p e r a t i v e l y _ R R   ; _ ;   h o w e v e r _ R R   , _ ,   2 _ M C   o f _ I O   t h e _ A T   5 1 _ M C   t r a n s f u s e d _ J J   p a t i e n t s _ N N 2   r e c e i v e d _ V V D   b l o o d _ N N 1   p r o d u c t s _ N N 2   p o s t o p e r a t i v e l y _ R R   . _ .   
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 A c k n o w l e d g m e n t s _ N P 1   : _ :   T h e _ A T   a u t h o r s _ N N 2   t h a n k _ V V 0   P a t r i z i o _ N P 1   P a s q u a l - e t t i _ N P 1   , _ ,   P h D _ N N A   w h o _ P N Q S   w r o t e _ V V D   t h e _ A T   s t a t i s t i c a l _ J J   r e s u l t s _ N N 2   o f _ I O   c u r r e n t _ J J   i n v e s t i g a t i o n _ N N 1   a n d _ C C   V a l e n t i n e _ N P 1   N e g r o u k _ N P 1   , _ ,   P h D _ N N A   f o r _ C S   p r e c i s i o n _ N N 1   t e s t _ N N 1   r e p l i c a t i o n _ N N 1   a n d _ C C   m e a s u r e m e n t s _ N N 2   o f _ I O   n o n - C p _ N P 1   C u _ F O   i n _ I I   h e a l t h y _ J J   U S _ N P 1   s u b j e c t s _ N N 2   a t _ I I   I G E A _ N P 1   R e s e a r c h _ N N 1   C o r p o r a t i o n _ N N 1   , _ ,   M i a m i _ N P 1   , _ ,   F L _ N N U   , _ ,   U S A _ N P 1   . _ .   
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 T h i s _ D D 1   m i s t a k e _ N N 1   i n _ I I   t h e _ A T   i n i t i a l _ J J   c l a s s i f i c a t i o n _ N N 1   o f _ I O   p 5 3 _ F O   w a s _ V B D Z   t h e _ A T   r e s u l t _ N N 1   o f _ I O   a _ A T 1   s i m p l e _ J J   e r r o r _ N N 1   ; _ ;   t h e _ A T   T P 5 3 _ F O   g e n e _ N N 1   t h a t _ C S T   h a d _ V H D   b e e n _ V B N   c l o n e d _ V V N   a n d _ C C   u s e d _ V V N   i n _ I I   t h e _ A T   i n i t i a l _ J J   e x p e r i m e n t s _ N N 2   e n c o d e d _ V V D   a _ A T 1   m u t a n t _ N N 1   v e r s i o n _ N N 1   o f _ I O   t h e _ A T   w i l d - t y p e _ J J   g e n e _ N N 1   . _ .   
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 C h a n g e s _ N N 2   i n _ I I   m a l e _ N N 1   a n d _ C C   f e m a l e _ J J   B M I _ N N 2   w e r e _ V B D R   w e a k l y _ R R   c o r r e l a t e d _ V V N   a c r o s s _ I I   c o u n t r i e s _ N N 2   . _ .   
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 T h e _ A T   c l i n i c a l _ J J   s i g n i f i c a n c e _ N N 1   o f _ I O   t h i s _ D D 1   d i f f e r e n c e _ N N 1   i s _ V B Z   u n d e r s c o r e d _ V V N   b y _ I I   r e s u l t s _ N N 2   o f _ I O   t h e _ A T   E a r l y _ J J   M a n i f e s t _ J J   G l a u c o m a _ N N 1   T r i a l _ N N 1   , _ ,   w h i c h _ D D Q   f o u n d _ V V D   t h a t _ C S T   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   O A G _ N P 1   , _ ,   e a c h _ D D 1   m i l l i m e t e r _ N N 1   o f _ I O   m e r c u r y _ N N 1   o f _ I O   I O P _ N P 1   r e d u c t i o n _ N N 1   f r o m _ I I   b a s e l i n e _ N N 1   a t _ I I   t h e _ A T   f i r s t _ M D   f o l l o w - u p _ J J   v i s i t _ N N 1   ( _ (   3 _ M C   m o n t h s _ N N T 2   ) _ )   w a s _ V B D Z   a s s o c i a t e d _ V V N   w i t h _ I W   a n _ A T 1   a p p r o x i m a t e l y _ R R   1 0 % _ N N U   r e d u c t i o n _ N N 1   i n _ I I   p r o g r e s s i o n _ N N 1   o f _ I O   v i s u a l _ J J   f i e l d _ N N 1   l o s s . 9 _ F O   M o r e _ R R R   r e c e n t l y _ R R   , _ ,   H e i j l 2 9 _ F O   s u g g e s t e d _ V V D   a _ A T 1   1 9 % _ N N U   r e d u c t i o n _ N N 1   i n _ I I   t h e _ A T   r i s k _ N N 1   o f _ I O   v i s u a l _ J J   f i e l d _ N N 1   p r o g r e s s i o n _ N N 1   f o r _ I F   e v e r y _ A T 1   1 _ M C 1   m m H g _ N N U   I O P _ N N 1   r e d u c t i o n _ N N 1   o n _ I I   t h e _ A T   b a s i s _ N N 1   o f _ I O   a _ A T 1   r e v i e w _ N N 1   o f _ I O   d a t a _ N N   f r o m _ I I   t h e _ A T   U K _ N P 1   G l a u c o m a _ N P 1   T r e a t m e n t _ N N 1   S t u d y _ N N 1   e v a l u a t i n g _ V V G   t h e _ A T   e f f e c t _ N N 1   o f _ I O   l a t a n o p r o s t _ N N 1   0 . 0 0 5 % _ F O   c o m p a r e d _ V V N   w i t h _ I W   v e h i c l e _ N N 1   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   O A G . 1 1 , 2 9 _ F O   R e s u l t s _ N N 2   o f _ I O   s e c o n d a r y _ J J   e f f i c a c y _ N N 1   e n d _ N N 1   p o i n t s _ N N 2   w e r e _ V B D R   c o n s i s t e n t _ J J   w i t h _ I W   t h e _ A T   p r i m a r y _ J J   o u t c o m e _ N N 1   m e a s u r e s _ N N 2   . _ .   
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 F o r _ I F   t h e _ A T   m a j o r i t y _ N N 1   o f _ I O   s u b u n i t s _ N N 2   ( _ (   4 _ M C   o f _ I O   6 _ M C   ) _ )   , _ ,   p r o t e o l y t i c _ J J   a c t i v i t y _ N N 1   w a s _ V B D Z   s i g n i f i c a n t l y _ R R   h i g h e r _ J J R   i n _ I I   t h e _ A T   o l d _ J J   K O _ N N 1   t h a n _ C S N   W T _ N N 1   m i c e _ N N 2   . _ .   
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 T h i s _ D D 1   a w a r e n e s s _ N N 1   m a y _ V M   h a v e _ V H I   e n g a g e d _ V V N   t h e m _ P P H O 2   t o _ T O   u s e _ V V I   m o r e _ R G R   c o g n i t i v e _ J J   e f f o r t 4 5 _ F O   a n d _ C C   b e t t e r _ J J R   m o t o r _ N N 1   p l a n n i n g _ V V G   t o _ T O   i n c r e a s e _ V V I   t h e _ A T   e s s e n t i a l _ J J   r a n g e s _ N N 2   o f _ I O   a r m _ N N 1   m o t i o n _ N N 1   r e q u i r e d _ V V N   f o r _ I F   s u c c e s s f u l _ J J   p o i n t i n g _ J J   . _ .   
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 T h e _ A T   d i a g n o s t i c _ J J   c r i t e r i a _ N N 2   f o r _ I F   C R P S _ N P 1   w a s _ V B D Z   n o t _ X X   r e p o r t e d _ V V N   . _ .   
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 W i t h _ I W   t h e _ A T   e x c e p t i o n _ N N 1   o f _ I O   c e r e b r o v a s c u l a r _ J J   e v e n t s _ N N 2   , _ ,   t h e _ A T   i n c i d e n c e _ N N 1   o f _ I O   a l l _ D B   o t h e r _ J J   M A C C E _ N N 1   i n c r e a s e d _ V V N   a s _ C S A   p r e o p e r a t i v e _ J J   e G F R _ N N 1   d e c r e a s e d _ V V N   ( _ (   T a b l e _ N N 1   3 _ M C   ) _ )   . _ .   
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 T h e s e _ D D 2   r e s p o n s e s _ N N 2   o f _ I O   k e t a m i n e _ N N 1   a r e _ V B R   m e d i a t e d _ V V N   c e n t r a l l y _ R R   a n d _ C C   t h e _ A T   u s e _ N N 1   o f _ I O   a _ A T 1   c e n t r a l l y _ R R   d e p r e s s a n t _ J J   a g e n t _ N N 1   s u c h _ I I 2 1   a s _ I I 2 2   b e n z o d i a z e p i n e s _ N N 2   c a n _ V M   b l u n t _ J J   t h i s _ D D 1   e f f e c t _ N N 1   . _ .   
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 I n _ I I   t h e _ A T   c u r r e n t _ J J   r e p o r t _ N N 1   , _ ,   t h e r e _ E X   w e r e _ V B D R   n o _ A T   r e p o r t s _ N N 2   o f _ I O   b i r t h _ N N 1   d e f e c t s _ N N 2   a m o n g _ I I   f e t u s e s _ N N 2   o r _ C C   i n f a n t s _ N N 2   w i t h _ I W   p r e n a t a l _ J J   e x p o s u r e _ N N 1   t o _ I I   Z i k a _ N P 1   v i r u s _ N N 1   i n f e c t i o n _ N N 1   o n l y _ R R   i n _ I I   t h e _ A T   s e c o n d _ M D   t r i m e s t e r _ N N 1   ( _ (   0 % _ N N U   ; _ ;   9 5 % _ N N U   C I _ F O   , _ ,   0 % - 5 % _ F O   ) _ )   o r _ C C   t h i r d _ M D   t r i m e s t e r _ N N 1   ( _ (   0 % _ N N U   ; _ ;   9 5 % _ N N U   C I _ F O   , _ ,   0 % - 1 1 % _ F O   ) _ )   ; _ ;   h o w e v e r _ R R   , _ ,   t h e _ A T   c o n f i d e n c e _ N N 1   i n t e r v a l s _ N N 2   d e m o n s t r a t e d _ V V D   t h e _ A T   i m p r e c i s i o n _ N N 1   o f _ I O   t h e s e _ D D 2   e s t i m a t e s _ N N 2   b a s e d _ V V N   o n _ I I   c u r r e n t _ J J   d a t a _ N N   . _ .   
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 A u t h o r _ N N 1   c o n t r i b u t i o n s _ N N 2   : _ :   G u a r a n t o r s _ N N 2   o f _ I O   i n t e g r i t y _ N N 1   o f _ I O   e n t i r e _ J J   s t u d y _ N N 1   , _ ,   B . B . B . _ N P 1   , _ ,   P . A . B . _ N P 1   ; _ ;   s t u d y _ V V 0   c o n c e p t s / s t u d y _ F U   d e s i g n _ N N 1   o r _ C C   d a t a _ N N   a c q u i s i t i o n _ N N 1   o r _ C C   d a t a _ N N   a n a l y s i s / _ N N 1   i n t e r p r e t a t i o n _ N N 1   , _ ,   B . B . B . _ N P 1   , _ ,   P . A . B . _ N P 1   ; _ ;   m a n u s c r i p t _ N N 1   d r a f t i n g _ N N 1   o r _ C C   m a n u s c r i p t _ N N 1   r e v i s i o n _ N N 1   f o r _ I F   i m p o r t a n t _ J J   i n t e l l e c t u a l _ J J   c o n t e n t _ N N 1   , _ ,   B . B . B . _ N P 1   , _ ,   P . A . B . _ N P 1   ; _ ;   a p p r o v a l _ N N 1   o f _ I O   f i n a l _ J J   v e r s i o n _ N N 1   o f _ I O   s u b m i t t e d _ J J   m a n u s c r i p t _ N N 1   , _ ,   B . B . B . _ N P 1   , _ ,   P . A . B . _ N P 1   ; _ ;   a g r e e s _ V V Z   t o _ T O   e n s u r e _ V V I   a n y _ D D   q u e s t i o n s _ N N 2   r e l a t e d _ V V N   t o _ I I   t h e _ A T   w o r k _ N N 1   a r e _ V B R   a p p r o p r i a t e l y _ R R   r e s o l v e d _ V V N   , _ ,   B . B . B . _ N P 1   , _ ,   P . A . B . _ N P 1   ; _ ;   l i t e r a t u r e _ N N 1   r e s e a r c h _ N N 1   , _ ,   B . B . B . _ N P 1   , _ ,   P . A . B . _ N P 1   ; _ ;   s t a t i s t i c a l _ J J   a n a l y s i s _ N N 1   , _ ,   B . B . B . _ N P 1   , _ ,   P . A . B . _ N P 1   ; _ ;   a n d _ C C   m a n u s c r i p t _ N N 1   e d i t i n g _ N N 1   , _ ,   B . B . B . _ N P 1   , _ ,   P A . B _ N P 1   . _ .   
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 F i n a l l y _ R R   , _ ,   w e _ P P I S 2   s h o w _ V V 0   r e c e n t _ J J   e v i d e n c e _ N N 1   i n _ I I 3 1   s u p p o r t _ I I 3 2   o f _ I I 3 3   t h e _ A T   h y p o t h e s i s _ N N 1   t h a t _ C S T   t h e _ A T   c o m b i n a t i o n _ N N 1   o f _ I O   a c u t e _ J J   a n d _ C C   l o n g - t e r m _ J J   i n t e r v e n t i o n s _ N N 2   m i g h t _ V M   m a x i m i z e _ V V I   t h e _ A T   e f f e c t s _ N N 2   o f _ I O   c a r d i o v a s c u l a r _ J J   e x e r c i s e _ N N 1   o n _ I I   h u m a n _ J J   m e m o r y _ N N 1   . _ .   
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 T h e _ A T   m o l e c u l a r _ J J   g e n e t i c _ J J   b a s e s _ N N 2   o f _ I O   T - A L L _ J J   a r e _ V B R   w e l l _ R R   c h a r a c t e r i z e d _ V V N   ( _ (   V a n _ N P 1   V l i e r - b e r g h e _ N P 1   a n d _ C C   F e r r a n d o _ N P 1   , _ ,   2 0 1 2 _ M C   ) _ )   , _ ,   y e t _ R R   t h i s _ D D 1   k n o w l e d g e _ N N 1   h a s _ V H Z   n o t _ X X   t r a n s l a t e d _ V V N   i n t o _ I I   t a r g e t e d _ J J   t h e r a p i e s _ N N 2   . _ .   
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 N e g a t i v e _ J J   p r e d i c t i v e _ J J   v a l u e _ N N 1   ( _ (   N P V _ N P 1   ) _ )   : _ :   t h e _ A T   p r o b a b i l i t y _ N N 1   t h a t _ C S T   a _ A T 1   p e r s o n _ N N 1   d o e s _ V D Z   n o t _ X X   h a v e _ V H I   t h e _ A T   c o n d i t i o n _ N N 1   w h e n _ C S   a _ A T 1   n e g a t i v e _ J J   t e s t _ N N 1   r e s u l t _ N N 1   i s _ V B Z   o b s e r v e d _ V V N   . _ .   
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 A l l _ D B   v a r i a b l e s _ N N 2   w e r e _ V B D R   f o r c e d _ V V N   i n t o _ I I   t h e _ A T   m u l t i v a r i a b l e _ J J   m o d e l s _ N N 2   u s i n g _ V V G   e n t e r _ V V 0   m e t h o d _ N N 1   , _ ,   w h i c h _ D D Q   w a s _ V B D Z   u s e d _ V V N   t o _ T O   f i t _ V V I   t h e _ A T   m u l t i v a r i a b l e _ J J   m o d e l _ N N 1   ( _ (   I B M _ N P 1   S P S S _ N P 1   v e r s i o n _ N N 1   2 2 . 0 _ M C   ; _ ;   I B M _ N P 1   I n c . _ J J   , _ ,   U S A _ N P 1   ) _ )   . _ .   
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 J W _ N P 1   a n d _ C C   S W C _ N P 1   d i d _ V D D   S N P _ N P 1   a r r a y _ N N 1   d a t a _ N N   a n a l y s i s _ N N 1   . _ .   
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 T h e _ A T   a s s o c i a t i o n s _ N N 2   w i t h _ I W   c o m p o s i t e _ J J   m o r b i d i t y _ N N 1   , _ ,   m e c h a n i c a l _ J J   v e n t i l a t i o n _ N N 1   , _ ,   a n d _ C C   s e v e r e _ J J   b r a i n _ N N 1   i n j u r y _ N N 1   ( _ (   w h i c h _ D D Q   w e r e _ V B D R   o b s e r v e d _ V V N   i n _ I I   t h e _ A T   o v e r a l l _ J J   S G A _ N N 1   g r o u p _ N N 1   ) _ )   w e r e _ V B D R   n o t _ X X   s t a t i s t i c a l l y _ R R   s i g n i f i c a n t _ J J   . _ .   
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 N e x t _ M D   , _ ,   w e _ P P I S 2   w i l l _ V M   c o m p a r e _ V V I   t h e _ A T   p a t t e r n s _ N N 2   o f _ I O   H C _ N P 1   l o s s _ N N 1   w e _ P P I S 2   o b s e r v e d _ V V D   i n _ I I   s o u n d _ J J   e x p o s e d _ J J   a n i m a l s _ N N 2   t o _ I I   t h a t _ D D 1   o b s e r v e d _ V V D   b y _ I I   o t h e r _ J J   i n v e s t i g a t o r s _ N N 2   . _ .   
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 S e x _ N N 1   d i f f e r e n c e s _ N N 2   i n _ I I   t h e _ A T   t i m i n g _ N N 1   o f _ I O   o n s e t _ N N 1   , _ ,   p r e v a l e n c e _ N N 1   , _ ,   a n d _ C C   c l i n i c a l _ J J   c o u r s e _ N N 1   o f _ I O   n e u r o p s y c h i a t r i c _ J J   a n d _ C C   s u b s t a n c e _ N N 1   u s e _ N N 1   d i s o r d e r s _ N N 2   p r o v i d e _ V V 0   c l u e s _ N N 2   t o _ I I   t h e _ A T   u n d e r l y i n g _ J J   p a t h o p h y s i o l o g y _ N N 1   o f _ I O   t h e s e _ D D 2   d i s o r d e r s _ N N 2   . _ .   
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 C o m p a r i s o n _ N N 1   w i t h _ I W   o t h e r _ J J   s t u d i e s _ N N 2   i s _ V B Z   n o t _ X X   s t r a i g h t f o r w a r d _ J J   a s _ C S A   m a n y _ D A 2   a u t h o r s _ N N 2   r e f e r r e d _ V V D   t h e _ A T   t r a n s i t _ N N 1   t i m e s _ N N T 2   t o _ I I   t h e _ A T   a b s o l u t e _ J J   i n j e c t i o n _ N N 1   t i m e _ N N T 1   , _ ,   1 6 , 3 9 _ M C   w h e r e a s _ C S   w e _ P P I S 2   f o c u s e d _ V V D   o n _ I I   r e l a t i v e _ J J   t r a n s i t _ N N 1   t i m e _ N N T 1   b e t w e e n _ I I   R V _ N P 1   a n d _ C C   L V _ M C   C o m p a r i s o n _ N N 1   o f _ I O   t h e _ A T   M e t h o d _ N N 1   W i t h _ I W   t h e _ A T   L i t e r a t u r e _ N N 1   T h e _ A T   a d o p t e d _ J J   M R _ N N B   s e q u e n c e _ N N 1   a n d _ C C   s m a l l _ J J   d o s e _ N N 1   o f _ I O   c o n t r a s t _ N N 1   a g e n t _ N N 1   e n s u r e s _ V V Z   t h e _ A T   l i n e a r i t y _ N N 1   o f _ I O   t h e _ A T   c o n t r a s t _ N N 1   a g e n t / M R _ F U   s i g n a l _ N N 1   r e l a t i o n s h i p _ N N 1   , _ ,   a _ A T 1   p r e r e q u i s i t e _ N N 1   f o r _ I F   i n d i c a t o r _ N N 1   d i l u t i o n _ N N 1   p a r a m e t e r _ N N 1   e s t i m a t e . 2 0 A p p r o a c h e s _ F O   b a s e d _ V V N   o n l y _ R R   o n _ I I   c o n t r a s t _ N N 1   a g e n t _ N N 1   a r r i v a l _ N N 1   t i m e _ N N T 1   d o _ V D 0   n o t _ X X   t a k e _ V V I   i n t o _ I I   a c c o u n t _ N N 1   s t a t i s t i c a l _ J J   a s p e c t s _ N N 2   o f _ I O   t h e _ A T   c o n t r a s t _ N N 1   a g e n t _ N N 1   t r a n s p o r t _ N N 1   k i n e t i c _ J J   : _ :   t h e y _ P P H S 2   n e g l e c t _ V V 0   t h e _ A T   m u l t i p a t h _ N N 1   t r a j e c t o r y _ N N 1   o f _ I O   t h e _ A T   i n d i c a t o r _ N N 1   t r a n s p o r t 4 0 _ F O   i n t r o d u c i n g _ V V G   a _ A T 1   b i a s _ N N 1   t o w a r d _ I I   t h e _ A T   s h o r t e s t _ J J T   p a t h _ N N 1   ; _ ;   b y _ I I   r e l y i n g _ V V G   o n _ I I   a _ A T 1   t h r e s h o l d _ N N 1   f o r _ I F   d e f i n i n g _ V V G   t h e _ A T   i n d i c a t o r _ N N 1   a r r i v a l _ N N 1   , _ ,   a n d _ C C   o n _ I I   o n l y _ R R   1 _ M C 1   p o i n t _ N N 1   o n _ I I   t h e _ A T   t i m e - e n h a n c e m e n t _ J J   c u r v e _ N N 1   , _ ,   t h e y _ P P H S 2   a r e _ V B R   m o r e _ R G R   s u s c e p t i b l e _ J J   t o _ I I   n o i s e _ N N 1   i n _ I I   t h e _ A T   i m a g e _ N N 1   a c q u i s i t i o n _ N N 1   . _ .   
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 M a n y _ D A 2   d i a g n o s t i c _ J J   t e s t s _ N N 2   a p p e a r _ V V 0   t o _ T O   h a v e _ V H I   s p e c i f i c i t y _ N N 1   u n t i l _ C S   t h e y _ P P H S 2   a r e _ V B R   t e s t e d _ V V N   u s i n g _ V V G   d i s e a s e s _ N N 2   t h a t _ C S T   c a n _ V M   b e _ V B I   c l i n i c a l l y _ R R   d i f f i c u l t _ J J   t o _ T O   d i f f e r e n t i a t e _ V V I   . _ .   
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 F i g . _ N N 1   1 _ M C 1   i l l u s t r a t e s _ V V Z   t h e _ A T   L A _ N P 1   t r a j e c t o r i e s _ N N 2   f o r _ I F   t h e _ A T   6 - s y l l a b l e _ J J   s i m p l e _ J J   n o n w o r d _ N N 1   , _ ,   / m _ F U   ? _ ?   b t a i b a p o t i b a / _ N N 1   f r o m _ I I   S e s s i o n s _ N N T 2   1 _ M C 1   a n d _ C C   2 _ M C   f o r _ I F   a _ A T 1   c o n t r o l _ N N 1   p a r t i c i p a n t _ N N 1   ( _ (   u p p e r _ J J   h a l f _ N N 1   ) _ )   a n d _ C C   a n _ A T 1   A W S _ N N 2   ( _ (   l o w e r _ J J R   h a l f _ N N 1   ) _ )   . _ .   
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 M a j o r _ J J   f u n d i n g _ N N 1   w a s _ V B D Z   a l s o _ R R   p r o v i d e d _ V V N   b y _ I I   t h e _ A T   N a t i o n a l _ J J   I n s t i t u t e _ N N 1   o n _ I I   A l c o h o l _ N N 1   A b u s e _ N N 1   a n d _ C C   A l c o h o l i s m _ N N 1   , _ ,   t h e _ A T   N a t i o n a l _ J J   I n s t i t u t e s _ N N 2   o f _ I O   H e a l t h _ N N 1   ( _ (   N I H _ N P 1   ) _ )   O f f i c e _ N N 1   o f _ I O   B e h a v i o r a l _ N P 1   a n d _ C C   S o c i a l _ J J   S c i e n c e s _ N N 2   R e s e a r c h _ V V 0   , _ ,   t h e _ A T   N I H _ N N 1   S u b s t a n c e _ N N 1   A b u s e _ N N 1   a n d _ C C   M e n t a l _ J J   H e a l t h _ N N 1   S e r v i c e s _ N N 2   A d m i n i s t r a t i o n _ N N 1   ( _ (   C e n t e r _ N N 1   f o r _ I F   M e n t a l _ J J   H e a l t h _ N N 1   S e r v i c e s _ N N 2   , _ ,   C e n t e r _ N N 1   f o r _ I F   S u b s t a n c e _ N N 1   A b u s e _ N N 1   P r e v e n t i o n _ N N 1   , _ ,   a n d _ C C   C e n t e r _ N N 1   f o r _ I F   S u b s t a n c e _ N N 1   A b u s e _ N N 1   T r e a t m e n t _ N N 1   ) _ )   , _ ,   t h e _ A T   N a t i o n a l _ J J   I n s t i t u t e _ N N 1   o n _ I I   M i n o r i t y _ N N 1   H e a l t h _ N N 1   a n d _ C C   H e a l t h _ N N 1   D i s p a r i t i e s _ N N 2   , _ ,   t h e _ A T   C e n t e r s _ N N 2   f o r _ I F   D i s e a s e _ N N 1   C o n t r o l _ N N 1   a n d _ C C   P r e v e n t i o n _ N N 1   ( _ (   N a t i o n a l _ J J   C e n t e r _ N N 1   f o r _ I F   I n j u r y _ N N 1   P r e v e n t i o n _ N N 1   a n d _ C C   C o n t r o l _ N N 1   a n d _ C C   N a t i o n a l _ J J   C e n t e r _ N N 1   f o r _ C S   H I V / A I D S _ F U   , _ ,   V i r a l _ J J   H e p a t i t i s _ N N 1   , _ ,   S T D _ N N 1   , _ ,   a n d _ C C   T B _ N N 1   P r e v e n t i o n _ N N 1   ) _ )   , _ ,   t h e _ A T   N I H _ N N 1   O f f i c e _ N N 1   o f _ I O   R e s e a r c h _ N N 1   o n _ I I   W o m e n _ N N 2   ' _ N U L L   s _ Z Z 1   H e a l t h _ N N 1   , _ ,   t h e _ A T   N I H _ N N 1   O f f i c e _ N N 1   o f _ I O   R a r e _ J J   D i s e a s e s _ N N 2   , _ ,   t h e _ A T   D e p a r t m e n t _ N N 1   o f _ I O   L a b o r _ N N 1   , _ ,   t h e _ A T   D e p a r t m e n t _ N N 1   o f _ I O   H o u s i n g _ N N 1   a n d _ C C   U r b a n _ J J   D e v e l o p m e n t _ N N 1   , _ ,   t h e _ A T   W i l l i a m _ N P 1   T . _ N P 1   G r a n t _ N P 1   F o u n d a t i o n _ N N 1   , _ ,   a n d _ C C   t h e _ A T   R o b e r t _ N P 1   W o o d _ N P 1   J o h n s o n _ N P 1   F o u n d a t i o n _ N N 1   . _ .   
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 I n c r e a s e d _ J J   p e r m e a b i l i t y _ N N 1   v a l u e s _ N N 2   h a v e _ V H 0   b e e n _ V B N   r e p o r t e d _ V V N   i n _ I I   p r e s u m a b l y _ R R   n o r m a l _ J J   b r a i n _ N N 1   t i s s u e _ N N 1   a s _ C S A   w e l l . 2 7 , 3 1 , 3 2 _ F O   T h i s _ D D 1   o b s e r v a t i o n _ N N 1   w a s _ V B D Z   a t t r i b u t e d _ V V N   t o _ I I   i m a g e _ N N 1   n o i s e _ N N 1   o r _ C C   t h e _ A T   v i c i n i t y _ N N 1   t o _ I I   b l o o d _ N N 1   v e s s e l s _ N N 2   c a r r y i n g _ V V G   C A _ N P 1   . _ .   
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 A n a l y s i s _ N N 1   o f _ I O   t h e _ A T   i s o m e t r i c _ J J   t w i t c h _ N N 1   r e v e a l e d _ V V D   a _ A T 1   s l o w i n g _ N N 1   o f _ I O   b o t h _ D B 2   t i m e - t o - p e a k _ J J   t e n s i o n _ N N 1   a n d _ C C   h a l f _ D B   r e l a x a t i o n _ N N 1   t i m e _ N N T 1   i n _ I I   b o t h _ R R   W T _ N N 1   a n d _ C C   K O _ N N 1   m i c e _ N N 2   ( _ (   T a b l e _ N N 1   S 1 _ F O   ) _ )   . _ .   
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 A l l _ D B   e x p e r t s _ N N 2   r e g u l a r l y _ R R   p e r f o r m e d _ V V D   U G R A _ N P 1   p r o c e d u r e s _ N N 2   a n d _ C C   w e r e _ V B D R   i n _ I I 3 1   c h a r g e _ I I 3 2   o f _ I I 3 3   t h e _ A T   U G R A _ N N 1   e d u c a t i o n _ N N 1   f o r _ I F   r e s i d e n t s _ N N 2   . _ .   
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 N o _ A T   w o n d e r _ N N 1   , _ ,   t h e n _ R T   , _ ,   t h a t _ D D 1   c o n s c i o u s n e s s _ N N 1   h a s _ V H Z   c o m e _ V V N   t o _ T O   b e _ V B I   s e e n _ V V N   a s _ C S A   f r a g i l e _ J J   . _ .   
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 I t e m s _ N N 2   c o l l a p s e _ V V 0   i n t o _ I I   f i v e _ M C   p r i m a r y _ J J   s c a l e s _ N N 2   t h a t _ C S T   a s s e s s _ V V 0   s u b j e c t i v e _ J J   r a t i n g s _ N N 2   o f _ I O   c u r r e n t _ J J   c o m p a r e d _ V V N   w i t h _ I W   p a s t _ J J   m e m o r y _ N N 1   f u n c t i o n i n g _ V V G   ( _ (   r e t r o s p e c t i v e _ J J   f u n c t i o n i n g _ N N 1   ) _ )   ; _ ;   h o w _ R G Q   o f t e n _ R R   p r o b l e m s _ N N 2   a r i s e _ V V 0   i n _ I I   s p e c i f i c _ J J   m e m o r y _ N N 1   s i t u a t i o n s _ N N 2   ( _ (   f r e q u e n c y _ N N 1   o f _ I O   f o r g e t t i n g _ V V G   ) _ )   ; _ ;   h o w _ R G Q   o f t e n _ R R   m e m o r y _ N N 1   p r o b l e m s _ N N 2   o c c u r _ V V 0   w h i l e _ C S   r e a d i n g _ V V G   b o o k s _ N N 2   a n d _ C C   n e w s p a p e r s _ N N 2   ( _ (   f o r g e t t i n g _ V V G   w h e n _ C S   r e a d i n g _ V V G   ) _ )   ; _ ;   s k i l l _ N N 1   a t _ I I   r e c a l l i n g _ V V G   p a s t _ J J   e v e n t s _ N N 2   ( _ (   p a s t _ J J   e v e n t s _ N N 2   ) _ )   ; _ ;   a n d _ C C   h o w _ R G Q   o f t e n _ R R   e x t e r n a l _ J J   m e m o r y _ N N 1   a i d s _ N N 2   a r e _ V B R   r e l i e d _ V V N   u p o n _ I I   t o _ T O   a i d _ V V I   m e m o r y _ N N 1   ( _ (   m n e m o n i c s _ N N 2   u s a g e _ N N 1   ) _ )   . _ .   
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 F o r _ I F   m a n y _ D A 2   o f _ I O   t h e _ A T   c a s e s _ N N 2   i n _ I I   w h i c h _ D D Q   A R I A - E _ N P 1   a n d _ C C   A R I A - H _ N P 1   o c c u r r e d _ V V D   i n _ I I   t h e _ A T   s a m e _ D A   g e n e r a l _ J J   r e g i o n _ N N 1   , _ ,   t h e _ A T   a b n o r m a l i t i e s _ N N 2   a p p e a r e d _ V V D   a t _ I I   d i f f e r e n t _ J J   t i m e s _ N N T 2   , _ ,   w e r e _ V B D R   a c c o m p a n i e d _ V V N   b y _ I I   a _ A T 1   f i n d i n g _ N N 1   i n _ I I   a n o t h e r _ D D 1   b r a i n _ N N 1   r e g i o n _ N N 1   , _ ,   o r _ C C   b o t h _ D B 2   . _ .   
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 T h e _ A T   e x p e c t e d _ J J   v a l u e _ N N 1   o f _ I O   t h e _ A T   E F _ N N 1   m e a s u r e s _ N N 2   w a s _ V B D Z   c a l c u l a t e d _ V V N   u s i n g _ V V G   f o r m u l a s _ N N 2   o b t a i n e d _ V V N   b y _ I I   p o l y n o m i a l _ N N 1   r e g r e s s i o n s _ N N 2   b e t w e e n _ I I   t h e _ A T   m e a s u r e s _ N N 2   o f _ I O   t h e _ A T   E F _ N N 1   t a s k s _ N N 2   a n d _ C C   a g e _ N N 1   i n _ I I   t h e _ A T   c o n t r o l _ N N 1   g r o u p _ N N 1   . _ .   
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 T h e _ A T   S T A R D 1 3 _ F O   g e n e _ N N 1   h a s _ V H Z   m o r e o v e r _ R R   b e e n _ V B N   a s s o c i a t e d _ V V N   ( _ (   P _ Z Z 1   l e s s _ R R R   t h a n _ C S N   1 _ M C 1   x _ Z Z 1   1 0 - 5 _ M C M C   ) _ )   w i t h _ I W   p l a s m a _ N N 1   l e v e l s _ N N 2   o f _ I O   a m y l o i d _ J J   b e t a _ N N 1   p e p t i d e s _ N N 2   t h a t _ C S T   , _ ,   a m o n g _ I I   o t h e r _ J J   t h i n g s _ N N 2   , _ ,   p l a y _ V V 0   a _ A T 1   r o l e _ N N 1   i n _ I I   A l z h e i m e r _ N P 1   ' _ N U L L   s _ Z Z 1   d i s e a s e _ N N 1   a n d _ C C   h y p e r t e n s i o n _ N N 1   ( _ (   C h o u r a k i _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 4 _ M C   ) _ )   . _ .   
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 T h e _ A T   c a u s e _ N N 1   a n d _ C C   n u m b e r _ N N 1   o f _ I O   T I P S _ N N 2   r e v i s i o n s _ N N 2   d u r i n g _ I I   t h e _ A T   s t u d y _ N N 1   p e r i o d _ N N 1   w e r e _ V B D R   n o t e d _ V V N   f o r _ I F   e a c h _ D D 1   p a t i e n t _ N N 1   . _ .   
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 F i g u r e s _ N N 2   2 C _ F O   t o _ I I   2 D _ N N U   s h o w _ V V 0   a v e r a g e _ J J   C o O _ N N 1   d i f f e r e n c e s _ N N 2   ( _ (   p u r e _ J J   s p a t i a l _ J J   m e a s u r e _ N N 1   ) _ )   a n d _ C C   i n t e r l i m b _ V V 0   p h a s i n g _ V V G   ( _ (   p u r e _ J J   t e m p o r a l _ J J   m e a s u r e _ N N 1   ) _ )   f o r _ I F   a l l _ D B   g r o u p s _ N N 2   a n d _ C C   t e s t i n g _ V V G   p e r i o d s _ N N 2   . _ .   
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 T h e _ A T   q u e s t i o n n a i r e s _ N N 2   r e q u i r e _ V V 0   a p p r o x i m a t e l y _ R R   2 0 _ M C   m i n u t e s _ N N T 2   c o m p l e t i n g _ V V G   a n d _ C C   m o s t _ D A T   w e r e _ V B D R   a d m i n i s t e r e d _ V V N   v i a _ I I   c o m p u t e r _ N N 1   t a b l e t _ N N 1   , _ ,   w h i c h _ D D Q   m i n i m i z e s _ V V Z   d a t a _ N N   e n t r y _ N N 1   e r r o r _ N N 1   . _ .   
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 F i n a l l y _ R R   , _ ,   a l t h o u g h _ C S   t h e _ A T   g e n d e r _ N N 1   d i s c r i m i n a t i o n _ N N 1   d a t a _ N N   i n d i c a t e d _ V V D   t h a t _ C S T   t h e _ A T   p a r t i c i p a n t s _ N N 2   w i t h _ I W   C D _ N N 1   a t t e n d e d _ V V N   t o _ I I   t h e _ A T   f a c i a l _ J J   s t i m u l i _ N N 2   , _ ,   t h e i r _ A P P G E   e y e - s c a n n i n g _ J J   p a t t e r n s _ N N 2   m a y _ V M   h a v e _ V H I   d i f f e r e d _ V V N   f r o m _ I I   t h o s e _ D D 2   o f _ I O   h e a l t h y _ J J   c o n t r o l s _ N N 2   . _ .   
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 S i m i l a r l y _ R R   , _ ,   a s _ C S A   r e p o r t e d _ V V N   b y _ I I   r e s e a r c h e r s _ N N 2   i n v e s t i g a t i n g _ V V G   p e r f o r m a n c e _ N N 1   o u t c o m e s _ N N 2   f o r _ I F   C I - S S D _ J J   r e c i p i e n t s _ N N 2   , _ ,   h e a r i n g _ V V G   p e r f o r m a n c e _ N N 1   p r o g r e s s _ N N 1   i s _ V B Z   o b s e r v e d _ V V N   t o _ T O   b e _ V B I   a _ A T 1   f u n c t i o n _ N N 1   o f _ I O   p o s t i m p l a n t _ N N 1   l i s t e n i n g _ N N 1   e x p e r i e n c e _ N N 1   , _ ,   e s p e c i a l l y _ R R   f o r _ I F   s p e e c h _ N N 1   t e s t s _ N N 2   p e r f o r m e d _ V V D   i n _ R P   s p a t i a l l y _ R R   s e p a r a t e d _ J J   s i g n a l _ N N 1   a n d _ C C   n o i s e _ N N 1   c o n d i t i o n s _ N N 2   ( _ (   A r n d t _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 1 c _ F O   ; _ ;   H a s s e p a s s _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 3 _ M C   ; _ ;   M e r t e n s _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 7 _ M C   ; _ ;   R a h n e _ N P 1   a n d _ C C   P l o n t k e _ N P 1   , _ ,   2 0 1 6 _ M C   ) _ )   . _ .   
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 I n t e r e s t i n g l y _ R R   , _ ,   t h e _ A T   t i m e _ N N T 1   n e e d e d _ V V N   t o _ T O   c o m p l e t e _ V V I   t h e _ A T   t e s t _ N N 1   w a s _ V B D Z   1 . 6 _ M C    _ F O   3 . 0 % _ F O   s h o r t e r _ J J R   w h e n _ C S   t h e _ A T   w o m e n _ N N 2   v o l l e y b a l l _ N N 1   p l a y e r s _ N N 2   i n g e s t e d _ V V D   t h e _ A T   c a f f e i n a t e d _ J J   e n e r g y _ N N 1   d r i n k _ N N 1   . _ .   
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 T h e _ A T   p r e s e n c e _ N N 1   o f _ I O   a _ A T 1   m e a s u r e a b l e _ J J   a m o u n t _ N N 1   o f _ I O   s m o o t h _ J J   m u s c l e _ N N 1   a s _ C S A   i d e n t i f i e d _ V V N   b y _ I I   s m o o t h _ J J   m u s c l e _ N N 1   a l p h a - a c t i n _ N N 1   , _ ,   c a l p o n i n - 1 _ M C 1   , _ ,   a n d _ C C   S M - 2 2 a l p h a _ N N 1   i n _ I I   t h e _ A T   c e r v i x _ N N 1   a t _ I I   d a y _ N N T 1   2 0 _ M C   o f _ I O   a _ A T 1   2 1 _ M C   d a y _ N N T 1   g e s t a t i o n _ N N 1   p e r i o d _ N N 1   i s _ V B Z   s u f f i c i e n t _ J J   p r o o f _ N N 1   o f _ I O   t h e _ A T   h y p o t h e s i s _ N N 1   t h a t _ C S T   s m o o t h _ J J   m u s c l e _ N N 1   p e r s i s t s _ V V Z   t h r o u g h _ I I   p r e g n a n c y _ N N 1   . _ .   
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 C o n c l u s i o n _ N N 1   : _ :   F i b r o s i s _ N P 1   i s _ V B Z   i n d e p e n d e n t l y _ R R   a s s o c i a t e d _ V V N   w i t h _ I W   t h e _ A T   M R _ N N B   v i s c o e l a s t i c _ N N 1   p a r a m e t e r s _ N N 2   a n d _ C C   i s _ V B Z   l e s s _ R G R   a s s o c i a t e d _ J J   w i t h _ I W   t h e _ A T   d i f f u s i o n _ N N 1   p a r a m e t e r s _ N N 2   t h a n _ C S N   i s _ V B Z   s t e a t o s i s _ N N 1   . _ .   
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 C u r r e n t _ J J   n a t i o n a l _ J J   p r i o r i t i e s _ N N 2   o f _ I O   q u a l i t y _ N N 1   i m p r o v e m e n t _ N N 1   , _ ,   f i s c a l _ J J   r e s p o n s i b i l i t y _ N N 1   , _ ,   a n d _ C C   t h e _ A T   n e e d _ N N 1   f o r _ I F   m e d i c a l _ J J   a d v a n c e m e n t _ N N 1   d e m a n d _ V V 0   t h a t _ C S T   w e _ P P I S 2   c o n f r o n t _ V V 0   t h e _ A T   n e e d s _ N N 2   o f _ I O   t h e _ A T   n e w _ J J   p e d i a t r i c _ J J   p o p u l a t i o n _ N N 1   a n d _ C C   i t s _ A P P G E   w o r k f o r c e _ N N 1   a n d _ C C   u s e _ V V 0   t h e _ A T   b r i g h t e s t _ J J T   m i n d s _ N N 2   f r o m _ I I   a l l _ D B   t o _ T O   s u c c e e d _ V V I   . _ .   
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 I n c i d e n c e s _ N N 2   o f _ I O   m a j o r _ J J   b l e e d i n g _ J J   i n _ I I   t h e _ A T   f i r s t _ M D   3 0 _ M C   d a y s _ N N T 2   i n _ I I   o t h e r _ J J   r i s k _ N N 1   c a t e g o r i e s _ N N 2   a n d _ C C   i n _ I I   t h e _ A T   e n o x a p a r i n / V K A _ N N 1   g r o u p _ N N 1   a r e _ V B R   g i v e n _ V V N   i n _ I I   T a b l e _ N N 1   3 _ M C   . _ .   
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 T h e _ A T   o x y g e n _ N N 1   f r a c t i o n _ N N 1   , _ ,   t i d a l _ J J   v o l u m e _ N N 1   , _ ,   a n d _ C C   r e s p i r a t o r y _ J J   r a t e _ N N 1   w e r e _ V B D R   m a i n t a i n e d _ V V N   u n c h a n g e d _ J J   f o r _ I F   t h e _ A T   e n t i r e _ J J   s t u d y _ N N 1   . _ .   
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 I t _ P P H 1   h a s _ V H Z   b e e n _ V B N   s h o w n _ V V N   t h a t _ C S T   t h e s e _ D D 2   m e t h o d s _ N N 2   a r e _ V B R   a b l e _ J K   t o _ T O   d e t e c t _ V V I   c o m p l e t e _ J J   d e f i c i e n c y _ N N 1   b u t _ C C B   f a i l _ V V 0   t o _ T O   d e t e c t _ V V I   p a r t i a l _ J J   d e f i c i e n t _ J J   c a s e s _ N N 2   . _ .   
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 A l t h o u g h _ C S   m o r e _ D A R   e x p e r i e n c e s _ N N 2   a r e _ V B R   r e q u i r e d _ V V N   t o _ T O   e v a l u a t e _ V V I   l o n g - t e r m _ J J   e f f i c a c y _ N N 1   a n d _ C C   c o s t - e f f e c t i v e n e s s _ N N 1   , _ ,   u l t r a s o u n d - g u i d e d _ J J   c o r e _ N N 1   b i o p s y _ N N 1   i s _ V B Z   a _ A T 1   c o n v e n i e n t _ J J   o f f i c e - b a s e d _ J J   p r o c e d u r e _ N N 1   f o r _ I F   b o t h _ D B 2   n e w _ J J   a n d _ C C   p r e v i o u s l y _ R R   t r e a t e d _ V V N   c a s e s _ N N 2   , _ ,   e s p e c i a l l y _ R R   h e l p f u l _ J J   f o r _ I F   t h o s e _ D D 2   p a t i e n t s _ N N 2   w h o _ P N Q S   a r e _ V B R   v u l n e r a b l e _ J J   t o _ I I   c u r r e n t _ J J   s a m p l i n g _ N N 1   m e t h o d s _ N N 2   . _ .   
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 S i m p l e _ J J   v i s u a l _ J J   h a l l u c i n a t i o n s _ N N 2   w e r e _ V B D R   r e p o r t e d _ V V N   m o r e _ R G R   o f t e n _ R R   t h a n _ C S N   c o m p l e x _ J J   o n e s _ N N 2   a n d _ C C   n o n c o l o r e d _ V V D   m o r e _ R G R   o f t e n _ R R   t h a n _ C S N   c o l o r e d _ J J   v i s u a l _ J J   h a l l u c i n a t i o n s _ N N 2   . _ .   
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 I n _ I I   8 9 . 2 % _ F O   o f _ I O   t h e _ A T   p a t i e n t s _ N N 2   , _ ,   t h e _ A T   c o n t r a s t _ N N 1   a g e n t _ N N 1   w a s _ V B D Z   i n j e c t e d _ V V N   a u t o m a t i c a l l y _ R R   a n d _ C C   i n _ I I   1 0 . 8 % _ F O   o f _ I O   t h e _ A T   p a t i e n t s _ N N 2   , _ ,   m a n u a l l y _ R R   . _ .   
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 T h e _ A T   q u a l i t y _ N N 1   o f _ I O   a n e s t h e s i a _ N N 1   w a s _ V B D Z   c o n s i d e r e d _ V V N   s a t i s f a c t o r y _ J J   w h e n _ C S   t h e _ A T   o c u l a r _ J J   m o b i l i t y _ N N 1   e v a l u a t i o n _ N N 1   s c o r e _ N N 1   a t _ I I   1 0 _ M C   m i n u t e s _ N N T 2   w a s _ V B D Z   l e s s _ D A R   t h a n _ C S N   4 _ M C   . _ .   
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 O n e _ M C 1   o f _ I O   t h e _ A T   m o s t _ R G T   o b v i o u s _ J J   g a p s _ N N 2   i n _ I I   t h e _ A T   l i t e r a t u r e _ N N 1   t o _ I I   d a t e _ N N 1   i s _ V B Z   t h e _ A T   l a c k _ N N 1   o f _ I O   r e s e a r c h _ N N 1   r e g a r d i n g _ I I   s o c i a l _ J J   a n x i e t y _ N N 1   d i s o r d e r _ N N 1   a m o n g _ I I   c h i l d r e n _ N N 2   a n d _ C C   a d o l e s c e n t s _ N N 2   w h o _ P N Q S   s t u t t e r _ V V 0   . _ .   
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 T h e _ A T   g e n o t y p e _ N N 1   f r e q u e n c i e s _ N N 2   f o r _ I F   t h e _ A T   t h r e e _ M C   e x a m i n e d _ J J   g e n o t y p e s _ N N 2   d i d _ V D D   n o t _ X X   d i f f e r _ V V I   s i g n i f i c a n t l y _ R R   f r o m _ I I   H a r d y - W e i n b e r g _ N P 1   e q u i l i b r i u m _ N N 1   : _ :   B D N F r s 6 2 6 5 _ F O   ( _ (   x 2 _ F O   = _ F O   0 . 8 3 7 _ M C   , _ ,   p _ Z Z 1   = _ F O   0 . 3 6 _ M C   ) _ )   , _ ,   C O M T r s 4 6 8 0 _ F O   ( _ (   x 2 _ F O   = _ F O   2 . 7 8 6 _ M C   , _ ,   p _ Z Z 1   = _ F O   0 . 1 0 _ M C   ) _ )   , _ ,   a n d _ C C   A P O E _ V V 0   r s 7 4 1 2 _ F O   , _ ,   r s 4 2 9 3 5 8 _ F O   ( _ (   x 2 _ F O   = _ F O   0 . 5 4 5 _ M C   , _ ,   p _ Z Z 1   = _ F O   0 . 9 0 9 _ M C   ) _ )   o r _ C C   a m o n g _ I I   a n y _ D D   b a s e l i n e _ N N 1   c h a r a c t e r i s t i c s _ N N 2   . _ .   
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 T h i s _ D D 1   i s _ V B Z   t h e _ A T   f i r s t _ M D   e v i d e n c e _ N N 1   s u g g e s t i n g _ V V G   t h a t _ D D 1   r i s k _ N N 1   a l l e l e s _ N N 2   f o r _ I F   B D _ N P 1   i n _ I I   C R E B 1 _ F O   a r o s e _ V V D   i n _ I I   E u r o p e a n s _ N N 2   t h r o u g h _ I I   g e n e t i c _ J J   h i t c h h i k i n g _ N N 1   d u e _ I I 2 1   t o _ I I 2 2   n a t u r a l _ J J   s e l e c t i o n _ N N 1   o n _ I I   i t s _ A P P G E   n e i g h b o r i n g _ J J   g e n e _ N N 1   . _ .   
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 T i m e _ N N T 1   t o _ T O   c o m p l e t e _ V V I   S t a g e _ N N 1   1 _ M C 1   h a s _ V H Z   b e e n _ V B N   u s e d _ V V N   a s _ I I   a n _ A T 1   o u t c o m e _ N N 1   m e a s u r e _ N N 1   o r _ C C   a _ A T 1   t a r g e t _ N N 1   f o r _ I F   r e g r e s s i o n _ N N 1   m o d e l i n g _ V V G   i n _ I I   m a n y _ D A 2   r e s e a r c h _ N N 1   s t u d i e s _ N N 2   i n t o _ I I   t h e _ A T   L i d c o m b e _ N P 1   P r o g r a m _ N N 1   ( _ (   e . g . _ R E X   , _ ,   K i n g s t o n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 3 _ M C   ; _ ;   K o u s h i k _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 1 _ M C   ; _ ;   L e w i s _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 8 _ M C   ) _ )   d u e _ I I 2 1   t o _ I I 2 2   i t s _ A P P G E   d o c u m e n t a t i o n _ N N 1   o f _ I O   t h e _ A T   t i m e _ N N T 1   c o m m i t m e n t _ N N 1   r e q u i r e d _ V V N   f r o m _ I I   t h e _ A T   S L P _ N P 1   , _ ,   p a r e n t _ N N 1   a n d _ C C   c h i l d _ N N 1   t o _ T O   o b t a i n _ V V I   e x t r e m e l y _ R R   l o w _ R R   s t u t t e r i n g _ V V G   l e v e l s _ N N 2   . _ .   
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 H i s t o r i c a l l y _ R R   u n d e r s t u d i e d _ J J   , _ ,   c h o l e s t e r o l _ N N 1   i n _ I I   t h e _ A T   r e t i n a _ N N 1   i s _ V B Z   r e c e i v i n g _ V V G   m o r e _ D A R   a t t e n t i o n _ N N 1   n o w _ R T   b e c a u s e _ I I 2 1   o f _ I I 2 2   g e n e t i c _ J J   s t u d i e s _ N N 2   s h o w i n g _ V V G   t h a t _ C S T   s e v e r a l _ D A 2   c h o l e s t e r o l - r e l a t e d _ J J   g e n e s _ N N 2   a r e _ V B R   r i s k _ N N 1   f a c t o r s _ N N 2   f o r _ I F   a g e - r e l a t e d _ J J   m a c u l a r _ J J   d e g e n e r a t i o n _ N N 1   ( _ (   A M D _ N P 1   ) _ )   a n d _ C C   b e c a u s e _ I I 2 1   o f _ I I 2 2   e y e _ N N 1   p a t h o l o g y _ N N 1   s t u d i e s _ N N 2   s h o w i n g _ V V G   h i g h _ J J   c h o l e s t e r o l _ N N 1   c o n t e n t _ N N 1   o f _ I O   d r u s e n _ N N 1   , _ ,   a g i n g _ V V G   B r u c h _ N P 1   ' _ N U L L   s _ Z Z 1   m e m b r a n e _ N N 1   , _ ,   a n d _ C C   n e w l y _ R R   f o u n d _ V V N   s u b r e t i n a l _ J J   l e s i o n s _ N N 2   . _ .   
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 P u l s e _ N N 1   s e q u e n c e s _ N N 2   i n c l u d e d _ V V D   a x i a l _ J J   t u r b o _ N N 1   s p i n - e c h o _ J J   T 2 - w e i g h t e d _ J J   i m a g i n g _ N N 1   ( _ (   r e p e t i t i o n _ N N 1   t i m e _ N N T 1   m s e c / e c h o _ N N 1   t i m e _ N N T 1   m s e c _ N N 1   , _ ,   4 0 0 0 - 4 9 6 0 / 1 0 5 _ M C M C   ; _ ;   s e c t i o n _ N N 1   t h i c k n e s s _ N N 1   , _ ,   3 _ M C   m m _ N N U   ; _ ;   f i e l d _ N N 1   o f _ I O   v i e w _ N N 1   , _ ,   1 8 0 _ M C   X _ Z Z 1   1 8 0 _ M C   m m _ N N U   ; _ ;   m a t r i x _ N N 1   , _ ,   2 5 6 _ M C   X _ Z Z 1   2 5 6 _ M C   ; _ ;   p a r a l l e l _ R R   i m a g i n g _ V V G   f a c t o r _ N N 1   , _ ,   t w o _ M C   ; _ ;   t h r e e _ M C   s i g n a l s _ N N 2   a c q u i r e d _ V V N   ) _ )   a n d _ C C   s i n g l e - s h o t _ J J   e c h o - p l a n a r _ J J   D W I _ N N 2   ( _ (   4 1 0 0 / 8 6 _ M F   ; _ ;   s e c t i o n _ N N 1   t h i c k n e s s _ N N 1   , _ ,   3 _ M C   m m _ N N U   ; _ ;   f i e l d _ N N 1   o f _ I O   v i e w _ N N 1   , _ ,   2 0 0 _ M C   X _ Z Z 1   2 0 0 _ M C   ; _ ;   m a t r i x _ N N 1   , _ ,   1 0 0 _ M C   X _ Z Z 1   1 0 0 _ M C   ; _ ;   p a r a l l e l _ R R   i m a g i n g _ V V G   f a c t o r _ N N 1   , _ ,   t w o _ M C   ; _ ;   1 0 _ M C   s i g n a l s _ N N 2   a c q u i r e d _ V V N   ; _ ;   b _ Z Z 1   v a l u e s _ N N 2   , _ ,   5 0 _ M C   a n d _ C C   1 0 0 0 _ M C   s e c / m m 2 _ F U   ) _ )   w i t h _ I W   i n l i n e _ N N 1   r e c o n s t r u c t i o n _ N N 1   v i a _ I I   a _ A T 1   m o n o e x p o n e n t i a l _ J J   f i t _ N N 1   o f _ I O   t h e _ A T   a p p a r e n t _ J J   d i f f u s i o n _ N N 1   c o e f f i c i e n t _ N N 1   m a p _ N N 1   a n d _ C C   a _ A T 1   c a l c u l a t e d _ J J   h i g h - b - v a l u e _ J J   i m a g e _ N N 1   s e t _ V V N   a t _ I I   a _ A T 1   b _ Z Z 1   v a l u e _ N N 1   o f _ I O   1 5 0 0 _ M C   s e c / m m 2 _ F U   . _ .   
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 B r a i n _ N N 1   w a s _ V B D Z   r e m o v e d _ V V N   , _ ,   g e n t l y _ R R   r i n s e d _ V V N   i n _ I I   c o l d _ N N 1   0 . 9 % _ F O   P B S _ N P 1   a n d _ C C   i m m e d i a t e l y _ R R   d i s s e c t e d _ V V N   i n _ I I   t w o _ M C   h a l v e s _ N N 2   . _ .   
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 I n _ I I   T e t r a h y m e n a _ N P 1   , _ ,   h i s t a m i n e _ N N 1   c a n _ V M   s t i m u l a t e _ V V I   a _ A T 1   n u m b e r _ N N 1   o f _ I O   c e l l _ N N 1   f u n c t i o n s _ N N 2   , _ ,   i n c l u d i n g _ I I   p h a g o c y t o s i s _ N N 1   , _ ,   c h e m o s e n s o r y _ J J   b e h a v i o r _ N N 1   , _ ,   g l u c o s e _ N N 1   u p t a k e _ N N 1   , _ ,   a n d _ C C   c e l l _ N N 1   d i v i s i o n _ N N 1   v i a _ I I   h i s t a m i n e _ N N 1   H 1 _ F O   a n d _ C C   H 2 _ F O   r e c e p t o r _ N N 1   a c t i v a t i o n _ N N 1   ( _ (   7 , 1 7 _ M C   ) _ )   . _ .   
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 D u l o x e t i n e _ N N 1   s p e c i f i c a l l y _ R R   i m p r o v e d _ V V N   p h y s i c a l _ J J   c o m f o r t _ N N 1   , _ ,   i n d e p e n d e n c e _ N N 1   , _ ,   e m o t i o n a l _ J J   , _ ,   a n d _ C C   p a i n _ N N 1   s u b c o m p o n e n t s _ N N 2   i n _ I I   t h e _ A T   q u a l i t y _ N N 1   o f _ I O   r e c o v e r y _ N N 1   s c o r e _ N N 1   . _ .   
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 S e n t a r a _ N P 1   N o r t h e r n _ J J   V i r g i n i a _ N P 1   M e d i c a l _ J J   C e n t e r _ N N 1   , _ ,   W o o d b r i d g e _ N P 1   , _ ,   V i r g i n i a _ N P 1   : _ :   J . _ N P 1   A g o l a _ N P 1   , _ ,   R . _ N P 1   Z w e i f l e r _ N P 1   , _ ,   J . _ N P 1   R a t h b u n _ N P 1   , _ ,   S . _ N P 1   C u m m i n g s _ N P 1   , _ ,   P . _ N P 1   H o l l s t e n _ N P 1   , _ ,   a n d _ C C   S . _ N P 1   B r i g h t _ N P 1   . _ .   
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 T h e _ A T   s u b j e c t s _ N N 2   u n d e r w e n t _ V V D   a _ A T 1   g e n e r a l _ J J   m e d i c a l _ J J   e x a m i n a t i o n _ N N 1   , _ ,   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   a _ A T 1   c l i n i c a l _ J J   a n a m n e s i s _ N N 1   , _ ,   t o _ T O   r u l e _ V V I   o u t _ R P   t h e _ A T   p r e s e n c e _ N N 1   o f _ I O   a n y _ D D   c a r d i - o l o g i c _ J J   s y m p t o m s _ N N 2   c o n t r a i n d i c a t i n g _ V V G   e x e r c i s e _ N N 1   , _ ,   o r _ C C   t h e _ A T   p r e s e n c e _ N N 1   o f _ I O   r e d u c e d _ J J   e f f o r t _ N N 1   t o l e r a n c e _ N N 1   . _ .   
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 J a m e s o n _ N N 1   a n d _ C C   L o n g o _ N P 1   d e f i n e _ V V 0   p r e c i s i o n _ N N 1   m e d i c i n e _ N N 1   a s _ C S A   " _ "   t r e a t m e n t s _ N N 2   t a r g e t e d _ V V N   t o _ I I   t h e _ A T   n e e d s _ N N 2   o f _ I O   i n d i v i d u a l _ J J   p a t i e n t s _ N N 2   o n _ I I   t h e _ A T   b a s i s _ N N 1   o f _ I O   g e n e t i c _ J J   ' _ N U L L   b i o m a r k e r _ N N 1   ' _ N U L L   p h e n o t y p i c _ J J   o r _ C C   p s y c h o s o c i a l _ J J   c h a r a c t e r i s t i c s _ N N 2   t h a t _ C S T   d i s t i n g u i s h _ V V 0   a _ A T 1   g i v e n _ J J   p a t i e n t _ N N 1   f r o m _ I I   o t h e r _ J J   p a t i e n t s _ N N 2   w i t h _ I W   s i m i l a r _ J J   c l i n i c a l _ J J   p r e s e n t a t i o n s _ N N 2   " _ "   ( _ (   J a m e s o n _ N P 1   a n d _ C C   L o n g o _ N P 1   ' _ N U L L   2 0 1 5 _ M C   ) _ )   . _ .   
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 W e _ P P I S 2   u s e d _ V V D   t h i s _ D D 1   p e r c e n t a g e _ N N 1   a s _ I I   a _ A T 1   m e a s u r e _ N N 1   o f _ I O   a g e - r e l a t e d _ J J   G M D _ N P 1   d e c l i n e _ N N 1   a n d _ C C   f o u n d _ V V D   t h a t _ C S T   t h e _ A T   a r e a s _ N N 2   m o s t _ R G T   s e n s i t i v e _ J J   t o _ I I   G M D _ N P 1   d e c r e a s e s _ N N 2   w e r e _ V B D R   t h e _ A T   l e f t _ J J   I F G _ N N 1   t r i a n g u l a r i s _ N N 1   ( _ (   6 4 % _ N N U   ) _ )   a n d _ C C   b i l a t e r a l _ J J   I F G _ N N 1   o p e r c u l a r i s _ N N 1   ( _ (   l e f t _ V V N   : _ :   6 7 % _ N N U   ; _ ;   r i g h t _ R R   : _ :   8 0 % _ N N U   ) _ )   . _ .   
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 T h i s _ D D 1   p r o b l e m _ N N 1   i s _ V B Z   i l l u s t r a t e d _ V V N   b y _ I I   t h e _ A T   r e p o r t e d _ J J   i n c i d e n c e _ N N 1   o f _ I O   t h e _ A T   o u t c o m e _ N N 1   ( _ (   0 . 2 _ M C   a n d _ C C   2 . 3 % _ F O   , _ ,   r e s p e c t i v e l y _ R R   ) _ )   , _ ,   w h i c h _ D D Q   w a s _ V B D Z   m u c h _ R R   l o w e r _ J J R   t h a n _ C S N   r e p o r t e d _ V V N   i n _ I I   o t h e r _ J J   s t u d i e s _ N N 2   . _ .   
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 A l m o s t _ R R   h a l f _ D B   o f _ I O   t h e _ A T   p a t i e n t _ J J   p a r t i c i p a n t s _ N N 2   h a d _ V H D   a _ A T 1   p e r s o n a l _ J J   o r _ C C   f a m i l y _ N N 1   h i s t o r y _ N N 1   o f _ I O   d r u g _ N N 1   u s e _ N N 1   o r _ C C   o f _ I O   m e n t a l _ J J   h e a l t h _ N N 1   p r o b l e m s _ N N 2   , _ ,   o r _ C C   b o t h _ R R   , _ ,   w h i c h _ D D Q   o v e r - r e p r e s e n t s _ V V Z   t h e _ A T   t y p i c a l _ J J   r a t e _ N N 1   e s t i m a t e d _ V V N   i n _ I I   i n d i v i d u a l s _ N N 2   w i t h _ I W   c h r o n i c _ J J   p a i n _ N N 1   . _ .   
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 D e s p i t e _ I I   t h e s e _ D D 2   f i n d i n g s _ N N 2   , _ ,   t h e _ A T   a m o u n t _ N N 1   a n d _ C C   i n t e n s i t y _ N N 1   o f _ I O   l o c o m o t o r _ N N 1   p r a c t i c e _ N N 1   o b s e r v e d _ V V N   d u r i n g _ I I   i n p a t i e n t _ N N 1   r e h a b i l i t a t i o n _ N N 1   o f _ I O   i n d i v i d u a l s _ N N 2   p o s t s t r o k e _ V V 0   r e m a i n _ V V 0   l i m i t e d _ J J   . _ .   
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 O u r _ A P P G E   r e s u l t s _ N N 2   s u g g e s t _ V V 0   t h a t _ C S T   a t _ I I   l o w _ J J   l e v e l s _ N N 2   o f _ I O   s c r e e n - d e t e c t e d _ J J   D C I S _ N N 1   , _ ,   u p _ R G 2 1   t o _ R G 2 2   1 _ M C 1   . _ .   
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 5 _ M C   p e r _ I I   1 0 0 0 _ M C   , _ ,   a _ A T 1   r e d u c t i o n _ N N 1   o f _ I O   o n e _ M C 1   i n v a s i v e _ J J   i n t e r v a l _ N N 1   c a n c e r _ N N 1   i s _ V B Z   o b s e r v e d _ V V N   p e r _ I I   1 _ M C 1   . _ .   
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 D r . _ N N B   C h a n _ N P 1   a n d _ C C   c o l l e a g u e s _ N N 2   p e r f o r m e d _ V V D   a _ A T 1   s i n g l e - c e n t e r _ N N 1   , _ ,   p r o s p e c t i v e _ J J   c o h o r t _ N N 1   s t u d y _ N N 1   o f _ I O   a d u l t _ N N 1   p a t i e n t s _ N N 2   w i t h _ I W   c a n c e r _ N N 1   w h o _ P N Q S   h a d _ V H D   s o l i d _ J J   t u m o r s _ N N 2   o r _ C C   l y m p h o m a _ N N 1   , _ ,   h a d _ V H D   r e c e i v e d _ V V N   c h e m o t h e r a p y _ N N 1   , _ ,   a n d _ C C   d e v e l o p e d _ V V N   F N _ N P 1   b e t w e e n _ I I   J a n u a r y _ N P M 1   2 0 0 9 _ M C   a n d _ C C   J a n u a r y _ N P M 1   2 0 1 2 _ M C   . _ .   
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 T h e _ A T   i n j e c t e d _ J J   a c t i v i t y _ N N 1   , _ ,   s p e c i f i c _ J J   a c t i v i t y _ N N 1   , _ ,   a n d _ C C   i n j e c t e d _ V V D   m a s s _ J J   d o s e _ N N 1   o f _ I O   b o t h _ D B 2   r a d i o l i g a n d s _ N N 2   w e r e _ V B D R   s i m i l a r _ J J   f o r _ I F   m o n k e y s _ N N 2   t h a t _ C S T   w e r e _ V B D R   a d m i n i s t e r e d _ V V N   e i t h e r _ R R   p l a c e b o _ N N 1   o r _ C C   f l u o x e t i n e _ N N 1   ( _ (   s e e _ V V 0   T a b l e _ N N 1   S 1 _ F O   i n _ I I   t h e _ A T   o n l i n e _ J J   d a t a _ N N   s u p p l e m e n t _ V V 0   ) _ )   . _ .   
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 C a l c u l a t i o n _ N N 1   o f _ I O   B i n d i n g _ J J   P o t e n t i a l _ N N 1   ( _ (   B P N d _ N P 1   ) _ )   U s i n g _ V V G   a _ A T 1   R e f e r e n c e _ N N 1   T i s s u e _ N N 1   M o d e l _ N N 1   B i n d i n g _ J J   p o t e n t i a l _ N N 1   ( _ (   B P N d _ N P 1   ) _ )   , _ ,   w h i c h _ D D Q   i s _ V B Z   t h e _ A T   r a t i o _ N N 1   a t _ I I   e q u i l i b r i u m _ N N 1   o f _ I O   s p e c i f i c _ J J   b i n d i n g _ N N 1   t o _ I I   n o n d i s p l a c e a b l e _ J J   u p t a k e _ N N 1   i n _ I I   t h e _ A T   b r a i n _ N N 1   , _ ,   w a s _ V B D Z   u s e d _ J J   t o _ I I   m e a s u r e _ N N 1   r e c e p t o r _ N N 1   d e n s i t y _ N N 1   . _ .   
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 I n _ I I   t h e _ A T   e a r l y _ J J   g r o u p _ N N 1   , _ ,   R R T _ N P 1   w a s _ V B D Z   s t a r t e d _ V V N   a f t e r _ I I   s e r u m _ N N 1   c r e a t i n i n e _ N N 1   e x c e e d e d _ V V D   7 _ M C   m g / d L _ F U   o r _ C C   s e r u m _ N N 1   u r e a _ N N 1   e x c e e d e d _ V V D   2 5 _ M C   m m o l / L _ F U   r e g a r d l e s s _ R R   o f _ I O   o t h e r _ J J   A K I _ J J   c o m p l i c a t i o n s _ N N 2   . _ .   
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 T h e _ A T   c a n c e r _ N N 1   p r o f i l e _ N N 1   i n _ I I   U S _ N P 1   H i s p a n i c s _ N P 1   r e f l e c t s _ V V Z   t h e _ A T   r i s k _ N N 1   i n _ I I   i m m i g r a n t _ J J   c o u n t r i e s _ N N 2   o f _ I O   o r i g i n _ N N 1   . _ .   
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 T h e _ A T   1 2 - _ N N 1   a n d _ C C   1 8 - m o n t h _ J J   a s s e s s m e n t s _ N N 2   m e a s u r e d _ V V D   t h e _ A T   m a i n t e n a n c e _ N N 1   o f _ I O   e f f e c t s _ N N 2   o v e r _ I I   t i m e _ N N T 1   . _ .   
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 A s _ C S A   d i s e a s e _ N N 1   m a n a g e m e n t _ N N 1   b e c o m e s _ V V Z   i n c r e a s i n g l y _ R R   c o m p l e x _ J J   , _ ,   b r i n g i n g _ V V G   t o g e t h e r _ R L   a _ A T 1   g r o u p _ N N 1   o f _ I O   e x p e r t s _ N N 2   , _ ,   a l l _ D B   o f _ I O   w h o m _ P N Q O   c a n _ V M   i n d e p e n d e n t l y _ R R   c o n t r i b u t e _ V V I   t o _ I I   a _ A T 1   d i a g n o s i s _ N N 1   a n d _ C C   s u g g e s t e d _ J J   t r e a t m e n t _ N N 1   s t r a t e g y _ N N 1   i s _ V B Z   i m p o r t a n t _ J J   . _ .   
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 S t u d e n t _ N N 1   ' _ N U L L   s _ Z Z 1   t - t e s t _ J J   o r _ C C   o n e - w a y _ J J   a n o v a _ N N 1   w a s _ V B D Z   u s e d _ V V N   f o r _ I F   c o m p a r i n g _ V V G   m e a n _ J J   d a t a _ N N   f r o m _ I I   s e p a r a t e _ J J   e x p e r i m e n t s _ N N 2   . _ .   
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 T h e _ A T   e f f e c t _ N N 1   o f _ I O   t h e _ A T   C P T _ N P 1   a n d _ C C   e x e r c i s e _ V V 0   c o n d i t i o n s _ N N 2   o n _ I I   p a i n _ N N 1   s e n s i t i v i t y _ N N 1   p a r a m e t e r s _ N N 2   w a s _ V B D Z   a n a l y z e d _ V V N   u s i n g _ V V G   a _ A T 1   3 - w a y _ J J   R M - A N O V A _ N N 1   w i t h _ I W   f a c t o r _ N N 1   c o n d i t i o n _ N N 1   ( _ (   t h e _ A T   C P T _ N P 1   , _ ,   b i c y c l i n g _ V V G   , _ ,   a n d _ C C   i s o m e t r i c _ J J   c o n t r a c t i o n s _ N N 2   ) _ )   a n d _ C C   t i m e _ N N T 1   ( _ (   b e f o r e _ R T   , _ ,   i m m e d i a t e l y _ R R   a f t e r _ C S   , _ ,   a n d _ C C   1 5 _ M C   m i n _ N N U   a f t e r _ I I   ) _ )   a s _ C S A   r e p e a t e d _ V V N   m e a s u r e s _ N N 2   a n d _ C C   p a i n _ N N 1   s e n s i t i v i t y _ N N 1   g r o u p _ N N 1   a s _ I I   t h e _ A T   g r o u p _ N N 1   f a c t o r _ N N 1   . _ .   
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 A M _ V B M   t r e a t m e n t _ N N 1   a l s o _ R R   s i g n i f i c a n t l y _ R R   i n c r e a s e d _ V V D   t h e _ A T   n u m b e r _ N N 1   o f _ I O   c a p i l l a r i e s _ N N 2   i n _ I I   i s c h e m i c _ J J   l i m b s _ N N 2   . _ .   
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 F u r t h e r _ J J R   s t u d i e s _ N N 2   a r e _ V B R   n e e d e d _ V V N   t o _ T O   e v a l u a t e _ V V I   t h e _ A T   n u m b e r _ N N 1   o f _ I O   T A C E _ N P 1   p r o c e d u r e s _ N N 2   n e e d e d _ V V N   b e f o r e _ I I   t h i s _ D D 1   t h e r a p y _ N N 1   i s _ V B Z   a b a n d o n e d _ V V N   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   N E L M _ N P 1   w h o _ P N Q S   a r e _ V B R   n o n r e s p o n d e r s _ N N 2   . _ .   
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 T a b l e _ N N 1   2 _ M C   s h o w s _ V V Z   t h e _ A T   l e v e l _ N N 1   o f _ I O   p a i n _ N N 1   t h a t _ C S T   p a t i e n t s _ N N 2   e x p e r i e n c e d _ V V N   a n d _ C C   t h e i r _ A P P G E   a b i l i t y _ N N 1   t o _ T O   u n d e r t a k e _ V V I   c e r t a i n _ J J   a c t i v i t i e s _ N N 2   a t _ I I   1 0 _ M C   d a y s _ N N T 2   , _ ,   6 _ M C   w e e k s _ N N T 2   , _ ,   3 _ M C   m o n t h s _ N N T 2   , _ ,   a n d _ C C   1 2 _ M C   m o n t h s _ N N T 2   . _ .   
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 R e p a n s h e k _ N P 1   s u g g e s t e d _ V V D   t h a t _ C S T   i n _ I I   a n _ A T 1   i d e a l _ J J   w o r l d _ N N 1   , _ ,   a _ A T 1   s e c o n d a r y _ J J   a n a l y s i s _ N N 1   o f _ I O   b o t h _ R R   r e s p o n d e n t s _ N N 2   a n d _ C C   n o n r e s p o n d e n t s _ N N 2   t o _ I I   t h e _ A T   P r e s s _ N N 1   G a n e y _ N P 1   s u r v e y _ N N 1   s h o u l d _ V M   b e _ V B I   c o n d u c t e d _ V V N   t o _ T O   d e t e r m i n e _ V V I   t h e i r _ A P P G E   d e m o g r a p h i c _ J J   , _ ,   p a t i e n t _ J J   p r o f i l e _ N N 1   , _ ,   a n d _ C C   s a t i s f a c t i o n _ N N 1   d i f f e r e n c e s _ N N 2   . _ .   
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 T h e _ A T   ' _ N U L L   h i g h _ J J   a v o i d a n c e _ N N 1   , _ ,   l o w _ J J   o v e r a c t i v i t y _ N N 1   ' _ N U L L   s u b g r o u p _ N N 1   w e r e _ V B D R   t h e _ A T   g r o u p _ N N 1   m o s t _ R G T   l i k e l y _ J J   t o _ T O   r e p o r t _ V V I   d i f f i c u l t i e s _ N N 2   ( _ (   O R = 5 . 1 0 _ F O   , _ ,   P = 0 . 0 0 3 _ F O   ; _ ;   9 5 % _ N N U   C I _ F O   , _ ,   0 . 5 6 - 2 . 7 0 _ M C M C   ) _ )   , _ ,   f o l l o w e d _ V V N   b y _ I I   t h e _ A T   ' _ N U L L   h i g h _ J J   a v o i d a n c e _ N N 1   , _ ,   h i g h _ J J   o v e r a c t i v i t y _ N N 1   ' _ N U L L   s u b g r o u p _ N N 1   ( _ (   O R = 3 . 7 0 _ F O   , _ ,   P = 0 . 0 0 9 _ F O   ; _ ;   9 5 % _ N N U   C I _ F O   , _ ,   0 . 3 3 - 2 . 3 _ M C M C   ) _ )   , _ ,   t h e n _ R T   t h e _ A T   ' _ N U L L   h i g h _ J J   o v e r a c t i v i t y _ N N 1   , _ ,   l o w _ J J   a v o i d a n c e _ N N 1   ' _ N U L L   s u b g r o u p _ N N 1   ( _ (   O R = 2 . 9 9 _ F O   , _ ,   P = 0 . 0 3 _ F O   ; _ ;   9 5 % _ N N U   C I _ F O   , _ ,   0 . 0 8 - 2 . 1 1 _ M C M C   ) _ )   . _ .   
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 F o r _ I F   e a c h _ D D 1   m a j o r _ J J   c a u s e _ N N 1   o f _ I O   d e a t h _ N N 1   , _ ,   B M I _ N P 1   w a s _ V B D Z   n o n - l i n e a r l y _ R R   a s s o c i a t e d _ V V N   w i t h _ I W   m o r t a l i t y _ N N 1   i n _ I I   e a c h _ D D 1   m a j o r _ J J   r e g i o n _ N N 1   w e _ P P I S 2   s t u d i e d _ V V D   ( _ (   a p p e n d i x _ N N 1   p p _ N N U 2   2 7 - 2 9 _ M C M C   , _ ,   4 1 _ M C   , _ ,   4 2 _ M C   ) _ )   . _ .   
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 A _ Z Z 1   s h o r t e n e d _ V V D   C S P _ N P 1   i n d i c a t e s _ V V Z   a _ A T 1   d y s f u n c t i o n _ N N 1   i n _ I I   t h e _ A T   i n h i b i t o r y _ J J   m e c h a n i s m s _ N N 2   , _ ,   i n _ I I   e s s e n c e _ N N 1   ' _ N U L L   t o o _ R G   l i t t l e _ D A 1   ' _ N U L L   i n h i b i t i o n _ N N 1   . _ .   
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 E n h a n c e d _ J J   M I T F _ N N 1   e x p r e s s i o n _ N N 1   i s _ V B Z   l i n k e d _ V V N   t o _ I I   i n n a t e _ J J   r e s i s t a n c e _ N N 1   , _ ,   a n d _ C C   i n c r e a s e d _ J J   M I T F _ N N 1   e x p r e s s i o n _ N N 1   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   M I T F _ N P 1   a m p l i f i c a t i o n _ N N 1   i s f o u n d _ N N 1   i n _ I I   s o m e _ D D   p r o g r e s s e d _ V V D   m e l a n o m a s _ N N 2   ( _ (   G o p a l _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 4 _ M C   ; _ ;   J i _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 5 _ M C   ; _ ;   M u l l e r _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 4 _ M C   ; _ ;   V a n _ N P 1   A l l e n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 4 _ M C   ) _ )   . _ .   
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 B D _ N P 1   s a m p l e s _ N N 2   w e r e _ V B D R   e x c l u d e d _ V V N   i f _ C S   a n y _ D D   o f _ I O   t h e _ A T   f o l l o w i n g _ J J   Q C _ N N 1   s t a t i s t i c s _ N N   c o n s t i t u t e d _ V V D   a n _ A T 1   o u t l i e r _ J J R   w i t h i n _ I I   t h e i r _ A P P G E   s o u r c e _ N N 1   d a t a _ N N   s e t _ V V 0   : _ :   L o g _ V V 0   R _ Z Z 1   r a t i o s _ N N 2   s . d . _ N N U   , _ ,   B - a l l e l e _ J J   f r e q u e n c y _ N N 1   d r i f t _ N N 1   , _ ,   w a v e _ N N 1   f a c t o r _ N N 1   a n d _ C C   t o t a l _ J J   n u m b e r _ N N 1   o f _ I O   C N V s _ N P 1   . _ .   
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 N e e d l e _ N N 1   T i p _ N N 1   I n t e r p r e t a t i o n _ N N 1   A c c u r a t e _ J J   a n d _ C C   r e l i a b l e _ J J   p r e s e n t a t i o n _ N N 1   o f _ I O   t h e _ A T   n e e d l e _ N N 1   t i p _ N N 1   b y _ I I   t h e _ A T   U S _ N P 1   m a c h i n e _ N N 1   i s _ V B Z   o n l y _ R R   u s e f u l _ J J   i f _ C S   t h e _ A T   n e e d l e _ N N 1   t i p _ N N 1   c a n _ V M   b e _ V B I   i n t e r p r e t e d _ V V N   a s _ C S A   s u c h _ D A   b y _ I I   t h e _ A T   p r o v i d e r _ N N 1   . _ .   
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 T h e _ A T   v i e w s _ N N 2   e x p r e s s e d _ V V N   a r e _ V B R   t h o s e _ D D 2   o f _ I O   t h e _ A T   a u t h o r s _ N N 2   a n d _ C C   n o t _ X X   n e c e s s a r i l y _ R R   t h o s e _ D D 2   o f _ I O   t h e _ A T   N a t i o n a l _ J J   H e a l t h _ N N 1   S e r v i c e _ N N 1   , _ ,   N I H R _ N P 1   , _ ,   o r _ C C   U K _ N P 1   D e p a r t m e n t _ N N 1   o f _ I O   H e a l t h _ N N 1   . _ .   
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 T h e _ A T   e v a l u a t i o n _ N N 1   q u e s t i o n n a i r e _ N N 1   c o n s i s t e d _ V V N   o f 6 q u e s t i o n s _ F O   , _ ,   3 _ M C   o f _ I O   w h i c h _ D D Q   w e r e _ V B D R   u s e d _ V V N   t o _ T O   o b t a i n _ V V I   b a c k g r o u n d _ N N 1   i n f o r m a t i o n _ N N 1   r e g a r d i n g _ I I   a g e _ N N 1   , _ ,   s e x _ N N 1   , _ ,   d i a g n o s i s _ N N 1   . _ .   
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 T h e _ A T   m e a n _ J J   d u r a t i o n _ N N 1   o f _ I O   D M E _ N N 1   b e f o r e _ I I   s t u d y _ N N 1   e n t r y _ N N 1   w a s _ V B D Z   2 4 . 9 _ M C   m o n t h s _ N N T 2   ( _ (   m e d i a n _ N N 1   , _ ,   1 6 _ M C   ) _ )   . _ .   
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 H o w e v e r _ R R   , _ ,   t h e _ A T   s t a t i s t i c a l _ J J   h e t e r o g e n e i t y _ N N 1   s u g g e s t e d _ V V D   t h a t _ C S T   r e a s o n a b l e _ J J   c a u t i o n s _ N N 2   c o u l d _ V M   b e _ V B I   t a k e n _ V V N   w i t h _ I W   t h e _ A T   n u m e r i c a l _ J J   v a l u e _ N N 1   o f _ I O   H R _ N N U   . _ .   
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 W r i t t e n _ V V N   i n f o r m e d _ J J   c o n s e n t _ N N 1   w a s _ V B D Z   o b t a i n e d _ V V N   f r o m _ I I   a l l _ D B   s t u d y _ N N 1   p a r t i c i p a n t s _ N N 2   . _ .   
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 O t h e r _ J J   a p p l i c a t i o n s _ N N 2   , _ ,   s u c h _ I I 2 1   a s _ I I 2 2   m a c h i n e - l e a r n i n g _ J J   a l g o r i t h m s _ N N 2   f o r _ I F   p r e d i c t i n g _ V V G   p n e u m o n i a _ N N 1   m o r t a l i t y _ N N 1   a n d _ C C   p r e s e n c e _ N N 1   o f _ I O   m y o c a r d i a l _ J J   i n f a r c t i o n _ N N 1   , _ ,   h a v e _ V H 0   a l s o _ R R   b e e n _ V B N   d e v e l o p e d _ V V N   . _ .   
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 A d e q u a t e _ J J   d i u r e s i s _ N N 1   t o g e t h e r _ R L   w i t h _ I W   n o _ A T   n e e d _ N N 1   f o r _ I F   r e n a l - r e p l a c e m e n t _ J J   t h e r a p y _ N N 1   w e r e _ V B D R   o b s e r v e d _ V V N   e a r l i e r _ R R R   i n _ I I   t h e _ A T   d e l a y e d - s t r a t e g y _ J J   g r o u p _ N N 1   t h a n _ C S N   i n _ I I   t h e _ A T   e a r l y - s t r a t e g y _ J J   g r o u p _ N N 1   ( _ (   P _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 0 1 _ M C   ) _ )   ( _ (   F i g . _ N N 1   2 _ M C   ) _ )   . _ .   
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 T o _ T O   c o n f i r m _ V V I   t h a t _ C S T   t h e _ A T   d V M A T _ N N 1   w e a k _ J J   e x p r e s s o r _ N N 1   w o u l d _ V M   r e s p o n d _ V V I   t o _ I I   d r u g s _ N N 2   t h a t _ C S T   a c t _ V V 0   p r e s y n a p t i c a l l y _ R R   , _ ,   w e _ P P I S 2   u s e d _ V V D   a m p h e t a m i n e _ N N 1   , _ ,   w h i c h _ D D Q   p r o m o t e s _ V V Z   t h e _ A T   p r e s y n a p t i c _ J J   r e l e a s e _ N N 1   o f _ I O   m o n o a m i n e s _ N N 2   i n _ I I   b o t h _ D B 2   m a m m a l s _ N N 2   ( _ (   1 0 _ M C   ) _ )   a n d _ C C   f l i e s _ N N 2   ( _ (   1 6 _ M C   ) _ )   . _ .   
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 T h e s e _ D D 2   r e s u l t s _ N N 2   a g r e e _ V V 0   w i t h _ I W   s t u d i e s _ N N 2   s h o w i n g _ V V G   i n c r e a s e d _ J J   v a s c u l a r _ J J   p e r m e a b i l i t y _ N N 1   i n _ I I   n o n - b a r r i e r _ J J   e n d o t h e l i u m _ N N 1   f r o m _ I I   C a v - 1 - / - _ F U   m i c e _ N N 2   ( _ (   S c h u b e r t _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   ' _ N U L L   
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 M o r e o v e r _ R R   , _ ,   e x c e s s i v e _ J J   w e i g h t _ N N 1   l o s s _ N N 1   i n _ I I   a _ A T 1   s h o r t _ J J   p e r i o d _ N N 1   o f _ I O   t i m e _ N N T 1   w a s _ V B D Z   d i s c o u r a g e d _ V V N   , _ ,   s i n c e _ C S   s u c h _ D A   a _ A T 1   r e d u c t i o n _ N N 1   i n _ I I   w e i g h t _ N N 1   h a s _ V H Z   b e e n _ V B N   r e p o r t e d _ V V N   t o _ T O   h a v e _ V H I   a _ A T 1   n e g a t i v e _ J J   e f f e c t _ N N 1   o n _ I I   t h e _ A T   o u t c o m e _ N N 1   o f _ I O   a s s i s t e d _ J J   r e p r o d u c t i v e _ J J   t e c h n o l o g y _ N N 1   a n d _ C C   t o _ T O   b e _ V B I   a s s o c i a t e d _ V V N   w i t h _ I W   a n _ A T 1   i n c r e a s e d _ J J   r i s k _ N N 1   o f _ I O   a d v e r s e _ J J   p r e g n a n c y _ N N 1   o u t c o m e s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   l o w _ J J   b i r t h _ N N 1   w e i g h t _ N N 1   o r _ C C   m i s c a r r i a g e _ N N 1   . _ .   
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 A _ A T 1   c l i n i c a l _ J J   d i a g n o s t i c _ J J   t r i a l _ N N 1   i s _ V B Z   r e q u i r e d _ V V N   t o _ T O   t e s t _ V V I   t h i s _ D D 1   m o d e l _ N N 1   o n _ I I   a _ A T 1   l a r g e r _ J J R   p o p u l a t i o n _ N N 1   t o _ T O   c o n f i r m _ V V I   t h e s e _ D D 2   f i n d i n g s _ N N 2   a n d _ C C   t o _ T O   f u r t h e r _ R R R   r e f i n e _ V V I   t h e _ A T   p r e d i c t i v e _ J J   v a l u e s _ N N 2   . _ .   
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 F i n a n c i a l _ J J   c o s t _ N N 1   o f _ I O   M e n i e t t _ N P 1   d e v i c e _ N N 1   T h e _ A T   c o s t _ N N 1   o f u s i n g _ V V G   t h e _ A T   M e n i e t t _ N P 1   d e v i c e _ N N 1   i n _ I I   t h e _ A T   U K _ N P 1   i s _ V B Z   G B P 2 0 0 0 _ F O   a n d _ C C   i n _ I I   N o r t h _ N D 1   A m e r i c a _ N P 1   i s _ V B Z   a p p r o x i m a t e l y _ R R   $ 2 5 0 0 _ N N U   . _ .   
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 T h i s _ D D 1   m a k e s _ V V Z   i t _ P P H 1   v e r y _ R G   u n l i k e l y _ J J   t h a t _ C S T   t h e _ A T   o b e s i t y _ N N 1   e p i d e m i c _ N N 1   i s _ V B Z   c a u s e d _ V V N   b y _ I I   e n v i r o n - m e n t a l _ J J   c h a n g e s _ N N 2   t h a t _ C S T   a f f e c t _ V V 0   c e r t a i n _ J J   s o c i o d e m o g r a p h i c _ J J   s u b - g r o u p s _ N N 2   d i s p r o p o r t i o n a l l y _ R R   . _ .   
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 T h a t _ D D 1   s a i d _ V V D   , _ ,   c h i l d r e n _ N N 2   w h o _ P N Q S   d o _ V D 0   n o t _ X X   s t u t t e r _ V V I   h a d _ V H D   a _ A T 1   h i g h e r _ J J R   m e a n _ J J   s c o r e _ N N 1   o n _ I I   s u b s e c t i o n _ N N 1   I B _ N N 1   ( _ (   i n d i c a t i n g _ V V G   l e s s _ D A R   k n o w l e d g e _ N N 1   o f _ I O   s t u t t e r i n g _ V V G   ) _ )   i n _ I I 3 1   c o m p a r i s o n _ I I 3 2   w i t h _ I I 3 3   c h i l d r e n _ N N 2   w h o _ P N Q S   s t u t t e r _ V V 0   . _ .   
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 F o r t u n a t e l y _ R R   , _ ,   L i u _ N P 1   e t _ N P 1   a l 1 _ F O   f o u n d _ V V D   n o _ A T   e p i s o d e s _ N N 2   o f _ I O   c a r d i a c _ J J   a r r e s t _ N N 1   r e l a t e d _ V V D   t o _ T O   L A S T _ V V I   . _ .   
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 H o w e v e r _ R R   , _ ,   o t h e r _ J J   s t u d i e s _ N N 2   o n _ I I   N M D A R _ N P 1   b i n d i n g _ N N 1   h a v e _ V H 0   r e p o r t e d _ V V N   a n _ A T 1   i n c r e a s e _ N N 1   , _ ,   o r _ C C   n o _ A T   c h a n g e _ N N 1   i n _ I I   N M D A R _ N P 1   b i n d i n g _ V V G   i n _ I I   t h e _ A T   b r a i n s _ N N 2   o f _ I O   p e o p l e _ N N   w i t h _ I W   s c h i z o p h r e n i a _ N N 1   . _ .   
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 A s _ C S A   s k e l e t a l _ J J   m u s c l e s _ N N 2   c o n t r a c t _ N N 1   , _ ,   t h e _ A T   e l e v a t i o n _ N N 1   i n _ I I   e x t r a v a s c u l a r _ J J   p r e s s u r e _ N N 1   c a u s e s _ V V Z   c o m p r e s s i o n _ N N 1   o r _ C C   d i s t o r t i o n _ N N 1   o f _ I O   t h e _ A T   r e s i s t a n c e _ N N 1   v e s s e l s _ N N 2   , _ ,   t h u s _ R R   e x p o s i n g _ V V G   t h e _ A T   e r y t h r o c y t e s _ N N 2   t o _ I I   e v e n _ R R   g r e a t e r _ J J R   m e c h a n i c a l _ J J   s t r e s s _ N N 1   d u r i n g _ I I   e x e r c i s e _ N N 1   . _ .   
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 D u r i n g _ I I   t h e _ A T   i n i t i a l _ N N 1   t w o _ M C   s e s s i o n s _ N N T 2   , _ ,   s i t u a t i o n s _ N N 2   o r _ C C   p r o b l e m s _ N N 2   t h a t _ C S T   t r i g g e r _ V V 0   n e g a t i v e _ J J   e m o t i o n s _ N N 2   o r _ C C   i n h i b i t _ V V 0   p o s i t i v e _ J J   e m o t i o n s _ N N 2   ( _ (   e . g . _ R E X   l a c k _ N N 1   o f _ I O   p l e a s u r a b l e _ J J   a c t i v i t i e s _ N N 2   ) _ )   a r e _ V B R   i d e n t i f i e d _ V V N   . _ .   
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 P a r t i c i p a n t s _ N N 2   w e r e _ V B D R   r e c r u i t e d _ V V N   f r o m _ I I   t h e _ A T   d e r m a t o l o g y _ N N 1   d e p a r t m e n t _ N N 1   o f _ I O   a _ A T 1   r e g i o n a l _ J J   t e a c h i n g _ N N 1   h o s p i t a l _ N N 1   i n _ I I   t h e _ A T   U . K . _ N P 1   M i g r a i n e _ N P 1   s t u d i e s _ N N 2   d e m o n s t r a t e _ V V 0   a b n o r m a l _ J J   f u n c t i o n _ N N 1   , _ ,   s t r u c t u r e _ N N 1   a n d _ C C   c o n n e c t i v i t y _ N N 1   o f _ I O   b r a i n _ N N 1   r e g i o n s _ N N 2   t h a t _ C S T   p l a y _ V V 0   i m p o r t a n t _ J J   r o l e s _ N N 2   i n _ I I   d e t e r m i n i n g _ V V G   e m o t i o n a l _ J J   r e s p o n s e s _ N N 2   t o _ I I   p a i n _ N N 1   a n d _ C C   t o _ I I   o t h e r _ J J   s e n s o r y _ J J   s t i m u l i _ N N 2   , _ ,   a n d _ C C   i n _ I I   d e t e r m i n i n g _ V V G   g e n e r a l _ J J   a f f e c t _ N N 1   a n d _ C C   m o o d _ N N 1   . _ .   
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 R e c e n t _ J J   e v i d e n c e _ N N 1   d e m o n s t r a t e d _ V V D   t h a t _ C S T   s o c i a l _ J J   d i s t r e s s _ N N 1   m a y _ V M   h a v e _ V H I   a n _ A T 1   i m p a c t _ N N 1   o n _ I I   p a i n _ N N 1   . _ .   
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 N o n e t h e l e s s _ R R   , _ ,   o u r _ A P P G E   s t u d y _ N N 1   w a s _ V B D Z   a b l e _ J K   t o _ T O   r e p o r t _ V V I   d i s c h a r g e _ N N 1   d e s t i n a t i o n _ N N 1   , _ ,   a m b u l a t o r y _ J J   s t a t u s _ N N 1   , _ ,   a n d _ C C   m R S _ N N U   s c o r e s _ N N 2   , _ ,   w h i c h _ D D Q   h a v e _ V H 0   s t r o n g _ J J   a s s o c i a t i o n s _ N N 2   w i t h _ I W   l o n g - t e r m _ J J   f u n c t i o n a l _ J J   o u t c o m e s _ N N 2   a t _ I I   9 0 _ M C   d a y s . 3 9 _ F O   L a s t _ M D   , _ ,   t h e _ A T   G W T G - S t r o k e _ J J   r e g i s t r y _ N N 1   i s _ V B Z   a _ A T 1   v o l u n t a r y _ J J   p r o g r a m _ N N 1   . _ .   
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 T h i s _ D D 1   r e s u l t _ N N 1   i s _ V B Z   r e m a r k a b l e _ J J   w i t h _ I I 3 1   r e s p e c t _ I I 3 2   t o _ I I 3 3   t h e _ A T   c o m p a r a b l e _ J J   l o w _ J J   s e n s i t i v i t y _ N N 1   o f _ I O   c o n f r o n t a t i o n _ N N 1   v i s u a l _ J J   f i e l d _ N N 1   t e s t s _ N N 2   f r e q u e n t l y _ R R   u s e d _ V V N   i n _ I I   c l i n i c a l _ J J   d i a g n o s t i c _ J J   s e t t i n g s _ N N 2   . _ .   
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 O n e _ M C 1   r o u t e _ N N 1   t o _ I I   p a t h o b i o l o g y _ N N 1   i n s i g h t _ N N 1   i s _ V B Z   t o _ T O   a s k _ V V I   i f _ C S W   a g i n g _ J J   r e t i n a _ N N 1   r e v e a l s _ V V Z   b i o l o g i c _ J J   p r o c e s s e s _ N N 2   t h a t _ C S T   s e r v e _ V V 0   a s _ R G   a n a t o m i c a l _ J J   , _ ,   p h y s i o l o g i c a l _ J J   , _ ,   a n d _ C C   m o l e c u l a r _ J J   p r e d i c t o r s _ N N 2   f o r _ I F   d i s e a s e _ N N 1   i n i t i a t i o n _ N N 1   a n d _ C C   a d v a n c e m e n t _ N N 1   . _ .   
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 T h e _ A T   i m a g e s _ N N 2   a r e _ V B R   t h e n _ R T   r e g i s t e r e d _ V V N   t o _ I I   s u b - p i x e l _ J J   a c c u r a c y _ N N 1   u s i n g _ V V G   a _ A T 1   1 2 - d i m e n s i o n a l _ J J   m a p p i n g _ N N 1   t h a t _ C S T   a c c o u n t s _ V V Z   f o r _ I F   t h e _ A T   u n k n o w n _ J J   r e t i n a l _ J J   c u r v a t u r e _ N N 1   a n d _ C C   c a m e r a _ N N 1   p a r a m e t e r s _ N N 2   . _ .   
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 I n _ I I 3 1   a d d i t i o n _ I I 3 2   t o _ I I 3 3   N S C L C _ N P 1   c e l l _ N N 1   l i n e s _ N N 2   , _ ,   B D A - 3 6 6 _ M C   a l s o _ R R   e f f i c i e n t l y _ R R   s u p p r e s s e d _ V V N   g r o w t h _ N N 1   o f _ I O   S C L C _ N P 1   c e l l _ N N 1   l i n e s _ N N 2   ( _ (   F i g u r e _ N N 1   1 _ M C 1   ) _ )   . _ .   
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 I n _ I I   w i l d - t y p e _ J J   l i v e r s _ N N 2   , _ ,   N E M O _ N P 1   p r e v e n t s _ V V Z   h e p a t o c y t e _ N N 1   a p o p t o s i s _ N N 1   b y _ I I   i n h i b i t i n g _ V V G   t h e _ A T   f o r m a t i o n _ N N 1   o f _ I O   t h e _ A T   d e a t h - i n d u c i n g _ J J   R I P K 1 / F A D D / C a s p a s e - 8 _ N N 1   s i g n a l i n g _ V V G   c o m p l e x _ N N 1   ( _ (   c o m p l e x _ J J   I I b _ N P 1   ) _ )   . _ .   
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 T o _ T O   v e r i f y _ V V I   t h i s _ D D 1   h y p o t h e s i s _ N N 1   , _ ,   w e _ P P I S 2   f u r t h e r _ R R R   e x a m i n e d _ V V D   t h e _ A T   m R N A _ N N 1   a n d _ C C   p r o t e i n _ N N 1   l e v e l s _ N N 2   o f _ I O   I L - 1 m i u _ N N 1   i n _ I I   A 1 7 2 _ F O   c e l l s _ N N 2   t r e a t e d _ V V N   w i t h _ I W   N S 3 9 8 _ F O   ( _ (   5 0 _ M C   m i u m _ N N 1   ) _ )   . _ .   
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 C e r e b r a l _ J J   i s c h e m i a _ N N 1   t r i g g e r s _ V V Z   r e a c t i v e _ J J   a s t r o g l i o s i s _ N N 1   , _ ,   a _ A T 1   c o n d i t i o n _ N N 1   c h a r a c t e r i z e d _ V V N   b y _ I I   a n _ A T 1   i n c r e a s e _ N N 1   o f _ I O   G F A P _ N N 1   l e v e l s _ N N 2   i n _ I I   a s t r o c y t e s _ N N 2   ( _ (   F a r k a s _ N N 2   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 7 _ M C   ) _ )   . _ .   
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 A g e _ V V 0   a t _ R R 2 1   l e a s t _ R R 2 2   1 8 _ M C   y e a r s _ N N T 2   a n d _ C C   e v i d e n c e _ N N 1   o f _ I O   e l e v a t e d _ J J   N T - p r o B N P _ J J   v a l u e _ N N 1   , _ ,   e i t h e r _ R R   b e f o r e _ C S   o r _ C C   s o o n _ R R   a f t e r _ I I   s u r g e r y _ N N 1   , _ ,   w e r e _ V B D R   t h e _ A T   o n l y _ J J   i n c l u s i o n _ N N 1   c r i t e r i a _ N N 2   . _ .   
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 I n _ I I   t h e _ A T   p r e s e n t _ J J   s t u d y _ N N 1   , _ ,   t h e _ A T   e v a l u a t i o n _ N N 1   o f _ I O   a n e s t h e s i a _ N N 1   q u a l i t y _ N N 1   w a s _ V B D Z   p e r f o r m e d _ V V N   b y _ I I   a _ A T 1   s i n g l e _ J J   a u t h o r _ N N 1   ( _ (   H . M . C . _ N P 1   ) _ )   w h o _ P N Q S   h a d _ V H D   n o _ A T   p r i o r _ J J   i n f o r m a t i o n _ N N 1   a b o u t _ I I   t h e _ A T   C T _ N N 1   r e s u l t s _ N N 2   f o r _ I F   t h e _ A T   n e e d l e _ N N 1   p a t h _ N N 1   o r _ C C   t h e _ A T   a n e s t h e t i c _ J J   d i s p e r s i o n _ N N 1   , _ ,   a t _ R R 2 1   l e a s t _ R R 2 2   r e d u c i n g _ V V G   t h i s _ D D 1   p o t e n t i a l _ J J   b i a s _ N N 1   i n c l u s i o n _ N N 1   . _ .   
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 T h e _ A T   c o n s t r u c t i o n _ N N 1   t e c h n i q u e s _ N N 2   o f _ I O   f l u t i n g _ V V G   t h e _ A T   p l a s t i c _ N N 1   , _ ,   h o w e v e r _ R R   , _ ,   d o e s _ V D Z   h e l p _ V V I   t o _ T O   p r o m o t e _ V V I   s t r e n g t h _ N N 1   a l o n g _ I I   t h e _ A T   r i d g e _ N N 1   . _ .   
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 A m o n g _ I I   t h e _ A T   r e m a i n i n g _ J J   7 2 1 _ M C   c a s e s _ N N 2   , _ ,   2 8 5 _ M C   p a t i e n t s _ N N 2   d i d _ V D D   n o t _ X X   m e e t _ V V I   o u r _ A P P G E   d i a g n o s t i c _ J J   c r i t e r i a _ N N 2   o f _ I O   P D _ N P 1   a n d _ C C   w e r e _ V B D R   n o t _ X X   c o u n t e d _ V V N   a s _ C S A   c a s e s _ N N 2   . _ .   
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 A _ A T 1   p o p u l a t i o n - b a s e d _ J J   s t u d y _ N N 1   o f _ I O   b a b i e s _ N N 2   w h o _ P N Q S   w e r e _ V B D R   e x p o s e d _ V V N   t o _ I I   a n t i e p i l e p t i c _ J J   d r u g s _ N N 2   ( _ (   A E D s _ N P 2   ) _ )   i n _ I I   u t e r o _ N N 1   r e v e a l e d _ V V D   i m p a i r m e n t _ N N 1   o f _ I O   f i n e _ J J   m o t o r _ N N 1   a n d _ C C   s o c i a l _ J J   s k i l l s _ N N 2   a s _ R G   e a r l y _ R R   a s _ C S A   6 _ M C   m o n t h s _ N N T 2   o f _ I O   a g e _ N N 1   . _ .   
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 L o n g e r _ J J R   f o l l o w - u p _ N N 1   o f _ I O   u p _ R G 2 1   t o _ R G 2 2   4 . 8 _ M C   y e a r s _ N N T 2   w a s _ V B D Z   c a r r i e d _ V V N   o u t _ R P   v i a _ I I   t e l e p h o n e _ N N 1   c o n s u l t a t i o n _ N N 1   a n d _ C C   c h e c k i n g _ V V G   m e d i c a l _ J J   r e c o r d s _ N N 2   t o _ T O   a s c e r t a i n _ V V I   w h e t h e r _ C S W   t h e r e _ E X   w a s _ V B D Z   a n y _ D D   f u r t h e r _ J J R   d e t e r i o r a t i o n _ N N 1   i n _ I I   h e a r i n g _ N N 1   o r _ C C   c o n s u l t a t i o n s _ N N 2   r e g a r d i n g _ I I   t h i s _ D D 1   . _ .   
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 T r a n s c r a n i a l _ J J   D i r e c t _ J J   C u r r e n t _ J J   S t i m u l a t i o n - T r a n s c r a n i a l _ J J   d i r e c t _ J J   c u r r e n t _ J J   s t i m u l a t i o n _ N N 1   ( _ (   t D C S _ N N U   ) _ )   i n v o l v e s _ V V Z   a n _ A T 1   e n e r g y _ N N 1   s o u r c e _ N N 1   t h a t _ C S T   d e l i v e r s _ V V Z   c o n s t a n t _ J J   , _ ,   w e a k _ J J   ( _ (   t y p i c a l l y _ R R   l e s s _ D A R   t h a n _ C S N   1 _ M C 1   m A _ N N 1   ) _ )   e l e c t r i c a l _ J J   c u r r e n t _ J J   t h r o u g h _ I I   s c a l p _ N N 1   e l e c t r o d e s _ N N 2   . _ .   
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 W h i l e _ C S   p r e v i o u s _ J J   s t u d i e s _ N N 2   h a v e _ V H 0   d e t e r m i n e d _ V V N   t h a t _ C S T   t h e _ A T   H i p p o _ N N 1   k i n a s e s _ N N 2   M S T 1 / 2 _ F U   a n d _ C C   L A T S 1 / 2 _ F U   a r e _ V B R   d o w n r e g u l a t e d _ V V N   a n d _ C C   Y A P _ N N 1   i s _ V B Z   u p r e g u l a t e d _ J J   i n a s u b s e t _ N N 1   o f _ I O   p r i m a r y h u m a n _ N N 1   p r o s t a t e _ N N 1   c a n c e r s _ N N 2   ( _ (   C i n a r e t _ V V 0   a l . _ N N U   , _ ,   2 0 0 7 _ M C   ; _ ;   S t e i n h a r d t _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 8 _ M C   ; _ ;   Z h a o _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 2 _ M C   ) _ )   , _ ,   t h e _ A T   c a u s e s _ N N 2   a n d _ C C   c o n s e q u e n c e s _ N N 2   o f _ I O   Y A P 1 _ F O   a c t i v a t i o n _ N N 1   h a v e _ V H 0   n o t _ X X   b e e n _ V B N   d e f i n e d _ V V N   , _ ,   n o r _ C C   h a v e _ V H 0   c a u s a l _ J J   r o l e s _ N N 2   f o r _ I F   H i p p o _ N N 1   s i g n a l i n g _ V V G   i n _ I I   t h e _ A T   g e n e s i s _ N N 1   o f _ I O   p r o s t a t e _ N N 1   c a n c e r _ N N 1   b e e n _ V B N   e s t a b l i s h e d _ V V N   . _ .   
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 F o u r _ M C   w e e k s _ N N T 2   a f t e r _ I I   c a t a r a c t _ N N 1   s u r g e r y _ N N 1   c u l t u r e - p o s i t i v e _ J J   S t r e p t o c o c c u s _ N N 1   p n e u m o n i a e _ N N 2   e n d o p h t h a l m i t i s _ N N 1   d e v e l o p e d _ V V D   , _ ,   l e a d i n g _ V V G   t o _ I I   r a p i d _ J J   c o r n e a l _ J J   p e r f o r a t i o n _ N N 1   a n d _ C C   s u b s e q u e n t _ J J   e v i s c e r a t i o n _ N N 1   . _ .   
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 S m o k e r s _ N N 2   w i t h _ I W   e x p i r e d _ J J   a i r _ N N 1   C O _ F O   l e v e l s _ N N 2   g r e a t e r _ J J R   t h a n _ C S N   a n d _ C C   l e s s _ D A R   t h a n _ C S N   3 0 _ M C   p p m _ N N U   ( _ (   t h e _ A T   m e d i a n _ N N 1   C O _ F O   f o r _ I F   a l l _ D B   s u b j e c t s _ N N 2   ) _ )   w e r e _ V B D R   a s s i g n e d _ V V N   t o _ I I   4 2 _ M C   m g / 2 4 _ F U   h _ Z Z 1   a n d _ C C   2 1 _ M C   m g / 2 4 _ F U   h _ Z Z 1   n i c o t i n e _ N N 1   p a t c h _ N N 1   d o s e s _ N N 2   , _ ,   r e s p e c t i v e l y _ R R   ( _ (   G l a x o S m i t h K l i n e _ N P 1   ) _ )   . _ .   
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 G u i d e d _ V V N   b y _ I I   p r e v i o u s _ J J   l i t e r a t u r e _ N N 1   , _ ,   t h e _ A T   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   1 2 _ M C   c o - m o r b i d i t i e s _ N N 2   a n d _ C C   t h e _ A T   o u t c o m e _ N N 1   w a s _ V B D Z   a s s e s s e d _ V V N   i n _ I I   u n i v a r i a b l e _ J J   m o d e l s _ N N 2   . _ .   
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 I n _ I I   a n _ A T 1   e x p l o r a t o r y _ J J   a n a l y s i s _ N N 1   o f _ I O   a _ A T 1   p r e d e f i n e d _ J J   s u b g r o u p _ N N 1   o f _ I O   5 0 2 _ M C   p a t i e n t s _ N N 2   w i t h _ I W   p o o r _ J J   p r o g n o s i s _ N N 1   d i s e a s e _ N N 1   , _ ,   3 3 2 _ M C   ( _ (   6 6 % _ N N U   ) _ )   d i e d _ V V D   ( _ (   1 7 4 _ M C   i n _ I I   t h e _ A T   s t a n d a r d _ J J   c h e m o t h e r a p y _ N N 1   g r o u p _ N N 1   a n d _ C C   1 5 8 _ M C   i n _ I I   t h e _ A T   b e v a c i z u m a b _ N N 1   g r o u p _ N N 1   ) _ )   , _ ,   a n d _ C C   a _ A T 1   s i g n i f i c a n t _ J J   d i f f e r e n c e _ N N 1   i n _ I I   o v e r a l l _ J J   s u r v i v a l _ N N 1   w a s _ V B D Z   n o t e d _ V V N   b e t w e e n _ I I   w o m e n _ N N 2   w h o _ P N Q S   r e c e i v e d _ V V D   b e v a c i z u m a b _ N N 1   p l u s _ I I   c h e m o t h e r a p y _ N N 1   a n d _ C C   t h o s e _ D D 2   w h o _ P N Q S   r e c e i v e d _ V V D   c h e m o t h e r a p y _ N N 1   a l o n e _ R R   ( _ (   r e s t r i c t e d _ J J   m e a n _ J J   s u r v i v a l _ N N 1   t i m e _ N N T 1   3 4 . 5 _ M C   m o n t h s _ N N T 2   & l s q b ; _ (   9 5 % _ N N U   C I _ F O   3 2 * 0 _ F O   ' _ N U L L   3 7 * 0 _ F O   & r s q b ; _ )   w i t h _ I W   s t a n d a r d _ J J   c h e m o t h e r a p y _ N N 1   v s _ I I   3 9 . 3 _ M C   m o n t h s _ N N T 2   & l s q b ; _ (   3 7 * 0 _ F O   ' _ N U L L   4 1 * 7 _ F O   & r s q b ; _ )   w i t h _ I W   b e v a c i z u m a b _ N N 1   ; _ ;   l o g - r a n k _ N N 1   p = 0 * 0 3 _ F O   ) _ )   . _ .   
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 T h e r e _ E X   w a s _ V B D Z   a _ A T 1   d i f f e r e n c e _ N N 1   i n _ I I   n u m b e r _ N N 1   o f _ I O   p a t i e n t s _ N N 2   w i t h _ I W   a _ A T 1   s u p r a p u b i c _ J J   u r i n a r y _ J J   c a t h e t e r _ N N 1   ( _ (   T a b l e _ N N 1   3 _ M C   ) _ )   , _ ,   a n d _ C C   o v e r a l l _ R R   1 5 . 8 % _ F O   o f _ I O   t h e _ A T   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   l a v a g e _ N N 1   g r o u p _ N N 1   d i d _ V D D   n o t _ X X   n e e d _ V V I   a _ A T 1   u r i n a r y _ J J   c a t h e t e r _ N N 1   c o m p a r e d _ V V N   t o _ I I   n o _ A T   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   H a r t m a n n _ N P 1   ' _ N U L L   s _ Z Z 1   g r o u p _ N N 1   ( _ (   P _ Z Z 1   = _ F O   0 . 0 2 5 _ M C   ) _ )   . _ .   
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 R o l e _ N N 1   o f _ I O   t h e _ A T   S p o n s o r _ N N 1   : _ :   T h e _ A T   f u n d i n g _ N N 1   a g e n c y _ N N 1   h a d _ V H D   n o _ A T   r o l e _ N N 1   i n _ I I   t h e _ A T   d e s i g n _ N N 1   a n d _ C C   c o n d u c t _ N N 1   o f _ I O   t h e _ A T   s t u d y _ N N 1   ; _ ;   c o l l e c t i o n _ N N 1   , _ ,   m a n a g e m e n t _ N N 1   , _ ,   a n a l y s i s _ N N 1   , _ ,   o r _ C C   i n t e r p r e t a t i o n _ N N 1   o f _ I O   t h e _ A T   d a t a _ N N   ; _ ;   p r e p a r a t i o n _ N N 1   , _ ,   r e v i e w _ N N 1   , _ ,   o r _ C C   a p p r o v a l _ N N 1   o f _ I O   t h e _ A T   m a n u s c r i p t _ N N 1   ; _ ;   a n d _ C C   d e c i s i o n _ N N 1   t o _ T O   s u b m i t _ V V I   t h e _ A T   m a n u s c r i p t _ N N 1   f o r _ I F   p u b l i c a t i o n _ N N 1   . _ .   
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 T h i s _ D D 1   s u g g e s t s _ V V Z   t h a t _ C S T   t h e s e _ D D 2   l o c i _ N N 2   a r e _ V B R   r e s p o n s i b l e _ J J   a t _ R R 2 1   l e a s t _ R R 2 2   i n _ R R 2 1   p a r t _ R R 2 2   f o r _ I F   t h e _ A T   i n i t i a t i o n _ N N 1   o f _ I O   O A G _ N P 1   , _ ,   c o n s i s t e n t _ J J   w i t h _ I W   t h e i r _ A P P G E   r o l e _ N N 1   i n _ I I   d e t e r m i n a t i o n _ N N 1   o f _ I O   t h e s e _ D D 2   r i s k _ V V 0   f a c t o r _ N N 1   t r a i t s _ N N 2   , _ ,   w h i c h _ D D Q   a r e _ V B R   t h e m s e l v e s _ P P X 2   p r e d i c t i v e _ J J   f o r _ I F   O A G _ N N 1   d e v e l o p m e n t _ N N 1   . _ .   
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 L a c k _ N N 1   o f _ I O   f u n c t i o n a l _ J J   M T P _ N P 1   a n d _ C C   a p o B _ N N 1   i s _ V B Z   t h e _ A T   b a s i s _ N N 1   o f _ I O   a b e t a l i p o p r o t e i n e m i a _ N N 1   a n d _ C C   h y p o b e t a l i p o p r o t e i n e m i a _ N N 1   , _ ,   r e s p e c t i v e l y _ R R   , _ ,   t w o _ M C   r a r e _ J J   i n h e r i t e d _ J J   d i s o r d e r s _ N N 2   t h a t _ C S T   i n c l u d e _ V V 0   p i g m e n t a r y _ J J   r e t i n o p a t h i e s _ N N 2   , _ ,   h i s t o r i c a l l y _ R R   a t t r i b u t e d _ V V N   t o _ I I   i m p a i r e d _ J J   d i e t a r y _ J J   d e l i v e r y _ N N 1   o f _ I O   l i p o p h i l i c _ J J   v i t a m i n s _ N N 2   b y _ I I   p l a s m a _ N N 1   a p o B - c o n t a i n i n g _ N N 1   l i p o p r o t e i n s _ N N 2   b u t _ C C B   n o t _ X X   r e v e r s i b l e _ J J   b y _ I I   l o n g - t e r m _ J J   s u p p l e m e n t a t i o n _ N N 1   ( _ (   C h o w e r s _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 1 _ M C   ) _ )   . _ .   
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 R e s p i r a t o r y _ J J   i n d u c t a n c e _ N N 1   p l e t h y s m o g r a p h y _ N N 1   ( _ (   R I P _ N P 1   ) _ )   p e r m i t s _ V V Z   m e a s u r e m e n t _ N N 1   o f _ I O   r e s p i r a t o r y _ J J   m o t i o n _ N N 1   i n _ I I   c l i n i c a l _ J J   s e t t i n g s _ N N 2   n o t _ X X   c o n d u c i v e _ J J   t o _ I I   s p i r o m e t r y _ N N 1   , _ ,   b u t _ C C B   c o r r e l a t i o n _ N N 1   o f _ I O   R I P _ N P 1   v o l u m e _ N N 1   c h a n g e s _ N N 2   a n d _ C C   s p i r o m e t e r _ J J R   f l o w _ N N 1   i n _ I I   t h e _ A T   t i m e _ N N T 1   d o m a i n _ N N 1   i s _ V B Z   d e g r a d e d _ V V N   b y _ I I   t h e _ A T   d e v e l o p m e n t _ N N 1   o f _ I O   p a r a d o x i c a l _ J J   b r e a t h i n g _ N N 1   . _ .   
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 T h e _ A T   R V _ N P 1   t h r e s h o l d _ N N 1   u s e d _ V V D   , _ ,   a l b e i t _ C S   p r e s p e c i f i e d _ V V N   , _ ,   w a s _ V B D Z   a r b i t r a r i l y _ R R   c h o s e n _ V V N   , _ ,   a n d _ C C   a _ A T 1   p o s t _ J J 2 1   h o c _ J J 2 2   s e n s i t i v i t y _ N N 1   a n a l y s i s _ N N 1   ( _ (   e T a b l e _ J J   8 _ M C   i n _ I I   S u p p l e m e n t _ N N 1   2 _ M C   ) _ )   i n d i c a t e d _ V V D   t h a t _ C S T   2 0 0 % _ N N U   p r e d i c t e d _ V V N   m a y _ V M   b e _ V B I   a _ A T 1   m o r e _ R G R   s e n s i t i v e _ J J   r e s p o n s e _ N N 1   t h r e s h o l d _ N N 1   . _ .   
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 T h e _ A T   d a t a _ N N   w e _ P P I S 2   p r e s e n t _ V V 0   a d d _ V V 0   a _ A T 1   n e w _ J J   c o n t r i b u t i o n _ N N 1   t o _ I I   t h i s _ D D 1   d i s c u s s i o n _ N N 1   , _ ,   a n d _ C C   l e n d _ V V 0   s u p p o r t _ N N 1   t o _ I I   t h e _ A T   c o n c e p t s _ N N 2   p u t _ V V 0   f o r t h _ R R   b y _ I I   B o h n e _ N P 1   a n d _ C C   H a r d i n g _ N P 1   i n _ I I   t h e i r _ A P P G E   c h i n c h i l l a _ N N 1   m o d e l _ N N 1   o f _ I O   n o i s e _ N N 1   e x p o s u r e _ N N 1   . _ .   
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 T h i s _ D D 1   r i s k _ N N 1   i s _ V B Z   a m p l i f i e d _ V V N   b y _ I I   t h e _ A T   s h o r t _ J J   r a n g e _ N N 1   o f _ I O   t h e _ A T   s t r o n t i u m _ N N 1   p _ Z Z 1   p a r t i c l e s _ N N 2   i n _ I I   t i s s u e _ N N 1   , _ ,   5 _ M C   c o m p o u n d e d _ V V D   b y _ I I   t h e _ A T   f a c t _ N N 1   t h a t _ C S T   s u r g e o n s _ N N 2   m a y _ V M   h o l d _ V V I   t h e _ A T   p r o b e _ N N 1   a w a y _ I I 2 1   f r o m _ I I 2 2   t h e _ A T   r e t i n a l _ J J   s u r f a c e _ N N 1   t o _ T O   r e d u c e _ V V I   t h e _ A T   r i s k _ N N 1   o f _ I O   t r a u m a _ N N 1   . _ .   
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 P h a s e _ N N 1   I I _ M C   r e s e a r c h _ N N 1   i s _ V B Z   a l s o _ R R   r e c o m m e n d e d _ V V N   , _ ,   t o _ T O   c o n t i n u e _ V V I   e x p l o r a t i o n _ N N 1   o f _ I O   t h e _ A T   v i a b i l i t y _ N N 1   o f _ I O   t h e _ A T   L i d c o m b e _ N P 1   P r o g r a m _ N N 1   f o r _ I F   C h i n e s e - M a l a y s i a n _ J J   f a m i l i e s _ N N 2   a n d _ C C   t o _ T O   e s t i m a t e _ V V I   t h e _ A T   p r o p o r t i o n _ N N 1   o f _ I O   t h o s e _ D D 2   w h o _ P N Q S   w i l l _ V M   r e s p o n d _ V V I   t o _ I I   t h e _ A T   t r e a t m e n t _ N N 1   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   t h e _ A T   c o r t i c a l _ J J   s i l e n t _ J J   p e r i o d _ N N 1   h a s _ V H Z   c o n s i s t e n t l y _ R R   b e e n _ V B N   s h o w n _ V V N   t o _ T O   l e n g t h e n _ V V I   d u r i n g _ I I   s u s t a i n e d _ J J   i s o l a t e d _ J J   m u s c l e _ N N 1   e x e r c i s e _ N N 1   , _ ,   i n c l u d i n g _ V V G   f o r _ I F   k n e e _ N N 1   e x t e n s o r _ N N 1   c o n t r a c t i o n s _ N N 2   b u t _ C C B   r e c o v e r y _ N N 1   o n _ I I   e x e r c i s e _ N N 1   c e s s a t i o n _ N N 1   i s _ V B Z   r a p i d _ J J   . _ .   
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 T h e _ A T   r e v i e w _ N N 1   c o n c l u d e d _ V V D   t h a t _ C S T   i f _ C S   a c u t e _ J J   s y s t e m i c _ J J   f a c t o r s _ N N 2   a r e _ V B R   i n _ I I   f a c t _ N N 1   i n v o l v e d _ J J   i n _ I I   t h e _ A T   p o s t - e x e r c i s e _ J J   h y p e r t r o p h i c _ J J   r e s p o n s e _ N N 1   , _ ,   t h e _ A T   o v e r a l l _ J J   m a g n i t u d e _ N N 1   o f _ I O   t h e _ A T   e f f e c t _ N N 1   w o u l d _ V M   b e _ V B I   o f _ I O   s m a l l _ J J   c o n s e q u e n c e _ N N 1   . _ .   
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 T r a i n e r s _ N N 2   t r a c k e d _ V V D   p a r t i c i p a n t s _ N N 2   ' _ N U L L   a b i l i t y _ N N 1   a n d _ C C   c o m f o r t _ V V 0   c o m p l e t i n g _ V V G   e x e r c i s e s _ N N 2   d u r i n g _ I I   e a c h _ D D 1   s e s s i o n _ N N T 1   a s _ C S A   1 _ M C 1   i n d i c a t o r _ N N 1   o f _ I O   t o l e r a b i l i t y _ N N 1   . _ .   
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 C o n f l i c t _ N N 1   o f _ I O   I n t e r e s t _ N N 1   : _ :   T h e _ A T   r e s u l t s _ N N 2   o f _ I O   t h e _ A T   p r e s e n t _ J J   s t u d y _ N N 1   d o _ V D 0   n o t _ X X   c o n s t i t u t e _ V V I   e n d o r s e m e n t _ N N 1   b y _ I I   A C S M _ N P 1   . _ .   
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 A f t e r _ C S   c o m p l e t i o n _ N N 1   o f _ I O   t h e _ A T   e x p e r i m e n t s _ N N 2   , _ ,   t h e _ A T   c h r o n i c a l l y _ R R   i n s t r u m e n t e d _ V V D   d o g s _ N N 2   w e r e _ V B D R   m a i n t a i n e d _ V V N   f o r _ I F   t h e _ A T   r e s t _ N N 1   o f _ I O   t h e i r _ A P P G E   l i v e s _ N N 2   i n _ I I   t h e _ A T   a n i m a l _ N N 1   r e s e a r c h _ N N 1   f a c i l i t y _ N N 1   o f _ I O   o u r _ A P P G E   i n s t i t u t i o n _ N N 1   , _ ,   f o r _ I F   u s e _ N N 1   i n _ I I   o t h e r _ J J   e x p e r i m e n t s _ N N 2   u n t i l _ C S   t h e y _ P P H S 2   d i e d _ V V D   o f _ I O   n a t u r a l _ J J   c a u s e s _ N N 2   . _ .   
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 T h e _ A T   i n c r e a s i n g _ J J   A D C T E _ N N 1   w i t h _ I W   i n c r e a s i n g _ V V G   T 2 _ F O   r e l a x a t i o n _ N N 1   t i m e s _ N N T 2   c a n _ V M   a l s o _ R R   b e _ V B I   d e t e c t e d _ V V N   i n _ I I   t h e _ A T   c a l c u l a t e d _ J J   e f f e c t _ N N 1   s i z e s _ N N 2   . _ .   
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 A l l _ D B   p a t i e n t s _ N N 2   u n d e r w e n t _ V V D   a u t o p s y _ N N 1   f o r _ I F   a n a l y s i s _ N N 1   o f _ I O   t i s s u e _ N N 1   r e s p o n s e _ N N 1   t o _ I I   i m p l a n t a t i o n _ N N 1   a n d _ C C   f o r _ I F   t h e _ A T   i d e n t i f i c a t i o n _ N N 1   o f _ I O   t h e _ A T   c o n t i n u e d _ J J   p r e s e n c e _ N N 1   o f _ I O   t h e _ A T   t r a n s p l a n t e d _ J J   c e l l s _ N N 2   w i t h i n _ I I   t h e _ A T   s p i n a l _ J J   c o r d _ N N 1   . _ .   
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 T h e _ A T   p r o b l e m _ N N 1   c a n _ V M   b e _ V B I   e x a c e r b a t e d _ V V N   i n _ I I   p a t i e n t _ J J   p o p u l a t i o n s _ N N 2   t h a t _ C S T   h a v e _ V H 0   i n f e r i o r _ J J   f i x a t i o n _ N N 1   a b i l i t y _ N N 1   . _ .   
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 A t _ I I   t h e _ A T   l a s t _ M D   B C H _ N P 1   f o l l o w - u p _ J J   v i s i t _ N N 1   , _ ,   1 1 _ M C   ( _ (   6 . 6 % _ F O   ) _ )   o f _ I O   1 6 6 _ M C   p a t i e n t s _ N N 2   w h o _ P N Q S   h a d _ V H D   a _ A T 1   l u m b a r _ N N 1   h e r n i a t i o n _ N N 1   a n d _ C C   r a d i c u l o p a t h y _ N N 1   w e r e _ V B D R   r e c e i v i n g _ V V G   o p i o i d s _ N N 2   . _ .   
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 D e x m e d e t o m i d i n e _ V V 0   a l s o _ R R   d e c r e a s e s _ V V Z   H R _ N N U   a n d _ C C   b l o o d _ N N 1   p r e s s u r e _ N N 1   i n _ I I   a _ A T 1   d o s e - d e p e n d e n t _ J J   m a n n e r _ N N 1   . _ .   
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 T h e _ A T   d i s c r e p a n c y _ N N 1   b e t w e e n _ I I   t h e _ A T   f i n d i n g s _ N N 2   m a y _ V M   b e _ V B I   d u e _ I I 2 1   t o _ I I 2 2   t h e _ A T   a n a t o m i c a l _ J J   s p e c i f i c i t y _ N N 1   a n d / o r _ C C   m e t h o d _ N N 1   o f _ I O   a n a l y s i s _ N N 1   u s e d _ V V N   i n _ I I   t h e _ A T   s t u d i e s _ N N 2   ( _ (   i . e . _ R E X   d i f f e r e n c e s _ N N 2   i n _ I I   s p l i c e _ N N 1   v a r i a n t s _ N N 2   a m p l i f i e d _ V V N   b y _ I I   t h e _ A T   d i f f e r e n t _ J J   p r i m e r s _ N N 2   o f _ I O   d i f f e r e n t _ J J   g r o u p s _ N N 2   ) _ )   . _ .   
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 T h e _ A T   m o s t _ R G T   i m p o r t a n t _ J J   r e a s o n _ N N 1   t h a t _ C S T   t h i s _ D D 1   s t u d y _ N N 1   u s e d _ V V D   d u c t - t o - m u c o s a _ J J   P J _ N P 1   w a s _ V B D Z   t o _ T O   d e c o m p r e s s _ V V I   t h e _ A T   m a i n _ J J   p a n c r e a t i c _ J J   d u c t _ N N 1   a n d _ C C   r e d u c e _ V V I   p a n c r e a t i c _ J J   j u i c e _ N N 1   l e a k a g e _ N N 1   f r o m _ I I   t h e _ A T   b r a n c h _ N N 1   p a n c r e a t i c _ J J   d u c t _ N N 1   . _ .   
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 E n d o t h e l i a l _ J J   D y s f u n c t i o n _ N N 1   i n _ I I   A d v a n c e d _ J J   C K D _ N P 1   : _ :   E v i d e n c e _ N N 1   f o r _ I F   a _ A T 1   " _ "   U r e m i _ N N 1   S w i t c h _ V V 0   " _ "   T h e _ A T   s t i m u l u s _ N N 1   f o r _ I F   d e c r e a s e d _ J J   L - a r g i n i n e _ J J   t r a n s p o r t _ N N 1   s e e m s _ V V Z   t o _ T O   b e _ V B I   r e l a t e d _ V V N   t o _ I I   a n _ A T 1   i n c r e a s e _ N N 1   i n _ I I   c i r c u l a t i n g _ V V G   u r e a _ N N 1   a n d _ C C   o t h e r _ J J   u r e m i c _ J J   t o x i n s _ N N 2   t h a t _ C S T   o c c u r s _ V V Z   w i t h _ I W   C K D _ N P 1   . _ .   
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 T h e _ A T   a s s u m p t i o n _ N N 1   o f _ I O   p r o p o r t i o n a l _ J J   o d d s _ N N 2   w a s _ V B D Z   a s s e s s e d _ V V N   w i t h _ I W   t h e _ A T   s c o r e _ N N 1   t e s t _ N N 1   a n d _ C C   w a s _ V B D Z   v a l i d _ J J   ( _ (   p _ N N U   g r e a t e r _ J J R   t h a n _ C S N   0 . 3 _ M C   ) _ )   f o r _ I F   a l l _ D B   a n a l y s e s _ N N 2   . _ .   
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 S u b s e q u e n t _ J J   m o d e l _ N N 1   t r i m m i n g _ N N 1   e l i m i n a t e d _ V V D   a l l _ D B   t e r m s _ N N 2   t h a t _ C S T   i n c l u d e d _ V V D   s e v e r i t y _ N N 1   , _ ,   i n d i c a t i n g _ V V G   t h a t _ D D 1   s e v e r i t y _ N N 1   d i d _ V D D   n o t _ X X   h a v e _ V H I   m a i n _ J J   o r _ C C   m o d e r a t i o n _ N N 1   e f f e c t s _ N N 2   o n _ I I   t h e _ A T   m a i n t e n a n c e _ N N 1   o f _ I O   t r e a t m e n t _ N N 1   e f f e c t s _ N N 2   . _ .   
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 E H S _ N N 2   p r o v i d e d _ V V D   t h e _ A T   n u m b e r _ N N 1   o f _ I O   h o u r s _ N N T 2   w o r k e d _ V V N   b y _ I I   E M _ F U   r e s i d e n t s _ N N 2   a n d _ C C   t h e _ A T   o p e r a t i n g _ N N 1   c o s t s _ N N 2   o f _ I O   t h e _ A T   r e s i d e n c y _ N N 1   p r o g r a m _ N N 1   . _ .   
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 I n _ I I   t h e _ A T   l a s t _ M D   t w o _ M C   d e c a d e s _ N N T 2   , _ ,   a _ A T 1   n u m b e r _ N N 1   o f _ I O   s t u d i e s _ N N 2   h a v e _ V H 0   b e e n _ V B N   p u b l i s h e d _ V V N   o n _ I I   t h e _ A T   p r o g n o s t i c _ J J   v a l u e _ N N 1   o f _ I O   M R I _ N N 2   i n _ I I   a c u t e _ J J   h a m s t r i n g _ N N 1   i n j u r i e s _ N N 2   t h a t _ C S T   r e p o r t e d _ V V D   m u l t i p l e _ J J   f i n d i n g s _ N N 2   a s _ C S A   i n d i c a t o r s _ N N 2   f o r _ I F   t h e _ A T   t i m e _ N N T 1   t o _ I I   R T P _ N P 1   , _ ,   b u t _ C C B   t h e _ A T   l a r g e _ J J   v a r i a t i o n _ N N 1   o f _ I O   t h e _ A T   t i m e _ N N T 1   t o _ I I   R T P _ N P 1   f r o m _ I I   1 _ M C 1   d a y _ N N T 1   a l l _ D B   t h e _ A T   w a y _ N N 1   u p _ R G 2 1   t o _ R G 2 2   1 0 4 _ M C   w e e k s _ N N T 2   m a k e s _ V V Z   e s t i m a t i n g _ V V G   t h e _ A T   p r o g n o s i s _ N N 1   a _ A T 1   c h a l l e n g e _ N N 1   . _ .   
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 S p e c i f i c _ J J   s u r v e y _ N N 1   c o n t e n t _ N N 1   i s _ V B Z   f o u n d _ V V N   i n _ I I   T a b l e s _ N N 2   1 - 6 _ M C M C   , _ ,   a n d _ C C   d i s t r i b u t i o n _ N N 1   m e t h o d s _ N N 2   a r e _ V B R   d e t a i l e d _ V V N   b e l o w _ R L   f o r _ I F   e a c h _ D D 1   o f _ I O   t h e _ A T   s i x _ M C   g r o u p s _ N N 2   . _ .   
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 A t _ I I   t h e _ A T   d i s c r e t i o n _ N N 1   o f _ I O   t h e _ A T   i n v e s t i g a t o r _ N N 1   , _ ,   t h i s _ D D 1   c o u l d _ V M   b e _ V B I   e x t e n d e d _ V V N   t o _ I I   6 0 _ M C   ( _ (   p l u s _ N N 1   a n d _ C C   m i n u s 7 _ F O   ) _ )   d a y s _ N N T 2   o r _ C C   9 0 _ M C   ( _ (   p l u s _ N N 1   a n d _ C C   m i n u s 7 _ F O   ) _ )   d a y s _ N N T 2   f o r _ I F   p a t i e n t s _ N N 2   w h o _ P N Q S   d i d _ V D D   n o t _ X X   r e c e i v e _ V V I   t r e a t m e n t _ N N 1   . _ .   
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 I t _ P P H 1   i s _ V B Z   o f t e n _ R R   a s s o c i a t e d _ V V N   w i t h _ I W   s e v e r e _ J J   p a i n _ N N 1   a n d _ C C   m a y _ V M   b e _ V B I   a s s o c i a t e d _ V V N   w i t h _ I W   s i g h t - t h r e a t e n i n g _ N N 1   c o m p l i c a t i o n s . 4 _ F O   N o n - i n f e c t i o u s _ J J   o r _ C C   a u t o i m m u n e _ N N 1   s c l e r i t i s _ N N 1   i s _ V B Z   t h o u g h t _ V V N   t o _ T O   a r i s e _ V V I   f r o m _ I I   i m m u n e - m e d i a t e d _ J J   m e c h a n i s m s _ N N 2   t h a t _ C S T   a r e _ V B R   n o t _ X X   w e l l _ R R   u n d e r s t o o d _ V V N   . _ .   
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 B a r r i e r s _ N N 2   t o _ I I   r o u t i n e _ N N 1   i n t e g r a t i o n _ N N 1   o f _ I O   t r a u m a - i n f o r m e d _ J J   a p p r o a c h e s _ N N 2   i n t o _ I I   p e d i a t r i c _ J J   m e d i c i n e _ N N 1   i n c l u d e _ V V 0   a _ A T 1   l a c k _ N N 1   o f _ I O   a v a i l a b l e _ J J   t r a i n i n g _ N N 1   a n d _ C C   u n c l e a r _ J J   b e s t _ J J T   p r a c t i c e _ N N 1   g u i d e l i n e s _ N N 2   . _ .   
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 T h e _ A T   C B F V m e a n _ N N 1   a t _ I I   b a s e l i n e _ N N 1   a n d _ C C   a t _ I I   3 _ M C   H E A _ N N 1   i n t e r v a l s _ N N 2   d u r i n g _ I I   s u r g e r y _ N N 1   w a s _ V B D Z   4 6 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   1 2 _ M C   ( _ (   S D _ N P 1   ) _ )   , _ ,   4 5 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   1 2 _ M C   , _ ,   4 7 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   1 4 _ M C   , _ ,   a n d _ C C   4 7 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   1 4 _ M C   c m _ N N U   s - 1 _ F O   , _ ,   r e s p e c t i v e l y _ R R   . _ .   
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 A u t h o r A f f i l i a t i o n s _ N P 1   : _ :   D u k e C l i n i c a l _ J J   R e s e a r c h _ N N 1   I n s t i t u t e _ N N 1   , _ ,   D u r h a m _ N P 1   , _ ,   N o r t h _ N D 1   C a r o l i n a _ N P 1   ( _ (   X i a n _ J J   , _ ,   G r a u - S e p u l v e d a _ N P 1   , _ ,   H e r n a n d e z _ N P 1   , _ ,   T h o m a s _ N P 1   , _ ,   W e b b _ N P 1   , _ ,   B e t t g e r _ N P 1   , _ ,   P e t e r s o n _ N P 1   ) _ )   ; _ ;   m e d i c a l _ J J   s t u d e n t _ N N 1   a t _ I I   U n i v e r s i t y _ N N 1   o f _ I O   N o r t h _ N D 1   C a r o l i n a _ N P 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   , _ ,   C h a p e l _ N P 1   H i l l _ N N L 1   ( _ (   F e d e r s p i e l _ N P 1   ) _ )   ; _ ;   c u r r e n t l y _ R R   w i t h _ I W   D e p a r t m e n t _ N N 1   o f _ I O   G y n e c o l o g y _ N P 1   a n d _ C C   O b s t e t r i c s _ N N 1   , _ ,   J o h n s _ N P 1   H o p k i n s _ N P 1   S c h o o l _ N N 1   o f M e d i c i n e _ N N 1   , _ ,   B a l t i m o r e _ N P 1   , _ ,   M a r y l a n d _ N P 1   ( _ (   F e d e r s p i e l _ N P 1   ) _ )   ; _ ;   D i v i s i o n _ N N 1   o f _ I O   N e u r o l o g y _ N P 1   , _ ,   M a s s a c h u s e t t s _ N P 1   G e n e r a l _ J J   H o s p i t a l _ N N 1   , _ ,   B o s t o n _ N P 1   ( _ (   S c h w a m m _ N P 1   ) _ )   ; _ ;   B r i g h a m _ N P 1   a n d _ C C   W o m e n _ N N 2   ' _ N U L L   s _ Z Z 1   H o s p i t a l _ N N 1   H e a r t _ N N 1   a n d _ C C   V a s c u l a r _ J J   C e n t e r _ N N 1   a n d _ C C   H a r v a r d _ N P 1   M e d i c a l _ J J   S c h o o l _ N N 1   , _ ,   B o s t o n _ N P 1   , _ ,   M a s s a c h u s e t t s _ N P 1   ( _ (   B h a t t _ N P 1   ) _ )   ; _ ;   D e p a r t m e n t _ N N 1   o f C l i n i c a l _ J J   N e u r o s c i e n c e s _ N P 2   , _ ,   U n i v e r s i t y _ N N 1   o f C a l g a r y _ N N 1   , _ ,   C a l g a r y _ N P 1   , _ ,   A l b e r t a _ N P 1   , _ ,   C a n a d a _ N P 1   ( _ (   S m i t h _ N P 1   ) _ )   ; _ ;   H o t c h k i s s _ N P 1   B r a i n _ N N 1   l n s t i t u t e _ N N 1   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   C a l g a r y _ N P 1   , _ ,   C a l g a r y _ N P 1   , _ ,   A l b e r t a _ N P 1   , _ ,   C a n a d a _ N P 1   ( _ (   S m i t h _ N P 1   ) _ )   ; _ ;   D e p a r t m e n t _ N N 1   o f _ I O   E p i d e m i o l o g y _ N P 1   , _ ,   M i c h i g a n _ N P 1   S t a t e _ N N 1   U n i v e r s i t y _ N N 1   , _ ,   E a s t _ N D 1   L a n s i n g _ N P 1   ( _ (   R e e v e s _ N P 1   ) _ )   ; _ ;   D e p a r t m e n t _ N N 1   o f _ I O   N e u r o l o g y _ N P 1   , _ ,   D u k e _ N N 1   U n i v e r s i t y _ N N 1   M e d i c a l _ J J   C e n t e r _ N N 1   , _ ,   D u r h a m _ N P 1   , _ ,   N o r t h _ N D 1   C a r o l i n a _ N P 1   ( _ (   L a s k o w i t z _ N P 1   ) _ )   ; _ ;   D i v i s i o n _ N N 1   o f _ I O   C a r d i o l o g y _ N P 1   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   C a l i f o r n i a _ N P 1   , _ ,   L o s _ N P 1   A n g e l e s _ N P 1   ( _ (   F o n a r o w _ N P 1   ) _ )   . _ .   
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 I n f l a m m a t i o n _ N N 1   , _ ,   e v a l u a t e d _ V V N   a s _ I I   t h e _ A T   n u m b e r _ N N 1   o f _ I O   c e l l s _ N N 2   a n d _ C C   f l a r e _ N N 1   b y _ I I   l a s e r _ N N 1   p h o t o m e t r y _ N N 1   , _ ,   w a s _ V B D Z   l e s s _ R R R   p r o n o u n c e d _ V V N   i n _ I I   t h e _ A T   N S A I D _ J J   g r o u p _ N N 1   a f t e r _ I I   1 _ M C 1   w e e k _ N N T 1   o f _ I O   t r e a t m e n t _ N N 1   . _ .   
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 R e s p o n d e n t s _ N N 2   w e r e _ V B D R   a s k e d _ V V N   t o _ T O   e v a l u a t e _ V V I   t h e _ A T   s u r v e y - i t e m s _ N N 2   o n _ I I   a _ A T 1   L i k e r t - t y p e _ J J   s c a l e _ N N 1   , _ ,   w i t h _ I W   g r a d u a l _ J J   i n c r e a s e _ N N 1   i n _ I I   s t r e n g t h _ N N 1   o f _ I O   a g r e e m e n t _ N N 1   f r o m _ I I   1 _ M C 1   t o _ I I   5 _ M C   . _ .   
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 O v e r a l l _ J J   c u r r i c u l u m _ N N 1   s a t i s f a c t i o n _ N N 1   f o r _ I F   a l l _ D B   t r a i n e e s _ N N 2   r a n g e d _ V V N   f r o m _ I I   3 . 6 - 4 . 6 _ M C M C   & l s q b ; _ (   m e a n = _ F O   4 . 1 _ M C   , _ ,   S t a n d a r d _ J J   D e v i a t i o n _ N N 1   ( _ (   S D _ N P 1   ) _ )   = _ F O   0 . 3 _ M C   & r s q b ; _ )   . _ .   
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 T h e _ A T   s e c t i o n s _ N N 2   w e r e _ V B D R   i n c u b a t e d _ V V N   w i t h _ I W   p o l y c l o n a l _ J J   a n t i b o d y _ N N 1   a n t i - B M P - 4 _ J J   ( _ (   N o v o c a s t r a _ N P 1   , _ ,   N e w c a s t l e _ N P 1   , _ ,   U K _ N P 1   ) _ )   a n d _ C C   m o n o c l o n a l _ J J   a n t i b o d y _ N N 1   a n t i - M M P - 1 3 _ J J   ( _ (   S a n t a _ N P 1   C r u z _ N P 1   B i o t e c h n o l o g y _ N N 1   , _ ,   S a n t a _ N P 1   C r u z _ N P 1   , _ ,   C A _ N P 1   ) _ )   . _ .   
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 A m o n g _ I I   t h e m _ P P H O 2   , _ ,   1 4 1 _ M C   p e p t i d e s _ N N 2   c o n t a i n e d _ V V D   a t _ R R 2 1   l e a s t _ R R 2 2   o n e _ M C 1   a c i d i c _ J J   r e s i d u e _ N N 1   s u r r o u n d i n g _ V V G   t h e _ A T   p h o s p h o r y l a t e d _ J J   T y r _ N N 1   , _ ,   a n d _ C C   w e r e _ V B D R   , _ ,   t h e r e f o r e _ R R   , _ ,   c o n s i d e r e d _ V V D   p o t e n t i a l _ J J   s u b s t r a t e s _ N N 2   f o r _ I F   S Y K _ N P 1   ( _ (   X u e _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 2 _ M C   , _ ,   2 0 1 3 _ M C   ) _ )   . _ .   
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 T o _ T O   d e f i n e _ V V I   n o r m a l _ J J   w e i g h t _ N N 1   , _ ,   o v e r w e i g h t _ J J   a n d _ C C   o b e s i t y _ N N 1   , _ ,   w e _ P P I S 2   u s e d _ V V D   B M I _ J J   c u t - p o i n t s _ N N 2   2 5 . 0 _ M C   a n d _ C C   3 0 . 0 k g / m 2 _ F U   r e s p e c t i v e l y _ R R   . _ .   
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 I r o n _ N N 1   t o x i c i t y _ N N 1   B o u n d _ V V D   i r o n _ N N 1   i s _ V B Z   c o n s i d e r e d _ V V N   ' _ N U L L   s a f e _ J J   , _ ,   ' _ N U L L   b u t _ C C B   f r e e _ J J   i r o n _ N N 1   i s _ V B Z   m o r e _ R G R   l i k e l y _ J J   t o _ T O   e x c h a n g e _ V V I   e l e c t r o n s _ N N 2   w i t h _ I W   n e a r b y _ J J   m o l e c u l e s _ N N 2   a n d _ C C   p r o d u c e _ V V I   f r e e _ J J   r a d i c a l s _ N N 2   . _ .   
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 S e c o n d _ M D   , _ ,   t h e _ A T   p r e v i o u s l y _ R R   a n o x i c _ J J   c e l l s _ N N 2   a n d _ C C   t i s s u e s _ N N 2   a r e _ V B R   n o w _ R T   e x p o s e d _ V V N   t o _ I I   o x y g e n _ N N 1   , _ ,   w h i c h _ D D Q   c a n _ V M   l e a d _ V V I   t o _ I I   o x i d a t i v e _ J J   d a m a g e _ N N 1   i n _ I I   m y o c y t e s _ N N 2   b y _ I I   p r o m o t i n g _ V V G   f o r m a t i o n _ N N 1   o f _ I O   R O S _ N P 1   g e n e r a t i o n _ N N 1   ( _ (   1 8 _ M C   ) _ )   . _ .   
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 U n d e r _ I I   b a s a l _ J J   c o n d i t i o n s _ N N 2   , _ ,   m o s t _ D A T   o f _ I O   t h e _ A T   o x y g e n _ N N 1   e n t e r i n g _ V V G   c e l l s _ N N 2   a r e _ V B R   r e d u c e d _ V V N   t o _ I I   m o l e c u l a r _ J J   w a t e r _ N N 1   i n _ I I   t h e _ A T   m i t o c h o n d r i a l _ J J   m a t r i x _ N N 1   . _ .   
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 P a i n _ N N 1   b u r d e n _ N N 1   a n d _ C C   o r a l _ J J   o p i o i d _ J J   c o n s u m p t i o n _ N N 1   w e r e _ V B D R   a l s o _ R R   i n c r e a s e d _ V V N   i n _ I I   s u b j e c t s _ N N 2   w h o _ P N Q S   d e m o n s t r a t e d _ V V D   a _ A T 1   h i g h _ J J   s e n s o r y _ J J   s p r e a d _ N N 1   a f t e r _ I I   t h e _ A T   t e s t _ N N 1   d o s e _ N N 1   . _ .   
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 I m p o r t a n t l y _ R R   , _ ,   w e s t e r n _ J J   b l o t _ N N 1   a n a l y s i s _ N N 1   a n d _ C C   t u m o r _ N N 1   s t a i n i n g _ V V G   r e v e a l e d _ J J   E R K _ N N 1   t a r g e t _ N N 1   i n h i b i t i o n _ N N 1   , _ ,   a s _ C S A   m e a s u r e d _ V V N   b y _ I I   d e c r e a s e s _ N N 2   i n _ I I   p E R K _ N N 1   , _ ,   p R S K _ N N U   , _ ,   p S 6 _ F O   , _ ,   a n d _ C C   p 4 E - B P 1 _ J J   l e v e l s _ N N 2   ( _ (   F i g u r e s _ V V Z   S 6 J _ F O   a n d _ C C   S 6 K _ F O   ) _ )   . _ .   
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 O u t c o m e _ N N 1   M e a s u r e s _ V V Z   R e l e v a n t _ J J   f u l l - t e x t _ J J   a r t i c l e s _ N N 2   w e r e _ V B D R   s e p a r a t e d _ V V N   i n t o _ I I   t y p e _ N N 1   o f _ I O   r e g i o n a l _ J J   a n e s t h e s i a _ N N 1   ( _ (   p e r i p h e r a l _ J J   o r _ C C   n e u r a x i a l _ J J   b l o c k a d e _ N N 1   ) _ )   a n d _ C C   s u b s e q u e n t l y _ R R   r e v i e w e d _ V V N   . _ .   
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 H e _ P P H S 1   w a s _ V B D Z   s t a r t e d _ V V N   o n _ I I   l e v o d o p a / c a r b i d o p a _ N N 1   1 1 0 _ M C   m g _ N N U   t w i c e _ R R   d a i l y _ R R   2 _ M C   y e a r s _ N N T 2   a f t e r _ I I   d i a g n o s i s _ N N 1   . _ .   
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 I n _ I I   p r e d i c t i o n _ N N 1   d i c h o t o m i z i n g _ V V G   c o n t i n u o u s _ J J   p r e d i c t o r s _ N N 2   i s _ V B Z   a r g u a b l e _ J J   , _ ,   b e c a u s e _ I I 2 1   o f _ I I 2 2   a _ A T 1   l o s s _ N N 1   o f _ I O   i n f o r m a t i o n _ N N 1   & l s q b ; _ (   1 2 _ M C   & r s q b ; _ )   . _ .   
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 F u r t h e r _ R R R   , _ ,   p l a s m a _ N N 1   b i o m a r k e r _ N N 1   c o n c e n t r a t i o n s _ N N 2   w e r e _ V B D R   n o t _ X X   m e a s u r e d _ V V N   i n _ I I   a l l _ D B   p a t i e n t s _ N N 2   e n r o l l e d _ V V N   i n _ I I   t h e _ A T   p r i m a r y _ J J   s t u d y _ N N 1   d u e _ I I 2 1   t o _ I I 2 2   l o g i s t i c _ J J   i s s u e s _ N N 2   . _ .   
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 T h i s _ D D 1   p a r i t y _ N N 1   i s _ V B Z   o b s e r v e d _ V V N   o n l y _ R R   i f _ C S   , _ ,   i n _ I I   t h e _ A T   n o i s e - e x p o s u r e _ J J   m o d e l _ N N 1   , _ ,   O H C _ N P 1   f u n c t i o n _ N N 1   h a s _ V H Z   r e t u r n e d _ V V N   t o _ I I   n o r m a l _ J J   , _ ,   a s _ C S A   e v i d e n c e d _ V V N   b y _ I I   f u l l _ J J   r e c o v e r y _ N N 1   o f _ I O   o t o a c o u s t i c _ J J   e m i s s i o n _ N N 1   t h r e s h o l d s _ N N 2   a n d _ C C   s u p r a t h r e s h o l d _ V V 0   r e s p o n s e _ N N 1   a m p l i t u d e s _ N N 2   . _ .   
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 H o w e v e r _ R R   , _ ,   m o s t _ D A T   ( _ (   8 5 _ M C   ' _ N U L L   9 5 % _ N N U   ) _ )   c a s e s _ N N 2   o f _ I O   d i a b e t e s _ N N 1   i n _ I I   a d u l t s _ N N 2   a r e _ V B R   t y p e _ N N 1   2 , 5 0 _ M C   , _ ,   5 2 _ M C   s o _ R R   t h e _ A T   o b s e r v e d _ J J   r i s e _ N N 1   i n _ I I   d i a b e t e s _ N N 1   p r e v a l e n c e _ N N 1   i n _ I I   a d u l t s _ N N 2   i s _ V B Z   q u i t e _ R G   l i k e l y _ J J   d u e _ I I 2 1   t o _ I I 2 2   i n c r e a s e s _ N N 2   i n _ I I   t y p e _ N N 1   2 _ M C   d i a b e t e s _ N N 1   . _ .   
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 O u r _ A P P G E   c u r r e n t _ J J   s t u d i e s _ N N 2   p r o v i d e _ V V 0   t h e _ A T   k e y _ N N 1   i n _ R R 2 1   v i v o _ R R 2 2   e x p e r i m e n t a l _ J J   e v i d e n c e _ N N 1   d e m o n s t r a t i n g _ V V G   t h e _ A T   r e q u i r e m e n t _ N N 1   o f _ I O   K D M 4 C _ F O   f o r _ I F   c a n c e r _ N N 1   d e v e l o p m e n t _ N N 1   a n d _ C C   i t s _ A P P G E   f u n c t i o n a l _ J J   c r o s s t a l k _ N N 1   w i t h _ I W   P R M T 1 _ F O   i n _ I I   t h e _ A T   e s t a b l i s h m e n t _ N N 1   o f _ I O   h i s t o n e _ N N 1   c o d e s _ N N 2   f o r _ I F   t r a n s c r i p t i o n a l _ J J   d e r e g u l a t i o n _ N N 1   i n _ I I   A M L _ N P 1   . _ .   
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 A l l _ D B   p r e d i c t o r _ N N 1   v a r i a b l e s _ N N 2   w e r e _ V B D R   e n t e r e d _ V V N   i n t o _ I I   t h e _ A T   r e g r e s s i o n _ N N 1   i n _ I I   a _ A T 1   s i n g l e _ J J   s t e p _ N N 1   b e c a u s e _ C S   f i l t e r i n g _ V V G   v a r i a b l e s _ N N 2   b a s e d _ V V N   o n _ I I   u n a d j u s t e d _ J J   P _ Z Z 1   v a l u e s _ N N 2   c o n s u m e s _ V V Z   d e g r e e s _ N N 2   o f _ I O   f r e e d o m _ N N 1   a n d _ C C   c a n _ V M   l e a d _ V V I   t o _ I I   a n _ A T 1   o v e r f i t t e d _ J J   m o d e l _ N N 1   . _ .   
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 K P N C _ N P 1   i s _ V B Z   t h e _ A T   p i o n e e r _ N N 1   i n _ I I   l e a d i n g _ J J   i n i t i a t i v e s _ N N 2   t o _ T O   l a u n c h _ V V I   p o p u l a t i o n - b a s e d _ J J   a p p r o a c h e s _ N N 2   f o r _ I F   C R C _ N P 1   s c r e e n i n g _ N N 1   , _ ,   f o l l o w e d _ V V N   b y _ I I   s i m i l a r _ J J   e f f o r t s _ N N 2   b y _ I I   K a i s e r _ N N 1   i n _ I I   S o u t h e r n _ J J   C a l i f o r n i a _ N P 1   . _ .   
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 I n i t i a l l y _ R R   , _ ,   t h e _ A T   p r o g r a m _ N N 1   i n c l u d e d _ V V D   o n e _ M C 1   g r o u p _ N N 1   f a c e - t o - f a c e _ J J   i n f o r m a t i o n _ N N 1   s e s s i o n _ N N T 1   p l u s _ I I   a _ A T 1   p r o g r a m _ N N 1   h a n d b o o k _ N N 1   . _ .   
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 A s _ I I   t h e _ A T   e x p a n s i o n _ N N 1   p r o g r e s s e d _ V V D   , _ ,   i t _ P P H 1   b e c a m e _ V V D   c l e a r _ J J   t h a t _ C S T   e f f o r t s _ N N 2   t o _ T O   i n i t i a t e _ V V I   t r e a t m e n t _ N N 1   a t _ I I   t h e _ A T   p r i m a r y - c a r e _ J J   l e v e l _ N N 1   w e r e _ V B D R   a l s o _ R R   n e e d e d _ V V N   ; _ ;   b y _ I I   t h e _ A T   t i m e _ N N T 1   w o m e n _ N N 2   r e a c h e d _ V V D   t h e _ A T   h o s p i t a l _ N N 1   , _ ,   t h e _ A T   c o n d i t i o n _ N N 1   h a d _ V H D   o f t e n _ R R   p r o g r e s s e d _ V V N   p a s t _ I I   t h e _ A T   p o i n t _ N N 1   o f _ I O   e f f e c t i v e _ J J   t r e a t m e n t _ N N 1   . _ .   
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 R E S U L T S _ N N 2   A S D _ V V 0   i s _ V B Z   n o t _ X X   a s s o c i a t e d _ V V N   w i t h _ I W   s y s t e m i c _ J J   d i f f e r e n c e s _ N N 2   i n _ I I   g l o b a l _ J J   D N A _ N N 1   m e t h y l a t i o n _ N N 1   A s _ C S A   e x p e c t e d _ V V N   , _ ,   w i t h i n - t w i n _ N N 1   p a t t e r n s _ N N 2   o f _ I O   D N A _ N N 1   m e t h y l a t i o n _ N N 1   w e r e _ V B D R   h i g h l y _ R R   c o r r e l a t e d _ V V N   a c r o s s _ I I   a l l _ D B   M Z _ N P 1   t w i n _ N N 1   p a i r s _ N N 2   ( _ (   a v e r a g e _ J J   w i t h i n - t w i n _ N N 1   r _ Z Z 1   a c r o s s _ I I   a l l _ D B   p r o b e s _ N N 2   = _ F O   0 . 9 9 _ M C   ) _ )   , _ ,   i n d i c a t i n g _ V V G   t h a t _ D D 1   A S D _ N N 1   a n d _ C C   r e l a t e d _ J J   t r a i t s _ N N 2   a r e _ V B R   n o t _ X X   a s s o c i a t e d _ V V N   w i t h _ I W   s y s t e m i c _ J J   c h a n g e s _ N N 2   i n _ I I   e p i g e n e t i c _ J J   p r o g r a m m i n g _ N N 1   . _ .   
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 M E T H O D S _ N N 2   P a r t i c i p a n t s _ N N 2   T a b l e _ N N 1   1 _ M C 1   p r o v i d e s _ V V Z   d e s c r i p t i v e _ J J   c h a r a c t e r i s t i c s _ N N 2   o f _ I O   p a r t i c i p a n t s _ N N 2   f r o m _ I I   b o t h _ D B 2   s t u d i e s _ N N 2   . _ .   
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 N o _ A T   s i g n i f i c a n t _ J J   d i f f e r e n c e s _ N N 2   i n _ I I   t h e _ A T   m e a n _ J J   l i m b a l _ J J   b a s a l _ J J   c e l l _ N N 1   d e n s i t y _ N N 1   w e r e _ V B D R   f o u n d _ V V N   a m o n g _ I I   d i f f e r e n t _ J J   s t a g e s _ N N 2   . _ .   
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 I n _ I I   t h e _ A T   s e n s i t i v i t y _ N N 1   a n a l y s i s _ N N 1   l i m i t i n g _ V V G   t h e _ A T   r e p o r t s _ N N 2   t o _ I I   c o m p l e t e d _ J J   p r e g n a n c i e s _ N N 2   w i t h _ I W   s y m p t o m _ N N 1   o n s e t _ N N 1   o r _ C C   e x p o s u r e _ N N 1   e x c l u s i v e l y _ R R   d u r i n g _ I I   t h e _ A T   f i r s t _ M D   t r i m e s t e r _ N N 1   ( _ (   o r _ C C   f i r s t _ M D   t r i m e s t e r _ N N 1   a n d _ C C   p e r i c o n c e p t i o n a l _ J J   p e r i o d _ N N 1   ) _ )   a n d _ C C   a n _ A T 1   E D D _ N N 1   f r o m _ I I   A p r i l _ N P M 1   2 0 1 6 _ M C   t h r o u g h _ I I   A u g u s t _ N P M 1   2 0 1 6 _ M C   , _ ,   t h e _ A T   p r o p o r t i o n _ N N 1   w i t h _ I W   b i r t h _ N N 1   d e f e c t s _ N N 2   w a s _ V B D Z   c o m p a r a b l e _ J J   w i t h _ I W   t h e _ A T   o v e r a l l _ J J   a n a l y s i s _ N N 1   , _ ,   w i t h _ I W   7 _ M C   f e t u s e s _ N N 2   o r _ C C   i n f a n t s _ N N 2   p r e s e n t i n g _ V V G   w i t h _ I W   b i r t h _ N N 1   d e f e c t s _ N N 2   a m o n g _ I I   4 9 _ M C   c o m p l e t e d _ J J   p r e g n a n c i e s _ N N 2   ( _ (   1 4 % _ N N U   ; _ ;   9 5 % _ N N U   C I _ F O   , _ ,   7 % - 2 7 % _ F O   ) _ )   , _ ,   c o m p a r a b l e _ J J   w i t h _ I W   t h e _ A T   1 1 % _ N N U   o b s e r v e d _ V V N   i n _ I I   t h e _ A T   p r i m a r y _ J J   a n a l y s i s _ N N 1   . _ .   
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 C o m p u t e r - a i d e d _ J J   d e t e c t i o n _ N N 1   ( _ (   C A D _ N N 1   ) _ )   h a s _ V H Z   b e e n _ V B N   d e v e l o p e d _ V V N   t o _ T O   i m p r o v e _ V V I   d e t e c t i o n _ N N 1   o f _ I O   p u l m o n a r y _ J J   n o d u l e s _ N N 2   a n d _ C C   n u m e r o u s _ J J   p r e v i o u s _ J J   s t u d i e s _ N N 2   i n _ I I   s t a n d a r d _ J J   d o s e _ N N 1   C T _ N N 1   s h o w e d _ V V D   t h a t _ D D 1   C A D _ N N 1   u s e d _ V V N   a s _ I I   a _ A T 1   s e c o n d _ M D   r e a d e r _ N N 1   s i g n i f i c a n t l y _ R R   i m p r o v e d _ J J   d e t e c t i o n _ N N 1   r a t e _ N N 1   o f _ I O   p u l m o n a r y _ J J   n o d u l e s _ N N 2   . _ .   
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 S u b s e q u e n t _ J J   a n a l y s i s _ N N 1   s h o w e d _ V V D   t h a t _ C S T   7 6 . 9 % _ F O   o f _ I O   t h e _ A T   s t a t e m e n t s _ N N 2   o f _ I O   t h e _ A T   A W N S _ N P 2   w e r e _ V B D R   c l a s s i f i e d _ V V N   a s _ C S A   n e u t r a l _ J J   w h i l e _ C S   f e w e r _ D A R   s t a t e m e n t s _ N N 2   o f _ I O   t h e _ A T   A W S _ N P 2   w e r e _ V B D R   c l a s s i f i e d _ V V N   a s _ C S A   n e u t r a l _ J J   b o t h _ R R   p r i o r _ I I 2 1   t o _ I I 2 2   ( _ (   7 2 . 5 % _ F O   ) _ )   a n d _ C C   f o l l o w i n g _ V V G   t h e r a p y _ N N 1   ( _ (   6 8 . 6 % _ F O   ) _ )   . _ .   
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 B e c a u s e _ C S   t h e _ A T   i m p a c t _ N N 1   o f _ I O   t h e _ A T   d r a m a t i c _ J J   c h a n g e s _ N N 2   i n _ I I   U S _ N P 1   d e m o g r a p h i c s _ N N 1   i s _ V B Z   m a n i f e s t i n g _ V V G   f i r s t _ M D   i n _ I I   t h e _ A T   p e d i a t r i c _ J J   p o p u l a t i o n _ N N 1   , _ ,   w e _ P P I S 2   m u s t _ V M   l e a d _ V V I   t h e _ A T   m e d i c a l _ J J   p r o f e s s i o n _ N N 1   i n _ I I   c r e a t i n g _ V V G   a _ A T 1   n a t i o n a l _ J J   s t r a t e g y _ N N 1   t o _ T O   a d d r e s s _ V V I   o r g a n i z a t i o n a l _ J J   c h a n g e _ N N 1   i n _ I I   t h e _ A T   a c a d e m i c _ J J   a n d _ C C   p r a c t i c e _ N N 1   w o r k - f o r c e _ N N 1   a n d _ C C   t h u s _ R R   e n s u r e _ V V 0   t h e _ A T   b e s t _ J J T   h e a l t h _ N N 1   o u t c o m e s _ N N 2   i n _ I I   t h e _ A T   2 1 s t _ M D   c e n t u r y _ N N T 1   . _ .   
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 T h i s _ D D 1   i s _ V B Z   c o n s i s t e n t _ J J   w i t h _ I W   p a s t _ J J   r e s e a r c h _ N N 1   t h a t _ C S T   h a s _ V H Z   f o u n d _ V V N   t h e _ A T   e x p e r i e n c e _ N N 1   o f _ I O   M S _ N N 1   p a i n _ N N 1   m a y _ V M   b e _ V B I   b u f f e r e d _ V V N   b y _ I I   s o c i a l _ J J   f a c t o r s _ N N 2   , _ ,   s u c h _ I I 2 1   a s _ I I 2 2   p e r c e i v e d _ J J   s u p p o r t . 4 2 _ F O   T h e _ A T   c u r r e n t _ J J   r e s u l t s _ N N 2   s u g g e s t _ V V 0   t h a t _ C S T   p o t e n t i a l l y _ R R   i n c r e a s i n g _ J J   s o c i a l _ J J   s u p p o r t _ N N 1   m a y _ V M   b e _ V B I   a _ A T 1   c r i t i c a l _ J J   t r e a t m e n t _ N N 1   t a r g e t _ N N 1   i n _ I I   i m p r o v i n g _ J J   p a i n _ N N 1   , _ ,   p s y c h o l o g i c a l _ J J   , _ ,   a n d _ C C   p h y s i c a l _ J J   f u n c t i o n i n g _ N N 1   i n _ I I   t h e _ A T   c o n t e x t _ N N 1   o f _ I O   M S _ N N 1   . _ .   
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 S a m p l e _ N N 1   s i z e s _ N N 2   w e r e _ V B D R   s m a l l _ J J   ( _ (   r a n g e _ N N 1   1 1 _ M C   - _ -   1 0 8 _ M C   ) _ )   . _ .   
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 T h e _ A T   a s s e s s m e n t _ N N 1   o f _ I O   t h o r a c i c _ J J   f l u i d _ N N 1   v o l u m e s _ N N 2   i s _ V B Z   c r u c i a l _ J J   f o r _ I F   t h e _ A T   d i a g n o s i s _ N N 1   , _ ,   m a n a g e m e n t _ N N 1   , _ ,   a n d _ C C   s t r a t i f i c a t i o n _ N N 1   a n d _ C C   f o l l o w - u p _ N N 1   o f _ I O   h e a r t _ N N 1   f a i l u r e _ N N 1   ( _ (   H F _ N P 1   ) _ )   p a t i e n t s _ N N 2   . _ .   
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 O n e _ M C 1   s t u d y _ N N 1   r e p o r t e d _ V V D   a _ A T 1   h i g h e r _ J J R   i n c i d e n c e _ N N 1   o f _ I O   n u i s a n c e _ N N 1   a d v e r s e _ J J   e f f e c t s _ N N 2   ( _ (   n o t _ X X   l e a d i n g _ V V G   t o _ I I   t r e a t m e n t _ N N 1   d i s c o n t i n u a t i o n _ N N 1   ) _ )   w i t h _ I W   F A E s _ N N 2   c o m p a r e d _ V V N   w i t h _ I W   p l a c e b o _ N N 1   ( _ (   R R _ N P 1   4 . 7 2 _ M C   , _ ,   9 5 % _ N N U   C I _ N N 1   2 . 4 5 - 9 . 0 8 _ M C M C   ; _ ;   9 9 _ M C   p a r t i c i p a n t s _ N N 2   ; _ ;   m o d e r a t e - q u a l i t y _ J J   e v i d e n c e _ N N 1   ) _ )   , _ ,   a f f e c t i n g _ V V G   7 6 % _ N N U   o f _ I O   p a r t i c i p a n t s _ N N 2   g i v e n _ V V N   F A E s _ N N 2   ( _ (   n _ Z Z 1   = _ F O   4 9 _ M C   ) _ )   a n d _ C C   1 6 % _ N N U   o f _ I O   t h e _ A T   p l a c e b o _ N N 1   g r o u p _ N N 1   ( _ (   n _ Z Z 1   = _ F O   5 0 _ M C   ) _ )   , _ ,   r e p r e s e n t i n g _ V V G   a _ A T 1   n u m b e r _ N N 1   n e e d e d _ V V D   t o _ T O   t r e a t _ V V I   t o _ T O   h a r m _ V V I   o f _ I O   2 _ M C   . _ .   
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 T h e _ A T   n e t _ J J   e f f e c t _ N N 1   i s _ V B Z   t o _ T O   p r o m o t e _ V V I   i n f l a m m a t i o n _ N N 1   a n d _ C C   t y p e _ N N 1   I _ Z Z 1   c h o r o i d a l _ J J   n e o v a s c u l a r i z a t i o n _ N N 1   i n _ I I   a _ A T 1   n a r r o w _ J J   c l e a v a g e _ N N 1   p l a n e _ N N 1   b e t w e e n _ I I   t h e _ A T   R P E _ N N 1   b a s a l _ J J   l a m i n a _ N N 1   a n d _ C C   t h e _ A T   i n n e r _ J J   c o l l a g e n o u s _ J J   l a y e r _ N N 1   o f _ I O   B r M _ N P 1   , _ ,   a s _ C S A   p r o p o s e d _ V V N   e a r l y _ R R   ( _ (   S p a i d e _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 3 _ M C   ) _ )   . _ .   
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 O f _ I O   t h e _ A T   1 4 _ M C   s e r i o u s _ J J   a d v e r s e _ J J   e v e n t s _ N N 2   t h a t _ C S T   o c c u r r e d _ V V D   i n _ I I   t h e _ A T   r i v a s t i g m i n e _ N N 1   g r o u p _ N N 1   , _ ,   o n l y _ R R   t w o _ M C   w e r e _ V B D R   a s s e s s e d _ V V N   a s _ C S A   b e i n g _ V B G   p r o b a b l y _ R R   o r _ C C   d e f i n i t e l y _ R R   r e l a t e d _ V V N   t o _ I I   t h e _ A T   t r e a t m e n t _ N N 1   , _ ,   b o t h _ D B 2   o f _ I O   w h i c h _ D D Q   w e r e _ V B D R   w o r s e n i n g _ J J   o f _ I O   p a r k i n s o n i s m _ N N 1   . _ .   
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 L i p o p o l y s a c c h a r i d e _ V V 0   a l o n e _ R R   a l s o _ R R   r e d u c e d _ V V D   t h e _ A T   f r e e z i n g _ J J   s c o r e s _ N N 2   ( _ (   F _ Z Z 1   ( _ (   1 _ M C 1   6 5 _ M C   ) _ )   = _ F O   2 0 . 5 6 _ M C   , _ ,   n _ Z Z 1   = _ F O   1 0 _ M C   o r _ C C   1 1 _ M C   , _ ,   P _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 0 0 1 _ M C   , _ ,   t w o - w a y _ J J   A N O V A _ N N 1   ; _ ;   f i g . _ N N 1   6 D _ N N U   ) _ )   . _ .   
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 R a n d o m i z a t i o n _ N N 1   a n d _ C C   I n t e r v e n t i o n s _ N N 2   P a t i e n t s _ N N 2   w e r e _ V B D R   r a n d o m i z e d _ V V N   i n _ I I   a _ A T 1   1 : 1 _ M C   r a t i o _ N N 1   t o _ I I   1 _ M C 1   o f _ I O   t h e _ A T   2 _ M C   t r e a t m e n t _ N N 1   g r o u p s _ N N 2   u s i n g _ V V G   a _ A T 1   c o m p u t e r i z e d _ J J   s y s t e m _ N N 1   . _ .   
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 E a c h _ D D 1   v o l l e y b a l l _ N N 1   t e a m _ N N 1   w a s _ V B D Z   r e p r e s e n t e d _ V V N   o n _ I I   c o u r t _ N N 1   b y _ I I   a _ A T 1   s e t t e r _ N N 1   , _ ,   t w o _ M C   r e c e i v e r s _ N N 2   , _ ,   t w o _ M C   m i d d l e s _ N N 2   a n d _ C C   t h e _ A T   o p p o s i t e _ J J   w h i l e _ C S   t h e _ A T   l i b e r o _ N N 1   s u b s t i t u t e d _ V V N   f o r _ I F   m i d d l e _ J J   p l a y e r s _ N N 2   w h e n _ C S   t h e y _ P P H S 2   w e r e _ V B D R   p o s i t i o n e d _ V V N   i n _ I I   b a c k c o u r t _ N N 1   o r _ C C   i n _ I I   d e f e n s i v e _ J J   p o s i t i o n s _ N N 2   . _ .   
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 I t _ P P H 1   i s _ V B Z   i m p o r t a n t _ J J   t o _ T O   i d e n t i f y _ V V I   e a c h _ D D 1   t e a m _ N N 1   m e m b e r _ N N 1   ' _ N U L L   s _ Z Z 1   r o l e _ N N 1   i n _ I I   t h e _ A T   t r a n s i t i o n _ N N 1   t o _ T O   h e l p _ V V I   t h e _ A T   c h i l d _ N N 1   t o _ T O   b e g i n _ V V I   t o _ T O   t a k e _ V V I   o n _ R P   a _ A T 1   m o r e _ R G R   i n d e p e n d e n t _ J J   r o l e _ N N 1   i n _ I I   h i s _ A P P G E   o r _ C C   h e r _ A P P G E   h e a l t h _ N N 1   c a r e _ N N 1   . _ .   
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 A _ A T 1   m e t a - a n a l y s i s _ N N 1   e x a m i n e d _ V V D   t h e _ A T   r e l a t i o n s h i p _ N N 1   b e t w e e n _ I I   a n t i d e p r e s s a n t _ J J   r e s p o n s e _ N N 1   a n d _ C C   n e u r o p s y c h o l o g i c a l _ J J   t e s t _ N N 1   p e r f o r m a n c e _ N N 1   a m o n g _ I I   d e p r e s s e d _ J J   a d u l t s _ N N 2   . _ .   
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 H e r e _ R L   w e _ P P I S 2   r e p o r t _ V V 0   a _ A T 1   f a m i l y _ N N 1   c o m p r i s i n g _ V V G   t h r e e _ M C   a f f e c t e d _ J J   i n d i v i d u a l s _ N N 2   w h o _ P N Q S   h a r b o u r _ V V 0   a _ A T 1   h e t e r o z y g o u s _ J J   I F I H 1 _ F O   m u t a t i o n _ N N 1   , _ ,   v a r i a b l y _ R R   e x p r e s s i n g _ V V G   a _ A T 1   s k i n _ N N 1   a n d _ C C   a _ A T 1   n e u r o l o g i c a l _ J J   p h e n o t y p e _ N N 1   . _ .   
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 A s _ C S A   i n _ I I   t h e _ A T   p r e v i o u s _ J J   f i g u r e _ N N 1   , _ ,   i m a g e _ N N 1   q u a l i t y _ N N 1   a n d _ C C   S N R _ N P 1   a r e _ V B R   e s s e n t i a l l y _ R R   e q u i v a l e n t _ J J   , _ ,   w i t h _ I W   a _ A T 1   r e d u c t i o n _ N N 1   i n _ I I   s c a n _ N N 1   t i m e _ N N T 1   f r o m _ I I   7 : 1 4 _ M C   t o _ I I   3 : 4 8 _ M C   m i n : s _ F O   . _ .   
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 T h e _ A T   s c a n _ N N 1   t i m e _ N N T 1   w i t h _ I W   S M S _ N P 1   i s _ V B Z   s u f f i c i e n t l y _ R R   s h o r t _ J J   t o _ T O   m a k e _ V V I   s u c h _ D A   a _ A T 1   h i g h _ J J   s p a t i a l _ J J   r e s o l u t i o n _ N N 1   a c q u i s i t i o n _ N N 1   ( _ (   w i t h _ I W   a _ A T 1   0 . 4 _ M C   x _ Z Z 1   0 . 4 _ M C   m m 2 _ F O   p i x e l _ N N 1   ) _ )   c l i n i c a l l y _ R R   f e a s i b l e _ J J   . _ .   
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 V o x e l - b a s e d _ J J   m o r p h o m e t r i c _ J J   ( _ (   V B M _ N P 1   ) _ )   a n a l y s i s _ N N 1   w a s _ V B D Z   p e r f o r m e d _ V V N   t o _ T O   e x p l o r e _ V V I   t h e _ A T   b r a i n _ N N 1   r e g i o n s _ N N 2   w h e r e _ R R Q   a t r o p h y _ N N 1   m i g h t _ V M   b e _ V B I   a s s o c i a t e d _ V V N   w i t h _ I W   t h e _ A T   d e c l i n e s _ V V Z   o f _ I O   t h e _ A T   c o r e _ N N 1   E F _ N N 1   c o m p o n e n t s _ N N 2   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   a M C I _ N N 2   , _ ,   w h i c h _ D D Q   w a s _ V B D Z   t h e _ A T   m a i n _ J J   a i m _ N N 1   o f _ I O   t h i s _ D D 1   s t u d y _ N N 1   . _ .   
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 H o w e v e r _ R R   , _ ,   t h e _ A T   m a i n _ J J   e f f e c t _ N N 1   o f _ I O   d i s c l o s u r e _ N N 1   s h o u l d _ V M   n o t _ X X   a f f e c t _ V V I   t h e _ A T   e x p r e s s i o n _ N N 1   o f _ I O   t h e _ A T   o b s e r v e d _ J J   i n t e r a c t i o n _ N N 1   e f f e c t _ N N 1   o f _ I O   g e n o t y p e _ N N 1   b y _ I I   d i s c l o s u r e _ N N 1   s t a t u s _ N N 1   , _ ,   s i n c e _ C S   p e r f o r m a n c e _ N N 1   o n _ I I   t h e _ A T   m e m o r y _ N N 1   t e s t _ N N 1   w a s _ V B D Z   n o t _ X X   n e a r _ I I   f l o o r _ N N 1   o r _ C C   c e i l i n g _ N N 1   l e v e l s _ N N 2   i n _ I I   a n y _ D D   o f _ I O   t h e _ A T   f o u r _ M C   g r o u p s _ N N 2   . _ .   
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 W e _ P P I S 2   d e m o n s t r a t e d _ V V D   t h a t _ C S T   t h e _ A T   l o n g e v i t y _ N N 1   e f f e c t _ N N 1   o f _ I O   I G F - 1 R + / - _ F U   m u t a t i o n _ N N 1   o n _ I I   1 2 9 / S v P a s _ F U   g e n e t i c _ J J   b a c k g r o u n d _ N N 1   i s _ V B Z   s e x u a l l y _ R R   d i m o r p h i c _ J J   , _ ,   b e c a u s e _ C S   l i f e s p a n _ N N 1   w a s _ V B D Z   e x t e n d e d _ V V N   b y _ I I   3 3 % _ N N U   i n _ I I   f e m a l e s _ N N 2   , _ ,   w h i l e _ C S   t h e _ A T   e f f e c t _ N N 1   w a s _ V B D Z   n o t _ X X   s i g n i f i c a n t _ J J   i n _ I I   m a l e s _ N N 2   ( _ (   H o l z e n b e r g e r _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 3 _ M C   ) _ )   . _ .   
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 A l t h o u g h _ C S   f u r t h e r _ J J R   r e s e a r c h _ N N 1   i s _ V B Z   r e q u i r e d _ V V N   , _ ,   i n i t i a l _ J J   o b s e r v a t i o n s _ N N 2   s u p p o r t _ V V 0   a n _ A T 1   e r g o g e n i c _ J J   e f f e c t _ N N 1   a f t e r _ I I   s h o r t - t e r m _ J J   N O 3 - s u p p l e m e n t a t i o n _ N N 1   i n _ I I   m o d e r a t e l y _ R R   t r a i n e d _ V V N   t e a m - s p o r t _ J J   a t h l e t e s _ N N 2   , _ ,   b u t _ C C B   n o t _ X X   n e c e s s a r i l y _ R R   a f t e r _ I I   a c u t e _ J J   N O 3 - _ J J   i n g e s t i o n _ N N 1   a n d / o r _ C C   w h e n _ R R Q   e l i t e _ N N 1   e n d u r a n c e _ N N 1   a t h l e t e s _ N N 2   c o m p l e t e _ V V 0   s h o r t - d u r a t i o n _ J J   h i g h - i n t e n s i t y _ J J   i n t e r m i t t e n t _ J J   e x e r c i s e _ N N 1   . _ .   
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 H o w e v e r _ R R   , _ ,   a g e _ N N 1   d i d _ V D D   c o r r e l a t e _ V V I   w i t h _ I W   w h i t e _ J J   m a t t e r _ N N 1   m i c r o s t r u c t u r e _ N N 1   , _ ,   w i t h _ I W   h i g h e r _ J J R   F A _ N P 1   a n d _ C C   l o w e r _ J J R   M D _ N N 1   a n d _ C C   R D _ N N 1   w i t h _ I W   i n c r e a s i n g _ J J   a g e _ N N 1   . _ .   
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 S e m e n _ N N 1   q u a l i t y _ N N 1   w a s _ V B D Z   a s s e s s e d _ V V N   b y _ I I   s p e r m _ N N   c o n c e n t r a t i o n _ N N 1   , _ ,   m o t i l i t y _ N N 1   , _ ,   m o r p h o l o g y _ N N 1   a n d _ C C   t o t a l _ J J   s p e r m _ N N   c o u n t _ V V 0   . _ .   
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 E a r l i e r _ J J R   s t u d i e s _ N N 2   c o n d u c t e d _ V V N   o n _ I I   C H A M P _ N N 1   p o p u l a t i o n _ N N 1   a s s e s s e d _ V V N   t h e _ A T   S I R T 1 _ F O   e x p r e s s i o n _ N N 1   i n _ I I   S K _ N P 1   H e p 1 _ F O   c e l l s _ N N 2   g r o w n _ V V N   i n _ I I   t h e _ A T   p r e s e n c e _ N N 1   o f _ I O   s e r u m _ N N 1   s a m p l e s _ N N 2   o b t a i n e d _ V V N   f r o m _ I I   f r a i l _ J J   o r _ C C   n o n f r a i l _ V V 0   i n d i v i d u a l s _ N N 2   a n d _ C C   f o u n d _ V V D   t h e r e _ E X   w a s _ V B D Z   n o _ A T   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   f r a i l t y _ N N 1   a n d _ C C   S I R T 1 _ F O   e x p r e s s i o n _ N N 1   i n _ I I   c e l l s _ N N 2   . _ .   
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 H e n c e _ R R   , _ ,   t h i s _ D D 1   i s s u e _ N N 1   n e e d s _ V V Z   t o _ T O   b e _ V B I   f u r t h e r _ R R R   i n v e s t i g a t e d _ V V N   , _ ,   p r e f e r e n t i a l l y _ R R   w i t h _ I W   f u l l - l e n g t h _ J J   m e l a n o p s i n s _ N N 2   i n _ I I   a n _ A T 1   a r t i f i c i a l _ J J   m e m b r a n e _ N N 1   , _ ,   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   i n _ J J 2 1   v i v o _ J J 2 2   . _ .   
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 T h e r e _ E X   a r e _ V B R   , _ ,   h o w e v e r _ R R   , _ ,   l i m i t e d _ J J   p r o s p e c t i v e _ J J   s t u d i e s _ N N 2   e x a m i n i n g _ V V G   w h e t h e r _ C S W   H P V _ N P 1   i s _ V B Z   f o u n d _ V V N   i n _ I I   o t h e r _ J J   c l i n i c a l _ J J   c o n d i t i o n s _ N N 2   ( _ (   i e _ R E X   , _ ,   b r a n c h i a l _ J J   c l e f t _ J J   c y s t s _ N N 2   , _ ,   b e n i g n _ J J   l y m p h _ N N 1   n o d e s _ N N 2   , _ ,   o r _ C C   i n _ I I   m e t a s t a s i s _ N N 1   f r o m _ I I   H N S C C _ N P 1   ) _ )   , _ ,   o t h e r _ I I 2 1   t h a n _ I I 2 2   t o n s i l l a r _ J J   S C C _ N P 1   o r _ C C   B O T _ N P 1   S C C _ N P 1   . _ .   
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 A s _ I I   a _ A T 1   r e s u l t _ N N 1   , _ ,   a n _ A T 1   A N C O V A _ N N 1   w a s _ V B D Z   c o n d u c t e d _ V V N   w i t h _ I W   a g e _ N N 1   ( _ (   m a s s e t e r _ N N 1   a n d _ C C   F D I _ N P 1   ) _ )   a n d _ C C   s y m p t o m _ N N 1   d u r a t i o n _ N N 1   ( _ (   F D I _ N P 1   ) _ )   a s _ C S A   c o v a r i a t e s _ V V Z   . _ .   
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 O P P O R T U N I T I E S _ N N 2   I N _ I I   E M E R G E N C Y _ N N 1   C A R E _ V V 0   N o w h e r e _ R L   i s _ V B Z   t h e _ A T   n e e d _ N N 1   t o _ T O   e x p l o r e _ V V I   t h e _ A T   v a l u e _ N N 1   o f _ I O   n e w - w a v e _ J J   p r e d i c t i v e _ J J   a n a l y t i c s _ N N 2   m o r e _ R G R   e v i d e n t _ J J   t h a n _ C S N   i n _ I I   h i g h - f l o w _ N N 1   , _ ,   a c u t e _ J J   c a r e _ N N 1   s e t t i n g s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   t h e _ A T   E D _ N P 1   . _ .   
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 F u r t h e r _ J J R   s u p p o r t _ N N 1   w a s _ V B D Z   r e c e i v e d _ V V N   t h r o u g h _ I I   t h e _ A T   I n t r a m u r a l _ J J   R e s e a r c h _ N N 1   P r o g r a m _ N N 1   o f _ I O   t h e _ A T   E u n i c e _ N P 1   K e n n e d y _ N P 1   S h r i v e r _ N P 1   N a t i o n a l _ J J   I n s t i t u t e _ N N 1   o f _ I O   C h i l d _ N N 1   H e a l t h _ N N 1   a n d _ C C   H u m a n _ J J   D e v e l o p m e n t _ N N 1   ( _ (   C o n t r a c t _ N N 1   N 0 1 H D 3 3 3 4 8 _ F O   ) _ )   . _ .   
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 M o r e _ D A R   f a l l s _ N N 2   w i l l _ V M   b e _ V B I   a s s o c i a t e d _ V V N   w i t h _ I W   a _ A T 1   p r o p o r t i o n a l _ J J   i n c r e a s e _ N N 1   i n _ I I   f a l l - r e l a t e d _ J J   m o r b i d i t y _ N N 1   a n d _ C C   m o r t a l i t y _ N N 1   s e c o n d a r y _ N N 1   t o _ I I   i n j u r y _ N N 1   . _ .   
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 T h e _ A T   c l o s e d _ J J   s o c i e t y _ N N 1   w h e r e _ R R Q   t e r r o r i s t s _ N N 2   a r e _ V B R   i n d o c t r i n a t e d _ V V N   i s _ V B Z   t h e _ A T   v e r y _ J J   h e a r t _ N N 1   o f _ I O   t h e i r _ A P P G E   d e h u m a n i z a t i o n _ N N 1   . _ .   
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 S o c i o d e m o g r a p h i c _ J J   m a r g i n a l i z a t i o n _ N N 1   a n d _ C C   p s y c h o s o c i a l _ J J   d e p r i v a t i o n _ N N 1   h a v e _ V H 0   b e e n _ V B N   a s s o c i a t e d _ V V N   w i t h _ I W   e a r l i e r _ J J R   d i a g n o s i s _ N N 1   o f _ I O   G D M _ N P 1   , _ ,   h i g h e r _ J J R   p l a s m a _ N N 1   g l u c o s e _ N N 1   l e v e l _ N N 1   a t _ I I   d i a g n o s i s _ N N 1   , _ ,   a n d _ C C   n e e d _ V V 0   f o r _ I F   i n s u l i n _ N N 1   t h e r a p y _ N N 1   . _ .   
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 T h e r e f o r e _ R R   , _ ,   i t _ P P H 1   w o u l d _ V M   b e _ V B I   u n l i k e l y _ J J   f o r _ I F   h e a d g e a r _ N N 1   t o _ T O   h a v e _ V H I   a _ A T 1   c l i n i c a l l y _ R R   r e l e v a n t _ J J   e f f e c t _ N N 1   f o r _ I F   t h e s e _ D D 2   t y p e s _ N N 2   o f _ I O   i m p a c t s _ N N 2   . _ .   
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 I n _ I I   b o t h _ D B 2   g r o u p s _ N N 2   , _ ,   h i g h - d e g r e e _ J J   h u b s _ N N 2   i n _ I I   b i l a t e r a l _ J J   p r e c u n e u s _ N N   , _ ,   s u p e r i o r _ J J   f r o n t a l _ J J   c o r t e x _ N N 1   , _ ,   s u p e r i o r _ J J   p a r i e t a l _ J J   c o r t e x _ N N 1   , _ ,   a n d _ C C   i n s u l a _ N N 1   c o m p o s e d _ V V D   a _ A T 1   r i c h _ J J   c l u b _ N N 1   , _ ,   b u t _ C C B   t h e _ A T   d e n s i t y _ N N 1   o f _ I O   c o n n e c t i o n s _ N N 2   b e t w e e n _ I I   r i c h _ J J   c l u b _ N N 1   n o d e s _ N N 2   w a s _ V B D Z   s i g n i f i c a n t l y _ R R   a n d _ C C   s p e c i f i c a l l y _ R R   r e d u c e d _ V V N   i n _ I I   t h e _ A T   p a t i e n t _ J J   g r o u p _ N N 1   . _ .   
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 B e c a u s e _ C S   t h e _ A T   C I _ N N 1   i s _ V B Z   i n f l u e n c e d _ V V N   b y _ I I   t h e _ A T   s a m p l e _ N N 1   s i z e _ N N 1   , _ ,   i t _ P P H 1   i s _ V B Z   a n t i c i p a t e d _ V V N   t h a t _ C S T   i n _ I I   a _ A T 1   l a r g e r _ J J R   , _ ,   a d e q u a t e l y _ R R   p o w e r e d _ J J   p h a s e _ N N 1   I I I _ M C   s t u d y _ N N 1   o f s i m i l a r _ J J   d e s i g n _ N N 1   t h e _ A T   n o n i n f e r i o r i t y _ N N 1   m a r g i n _ N N 1   w o u l d _ V M   b e _ V B I   m e t _ V V N   i n _ I I   m o s t _ D A T   t i m e _ V V 0   p o i n t s _ N N 2   f o r _ I F   t h e _ A T   t r a d i t i o n a l _ J J   I O P _ N N 1   a s s e s s m e n t s _ N N 2   w i t h i n _ I I   t h e _ A T   f i r s t _ M D   1 2 w e e k s _ F O   . _ .   
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 O n e _ M C 1   p o s s i b i l i t y _ N N 1   i s _ V B Z   t h a t _ C S T   C a v - 1 _ M C 1   d e f i c i e n c y _ N N 1   a l t e r s _ V V Z   t h e _ A T   i o n i c _ J J   m i l i e u _ N N 1   s u r r o u n d i n g _ V V G   p h o t o r e c e p t o r s _ N N 2   ' _ N U L L   i n _ R R 2 1   s i t u _ R R 2 2   . _ .   
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 T h e _ A T   m o s t _ R G T   r e l e v a n t _ J J   s t u d i e s _ N N 2   i n _ I I   E u r o p e _ N P 1   d e a l i n g _ V V G   w i t h _ I W   A A D D _ N N 1   i n _ I I   p a t i e n t s _ N N 2   o f _ I O   a n y _ D D   a g e _ N N 1   s u c h _ I I 2 1   a s _ I I 2 2   t h a t _ D D 1   o f _ I O   D o u m a _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 & l s q b ; _ (   1 4 _ M C   & r s q b ; _ )   , _ ,   c o m p r i s i n g _ V V G   t h r e e _ M C   c o h o r t s _ N N 2   , _ ,   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   t h e _ A T   v a l i d a t i o n _ N N 1   p r o s p e c t i v e _ J J   s t u d y _ N N 1   r e p o r t e d _ V V N   b y _ I I   R i g h i n i _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 & l s q b ; _ (   1 5 _ M C   & r s q b ; _ )   , _ ,   s h o w _ V V 0   a _ A T 1   c l i n i c a l _ J J   u s e f u l n e s s _ N N 1   w i t h _ I W   t h e _ A T   u s e _ N N 1   o f _ I O   A A D D _ N N 1   o f _ I O   4 2 _ M C   , _ ,   5 1 _ M C   , _ ,   4 0 _ M C   a n d _ C C   3 9 . 8 _ M C   % _ N N U   , _ ,   r e s p e c t i v e l y _ R R   , _ ,   a m o n g _ I I   p a t i e n t s _ N N 2   w i t h _ I W   n o n - h i g h _ J J   P T P _ N P 1   o f _ I O   P E _ N N 1   . _ .   
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 B u t _ C C B   t h e r e _ E X   w e r e _ V B D R   n o _ A T   s u c h _ D A   c o m p l i c a t i o n s _ N N 2   r e c o r d e d _ V V N   i n _ I I   g r o u p _ N N 1   M _ N N 1   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   g r o u p _ N N 1   S . _ N P 1   M a x i l l a r y _ N P 1   b l o c k _ N N 1   i s _ V B Z   n o w _ R T   u s e d _ V V N   c o m m o n l y _ R R   i n _ I I   d e n t a l _ J J   o f f i c e s _ N N 2   f o r _ I F   v a r i o u s _ J J   d e n t a l _ J J   p r o c e d u r e s _ N N 2   . _ .   
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 F o c u s _ N N 1   w a s _ V B D Z   p l a c e d _ V V N   o n _ I I   t h e _ A T   r i g h t _ J J   a r m _ N N 1   m u s c l e s _ N N 2   , _ ,   b a s e d _ V V N   o n _ I I   d a t a _ N N   f r o m _ I I   S h a n _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 ( _ (   3 2 _ M C   ) _ )   i n d i c a t i n g _ V V G   t h a t _ D D 1   r i g h t _ N N 1   ( _ (   b o w i n g _ V V G   ) _ )   a r m _ N N 1   m o v e m e n t s _ N N 2   h a v e _ V H 0   t h e _ A T   l a r g e s t _ J J T   a m p l i t u d e s _ N N 2   a n d _ C C   v e l o c i t y _ N N 1   d u r i n g _ I I   v i o l i n _ N N 1   p e r f o r m a n c e _ N N 1   . _ .   
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 I f _ C S   d a t a _ N N   w e r e _ V B D R   s t i l l _ R R   m i s s i n g _ V V G   a f t e r _ I I   a t t e m p t i n g _ V V G   t o _ T O   c o n t a c t _ V V I   t h e _ A T   a u t h o r _ N N 1   , _ ,   w e _ P P I S 2   c l a s s i f i e d _ V V D   t h e _ A T   s t u d y _ N N 1   a s _ C S A   u n c l e a r _ J J   . _ .   
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 T h e _ A T   e f f e c t i v e n e s s _ N N 1   o f _ I O   u s t e k i n u m a b _ N N 1   f o r _ I F   r e d u c i n g _ V V G   i n f l a m m a t i o n _ N N 1   i n _ I I   B S C R _ N P 1   r e m a i n s _ V V Z   t o _ T O   b e _ V B I   d e t e r m i n e d _ V V N   ' _ N U L L   b u t _ C C B   t h e r e _ E X   i s _ V B Z   a n _ A T 1   u p c o m i n g _ J J   p h a s e _ N N 1   1 _ M C 1   a n d _ C C   2 _ M C   s t u d y _ N N 1   f o r _ I F   t h e _ A T   u s e _ N N 1   o f _ I O   u s t e k i n u m a b _ N N 1   i n _ I I   u v e i t i s _ N N 1   t h a t _ C S T   i s _ V B Z   e x p e c t e d _ V V N   t o _ T O   b e _ V B I   c o m p l e t e d _ V V N   i n _ I I   J u n e _ N P M 1   2 0 1 5 _ M C   ( _ (   C l i n i c a l - T r i a l s . g o v _ N P 1   I d e n t i f i e r _ N N 1   : _ :   N C T 0 1 6 4 7 1 5 2 _ F O   ) _ )   . _ .   
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 E R G _ N P 1   I n t e r a c t s _ V V Z   w i t h _ I W   T E A D - O c c u p i e d _ J J   C h r o m a t i n _ N N 1   R e g i o n s _ N N 2   , _ ,   I n c r e a s e s _ V V Z   H i s t o n e _ N P 1   A c e t y l a t i o n _ N N 1   , _ ,   a n d _ C C   P r o m o t e s _ V V Z   Y A P 1 - D e p e n d e n t _ J J   T r a n s c r i p t i o n _ N N 1   S i n c e _ C S   E R G _ N P 1   a n d _ C C   Y A P 1 _ F O   b o t h _ D B 2   l o c a l i z e _ V V 0   t o _ I I   t h e _ A T   n u c l e u s _ N N 1   ( _ (   F i g u r e s _ V V Z   1 L _ N N U   , _ ,   3 G _ N N U   , _ ,   a n d _ C C   3 H _ F O   ) _ )   , _ ,   w e _ P P I S 2   h y p o t h e s i z e d _ V V D   t h a t _ C S T   E R G _ V V 0   d i r e c t l y _ R R   b i n d s _ V V Z   a n d _ C C   a c t i v a t e s _ V V Z   Y A P 1 _ F O   t a r g e t _ N N 1   g e n e s _ N N 2   . _ .   
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 S e c o n d _ M D   ' _ N U L L   G P A _ N P 1   ' _ N U L L   T E D _ N P 1   ' _ N U L L   a n d _ C C   s a r c o i d o s i s _ N N 1   i n _ I I   t h e _ A T   o r b i t _ N N 1   s h o w _ V V 0   d i s t i n c t i v e _ J J   m o l e c u l a r _ J J   s i g n a t u r e s _ N N 2   ( _ (   R o s e n b a u m _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   ' _ N U L L   
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 R i c h a r d _ N P 1   G . _ N P 1   W e l e b e r _ N P 1   , _ ,   O r e g o n _ N P 1   R e t i n a l _ N P 1   D e g e n e r a t i o n _ N N 1   C e n t e r _ N N 1   , _ ,   C a s e y _ N P 1   E y e _ N P 1   I n s t i t u t e _ N N 1   , _ ,   O r e g o n _ N P 1   H e a l t h _ N N 1   & ; _ N U L L   S c i e n c e _ N N 1   U n i v e r s i t y _ N N 1   , _ ,   3 3 7 5 _ M C   S W _ N D 1   T e r w i l l i g e r _ N P 1   B o u l e v a r d _ N P 1   , _ ,   P o r t l a n d _ N P 1   , _ ,   O R _ C C   9 7 2 3 9 - 4 1 9 7 _ M C M C   . _ .   
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 A _ A T 1   s m a l l _ J J   b u t _ C C B   g r o w i n g _ J J   b o d y _ N N 1   o f _ I O   e v i d e n c e _ N N 1   i n d i c a t e s _ V V Z   t h a t _ C S T   c a v e o l a e _ N N 2   a r e _ V B R   a l s o _ R R   i n v o l v e d _ J J   i n _ I I   p a t h o g e n _ N N 1   u p t a k e _ N N 1   a n d _ C C   i n f l a m m a t o r y _ J J   r e s p o n s e s _ N N 2   a t _ I I   t h e _ A T   o c u l a r _ J J   s u r f a c e _ N N 1   . _ .   
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 T h e _ A T   m a i n _ J J   r e a s o n _ N N 1   w a s _ V B D Z   t h a t _ C S T   t h e _ A T   a t t e n d i n g _ V V G   a n e s t h e s i o l o g i s t s _ N N 2   h a v e _ V H 0   1 3 _ M C   t o _ I I   1 5 _ M C   y e a r s _ N N T 2   o f _ I O   c l i n i c a l _ J J   e x p e r i e n c e _ N N 1   a n d _ C C   w e r e _ V B D R   f a m i l i a r _ J J   w i t h _ I W   t h e _ A T   p h a r m a c o l o g i c a l _ J J   c h a r a c t e r i s t i c s _ N N 2   o f _ I O   p r o p o f o l _ N N 1   , _ ,   r e m i f e n t a n i l _ V V 0   , _ ,   a n d _ C C   D E X _ N P 1   . _ .   
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 S e l e c t i o n _ N N 1   o f _ I O   P a r t i c i p a n t s _ N N 2   R e s e a r c h _ V V 0   A s s i s t a n t s _ N N 2   ( _ (   R A s _ N P 2   ) _ )   w e r e _ V B D R   a s s i g n e d _ V V N   t o _ I I   s h i f t s _ N N 2   t h a t _ C S T   c o v e r e d _ V V D   a l l _ D B   d a y s _ N N T 2   o f _ I O   t h e _ A T   w e e k _ N N T 1   a n d _ C C   a l l _ D B   t i m e _ N N T 1   p e r i o d s _ N N 2   a t _ I I   b o t h _ D B 2   E D s _ N N 2   . _ .   
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 T h e _ A T   d u r a t i o n _ N N 1   o f _ I O   g e n e r a l _ J J   a n e s t h e s i a _ N N 1   ( _ (   5 _ M C   v s _ I I   7 1 _ M C   m i n _ N N U   , _ ,   P _ N N U   l e s s _ D A R   t h a n _ C S N   . 0 0 1 _ M C   ) _ )   a n d _ C C   t i m e _ N N T 1   i n _ I I   t h e _ A T   p o s t - a n e s t h e s i a _ J J   c a r e _ N N 1   u n i t _ N N 1   ( _ (   3 7 _ M C   v s _ I I   9 3 _ M C   m i n _ N N U   , _ ,   P _ N N U   l e s s _ D A R   t h a n _ C S N   . 0 0 1 _ M C   ) _ )   w e r e _ V B D R   s i g n i f i c a n t l y _ R R   s h o r t e r _ J J R   i n _ I I   t h e _ A T   c h e m o d e n e r v a t i o n _ N N 1   g r o u p _ N N 1   . _ .   
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 M u c h _ D A 1   o f _ I O   o u r _ A P P G E   u n d e r s t a n d i n g _ N N 1   o f _ I O   t h i s _ D D 1   c o m m u n i c a t i o n _ N N 1   , _ ,   t h e _ A T   s u b j e c t _ N N 1   o f _ I O   t h e _ A T   f i e l d _ N N 1   o f _ I O   p s y c h o n e u r o i m m u n o l o g y _ N N 1   ( _ (   P N I _ N P 1   ) _ )   , _ ,   c o m e s _ V V Z   f r o m _ I I   b o t h _ D B 2   e x p e r i m e n t a l _ J J   a n i m a l _ N N 1   m a n i p u l a t i o n s _ N N 2   a n d _ C C   c l i n i c a l _ J J   o b s e r v a t i o n s _ N N 2   t h a t _ C S T   d e m o n s t r a t e _ V V 0   t h a t _ C S T   a _ A T 1   w i d e _ J J   v a r i e t y _ N N 1   o f _ I O   p s y c h o l o g i c a l _ J J   , _ ,   p h y s i c a l _ J J   o r _ C C   p h y s i o l o g i c a l _ J J   s t r e s s o r s _ N N 2   c a n _ V M   a f f e c t _ V V I   i n n a t e _ J J   a n d _ C C   a d a p t i v e _ J J   i m m u n e _ J J   f u n c t i o n _ N N 1   a s _ C S A   e x a m i n e d _ V V N   e i t h e r _ R R   i n _ J J 2 1   v i v o _ J J 2 2   o r _ C C   i n _ R R 2 1   v i t r o _ R R 2 2   . _ .   
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 T o _ T O   c o m p l i c a t e _ V V I   t h i n g s _ N N 2   f u r t h e r _ R R R   , _ ,   o p t i m a l _ J J   v a l u e s _ N N 2   c a n _ V M   b e _ V B I   s u b s t a n t i a l l y _ R R   d i f f e r e n t _ J J   b e t w e e n _ I I   m e t h o d s _ N N 2   , _ ,   a n d _ C C   v a l u e s _ N N 2   a p p l y _ V V 0   o n l y _ R R   f o r _ I F   t h e _ A T   s p e c i f i c _ J J   a p p l i c a t i o n _ N N 1   i n _ I I   w h i c h _ D D Q   t h e y _ P P H S 2   h a v e _ V H 0   b e e n _ V B N   u s e d _ V V N   a n d _ C C   o p t i m i z e d _ J J   . _ .   
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 A l t h o u g h _ C S   a n o t h e r _ D D 1   r e l e v a n t _ J J   g e n e _ N N 1   , _ ,   t h e F O X O 3 A _ F O   , _ ,   h a s _ V H Z   b e e n _ V B N   r e p l i c a t e d _ V V N   i n _ I I   s e v e r a l _ D A 2   c a n d i d a t e _ N N 1   g e n e _ N N 1   s t u d i e s _ N N 2   ( _ (   A n s e l m i _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 9 _ M C   ; _ ;   D u m e r _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 4 _ M C   ; _ ;   F l a c h s b a r t _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 9 _ M C   ; _ ;   W i l l c o x _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 8 _ M C   ) _ )   , _ ,   n o _ A T   c o n s i s t e n c y _ N N 1   f o r _ I F   i t _ P P H 1   h a s _ V H Z   b e e n _ V B N   o b t a i n e d _ V V N   i n _ I I   t h e _ A T   G W A S _ N P 2   . _ .   
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 F o r _ I F   t h e _ A T   n o n i n f e r i o r i t y _ N N 1   o u t c o m e _ N N 1   , _ ,   a _ A T 1   2 - s i d e d _ J J   t e s t _ N N 1   a t _ I I   t h e _ A T   0 . 0 5 _ M C   s i g n i f i c a n c e _ N N 1   l e v e l _ N N 1   i s _ V B Z   e q u i v a l e n t _ J J   t o _ I I   a _ A T 1   1 - s i d e d _ J J   t e s t _ N N 1   a t _ I I   t h e _ A T   0 . 0 2 5 _ M C   s i g n i f i c a n c e _ N N 1   l e v e l _ N N 1   . _ .   
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 S e v e n _ M C   n e u r o l o g i c a l _ J J   i s s u e s _ N N 2   d e s c r i b e d _ V V N   d u r i n g _ I I   t h e _ A T   3 0 _ M C   d a y s _ N N T 2   a f t e r _ I I   G B C A _ N P 1   a d m i n i s t r a t i o n _ N N 1   i n c l u d e d _ V V D   m i g r a i n e _ N N 1   h e a d a c h e _ N N 1   , _ ,   l o s s _ N N 1   o f _ I O   c o n s c i o u s n e s s _ N N 1   , _ ,   m e m o r y _ N N 1   l o s s _ N N 1   ( _ (   2 _ M C   p a t i e n t s _ N N 2   ) _ )   , _ ,   f a l l i n g _ V V G   , _ ,   l i g h t h e a d e d n e s s _ N N 1   , _ ,   a n d _ C C   a t a x i a _ N N 1   w e r e _ V B D R   a l s o _ R R   p r e s e n t _ J J   b e f o r e _ I I   G B C A _ N P 1   e x p o s u r e _ N N 1   . _ .   
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 T h e _ A T   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   C S F _ N P 1   A B _ F O   a n d _ C C   C A A _ N P 1   d i s e a s e _ N N 1   p r o g r e s s i o n _ N N 1   h a s _ V H Z   y e t _ R R   t o _ T O   b e _ V B I   e x p l o r e d _ V V N   ; _ ;   b y _ I I   a n a l o g y _ N N 1   t o _ I I   A D _ R A   , _ ,   9 3 _ M C   o n e _ M C 1   m i g h t _ V M   e x p e c t _ V V I   t h e _ A T   r e d u c t i o n s _ N N 2   i n _ I I   C S F _ N P 1   A B _ F O   i n _ I I   C A A _ N P 1   t o _ T O   c o r r e l a t e _ V V I   i n v e r s e l y _ R R   w i t h _ I W   , _ ,   a n d _ C C   c a r r y _ V V I   r o u g h l y _ R R   t h e _ A T   s a m e _ D A   i n f o r m a t i o n _ N N 1   a s _ C S A   , _ ,   a m y l o i d _ J J   b u r d e n _ N N 1   i n _ I I   C A A _ N P 1   m e a s u r e d _ V V D   b y _ I I   P i B - P E T _ N N 1   . _ .   
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 S t u t t e r i n g _ V V G   s e v e r i t y _ N N 1   w a s _ V B D Z   h i g h e r _ J J R   i n _ I I   E n g l i s h _ N N 1   ( _ (   h e r _ A P P G E   l e s s _ R G R   p r o f i c i e n t _ J J   l a n g u a g e _ N N 1   ) _ )   t h a n _ C S N   i n _ I I   M a n d a r i n _ N N 1   . _ .   
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 F i v e _ M C   s t u d i e s _ N N 2   c o n c l u d e d _ V V D   t h a t _ C S T   t h e r e _ E X   w e r e _ V B D R   n o _ A T   d i f f e r e n c e s _ N N 2   b e t w e e n _ I I   n e r v e _ N N 1   l o c a l i z a t i o n _ N N 1   t e c h n i q u e s _ N N 2   . _ .   
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 T h e _ A T   S t a t S e n s o r _ N P 1   X p r e s s _ N P 1   ( _ (   h t t p _ N N U   : _ :   s t a t s e n s o r - c r e a t i n i n e / _ N N 1   ) _ )   m e a s u r e m e n t _ N N 1   w a s _ V B D Z   p e r f o r m e d _ V V N   i n _ I I   d u p l i c a t e _ N N 1   u s i n g _ V V G   c a p i l l a r y _ J J   b l o o d _ N N 1   f r o m _ I I   t h e _ A T   s a m e _ D A   f i n g e r _ N N 1   s t i c k _ N N 1   . _ .   
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 M a t c h i n g _ J J   G P _ N N 1   r e c o r d s _ N N 2   t o _ I I   p r a c t i c e _ N N 1   r e c o r d s _ N N 2   r e s u l t e d _ V V N   i n _ I I   3 2 2 7 _ M C   l e t t e r s _ N N 2   b e i n g _ V B G   i s s u e d _ V V N   . _ .   
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 T h i s _ D D 1   f i n d i n g _ N N 1   m a y _ V M   b e _ V B I   t h e _ A T   r e s u l t _ N N 1   o f _ I O   h e t e r o g e n e i t y _ N N 1   b e t w e e n _ I I   s t u d i e s _ N N 2   m e a s u r i n g _ V V G   c o n t r o l _ N N 1   b e l i e f s _ N N 2   ; _ ;   w i t h _ I W   3 _ M C   d i f f e r e n t _ J J   c o n s t r u c t s _ N N 2   o f _ I O   c o n t r o l _ N N 1   ( _ (   i e _ R E X   , _ ,   L o c u s _ N N 1   o f _ I O   C o n t r o l _ N N 1   , _ ,   p e r c e i v e d _ V V D   c o n t r o l _ N N 1   o f _ I O   m a n a g i n g _ J J   p a i n _ N N 1   , _ ,   p e r c e i v e d _ V V D   c o n t r o l _ N N 1   o f _ I O   t r e a t m e n t _ N N 1   ) _ )   b e i n g _ V B G   m e a s u r e d _ V V N   a m o n g _ I I   f o u r _ M C   s t u d i e s _ N N 2   . _ .   
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 A l t h o u g h _ C S   s o c c e r _ N N 1   p l a y e r s _ N N 2   m a y _ V M   e n g a g e _ V V I   i n _ R P   m e n t a l l y _ R R   f a t i g u i n g _ V V G   t a s k s _ N N 2   b e f o r e _ I I   a _ A T 1   m a t c h _ N N 1   , _ ,   i t _ P P H 1   i s _ V B Z   u n l i k e l y _ J J   t h a t _ C S T   a n y _ D D   p l a y e r s _ N N 2   w o u l d _ V M   p e r f o r m _ V V I   a _ A T 1   t a s k _ N N 1   s i m i l a r _ J J   t o _ I I   t h e _ A T   S t r o o p _ N N 1   t a s k _ N N 1   b e f o r e _ I I   c o m p e t i t i o n _ N N 1   . _ .   
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 R a d i a t i o n _ N N 1   e x p o s u r e _ N N 1   o f _ I O   d y n a m i c _ J J   p e r f u s i o n _ N N 1   i m a g i n g _ N N 1   i s _ V B Z   h i g h e r _ R R R   c o m p a r e d _ V V N   w i t h _ I W   " _ "   s t a t i c _ J J   " _ "   p e r f u s i o n _ N N 1   i m a g i n g _ N N 1   . _ .   
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 W e _ P P I S 2   r e s t r i c t e d _ V V D   t h e _ A T   s a m p l e _ N N 1   t o _ I I   p a t i e n t s _ N N 2   w h o _ P N Q S   w e r e _ V B D R   d i s c h a r g e d _ V V N   h o m e _ R L   f r o m _ I I   t h e _ A T   E D _ N P 1   t o _ T O   f o c u s _ V V I   o n _ I I   a _ A T 1   g r o u p _ N N 1   o f _ I O   p a t i e n t s _ N N 2   w h o s e _ D D Q G E   i n i t i a l _ J J   c a r e _ N N 1   w a s _ V B D Z   p r o v i d e d _ V V N   p r i m a r i l y _ R R   , _ ,   a n d _ C C   o f t e n _ R R   e x c l u s i v e l y _ R R   , _ ,   b y _ I I   e m e r g e n c y _ N N 1   p h y s i c i a n s _ N N 2   . _ .   
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 D a t a _ N N   f r o m _ I I   a n i m a l _ N N 1   s t u d i e s _ N N 2   h a v e _ V H 0   s h o w n _ V V N   t h a t _ C S T   i n c r e a s e d _ J J   s e r u m _ N N 1   c o r t i c o s t e r o n e _ N N 1   c o n c e n t r a t i o n _ N N 1   m a y _ V M   a l s o _ R R   p l a y _ V V I   a _ A T 1   r o l e _ N N 1   i n _ I I   t h e _ A T   C R - i n d u c e d _ J J   p r o t e c t i v e _ J J   e f f e c t s _ N N 2   a g a i n s t _ I I   c a n c e r _ N N 1   , _ ,   a s _ C S A   a d r e n a l e c t o m y _ N N 1   c o m p l e t e l y _ R R   r e v e r s e s _ V V Z   t h e _ A T   t u m o r _ N N 1   i n h i b i t o r y _ J J   e f f e c t _ N N 1   o f _ I O   C R _ N P 1   i n _ I I   s o m e _ D D   s t u d i e s _ N N 2   ( _ (   P a s h k o _ N P 1   & ; _ N U L L   S c h w a r t z _ N P 1   , _ ,   1 9 9 2 _ M C   , _ ,   1 9 9 6 _ M C   ; _ ;   S t e w a r t _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 5 _ M C   ) _ )   . _ .   
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 N e v e r t h e l e s s _ R R   t h e _ A T   f i r s t _ M D   a u t h o r _ N N 1   o b t a i n e d _ V V D   e x c e p t i o n a l l y _ R R   h i g h _ J J   i n t r a - j u d g e _ J J   k a p p a s _ N N 2   o f _ I O   . 8 1 _ M C   a n d _ C C   . 9 1 _ M C   f o r _ I F   O r i g i n _ N N 1   a n d _ C C   P a w n _ N N 1   s c o r i n g _ N N 1   w h i l e _ C S   a c c e p t a b l e _ J J   i n t e r - j u d g e _ J J   k a p p a s _ N N 2   ( _ (   . 7 0 _ M C   f o r _ I F   O r i g i n _ N N 1   a n d _ C C   . 7 5 _ M C   f o r _ I F   P a w n _ N N 1   ) _ )   w e r e _ V B D R   o b t a i n e d _ V V N   . _ .   
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 T h e _ A T   s t u d y _ N N 1   i n c l u d e d _ V V D   s i x _ M C   v i s i t s _ N N 2   o v e r _ R G   f o u r _ M C   m o n t h s _ N N T 2   w i t h _ I W   a n _ A T 1   e x t e n s i o n _ N N 1   p h a s e _ N N 1   t o _ I I   o n e _ M C 1   y e a r _ N N T 1   f o r _ I F   p a r t i c i p a n t s _ N N 2   w h o _ P N Q S   m e t _ V V D   t h e _ A T   p r i m a r y _ J J   o u t c o m e _ N N 1   . _ .   
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 T h e r e _ E X   i s _ V B Z   s o m e _ D D   e v i d e n c e _ N N 1   t h a t _ C S T   i t _ P P H 1   e n c o u r a g e s _ V V Z   m o r e _ R G R   ' _ N U L L   e v i d e n c e d - b a s e d _ J J   , _ ,   p r a c t i c e _ N N 1   p a r t i c u l a r l y _ R R   w i t h _ I W   u s e _ N N 1   o f _ I O   d e c i s i o n _ N N 1   s u p p o r t _ N N 1   s y s t e m s _ N N 2   . _ .   
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 B a s e d _ V V N   o n _ I I   t h e _ A T   2 9 4 _ M C   i n f a n t s _ N N 2   m e e t i n g _ V V G   t h e _ A T   i n c l u s i o n _ N N 1   c r i t e r i a _ N N 2   , _ ,   t h e _ A T   n u m b e r _ N N 1   o f _ I O   i n f a n t s _ N N 2   w i t h _ I W   m o d e r a t e _ J J   o r _ C C   s e v e r e _ J J   H I E _ N P 1   i n _ I I   2 0 0 8 _ M C   w a s _ V B D Z   p r o j e c t e d _ V V N   t o _ T O   b e _ V B I   3 8 0 _ M C   ( _ (   2 9 4 / 0 . 7 7 3 _ M F   ) _ )   . _ .   
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 T e n _ M C   p a t i e n t s _ N N 2   i n i t i a l l y _ R R   d i d _ V D D   n o t _ X X   r e s p o n d _ V V I   t o _ I I   t h e _ A T   a p p l i e d _ J J   s h a m _ N N 1   m a n o e u v r e _ N N 1   ; _ ;   t h r e e _ M C   r e m a i n e d _ V V D   p o s i t i v e _ J J   a t _ I I   a l l _ D B   f o l l o w - u p _ J J   v i s i t s _ N N 2   , _ ,   t w o _ M C   r e m a i n e d _ V V D   p o s i t i v e _ J J   a n d _ C C   a l s o _ R R   d e v e l o p e d _ V V D   B P P V _ N P 1   a t _ I I   t h e _ A T   c o n t r a l a t e r a l _ J J   s i d e _ N N 1   , _ ,   a n d _ C C   t h r e e _ M C   w e r e _ V B D R   i n i t i a l l y _ R R   n o t _ X X   r e s p o n s i v e _ J J   b u t _ C C B   t h e _ A T   B P P V _ N P 1   s p o n t a n e o u s l y _ R R   r e s o l v e d _ V V N   d u r i n g _ I I   f o l l o w - u p _ N N 1   . _ .   
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 T h e _ A T   r o l e _ N N 1   o f _ I O   s u b s t r a t e _ N N 1   s t i f f n e s s _ N N 1   a n d _ C C   t h e _ A T   e x t r a c e l l u l a r _ J J   m a t r i x _ N N 1   T h e _ A T   p h y s i o l o g i c a l _ J J   s u b s t r a t e _ N N 1   o f _ I O   t h e _ A T   S C _ F O   c e l l _ N N 1   i s _ V B Z   t h e _ A T   j C T _ N N U   ' _ N U L L   t h e _ A T   m o s t _ R G T   e x t e r n a l _ J J   a s p e c t _ N N 1   o f _ I O   t h e _ A T   T M _ N P 1   . _ .   
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 M E T H O D S _ N N 2   F r o m _ I I   A u g u s t _ N P M 1   2 0 1 1 _ M C   t o _ I I   J u n e _ N P M 1   2 0 1 3 _ M C   , _ ,   w e _ P P I S 2   a s s e s s e d _ V V D   c o n s e c u t i v e _ J J   H I V - i n f e c t e d _ J J   Z a m b i a n _ J J   a d u l t s _ N N 2   p r e s e n t i n g _ V V G   w i t h _ I W   n e w - o n s e t _ J J   s e i z u r e _ N N 1   f o r _ I F   e n r o l l m e n t _ N N 1   i n t o _ I I   t h e _ A T   C o h o r t _ N N 1   o f H I V - A s s o c i a t e d _ N N 1   S e i z u r e _ N N 1   a n d _ C C   E p i l e p s y _ N P 1   ( _ (   C H A S E _ N N 1   ) _ )   s t u d y _ N N 1   . _ .   
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 A p p l y i n g _ V V G   t h i s _ D D 1   t e c h n i q u e _ N N 1   t o _ I I   t h e _ A T   c a s e _ N N 1   i n _ I I   F i g u r e s _ N N 2   8 _ M C   , _ ,   a _ A T 1   3 D _ N N U   g r a p h i c _ J J   i m a g e _ N N 1   o f _ I O   t h e _ A T   b r a i n _ N N 1   c a n _ V M   b e _ V B I   r e n d e r e d _ V V N   t h a t _ C S T   s i m u l t a n e o u s l y _ R R   d e m o n s t r a t e s _ V V Z   n o t _ X X   j u s t _ R R   w h e r e _ C S   t h e _ A T   f o c a l _ J J   l e s i o n _ N N 1   i s _ V B Z   l o c a t e d _ V V N   b u t _ C C B   w h e r e _ R R Q   o t h e r _ J J   c o r t i c a l _ J J   v o l u m e _ N N 1   l o s s e s _ N N 2   h a v e _ V H 0   o c c u r r e d _ V V N   ( _ (   w a r m _ J J   c o l o r s _ N N 2   , _ ,   y e l l o w _ J J   t o _ I I   r e d _ J J   ) _ )   b e y o n d _ I I   t h o s e _ D D 2   v i s u a l l y _ R R   d e t e c t e d _ V V N   b y _ I I   j u s t _ R R   v i e w i n g _ V V G   t h e _ A T   i m a g e s _ N N 2   . _ .   
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 T o _ T O   r e d u c e _ V V I   s u b j e c t i v i t y _ N N 1   a n d _ C C   t h e _ A T   p o t e n t i a l _ N N 1   f o r _ I F   b i a s _ N N 1   , _ ,   s c r e e n i n g _ V V G   , _ ,   a b s t r a c t i o n _ N N 1   , _ ,   a n d _ C C   e v a l u a t i o n _ N N 1   o f _ I O   a l l _ D B   r e c o r d s _ N N 2   w e r e _ V B D R   c o n d u c t e d _ V V N   b y _ I I   a t _ R R 2 1   l e a s t _ R R 2 2   t w o _ M C   i n d e p e n d e n t _ J J   r e v i e w e r s _ N N 2   , _ ,   a n d _ C C   a l l _ D B   d i f f e r e n c e s _ N N 2   w e r e _ V B D R   r e s o l v e d _ V V N   t h r o u g h _ I I   c o n s e n s u s _ N N 1   . _ .   
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 E v e n _ C S 2 1   t h o u g h _ C S 2 2   d i s c h a r g e _ N N 1   d a y s _ N N T 2   v a r i e d _ J J   a n d _ C C   d a t a _ N N   c o l l e c t e d _ V V N   a r o u n d _ I I   d a y _ N N T 1   1 0 _ M C   a n d _ C C   a t _ I I   d i s c h a r g e _ N N 1   t i m e _ N N T 1   w e r e _ V B D R   s p a r s e _ J J   , _ ,   i t _ P P H 1   a p p e a r s _ V V Z   t h a t _ C S T   t h e _ A T   m a r k e r _ N N 1   v a l u e s _ N N 2   b e t w e e n _ I I   t h e _ A T   H B O C - 2 0 1 _ M C   a n d _ C C   t h e _ A T   R B C _ N P 1   g r o u p s _ N N 2   s t a r t e d _ V V D   t o _ T O   c o n v e r g e _ V V I   f r o m _ I I   d a y _ N N T 1   4 _ M C   t o _ I I   d a y _ N N T 1   1 0 _ M C   . _ .   
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 T h e _ A T   p r i m a r y _ J J   o b j e c t i v e _ N N 1   o f _ I O   t h i s _ D D 1   s t u d y _ N N 1   i s _ V B Z   t o _ T O   i d e n t i f y _ V V I   r i s k _ N N 1   f a c t o r s _ N N 2   f o r _ I F   a _ A T 1   s e v e r e _ J J   d i s e a s e _ N N 1   c o u r s e _ N N 1   a m o n g _ I I   c h i l d r e n _ N N 2   w i t h _ I W   n o n - i n f e c t i o u s _ J J   u v e i t i s _ N N 1   , _ ,   d e f i n e d _ V V N   a s _ I I   a _ A T 1   h i s t o r y _ N N 1   o f _ I O   o c u l a r _ J J   c o m p l i c a t i o n s _ N N 2   o r _ C C   a _ A T 1   V A _ F W   o f _ I O   2 0 / 2 0 0 _ M F   o r _ C C   w o r s e _ J J R   . _ .   
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 T h e _ A T   a u t h o r s _ N N 2   s u g g e s t e d _ V V D   t h a t _ D D 1   c o m p l i a n c e _ N N 1   w a s _ V B D Z   l o w _ J J   d u e _ I I 2 1   t o _ I I 2 2   t h e _ A T   n e c e s s i t y _ N N 1   o f _ I O   h a v i n g _ V H G   d i f f e r e n t _ J J   d i s c i p l i n e s _ N N 2   p r o v i d i n g _ V V G   c a r e _ N N 1   t o _ I I   t h e _ A T   s a m e _ D A   p a t i e n t s _ N N 2   , _ ,   a n d _ C C   a _ A T 1   f e w _ D A 2   s t r a t e g i e s _ N N 2   t o _ T O   i n c r e a s e _ V V I   c o m p l i a n c e _ N N 1   w e r e _ V B D R   s u g g e s t e d _ V V N   : _ :   e d u c a t i o n _ N N 1   a n d _ C C   r e e d u c a t i o n _ N N 1   o f _ I O   t h e _ A T   m u l t i d i s c i p l i n a r y _ J J   t e a m _ N N 1   a n d _ C C   h a v i n g _ V H G   p a t i e n t s _ N N 2   c o m p l e t e _ V V I   d a i l y _ J J   a c t i v i t y _ N N 1   l o g s _ N N 2   . _ .   
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 T h i s _ D D 1   s t r a t e g y _ N N 1   w a s _ V B D Z   u s e d _ V V N   t o _ T O   s e l e c t _ V V I   c o n s i s t e n t _ J J   s t a r t _ N N 1   a n d _ C C   e n d _ V V I   p o i n t s _ N N 2   f o r _ I F   t h e _ A T   e x t r a c t i o n _ N N 1   o f _ I O   o r a l _ J J   m o v e m e n t _ N N 1   t r a j e c t o r i e s _ N N 2   o n _ I I   t h e _ A T   b a s i s _ N N 1   o f _ I O   l o w e r _ J J R   l i p _ N N 1   p e a k _ N N 1   o p e n i n g _ N N 1   v e l o c i t i e s _ N N 2   f o r _ I F   t h e _ A T   k i n e m a t i c _ J J   a n a l y s i s _ N N 1   . _ .   
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 M u l d e r s _ N N 2   a n d _ C C   R o b e r t s o n _ N P 1   ( _ (   2 0 0 1 _ M C   , _ ,   2 0 0 5 _ M C   ) _ )   s h o w e d _ V V D   t h a t _ C S T   t h e _ A T   l o c u s _ N N 1   c o e r u l e u s _ N N   s e n d s _ V V Z   n o r a d r e n e r g i c _ J J   p r o j e c t i o n s _ N N 2   t o _ I I   t h e _ A T   S O C _ N N 1   a n d _ C C   m a d e _ V V D   t h e _ A T   c l a i m _ N N 1   t h a t _ C S T   t h i s _ D D 1   w a s _ V B D Z   t h e _ A T   o n l y _ J J   c a t e c h o l a m i n e r g i c _ J J   i n n e r v a t i o n _ N N 1   o f _ I O   t h e _ A T   S O C _ N N 1   . _ .   
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 W h e n _ C S   m a k i n g _ V V G   t h e _ A T   m a t c h _ N N 1   l i s t _ N N 1   , _ ,   o b s t e t r i c s _ N N 1   a n d _ C C   g y n e c o l o g y _ N N 1   f a c u l t y _ N N 1   s e r v e d _ V V N   a s _ I I   t h e _ A T   p r i m a r y _ J J   a d v i s o r _ N N 1   f o r _ I F   2 7 % _ N N U   ( _ (   n 5 6 3 _ F O   ) _ )   , _ ,   t h e _ A T   c l e r k s h i p _ N N 1   d i r e c t o r _ N N 1   f o r _ I F   2 4 % _ N N U   ( _ (   n 5 5 6 _ F O   ) _ )   , _ ,   a n d _ C C   t h e _ A T   d e p a r t m e n t _ N N 1   c h a i r _ N N 1   f o r _ I F   1 3 % _ N N U   ( _ (   n 5 2 9 _ F O   ) _ )   o f _ I O   t h e _ A T   r e s p o n d e n t s _ N N 2   . _ .   
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 W h e r e a s _ C S   a n _ A T 1   X b p 1 _ F O   s i g n a t u r e _ N N 1   d e r i v e d _ V V N   f r o m _ I I   o v e r e x p r e s s i o n _ N N 1   o f _ I O   X b p 1 _ F O   i n _ I I   B _ Z Z 1   c e l l s _ N N 2   ( _ (   S h a f f e r _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 4 _ M C   ) _ )   w a s _ V B D Z   m o d e r a t e l y _ R R   e n r i c h e d _ V V N   i n _ I I   B T Z - s e n s i t i v e _ J J   p r i m a r y _ N N 1   M M _ N N U   t u m o r s _ N N 2   ( _ (   q _ Z Z 1   = _ F O   0 . 0 7 _ M C   ; _ ;   F i g u r e _ N N 1   2 C _ F O   ) _ )   , _ ,   a _ A T 1   s e c o n d _ N N T 1   X b p 1 _ F O   s i g n a t u r e _ N N 1   r e p r e s e n t i n g _ V V G   g e n e s _ N N 2   w i t h _ I W   X b p 1 - b i n d i n g _ J J   p r o m o t e r s _ N N 2   , _ ,   w a s _ V B D Z   s i g n i f i c a n t l y _ R R   e n r i c h e d _ V V N   ( _ (   q _ Z Z 1   = _ F O   0 . 0 2 6 _ M C   ; _ ;   F i g u r e _ N N 1   2 D _ N N U   ) _ )   . _ .   
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 A d u l t _ N N 1   m a l e _ N N 1   I C R _ N N 1   m i c e _ N N 2   a n d _ C C   2 4 _ M C   h _ Z Z 1   n e o n a t a l _ J J   S p r a g u e - D a w l e y _ N N 1   ( _ (   S D _ N P 1   ) _ )   r a t s _ N N 2   w e r e _ V B D R   p u r c h a s e d _ V V N   f r o m _ I I   S h a n g h a i _ N P 1   S L A C _ N P 1   L a b o r a t o r y _ N N 1   A n i m a l _ N N 1   C o r p o r a t i o n _ N N 1   ( _ (   S h a n g h a i _ N P 1   , _ ,   C h i n a _ N P 1   ) _ )   . _ .   
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 T h e _ A T   t w o _ M C   e x t r e m e _ J J   c a t e g o r i e s _ N N 2   h a d _ V H D   l i t t l e _ D A 1   c r o s s o v e r _ N N 1   . _ .   
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 A _ A T 1   p a n o r a m i c _ J J   u l t r a s o u n d _ N N 1   e x a m i n a t i o n _ N N 1   w a s _ V B D Z   f i r s t _ M D   p e r f o r m e d _ V V N   f o r _ I F   t h e _ A T   h e a d _ N N 1   a n d _ C C   n e c k _ N N 1   w i t h _ I W   a _ A T 1   1 2 _ M C   M H z _ N N U   l i n e a r _ J J   p r o b e _ N N 1   ( _ (   T o s h i b a _ N P 1   A p l i o _ N P 1   S S A 7 9 0 _ F O   , _ ,   T o s h i b a _ N P 1   M e d i c a l _ J J   S y s t e m s _ N N 2   , _ ,   T o c h i g i - k e n _ N N 1   , _ ,   J a p a n _ N P 1   ) _ )   . _ .   
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 H o w e v e r _ R R   , _ ,   i n _ I I   t h i s _ D D 1   s e l e c t e d _ J J   p a t i e n t _ J J   c o h o r t _ N N 1   ( _ (   w h i c h _ D D Q   e x c l u d e s _ V V Z   p a t i e n t s _ N N 2   w i t h _ I W   h i g h - g r a d e _ J J   k i d n e y _ N N 1   d y s f u n c t i o n _ N N 1   a s _ C S A   s u c h _ D A   p a t i e n t s _ N N 2   w e r e _ V B D R   n o _ A T   c a n d i d a t e s _ N N 2   f o r _ I F   a _ A T 1   l a r g e _ J J   s u r g i c a l _ J J   p r o c e d u r e _ N N 1   ) _ )   , _ ,   w e _ P P I S 2   o b s e r v e d _ V V D   n o _ A T   a s s o c i a t i o n _ N N 1   o f _ I O   k i d n e y _ N N 1   f u n c t i o n _ N N 1   ( _ (   r e f l e c t e d _ V V N   b y _ I I   c r e a t i n i n e _ N N 1   l e v e l s _ N N 2   ) _ )   a n d _ C C   C S S _ N P 1   ( _ (   p = 0 . 8 5 9 _ F O   , _ ,   H R _ N N U   1 . 1 _ M C   , _ ,   9 5 % _ N N U   C I _ N N 1   0 . 3 7 - 3 . 2 _ M C M C   ) _ )   . _ .   
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 C o n s i d e r _ V V 0   t h e _ A T   p r o m o t i o n _ N N 1   o f _ I O   h e a l t h y _ J J   l i f e s t y l e _ N N 1   a n d _ C C   p h y s i c a l _ J J   a c t i v i t y _ N N 1   i n t e r v e n t i o n s _ N N 2   i n _ I I   a l l _ D B   p e o p l e _ N N   w i t h _ I W   m e n t a l _ J J   i l l n e s s _ N N 1   . _ .   
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 A _ A T 1   s i g n i f i c a n t _ J J   p o s i t i v e _ J J   r e g r e s s i o n _ N N 1   c o e f f i c i e n t _ N N 1   f o r _ I F   t h e _ A T   c a s e / c o n t r o l _ N N 1   t e r m _ N N 1   i s _ V B Z   t a k e n _ V V N   a s _ C S A   e v i d e n c e _ N N 1   t h a t _ C S T   c a s e _ N N 1   C N V s _ N P 1   i n _ I I   1 _ M C 1   s a m p l e _ N N 1   a r e _ V B R   m o r e _ R G R   l i k e l y _ J J   t h a n _ C S N   t h e i r _ A P P G E   c o r r e s p o n d i n g _ J J   c o n t r o l _ N N 1   C N V s _ N P 1   t o _ T O   o v e r l a p _ V V I   c a s e _ N N 1   C N V s _ N P 1   i n _ I I   t h e _ A T   o t h e r _ J J   s a m p l e _ N N 1   , _ ,   a l l o w i n g _ V V G   f o r _ I F   C N V _ N P 1   s i z e _ N N 1   ( _ (   l a r g e _ J J   C N V s _ N P 1   b e i n g _ V B G   m o r e _ R G R   l i k e l y _ J J   t o _ T O   o v e r l a p _ V V I   t h a n _ C S N   s m a l l _ J J   o n e s _ N N 2   ) _ )   . _ .   
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 P r e v i o u s _ J J   r e l a t i v e _ J J   a g e _ N N 1   r e s e a r c h _ N N 1   c o u l d _ V M   a c c u r a t e l y _ R R   b e _ V B I   d e s c r i b e d _ V V N   a s _ C S A   v a r i a b l e - o r i e n t e d _ J J   a n a l y s e s _ N N 2   . _ .   
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 T h e _ A T   l i m i t e d _ J J   e v i d e n c e _ N N 1   a v a i l a b l e _ J J   s u g g e s t s _ V V Z   t h a t _ D D 1   g e n e r a l i z a t i o n _ N N 1   t o _ I I   n o n t r e a t e d _ J J   l a n g u a g e s _ N N 2   m i g h t _ V M   o c c u r _ V V I   w i t h _ I W   t h e _ A T   L i d c o m b e _ N P 1   P r o g r a m _ N N 1   f o r _ I F   s o m e _ D D   p r e s c h o o l e r s _ N N 2   . _ .   
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 I n _ I I   W a s h i n g t o n _ N P 1   S t a t e _ N N 1   , _ ,   o v e r _ I I   t h e _ A T   l a s t _ M D   2 6 _ M C   y e a r s _ N N T 2   , _ ,   t h e _ A T   a g e - _ N N 1   a n d _ C C   s e x - a d j u s t e d _ J J   i n c i d e n c e _ N N 1   o f _ I O   e l e c t i v e _ J J   c o l e c t o m y _ N N 1   f o r _ I F   d i v e r t i c u l i t i s _ N N 1   m o r e _ R R R   t h a n _ C S N   d o u b l e d _ V V N   . _ .   
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 B e f o r e _ C S   m o d e r a t e _ J J   h y p o f r a c t i o n a t i o n _ N N 1   c a n _ V M   b e _ V B I   r e c o m m e n d e d _ V V N   i n _ I I   d a i l y _ J J   p r a c t i c e _ N N 1   f o r _ I F   l o w - r i s k _ N N 1   a n d _ C C   i n t e r m e d i a t e - r i s k _ J J   p r o s t a t e _ N N 1   c a n c e r _ N N 1   , _ ,   1 0 _ M C   m a t u r e _ J J   d a t a _ N N   f r o m _ I I   t h e _ A T   C H H i P _ N N 1   t r i a l _ N N 1   a r e _ V B R   n e e d e d _ V V N   ( _ (   s h o w i n g _ V V G   t h e _ A T   n o n - i n f e r i o r i t y _ N N 1   o f _ I O   h y p o f r a c t i o n a t e d _ J J   r e g i m e n s _ N N 2   a n d _ C C   5 - y e a r _ J J   u r i n a r y _ N N 1   , _ ,   b o w e l _ N N 1   , _ ,   a n d _ C C   s e x u a l _ J J   a d v e r s e _ J J   e v e n t _ N N 1   d a t a _ N N   ) _ )   , _ ,   a s _ C S A   a r e _ V B R   r e s u l t s _ N N 2   f r o m _ I I   t r i a l s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   t h e _ A T   R a d i a t i o n _ N N 1   T h e r a p y _ N N 1   O n c o l o g y _ N N 1   G r o u p _ N N 1   0 4 1 5 _ M C   t r i a l _ N N 1   a n d _ C C   t h e _ A T   P R O F I T _ N N 1   t r i a l _ N N 1   f r o m _ I I   t h e _ A T   O n t a r i o _ N P 1   C l i n i c a l _ J J   O n c o l o g y _ N N 1   G r o u p _ N N 1   . _ .   
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 I n i t i a l _ J J   a n a l y s i s _ N N 1   o f _ I O   t h e _ A T   q u a l i t y _ N N 1   c r i t e r i o n _ N N 1   o f _ I O   a t _ R R 2 1   l e a s t _ R R 2 2   a _ A T 1   5 0 % _ N N U   r e s p o n s e _ N N 1   r a t e _ N N 1   t o _ T O   i n d i c a t e _ V V I   s t u d i e s _ N N 2   o f _ I O   q u a l i t y _ N N 1   s h o w e d _ V V D   t h a t _ C S T   t h i s _ D D 1   w a s _ V B D Z   a _ A T 1   v a l i d _ J J   c u t - o f f _ N N 1   p o i n t _ N N 1   . _ .   
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 A d d i t i o n a l l y _ R R   , _ ,   a _ A T 1   n u m b e r _ N N 1   o f _ I O   p a t i e n t s _ N N 2   h a v e _ V H 0   b e e n _ V B N   r e p o r t e d _ V V N   w i t h _ I W   p s o r i a s i s _ N N 1   a n d _ C C   g l a u c o m a _ N N 1   , _ ,   t h e _ A T   l a t t e r _ D A   b e i n g _ V B G   a _ A T 1   c o m m o n _ J J   f e a t u r e _ N N 1   i n _ I I   A G S _ N N 2   a l s o _ R R   . _ .   
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 P u b l i s h e d _ V V N   o n l i n e _ R R   : _ :   1 2 _ M C   J a n u a r y _ N P M 1   2 0 1 6 _ M C   ( _ (   C _ Z Z 1   ) _ )   S I M I _ N N 1   2 0 1 6 _ M C   A b s t r a c t _ J J   A c u t e _ J J   l u n g _ N N 1   i n j u r y _ N N 1   ( _ (   A L I _ N P 1   ) _ )   i s _ V B Z   a _ A T 1   c o m m o n _ J J   c o m p l i c a t i o n _ N N 1   i n _ I I   e l d e r l y _ J J   p n e u m o n i a _ N N 1   p a t i e n t s _ N N 2   w h o _ P N Q S   h a v e _ V H 0   a _ A T 1   r a p i d _ J J   p r o g r e s s i o n _ N N 1   , _ ,   a n d _ C C   i s _ V B Z   a c c o m p a n i e d _ V V N   b y _ I I   a _ A T 1   h i g h _ J J   m o r t a l i t y _ N N 1   r a t e _ N N 1   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   a n _ A T 1   a r r o w _ N N 1   w a s _ V B D Z   p l a c e d _ V V N   p o i n t i n g _ V V G   t o _ I I   t h e _ A T   a p p r o x i m a t e _ J J   c e n t e r _ N N 1   o f _ I O   t h e _ A T   t a r g e t _ N N 1   , _ ,   a n d _ C C   a _ A T 1   n o t a t i o n _ N N 1   w a s _ V B D Z   p r o v i d e d _ V V N   a s s i g n i n g _ V V G   t h e _ A T   l e s i o n _ N N 1   t o _ I I   t h e _ A T   P Z _ N P 1   o r _ C C   T Z _ N P 1   i n _ I I 3 1   v i e w _ I I 3 2   o f _ I I 3 3   d i s t i n c t _ J J   P I - R A D S _ N N 2   V 2 _ F O   c r i t e r i a _ N N 2   f o r _ I F   P Z _ N P 1   a n d _ C C   T Z _ N P 1   l e s i o n s _ N N 2   . _ .   
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 I n _ I I   a _ A T 1   C h i n e s e _ J J   s t u d y _ N N 1   o f _ I O   p a t i e n t s _ N N 2   w i t h _ I W   i n i t i a l _ N N 1   N 0 _ F O   d i s e a s e _ N N 1   , _ ,   e l e c t i v e _ J J   n o d a l _ J J   i r r a d i a t i o n _ N N 1   w a s _ V B D Z   d e l i v e r e d _ V V N   t o _ I I   l e v e l s _ N N 2   I b _ V V 0   , _ ,   I I _ M C   , _ ,   a n d _ C C   I I I _ M C   c e r v i c a l _ J J   n o d e s _ N N 2   a t _ I I   t h e _ A T   d i s c r e t i o n _ N N 1   o f _ I O   t h e _ A T   t r e a t i n g _ V V G   o n c o l o g i s t _ N N 1   b u t _ C C B   n o t _ X X   s p e c i f i c a l l y _ R R   t o _ I I   t h e _ A T   R P L N s _ N P 1   . _ .   
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 T h e _ A T   n u m b e r _ N N 1   o f _ I O   a t t e m p t s _ N N 2   r e q u i r e d _ V V N   f o r _ I F   i n s e r t i o n _ N N 1   o f _ I O   t h e _ A T   I n t l o c k _ N P 1   b l a d e _ N N 1   , _ ,   a n d _ C C   t h e _ A T   n u m b e r _ N N 1   o f _ I O   a t t e m p t s _ N N 2   r e q u i r e d _ V V N   f o r _ I F   t r a c h e a l _ J J   i n t u b a t i o n _ N N 1   w a s _ V B D Z   c o u n t e d _ V V N   . _ .   
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 I t _ P P H 1   w a s _ V B D Z   c o n d u c t e d _ V V N   i n _ I I   a _ A T 1   h e a l t h y _ J J   a g i n g _ J J   s a m p l e _ N N 1   w i t h _ I W   a _ A T 1   n a r r o w _ J J   r a n g e _ N N 1   o f _ I O   a g e s _ N N 2   , _ ,   w h i c h _ D D Q   e l i m i n a t e d _ V V D   m o s t _ D A T   o f _ I O   t h e _ A T   p o t e n t i a l l y _ R R   c o n f o u n d i n g _ V V G   e f f e c t _ N N 1   o f _ I O   v a r i a t i o n s _ N N 2   i n _ I I   a g e _ N N 1   . _ .   
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 T h i s _ D D 1   d e m o n s t r a t e s _ V V Z   t h a t _ C S T   p e r i o p e r a t i v e _ J J   i r o n _ N N 1   r e p l e t i o n _ N N 1   h a s _ V H Z   s u b s t a n t i a l _ J J   b e n e f i t _ N N 1   i n _ I I   t h e _ A T   p o s t o p e r a t i v e _ J J   r e c o v e r y _ N N 1   p e r i o d _ N N 1   , _ ,   p o t e n t i a l l y _ R R   d u e _ I I 2 1   t o _ I I 2 2   t h e _ A T   i r o n _ N N 1   r e p l e t i o n _ N N 1   a l l o w i n g _ V V G   b o n e _ N N 1   m a r r o w _ N N 1   t o _ T O   i n c r e a s e _ V V I   e r y t h r o p o i e s i s _ N N 1   , _ ,   c o m p a r e d _ V V N   w i t h _ I W   t r a n s f u s e d _ J J   R B C s _ N P 1   w h i c h _ D D Q   a r e _ V B R   r a p i d l y _ R R   c l e a r e d _ V V N   f r o m _ I I   t h e _ A T   c i r c u l a t i o n _ N N 1   a n d _ C C   h a v e _ V H 0   a _ A T 1   s h o r t e r _ J J R   l i f e s p a n _ N N 1   t h a n _ C S N   n o r m a l _ J J   R B C s _ N P 1   . _ .   
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 E n d o p l a s m i c _ J J   r e t i c u l u m _ N N 1   : _ :   s t r u c t u r e _ N N 1   a n d _ C C   f u n c t i o n _ V V 0   T h e _ A T   E R _ N P 1   i s _ V B Z   a _ A T 1   m a j o r _ J J   e n d o m e m b r a n e _ N N 1   c o m p a r t m e n t _ N N 1   c o n s i s t i n g _ V V G   o f _ I O   a n _ A T 1   e x t e n s i v e l y _ R R   f o l d e d _ J J   t u b u l o v e s i c u l a r _ J J   m e m b r a n e _ N N 1   n e t w o r k _ N N 1   s u p p o r t e d _ V V N   b y _ I I   t h e _ A T   g e l - l i k e _ J J   c y t o p l a s m i c _ J J   m a t r i x _ N N 1   ( _ (   r e v i e w e d _ V V N   i n _ I I   E n g l i s h _ N N 1   a n d _ C C   V o e l t z _ N P 1   , _ ,   2 0 1 3 _ M C   ) _ )   . _ .   
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 T o _ T O   r e d u c e _ V V I   t h e _ A T   r i s k _ N N 1   o f _ I O   t h i s _ D D 1   c o m p l i c a t i o n _ N N 1   , _ ,   p a r t i c u l a r _ J J   a t t e n t i o n _ N N 1   s h o u l d _ V M   b e _ V B I   p a i d _ V V N   t o _ I I   d r u g _ N N 1   r e s e r v o i r _ N N 1   v o l u m e _ N N 1   d i s c r e p a n c i e s _ N N 2   a n d _ C C   o v e r d o s e _ V V 0   s y m p t o m s _ N N 2   r e p o r t e d _ V V N   b y _ I I   p a t i e n t s _ N N 2   . _ .   
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 M o d u l a t i o n _ N N 1   o f _ I O   A P P _ N P 1   E x p r e s s i o n _ N N 1   R e d u c e s _ V V Z   A p _ N P 1   D e p o s i t i o n _ N N 1   i n _ I I   a _ A T 1   M o u s e _ N N 1   M o d e l _ N N 1   A y o d e j i _ N P 1   A . _ N P 1   A s u n i 1 _ F O   , _ ,   M a i t e a _ N P 1   G u r i d i 1 _ F O   , _ ,   J o a n n a _ N P 1   E . _ N P 1   P a n k i e w i c z _ N P 1   , _ ,   S a n d r i n e _ N P 1   S a n c h e z 1 _ F O   , _ ,   a n d _ C C   M a r t i n _ N P 1   J . _ N P 1   S a d o w s k i _ N P 1   D e p a r t m e n t _ N N 1   o f _ I O   N e u r o l o g y _ N P 1   , _ ,   N e w _ N P 1   Y o r k _ N P 1   U n i v e r s i t y _ N N 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   , _ ,   N e w _ N P 1   Y o r k _ N P 1   , _ ,   N Y _ N P 1   1 0 0 1 6 _ M C   D e p a r t m e n t _ N N 1   o f _ I O   P s y c h i a t r y _ N P 1   , _ ,   N e w _ N P 1   Y o r k _ N P 1   U n i v e r s i t y _ N N 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   , _ ,   N e w _ N P 1   Y o r k _ N P 1   , _ ,   N Y _ N P 1   1 0 0 1 6 _ M C   D e p a r t m e n t _ N N 1   o f _ I O   B i o c h e m i s t r y _ N P 1   a n d _ C C   M o l e c u l a r _ J J   P h a r m a c o l o g y _ N N 1   , _ ,   N e w _ N P 1   Y o r k _ N P 1   U n i v e r s i t y _ N N 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   , _ ,   N e w _ N P 1   Y o r k _ N P 1   , _ ,   N Y _ N P 1   1 0 0 1 6 _ M C   A b s t r a c t _ J J   O b j e c t i v e - P r o t e o l y t i c _ J J   c l e a v a g e _ N N 1   o f _ I O   t h e _ A T   a m y l o i d _ J J   p r e c u r s o r _ N N 1   p r o t e i n _ N N 1   ( _ (   A P P _ N P 1   ) _ )   g e n e r a t e s _ V V Z   P - a m y l o i d _ N N 1   ( _ (   A P _ N P 1   ) _ )   p e p t i d e s _ N N 2   . _ .   
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 T h e _ A T   b e h a v i o u r a l _ J J   i n t e r v e n t i o n _ N N 1   h a d _ V H D   l i t t l e _ D A 1   f o c u s _ N N 1   o n _ I I   s e d e n t a r y _ J J   t i m e _ N N T 1   d u r i n g _ I I   t h e _ A T   d a y _ N N T 1   . _ .   
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 P r e g n a n c y - a s s o c i a t e d _ J J   h y p e r t e n s i o n _ N N 1   w a s _ V B D Z   a l s o _ R R   s h o w n _ V V N   t o _ T O   h a v e _ V H I   a _ A T 1   m o d e r a t e _ J J   e f f e c t _ N N 1   o n _ I I   S I D S _ N P 2   o c c u r r e n c e _ N N 1   , _ ,   p o s s i b l y _ R R   a _ A T 1   c o n s e q u e n c e _ N N 1   o f _ I O   t h e _ A T   i n c r e a s e d _ J J   s u s c e p t i b i l i t y _ N N 1   t o _ I I   p r e g n a n c y - i n d u c e d _ J J   h y p e r t e n s i o n _ N N 1   c o m p l i c a t i o n s _ N N 2   , _ ,   s u c h _ I I 2 1   a s _ I I 2 2   p l a c e n t a _ N N 1   a b r u p t i o n _ N N 1   , _ ,   w h i c h _ D D Q   i s _ V B Z   i t s e l f _ P P X 1   a _ A T 1   c a u s e _ N N 1   o f _ I O   i n t r a u t e r i n e _ J J   h y p o x i a _ N N 1   . _ .   
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 N e v e r t h e l e s s _ R R   , _ ,   i t _ P P H 1   i s _ V B Z   i m p o r t a n t _ J J   t o _ T O   n o t e _ V V I   t h a t _ C S T   d e s p i t e _ I I   b e i n g _ V B G   p r e d o m i n a n t l y _ R R   e u t h y m i c _ J J   , _ ,   o v e r _ R G   5 0 % _ N N U   o f _ I O   t h e _ A T   y o u t h s _ N N 2   i n _ I I   c l a s s _ N N 1   1 _ M C 1   c o n t i n u e d _ J J   t o _ T O   e x p e r i e n c e _ V V I   n e w _ J J   s y n d r o m a l _ J J   m a n i c _ J J   o r _ C C   d e p r e s s i v e _ N N 1   e p i s o d e s _ N N 2   , _ ,   i n d i c a t i n g _ V V G   t h a t _ C S T   t h e y _ P P H S 2   c o n t i n u e d _ V V D   t o _ T O   h a v e _ V H I   a c t i v e _ J J   , _ ,   c l i n i c a l l y _ R R   m e a n i n g f u l _ J J   b i p o l a r _ J J   s y m p t o m s _ N N 2   a n d _ C C   t h e _ A T   n e e d _ N N 1   f o r _ I F   m a i n t e n a n c e _ N N 1   t r e a t m e n t _ N N 1   . _ .   
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 I n _ I I   s t u d i e s _ N N 2   d e p e n d i n g _ V V G   u p o n _ I I   c o n t r a s t _ N N 1   i n j e c t i o n _ N N 1   , _ ,   t h i s _ D D 1   w o u l d _ V M   a l s o _ R R   r e q u i r e _ V V I   2 _ M C   s e p a r a t e _ J J   p a t i e n t _ J J   e x a m i n a t i o n s _ N N 2   . _ .   
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 S h e _ P P H S 1   h a d _ V H D   d i f f i c u l t y _ N N 1   r i s i n g _ V V G   f r o m _ I I   a _ A T 1   c h a i r _ N N 1   a n d _ C C   h e r _ A P P G E   g a i t _ N N 1   w a s _ V B D Z   o f _ I O   r e d u c e d _ J J   s t r i d e _ N N 1   l e n g t h _ N N 1   , _ ,   w i t h _ I W   e p i s o d e s _ N N 2   o f _ I O   f r e e z i n g _ J J   . _ .   
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 T h e _ A T   m e d i a n _ J J   f i e l d _ N N 1   o f _ I O   v i e w _ N N 1   w a s _ V B D Z   3 7 . 0 _ M C   c m _ N N U   ( _ (   I Q R _ N P 1   , _ ,   3 5 . 0 - 4 1 . 0 _ M C M C   c m _ N N U   ) _ )   a n d _ C C   w a s _ V B D Z   u s e d _ V V N   a s _ I I   a n _ A T 1   e s t i m a t e _ N N 1   o f _ I O   p a t i e n t _ J J   b o d y _ N N 1   h a b i t u s _ N N 1   , _ ,   b e c a u s e _ C S   b o d y _ N N 1   m a s s _ N N 1   i n d e x _ N N 1   w a s _ V B D Z   i n c o n s i s t e n t l y _ R R   a v a i l a b l e _ J J   . _ .   
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 T h i s _ D D 1   s u b g r o u p _ N N 1   w a s _ V B D Z   s e l e c t e d _ V V N   b e c a u s e _ C S   t h e y _ P P H S 2   a r e _ V B R   l e a d e r s _ N N 2   i n _ I I   i n s t i t u t i o n s _ N N 2   w h e r e _ C S   t h e r e _ E X   i s _ V B Z   l i k e l y _ J J   t o _ T O   b e _ V B I   a _ A T 1   r e s i d e n c y _ N N 1   t r a i n i n g _ N N 1   p r o g r a m _ N N 1   , _ ,   a _ A T 1   b r o a d _ J J   s c o p e _ N N 1   o f _ I O   s u r g i c a l _ J J   p r a c t i t i o n e r s _ N N 2   , _ ,   a _ A T 1   c o n n e c t i o n _ N N 1   i n c l u d i n g _ I I   s o m e _ D D   o v e r s i g h t _ N N 1   o f _ I O   t h o s e _ D D 2   p r a c t i t i o n e r s _ N N 2   , _ ,   a n d _ C C   o p p o r t u n i t i e s _ N N 2   f o r _ I F   i n n o v a t i o n _ N N 1   . _ .   
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 I n c l u d e d _ V V N   a m o n g _ I I   D N A _ N N 1   t r a n s - p o s o n s _ N N 2   a r e _ V B R   t h e _ A T   S I N E s _ N N 2   ( _ (   S I N E 1 _ F O   , _ ,   S I N E 2 _ F O   , _ ,   a n d _ C C   S I N E 3 _ F O   ) _ )   , _ ,   w h i c h _ D D Q   a r e _ V B R   h i g h l y _ R R   r e p e t i t i v e _ J J   D N A _ N N 1   s e q u e n c e s _ N N 2   t h a t _ C S T   a r e _ V B R   t y p i c a l l y _ R R   l e s s _ D A R   t h a n _ C S N   5 0 0 b p _ F O   i n _ I I   s i z e _ N N 1   a n d _ C C   s c a t t e r e d _ V V N   t h r o u g h o u t _ I I   t h e _ A T   g e n o m e _ N N 1   . _ .   
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 W e _ P P I S 2   s h o w _ V V 0   t h a t _ C S T   " _ "   m a g n i t u d e - b a s e d _ J J   i n f e r e n c e _ N N 1   " _ "   i s _ V B Z   n o t _ X X   a _ A T 1   p r o g r e s s i v e _ J J   i m p r o v e m e n t _ N N 1   o n _ I I   m o d e r n _ J J   s t a t i s t i c s _ N N   . _ .   
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 T h e _ A T   i n c l u s i o n _ N N 1   o f _ I O   s t r a t e g i e s _ N N 2   i n _ I I   r o u t i n e _ N N 1   p r o g r a m m e _ N N 1   d e l i v e r y _ N N 1   p r o v i d e s _ V V Z   a _ A T 1   m o d e l _ N N 1   f o r _ I F   f u t u r e _ J J   r e s e a r c h _ N N 1   , _ ,   a n d _ C C   t h e r e _ E X   m i g h t _ V M   b e _ V B I   s c o p e _ N N 1   t o _ T O   t e s t _ V V I   c h a n g e s _ N N 2   t o _ I I   t h e _ A T   i n t e r v e n t i o n s _ N N 2   t h a t _ C S T   c o u l d _ V M   s t r e n g t h e n _ V V I   t h e _ A T   e f f e c t s _ N N 2   . _ .   
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 A t _ R R 2 1   l e a s t _ R R 2 2   5 _ M C   c o n s e c u t i v e _ J J   e n h a n c e d _ J J   M R I _ J J   s c a n s _ N N 2   p e r f o r m e d _ V V N   w i t h _ I W   t h e _ A T   e x c l u s i v e _ J J   u s e _ N N 1   o f _ I O   l G B C A _ N N 1   , _ ,   f o l l o w e d _ V V N   b y _ I I   a t _ R R 2 1   l e a s t _ R R 2 2   5 _ M C   s c a n s _ N N 2   w i t h _ I W   t h e _ A T   e x c l u s i v e _ J J   u s e _ N N 1   o f _ I O   m c G B C A - 1 _ M C 1   f o l l o w e d _ V V N   b y _ I I   a n o t h e r _ D D 1   M R I _ N N 1   w i t h _ I W   a n _ A T 1   u n e n h a n c e d _ J J   T 1 _ F O   M R I _ N N 2   f o r _ I F   r e f e r e n c e _ N N 1   . _ .   
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 R i b e y e _ N N 1   i s _ V B Z   a _ A T 1   k e y _ J J   o r g a n i z e r _ N N 1   o f _ I O   h a i r - c e l l _ J J   s y n a p s e s _ N N 2   I n _ I I   b o t h _ D B 2   f i s h _ V V 0   a n d _ C C   m a m m a l i a n _ J J   n a s c e n t _ J J   h a i r _ N N 1   c e l l s _ N N 2   , _ ,   R i b e y e _ N P 1   c a n _ V M   b e _ V B I   d e t e c t e d _ V V N   a s _ C S A   s m a l l _ J J   p a r t i c l e s _ N N 2   t h r o u g h o u t _ I I   t h e _ A T   c y t o p l a s m _ N N 1   ( _ (   S h e e t s _ N N 2   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 , _ ,   2 0 1 1 _ M C   ; _ ;   S o b k o w i c z _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 , _ ,   1 9 8 6 _ M C   ; _ ;   Y u _ N P 1   a n d _ C C   G o o d r i c h _ N P 1   , _ ,   2 0 1 4 _ M C   ) _ )   . _ .   
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 F l a v a n o l s _ N N 2   h a v e _ V H 0   b e e n _ V B N   p r o p o s e d _ V V N   t o _ T O   h a v e _ V H I   m u l t i m o d a l _ J J   a c t i v i t i e s _ N N 2   ( _ (   M a n d e l _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 8 _ M C   ) _ )   , _ ,   c o n c u r r e n t l y _ R R   a c t i n g _ V V G   a t _ I I   m u l t i p l e _ J J   t a r g e t s _ N N 2   a n d _ C C   c o u l d _ V M   p o t e n t i a l l y _ R R   i m p a c t _ N N 1   o n _ I I   A b _ F O   a g g r e g a t i o n _ N N 1   b y _ I I   f a v o r i n g _ V V G   t h e _ A T   f o r m a t i o n _ N N 1   o f _ I O   o f f - t a r g e t _ J J   o l i g o m e r s _ N N 2   ( _ (   E h r n h o e f e r _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 8 _ M C   ) _ )   b u t _ C C B   o n l y _ R R   i f _ C S   m i c r o m o l a r _ J J   c o n c e n t r a t i o n s _ N N 2   c o u l d _ V M   b e _ V B I   a c h i e v e d _ V V N   i n _ R R 2 1   v i v o _ R R 2 2   . _ .   
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 I n _ I I   s u m m a r y _ N N 1   , _ ,   r e a l - t i m e _ J J   c a p t i o n i n g _ N N 1   o f _ I O   p h y s i c i a n s _ N N 2   ' _ N U L L   s p e e c h _ N N 1   , _ ,   m a d e _ V V D   p o s s i b l e _ J J   b y _ I I   t h e _ A T   i n c r e a s i n g _ J J   a v a i l a b i l i t y _ N N 1   o f _ I O   d i g i t a l _ J J   d e v i c e s _ N N 2   w i t h _ I W   s p e e c h - t o - t e x t _ J J   c a p a b i l i t i e s _ N N 2   , _ ,   h a s _ V H Z   t h e _ A T   p o t e n t i a l _ J J   t o _ T O   i m p r o v e _ V V I   c o m m u n i c a t i o n _ N N 1   d u r i n g _ I I   t h e _ A T   i n f o r m e d _ J J   d e c i s i o n - m a k i n g _ J J   p r o c e s s _ N N 1   a n d _ C C   i n _ I I   p h y s i c i a n - p a t i e n t _ N N 1   e n c o u n t e r s _ V V Z   i n _ R R 2 1   g e n e r a l _ R R 2 2   . _ .   
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 T h e r a p i s t s _ N N 2   m e t _ V V N   w i t h _ I W   r e s e a r c h e r s _ N N 2   w e e k l y _ R R   d u r i n g _ I I   t h e _ A T   f i r s t _ M D   3 _ M C   m o n t h s _ N N T 2   o f _ I O   t h e _ A T   i m p l e m e n t a t i o n _ N N 1   p r o c e s s _ N N 1   t o _ T O   d i s c u s s _ V V I   p o t e n t i a l _ J J   b a r r i e r s _ N N 2   a n d _ C C   f a c i l i t a t o r s _ N N 2   o f _ I O   d e l i v e r i n g _ V V G   t h e s e _ D D 2   i n t e r v e n t i o n s _ N N 2   i n _ I I   c l i n i c a l _ J J   c a r e _ N N 1   , _ ,   i n c l u d i n g _ I I   e n s u r i n g _ V V G   c o n s i s t e n t _ J J   o u t c o m e _ N N 1   m e a s u r e _ N N 1   c o l l e c t i o n _ N N 1   , _ ,   w i t h _ I W   i n t e r m i t t e n t _ J J   , _ ,   i n f o r m a l _ J J   m e e t i n g s _ N N 2   o v e r _ I I   t h e _ A T   1 6 - m o n t h _ J J   d u r a t i o n _ N N 1   . _ .   
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 T h e _ A T   p o r t i o n _ N N 1   o f _ I O   t h e j a w _ N N 1   d i s p l a c e m e n t _ N N 1   s i g n a l _ N N 1   u s e d _ V V N   f o r _ I F   t h e _ A T   S T I _ J J   c a l c u l a t i o n _ N N 1   i n c l u d e d _ V V D   p o i n t s _ N N 2   b e t w e e n _ I I   t h e _ A T   p e a k _ N N 1   v e l o c i t y _ N N 1   o f _ I O   t h e _ A T   f i r s t _ M D   d o w n w a r d _ J J   m o t i o n _ N N 1   o f _ I O   t h e _ A T   j a w _ N N 1   i n _ I I   t h e _ A T   f i r s t _ M D   s y l l a b l e _ N N 1   o f _ I O   ' _ N U L L   b u y _ N N 1   ' _ N U L L   a n d _ C C   t h e _ A T   l a s t _ M D   u p w a r d _ J J   j a w _ N N 1   m o t i o n _ N N 1   i n _ I I   t h e _ A T   s e c o n d _ N N T 1   t o _ I I   t h e _ A T   l a s t _ M D   s y l l a b l e _ N N 1   ' _ N U L L   p u p _ N N 1   ' _ N U L L   . _ .   
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 T h e _ A T   p a i n _ N N 1   m e a s u r e m e n t s _ N N 2   i n _ I I   t h e _ A T   B i s w a s _ N N 2   e t _ R A 2 1   a l _ R A 2 2   s t u d y _ N N 1   1 8 _ M C   m a y _ V M   b e _ V B I   a f f e c t e d _ V V N   b y _ I I   t h i s _ D D 1   b i a s _ N N 1   . _ .   
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 T h e _ A T   a n i m a l _ N N 1   w a s _ V B D Z   b r i e f l y _ R R   r e a n e s t h e t i z e d _ V V N   f o r _ I F   t w o _ M C   s u b s e q u e n t _ J J   b l o o d _ N N 1   d r a w s _ N N 2   ( _ (   i e _ R E X   , _ ,   a t _ I I   3 - h o u r _ N N T 1   a n d _ C C   2 4 - h o u r _ J J   t i m e _ N N T 1   p o i n t s _ N N 2   ) _ )   , _ ,   f o l l o w e d _ V V N   b y _ I I   e u t h a n a s i a _ N N 1   . _ .   
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 A n o t h e r _ D D 1   l i m i t a t i o n _ N N 1   i s _ V B Z   t h e _ A T   r e l i a n c e _ N N 1   o n _ I I   p r e v i o u s _ J J   g u i d e l i n e s _ N N 2   f o r _ I F   s u r v e i l l a n c e _ N N 1   a n d _ C C   s y m p t o m _ N N 1   m a n a g e m e n t _ N N 1   . _ .   
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 H H T _ N P 1   c a n _ V M   q u a n t i f y _ V V I   t h i s _ D D 1   p h a s e _ N N 1   s h i f t _ V V 0   s o _ C S 2 1   t h a t _ C S 2 2   i t _ P P H 1   c a n _ V M   b e _ V B I   i n c l u d e d _ V V N   i n _ I I   t h e _ A T   r e g r e s s i o n _ N N 1   , _ ,   w h i l e _ C S   t h i s _ D D 1   c a n _ V M   n o t _ X X   b e _ V B I   d o n e _ V D N   i n _ I I   t h e _ A T   t i m e _ N N T 1   d o m a i n _ N N 1   . _ .   
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 C a s e _ N N 1   s e r i e s _ N N   i n v o l v i n g _ V V G   f e w e r _ D A R   t h a n _ C S N   1 0 _ M C   p a t i e n t s _ N N 2   , _ ,   c a s e _ N N 1   r e p o r t s _ N N 2   , _ ,   l e t t e r s _ N N 2   t o _ I I   e d i t o r s _ N N 2   , _ ,   a n d _ C C   e x p e r t _ N N 1   r e v i e w s _ N N 2   w e r e _ V B D R   e x c l u d e d _ V V N   . _ .   
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 A W S _ N N 2   a n d _ C C   c o n t r o l _ N N 1   g r o u p s _ N N 2   w e r e _ V B D R   c o m p a r e d _ V V N   i n _ I I   s p e e c h _ N N 1   a c c u r a c y _ N N 1   a n d _ C C   s p e e c h _ N N 1   k i n e m a t i c s _ N N 2   ( _ (   l i p _ N N 1   a p e r t u r e _ N N 1   v a r i a b i l i t y _ N N 1   a n d _ C C   s p e e c h _ N N 1   d u r a t i o n _ N N 1   ) _ )   . _ .   
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 S t u d i e s _ N N 2   f u r t h e r _ R R R   i d e n t i f i e d _ V V N   D N A - P K c s _ N N 2   a s _ I I   a _ A T 1   m o d u l a t o r _ N N 1   o f _ I O   c a n c e r - a s s o c i a t e d _ J J   p a t h w a y s _ N N 2   d i s t i n c t _ J J   f r o m _ I I   D N A _ N N 1   r e p a i r _ N N 1   , _ ,   i n c l u d i n g _ I I   h y p o x i a _ N N 1   , _ ,   m e t a b o l i s m _ N N 1   , _ ,   i n f l a m m a t o r y _ J J   r e s p o n s e _ N N 1   , _ ,   a n d _ C C   t r a n s c r i p t i o n a l _ J J   r e g u l a t i o n _ N N 1   ( _ (   G o o d w i n _ N P 1   a n d _ C C   K n u d s e n _ N P 1   , _ ,   2 0 1 4 _ M C   ) _ )   . _ .   
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 I n _ I I   t h e _ A T   C o h e n _ N P 1   s t u d y _ N N 1   , _ ,   h o w e v e r _ R R   , _ ,   t h e r e _ E X   w a s _ V B D Z   n o _ A T   a d v a n t a g e _ N N 1   t o _ I I   u t i l i z i n g _ V V G   5 0 % _ N N U   o r _ C C   8 0 % _ N N U   r e l i e f _ N N 1   i n _ I I   p r e d i c t i n g _ V V G   R F _ N P 1   n e u r o t o m y _ N N 1   o u t c o m e s _ N N 2   . _ .   
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 I n _ I I   4 6 . 6 % _ F O   o f _ I O   s h o r t a g e s _ N N 2   , _ ,   m a n u f a c t u r e r s _ N N 2   d i d _ V D D   n o t _ X X   g i v e _ V V I   a _ A T 1   r e a s o n _ N N 1   . _ .   
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 D i s c u s s i o n _ N N 1   M o s t _ D A T   g u i d e l i n e s _ N N 2   f o r _ I F   t h y r o i d _ J J   n o d u l e s _ N N 2   c o m m o n l y _ R R   r e c o m m e n d _ V V 0   F N A _ N N 1   i n _ I I   n o d u l e s _ N N 2   t h a t _ C S T   a r e _ V B R   1 _ M C 1   c m _ N N U   o r _ C C   l a r g e r _ J J R   w i t h _ I W   t h e _ A T   e x c e p t i o n _ N N 1   o f _ I O   h i g h - r i s k _ J J   p a t i e n t s _ N N 2   b e c a u s e _ C S   t h e r e _ E X   i s _ V B Z   a _ A T 1   l a c k _ N N 1   o f _ I O   e v i d e n c e _ N N 1   r e g a r d i n g _ V V G   w h e t h e r _ C S W   d i a g n o s i s _ N N 1   o f _ I O   m i c r o c a r c i n o m a s _ N N 2   p r o v i d e s _ V V Z   b e n e f i t _ N N 1   f o r _ I F   p a t i e n t _ J J   s u r v i v a l _ N N 1   . _ .   
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 W e _ P P I S 2   b e l i e v e _ V V 0   t h a t _ C S T   t h e _ A T   a c c e s s i b i l i t y _ N N 1   o f _ I O   t h i s _ D D 1   n o n - i n v a s i v e _ J J   m o n i t o r _ N N 1   e n a b l e s _ V V Z   m e a s u r e m e n t _ N N 1   o f _ I O   C O _ N P 1   a t _ I I   a n _ A T 1   e a r l y _ J J   s t a g e _ N N 1   i n _ I I   o b s t e t r i c _ J J   p a t i e n t s _ N N 2   , _ ,   b e f o r e _ C S   s i g n i f i c a n t _ J J   c l i n i c a l _ J J   d e t e r i o r a t i o n _ N N 1   h a s _ V H Z   o c c u r r e d _ V V N   . _ .   
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 T h r o u g h _ I I   t h i s _ D D 1   n e u r o p s y c h i a t r i c _ J J   e v a l u a t i o n _ N N 1   a _ A T 1   d e s c r i p t i v e _ J J   d i a g n o s i s _ N N 1   a n d _ C C   i f _ C S   a p p r o p r i a t e _ J J   a _ A T 1   c a t e g o r i c a l _ J J   D i a g n o s t i c _ J J   a n d _ C C   S t a t i s t i c a l _ J J   M a n u a l _ N N 1   o f _ I O   M e n t a l _ J J   D i s o r d e r s _ N N 2   4 t h _ M D   E d i t i o n _ N N 1   ( _ (   D S M 4 _ F O   ) _ )   d i a g n o s i s _ N N 1   w a s _ V B D Z   m a d e _ V V N   . _ .   
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 W h i l e _ C S   A A N H P I s _ N P 1   h a v e _ V H 0   3 0 % _ N N U   t o _ I I   4 0 % _ N N U   l o w e r _ J J R   i n c i d e n c e _ N N 1   a n d _ C C   m o r t a l i t y _ N N 1   r a t e s _ N N 2   t h a n _ C S N   n o n - H i s p a n i c _ J J   w h i t e s _ N N 2   f o r _ I F   a l l _ D B   c a n c e r s _ N N 2   c o m b i n e d _ V V D   , _ ,   r i s k _ N N 1   o f _ I O   s t o m a c h _ N N 1   a n d _ C C   l i v e r _ N N 1   c a n c e r s _ N N 2   i s _ V B Z   d o u b l e _ J J   . _ .   
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 A _ A T 1   s e c o n d _ M D   s t i m u l a t i o n _ N N 1   s e q u e n c e _ N N 1   w a s _ V B D Z   c o n s t r u c t e d _ V V N   b a s e d _ V V N   o n _ I I   t h e _ A T   a s c e n d i n g _ J J   s e q u e n c e _ N N 1   r e s u l t s _ N N 2   . _ .   
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 T h e _ A T   e l e c t r o d e _ N N 1   , _ ,   f i l l e d _ V V N   w i t h _ I W   c o n d u c t i v e _ J J   g e l _ N N 1   , _ ,   w a s _ V B D Z   c o n n e c t e d _ V V N   v i a _ I I   e x t e n s i o n _ N N 1   c a b l e _ N N 1   t o _ I I   a _ A T 1   c o n s t a n t _ J J   c u r r e n t _ J J   s t i m u l a t o r _ N N 1   ( _ (   m o d e l _ N N 1   D S 7 A _ F O   ; _ ;   D i g i t i m e r _ N P 1   ) _ )   i n _ I I   t h e _ A T   e x p e r i m e n t e r _ N N 1   r o o m _ N N 1   . _ .   
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 M e d i a n _ J J   f a l l _ N N 1   r a t e _ N N 1   i n _ I I   t h e _ A T   r i v a s t i g m i n e _ N N 1   g r o u p _ N N 1   ( _ (   n = 6 4 _ F O   ; _ ;   o n e _ P N 1   o u t l i e r _ J J R   e x c l u d e d _ J J   ) _ )   w a s _ V B D Z   0 . 5 0 _ M C   ( _ (   I Q R _ N P 1   0 . 1 4 0 . 8 9 _ M C   ) _ )   , _ ,   c o m p a r e d _ V V N   w i t h _ I W   1 . 1 4 _ M C   ( _ (   0 - 2 7 - 2 - 6 _ M C M C   ) _ )   i n _ I I   t h e _ A T   p l a c e b o _ N N 1   g r o u p _ N N 1   ( _ (   n = 6 5 _ F O   ; _ ;   f i g u r e _ N N 1   2 _ M C   ) _ )   . _ .   
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 T h i s _ D D 1   h a s _ V H Z   b e e n _ V B N   r e c o g n i s e d _ V V N   b y _ I I   t h e _ A T   E W G S O P _ N N 1   w h o _ P N Q S   h a v e _ V H 0   r e c o m m e n d e d _ V V N   t h a t _ C S T   m o r e _ D A R   r e s e a r c h _ N N 1   i s _ V B Z   u r g e n t l y _ R R   n e e d e d _ V V N   i n _ B C L 2 1   o r d e r _ B C L 2 2   t o _ T O   o b t a i n _ V V I   g o o d _ J J   r e f e r e n c e _ N N 1   v a l u e s _ N N 2   f o r _ I F   p o p u l a t i o n s _ N N 2   a r o u n d _ I I   t h e _ A T   w o r l d _ N N 1   . _ .   
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 A l l _ D B   C T _ N N 1   e x a m i n a t i o n s _ N N 2   w e r e _ V B D R   a d e q u a t e _ J J   f o r _ I F   B M D _ N P 1   a n d _ C C   t r a b e c u l a r _ J J   t e x t u r e _ N N 1   a n a l y s i s _ N N 1   . _ .   
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 S t a t i s t i c a l _ J J   A n a l y s e s _ N N 2   T o _ T O   d e t e r m i n e _ V V I   t h e _ A T   g e n o t y p i c _ J J   e f f e c t s _ N N 2   o n _ I I   G 7 2 _ F O   e x p r e s s i o n _ N N 1   a n d _ C C   b e h a v i o r a l _ J J   r e s p o n s e s _ N N 2   , _ ,   a _ A T 1   t w o - w a y _ J J   a n a l y s i s _ N N 1   o f _ I O   v a r i a n c e _ N N 1   ( _ (   A N O V A _ N P 1   ) _ )   w a s _ V B D Z   u s e d _ V V N   , _ ,   f o l l o w e d _ V V N   b y _ I I   a _ A T 1   p o s t _ J J 2 1   h o c _ J J 2 2   a n a l y s i s _ N N 1   o r _ C C   t h e _ A T   S t u d e n t _ N N 1   ' _ N U L L   s _ Z Z 1   t - t e s t _ J J   w h e r e _ C S   a p p r o p r i a t e _ J J   . _ .   
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 C l e a r l y _ R R   , _ ,   t h e r e _ E X   i s _ V B Z   r o o m _ N N 1   f o r _ I F   i m p r o v e m e n t _ N N 1   a n d _ C C   i n _ I I   m e l a n o m a _ N N 1   t h i s _ D D 1   i s _ V B Z   h i g h l i g h t e d _ V V N   b y _ I I   t h e _ A T   o b s e r v e d _ J J   i n c r e a s e _ N N 1   i n _ I I   p r o g r e s s i o n - f r e e _ J J   s u r v i v a l _ N N 1   i n _ I I   B R A F / M E K _ N P 1   i n h i b i t o r _ N N 1   c o m b i n a t i o n _ N N 1   t h e r a p i e s _ N N 2   c o m p a r e d _ V V N   w i t h _ I W   B R A F _ N P 1   i n h i b i t o r _ N N 1   m o n o t h e r a p i e s _ N N 2   ( _ (   L a r k i n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 4 _ M C   ; _ ;   L o n g _ R R   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 5 _ M C   ) _ )   . _ .   
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 I n _ I I   B R A F _ N P 1   m u t a n t _ N N 1   m e l a n o m a _ N N 1   c e l l s _ N N 2   , _ ,   B R A F _ N P 1   i s _ V B Z   t h e _ A T   d r i v e r _ N N 1   o f _ I O   c e l l u l a r _ J J   s i g n a l i n g _ V V G   ' _ N U L L   t h e _ A T   p r e r e q u i s i t e _ N N 1   t o _ I I   B R A F - t a r g e t e d _ J J   t h e r a p y _ N N 1   ( _ (   S a l a m a _ N P 1   a n d _ C C   F l a h e r t y _ N P 1   , _ ,   2 0 1 3 _ M C   ) _ )   . _ .   
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 B e c a u s e _ I I 2 1   o f _ I I 2 2   p r o g r e s s i v e _ J J   e a r _ N N 1   d e f o r m i t y _ N N 1   a n d _ C C   o b s t r u c t i o n _ N N 1   , _ ,   a t _ I I   a g e _ N N 1   7 _ M C   m o n t h s _ N N T 2   s u r g i c a l _ J J   e x c i s i o n _ N N 1   w a s _ V B D Z   p e r f o r m e d _ V V N   w i t h _ I W   t h e _ A T   u s e _ N N 1   o f _ I O   g e n e r a l _ J J   a n e s t h e s i a _ N N 1   . _ .   
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 R e c e n t l y _ R R   t h e r e _ E X   h a s _ V H Z   b e e n _ V B N   i n c r e a s i n g _ J J   i n t e r e s t _ N N 1   i n _ I I   i m p r o v i n g _ V V G   C R C _ N P 1   p r o g n o s t i c a t i o n _ N N 1   u s i n g _ V V G   c l i n i c a l _ J J   , _ ,   i n f l a m m a t o r y _ J J   , _ ,   a n d _ C C   m o l e c u l a r _ J J   b i o m a r k e r s _ N N 2   ; _ ;   h o w e v e r _ R R   , _ ,   t h e r e _ E X   r e m a i n s _ V V Z   a _ A T 1   l a c k _ N N 1   o f _ I O   r e l i a b l e _ J J   , _ ,   r e p r o d u c i b l e _ J J   , _ ,   a n d _ C C   l o w - c o s t _ J J   b i o m a r k e r s _ N N 2   t h a t _ C S T   c a n _ V M   b e _ V B I   r e a d i l y _ R R   i n c o r p o r a t e d _ V V N   i n t o _ I I   r o u t i n e _ N N 1   p r a c t i c e _ N N 1   t o _ T O   o p t i m a l l y _ R R   p r e d i c t _ V V I   p r o g n o s i s _ N N 1   a n d _ C C   g u i d e _ V V 0   t r e a t m e n t _ N N 1   . _ .   
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 T h e _ A T   a r e a _ N N 1   o f _ I O   v a s t u s _ J J   l a t e r a l i s _ N N 1   M E P _ N P 1   w a s _ V B D Z   n o r m a l i z e d _ V V N   t o _ I I   t h e _ A T   M m a x _ N N 1   m e a s u r e d _ V V N   d u r i n g _ I I   t h e _ A T   M V C _ N P 1   t o _ T O   e n s u r e _ V V I   t h e _ A T   m a g n e t i c _ J J   s t i m u l u s _ N N 1   w a s _ V B D Z   a c t i v a t i n g _ V V G   a _ A T 1   h i g h _ J J   p r o p o r t i o n _ N N 1   o f _ I O   t h e _ A T   k n e e - e x t e n s o r _ J J   m o t o r _ N N 1   u n i t s _ N N 2   , _ ,   a n d _ C C   t o _ T O   q u a n t i f y _ V V I   c o r t i c o s p i n a l _ J J   e x c i t a b i l i t y _ N N 1   d u r i n g _ I I   c o n t r a c t i o n _ N N 1   . _ .   
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 A f t e r _ C S   s o m e _ D D   p r o t o c o l _ N N 1   a d j u s t m e n t _ N N 1   h a l f w a y _ R R   t h r o u g h _ I I   t h e _ A T   t r i a l _ N N 1   i n c l u d i n g _ I I   d e v i c e _ N N 1   d e s i g n _ N N 1   i m p r o v e m e n t _ N N 1   , _ ,   s u r g i c a l _ J J   m o d i f i c a t i o n s _ N N 2   , _ ,   a n d _ C C   t h e _ A T   a d d i t i o n _ N N 1   o f _ I O   a _ A T 1   p r o p h y l a c t i c _ J J   i n t r a - v i t r e a l _ J J   a n t i b i o t i c _ N N 1   i n j e c t i o n _ N N 1   a t _ I I   t h e _ A T   e n d _ N N 1   o f _ I O   s u r g i c a l _ J J   i m p l a n t a t i o n _ N N 1   , _ ,   t h e _ A T   r a t e _ N N 1   o f _ I O   S A E s _ N N 2   r e d u c e d _ V V D   s i g n i f i c a n t l y _ R R   , _ ,   a n d _ C C   t h e r e _ E X   w e r e _ V B D R   n o _ A T   f u r t h e r _ J J R   c a s e s _ N N 2   o f _ I O   e n d o p h t h a l m i t i s _ N N 1   i n _ I I   t h e _ A T   s e c o n d _ M D   h a l f _ N N 1   o f _ I O   t h e _ A T   s t u d y _ N N 1   ( _ (   i . e . _ R E X   t h e _ A T   l a s t _ M D   1 5 _ M C   c a s e s _ N N 2   ) _ )   ( _ (   H u m a y u n _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   ? _ A T 1   2 0 1 2 _ M C   ) _ )   . _ .   
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 ( _ (   2 0 1 4 _ M C   ) _ )   r e p o r t e d _ V V D   t h e _ A T   o u t c o m e _ N N 1   o f _ I O   a _ A T 1   1 2 - m o n t h _ J J   f o l l o w - u p _ N N 1   o f _ I O   6 _ M C   p a t i e n t s _ N N 2   w h o _ P N Q S   r e c e i v e d _ V V D   t h e _ A T   i m p l a n t _ N N 1   i n _ I I   a _ A T 1   s i n g l e _ J J   c e n t r e _ N N 1   p e r f o r m e d _ V V N   b y _ I I   a _ A T 1   s i n g l e _ J J   s u r g e o n _ N N 1   . _ .   
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 N e x t _ M D   , _ ,   t h e _ A T   p r o b e _ N N 1   w a s _ V B D Z   r o t a t e d _ V V N   9 0 _ M C   i n _ I I   t h e _ A T   c l o c k w i s e _ J J   d i r e c t i o n _ N N 1   , _ ,   a n d _ C C   t h e _ A T   t r a n s v e r s e _ J J   d i a m e t e r _ N N 1   ( _ (   D 1 _ F O   ) _ )   a n d _ C C   a n t e r o p o s t e r i o r _ J J   d i a m e t e r _ N N 1   ( _ (   D 2 _ F O   ) _ )   o f _ I O   t h e _ A T   l a r g e s t _ J J T   a x i a l _ J J   p l a n e _ N N 1   o f _ I O   t h e _ A T   c e r v i x _ N N 1   w e r e _ V B D R   m e a s u r e d _ V V N   ( _ (   F i g . _ N N 1   1 A _ F O   ) _ )   . _ .   
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 B e c a u s e _ I I 2 1   o f _ I I 2 2   v i o l a t i o n s _ N N 2   o f _ I O   m u l t i v a r i a t e _ J J   n o r m a l i t y _ N N 1   , _ ,   a l l _ D B   a n a l y s e s _ N N 2   u s e d _ V V D   t h e _ A T   M L R _ N P 1   e s t i m a t o r _ N N 1   , _ ,   w h i c h _ D D Q   c o m p u t e s _ V V Z   t h e _ A T   Y u a n _ N N U   a n d _ C C   B e n t l e r _ N P 1   T * W 2 _ F O   t e s t _ N N 1   s t a t i s t i c _ N N 1   t h a t _ C S T   a s s e s s e s _ V V Z   t h e _ A T   s t a t i s t i c a l _ J J   s i g n i f i c a n c e _ N N 1   o f _ I O   d e v i a t i o n _ N N 1   o f _ I O   t h e _ A T   e s t i m a t e d _ J J   c o v a r i a n c e _ N N 1   m a t r i x _ N N 1   f r o m _ I I   t h e _ A T   a c t u a l _ J J   m a t r i x . 3 0 _ F O   T h e _ A T   M L R _ N P 1   e s t i m a t o r _ N N 1   a l s o _ R R   g i v e s _ V V Z   r o b u s t _ J J   S E s _ N P 2   t h a t _ C S T   a r e _ V B R   u s e d _ V V N   i n _ I I   d e t e r m i n a t i o n _ N N 1   o f _ I O   t h e _ A T   s t a t i s t i c a l _ J J   s i g n i f i c a n c e _ N N 1   o f _ I O   p a r a m e t e r _ N N 1   e s t i m a t e s _ N N 2   . _ .   
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 T h i s _ D D 1   s t a b l e _ J J   p h o t o p r o d u c t _ N N 1   w a s _ V B D Z   s u g g e s t e d _ V V N   t o _ T O   r e p r e s e n t _ V V I   t h e _ A T   m e t a m e l a n o p s i n _ N N 1   , _ ,   b u t _ C C B   i t _ P P H 1   w a s _ V B D Z   r e m a r k a b l y _ R R   i n s e n s i t i v e _ J J   t o _ I I   s u b s e q u e n t _ J J   t r e a t m e n t _ N N 1   w i t h _ I W   h y d r o x y l - a m i n e _ N N 1   . _ .   
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 H y p o f r a c t i o n a t e d _ J J   r a d i o t h e r a p y _ N N 1   v e r s u s _ I I   c o n v e n t i o n a l l y _ R R   f r a c t i o n a t e d _ J J   r a d i o t h e r a p y _ N N 1   f o r _ I F   p a t i e n t s _ N N 2   w i t h _ I W   i n t e r m e d i a t e - r i s k _ J J   l o c a l i s e d _ J J   p r o s t a t e _ N N 1   c a n c e r _ N N 1   : _ :   2 - y e a r _ J J   p a t i e n t - r e p o r t e d _ J J   o u t c o m e s _ N N 2   o f _ I O   t h e _ A T   r a n d o m i s e d _ J J   , _ ,   n o n - i n f e r i o r i t y _ N N 1   , _ ,   p h a s e _ N N 1   3 _ M C   C H H i P _ N P 1   t r i a l _ N N 1   A n n a _ N P 1   W i l k i n s _ N P 1   , _ ,   H e l e n _ N P 1   M o s s o p _ N P 1   , _ ,   I s a b e l _ N P 1   S y n d i k u s _ N P 1   , _ ,   V i n c e n t _ N P 1   K h o o _ N P 1   , _ ,   D a v i d _ N P 1   B l o o m f i e l d _ N P 1   , _ ,   C h r i s _ N P 1   P a r k e r / j o h n _ F U   L o g u e _ N N 1   , _ ,   C h r i s t o p h e r S c r a s e _ N P 1   , _ ,   H e l e n _ N P 1   P a t t e r s o n f _ N P 1   , _ ,   A l i s o n _ N P 1   B i r t l e _ N P 1   , _ ,   j o h n _ N N 1   S t a f f u r t h _ N N 1   , _ ,   Z a f a r _ N P 1   M a l i k _ N P 1   , _ ,   M i g u e l _ N P 1   P a n a d e s _ N P 2   , _ ,   C h i n n a m a n i _ N P 1   E s w a r _ N P 1   , _ ,   j o h n _ N N 1   G r a h a m _ N P 1   , _ ,   M a r t i n _ N P 1   R u s s e l l _ N P 1   , _ ,   P e t e r _ N P 1   K i r k b r i d e _ N P 1   , _ ,   j o e _ V V 0   M _ Z Z 1   O _ Z Z 1   ' _ N U L L   S u l l i v a n _ N P 1   , _ ,   A n n i e _ N P 1   G a o _ N P 1   , _ ,   C l a r e _ N P 1   C r u i c k s h a n k _ N P 1   , _ ,   C l a r e _ N P 1   G r i f f i n _ N P 1   , _ ,   D a v i d _ N P 1   D e a r n a l e y * _ F O   , _ ,   E m m a _ N P 1   H a l l * _ F O   I n s t i t u t e _ N N 1   o f _ I O   C a n c e r _ N N 1   R e s e a r c h _ N N 1   , _ ,   L o n d o n _ N P 1   , _ ,   U K _ N P 1   ( _ (   A _ Z Z 1   W i l k i n s _ N P 1   F R C R _ N P 1   , _ ,   H _ Z Z 1   M o s s o p _ N P 1   M M a t h S t a t _ N P 1   , _ ,   V _ Z Z 1   K h o o _ N P 1   M D _ N N A   , _ ,   A _ Z Z 1   G a o _ N P 1   M S c _ N N A   , _ ,   C _ N P 1   C r u i c k s h a n k _ N P 1   B S c _ N N A   ( _ (   H o n s _ N N 2   ) _ )   , _ ,   C _ N P 1   G r i f f i n _ N P 1   M S c _ N N A   , _ ,   P r o f _ N N B   D _ N P 1   D e a r n a l e y _ N P 1   F R C R _ N P 1   , _ ,   E _ N P 1   H a l l _ N P 1   P h D _ N N A   ) _ )   ; _ ;   C l a t t e r b r i d g e _ N P 1   C a n c e r _ N N 1   C e n t r e _ N N 1   , _ ,   W i r r a l _ N P 1   , _ ,   U K _ N P 1   ( _ (   I _ Z Z 1   S y n d i k u s _ N P 1   F R C R _ N P 1   ) _ )   ; _ ;   R o y a l _ J J   M a r s d e n _ N P 1   N H S _ N P 1   F o u n d a t i o n _ N N 1   T r u s t _ N N 1   , _ ,   L o n d o n _ N P 1   , _ ,   U K _ N P 1   ( _ (   V _ Z Z 1   K h o o _ N P 1   , _ ,   C _ N P 1   P a r k e r _ N P 1   F R C R _ N P 1   , _ ,   P r o f _ N N B   D _ N P 1   D e a r n a l e y _ N P 1   ) _ )   ; _ ;   B r i g h t o n _ N P 1   a n d _ C C   S u s s e x _ N P 1   U n i v e r s i t y _ N N 1   H o s p i t a l s _ N N 2   , _ ,   B r i g h t o n _ N P 1   , _ ,   U K _ N P 1   ( _ (   D _ Z Z 1   B l o o m f i e l d _ N P 1   F R C R _ N P 1   ) _ )   ; _ ;   C h r i s t i e _ N P 1   H o s p i t a l _ N N 1   , _ ,   M a n c h e s t e r _ N P 1   , _ ,   U K _ N P 1   ( _ (   ' _ N U L L   L o g u e _ N P 1   F R C R _ N P 1   ) _ )   ; _ ;   I p s w i c h _ N P 1   H o s p i t a l _ N N 1   , _ ,   I p s w i c h _ N P 1   , _ ,   U K _ N P 1   ( _ (   C _ N P 1   S c r a s e _ N P 1   F R C R _ N P 1   ) _ )   ; _ ;   A d d e n b r o o k e _ N P 1   ' _ N U L L   s _ Z Z 1   H o s p i t a l _ N N 1   , _ ,   C a m b r i d g e _ N P 1   , _ ,   U K _ N P 1   ( _ (   H _ Z Z 1   P a t t e r s o n _ N P 1   F R C R _ N P 1   ) _ )   ; _ ;   R o s e m e r e _ N P 1   C a n c e r _ N N 1   C e n t r e _ N N 1   , _ ,   R o y a l _ J J   P r e s t o n _ N P 1   H o s p i t a l _ N N 1   , _ ,   U K _ N P 1   ( _ (   A _ Z Z 1   B i r t l e _ N P 1   F R C R _ N P 1   ) _ )   ; _ ;   C a r d i f f _ N P 1   U n i v e r s i t y _ N N 1   , _ ,   C a r d i f f _ N P 1   , _ ,   U K _ N P 1   ( _ (   ' _ N U L L   S t a f f u r t h _ N P 1   M D _ N N A   ) _ )   ; _ ;   V e l i n d r e _ N P 1   C a n c e r _ N N 1   C e n t r e _ N N 1   , _ ,   C a r d i f f _ N P 1   , _ ,   U K _ N P 1   ( _ (   ' _ N U L L   S t a f f u r t h _ N P 1   ) _ )   ; _ ;   W h i s t o n _ N P 1   H o s p i t a l _ N N 1   , _ ,   P r e s c o t _ N P 1   , _ ,   U K _ N P 1   ( _ (   Z _ Z Z 1   M a l i k _ N P 1   F R C R _ N P 1   ) _ )   ; _ ;   L i n c o l n _ N P 1   C o u n t y _ N N 1   H o s p i t a l _ N N 1   , _ ,   L i n c o l n _ N P 1   , _ ,   U K _ N P 1   ( _ (   M _ Z Z 1   P a n a d e s _ V V Z   M R C R _ N P 1   ) _ )   ; _ ;   S o u t h p o r t _ N P 1   G e n e r a l _ J J   I n f i r m a r y _ N N 1   , _ ,   S o u t h p o r t _ N P 1   , _ ,   U K _ N P 1   ( _ (   C _ N P 1   E s w a r _ N P 1   F R C R _ N P 1   ) _ )   ; _ ;   B e a c o n _ N P 1   C e n t r e _ N N 1   , _ ,   M u s g r o v e _ N P 1   P a r k _ N N 1   H o s p i t a l _ N N 1   , _ ,   T a u n t o n _ N P 1   , _ ,   U K _ N P 1   ( _ (   G r a h a m _ N P 1   F R C R _ N P 1   ) _ )   ; _ ;   B e a t s o n _ N P 1   W e s t _ N D 1   o f _ I O   S c o t l a n d _ N P 1   C a n c e r _ N N 1   C e n t r e _ N N 1   , _ ,   G l a s g o w _ N P 1   , _ ,   U K _ N P 1   ( _ (   M _ Z Z 1   R u s s e l l _ N P 1   F R C R _ N P 1   ) _ )   ; _ ;   S h e f f i e l d _ N P 1   T e a c h i n g _ V V G   H o s p i t a l s _ N N 2   F o u n d a t i o n _ N N 1   T r u s t _ N N 1   , _ ,   S h e f f i e l d _ N P 1   , _ ,   U K _ N P 1   ( _ (   P _ Z Z 1   K i r k b r i d e _ N P 1   F R C R _ N P 1   ) _ )   ; _ ;   a n d _ C C   Q u e e n _ N N 1   ' _ N U L L   s _ Z Z 1   U n i v e r s i t y _ N N 1   B e l f a s t _ N P 1   , _ ,   B e l f a s t _ N P 1   , _ ,   U K _ N P 1   ( _ (   P r o f _ N N B   ' _ N U L L   M _ N P 1   O _ N P 1   ' _ N U L L   S u l l i v a n _ N P 1   F R C R _ N P 1   ) _ )   C o r r e s p o n d e n c e _ N N 1   t o _ I I   : _ :   D r _ N N B   E m m a _ N P 1   H a l l _ N P 1   , _ ,   C l i n i c a l _ J J   T r i a l s _ N N 2   a n d _ C C   S t a t i s t i c s _ N N   U n i t _ N N 1   , _ ,   T h e _ A T   I n s t i t u t e _ N N 1   o f _ I O   C a n c e r _ N N 1   R e s e a r c h _ N N 1   , _ ,   L o n d o n _ N P 1   S M 2 _ F O   5 N G _ F O   , _ ,   U K _ N P 1   e m m a _ N N 1   . _ .   
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 R e c e n t l y _ R R   t h e r e _ E X   i s _ V B Z   a _ A T 1   r i s i n g _ J J   i n t e r e s t _ N N 1   o f _ I O   S B _ N P 1   c o n s e q u e n c e s _ N N 2   a n d _ C C   t h e _ A T   i d e a _ N N 1   o f _ I O   c l e a r l y _ R R   d i f f e r e n t i a t i n g _ V V G   b e t w e e n _ I I   t h e _ A T   d i s t i n c t _ J J   b e h a v i o u r s _ N N 2   o f _ I O   S B _ N P 1   a n d _ C C   P A _ N N 1   . _ .   
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 D e p e n d i n g _ I I 2 1   o n _ I I 2 2   w h e t h e r _ C S W   t h e y _ P P H S 2   f a v o r e d _ V V D   t h e _ A T   h y p o t h e s i s _ N N 1   o f _ I O   r e c r u i t m e n t _ N N 1   o f _ I O   p e r i l e s i o n a l _ J J   r e g i o n s _ N N 2   o r _ C C   t h e _ A T   e f f e c t _ N N 1   o f _ I O   t h e _ A T   n o n d o m i n a n t _ J J   h e m i s p h e r e _ N N 1   , _ ,   t h e _ A T   i n v e s t i g a t o r s _ N N 2   o f _ I O   c o r t i c a l _ J J   s t i m u l a t i o n _ N N 1   c h o s e _ V V D   t o _ T O   s t i m u l a t e _ V V I   t h e _ A T   d o m i n a n t _ J J   h e m i s p h e r e _ N N 1   o r _ C C   t o _ T O   i n h i b i t _ V V I   t h e _ A T   n o n d o m i n a n t _ J J   h e m i s p h e r e _ N N 1   , _ ,   r e s p e c t i v e l y _ R R   . _ .   
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 L o w e r _ J J R   b a s e l i n e _ N N 1   e G F R _ N N 1   , _ ,   p r e o p e r a t i v e _ J J   h y p e r t e n s i o n _ N N 1   , _ ,   l o n g e r _ J J R   d u r a t i o n _ N N 1   o f _ I O   t h e _ A T   p r o c e d u r e _ N N 1   , _ ,   l o n g e r _ J J R   i s c h a e m i a _ N N 1   t i m e _ N N T 1   , _ ,   a n d _ C C   w a r m _ J J   i s c h a e m i a _ N N 1   ( _ (   a s _ C S A   c o m p a r e d _ V V N   w i t h _ I W   c o l d _ J J   i s c h a e m i a _ N N 1   ) _ )   w e r e _ V B D R   a s s o c i a t e d _ V V N   w i t h _ I W   w o r s e _ J J R   p o s t o p e r a t i v e _ J J   r e n a l _ J J   f u n c t i o n _ N N 1   ( _ (   l o w e r _ J J R   e G F R _ N N 1   ) _ )   ( _ (   T a b l e 2 _ F O   ; _ ;   P = 0 . 0 0 1 _ F O   f o r _ I F   h y p e r t e n s i o n _ N N 1   a n d P _ V V 0   l e s s _ D A R   t h a n _ C S N   0 . 0 0 1 _ M C   f o r _ I F   t h e _ A T   o t h e r _ J J   f a c t o r s _ N N 2   ) _ )   . _ .   
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 I n _ I I   t h i s _ D D 1   s t u d y _ N N 1   , _ ,   w e _ P P I S 2   t e s t e d _ V V D   t h e _ A T   c o n c e p t _ N N 1   t h a t _ C S T   b e s i d e s _ I I   t h e _ A T   o n c o g e n e _ N N 1   i t s e l f _ P P X 1   , _ ,   f a c t o r s _ N N 2   t h a t _ C S T   e n a b l e _ V V 0   p e r m i s s i v e n e s s _ N N 1   o f _ I O   n o r m a l _ J J   p r e - B _ J J   c e l l s _ N N 2   t o _ I I   o n c o g e n i c _ J J   s i g n a l i n g _ N N 1   r e p r e s e n t _ V V 0   a _ A T 1   c l a s s _ N N 1   o f t h e r a p e u t i c _ J J   t a r g e t s _ N N 2   f o r t h e _ V V 0   t r e a t m e n t _ N N 1   o f _ I O   a c u t e _ J J   l y m p h o b l a s t i c _ J J   l e u k e m i a _ N N 1   ( _ (   A L L _ R R   ) _ )   . _ .   
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 T h e _ A T   m a i n _ J J   e f f e c t _ N N 1   o f _ I O   g r o u p _ N N 1   w a s _ V B D Z   a g a i n _ R T   s i g n i f i c a n t _ J J   f o r _ I F   t h e _ A T   m a x i m u m _ J J   u r g e _ N N 1   r a t i n g _ V V G   a c r o s s _ I I   a l l _ D B   p h a s e s _ N N 2   ( _ (   P _ Z Z 1   = _ F O   . 0 2 1 _ M C   ; _ ;   U U I _ N P 1   p a r t i c i p a n t s _ N N 2   & l s q b ; _ (   6 . 4 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   2 . 2 _ M C   & r s q b ; _ )   > _ F O   c o n t r o l s _ N N 2   & l s q b ; _ (   4 . 8 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   3 . 0 _ M C   & r s q b ; _ )   ) _ )   , _ ,   w h i l e _ C S   t h e _ A T   m a i n _ J J   e f f e c t _ N N 1   o f _ I O   p h a s e _ N N 1   r e m a i n e d _ V V D   s i g n i f i c a n t _ J J   f o r _ I F   a l l _ D B   m e a s u r e s _ N N 2   ( _ (   a l l _ R R   P _ N N U   l e s s _ D A R   t h a n _ C S N   . 0 0 1 _ M C   ) _ )   . _ .   
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 A l m o s t _ R R   h a l f _ D B   o f _ I O   t h e _ A T   p a t i e n t s _ N N 2   w i t h _ I W   S W E D D _ N P 1   ( _ (   4 0 / 9 0 _ M F   ) _ )   i n _ I I   t h e _ A T   P R E C E P T _ N P 1   P a r k i n s o n _ N P 1   ' _ N U L L   s _ Z Z 1   d i s e a s e _ N N 1   c l i n i c a l _ J J   t r i a l _ N N 1   ( _ (   N _ Z Z 1   = _ F O   7 9 9 _ M C   ) _ )   h a d _ V H D   t h e i r _ A P P G E   d i a g n o s i s _ N N 1   c h a n g e d _ V V N   t o _ I I   a _ A T 1   c o n d i t i o n _ N N 1   n o t _ X X   a s s o c i a t e d _ V V N   w i t h _ I W   d o p a m i n e _ N N 1   d e n e r v a t i o n _ N N 1   a t _ I I   2 2 - m o n t h _ J J   f o l l o w - u p _ N N 1   b y _ I I   s t u d y _ N N 1   i n v e s t i g a t o r s _ N N 2   b l i n d e d _ V V N   t o _ I I   t h e _ A T   d o p a m i n e r g i c _ J J   s c a n _ N N 1   s t a t u s _ N N 1   w i t h _ I W   t h e _ A T   m o s t _ R G T   c o m m o n _ J J   r e v i s e d _ J J   d i a g n o s i s _ N N 1   b e i n g _ V B G   t r e m o r _ N N 1   , _ ,   f o l l o w e d _ V V N   b y _ I I   ' _ N U L L   n o _ A T   n e u r o l o g i c a l _ J J   d i a g n o s i s _ N N 1   ' _ N U L L   a n d _ C C   v a s c u l a r _ J J   p a r k i n s o n i s m _ N N 1   , _ ,   h i g h l i g h t i n g _ V V G   t h e _ A T   d i a g n o s t i c _ J J   d i f f i c u l t i e s _ N N 2   i n _ I I   t h e _ A T   e a r l y _ J J   d i s e a s e _ N N 1   s t a g e _ N N 1   , _ ,   a n d _ C C   e v e n _ R R   i n _ I I   P a r k i n s o n _ N P 1   ' _ N U L L   s _ Z Z 1   d i s e a s e _ N N 1   p a t i e n t s _ N N 2   w i t h _ I W   S P E C T - c o n f i r m e d _ J J   d o p a m i n e r g i c _ J J   d e f i c i t s _ N N 2   ( _ (   N = 7 0 7 _ F O   ) _ )   , _ ,   5 _ M C   c a s e s _ N N 2   h a d _ V H D   b e e n _ V B N   r e - e v a l u a t e d _ V V N   a s _ C S A   h a v i n g _ V H G   a _ A T 1   t r e m o r _ N N 1   s y n d r o m e _ N N 1   n o t _ X X   a s s o c i a t e d _ V V N   w i t h _ I W   d o p a m i n e _ N N 1   d e n e r v a t i o n _ N N 1   a n d _ C C   1 3 _ M C   h a d _ V H D   t h e i r _ A P P G E   d i a g n o s i s _ N N 1   r e v i s e d _ V V N   t o _ I I   v a s c u l a r _ J J   p a r k i n s o n i s m _ N N 1   . _ .   
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 A l t h o u g h _ C S   t h e _ A T   t e l e m e t r i c _ J J   p r o g r a m m e r _ N N 1   h a d _ V H D   i n d i c a t e d _ V V N   t h a t _ C S T   t h e _ A T   p u m p _ N N 1   w a s _ V B D Z   e x p e c t e d _ V V N   t o _ T O   h a v e _ V H I   2 1 . 8 _ M C   m L _ N N U   o f _ I O   f e n t a n y l _ N N 1   l e f t _ V V N   i n _ I I   t h e _ A T   r e s e r v o i r _ N N 1   , _ ,   o n l y _ R R   1 2 . 5 _ M C   m L _ N N U   o f _ I O   f e n t a n y l _ N N 1   w a s _ V B D Z   a s p i r a t e d _ V V N   . _ .   
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 A _ A T 1   b r a i n _ N N 1   a n d _ C C   a b d o m i n a l _ J J   e x a m i n a t i o n _ N N 1   w a s _ V B D Z   c a r r i e d _ V V N   o u t _ R P   f o r _ I F   t h e _ A T   1 2 _ M C   v o l u n t e e r s _ N N 2   ( _ (   8 _ M C   m a l e s _ N N 2   ; _ ;   a g e _ N N 1   , _ ,   3 1 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   8 _ M C   y e a r s _ N N T 2   ) _ )   . _ .   
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 T h e y _ P P H S 2   w e r e _ V B D R   t e s t e d _ V V N   t w i c e _ R R   w i t h _ I W   1 _ M C 1   h _ Z Z 1   g a p _ N N 1   b e t w e e n _ I I   s e s s i o n s _ N N T 2   . _ .   
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 T h e _ A T   h y p o t h e s i s _ N N 1   t h a t _ C S T   c o g n i t i o n _ N N 1   i s _ V B Z   a n _ A T 1   i n t e r m e d i a t e _ J J   p h e n o t y p e _ N N 1   f o r _ I F   s c h i z o p h r e n i a _ N N 1   i m p l i e s _ V V Z   t h a t _ C S T   r s 1 0 1 7 4 4 0 0 _ F O   s h o u l d _ V M   d i s c r i m i n a t e _ V V I   c a s e s _ N N 2   f r o m _ I I   c o n t r o l s _ N N 2   , _ ,   a t _ R R 2 1   l e a s t _ R R 2 2   t o _ I I   s o m e _ D D   d e g r e e . 1 7 _ F O   N o _ A T   c a s e / _ N N 1   c o n t r o l _ N N 1   s i g n a l _ N N 1   w a s _ V B D Z   o b s e r v e d _ V V N   i n _ I I   t h e _ A T   d i s c o v e r y _ N N 1   s a m p l e _ N N 1   . _ .   
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 F u r t h e r _ J J R   d e t a i l s _ N N 2   a b o u t _ I I   I Y _ N P 1   g r o u p s _ N N 2   a r e _ V B R   a v a i l a b l e _ J J   ( _ (   h t t p _ N N U   : _ :   ) _ )   . _ .   
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 A c k n o w l e d g e m e n t s _ N N 2   W e _ P P I S 2   w o u l d _ V M   l i k e _ V V I   t o _ T O   t h a n k _ V V I   M r _ N N B   M i c h a i l _ N P 1   T s a k a l i d i s _ N P 1   w h o _ P N Q S   p a r t i c i p a t e d _ V V D   i n _ I I   w r i t i n g _ N N 1   a n d _ C C   t e c h n i c a l _ J J   e d i t i n g _ N N 1   o f _ I O   t h e _ A T   m a n u s c r i p t _ N N 1   . _ .   
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 T r a u m a _ N N 1   c e n t e r s _ N N 2   t r e a t e d _ V V N   h i g h e r _ J J R   p r o p o r t i o n s _ N N 2   o f _ I O   m o d e r a t e _ J J   i n j u r i e s _ N N 2   ( _ (   N e w _ J J   I n j u r y _ N N 1   S e v e r i t y _ N N 1   S c o r e _ N N 1   5 _ M C   t o _ I I   1 5 _ M C   ) _ )   c o m p a r e d _ V V N   w i t h _ I W   n o n t r a u m a _ N N 1   c e n t e r s _ N N 2   a n d _ C C   t r e a t e d _ V V N   d i f f e r e n t _ J J   t y p e s _ N N 2   o f _ I O   i n j u r i e s _ N N 2   . _ .   
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 O C A 1 _ F O   h a d _ V H D   h i g h e r _ J J R   A U R O C _ N N 1   c u r v e _ N N 1   v a l u e s _ N N 2   t h a n _ C S N   O C A 3 _ F O   i n _ I I   a l l _ D B   q u a d r a n t s _ N N 2   . _ .   
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 T h i s _ D D 1   a r t i c l e _ N N 1   i s _ V B Z   p u b l i s h e d _ V V N   w i t h _ I W   o p e n _ J J   a c c e s s _ N N 1   a t _ I I   S p r i n g e r l i n k . c o m _ N P 1   A b s t r a c t _ V V 0   W e _ P P I S 2   p r e s e n t _ V V 0   p r o s p e c t i v e _ J J   b l o o d _ N N 1   p r e s s u r e _ N N 1   ( _ (   B P _ N P 1   ) _ )   a n d _ C C   h e a r _ V V 0   r a t e _ N N 1   ( _ (   H R _ N N U   ) _ )   c h a n g e s _ N N 2   i n _ I I   s m o k e r s _ N N 2   i n v i t e d _ V V N   t o _ T O   s w i t c h _ V V I   t o _ I I   e - c i g a r e t t e s _ N N 2   i n _ I I   t h e _ A T   E C L A T _ N N 1   s t u d y _ N N 1   . _ .   
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 I n _ I I   2 0 0 6 _ M C   , _ ,   p a t i e n t s _ N N 2   w i t h _ I W   o n e _ M C 1   o r _ C C   m o r e _ D A R   c o m p l e x _ J J   c h r o n i c _ J J   c o n d i t i o n s _ N N 2   a c c o u n t e d _ V V N   f o r _ I F   1 0 . 1 % _ F O   o f _ I O   p e d i a t r i c _ J J   h o s p i t a l _ N N 1   a d m i s s i o n s _ N N 2   , _ ,   4 0 . 6 % _ F O   o f _ I O   p e d i a t r i c _ J J   h o s p i t a l _ N N 1   c h a r g e s _ N N 2   , _ ,   a n d _ C C   4 3 . 2 % _ F O   o f _ I O   p e d i a t r i c _ J J   d e a t h s _ N N 2   . _ .   
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 I n _ I I   t h e _ A T   c o c h l e a e _ N N 2   o f _ I O   w i l d _ J J   t y p e _ N N 1   m i c e _ N N 2   , _ ,   C x 3 0 _ F O   p u n c t a _ N N 1   w e r e _ V B D R   l o c a l i z e d _ V V N   i n _ I I   t h e _ A T   s p i r a l _ J J   l i m b u s _ N N 1   a r e a _ N N 1   a n d _ C C   m e d i a l _ J J   t o _ I I   t h e _ A T   i n n e r _ J J   h a i r _ N N 1   c e l l _ N N 1   a r e a _ N N 1   ( _ (   F i g . _ N N 1   3 A _ F O   ) _ )   a n d _ C C   i n _ I I   p i l l a r _ N N 1   a n d _ C C   D e i t e r s _ N P 1   c e l l s _ N N 2   ( _ (   n o t _ X X   s h o w n _ V V N   ) _ )   . _ .   
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 S u r v i v a l _ N N 1   w a s _ V B D Z   t h e _ A T   o n l y _ J J   i d e n t i f i a b l e _ J J   r i s k _ N N 1   f a c t o r _ N N 1   f o r _ I F   s e i z u r e _ N N 1   r e c u r r e n c e _ N N 1   . _ .   
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 D e s p i t e _ I I   t h i s _ D D 1   , _ ,   a _ A T 1   g o l d _ N N 1   s t a n d a r d _ N N 1   o r _ C C   u n i v e r s a l l y _ R R   p r e f e r r e d _ J J   s c a l e _ N N 1   t h a t _ C S T   d i f f e r e n t i a t e s _ V V Z   b e t w e e n _ I I   d i s t r e s s _ N N 1   a n d _ C C   p a i n _ N N 1   i s _ V B Z   y e t _ R R   t o _ T O   e m e r g e _ V V I   f r o m _ I I   p u b l i s h e d _ J J   r e s e a r c h _ N N 1   . _ .   
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 C o n v e r s e l y _ R R   , _ ,   l a p a r o s c o p i c _ J J   s u r g e r i e s _ N N 2   a r e _ V B R   a s s o c i a t e d _ V V N   w i t h _ I W   a _ A T 1   f a s t e r _ J J R   r e c o v e r y _ N N 1   o f _ I O   g r i p _ N N 1   s t r e n g t h _ N N 1   a n d _ C C   i n s p i r a t o r y _ J J   f o r c e _ N N 1   a s _ R G   e a r l y _ R R   a s _ C S A   2 _ M C   t o _ I I   3 _ M C   h _ Z Z 1   a f t e r _ I I   e m e r g e n c e _ N N 1   f r o m _ I I   a n e s t h e s i a _ N N 1   . _ .   
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 R R _ N P 1   h a s _ V H Z   r e c e i v e d _ V V N   a _ A T 1   g r a n t _ N N 1   f r o m _ I I   t h e _ A T   H e a l t h _ N N 1   F o u n d a t i o n _ N N 1   a n d _ C C   L e g a l _ J J   a n d _ C C   G e n e r a l _ J J   a n d _ C C   t h e _ A T   D u n h i l l _ N P 1   M e d i c a l _ J J   . _ .   
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 U . _ N P 1   M e i e r - K r i e s c h e _ N P 1   i s _ V B Z   a _ A T 1   s a l a r i e d _ J J   e m p l o y e e _ N N 1   o f _ I O   B r i s t o l - M y e r s _ N P 1   S q u i b b _ N P 1   . _ .   
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 T h e _ A T   e p o c h s _ N N 2   c o n t a m i n a t e d _ V V N   b y _ I I   a r t i f a c t s _ N N 2   e x c e e d i n g _ V V G    1 2 5 V _ F O   a t _ I I   a n y _ D D   e l e c t r o d e _ N N 1   w e r e _ V B D R   o m i t t e d _ V V N   f r o m _ I I   t h e _ A T   a v e r a g i n g _ N N 1   p r o c e d u r e _ N N 1   . _ .   
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 A _ A T 1   r e c e n t _ J J   r e p o r t _ N N 1   1 3 _ M C   s h o w e d _ V V D   h i g h - r e s o l u t i o n _ J J   O C T _ N P M 1   t r a c e s _ N N 2   s u g g e s t i n g _ V V G   E Z _ N N 1   i m p r o v e m e n t _ N N 1   a s _ R G   e a r l y _ R R   a s _ C S A   2 _ M C   m o n t h s _ N N T 2   a f t e r _ I I   c e s s a t i o n _ N N 1   o f _ I O   t h e _ A T   d r u g _ N N 1   . _ .   
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 T h e _ A T   A s s o c i a t i o n _ N N 1   o f _ I O   A m e r i c a n _ J J   M e d i c a l _ J J   C o l l e g e s _ N N 2   d e f i n i t i o n _ N N 1   o f _ I O   t h o s e _ D D 2   u n d e r r e p r e s e n t e d _ J J   i n _ I I   m e d i c i n e _ N N 1   ( _ (   U R M _ N P 1   ) _ )   i s _ V B Z   e v o l v i n g _ V V G   d e p e n d i n g _ I I 2 1   o n _ I I 2 2   c h a n g i n g _ J J   d e m o g r a p h i c s _ N N 2   i n _ I I   t h e _ A T   g e n e r a l _ J J   p o p u l a t i o n _ N N 1   . _ .   
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 C h i l d r e n _ N N 2   w i t h _ I W   A D H D _ N P 1   a n d / o r _ C C   C D _ N N 1   b e h a v i o r s _ N N 2   c a n _ V M   b e _ V B I   m o n i t o r e d _ V V N   f o r _ C S   o v e r w e i g h t / o b e s i t y _ F U   a t _ I I   a n _ A T 1   e a r l y _ J J   s t a g e _ N N 1   , _ ,   t h u s _ R R   p o t e n t i a l l y _ R R   a v e r t i n g _ V V G   a _ A T 1   d e v e l o p m e n t a l _ J J   t r a j e c t o r y _ N N 1   o f _ I O   o b e s i t y _ N N 1   . _ .   
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 P e a k _ N N 1   t u m o r _ N N 1   u p t a k e _ N N 1   f o r _ I F   I - S G M I B - N a n o b o d y _ N P 1   w a s _ V B D Z   2 4 . 5 0 % _ F O    _ F O   9 . 8 9 % _ F O   i n j e c t e d _ V V D   d o s e / g _ F U   a t _ I I   2 _ M C   h _ Z Z 1   , _ ,   2 - _ N N 1   t o _ I I   4 - f o l d _ J J   h i g h e r _ J J R   t h a n _ C S N   o b s e r v e d _ V V N   w i t h _ I W   o t h e r _ J J   l a b e l i n g _ J J   m e t h o d s _ N N 2   , _ ,   a n d _ C C   w a s _ V B D Z   r e d u c e d _ V V N   b y _ I I   9 0 % _ N N U   w i t h _ I W   t r a s t u z u m a b _ N N 1   b l o c k i n g _ N N 1   , _ ,   c o n f i r m i n g _ V V G   t h e _ A T   H E R 2 _ F O   s p e c i f i c i t y _ N N 1   o f _ I O   l o c a l i z a t i o n _ N N 1   . _ .   
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 W e _ P P I S 2   c a n _ V M   s p e c u l a t e _ V V I   t h a t _ C S T   b i o m a r k e r s _ N N 2   u s e d _ V V D   s i n g u l a r l y _ R R   c o u l d _ V M   b e _ V B I   m o r e _ R G R   u s e f u l _ J J   i n _ I I   p r e d i c t i n g _ V V G   o u t c o m e s _ N N 2   . _ .   
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 O f _ I O   n o t e _ N N 1   , _ ,   P F - 0 6 4 6 3 9 2 2 _ M C   s i g n i f i c a n t l y _ R R   i n h i b i t e d _ J J   t u m o r _ N N 1   g r o w t h _ N N 1   i n _ I I   c r i z o t i n i b - r e s i s t a n t _ J J   m o d e l s _ N N 2   h a r b o r i n g _ V V G   m u t a n t _ N N 1   A L K _ N N 1   , _ ,   i n c l u d i n g _ I I   t h e _ A T   m o s t _ R G T   r e s i s t a n t _ J J   G 1 2 0 2 R _ F O   m u t a n t _ N N 1   . _ .   
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 A t _ I I   t h e _ A T   e n d _ N N 1   o f _ I O   t h e _ A T   e x p e r i m e n t _ N N 1   ( _ (   1 4 _ M C   m o n t h s _ N N T 2   p o s t i n j e c t i o n _ N N 1   ) _ )   , _ ,   a l l _ D B   m o n k e y s _ N N 2   w e r e _ V B D R   e u t h a n i z e d _ V V N   b y _ I I   s o d i u m _ N N 1   p e n t o b a r b i t a l _ J J   o v e r d o s e _ N N 1   ( _ (   1 5 0 m g / k g _ N N U   i v _ M C   ) _ )   , _ ,   f o l l o w e d _ V V N   b y _ I I   p e r f u s i o n _ N N 1   w i t h _ I W   s a l i n e _ J J   s o l u t i o n _ N N 1   ( _ (   c o n t a i n i n g _ V V G   1 % _ N N U   h e p a r i n _ N N 1   ) _ )   a n d _ C C   4 % _ N N U   p a r a f o r m a l d e h y d e _ N N 1   , _ ,   a n d _ C C   b r a i n s _ N N 2   w e r e _ V B D R   q u i c k l y _ R R   r e m o v e d _ V V N   a n d _ C C   p r o c e s s e d _ V V N   f o r _ I F   h i s t o l o g i c a l _ J J   s t u d i e s _ N N 2   . _ .   
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 H o w e v e r _ R R   , _ ,   u n p u b l i s h e d _ J J   N a t s a l _ N N 1   d a t a _ N N   s h o w _ V V 0   a _ A T 1   t w o - f o l d _ J J   i n c r e a s e _ N N 1   i n _ I I   u s e _ N N 1   o f _ I O   l o n g - a c t i n g _ J J   r e v e r s i b l e _ J J   c o n t r a c e p t i o n _ N N 1   m e t h o d s _ N N 2   b y _ I I   s e x u a l l y _ R R   a c t i v e _ J J   1 6 - 1 7 _ M C M C   y e a r _ N N T 1   o l d s _ N N 2   b e t w e e n _ I I   N a t s a l - 2 _ M C   a n d _ C C   N a t s a l - 3 _ M C   . _ .   
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 A f t e r _ I I   s c r e e n i n g _ V V G   b y _ I I   t i t l e _ N N 1   a n d _ C C   a b s t r a c t _ J J   , _ ,   f u l l _ J J   a r t i c l e s _ N N 2   w e r e _ V B D R   t h e n _ R T   o b t a i n e d _ V V N   f o r _ I F   1 0 _ M C   t r i a l s _ N N 2   a n d _ C C   t h e i r _ A P P G E   e l i g i b i l i t y _ N N 1   a s s e s s e d _ V V N   a g a i n s t _ I I   t h e _ A T   i n c l u s i o n _ N N 1   c r i t e r i a _ N N 2   . _ .   
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 I _ P P I S 1   s c o r e _ V V 0   , _ ,   a n a l y s e d _ V V N   i n _ I I   a l l _ D B   p a r t i c i p a n t s _ N N 2   w i t h _ I W   a t _ R R 2 1   l e a s t _ R R 2 2   o n e _ M C 1   p o s t b a s e l i n e _ N N 1   m e a s u r e m e n t _ N N 1   . _ .   
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 W e _ P P I S 2   o b s e r v e d _ V V D   a _ A T 1   f a v o r a b l e _ J J   s h o r t - t e r m _ J J   c o m p l i c a t i o n _ N N 1   p r o f i l e _ N N 1   , _ ,   s u p p o r t i n g _ V V G   t h e _ A T   e a r l y _ J J   p o s t o p e r a t i v e _ J J   s a f e t y _ N N 1   o f _ I O   W L S _ N P 1   i n _ I I   s e l e c t _ J J   a d o l e s c e n t s _ N N 2   . _ .   
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 T h i s _ D D 1   s i n g l e - b l i n d _ N N 1   r a n d o m i z e d _ V V D   c o n t r o l l e d _ J J   t r i a l _ N N 1   c o m p a r e d _ V V D   l a n g u a g e _ N N 1   o u t c o m e s _ N N 2   f r o m _ I I   4 _ M C   i n v e s t i g a t i o n a l _ J J   p a r t i c i p a n t s _ N N 2   w h o _ P N Q S   r e c e i v e d _ V V D   C S _ N P 2   p l u s _ I I   l a n g u a g e _ N N 1   t h e r a p y _ N N 1   ( _ (   C S / L T _ F U   ) _ )   a n d _ C C   4 _ M C   c o n t r o l s _ N N 2   w h o _ P N Q S   r e c e i v e d _ V V D   t h e _ A T   i d e n t i c a l _ J J   L T _ N N B   b u t _ C C B   n o _ A T   C S _ N P 2   . _ .   
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 A n _ A T 1   e x a m p l e _ N N 1   o f _ I O   t h e _ A T   m a g n i t u d e _ N N 1   o f _ I O   h e t e r o g e n e i t y _ N N 1   b e t w e e n _ I I   o u r _ A P P G E   m e t a b o l o m i c s _ N N 1   d a t a _ N N   a n d _ C C   e x i s t i n g _ J J   e x p r e s s i o n _ N N 1   d a t a _ N N   w a s _ V B D Z   i n _ I I   t h e _ A T   g e n e s _ N N 2   a n d _ C C   m e t a b o l i t e s _ N N 2   c o n s t i t u t i n g _ V V G   t h e _ A T   K E G G _ N P 1   T C A _ N P 1   c y c l e _ N N 1   p a t h w a y _ N N 1   . _ .   
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 F o r _ I F   t h i s _ D D 1   s t u d y _ N N 1   w e _ P P I S 2   s e l e c t e d _ V V D   p a t i e n t s _ N N 2   w i t h _ I W   m i l d _ J J   d e m e n t i a _ N N 1   a t _ I I   b a s e l i n e _ N N 1   ( _ (   F u n c t i o n a l _ J J   A s s e s s m e n t _ N N 1   S t a g i n g _ N N 1   s c o r e _ N N 1   , _ ,   3 - 4 _ M C M C   ; _ ;   a n d _ C C   C l i n i c a l _ J J   D e m e n t i a _ N N 1   R a t i n g _ N N 1   s c o r e _ N N 1   , _ ,   0 . 5 - 1 _ M C M C   ) _ )   . _ .   
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 A n _ A T 1   i n t e r e s t i n g _ J J   f i n d i n g _ N N 1   w a s _ V B D Z   t h a t _ D D 1   p a i n _ N N 1   a r e a s _ N N 2   w e r e _ V B D R   d r a w n _ V V N   s l i g h t l y _ R R   l a r g e r _ J J R   o n _ I I   t h e _ A T   2 D _ N N U   l i n e _ N N 1   d r a w i n g s _ N N 2   i n _ I I 3 1   c o m p a r i s o n _ I I 3 2   w i t h _ I I 3 3   t h e _ A T   3 D _ N N U   b o d y _ N N 1   s c h e m a _ N N 1   , _ ,   i n _ I I   a _ A T 1   f i x e d _ J J   a n d _ C C   s y s t e m a t i c _ J J   f a s h i o n _ N N 1   . _ .   
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 H o w _ R R Q   t o _ T O   i r r a d i a t e _ V V I   E x p e r i e n c e s _ N N 2   w i t h _ I W   r e - t r e a t m e n t _ N N 1   o f _ I O   p a t i e n t s _ N N 2   w i t h _ I W   h e a d _ N N 1   a n d _ C C   n e c k _ N N 1   c a n c e r _ N N 1   g a i n e d _ V V N   d u r i n g _ I I   t h e _ A T   l a s t _ M D   d e c a d e s _ N N T 2   p r o v i d e _ V V 0   a _ A T 1   s o l i d _ J J   g r o u n d _ N N 1   f o r _ I F   r e f i n e m e n t _ N N 1   o f _ I O   t h e _ A T   e x i s t i n g _ J J   r e i r r a d i a t i o n _ N N 1   s t r a t e g i e s _ N N 2   . _ .   
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 H o w e v e r _ R R   , _ ,   i t _ P P H 1   i s _ V B Z   n o t _ X X   k n o w n _ V V N   w h e t h e r _ C S W   t h e _ A T   d i r e c t _ J J   p r o t e c t i v e _ J J   e f f e c t s _ N N 2   o f _ I O   a m a n t a d i n e _ N N 1   o n _ I I   n e u r o n s _ N N 2   p l a y _ V V 0   a _ A T 1   r o l e _ N N 1   i n _ I I   i t s _ A P P G E   i m p r o v e m e n t _ N N 1   o f _ I O   c o g n i t i v e _ J J   i m p a i r m e n t _ N N 1   a f t e r _ I I   s u r g e r y _ N N 1   . _ .   
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 L i k e _ I I   P R P H 2 / R D S _ F U   , _ ,   R O M - 1 _ M C 1   i s _ V B Z   l o c a l i z e d _ V V N   t o _ I I   t h e _ A T   r i m _ N N 1   r e g i o n _ N N 1   o f _ I O   b o t h _ R R   r o d _ N N 1   a n d _ C C   c o n e _ N N 1   O S s _ N N 1   ( _ (   d e s p i t e _ I I   t h e _ A T   n a m e _ N N 1   ) _ )   ( _ (   B a s c o m _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 9 9 2 _ M C   ; _ ;   M o r i t z _ N P 1   a n d _ C C   M o l d a y _ N P 1   , _ ,   1 9 9 6 _ M C   ) _ )   . _ .   
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 A d e q u a t e _ J J   l e v e l s _ N N 2   o f _ I O   b a s a l _ J J   c o r t i s o l _ N N 1   a r e _ V B R   n e c e s s a r y _ J J   f o r _ I F   n o r m a l _ J J   b r a i n _ N N 1   f u n c t i o n _ N N 1   a s _ C S A   t h e y _ P P H S 2   p l a y _ V V 0   a _ A T 1   r o l e _ N N 1   i n _ I I   p l a s t i c i t y _ N N 1   a n d _ C C   s u r v i v a l _ N N 1   o f _ I O   n e u r o n s _ N N 2   . _ .   
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 P a t i e n t _ J J   p a r t i c i p a n t s _ N N 2   w e r e _ V B D R   a s k e d _ V V N   t o _ T O   p r o v i d e _ V V I   r e a c t i o n s _ N N 2   i n d i v i d u a l l y _ R R   t o _ I I   d e s c r i p t i o n s _ N N 2   o f _ I O   t h e _ A T   e m e r g i n g _ J J   t h e m e s _ N N 2   o f _ I O   t h e _ A T   s t u d y _ N N 1   , _ ,   a n d _ C C   t h e n _ R T   e n g a g e _ V V 0   i n _ I I   d i a l o g u e _ N N 1   w i t h _ I W   t h e _ A T   o t h e r _ J J   p a r t i c i p a n t s _ N N 2   . _ .   
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 D a t a _ N N   w e r e _ V B D R   a n a l y z e d _ V V N   u s i n g _ V V G   t h e _ A T   1 - w a y _ J J   a n a l y s i s _ N N 1   o f _ I O   v a r i a n c e _ N N 1   ( _ (   A N O V A _ N P 1   ) _ )   , _ ,   p o s t _ R R 2 1   h o c _ R R 2 2   l e a s t _ R G T   s i g n i f i c a n t _ J J   d i f f e r e n c e _ N N 1   , _ ,   r e p e a t e d - m e a s u r e _ J J   A N O V A _ N N 1   , _ ,   a n d _ C C   & l s q b ; _ (   c h i _ N N 1   & r s q b ; _ )   2 _ M C   t e s t _ N N 1   . _ .   
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 A _ A T 1   m a j o r _ J J   o b s t a c l e _ N N 1   l i m i t i n g _ J J   g e n e _ N N 1   t h e r a p y _ N N 1   f o r _ I F   m u s c l e _ N N 1   d i s e a s e s _ N N 2   c o m e s _ V V Z   f r o m _ I I   t h e _ A T   f a c t _ N N 1   t h a t _ C S T   s y s t e m i c _ J J   g e n e _ N N 1   t r a n s f e r _ N N 1   t o _ I I   s t r i a t e d _ J J   m u s c l e s _ N N 2   i s _ V B Z   h a m p e r e d _ V V N   b y _ I I   t h e _ A T   v a s c u l a r _ J J   e n d o t h e l i u m _ N N 1   , _ ,   w h i c h _ D D Q   r e p r e s e n t s _ V V Z   a _ A T 1   b a r r i e r _ N N 1   t o _ I I   d i s t r i b u t i o n _ N N 1   o f _ I O   v e c t o r s _ N N 2   t h r o u g h _ I I   t h e _ A T   b l o o d s t r e a m _ N N 1   . _ .   
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 S e v e r a l _ D A 2   l a b o r a t o r i e s _ N N 2   h a v e _ V H 0   s h o w n _ V V N   t h a t _ D D 1   e x e r c i s e _ N N 1   e n h a n c e s _ V V Z   i n s u l i n _ N N 1   s e n s i t i v i t y _ N N 1   i n _ I I   i n d i v i d u a l s _ N N 2   a c r o s s _ I I   t h e _ A T   g l u c o s e _ N N 1   t o l e r a n c e _ N N 1   c o n t i n u u m _ N N 1   , _ ,   a n d _ C C   t h e _ A T   i n c r e a s e _ N N 1   i n _ I I   s k e l e t a l _ J J   m u s c l e _ N N 1   g l u c o s e _ N N 1   d i s p o s a l _ N N 1   o f t e n _ R R   i s _ V B Z   u s e d _ V V N   a s _ I I   a _ A T 1   p r i m a r y _ J J   m e c h a n i s m _ N N 1   t o _ T O   e x p l a i n _ V V I   r e d u c t i o n s _ N N 2   i n _ I I   p o s t p r a n d i a l _ J J   b l o o d _ N N 1   g l u c o s e _ N N 1   a f t e r _ I I   e x e r c i s e _ N N 1   t r a i n i n g _ N N 1   ( _ (   1 4 _ M C   ) _ )   . _ .   
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 R a t e s _ N N 2   o f _ I O   p a t i e n t _ J J   p a r t i c i p a t i o n _ N N 1   i n _ I I   A - C H E S S _ N N 1   w e r e _ V B D R   h i g h _ R R   c o m p a r e d _ V V N   t o _ I I   u s u a l _ J J   r a t e s _ N N 2   o f _ I O   p a r t i c i p a t i o n _ N N 1   i n _ I I   a f t e r c a r e _ N N 1   f o r _ I F   A U D s _ N N 2   . _ .   
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 F o u r t h _ M D   , _ ,   w e _ P P I S 2   c a n _ V M   n o t _ X X   o b s e r v e _ V V I   a n y _ D D   s e r v i c e s _ N N 2   u s e d _ V V N   b y _ I I   h e a l t h _ N N 1   c a r e _ N N 1   p r o f e s s i o n a l s _ N N 2   w h o _ P N Q S   w e r e _ V B D R   n o t _ X X   p a i d _ V V N   b y _ I I   M e d i c a i d _ N P 1   , _ ,   f o r _ R E X 2 1   e x a m p l e _ R E X 2 2   , _ ,   p s y c h o s o c i a l _ J J   s e r v i c e s _ N N 2   i n _ I I   s c h o o l _ N N 1   , _ ,   a n d _ C C   w e _ P P I S 2   d o _ V D 0   n o t _ X X   h a v e _ V H I   i n f o r m a t i o n _ N N 1   o n _ I I   t h e _ A T   q u a l i t y _ N N 1   o r _ C C   t y p e _ N N 1   o f _ I O   p s y c h o s o c i a l _ J J   s e r v i c e s _ N N 2   d e l i v e r e d _ V V D   . _ .   
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 m o r p h i n e _ N N 1   i n d u c e s _ V V Z   s c r a t c h i n g _ V V G   b e h a v i o r _ N N 1   i n _ I I   m i c e _ N N 2   . _ .   
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 F o r _ R E X 2 1   e x a m p l e _ R E X 2 2   , _ ,   i m p r o v e m e n t s _ N N 2   i n _ I I   v i s u a l _ J J   m e m o r y _ N N 1   a f t e r _ I I   6 _ M C   m i n _ N N U   o f _ I O   m o d e r a t e - i n t e n s i t y _ J J   c y c l i n g _ N N 1   h a v e _ V H 0   b e e n _ V B N   a s s o c i a t e d _ V V N   w i t h _ I W   i n c r e a s e s _ N N 2   i n _ I I   n o r e p i n e p h r i n e _ N N 1   a s s e s s e d _ V V N   f r o m _ I I   s a l i v a _ N N 1   i m m e d i a t e l y _ R R   a f t e r _ I I   e x e r c i s e _ N N 1   b o t h _ R R   i n _ I I   h e a l t h y _ J J   e l d e r l y _ J J   s u b j e c t s _ N N 2   a n d _ C C   s u b j e c t s _ N N 2   w i t h _ I W   m i l d _ J J   c o g n i t i v e _ J J   i m p a i r m e n t _ N N 1   ( _ (   2 4 _ M C   ) _ )   . _ .   
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 B a s e l i n e _ N N 1   c h a r a c t e r i s t i c s _ N N 2   ( _ (   a g e _ N N 1   , _ ,   s e x _ N N 1   , _ ,   e t h n i c i t y _ N N 1   , _ ,   d i a g n o s i s _ N N 1   m e t h o d _ N N 1   , _ ,   t u m o r _ N N 1   c e l l _ N N 1   t y p e _ N N 1   a n d _ C C   g r a d e _ N N 1   , _ ,   p e r f o r m a n c e _ N N 1   s t a t u s _ N N 1   , _ ,   e x t r a h e p a t i c _ J J   d i s e a s e _ N N 1   , _ ,   p o r t a l _ N N 1   v e i n _ N N 1   t h r o m b o s i s _ N N 1   , _ ,   h y p o v a s c u l a r _ J J   l e s i o n s _ N N 2   , _ ,   p r e v i o u s _ J J   n o n l i v e r - d i r e c t e d _ J J   t r e a t m e n t _ N N 1   , _ ,   c o n c u r r e n t _ J J   s o m a t o s t a t i n _ N N 1   t h e r a p y _ N N 1   , _ ,   t y p e _ N N 1   a n d _ C C   n u m b e r _ N N 1   o f _ I O   T A C E _ N P 1   p r o c e d u r e s _ N N 2   , _ ,   d u r a t i o n _ N N 1   b e t w e e n _ I I   i m a g i n g _ N N 1   a n d _ C C   T A C E _ N P 1   , _ ,   a n d _ C C   n u m b e r _ N N 1   o f _ I O   d e a t h s _ N N 2   ) _ )   w e r e _ V B D R   r e c o r d e d _ V V N   . _ .   
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 H o w e v e r _ R R   , _ ,   i t _ P P H 1   w a s _ V B D Z   l a t e r _ R R R   r e a l i z e d _ V V N   t h a t _ C S T   s o m e _ D D   p a t h o l o g i c a l _ J J   d e f i n i t i o n s _ N N 2   w e r e _ V B D R   n e c e s s a r y _ J J   t o _ T O   o b t a i n _ V V I   a _ A T 1   r e p r o d u c i b l e _ J J   p a t i e n t _ J J   s t r a t i f i c a t i o n _ N N 1   , _ ,   a n d _ C C   a _ A T 1   s e c o n d _ M D   c o n s e n s u s _ N N 1   f o r _ I F   o b t a i n i n g _ V V G   u n i f o r m _ J J   p r o c e s s i n g _ N N 1   o f _ I O   e n u c l e a t e d _ J J   e y e s _ N N 2   a n d _ C C   f o r _ I F   u s i n g _ V V G   s i m i l a r _ J J   d e f i n i t i o n s _ N N 2   f o r _ I F   p a t h o l o g i c a l _ J J   e x a m i n a t i o n _ N N 1   w a s _ V B D Z   o b t a i n e d _ V V N   . _ .   
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 E x p o s u r e _ N N 1   o f _ I O   r e t i n a l _ J J   m i c r o g l i a _ N N 1   t o _ I I   o t h e r _ J J   r e t i n o i d s _ N N 2   ( _ (   1 3 - c i s _ J J   r e t i n a l _ J J   a n d _ C C   a l l - t r a n s _ N N 2   r e t i n a l _ J J   ) _ )   d i d _ V D D   n o t _ X X   a l t e r _ V V I   t h e _ A T   m R N A _ N N 1   e x p r e s s i o n _ N N 1   o f _ I O   C F B _ N P 1   a n d _ C C   C F H _ N P 1   s i g n i f i c a n t l y _ R R   ( _ (   S u p p l e m e n t a r y _ J J   F i g . _ N N 1   2 C _ F O   ) _ )   . _ .   
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 H u i j n e n _ N P 1   e t _ R A 2 1   a l _ R A 2 2   a n d _ C C   M c C r a c k e n _ N P 1   a n d _ C C   S a m u e l _ N P 1   1 8 f o u n d _ F O   t h a t _ D D 1   s u b g r o u p s _ V V Z   o f _ I O   i n d i v i d u a l s _ N N 2   w h o _ P N Q S   r e p o r t e d _ V V D   h i g h _ J J   l e v e l s _ N N 2   o f _ I O   b o t h _ R R   a v o i d a n c e _ N N 1   a n d _ C C   o v e r a c t i v i t y _ N N 1   , _ ,   o r _ C C   h i g h _ J J   l e v e l s _ N N 2   o f _ I O   a v o i d a n c e _ N N 1   b u t _ C C B   l o w _ J J   l e v e l s _ N N 2   o f _ I O   o v e r a c t i v i t y _ N N 1   , _ ,   h a d _ V H D   h i g h e r _ J J R   l e v e l s _ N N 2   o f _ I O   s e l f - r e p o r t e d _ J J   d i s a b i l i t y _ N N 1   c o m p a r e d _ V V N   w i t h _ I W   a _ A T 1   ' _ N U L L   l o w _ J J   a v o i d a n c e _ N N 1   , _ ,   h i g h _ J J   o v e r a c t i v i t y _ N N 1   ' _ N U L L   s u b g r o u p _ N N 1   . _ .   
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 O n l y _ R R   1 _ M C 1   s t u d y _ N N 1   i n _ I I   o u r _ A P P G E   m e t a - a n a l y s i s _ N N 1   i n v e s t i g a t e d _ V V D   t h e _ A T   n e u r o p s y c h o l o g i c a l _ J J   c o r r e l a t e s _ N N 2   o f _ I O   p s y c h o t i c _ J J   e x p e r i e n c e s _ N N 2   a c r o s s _ I I   a d u l t h o o d 5 _ F O   a n d _ C C   r e p o r t e d _ V V N   o n _ I I   a _ A T 1   s i n g l e _ J J   c o g n i t i v e _ J J   d o m a i n _ N N 1   . _ .   
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 T h e _ A T   e x p o s u r e _ N N 1   d u r a t i o n _ N N 1   a t _ I I   a _ A T 1   s i n g l e _ J J   f o c a l _ J J   s p o t _ N N 1   w a s _ V B D Z   c h o s e n _ V V N   t o _ T O   b e _ V B I   3 0 _ M C   s e c o n d s _ N N T 2   , _ ,   w h i c h _ D D Q   c o r r e s p o n d e d _ V V D   t o _ I I   t h e _ A T   d e l i v e r y _ N N 1   o f _ I O   3 0 _ M C   p u l s e s _ N N 2   , _ ,   a f t e r _ I I   w h i c h _ D D Q   t h e _ A T   s i z e _ N N 1   o f _ I O   t h e _ A T   l y s e d _ J J   l e s i o n _ N N 1   r e a c h e s _ V V Z   s a t u r a t i o n _ N N 1   . _ .   
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 F o r _ I F   n e t w o r k _ N N 1   i n f e r e n c e _ N N 1   , _ ,   a _ A T 1   t r a d e - o f f _ N N 1   e x i s t s _ V V Z   b e t w e e n _ I I   t h e _ A T   s p a r s i t y _ N N 1   a n d _ C C   t h e _ A T   q u a l i t y _ N N 1   o f _ I O   t h e _ A T   e m p l o y e d _ J J   g e n e - g e n e _ J J   i n t e r a c t i o n s _ N N 2   . _ .   
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 T h e r e f o r e _ R R   , _ ,   i d e n t i f y i n g _ V V G   c o m p o u n d s _ N N 2   t h a t _ C S T   i n d u c e _ V V 0   a n d _ C C   i n c r e a s e _ V V 0   P G C - 1 & l s q b ; a l p h a & r s q b ; _ J J   e x p r e s s i o n _ N N 1   m a y _ V M   b e _ V B I   a _ A T 1   n o v e l _ N N 1   a n d _ C C   u s e f u l _ J J   t h e r a p e u t i c _ J J   s t r a t e g y _ N N 1   i n _ I I   t h e _ A T   p r e v e n t i o n _ N N 1   o f _ I O   I C U A W _ N N 1   i n _ I I   c r i t i c a l l y _ R R   i l l _ J J   i m m o b i l e _ J J   p a t i e n t s _ N N 2   . _ .   
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 T h e _ A T   p r o p o r t i o n _ N N 1   o f _ I O   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   H B O C - 2 0 1 _ M C   g r o u p _ N N 1   t h a t _ C S T   a v o i d e d _ V V D   R B C _ N P 1   t r a n s f u s i o n _ N N 1   w a s _ V B D Z   0 . 4 2 7 _ M C   ( _ (   9 5 % _ N N U   c o n f i d e n c e _ N N 1   i n t e r v a l _ N N 1   , _ ,   0 . 3 2 1 _ M C   - _ -   0 . 5 3 3 _ M C   ) _ )   . _ .   
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 I n _ I I   h u m a n s _ N N 2   , _ ,   e n d o t h e l i a l _ J J   e n r i c h e d _ J J   m i R - 1 2 6 _ M C   l e v e l s _ N N 2   i n _ I I   p l a s m a _ N N 1   n e g a t i v e l y _ R R   c o r r e l a t e d _ V V N   w i t h _ I W   a g e _ N N 1   i n _ I I   a s y m p t o m a t i c _ J J   c o n t r o l _ N N 1   p a t i e n t s _ N N 2   , _ ,   s t a t i n g _ V V G   a _ A T 1   r e f l e c t i o n _ N N 1   o f _ I O   a g e _ N N 1   a s s o c i a t e d _ V V N   i n t r i n s i c _ J J   d e c l i n e _ N N 1   i n _ I I   e n d o t h e l i a l _ J J   f u n c t i o n _ N N 1   . _ .   
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 W i l c o x o n _ N P 1   S i g n e d _ V V D   R a n k _ N P 1   t e s t _ N N 1   ) _ )   , _ ,   i n d i c a t i n g _ V V G   t h a t _ C S T   t h e _ A T   p a t i e n t s _ N N 2   w e r e _ V B D R   a b l e _ J K   t o _ T O   u s e _ V V I   r e t i n o t o p i c a l l y _ R R   r e p r e s e n t e d _ V V N   v i s u a l _ J J   f o r m _ N N 1   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   o t h e r _ J J   n o n - g e o m e t r i c _ J J   c u e s _ N N 2   t o _ T O   i d e n t i f y _ V V I   t h e _ A T   o b j e c t s _ N N 2   ( _ (   s e e _ V V 0   F i g . _ N N 1   1 7 _ M C   ) _ )   . _ .   
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 U n s u r p r i s i n g l y _ R R   , _ ,   t h e _ A T   s a m e _ D A   t w o _ M C   p a t i e n t s _ N N 2   w h o _ P N Q S   p e r f o r m e d _ V V D   w e l l _ R R   i n _ I I   s h a p e _ N N 1   r e c o g n i t i o n _ N N 1   a n d _ C C   l e t t e r _ N N 1   r e a d i n g _ N N 1   t a s k s _ N N 2   , _ ,   a l s o _ R R   p e r f o r m e d _ V V N   s u b s t a n t i a l l y _ R R   b e t t e r _ R R R   t h a n _ C S N   t h e _ A T   r e s t _ N N 1   o f _ I O   t h e _ A T   g r o u p _ N N 1   i n _ I I   t h i s _ D D 1   o b j e c t _ N N 1   r e c o g n i t i o n _ N N 1   t a s k _ N N 1   , _ ,   a c h i e v i n g _ V V G   6 8 . 8 % _ F O   a n d _ C C   3 7 . 5 % _ F O   c o r r e c t _ J J   i d e n t i f i c a t i o n _ N N 1   o f _ I O   t h e _ A T   s o l i d _ J J   o b j e c t s _ N N 2   , _ ,   a n d _ C C   7 5 % _ N N U   a n d _ C C   5 0 % _ N N U   c o r r e c t _ J J   i d e n t i f i c a t i o n _ N N 1   o f _ I O   t h e _ A T   o u t l i n e d _ J J   o b j e c t s _ N N 2   r e s p e c t i v e l y _ R R   . _ .   
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 I n _ I I   r e g i o n s _ N N 2   w h e r e _ R R Q   f i l t r a t i o n _ N N 1   d e m a n d _ N N 1   a n d _ C C   t h e _ A T   t r a n s e n d o t h e l i a l _ J J   p r e s s u r e _ N N 1   d r o p _ N N 1   i s _ V B Z   l a r g e r _ J J R   ' _ N U L L   S C _ F O   c e l l s _ N N 2   e x p e r i e n c e _ V V 0   l a r g e r _ J J R   d e f o r m a t i o n s _ N N 2   o n _ I I 3 1   a c c o u n t _ I I 3 2   o f _ I I 3 3   g i a n t _ J J   v a c u o l e _ N N 1   f o r m a t i o n _ N N 1   o r _ C C   ' _ N U L L   b a l l o o n i n g _ N N 1   ' _ N U L L   o f _ I O   t h e _ A T   i n n e r _ J J   w a l l _ N N 1   . _ .   
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 W o m e n _ N N 2   d i s c o n t i n u e d _ V V D   t h e _ A T   i n t e r v e n t i o n _ N N 1   i f _ C S   a n _ A T 1   o n g o i n g _ J J   p r e g n a n c y _ N N 1   w a s _ V B D Z   a c h i e v e d _ V V N   , _ ,   a n d _ C C   i f _ C S   a _ A T 1   p r e g n a n c y _ N N 1   e n d e d _ V V N   i n _ I I   a _ A T 1   m i s c a r r i a g e _ N N 1   , _ ,   t h e y _ P P H S 2   w e r e _ V B D R   a l l o w e d _ V V N   t o _ T O   r e s u m e _ V V I   t h e _ A T   i n t e r v e n t i o n _ N N 1   . _ .   
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 A _ Z Z 1   2 0 1 1 _ M C   s t u d y _ N N 1   c o m p a r i n g _ V V G   t h e _ A T   r a t e _ N N 1   o f _ I O   b u r n o u t _ N N 1   i n _ I I   U . S . _ N P 1   p h y s i c i a n s _ N N 2   t o _ I I   t h a t _ D D 1   o f _ I O   t h e _ A T   g e n e r a l _ J J   p o p u l a t i o n _ N N 1   f o u n d _ V V D   t h a t _ C S T   a l m o s t _ R R   h a l f _ D B   o f _ I O   p h y s i c i a n s _ N N 2   e x p e r i e n c e d _ V V D   a t _ R R 2 1   l e a s t _ R R 2 2   o n e _ M C 1   s y m p t o m _ N N 1   , _ ,   w h i c h _ D D Q   w a s _ V B D Z   s i g n i f i c a n t l y _ R R   h i g h e r _ J J R   t h a n _ C S N   p o p u l a t i o n _ N N 1   c o n t r o l s _ N N 2   ( _ (   2 7 . 8 % _ F O   ) _ )   . 2 2 _ M C   I t _ P P H 1   a l s o _ R R   c o m p a r e d _ V V N   r a t e s _ N N 2   o f _ I O   b u r n o u t _ N N 1   a m o n g _ I I   p h y s i c i a n _ N N 1   s p e c i a l t i e s _ N N 2   a n d _ C C   f o u n d _ V V D   t h a t _ D D 1   p e d i a t r i c s _ N N 1   s u b s p e c i a l t i e s _ N N 2   h a d _ V H D   o n e _ M C 1   o f _ I O   t h e _ A T   l o w e s t _ J J T   r a t e s _ N N 2   ( _ (   4 2 % _ N N U   ) _ )   , _ ,   b u t _ C C B   E M _ F U   h a d _ V H N   t h e _ A T   h i g h e s t _ J J T   ( _ (   6 7 % _ N N U   ) _ )   . _ .   
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 D i s c u s s i o n _ N N 1   T h i s _ D D 1   s t u d y _ N N 1   i n v e s t i g a t e d _ V V D   4 _ M C   c o m m o n l y _ R R   u s e d _ V V D   3 D _ N N U   s e q u e n c e s _ N N 2   i n c l u d i n g _ V V G   p r e _ I I   c o n t r a s t _ N N 1   3 D _ N N U   F L A I R _ N N 1   , _ ,   3 D _ N N U   F I E S T A - C _ N P 1   , _ ,   p o s t _ N N 1   c o n t r a s t _ N N 1   3 D _ N N U   F L A I R _ N N 1   a n d _ C C   3 D _ N N U   F S P G R _ N P 1   t o _ I I   i m a g e _ N N 1   p a t i e n t s _ N N 2   w i t h _ I W   u n i l a t e r a l _ J J   I S S N H L _ N P 1   a n d _ C C   t e s t e d _ V V D   w h e t h e r _ C S W   F L A I R _ N N 1   h i g h _ J J   s i g n a l _ N N 1   i s _ V B Z   a _ A T 1   r e l e v a n t _ J J   c l i n i c a l _ J J   p r o g n o s t i c _ J J   p r e d i c t o r _ N N 1   o f _ I O   h e a r i n g _ V V G   o u t c o m e s _ N N 2   . _ .   
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 A m o n g _ I I   a d u l t _ J J   c h r o n i c _ J J   p a i n _ N N 1   p a t i e n t s _ N N 2   , _ ,   t h e r e _ E X   i s _ V B Z   a n _ A T 1   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   p s y c h i a t r i c _ J J   c o m o r b i d i t i e s _ N N 2   a n d _ C C   l i k e l i h o o d _ N N 1   o f _ I O   p r o g r e s s i n g _ V V G   t o _ T O   a b u s e _ V V I   o f _ I O   o p i o i d s . 2 8 - 3 1 _ M C   F u t u r e _ J J   s t u d i e s _ N N 2   t o _ T O   b e t t e r _ R R R   c h a r a c t e r i z e _ V V I   r i s k _ N N 1   f a c t o r s _ N N 2   a n d _ C C   r e a s o n s _ N N 2   f o r _ I F   a n a l g e s i c _ N N 1   n o n a d h e r e n c e _ N N 1   i n _ I I   t h e _ A T   p e d i a t r i c _ J J   p a i n _ N N 1   p o p u l a t i o n _ N N 1   m a y _ V M   b e _ V B I   h e l p f u l _ J J   i n _ I I   i d e n t i f y i n g _ V V G   t h o s e _ D D 2   f o r _ I F   w h o m _ P N Q O   i n c r e a s e d _ J J   m o n i t o r i n g _ N N 1   m a y _ V M   b e _ V B I   u s e f u l _ J J   . _ .   
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 W i d e s p r e a d _ J J   P P T _ N P 1   w a s _ V B D Z   c h o s e n _ V V N   t o _ T O   p r e v e n t _ V V I   a _ A T 1   v e r y _ R G   l o w _ J J   P P T _ N P 1   i n _ I I   1 _ M C 1   p a i n f u l _ J J   r e g i o n _ N N 1   f r o m _ I I   l a r g e l y _ R R   a f f e c t i n g _ V V G   w h e t h e r _ C S W   a _ A T 1   p a t i e n t _ N N 1   w a s _ V B D Z   c l a s s i f i e d _ V V N   a s _ C S A   h a v i n g _ V H G   l o w _ J J   o r _ C C   h i g h _ J J   p a i n _ N N 1   s e n s i t i v i t y _ N N 1   ( _ (   s e e _ V V 0   t h e _ A T   S u b g r o u p i n g _ N N 1   o f _ I O   p a t i e n t s _ N N 2   s e c t i o n _ N N 1   ) _ )   . _ .   
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 T w o _ M C   f u r t h e r _ R R R   r a n d o m i s e d _ J J   t r i a l s _ N N 2   i n _ I I   r e c u r r e n t _ J J   o v a r i a n _ J J   c a n c e r _ N N 1   h a v e _ V H 0   s h o w n _ V V N   s i g n i f i c a n t _ J J   i m p r o v e m e n t _ N N 1   i n _ I I   p r o g r e s s i o n - f r e e _ J J   s u r v i v a l _ N N 1   t h r o u g h _ I I   t h e _ A T   a d d i t i o n _ N N 1   o f _ I O   b e v a c i z u m a b _ N N 1   t o _ I I   c o n v e n t i o n a l l y _ R R   a d m i n i s t e r e d _ V V N   c a r b o p l a t i n _ N N 1   a n d _ C C   g e m c i t a b i n e _ V V 0   c h e m o t h e r a p y _ N N 1   b o t h _ R R   i n _ I I   t h e _ A T   p l a t i n u m - s e n s i t i v e _ J J   a n d _ C C   p l a t i n u m - r e s i s t a n t _ J J   r e l a p s e d _ J J   s e t t i n g . 7 , 8 _ F O   T h e s e _ D D 2   d a t a _ N N   w e r e _ V B D R   u s e d _ V V N   t o _ T O   s u p p o r t _ V V I   b e v a c i z u m a b _ N N 1   l i c e n s i n g _ V V G   t h r o u g h _ I I   t h e _ A T   E u r o p e a n _ J J   M e d i c i n e s _ N N 2   A g e n c y _ N N 1   f o r _ I F   u s e _ N N 1   i n _ I I   t h e _ A T   f i r s t - l i n e _ J J   s e t t i n g _ N N 1   f o r _ I F   p a t i e n t s _ N N 2   w i t h _ I W   a t _ R R 2 1   l e a s t _ R R 2 2   I n t e r n a t i o n a l _ J J   F e d e r a t i o n _ N N 1   o f _ I O   G y n e c o l o g y _ N P 1   a n d _ C C   O b s t e t r i c s _ N N 1   ( _ (   F I G O _ N P 1   ) _ )   s t a g e _ N N 1   I I I B _ N N 1   d i s e a s e _ N N 1   ( _ (   a c c o r d i n g _ I I 2 1   t o _ I I 2 2   1 9 8 8 _ M C   s t a g i n g _ N N 1   c r i t e r i a _ N N 2   ) _ )   , _ ,   a t _ R R 2 1   f i r s t _ R R 2 2   r e c u r r e n c e _ N N 1   f o r _ I F   p a t i e n t s _ N N 2   w i t h _ I W   p l a t i n u m - s e n s i t i v e _ J J   d i s e a s e _ N N 1   n o t _ X X   p r e v i o u s l y _ R R   t r e a t e d _ V V N   w i t h _ I W   b e v a c i z u m a b _ N N 1   o r _ C C   o t h e r _ J J   V E G F - t a r g e t e d _ J J   d r u g s _ N N 2   , _ ,   a n d _ C C   i n _ I I   t h e _ A T   s e t t i n g _ N N 1   o f _ I O   p l a t i n u m - r e s i s t a n t _ J J   r e c u r r e n c e _ N N 1   c o m b i n e d _ V V N   w i t h _ I W   p a c l i t a x e l _ N N 1   , _ ,   t o p o t e c a n _ N N 1   , _ ,   o r _ C C   p e g y l a t e d _ V V D   l i p o s o m a l _ J J   d o x o r u b i c i n . 9 _ F O   B e v a c i z u m a b _ N P 1   h a s _ V H Z   a l s o _ R R   b e e n _ V B N   a p p r o v e d _ V V N   i n _ I I   t h e _ A T   p l a t i n u m - r e f r a c t o r y _ J J   s e t t i n g _ N N 1   b y _ I I   t h e _ A T   U S _ N P 1   F o o d _ N N 1   a n d _ C C   D r u g _ N N 1   A d m i n i s t r a t i o n _ N N 1   . _ .   
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 I t _ P P H 1   i s _ V B Z   m o r e _ R G R   d u r a b l e _ J J   t h a n _ C S N   f o a m s _ N N 2   a n d _ C C   g e l s _ N N 2   w i t h _ I W   h i g h e r _ J J R   s h o c k _ N N 1   a t t e n u a t i o n _ N N 1   . _ .   
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 W e _ P P I S 2   f o u n d _ V V D   t h a t _ C S T   f e t a l _ J J   s i d e _ N N 1   p l a c e n t a l _ J J   i n f l a m m a t i o n - n o t _ X X   H C A - w a s _ V B D Z   a s s o c i a t e d _ V V N   w i t h _ I W   a d v e r s e _ J J   n e u r o l o g i c a l _ J J   o u t c o m e _ N N 1   a t _ I I   6 _ M C   m o n t h s _ N N T 2   , _ ,   s i m i l a r _ J J   t o _ I I   f i n d i n g s _ N N 2   d e s c r i b e d _ V V N   b y _ I I   R e d l i n e _ N P 1   e t _ R A 2 1   a l _ R A 2 2   i n _ I I   a n _ A T 1   e x t r e m e l y _ R R   l o w - b i r t h w e i g h t _ J J   p o p u l a t i o n _ N N 1   . _ .   
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 P e r c u t a n e o u s _ J J   h i s t o l o g i c _ J J   a d e n o c a r c i n o m a _ N N 1   ( _ (   w e l l _ R R   d i f f e r e n t i a t e d _ V V N   , _ ,   G 1 _ F O   ; _ ;   m o d e r a t e l y _ R R   d i f f e r e n t i a t e d _ V V N   , _ ,   G 2 _ F O   ; _ ;   p o o r l y _ R R   d i f f e r e n t i a t e d _ V V N   a d e n o c a r c i n o m a _ N N 1   , _ ,   G 3 _ F O   ) _ )   o r _ C C   b i l i a r y _ J J   c y t o l o g i c _ J J   a d e n o c a r c i n o m a _ N N 1   w a s _ V B D Z   e v a l u a t e d _ V V N   . _ .   
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 S p e c i m e n s _ N N 2   w e r e _ V B D R   c e n t r i f u g e d _ V V N   a t _ I I   3 0 0 0 _ M C   x g _ N N U   d u r i n g _ I I   1 5 _ M C   m i n _ N N U   t o _ T O   o b t a i n _ V V I   p l a t e l e t _ N N 1   p o o r _ J J   p l a s m a _ N N 1   , _ ,   w h i c h _ D D Q   w a s _ V B D Z   a l i q u o t e d _ V V N   a n d _ C C   s t o r e d _ V V N   a t _ I I   ' _ N U L L   7 0 _ M C   C . _ N P 1   A d d i t i o n a l _ J J   v a l i d a t i o n _ N N 1   m i g h t _ V M   e l i m i n a t e _ V V I   s o m e _ D D   c a n d i d a t e _ N N 1   t r a n s c r i p t s _ N N 2   a n d _ C C   i t _ P P H 1   s h o u l d _ V M   a l l o w _ V V I   f u t u r e _ J J   d i a g n o s t i c _ J J   d i s t i n c t i o n s _ N N 2   o n _ I I   t h e _ A T   b a s i s _ N N 1   o f _ I O   a _ A T 1   m u c h _ R R   s m a l l e r _ J J R   s e t _ N N 1   o f _ I O   t r a n s c r i p t s _ N N 2   . _ .   
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 S c o r i n g _ V V G   B e f o r e _ I I   s c o r i n g _ V V G   a _ A T 1   p a t i e n t - p a r t i c i p a n t _ J J   ' _ N U L L   s _ Z Z 1   r e s p o n s e s _ N N 2   f o r _ I F   a _ A T 1   p a r t i c u l a r _ J J   e n c o u n t e r _ N N 1   , _ ,   t h e _ A T   r e c o r d i n g _ N N 1   o f _ I O   t h a t _ D D 1   e n c o u n t e r _ N N 1   w a s _ V B D Z   e x a m i n e d _ V V N   i n _ B C L 2 1   o r d e r _ B C L 2 2   t o _ T O   d e t e r m i n e _ V V I   w h i c h _ D D Q   o f _ I O   t h e _ A T   k e y _ J J   i t e m s _ N N 2   t h e _ A T   p h y s i c i a n _ N N 1   h a d _ V H D   c o v e r e d _ V V N   . _ .   
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 F o r _ I F   p a r t i c i p a n t s _ N N 2   w i t h _ I W   o u t s t a n d i n g _ J J   a s s e s s m e n t _ N N 1   s e s s i o n s _ N N T 2   a t _ I I   s t u d y _ N N 1   c o m p l e t i o n _ N N 1   ( _ (   n = 8 _ F O   ) _ )   , _ ,   a l l _ D B   a v a i l a b l e _ J J   d a t a _ N N   w a s _ V B D Z   i n c l u d e d _ V V N   . _ .   
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 P a t i e n t s _ N N 2   w h o _ P N Q S   d i d _ V D D   n o t _ X X   c o m p l e t e _ V V I   t h e _ A T   2 - y e a r _ J J   f o l l o w - u p _ N N 1   w e r e _ V B D R   c e n s o r e d _ V V N   a t _ I I   d r o p _ N N 1   o u t _ R P   . _ .   
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 T a b l e _ N N 1   4 _ M C   ( _ (   a v a i l a b l e _ J J   a t _ I I   w w w . a a o j o u r n a l . o r g _ N N U   ) _ )   s h o w s _ V V Z   i n t r a o c u l a r _ J J   p r e s s u r e _ N N 1   a n d _ C C   v i s u a l _ J J   f i e l d _ N N 1   m e a n _ J J   d e v i a t i o n _ N N 1   a c c o r d i n g _ I I 2 1   t o _ I I 2 2   d i a g n o s i s _ N N 1   . _ .   
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 O n c e _ C S   t h e _ A T   t u m o r s _ N N 2   r e a c h e d _ V V D   a _ A T 1   m e d i a n _ J J   t u m o r _ N N 1   v o l u m e _ N N 1   o f _ I O   2 3 0 2 4 0 _ M C   m m 3 _ F O   , _ ,   P D X - b e a r i n g _ J J   m i c e _ N N 2   w e r e _ V B D R   r a n d o m i z e d _ V V N   i n t o _ I I   s t a t i s t i c a l l y _ R R   i d e n t i c a l _ J J   c o h o r t s _ N N 2   ( _ (   1 0 _ M C   m i c e / g r o u p _ F U   ) _ )   a n d _ C C   t r e a t e d _ V V N   c o n t i n u o u s l y _ R R   w i t h _ I W   1 0 0 _ M C   m g / k g _ N N U   o n c e _ R R   d a i l y _ J J   o f _ I O   A B T - 1 9 9 _ M C   ; _ ;   3 0 _ M C   m g / k g _ N N U   o n c e _ R R   d a i l y _ J J   o f _ I O   M L N 8 2 3 7 _ F O   f o r _ I F   1 _ M C 1   w e e k _ N N T 1   , _ ,   f o l l o w e d _ V V N   b y _ I I   2 _ M C   w e e k s _ N N T 2   w i t h o u t _ I W   t r e a t m e n t _ N N 1   a n d _ C C   t h e _ A T   c y c l e _ N N 1   r e s u m e d _ V V N   o n _ I I   w e e k _ N N T 1   4 _ M C   ; _ ;   t h e _ A T   c o m b i n a t i o n _ N N 1   o f _ I O   A B T - 1 9 9 _ M C   1 0 0 _ M C   m g / k g _ N N U   o n c e _ R R   d a i l y _ R R   b e i n g _ V B G   g i v e n _ V V N   c o n t i n u o u s l y _ R R   w i t h _ I W   t h e _ A T   M L N 8 2 3 7 _ F O   3 0 _ M C   m g / k g _ N N U   o n c e _ R R   d a i l y _ R R   d o s e d _ V V N   f o r _ I F   1 _ M C 1   w e e k _ N N T 1   w i t h _ I W   2 _ M C   w e e k s _ N N T 2   b r e a k _ N N 1   ; _ ;   a p p r o p r i a t e _ J J   v e h i c l e _ N N 1   c o n t r o l _ N N 1   o f _ I O   6 0 % _ N N U   P h o s a l 5 0 _ F O   , _ ,   3 0 % _ N N U   P E G 4 0 0 _ F O   , _ ,   1 0 % _ N N U   E t O H _ N N 1   a s _ C S A   A B T - 1 9 9 _ M C   v e h i c l e _ N N 1   a n d _ C C   1 0 % _ N N U   , _ ,   1 % _ N N U   N a _ F O   b u t y r a t e _ N N 1   a s _ C S A   v e h i c l e _ N N 1   f o r _ I F   M L N 8 2 3 7 _ F O   b y _ I I   o r a l _ J J   g a v a g e _ N N 1   i n _ I I   1 0 0 _ M C   m l / 1 0 _ F U   g _ N N U   o f _ I O   b o d y _ N N 1   w e i g h t _ N N 1   . _ .   
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 A s _ I I   a _ A T 1   r e s u l t _ N N 1   , _ ,   r e - e x p r e s s i o n _ N N 1   o f _ I O   K D M 4 C _ F O   w a s _ V B D Z   a b l e _ J K   t o _ T O   r e s c u e _ V V I   t h e _ A T   t r a n s f o r m a t i o n _ N N 1   d e f e c t s _ N N 2   a s s o c i a t e d _ V V N   K d m 4 c _ F O   s h R N A s _ N N 2   ( _ (   F i g u r e _ N N 1   S 5 D _ F O   ) _ )   . _ .   
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 B o n u s _ N N 1   p r o g r a m s _ N N 2   i n _ I I   w h i c h _ D D Q   p a t i e n t s _ N N 2   r e c e i v e _ V V 0   i n c e n t i v e s _ N N 2   i f _ C S   t h e y _ P P H S 2   r e c e i v e _ V V 0   c a r e _ N N 1   f r o m _ I I   l e s s _ R G R   e x p e n s i v e _ J J   c l i n i c i a n s _ N N 2   o r _ C C   f a c i l i t i e s _ N N 2   m a y _ V M   a l s o _ R R   i n c r e a s e _ V V I   p a t i e n t _ J J   i n t e r e s t _ N N 1   i n _ I I   p r i c e _ N N 1   d a t a _ N N   . _ .   
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 A _ A T 1   m e a s u r e m e n t _ N N 1   a s _ C S A   o b t a i n e d _ V V N   w i t h _ I W   t h i s _ D D 1   a p p r o a c h _ N N 1   i s _ V B Z   p r e s e n t e d _ V V N   i n _ I I   F i g . _ N N 1   1 5 _ M C   . _ .   
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 W e _ P P I S 2   u s e d _ V V D   R _ N P 1   v e r s i o n _ N N 1   3 . 0 . 2 _ M C   f o r _ I F   G r a y _ N P 1   ' _ N U L L   s _ Z Z 1   t e s t _ N N 1   a n d _ C C   I n t e r c o o l e d _ J J   S t a t a _ N N 1   v e r s i o n _ N N 1   1 2 . 1 _ M C   f o r _ I F   a l l _ D B   o t h e r _ J J   a n a l y s e s _ N N 2   . _ .   
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 A m o n g _ I I   t h e _ A T   m a n y _ D A 2   m o l e c u l e s _ N N 2   p r o b e d _ V V N   f o r _ I F   r e t i n a l _ J J   r e p a i r _ N N 1   , _ ,   w e _ P P I S 2   s e l e c t e d _ V V D   t r e a t m e n t s _ N N 2   ( _ (   d e e m e d _ V V N   a s _ C S A   h a v i n g _ V H G   a _ A T 1   s t r o n g _ J J   r a t i o n a l e _ N N 1   ) _ )   d e s i g n e d _ V V D   f o r _ I F   i n c r e a s i n g _ J J   n e u r o p r o t e c t i o n _ N N 1   , _ ,   o r _ C C   d e c r e a s i n g _ J J   c e l l u l a r _ J J   o x i d a t i v e _ J J   s t r e s s _ N N 1   , _ ,   o r _ C C   i n h i b i t i n g _ V V G   p h o t o r e c e p t o r _ N N 1   a p o p t o s i s _ N N 1   , _ ,   o r _ C C   a t t e n u a t i n g _ V V G   r e t i n a l _ J J   i n f l a m m a t i o n _ N N 1   . _ .   
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 C o n c u s s i o n s _ N N 2   w i l l _ V M   n e v e r _ R R   b e _ V B I   e l i m i n a t e d _ V V N   f r o m _ I I   s p o r t s _ N N 2   . _ .   
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 M o r e o v e r _ R R   , _ ,   c o m p r e h e n s i v e _ J J   l i v e r _ N N 1   f u n c t i o n _ N N 1   c a n _ V M   b e _ V B I   a s s e s s e d _ V V N   b y _ I I   a _ A T 1   b l o o d _ N N 1   t e s t _ N N 1   , _ ,   b u t _ C C B   t h i s _ D D 1   c a n _ V M   n o t _ X X   a s s e s s _ V V I   t h e _ A T   f u n c t i o n _ N N 1   o f l i v e r _ N N 1   s e g m e n t s _ N N 2   o r _ C C   s u b - s e g m e n t s _ N N 2   . _ .   
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 O f _ I O   t h e _ A T   5 7 0 _ M C   f e t u s e s _ N N 2   , _ ,   3 6 9 _ M C   ( _ (   6 5 % _ N N U   ) _ )   w e r e _ V B D R   i n _ I I   t h e _ A T   1 8 _ M C   w e e k s _ N N T 2   t o _ I I   l e s s _ D A R   t h a n _ C S N   2 4 _ M C   w e e k s _ N N T 2   g r o u p _ N N 1   ( _ (   1 1 0 % _ N N U   o f _ I O   r e q u i r e d _ J J   ) _ )   a n d _ C C   2 0 1 _ M C   ( _ (   3 5 % _ N N U   ) _ )   i n _ I I   t h e _ A T   2 4 _ M C   w e e k s _ N N T 2   a n d _ C C   o l d e r _ J J R   g r o u p _ N N 1   ( _ (   1 2 0 % _ N N U   o f _ I O   r e q u i r e d _ J J   ) _ )   . _ .   
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 A l l _ D B   p a t i e n t s _ N N 2   h a v e _ V H 0   h a d _ V H N   a _ A T 1   h i s t o r y _ N N 1   o f _ I O   e p i t h e l i a l _ J J   h e r p e t i c _ J J   k e r a t i t i s _ N N 1   w i t h _ I W   n o _ A T   s t r o m a l _ J J   i n v o l v e m e n t _ N N 1   . _ .   
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 N o n e _ P N   o f _ I O   t h e _ A T   s t u d i e s _ N N 2   d e a l i n g _ V V G   w i t h _ I W   m e a s u r e m e n t _ N N 1   e r r o r _ N N 1   d e f i n e d _ V V D   a _ A T 1   m i n i m a l _ J J   i m p o r t a n t _ J J   c h a n g e _ N N 1   . _ .   
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 T h e _ A T   T G F B R 1 _ F O   i n h i b i t o r _ N N 1   , _ ,   S D 2 0 8 _ F O   , _ ,   p r e v e n t e d _ V V D   p r o m o t e r _ N N 1   a c t i v a t i o n _ N N 1   b y _ I I   T G F - p _ N N U   ( _ (   F i g u r e _ N N 1   4 C _ F O   ) _ )   . _ .   
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 F u r t h e r m o r e _ R R   , _ ,   d i s t i n g u i s h e d _ J J   a u t h o r s _ N N 2   f r o m _ I I   t h i s _ D D 1   r e s e a r c h _ N N 1   a r e a _ N N 1   w e r e _ V B D R   c o n t a c t e d _ V V N   t h r o u g h _ I I   e m a i l _ N N 1   f o r _ I F   a n y _ D D   m i s s e d _ J J   a n d _ C C   r e l e v a n t _ J J   s t u d i e s _ N N 2   . _ .   
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 T h i s _ D D 1   s t u d y _ N N 1   w a s _ V B D Z   s u p p o r t e d _ V V N   b y _ I I   t h e _ A T   I n s t i t u t e _ N N 1   f o r _ I F   C l i n i c a l _ J J   E v a l u a t i v e _ J J   S c i e n c e s _ N N 2   ( _ (   I C E S _ N N 2   ) _ )   , _ ,   w h i c h _ D D Q   i s _ V B Z   f u n d e d _ V V N   b y _ I I   a n _ A T 1   a n n u a l _ J J   g r a n t _ N N 1   f r o m _ I I   t h e _ A T   O n t a r i o _ N P 1   M i n i s t r y _ N N 1   o f _ I O   H e a l t h _ N N 1   a n d _ C C   L o n g - T e r m _ J J   C a r e _ N N 1   ( _ (   M O H L T C _ N P 1   ) _ )   . _ .   
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 H o w e v e r _ R R   , _ ,   d e s p i t e _ I I   t h e s e _ D D 2   l i m i t a t i o n s _ N N 2   , _ ,   s i g n i f i c a n t _ J J   b e t w e e n - g r o u p _ J J   d i f f e r e n c e s _ N N 2   w e r e _ V B D R   f o u n d _ V V N   i n _ I I   t h e _ A T   p r i m a r y _ J J   o u t c o m e _ N N 1   m e a s u r e _ N N 1   . _ .   
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 F o r _ I F   t h e _ A T   c o n d i t i o n _ N N 1   t o _ T O   b e _ V B I   c o n s i d e r e d _ V V N   ' _ N U L L   a c u t e _ J J   , _ ,   ' _ N U L L   t h e r e _ E X   h a d _ V H D   t o _ T O   b e _ V B I   a _ A T 1   s u d d e n _ J J   i n w a r d _ J J   d e v i a t i o n _ N N 1   o f _ I O   t h e _ A T   e y e s _ N N 2   a s _ C S A   n o t e d _ V V N   b y _ I I   t h e _ A T   p a t i e n t _ N N 1   ( _ (   b y _ I I   t h e _ A T   o n s e t _ N N 1   o f _ I O   d i p l o p i a _ N N 1   ) _ )   o r _ C C   b y _ I I   a _ A T 1   c a r e g i v e r _ N N 1   o b s e r v i n g _ V V G   a _ A T 1   s u d d e n _ J J   a n d _ C C   d r a m a t i c _ J J   c h a n g e _ N N 1   i n _ I I   e y e _ N N 1   a l i g n m e n t _ N N 1   . _ .   
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 T h e _ A T   U P S I T _ N N 1   w a s _ V B D Z   a d m i n i s t e r e d _ V V N   e v e r y _ A T 1   8 _ M C   w e e k s _ N N T 2   ; _ ;   s c o r e s _ N N 2   r a n g e _ V V 0   f r o m _ I I   0 _ M C   t o _ I I   4 0 _ M C   ( _ (   h i g h e r _ J J R   s c o r e s _ N N 2   o f _ I O   3 5 - 4 0 _ M C M C   i n d i c a t e _ V V 0   n o r m a l _ J J   s e n s e _ N N 1   o f _ I O   s m e l l _ N N 1   a n d _ C C   l o w e r _ J J R   s c o r e s _ N N 2   o f _ I O   0 - 1 8 _ M C M C   i n d i c a t e _ V V 0   a n o s m i a _ N N 1   ) _ )   . _ .   
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 F i n a l l y _ R R   , _ ,   o u r _ A P P G E   r e s u l t s _ N N 2   , _ ,   o b t a i n e d _ V V D   m a i n l y _ R R   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   C h i l d - P u g h _ N P 1   c l a s s _ N N 1   A _ Z Z 1   c i r r h o s i s _ N N 1   , _ ,   m a y _ V M   n o t _ X X   b e _ V B I   g e n e r a l i z e d _ V V N   t o _ I I   t h o s e _ D D 2   w i t h _ I W   a d v a n c e d _ J J   c i r r h o s i s _ N N 1   . _ .   
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 O t h e r _ J J   v a r i a b l e s _ N N 2   i n c l u d e d _ V V D   w h e t h e r _ C S W   r e s p o n d e n t s _ N N 2   h a d _ V H D   r e p o r t e d _ V V N   a n y _ D D   t y p e _ N N 1   o f _ I O   e m p l o y m e n t _ N N 1   o u t s i d e _ I I   t h e _ A T   h o m e _ N N 1   i n _ I I   t h e _ A T   w e e k _ N N T 1   p r i o r _ I I 2 1   t o _ I I 2 2   c o m p l e t i n g _ V V G   t h e _ A T   s u r v e y _ N N 1   , _ ,   t h e _ A T   n u m b e r _ N N 1   o f _ I O   l i v e _ J J   d e l i v e r i e s _ N N 2   t h e y _ P P H S 2   h a d _ V H D   e x p e r i e n c e d _ V V N   , _ ,   a n d _ C C   w h e t h e r _ C S W   t h e y _ P P H S 2   r e p o r t e d _ V V D   h a v i n g _ V H G   h e a l t h _ N N 1   i n s u r a n c e _ N N 1   . _ .   
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 T h e _ A T   m e a n _ J J   t o t a l _ J J   V o i S S _ N N 1   ( _ (   m a x i m u m _ J J   s c o r e _ N N 1   1 2 0 _ M C   ) _ )   f o r _ I F   a l l _ D B   p a t i e n t s _ N N 2   w a s _ V B D Z   3 9 . 7 _ M C   ( _ (   S D _ N P 1   2 2 . 2 _ M C   ) _ )   . _ .   
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 S i m i l a r l y _ R R   , _ ,   i n _ I I   a c n e _ N N 1   a _ A T 1   r e c e n t _ J J   e y e - t r a c k i n g _ J J   s t u d y _ N N 1   d e m o n s t r a t e d _ V V D   t h a t _ C S T   p a r t i c i p a n t s _ N N 2   e x h i b i t e d _ V V D   a n _ A T 1   a t t e n t i o n a l _ J J   b i a s _ N N 1   t o w a r d s _ I I   a c n e _ N N 1   l e s i o n s _ N N 2   i n _ I I 3 1   c o m p a r i s o n _ I I 3 2   w i t h _ I I 3 3   c o n t r o l s _ N N 2   . _ .   
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 I n _ I I 3 1   v i e w _ I I 3 2   o f _ I I 3 3   t h e _ A T   e x t e n t _ N N 1   o f _ I O   l i n k a g e _ N N 1   d i s e q u i l i b r i u m _ N N 1   b e t w e e n _ I I   t h e _ A T   v a r i a n t s _ N N 2   a s s o c i a t e d _ V V N   w i t h _ I W   a l l _ D B   e p i l e p s y _ N N 1   i n _ I I   t h e _ A T   2 q 2 4 . 3 _ F O   r e g i o n _ N N 1   ( _ (   f i g u r e _ N N 1   2 _ M C   ) _ )   , _ ,   w e _ P P I S 2   d i d _ V D D   l o g i s t i c _ J J   r e g r e s s i o n _ N N 1   c o n d i t i o n e d _ V V N   o n _ I I   t h e _ A T   m o s t _ R G T   s i g n i f i c a n t _ J J   v a r i a n t _ N N 1   i d e n t i f i e d _ V V N   f r o m _ I I   t h e _ A T   u n i v a r i a t e _ N N 1   a n a l y s i s _ N N 1   ( _ (   r s 6 7 3 2 6 5 5 _ F O   ) _ )   . _ .   
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 A S B _ N P 1   a c t i v i t y _ N N 1   r e m a i n e d _ V V D   s t a b l e _ J J   i n _ I I   a l l _ D B   a n a l y s e s _ N N 2   , _ ,   i . e . _ R E X   , _ ,   f o r _ I F   6 0 _ M C   d a y s _ N N T 2   , _ ,   a s _ C S A   s h o w n _ V V N   b y _ I I   C a s t i l h o s _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . . _ . . .   
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 S p e c t r a l _ J J   I m a g i n g _ N N 1   C o n f o c a l _ J J   M i c r o s c o p e _ N N 1   S y s t e m _ N N 1   a t _ I I   t h e _ A T   N i k o n _ N N 1   I m a g i n g _ N N 1   C e n t e r _ N N 1   a n d _ C C   C e l l _ N N 1   I m a g i n g _ N N 1   F a c i l i t y _ N N 1   a t _ I I   N o r t h w e s t e r n _ J J   U n i v e r s i t y _ N N 1   . _ .   
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 S t a t i s t i c a l _ J J   A n a l y s i s _ N N 1   P r e o p e r a t i v e _ J J   p a t i e n t _ J J   c h a r a c t e r i s t i c s _ N N 2   w e r e _ V B D R   s u m m a r i z e d _ V V N   u s i n g _ V V G   c o u n t s _ N N 2   a n d _ C C   p r o p o r t i o n s _ N N 2   f o r _ I F   c a t e g o r i c a l _ J J   v a r i a b l e s _ N N 2   a n d _ C C   m e d i a n _ J J   a n d _ C C   i n t e r q u a r t i l e _ J J   r a n g e _ N N 1   f o r _ I F   c o n t i n u o u s _ J J   v a r i a b l e s _ N N 2   . _ .   
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 T h e _ A T   u s e _ N N 1   o f _ I O   h e a l t h y _ J J   c o n t r o l s _ N N 2   f o r _ I F   g e n e t i c _ J J   a s s o c i a t i o n _ N N 1   a t _ I I   t h e _ A T   l e v e l _ N N 1   o f _ I O   b r a i n _ N N 1   f u n c t i o n _ N N 1   a v o i d s _ V V Z   p o t e n t i a l _ J J   c o n f o u n d e r s _ N N 2   r e l a t e d _ V V N   t o _ I I   c h r o n i c _ J J   i l l n e s s _ N N 1   a n d _ C C   m e d i c a l _ J J   t r e a t m e n t _ N N 1   . _ .   
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 T h e _ A T   m a i n _ J J   h y p o t h e s i s _ N N 1   w a s _ V B D Z   t h a t _ C S T   t h e _ A T   V N S _ N P 1   w o u l d _ V M   b e _ V B I   a _ A T 1   b e t t e r _ J J R   a n d _ C C   m o r e _ R G R   c o n s i s t e n t _ J J   i n d i c a t o r _ N N 1   o f _ I O   t r e a t m e n t _ N N 1   s u c c e s s _ N N 1   t h a n _ C S N   p e r c e n t a g e _ N N 1   r e p i g m e n t a t i o n _ N N 1   . _ .   
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 S e v e r a l _ D A 2   a p p r o a c h e s _ N N 2   t o _ I I   v a c c i n e _ N N 1   d e v e l o p m e n t _ N N 1   a r e _ V B R   b e i n g _ V B G   i n v e s t i g a t e d . 6 8 _ F O   A _ Z Z 1   l i v e _ J J   a t t e n u a t e d _ J J   v a c c i n e _ N N 1   f o r _ I F   i n t r a n a s a l _ J J   a d m i n i s t r a t i o n _ N N 1   w o u l d _ V M   s t i m u l a t e _ V V I   b o t h _ R R   t o p i c a l _ J J   a n d _ C C   s y s t e m i c _ J J   i m m u n i t y _ N N 1   ; _ ;   s u c h _ D A   a _ A T 1   v a c c i n e _ N N 1   i s _ V B Z   b e i n g _ V B G   d e v e l o p e d _ V V N   w i t h _ I W   t h e _ A T   u s e _ N N 1   o f _ I O   r e v e r s e _ J J   g e n e t i c s _ N N 1   t o _ T O   m o d i f y _ V V I   s p e c i f i c _ J J   g e n e s _ N N 2   . _ .   
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 T h u s _ R R   , _ ,   f o r _ R E X 2 1   e x a m p l e _ R E X 2 2   , _ ,   t h e _ A T   m i n o r _ J J   a l l e l e _ N N 1   o f _ I O   t h e _ A T   S N P _ N P 1   r s 1 3 7 0 2 _ F O   i n _ I I   t h e _ A T   l i p o p r o t e i n _ N N 1   l i p a s e _ N N 1   ( _ (   L P L _ N P 1   ) _ )   3 U T R _ F O   g e n e _ N N 1   d i s r u p t s _ V V Z   a n _ A T 1   m i R N A _ N N 1   r e c o g n i t i o n _ N N 1   e l e m e n t _ N N 1   s e e d _ N N 1   s i t e _ N N 1   f o r _ I F   t h e _ A T   h u m a n _ N N 1   m i R N A - 4 1 0 _ M C   , _ ,   r e s u l t i n g _ V V G   i n _ I I   a _ A T 1   g a i n - o f - f u n c t i o n _ N N 1   a n d _ C C   l o w e r _ J J R   p l a s m a _ N N 1   t r i g l y c e r i d e s _ N N 2   a n d _ C C   i n t e r a c t i o n s _ N N 2   w i t h _ I W   P U F A _ N P 1   i n t a k e _ N N 1   i n _ I I   d e t e r m i n i n g _ J J   p l a s m a _ N N 1   t r i g l y c e r i d e s _ N N 2   ( _ (   R i c h a r d s o n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 3 _ M C   ) _ )   . _ .   
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 S o c i o d e m o g r a p h i c _ J J   a n d _ C C   P s y c h i a t r i c _ J J   C o v a r i a t e s _ N N 2   W e _ P P I S 2   u s e d _ V V D   m e a n _ J J   l i f e t i m e _ N N T 1   d i s p o s a b l e _ J J   i n c o m e _ N N 1   ( _ (   d i v i d e d _ V V N   i n t o _ I I   t h i r d s _ M F   ) _ )   , _ ,   d i c h o t o m i z e d _ V V D   i n t o _ I I   l o w e s t _ J J T   t e r t i l e _ J J   v s _ I I   t o p _ N N 1   2 _ M C   t e r t i l e s _ N N 2   . _ .   
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 A l s o _ R R   , _ ,   t h e _ A T   a u t h o r s _ N N 2   d e s c r i b e d _ V V D   t h a t _ C S T   a _ A T 1   p a n e l _ N N 1   i n c l u d i n g _ I I   m i R - 1 4 1 _ M C   , _ ,   1 5 1 - 3 p _ N N U   , _ ,   1 5 2 _ M C   a n d _ C C   4 2 3 - 3 p _ N N U   w a s _ V B D Z   a s s o c i a t e d _ V V N   w i t h _ I W   a _ A T 1   p o o r e r _ J J R   o u t c o m e _ N N 1   a n d / o r _ C C   a _ A T 1   h i g h e r _ J J R   G l e a s o n _ N N 1   s c o r e _ N N 1   . _ .   
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 T h e r e _ E X   i s _ V B Z   a n _ A T 1   e m e r g i n g _ J J   c o n s e n s u s _ N N 1   t h a t _ C S T   d e p r e s s i o n _ N N 1   i s _ V B Z   c h a r a c t e r i z e d _ V V N   b y _ I I   a _ A T 1   f u n d a m e n t a l _ J J   m o o d - c o n g r u e n t _ J J   p r o c e s s i n g _ N N 1   b i a s _ N N 1   ; _ ;   t h a t _ R E X 2 1   i s _ R E X 2 2   , _ ,   a _ A T 1   g r e a t e r _ J J R   s e n s i t i v i t y _ N N 1   t o _ I I   p u n i s h m e n t _ N N 1   a n d _ C C   a n _ A T 1   i m p a i r e d _ J J   h e d o n i c _ J J   c a p a c i t y _ N N 1   . _ .   
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 A l t h o u g h _ C S   e a r l y _ R R   n e u r o d e v e l o p m e n t a l _ J J   a s s e s s m e n t _ N N 1   i s _ V B Z   i m p o r t a n t _ J J   f o r _ I F   t h e _ A T   t i m e l y _ J J   i d e n t i f i c a t i o n _ N N 1   o f _ I O   c h i l d r e n _ N N 2   a t _ I I   r i s k _ N N 1   f o r _ I F   l o n g - t e r m _ J J   n e u r o l o g i c _ J J   i m p a i r m e n t _ N N 1   o r _ C C   d e v e l o p m e n t a l _ J J   d e l a y _ N N 1   , _ ,   i t s _ A P P G E   c a p a c i t y _ N N 1   t o _ T O   p r e d i c t _ V V I   l a t e r _ J J R   f u n c t i o n i n g _ N N 1   i s _ V B Z   l i m i t e d . 3 5 - 3 7 _ M C   M a n y _ D A 2   c h i l d r e n _ N N 2   w i l l _ V M   c a t c h _ V V I   u p _ I I 2 1   t o _ I I 2 2   t h e i r _ A P P G E   p e e r s _ N N 2   b y _ I I   s c h o o l _ N N 1   a g e _ N N 1   , _ ,   w h e r e a s _ C S   o t h e r _ J J   c h i l d r e n _ N N 2   w i l l _ V M   h a v e _ V H I   p e r s i s t e n t _ J J   i m p a i r m e n t _ N N 1   . _ .   
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 N i e v e r g e l t _ V V 0   , _ ,   a n d _ C C   B a k e r _ N P 1   h a d _ V H D   f u l l _ J J   a c c e s s _ N N 1   t o _ I I   a l l _ D B   t h e _ A T   d a t a _ N N   i n _ I I   t h e _ A T   s t u d y _ N N 1   a n d _ C C   t a k e _ V V 0   r e s p o n s i b i l i t y _ N N 1   f o r _ I F   t h e _ A T   i n t e g r i t y _ N N 1   o f _ I O   t h e _ A T   d a t a _ N N   a n d _ C C   t h e _ A T   a c c u r a c y _ N N 1   o f _ I O   t h e _ A T   d a t a _ N N   a n a l y s i s _ N N 1   . _ .   
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 T h e _ A T   r e a s o n _ N N 1   f o r _ I F   t h i s _ D D 1   i m p r o v e m e n t _ N N 1   i s _ V B Z   n o t _ X X   c l e a r _ J J   a n d _ C C   i s _ V B Z   l i k e l y _ J J   t o _ T O   b e _ V B I   p r e d o m i n a n t l y _ R R   d u e _ I I 2 1   t o _ I I 2 2   i m p r o v e d _ J J   o d o r a n t _ J J   d e l i v e r y _ N N 1   t o _ I I   t h e _ A T   o l f a c t o r y _ J J   e p i t h e l i u m _ N N 1   ; _ ;   h o w e v e r _ R R   , _ ,   t h i s _ D D 1   i m p r o v e m e n t _ N N 1   r e m a i n s _ V V Z   c l i n i c a l l y _ R R   i n s i g n i f i c a n t _ J J   . _ .   
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 I n _ I I   t u m o r s _ N N 2   w i t h _ I W   a _ A T 1   2 + _ F O   s c o r e _ N N 1   , _ ,   g e n e _ N N 1   a m p l i f i c a t i o n _ N N 1   b y _ I I   u s i n g _ V V G   f l u o r e s c e n c e _ N N 1   i n _ R R 2 1   s i t u _ R R 2 2   h y b r i d i z a t i o n _ N N 1   w a s _ V B D Z   u s e d _ V V N   t o _ T O   d e t e r m i n e _ V V I   H E R 2 _ F O   s t a t u s _ N N 1   . _ .   
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 T h i s _ D D 1   c o u l d _ V M   r e f i n e _ V V I   o u r _ A P P G E   u n d e r s t a n d i n g _ N N 1   o f _ I O   t h e _ A T   r e l a t i o n s h i p _ N N 1   b e t w e e n _ I I   v a r i a b i l i t y _ N N 1   a n d _ C C   r i s k _ N N 1   b y _ I I   d e t e r m i n i n g _ V V G   t h e _ A T   i m p o r t a n c e _ N N 1   o f _ I O   t h e _ A T   r a t e _ N N 1   a n d _ C C   f r e q u e n c y _ N N 1   o f _ I O   S T _ N P 1   s e g m e n t _ N P 1   c h a n g e s _ N N 2   . _ .   
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 O n l y _ R R   o n e _ M C 1   o f _ I O   t h e _ A T   t h r e e _ M C   p a t i e n t s _ N N 2   w h o _ P N Q S   d i e d _ V V D   o f _ I O   p r o g r e s s i v e _ J J   d i s e a s e _ N N 1   c a r r i e d _ V V D   a _ A T 1   B R A F _ N N 1   m u t a t i o n _ N N 1   . _ .   
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 I C G _ N P 1   h a d _ V H D   b e e n _ V B N   u s e d _ V V N   e x t e n s i v e l y _ R R   f o r _ I F   m e d i c a l _ J J   p u r p o s e s _ N N 2   s i n c e _ I I   1 9 5 7 _ M C   , _ ,   a n d _ C C   , _ ,   c u r r e n t l y _ R R   , _ ,   i t s _ A P P G E   a p p l i c a t i o n _ N N 1   i s _ V B Z   m a i n l y _ R R   i n v o l v e d _ J J   i n _ I I   t h e _ A T   m e a s u r e m e n t _ N N 1   o f _ I O   b l o o d _ N N 1   f l o w _ N N 1   a n d _ C C   i n _ I I   o p h t h a l m o l o g y _ N N 1   f o r _ I F   t h e _ A T   d i a g n o s i s _ N N 1   o f _ I O   a g e - r e l a t e d _ J J   m a c u l a r _ J J   d e g e n e r a t i o n _ N N 1   . _ .   
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 T h e _ A T   c e l l s _ N N 2   a r e _ V B R   o b t a i n e d _ V V N   f r o m _ I I   a _ A T 1   n o n - w e i g h t - b e a r i n g _ J J   r e g i o n _ N N 1   o f _ I O   t h e _ A T   k n e e _ N N 1   a n d _ C C   t h e n _ R T   g r o w n _ V V N   i n _ R R 2 1   v i t r o _ R R 2 2   f o r _ I F   4 _ M C   t o _ I I   6 _ M C   w e e k s _ N N T 2   . _ .   
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 I n _ I I 3 1   t e r m s _ I I 3 2   o f _ I I 3 3   a _ A T 1   ? w h y _ J J   n o t ? _ N N 1   m e n t a l i t y _ N N 1   , _ ,   i n _ I I   s o m e _ D D   i n s t a n c e s _ N N 2   , _ ,   p a r t i c i p a n t s _ N N 2   w e r e _ V B D R   n o t _ X X   a w a r e _ J J   o f _ I O   s p e c i f i c _ J J   b e n e f i t s _ N N 2   o f _ I O   c o u n s e l i n g _ N N 1   , _ ,   a n d _ C C   d i d _ V D D   n o t _ X X   a l w a y s _ R R   h a v e _ V H I   c o n c r e t e _ J J   r e a s o n s _ N N 2   f o r _ I F   p a r t i c i p a t i n g _ V V G   . _ .   
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 T h e _ A T   E E G _ N N 1   w a s _ V B D Z   r e c o r d e d _ V V N   b y _ I I   B r a i n V i s i o n _ N P 1   R e c o r d e r ( C ) _ N P 1   v . 1 . 1 0 _ F O   s o f t w a r e _ N N 1   ( _ (   B r a i n _ N N 1   P r o d u c t s _ N N 2   , _ ,   G e r m a n y _ N P 1   ) _ )   . _ .   
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 A n o t h e r _ D D 1   a d v a n t a g e _ N N 1   o f _ I O   D O C T _ N P 1   r e l a t e s _ V V Z   t o _ I I   i t s _ A P P G E   e a s y _ J J   o p e r a t i o n _ N N 1   a n d _ C C   s h o r t _ J J   m e a - s u r e m e n t _ N N 1   t i m e _ N N T 1   , _ ,   a _ A T 1   f e a t u r e _ N N 1   t h a t _ C S T   w a s _ V B D Z   a l r e a d y _ R R   i m p o r t a n t _ J J   w h e n _ C S   c l a s s i c a l _ J J   O C T _ N P M 1   f o u n d _ V V D   i t s _ A P P G E   w a y _ N N 1   i n t o _ I I   c l i n i c a l _ J J   r o u t i n e _ N N 1   . _ .   
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 W e _ P P I S 2   u s e d _ V V D   t h e _ A T   d a t a _ N N   p u b l i s h e d _ V V N   b y _ I I   E s m a o g l u _ N P 1   a n d _ C C   c o l l e a g u e s _ N N 2   , _ ,   w h o _ P N Q S   s h o w e d _ V V D   p r o l o n g a t i o n _ N N 1   o f _ I O   s e n s o r y _ J J   b l o c k _ N N 1   f r o m _ I I   6 7 0 _ M C   ( _ (   7 0 _ M C   ) _ )   t o _ I I   8 8 0 _ M C   ( _ (   7 0 _ M C   ) _ )   m i n _ N N U   i n _ I I   h u m a n s _ N N 2   r e c e i v i n g _ V V G   a x i l l a r y _ J J   p l e x u s _ N N 1   b l o c k _ N N 1   . _ .   
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 T h e _ A T   n o v e l t y _ N N 1   o f _ I O   t h e _ A T   p r e s e n t _ J J   i n v e s t i g a t i o n _ N N 1   i s _ V B Z   t h a t _ C S T   w e _ P P I S 2   t e s t e d _ V V D   t h e _ A T   e f f e c t s _ N N 2   o f _ I O   c a f f e i n a t e d _ J J   e n e r g y _ N N 1   d r i n k s _ N N 2   o n _ I I   t r a d i t i o n a l _ J J   ( _ (   e . g . _ R E X   , _ ,   s q u a t _ J J   a n d _ C C   c o u n t e r m o v e m e n t _ N N 1   j u m p s _ V V Z   ) _ )   a n d _ C C   v o l l e y b a l l - s p e c i f i c _ J J   j u m p s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   t h e _ A T   b l o c k _ N N 1   j u m p _ N N 1   a n d _ C C   s p i k e _ V V 0   j u m p _ N N 1   . _ .   
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 T h e _ A T   L o B _ N P 1   i s _ V B Z   0 . 0 4 9 2 _ M C   m i u m o l / L _ F U   a n d _ C C   t h e _ A T   d e l t a _ N N 1   p e r c e n t i l e _ N N 1   L o D _ N P 1   i s _ V B Z   0 . 3 4 9 _ M C   m i u m o l / L _ F U   . _ .   
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 A l t h o u g h _ C S   p r e v i o u s _ J J   s t u d i e s _ N N 2   i n c l u d i n g _ I I   t h e _ A T   C o c h r a n e _ N P 1   R e v i e w _ N P 1   h a v e _ V H 0   d e m o n s t r a t e d _ V V N   n o _ A T   b e n e f i t _ N N 1   a n d _ C C   h i g h e r _ J J R   c o s t _ N N 1   t o _ I I   r o b o t i c _ J J   s u r g e r y _ N N 1   c o m p a r e d _ V V N   w i t h _ I W   t r a d i t i o n a l _ J J   l a p a r o s c o p y _ N N 1   , _ ,   m a n y _ D A 2   s t u d i e s _ N N 2   w e r e _ V B D R   l i m i t e d _ V V N   b y _ I I   s m a l l e r _ J J R   s a m p l e s _ N N 2   a n d _ C C   s i n g l e _ J J   h i g h - v o l u m e _ J J   i n s t i t u t i o n s _ N N 2   a n d _ C C   p r i o r _ J J   c o s t _ N N 1   d a t a _ N N   d o _ V D 0   n o t _ X X   a c c o u n t _ V V I   f o r _ I F   t h e _ A T   p o t e n t i a l _ J J   i n c r e a s e d _ J J   m o r b i d i t y _ N N 1   a n d _ C C   c o s t _ N N 1   a s s o c i a t e d _ V V N   w i t h _ I W   c o n v e r s i o n _ N N 1   . _ .   
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 S m a l l _ N P 1   t o _ I I   m e d i u m _ J J   t r e a t m e n t _ N N 1   e f f e c t s _ N N 2   f a v o r i n g _ V V G   r e s p o n s e _ N N 1   t o _ I I   p s y c h o t h e r a p y _ N N 1   w e r e _ V B D R   o b s e r v e d _ V V N   f o r _ I F   p a t i e n t s _ N N 2   w i t h _ I W   o n l y _ R R   o n e _ M C 1   c u r r e n t _ J J   a n x i e t y _ N N 1   d i s o r d e r _ N N 1   ( _ (   n u m b e r _ N N 1   n e e d e d _ V V N   t o _ I I   t r e a t = 4 . 7 6 _ F O   ) _ )   , _ ,   w h e r e a s _ C S   t h e r e _ E X   w a s _ V B D Z   l e s s _ D A R   o f _ I O   a _ A T 1   d i f f e r e n c e _ N N 1   i n _ I I   r e c o v e r y _ N N 1   r a t e s _ N N 2   f o r _ I F   p s y c h o t h e r a p y _ N N 1   c o m p a r e d _ V V N   w i t h _ I W   c o l l a b o r a t i v e _ J J   c a r e _ N N 1   f o r _ I F   i n d i v i d u a l s _ N N 2   w i t h _ I W   t w o _ M C   o r _ C C   m o r e _ R G R   c u r r e n t _ J J   a n x i e t y _ N N 1   d i s o r d e r s _ N N 2   ( _ (   n u m b e r _ N N 1   n e e d e d _ V V N   t o _ I I   t r e a t = 7 . 6 9 _ F O   , _ ,   s m a l l _ J J   t o _ I I   m e d i u m _ J J   e f f e c t _ N N 1   ) _ )   . _ .   
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 T h e _ A T   F r e e S u r f e r _ N N 1   p r o c e s s i n g _ N N 1   p r o t o c o l _ N N 1   a p p l i e d _ V V N   t o _ I I   t h e _ A T   p r e s e n t _ J J   d a t a _ N N   i n c l u d e d _ V V D   t h o r o u g h _ J J   h u m a n _ J J   q u a l i t y _ N N 1   c o n t r o l _ N N 1   ( _ (   Q C _ N N 1   ) _ )   s u p e r v i s i o n _ N N 1   , _ ,   b y _ I I   w h i c h _ D D Q   t h e _ A T   p a r c e l l a t i o n _ N N 1   r e s u l t s _ N N 2   w e r e _ V B D R   d e s i g n a t e d _ V V N   a s _ C S A   p a s s _ N N 1   o r _ C C   f a i l _ V V 0   f o r _ I F   t h e _ A T   h i p p o c a m p u s _ N N 1   ( _ (   h t t p _ N N U   : _ :   ) _ )   . _ .   
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 T h e _ A T   a u t h o r s _ N N 2   i n t e r p r e t e d _ V V D   t h e i r _ A P P G E   f i n d i n g s _ N N 2   a s _ C S A   e v i d e n c e _ N N 1   t h a t _ C S T   t h e _ A T   n e g a t i v e _ J J   e f f e c t s _ N N 2   o f _ I O   d i a b e t e s _ N N 1   o n _ I I   a r t e r i a l _ J J   w a l l _ N N 1   p r o p e r t i e s _ N N 2   i n _ I I   t h e i r _ A P P G E   c o h o r t _ N N 1   w a s _ V B D Z   m o r e _ R G R   e v i d e n t _ J J   i n _ I I   t h e _ A T   l a r g e _ J J   c e n t r a l _ J J   a r t e r i e s _ N N 2   t h a n _ C S N   i n _ I I   t h e _ A T   s m a l l e r _ J J R   p e r i p h e r a l _ J J   a r t e r i e s _ N N 2   . _ .   
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 I t _ P P H 1   i s _ V B Z   t h u s _ R R   e n v i s a g e d _ V V N   t h a t _ C S T   f o c a l _ J J   e l e c t r i c a l _ J J   s t i m u l a t i n g _ J J   p a t t e r n s _ N N 2   w i t h _ I W   a _ A T 1   m u l t i - e l e c t r o d e _ J J   a r r a y _ N N 1   i n _ I I   t h e _ A T   m a c u l a r _ J J   r e g i o n _ N N 1   w o u l d _ V M   m o r e _ R G R   l i k e l y _ R R   m a n i f e s t _ V V I   r e t i n o t o p i c _ J J   c o r r e l a t i o n s _ N N 2   a l o n g _ I I   t h e _ A T   v i s u a l _ J J   p a t h w a y _ N N 1   . _ .   
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 T h e _ A T   s e t t i n g _ N N 1   w a s _ V B D Z   a m o n g _ I I   i n d i v i d u a l s _ N N 2   w i t h _ I W   f a m i l i a l _ J J   P D _ N P 1   e n r o l l e d _ V V D   f r o m _ I I   a c a d e m i c _ J J   m o v e m e n t _ N N 1   d i s o r d e r _ N N 1   s p e c i a l t y _ N N 1   c l i n i c s _ N N 2   a c r o s s _ I I   t h e _ A T   U n i t e d _ N P 1   S t a t e s _ N P 1   . _ .   
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 T h e _ A T   p r i m a r y _ J J   a u d i t o r y _ J J   c o r t e x _ N N 1   h e m o d y n a m i c _ J J   r e s p o n s e s _ N N 2   d u e _ I I 2 1   t o _ I I 2 2   d i f f e r e n t _ J J   t e m p o r a l _ J J   p a t t e r n s _ N N 2   o f _ I O   i m a g i n g _ V V G   r e l a t e d _ J J   a c o u s t i c _ J J   n o i s e _ N N 1   w e r e _ V B D R   c o m p a r e d _ V V N   a c r o s s _ I I   c o n d i t i o n s _ N N 2   a n d _ C C   h e m i s p h e r e s _ N N 2   . _ .   
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 T h e _ A T   H e a l t h _ N N 1   S e r v i c e s _ N N 2   R e s e a r c h _ N N 1   U n i t _ N N 1   i s _ V B Z   c o r e _ N N 1   f u n d e d _ V V N   b y _ I I   t h e _ A T   C h i e f _ J J   S c i e n t i s t _ N N 1   O f f i c e _ N N 1   o f _ I O   t h e _ A T   S c o t t i s h _ J J   G o v e r n m e n t _ N N 1   H e a l t h _ N N 1   a n d _ C C   S o c i a l _ J J   C a r e _ N N 1   D i r e c t o r a t e s _ N N 2   . _ .   
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 B y _ I I   u s i n g _ V V G   t h e s e _ D D 2   r e s e a r c h _ N N 1   v a l u e s _ N N 2   , _ ,   w e _ P P I S 2   c o m p a r e d _ V V D   t h e _ A T   U F - 1 0 0 0 i _ F O   a n d _ C C   t h e _ A T   X N - 1 0 0 0 _ M C   i n _ I I   t h e _ A T   l o w e r _ J J R   c o n c e n t r a t i o n _ N N 1   r a n g e _ N N 1   ( _ (   l e s s _ D A R   t h a n _ C S N   1 0 0 0 _ M C   x _ Z Z 1   1 0 _ M C   6 / L _ M C   ) _ )   . _ .   
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 M e t h o d s _ N N 2   ' _ N U L L   I n _ I I   t h i s _ D D 1   r a n d o m i s e d _ J J   , _ ,   d o u b l e - b l i n d _ J J   , _ ,   p l a c e b o - c o n t r o l l e d _ J J   t r i a l _ N N 1   w e _ P P I S 2   r e c r u i t e d _ V V D   p a r t i c i p a n t s _ N N 2   a g e d _ V V N   3 0 - 8 0 _ M C M C   y e a r s _ N N T 2   w i t h _ I W   p o s s i b l e _ J J   o r _ C C   p r o b a b l e _ J J   m u l t i p l e _ J J   s y s t e m _ N N 1   a t r o p h y _ N N 1   f r o m _ I I   t e n _ M C   U S _ N P 1   m e d i c a l _ J J   c e n t r e s _ N N 2   . _ .   
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 T h e _ A T   r e l a t i o n s h i p _ N N 1   b e t w e e n _ I I   c o g n i t i o n _ N N 1   , _ ,   s t r e s s _ N N 1   , _ ,   g l u c o c o r t i c o i d s _ N N 2   , _ ,   a n d _ C C   o t h e r _ J J   s t r e s s - r e s p o n s e _ J J   h o r m o n e s _ N N 2   a n d _ C C   n e u r o - c h e m i c a l s _ N N 2   i s _ V B Z   c o m p l i c a t e d _ J J   b u t _ C C B   w o r t h _ I I   e x p l o r i n g _ V V G   i n _ I I   t h i s _ D D 1   c o n t e x t _ N N 1   . _ .   
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 T o _ T O   d e t e r m i n e _ V V I   i f _ C S W   t h e _ A T   l o w _ J J   c o n c e n t r a t i o n _ N N 1   o f _ I O   c h e l a t e d _ J J   m a n g a n e s e _ N N 1   i n _ I I   T e s l a s c a n _ N N 1   w o u l d _ V M   b e _ V B I   u s e f u l _ J J   i n _ I I   f u n c t i o n a l _ J J   s t u d i e s _ N N 2   , _ ,   i t _ P P H 1   w a s _ V B D Z   o b s e r v e d _ V V N   t h a t _ C S T   t h e _ A T   M n 2 + _ F O   i n _ I I   T e s l a s c a n _ N N 1   i s _ V B Z   t a k e n _ V V N   u p _ R P   b y _ I I   t h e _ A T   r a t _ N N 1   r e t i n a _ N N 1   i n _ I I   a _ A T 1   s t i m u l u s - d e p e n d e n t _ J J   m a n n e r _ N N 1   ( _ (   B e r k o w i t z _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 3 _ M C   ; _ ;   T o f t s _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 0 _ M C   ) _ )   . _ .   
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 D e p l e t i o n _ N N 1   o f _ I O   I L - 1 0 _ M C   w i t h _ I W   I L - 1 0 _ M C   m A b _ V V 0   s i g n i f i c a n t l y _ R R   u p r e g u l a t e d _ V V D   I F N g _ N P 1   a n d _ C C   T N F a _ N P 1   e x p r e s s i o n _ N N 1   i n _ I I   C D 4 + _ F O   T _ Z Z 1   c e l l s _ N N 2   ( _ (   F i g . _ N N 1   4 b _ F O   , _ ,   c _ Z Z 1   ) _ )   . _ .   
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 T h e _ A T   g r e a t _ J J   m a j o r i t y _ N N 1   o f _ I O   l i f e s p a n - a u g m e n t i n g _ J J   m u t a t i o n s _ N N 2   w e r e _ V B D R   d i s c o v e r e d _ V V N   i n _ I I   t h e _ A T   n e m a t o d e _ N N 1   C . _ N P 1   e l e g a n s _ N P 1   ( _ (   K l a s s _ N P 1   , _ ,   1 9 8 3 _ M C   ) _ )   a n d _ C C   f u r t h e r _ R R R   r e p l i c a t e d _ V V N   i n _ I I   o t h e r _ J J   m o d e l _ N N 1   o r g a n i s m s _ N N 2   f r o m _ I I   y e a s t _ N N 1   t o _ I I   m i c e _ N N 2   ( _ (   G e m s _ N N 2   a n d _ C C   P a r t r i d g e _ N N   , _ ,   2 0 1 3 _ M C   ) _ )   . _ .   
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 T h e s e _ D D 2   p r o t e i n s _ N N 2   c a n _ V M   b i n d _ V V I   t o _ I I   s m a l l _ J J   m o l e c u l e s _ N N 2   l i k e _ I I   D N A _ N N 1   o r _ C C   t o _ I I   o t h e r _ J J   p r o t e i n s _ N N 2   ' _ N U L L   w h i c h _ D D Q   r e s u l t s _ V V Z   i n _ I I   a n _ A T 1   e l e c t r o s t a t i c _ J J   c o m p l e x _ N N 1   . _ .   
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 A l l _ D B   d a t a _ N N   w e r e _ V B D R   m a d e _ V V N   a n o n y m o u s _ J J   a n d _ C C   t r a n s f e r r e d _ V V N   t h r o u g h _ I I   t h e _ A T   i n t e r n e t _ N N 1   ( _ (   h t t p _ N N U   : _ :   / / w w w . q u i p s - p r o j e k t . d e / _ J J   ) _ )   t o _ I I   t h e _ A T   e x t e r n a l _ J J   d a t a b a s e _ N N 1   f o r _ I F   t h e _ A T   b e n c h m a r k _ N N 1   p r o j e c t _ N N 1   o f _ I O   Q U I P S _ N P 2   a l l o w i n g _ V V G   a n _ A T 1   a n o n y m o u s _ J J   c o m p a r i s o n _ N N 1   w i t h _ I W   t h e _ A T   r e s u l t s _ N N 2   o f _ I O   o t h e r _ J J   p a r t i c i p a t i n g _ J J   h o s p i t a l s _ N N 2   ( _ (   p r o c e d u r e _ N N 1   c o d e s _ N N 2   i n _ I I   S u p p l e m e n t a l _ J J   T a b l e _ N N 1   1 _ M C 1   , _ ,   S u p p l e m e n t a l _ J J   D i g i t a l _ J J   C o n t e n t _ N N 1   1 _ M C 1   , _ ,   h t t p _ N N U   : _ :   / / l i n k s . l w w . c o m / C J P / _ V V 0   A 7 8 _ F O   ) _ )   . _ .   
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 T h e y _ P P H S 2   a l s o _ R R   i n c l u d e d _ V V D   m a n y _ D A 2   i m p o r t a n t _ J J   c o v a r i a t e s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   b a s e l i n e _ N N 1   c o g n i t i v e _ J J   s t a t u s _ N N 1   , _ ,   t h u s _ R R   s t r e n g t h e n i n g _ V V G   c a u s a l i t y _ N N 1   f o l l o w i n g _ V V G   m u l t i v a r i a b l e _ J J   a d j u s t m e n t _ N N 1   . _ .   
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 D e c l a r a t i o n _ N N 1   o f _ I O   i n t e r e s t s _ N N 2   E D A _ N P 1   r e c e i v e d _ V V D   r e s e a r c h _ N N 1   f u n d i n g _ N N 1   f r o m _ I I   U K _ N P 1   M e d i c a l _ J J   R e s e a r c h _ N N 1   C o u n c i l _ N N 1   , _ ,   B r i t i s h _ J J   H e a r t _ N N 1   F o u n d a t i o n _ N N 1   , _ ,   N a t i o n a l _ J J   I n s t i t u t e _ N N 1   o f _ I O   H e a l t h _ N N 1   R e s e a r c h _ N N 1   , _ ,   N H S _ N P 1   B l o o d _ N N 1   a n d _ C C   T r a n s p l a n t _ N N 1   , _ ,   E u r o p e a n _ J J   C o m m i s s i o n _ N N 1   F r a m e w o r k _ N N 1   P r o g r a m m e _ N N 1   d u r i n g _ I I   t h e _ A T   c o n d u c t _ N N 1   o f _ I O   t h e _ A T   s t u d y _ N N 1   ; _ ;   a n d _ C C   p e r s o n a l _ J J   f e e s _ N N 2   f r o m _ I I   E l s e v i e r _ N P 1   ( _ (   F r a n c e _ N P 1   ) _ )   . _ .   
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 M o r e o v e r _ R R   , _ ,   t h e _ A T   V p _ N P 1   r e p e r t o i r e _ N N 1   r e v e a l e d _ V V D   t h a t _ D D 1   t u m o r _ N N 1   c e l l s _ N N 2   a r e _ V B R   s p e c i f i c a l l y _ R R   e n r i c h e d _ V V N   i n _ I I   t h e _ A T   C D 7 N _ F O   f r a c t i o n _ N N 1   , _ ,   u s u a l l y _ R R   t o _ I I   a l m o s t _ R R   1 0 0 % _ N N U   a f t e r _ I I   a s s e s s i n g _ V V G   c l o n a l i t y _ N N 1   i n _ I I   t h e _ A T   c o n t e x t _ N N 1   o f _ I O   t h e _ A T   T - c e l l _ N N 1   r e c e p t o r _ N N 1   . _ .   
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 A l l _ D B   t h e s e _ D D 2   d a t a _ N N   s u p p o r t _ V V 0   t h e _ A T   s i g n i f i c a n t _ J J   r o l e _ N N 1   o f _ I O   t h e _ A T   n o n - e n z y m a t i c _ J J   p o s t - t r a n s l a t i o n a l _ J J   r e a c t i o n s _ N N 2   a n d _ C C   t h e i r _ A P P G E   b y - p r o d u c t s _ N N 2   i n _ I I   t h e _ A T   o c c u r r e n c e _ N N 1   o f _ I O   c a r d i o v a s c u l a r _ J J   e v e n t s _ N N 2   a n d _ C C   e s p e c i a l l y _ R R   i n _ I I   t h e _ A T   d e v e l o p m e n t _ N N 1   o f _ I O   C A D _ N N 1   . _ .   
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 I n _ I I   p o o l e d _ J J   a n a l y s i s _ N N 1   w e _ P P I S 2   s u b s e q u e n t l y _ R R   d i c h o t o m i z e d _ V V D   p a t i e n t s _ N N 2   i n t o _ I I   l o w _ J J   L M R _ N P 1   ( _ (   l e s s _ R R R   t h a n _ C S N   a n d _ C C   e q u a l _ J J   t o _ I I   2 . 3 8 _ M C   ) _ )   a n d _ C C   h i g h _ J J   L M R _ N P 1   ( _ (   > 2 . 3 8 _ F O   ) _ )   g r o u p s _ N N 2   . _ .   
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 D u r i n g _ I I   e x t e n d e d _ J J   f o l l o w - u p _ N N 1   o f _ I O   o v e r a l l _ J J   s u r v i v a l _ N N 1   , _ ,   o n e _ M C 1   f u r t h e r _ J J R   t r e a t m e n t - r e l a t e d _ J J   g r a d e _ N N 1   3 _ M C   e v e n t _ N N 1   ( _ (   g a s t r o i n t e s t i n a l _ J J   f i s t u l a _ N N 1   i n _ I I   a _ A T 1   b e v a c i z u m a b - t r e a t e d _ J J   p a t i e n t _ N N 1   ) _ )   , _ ,   t h r e e _ M C   g r a d e _ N N 1   2 _ M C   t r e a t m e n t - r e l a t e d _ J J   e v e n t s _ N N 2   ( _ (   c a r d i a c _ J J   f a i l u r e _ N N 1   , _ ,   s a r c o i d o s i s _ N N 1   , _ ,   a n d _ C C   f o o t _ N N 1   f r a c t u r e _ N N 1   , _ ,   a l l _ D B   i n _ I I   b e v a c i z u m a b - t r e a t e d _ J J   p a t i e n t s _ N N 2   ) _ )   , _ ,   a n d _ C C   o n e _ M C 1   g r a d e _ N N 1   1 _ M C 1   t r e a t m e n t - r e l a t e d _ J J   e v e n t _ N N 1   ( _ (   v a g i n a l _ J J   h a e m o r r h a g e _ N N 1   , _ ,   i n _ I I   a _ A T 1   p a t i e n t _ N N 1   t r e a t e d _ V V N   w i t h _ I W   s t a n d a r d _ J J   c h e m o t h e r a p y _ N N 1   ) _ )   w e r e _ V B D R   a l s o _ R R   r e p o r t e d _ V V N   . _ .   
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 M u n d y _ N P 1   e t _ R A 2 1   a l _ R A 2 2   e v a l u a t e d _ V V D   t h e _ A T   e f f e c t s _ N N 2   o f _ I O   e a r l y _ J J   m o b i l i s a t i o n _ N N 1   p e r f o r m e d _ V V N   b y _ I I   n u r s e s _ N N 2   o n _ I I   4 5 6 _ M C   p a t i e n t s _ N N 2   w h o _ P N Q S   w e r e _ V B D R   h o s p i t a l i s e d _ V V N   f o r _ I F   c o m m u n i t y - a c q u i r e d _ J J   p n e u m o n i a _ N N 1   a n d _ C C   f o u n d _ V V N   t h a t _ D D 1   h o s p i t a l i s a t i o n _ N N 1   l e n g t h _ N N 1   a n d _ C C   c o s t s _ N N 2   w e r e _ V B D R   r e d u c e d _ V V N   , _ ,   w i t h _ I W   n o _ A T   a d v e r s e _ J J   e v e n t s _ N N 2   . _ .   
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 T h i s _ D D 1   a l s o _ R R   i s _ V B Z   t r u e _ J J   f o r _ I F   f a l l s _ N N 2   t h a t _ C S T   h a v e _ V H 0   a _ A T 1   l a r g e _ J J   l a t e r a l l y _ R R   d i r e c t e d _ V V N   c o m p o n e n t _ N N 1   t o _ I I   w h i c h _ D D Q   o l d e r _ J J R   a d u l t s _ N N 2   g e n e r a l l y _ R R   s e e m _ V V 0   t o _ T O   b e _ V B I   v u l n e r a b l e _ J J   . _ .   
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 N o _ A T   s i g n i f i c a n t _ J J   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   K t r a n s _ N N 2   v a l u e s _ N N 2   a n d _ C C   t h e _ A T   p r e s e n c e _ N N 1   o f _ I O   H A R M _ N N 1   s i g n _ N N 1   , _ ,   w h i c h _ D D Q   w a s _ V B D Z   s e e n _ V V N   i n _ I I   o n l y _ R R   7 _ M C   p a t i e n t s _ N N 2   , _ ,   w a s _ V B D Z   o b s e r v e d _ V V N   . _ .   
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 H o w e v e r _ R R   , _ ,   t h e _ A T   v e h i c l e - f e d _ J J   g r o u p _ N N 1   t h a t _ C S T   w a s _ V B D Z   s u b j e c t e d _ V V N   t o _ I I   S D _ N P 1   b e f o r e _ I I   t h e _ A T   s t a r v a t i o n _ N N 1   p e r i o d _ N N 1   s h o w e d _ V V D   a _ A T 1   s i g n i f i c a n t _ J J   i n c r e a s e _ N N 1   i n _ I I   s l e e p _ N N 1   t h a t _ C S T   l a s t e d _ V V D   t h r o u g h _ I I   t h e _ A T   s e c o n d _ M D   d a y t i m e _ N N T 1   p e r i o d _ N N 1   o f _ I O   r e c o v e r y _ N N 1   ( _ (   f i g . _ N N 1   7 C _ F O   ) _ )   . _ .   
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 W e _ P P I S 2   a s s u m e _ V V 0   o u r _ A P P G E   r e s u l t _ N N 1   t o _ T O   b e _ V B I   m o r e _ R G R   p r e c i s e _ J J   , _ ,   s i n c e _ C S   L e e _ N P 1   e t _ R A 2 1   a l _ R A 2 2   u s e d _ V V D   a _ A T 1   p e r - l e s i o n - b a s e d _ J J   a n a l y s i s _ N N 1   , _ ,   a l l o w i n g _ V V G   t o _ T O   c o u n t _ V V I   e i t h e r _ R R   t r u e - p o s i t i v e _ J J   o r _ C C   f a l s e - n e g a t i v e _ J J   l e s i o n s _ N N 2   , _ ,   i g n o r i n g _ V V G   A E F _ N N 1   m e a s u r e m e n t s _ N N 2   i n _ I I   t r u e - n e g a t i v e _ J J   l i v e r _ N N 1   s e g m e n t s _ N N 2   . _ .   
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 P a t i e n t s _ N N 2   w i t h _ I W   a n _ A T 1   o c u l a r _ J J   c o m p l i c a t i o n _ N N 1   d u r i n g _ I I   b a s e l i n e _ N N 1   w e r e _ V B D R   e x c l u d e d _ V V N   . _ .   
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 E n d o p l a s m i c _ J J   r e t i c u l u m _ N N 1   ( _ (   E R _ F U   ) _ )   s t r e s s _ N N 1   , _ ,   a s _ C S A   m e a s u r e d _ V V N   b y _ I I   B i P _ N P 1   , _ ,   P D I _ N P 1   , _ ,   a n d _ C C   C H O P _ V V 0   e x p r e s s i o n _ N N 1   , _ ,   w a s _ V B D Z   a l s o _ R R   e x a m i n e d _ V V N   a s _ I I   a _ A T 1   f u n c t i o n _ N N 1   o f _ I O   a g e _ N N 1   i n _ I I   t h e _ A T   W T _ N N 1   a n d _ C C   K O _ N N 1   m i c e _ N N 2   ( _ (   F i g . _ N N 1   5 _ M C   ) _ )   . _ .   
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 A l t h o u g h _ C S   s k e l e t a l _ J J   m u s c l e _ N N 1   t i t i n _ N N 1   i s o f o r m _ N N 1   p r e s e n t e d _ V V D   m o r e _ D A R   s i t e s _ N N 2   f o r _ I F   a r g i n y l a t i o n _ N N 1   t h a n _ C S N   c a r d i a c _ J J   t i t i n _ N N 1   , _ ,   o n e _ M C 1   s i t e _ N N 1   f o u n d _ V V N   i n _ I I   t h e _ A T   h e a r t _ N N 1   i s _ V B Z   l o c a t e d _ V V N   i n _ I I   t h e _ A T   t i t i n _ N N 1   s e r i n e - t h r e o n i n e _ N N 1   k i n a s e _ N N 1   d o m a i n _ N N 1   ( _ (   C 2 4 8 1 8 _ F O   ) _ )   . _ .   
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 L o n g e r - t e r m _ J J   o b s e r v a t i o n a l _ J J   s t u d i e s _ N N 2   t h a t _ C S T   e x a m i n e _ V V 0   r i s k _ N N 1   s t a t u s _ N N 1   c o u l d _ V M   s u p p o r t _ V V I   r e g i s t r i e s _ N N 2   t h r o u g h _ I I   w h i c h _ D D Q   s u b j e c t s _ N N 2   i n d i c a t e _ V V 0   t h e i r _ A P P G E   w i l l i n g n e s s _ N N 1   t o _ T O   p a r t i c i p a t e _ V V I   i n _ I I   f u t u r e _ J J   c l i n i c a l _ J J   t r i a l s _ N N 2   a n d _ C C   b i o m a r k e r _ N N 1   i n i t i a t i v e s _ N N 2   . _ .   
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 P r o p e n s i t y _ N N 1   s c o r e _ N N 1   m a t c h i n g _ N N 1   r e s u l t e d _ V V N   i n _ I I   2 6 0 _ M C   p a i r s _ N N 2   o f _ I O   m a t c h e d _ J J   p a t i e n t s _ N N 2   . _ .   
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 H o w e v e r _ R R   , _ ,   n e i t h e r _ R R   S B P - 1 _ M C 1   , _ ,   N H R - 4 9 _ M C   , _ ,   n o r _ C C   t h e _ A T   d e t o x i f i c a t i o n _ N N 1   r e g u l a t o r _ N N 1   N H R - 8 _ M C   ( _ (   L i n d b l o m _ N P 1   & ; _ N U L L   D o d d _ N P 1   , _ ,   2 0 0 6 _ M C   ) _ )   a f f e c t _ V V 0   M D T - 1 5 - d e p e n d e n t _ N P 1   d e t o x i f i c a t i o n _ N N 1   g e n e s _ N N 2   ( _ (   T a u b e r t _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 8 _ M C   ) _ )   , _ ,   s u g g e s t i n g _ V V G   t h a t _ C S T   M D T - 1 5 _ M C   m u s t _ V M   i n t e r a c t _ V V I   w i t h _ I W   y e t _ R R   u n i d e n t i f i e d _ J J   t r a n s c r i p t i o n _ N N 1   f a c t o r s _ N N 2   t o _ T O   r e g u l a t e _ V V I   s t r e s s _ N N 1   r e s p o n s e _ N N 1   g e n e s _ N N 2   . _ .   
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 C r i c o i d _ J J   p r e s s u r e _ N N 1   w a s _ V B D Z   a p p l i e d _ V V N   a t _ I I   a _ A T 1   s t a n d a r d i z e d _ J J   f o r c e _ N N 1   o f _ I O   3 0 _ M C   N _ N N U   , _ ,   w h i c h _ D D Q   s u f f i c i e n t l y _ R R   p r e v e n t s _ V V Z   r e g u r g i t a t i o n _ N N 1   i n t o _ I I   t h e _ A T   p h a r y n x _ N N 1   , _ ,   e v e n _ R R   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   a _ A T 1   f u l l _ J J   s t o m a c h _ N N 1   u n d e r g o i n g _ V V G   C a e s a r e a n _ N N 1   s e c t i o n _ N N 1   . _ .   
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 D e s p i t e _ I I   t h i s _ D D 1   , _ ,   i t _ P P H 1   i s _ V B Z   g e n e r a l l y _ R R   a g r e e d _ V V N   t h a t _ C S T   t h e _ A T   c h a r a c t e r i s t i c s _ N N 2   o f _ I O   a _ A T 1   h e a l t h y _ J J   m i c r o b i o t a _ N N 1   i n c l u d e _ V V 0   c o m m u n i t y _ N N 1   s t a b i l i t y _ N N 1   a n d _ C C   i n c r e a s e d _ J J   s p e c i e s _ N N   d i v e r s i t y _ N N 1   . _ .   
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 T h e _ A T   m e d i a n _ J J   v a l u e s _ N N 2   o f _ I O   N - t e r m i n a l _ J J   p r o - b r a i n _ J J   n a t r i u r e t i c _ J J   p e p t i d e _ N N 1   ( _ (   N T _ N P 1   p r o - B N P _ J J   ) _ )   o r _ C C   B N P _ N P 1   w e r e _ V B D R   3 , 6 1 0 _ M C   & l s q b ; _ (   2 2 _ M C   & r s q b ; _ )   , _ ,   w i t h _ I W   4 4 0 _ M C   c a s e s _ N N 2   ( _ (   3 5 . 7 _ M C   % _ N N U   ) _ )   w i t h _ I W   v a l u e s _ N N 2   o v e r _ I I   g r e a t e r _ J J R   t h a n _ C S N   5 0 0 0 _ M C   p g / m L _ F U   . _ .   
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 T r o p o n i n - T _ N P 1   o r _ C C   I _ P P I S 1   , _ ,   r e g i s t e r e d _ V V N   i n _ I I   1 0 2 5 _ M C   c a s e s _ N N 2   ( _ (   8 3 . 1 _ M C   % _ N N U   o f _ I O   c a s e s _ N N 2   ) _ )   , _ ,   w e r e _ V B D R   o v e r _ I I   c u t - o f f _ N N 1   l e v e l s _ N N 2   i n _ I I   2 7 8 _ M C   c a s e s _ N N 2   ( _ (   2 2 . 5 _ M C   % _ N N U   ) _ )   . _ .   
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 F o r t h e _ V V 0   l a t t e r _ D A   , _ ,   w e _ P P I S 2   d e m o n s t r a t e d _ V V D   t h a t _ C S T   R 4 0 6 _ F O   s u p p r e s s e d _ J J   p h o s p h o r y l a t i o n _ N N 1   o f _ I O   o t h e r _ J J   S Y K _ N N 1   s u b s t r a t e s _ N N 2   i n c l u d i n g _ I I   p S T A T 3 _ F O   a n d _ C C   p A K T _ N N 1   o f _ I O   w h i c h _ D D Q   p h o s p h o r y l a t i o n _ N N 1   w a s _ V B D Z   r e p o r t e d _ V V N   t o _ T O   p r o t e c t _ V V I   t u m o r _ N N 1   c e l l s _ N N 2   f r o m _ I I   c h e m o t h e r a p y - i n d u c e d _ J J   c y t o t o x i c i t y _ N N 1   . _ .   
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 T h i s _ D D 1   r e m a i n s _ V V Z   a _ A T 1   r i p e _ J J   a r e a _ N N 1   f o r _ I F   f u t u r e _ J J   i n q u i r y _ N N 1   . _ .   
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 P a t i e n t s _ N N 2   r e p o r t i n g _ V V G   c h r o n i c _ J J   p a i n _ N N 1   h a d _ V H D   m o r e _ D A R   p o s t o p e r a t i v e _ J J   p a i n _ N N 1   b u t _ C C B   p a t i e n t s _ N N 2   w i t h _ I W   h i g h e r _ J J R   A S A _ N N 1   s t a t u s _ N N 1   r e p o r t e d _ V V D   l e s s _ D A R   p a i n _ N N 1   . _ .   
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 A d d i t i o n a l _ J J   s u p p o r t i v e _ J J   a n a l y s e s _ N N 2   w e r e _ V B D R   c o n d u c t e d _ V V N   f o r _ I F   t h e _ A T   c h a n g e _ N N 1   f r o m _ I I   b a s e l i n e _ N N 1   i n _ I I   C S F T _ N P 1   a n d _ C C   B C V A _ N N 1   a t _ I I   a l l _ D B   t i m e _ N N T 1   p o i n t s _ N N 2   i n _ I I   t h e _ A T   s t u d y _ N N 1   . _ .   
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 T h e _ A T   h e m o g l o b i n _ N N 1   c o n c e n t r a t i o n _ N N 1   i s _ V B Z   s e p a r a t e l y _ R R   m e a s u r e d _ V V N   a n d _ C C   G 6 P D _ F O   a c t i v i t y _ N N 1   i s _ V B Z   d e r i v e d _ V V N   b y _ I I   m a n u a l _ J J   c a l c u l a t i o n _ N N 1   a n d _ C C   e x p r e s s e d _ V V N   a s _ C S A   u n i t s _ N N 2   p e r _ I I   g r a m _ N N U 1   o f _ I O   h e m o g l o b i n _ N N 1   . _ .   
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 W e _ P P I S 2   a r e _ V B R   g r a t e f u l _ J J   t o _ I I   t h e _ A T   U n i v e r s i t y _ N N 1   o f _ I O   P e r n a m b u c o _ N P 1   , _ ,   t h e _ A T   F e d e r a l _ J J   U n i v e r s i t y _ N N 1   o f _ I O   P e r n a m b u c o _ N P 1   , _ ,   t h e _ A T   L o n d o n _ N P 1   S c h o o l _ N N 1   o f _ I O   H y g i e n e _ N N 1   & ; _ N U L L   T r o p i c a l _ J J   M e d i c i n e _ N N 1   , _ ,   a n d _ C C   F i o c r u z _ N P 1   P e r n a m b u c o _ N P 1   f o r _ I F   g i v i n g _ V V G   t h e _ A T   i n v e s t i g a t o r s _ N N 2   t i m e _ V V 0   t o _ T O   w o r k _ V V I   i n _ I I   t h e _ A T   s t u d y _ N N 1   ( _ (   R A A X _ N P 1   , _ ,   T V B A _ N P 1   , _ ,   D B M - F _ N P 1   , _ ,   L C R _ N P 1   , _ ,   W V S _ N P 1   , _ ,   M F P M A _ N P 1   , _ ,   C B _ N P 1   , _ ,   C M T M _ N P 1   , _ ,   S V _ N P 1   , _ ,   A P L M _ N P 1   , _ ,   E T A M - J _ N P 1   , _ ,   R D _ N N 1   , _ ,   M T C _ N P 1   , _ ,   a n d _ C C   U R M _ N P 1   ) _ )   . _ .   
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 T h e r e _ E X   i s _ V B Z   s o m e _ D D   r e s e a r c h _ N N 1   s h o w i n g _ V V G   t h a t _ C S T   s t e r o i d s _ N N 2   p r e s c r i b e d _ V V N   f o r _ I F   m e d i c a l _ J J   p u r p o s e s _ N N 2   c a n _ V M   l e a d _ V V I   t o _ I I   c o g n i t i v e _ J J   i m p a i r m e n t _ N N 1   , _ ,   t h o u g h _ C S   i t _ P P H 1   i s _ V B Z   u n c l e a r _ J J   w h e t h e r _ C S W   t h e s e _ D D 2   i m p a i r m e n t s _ N N 2   a r e _ V B R   p e r s i s t e n t _ J J   . _ .   
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 W h o l e - m o u n t _ J J   d i s s e c t i o n s _ N N 2   ( _ (   F i g . _ N N 1   1 B _ F O   ) _ )   a l l o w e d _ V V D   f o r _ I F   a _ A T 1   c o n s i s t e n t _ J J   v i e w _ N N 1   o f _ I O   t h e _ A T   H C s _ N P 2   f o r _ I F   t h e _ A T   e n t i r e _ J J   l e n g t h _ N N 1   o f _ I O   t h e _ A T   O r g a n _ N N 1   o f _ I O   C o r t i _ N P 1   , _ ,   a n d _ C C   t h i s _ D D 1   t i s s u e _ N N 1   p r e p a r a t i o n _ N N 1   a l l o w e d _ V V D   u s _ P P I O 2   t o _ T O   l a b e l _ V V I   v a r i o u s _ J J   f e a t u r e s _ N N 2   u s i n g _ V V G   i m m u n o h i s t o c h e m i c a l _ J J   m a r k e r s _ N N 2   . _ .   
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 O b s t e t r i c s _ N N 1   a n d _ C C   g y n e c o l o g y _ N N 1   f a c u l t y _ N N 1   ( _ (   2 5 % _ N N U   ) _ )   a n d _ C C   t h e _ A T   o b s t e t r i c s _ N N 1   a n d _ C C   g y n e c o l o g y _ N N 1   p r o g r a m _ N N 1   d i r e c t o r _ N N 1   ( _ (   1 8 % _ N N U   ) _ )   a t _ I I   a _ A T 1   s t u d e n t _ N N 1   ' _ N U L L   s _ Z Z 1   h o m e _ N N 1   i n s t i t u t i o n _ N N 1   w e r e _ V B D R   a l s o _ R R   c o m m o n l y _ R R   c i t e d _ V V N   a s _ I I   t h e _ A T   p r i m a r y _ J J   a d v i s o r _ N N 1   ( _ (   T a b l e _ N N 1   2 _ M C   ) _ )   . _ .   
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 L a s t _ M D   b u t _ C C B   n o t _ X X   l e a s t _ R R T   , _ ,   t h e r e _ E X   i s _ V B Z   t h e _ A T   p o s s i b i l i t y _ N N 1   t h a t _ C S T   s u c h _ D A   s t u d i e s _ N N 2   d o _ V D 0   n o t _ X X   t a k e _ V V I   i n t o _ I I   a c c o u n t _ N N 1   o t h e r _ J J   p o p u l a t i o n _ N N 1   c h a r a c t e r i s t i c s _ N N 2   ( _ (   e . g . _ R E X   , _ ,   a g e _ N N 1   , _ ,   g e n d e r _ N N 1   , _ ,   w e i g h t _ N N 1   i n c r e a s e _ N N 1   , _ ,   c a f f e i n e _ N N 1   a n d _ C C   a l c o h o l _ N N 1   i n t a k e _ N N 1   ) _ )   , _ ,   w h i c h _ D D Q   m a y _ V M   p l a y _ V V I   a _ A T 1   c r u c i a l _ J J   r o l e _ N N 1   w h e n _ C S   d e t e r m i n i n g _ V V G   p o t e n t i a l _ J J   c a u s a t i o n _ N N 1   . _ .   
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 I n _ I I   t h e _ A T   1 9 6 0 s _ M C 2   , _ ,   f e w e r _ D A R   t h a n _ C S N   h a l f _ D B   t h e _ A T   c h i l d r e n _ N N 2   i n _ I I   w h o m _ P N Q O   c a n c e r _ N N 1   w a s _ V B D Z   d i a g n o s e d _ V V N   w e r e _ V B D R   s t i l l _ R R   a l i v e _ J J   5 _ M C   y e a r s _ N N T 2   l a t e r _ R R R   . _ .   
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 A m o n g _ I I   f e m a l e s _ N N 2   , _ ,   n o _ A T   d i a g n o s t i c _ J J   p r o f i l e _ N N 1   p r e d o m i n a t e d _ V V D   a t _ I I   f o l l o w - u p _ N N 1   . _ .   
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 T h e _ A T   d i f f e r e n c e _ N N 1   s u g g e s t e d _ V V D   t h a t _ C S T   t h e _ A T   c h a n g e _ N N 1   i n _ I I   t h e _ A T   C D 7 N _ F O   p r o p o r t i o n _ N N 1   c o u l d _ V M   b e _ V B I   m o r e _ R G R   i m p o r t a n t _ J J   t o _ T O   p r e d i c t _ V V I   t h e _ A T   p r o g n o s i s _ N N 1   . _ .   
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 T o _ I I   o u r _ A P P G E   k n o w l e d g e _ N N 1   , _ ,   t h i s _ D D 1   i s _ V B Z   t h e _ A T   f i r s t _ M D   s t u d y _ N N 1   t o _ T O   r e p o r t _ V V I   t h e _ A T   p r e v a l e n c e _ N N 1   o f _ I O   F R A s _ N P 2   i n _ I I   a _ A T 1   s a m p l e _ N N 1   o f _ I O   c h i l d r e n _ N N 2   w i t h _ I W   A S D _ N P 1   w h o _ P N Q S   d i d _ V D D   n o t _ X X   p o s s e s s _ V V I   s i g n i f i c a n t _ J J   n e u r o l o g i c a l _ J J   a b n o r m a l i t i e s _ N N 2   . _ .   
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 R E S U L T S _ N N 2   ' _ N U L L   T h e _ A T   o v e r a l l _ J J   t i s s u e _ N N 1   p r e p a r a t i o n _ N N 1   f a i l u r e _ N N 1   r a t e _ N N 1   w a s _ V B D Z   5 . 2 % _ F O   . _ .   
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 A _ A T 1   l o s s _ N N 1   o f _ I O   b e i n g _ V B G   t h a t _ R G   - 1 _ M C   a r g u e _ V V 0   - _ -   i s _ V B Z   a t _ I I   t h e _ A T   o r i g i n _ N N 1   o f _ I O   t h e _ A T   o r d i n a r i n e s s _ N N 1   o f _ I O   t e r r o r i s t s _ N N 2   a n d _ C C   t h e _ A T   e x p e r i e n c e _ N N 1   o f _ I O   v o i d _ N N 1   i n _ I I   p s y c h o t i c s _ N N 1   . _ .   
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 T h e s e _ D D 2   s t u d i e s _ N N 2   r e v e a l _ V V 0   n u m e r o u s _ J J   d i s p a r i t i e s _ N N 2   f o r _ I F   p a t i e n t s _ N N 2   w i t h _ I W   S M I _ N N 2   a n d _ C C   c a n c e r _ N N 1   i n _ I I   d i a g n o s i s _ N N 1   a n d _ C C   t i m e _ N N T 1   t o _ I I   t r e a t m e n t _ N N 1   ; _ ;   r e c e i p t _ N N 1   o f _ I O   c h e m o t h e r a p y _ N N 1   , _ ,   r a d i a t i o n _ N N 1   , _ ,   a n d _ C C   s u r g e r y _ N N 1   ; _ ;   a n d _ C C   c l i n i c a l _ J J   t r i a l _ N N 1   p a r t i c i p a t i o n _ N N 1   . _ .   
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 T h e _ A T   f i n d i n g _ N N 1   t h a t _ C S T   Y M S M _ N P 1   w h o _ P N Q S   d i s c l o s e d _ V V D   t h e i r _ A P P G E   H I V _ N P 1   s t a t u s _ N N 1   t o _ I I   s e x _ N N 1   p a r t n e r s _ N N 2   w e r e _ V B D R   m o r e _ R G R   l i k e l y _ J J   t o _ T O   r e p o r t _ V V I   a n y _ D D   C A I _ J J   t h a n _ C S N   t h o s e _ D D 2   n o t _ X X   d i s c l o s i n g _ V V G   t h e i r _ A P P G E   s t a t u s _ N N 1   i s _ V B Z   c o n s i s t e n t _ J J   w i t h _ I W   o t h e r _ J J   r e s e a r c h _ N N 1   a n d _ C C   m a y _ V M   s u g g e s t _ V V I   t h a t _ C S T   m a n y _ D A 2   Y M S M _ N N 1   i n _ I I   t h e _ A T   s a m p l e _ N N 1   e n g a g e d _ V V N   i n _ I I   s e r o s o r t i n g _ V V G   a s _ I I   a _ A T 1   h a r m _ N N 1   r e d u c t i o n _ N N 1   s t r a t e g y _ N N 1   , _ ,   g i v e n _ V V N   t h e _ A T   s i g n i f i c a n t _ J J   a s s o c i a t i o n _ N N 1   o f _ I O   d i s c l o s u r e _ N N 1   t o _ I I   a n y _ D D   C A I _ N N 2   b u t _ C C B   n o t _ X X   t o _ I I   s e r o d i s c o r d a n t _ J J   C A I _ N N 2   . _ .   
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 I n _ I I   t h e _ A T   a b s e n c e _ N N 1   o f _ I O   p o l i t i c a l _ J J   a c t i o n _ N N 1   , _ ,   o n l y _ R R   t r a d i t i o n a l _ J J   M e d i c a r e _ N P 1   b e n e f i c i a r i e s _ N N 2   w i l l _ V M   b e _ V B I   e x c l u d e d _ V V N   f r o m _ I I   t h e _ A T   b e n e f i t s _ N N 2   o f _ I O   t e l e h e a l t h _ N N 1   t h a t _ C S T   n o w _ R T   i n c r e a s i n g l y _ R R   e x t e n d _ V V 0   t o _ I I   t h e _ A T   c o m m e r c i a l l y _ R R   i n s u r e d _ V V N   , _ ,   M e d i c a i d _ N P 1   b e n e f i c i a r i e s _ N N 2   , _ ,   m i l i t a r y _ J J   p e r s o n n e l _ N N 2   , _ ,   p r i s o n e r s _ N N 2   , _ ,   a n d _ C C   v e t e r a n s _ N N 2   . _ .   
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 T h e _ A T   d i f f e r e n c e _ N N 1   i n _ I I   c h a n g e _ N N 1   f r o m _ I I   b a s e l i n e _ N N 1   t o _ I I   1 2 _ M C   m o n t h s _ N N T 2   b e t w e e n _ I I   t h e _ A T   t w o _ M C   s t u d y _ N N 1   g r o u p s _ N N 2   w a s _ V B D Z   a n a l y s e d _ V V N   u s i n g _ V V G   t h e _ A T   M a n n - W h i t n e y _ N P 1   U _ J J   t e s t _ N N 1   d u e _ I I 2 1   t o _ I I 2 2   t h e _ A T   n o n - n o r m a l i t y _ N N 1   o f _ I O   t h e _ A T   d a t a _ N N   . _ .   
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 T o _ T O   a d d r e s s _ V V I   t h i s _ D D 1   , _ ,   a _ A T 1   c e l l _ N N 1   f r e e _ J J   r e c o m b i n a n t _ N N 1   B A C E 1 _ F O   a s s a y _ N N 1   w a s _ V B D Z   u s e d _ V V N   . _ .   
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 C o n s i s t e n t _ J J   w i t h _ I W   p r e v i o u s _ J J   r e s u l t s _ N N 2   , _ ,   w e _ P P I S 2   f o u n d _ V V D   n o _ A T   a d v e r s e _ J J   e f f e c t _ N N 1   o f _ I O   n o n g l y c o s y l a t e d _ J J   P R P H 2 / R D S _ F U   i n _ I I   r o d s _ N N 2   ; _ ;   r d s N 2 2 9 S N 2 2 9 S _ F O   a n i m a l s _ N N 2   e x h i b i t e d _ V V D   n o r m a l _ J J   P R P H 2 / R D S _ F U   a n d _ C C   R O M - 1 _ M C 1   l e v e l s _ N N 2   a n d _ C C   n o _ A T   d e f e c t s _ N N 2   i n _ I I   r e t i n a l _ J J   s t r u c t u r e _ N N 1   o r _ C C   f u n c t i o n _ N N 1   . _ .   
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 C r i t i c a l _ J J   r e v i s i o n _ N N 1   o f _ I O   t h e _ A T   m a n u s c r i p t _ N N 1   f o r _ I F   i m p o r t a n t _ J J   i n t e l l e c t u a l _ J J   c o n t e n t _ N N 1   : _ :   V a n _ N P 1   D r i e s t _ N P 1   , _ ,   W e l l s _ N P 1   , _ ,   S t a l l i n g s _ N N 2   , _ ,   B u s h _ N P 1   , _ ,   G o r d o n _ N P 1   , _ ,   N i c k e r s o n _ N P 1   , _ ,   K i m _ N P 1   , _ ,   C r o s s l i n _ N P 1   , _ ,   J a r v i k _ N P 1   , _ ,   C a r r e l l _ N P 1   , _ ,   R a l s t o n _ N P 1   , _ ,   L a r s o n _ N P 1   , _ ,   B i e l i n s k i _ N P 1   , _ ,   O l s o n _ N P 1   , _ ,   Y e _ P P Y   , _ ,   K u l l o _ N P 1   , _ ,   A b u l - H u s n _ N P 1   , _ ,   S c o t t _ N P 1   , _ ,   B o t t i n g e r _ N P 1   , _ ,   A l m o g u e r a _ N P 1   , _ ,   C o n n o l l y _ N P 1   , _ ,   C h i a v a c c i _ N P 1   , _ ,   H a k o n a r s o n _ N P 1   , _ ,   R a s m u s s e n - T o r v i k _ N P 1   , _ ,   P a n _ N P 1   , _ ,   P e r s e l l _ N P 1   , _ ,   S m i t h _ N P 1   , _ ,   C h i s h o l m _ N P 1   , _ ,   K i t c h n e r _ N P 1   , _ ,   W a l l a c e _ N P 1   , _ ,   D o h e n y _ N P 1   , _ ,   S h o e m a k e r _ N N 1   , _ ,   L i _ N P 1   , _ ,   M a n o l i o _ N P 1   , _ ,   C a l l i s _ N P 1   , _ ,   M a c a y a _ N P 1   , _ ,   W i l l i a m s _ N P 1   , _ ,   C a r e y _ N P 1   , _ ,   K a p p l i n g e r _ N P 1   , _ ,   A c k e r m a n _ N P 1   , _ ,   R i t c h i e _ N P 1   , _ ,   D e n n y _ N P 1   , _ ,   R o d e n _ N P 1   . _ .   
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 S e n t e n c e _ N N 1   i d e n t i f i c a t i o n _ N N 1   s c o r e s _ N N 2   , _ ,   s h o w n _ V V N   i n _ I I   F i g u r e _ N N 1   4 _ M C   , _ ,   w e r e _ V B D R   a l s o _ R R   c o n s i s t e n t _ J J   w i t h _ I W   t h e _ A T   s p e e c h t r a c k i n g _ N N 1   a n d _ C C   c o n s o n a n t _ J J   i d e n t i f i c a t i o n _ N N 1   s c o r e s _ N N 2   : _ :   t h e r e _ E X   w a s _ V B D Z   a _ A T 1   s i g n i f i c a n t _ J J   g r o u p _ N N 1   b y _ I I   i n t e r v a l _ N N 1   i n t e r a c t i o n _ N N 1   ( _ (   p _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 1 _ M C   ) _ )   a n d _ C C   a n _ A T 1   a d v a n t a g e _ N N 1   f o r _ I F   t h e _ A T   g r a d u a l _ J J   g r o u p _ N N 1   a t _ I I   t e s t _ N N 1   i n t e r v a l _ N N 1   1 _ M C 1   ( _ (   p _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 5 _ M C   ) _ )   t h a t _ C S T   d i s a p p e a r e d _ V V D   a t _ I I   l a t e r _ J J R   t e s t _ N N 1   i n t e r v a l s _ N N 2   . _ .   
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 A l l _ D B   a p p r o a c h e s _ N N 2   h a v e _ V H 0   s t r e n g t h s _ N N 2   a n d _ C C   l i m i t a t i o n s _ N N 2   a n d _ C C   p r o v i d e _ V V 0   d i f f e r e n t _ J J   i n s i g h t s _ N N 2   a b o u t _ I I   v a s c u l a r _ J J   f u n c t i o n _ N N 1   , _ ,   a s _ C S A   r e v i e w e d _ V V N   e l s e w h e r e _ R L   ; _ ;   t h i s _ D D 1   v a r i a t i o n _ N N 1   m a y _ V M   c o m p l i c a t e _ V V I   c o m p a r i s o n s _ N N 2   a m o n g _ I I   s t u d i e s _ N N 2   t h a t _ C S T   u s e _ V V 0   d i f f e r e n t _ J J   m e t h o d s _ N N 2   . _ .   
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 A s _ C S A   S p i e l m a n _ N P 1   a n d _ C C   Y o o _ N P 1   ( _ (   3 2 _ M C   ) _ )   a d v i s e _ V V 0   : _ :   " _ "   I f _ C S   y o u _ P P Y   ' _ N U L L   r e _ I I   g o i n g _ V V G K   t o _ T O   s p e n d _ V V I   t i m e _ N N T 1   a n d _ C C   m o n e y _ N N 1   p a i n t i n g _ V V G   a _ A T 1   p i c t u r e _ N N 1   o f _ I O   t h e _ A T   r e l a t i o n s h i p _ N N 1   b e t w e e n _ I I   t h e _ A T   e n v i r o n m e n t _ N N 1   a n d _ C C   h e a l t h _ N N 1   , _ ,   i n v e s t _ V V 0   i n _ I I   t h e _ A T   f r a m e _ N N 1   - _ -   u n l e s s _ C S   t h e _ A T   f r a m e _ N N 1   i s _ V B Z   w e l l _ R R   d e s i g n e d _ V V N   , _ ,   t h e _ A T   p a i n t i n g _ N N 1   i s n _ N N 1   ' _ N U L L   t _ Z Z 1   g o i n g _ V V G   t o _ T O   b e _ V B I   v e r y _ R G   g o o d _ J J   . _ .   " _ "   
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 W e _ P P I S 2   f o u n d _ V V D   t h a t _ D D 1   M R - p r o A N P _ N N 1   m e a s u r e d _ V V N   d u r i n g _ I I   t h e _ A T   i n d e x _ N N 1   v i s i t _ N N 1   a n d _ C C   7 _ M C   d a y s _ N N T 2   l a t e r _ R R R   w a s _ V B D Z   a _ A T 1   s t r o n g _ J J   p r e d i c t o r _ N N 1   f o r _ I F   1 0 - y e a r _ J J   a l l - c a u s e _ J J   m o r t a l i t y _ N N 1   w i t h _ I W   r o b u s t _ J J   r e s u l t s _ N N 2   a c r o s s _ I I   s e v e r a l _ D A 2   s u b g r o u p s _ N N 2   . _ .   
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 I n _ R R 2 1   p a r t i c u l a r _ R R 2 2   , _ ,   s t u d i e s _ N N 2   t h a t _ C S T   c o m p a r e _ V V 0   t h e _ A T   e f f e c t i v e n e s s _ N N 1   o f _ I O   p r o v i d i n g _ V V G   p a r t i c i p a n t s _ N N 2   w i t h _ I W   a _ A T 1   s o c i o c u l t u r a l l y _ R R   r e l e v a n t _ J J   p h y s i c a l _ J J   a c t i v i t y _ N N 1   p r o g r a m _ N N 1   c o m p a r e d _ V V N   w i t h _ I W   a _ A T 1   s t a n d a r d i z e d _ J J   p r o g r a m _ N N 1   ( _ (   o r _ C C   a _ A T 1   p r o g r a m _ N N 1   t h a t _ C S T   h a d _ V H D   b e e n _ V B N   s o c i o c u l t u r a l l y _ R R   t a r g e t e d _ V V N   f o r _ I F   a _ A T 1   d i f f e r e n t _ J J   s u b g r o u p _ N N 1   ) _ )   w o u l d _ V M   p r o v i d e _ V V I   v a l u a b l e _ J J   d a t a _ N N   t o _ T O   t e s t _ V V I   t h e _ A T   m o d e l _ N N 1   . _ .   
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 I t _ P P H 1   h a s _ V H Z   b e e n _ V B N   e s t i m a t e d _ V V N   t h a t _ C S T   u p _ R G 2 1   t o _ R G 2 2   2 9 9 , 0 0 0 _ M C   n e w _ J J   p a t i e n t s _ N N 2   e a c h _ D D 1   y e a r _ N N T 1   m a y _ V M   e x p e r i e n c e _ V V I   p e r s i s t e n t _ J J   p a i n _ N N 1   f o l l o w i n g _ I I   T K R _ N P 1   ; _ ;   t h i s _ D D 1   n u m b e r _ N N 1   m a y _ V M   i n c r e a s e _ V V I   t o _ I I   b e t w e e n _ I I   7 0 0 , 0 0 0 _ M C   a n d _ C C   1 . 5 _ M C   m i l l i o n _ N N O   a s _ I I   t h e _ A T   f r e q u e n c y _ N N 1   o f _ I O   T K R _ N P 1   i n c r e a s e s _ V V Z   . _ .   
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 M A L A T 1 _ F O   i s _ V B Z   a _ A T 1   l o n g _ J J   i n t e r g e n i c _ J J   n o n c o d i n g _ N N 1   ( _ (   l i n c _ N N 1   ) _ )   R N A _ N N 1   , _ ,   a l r e a d y _ R R   d e s c r i b e d _ V V N   i n _ I I   t h e _ A T   l i t e r a t u r e _ N N 1   a s _ I I   a _ A T 1   r e g u l a t o r _ N N 1   o f _ I O   c e l l _ N N 1   c y c l e _ N N 1   p r o g r e s s i o n _ N N 1   ( _ (   T r i p a t h i _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 3 _ M C   ) _ )   . _ .   
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 N o _ A T   b i n d i n g _ N N 1   o f _ I O   t h e _ A T   n o n t a r g e t e d U S P I O _ N N 1   t o _ I I   H U V E C _ N P 1   o r _ C C   M D A - M B - 2 3 1 _ N P 1   c e l l s _ N N 2   w a s _ V B D Z   o b s e r v e d _ V V N   ( _ (   F i g . _ N N 1   1 1 C _ F O   ) _ )   . _ .   
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 T h e s e _ D D 2   v a s c u l a r _ J J   e f f e c t s _ N N 2   m a y _ V M   e x p l a i n _ V V I   h o w _ R R Q   h i s t a m i n e _ V V 0   a l s o _ R R   i s _ V B Z   i n v o l v e d _ J J   i n _ I I   g l u c o s e _ N N 1   d e l i v e r y _ N N 1   a n d _ C C   u p t a k e _ N N 1   ; _ ;   h o w e v e r _ R R   , _ ,   n o n v a s c u l a r _ J J   e f f e c t s _ N N 2   a l s o _ R R   m a y _ V M   b e _ V B I   i m p o r t a n t _ J J   . _ .   
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 I n t e r v e n t i o n _ N N 1   e f f e c t s _ N N 2   F i g u r e _ N N 1   3 _ M C   p r e s e n t s _ V V Z   t h e _ A T   o b s e r v e d _ J J   d a t a _ N N   o f _ I O   o b j e c t i v e l y _ R R   m e a s u r e d _ V V N   , _ ,   w h e e l e d _ V V D   p h y s i c a l _ J J   a c t i v i t y _ N N 1   . _ .   
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 A t _ I I   n o d u l e - l e v e l _ J J   a n a l y s i s _ N N 1   , _ ,   t h e _ A T   g e n e r a l i z e d _ J J   e s t i m a t i n g _ V V G   e q u a t i o n _ N N 1   m e t h o d _ N N 1   w a s _ V B D Z   u s e d _ V V N   f o r _ I F   c o m p a r i s o n _ N N 1   . _ .   
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 T h e _ A T   p r e o p e r a t i v e _ J J   c l i n i c a l _ J J   c h a r a c t e r i s t i c s _ N N 2   o f _ I O   t h e _ A T   p a t i e n t s _ N N 2   w e r e _ V B D R   c o m p a r a b l e _ J J   b e t w e e n _ I I   t h e _ A T   2 _ M C   g r o u p s _ N N 2   a s _ C S A   s h o w n _ V V N   i n _ I I   T a b l e _ N N 1   2 _ M C   . _ .   
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 T h e _ A T   m o s t _ R G T   f r e q u e n t _ J J   p a i n _ N N 1   t h e r a p y _ N N 1   s i d e _ N N 1   e f f e c t _ N N 1   w a s _ V B D Z   d r o w s i n e s s _ N N 1   ( _ (   5 3 % _ N N U   ) _ )   . _ .   
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 A l l _ D B   o f _ I O   t h e _ A T   c o n c e r t s _ N N 2   h a d _ V H D   a l c o h o l _ N N 1   p r e s e n c e _ N N 1   , _ ,   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   9 0 . 9 1 _ M C   % _ N N U   o f _ I O   t h e _ A T   f o o t b a l l _ N N 1   g a m e s _ N N 2   ( _ (   m o s t l y _ R R   t h r o u g h _ I I   ) _ )   . _ .   
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 F u r t h e r _ J J R   r e s e a r c h _ N N 1   i n _ I I   t h e _ A T   f o r m _ N N 1   o f _ I O   a _ A T 1   f a c t o r i a l _ J J   s t u d y _ N N 1   ( _ (   w h e r e b y _ R R Q   p a r t i c i p a n t s _ N N 2   a r e _ V B R   r a n d o m i s e d _ V V N   t o _ T O   r e c e i v e _ V V I   a _ A T 1   p e r s o n a l i s e d _ J J   i n v i t a t i o n _ N N 1   t o _ I I   a _ A T 1   l o c a l _ J J   S S S _ N P 1   , _ ,   o r _ C C   a n _ A T 1   i n v i t a t i o n _ N N 1   t o _ I I   a _ A T 1   t a s t e r _ N N 1   s e s s i o n _ N N T 1   , _ ,   o r _ C C   b o t h _ R R   , _ ,   o r _ C C   n e i t h e r _ R R   ) _ )   i s _ V B Z   n e c e s s a r y _ J J   t o _ T O   e s t i m a t e _ V V I   t h e _ A T   s e p a r a t e _ J J   e f f e c t s _ N N 2   o f _ I O   t h e _ A T   t w o _ M C   c o m p o n e n t s _ N N 2   . _ .   
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 L e _ N P 1   e t _ R A 2 1   a l _ R A 2 2   r e p o r t e d _ V V D   t h a t _ C S T   t h e _ A T   o v e r a l l _ J J   r i s k _ N N 1   o f _ I O   n o d a l _ J J   i n v o l v e m e n t _ N N 1   a t _ I I   d i a g n o s i s _ N N 1   a n d _ C C   o n _ I I   f o l l o w - u p _ N N 1   w a s _ V B D Z   2 8 % _ N N U   f o r _ I F   s q u a m o u s _ J J   c e l l _ N N 1   c a r c i n o m a _ N N 1   o f _ I O   t h e _ A T   m a x i l l a r y _ J J   s i n u s _ N N 1   . _ .   
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 T o _ T O   f u r t h e r _ R R R   a s s e s s _ V V I   c l i n i c a l l y _ R R   r e l e v a n t _ J J   t r e n d s _ N N 2   i d e n t i f i e d _ V V N   i n _ I I   t h e _ A T   u n i v a r i a b l e _ J J   a n a l y s i s _ N N 1   , _ ,   w e _ P P I S 2   c o m p a r e d _ V V D   t h e _ A T   c h a r a c t e r i s t i c s _ N N 2   o f _ I O   p a t i e n t s _ N N 2   w h o _ P N Q S   r e q u i r e d _ V V D   n o _ A T   i n j e c t i o n s _ N N 2   ( _ (   n _ Z Z 1   = _ F O   1 2 1 _ M C   ; _ ;   2 4 _ M C   . _ .   
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 A l t h o u g h _ C S   t h e s e _ D D 2   f i n d i n g s _ N N 2   a r e _ V B R   c o n s i s t e n t _ J J   w i t h _ I W   t h e _ A T   d e c r e a s e d _ J J   D P O A E s _ N P 2   i n _ I I   t h e _ A T   c u r r e n t _ J J   s t u d y _ N N 1   , _ ,   l o n g i t u d i n a l _ J J   s t u d i e s _ N N 2   w i l l _ V M   b e _ V B I   n e c e s s a r y _ J J   t o _ T O   d e t e r m i n e _ V V I   i f _ C S W   t h e _ A T   t r e n d s _ N N 2   n o t e d _ V V N   i n _ I I   t h i s _ D D 1   s t u d y _ N N 1   a r e _ V B R   c o n s i s t e n t _ J J   w i t h _ I W   p r o g r e s s i v e _ J J   h e a r i n g _ N N 1   l o s s _ N N 1   i n _ I I   d i a b e t e s _ N N 1   . _ .   
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 D e s p i t e _ I I   n o r m o l i p i d e m i a _ N N 1   , _ ,   t h e _ A T   s u b j e c t s _ N N 2   w i t h _ I W   t h e _ A T   u n f a v o r a b l e _ J J   a p o B / a p o A - I _ N N 1   r a t i o _ N N 1   h a d _ V H D   h i g h e r _ J J R   v a l u e s _ N N 2   o f _ I O   T G _ N P 1   a n d _ C C   A I P _ N P 1   a n d _ C C   l o w e r _ J J R   v a l u e s _ N N 2   o f _ I O   L D L - C / a p o B _ N N 1   r a t i o _ N N 1   , _ ,   w h i c h _ D D Q   i n d i c a t e s _ V V Z   a n _ A T 1   i n c r e a s e _ N N 1   o f _ I O   t h e _ A T   n u m b e r _ N N 1   o f _ I O   T G - r i c h _ J J   l i p o p r o t e i n s _ N N 2   a n d _ C C   s m a l l _ J J   , _ ,   d e n s e _ J J   l o w - d e n s i t y _ J J   l i p o p r o t e i n s _ N N 2   . _ .   
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 T h e _ A T   n u m b e r _ N N 1   o f _ I O   t u m o r s _ N N 2   i n _ I I   P i k 3 c a R B D / - _ F U   m i c e _ N N 2   w a s _ V B D Z   s t r i k i n g l y _ R R   r e d u c e d _ V V N   w h e n _ C S   c o m p a r e d _ V V N   t o _ I I   t h e i r _ A P P G E   c o n t r o l _ N N 1   c o u n t e r p a r t s _ N N 2   , _ ,   i n d i c a t i n g _ V V G   t h a t _ D D 1   s u p p r e s s i o n _ N N 1   o f _ I O   R A S _ N P 2   i n t e r a c t i o n _ N N 1   w i t h _ I W   p 1 1 0 a _ F O   g r e a t l y _ R R   i m p a i r s _ V V Z   t u m o r _ N N 1   g r o w t h _ N N 1   a n d _ C C   m a i n t e n a n c e _ N N 1   a t _ I I   t h i s _ D D 1   s t a g e ( F i g u r e 1 B ) . W e _ F O   a l s o _ R R   o b s e r v e d _ V V N   a _ A T 1   d e c r e a s e _ N N 1   i n _ I I   t u m o r _ N N 1   n u m b e r _ N N 1   i n _ I I   P i k 3 c a R B D / - _ F U   m i c e _ N N 2   a t _ I I   t h e _ A T   e n d _ N N 1   o f _ I O   t h e _ A T   e x p e r i m e n t _ N N 1   w h e n _ C S   c o m p a r e d _ V V N   t o _ I I   P i k 3 c a R B D / f l o x _ N N 1   m i c e a t 4 w e e k s _ F O   o f _ I O   a g e _ N N 1   p r i o r _ I I 2 1   t o _ I I 2 2   t h e _ A T   b e g i n n i n g _ N N 1   o f _ I O   t a m o x i f e n _ J J   t r e a t m e n t _ N N 1   , _ ,   t h u s _ R R   s u g g e s t i n g _ V V G   t u m o r _ N N 1   r e g r e s s i o n _ N N 1   i n _ I I   P i k 3 c a R B D / - _ F U   m i c e _ N N 2   a n d _ C C   n o t _ X X   j u s t _ R R   s l o w e r _ J J R   t u m o r _ N N 1   d e v e l o p m e n t _ N N 1   . _ .   
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 D u r i n g _ I I   t h e _ A T   s e s s i o n _ N N T 1   , _ ,   p a t i e n t s _ N N 2   p a r t i a l l y _ R R   c o m p l e t e d _ V V D   t h e i r _ A P P G E   t h e r a p e u t i c _ J J   t a s k s _ N N 2   ( _ (   5 0 % _ N N U   ) _ )   f o r _ I F   t h e _ A T   d a y _ N N T 1   u n d e r _ I I   t h e _ A T   s t u d y _ N N 1   c o o r d i n a t o r _ N N 1   ' _ N U L L   s _ Z Z 1   s u p e r v i s i o n _ N N 1   a n d _ C C   c l a r i f i e d _ V V D   a n y _ D D   q u e s t i o n s _ N N 2   r e g a r d i n g _ I I   t h e i r _ A P P G E   s w a l l o w i n g _ V V G   . _ .   
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 W h i l e _ C S   t h e s e _ D D 2   f i n d i n g s _ N N 2   i n d i c a t e _ V V 0   t h e _ A T   i m p o r t a n c e _ N N 1   o f _ I O   t h e _ A T   U P R _ N N 1   a n d _ C C   E R _ N P 1   f u n c t i o n _ N N 1   i n _ I I   b o t h _ D B 2   n o r m a l _ J J   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   d i s e a s e - r e l a t e d _ J J   c e l l u l a r _ J J   a c t i v i t i e s _ N N 2   , _ ,   t h e y _ P P H S 2   a l s o _ R R   r e f l e c t _ V V 0   t h e _ A T   c o m p l e x i t y _ N N 1   a n d _ C C   c h a l l e n g e s _ N N 2   i n _ I I   f u l l y _ R R   u n d e r s t a n d i n g _ V V G   t h e _ A T   m e c h a n i s m s _ N N 2   a n d _ C C   p h y s i o l o g i c a l _ J J   s i g n i f i c a n c e _ N N 1   o f _ I O   t h e s e _ D D 2   p a t h w a y s _ N N 2   . _ .   
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 I n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   g l a u c o m a _ N N 1   ' _ N U L L   h i g h _ J J   p r e o p e r a t i v e _ J J   I O P _ N N 1   ' _ N U L L   o r _ C C   b o t h _ R R   ' _ N U L L   i t _ P P H 1   c a n _ V M   b e _ V B I   d i f f i c u l t _ J J   t o _ T O   d i s t i n g u i s h _ V V I   w h e t h e r _ C S W   t h e _ A T   i n c r e a s e _ N N 1   i n _ I I   I O P _ N P 1   i s _ V B Z   p r i m a r i l y _ R R   a _ A T 1   p o s t o p e r a t i v e _ J J   c o m p l i c a t i o n _ N N 1   ' _ N U L L   o r _ C C   r a t h e r _ R R   p a r t _ N N 1   o f _ I O   a _ A T 1   g l a u c o m a _ N N 1   c o n d i t i o n _ N N 1   i t s e l f _ P P X 1   . _ .   
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 W e _ P P I S 2   c o n s t r u c t e d _ V V D   f i r s t - l e v e l _ J J   m a p s _ N N 2   t o _ T O   i s o l a t e _ V V I   ( _ (   1 _ M C 1   ) _ )   i n t e r f e r e n c e - r e l a t e d _ J J   a c t i v i t y _ N N 1   d u r i n g _ I I   c o r r e c t _ J J   t r i a l s _ N N 2   ( _ (   i n c o n g r u e n t _ J J   c o r r e c t _ J J   v s _ I I   c o n g r u e n t _ J J   c o r r e c t _ J J   t r i a l s _ N N 2   ) _ )   a n d _ C C   ( _ (   2 _ M C   ) _ )   e r r o r - r e l a t e d _ J J   a c t i v i t y _ N N 1   ( _ (   i n - c o n g r u e n t _ J J   i n c o r r e c t _ J J   v s _ I I   i n c o n g r u e n t _ J J   c o r r e c t _ J J   t r i a l s _ N N 2   ) _ )   . _ .   
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 W i t h o u t _ I W   t h i s _ D D 1   u n d e r s t a n d i n g _ N N 1   , _ ,   i t _ P P H 1   i s _ V B Z   i m p o s s i b l e _ J J   t o _ T O   k n o w _ V V I   w h e t h e r _ C S W   e f f o r t s _ N N 2   s h o u l d _ V M   t a r g e t _ V V I   d e c r e a s i n g _ J J   u s e _ N N 1   o f _ I O   l a b o r a t o r i e s _ N N 2   a n d _ C C   i m a g i n g _ N N 1   o r _ C C   i n c r e a s i n g _ V V G   t h e _ A T   u s e _ N N 1   o f _ I O   t h e s e _ D D 2   t o o l s _ N N 2   t o _ T O   d e c r e a s e _ V V I   m i s s e d _ J J   p u l m o n a r y _ J J   e m b o l i s m _ N N 1   d i a g n o s e s _ N N 2   . _ .   
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 I f _ C S   t h e _ A T   u s e _ N N 1   o f _ I O   p s y c h o t r o p i c _ J J   m e d i c a t i o n _ N N 1   i n c r e a s e s _ V V Z   t h e _ A T   r i s k _ N N 1   o f _ I O   p r e t e r m _ N N 1   b i r t h _ N N 1   , _ ,   t h e n _ R T   w o m e n _ N N 2   w h o _ P N Q S   a r e _ V B R   a b l e _ J K   t o _ T O   a t _ I I   l e a s t _ R G T   t e m p o r a r i l y _ R R   d i s c o n t i n u e _ V V 0   t r e a t m e n t _ N N 1   m a y _ V M   e l e c t _ V V I   t o _ T O   d o _ V D I   s o _ R R   . _ .   
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 S t u d y _ N N 1   s u p e r v i s i o n _ N N 1   : _ :   U u s i t a l o _ N P 1   , _ ,   L e r n m a r k _ N P 1   , _ ,   H a g o p i a n _ J J   , _ ,   S h e _ P P H S 1   , _ ,   T o p p a r i _ N P 1   , _ ,   Z i e g l e r _ N P 1   , _ ,   K r i s c h e r _ N P 1   , _ ,   N o r r i s _ N P 1   , _ ,   V i r t a n e n _ N P 1   . _ .   
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 T h e _ A T   d i f f e r e n c e _ N N 1   w a s _ V B D Z   n o t _ X X   s i g n i f i c a n t _ J J   , _ ,   p e r h a p s _ R R   d u e _ I I 2 1   t o _ I I 2 2   s m a l l _ J J   s a m p l e _ N N 1   s i z e _ N N 1   . _ .   
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 T r a n s i e n t _ J J   p o s t o p e r a t i v e _ J J   p t o s i s _ N N 1   ( _ (   5 0 % _ N N U   ) _ )   a n d _ C C   e x o t r o p i a _ N N 1   ( _ (   5 6 % _ N N U   ) _ )   w e r e _ V B D R   c o m m o n _ J J   i n _ I I   t h e _ A T   c h e m o d e n e r v a t i o n _ N N 1   g r o u p _ N N 1   . _ .   
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 T h e r e _ E X   w e r e _ V B D R   2 3 _ M C   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   p l a c e b o _ N N 1   g r o u p _ N N 1   w h o _ P N Q S   c o m p l e t e d _ V V D   t h e _ A T   1 6 - w e e k _ J J   t r e a t m e n t _ N N 1   p e r i o d _ N N 1   a n d _ C C   2 8 _ M C   i n _ I I   t h e _ A T   d u p i l u m a b _ N N 1   g r o u p _ N N 1   . _ .   
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 T o _ I I   o u r _ A P P G E   k n o w l e d g e _ N N 1   , _ ,   t h e _ A T   P Q _ N P 1   i s _ V B Z   t h e _ A T   f i r s t _ M D   t o o l _ N N 1   t h a t _ C S T   c o m b i n e s _ V V Z   t h e _ A T   b e n e f i t s _ N N 2   o f _ I O   e l e c t r o n i c _ J J   a d m i n i s t r a t i o n _ N N 1   , _ ,   r e a l - t i m e _ J J   d a t a _ N N   c o l l e c t i o n _ N N 1   , _ ,   a n d _ C C   i l l u s t r a t i o n _ N N 1   o f _ I O   p a i n _ N N 1   t h r o u g h _ I I   a _ A T 1   m i x t u r e _ N N 1   o f _ I O   i c o n s _ N N 2   a n d _ C C   w o r d _ N N 1   d e s c r i p t o r s _ N N 2   o n _ I I   a _ A T 1   d e t a i l e d _ J J   v i r t u a l _ J J   b o d y - m a p _ N N 1   . _ .   
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 W i t h _ I W   t h e _ A T   c u r r e n t _ J J   i m p l e m e n t a t i o n _ N N 1   , _ ,   i n _ I I   c o n v e n t i o n a l _ J J   2 - d i m e n s i o n a l _ J J   b r a i n _ N N 1   i m a g i n g _ N N 1   , _ ,   s l i c e _ V V 0   a c c e l e r a t i o n _ N N 1   f a c t o r s _ N N 2   o f _ I O   2 _ M C   o r _ C C   3 _ M C   c a n _ V M   b e _ V B I   u s e d _ V V N   , _ ,   p r e s e r v i n g _ V V G   S N R _ N P 1   w h e n _ C S   c o m p a r e d _ V V N   w i t h _ I W   t h e _ A T   i d e n t i c a l _ J J   n o n a c c e l e r a t e d _ J J   s c a n _ N N 1   , _ ,   w i t h _ I W   l i t t l e _ D A 1   t o _ I I   n o _ A T   i m a g e _ N N 1   a r t i f a c t s _ N N 2   ( _ (   F i g . _ N N 1   6 _ M C   ) _ )   . _ .   
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 m e a s u r e d _ V V D   t h e _ A T   s e r u m _ N N 1   c o n c e n t r a t i o n _ N N 1   o f _ I O   M C P - 1 _ M C 1   i n _ I I   5 0 _ M C   p a t i e n t s _ N N 2   w i t h _ I W   a n k y l o s i n g _ V V G   s p o n d y l i t i s _ N N 1   , _ ,   2 7 _ M C   p a t i e n t s _ N N 2   w i t h _ I W   m e c h a n i c a l _ J J   L B P _ N P 1   a n d _ C C   5 3 _ M C   h e a l t h y _ J J   i n d i v i d u a l s _ N N 2   . _ .   
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 W e _ P P I S 2   p r o p o s e d _ V V D   t o _ T O   s t u d y _ V V I   a _ A T 1   c o n v e n i e n t _ J J   s a m p l e _ N N 1   s i z e _ N N 1   , _ ,   w i t h _ I W   4 0 _ M C   p a r t i c i p a n t s _ N N 2   i n _ I I   e a c h _ D D 1   g r o u p _ N N 1   . _ .   
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 T h e _ A T   s u b j e c t s _ N N 2   h a d _ V H D   n o _ A T   a c u t e _ J J   o r _ C C   c h r o n i c _ J J   p a i n _ N N 1   c o n d i t i o n s _ N N 2   , _ ,   a n d _ C C   n o n e _ P N   t o o k _ V V D   m e d i c a t i o n _ N N 1   o n e _ M C 1   d a y _ N N T 1   p r i o r _ I I 2 1   t o _ I I 2 2   t h e _ A T   s t u d y _ N N 1   . _ .   
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 I n d e e d _ R R   , _ ,   d r u g - t o l e r a n t _ J J   A 3 7 5 - G F P _ J J   c e l l s _ N N 2   d i s p l a y _ V V 0   i n c r e a s e d _ J J   e x p r e s s i o n _ N N 1   o f _ I O   g e n e s _ N N 2   c h a r a c t e r i s t i c _ N N 1   f o r _ I F   r e w i r e d _ J J   c e l l s _ N N 2   ( _ (   F i g u r e _ N N 1   S 1 F _ F O   ) _ )   . _ .   
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 N o v e l _ J J   s e l e c t i v e _ J J   c h e m i c a l _ J J   i n h i b i t o r s _ N N 2   f o r _ I F   e n d o p l a s m i c _ J J   a m i n o p e p t i d a s e s _ N N 2   a r e _ V B R   c u r r e n t l y _ R R   b e e n _ V B N   d e v e l o p e d _ V V N   ( _ (   P a p a k y r i a k o u _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   ' _ N U L L   
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 2 0 1 3 _ M C   ; _ ;   Z e r v o u d i _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   ' _ N U L L   
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 W h e n _ C S   a n a l y z i n g _ V V G   t h e _ A T   i n c i d e n c e _ N N 1   o f _ I O   a d v e r s e _ J J   e v e n t s _ N N 2   i n _ I I   P S A _ N P 1   i n _ I I   R C T s _ N P 1   , _ ,   w e _ P P I S 2   f o u n d _ V V D   t h a t _ C S T   t h e _ A T   i n c i d e n c e _ N N 1   o f _ I O   a g i t a t i o n _ N N 1   , _ ,   a p n e a _ N N 1   , _ ,   b r a d y c a r d i a _ N N 1   , _ ,   h y p o t e n s i o n _ N N 1   , _ ,   h y p o x i a _ N N 1   , _ ,   a n d _ C C   v o m i t i n g _ N N 1   w e r e _ V B D R   h i g h e r _ J J R   . _ .   
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 M e a s u r i n g _ V V G   s i t e s _ N N 2   f o r _ I F   a i r w a y _ N N 1   p r e s s u r e _ N N 1   ( _ (   P a w _ N P 1   ) _ )   a n d _ C C   f l o w _ N N 1   a r e _ V B R   a t _ I I   t h e _ A T   p r o x i m a l _ J J   e n d _ N N 1   o f _ I O   t h e _ A T   D L T _ N P 1   . _ .   
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 P a r t i c i p a n t s _ N N 2   i n _ I I   t h e _ A T   c o n t r o l _ N N 1   g r o u p _ N N 1   r e p o r t e d _ V V D   s i g n i f i c a n t _ J J   p r e t r e a t m e n t _ N N 1   t o _ I I   p o s t t r e a t m e n t _ N N 1   i m p r o v e m e n t s _ N N 2   i n _ I I   l i f e _ N N 1   s a t i s f a c t i o n _ N N 1   , _ ,   a n d _ C C   p r e t r e a t m e n t _ N N 1   t o _ I I   f o l l o w - u p _ J J   i m p r o v e m e n t s _ N N 2   i n _ I I   p a i n _ N N 1   i n t e n s i t y _ N N 1   a n d _ C C   p a i n _ N N 1   c o n t r o l _ N N 1   . _ .   
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 P a i n _ N N 1   c a t a s t r o p h i z i n g _ V V G   : _ :   T h e _ A T   1 3 - i t e m _ J J   P a i n _ N N 1   C a t a s t r o p h i z i n g _ V V G   S c a l e _ N N 1   ( _ (   P C S _ N N 2   ) _ )   8 0 _ M C   a s s e s s e s _ V V Z   3 _ M C   d o m a i n s _ N N 2   o f _ I O   p a i n - r e l a t e d _ J J   c a t a s t r o p h i z i n g _ N N 1   ( _ (   r u m i n a t i o n _ N N 1   , _ ,   h e l p l e s s n e s s _ N N 1   , _ ,   a n d _ C C   m a g n i f i c a t i o n _ N N 1   ) _ )   u s i n g _ V V G   a _ A T 1   0 t o _ F O   4 _ M C   r a t i n g _ N N 1   s c a l e _ N N 1   ( _ (   ' _ N U L L   N o t _ X X   a t _ I I   a l l _ D B   ' _ N U L L   t o _ I I   ' _ N U L L   A l l _ D B   t h e _ A T   t i m e _ N N T 1   ' _ N U L L   ) _ )   . _ .   
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 H o w e v e r _ R R   , _ ,   i t s _ A P P G E   o r i g i n _ N N 1   w a s _ V B D Z   a t _ I I   t h e _ A T   l o w e r _ J J R   a r e a _ N N 1   o f _ I O   t h e _ A T   w a l l _ N N 1   , _ ,   a t _ I I   a n _ A T 1   a r e a _ N N 1   t h a t _ C S T   , _ ,   a l t h o u g h _ C S   c l o s e _ J J   , _ ,   d i d _ V D D   n o t _ X X   a d j o i n _ V V I   t h e _ A T   m a r g i n s _ N N 2   o f _ I O   t h e _ A T   m i d d l e _ J J   m e a t a l _ J J   a n t r o s t o m y _ N N 1   . _ .   
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 T h e _ A T   i m a g e s _ N N 2   a r e _ V B R   t r a n s f e r r e d _ V V N   t o _ I I   t h e _ A T   c l o u d _ N N 1   f o r _ I F   a n a l y s i s _ N N 1   . _ .   
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 T h i s _ D D 1   p o i n t s _ V V Z   t o _ I I   t h e _ A T   i m p o r t a n c e _ N N 1   o f _ I O   m a i n t a i n i n g _ V V G   m e s h e s _ N N 2   i n _ I I   a _ A T 1   f l a t _ N N 1   ( _ (   a s _ I I 3 1   o p p o s e d _ I I 3 2   t o _ I I 3 3   f o l d e d _ J J   ) _ )   c o n f i g u r a t i o n _ N N 1   t o _ T O   m i n i m i z e _ V V I   t h e _ A T   a m o u n t _ N N 1   o f _ I O   m a t e r i a l _ N N 1   p e r _ I I   a r e a _ N N 1   a n d _ C C   o f _ I O   c h o o s i n g _ V V G   m e s h e s _ N N 2   i n _ I I   w h i c h _ D D Q   t h e _ A T   s p a c e s _ N N 2   b e t w e e n _ I I   f i b e r s _ N N 2   ( _ (   p o r e s _ N N 2   ) _ )   a r e _ V B R   w i d e _ J J   e n o u g h _ R R   t h a t _ C S T   t h e _ A T   h o s t _ N N 1   r e s p o n s e _ N N 1   t o _ I I   2 _ M C   a d j a c e n t _ J J   f i b e r s _ N N 2   d o e s _ V D Z   n o t _ X X   o v e r l a p _ V V I   . _ .   
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 B y _ I I   a n a l y z i n g _ V V G   t h e _ A T   f i n d i n g s _ N N 2   f r o m _ I I   1 8 _ M C   p u b l i s h e d _ J J   s t u d i e s _ N N 2   i n c l u d i n g _ I I   4 , 6 0 7 _ M C   p a r t i c i p a n t s _ N N 2   , _ ,   t h e _ A T   a u t h o r s _ N N 2   f o u n d _ V V D   t h a t _ C S T   t h e _ A T   e f f e c t _ N N 1   o f _ I O   O P R M 1 _ F O   A 1 1 8 G _ F O   o n _ I I   p o s t o p e r a t i v e _ J J   p a i n _ N N 1   i s _ V B Z   g r e a t l y _ R R   d r i v e n _ V V N   b y _ I I   e t h n i c i t y _ N N 1   a n d _ C C   i s _ V B Z   m o s t _ R G T   o b v i o u s _ J J   i n _ I I   A s i a n _ J J   b u t _ C C B   n o t _ X X   C a u c a s i a n _ J J   p a t i e n t _ J J   p o p u l a t i o n s _ N N 2   . _ .   
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 T h e _ A T   m o s t _ R G T   c o m m o n _ J J   T E A E s _ N P 2   l e a d i n g _ V V G   t o _ I I   d i s c o n t i n u a t i o n _ N N 1   w e r e _ V B D R   i n s o m n i a _ N N 1   ( _ (   8 _ M C   p a t i e n t s _ N N 2   , _ ,   2 . 9 % _ F O   ) _ )   , _ ,   a g g r e s s i o n _ N N 1   ( _ (   5 _ M C   p a t i e n t s _ N N 2   , _ ,   1 . 8 % _ F O   ) _ )   , _ ,   a n d _ C C   d e c r e a s e d _ J J   a p p e t i t e _ N N 1   , _ ,   h e a d a c h e _ N N 1   , _ ,   a n d _ C C   d e p r e s s e d _ J J   m o o d _ N N 1   ( _ (   e a c h _ D D 1   i n _ I I   4 _ M C   p a r t i c i p a n t s _ N N 2   , _ ,   1 . 4 % _ F O   ) _ )   . _ .   
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 O n _ I I   t h e _ A T   c o n t r a r y _ N N 1   , _ ,   l e s i o n _ N N 1   s i z e _ N N 1   w a s _ V B D Z   l a r g e r _ J J R   i n _ I I   A M + / _ J J   C N V _ N P 1   m o d e l _ N N 1   m i c e _ N N 2   , _ ,   p r e s u m a b l y _ R R   d u e _ I I 2 1   t o _ I I 2 2   t h e _ A T   a n t i i n f l a m m a t o r y _ J J   f u n c t i o n _ N N 1   o f _ I O   A M . D e s p i t e _ N P 1   t h e _ A T   s u c c e s s _ N N 1   o f _ I O   a n t i - v a s c u l a r _ J J   e n d o t h e l i a l _ J J   g r o w t h _ N N 1   f a c t o r _ N N 1   a g e n t s _ N N 2   f o r _ I F   t h e _ A T   t r e a t m e n t _ N N 1   o f _ I O   r e t i n o c h o r o i d a l _ J J   d i s e a s e _ N N 1   , _ ,   t h e r a p e u t i c _ J J   s h o r t c o m i n g s _ N N 2   r e m a i n _ V V 0   . _ .   
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 T h e _ A T   p e r c e n t _ N N U   i m p r o v e m e n t _ N N 1   i n _ I I   t h e _ A T   g l o b a l _ J J   w a l l - m o t i o n _ J J   i n d e x _ N N 1   w a s _ V B D Z   l a r g e r _ J J R   f o r _ I F   p a t i e n t s _ N N 2   w h o _ P N Q S   w e r e _ V B D R   f r e e _ J J   o f _ I O   m o d e r a t e _ J J   o r _ C C   s e v e r e _ J J   m i t r a l _ J J   r e g u r g i t a t i o n _ N N 1   a t _ I I   2 _ M C   y e a r s _ N N T 2   t h a n _ C S N   f o r _ I F   t h o s e _ D D 2   w i t h _ I W   s u c h _ D A   m i t r a l _ J J   r e g u r g i t a t i o n _ N N 1   ( _ (   1 6 . 5 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   2 0 . 1 % _ F O   v s . _ I I   7 . 4 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   1 6 . 7 % _ F O   , _ ,   P = 0 . 0 0 8 _ F O   ) _ )   ( _ (   F i g . _ N N 1   1 _ M C 1   ) _ )   . _ .   
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 F u n c t i o n a l _ J J   a s p e c t s _ N N 2   o f _ I O   r i b b o n _ N N 1   s y n a p s e s _ V V Z   T h e _ A T   s t u d y _ N N 1   o f _ I O   r i b b o n _ N N 1   s y n a p s e s _ V V Z   i n _ I I   z e b r a f i s h _ N N 1   h a i r _ N N 1   c e l l s _ N N 2   h a s _ V H Z   p r o f i t e d _ V V N   f r o m _ I I   r e c e n t l y _ R R   d e v e l o p e d _ J J   m e t h o d s _ N N 2   t h a t _ C S T   e n a b l e _ V V 0   q u a n t i f i c a t i o n _ N N 1   o f _ I O   d e f i c i t s _ N N 2   i n _ I I   s y n a p t i c _ J J   t r a n s m i s s i o n _ N N 1   . _ .   
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 T h i s _ D D 1   i s _ V B Z   p r o b a b l y _ R R   d u e _ I I 2 1   t o _ I I 2 2   i t s _ A P P G E   b r o a d e r _ J J R   a p p r o a c h _ N N 1   t o _ I I   t h e _ A T   d i a g n o s i s _ N N 1   o f _ I O   f r a i l t y _ N N 1   a n d _ C C   t h e _ A T   i n c l u s i o n _ N N 1   o f _ I O   c o g n i t i v e _ J J   a n d _ C C   p s y c h o s o c i a l _ J J   m a r k e r s _ N N 2   r a t h e r _ I I 2 1   t h a n _ I I 2 2   s o l e l y _ R R   r e l y i n g _ V V G   o n _ I I   p h y s i c a l _ J J   m a r k e r s _ N N 2   . _ .   
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 F o r _ I F   t h o s e _ D D 2   o f _ I O   u s _ P P I O 2   w h o _ P N Q S   h a v e _ V H 0   a l r e a d y _ R R   i n t r o d u c e d _ V V N   m i n d f u l n e s s _ N N 1   i n t o _ I I   o u r _ A P P G E   i n t e g r a t e d _ J J   t h e r a p y _ N N 1   p r o g r a m s _ N N 2   f o r _ I F   m a n y _ D A 2   y e a r s _ N N T 2   n o w _ R T   , _ ,   w e _ P P I S 2   h a v e _ V H 0   a _ A T 1   n e w _ J J   p r a c t i c a l _ J J   t o o l _ N N 1   t o _ T O   u s e _ V V I   w i t h _ I W   o u r _ A P P G E   c l i e n t s _ N N 2   . _ .   
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 O t h e r _ J J   f a c t o r s _ N N 2   a s s o c i a t e d _ V V N   w i t h _ I W   p e r s i s t e n t _ J J   m u s c l e _ N N 1   w e a k n e s s _ N N 1   i n c l u d e _ V V 0   o l d e r _ J J R   a g e _ N N 1   , _ ,   d e m e n t i a _ N N 1   , _ ,   c a n c e r _ N N 1   d i a g n o s e s _ N N 2   , _ ,   m a l n u t r i t i o n _ N N 1   , _ ,   s o c i a l _ J J   i s o l a t i o n _ N N 1   , _ ,   a n d _ C C   p r e e x i s t i n g _ V V G   f u n c t i o n a l _ J J   i m m o b i l i t y _ N N 1   . _ .   
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 I n c l u d e _ V V 0   h e a l t h y _ J J   l i f e s t y l e _ N N 1   g o a l s _ N N 2   i n _ I I   t r e a t m e n t _ N N 1   p l a n n i n g _ V V G   f o r _ I F   p e o p l e _ N N   w i t h _ I W   m e n t a l _ J J   i l l n e s s _ N N 1   . _ .   
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 D e c l a r a t i o n _ N N 1   o f _ I O   i n t e r e s t s _ N N 2   A l l _ D B   a u t h o r s _ N N 2   r e p o r t _ N N 1   g r a n t s _ V V Z   f r o m _ I I   t h e _ A T   N a t i o n a l _ J J   I n s t i t u t e _ N N 1   f o r _ I F   H e a l t h _ N N 1   R e s e a r c h _ N N 1   ( _ (   N I H R _ N P 1   ) _ )   d u r i n g _ I I   t h e _ A T   c o u r s e _ N N 1   o f _ I O   t h e _ A T   s t u d y _ N N 1   . _ .   
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 G a b a p e n t i n _ N N 1   G r o u p _ N N 1   : _ :   G r o u p _ N N 1   G _ N P 1   T h i s _ D D 1   g r o u p _ N N 1   r e c e i v e d _ V V D   G a b a p e n t i n _ N P 1   c a p s u l e s _ N N 2   ( _ (   N e u r o n t i n _ N P 1   C a p s u l e _ N N 1   ; _ ;   P f i z e r _ N P 1   ) _ )   : _ :   1 2 0 0 _ M C   m g _ N N U   ( _ (   3 _ M C   c a p s u l e s _ N N 2   o f _ I O   4 0 0 _ M C   m g _ N N U   d o s a g e _ N N 1   ) _ )   2 _ M C   h o u r s _ N N T 2   b e f o r e _ I I   s u r g e r y _ N N 1   a n d _ C C   1 2 _ M C   h o u r s _ N N T 2   a f t e r _ I I   s u r g e r y _ N N 1   a n d _ C C   4 0 0 _ M C   m g _ N N U   3 _ M C   t i m e s _ N N T 2   d a i l y _ R R   f o r _ I F   2 _ M C   d a y s _ N N T 2   . _ .   
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 R e g a r d l e s s _ R R   , _ ,   t h e _ A T   d e t e c t i o n _ N N 1   o f _ I O   S S 1 8 - S S X _ J J   g e n e _ N N 1   f u s i o n _ N N 1   r e m a i n s _ V V Z   t h e _ A T   g o l d _ N N 1   s t a n d a r d _ N N 1   . _ .   
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 A v o i d a n c e _ N N 1   s t r a t e g i e s _ N N 2   i n c l u d e d _ V V D   a n y b e h a v i o r a l _ J J   r e s p o n s e _ N N 1   t o _ I I   a n t i c i p a t i o n _ N N 1   t h a t _ C S T   p a r t i c i p a n t s _ N N 2   r e p o r t e d _ V V D   e m p l o y i n g _ V V G   i n _ I I   a n _ A T 1   a t t e m p t _ N N 1   t o _ T O   h i d e _ V V I   o r e s c a p e _ N N 1   f r o m _ I I   a n _ A T 1   i m p e n d i n g _ J J   m o m e n t _ N N 1   o f _ I O   s t u t t e r i n g _ V V G   . _ .   
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 A _ A T 1   s e c o n d _ N N T 1   l a r g e r _ J J R   r e t r o s p e c t i v e _ J J   s t u d y _ N N 1   o f _ I O   3 5 3 3 _ M C   n u l l i p a r o u s _ J J   w o m e n _ N N 2   w i t h _ I W   p r o l o n g e d _ J J   s e c o n d _ M D   s t a g e _ N N 1   p l u s _ I I   e p i d u r a l _ N N 1   w h o _ P N Q S   w e r e _ V B D R   a l l o w e d _ V V N   t o _ T O   l a b o r _ V V I   l o n g e r _ R R R   a l s o _ R R   c o n f i r m e d _ V V D   a _ A T 1   s i m i l a r _ J J   C D _ N N 1   r a t e _ N N 1   o f _ I O   2 0 . 0 % _ F O   . _ .   
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 S t u d i e s _ N N 2   f o c u s e d _ V V N   o n _ I I   d i r e c t _ J J   h e a d _ N N 1   i m p a c t s _ N N 2   t o _ I I   a n i m a l s _ N N 2   a n d _ C C   c a d a v e r s _ N N 2   , _ ,   w h i c h _ D D Q   r e l a t e d _ V V D   t h e _ A T   r e s u l t i n g _ J J   l i n e a r _ J J   a c c e l e r a t i o n s _ N N 2   t o _ I I   i n j u r y _ N N 1   t o l e r a n c e _ N N 1   . _ .   
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 T h e _ A T   p r e v a i l i n g _ J J   h y p o t h e s i s _ N N 1   i n _ I I   t h e _ A T   A D _ N N 1   f i e l d _ N N 1   p r e v i o u s l y _ R R   w a s _ V B D Z   t h a t _ D D 1   a t o p y _ N N 1   i s _ V B Z   d u e _ I I 2 1   t o _ I I 2 2   a n _ A T 1   ' _ N U L L   o v e r a c t i v e _ J J   ' _ N U L L   T h - 2 _ M C   i m m u n e _ J J   s y s t e m _ N N 1   . _ .   
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 M e a n _ J J   B M I _ N N 1   w a s _ V B D Z   a l s o _ R R   h i g h _ J J   i n _ I I   m e n _ N N 2   a n d _ C C   w o m e n _ N N 2   i n _ I I   h i g h - i n c o m e _ J J   E n g l i s h - s p e a k i n g _ J J   c o u n t r i e s _ N N 2   , _ ,   a n d _ C C   i n _ I I   w o m e n _ N N 2   i n _ I I   s o u t h e r n _ J J   A f r i c a _ N P 1   a n d _ C C   i n _ I I   t h e _ A T   M i d d l e _ J J   E a s t _ N D 1   a n d _ C C   n o r t h _ N D 1   A f r i c a _ N P 1   . _ .   
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 T h e _ A T   d i r e c t _ J J   e f f e c t _ N N 1   o f r a d i a t i o n _ N N 1   o n _ I I   m u s c l e _ N N 1   u l t i m a t e l y _ R R   r e s u l t s _ V V Z   i n _ I I   f i b r o s i s _ N N 1   a n d _ C C   c o n t r a c t u r e _ V V 0   w i t h _ I W   a _ A T 1   g r a d u a l _ J J   o n s e t _ N N 1   n o t e d _ V V N   a t _ I I   a b o u t _ R G   9 _ M C   w e e k s _ N N T 2   a f t e r _ I I   t r e a t m e n t _ N N 1   i s _ V B Z   c o m p l e t e d _ V V N   . _ .   
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 T h e _ A T   O A S E S - S _ N P 1   a s s e s s e s _ V V Z   a l l _ D B   o f _ I O   t h e _ A T   a s p e c t s _ N N 2   o f _ I O   a _ A T 1   c h i l d _ N N 1   ' _ N U L L   s _ Z Z 1   e x p e r i e n c e _ N N 1   o f _ I O   t h e _ A T   s t u t t e r i n g _ J J   d i s o r d e r _ N N 1   a s _ C S A   r e f l e c t e d _ V V N   i n _ I I   t h e _ A T   I C F _ N N 1   . _ .   
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 T h i s _ D D 1   e d u c a t i o n a l _ J J   i n i t i a t i v e _ N N 1   t o _ T O   p r o m o t e _ V V I   s c h o l a r l y _ J J   d i a l o g u e _ N N 1   i n _ I I   t h e _ A T   d i g i t a l _ J J   c o m m u n i t y _ N N 1   a t t r a c t e d _ V V D   a _ A T 1   g l o b a l _ J J   a u d i e n c e _ N N 1   b y _ I I   u s i n g _ V V G   v a r i o u s _ J J   s o c i a l _ J J   m e d i a _ N N   p l a t f o r m s _ N N 2   , _ ,   i n c l u d i n g _ I I   a _ A T 1   b l o g _ N N 1   , _ ,   T w i t t e r _ V V 0   , _ ,   a n d _ C C   G o o g l e _ N P 1   H a n g o u t _ N P 1   . _ .   
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 L o c a t e d _ V V N   a t _ I I   2 p 1 6 . 1 _ F O   , _ ,   t h e _ A T   i n t e r v a l _ N N 1   c o n t a i n e d _ V V D   g e n e s _ N N 2   e n c o d i n g _ V V G   v a c c i n i a - r e l a t e d _ J J   k i n a s e _ N N 1   2 _ M C   ( _ (   V R K 2 _ F O   ) _ )   a n d _ C C   F a n c o n i _ J J   a n a e m i a _ N N 1   , _ ,   c o m p l e m e n t a t i o n _ N N 1   g r o u p _ N N 1   L _ Z Z 1   ( _ (   F A N C L _ N P 1   ; _ ;   f i g u r e _ N N 1   4 _ M C   ) _ )   . _ .   
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 T h e _ A T   c o m b i n a t i o n _ N N 1   o f _ I O   a _ A T 1   c h a n g i n g _ J J   l e g i s l a t i v e _ J J   e n v i r o n m e n t _ N N 1   a n d _ C C   s e v e r a l _ D A 2   r e c e n t _ J J   m e d i c a l _ J J   d e v i c e _ N N 1   c o n t r o v e r s i e s _ N N 2   i n _ I I   t h e _ A T   f i e l d _ N N 1   u n d e r s c o r e s _ V V Z   t h e _ A T   n e e d _ N N 1   f o r _ I F   t o _ T O   u n d e r s t a n d _ V V I   c r i t i c a l _ J J   i s s u e s _ N N 2   s u r r o u n d i n g _ V V G   m e d i c a l _ J J   d e v i c e _ N N 1   r e g u l a t i o n _ N N 1   . _ .   
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 L a t e r _ J J R   p a t i e n t s _ N N 2   u n d e r g o _ V V 0   a _ A T 1   p r o g r e s s i v e _ J J   d e c l i n e _ N N 1   o f _ I O   v i s u a l _ J J   a c u i t y _ N N 1   i n _ I I   t h e _ A T   c e n t r a l _ J J   f i e l d _ N N 1   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   a n _ A T 1   i m p a i r m e n t _ N N 1   o f c h r o m a t i c _ J J   d i s c r i m i n a t i o n _ N N 1   , _ ,   d u e _ I I 2 1   t o _ I I 2 2   t h e _ A T   g r a d u a l _ J J   d e m i s e _ N N 1   o f _ I O   c o n e s _ N N 2   . _ .   
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 I f _ C S   c e r e b r a l _ J J   m o t o r _ N N 1   s t r u c t u r e s _ N N 2   c o n t r o l l i n g _ V V G   l e g _ N N 1   m o v e m e n t s _ N N 2   a r e _ V B R   n e c e s s a r y _ J J   f o r _ I F   l o c o m o t o r _ N N 1   a d a p t a t i o n _ N N 1   o f _ I O   s p a t i a l _ J J   g a i t _ N N 1   p a r a m e t e r s _ N N 2   , _ ,   w e _ P P I S 2   w o u l d _ V M   e x p e c t _ V V I   p e r s o n s _ N N 2   w i t h _ I W   p o s t s t r o k e _ N N 1   h e m i p a r e s i s _ N N 1   t o _ T O   d e m o n s t r a t e _ V V I   r e d u c e d _ J J   a d a p t a t i o n _ N N 1   o f _ I O   t h e _ A T   s t e p _ N N 1   l e n g t h _ N N 1   s p a t i a l _ J J   c o m p o n e n t _ N N 1   . _ .   
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 T e c h n o l o g y _ N N 1   a n d _ C C   V e n d o r s _ N N 2   A l t h o u g h _ C S   t e c h n o l o g i c a l _ J J   c a p a b i l i t y _ N N 1   i s _ V B Z   n o t _ X X   a _ A T 1   t r u e _ J J   b a r r i e r _ N N 1   , _ ,   t h e _ A T   i m p l e m e n t a t i o n _ N N 1   o f _ I O   t e c h n o l o g y _ N N 1   a n d _ C C   e x e c u t i o n _ N N 1   o f _ I O   u s e _ N N 1   c a s e s _ N N 2   b y _ I I   h e a l t h _ N N 1   i n f o r m a t i o n _ N N 1   e x c h a n g e s _ N N 2   a n d _ C C   t h e i r _ A P P G E   v e n d o r s _ N N 2   r e m a i n _ V V 0   a _ A T 1   m a j o r _ J J   b a r r i e r _ N N 1   . _ .   
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 F i n a l l y _ R R   , _ ,   t h e _ A T   f a c t _ N N 1   t h a t _ C S T   t h e _ A T   s a m p l e _ N N 1   w a s _ V B D Z   d r a w n _ V V N   f r o m _ I I   a _ A T 1   s p e c i a l i s t _ N N 1   d e r m a t o l o g y _ N N 1   c l i n i c _ N N 1   a l s o _ R R   p l a c e s _ V V Z   b o u n d a r i e s _ N N 2   o n _ I I   t h e _ A T   g e n e r a l i z a b i l i t y _ N N 1   o f _ I O   t h e _ A T   r e s u l t s _ N N 2   . _ .   
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 I m p o r t a n t l y _ R R   , _ ,   a l t h o u g h _ C S   w e _ P P I S 2   w e r e _ V B D R   a b l e _ J K   t o _ T O   d e f i n e _ V V I   a t _ I I   b a s e l i n e _ N N 1   s u b g r o u p s _ N N 2   o f _ I O   w o m e n _ N N 2   w i t h _ I W   h i g h e r _ J J R   r a t e s _ N N 2   o f _ I O   p r e t e r m _ N N 1   b i r t h _ N N 1   ( _ (   i n c l u d i n g _ I I   t h o s e _ D D 2   w i t h _ I W   a _ A T 1   s h o r t _ J J   c e r v i x _ N N 1   a n d _ C C   t h o s e _ D D 2   w i t h _ I W   a _ A T 1   p o s i t i v e _ J J   f i b r o n e c t i n _ N N 1   t e s t _ N N 1   ) _ )   , _ ,   o u r _ A P P G E   d a t a _ N N   s u g g e s t _ V V 0   t h a t _ C S T   t h e _ A T   e f f i c a c y _ N N 1   o f _ I O   p r o g e s t e r o n e _ N N 1   ( _ (   f o r _ I F   a l l _ D B   o u t c o m e s _ N N 2   ) _ )   i s _ V B Z   s i m i l a r _ J J   a c r o s s _ I I   g r o u p s _ N N 2   . _ .   
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 A n a t o m i c a l l y _ R R   , _ ,   t h e s e _ D D 2   n u c l e i _ N N 2   c a n _ V M   b e _ V B I   r e a d i l y _ R R   a p p r e c i a t e d _ V V N   m a c r o s c o p i c a l l y _ R R   b e c a u s e _ I I 2 1   o f _ I I 2 2   a _ A T 1   p i g m e n t _ N N 1   a c c u m u l a t e d _ V V N   w i t h i n _ I I   t h e _ A T   c e l l s _ N N 2   c a l l e d _ V V N   n e u r o m e l a n i n _ N N 1   . _ .   
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 T r a d i t i o n a l _ J J   s u r g i c a l _ J J   a p p r o a c h e s _ N N 2   h a v e _ V H 0   b e e n _ V B N   p e r f o r m e d _ V V N   t h r o u g h _ I I   e x t e r n a l - a c c e s s _ J J   i n c i s i o n s _ N N 2   ( _ (   l a t e r a l _ J J   r h i n o t o m y _ N N 1   , _ ,   b i c o r o n a l _ J J   f l a p _ N N 1   , _ ,   o r _ C C   a _ A T 1   c o m b i n a t i o n _ N N 1   o f _ I O   t h e _ A T   t w o _ M C   ) _ )   , _ ,   a n d _ C C   s u c h _ D A   a p p r o a c h e s _ N N 2   c a n _ V M   l e a d _ V V I   t o _ I I   l o c a l _ J J   c o m p l i c a t i o n s _ N N 2   . _ .   
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 T h e _ A T   r e s u l t s _ N N 2   o b t a i n e d _ V V N   f o r _ I F   t h e _ A T   s a f e t y - a n a l y s i s _ J J   s e t _ N N 1   w e r e _ V B D R   c o n s i s t e n t _ J J   w i t h _ I W   t h o s e _ D D 2   o b t a i n e d _ V V N   f o r _ I F   t h e _ A T   I T T _ N P 1   s e t _ V V D   . _ .   
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 T h e r e f o r e _ R R   , _ ,   t h i s _ D D 1   f i n d i n g _ N N 1   w a s _ V B D Z   c o n c l u d e d _ V V N   n o t _ X X   t o _ T O   c o n t r i b u t e _ V V I   t o _ I I   t h e _ A T   m o l e c u l a r _ J J   d i a g n o s i s _ N N 1   o f _ I O   I R D _ N N 1   f o r _ I F   t h i s _ D D 1   i n d i v i d u a l _ N N 1   . _ .   
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 A b s t r a c t _ J J   G e n o m e - w i d e _ J J   a s s o c i a t i o n _ N N 1   s t u d i e s _ N N 2   h a v e _ V H 0   i d e n t i f i e d _ V V N   S N P s _ N P 2   t h a t _ C S T   a r e _ V B R   s e n s i t i v e _ J J   f o r _ I F   t a u _ N N 1   o r _ C C   T D P - 4 3 _ M C   p a t h o l o g y _ N N 1   i n _ I I   f r o n t o t e m p o r a l _ J J   l o b a r _ N N 1   d e g e n e r a t i o n _ N N 1   ( _ (   F T L D _ N P 1   ) _ )   . _ .   
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 W e _ P P I S 2   g e n e r a t e d _ V V D   a _ A T 1   k n o c k i n _ N N 1   m o u s e _ N N 1   m o d e l _ N N 1   c a r r y i n g _ V V G   t h e _ A T   N 2 2 9 S _ F O   m u t a t i o n _ N N 1   i n _ I I   t h e _ A T   e n d o g e n o u s _ J J   R d s _ N N 2   l o c u s _ N N 1   ( _ (   S t u c k _ J J   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 5 _ M C   ) _ )   . _ .   
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 T h e s e _ D D 2   r e s u l t s _ N N 2   s u g g e s t _ V V 0   t h a t _ C S T   o n _ I I   o c c a s i o n _ N N 1   t h e _ A T   i n t r a c e l l u l a r _ J J   c a l c i u m _ N N 1   l e v e l _ N N 1   m a y _ V M   b e _ V B I   h i g h _ J J   e n o u g h _ R R   t o _ T O   a l l o w _ V V I   f o r _ I F   s p o n t a n e o u s _ J J   r e l e a s e _ N N 1   , _ ,   b u t _ C C B   o t h e r w i s e _ R R   e v o k e d _ V V N   a c t i v i t y _ N N 1   i s _ V B Z   a b s e n t _ J J   i n _ I I   c a v 1 _ F O   . _ .   
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 I m p o r t a n t l y _ R R   , _ ,   f a t i g u e _ N N 1   c a n _ V M   o c c u r _ V V I   a t _ I I   d i f f e r e n t _ J J   l e v e l s _ N N 2   f r o m _ I I   t h e _ A T   b r a i n _ N N 1   t o _ I I   t h e _ A T   s k e l e t a l _ J J   m u s c l e s _ N N 2   . _ .   
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 A _ A T 1   s t u d y _ N N 1   o f _ I O   M S _ N N 1   p l a q u e s _ N N 2   r e v e a l e d _ V V D   d e c r e a s e d _ J J   l e v e l s _ N N 2   o f _ I O   a n t i o x i d a n t s _ N N 2   a n d _ C C   i n c r e a s e d _ J J   f r e e - r a d i c a l _ J J   a c t i v i t y _ N N 1   ( _ (   L a n g e m a n n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 9 9 2 _ M C   ) _ )   . _ .   
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 T h e _ A T   m a n u s c r i p t _ N N 1   w i l l _ V M   u n d e r g o _ V V I   c o p y e d i t i n g _ V V G   , _ ,   t y p e s e t t i n g _ N N 1   , _ ,   a n d _ C C   r e v i e w _ N N 1   o f _ I O   t h e _ A T   r e s u l t i n g _ J J   p r o o f _ N N 1   b e f o r e _ C S   i t _ P P H 1   i s _ V B Z   p u b l i s h e d _ V V N   i n _ I I   i t s _ A P P G E   f i n a l _ J J   c i t a b l e _ J J   f o r m _ N N 1   . _ .   
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 T o _ I I   d a t e _ N N 1   , _ ,   o v e r _ R G   1 0 0 _ M C   d e v i c e s _ N N 2   h a v e _ V H 0   b e e n _ V B N   i m p l a n t e d _ V V N   w o r l d w i d e _ R L   , _ ,   r e p r e s e n t i n g _ V V G   t h e _ A T   l a r g e s t _ J J T   g r o u p _ N N 1   o f _ I O   p a t i e n t s _ N N 2   c u r r e n t l y _ R R   t r e a t e d _ V V N   w i t h _ I W   v i s u a l _ J J   p r o s t h e s e s _ N N 2   . _ .   
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 T h o s e _ D D 2   t r a i n i n g _ V V G   i n _ I I   V E _ N P 1   i m p r o v e d _ V V D   M A L - A S _ N P 2   s c o r e s _ N N 2   a t _ I I   P O S T _ N N 1   b y _ I I   0 . 5 _ M C   p o i n t s _ N N 2   ( _ (   t _ Z Z 1   = _ F O   1 . 9 7 _ M C   ; _ ;   p _ N N U   l e s s _ D A R   t h a n _ C S N   . 0 5 _ M C   ; _ ;   E S _ N P 1   = _ F O   0 . 6 3 _ M C   ; _ ;   F i g u r e _ N N 1   4 G _ N N U   ) _ )   a n d _ C C   R P S S _ N P 1   5 3 _ M C   c l o s e _ J J   t o t a l _ J J   s c o r e s _ N N 2   a t _ I I   R E T _ N P 1   b y _ I I   2 . 2 _ M C   p o i n t s _ N N 2   ( _ (   t _ Z Z 1   = _ F O   2 . 3 8 _ M C   ; _ ;   p _ N N U   l e s s _ D A R   t h a n _ C S N   . 0 5 _ M C   ; _ ;   E S _ N P 1   = 5 1 0 . 4 7 _ F O   ; _ ;   F i g u r e _ N N 1   4 E _ F O   ) _ )   . _ .   
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 I n t r o d u c t i o n _ N N 1   M i g r a i n e _ N P 1   a f f e c t s _ V V Z   1 2 % _ N N U   o f _ I O   a d u l t s _ N N 2   i n _ I I   t h e _ A T   U S A _ N P 1   , _ ,   m a k i n g _ V V G   t h i s _ D D 1   c o n d i t i o n _ N N 1   a _ A T 1   c o m m o n _ J J   c o n c e r n _ N N 1   f o r _ I F   m a n y _ D A 2   p a t i e n t s _ N N 2   a n d _ C C   t h e i r _ A P P G E   d o c t o r s . 1 _ F O   O f t e n _ R R   o v e r l o o k e d _ V V N   i s _ V B Z   t h e _ A T   h i g h _ J J   p r e v a l e n c e _ N N 1   o f _ I O   p s y c h i a t r i c _ J J   c o m o r b i d i t i e s _ N N 2   a s s o c i a t e d _ V V N   w i t h _ I W   m i g r a i n e _ N N 1   , _ ,   s u c h _ I I 2 1   a s _ I I 2 2   d e p r e s s i o n _ N N 1   , _ ,   a n x i e t y _ N N 1   a n d _ C C   p o s t - t r a u m a t i c _ J J   s t r e s s _ N N 1   d i s o r d e r . 2 _ F O   ' _ N U L L   4 _ M C   M i g r a i n e u r s _ N N 2   w i t h _ I W   p s y c h i a t r i c _ J J   c o m o r b i d i t y _ N N 1   h a v e _ V H 0   h i g h e r _ J J R   h e a l t h c a r e _ N N 1   u t i l i s a t i o n _ N N 1   t e n d e n c i e s _ N N 2   t h a n _ C S N   m i g r a i n e u r s _ N N 2   w i t h o u t _ I W   p s y c h i a t r i c _ J J   c o m o r b i d i t y . 5 _ F O   I f _ C S   l e f t _ J J   u n t r e a t e d _ J J   , _ ,   t h e s e _ D D 2   c o m o r b i d _ J J   p s y c h i a t r i c _ J J   c o n d i t i o n s _ N N 2   c a n _ V M   i n c r e a s e _ V V I   t h e _ A T   r i s k _ N N 1   o f _ I O   m i g r a i n e _ N N 1   c h r o n i f i c a t i o n _ N N 1   , _ ,   t h e _ A T   e v o l u t i o n _ N N 1   o f _ I O   e p i s o d i c _ J J   m i g r a i n e _ N N 1   ( _ (   E M _ F U   ) _ )   i n t o _ I I   c h r o n i c _ J J   m i g r a i n e _ N N 1   ( _ (   C M _ N N U   ) _ )   ( _ (   i e _ R E X   , _ ,   a t _ R R 2 1   l e a s t _ R R 2 2   1 5 _ M C   h e a d a c h e _ N N 1   d a y s _ N N T 2   a _ A T 1   m o n t h _ N N T 1   , _ ,   i n c l u d i n g _ V V G   a t _ R R 2 1   l e a s t _ R R 2 2   8 _ M C   d a y s / m o n t h _ F U   w i t h _ I W   f u l l - b l o w n _ J J   m i g r a i n e s _ N N 2   ) _ )   . _ .   
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 T h e _ A T   s u p e r i o r _ J J   a n d _ C C   n a s a l _ J J   q u a d r a n t s _ N N 2   o f _ I O   O C A 1 _ F O   a n d _ C C   O C A 3 _ F O   h a d _ V H D   t h e _ A T   s i m i l a r _ J J   R O C _ N N 1   c u r v e s _ N N 2   ( _ (   p s u p e r i o r = 0 . _ F O   4 7 8 4 _ M C   a n d _ C C   p n a s a i = _ F O   0 _ M C   . _ .   
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 I n _ I I   a _ A T 1   s e p a r a t e _ J J   s t u d y _ N N 1   b y _ I I   t h e _ A T   s a m e _ D A   g r o u p _ N N 1   u s i n g _ V V G   m o n o - p o l a r _ J J   c a t h o d e _ N N 1   s t i m u l a t i o n _ N N 1   , _ ,   t h e _ A T   a u t h o r s _ N N 2   f o u n d _ V V D   t h a t _ C S T   w i t h _ I W   s m a l l e r _ J J R   e l e c t r o d e _ N N 1   s i z e s _ N N 2   ( _ (   5 _ M C   m m _ N N U   i n _ I I   d i a m e t e r _ N N 1   ) _ )   , _ ,   a n d _ C C   s h o r t e r _ J J R   s t i m u l a t i n g _ J J   d u r a t i o n s _ N N 2   ( _ (   0 . 1 _ M C   m s _ N N 1   p u l s e s _ N N 2   ) _ )   , _ ,   t h e _ A T   t h r e s h o l d _ N N 1   f o r _ I F   d i r e c t l y _ R R   a c t i v a t i n g _ V V G   R G C _ N P 1   w a s _ V B D Z   m u c h _ R R   l o w e r _ J J R   ( _ (   3 7 _ M C   t i m e s _ N N T 2   l o w e r _ R R R   ) _ )   t h a n _ C S N   t h a t _ D D 1   r e q u i r e d _ V V N   t o _ T O   a c t i v a t e _ V V I   t h e _ A T   R G C _ N P 1   i n d i r e c t l y _ R R   v i a _ I I   s y n a p t i c _ J J   t r a n s m i s s i o n _ N N 1   . _ .   
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 T h u s _ R R   r e t u r n _ V V 0   o n _ I I   e f f o r t _ N N 1   a n d _ C C   i n v e s t m e n t _ N N 1   i n _ I I   t h i s _ D D 1   a r e a _ N N 1   s h o u l d _ V M   b e _ V B I   s u b s t a n t i a l _ J J   . _ .   
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 T h e _ A T   R a d i a t i o n _ N N 1   T h e r a p y _ N N 1   O n c o l o g y _ N N 1   G r o u p _ N N 1   ( _ (   R T O G _ N P 1   ) _ )   a n d _ C C   t h e _ A T   E u r o p e a n _ J J   O r g a n i z a t i o n _ N N 1   f o r _ I F   R e s e a r c h _ N N 1   a n d _ C C   T r e a t m e n t _ N N 1   o f _ I O   C a n c e r _ N N 1   c o l l a b o r a t e d _ V V D   t o _ T O   d e v e l o p _ V V I   ' _ N U L L   l a t e _ J J   e f f e c t s _ N N 2   i n _ I I   n o r m a l _ J J   t i s s u e _ N N 1   ' _ N U L L   m o r b i d i t y _ N N 1   s c a l e s _ N N 2   , _ ,   a n d _ C C   t h e _ A T   N a t i o n a l _ J J   C a n c e r _ N N 1   I n s t i t u t e _ N N 1   c o n s e n s u s _ N N 1   c o n f e r e n c e s _ N N 2   h a v e _ V H 0   i n t r o d u c e d _ V V N   t h e _ A T   s u b j e c t i v e _ J J   , _ ,   o b j e c t i v e _ N N 1   , _ ,   m a n a g e m e n t _ N N 1   , _ ,   a n a l y s i s _ N N 1   ( _ (   S O M A _ N P 1   ) _ )   c l a s s i f i c a t i o n _ N N 1   f o r _ I F   l a t e _ J J   c a n c e r _ N N 1   t h e r a p y _ N N 1   t o x i c i t i e s _ N N 2   . _ .   
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 W e _ P P I S 2   u s e d _ V V D   t h e _ A T   A d u l t _ N N 1   S e r v i c e _ N N 1   U s e _ N N 1   S c h e d u l e _ N N 1   t o _ T O   m e a s u r e _ V V I   o t h e r _ J J   h e a l t h _ N N 1   a n d _ C C   s o c i a l _ J J   c a r e _ N N 1   s e r v i c e s _ N N 2   u s e d _ V V D   , _ ,   i n c l u d i n g _ I I   p s y c h o t r o p i c _ J J   m e d i c a t i o n s _ N N 2   . _ .   
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 I t s _ A P P G E   a x i s _ N N 1   o f _ I O   r o t a t i o n _ N N 1   , _ ,   t h i c k n e s s _ N N 1   , _ ,   w e l l _ R R   h i d d e n _ V V N   d o n o r _ N N 1   s i t e _ N N 1   s c a r _ N N 1   , _ ,   t h i n _ J J   p l i a b l e _ J J   s k i n _ N N 1   , _ ,   a n d _ C C   s u p e r i o r _ J J   s k i n _ N N 1   c o l o r _ N N 1   m a t c h _ N N 1   w i t h _ I W   t h e _ A T   f a c e _ N N 1   m a k e _ V V 0   i t _ P P H 1   a n _ A T 1   a p p e a l i n g _ J J   f l a p _ N N 1   i n _ I I   c e r v i c o f a c i a l _ J J   r e c o n s t r u c t i o n _ N N 1   . _ .   
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 I m p a i r m e n t _ N N 1   o f _ I O   P r o t e i n _ N N 1   S y n t h e s i s _ N N 1   A l t h o u g h _ C S   t h e r e _ E X   i s _ V B Z   e v i d e n c e _ N N 1   f r o m _ I I   h u m a n _ J J   s t u d i e s _ N N 2   d e m o n s t r a t i n g _ V V G   t h a t _ C S T   t h e _ A T   b a s a l _ J J   r a t e _ N N 1   o f _ I O   p r o t e i n _ N N 1   s y n t h e s i s _ N N 1   b e g i n s _ V V Z   t o _ T O   d e c r e a s e _ V V I   i n _ I I   t h e _ A T   i m m e d i a t e _ J J   p e r i o d _ N N 1   a f t e r _ I I   d i s u s e _ N N 1   , _ ,   t h e _ A T   c e l l u l a r _ J J   m e c h a n i s m s _ N N 2   r e s p o n s i b l e _ J J   f o r _ I F   t h i s _ D D 1   r e d u c t i o n _ N N 1   i n _ I I   p r o t e i n _ N N 1   s y n t h e s i s _ N N 1   a r e _ V B R   p o o r l y _ R R   u n d e r s t o o d _ V V N   . _ .   
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 E x p o s u r e _ N N 1   t h e r a p y _ N N 1   h a s _ V H Z   b e e n _ V B N   s h o w n _ V V N   t o _ T O   l e a d _ V V I   t o _ I I   r e d u c t i o n s _ N N 2   i n _ I I   t i c s _ N N 2   a n d _ C C   p r e m o n i t o r y _ J J   u r g e s _ N N 2   , _ ,   a n d _ C C   a _ A T 1   s i m i l a r _ J J   m e c h a n i s m _ N N 1   i s _ V B Z   t h o u g h t _ V V N   t o _ T O   u n d e r l i e _ V V I   b e h a v i o r _ N N 1   t h e r a p y _ N N 1   f o r _ I F   t i c s _ N N 2   . _ .   
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 G i v e n _ C S 2 1   t h a t _ C S 2 2   a _ A T 1   b e t t e r _ J J R   u n d e r s t a n d i n g _ N N 1   o f _ I O   t h e s e _ D D 2   m e c h a n i s m s _ N N 2   m a y _ V M   a l l o w _ V V I   t h e _ A T   d e v e l o p m e n t _ N N 1   o f _ I O   n e w _ J J   t h e r a p e u t i c _ J J   a p p r o a c h e s _ N N 2   , _ ,   t r a n s c r i p t o m i c _ J J   a n d _ C C   p r o t e o m i c _ J J   s t u d i e s _ N N 2   h a v e _ V H 0   r e c e n t l y _ R R   b e e n _ V B N   p e r f o r m e d _ V V N   t o _ T O   u n r a v e l _ V V I   t h i s _ D D 1   i s s u e _ N N 1   ( _ (   T a b a b a t - K h a n i _ N N 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 5 _ M C   ; _ ;   Q u i n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 5 _ M C   ) _ )   . _ .   
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 I n t r a v i t r e a l _ J J   a n t i - v a s c u l a r _ J J   e n d o t h e l i a l _ J J   g r o w t h _ N N 1   f a c t o r _ N N 1   ( _ (   V E G F _ N P 1   ) _ )   a g e n t s _ N N 2   h a v e _ V H 0   e m e r g e d _ V V N   a s _ C S A   n e w _ J J   t r e a t m e n t s _ N N 2   f o r _ I F   t h e _ A T   m o r e _ R G R   a d v a n c e d _ J J   s t a g e s _ N N 2   o f _ I O   D R _ N N B   . _ .   
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 A s _ R R 2 1   w e l l _ R R 2 2   , _ ,   m o s t _ D A T   p a r t i c i p a n t s _ N N 2   f e l t _ V V D   t h a t _ C S T   e d u c a t i o n a l _ J J   i n t e r v e n t i o n s _ N N 2   f o r _ I F   t h e _ A T   p e r i o p e r a t i v e _ J J   m u l t i d i s c i p l i n a r y _ J J   t e a m _ N N 1   m e m b e r s _ N N 2   , _ ,   p a t i e n t s _ N N 2   , _ ,   a n d _ C C   f a m i l i e s _ N N 2   w e r e _ V B D R   e s s e n t i a l _ J J   t o _ I I   s u c c e s s f u l _ J J   i m p l e m e n t a t i o n _ N N 1   a n d _ C C   u p t a k e _ N N 1   . _ .   
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 P a t i e n t s _ N N 2   s h o u l d _ V M   n o t _ X X   d i s c o n t i n u e _ V V I   t h e _ A T   u s e _ N N 1   o f _ I O   p r e s c r i p t i o n _ N N 1   f l u o r i d e _ N N 1   u n t i l _ C S   i n s t r u c t e d _ V V N   t o _ T O   d o _ V D I   s o _ R R   b y _ I I   t h e _ A T   d e n t a l _ J J   p r o f e s s i o n a l _ J J   . _ .   
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 I n _ B C L 2 1   o r d e r _ B C L 2 2   t o _ T O   i d e n t i f y _ V V I   m e l a n o p s i n - e x p r e s s i n g _ J J   c e l l s _ N N 2   u s u a l l y _ R R   a _ A T 1   f l u o r e s c e n t _ J J   r e p o r t e r _ N N 1   i s _ V B Z   c o - e x p r e s s e d _ V V N   . _ .   
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 F r o m _ I I   t h e _ A T   d i f f e r e n c e _ N N 1   i n _ I I   T T P s _ N P 1   , _ ,   t h e _ A T   p e a k - t o - p e a k _ J J   t r a n s i t _ N N 1   t i m e _ N N T 1   c o u l d _ V M   b e _ V B I   c a l c u l a t e d _ V V N   . _ .   
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 P u n c t u r e _ N N 1   a n d _ C C   P o s t d u r a l _ J J   P u n c t u r e _ N N 1   H e a d a c h e _ N N 1   W h a t _ D D Q   A r e _ V B R   O u r _ A P P G E   O p t i o n s _ N N 2   ? _ ?   
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 H e n c e _ R R   , _ ,   i t _ P P H 1   i s _ V B Z   e x p e c t e d _ V V N   t h a t _ C S T   i n _ I I   a _ A T 1   f e w _ D A 2   y e a r s _ N N T 2   i t _ P P H 1   w i l l _ V M   b e _ V B I   p o s s i b l e _ J J   t o _ T O   i d e n t i f y _ V V I   t h e _ A T   d i s e a s e - c a u s i n g _ J J   g e n e s _ N N 2   a n d _ C C   m u t a t i o n s _ N N 2   i n _ I I   a p p r o x i m a t e l y _ R R   9 5 % _ N N U   o f _ I O   a l l _ D B   t h e _ A T   R P _ N P 1   p a t i e n t s _ N N 2   , _ ,   a l b e i t _ C S   t h e _ A T   n u m b e r _ N N 1   o f _ I O   s t i l l _ R R   u n k n o w n _ J J   R P _ N P 1   g e n e s _ N N 2   c a n _ V M   n o t _ X X   b e _ V B I   r e l i a b l y _ R R   p r e d i c t e d _ V V N   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   a n _ A T 1   A N C O V A _ N N 1   o f _ I O   C F B _ N P 1   i n _ I I   m e a n _ J J   d i u r n a l _ J J   I O P _ N N 1   w a s _ V B D Z   p e r f o r m e d _ V V N   w i t h _ I W   f i x e d - e f f e c t _ J J   t e r m s _ N N 2   f o r _ I F   t r e a t m e n t _ N N 1   a n d _ C C   d i u r n a l _ J J   b a s e l i n e _ N N 1   I O P _ N N 1   a t _ I I   e a c h _ D D 1   p o s t b a s e l i n e _ N N 1   v i s i t _ N N 1   . _ .   
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 W e _ P P I S 2   a p p r e c i a t e _ V V 0   t h a t _ C S T   n o t _ X X   a l l _ D B   w o u l d _ V M   a g r e e _ V V I   w i t h _ I W   i n c l u d i n g _ V V G   d e e p _ R R   g r a y _ J J   a n d _ C C   w h i t e _ J J   m a t t e r _ N N 1   h y p e r i n t e n s i t i e s _ N N 2   i n _ I I   t h e _ A T   t e r m _ N N 1   W M H _ N P 1   , _ ,   b u t _ C C B   w e _ P P I S 2   a r e _ V B R   s i m p l y _ R R   u s i n g _ V V G   i t _ P P H 1   a s _ I I   a n _ A T 1   o p e r a t i o n a l _ J J   t e r m _ N N 1   i n _ I I   t h i s _ D D 1   i n s t a n c e _ N N 1   . _ .   
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 S u b s e q u e n t _ J J   c o m p a r i s o n s _ N N 2   o f _ I O   t h e _ A T   L i k e r t _ N P 1   a n d _ C C   P I R A D S _ N N 2   r e p o r t i n g _ V V G   s c h e m e s _ N N 2   h a v e _ V H 0   y i e l d e d _ V V N   s i m i l a r _ J J   r e s u l t s . 1 4 _ F O   , _ ,   1 5 _ M C   T o _ T O   a s s e s s _ V V I   i n t e r - o b s e r v e r _ J J   a g r e e m e n t _ N N 1   , _ ,   1 3 2 _ M C   s c a n s _ N N 2   f r o m _ I I   t h e _ A T   l e a d _ N N 1   s i t e _ N N 1   w e r e _ V B D R   r e - r e p o r t e d _ V V N   b y _ I I   a _ A T 1   b l i n d e d _ J J   s e c o n d _ M D   r a d i o l o g i s t _ N N 1   b a s e d _ V V N   a t _ I I   t h a t _ D D 1   s i t e _ N N 1   . _ .   
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 S e a r c h _ N N 1   S t r a t e g y _ N N 1   M e d l i n e _ N P 1   , _ ,   E M B A S E _ N P 1   , _ ,   C I N A H L _ N P 1   , _ ,   a n d _ C C   t h e _ A T   C o c h r a n e _ N P 1   L i b r a r y _ N N 1   d a t a b a s e s _ N N 2   w e r e _ V B D R   s e a r c h e d _ V V N   t h r o u g h _ I I   J u l y _ N P M 1   2 0 1 3 _ M C   . _ .   
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 F e w e r _ D A R   A s i a n _ J J   A m e r i c a n s _ N N 2   ( _ (   4 9 % _ N N U   ) _ )   c o n s u m e _ V V 0   a l c o h o l _ N N 1   t h a n _ C S N   N H W s _ N P 1   ( _ (   7 2 % _ N N U   ) _ )   , _ ,   a l t h o u g h _ C S   t h e _ A T   p r e v a l e n c e _ N N 1   i n _ I I   A s i a n _ J J   A m e r i c a n _ J J   m e n _ N N 2   ( _ (   6 0 % _ N N U   ) _ )   i s _ V B Z   m u c h _ R R   h i g h e r _ J J R   t h a n _ C S N   i n _ I I   A s i a n _ J J   A m e r i c a n _ J J   w o m e n _ N N 2   ( _ (   3 9 % _ N N U   ) _ )   . 2 0 _ M C   U S - b o r n _ J J   A s i a n _ J J   A m e r i c a n s _ N N 2   ( _ (   6 1 % _ N N U   ) _ )   a r e _ V B R   a l s o _ R R   m o r e _ R G R   l i k e l y _ J J   t o _ T O   c o n s u m e _ V V I   a l c o h o l _ N N 1   t h a n _ C S N   t h o s e _ D D 2   w h o _ P N Q S   a r e _ V B R   f o r e i g n - b o r n _ J J   ( _ (   4 6 % _ N N U   ) _ )   . 2 0 _ M C   S c r e e n i n g _ N N 1   , _ ,   b r i e f _ J J   i n t e r v e n t i o n _ N N 1   , _ ,   a n d _ C C   r e f e r r a l _ N N 1   t o _ I I   t r e a t m e n t _ N N 1   b y _ I I   a _ A T 1   c l i n i c i a n _ N N 1   f o r _ I F   a l c o h o l _ N N 1   u s e _ N N 1   , _ ,   i n c l u d i n g _ I I   u s e _ N N 1   t h a t _ C S T   d o e s _ V D Z   n o t _ X X   c o n s t i t u t e _ V V I   a n _ A T 1   a l c o h o l _ N N 1   u s e _ N N 1   d i s o r d e r _ N N 1   b u t _ C C B   d o e s _ V D Z   p u t _ V V I   t h e _ A T   p a t i e n t _ N N 1   a t _ I I   r i s k _ N N 1   f o r _ I F   a l c o h o l - r e l a t e d _ J J   d i s e a s e s _ N N 2   , _ ,   c a n _ V M   b e _ V B I   e f f e c t i v e _ J J   i n _ I I   r e d u c i n g _ V V G   a l c o h o l _ N N 1   u s e . 1 2 1 _ F O   C u l t u r a l l y _ R R   s p e c i f i c _ J J   a p p r o a c h e s _ N N 2   f o r _ I F   a d d r e s s i n g _ V V G   a l c o h o l _ N N 1   u s e _ N N 1   i n _ I I   A s i a n _ J J   A m e r i c a n s _ N N 2   i n c l u d e _ V V 0   u s i n g _ V V G   t r a n s l a t e d _ J J   m a t e r i a l s _ N N 2   , _ ,   i n c r e a s i n g _ J J   a w a r e n e s s _ N N 1   o f _ I O   t h e _ A T   h e a l t h _ N N 1   h a z a r d s _ N N 2   o f _ I O   e x c e s s i v e _ J J   a l c o h o l _ N N 1   u s e _ N N 1   , _ ,   a n d _ C C   r e c o g n i z i n g _ V V G   f a m i l i a l _ J J   c o n s e q u e n c e s . 1 2 1 _ F O   I n f e c t i o u s _ J J   a g e n t s _ N N 2   H . _ N P 1   p y l o r i _ N N 2   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   f r o m _ I I   t h e _ A T   d a t a _ N N   , _ ,   i t _ P P H 1   c a n _ V M   n o t _ X X   b e _ V B I   e x t r a p o l a t e d _ V V N   w h e t h e r _ C S W   t h e r e _ E X   h a d _ V H D   i n d e e d _ R R   b e e n _ V B N   a n y _ D D   M A L T _ N N 1   l y m p h o m a s _ N N 2   a m o n g _ I I   t h e s e _ D D 2   p a t i e n t s _ N N 2   ; _ ;   n e v e r t h e l e s s _ R R   , _ ,   t h e _ A T   m o d e _ N N 1   o f _ I O   a c t i o n _ N N 1   m a k e s _ V V Z   i d e l a l i s i b _ V V I   a n _ A T 1   i n t e r e s t i n g _ J J   a g e n t _ N N 1   f o r _ I F   M A L T _ N N 1   l y m p h o m a _ N N 1   . _ .   
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 I n _ I I   c o n t r a s t _ N N 1   t o _ I I   t h e _ A T   q u i v e r i n g _ J J   m u t a n t s _ N N 2   , _ ,   i n _ I I   K v 1 . 1 _ F O   m u t a n t s _ N N 2   a l l _ D B   A B R _ V V 0   w a v e _ N N 1   c o m p o n e n t s _ N N 2   w e r e _ V B D R   p r e s e n t _ J J   a n d _ C C   A B R _ V V 0   t h r e s h o l d s _ N N 2   w e r e _ V B D R   n o t _ X X   s i g n i f i c a n t l y _ R R   d i f f e r e n t _ J J   b e t w e e n _ I I   m u t a n t _ N N 1   a n d _ C C   w i l d - t y p e _ J J   m i c e _ N N 2   ( _ (   A l l e n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 2 _ M C   ) _ )   . _ .   
 
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 D e s i g n _ N N 1   S m o k e r s _ N N 2   p a r t i c i p a t e d _ V V D   i n _ I I   t h e _ A T   f o l l o w i n g _ J J   2 _ M C   i m a g i n g _ J J   s e s s i o n s _ N N T 2   : _ :   a f t e r _ I I   2 4 _ M C   h o u r s _ N N T 2   o f _ I O   b i o c h e m i c a l l y _ R R   c o n f i r m e d _ V V N   a b s t i n e n c e _ N N 1   ( _ (   c a r b o n _ N N 1   m o n o x i d e _ N N 1   l e v e l _ N N 1   , _ ,   l e s s _ D A R   t h a n _ C S N   1 0 _ M C   p p m _ N N U   ) _ )   a n d _ C C   a f t e r _ I I   s m o k i n g _ V V G   a s _ R R 2 1   u s u a l _ R R 2 2   ( _ (   l a s t _ M D   c i g a r e t t e _ N N 1   a b o u t _ R G   2 0 _ M C   m i n u t e s _ N N T 2   b e f o r e _ I I   t h e _ A T   s c a n _ N N 1   ) _ )   . _ .   
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 W h e n _ C S   p r e - M R I _ J J   a n d _ C C   p o s t - M R I _ J J   b a t t e r y _ N N 1   v o l t a g e _ N N 1   m e a s u r e m e n t s _ N N 2   w e r e _ V B D R   c o m p a r e d _ V V N   , _ ,   a _ A T 1   s m a l l _ J J   d e c r e a s e _ N N 1   w a s _ V B D Z   n o t e d _ V V N   f o r _ I F   b o t h _ R R   p a c e m a k e r s _ N N 2   a n d _ C C   I C D s _ N P 2   . _ .   
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 A s _ C S A   e x p e c t e d _ V V N   , _ ,   r a d i a t i o n - i n d u c e d _ J J   c o m p l i c a t i o n s _ N N 2   o c c u r _ V V 0   w i t h _ I W   g r e a t e r _ J J R   f r e q u e n c y _ N N 1   a n d _ C C   s e v e r i t y _ N N 1   f o r _ I F   r e p e a t _ N N 1   E P B T _ N N 1   t h a n _ C S N   f o r _ I F   p r i m a r y _ J J   E P B T _ N N 1   a l o n e _ R R   . _ .   
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 E R G _ N P 1   m e a s u r e s _ V V Z   a n _ A T 1   i m p o r t a n t _ J J   b u t _ C C B   l i m i t e d _ J J   a s p e c t _ N N 1   o f _ I O   g l o b a l _ J J   r o d _ N N 1   f u n c t i o n _ N N 1   : _ :   m o v e m e n t _ N N 1   o f _ I O   m o n o v a l e n t _ J J   i o n s _ N N 2   o n _ I I   a _ A T 1   m i l l i s e c o n d _ N N T 1   t i m e _ N N T 1   s c a l e _ N N 1   a f t e r _ I I   a _ A T 1   f l a s h _ N N 1   o f _ I O   l i g h t _ N N 1   i n _ R R 2 1   v i v o _ R R 2 2   . _ .   
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 P C R _ N P 1   r e a c t i o n s _ N N 2   w e r e _ V B D R   p e r f o r m e d _ V V N   i n _ I I   a _ A T 1   t o t a l _ J J   v o l u m e _ N N 1   o f _ I O   2 5 _ M C   L _ N N U   i n _ I I   L i g h t C y c l e r _ N P 1   p l a q u e s _ N N 2   w i t h _ I W   a _ A T 1   r e a c t i o n _ N N 1   m i x t u r e _ N N 1   c o n t a i n i n g _ V V G   5 _ M C   L _ N N U   o f _ I O   D N A _ N N 1   s a m p l e _ N N 1   , _ ,   0 . 5 _ M C   M _ N N U   o f _ I O   e a c h _ D D 1   g e n e r i c _ J J   p r i m e r _ N N 1   , _ ,   2 . 5 _ M C   ( _ (   i M _ N N 1   o f _ I O   t h e _ A T   b l o c k i n g _ J J   p r i m e r _ N N 1   , _ ,   2 . 8 _ M C   ( _ (   i M _ V V 0   M g C _ N P 1   , _ ,   0 . 9 5 _ M C   ( _ (   i L _ F W   o f _ I O   d i s t i l l e d _ J J   w a t e r _ N N 1   a n d _ C C   1 2 . 5 _ M C   ( _ (   i L _ F W   o f _ I O   L i g h t C y c l e r ( R ) _ N P 1   4 8 0 _ M C   H R M _ N P 1   M a s t e r _ N N 1   ( _ (   R o c h e _ N P 1   D i a g n o s t i c s _ N N 1   , _ ,   B a s e l _ N P 1   , _ ,   S w i t z e r l a n d _ N P 1   ) _ )   . _ .   
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 T h e _ A T   p r o p o r t i o n _ N N 1   o f _ I O   p a t i e n t s _ N N 2   i n _ I I   w h o m _ P N Q O   p o s t o p e r a t i v e _ J J   a t r i a l _ J J   f i b r i l l a t i o n _ N N 1   d e v e l o p e d _ V V D   w a s _ V B D Z   2 8 . 1 % _ F O   a m o n g _ I I   t h o s e _ D D 2   w h o _ P N Q S   h a d _ V H D   u n d e r g o n e _ V V N   i s o l a t e d _ J J   C A B G _ N N 1   , _ ,   3 3 . 7 % _ F O   a m o n g _ I I   t h o s e _ D D 2   w h o _ P N Q S   h a d _ V H D   u n d e r g o n e _ V V N   i s o l a t e d _ J J   v a l v e _ N N 1   s u r g e r y _ N N 1   , _ ,   a n d _ C C   4 7 . 3 % _ F O   a m o n g _ I I   t h o s e _ D D 2   w h o _ P N Q S   h a d _ V H D   u n d e r g o n e _ V V N   c o m b i n e d _ J J   p r o c e d u r e s _ N N 2   . _ .   
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 M c A r d l e _ N P 1   d i s e a s e _ N N 1   p a t i e n t s _ N N 2   w i t h _ I W   a p p r o p r i a t e _ J J   e x e r c i s e _ N N 1   h a b i t s _ N N 2   c a n _ V M   b e _ V B I   a l m o s t _ R R   a s _ C S A   a e r o b i c a l l y _ R R   f i t _ V V 0   a s _ R G   u n a f f e c t e d _ J J   p e o p l e _ N N   . _ .   
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 T h e s e _ D D 2   r e s u l t s _ N N 2   , _ ,   w h i c h _ D D Q   l i k e l y _ R R   p r o v i d e _ V V 0   a _ A T 1   p r o x y _ N N 1   m e a s u r e _ N N 1   o f _ I O   g a d o l i n i u m _ N N 1   d e p o s i t i o n _ N N 1   , _ ,   c o n f i r m _ V V 0   p r e v i o u s _ J J   r e s e a r c h _ N N 1   f i n d i n g s _ N N 2   t h a t _ C S T   t h e r e _ E X   i s _ V B Z   g a d o l i n i u m _ N N 1   d e p o s i t i o n _ N N 1   i n _ I I   w i d e _ J J   r e g i o n s _ N N 2   o f _ I O   t h e _ A T   b r a i n _ N N 1   , _ ,   i n c l u d i n g _ I I   h e m i s p h e r i c _ J J   g r a y _ J J   m a t t e r _ N N 1   . _ .   
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 W h e n _ C S   a n _ A T 1   e r r o r _ N N 1   w a s _ V B D Z   m a d e _ V V N   , _ ,   p a r t i c i p a n t s _ N N 2   w e r e _ V B D R   r e q u i r e d _ V V N   t o _ T O   r e t u r n _ V V I   t o _ I I   t h e _ A T   s t a r t _ N N 1   o f _ I O   t h e _ A T   c u r r e n t _ J J   r o w _ N N 1   o f _ I O   w o r d s _ N N 2   a n d _ C C   c o n t i n u e _ V V 0   a s _ R G   n o r m a l _ J J   . _ .   
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 T h e _ A T   a c t i v a t i o n _ N N 1   o f _ I O   a l l _ D B   t h e s e _ D D 2   p a t h w a y s _ N N 2   l e a d s _ V V Z   t o _ I I   a b n o r m a l i t i e s _ N N 2   i n _ I I   b o t h _ D B 2   t h e _ A T   n e u r a l _ J J   r e t i n a _ N N 1   ( _ (   r e t i n a l _ J J   n e u r o d e g e n e r a t i o n _ N N 1   ) _ )   a n d _ C C   t h e _ A T   c a p i l l a r y _ J J   b e d _ N N 1   l o c a t e d _ V V N   i n _ I I   t h e _ A T   i n n e r _ J J   r e t i n a _ N N 1   ( _ (   m i c r o a n g i o p a t h i c _ J J   i n j u r y _ N N 1   ) _ )   . 3 . 1 . 1 _ M C   . _ .   
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 A d v a n c e d _ J J   g l y c a t e d _ J J   e n d _ N N 1   p r o d u c t s _ N N 2   A d v a n c e d _ V V D   g l y c a t e d _ J J   e n d _ N N 1   p r o d u c t s _ N N 2   ( _ (   A G E s _ N N 2   ) _ )   a n d _ C C   i t s _ A P P G E   r e c e p t o r s _ N N 2   ( _ (   R A G E s _ V V Z   ) _ )   h a v e _ V H 0   b e e n _ V B N   d e t e c t e d _ V V N   i n _ I I   v a s c u l a r _ J J   c e l l s _ N N 2   , _ ,   n e u r o n s _ N N 2   a n d _ C C   g l i a _ N N 1   o f _ I O   d i a b e t i c _ J J   r e t i n a _ N N 1   ( _ (   C h e n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 3 _ M C   ) _ )   . _ .   
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 A l t h o u g h _ C S   t h i s _ D D 1   a r t i c l e _ N N 1   f o c u s e s _ V V Z   o n _ I I   h e a l t h _ N N 1   i n f o r m a t i o n _ N N 1   e x c h a n g e _ N N 1   a s _ C S A   i t _ P P H 1   r e l a t e s _ V V Z   t o _ I I   t h e _ A T   p r a c t i c e _ N N 1   o f _ I O   e m e r g e n c y _ N N 1   m e d i c i n e _ N N 1   , _ ,   t h e r e _ E X   a r e _ V B R   s o m e _ D D   c o m m o n _ J J   r e q u i r e m e n t s _ N N 2   t h a t _ C S T   c r o s s _ V V 0   s p e c i a l t i e s _ N N 2   t h a t _ C S T   a r e _ V B R   a l s o _ R R   d i s c u s s e d _ V V N   . _ .   
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 W e _ P P I S 2   f u r t h e r _ R R R   d e m o n s t r a t e d _ V V D   t h a t _ C S T   t h e _ A T   s e l e c t i v e _ J J   C x 3 6 _ F O   b l o c k e r _ N N 1   M e f l o _ N P 1   c o u l d _ V M   r e v e r s e _ V V I   t h e _ A T   a c t i v a t i o n _ N N 1   o f _ I O   g a m m a - f r e q u e n c y _ J J   o s c i l l a t o r y _ J J   a c t i v i t y _ N N 1   a n d _ C C   r e l i e v e _ V V 0   t h e _ A T   b e h a v i o r a l _ J J   s e n s i t i z a t i o n _ N N 1   i n d u c e d _ V V N   b y _ I I   C C I _ M C   . _ .   
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 W i t h _ I I 3 1   r e g a r d _ I I 3 2   t o _ I I 3 3   a g e _ N N 1   , _ ,   t h e _ A T   g r e a t e s t _ J J T   f a l l _ N N 1   i n _ I I   p r o b a b i l i t y _ N N 1   o f _ I O   s u r v i v a l _ N N 1   w a s _ V B D Z   s e e n _ V V N   i n _ I I   t h e _ A T   a g e _ N N 1   r a n g e _ N N 1   4 5 _ M C   t o _ I I   7 0 _ M C   y e a r s _ N N T 2   & l s q b ; _ (   4 5 _ M C   y e a r s _ N N T 2   3 0 - d a y _ J J   s u r v i v a l _ N N 1   p r o b a b i l i t y _ N N 1   = _ F O   0 . 8 6 _ M C   ; _ ;   9 5 % _ N N U   c o n f i d e n c e _ N N 1   i n t e r v a l _ N N 1   ( _ (   9 5 % _ N N U   C I _ F O   ) _ )   0 . 7 8 _ M C   ' _ N U L L   0 . 9 1 _ M C   , _ ,   7 0 _ M C   y e a r s _ N N T 2   3 0 - d a y _ J J   s u r v i v a l _ N N 1   p r o b a b i l i t y _ N N 1   = _ F O   0 . 7 1 _ M C   ; _ ;   9 5 % _ N N U   C I _ F O   0 . 5 9 _ M C   ' _ N U L L   0 . 8 0 _ M C   & r s q b ; _ )   , _ ,   i n _ I I   c o n t r a s t _ N N 1   t o _ I I   a _ A T 1   s t e a d y _ J J   d e c l i n e _ N N 1   e l s e w h e r e _ R L   ( _ (   F i g . _ N N 1   3 _ M C   ) _ )   . _ .   
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 R o l e _ N N 1   o f _ I O   t h e _ A T   F u n d e r / S p o n s o r _ N N 1   : _ :   T h e _ A T   f u n d i n g _ N N 1   s o u r c e _ N N 1   h a d _ V H D   n o _ A T   r o l e _ N N 1   i n _ I I   t h e _ A T   d e s i g n _ N N 1   a n d _ C C   c o n d u c t _ N N 1   o f _ I O   t h e _ A T   s t u d y _ N N 1   ; _ ;   c o l l e c t i o n _ N N 1   , _ ,   m a n a g e m e n t _ N N 1   , _ ,   a n a l y s i s _ N N 1   , _ ,   a n d _ C C   i n t e r p r e t a t i o n _ N N 1   o f _ I O   t h e _ A T   d a t a _ N N   ; _ ;   p r e p a r a t i o n _ N N 1   , _ ,   r e v i e w _ N N 1   , _ ,   o r _ C C   a p p r o v a l _ N N 1   o f _ I O   t h e _ A T   m a n u s c r i p t _ N N 1   ; _ ;   a n d _ C C   d e c i s i o n _ N N 1   t o _ T O   s u b m i t _ V V I   t h e _ A T   m a n u s c r i p t _ N N 1   f o r _ I F   p u b l i c a t i o n _ N N 1   . _ .   
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 G i v e n _ C S 2 1   t h a t _ C S 2 2   U S _ N P 1   p l a y s _ V V Z   s u c h _ D A   a n _ A T 1   e s s e n t i a l _ J J   r o l e _ N N 1   i n _ I I   t o d a y _ R T   ' _ N U L L   s _ Z Z 1   p r a c t i c e _ N N 1   o f _ I O   E M _ F U   , _ ,   i t _ P P H 1   i s _ V B Z   i m p o r t a n t _ J J   t h a t _ C S T   i t s _ A P P G E   a p p l i c a t i o n _ N N 1   i s _ V B Z   s t a n d a r d i z e d _ V V N   a c r o s s _ I I   r e s i d e n c y _ N N 1   p r o g r a m s _ N N 2   . _ .   
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 C o n c l u s i o n _ N N 1   : _ :   T h e _ A T   r e s u l t s _ N N 2   i n d i c a t e _ V V 0   t h a t _ C S T   n e g a t i v e _ J J   c o m m u n i c a t i o n _ N N 1   a t t i t u d e s _ N N 2   c a n _ V M   b e _ V B I   a n _ A T 1   e f f e c t _ N N 1   o f _ I O   s t u t t e r i n g _ V V G   . _ .   
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 I n _ I I   2 V O - m o d e l _ N N 1   t h e r e _ E X   i s _ V B Z   n e u r o d e g e n e r a t i o n _ N N 1   o f _ I O   v a r i o u s _ J J   c e r e b r a l _ J J   s t r u c t u r e s _ N N 2   , _ ,   p a r t i c u l a r l y _ R R   i n _ I I   t h e _ A T   C A 1 _ F O   p y r a m i d a l _ J J   c e l l _ N N 1   l a y e r _ N N 1   o f _ I O   t h e _ A T   h i p p o c a m p u s _ N N 1   , _ ,   a _ A T 1   b r a i n _ N N 1   r e g i o n _ N N 1   k n o w n _ V V N   t o _ T O   b e _ V B I   h i g h l y _ R R   i m p l i c a t e d _ V V N   i n _ I I   s p a t i a l _ J J   l e a r n i n g _ N N 1   a n d _ C C   m e m o r y _ N N 1   ( _ (   R o l l s _ N P 1   a n d _ C C   K e s n e r _ N P 1   , _ ,   2 0 0 6 _ M C   ) _ )   , _ ,   a n d _ C C   a l s o _ R R   s u s c e p t i b l e _ J J   t o _ I I   p o s t - i s c h e m i c _ J J   i n f l a m m a t o r y _ J J   p h e n o m e n a _ N N 2   a n d _ C C   p - a m y l o i d _ J J   a c c u m u l a t i o n _ N N 1   ( _ (   S e k e l j i c _ N N 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 2 _ M C   ) _ )   . _ .   
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 U s i n g _ V V G   a _ A T 1   d u a l - h e a d _ N N 1   p o w e r _ N N 1   i n j e c t o r _ N N 1   ( _ (   N e m o t o _ N P 1   K y o r i n d o _ N P 1   , _ ,   T o k y o _ N P 1   , _ ,   J a p a n _ N P 1   ) _ )   , _ ,   a _ A T 1   6 0 % _ N N U   i o p a m i d o l _ N N 1   3 0 0 _ M C   m g _ N N U   I / m L _ F U   ( _ (   I o p a m i r o n _ N P 1   3 0 0 _ M C   ; _ ;   B a y e r _ N P 1   Y a k u h i n _ N P 1   L t d _ J J   , _ ,   O s a k a _ N P 1   , _ ,   J a p a n _ N P 1   ) _ )   / 4 0 % _ F U   s a l i n e _ J J   ( _ (   1 8 0 _ M C   m g _ N N U   I / m L _ F U   ) _ )   v o l / v o l _ N N 1   b o l u s _ N N 1   w a s _ V B D Z   i n j e c t e d _ V V N   , _ ,   f o l l o w e d _ V V N   b y _ I I   2 0 _ M C   m L _ N N U   o f _ I O   s a l i n e _ J J   f l u s h _ N N 1   , _ ,   v i a _ I I   a _ A T 1   2 0 - _ N N 1   t o _ I I   2 2 - g a u g e _ J J   c a t h e t e r _ N N 1   i n _ I I   t h e _ A T   r i g h t _ J J   a n t e c u b i t a l _ J J   v e i n _ N N 1   . _ .   
 
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 A f t e r w a r d s _ R T   , _ ,   i n d e p e n d e n t _ J J   b a c k _ N N 1   t r a n s l a t i o n s _ N N 2   w e r e _ V B D R   p e r f o r m e d _ V V N   b y _ I I   t w o _ M C   E n g l i s h _ J J   n a t i v e _ J J   s p e a k e r s _ N N 2   w h o _ P N Q S   w e r e _ V B D R   a l s o _ R R   f l u e n t _ J J   i n _ I I   P o r t u g u e s e _ N N 1   . _ .   
 
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 A f t e r _ C S   w r i t t e n _ V V N   i n f o r m e d _ J J   c o n s e n t _ N N 1   w a s _ V B D Z   o b t a i n e d _ V V N   , _ ,   6 0 _ M C   p a t i e n t s _ N N 2   a g e d _ I I   2 0 _ M C   ' _ N U L L   8 5 _ M C   y r _ N N U   w h o _ P N Q S   w e r e _ V B D R   t o _ T O   u n d e r g o _ V V I   g e n e r a l _ J J   a n a e s t h e s i a _ N N 1   i n _ I I   t h e _ A T   s u p i n e _ J J   p o s i t i o n _ N N 1   w e r e _ V B D R   r a n d o m l y _ R R   a s s i g n e d _ V V N   , _ ,   u s i n g _ V V G   t h e _ A T   e n v e l o p e _ N N 1   m e t h o d _ N N 1   , _ ,   t o _ I I   o n e _ M C 1   o f _ I O   t w o _ M C   g r o u p s _ N N 2   : _ :   t h e _ A T   c r i c o i d _ J J   p r e s s u r e _ N N 1   ( _ (   C P _ N P 1   ) _ )   g r o u p _ N N 1   ( _ (   n = 3 0 _ F O   ) _ )   o r _ C C   t h e _ A T   s h a m _ N N 1   g r o u p _ N N 1   ( _ (   n = 3 0 _ F O   ) _ )   . _ .   
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 C a l c u l a t i o n s _ N N 2   e s t i m a t e d _ V V D   t h e _ A T   h e r i t a b i l i t y _ N N 1   t o _ T O   b e _ V B I   0 . 3 5 _ M C   , _ ,   m e a n i n g _ V V G   t h a t _ D D 1   g e n e t i c _ J J   f a c t o r s _ N N 2   e x p l a i n e d _ V V D   3 5 % _ N N U   o f _ I O   v a r i a n c e _ N N 1   ( _ (   9 5 % _ N N U   c o n f i d e n c e _ N N 1   i n t e r v a l _ N N 1   & l s q b ; _ (   C I _ F O   & r s q b ; _ )   , _ ,   1 3 ? _ F O   " _ "   5 4 _ M C   ) _ )   i n _ I I   p r o g r e s s i o n _ N N 1   o f _ I O   n u c l e a r _ J J   c a t a r a c t _ N N 1   , _ ,   w i t h _ I W   i n d i v i d u a l _ J J   e n v i r o n m e n t a l _ J J   f a c t o r s _ N N 2   a c c o u n t i n g _ V V G   f o r _ I F   t h e _ A T   r e m a i n i n g _ J J   6 5 % _ N N U   ( _ (   9 5 % _ N N U   C I _ F O   , _ ,   4 6 ? _ F O   " _ "   8 7 _ M C   ) _ )   . _ .   
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 T o _ T O   t e s t _ V V I   a s s o c i a t i o n s _ N N 2   b e t w e e n _ I I   m i c r o n u t r i e n t _ J J   i n t a k e _ N N 1   a n d _ C C   c a t a r a c t _ V V I   p r o g r e s s i o n _ N N 1   , _ ,   w e _ P P I S 2   u s e d _ V V D   u n i v a r i a b l e _ J J   r e g r e s s i o n _ N N 1   ( _ (   T a b l e _ N N 1   2 _ M C   ) _ )   f o l l o w e d _ V V D   b y _ I I   s t e p w i s e _ J J   r e g r e s s i o n _ N N 1   i n _ I I   2 0 5 4 _ M C   f e m a l e _ J J   t w i n s _ N N 2   w h o _ P N Q S   h a d _ V H D   b a s e l i n e _ N N 1   d a t a _ N N   o n _ I I   n u t r i e n t _ N N 1   i n t a k e _ N N 1   . _ .   
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 T h i s _ D D 1   w o r k _ N N 1   w a s _ V B D Z   s u p p o r t e d _ V V N   b y _ I I   t h e _ A T   M e d i c a l _ J J   R e s e a r c h _ N N 1   C o u n c i l _ N N 1   ( _ (   G 0 7 0 0 3 5 5 t o _ F O   W N _ N P 1   ) _ )   , _ ,   t h e _ A T   N I H R _ N P 1   B R C _ N P 1   f o r _ I F   M e n t a l _ J J   H e a l t h _ N N 1   a t _ I I   t h e _ A T   S o u t h _ N D 1   L o n d o n _ N P 1   a n d _ C C   M a u d s l e y _ N P 1   N H S _ N P 1   F o u n d a t i o n _ N N 1   T r u s t _ N N 1   , _ ,   t h e _ A T   N a t i o n a l _ J J   C o u n c i l _ N N 1   f o r _ I F   R e p l a c e m e n t _ N N 1   , _ ,   R e f i n e m e n t _ N N 1   a n d _ C C   R e d u c t i o n _ N N 1   o f _ I O   A n i m a l s _ N N 2   i n _ I I   R e s e a r c h _ N N 1   , _ ,   a n d _ C C   t h e _ A T   P r o g r e s s i v e _ J J   S u p r a n u c l e a r _ J J   P a l s y _ N N 1   ( _ (   P S P _ N P 1   ) _ )   A s s o c i a t i o n _ N N 1   . _ .   
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 A g g r e g a t i n g _ V V G   G P S _ N N 2   p o i n t s _ V V Z   i n t o _ I I   s p e c i f i c _ J J   a n d _ C C   m e a n i n g f u l _ J J   s p a t i a l _ J J   e l e m e n t s _ N N 2   i s _ V B Z   e s s e n t i a l _ J J   f o r _ I F   t r a n s f o r m i n g _ V V G   t h e _ A T   o v e r w h e l m i n g _ J J   a m o u n t _ N N 1   o f _ I O   G P S _ N N 2   p o i n t s _ V V Z   i n t o _ I I   m o r e _ R G R   m a n a g e a b l e _ J J   d a t a _ N N   s e t s _ N N 2   , _ ,   a s _ R G   w e l l _ R R   a s _ C S A   f o r _ I F   t h e _ A T   d e v e l o p m e n t _ N N 1   o f _ I O   m o r e _ R G R   t a r g e t e d _ J J   r e s e a r c h _ N N 1   q u e s t i o n s _ N N 2   . _ .   
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 S R C _ N P 1   o r _ C C   m i l d _ J J   t r a u m a t i c _ J J   b r a i n _ N N 1   i n j u r y _ N N 1   ( _ (   m T B I _ N N 2   ) _ )   a c c o u n t s _ V V Z   f o r _ I F   8 0 % _ N N U   o f _ I O   a l l _ D B   r e p o r t e d _ V V D   T B I s _ N P 1   . _ .   
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 R e a l - T i m e _ N N 1   C a p t i o n i n g _ V V G   f o r _ I F   I m p r o v i n g _ V V G   I n f o r m e d _ J J   C o n s e n t _ N N 1   : _ :   P a t i e n t _ J J   a n d _ C C   P h y s i c i a n _ N N 1   B e n e f i t s _ N N 2   A u t h o r _ N N 1   : _ :   S p e h a r _ N P 1   , _ ,   B r e n t _ N P 1   P h D * _ F O   ; _ ;   T y e - M u r r a y _ N P 1   , _ ,   N a n c y _ N P 1   P h D * _ F O   ; _ ;   M y e r s o n _ N P 1   , _ ,   J o e l _ N P 1   P h D _ N N A   ; _ ;   M u r r a y _ N P 1   , _ ,   D a v i d _ N P 1   J . _ N P 1   M D _ N N A   A b s t r a c t _ J J   B a c k g r o u n d _ N N 1   a n d _ C C   O b j e c t i v e s _ N N 2   : _ :   N e w _ J J   m e t h o d s _ N N 2   a r e _ V B R   n e e d e d _ V V N   t o _ T O   i m p r o v e _ V V I   p h y s i c i a n s _ N N 2   ' _ N U L L   s k i l l _ N N 1   i n _ I I   c o m m u n i c a t i n g _ J J   i n f o r m a t i o n _ N N 1   a n d _ C C   t o _ T O   e n h a n c e _ V V I   p a t i e n t s _ N N 2   ' _ N U L L   a b i l i t y _ N N 1   t o _ T O   r e c a l l _ V V I   t h a t _ D D 1   i n f o r m a t i o n _ N N 1   . _ .   
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 T h e _ A T   e x p o s u r e _ N N 1   v a r i a b l e s _ N N 2   e x p l o r e d _ V V N   i n _ I I   t h e _ A T   a n a l y s i s _ N N 1   w e r e _ V B D R   a g e _ N N 1   , _ ,   e t h n i c i t y _ N N 1   , _ ,   B M I _ N P 1   , _ ,   m a r i t a l _ J J   s t a t u s _ N N 1   , _ ,   s u b s t a n c e _ N N 1   m i s u s e _ N N 1   , _ ,   s m o k i n g _ J J   s t a t u s _ N N 1   d u r i n g _ I I   p r e g n a n c y _ N N 1   , _ ,   p r e v i o u s _ J J   p r e g n a n c y _ N N 1   p r o b l e m s _ N N 2   , _ ,   p r e e x i s t i n g _ V V G   m e d i c a l _ J J   p r o b l e m s _ N N 2   ( _ (   f u r t h e r _ R R R   i n f o r m a t i o n _ N N 1   i n _ I I   S u p p o r t i n g _ J J   I n f o r m a t i o n _ N N 1   A p p e n d i x _ N N 1   S 1 _ F O   ) _ )   , _ ,   g e s t a t i o n a l _ J J   d i a b e t e s _ N N 1   , _ ,   p r e v i o u s _ J J   f e t a l _ J J   l o s s _ N N 1   o r _ C C   t e r m i n a t i o n _ N N 1   , _ ,   p a r i t y _ N N 1   , _ ,   m u l t i p l e _ J J   p r e g n a n c y _ N N 1   a n d _ C C   i n a d e q u a t e _ J J   u s e _ N N 1   o f _ I O   a n t e n a t a l _ J J   c a r e _ N N 1   . _ .   
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 C O N C L U S I O N S _ N N 2   C a l c i u m _ N N 1   l e v e l s _ N N 2   s e e m _ V V 0   t o _ T O   p l a y _ V V I   a n _ A T 1   i m p o r t a n t _ J J   r o l e _ N N 1   i n _ I I   c e l l _ N N 1   s u r v i v a l _ N N 1   o f _ I O   b u p i v a c a i n e - i n d u c e d _ J J   c e l l _ N N 1   d e a t h _ N N 1   w i t h i n _ I I   t h e _ A T   i n v e s t i g a t e d _ J J   c o n c e n t r a t i o n _ N N 1   r a n g e _ N N 1   ( _ (   1 . 6 _ M C   ' _ N U L L   7 . 9 _ M C   m M _ N N U   ) _ )   . _ .   
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 R e t i n a l _ J J   c o n c e n t r a t i o n s _ N N 2   o f _ I O   5 - c h o l e s t e n o i c _ J J   a c i d _ N N 1   w e r e _ V B D R   d i s c o v e r e d _ V V N   t o _ T O   v a r y _ V V I   g r e a t e r _ J J R   t h a n _ C S N   5 - f o l d _ J J   i n _ I I   d i f f e r e n t _ J J   i n d i v i d u a l s _ N N 2   a n d _ C C   d i d _ V D D   n o t _ X X   c o r r e l a t e _ V V I   w i t h _ I W   t h e _ A T   C Y P 2 7 A 1 _ F O   p r o t e i n _ N N 1   l e v e l s _ N N 2   ( _ (   L i a o _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 1 _ M C   ) _ )   . _ .   
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 R e a l - t i m e _ J J   u l t r a s o n o g r a p h i c _ J J   v i s u a l i z a t i o n _ N N 1   o f _ I O   p e r i p h e r a l _ J J   n e r v e s _ N N 2   , _ ,   n e e d l e _ N N 1   p l a c e m e n t _ N N 1   , _ ,   a n d _ C C   l o c a l _ J J   a n e s t h e t i c _ J J   s p r e a d _ N N 1   h a s _ V H Z   a l l o w e d _ V V N   a _ A T 1   g r e a t e r _ J J R   n u m b e r _ N N 1   o f _ I O   a n e s t h e s i o l o g i s t s _ N N 2   t o _ T O   h a v e _ V H I   c o n f i d e n c e _ N N 1   t o _ T O   p r o v i d e _ V V I   t h e _ A T   o p i o i d _ N N 1   s p a r i n g _ V V G   a n d _ C C   a n a l g e s i c _ N N 1   b e n e f i t s _ N N 2   o f _ I O   r e g i o n a l _ J J   a n e s t h e s i a _ N N 1   ( _ (   R A _ N P 1   ) _ )   . _ .   
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 C D E s _ N N 2   c a n _ V M   b e _ V B I   a p p l i e d _ V V N   t o _ I I   c l i n i c a l _ J J   p r a c t i c e _ N N 1   , _ ,   r e s e a r c h _ N N 1   , _ ,   a n d _ C C   p e r f o r m a n c e _ N N 1   i m p r o v e m e n t _ N N 1   i n i t i a t i v e s _ N N 2   i n _ I I   r a d i o l o g y _ N N 1   . _ .   
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 O f _ I O   t h e _ A T   8 _ M C   p a r t i c i p a n t s _ N N 2   i n _ I I   t h e _ A T   M T D _ N P 1   g r o u p _ N N 1   , _ ,   6 _ M C   r e s p o n d e d _ V V D   t o _ I I   f o l l o w - u p _ J J   q u e s t i o n i n g _ N N 1   w i t h _ I W   5 _ M C   r e p o r t i n g _ V V G   g o o d _ J J   b e n e f i t _ N N 1   f r o m _ I I   b e h a v i o r a l _ J J   v o i c e _ N N 1   t h e r a p y _ N N 1   a n d _ C C   1 _ M C 1   r e p o r t i n g _ N N 1   f a i r _ J J   b e n e f i t _ N N 1   f r o m _ I I   b e h a v i o r a l _ J J   v o i c e _ N N 1   t h e r a p y _ N N 1   . _ .   
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 B e c a u s e _ I I 2 1   o f _ I I 2 2   i t s _ A P P G E   l o w _ J J   i n s t a n t a n e o u s _ J J   p r e s s u r e _ N N 1   , _ ,   r i g h t _ J J   a t r i u m _ N N 1   w a l l _ N N 1   c o l l a p s e _ N N 1   d u r i n g _ I I   v e n t r i c u l a r _ J J   s y s t o l e _ N N 1   i s _ V B Z   t h e _ A T   e a r l i e s t _ J J T   e c h o c a r - d i o g r a p h i c _ J J   f i n d i n g _ N N 1   o f _ I O   c o m p r e s s i o n _ N N 1   , _ ,   f o l l o w e d _ V V N   b y _ I I   e a r l y _ J J   d i a s t o l i c _ J J   c o l l a p s e _ N N 1   o f _ I O   t h e _ A T   r i g h t _ J J   v e n t r i c l e _ N N 1   . _ .   
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 E a c h _ D D 1   o b j e c t _ N N 1   w a s _ V B D Z   p r e s e n t e d _ V V N   t w i c e _ R R   i n _ I I   r a n d o m _ J J   o r d e r _ N N 1   p e r _ I I   t r i a l _ N N 1   , _ ,   a n d _ C C   t h e _ A T   p a t i e n t _ N N 1   w a s _ V B D Z   a l l o w e d _ V V N   3 0 _ M C   s _ Z Z 1   t o _ T O   g i v e _ V V I   a _ A T 1   f o r c e d - c h o i c e _ N N 1   a n s w e r _ N N 1   . _ .   
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 C o n c l u s i o n s : P a t i e n t s _ F O   w i t h _ I W   h i g h _ J J   r C B V N E R _ N N 1   a n d _ C C   N E R _ F U   c r o s s i n g _ N N 1   t h e _ A T   m i d l i n e _ N N 1   a n d _ C C   t h o s e _ D D 2   w i t h _ I W   h i g h _ J J   r C B V N E R _ N N 1   a n d _ C C   w i l d - t y p e _ J J   E G F R _ N N 1   m u t a t i o n _ N N 1   s h o w e d _ V V D   p o o r _ J J   s u r v i v a l _ N N 1   . _ .   
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 E l u a n t s _ N N 2   w e r e _ V B D R   m o n i t o r e d _ V V N   a t _ I I   4 3 0 _ M C   a n d _ C C   3 2 0 _ M C   n m _ F U   ; _ ;   t h e _ A T   f r a c t i o n s _ N N 2   c o n t a i n i n g _ V V G   A 2 E _ F O   w e r e _ V B D R   c o l l e c t e d _ V V N   , _ ,   p o o l e d _ V V D   , _ ,   a n d _ C C   d r i e d _ V V N   u n d e r _ I I   n i t r o g e n _ N N 1   . _ .   
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 S i m i l a r l y _ R R   , _ ,   i n t r a - c l a s s _ J J   c o r r e l a t i o n _ N N 1   a n a l y s e s _ N N 2   w e r e _ V B D R   p e r f o r m e d _ V V N   o n _ I I   b l i n d e d _ J J   r e c o u n t s _ N N 2   o f _ I O   t i s s u e _ N N 1   f r o m _ I I   b o t h _ D B 2   t i s s u e _ N N 1   p r e p a r a t i o n _ N N 1   m e t h o d s _ N N 2   t o _ T O   p r o v i d e _ V V I   a _ A T 1   m e a s u r e _ N N 1   o f _ I O   i n t r a - r a t e r _ J J   r e l i a b i l i t y _ N N 1   . _ .   
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 W e _ P P I S 2   a l s o _ R R   h a d _ V H D   d e t a i l e d _ V V N   i n f o r m a t i o n _ N N 1   o n _ I I   a _ A T 1   v a r i e t y _ N N 1   o f _ I O   l i f e s t y l e _ N N 1   r i s k _ N N 1   f a c t o r s _ N N 2   w h i c h _ D D Q   i m p r o v e d _ V V D   o u r _ A P P G E   a b i l i t y _ N N 1   t o _ T O   a d j u s t _ V V I   f o r _ I F   c o n f o u n d i n g _ V V G   . _ .   
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 T h e _ A T   c o p y _ N N 1   n u m b e r _ N N 1   c h a n g e s _ N N 2   i n _ I I   t h e _ A T   P I K 3 C A _ F O   g e n e _ N N 1   w e r e _ V B D R   e v a l u a t e d _ V V N   w i t h _ I W   r e a l - t i m e _ J J   q u a n t i t a t i v e _ J J   P C R _ N P 1   , _ ,   a s _ C S A   p r e v i o u s l y _ R R   r e p o r t e d _ V V N   u s i n g _ V V G   t h e _ A T   7 5 0 0 _ M C   R e a l _ J J   T i m e _ N N T 1   P C R _ N P 1   S y s t e m _ N N 1   ( _ (   A p p l i e d _ J J   B i o s y s t e m s _ N N 2   ) _ )   . _ .   
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 T a k e n _ V V N   a l l _ D B   t o g e t h e r _ R L   , _ ,   o n e _ P N 1   c o n c l u d e s _ V V Z   : _ :   i m p r o v e d _ J J   m e m o r y _ N N 1   a b i l i t i e s _ N N 2   s e e n _ V V N   i n _ I I   K T P - d e r i v a t i v e s - t r e a t e d _ N P 1   2 V O _ F O   f e m a l e _ J J   r a t s _ N N 2   i s _ V B Z   d u e _ I I 2 1   t o _ I I 2 2   t h e _ A T   n e u r o p r o t e c t i v e _ J J   e f f e c t s _ N N 2   o f p e p t i d e s _ V V Z   o n _ I I   C A 1 _ F O   n e u r o n s _ N N 2   . _ .   
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 T h e _ A T   P W T _ N P 1   v a l u e s _ N N 2   o f _ I O   t h e _ A T   R L _ N P 1   g r o u p _ N N 1   a t _ I I   0 . 5 _ M C   h o u r _ N N T 1   ( _ (   4 0 . 9 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   3 . 0 _ M C   g _ N N U   ) _ )   a n d _ C C   2 _ M C   h o u r s _ N N T 2   ( _ (   4 4 . 6 _ M C   p l u s _ I I   a n d _ C C   m i n u s _ I I   1 . 6 _ M C   g _ N N U   ) _ )   a f t e r _ I I   d i s c o n t i n u i n g _ V V G   i n f u s i o n _ N N 1   w e r e _ V B D R   a l s o _ R R   l o w e r _ J J R   t h a n _ C S N   t h e _ A T   b a s e l i n e _ N N 1   l e v e l _ N N 1   ( _ (   P _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 5 _ M C   ) _ )   b u t _ C C B   h i g h e r _ J J R   t h a n _ C S N   t h e _ A T   c o r r e s p o n d i n g _ J J   v a l u e s _ N N 2   i n _ I I   t h e _ A T   g r o u p _ N N 1   r e c e i v i n g _ V V G   R _ Z Z 1   ( _ (   P _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 5 _ M C   ) _ )   . _ .   
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 T h i s _ D D 1   i s _ V B Z   a n _ A T 1   i n d e x _ N N 1   o f _ I O   p h o n o l o g i c a l _ J J   c o m p l e x i t y b a s e d _ J J   o n _ I I   s p e e c h _ N N 1   s a m p l e s _ N N 2   f r o m _ I I   s e v e n _ M C   c h i l d r e n _ N N 2   ( _ (   1 7 - 4 8 _ M C   m o n t h s _ N N T 2   ) _ )   n e a r t h e _ V V 0   a g e _ N N 1   o f _ I O   s t u t t e r i n g _ V V G   o n s e t _ N N 1   . _ .   
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 T h e s e _ D D 2   d a t a _ N N   s u p p o r t _ V V 0   o u r _ A P P G E   . _ .   n d i n g _ V V G   t h a t _ D D 1   I k B / c a c t u s _ N N 1   c o o p e r a t e s _ V V Z   w i t h _ I W   P o l y c o m b - m e d i a t e d _ J J   r e p r e s s i o n _ N N 1   , _ ,   i n d e p e n d e n t l y _ R R   o f _ I O   N F - k B / d o r s a l _ J J   , _ ,   w h i c h _ D D Q   i s _ V B Z   r e l e v a n t _ J J   f o r _ I F   t h e _ A T   r e g u l a t i o n _ N N 1   o f _ I O   e p i d e r m a l _ J J   d e v e l o p m e n t _ N N 1   i n _ I I   t h e _ A T   . _ .   y _ Z Z 1   . _ .   
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 T a k e n _ V V N   t o g e t h e r _ R L   , _ ,   t h e s e _ D D 2   r e s u l t s _ N N 2   s u g g e s t _ V V 0   t h a t _ C S T   t h e _ A T   g r a d u a l _ J J   g r o u p _ N N 1   w a s _ V B D Z   a b l e _ J K   t o _ T O   a c h i e v e _ V V I   a s y m p t o t i c _ J J   s p e e c h _ N N 1   p e r c e p t i o n _ N N 1   s c o r e s _ N N 2   m u c h _ R R   e a r l i e r _ R R R   t h a n _ C S N   t h e _ A T   s t a n d a r d _ J J   g r o u p _ N N 1   f o r _ I F   t h e _ A T   c o n s o n a n t _ N N 1   , _ ,   s e n t e n c e _ N N 1   , _ ,   a n d _ C C   s p e e c h t r a c k i n g _ V V G   t a s k s _ N N 2   b u t _ C C B   n o t _ X X   f o r _ I F   t h e _ A T   v o w e l _ N N 1   t a s k _ N N 1   , _ ,   w h e r e _ C S   t h e r e _ E X   w a s _ V B D Z   n o _ A T   d i f f e r e n c e _ N N 1   b e t w e e n _ I I   t h e _ A T   t w o _ M C   g r o u p s _ N N 2   . _ .   
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 I f _ C S   t h e s e _ D D 2   w e r e _ V B D R   n o t _ X X   a v a i l a b l e _ J J   , _ ,   p u b l i s h e d _ V V D   d a t a _ N N   o n _ I I   v a s c u l a r _ J J   e v e n t s _ N N 2   w e r e _ V B D R   e x t r a c t e d _ V V N   f r o m _ I I   t r i a l _ N N 1   r e p o r t s _ N N 2   . _ .   
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 T h e _ A T   G e r m a n _ J J   S 3 - G u i d e l i n e / N a t i o n a l _ J J   D i s e a s e _ N N 1   M a n a g e m e n t _ N N 1   G u i d e l i n e _ N N 1   U n i p o l a r _ N P 1   D e p r e s s i o n 1 2 _ F O   r e c o m m e n d s _ V V Z   p s y c h o e d u c a t i o n _ N N 1   o r _ C C   m o r e _ R G R   i n t e n s i v e _ J J   p s y c h o l o g i c a l _ J J   i n t e r v e n t i o n s _ N N 2   , _ ,   a n d _ C C   t h e _ A T   p r e s c r i p t i o n _ N N 1   o f _ I O   a n t i d e p r e s s a n t _ J J   m e d i c a t i o n _ N N 1   , _ ,   i f _ C S   d e p r e s s i v e _ N N 1   s y m p t o m s _ N N 2   i n t e n s i f y _ V V 0   ( _ (   e g _ R E X   , _ ,   i f _ C S   M D D _ N P 1   i s _ V B Z   d i a g n o s e d _ V V N   ) _ )   . _ .   
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 D i s c u s s i o n _ N N 1   I n _ I I   t h i s _ D D 1   s t u d y _ N N 1   , _ ,   w e _ P P I S 2   u n c o v e r e d _ V V D   a _ A T 1   n o v e l _ J J   v a r i a n t _ N N 1   a t _ I I   1 6 p 1 1 . 2 _ F O   , _ ,   r s 4 5 8 3 2 5 5 & l s q b ; T & r s q b ; _ F O   , _ ,   s h o w i n g _ V V G   g e n o m e - w i d e _ J J   s i g n i f i c a n t _ J J   a s s o c i a t i o n _ N N 1   w i t h _ I W   p s y c h o s i s _ N N 1   ( _ (   O R _ C C   = _ F O   1 . 0 8 _ M C   , _ ,   P _ Z Z 1   = _ F O   6 . 6 _ M C   x _ Z Z 1   1 0 - 1 1 _ M C M C   ) _ )   . _ .   
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 T h r e e _ M C   s i m p l e _ J J   r e p r e s e n t a t i v e _ J J   e x a m p l e s _ N N 2   w i l l _ V M   i l l u s t r a t e _ V V I   t h e _ A T   p o i n t _ N N 1   . _ .   
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 T h e r e f o r e _ R R   , _ ,   o u r _ A P P G E   n o n - i n f e r i o r i t y _ J J   m a r g i n _ N N 1   w a s _ V B D Z   1 . 9 _ M C   P H Q - 9 _ M C   p o i n t s _ N N 2   ( _ (   i e _ R E X   , _ ,   0 . 5 x 3 . 8 _ F O   ) _ )   . _ .   
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 A t _ I I   t h e _ A T   e n d _ N N 1   o f _ I O   t h e _ A T   s t u d y _ N N 1   , _ ,   t u m o r s _ N N 2   w e r e _ V B D R   h a r v e s t e d _ V V N   a n d _ C C   a n a l y z e d _ V V N   f o r _ I F   p r o l i f e r a t i o n _ N N 1   a n d _ C C   a p o p t o s i s _ N N 1   . _ .   
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 T h e s e _ D D 2   e f f o r t s _ N N 2   a r e _ V B R   l a r g e l y _ R R   s p e c i f i c a t i o n s _ N N 2   o f _ I O   b e s t _ J J T   p r a c t i c e s _ N N 2   f o r _ I F   c r e a t i n g _ V V G   r e p o r t s _ N N 2   i n _ I I   s p e c i f i c _ J J   c l i n i c a l _ J J   c o n t e x t s _ N N 2   , _ ,   d e t a i l i n g _ V V G   t h e _ A T   t y p e s _ N N 2   o f _ I O   i n f o r m a t i o n _ N N 1   t h a t _ C S T   s h o u l d _ V M   b e _ V B I   i n c l u d e d _ V V N   i n _ I I   a _ A T 1   r e p o r t _ N N 1   , _ ,   a n d _ C C   d e t e r m i n i n g _ V V G   w h i c h _ D D Q   t e r m s _ V V Z   t o _ T O   u s e _ V V I   a s _ C S A   d e s c r i p t o r s _ N N 2   . _ .   
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 I n _ I I   1 9 9 4 _ M C   , _ ,   W H O _ P N Q S   r e c o m m e n d e d _ V V D   m a g n e s i u m _ N N 1   s u l f a t e _ N N 1   a s _ I I   t h e _ A T   s t a n d a r d _ J J   t r e a t m e n t _ N N 1   f o r _ I F   p r e - e c l a m p s i a _ N N 1   a n d _ C C   e c l a m p s i a _ N N 1   , _ ,   a n d _ C C   w i t h i n _ I I   2 _ M C   y e a r s _ N N T 2   , _ ,   i t _ P P H 1   w a s _ V B D Z   p l a c e d _ V V N   o n _ I I   W H O _ N P 1   ' _ N U L L   s _ Z Z 1   E s s e n t i a l _ J J   M e d i c i n e s _ N N 2   L i s t _ N N 1   . _ .   
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 A c k n o w l e d g e m e n t s _ N N 2   T h e _ A T   a u t h o r s _ N N 2   t h a n k _ V V 0   P r o f . _ N N B   N i c h o l a s _ N P 1   B r e n n a n _ N P 1   f o r _ I F   h i s _ A P P G E   h e l p f u l _ J J   s u g g e s t i o n s _ N N 2   i n _ I I   t h e _ A T   m a n u s c r i p t _ N N 1   ' _ N U L L   s _ Z Z 1   r e v i s i o n _ N N 1   . _ .   
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 A l l _ D B   s c a n s _ N N 2   w e r e _ V B D R   p e r f o r m e d _ V V N   b y _ I I   o n e _ M C 1   o p e r a t o r _ N N 1   ( _ (   J . W . _ N P 1   ) _ )   w i t h _ I W   t h e _ A T   s u b j e c t _ N N 1   w e a r i n g _ V V G   l i g h t _ J J   i n d o o r _ J J   c l o t h i n g _ N N 1   . _ .   
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 D e s p i t e _ I I   t h e _ A T   s c o p e _ N N 1   o f _ I O   I H _ N P 1   a n d _ C C   m o d e s t _ J J   r e s u l t s _ N N 2   o f _ I O   r e a c t i v e _ J J   t r e a t m e n t _ N N 1   s t r a t e g i e s _ N N 2   , _ ,   a p p r o a c h e s _ V V Z   t o _ I I   t h i s _ D D 1   c o m p l e x _ N N 1   , _ ,   m u l t i f a c t o r i a l _ J J   p r o c e s s _ N N 1   h a v e _ V H 0   n o t _ X X   e v o l v e d _ V V N   w i t h _ I W   t h e _ A T   g e n e r a l _ J J   z e i t g e i s t _ N N 1   o f _ I O   p r e v e n t a t i v e _ J J   m e d i c a l _ J J   c a r e _ N N 1   . _ .   
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 I n d i v i d u a l _ J J   s t i m u l i _ N N 2   w e r e _ V B D R   g i v e n _ V V N   1 0 _ M C   s _ Z Z 1   a p a r t _ R L   . _ .   
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 T h e _ A T   a v e r a g e _ J J   a g e _ N N 1   w a s _ V B D Z   6 3 . 3 _ M C   a n d _ C C   i t _ P P H 1   d e c r e a s e d _ V V D   f r o m _ I I   6 7 . 4 _ M C   t o _ I I   6 2 . 5 _ M C   ( _ (   P _ N N U   l e s s _ D A R   t h a n _ C S N   0 . 0 0 1 _ M C   ) _ )   ( _ (   T a b l e _ N N 1   1 _ M C 1   ) _ )   o v e r _ I I   t h e _ A T   s t u d y _ N N 1   p e r i o d _ N N 1   . _ .   
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 T h e _ A T   f o l l o w i n g _ J J   a n t i b o d i e s _ N N 2   a n d _ C C   t i t e r s _ N N 2   w e r e _ V B D R   u s e d _ V V N   : _ :   M o u s e _ N N 1   a n t i - h u m a n _ N N 1   S I R T 1 _ F O   m o n o c l o n a l _ J J   I g G _ N N 1   ( _ (   1 : 3 0 0 _ M C   ) _ )   , _ ,   G o a t _ N N 1   a n t i - h u m a n _ N N 1   S I R T 2 _ F O   m o n o c l o n a l _ J J   I g G _ N N 1   ( _ (   1 : 2 0 0 _ M C   ) _ )   , _ ,   a n d _ C C   R a b b i t _ N N 1   a n t i - h u m a n _ N N 1   S I R T 3 _ F O   p o l y c l o n a l _ J J   I g G _ N N 1   ( _ (   1 : 5 0 0 _ M C   ) _ )   . _ .   
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 P r e v i o u s _ J J   r e p o r t s _ N N 2   o n _ I I   a u d i t o r y _ J J   f u n c t i o n _ N N 1   i n _ I I   t h e s e _ D D 2   m o n k e y s _ N N 2   h a v e _ V H 0   b e e n _ V B N   p u b l i s h e d _ V V N   ( _ (   F o w l e r _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 2 _ M C   ; _ ;   F o w l e r _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 8 _ M C   ; _ ;   F o w l e r _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 0 _ M C   ) _ )   . _ .   
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 U s i n g _ V V G   t h e _ A T   b i o p s y c h o s o c i a l _ J J   f r a m e w o r k _ N N 1   , _ ,   f u t u r e _ J J   s t u d i e s _ N N 2   s h o u l d _ V M   c o l l e c t _ V V I   d e t a i l e d _ J J   i n f o r m a t i o n _ N N 1   a b o u t _ I I   p a i n _ N N 1   a n d _ C C   t h e _ A T   s o c i a l _ J J   f a c t o r s _ N N 2   t h a t _ C S T   a f f e c t _ V V 0   p a i n _ N N 1   p e r c e p t i o n s _ N N 2   . _ .   
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 W e _ P P I S 2   u s e d _ V V D   I C D - 9 _ M C   a n d _ C C   I C D - 1 0 _ M C   c o d i n g _ N N 1   t o _ I I   g r o u p _ N N 1   t h e _ A T   d e a t h s _ N N 2   i n t o _ I I   t h r e e _ M C   m u t u a l l y _ R R   e x c l u s i v e _ J J   c a t e g o r i e s _ N N 2   : _ :   r e c u r r e n c e _ N N 1   o r _ C C   p r o g r e s s i o n _ N N 1   o f _ I O   t h e _ A T   p r i m a r y _ J J   c a n c e r _ N N 1   ; _ ;   e x t e r n a l _ J J   c a u s e s _ N N 2   , _ ,   i n c l u d i n g _ I I   a c c i d e n t s _ N N 2   , _ ,   s u i c i d e s _ N N 2   , _ ,   a n d _ C C   p o i s o n i n g s _ N N 2   ( _ (   I C D - 9 _ M C   c o d e s _ N N 2   8 0 0 - 9 9 9 _ M C M C   a n d _ C C   I C D - 1 0 _ M C   c o d e s _ N N 2   V 0 0 - V 9 9 _ N N 1   , _ ,   W 0 0 - W 9 9 _ N N 1   , _ ,   X 0 0 - X 9 9 _ N N 1   , _ ,   a n d _ C C   Y 0 0 - Y 8 9 _ N N 1   ) _ )   ; _ ;   a n d _ C C   h e a l t h - r e l a t e d _ J J   c a u s e s _ N N 2   , _ ,   i n c l u d i n g _ I I   s u b s e q u e n t _ J J   n e o p l a s m s _ N N 2   ( _ (   I C D - 9 _ M C   c o d e s _ N N 2   1 4 0 - 2 3 9 _ M C M C   a n d _ C C   I C D - 1 0 _ M C   c o d e s _ N N 2   C 0 0 - C 9 7 _ N N 1   a n d _ C C   D 1 0 - D 3 6 _ N N 1   ) _ )   , _ ,   c a r d i a c _ J J   c a u s e s _ N N 2   ( _ (   I C D - 9 _ M C   c o d e s _ N N 2   3 9 0 - 3 9 8 _ M C M C   , _ ,   4 0 2 _ M C   , _ ,   4 0 4 _ M C   , _ ,   a n d _ C C   4 1 0 - 4 2 9 _ M C M C   a n d _ C C   I C D - 1 0 _ M C   c o d e s _ N N 2   I 0 0 - I 0 2 _ N N 1   , _ ,   I 0 5 - I 0 9 _ N N 1   , _ ,   I 1 1 _ F O   , _ ,   I 1 3 _ F O   , _ ,   I 1 4 _ F O   , _ ,   I 2 0 - I 2 8 _ N N 1   , _ ,   a n d _ C C   I 3 0 - I 5 2 _ N N 1   ) _ )   , _ ,   p u l m o n a r y _ J J   c a u s e s _ N N 2   ( _ (   I C D - 9 _ M C   c o d e s _ N N 2   4 6 0 - 5 1 9 _ M C M C   a n d _ C C   I C D - 1 0 _ M C   c o d e s _ N N 2   J 0 0 - J 9 9 _ N N 1   ) _ )   , _ ,   a n d _ C C   a l l _ D B   o t h e r _ J J   c a u s e s _ N N 2   . _ .   
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 P a t i e n t _ J J   m e d i c a l _ J J   r e c o r d s _ N N 2   w e r e _ V B D R   r e v i e w e d _ V V N   , _ ,   a n d _ C C   p a t i e n t _ J J   a g e _ N N 1   a n d _ C C   s e x _ N N 1   w e r e _ V B D R   r e c o r d e d _ V V N   . _ .   
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 I n _ I I   t h i s _ D D 1   s t u d y _ N N 1   , _ ,   r e m o t e n e s s _ N N 1   w a s _ V B D Z   n o t _ X X   f o u n d _ V V N   t o _ T O   b e _ V B I   a _ A T 1   s i g n i f i c a n t _ J J   p r e d i c t o r _ N N 1   o f _ I O   o u t c o m e _ N N 1   . _ .   
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 T h e _ A T   p r o t o c o l _ N N 1   w a s _ V B D Z   a p p r o v e d _ V V N   b y _ I I   I n s t i t u t i o n a l _ J J   A n i m a l _ N N 1   C a r e _ N N 1   a n d _ C C   U s e _ V V 0   C o m m i t t e e _ N N 1   o f _ I O   t h e _ A T   S a i n t _ N P 1   L o u i s _ N P 1   U n i v e r s i t y _ N N 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   . _ .   
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 H o w e v e r _ R R   , _ ,   n o n e _ P N   o f _ I O   t h e _ A T   o t h e r _ J J   R O I s _ N N 2   w e r e _ V B D R   c o r r e l a t e d _ V V N   w i t h _ I W   p a r e n t - r e p o r t e d _ N N 1   C U _ F O   t r a i t s _ N N 2   . _ .   
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 T h e _ A T   c o n v e n t i o n a l _ J J   t h r e s h o l d _ N N 1   f o r _ I F   a _ A T 1   p o s i t i v e _ J J   t e s t _ N N 1   r e s u l t _ N N 1   i s _ V B Z   5 0 0 _ M C   n g / d L _ N N 1   , _ ,   w i t h _ I W   r e c o m m e n d a t i o n s _ N N 2   t o _ T O   o r d e r _ V V I   i m a g i n g _ V V G   f o r _ I F   r e s u l t s _ N N 2   a b o v e _ I I   t h a t _ D D 1   l e v e l _ N N 1   . _ .   
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 M e t h o d s _ N N 2   : _ :   A _ Z Z 1   m o n o c l o n a l _ J J   a n t i b o d y _ N N 1   r a i s e d _ V V N   a g a i n s t _ I I   h u m a n _ J J   H p _ N N 1   w a s _ V B D Z   s h o w n _ V V N   t o _ T O   d i s t i n g u i s h _ V V I   b e t w e e n _ I I   t h e _ A T   t h r e e _ M C   H p _ N N U   p h e n o t y p e s _ N N 2   i n _ I I   a n _ A T 1   e n z y m e _ N N 1   l i n k e d _ V V N   i m m u n o s o r b e n t _ J J   a s s a y _ N N 1   ( _ (   E L I S A _ N P 1   ) _ )   . _ .   
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 I t _ P P H 1   i s _ V B Z   u n k n o w n _ J J   w h e t h e r _ C S W   t h i s _ D D 1   a g e - r e l a t e d _ J J   r e d u c t i o n _ N N 1   i n _ I I   e n d o t h e l i a l _ J J   p r o g e n i t o r _ N N 1   c e l l s _ N N 2   r e s u l t s _ N N 2   i n _ I I   s e n e s c e n c e _ N N 1   ' _ N U L L   a p o p t o s i s _ N N 1   a n d _ C C   d e p l e t i o n _ N N 1   o f _ I O   t h e _ A T   p r o g e n i t o r _ N N 1   p o o l _ N N 1   i n _ I I   t h e _ A T   b o n e _ N N 1   m a r r o w _ N N 1   o r _ C C   f r o m _ I I   r e d u c e d _ J J   l e v e l s _ N N 2   o f _ I O   a n g i o g e n i c _ J J   a n d _ C C   m o b i l i z i n g _ V V G   c y t o k i n e s _ N N 2   ' _ N U L L   s u c h _ I I 2 1   a s _ I I 2 2   v a s c u l a r _ J J   e n d o t h e l i a l _ J J   g r o w t h _ N N 1   f a c t o r _ N N 1   a n d _ C C   n i t r i c _ J J   o x i d e _ N N 1   . _ .   
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 T h e s e _ D D 2   p e d i g r e e s _ N N 2   i l l u s t r a t e _ V V 0   p o s s i b l e _ J J   i n t r a f a m i l y _ R R   o l i g o g e n i c _ J J   i n h e r i t a n c e _ N N 1   o r _ C C   p h e n o c o p i e s _ N N 2   t h a t _ C S T   w o u l d _ V M   l i k e l y _ R R   b e _ V B I   m i s s e d _ V V N   b y _ I I   f a m i l y - b a s e d _ J J   s e q u e n c i n g _ N N 1   s t u d y _ N N 1   d e s i g n s _ N N 2   b a s e d _ V V N   o n _ I I   m o n o g e n i c _ J J   a n d _ C C   c o m p l e t e l y _ R R   p e n e t r a n t _ J J   i n h e r i t a n c e _ N N 1   m o d e l s _ N N 2   . _ .   
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 I t _ P P H 1   m u s t _ V M   a l s o _ R R   b e _ V B I   n o t e d _ V V N   t h a t _ D D 1   t r e a t m e n t _ N N 1   o f _ I O   l o c a l l y _ R R   a d v a n c e d _ V V D   S C C H N _ N P 1   i n _ I I   A s i a _ N P 1   i s _ V B Z   g e n e r a l l y _ R R   b a s e d _ V V N   o n _ I I   s u r g i c a l _ J J   a p p r o a c h e s _ N N 2   a n d _ C C   r a d i o t h e r a p y _ N N 1   r a t h e r _ I I 2 1   t h a n _ I I 2 2   c h e m o t h e r a p y _ N N 1   . _ .   
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 C o r r e s p o n d e n c e _ N N 1   t o _ I I   : _ :   T a t s u y a _ N P 1   N i s h i i _ N P 1   , _ ,   M D _ N N A   , _ ,   P h D _ N N 1   , _ ,   D e p a r t m e n t _ N N 1   o f _ I O   R a d i o l o g y _ N P 1   , _ ,   K o b e _ N P 1   U n i v e r s i t y _ N N 1   G r a d u a t e _ N N 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   , _ ,   7 - 5 - 1 _ M C M C   K u s u n o k i - c h o _ N N 1   , _ ,   C h u o - k u _ N N 1   , _ ,   K o b e _ N P 1   , _ ,   H y o g o _ N P 1   6 5 0 - 0 0 1 7 _ M C M C   , _ ,   J a p a n _ N P 1   . _ .   
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 T h e s e _ D D 2   f i n d i n g s _ N N 2   a r e _ V B R   n o t _ X X   c o n s i s t e n t _ J J   w i t h _ I W   a _ A T 1   p a t h o l o g i c _ J J   i n f l a m m a t o r y _ J J   r e s p o n s e . 2 5 _ F O   R a t h e r _ R R   , _ ,   t h e _ A T   p r e s e n c e _ N N 1   o f _ I O   a b u n d a n t _ J J   v i r a l _ J J   a n t i g e n _ N N 1   s u g g e s t s _ V V Z   a c t i v e _ J J   R S V _ N P 1   r e p l i c a t i o n _ N N 1   a n d _ C C   d i r e c t _ J J   v i r a l l y _ R R   i n d u c e d _ V V N   c y t o t o x i c i t y . 2 5 _ F O   A t _ R R 2 1   l e a s t _ R R 2 2   i n _ I I   i n f a n t s _ N N 2   w h o _ P N Q S   h a v e _ V H 0   n o t _ X X   h a d _ V H N   a _ A T 1   p r e v i o u s _ J J   i n f e c t i o n _ N N 1   , _ ,   o v e r w h e l m i n g _ J J   R S V _ N P 1   d i s e a s e _ N N 1   a p p e a r s _ V V Z   t o _ T O   b e _ V B I   r e l a t e d _ V V N   t o _ I I   t h e _ A T   l a c k _ N N 1   o f _ I O   a n _ A T 1   a d a p t i v e _ J J   c y t o t o x i c _ J J   T - c e l l _ N N 1   r e s p o n s e _ N N 1   i n _ I I   t h e _ A T   h o s t _ N N 1   ; _ ;   t h e _ A T   r e s u l t _ N N 1   i s _ V B Z   d e p e n d e n c e _ N N 1   o n _ I I   t h e _ A T   l e s s _ R G R   e f f e c t i v e _ J J   i n n a t e _ J J   i m m u n e _ J J   r e s p o n s e _ N N 1   f o r _ I F   t h e _ A T   t e r m i n a t i o n _ N N 1   o f _ I O   v i r a l _ J J   r e p l i c a t i o n _ N N 1   . _ .   
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 I n _ I I   a n _ A T 1   e q u i n e _ J J   p o p u l a t i o n _ N N 1   , _ ,   F o r t i e r _ N P 1   a n d _ C C   c o l l e a g u e s _ N N 2   c r e a t e d _ V V D   f u l l - t h i c k n e s s _ J J   d e f e c t s _ N N 2   i n _ I I   t h e _ A T   f e m o r a l _ J J   l a t e r a l _ J J   t r o c h l e a r _ N N 1   r i d g e _ N N 1   a n d _ C C   p e r f o r m e d _ V V D   m a r r o w _ N N 1   s t i m u l a t i o n _ N N 1   w i t h _ I W   o r _ C C   w i t h o u t _ I W   t h e _ A T   i n j e c t i o n _ N N 1   o f _ I O   a u t o l o g o u s _ J J   B M A C _ N N 1   . _ .   
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 T h e _ A T   s e a r c h _ N N 1   t e r m s _ N N 2   " _ "   a m y l o i d _ J J   a n g i o p a t h y _ N N 1   , _ ,   " _ "   " _ "   c o n g o p h i l i c _ J J   a n g i o p a t h y _ N N 1   , _ ,   " _ "   " _ "   C A A _ N P 1   , _ ,   " _ "   " _ "   i n t r a c r a n i a l _ J J   h ( a ) e m o r r h a g e _ N N 1   , _ ,   " _ "   " _ "   i n t r a c e r e b r a l _ J J   h ( a ) e m o r r h a g e _ N N 1   , _ ,   " _ "   " _ "   c e r e b r a l / b r a i n _ F U   , _ ,   " _ "   " _ "   c e r e b r a l / _ J J   c o r t i c a l / b r a i n _ F U   m i c r o i n f a r c t _ N N 1   , _ ,   " _ "   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   a _ A T 1   b r o a d e r _ J J R   s e a r c h _ N N 1   s t r a t e g y _ N N 1   f o r _ I F   I C H _ F W   s t u d i e s 4 _ F O   w e r e _ V B D R   u s e d _ V V N   . _ .   
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 M o r e o v e r _ R R   , _ ,   n o n e _ P N   o f _ I O   t h e s e _ D D 2   r e v i e w s _ N N 2   d i f f e r e n t i a t e d _ V V N   b e t w e e n _ I I   a s s e s s m e n t s _ N N 2   c o n c e n t r a t i n g _ V V G   o n _ I I   t h e _ A T   e v a l u a t i o n _ N N 1   o f _ I O   t r u e _ J J   r e c o v e r y _ N N 1   a n d _ C C   t h o s e _ D D 2   a l l o w i n g _ V V G   c o m p e n s a t o r y _ J J   s t r a t e g i e s _ N N 2   . _ .   
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 C e r v i c o m e d u l l a r y _ J J   m o t o r _ N N 1   e v o k e d _ V V D   p o t e n t i a l s _ N N 2   w e r e _ V B D R   g e n e r a l l y _ R R   u n c h a n g e d _ J J   i m m e d i a t e l y _ R R   a f t e r _ I I   t r a i n i n g _ N N 1   . _ .   
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 T h e _ A T   5 - y e a r _ J J   d i s e a s e - f r e e _ J J   s u r v i v a l _ N N 1   r a t e _ N N 1   w a s _ V B D Z   8 1 . 9 % _ F O   a n d _ C C   7 8 . 7 % _ F O   , _ ,   r e s p e c t i v e l y _ R R   ( _ (   P _ Z Z 1   = _ F O   0 . 5 4 7 _ M C   ) _ )   . _ .   
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 A l l _ D B   a u t h o r s _ N N 2   r e a d _ V V 0   a n d _ C C   a p p r o v e d _ V V D   t h e _ A T   f i n a l _ J J   m a n u s c r i p t _ N N 1   . _ .   
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 E E _ U H   c o n t r i b u t e d _ V V N   t o _ I I   t h e _ A T   c o n t e n t _ N N 1   a n d _ C C   r e v i e w e d _ V V N   t h e _ A T   m a n u s c r i p t _ N N 1   . _ .   
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 N e v e r t h e l e s s _ R R   , _ ,   t e m p o r a l _ J J   c h a n g e s _ N N 2   i n _ I I   t h e _ A T   g a p s _ N N 2   b e t w e e n _ I I   g r o u p s _ N N 2   a r e _ V B R   s e c o n d a r y _ J J   t o _ I I   t h e _ A T   i n c r e a s e _ N N 1   t h a t _ C S T   a l l _ D B   g r o u p s _ N N 2   e x p e r i e n c e _ V V 0   o v e r _ I I   t i m e _ N N T 1   . _ .   
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 A f t e r _ I I   e x c l u d i n g _ V V G   c o n t a m i n a t e d _ J J   o r _ C C   d i r t y _ J J   c a s e s _ N N 2   ( _ (   i . e . _ R E X   , _ ,   e x c l u s i o n _ N N 1   b a s e d _ V V N   o n _ I I   w o u n d _ N N 1   c l a s s i f i c a t i o n _ N N 1   ) _ )   , _ ,   8 6 0 _ M C   p a t i e n t s _ N N 2   r e m a i n e d _ V V D   , _ ,   a n d _ C C   a t t e n d i n g _ V V G   h a n d o f f s _ N N 2   r e m a i n e d _ V V D   s i g n i f i c a n t l y _ R R   a s s o c i a t e d _ V V N   w i t h _ I W   c o m p l i c a t i o n s _ N N 2   e v e n _ R R   a f t e r _ I I   a d j u s t m e n t _ N N 1   ( _ (   O R _ C C   = _ F O   1 . 4 0 _ M C   , _ ,   P _ Z Z 1   = _ F O   0 . 0 3 2 9 _ M C   ) _ )   . _ .   
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 I n _ I I   o t h e r _ J J   w o r d s _ N N 2   , _ ,   a n a l g e s i c s _ N N 2   a r e _ V B R   p r e s c r i b e d _ V V N   w i t h o u t _ I W   r e g a r d _ N N 1   f o r _ I F   t h e _ A T   p a t i e n t _ N N 1   ' _ N U L L   s _ Z Z 1   i n n a t e _ J J   s u i t a b i l i t y _ N N 1   t o _ T O   m e t a b o l i z e _ V V I   t h e s e _ D D 2   m e d i c a t i o n s _ N N 2   . _ .   
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 N e u r o n s _ N N 2   i n _ I I   t h e _ A T   S P N _ N P 1   p o s s e s s _ V V 0   b o t h _ R R   i n t r i n s i c _ J J   ( _ (   F e l i x _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 , _ ,   2 0 1 1 _ M C   ) _ )   a n d _ C C   s y n a p t i c _ J J   ( _ (   K u l e s z a _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 , _ ,   2 0 0 7 _ M C   ) _ )   p r o p e r t i e s _ N N 2   t h a t _ C S T   m a k e _ V V 0   t h e m _ P P H O 2   w e l l _ R R   s u i t e d _ V V N   f o r _ I F   e n c o d i n g _ V V G   c o a r s e _ J J   t e m p o r a l _ J J   i n f o r m a t i o n _ N N 1   i m p o r t a n t _ J J   f o r _ I F   v o c a l i z a t i o n _ N N 1   p r o c e s s i n g _ N N 1   ( _ (   E g g e r m o n t _ N P 1   , _ ,   2 0 1 0 _ M C   ) _ )   . _ .   
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 H e r _ A P P G E   l e a d e r s h i p _ N N 1   w a s _ V B D Z   i n s i g h t f u l _ J J   , _ ,   i m p o r t a n t _ J J   , _ ,   e n e r g i z i n g _ V V G   , _ ,   a n d _ C C   c r i t i c a l _ J J   t o _ I I   t h e _ A T   s u c c e s s _ N N 1   o f _ I O   t h e _ A T   c o l l a b o r a t i o n _ N N 1   . _ .   
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 N o g o - A _ N P 1   i s _ V B Z   e x p r e s s e d _ V V N   b y _ I I   b o t h _ R R   o l i g o d e n d r o c y t e s _ N N 2   a n d _ C C   n e u r o n s _ N N 2   i n _ I I   t h e _ A T   a g e d _ J J   h i p p o c a m p a l _ J J   f o r m a t i o n _ N N 1   a n d _ C C   o v e r - e x p r e s s e d _ V V N   b y _ I I   h i p p o c a m p a l _ J J   n e u r o n s _ N N 2   i n _ I I   A D _ R A   ( _ (   G i l _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 6 _ M C   ) _ )   . _ .   
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 A l t h o u g h _ C S   a l l _ D B   p r e g n a n t _ J J   w o m e n _ N N 2   a t _ I I   2 0 _ M C   w e e k s _ N N T 2   o f _ I O   g e s t a t i o n _ N N 1   w e r e _ V B D R   i n c l u d e d _ V V N   i n _ I I   t h e _ A T   a n a l y s e s _ N N 2   o f _ I O   e a r l y - o n s e t _ J J   p r e e c l a m p s i a _ N N 1   , _ ,   o n l y _ R R   t h o s e _ D D 2   w i t h _ I W   o n g o i n g _ J J   p r e g n a n c i e s _ N N 2   a t _ I I   3 4 _ M C   w e e k s _ N N T 2   w e r e _ V B D R   i n c l u d e d _ V V N   i n _ I I   t h e _ A T   a n a l y s e s _ N N 2   o f _ I O   l a t e - o n s e t _ J J   p r e e c l a m p s i a _ N N 1   . _ .   
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 D i f f e r e n c e s _ N N 2   i n _ I I   s e v e r e _ J J   c a r d i o t o x i c i t y _ N N 1   a c r o s s _ I I   s u b g r o u p s _ N N 2   o f _ I O   E B C _ N N 1   p a t i e n t s _ N N 2   S e v e r e _ J J   c a r d i o t o x i c i t y _ N N 1   A c r o s s _ I I   5 8 _ M C   s t u d i e s _ N N 2   , _ ,   8 4 4 _ M C   t o t a l _ J J   i n c i d e n t _ N N 1   c a s e s _ N N 2   o f _ I O   s e v e r e _ J J   c a r d i a c _ J J   e v e n t s _ N N 2   w e r e _ V B D R   r e p o r t e d _ V V N   d u r i n g _ I I   f o l l o w - u p _ N N 1   ; _ ;   o f _ I O   t h e s e _ D D 2   , _ ,   5 5 7 _ M C   o c c u r r e d _ V V D   i n _ I I   E B C _ N P 1   , _ ,   2 0 3 _ M C   i n _ I I   M B C _ N P 1   , _ ,   a n d _ C C   8 4 _ M C   i n _ I I   m i x e d _ J J   p o p u l a t i o n s _ N N 2   . _ .   
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 D i s t a n t _ J J   m e t a s t a s i s _ N N 1   w a s _ V B D Z   d e t e c t e d _ V V N   i n _ I I   1 2 _ M C   p a t i e n t s _ N N 2   ( _ (   1 . 4 % _ F O   ; _ ;   1 2 _ M C   o f _ I O   8 7 3 _ M C   ) _ )   , _ ,   i n _ I I   t h r e e _ M C   p a t i e n t s _ N N 2   a t _ I I   i n i t i a l _ J J   d i a g n o s i s _ N N 1   o f _ I O   t h y r o i d _ J J   c a n c e r _ N N 1   a n d _ C C   i n _ I I   n i n e _ M C   p a t i e n t s _ N N 2   d u r i n g _ I I   f o l l o w - u p _ J J   s u r v e i l l a n c e _ N N 1   ( _ (   m e a n _ J J   i n t e r v a l _ N N 1   f r o m _ I I   s u r g e r y _ N N 1   , _ ,   5 6 . 0 _ M C   m o n t h s _ N N T 2   ; _ ;   r a n g e _ N N 1   , _ ,   9 - 9 8 _ M C M C   m o n t h s _ N N T 2   ) _ )   . _ .   
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 I n _ I I   c o n t r a s t _ N N 1   , _ ,   a f t e r _ C S   M D T _ N P 1   d i s c u s s i o n _ N N 1   , _ ,   p a t i e n t s _ N N 2   w i t h _ I W   m o r e _ R G R   c o m p l e x _ J J   d i s e a s e _ N N 1   h a d _ V H D   t h e i r _ A P P G E   m a n a g e m e n t _ N N 1   c h a n g e d _ V V N   i n _ I I   m o r e _ D A R   t h a n _ C S N   5 0 % _ N N U   o f _ I O   p a t i e n t s _ N N 2   . _ .   
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 A l t e r n a t e _ J J   m e a s u r e s _ N N 2   o f _ I O   p h y s i c a l _ J J   a c t i v i t y _ N N 1   w e r e _ V B D R   a l s o _ R R   c a l c u l a t e d _ V V N   i n c l u d i n g _ I I   t o t a l _ J J   m e t a b o l i c _ J J   e q u i v a l e n t s _ N N 2   ( _ (   M E T s _ N N 2   ) _ )   a n d _ C C   m o d e r a t e - t o - v i g o r o u s _ J J   M E T s _ N N 2   . _ .   
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 D e l e t i o n _ N N 1   s i t e s _ N N 2   a r e _ V B R   n o t _ X X   f u l l y _ R R   s a t u r a t e d _ V V N   . _ .   
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 O t h e r _ J J   s i m i l a r _ J J   i n s t r u m e n t s _ N N 2   h a v e _ V H 0   a _ A T 1   l e s s _ R G R   w e l l - d e f i n e d _ J J   f a c t o r _ N N 1   s t r u c t u r e _ N N 1   . _ .   
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 T h e _ A T   a u t h o r s _ N N 2   w o u l d _ V M   l i k e _ V V I   t o _ T O   t h a n k _ V V I   t h e _ A T   E x o m e _ N N 1   A g g r e g a t i o n _ N N 1   C o n s o r t i u m _ N N 1   ( _ (   E x A C _ N P 1   ) _ )   , _ ,   C a m b r i d g e _ N P 1   , _ ,   M A _ N N A   , _ ,   U . S . A . _ N P 1   ( _ (   h t t p _ N N U   : _ :   / / _ V V 0   e x a c . b r o a d i n s t i t u t e . o r g _ N N U   ) _ )   . _ .   
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 T h e _ A T   r e s e a r c h e r _ N N 1   a n d _ C C   t h e _ A T   m o t h e r s _ N N 2   ( _ (   w h e n _ C S   p r e s e n t _ J J   ) _ )   c o m p l e t e d _ V V D   a n _ A T 1   1 1 - p o i n t _ J J   B o x _ N N 1   S c a l e _ N N 1   3 0 _ M C   d u r i n g _ I I   t h e _ A T   h e e l _ N N 1   l a n c e _ N N 1   . _ .   
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 A l l _ D B   p a t i e n t s _ N N 2   n o t _ X X   w i t h d r a w n _ V V N   f r o m _ I I   t h e _ A T   t r i a l _ N N 1   ( _ (   S D - r A T G _ N N 1   4 2 _ M C   o f _ I O   4 4 _ M C   p a t i e n t s _ N N 2   a n d _ C C   D D - r A T G _ N N 1   4 9 _ M C   o f _ I O   5 1 _ M C   p a t i e n t s _ N N 2   ) _ )   w e r e _ V B D R   f o l l o w e d _ V V N   f o r _ I F   1 2 _ M C   m o n t h s _ N N T 2   ( _ (   F i g u r e _ N N 1   1 _ M C 1   ) _ )   . _ .   
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 T a b l e s _ N N 2   3 _ M C   a n d _ C C   4 _ M C   s h o w _ V V 0   a _ A T 1   s u m m a r y _ N N 1   o f _ I O   t h e _ A T   v a r i a b l e s _ N N 2   i n c l u d e d _ V V N   i n _ I I   t h e _ A T   m o d e l s _ N N 2   w i t h _ I W   t h e i r _ A P P G E   c o e f f i c i e n t s _ N N 2   , _ ,   s t a n d a r d _ J J   e r r o r _ N N 1   , _ ,   o d d s _ N N 2   r a t i o s _ N N 2   a n d _ C C   9 5 % _ N N U   c o n f i d e n c e _ N N 1   i n t e r v a l s _ N N 2   . _ .   
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 T h e _ A T   c o n c e n t r a t i o n s _ N N 2   w e r e _ V B D R   m e a s u r e d _ V V N   d u r i n g _ I I   a n d _ C C   a f t e r _ C S   t h e _ A T   t r e a t m e n t _ N N 1   p e r i o d _ N N 1   . _ .   
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 K e y p o i n t s : T h e _ F O   E p l e y _ N P 1   m a n o e u v r e _ N N 1   i s _ V B Z   a _ A T 1   h i g h l y _ R R   e f f e c t i v e _ J J   t r e a t m e n t _ N N 1   f o r _ I F   p o s t e r i o r _ J J   c a n a l _ N N 1   B P P V _ N P 1   i n _ I I   b o t h _ D B 2   t h e _ A T   s h o r t _ J J   a n d _ C C   l o n g _ J J   t e r m _ N N 1   . _ .   
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 C o r r e s p o n d i n g _ J J   a u t h o r _ N N 1   : _ :   D . _ N P 1   S . _ N P 1   F i n k _ N P 1   , _ ,   D e p a r t m e n t _ N N 1   o f _ I O   O t o l a r y n g o l o g y - H e a d _ N N 1   a n d _ C C   N e c k _ N N 1   S u r g e r y _ N N 1   , _ ,   L o u i s i a n a _ N P 1   S t a t e _ N N 1   U n i v e r s i t y _ N N 1   H e a l t h _ N N 1   S c i e n c e s _ N N 2   C e n t e r _ N N 1   , _ ,   4 9 9 5 _ M C   E s s e n _ N P 1   L a n e _ N N L 1   , _ ,   S u i t e _ N N 1   B _ Z Z 1   , _ ,   B a t o n _ N P 1   R o u g e _ N P 1   , _ ,   L A _ N P 1   7 0 8 1 0 _ M C   . _ .   
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 C e l l s _ N N 2   a r e _ V B R   a l s o _ R R   e v e n l y _ R R   d i s t r i b u t e d _ V V N   t h r o u g h o u t _ I I   t h e _ A T   m e m b r a n e _ N N 1   , _ ,   a n d _ C C   M A C I _ N N 2   r a r e l y _ R R   r e q u i r e s _ V V Z   a _ A T 1   l a r g e _ J J   a r t h r o t o m y _ N N 1   . _ .   
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 I n _ I I   o u r _ A P P G E   s t u d y _ N N 1   , _ ,   w e _ P P I S 2   a t t e m p t e d _ V V D   q u a n t i t a t i v e _ J J   a s s e s s m e n t _ N N 1   b y _ I I   u s i n g _ V V G   c h a n g e s _ N N 2   i n _ I I   T 1 _ F O   a n d _ C C   T 2 _ F O   r e g i o n a l l y _ R R   a n d _ C C   g l o b a l l y _ R R   . _ .   
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 W e _ P P I S 2   s e q u e n t i a l l y _ R R   e v a l u a t e d _ V V D   t h e _ A T   p e r f o r m a n c e s _ N N 2   o f _ I O   t w o _ M C   n u c l e i c _ J J   a c i d _ N N 1   a m p l i f i c a t i o n _ N N 1   t e s t s _ N N 2   ( _ (   N A A T s _ N P 2   ) _ )   a n d _ C C   o n e _ M C 1   s e r o l o g y _ N N 1   a s s a y _ N N 1   f o r _ I F   H C V _ N P 1   g e n o t y p e _ N N 1   : _ :   A b b o t t _ N P 1   R e a l T i m e _ N N T 1   g e n o t y p e _ N N 1   I I _ M C   ( _ (   R e a l T i m e _ N N T 1   I I _ M C   ) _ )   , _ ,   G e n e M a t r i x _ N P 1   r e s t r i c t i o n _ N N 1   f r a g m e n t _ N N 1   m a s s _ N N 1   p o l y m o r p h i s m _ N N 1   ( _ (   R F M P _ N P 1   ) _ )   , _ ,   a n d _ C C   S y s m e x _ N P 1   H I S C L _ N P 1   H C V _ N P 1   G r _ N P 1   ( _ (   H I S C L _ N P 1   G r _ N P 1   ) _ )   . _ .   
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 A l l _ D B   a d m i n i s t r a t i o n s _ N N 2   o f _ I O   g a d o d i a m i d e _ N N 1   o r _ C C   g a d o p e n t e t a t e _ V V 0   d i m e g l u m i n e _ N N 1   o c c u r r e d _ V V D   b e f o r e _ I I   t h e _ A T   F D A _ N N 1   c o n t r a i n d i c a t i o n _ N N 1   o n _ I I   u s i n g _ V V G   t h e s e _ D D 2   a g e n t s _ N N 2   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   G F R _ N P 1   l e s s _ D A R   t h a n _ C S N   3 0 _ M C   m L / m i n _ N N U   p e r _ I I   1 . 7 3 _ M C   m 2 _ F O   . _ .   
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 F o u r _ M C   p a r t i c i p a n t s _ N N 2   ( _ (   2 _ M C   c o n t r o l s _ N N 2   , _ ,   1 _ M C 1   u n i l a t e r a l _ J J   c a s e _ N N 1   , _ ,   a n d _ C C   1 _ M C 1   b i l a t e r a l _ J J   c a s e _ N N 1   ) _ )   d i d _ V D D   n o t _ X X   a n s w e r _ V V I   q u e s t i o n s _ N N 2   o n _ I I   h o m e _ N N 1   p e s t i c i d e _ N N 1   u s e _ N N 1   a n d _ C C   w e r e _ V B D R   t h e r e f o r e _ R R   e x c l u d e d _ V V N   f r o m _ I I   t h e _ A T   p r e s e n t _ J J   a n a l y s e s _ N N 2   . _ .   
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 T h o s e _ D D 2   p a t i e n t s _ N N 2   , _ ,   p l u s _ I I   a n _ A T 1   a d d i t i o n a l _ J J   p a t i e n t _ N N 1   f r o m _ I I   a n _ A T 1   a s _ R R 2 1   y e t _ R R 2 2   u n p u b l i s h e d _ J J   r e p o r t _ N N 1   , _ ,   h a v e _ V H 0   b e e n _ V B N   p l o t t e d _ V V N   o n _ I I   M i l h o r n _ N P 1   a n d _ C C   K o r p i - S t e i n e r _ N P 1   ' _ N U L L   s _ Z Z 1   F i g u r e _ N N 1   2 _ M C   ( _ (   w h i c h _ D D Q   w a s _ V B D Z   m o d i f i e d _ V V N   f r o m _ I I   M c C h e s n e y _ N P 1   ) _ )   ( _ (   F i g . _ N N 1   1 _ M C 1   ) _ )   . _ .   
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 T h e r e f o r e _ R R   , _ ,   a u t o m a t e d _ J J   C S F _ N P 1   T F _ N N 1   a s s a y _ N N 1   i n _ I I   c l i n i c a l _ J J   b i o c h e m i s t r y _ N N 1   l a b o r a t o r i e s _ N N 2   i s _ V B Z   a _ A T 1   g o o d _ J J   s c r e e n i n g _ N N 1   t o o l _ N N 1   f o r _ I F   C F D _ N P 1   . _ .   
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 A s _ C S A   i n c r e a s e s _ V V Z   , _ ,   t h e _ A T   p o i n t s _ N N 2   a r e _ V B R   d i s t r i b u t e d _ V V N   a l o n g _ R P   a n d _ C C   a r o u n d _ I I   a _ A T 1   c u r v e _ N N 1   ; _ ;   F i g u r e _ N N 1   3 _ M C   s h o w s _ V V Z   t h e _ A T   d i s t r i b u t i o n _ N N 1   f o r _ I F   . _ .   
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 F o r c e d _ J J   m o u t h _ N N 1   o p e n i n g _ V V G   u n d e r _ I I   g e n e r a l _ J J   a n a e s t h e s i a _ N N 1   c a n _ V M   i m p r o v e _ V V I   t r i s m u s _ N N 1   , _ ,   b u t _ C C B   t h e _ A T   e f f e c t _ N N 1   i s _ V B Z   o f t e n _ R R   s h o r t - l i v e d _ J J   a n d _ C C   p o t e n t i a l l y _ R R   c o m p l i c a t e d _ V V N   b y _ I I   a l v e o l u s _ N N 1   f r a c t u r e _ N N 1   a n d _ C C   a d j a c e n t _ J J   s o f t _ J J   t i s s u e _ N N 1   i n j u r y _ N N 1   . _ .   
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 B y _ I I   d e l i v e r i n g _ V V G   n o c i c e p t i v e _ J J   s e l e c t i v e _ J J   s t i m u l i _ N N 2   t o _ I I   t h e _ A T   s a m e _ D A   s i t e s _ N N 2   , _ ,   w e _ P P I S 2   a l s o _ R R   d e t e c t e d _ V V N   , _ ,   f o r _ I F   t h e _ A T   f i r s t _ M D   t i m e _ N N T 1   , _ ,   a _ A T 1   c l e a r _ J J   g r a d i e n t _ N N 1   o f _ I O   s p a t i a l _ J J   a c u i t y _ N N 1   f o r _ I F   p a i n _ N N 1   . _ .   
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 S u r g e r y _ N N 1   e a r l y _ R R   a f t e r _ I I   P C I _ N P 1   i s _ V B Z   o f t e n _ R R   u r g e n t _ J J   b e c a u s e _ C S   t h e _ A T   A C C / A H A _ F U   g u i d e l i n e s _ N N 2   r e c o m m e n d _ V V 0   p o s t p o n i n g _ V V G   e a r l y _ R R   e l e c t i v e _ J J   s u r g e r y _ N N 1   , _ ,   a n d _ C C   t h i s _ D D 1   f a c t _ N N 1   p r o b a b l y _ R R   c o n t r i b u t e d _ V V N   t o _ I I   t h e _ A T   h i g h _ J J   i n c i d e n c e _ N N 1   o f _ I O   M A C E _ N N 1   i n _ I I   t h e _ A T   s t u d y _ N N 1   b y _ I I   V i c e n z i _ N P 1   a n d _ C C   c o l l e a g u e s _ N N 2   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   f e a t u r e s _ N N 2   o f _ I O   s o c i a l _ J J   a n x i e t y _ N N 1   d i s o r d e r _ N N 1   , _ ,   s u c h _ I I 2 1   a s _ I I 2 2   f e a r _ N N 1   o f _ I O   n e g a t i v e _ J J   e v a l u a t i o n _ N N 1   a n d _ C C   s a f e t y _ N N 1   b e h a v i o u r s _ N N 2   , _ ,   h a v e _ V H 0   b e e n _ V B N   f o u n d _ V V N   t o _ T O   f e a t u r e _ V V I   p r o m i n e n t l y _ R R   i n _ I I   s t u t t e r i n g _ V V G   , _ ,   a n d _ C C   m a y _ V M   a l s o _ R R   s e r v e _ V V I   t o _ T O   m a i n t a i n _ V V I   s o c i a l _ J J   a n x i e t y _ N N 1   a n d _ C C   e x a c e r b a t e _ V V I   s t u t t e r i n g _ V V G   . _ .   
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 H o w e v e r _ R R   , _ ,   d e s p i t e _ I I   t h e _ A T   i n c r e a s e d _ J J   h e a l i n g _ J J   p o t e n t i a l _ N N 1   w i t h _ I W   b o n y _ J J   i n v o l v e m e n t _ N N 1   , _ ,   t h e _ A T   p r e d o m i n a n t _ J J   r e p a i r _ N N 1   t i s s u e _ N N 1   i s _ V B Z   f i b r o c a r t i l a g e _ N N 1   . _ .   
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 S q u a m o u s _ J J   c e l l _ N N 1   c a r c i n o m a _ N N 1   o f _ I O   t h e _ A T   o r o p h a r y n x _ N N 1   ( _ (   T 1 - T 2 _ N N 1   , _ ,   N 0 _ F O   ) _ )   O f f e r _ V V 0   p e o p l e _ N N   t h e _ A T   c h o i c e _ N N 1   o f _ I O   t r a n s o r a l _ J J   s u r g i c a l _ J J   r e s e c t i o n _ N N 1   o r _ C C   p r i m a r y _ J J   r a d i o t h e r a p y _ N N 1   f o r _ I F   T 1 - T 2 _ N N 1   N 0 _ F O   t u m o u r s _ N N 2   o f _ I O   t h e _ A T   o r o p h a r y n x _ N N 1   & l s q b ; _ (   B a s e d _ V V N   o n _ I I   v e r y _ R G   l o w - _ J J   t o _ I I   m o d e r a t e - q u a l i t y _ J J   e v i d e n c e _ N N 1   f r o m _ I I   r e t r o s p e c t i v e _ J J   s t u d i e s _ N N 2   a n d _ C C   t h e _ A T   e x p e r i e n c e _ N N 1   a n d _ C C   o p i n i o n _ N N 1   o f _ I O   t h e _ A T   G D G _ N P 1   & r s q b ; _ )   . _ .   
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 T e s t i c u l a r _ J J   g e r m _ N N 1   c e l l _ N N 1   t u m o r s _ N N 2   ( _ (   T G C T s _ N P 1   ) _ )   a c c o u n t _ V V 0   f o r _ I F   a p p r o x i m a t e l y _ R R   9 7 % _ N N U   o f _ I O   a l l _ D B   t e s t i c u l a r _ J J   c a n c e r s . 6 2 _ F O   T h e _ A T   2 _ M C   m a i n _ J J   t y p e s _ N N 2   o f _ I O   T G C T s _ N P 1   a r e _ V B R   s e m i n o m a s _ N N 2   a n d _ C C   n o n s e m i n o m a s _ N N 2   . _ .   
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 D i a b e t e s _ N N 1   w a s _ V B D Z   d e f i n e d _ V V N   a s _ I I   a _ A T 1   d i s c h a r g e _ N N 1   d i a g n o s i s _ N N 1   o f _ I O   d i a b e t e s _ N N 1   ( _ (   I C D - 1 0 _ M C   c o d e s _ N N 2   E 1 1 _ F O   ) _ )   w i t h i n _ I I   t h e _ A T   l a s t _ M D   1 0 _ M C   y e a r s _ N N T 2   o r _ C C   r e d e e m e d _ J J   p r e s c r i p t i o n _ N N 1   o f _ I O   a n t i d i a b e t i c _ J J   d r u g s _ N N 2   ( _ (   A T C _ N P 1   c o d e s _ N N 2   A 1 0 _ F O   ) _ )   w i t h i n _ I I   9 0 _ M C   d a y s _ N N T 2   . _ .   
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 T h e _ A T   l y s a t e s _ N N 2   w e r e _ V B D R   c l e a r e d _ V V N   o f _ I O   c e l l _ N N 1   m e m b r a n e _ N N 1   d e b r i s _ N N 1   b y _ I I   c e n t r i f u g a t i o n _ N N 1   a t _ I I   1 0 , 0 0 0 _ M C   x _ Z Z 1   g _ Z Z 1   f o r _ I F   2 0 m i n _ N N U   a t _ I I   4 C _ F O   , _ ,   a n d _ C C   t h e _ A T   t o t a l _ J J   p r o t e i n _ N N 1   c o n c e n t r a t i o n _ N N 1   i n _ I I   t h e _ A T   s u p e r n a t a n t _ N N 1   w a s _ V B D Z   d e t e r m i n e d _ V V N   u s i n g _ V V G   B C A _ N N 1   a s s a y _ N N 1   a n d _ C C   d i l u t e d _ V V N   t o _ I I   1 _ M C 1   n g / L _ F U   . _ .   
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 A P P _ N P 1   w a s _ V B D Z   i m m u n o p r e c i p i t a t e d _ V V N   w i t h _ I W   C - t e r m i n a l _ J J   m A b _ N N 1   ( _ (   c l o n e _ V V 0   C 1 / 6 . 1 _ F U   ; _ ;   C o v a n c e _ N P 1   I n c . _ J J   , _ ,   P r i n c e t o n _ N P 1   , _ ,   N J _ N P 1   ) _ )   1 8 _ M C   ( _ (   1 0 _ M C   m A b / 2 0 0 l _ F U   s a m p l e _ N N 1   ) _ )   . _ .   
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 T h e r e _ E X   w e r e _ V B D R   t w o _ M C   s c r e e n i n g _ N N 1   q u e s t i o n s _ N N 2   a b o u t _ I I   b u r n o u t _ N N 1   ( _ (   T a b l e _ N N 1   2 _ M C   ) _ )   . _ .   
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 I n _ I I   a l l _ D B   , _ ,   3 3 5 _ M C   p a t i e n t s _ N N 2   ( _ (   7 8 % _ N N U   ) _ )   w e r e _ V B D R   t r e a t e d _ V V N   w i t h _ I W   G - C S F _ N N 1   a f t e r _ I I   F N _ N P 1   d e v e l o p e d _ V V D   , _ ,   w h e r e a s _ C S   9 5 _ M C   p a t i e n t s _ N N 2   ( _ (   2 2 % _ N N U   ) _ )   d i d _ V D D   n o t _ X X   r e c e i v e _ V V I   t h e r a p e u t i c _ J J   G - C S F _ N N 1   . _ .   
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 F u r t h e r m o r e _ R R   , _ ,   a s _ I I   a _ A T 1   r e s u l t _ N N 1   o f _ I O   r e p e a t e d _ J J   m u s c l e _ N N 1   c o n t r a c t i o n s _ N N 2   , _ ,   i n c r e a s e s _ V V Z   i n _ I I   b l o o d _ N N 1   t e m p e r a t u r e _ N N 1   c a n _ V M   o c c u r _ V V I   a n d _ C C   t h i s _ D D 1   a l s o _ R R   m a y _ V M   c o n t r i b u t e _ V V I   t o _ I I   A T P _ N N 1   r e l e a s e _ N N 1   d u r i n g _ I I   e x e r c i s e _ N N 1   ( _ (   2 1 _ M C   ) _ )   . _ .   
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 T h e _ A T   c u t - o f f _ N N 1   p o i n t s _ N N 2   w e r e _ V B D R   a s _ C S A   f o l l o w s _ V V Z   : _ :   l e s s _ D A R   t h a n _ C S N   a n d _ C C   e q u a l _ J J   t o _ I I   - 2 . 6 0 _ M C   ( _ (   A L B I _ N P 1   g r a d e _ V V 0   1 _ M C 1   ) _ )   , _ ,   m o r e _ R R R   t h a n _ C S N   - 2 . 6 0 t o _ N N U   - 1 . 3 9 _ M C   o r l e s s _ J J   ( _ (   A L B I _ N P 1   g r a d e _ N N 1   2 _ M C   ) _ )   , _ ,   a n d _ C C   m o r e _ D A R   t h a n _ C S N   - 1 . 3 9 _ M C   ( _ (   A L B I _ N P 1   g r a d e _ N N 1   3 _ M C   ) _ )   . _ .   
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 R e s e a r c h _ N N 1   s h o w s _ V V Z   a _ A T 1   h i g h e r _ J J R   i n c i d e n c e _ N N 1   o f _ I O   b u r n o u t _ N N 1   , _ ,   d e p r e s s i o n _ N N 1   , _ ,   a n d _ C C   h o s t i l i t y _ N N 1   a m o n g _ I I   r e s i d e n t s _ N N 2   w h e n _ C S   c o m p a r e d _ V V N   t o _ I I   t h e _ A T   g e n e r a l _ J J   p o p u l a t i o n _ N N 1   . _ .   
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 A t _ R R 2 1   l e a s t _ R R 2 2   f o u r _ M C   s t u d i e s _ N N 2   h a v e _ V H 0   d e m o n s t r a t e d _ V V N   t h a t _ C S T   a m o n g _ I I   i n d i v i d u a l s _ N N 2   w i t h _ I W   G T S _ N P 1   , _ ,   m a l e s _ N N 2   a r e _ V B R   m o r e _ R G R   l i k e l y _ J J   t o _ T O   h a v e _ V H I   t i c s _ N N 2   , _ ,   w h i l e _ C S   f e m a l e s _ N N 2   a r e _ V B R   m o r e _ R G R   l i k e l y _ J J   t o _ T O   h a v e _ V H I   o b s e s s i v e _ J J   - _ -   c o m p u l s i v e _ J J   b e h a v i o u r s _ N N 2   ( _ (   O C B _ N P 1   ) _ )   / d i s o r d e r s _ F U   ( _ (   O C D _ N P 1   ) _ )   . _ .   
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 A l t e r n a t i v e _ J J   r i s k - r e d u c t i o n _ J J   s t r a t e g i e s _ N N 2   i n _ I I   y o u n g _ J J   d r i v e r s _ N N 2   w i t h _ I W   a _ A T 1   n e u r o b i o l o g i c a l _ J J   b a s i s _ N N 1   f o r _ I F   t h e i r _ A P P G E   d r i v i n g _ J J   r i s k _ N N 1   m a y _ V M   b e _ V B I   n e e d e d _ V V N   s u c h _ I I 2 1   a s _ I I 2 2   t h e _ A T   u s e _ N N 1   o f _ I O   i n - v e h i c l e _ J J   t e c h n o l o g i e s _ N N 2   ( _ (   e g _ R E X   , _ ,   h i g h _ J J   g - f o r c e _ J J   d e t e c t i o n _ N N 1   s y s t e m s _ N N 2   t e c h n o l o g y 4 7 , 4 8 _ F O   ) _ )   . _ .   
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 R e c u r r e n t _ J J   m e d u l l o b l a s t o m a _ N N 1   i s _ V B Z   a _ A T 1   c o n s i d e r a b l e _ J J   t h e r a p e u t i c _ J J   c h a l l e n g e _ N N 1   i n _ I I   p a e d i a t r i c _ J J   n e u r o - o n c o l o g y _ N N 1   : _ :   r e s c u e _ V V 0   t h e r a p y _ N N 1   i s _ V B Z   e f f e c t i v e _ J J   o n l y _ R R   i n _ I I   c h i l d r e n _ N N 2   w h o _ P N Q S   d i d _ V D D   n o t _ X X   r e c e i v e _ V V I   r a d i o t h e r a p y _ N N 1   a s _ I I   p a r t _ N N 1   o f _ I O   t h e i r _ A P P G E   f i r s t - l i n e _ J J   t r e a t m e n t _ N N 1   . _ .   
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 A l l _ D B   a n a l y s e s _ N N 2   w e r e _ V B D R   c o n d u c t e d _ V V N   u s i n g _ V V G   S A S _ N P 1   , _ ,   v e r s i o n _ N N 1   9 . 3 _ M C   , _ ,   w i t h _ I W   a n _ A T 1   & l s q b ; _ (   a l p h a _ N N 1   & r s q b ; _ )   l e v e l _ N N 1   o f _ I O   0 . 0 5 _ M C   t h r o u g h o u t _ R L   . _ .   
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 F o r _ R E X 2 1   e x a m p l e _ R E X 2 2   , _ ,   t h e r e _ E X   a r e _ V B R   f e w _ D A 2   e p i d e m i o l o g i c _ J J   d a t a _ N N   o n _ I I   H i s p a n i c s _ N P 1   , _ ,   n o w _ R T   t h e _ A T   l a r g e s t _ J J T   m i n o r i t y _ N N 1   g r o u p _ N N 1   i n _ I I   t h e _ A T   U n i t e d _ N P 1   S t a t e s _ N P 1   . _ .   
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 T h e _ A T   t e r m _ N N 1   ' _ N U L L   d e b r i d e m e n t _ N N 1   ' _ N U L L   i n _ I I   t h e _ A T   l i t e r a t u r e _ N N 1   i s _ V B Z   q u i t e _ R G   v a g u e _ J J   , _ ,   a n d _ C C   i t _ P P H 1   m a y _ V M   r e p r e s e n t _ V V I   a _ A T 1   v a r i e t y _ N N 1   o f _ I O   p r o c e d u r e s _ N N 2   i n c l u d i n g _ I I   c h o n d r o p l a s t y _ N N 1   , _ ,   s y n o v e c t o m y _ N N 1   , _ ,   a n d _ C C   m e n i s c e c t o m y _ N N 1   . _ .   
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 H o w e v e r _ R R   , _ ,   s l o p e _ N N 1   e s t i m a t e s _ V V Z   i n _ I I   p r o b a b l e _ J J   m u l t i p l e _ J J   s y s t e m _ N N 1   a t r o p h y _ N N 1   , _ ,   w h i c h _ D D Q   c o m p r i s e s _ V V Z   l a t e - s t a g e _ J J   d i s e a s e _ N N 1   , _ ,   r e a c h _ V V 0   a _ A T 1   p l a t e a u _ N N 1   p h a s e _ N N 1   w i t h _ I W   a _ A T 1   f l a t _ J J   s l o p e _ N N 1   o f _ I O   0 . 3 7 5 _ M C   f o r _ I F   U M S A R S _ N N 2   I . _ N P 1   T h e _ A T   d i f f e r e n c e _ N N 1   i n _ I I   E C D _ N P 1   l o s s _ N N 1   b e t w e e n _ I I   t h e _ A T   2 _ M C   g r o u p s _ N N 2   w a s _ V B D Z   s t a t i s t i c a l l y _ R R   s i g n i f i c a n t _ J J   ( _ (   9 5 % _ N N U   c o n f i d e n c e _ N N 1   i n t e r v a l _ N N 1   ' _ N U L L   - 0 . 5 % _ F O   t o _ I I   - 1 0 . 9 % _ F O   l o s s _ N N 1   ; _ ;   P _ Z Z 1   = _ F O   0 . 0 4 _ M C   ) _ )   . _ .   
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 P a t i e n t s _ N N 2   w h o _ P N Q S   e x p e r i e n c e d _ V V D   S T E M I _ N N 2   w i t h _ I W   T I M I _ J J   r i s k _ N N 1   s c o r e _ V V 0   g r e a t e r _ J J R   t h a n _ C S N   a n d _ C C   e q u a l _ J J   t o _ I I   4 _ M C   h a d _ V H D   o v e r _ R G   7 . 3 _ M C   % _ N N U   3 0 - d a y _ J J   m o r t a l i t y _ N N 1   a n d _ C C   o v e r _ R G   4 . 2 _ M C   % _ N N U   1 - y e a r _ J J   m o r t a l i t y _ N N 1   & l s q b ; _ (   1 3 _ M C   & r s q b ; _ )   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   c o m p a r e d _ V V N   w i t h _ I W   t h e _ A T   c o n t r o l _ N N 1   g r o u p _ N N 1   , _ ,   6 _ M C   w e e k s _ N N T 2   F C _ N P 1   d i e t _ N N 1   t r e a t m e n t _ N N 1   i n c r e a s e d _ V V D   t h e _ A T   l e v e l s _ N N 2   i n _ I I   t h e _ A T   h i p p o c a m p u s _ N N 1   o f _ I O   C h A T _ N N 1   w i t h _ I W   2 1 % _ N N U   . _ .   
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 B e h a v i o r a l _ J J   t e s t i n g _ N N 1   c o n d u c t e d _ V V N   t o w a r d s _ I I   t h e _ A T   e n d _ N N 1   o f _ I O   t h e _ A T   t r e a t m e n t _ N N 1   i n c l u d e d _ V V D   t h e _ A T   o b j e c t _ N N 1   r e c o g n i t i o n _ N N 1   a n d _ C C   t h e _ A T   r a d i a l _ J J   a r m _ N N 1   m a z e _ N N 1   t e s t s _ N N 2   , _ ,   w h i c h _ D D Q   b o t h _ D B 2   a s s e s s _ V V 0   a n i m a l s _ N N 2   ' _ N U L L   m e m o r y _ N N 1   . _ .   
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 S t u d i e s _ N N 2   i n v o l v i n g _ V V G   e x t r e m e l y _ R R   p r e m a t u r e _ J J   i n f a n t s _ N N 2   h a v e _ V H 0   s h o w n _ V V N   t h a t _ C S T   B a y l e y - I I I _ M C   C o g n i t i v e _ J J   C o m p o s i t e _ J J   s c o r e s _ N N 2   a r e _ V B R   , _ ,   o n _ I I   a v e r a g e _ N N 1   , _ ,   1 0 _ M C   t o _ I I   1 1 _ M C   p o i n t s _ V V Z   h i g h e r _ J J R   t h a n _ C S N   t h e _ A T   B a y l e y - I I _ M C   M e n t a l _ J J   D e v e l o p m e n t a l _ J J   I n d e x _ N N 1   s c o r e s . 1 7 , 1 8 _ F O   T o _ T O   a d d r e s s _ V V I   t h i s _ D D 1   l i m i t a t i o n _ N N 1   , _ ,   w e _ P P I S 2   d e f i n e d _ V V D   c o g n i t i v e _ J J   i m p a i r m e n t _ N N 1   u s i n g _ V V G   a _ A T 1   c o n s e r v a t i v e _ N N 1   B a y l e y - I I I _ M C   C o g n i t i v e _ J J   C o m p o s i t e _ J J   s c o r e _ N N 1   l o w e r _ J J R   t h a n _ C S N   8 5 _ M C   , _ ,   w h i c h _ D D Q   i s _ V B Z   o n e _ M C 1   s t a n d a r d _ J J   d e v i a t i o n _ N N 1   b e l o w _ I I   t h e _ A T   m e a n _ J J   s c o r e _ N N 1   o f _ I O   1 0 0 _ M C   . _ .   
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 A n o t h e r _ D D 1   a p p r o a c h _ N N 1   w o u l d _ V M   l o o k _ V V I   a t _ I I   t h e _ A T   p l o t _ N N 1   o f _ I O   p r e d i c t e d _ J J   v s . _ I I   o b s e r v e d _ J J   r i s k _ N N 1   - _ -   a n _ A T 1   i l l u s t r a t i o n _ N N 1   o f _ I O   t h i s _ D D 1   a p p r o a c h _ N N 1   h a s _ V H Z   b e e n _ V B N   p r e s e n t e d _ V V N   i n _ I I   a _ A T 1   r e c e n t _ J J   p a p e r _ N N 1   o n _ I I   r e p o r t i n g _ V V G   g u i d e l i n e s _ N N 2   f o r _ I F   b i o m a r k e r _ N N 1   s t u d i e s _ N N 2   i n _ I I   C V D _ N P 1   r i s k _ N N 1   p r e d i c t i o n _ N N 1   b y _ I I   H l a t k y _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . . _ . . .   
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 W e _ P P I S 2   s h o w _ V V 0   h e r e _ R L   t h a t _ C S T   g e n e t i c a l l y _ R R   b l o c k i n g _ V V G   t h e _ A T   i n t e r a c t i o n _ N N 1   o f _ I O   R A S _ N P 2   w i t h _ I W   p 1 1 0 a _ F O   c a u s e s _ V V Z   p a r t i a l _ J J   r e g r e s s i o n _ N N 1   o f _ I O   t u m o r s _ N N 2   , _ ,   f o l l o w e d _ V V N   b y _ I I   l o n g - t e r m _ J J   t u m o r _ N N 1   s t a s i s _ N N 1   , _ ,   a l t h o u g h _ C S   b y _ I I   i t s e l f _ P P X 1   i t _ P P H 1   i s _ V B Z   n o t _ X X   s u f f i c i e n t _ J J   t o _ T O   c a u s e _ V V I   c o m p l e t e _ J J   r e g r e s s i o n _ N N 1   o f _ I O   e s t a b l i s h e d _ J J   t u m o r s _ N N 2   i n _ I I   t h e _ A T   a u t o c h t h o n o u s _ J J   s e t t i n g _ N N 1   . _ .   
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 W e _ P P I S 2   f o c u s e d _ V V D   o n _ I I   t h e _ A T   m o s t _ R G T   p o p u l a t e d _ J J   c o u n t i e s _ N N 2   t o _ T O   m i n i m i z e _ V V I   f l u c t u a t i o n _ N N 1   t h a t _ C S T   w o u l d _ V M   b e _ V B I   s e e n _ V V N   w i t h _ I W   l o w - p o p u l a t i o n _ J J   c o u n t i e s _ N N 2   . _ .   
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 F r a i l t y _ N N 1   i s _ V B Z   a _ A T 1   g e r i a t r i c _ J J   s y n d r o m e _ N N 1   u s e d _ V M K   t o _ T O   d e f i n e _ V V I   o l d e r _ J J R   a d u l t s _ N N 2   w i t h _ I W   i m p a i r e d _ J J   r e s i s t a n c e _ N N 1   t o _ I I   s t r e s s o r s _ N N 2   d u e _ I I 2 1   t o _ I I 2 2   a _ A T 1   d e c l i n e _ N N 1   i n _ I I   p h y s i o l o g i c _ J J   r e s e r v e _ N N 1   ( _ (   B e r g m a n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 7 _ M C   ) _ )   . _ .   
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 M E C _ N P 1   0 5 - 2 4 0 _ M C M C   , _ ,   a p p r o v a l _ N N 1   d a t e _ N N 1   8 _ M C   M a r c h _ N P M 1   2 0 0 6 _ M C   ) _ )   . _ .   
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 R e s u l t s _ N N 2   : _ :   N o n e _ P N   o f _ I O   t h e _ A T   t h r e e _ M C   w a r m - u p _ J J   p r o t o c o l s _ N N 2   h a d _ V H D   s i g n i f i c a n t _ J J   e f f e c t s _ N N 2   o n _ I I   m u s c l e _ N N 1   a c t i v i t y _ N N 1   l e v e l s _ N N 2   ( _ (   P _ Z Z 1   > _ F O   0 . 1 0 _ M C   ) _ )   . _ .   
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 S u h _ N P 1   e t _ R A 2 1   a l _ R A 2 2   r e t r o s p e c t i v e l y _ R R   e v a l u a t e d _ V V D   1 2 _ M C   p a t i e n t s _ N N 2   w h o _ P N Q S   r e c e i v e d _ V V D   m i c r o - v a s c u l a r _ J J   f r e e _ J J   f l a p _ N N 1   r e c o n s t r u c t i o n _ N N 1   f o r _ I F   r e c u r r e n t _ N N 1   o r _ C C   s e c o n d _ M D   p r i m a r y _ J J   h e a d _ N N 1   a n d _ C C   n e c k _ N N 1   c a n c e r _ N N 1   i n _ I I   a _ A T 1   p r e v i o u s l y _ R R   i r r a d i a t e d _ J J   f i e l d _ N N 1   . _ .   
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 I f _ C S   t h e s e _ D D 2   e v e n t s _ N N 2   w e r e _ V B D R   m o r e _ R G R   c o m m o n _ J J   , _ ,   t h e _ A T   i n c r e a s e d _ J J   r i s k _ N N 1   o f _ I O   3 0 - d a y _ J J   s t r o k e _ N N 1   f o u n d _ V V N   i n _ I I   t h i s _ D D 1   s t u d y _ N N 1   w o u l d _ V M   r e s u l t _ V V I   i n _ I I   m u c h _ R R   l a r g e r _ J J R   n u m b e r s _ N N 2   o f _ I O   m i s s e d _ J J   p o s t e r i o r _ J J   f o s s a _ N N 1   s t r o k e s _ N N 2   . _ .   
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 A n _ A T 1   e x p l a n a t i o n _ N N 1   f o r _ I F   t h i s _ D D 1   f i n d i n g _ N N 1   i s _ V B Z   t h e _ A T   f a c t _ N N 1   t h a t _ C S T   i n _ I I   u n b o u n d e d _ J J   e v e n t s _ N N 2   , _ ,   t h e _ A T   a u d i e n c e _ N N 1   t e n d s _ V V Z   t o _ T O   b e _ V B I   w i d e l y _ R R   s c a t t e r e d _ V V N   , _ ,   a n d _ C C   i s _ V B Z   t h u s _ R R   m o r e _ R G R   v u l n e r a b l e _ J J   t o _ I I   t h e _ A T   h a z a r d s _ N N 2   o f _ I O   t h e _ A T   t e r r a i n _ N N 1   . _ .   
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 M o r e o v e r _ R R   , _ ,   t h e _ A T   f i r s t _ M D   , _ ,   m o r e _ R G R   s i m p l i f i e d _ J J   m o d e l _ N N 1   a l s o _ R R   p r e s e n t e d _ V V N   a _ A T 1   b e t t e r _ J J R   f i t _ N N 1   c o m p a r e d _ V V N   t o _ I I   t h e _ A T   m o d e l _ N N 1   i n c l u d i n g _ I I   t h e _ A T   3 - w a y _ J J   i n t e r a c t i o n _ N N 1   ( _ (   A I C _ N P 1   = _ F O   2 9 2 4 . 9 5 _ M C   v e r s u s _ I I   2 9 3 8 . 6 9 _ M C   ; _ ;   B I C _ N P 1   = _ F O   3 0 6 4 . 3 0 _ M C   v e r s u s _ I I   3 1 2 8 . 2 1 _ M C   , _ ,   r e s p e c t i v e l y _ R R   ) _ )   . _ .   
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 P o t e n t i a l _ J J   C o n f l i c t s _ N N 2   o f _ I O   I n t e r e s t _ N N 1   P . H . _ N N 1   : _ :   c o n s u l t a n c y _ N N 1   , _ ,   C o l g a t e _ N P 1   P a l m o l i v e _ N P 1   E u r o p e _ N P 1   . _ .   
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 A l t h o u g h _ C S   s e v e r a l _ D A 2   p r o m i s i n g _ J J   B A C E 1 _ F O   i n h i b i t o r s _ N N 2   a r e _ V B R   b e i n g _ V B G   t e s t e d _ V V N   i n _ I I   h u m a n _ J J   c l i n i c a l _ J J   t r i a l s _ N N 2   , _ ,   m a n y _ D A 2   q u e s t i o n s _ N N 2   r e m a i n _ V V 0   a b o u t _ I I   t h e _ A T   s a f e t y _ N N 1   o f _ I O   t h e s e _ D D 2   d r u g s _ N N 2   , _ ,   t h e _ A T   o p t i m u m _ J J   l e v e l _ N N 1   o f _ I O   B A C E 1 _ F O   i n h i b i t i o n _ N N 1   t o _ T O   a c h i e v e _ V V I   e f f i c a c y _ N N 1   w i t h o u t _ I W   u n a c c e p t a b l e _ J J   s i d e - e f f e c t s _ N N 2   , _ ,   a n d _ C C   t h e _ A T   s t a g e _ N N 1   o f _ I O   d i s e a s e _ N N 1   a t _ I I   w h i c h _ D D Q   t o _ T O   t r e a t _ V V I   f o r _ I F   g r e a t e s t _ J J T   t h e r a p e u t i c _ J J   g a i n _ N N 1   . _ .   
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 H i g h - d o s e _ J J   h o o k _ N N 1   e f f e c t _ N N 1   R e c o m b i n a n t _ J J   h u m a n _ J J   A M H _ N N 1   ( _ (   B e c k m a n _ N P 1   C o u l t e r _ N P 1   , _ ,   B r e a _ N P 1   , _ ,   C A _ N P 1   , _ ,   U S A _ N P 1   ) _ )   w a s _ V B D Z   a d d e d _ V V N   i n t o _ I I   t h e _ A T   P M _ N P 1   s e r u m _ N N 1   p o o l _ N N 1   ( _ (   s e e _ V V 0   a b o v e _ R L   ) _ )   i n _ I I   c o n c e n t r a t i o n s _ N N 2   u p _ R G 2 1   t o _ R G 2 2   1 3 , 0 0 0 _ M C   n g / m L _ F U   a n d _ C C   m e a s u r e d _ V V N   o n _ I I   c o b a s _ N N 2   e _ Z Z 1   4 1 1 _ M C   a n d _ C C   e _ Z Z 1   6 0 1 _ M C   , _ ,   r e s p e c t i v e l y _ R R   . _ .   
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 I n _ I I   t h i s _ D D 1   s t u d y _ N N 1   , _ ,   a s _ C S A   i n _ I I   o t h e r _ J J   s t u d i e s _ N N 2   ( _ (   S a c k _ V V 0   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 0 _ M C   R a l s t o n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 3 _ M C   a n d _ C C   M a t e e r _ N P 1   e t _ N P 1   a l . 1 6 _ F O   ) _ )   , _ ,   w e _ P P I S 2   f o u n d _ V V D   n o _ A T   a b d o m i n a l _ J J   t r a u m a _ N N 1   f o l l o w i n g _ V V G   t h e _ A T   u s e _ N N 1   o f _ I O   I A C - C P R _ N N 1   . _ .   
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 W e _ P P I S 2   i d e n t i f i e d _ V V D   f o u r _ M C   n o v e l _ J J   m u t a t i o n s _ N N 2   i n _ I I   P S E N 1 _ F O   a n d _ C C   o n e _ M C 1   n o v e l _ J J   m u t a t i o n _ N N 1   i n _ I I   A P P _ N P 1   . _ .   
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 J i a _ N P 1   Y i _ N P 1   a c h i e v e d _ V V D   a n d _ C C   m a i n t a i n e d _ V V D   l o w _ J J   r a t e s _ N N 2   o f _ I O   0 - 1 . 9 % _ F O   S S _ N P 1   a c r o s s _ I I   l a n g u a g e s _ N N 2   f o r _ I F   1 2 _ M C   m o n t h s _ N N T 2   p o s t - S t a g e _ N N 1   1 _ M C 1   . _ .   
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 B e c a u s e _ I I 2 1   o f _ I I 2 2   t h e _ A T   m a n y _ D A 2   c o m p a r i s o n s _ N N 2   m a d e _ V V N   w i t h _ I W   t h e s e _ D D 2   d a t a _ N N   , _ ,   P _ Z Z 1   v a l u e s _ N N 2   f o r _ I F   d i f f e r e n c e s _ N N 2   i n _ I I   m o r t a l i t y _ N N 1   a m o n g _ I I   p a t i e n t s _ N N 2   w i t h _ I W   s p e c i f i c _ J J   c a n c e r _ N N 1   t y p e s _ N N 2   o r _ C C   f r o m _ I I   s p e c i f i c _ J J   c a u s e s _ N N 2   s h o u l d _ V M   b e _ V B I   r e g a r d e d _ V V N   a s _ C S A   e x p l o r a t o r y _ J J   . _ .   
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 T h e _ A T   t i s s u e _ N N 1   w a s _ V B D Z   c o l l e c t e d _ V V N   o n l y _ R R   a f t e r _ I I   a c q u i r i n g _ V V G   c o n s e n t _ N N 1   f r o m _ I I   t h e _ A T   n e x t _ M D   o f _ I O   k i n _ N N   a l o n g _ I I 2 1   w i t h _ I I 2 2   p e r m i s s i o n _ N N 1   t o _ T O   r e v i e w _ V V I   m e d i c a l _ J J   r e c o r d s _ N N 2   a n d _ C C   t o _ T O   c o n d u c t _ V V I   a _ A T 1   t e l e p h o n e _ N N 1   i n t e r v i e w _ N N 1   w i t h _ I W   a _ A T 1   p r i m a r y _ J J   c a r e g i v e r _ N N 1   . _ .   
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 M o r e _ D A R   t h a n _ C S N   7 0 % _ N N U   o f _ I O   p a t i e n t s _ N N 2   w h o _ P N Q S   h a v e _ V H 0   b l a d d e r _ N N 1   c a n c e r _ N N 1   a r e _ V B R   d i a g n o s e d _ V V N   w i t h _ I W   n o n m u s c l e - i n v a s i v e _ J J   d i s e a s e . 1 1 _ F O   T r e a t m e n t _ N N 1   a n d _ C C   s u r v i v a l _ N N 1   F o r _ I F   n o n m u s c l e - i n v a s i v e _ J J   c a n c e r s _ N N 2   , _ ,   m o s t _ D A T   p a t i e n t s _ N N 2   a r e _ V B R   d i a g n o s e d _ V V N   a n d _ C C   t r e a t e d _ V V N   w i t h _ I W   t r a n s u r e t h r a l _ J J   r e s e c t i o n _ N N 1   o f _ I O   t h e _ A T   b l a d d e r _ N N 1   t u m o r _ N N 1   ( _ (   T U R B T _ N P 1   ) _ )   , _ ,   w h i c h _ D D Q   m a y _ V M   b e _ V B I   f o l l o w e d _ V V N   b y _ I I   i n t r a v e s i c a l _ J J   c h e m o t h e r a p y _ N N 1   ( _ (   2 2 % _ N N U   ) _ )   o r _ C C   b i o l o g i c _ J J   t h e r a p y _ N N 1   w i t h _ I W   b a c i l l u s _ N N 1   C a l m e t t e - G u e r i n _ N P 1   ( _ (   2 9 % _ N N U   ) _ )   . 1 4 _ M C   ( _ (   T h e _ A T   N C D B _ N P 1   d o e s _ V D Z   n o t _ X X   d i s t i n g u i s h _ V V I   b e t w e e n _ I I   s y s t e m i c _ J J   a n d _ C C   i n t r a v e s i c a l _ J J   c h e m o t h e r a p y _ N N 1   b u t _ C C B   , _ ,   b a s e d _ V V N   o n _ I I   t r e a t m e n t _ N N 1   g u i d e l i n e s _ N N 2   , _ ,   i t _ P P H 1   i s _ V B Z   l i k e l y _ J J   t h a t _ C S T   v i r t u a l l y _ R R   a l l _ D B   c h e m o t h e r a p y _ N N 1   i s _ V B Z   i n t r a v e s i c a l _ J J   a d m i n i s t r a t i o n _ N N 1   . _ .   ) _ )   
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 A m o n g _ I I   p a t i e n t s _ N N 2   w i t h _ I W   m u s c l e - i n v a s i v e _ J J   d i s e a s e _ N N 1   , _ ,   a b o u t _ I I   o n e - h a l f _ M F   u n d e r g o _ V V 0   T U R B T _ N P 1   , _ ,   a n d _ C C   3 9 % _ N N U   u n d e r g o _ V V 0   c y s t e c t o m y _ N N 1   , _ ,   w i t h _ I W   o r _ C C   w i t h o u t _ I W   c h e m o t h e r a p y _ N N 1   a n d / o r _ C C   r a d i a t i o n _ N N 1   ( _ (   F i g . _ N N 1   1 2 _ M C   ) _ )   . _ .   
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 C o n w a y _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 d e t e r m i n e d _ V V N   t h a t _ C S T   d i v i d i n g _ V V G   a _ A T 1   c a f f e i n e _ N N 1   d o s e _ N N 1   ( _ (   e . g . _ R E X   , _ ,   3 _ M C   m g / k g _ N N U   b e f o r e _ I I   e x e r c i s e _ N N 1   a n d _ C C   3 _ M C   m g / k g _ N N U   d u r i n g _ I I   e x e r c i s e _ N N 1   ) _ )   p r o d u c e s _ V V Z   n o _ A T   e r g o g e n i c _ J J   e f f e c t _ N N 1   o v e r _ I I   t h e _ A T   i n g e s t i o n _ N N 1   o f _ I O   a _ A T 1   b o l u s _ N N 1   d o s e _ N N 1   ( _ (   6 _ M C   m g / k g _ N N U   b e f o r e _ I I   e x e r c i s e _ N N 1   ) _ )   i n _ I I   a _ A T 1   g r o u p _ N N 1   o f _ I O   c y c l i s t _ N N 1   a n d _ C C   t r i a t h l e t e s _ N N 2   p e r f o r m i n g _ V V G   a _ A T 1   3 0 - m i n _ J J   c y c l i n g _ N N 1   t i m e _ N N T 1   t r i a l _ N N 1   . _ .   
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 A l l _ D B   m i c e _ N N 2   i n _ I I   t h e _ A T   c o n t r o l _ N N 1   g r o u p _ N N 1   w e r e _ V B D R   k i l l e d _ V V N   o n _ I I   d a y _ N N T 1   1 3 _ M C   , _ ,   2 4 _ M C   h r _ N N U   a f t e r _ I I   t h e _ A T   l a s t _ M D   d o s e _ N N 1   o f _ I O   v e h i c l e _ N N 1   . _ .   
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 T h e _ A T   h o m e - d e l i v e r e d _ J J   m e a l s _ N N 2   s o c i a l _ J J   w o r k e r _ N N 1   r e c o g n i z e d _ V V D   h e r _ A P P G E   d e p r e s s i o n _ N N 1   a n d _ C C   r e f e r r e d _ V V D   h e r _ P P H O 1   t o _ I I   t h e _ A T   s t u d y _ N N 1   . _ .   
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 T h e _ A T   f a c t _ N N 1   t h a t _ R G   e a r l y _ R R   m u t a t i o n s _ N N 2   a r e _ V B R   a l l o w e d _ V V N   t o _ T O   a c c u m u l a t e _ V V I   t o _ I I   s i g n i f i c a n t _ J J   l e v e l s _ N N 2   m a y _ V M   b e _ V B I   i n t e r p r e t e d _ V V N   a s _ C S A   e v i d e n c e _ N N 1   f o r _ I F   s o m e _ D D   s o r t _ N N 1   o f _ I O   s e l e c t i v e _ J J   p r e s s u r e _ N N 1   . _ .   
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 A c c o r d i n g l y _ R R   , _ ,   r e c e n t _ J J   r e s e a r c h _ N N 1   h a s _ V H Z   s o u g h t _ V V N   t o _ T O   e l u c i d a t e _ V V I   t h e _ A T   p o t e n t i a l _ N N 1   f o r _ I F   p r e f e r e n t i a l _ J J   e f f e c t s _ N N 2   o f _ I O   N O 3 - _ N N 1   o n _ I I   h u m a n _ J J   T y p e _ N N 1   I I _ M C   s k e l e t a l _ J J   m u s c l e _ N N 1   i n _ R R 2 1   v i v o _ R R 2 2   . _ .   
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 R N A _ N N 1   w a s _ V B D Z   e x t r a c t e d _ V V N   f r o m _ I I   s e r u m _ N N 1   o f _ I O   m o t h e r s _ N N 2   a n d _ C C   n e o n a t e s _ N N 2   ( _ (   c a s e s _ N N 2   a n d _ C C   c o n t r o l s _ N N 2   ) _ )   a n d _ C C   c e r e b r o s p i n a l _ J J   f l u i d _ N N 1   s a m p l e s _ N N 2   ( _ (   o f _ I O   c a s e s _ N N 2   ) _ )   a n d _ C C   a n a l y s e d _ V V N   b y _ I I   R T - P C R _ N N 1   f o r _ I F   d e t e c t i o n _ N N 1   o f _ I O   w o r l d w i d e _ J J   A f r i c a n _ J J   a n d _ C C   A s i a n _ J J   Z i k a _ N N 1   v i r u s _ N N 1   g e n o m e s _ N N 2   u s i n g _ V V G   p r i m e r s _ N N 2   d e s i g n e d _ V V N   b y _ I I   L a n c i o t t i _ N P 1   a n d _ C C   c o l l e a g u e s _ N N 2   . _ .   
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 W e _ P P I S 2   f o u n d _ V V D   t h a t _ D D 1   o f _ I O   t h e _ A T   2 3 7 8 _ M C   d e a t h s _ N N 2   t h a t _ C S T   o c c u r r e d _ V V D   6 _ M C   m o n t h s _ N N T 2   o r _ C C   m o r e _ R R R   a f t e r _ I I   d i a g n o s i s _ N N 1   , _ ,   a p p r o x i m a t e l y _ R R   h a l f _ D B   w e r e _ V B D R   d u e _ I I 2 1   t o _ I I 2 2   e x t e r n a l _ J J   c a u s e s _ N N 2   , _ ,   a l m o s t _ R R   e n t i r e l y _ R R   i n j u r i e s _ N N 2   a n d _ C C   s u i c i d e s _ N N 2   . _ .   
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 T h i s _ D D 1   c o n s i d e r a t i o n _ N N 1   h a s _ V H Z   l e d _ V V N   t o _ I I   t h e _ A T   d e v e l o p m e n t _ N N 1   o f _ I O   p r o s t h e t i c _ J J   g r o u p s _ N N 2   t h a t _ C S T   c a n _ V M   b e _ V B I   c o n j u g a t e d _ V V N   t o _ I I   i n t e r n a l i z i n g _ V V G   m A b s _ N N 2   s o _ R R   t h a t _ D D 1   l a b e l e d _ J J   c a t a b o l i t e s _ N N 2   g e n e r a t e d _ V V N   f r o m _ I I   t h e _ A T   c o n j u g a t e _ N N 1   a r e _ V B R   t r a p p e d _ V V N   w i t h i n _ I I   t h e _ A T   c e l l _ N N 1   . _ .   
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 U n f o r t u n a t e l y _ R R   , _ ,   d u e _ I I 2 1   t o _ I I 2 2   t h e _ A T   s m a l l _ J J   n u m b e r _ N N 1   o f _ I O   s a m p l e s _ N N 2   a v a i l a b l e _ J J   , _ ,   i t _ P P H 1   w a s _ V B D Z   n o t _ X X   p o s s i b l e _ J J   t o _ T O   c o r r e l a t e _ V V I   c a l p a i n - 1 _ M C 1   a c t i v i t y _ N N 1   a n d _ C C   N C X 3 _ F O   c l e a v a g e _ N N 1   i n _ I I   b r a i n _ N N 1   f r o m _ I I   o t h e r _ J J   t a u o p a t h i e s _ N N 2   . _ .   
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 I t _ P P H 1   i s _ V B Z   o n e _ M C 1   o f _ I O   t h e _ A T   m o s t _ R G T   f r e q u e n t _ J J   g e n e t i c _ J J   m y o p a t h i e s _ N N 2   , _ ,   e . g . _ R E X   a _ A T 1   p r e v a l e n c e _ N N 1   o f _ I O   1 / 1 6 7 , 0 0 0 _ M F   i n _ I I   S p a i n _ N P 1   a s _ I I 2 1   o f _ I I 2 2   J a n u a r y _ N P M 1   2 0 1 1 _ M C   , _ ,   w i t h _ I W   b o t h _ D B 2   s e x e s _ N N 2   e q u a l l y _ R R   a f f e c t e d _ V V N   . _ .   
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 T h e s e _ D D 2   d a t a _ N N   s u g g e s t e d _ V V D   t h a t _ C S T   i n _ I I   c o n e s _ N N 2   , _ ,   O S / l a m e l l a e _ F U   m o r p h o g e n e s i s _ N N 1   i s _ V B Z   i n i t i a t e d _ V V N   b y _ I I   t h e _ A T   a d d i t i o n _ N N 1   o f _ I O   o p s i n - c o n t a i n i n g _ J J   m e m b r a n e _ N N 1   , _ ,   w i t h _ I W   r i m _ N N 1   f o r m a t i o n _ N N 1   ( _ (   m e d i a t e d _ V V N   b y _ I I   P R P H 2 / R D S _ F U   ) _ )   o c c u r r i n g _ V V G   s e c o n d _ N N T 1   . _ .   
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 I n _ I I   s t u d y _ N N 1   1 _ M C 1   , _ ,   w e _ P P I S 2   i n v e s t i g a t e d _ V V D   w h e t h e r _ C S W   C S + R T _ F O   i n i t i a t e d _ V V D   1 4 _ M C   d a y s _ N N T 2   a f t e r _ I I   M C _ N N 1   i n f a r c t s _ N N 2   , _ ,   w i t h _ I W   o r _ C C   w i t h o u t _ I W   f o r c e d _ J J   u s e _ N N 1   , _ ,   y i e l d s _ V V Z   e n d u r i n g _ J J   i m p r o v e m e n t s _ N N 2   i n _ I I   s k i l l e d _ J J   m o t o r _ N N 1   f u n c t i o n _ N N 1   a s _ C S A   a s s e s s e d _ V V N   f o r _ I F   9 _ M C   t o _ I I   1 0 _ M C   m o n t h s _ N N T 2   p o s t t r e a t m e n t _ N N 1   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   i n _ J J 2 1   v i t r o _ J J 2 2   t e s t s _ N N 2   w e r e _ V B D R   p e r f o r m e d _ V V N   o n _ I I   1 7 _ M C   c o m m o n l y _ R R   u s e d _ J J   p h a r m a c e u t i c a l s _ N N 2   ( _ (   a c e t y l - c y s t e i n _ N N 1   , _ ,   a m p i c i l l i n _ N N 1   , _ ,   a s c o r b i c _ J J   a c i d _ N N 1   , _ ,   c y c l o s p o r i n e _ N N 1   , _ ,   c e f o x i t i n _ N N 1   , _ ,   h e p a r i n _ N N 1   , _ ,   i n t r a l i p i d ( R ) _ V V 0   , _ ,   l e v o d o p a _ N N 1   , _ ,   m e t h y l d o p a _ N N 1   , _ ,   m e t r o n i d a z o l e _ N N 1   , _ ,   p h e n y l b u t a z o n e _ V V 0   , _ ,   d o x y c y c l i n e _ V V 0   , _ ,   a c e t y l s a l i c y l i c _ J J   a c i d _ N N 1   , _ ,   r i f a m p i c i n _ N N 1   , _ ,   a c e t a m i n o p h e n _ N N 1   , _ ,   i b u - p r o f e n _ J J   a n d _ C C   t h e o p h y l l i n e _ N N 1   ) _ )   a t _ I I   a p p r o x i m a t e l y _ R R   f i v e _ M C   t i m e s _ N N T 2   t h e _ A T   a m o u n t _ N N 1   o f _ I O   t h e _ A T   c o m m o n _ J J   t h e r a p e u t i c _ J J   c o n c e n t r a t i o n _ N N 1   . _ .   
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 W e _ P P I S 2   p e r f o r m e d _ V V D   t h i s _ D D 1   s y s t e m a t i c _ J J   r e v i e w _ N N 1   a n d _ C C   m e t a - a n a l y s i s _ N N 1   t o _ T O   c o n c l u s i v e l y _ R R   d e t e r m i n e _ V V I   w h e t h e r _ C S W   T E N S _ M C 2   i s _ V B Z   a n _ A T 1   e f f e c t i v e _ J J   t h e r a p y _ N N 1   f o r _ I F   k n e e _ N N 1   O A _ N P 1   . _ .   
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 A s _ C S A   s h o w n _ V V N   i n _ I I   T a b l e _ N N 1   4 _ M C   , _ ,   t h e s e _ D D 2   e x p e c t a t i o n s _ N N 2   w e r e _ V B D R   s u p p o r t e d _ V V N   w i t h _ I W   m i n o r _ J J   e x c e p t i o n s _ N N 2   . _ .   
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 S a m p l e s _ N N 2   w e r e _ V B D R   a l s o _ R R   i m m u n o p r e c i p i t a t e d _ V V N   w i t h _ I W   m A b s _ N N 2   a g a i n s t _ I I   P - a c t i n _ N N 1   o r _ C C   c o n n e x i n _ N N 1   4 3 _ M C   ( _ (   c l o n e _ V V 0   C X N - 6 _ M C   ) _ )   . _ .   
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 H o w e v e r _ R R   , _ ,   i t _ P P H 1   i s _ V B Z   u n c l e a r _ J J   a s _ I I 2 1   t o _ I I 2 2   h o w _ R R Q   t h i s _ D D 1   m i g h t _ V M   a f f e c t _ V V I   c o n c u s s i o n _ N N 1   r i s k _ N N 1   i n _ I I   f o o t b a l l _ N N 1   p l a y e r s _ N N 2   . _ .   
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 S t u d i e s _ N N 2   i n c l u d e d _ V V D   w e r e _ V B D R   f r o m _ I I   t h e _ A T   d e v e l o p e d _ J J   w o r l d _ N N 1   , _ ,   t h e r e f o r e _ R R   l i m i t i n g _ V V G   m o r e _ R G R   g l o b a l _ J J   r e c o m m e n d a t i o n s _ N N 2   . _ .   
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 R e s u l t s _ N N 2   : _ :   W o m e n _ N N 2   w i t h _ I W   a n o r e x i a _ N N 1   n e r v o s a _ N N 1   h a d _ V H D   h i g h e r _ J J R   s k e w n e s s _ N N 1   a n d _ C C   k u r t o s i s _ N N 1   , _ ,   l o w e r _ J J R   M P P _ N P 1   ( _ (   P _ N N U   l e s s _ D A R   t h a n _ C S N   . 0 0 1 _ M C   ) _ )   , _ ,   a n d _ C C   a _ A T 1   t r e n d _ N N 1   t o w a r d _ I I   l o w e r _ J J R   e n t r o p y _ N N 1   ( _ (   P _ Z Z 1   = _ F O   . 0 7 _ M C   ) _ )   c o m p a r e d _ V V N   w i t h _ I W   c o n t r o l _ N N 1   s u b j e c t s _ N N 2   . _ .   
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 A l t h o u g h _ C S   c o m p a r i s o n s _ N N 2   t o _ I I   r e s u l t s _ N N 2   o b t a i n e d _ V V N   i n _ I I   o t h e r _ J J   x e n o g r a f t _ N N 1   m o d e l s _ N N 2   m u s t _ V M   b e _ V B I   d o n e _ V D N   w i t h _ I W   c a u t i o n _ N N 1   , _ ,   i t _ P P H 1   i s _ V B Z   e n c o u r a g i n g _ J J   t o _ T O   n o t e _ V V I   t h a t _ C S T   t h e _ A T   m a g n i t u d e _ N N 1   o f _ I O   t u m o r _ N N 1   a c c u m u l a t i o n _ N N 1   o b s e r v e d _ V V N   w i t h _ I W   I - S G M I B - N a n o b o d y _ N P 1   a l s o _ R R   w a s _ V B D Z   2 _ M C   - _ -   4 _ M C   t i m e s _ N N T 2   h i g h e r _ R R R   t h a n _ C S N   r e p o r t e d _ V V N   f o r _ I F   o t h e r _ J J   a n t i - H E R 2 _ N N 1   - _ -   t a r g e t e d _ V V D   N a n o b o d i e s _ N P 1   l a b e l e d _ V V D   w i t h _ I W   9 9 m T c _ F O   , _ ,   1 7 7 L u _ F O   , _ ,   a n d _ C C   6 8 G a _ F O   , _ ,   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   9 9 m T c - l a b e l e d _ J J   a n d _ C C   6 8 G a - l a b e l e d _ J J   N a n o b o d i e s _ N N 2   t a r g e t i n g _ V V G   E G F R _ N N 1   . _ .   
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 E s t i m a t e s _ N N 2   w e r e _ V B D R   b a s e d _ V V N   o n _ I I   p r e v i o u s l y _ R R   i d e n t i f i e d _ V V N   f a c t o r s _ N N 2   , _ ,   d e s c r i b e d _ V V N   i n _ I I   a _ A T 1   s y s t e m a t i c _ J J   r e v i e w _ N N 1   a n d _ C C   m e t a - a n a l y s i s . 1 6 _ J J   C r o s s - s e c t i o n a l _ J J   a n a l y s e s _ N N 2   h a v e _ V H 0   c o m p a r e d _ V V N   h i g h e r _ J J R   r i s k _ N N 1   s u b j e c t s _ N N 2   ( _ (   d e f i n e d _ V V N   a s _ C S A   t h o s e _ D D 2   a b o v e _ I I   t h e _ A T   1 5 t h _ M D   c e n t i l e _ J J   o f _ I O   r i s k _ N N 1   e s t i m a t e s _ V V Z   ) _ )   , _ ,   w i t h _ I W   l o w e r _ J J R   r i s k _ N N 1   s u b j e c t s _ N N 2   ( _ (   p a r t i c i p a n t s _ N N 2   w i t h _ I W   r i s k _ N N 1   e s t i m a t e s _ V V Z   b e l o w _ I I   t h e _ A T   8 5 t h _ M D   c e n t i l e _ J J   ) _ )   i n _ I I 3 1   t e r m s _ I I 3 2   o f _ I I 3 3   o b j e c t i v e _ J J   s m e l l _ N N 1   a n d _ C C   f i n g e r _ N N 1   t a p p i n g _ V V G   , _ ,   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   s u b j e c t i v e _ J J   R E M - s l e e p _ J J   b e h a v i o u r _ N N 1   d i s o r d e r _ N N 1   ( _ (   R B D _ N P 1   ) _ )   . 1 3 _ M C   D e t a i l e d _ J J   m e t h o d s _ N N 2   a r e _ V B R   d e s c r i b e d _ V V N   i n _ I I   t h e _ A T   o n l i n e _ J J   s u p p l e m e n t a r y _ J J   m a t e r i a l _ N N 1   . _ .   
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 A d d i t i o n a l _ J J   r e s e a r c h _ N N 1   a n d _ C C   p r o g r a m _ N N 1   d e v e l o p m e n t _ N N 1   i s _ V B Z   n e e d e d _ V V N   t o _ T O   a d d r e s s _ V V I   t h e _ A T   g a p s _ N N 2   i n _ I I   t h e _ A T   l i t e r a t u r e _ N N 1   s u c h _ I I 2 1   a s _ I I 2 2   s m a l l _ J J   s a m p l e _ N N 1   s i z e s _ N N 2   , _ ,   u s e _ N N 1   o f _ I O   q u e s t i o n a b l e _ J J   c o n t r o l _ N N 1   g r o u p s _ N N 2   , _ ,   l a c k _ N N 1   o f _ I O   i n f o r m a t i o n _ N N 1   o n _ I I   r e a s o n s _ N N 2   f o r _ I F   p o o r _ J J   a d h e r e n c e _ N N 1   , _ ,   n e e d _ V V 0   f o r _ I F   c o m p a r a t i v e _ J J   t r i a l s _ N N 2   i n c l u d i n g _ I I   d i f f e r e n t _ J J   t y p e s _ N N 2   o f _ I O   W e b _ N N 1   i n t e r v e n t i o n s _ N N 2   f o r _ I F   t h e _ A T   s a m e _ D A   d i s o r d e r _ N N 1   , _ ,   a n d _ C C   l a c k _ N N 1   o f _ I O   s a t i s f a c t i o n _ N N 1   r a t i n g s _ N N 2   b y _ I I   p a r t i c i p a n t s _ N N 2   . _ .   
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 C l i n i c a l _ J J   , _ ,   d e m o g r a p h i c _ J J   a n d _ C C   s o c i o e c o n o m i c _ J J   v a r i a b l e s _ N N 2   V i s u a l _ J J   a c u i t y _ N N 1   w a s _ V B D Z   m e a s u r e d _ V V N   u s i n g _ V V G   t h e _ A T   E a r l y _ J J   T r e a t m e n t _ N N 1   D i a b e t i c _ N N 1   R e t i n o p a t h y _ N N 1   S t u d y _ N N 1   c h a r t 2 1 _ F O   a n d _ C C   c h a n g e _ V V 0   i n _ I I   v i s u a l _ J J   a c u i t y _ N N 1   d u r i n g _ I I   f o l l o w - u p _ N N 1   w a s _ V B D Z   c a l c u l a t e d _ V V N   a s _ I I   t h e _ A T   d i f f e r e n c e _ N N 1   b e t w e e n _ I I   t h e _ A T   l o g M A R _ N N 1   v i s u a l _ J J   a c u i t y _ N N 1   a t _ I I   t h e _ A T   l a s t _ M D   f o l l o w u p _ N N 1   v i s i t _ N N 1   a n d _ C C   t h e _ A T   b a s e l i n e _ N N 1   v i s i t _ N N 1   . _ .   
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 O u t s i d e _ R L   v s . _ I I   i n s i d e _ R L   T h e r e _ E X   w e r e _ V B D R   4 5 _ M C   e v e n t s _ N N 2   ( _ (   5 6 . 9 6 _ M C   % _ N N U   ) _ )   h e l d _ V V D   o u t s i d e _ R L   . _ .   
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 B o d y _ N N 1   l e n g t h _ N N 1   s h o w e d _ V V D   c o n c o r d a n t _ J J   d i f f e r e n c e s _ N N 2   b e t w e e n _ I I   1 2 9 S 2 _ F O   a n d _ C C   B 6 _ F O   m i c e _ N N 2   ( _ (   F i g . _ N N 1   2 B _ F O   ) _ )   , _ ,   w i t h _ I W   B 6 _ F O   b e i n g _ V B G   s i g n i f i c a n t l y _ R R   s h o r t e r _ J J R   . _ .   
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 C o m p a r e d _ V V N   t o _ I I   c o n v e n t i o n a l _ J J   t e c h n i q u e s _ N N 2   , _ ,   n o _ A T   o b v i o u s _ J J   s u r v i v a l _ N N 1   a d v a n t a g e _ N N 1   c a n _ V M   b e _ V B I   o b s e r v e d _ V V N   w i t h _ I W   I M R T _ N P 1   o r _ C C   S B R T _ N P 1   . _ .   
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 D I S C U S S I O N _ N N 1   E N B _ N P 1   i s _ V B Z   a _ A T 1   r a r e _ J J   m a l i g n a n c y _ N N 1   o f _ I O   n e u r a l _ J J   c r e s t _ N N 1   o r i g i n _ N N 1   w i t h _ I W   o n l y _ R R   a b o u t _ R G   1 4 0 0 _ M C   c a s e s _ N N 2   r e p o r t e d _ V V N   s i n c e _ C S   i t _ P P H 1   w a s _ V B D Z   f i r s t _ M D   d e s c r i b e d _ V V N   b y _ I I   B e r g e r _ N P 1   e t _ R A 2 1   a l _ R A 2 2   i n _ I I   1 9 2 4 _ M C   . _ .   
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 O f _ I O   t h o s e _ D D 2   w i t h _ I W   a n y _ D D   l i f e t i m e _ N N T 1   p s y c h i a t r i c _ J J   a n d _ C C   s u b s t a n c e _ N N 1   a b u s e _ N N 1   c o m o r b i d i t y _ N N 1   , _ ,   1 4 6 1 _ M C   ( _ (   3 . 8 % _ F O   ) _ )   d i e d _ V V D   d u r i n g _ I I   t h e _ A T   f o l l o w - u p _ J J   p e r i o d _ N N 1   ( _ (   6 _ M C   m o n t h s _ N N T 2   a f t e r _ I I   T B I _ N P 1   ) _ )   c o m p a r e d _ V V N   w i t h _ I W   9 1 7 _ M C   ( _ (   0 . 5 % _ F O   ) _ )   o f _ I O   t h o s e _ D D 2   w i t h o u t _ I W   a n y _ D D   p s y c h i a t r i c _ J J   d i a g n o s e s _ N N 2   ( _ (   e F i g u r e _ V V 0   1 _ M C 1   i n _ I I   t h e _ A T   S u p p l e m e n t _ N N 1   ) _ )   . _ .   
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 T h e _ A T   4 0 _ M C   m i n - r e c o r d i n g _ N N 1   a l l o w e d _ V V N   f o r _ I F   s p e e c h _ N N 1   s a m p l e s _ N N 2   o f _ I O   1 0 0 0 + _ F O   s y l l a b l e s _ N N 2   . _ .   
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 G r o u p s _ N N 2   o f _ I O   1 0 _ M C   t u m o r - b e a r i n g _ J J   m i c e _ N N 2   w e r e _ V B D R   t r e a t e d _ V V N   w i t h _ I W   a _ A T 1   s a l i n e _ J J   p l a c e b o _ N N 1   , _ ,   7 . 4 _ M C   M B q _ N P 1   , _ ,   2 2 . 2 _ M C   M B q _ N P 1   o r _ C C   2 _ M C   x _ Z Z 1   1 4 . 8 _ M C   M B q _ N P 1   o f _ I O   1 8 8 R e - ( A r g 1 1 ) C C M S H _ N N 1   o n _ I I   d a y _ N N T 1   4 _ M C   a n d _ C C   7 _ M C   ( _ (   2 n d _ M D   d o s e _ N N 1   o f _ I O   2 _ M C   x _ Z Z 1   1 4 . 8 _ M C   M B q _ N P 1   ) _ )   . _ .   
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 O n l y _ R R   t h e _ A T   f i r s t _ M D   p h a s e _ N N 1   o f _ I O   c r o s s o v e r _ N N 1   t r i a l s _ N N 2   w a s _ V B D Z   i n c l u d e d _ V V N   t o _ T O   a v o i d _ V V I   c a r r y - o v e r _ J J   e f f e c t s _ N N 2   o f _ I O   i n t e r v e n t i o n s _ N N 2   w i t h _ I W   a _ A T 1   l o n g _ J J   d u r a t i o n _ N N 1   o f _ I O   a c t i o n _ N N 1   . _ .   
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 P A T H _ N N 1   i n t e g r a t e s _ V V Z   a _ A T 1   p r o b l e m _ N N 1   s o l v i n g _ N N 1   a p p r o a c h _ N N 1   w i t h _ I W   c o m p e n s a t o r y _ J J   s t r a t e g i e s _ N N 2   , _ ,   e n v i r o n m e n t a l _ J J   a d a p t a t i o n s _ N N 2   , _ ,   a n d _ C C   c a r e g i v e r _ V V 0   p a r t i c i p a t i o n _ N N 1   t o _ T O   i m p r o v e _ V V I   p a t i e n t s _ N N 2   ' _ N U L L   e m o t i o n _ N N 1   r e g u l a t i o n _ N N 1   . _ .   
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 A l l _ D B   p a r t i c i p a n t s _ N N 2   g a v e _ V V D   w r i t t e n _ J J   i n f o r m e d _ J J   c o n s e n t _ N N 1   . _ .   
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 T h e r e _ E X   s e e m s _ V V Z   t o _ T O   b e _ V B I   n o _ A T   s t a n d a r d _ N N 1   f o r _ I F   e x p e r i m e n t a l _ J J   p r o t o c o l s _ N N 2   . _ .   
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 B a s e d _ V V N   o n _ I I   t h e s e _ D D 2   r e s u l t s _ N N 2   , _ ,   t h e _ A T   t h r e e - _ N N 1   a n d _ C C   f o u r - f a c t o r _ J J   E F A _ N N 1   m o d e l s _ N N 2   w e r e _ V B D R   f u r t h e r _ R R R   e v a l u a t e d _ V V N   u s i n g _ V V G   C F A _ N P 1   i n _ B C L 2 1   o r d e r _ B C L 2 2   t o _ T O   b u i l d _ V V I   t h e _ A T   h i e r a r c h i c a l _ J J   m o d e l s _ N N 2   . _ .   
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 P r o c e d u r e s _ N N 2   D u r i n g _ I I   a n a l y s i s _ N N 1   , _ ,   t h e _ A T   d e p e n d e n t _ J J   v a r i a b l e _ N N 1   w a s _ V B D Z   t h e _ A T   s t u t t e r i n g _ J J   c l a s s i f i c a t i o n _ N N 1   o f _ I O   e a c h _ D D 1   i n i t i a l _ J J   w o r d _ N N 1   , _ ,   o r _ C C   r a t h e r _ R R   w h e t h e r _ C S W   t h e _ A T   w o r d _ N N 1   w a s _ V B D Z   p r o d u c e d _ V V N   w i t h _ I W   o r _ C C   w i t h o u t _ I W   a _ A T 1   s t u t t e r i n g - l i k e _ J J   d i s f l u e n c y ( S L D ) _ N N 1   . _ .   
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 W e _ P P I S 2   f o c u s e d _ V V D   o n _ I I   l a n g u a g e _ N N 1   c o m p r e h e n s i o n _ N N 1   b e c a u s e _ C S   i t _ P P H 1   i s _ V B Z   t y p i c a l l y _ R R   p r e s e r v e d _ V V N   a c r o s s _ I I   t h e _ A T   a d u l t _ N N 1   l i f e _ N N 1   s p a n _ N N 1   , _ ,   a n d _ C C   o n _ I I   s y n t a x _ N N 1   i n _ R R 2 1   p a r t i c u l a r _ R R 2 2   , _ ,   b e c a u s e _ C S   i t _ P P H 1   i s _ V B Z   k n o w n _ V V N   t o _ T O   i n v o l v e _ V V I   a _ A T 1   s t r o n g l y _ R R   l e f t - l a t e r a l i z e d _ J J   n e u r a l _ J J   s y s t e m _ N N 1   . _ .   
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 R e s p e c t i v e l y _ R R   , _ ,   o n e _ M C 1   , _ ,   t w o _ M C   , _ ,   t h r e e _ M C   , _ ,   a n d _ C C   f o u r _ M C   s t e n t s _ N N 2   w e r e _ V B D R   u s e d _ V V N   t o _ T O   c o m p l e t e _ V V I   t h e _ A T   T I P S _ N N 2   p r o c e d u r e _ N N 1   i n _ I I   1 9 _ M C   ( _ (   3 6 % _ N N U   ) _ )   , _ ,   2 6 _ M C   ( _ (   4 9 % _ N N U   ) _ )   , _ ,   s e v e n _ M C   ( _ (   1 3 % _ N N U   ) _ )   , _ ,   a n d _ C C   o n e _ M C 1   ( _ (   2 % _ N N U   ) _ )   p a t i e n t s _ N N 2   . _ .   
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 I n _ B C L 2 1   o r d e r _ B C L 2 2   t o _ T O   e x p l o r e _ V V I   t h e _ A T   r a t e _ N N 1   o f _ I O   c o m p l i c a t i o n s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   a q u e o u s _ J J   m i s d i r e c t i o n _ N N 1   o r _ C C   c o r n e a l _ J J   d e c o m p e n s a t i o n _ N N 1   a f t e r _ I I   L P I _ N P 1   , _ ,   w e _ P P I S 2   a l s o _ R R   a s s e s s e d _ V V N   t h e _ A T   p r o p o r t i o n _ N N 1   o f _ I O   p a t i e n t s _ N N 2   w h o _ P N Q S   u n d e r w e n t _ V V D   v i t r e c t o m y _ N N 1   o r _ C C   k e r a t o p l a s t y _ N N 1   a f t e r _ I I   t h e _ A T   b i l a t e r a l _ J J   L P I s _ N N 1   . _ .   
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 I n d i v i d u a l s _ N N 2   o f _ I O   m i x e d _ J J   e t h n i c i t y _ N N 1   w e r e _ V B D R   e x c l u d e d _ V V N   ; _ ;   H a p M a p _ V V 0   d a t a _ N N   h a s _ V H Z   1 _ M C 1   4 0 3 8 9 6 _ M C   S N P s _ N P 2   a v a i l a b l e _ J J   f r o m _ I I   1 1 _ M C   e t h n i c i t i e s _ N N 2   . _ .   
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 O u r _ A P P G E   s t u d y _ N N 1   s h o w s _ V V Z   t h a t _ C S T   t h e _ A T   e x p r e s s i o n _ N N 1   o f _ I O   P i t x 3 _ F O   , _ ,   O t x 2 _ F O   , _ ,   o r _ C C   D C C _ M C   i s _ V B Z   n o t _ X X   r e s t r i c t e d _ V V N   t o _ I I   p a r t i c u l a r _ J J   s u b p o p u l a t i o n s _ N N 2   o f _ I O   b r a i n s t e m _ N N 1   d o p a m i n e _ N N 1   n e u r o n s _ N N 2   i n _ I I   a g e d _ J J   h u m a n s _ N N 2   . _ .   
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 D I S C U S S I O N _ N N 1   M e t h y l n a l t r e x o n e _ N N 1   i s _ V B Z   a _ A T 1   p e r i p h e r a l l y _ R R   a c t i n g _ V V G   m i u - o p i o i d _ J J   r e c e p t o r _ N N 1   a n t a g o n i s t _ N N 1   t h a t _ C S T   t a r g e t s _ N N 2   t h e _ A T   u n d e r l y i n g _ J J   p a t h o p h y s i o l o g y _ N N 1   o f _ I O   O I C _ N P 1   : _ :   o p i o i d _ J J   a g o n i s m _ N N 1   o f _ I O   m i u - o p i o i d _ J J   r e c e p t o r s _ N N 2   i n _ I I   t h e _ A T   G I _ N N 1   t r a c t _ N N 1   . _ .   
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 I n _ I I   t h e _ A T   f i r s t - s t a g e _ J J   a n a l y s i s _ N N 1   o f _ I O   1 1 8 _ M C   s u b j e c t s _ N N 2   , _ ,   t h e _ A T   S N P s _ N P 2   t h a t _ C S T   s h o w e d _ V V D   s t a t i s t i c a l _ J J   P - v a l u e s _ N N 2   o f _ I O   l e s s _ D A R   t h a n _ C S N   0 . 0 5 _ M C   w e r e _ V B D R   s e l e c t e d _ V V N   a s _ I I   t h e _ A T   c a n d i d a t e _ N N 1   S N P s _ N P 2   f o r _ I F   t h e _ A T   s e c o n d - s t a g e _ J J   a n a l y s i s _ N N 1   a m o n g _ I I   t h e _ A T   2 9 5 _ M C   0 3 6 _ M C   S N P s _ N P 2   . _ .   
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 T h e _ A T   M e t a b o l i c _ J J   R e s e r v e _ N N 1   ( _ (   M R _ N N B   ) _ )   i n d e x _ N N 1   w a s _ V B D Z   d e v e l o p e d _ V V N   a s _ I I   a _ A T 1   c o m b i n a t o r i a l _ J J   i n d e x _ N N 1   t o _ T O   f a c i l i t a t e _ V V I   t h e _ A T   t r a n s l a t i o n _ N N 1   o f _ I O   p h a r m a c o g e n o m i c s _ N N 2   t o _ I I   p e r s o n a l i z e d _ J J   m e d i c i n e _ N N 1   f o r _ I F   d r u g s _ N N 2   t h a t _ C S T   a r e _ V B R   m e t a b o l i z e d _ V V N   o r _ C C   a c t i v a t e d _ V V N   b y _ I I   m u l t i p l e _ N N 1   C Y P 4 5 0 _ F O   i s o e n z y m e s . 6 _ F O   E a c h _ D D 1   o f _ I O   t h e _ A T   2 _ M C   a l l e l e s _ N N 2   f o r _ I F   C Y P 2 D 6 _ F O   , _ ,   C Y P 2 C 9 _ F O   , _ ,   a n d _ C C   C Y P 2 C 1 9 _ F O   a r e _ V B R   s c o r e d _ V V N   a n d _ C C   s u m m e d _ V V N   ( _ (   s e e _ V V 0   T a b l e _ N N 1   2 _ M C   f o r _ I F   a l l e l e _ N N 1   s c o r i n g _ N N 1   ) _ )   . _ .   
 
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 T h i s _ D D 1   r e d u c e d _ J J   v e n t i l a t i o n _ N N 1   o f _ I O   t h e _ A T   m i d d l e _ J J   e a r _ N N 1   i n _ I I   b o t t l e - f e d _ J J   i n f a n t s _ N N 2   m a y _ V M   b e _ V B I   a n o t h e r _ D D 1   m e c h a n i s m _ N N 1   f o r _ I F   i n c r e a s e d _ J J   r i s k _ N N 1   o f _ I O   O M _ N N 1   i n _ I I   t h i s _ D D 1   g r o u p _ N N 1   . _ .   
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 T U R B T _ N P 1   f o l l o w e d _ V V D   b y _ I I   c o m b i n e d _ J J   c h e m o t h e r a p y _ N N 1   a n d _ C C   r a d i a t i o n _ N N 1   t h e r a p y _ N N 1   i s _ V B Z   a s _ R G   e f f e c t i v e _ J J   a s _ C S A   c y s t e c t o m y _ N N 1   a t _ I I   p r e v e n t i n g _ V V G   r e c u r r e n c e _ N N 1   i n _ I I   a p p r o p r i a t e l y _ R R   s e l e c t e d _ V V N   c a s e s . 1 2 1 - 1 2 3 _ M C   C h e m o t h e r a p y _ N N 1   i s _ V B Z   u s u a l l y _ R R   t h e _ A T   f i r s t _ M D   t r e a t m e n t _ N N 1   f o r _ I F   c a n c e r s _ N N 2   t h a t _ C S T   h a v e _ V H 0   m e t a s t a s i z e d _ V V N   , _ ,   b u t _ C C B   o t h e r _ J J   t r e a t m e n t s _ N N 2   m i g h t _ V M   b e _ V B I   u s e d _ V V N   a s _ R R 2 1   w e l l _ R R 2 2   . _ .   
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 O B J E C T I V E _ J J   T o _ T O   c l a r i f y _ V V I   t h e _ A T   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   L O C _ N P 1   a t _ I I   o n s e t _ N N 1   o f _ I O   S A H _ N P 1   , _ ,   c o m p l i c a t i o n s _ N N 2   w h i l e _ C S   i n _ I I   t h e _ A T   h o s p i t a l _ N N 1   , _ ,   a n d _ C C   l o n g - t e r m _ J J   o u t c o m e _ N N 1   a f t e r _ I I   S A H . D E S I G N _ N P 1   , _ ,   S E T T I N G _ V V G   , _ ,   A N D _ C C   P A R T I C I P A N T S _ N N 2   A _ Z Z 1   r e t r o s p e c t i v e _ J J   a n a l y s i s _ N N 1   w a s _ V B D Z   c o n d u c t e d _ V V N   o f _ I O   1 4 6 0 _ M C   c o n s e c u t i v e l y _ R R   t r e a t e d _ V V N   p a t i e n t s _ N N 2   w i t h _ I W   s p o n t a n e o u s _ J J   S A H _ N N 1   w h o _ P N Q S   w e r e _ V B D R   p a r t _ N N 1   o f _ I O   a _ A T 1   p r o s p e c t i v e _ J J   o b s e r v a t i o n a l _ J J   c o h o r t _ N N 1   s t u d y _ N N 1   a t _ I I   a _ A T 1   l a r g e _ J J   u r b a n _ J J   a c a d e m i c _ J J   m e d i c a l _ J J   c e n t e r _ N N 1   ( _ (   t h e _ A T   C o l u m b i a _ N P 1   U n i v e r s i t y _ N N 1   S A H _ N N 1   O u t c o m e s _ N N 2   P r o j e c t _ N N 1   o r _ C C   S H O P _ N N 1   ) _ )   . _ .   
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 H o w e v e r _ R R   , _ ,   t h e _ A T   i m p a c t _ N N 1   o f _ I O   i n t e g r a t i n g _ V V G   h s - c T n _ J J   m e a s u r e s _ N N 2   i n t o _ I I   t h e _ A T   H E A R T _ N N 1   P a t h w a y _ N N 1   h a s _ V H Z   y e t _ R R   t o _ T O   b e _ V B I   d e t e r m i n e d _ V V N   . _ .   
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 T o _ T O   a s s e s s _ V V I   t h e _ A T   r e l a t i v e _ J J   c e l l _ N N 1   s u r f a c e _ N N 1   e x p r e s s i o n _ N N 1   o f _ I O   L - t y p e _ N N 1   C a 2 + _ F O   c h a n n e l s _ N N 2   i n _ I I   h i p p o c a m p a l _ J J   p y r a m i d a l _ J J   n e u r o n s _ N N 2   , _ ,   c e l l _ N N 1   s u r f a c e _ N N 1   b i o t i n y l a t i o n _ N N 1   e x p e r i m e n t s _ N N 2   w e r e _ V B D R   c o n d u c t e d _ V V N   o n _ I I   a c u t e _ J J   h i p p o c a m p a l _ J J   s l i c e s _ N N 2   ( _ (   n _ Z Z 1   = _ F O   8 , 2 5 0 _ M C   l m _ N N U   s l i c e s _ N N 2   p e r _ I I   r a t _ N N 1   ) _ )   f r o m _ I I   n i n e _ M C   y o u n g _ J J   a n d _ C C   n i n e _ M C   a g e d _ J J   r a t s _ N N 2   . _ .   
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 S i g n i f i c a n t l y _ R R   h i g h e r _ J J R   i m p r o v e m e n t _ N N 1   r a t i n g s _ N N 2   w e r e _ V B D R   f o u n d _ V V N   f o r _ I F   t r e a t e d _ J J   c o m p a r e d _ V V N   w i t h _ I W   u n t r e a t e d _ J J   c h i l d r e n _ N N 2   o n _ I I   r a t i n g s _ N N 2   o f _ I O   v e r b a l _ J J   c o m m u n i c a t i o n _ N N 1   ( _ (   p r i m a r y _ J J   o u t c o m e _ N N 1   ) _ )   , _ ,   r e c e p t i v e _ J J   a n d _ C C   e x p r e s s i v e _ J J   l a n g u a g e _ N N 1   , _ ,   a t t e n t i o n _ N N 1   a n d _ C C   s t e r e o t y p i c a l _ J J   b e h a v i o r _ N N 1   . _ .   
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 T h e _ A T   O I R _ N N 1   m o d e l _ N N 1   h a s _ V H Z   b e e n _ V B N   u s e d _ V V N   r e c e n t l y _ R R   t o _ T O   d e f i n e _ V V I   t h e _ A T   f u n c t i o n _ N N 1   o f _ I O   N R P 1 _ F O   a n d _ C C   i t s _ A P P G E   l i g a n d s _ N N 2   i n _ I I   r e t i n a l _ J J   n e o v a s c u l a r i s a t i o n _ N N 1   , _ ,   w h i l s t _ C S   a _ A T 1   m o u s e _ N N 1   m o d e l _ N N 1   o f _ I O   d i a b e t e s _ N N 1   h a s _ V H Z   a l s o _ R R   b e e n _ V B N   u s e d _ V V N   t o _ T O   s t u d y _ V V I   t h e _ A T   r o l e _ N N 1   o f _ I O   N R P 1 _ F O   a n d _ C C   i t s _ A P P G E   l i g a n d s _ N N 2   i n _ I I   d i a b e t i c _ J J   r e t i n o p a t h y _ N N 1   a n d _ C C   o c u l a r _ J J   o e d e m a _ N N 1   ( _ (   S e c t i o n _ N N 1   6 _ M C   ) _ )   . _ .   
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 R e t i n a l _ J J   v e i n _ N N 1   o c c l u s i o n s _ N N 2   ( _ (   R V O _ N P 1   ) _ )   a r e _ V B R   t h e _ A T   s e c o n d _ M D   m o s t _ R G T   c o m m o n _ J J   t y p e _ N N 1   o f _ I O   r e t i n a l _ J J   v a s c u l a r _ J J   d i s o r d e r _ N N 1   a f t e r _ I I   d i a b e t i c _ J J   r e t i n a l _ J J   d i s e a s e _ N N 1   , _ ,   c a n _ V M   o c c u r _ V V I   a t _ I I   a l m o s t _ R R   a n y _ D D   a g e _ N N 1   , _ ,   b u t _ C C B   m o s t l y _ R R   i n _ I I   p a t i e n t s _ N N 2   a g e d _ V V N   o v e r _ R G   5 0 _ M C   , _ ,   a n d _ C C   t h e y _ P P H S 2   c a u s e _ V V 0   s u d d e n _ J J   u n i l a t e r a l _ J J   l o s s _ N N 1   o f _ I O   v i s i o n _ N N 1   ( _ (   R o g e r s _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 0 _ M C   ) _ )   . _ .   
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 F i r s t _ M D   , _ ,   a f t e r _ I I   p e r f o r m i n g _ V V G   c o n t r a s t - e n h a n c e d _ J J   C T _ N N 1   o f _ I O   t h e _ A T   n e c k _ N N 1   i n _ I I   t h e _ A T   p o s t - R T _ N N 1   s e t t i n g _ N N 1   , _ ,   t h e _ A T   n e g a t i v e _ J J   p r e d i c t i v e _ J J   v a l u e _ N N 1   f o r _ I F   r e g i o n a l _ J J   m e t a s t a s e s _ N N 2   i s _ V B Z   g r e a t e r _ J J R   t h a n _ C S N   9 4 % _ N N U   . _ .   
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 S K N - 1 _ M C 1   i s _ V B Z   l a r g e l y _ R R   d i s p e n s a b l e _ J J   f o r _ I F   t B O O H - i n d u c e d _ J J   t r a n s c r i p t i o n _ N N 1   , _ ,   w h e r e a s _ C S   M D T - 1 5 _ M C   i s _ V B Z   n e c e s s a r y _ J J   ( _ (   F i g . _ N N 1   5 A _ F O   ) _ )   . _ .   
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 T r a i n e r s _ N N 2   k e p t _ V V D   a _ A T 1   l o g _ N N 1   o f _ I O   p a r t i c i p a n t s _ N N 2   ' _ N U L L   c o m p l e t i o n _ N N 1   , _ ,   m o d i f i c a t i o n _ N N 1   , _ ,   a n d _ C C   l e v e l _ N N 1   o f _ I O   d i f f i c u l t y _ N N 1   o f _ I O   e x e r c i s e s _ N N 2   c o m p l e t e d _ V V N   b y _ I I   e a c h _ D D 1   p a t i e n t _ N N 1   a n d _ C C   a n y _ D D   a d v e r s e _ J J   e v e n t s _ N N 2   a t _ I I   e a c h _ D D 1   s e s s i o n _ N N T 1   . _ .   
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 W i t h _ I W   t h e _ A T   s t r o n g e s t _ J J T   r e l a t i v e _ J J   d r o p _ N N 1   i n _ I I   e a r l y _ J J   a d u l t h o o d _ N N 1   , _ ,   t h i s _ D D 1   d e c r e m e n t _ N N 1   l e v e l e d _ V V D   o f f _ R P   b y _ I I   9 _ M C   m o n t h s _ N N T 2   , _ ,   r e a c h i n g _ V V G   a _ A T 1   f i n a l _ J J   6 5 % _ N N U   r e d u c t i o n _ N N 1   b y _ I I   1 2 _ M C   m o n t h s _ N N T 2   . _ .   
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 T h e _ A T   p r o - a p o p t o t i c _ J J   f u n c t i o n s _ N N 2   o f _ I O   p 5 3 _ F O   h a v e _ V H 0   a l s o _ R R   b e e n _ V B N   a c t i v e l y _ R R   i n v e s t i g a t e d _ V V N   i n _ I I   b o t h _ D B 2   c a n c e r o u s _ J J   a n d _ C C   n o n - c a n c e r o u s _ J J   t i s s u e _ N N 1   t y p e s _ N N 2   ' _ N U L L   w i t h _ I W   m a n y _ D A 2   s t u d i e s _ N N 2   s u p p o r t i n g _ V V G   t h e _ A T   r o l e _ N N 1   o f _ I O   p 5 3 _ F O   i n _ I I   c e l l _ N N 1   d e a t h _ N N 1   m e c h a n i s m s _ N N 2   i n _ I I   t h e _ A T   n e r v o u s _ J J   s y s t e m _ N N 1   . _ .   
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 A _ A T 1   p r e l i m i n a r y _ J J   a n a l y s i s _ N N 1   r e v e a l e d _ V V D   t h a t _ C S T   t h e _ A T   r e s u l t s _ N N 2   o f _ I O   t h i s _ D D 1   i n v e s t i g a t i o n _ N N 1   w e r e _ V B D R   n o t _ X X   a f f e c t e d _ V V N   b y _ I I   t h e _ A T   m e n s t r u a l _ J J   c y c l e _ N N 1   a n d _ C C   t h u s _ R R   , _ ,   a l l _ D B   p a r t i c i p a n t s _ N N 2   w e r e _ V B D R   t r e a t e d _ V V N   a s _ I I   a _ A T 1   s i n g l e _ J J   g r o u p _ N N 1   . _ .   
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 T h e _ A T   c o m b i n e d _ J J   P A S I _ N N 1   5 0 _ M C   w a s _ V B D Z   6 4 % _ N N U   w i t h _ I W   F A E s _ N N 2   , _ ,   c o m p a r e d _ V V N   w i t h _ I W   1 4 % _ N N U   f o r _ I F   p l a c e b o _ N N 1   , _ ,   r e p r e s e n t i n g _ V V G   a _ A T 1   n u m b e r _ N N 1   n e e d e d _ V V D   t o _ T O   t r e a t _ V V I   t o _ T O   b e n e f i t _ V V I   ( _ (   N N T B _ N P 1   ) _ )   o f _ I O   2 _ M C   . _ .   
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 T h i s _ D D 1   s u g g e s t s _ V V Z   t h a t _ C S T   d u r i n g _ I I   b i o g e n e s i s _ N N 1   o f _ I O   d i s c s _ N N 2   , _ ,   P R P H 2 / R D S _ F U   i s _ V B Z   i n i t i a l l y _ R R   c o n c e n t r a t e d _ V V N   a t _ I I   t h e _ A T   a x o n e m e _ N N 1   a n d _ C C   s u b s e q u e n t l y _ R R   s p r e a d s _ V V Z   t h r o u g h o u t _ I I   t h e _ A T   r i m _ N N 1   ( _ (   D i n g _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 5 _ M C   ) _ )   . _ .   
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 I n _ I I   c o n e s _ N N 2   , _ ,   e v e n _ R R   m a t u r e _ J J   d i s c s _ N N 2   r e m a i n _ V V 0   a t _ R R 2 1   l e a s t _ R R 2 2   p a r t i a l l y _ R R   ' _ N U L L   o p e n _ J J   ' _ N U L L   a n d _ C C   c o n t i g u o u s _ J J   w i t h _ I W   t h e _ A T   p l a s m a _ N N 1   m e m b r a n e _ N N 1   ( _ (   F i g . _ N N 1   3 B _ F O   ) _ )   , _ ,   t h u s _ R R   t o _ I I   a _ A T 1   c e r t a i n _ J J   e x t e n t _ N N 1   t h e y _ P P H S 2   r e s e m b l e _ V V 0   n e w l y _ R R   f o r m i n g _ V V G   r o d _ N N 1   d i s c s _ N N 2   . _ .   
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 H e r e i n _ R R   , _ ,   w e _ P P I S 2   d e s c r i b e _ V V 0   b r i e f l y _ R R   2 _ M C   e x a m p l e s _ N N 2   o f _ I O   m e a s u r i n g _ V V G   t h e s e _ D D 2   f o r m s _ N N 2   o f _ I O   c o o r d i n a t i o n _ N N 1   i n _ I I   t h e _ A T   m i d b r a i n _ N N 1   a n d _ C C   p r e f r o n t a l _ J J   c o r t e x _ N N 1   o f _ I O   r o d e n t s _ N N 2   . _ .   
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 I n c i d e n c e _ N N 1   r a t e s _ N N 2   a r e _ V B R   l o w e s t _ J J T   a m o n g _ I I   C h i n e s e _ N P 1   ( _ (   4 . 5 _ M C   ) _ )   a n d _ C C   A s i a n _ J J   I n d i a n / P a k i s t a n i _ N N 1   ( _ (   4 . 2 _ M C   ) _ )   w o m e n _ N N 2   . _ .   
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 T h i r d _ M D   , _ ,   t h e o r i e s _ N N 2   d o _ V D 0   n o t _ X X   i n c o r p o r a t e _ V V I   c o n c e p t s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   f l u c t u a t i o n _ N N 1   o r _ C C   s t a b i l i t y _ N N 1   o r _ C C   c o n s i d e r _ V V 0   h o w _ R R Q   t h e s e _ D D 2   p r o p e r t i e s _ N N 2   m a y _ V M   b e _ V B I   p r e d i c t i v e _ J J   o f _ I O   b e h a v i o r _ N N 1   a b o v e _ R L   a n d _ C C   b e y o n d _ I I   t h e _ A T   a v e r a g e _ J J   l e v e l s _ N N 2   o f _ I O   m e a s u r e d _ J J   c o n s t r u c t s _ N N 2   . _ .   
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 A t _ I I   3 1 _ M C   o f _ I O   t h e _ A T   3 3 _ M C   l o c i _ N N 2   , _ ,   O R s _ N N 2   i n _ I I   t h e _ A T   p s y c h o s i s _ N N 1   f o l l o w - u p _ N N 1   g r o u p _ N N 1   w e r e _ V B D R   i n _ I I   t h e _ A T   s a m e _ D A   d i r e c t i o n _ N N 1   a s _ C S A   i n _ I I   t h e _ A T   d i s c o v e r y _ N N 1   d a t a _ N N   s e t _ V V 0   ( _ (   S G E N E - p l u s + I S C + M G S _ F O   ) _ )   ( _ (   S u p p l e m e n t a r y _ J J   T a b l e _ N N 1   3 _ M C   ) _ )   . _ .   
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 T h i s _ D D 1   i s _ V B Z   p r o b l e m a t i c _ J J   b e c a u s e _ C S   c u r r e n t _ J J   r e g u l a t i o n s _ N N 2   a l l o w _ V V 0   f o r _ I F   c o n s i d e r a b l e _ J J   s t a t e - l e v e l _ J J   d i s c r e t i o n _ N N 1   i n _ I I   t h e _ A T   d e f i n i t i o n _ N N 1   o f _ I O   s p e c i f i c _ J J   p e d i a t r i c _ J J   e s s e n t i a l _ J J   h e a l t h _ N N 1   b e n e f i t s _ N N 2   , _ ,   i n c l u d i n g _ I I   h a b i l i t a t i v e _ J J   s e r v i c e s _ N N 2   , _ ,   w h i c h _ D D Q   a r e _ V B R   t h o s e _ D D 2   s e r v i c e s _ N N 2   a n d _ C C   d e v i c e s _ N N 2   t h a t _ C S T   h e l p _ V V 0   c h i l d r e n _ N N 2   w i t h _ I W   s p e c i a l _ J J   h e a l t h _ N N 1   c a r e _ N N 1   n e e d s _ N N 2   a t t a i n _ V V 0   a n d _ C C   m a i n t a i n _ V V 0   s k i l l s _ N N 2   a n d _ C C   f u n c t i o n i n g _ V V G   f o r _ I F   d a i l y _ J J   l i v i n g _ N N 1   . _ .   
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 T h e _ A T   p r o v i s i o n _ N N 1   o f _ I O   c a r e _ N N 1   a t _ I I   a _ A T 1   d i s t a n c e _ N N 1   c o u l d _ V M   h e l p _ V V I   a d d r e s s _ N N 1   l o n g - s t a n d i n g _ J J   c o n c e r n s _ N N 2   a b o u t _ I I   t h e _ A T   d i s t r i b u t i o n _ N N 1   a n d _ C C   n u m b e r _ N N 1   o f _ I O   p h y s i c i a n s 3 5 _ F O   a n d _ C C   p r o v i d e _ V V 0   g r e a t e r _ J J R   f l e x i b i l i t y _ N N 1   t o _ I I   b o t h _ R R   p a t i e n t s _ N N 2   a n d _ C C   c l i n i c i a n s _ N N 2   w i t h _ I I 3 1   r e s p e c t _ I I 3 2   t o _ I I 3 3   t h e i r _ A P P G E   l o c a t i o n _ N N 1   a n d _ C C   a v a i l a b i l i t y _ N N 1   . _ .   
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 T a b l e _ N N 1   S 4 _ F O   O v e r l a p _ N N 1   o f _ I O   D M R s _ N P 1   a n d _ C C   V M R s _ N P 1   w i t h _ I W   D N a s e _ N N 1   I _ M C 1   h y p e r s e n s i t i v i t y _ N N 1   h o t _ J J   s p o t s _ N N 2   o f _ I O   t h r e e _ M C   o t h e r _ J J   b l o o d _ N N 1   c e l l _ N N 1   t y p e s _ N N 2   . _ .   
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 R e s u l t s _ N N 2   : _ :   A l l _ D B   p a t i e n t s _ N N 2   w i t h _ I W   n o r m a l _ J J   a p p e a r i n g _ V V G   s t r e a m l i n e s _ V V Z   ( _ (   n _ Z Z 1   = _ F O   6 _ M C   ) _ )   s h o w e d _ V V D   a n _ A T 1   a c u t e _ J J   i n f l a m m a t o r y _ J J   d e m y e l i n a t i n g _ J J   p a t h o l o g y _ N N 1   i n _ I I   t h e _ A T   f u r t h e r _ J J R   c l i n i c a l _ J J   w o r k - u p _ N N 1   . _ .   
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 I n _ I I 3 1   a d d i t i o n _ I I 3 2   t o _ I I 3 3   t h e _ A T   h i g h e s t _ J J T   A U C _ N N 1   , _ ,   n T 2 _ F O   w a s _ V B D Z   a l s o _ R R   a s s o c i a t e d _ V V N   w i t h _ I W   t h e _ A T   l o w e s t _ J J T   A I C _ N P 1   v a l u e _ N N 1   , _ ,   i n d i c a t i n g _ V V G   i t s _ A P P G E   h i g h e s t _ J J T   p r e d i c t i v e _ J J   v a l u e _ N N 1   . _ .   
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 T h e _ A T   D H I _ N N 1   w a s _ V B D Z   s i g n i f i c a n t l y _ R R   l o w e r _ J J R   i n _ I I   t h e _ A T   E p l e y g r o u p _ N N 1   a t _ I I   a l l _ D B   f o l l o w - u p _ J J   a s s e s s m e n t s _ N N 2   ( _ (   m e d i a n _ J J   s c o r e s _ N N 2   1 2 _ M C   m o n t h s _ N N T 2   0 _ M C   ( _ (   0 _ M C   - _ -   5 1 _ M C   ) _ )   v e r s u s _ I I   2 0 _ M C   ( _ (   0 _ M C   - _ -   7 6 _ M C   ) _ )   , _ ,   P _ Z Z 1   = _ F O   0 . 0 0 3 _ M C   ) _ )   . _ .   
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 O B J E C T I V E _ N N 1   : _ :   T o _ T O   d e s c r i b e _ V V I   t h e _ A T   a d v i s i n g _ V V G   p r a c t i c e s _ N N 2   a t _ I I   m e d i c a l _ J J   s c h o o l s _ N N 2   a n d _ C C   i n t e r v i e w _ N N 1   p a t t e r n s _ N N 2   a m o n g _ I I   m e d i c a l _ J J   s t u d e n t s _ N N 2   p u r s u i n g _ V V G   o b s t e t r i c s _ N N 1   a n d _ C C   g y n e c o l o g y _ N N 1   r e s i d e n c y _ N N 1   t r a i n i n g _ N N 1   . _ .   
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 T h e _ A T   p r e s e n c e _ N N 1   o f _ I O   C P _ N P 1   a n t i g e n s _ N N 2   a n d _ C C   n u c l e i c _ J J   a c i d s _ N N 2   h a s _ V H Z   b e e n _ V B N   d e m o n s t r a t e d _ V V N   b y _ I I   i m m u n o h i s t o c h e m i s t r y _ N N 1   , _ ,   d o u b l e _ J J   i m m u n o f l u o r e s c e n c e _ N N 1   , _ ,   a n d _ C C   p o l y m e r a s e _ N N 1   c h a i n _ N N 1   r e a c t i o n _ N N 1   ( _ (   P C R _ N P 1   ) _ )   t e c h n i q u e s _ N N 2   o n _ I I   l a s e r - c a p t u r e d _ J J   c e l l s _ N N 2   . _ .   
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 S u b s e q u e n t l y _ R R   , _ ,   0 . 6 _ M C   m g / k g _ N N U   o f _ I O   r o c u r o n i u m _ N N 1   w a s _ V B D Z   a d m i n i s t e r e d _ V V N   , _ ,   a n d _ C C   a _ A T 1   l a r y n g e a l _ J J   m a s k _ N N 1   a i r w a y _ N N 1   ( _ (   L M A _ N P 1   , _ ,   L M A _ N P 1   S u p r e m e _ J J   ; _ ;   T e l e f l e x _ N P 1   M e d . _ N P 1   , _ ,   N C _ N P 1   ) _ )   i n s e r t e d _ V V D   f o l l o w e d _ V V N   b y _ I I   m e c h a n i c a l _ J J   v e n t i l a t i o n _ N N 1   . _ .   
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 T h e _ A T   ' _ N U L L   E r k - r e b o u n d _ J J   ' _ N U L L   s e t t i n g _ N N 1   a f t e r _ I I   i n i t i a l _ J J   l o w e r i n g _ N N 1   o f _ I O   E r k _ N N 1   s i g n a l i n g _ V V G   t h r e s h o l d s _ N N 2   ( _ (   P D 0 3 2 5 9 0 1 _ F O   ' _ N U L L   p r e t r e a t m e n t _ N N 1   ) _ )   s e n s i t i z e d _ V V D   p r e - B _ J J   A L L _ D B   c e l l s _ N N 2   t o _ I I   s u b s e q u e n t _ J J   D U S P 6 _ F O   i n h i b i t i o n _ N N 1   a n d _ C C   r e d u c e d _ V V D   t h e _ A T   l C 5 0 _ F O   f o r _ I F   B C I _ N P 1   f r o m _ I I   2 _ M C   . _ .   
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 I n _ I I   t h e _ A T   U N O S _ N P 2   E C D _ V V 0   c o h o r t _ N N 1   , _ ,   K a p l a n _ N P 1   ' _ N U L L   M e i e r _ N P 1   e s t i m a t e d _ V V D   r a t e s _ N N 2   o f _ I O   d e a t h _ N N 1   o r _ C C   g r a f t _ V V 0   l o s s _ N N 1   a t _ I I   m o n t h _ N N T 1   8 4 _ M C   f o r _ I F   M I _ N P 1   b e l a t a c e p t _ N N 1   , _ ,   L I _ N P 1   b e l a t a c e p t _ N N 1   a n d _ C C   C s A _ N P 1   w e r e _ V B D R   3 5 . 8 % _ F O   , _ ,   4 0 . 1 % _ F O   a n d _ C C   4 1 . 2 % _ F O   , _ ,   r e s p e c t i v e l y _ R R   . _ .   
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 T h e _ A T   d i s t i n c t i o n _ N N 1   b e t w e e n _ I I   d i f f e r e n t _ J J   t i s s u e s _ N N 2   i s _ V B Z   b a s e d _ V V N   o n _ I I   H o u n s f i e l d _ N P 1   u n i t s _ N N 2   ( _ (   H U _ N P 1   ) _ )   . _ .   
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 T h i s _ D D 1   s t a t e m e n t _ N N 1   i s _ V B Z   n o t _ X X   i n _ I I 3 1   k e e p i n g _ I I 3 2   w i t h _ I I 3 3   e s t a b l i s h e d _ J J   l i t e r a t u r e _ N N 1   a n d _ C C   p r a c t i c e _ N N 1   ; _ ;   h o w e v e r _ R R   , _ ,   o n _ I I   c l o s e r _ J J R   i n s p e c t i o n _ N N 1   o f _ I O   t h e _ A T   r e s u l t s _ N N 2   , _ ,   i t _ P P H 1   i s _ V B Z   c l e a r _ J J   t h a t _ C S T   t h e _ A T   t e a c h i n g _ N N 1   h o s p i t a l s _ N N 2   i n c l u d e d _ V V N   i n _ I I   t h e _ A T   s t u d y _ N N 1   w e r e _ V B D R   s e e i n g _ V V G   a _ A T 1   m o r e _ R G R   c o m p l e x _ J J   c a s e l o a d _ N N 1   . _ .   
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 O u r _ A P P G E   f i n d i n g s _ N N 2   i n t r o d u c e _ V V 0   n e w _ J J   k n o w l e d g e _ N N 1   a n d _ C C   p r o p o s e _ V V 0   n e w _ J J   h y p o t h e s e s _ N N 2   r e g a r d i n g _ I I   t h e _ A T   n e u r o p s y c h o l o g y _ N N 1   o f _ I O   p s y c h o t i c _ J J   e x p e r i e n c e s _ N N 2   i n _ I I   a d u l t s _ N N 2   . _ .   
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 A _ Z Z 1   V A _ F W   l o s s _ N N 1   o f _ I O   1 5 _ M C   l e t t e r s _ N N 2   o r _ C C   m o r e _ R R R   w a s _ V B D Z   r e p o r t e d _ V V N   i n _ I I   a _ A T 1   s i m i l a r _ J J   p e r c e n t a g e _ N N 1   ( _ (   5 . 3 % _ F O   ) _ )   o f _ I O   p a t i e n t s _ N N 2   r e c e i v i n g _ V V G   a f l i b e r c e p t _ N N 1   a t _ I I   w e e k _ N N T 1   5 2 _ M C   i n _ I I   t h e _ A T   C O P E R N I C U S _ N N 1   s t u d y _ N N 1   , _ ,   w h i c h _ D D Q   i n c l u d e d _ V V D   p a t i e n t s _ N N 2   w i t h _ I W   r e t i n a l _ J J   n o n p e r f u s i o n _ N N 1   a t _ I I   b a s e l i n e . 2 5 _ F O   M o r e o v e r _ R R   , _ ,   i n _ I I   t h e _ A T   C R Y S T A L _ N N 1   s t u d y _ N N 1   , _ ,   a t _ R R 2 1   l e a s t _ R R 2 2   i n _ I I   s o m e _ D D   p a t i e n t s _ N N 2   , _ ,   w i t h d r a w a l _ N N 1   o f _ I O   i n i t i a l _ J J   m o n t h l y _ J J   t r e a t m e n t s _ N N 2   a n d _ C C   s w i t c h _ V V 0   t o _ I I   a n _ A T 1   i n d i v i d u a l i z e d _ J J   d o s i n g _ N N 1   r e g i m e n _ N N 1   d r i v e n _ V V N   b y _ I I   V A _ F W   s t a b i l i z a t i o n _ N N 1   c r i t e r i a _ N N 2   m a y _ V M   h a v e _ V H I   o c c u r r e d _ V V N   t o o _ R G   e a r l y _ R R   , _ ,   b e c a u s e _ C S   t h e _ A T   s t a b i l i t y _ N N 1   a n d _ C C   r e t r e a t m e n t _ N N 1   c r i t e r i a _ N N 2   w e r e _ V B D R   b a s e d _ V V N   o n _ I I   V A _ F W   l o s s _ N N 1   a s _ I I   a _ A T 1   c o n s e q u e n c e _ N N 1   o f _ I O   d i s e a s e _ N N 1   a c t i v i t y _ N N 1   . _ .   
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 W h i l e _ C S   t h e r e _ E X   w e r e _ V B D R   c h a n g e s _ N N 2   i n _ I I   g e n e _ N N 1   e x p r e s s i o n _ N N 1   o f _ I O   s e v e r a l _ D A 2   n e u r o e n d o c r i n e _ J J   m a r k e r s _ N N 2   i n _ I I 3 1   r e s p o n s e _ I I 3 2   t o _ I I 3 3   G S K 2 8 7 9 5 5 2 _ F O   , _ ,   g a s t r i n _ N N 1   r e l e a s i n g _ V V G   p e p t i d e _ N N 1   ( _ (   G R P _ N P 1   ) _ )   e x p r e s s i o n _ N N 1   w a s _ V B D Z   m o s t _ R G T   c o n s i s t e n t l y _ R R   a l t e r e d _ V V N   a c r o s s _ I I   m u l t i p l e _ J J   c e l l _ N N 1   l i n e s _ N N 2   ( _ (   T a b l e _ N N 1   S 6 _ F O   ) _ )   . _ .   
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 A _ A T 1   c o m p a r i s o n _ N N 1   o f _ I O   t h e _ A T   f i t t e d _ J J   c u r v e s _ N N 2   ( _ (   f i g . _ N N 1   2 C _ F O   ) _ )   s h o w e d _ V V D   t h a t _ C S T   t h e _ A T   c u r r e n t _ N N 1   e v o k e d _ V V N   b y _ I I   G A B A _ N P 1   a n d _ C C   e t o m i d a t e _ N N 1   ( _ (   1 _ M C 1   m i u M _ N N 1   ) _ )   i n _ I I   I L - 1 m i u - t r e a t e d _ J J   n e u r o n s _ N N 2   w a s _ V B D Z   e q u i v a l e n t _ J J   t o _ I I   t h e _ A T   c u r r e n t _ N N 1   e v o k e d _ V V N   b y _ I I   a _ A T 1   m u c h _ R R   h i g h e r _ J J R   c o n c e n t r a t i o n _ N N 1   o f _ I O   e t o m i d a t e _ N N 1   ( _ (   4 . 3 _ M C   m i u M _ N N 1   ) _ )   i n _ I I   c o n t r o l _ N N 1   n e u r o n s _ N N 2   . _ .   
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 P s y c h o s o c i a l _ J J   s t r e s s _ N N 1   i s _ V B Z   a _ A T 1   b e h a v i o r a l _ J J   f a c t o r _ N N 1   i m p l i c a t e d _ V V D   i n _ I I   r i s k _ N N 1   o f _ I O   p r e t e r m _ N N 1   b i r t h _ N N 1   , _ ,   a l t h o u g h _ C S   n e g a t i v e _ J J   a s s o c i a t i o n s _ N N 2   a r e _ V B R   a l s o _ R R   f o u n d _ V V N   i n _ I I   t h e _ A T   l i t e r a t u r e _ N N 1   . _ .   
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 R e p l i c a t i o n _ N N 1   i n _ I I   a n _ A T 1   i n d e p e n d e n t _ J J   c o h o r t _ N N 1   c o n f i r m e d _ V V D   t h e s e _ D D 2   f i n d i n g s _ N N 2   f o r _ I F   f o u r _ M C   o f _ I O   f i v e _ M C   m o d u l e s _ N N 2   & l s q b ; _ (   F i g . _ N N 1   2 B _ F O   , _ ,   C _ Z Z 1   , _ ,   E _ Z Z 1   a n d _ C C   F _ Z Z 1   & r s q b ; _ )   , _ ,   u n d e r p i n n i n g _ V V G   t h e _ A T   r o b u s t n e s s _ N N 1   o f _ I O   t h e _ A T   p r o p o s e d _ J J   a p p r o a c h _ N N 1   . _ .   
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 W e _ P P I S 2   a l s o _ R R   a s s e s s e d _ V V D   t h e _ A T   a m o u n t _ N N 1   o f _ I O   N C X 1 _ F O   i n _ I I   t h e s e _ D D 2   b r a i n _ N N 1   s a m p l e s _ N N 2   t o _ T O   d e t e r m i n e _ V V I   w h e t h e r _ C S W   t h e r e _ E X   a r e _ V B R   a l t e r a t i o n s i n _ N N 1   t h e _ A T   a m o u n t s _ N N 2   o r _ C C   a c t i v i t y _ N N 1   o f _ I O   t h i s _ D D 1   r e l a t e d _ J J   i o n _ N N 1   e x c h a n g e r _ N N 1   i n _ I I   n e u r o d e g e n e r a t i v e _ J J   d i s e a s e _ N N 1   b r a i n _ N N 1   , _ ,   w h i c h _ D D Q   m a y _ V M   i n d i c a t e _ V V I   c o m p e n s a t i o n _ N N 1   f o r _ I F   l o s s _ N N 1   o f _ I O   N C X 3 _ F O   f u n c t i o n _ N N 1   . _ .   
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 T h e _ A T   f i n d i n g _ N N 1   t h a t _ C S T   R O C K 2 _ F O   a n d _ C C   D N A - P K c s _ N N 2   i n h i b i t o r s _ N N 2   f u n c t i o n e d _ V V D   c o o p e r a t i v e l y _ R R   t o _ T O   s u p p r e s s _ V V I   m i g r a t i o n _ N N 1   a n d _ C C   i n v a s i o n _ N N 1   s u g g e s t s _ V V Z   t h a t _ C S T   p a t h w a y s _ N N 2   i n _ I I 3 1   a d d i t i o n _ I I 3 2   t o _ I I 3 3   R h o / R a c _ F U   s i g n a l i n g _ N N 1   m a y _ V M   c o n t r i b u t e _ V V I   t o _ I I   D N A - P K c s - i n d u c e d _ J J   m e t a s t a s i s _ N N 1   ( _ (   e g _ R E X   W n t - p - c a t e n i n _ N P 1   , _ ,   T G F p _ N P 1   ) _ )   , _ ,   a n d _ C C   i t _ P P H 1   i s _ V B Z   i n t r i g u i n g _ J J   t o _ T O   s p e c u l a t e _ V V I   t h a t _ C S T   D N A - P K c s _ N N 2   f o r m s _ V V Z   a _ A T 1   c e n t r a l _ J J   s i g n a l i n g _ J J   p o i n t _ N N 1   m o d u l a t i n g _ V V G   m e t a s t a t i c _ J J   n e t w o r k s _ N N 2   . _ .   
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 A s _ I I   n o _ A T   d e f i n i t e _ J J   s e c o n d a r y _ J J   c a u s e _ N N 1   o f _ I O   h y p o k a l e m i a _ N N 1   c o u l d _ V M   b e _ V B I   f o u n d _ V V N   t h e _ A T   p a t i e n t _ N N 1   w a s _ V B D Z   n o t _ X X   p u t _ V V N   o n _ I I   a n y _ D D   p r o p h y l a c t i c _ J J   t h e r a p y _ N N 1   . _ .   
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 L i n e a r _ J J   a c c e l e r a t i o n _ N N 1   a n d _ C C   a n g u l a r _ J J   v e l o c i t y _ N N 1   w e r e _ V B D R   c o n t i n u o u s l y _ R R   s a m p l e d _ V V N   ( _ (   1 _ M C 1   k H z _ N N U   r a t e _ N N 1   ) _ )   a n d _ C C   t h e _ A T   s a m p l e s _ N N 2   c o l l e c t e d _ V V N   d u r i n g _ I I   t h e _ A T   5 - m i n _ J J   i n t e r v a l _ N N 1   w e r e _ V B D R   s t o r e d _ V V N   f o r _ I F   o f f - l i n e _ J J   a n a l y s i s _ N N 1   . _ .   
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 G i v e n _ V V N   l o w _ J J   l i t e r a c y _ N N 1   l e v e l s _ N N 2   i n _ I I   S i e r r a _ N P 1   L e o n e _ N P 1   , _ ,   a l l _ D B   p a r t i c i p a n t s _ N N 2   a g e d _ I I   1 8 _ M C   y e a r s _ N N T 2   a n d _ C C   o l d e r _ J J R   p r o v i d e d _ C S   v e r b a l _ J J   c o n s e n t _ N N 1   ; _ ;   t h o s e _ D D 2   y o u n g e r _ J J R   t h a n _ C S N   1 8 _ M C   y e a r s _ N N T 2   p r o v i d e d _ C S   v e r b a l _ J J   a s s e n t _ N N 1   , _ ,   a n d _ C C   a _ A T 1   p r i m a r y _ J J   c a r e g i v e r _ N N 1   p r o v i d e d _ C S   v e r b a l _ J J   c o n s e n t _ N N 1   . _ .   
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 D i s c u s s i o n _ N N 1   O v e r _ I I   t h e _ A T   p a s t _ J J   f o u r _ M C   d e c a d e s _ N N T 2   , _ ,   w e _ P P I S 2   h a v e _ V H 0   t r a n s i t i o n e d _ V V N   f r o m _ I I   a _ A T 1   w o r l d _ N N 1   i n _ I I   w h i c h _ D D Q   u n d e r w e i g h t _ J J   p r e v a l e n c e _ N N 1   w a s _ V B D Z   m o r e _ R R R   t h a n _ C S N   d o u b l e _ R R   t h a t _ D D 1   o f _ I O   o b e s i t y _ N N 1   , _ ,   t o _ I I   o n e _ P N 1   i n _ I I   w h i c h _ D D Q   m o r e _ D A R   p e o p l e _ N N   a r e _ V B R   o b e s e _ J J   t h a n _ C S N   u n d e r w e i g h t _ J J   , _ ,   b o t h _ R R   g l o b a l l y _ R R   a n d _ C C   i n _ I I   a l l _ D B   r e g i o n s _ N N 2   e x c e p t _ I I   p a r t s _ N N 2   o f _ I O   s u b - S a h a r a n _ J J   A f r i c a _ N P 1   a n d _ C C   A s i a _ N P 1   . _ .   
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 P e d i a t r i c s _ N N 1   i s _ V B Z   a _ A T 1   b r a n c h _ N N 1   o f _ I O   m e d i c i n e _ N N 1   t h a t _ C S T   s p e c i a l i z e s _ V V Z   i n _ I I   h e a l t h _ N N 1   c a r e _ N N 1   o f _ I O   c h i l d r e n _ N N 2   a n d _ C C   a d o l e s c e n t s _ N N 2   . _ .   
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 T h i s _ D D 1   f i n d i n g _ N N 1   s u g g e s t s _ V V Z   t h a t _ C S T   t h e _ A T   i m p r o v e m e n t _ N N 1   i n _ I I   c h i l d _ N N 1   c o m m u n i c a t i o n _ N N 1   a n d _ C C   a u t i s m _ N N 1   s y m p t o m s _ N N 2   d u r i n g _ I I   t r e a t m e n t _ N N 1   c o u l d _ V M   h a v e _ V H I   b e c o m e _ V V N   s e l f - s u s t a i n i n g _ N N 1   d u r i n g _ I I   t h e _ A T   y e a r s _ N N T 2   f o l l o w i n g _ R A   t h e _ A T   e n d _ N N 1   o f _ I O   t r e a t m e n t _ N N 1   , _ ,   i n d e p e n d e n t _ J J   o f _ I O   t h e _ A T   i n i t i a l _ J J   p a r e n t a l _ J J   b e h a v i o u r a l _ J J   c h a n g e _ N N 1   t h a t _ C S T   m e d i a t e d _ V V D   t h e m _ P P H O 2   . _ .   
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 T h e _ A T   p r e s e n t _ J J   s t u d y _ N N 1   a l s o _ R R   f o u n d _ V V N   a _ A T 1   h i g h _ J J   f e m a l e : m a l e _ F O   r a t i o _ N N 1   o f _ I O   7 . 8 : 1 _ M C   . _ .   
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 A l t h o u g h _ C S   t h e _ A T   f i r s t _ M D   e p i s o d e _ N N 1   o f _ I O   N M O _ N N 1   c a n _ V M   o c c u r _ V V I   a t _ I I   a n y _ D D   a g e _ N N 1   f r o m _ I I   c h i l d h o o d _ N N 1   t o _ I I   o l d _ J J   a g e _ N N 1   , _ ,   i n _ I I   m o s t _ D A T   r e p o r t e d _ J J   s e r i e s _ N N   t h e _ A T   a v e r a g e _ J J   a g e _ N N 1   a t _ I I   o n s e t _ N N 1   i s _ V B Z   i n _ I I   t h e _ A T   4 t h _ M D   d e c a d e _ N N T 1   . _ .   
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 C o r r e l a t i o n s _ N N 2   b e t w e e n _ I I   t e a c h e r _ N N 1   a n d _ C C   p a r e n t _ N N 1   r a t i n g s _ N N 2   w e r e _ V B D R   m o d e s t _ J J   a t _ I I   a g e _ N N 1   9 _ M C   ( _ (   r _ Z Z 1   = _ F O   . 3 2 _ M C   , _ ,   p _ N N U   l e s s _ D A R   t h a n _ C S N   . 0 0 1 _ M C   ) _ )   a n d _ C C   1 2 _ M C   ( _ (   r _ Z Z 1   = _ F O   . 2 5 _ M C   , _ ,   p _ N N U   l e s s _ D A R   t h a n _ C S N   . 0 0 1 _ M C   ) _ )   . _ .   
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 A n e s t h e s i o l o g y _ N N 1   ' _ N U L L   s _ Z Z 1   a r t i c l e s _ N N 2   a r e _ V B R   m a d e _ V V N   f r e e l y _ R R   a c c e s s i b l e _ J J   t o _ I I   a l l _ D B   r e a d e r s _ N N 2   , _ ,   f o r _ I F   p e r s o n a l _ J J   u s e _ N N 1   o n l y _ R R   , _ ,   6 _ M C   m o n t h s _ N N T 2   f r o m _ I I   t h e _ A T   c o v e r _ N N 1   d a t e _ N N 1   o f _ I O   t h e _ A T   i s s u e _ N N 1   . _ .   
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 I n _ I I   t h e _ A T   l a s t _ M D   d e c a d e _ N N T 1   , _ ,   t h e _ A T   U n i t e d _ J J   S t a t e s ? _ N N 1   u s e _ N N 1   o f _ I O   a d v a n c e d _ J J   i m a g i n g _ N N 1   ( _ (   c o m p u t e d _ J J   t o m o g r a p h y _ N N 1   & l s q b ; _ (   C T _ N P 1   & r s q b ; _ )   o r _ C C   m a g n e t i c _ J J   r e s o n a n c e _ N N 1   i m a g i n g _ N N 1   ) _ )   i n _ I I   t h e _ A T   e v a l u a t i o n _ N N 1   o f _ I O   i n j u r e d _ J J   p a t i e n t s _ N N 2   h a s _ V H Z   i n c r e a s e d _ V V N   a l m o s t _ R R   3 - f o l d _ J J   w i t h o u t _ I W   a n _ A T 1   e q u i v a l e n t _ J J   i n c r e a s e _ N N 1   i n _ I I   l i f e - t h r e a t e n i n g _ N N 1   c o n d i t i o n s . 1 _ F O   N o t _ X X   s u r p r i s i n g l y _ R R   , _ ,   t h e _ A T   a p p r o p r i a t e _ J J   c l i n i c a l _ J J   u t i l i t y _ N N 1   o f _ I O   p a n - C T _ N N 1   ( _ (   C T _ N N 1   o f _ I O   t h e _ A T   b r a i n _ N N 1   , _ ,   c e r v i c a l _ J J   s p i n e _ N N 1   , _ ,   c h e s t _ N N 1   , _ ,   a b d o m e n _ N N 1   , _ ,   a n d _ C C   p e l v i s _ N N 1   ) _ )   i n _ I I   t h e _ A T   e v a l u a t i o n _ N N 1   o f _ I O   t h e _ A T   s u b s e t _ N N 1   o f _ I O   i n j u r e d _ J J   p a t i e n t s _ N N 2   w h o _ P N Q S   s u s t a i n _ V V 0   b l u n t _ J J   t r a u m a _ N N 1   r e m a i n s _ V V Z   c o n t r o v e r s i a l _ J J   . _ .   
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 A d d r e s s _ N N 1   r e p r i n t _ N N 1   r e q u e s t s _ N N 2   t o _ I I   D r . _ N N B   M e i s s n e r _ N P 1   a t _ I I   T u f t s _ N N 2   M e d i c a l _ J J   C e n t e r _ N N 1   , _ ,   8 0 0 _ M C   W a s h i n g t o n _ N P 1   S t . _ N N L 1   , _ ,   B o s t o n _ N P 1   , _ ,   M A _ N N A   0 2 1 1 1 _ M C   , _ ,   o r _ C C   a t _ I I   . _ .   
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 S T A ( R ) - T h r o m b i n _ N P 1   2 _ M C   ( _ (   D i a g n o s t i c a _ N P 1   S t a g o _ N P 1   ) _ )   a n d _ C C   B i o p h e n _ N P 1   H e p a r i n _ N P 1   L R T _ N P 1   ( _ (   H y p h e n _ N N 1   B i o M e d _ V V D   , _ ,   A n d r e s y _ N P 1   , _ ,   F r a n c e _ N P 1   ) _ )   w e r e _ V B D R   u s e d _ J J   t o _ I I   m e a s u r e _ N N 1   , _ ,   r e s p e c t i v e l y _ R R   , _ ,   t h r o m b i n _ N N 1   t i m e _ N N T 1   ( _ (   T T _ U H   ) _ )   a n d _ C C   a n t i _ J J   X a _ N P 1   a c t i v i t y _ N N 1   . _ .   
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 T e l . _ N N 1   : _ :   + 3 1 7 1 5 2 6 9 7 3 5 _ M C   ; _ ;   f a x _ V V 0   : _ :   + 3 1 7 1 5 2 6 8 2 8 0 _ M C   ; _ ;   e - m a i l _ N N 1   : _ :   M . B e e k m a n @ l u m c . n l _ F O   a n d _ C C   M a r c e l _ N P 1   R e i n d e r s _ N P 1   , _ ,   T h e _ A T   D e l f t _ N P 1   B i o i n f o r m a t i c s _ N P 1   L a b _ N N 1   , _ ,   D e l f t _ N P 1   U n i v e r s i t y _ N N 1   o f _ I O   T e c h n o l o g y _ N N 1   , _ ,   M e k e l w e g _ N P 1   4 _ M C   , _ ,   2 6 2 8 _ M C   C D _ N N 1   D e l f t _ N N 1   , _ ,   T h e _ A T   N e t h e r l a n d s _ N P 1   . _ .   
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 T h e _ A T   r e s u l t s _ N N 2   o f _ I O   m u l t i v a r i a t e _ J J   l o g i s t i c _ J J   r e g r e s s i o n _ N N 1   a n a l y s i s _ N N 1   m a y _ V M   b e _ V B I   d e p e n d e n t _ J J   o n _ I I   t h e _ A T   r e g r e s s i o n _ N N 1   m e t h o d _ N N 1   u s e d _ V V N   ( _ (   i e _ R E X   , _ ,   t h e _ A T   b a c k w a r d _ J J   s t e p w i s e _ J J   e l i m i n a t i o n _ N N 1   m e t h o d _ N N 1   i n _ I I   o u r _ A P P G E   s t u d y _ N N 1   ) _ )   . _ .   
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 F a v o r a b l e _ J J   o u t c o m e _ N N 1   w a s _ V B D Z   d e f i n e d _ V V N   a s _ C S A   C e r e b r a l _ J J   P e r f o r m a n c e _ N N 1   C a t e g o r y _ N N 1   ( _ (   C P C _ N P 1   ) _ )   s c o r e _ V V 0   1 _ M C 1   o r _ C C   2 _ M C   , _ ,   t h a t _ R E X 2 1   i s _ R E X 2 2   , _ ,   ' _ N U L L   a l i v e _ J J   w i t h _ I W   g o o d _ J J   c e r e b r a l _ J J   p e r f o r m a n c e _ N N 1   o r _ C C   s u f f i c i e n t _ J J   c e r e b r a l _ J J   f u n c t i o n _ N N 1   f o r _ I F   i n d e p e n d e n t _ J J   a c t i v i t i e s _ N N 2   o f _ I O   d a i l y _ J J   l i f e _ N N 1   , _ ,   w i t h _ I W   o r _ C C   w i t h o u t _ I W   m i l d _ J J   n e u r o l o g i c a l _ J J   o r _ C C   p s y c h o l o g i c _ J J   d e f i c i t s _ N N 2   . _ .   
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 T o _ T O   d e c i d e _ V V I   t h i s _ D D 1   h y p o t h e s i s _ N N 1   , _ ,   a _ A T 1   t r i a l _ N N 1   u s i n g _ V V G   r a n d o m i z e d _ V V D   o n _ R P   a n d _ C C   o f f _ I I   d o u b l e - b l i n d _ J J   p e r i o d s _ N N 2   s h o u l d _ V M   b e _ V B I   d e s i g n e d _ V V N   , _ ,   t h e _ A T   o f f _ J J   p e r i o d s _ N N 2   c o r r e s p o n d i n g _ V V G   i n _ I I   t h i s _ D D 1   t e c h n i q u e _ N N 1   t o _ I I   a _ A T 1   s h a m _ N N 1   s t i m u l a t i o n _ N N 1   a s _ I I   E C S _ N P 2   d o e s _ V D Z   n o t _ X X   i n d u c e _ V V I   i m m e d i a t e _ J J   p e r c e p t i o n _ N N 1   b y _ I I   t h e _ A T   p a t i e n t _ N N 1   . _ .   
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 T h e s e _ D D 2   s u b j e c t - s p e c i f i c _ J J   a H D R s _ N N 2   w e r e _ V B D R   t h e n _ R T   a v e r a g e d _ V V N   a c r o s s _ I I   a l l _ D B   s u b j e c t s _ N N 2   t o _ T O   o b t a i n _ V V I   g r o u p _ N N 1   a H D R s _ N N 2   c o r r e s p o n d i n g _ V V G   t o _ I I   e a c h _ D D 1   e x p e r i m e n t a l _ J J   c o n d i t i o n _ N N 1   f o r _ I F   t h e _ A T   l e f t _ J J   a n d _ C C   r i g h t _ R R   p r i m a r y _ J J   a u d i t o r y _ J J   c o r t i c e s _ N N 2   . _ .   
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 T h i s _ D D 1   w o r k _ N N 1   w a s _ V B D Z   a l s o _ R R   s u p p o r t e d _ V V N   i n _ R R 2 1   p a r t _ R R 2 2   b y _ I I   a _ A T 1   g r a n t _ N N 1   f r o m _ I I   t h e _ A T   S h a n g h a i _ N P 1   M u n i c i p a l _ J J   G o v e r n m e n t _ N N 1   , _ ,   S h a n g h a i _ N P 1   , _ ,   C h i n a _ N P 1   ( _ (   g r a n t _ V V 0   n o . _ N N 1   2 0 1 1 4 2 1 7 _ M C   ) _ )   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   s e v e r a l _ D A 2   n e x t - g e n e r a t i o n _ J J   a n t i - i n f l a m m a t o r y _ J J   m e d i c a t i o n s _ N N 2   , _ ,   s u c h _ I I 2 1   a s _ I I 2 2   t o c i l i z u m a b _ N N 1   a n d _ C C   a n a k i n r a _ N N 1   , _ ,   h a v e _ V H 0   b e e n _ V B N   a p p r o v e d _ V V N   f o r _ I F   u s e _ N N 1   i n _ I I   h u m a n s _ N N 2   . _ .   
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 T h e _ A T   m a j o r _ J J   c h a l l e n g e s _ N N 2   t o _ I I   s u c c e s s f u l _ J J   c l i n i c a l _ J J   t r a n s l a t i o n _ N N 1   o f _ I O   r a d i o l a b e l e d _ J J   M C 1 - R _ N P 1   a v i d _ J J   p e p t i d e s _ N N 2   f o r _ I F   m e l a n o m a _ N N 1   i m a g i n g _ N N 1   a n d _ C C   t h e r a p y _ N N 1   a r e _ V B R   h i g h _ J J   n o n - s p e c i f i c _ J J   k i d n e y _ N N 1   u p t a k e _ N N 1   a n d _ C C   l o w _ J J   M C 1 - R _ N P 1   r e c e p t o r _ N N 1   n u m b e r s _ N N 2   p e r _ I I   t u m o r _ N N 1   c e l l _ N N 1   . _ .   
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 T h e y _ P P H S 2   a l s o _ R R   p r o p o s e d _ V V D   t h a t _ C S T   c l i n i c i a n s _ N N 2   m i g h t _ V M   a c c e p t _ V V I   l o w e r _ J J R   a c c u r a c y _ N N 1   o f _ I O   a _ A T 1   m o n i t o r _ N N 1   , _ ,   i n _ I I 3 1   r e t u r n _ I I 3 2   f o r _ I I 3 3   o t h e r _ J J   a d v a n t a g e s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   e a s e _ N N 1   o f _ I O   u s e _ N N 1   a n d _ C C   n o n - i n v a s i v e n e s s _ N N 1   . _ .   
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 R a t e r s _ N P 1   w e r e _ V B D R   t r a i n e d _ V V N   a n d _ C C   t h e i r _ A P P G E   r a t i n g _ N N 1   s k i l l _ N N 1   w a s _ V B D Z   t e s t e d _ V V N   p r i o r _ I I 2 1   t o _ I I 2 2   d a t a _ N N   c o l l e c t i o n _ N N 1   , _ ,   a n d _ C C   r e t e s t e d _ V V D   e v e r y _ A T 1   6 _ M C   m o n t h s _ N N T 2   t h r o u g h o u t _ I I   t h e _ A T   c o u r s e _ N N 1   o f _ I O   t h e _ A T   s t u d y _ N N 1   . _ .   
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 M u s t _ V M   b e _ V B I   r a n d o m i z e d _ V V N   c o n t r o l l e d _ J J   t r i a l _ N N 1   , _ ,   c o n t r o l l e d _ V V D   t r i a l _ N N 1   , _ ,   p r o s p e c t i v e _ J J   c a s e _ N N 1   s e r i e s _ N N   o r _ C C   c o h o r t _ N N 1   . _ .   
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 S u c h _ D A   a p p r o a c h e s _ N N 2   d e p e n d _ V V 0   , _ ,   h o w e v e r _ R R   , _ ,   o n _ I I   d e s i g n i n g _ V V G   e f f i c i e n t _ J J   m e c h a n i s m s _ N N 2   t h r o u g h _ I I   w h i c h _ D D Q   t o _ T O   t a r g e t _ V V I   m u t a n t _ N N 1   p 5 3 _ F O   , _ ,   a n _ A T 1   u n d e r s t a n d i n g _ N N 1   o f _ I O   t h e _ A T   a c t i v i t i e s _ N N 2   a n d _ C C   f u n c t i o n _ N N 1   o f _ I O   t h e _ A T   m a n y _ D A 2   d i f f e r e n t _ J J   m u t a n t s _ N N 2   , _ ,   a n d _ C C   t h e _ A T   c a p a c i t y _ N N 1   t o _ T O   i d e n t i f y _ V V I   w h i c h _ D D Q   m u t a t i o n _ N N 1   a _ A T 1   t u m o r _ N N 1   c a r r i e s _ V V Z   ( _ (   t h e _ A T   l a t t e r _ D A   l i k e l y _ J J   t o _ T O   b e _ V B I   t h e _ A T   m o s t _ R G T   e a s i l y _ R R   a t t a i n a b l e _ J J   g o a l _ N N 1   ) _ )   . _ .   
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 I n _ I I 3 1   v i e w _ I I 3 2   o f _ I I 3 3   t h e s e _ D D 2   c o n s i d e r a t i o n s _ N N 2   , _ ,   c o m p r e h e n s i v e _ J J   a n a l y s e s _ N N 2   o f _ I O   B A C E 1 - / - _ F U   m i c e _ N N 2   s h o u l d _ V M   h e l p _ V V I   t o _ T O   p a r s e _ V V I   d e v e l o p m e n t a l _ J J   v e r s u s _ I I   a d u l t _ N N 1   B A C E 1 _ F O   n u l l _ J J   p h e n o t y p e s _ N N 2   f o r _ I F   t h e _ A T   e v a l u a t i o n _ N N 1   o f _ I O   r i s k s _ N N 2   o f _ I O   B A C E 1 _ F O   i n h i b i t o r s _ N N 2   . _ .   
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 T h e _ A T   s i z e _ N N 1   o f _ I O   e a c h _ D D 1   R O I _ N N 1   w a s _ V B D Z   2 0 0 _ M C   m m 2 _ F O   . _ .   
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 T h e s e _ D D 2   p r e - a n a l y t i c a l _ J J   s t e p s _ N N 2   o r _ C C   a _ A T 1   c o m b i n a t i o n _ N N 1   o f _ I O   t h e m _ P P H O 2   c o u l d _ V M   h a v e _ V H I   l e d _ V V N   t o _ I I   c e l l u l a r _ J J   l o s s _ N N 1   o r _ C C   c e l l _ N N 1   l y s i s _ N N 1   w h i c h _ D D Q   c o u l d _ V M   h a v e _ V H I   r e s u l t e d _ V V N   i n _ I I   l o w e r _ J J R   c h a m b e r _ N N 1   c o u n t s _ N N 2   . _ .   
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 T h e r e _ E X   w a s _ V B D Z   a _ A T 1   s i g n i f i c a n t _ J J   c o r r e l a t i o n _ N N 1   b e t w e e n _ I I   N R S _ N P 1   s c o r e s _ N N 2   d u r i n g _ I I   t h e _ A T   C P T _ N P 1   a n d _ C C   c h a n g e _ V V 0   i n _ I I   p a i n _ N N 1   t o l e r a n c e _ N N 1   l i m i t _ N N 1   i m m e d i a t e l y _ R R   a f t e r _ I I   t h e _ A T   C P T _ N P 1   ( _ (   r 6 0 _ F O   = _ F O   0 . 3 9 7 _ M C   , _ ,   P _ Z Z 1   = _ F O   0 . 0 0 2 _ M C   ) _ )   . _ .   
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 A _ A T 1   p o s i t i v e _ J J   H e d g e s _ N N 2   ' _ N U L L   g _ Z Z 1   i n d i c a t e s _ V V Z   t h e _ A T   p r e s e n c e _ N N 1   o f _ I O   m o r e _ R G R   n e g a t i v e _ J J   c o m m u n i c a t i o n _ N N 1   a t t i t u d e s _ N N 2   a m o n g _ I I   C W S _ N P 1   t h a n _ C S N   C W N S _ N P 1   . _ .   
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 A c o u s t i c _ J J   r e c o r d i n g s _ N N 2   w e r e _ V B D R   m a d e _ V V N   w i t h _ I W   a _ A T 1   S h u r e _ N N 1   o m n i d i r e c t i o n a l _ J J   l a p e l _ N N 1   m i c r o p h o n e _ N N 1   ( _ (   M X 3 9 3 / O _ N P 1   ) _ )   w o r n _ V V N   b y _ I I   t h e _ A T   p a r t i c i p a n t _ N N 1   . _ .   
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 C e l l _ N N 1   L i n e s _ N N 2   a n d _ C C   C e l l _ N N 1   C u l t u r e _ N N 1   N o r m a l _ J J   s m a l l _ J J   a i r w a y _ N N 1   e p i t h e l i a l _ J J   c e l l s _ N N 2   ( _ (   S A E C s _ N P 2   ) _ )   a n d _ C C   l u n g _ N N 1   c a n c e r _ N N 1   c e l l _ N N 1   l i n e s _ N N 2   w e r e _ V B D R   p u r c h a s e d _ V V N   f r o m _ I I   A T C C _ N P 1   . _ .   
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 A l l _ D B   p a t i e n t s _ N N 2   p r e s e n t e d _ V V N   w i t h _ I W   s y m p t o m a t i c _ J J   o b s t r u c t i v e _ J J   j a u n d i c e _ N N 1   a n d _ C C   u n d e r w e n t _ V V N   p e r c u t a n e o u s l y _ R R   b i l i a r y _ J J   d r a i n a g e _ N N 1   w i t h _ I W   c a t h e t e r s _ N N 2   o r _ C C   s t e n t s _ N N 2   . _ .   
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 T h e _ A T   R A I _ N N 1   c o u l d _ V M   a l s o _ R R   b e _ V B I   a p p l i e d _ V V N   i n _ I I   o t h e r _ J J   d y s r e g u l a t e d _ J J   s t a t e s _ N N 2   a n d _ C C   r e l a t e d _ V V N   t o _ I I   f u n c t i o n a l _ J J   m a g n e t i c _ J J   r e s o n a n c e _ N N 1   i m a g i n g _ V V G   d a t a _ N N   a c q u i r e d _ V V N   f r o m _ I I   a _ A T 1   v a r i e t y _ N N 1   o f _ I O   t a s k s _ N N 2   . _ .   
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 H o w e v e r _ R R   , _ ,   t h e _ A T   c o s t _ N N 1   o f _ I O   t h e _ A T   d e v i c e _ N N 1   a n d _ C C   i t s _ A P P G E   r e l a t i v e _ J J   i m m o b i l i t y _ N N 1   c u r r e n t l y _ R R   d i s c o u r a g e s _ V V Z   i t _ P P H 1   f r o m _ I I   b e i n g _ V B G   u s e d _ V V N   o u t s i d e _ I I   e y e _ N N 1   c l i n i c s _ N N 2   , _ ,   a n d _ C C   t h e r e f o r e _ R R   a s _ I I   a _ A T 1   c o m p o n e n t _ N N 1   o f _ I O   a _ A T 1   t e l e - A M D _ N P 1   p r o g r a m _ N N 1   . _ .   
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 T h e _ A T   m a i n _ J J   p r o t e c t o r _ N N 1   o f _ I O   d o p a m i n e r g i c _ J J   n e u r o n s _ N N 2   a g a i n s t _ I I   t h i s _ D D 1   o x i d a t i v e _ J J   s t r e s s _ N N 1   i s _ V B Z   t h e _ A T   d o p a m i n e _ N N 1   t r a n s p o r t e r _ N N 1   ( _ (   D A T _ D D 1   ) _ )   . _ .   
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 I n _ I I   1 9 4 0 _ M C   , _ ,   t h e _ A T   w e b b e d _ J J   s t y l e _ N N 1   s u s p e n s i o n _ N N 1   w a s _ V B D Z   r e p l a c e d _ V V N   b y _ I I   a _ A T 1   p a d d e d _ J J   s t y l e _ N N 1   s u s p e n s i o n _ N N 1   . _ .   
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 N o _ A T   c o r r e l a t i o n s _ N N 2   w e r e _ V B D R   o b s e r v e d _ V V N   b e t w e e n _ I I   t h e _ A T   i n d i v i d u a l _ J J   C A E S _ N P 2   g r o u p _ N N 1   t h r e s h o l d _ N N 1   s h i f t s _ N N 2   a n d _ C C   m a x i m u m _ J J   c u r r e n t _ J J   l e v e l s _ N N 2   o r _ C C   d y n a m i c _ J J   r a n g e s _ N N 2   o f _ I O   s t i m u l a t i o n _ N N 1   . _ .   
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 G i v e n _ V V N   t h e _ A T   s u c c e s s _ N N 1   o f _ I O   m u l t i d i s c i p l i n a r y _ J J   p a i n _ N N 1   m a n a g e m e n t _ N N 1   i n t e r v e n t i o n s _ N N 2   t h a t _ C S T   i n c l u d e _ V V 0   s o m e _ D D   f o r m _ N N 1   o f _ I O   b e h a v i o r a l _ J J   t h e r a p y _ N N 1   , _ ,   i t _ P P H 1   w o u l d _ V M   s e e m _ V V I   l o g i c a l _ J J   t h a t _ C S T   b e h a v i o r a l _ J J   i n t e r v e n t i o n _ N N 1   w o u l d _ V M   b e _ V B I   a _ A T 1   u s e f u l _ J J   p a r t _ N N 1   o f _ I O   a n y _ D D   w e a n i n g _ J J   p r o g r a m _ N N 1   t o _ T O   h e l p _ V V I   w i t h _ I W   s l e e p _ N N 1   h y g i e n e _ N N 1   , _ ,   a n x i e t y / m o o d _ N N 1   s y m p t o m s _ N N 2   , _ ,   a n d _ C C   p a i n - r e l a t e d _ J J   s y m p t o m s _ N N 2   t h a t _ C S T   m a y _ V M   o c c u r _ V V I   d u r i n g _ I I   t h e _ A T   w e a n i n g _ J J   p e r i o d _ N N 1   . _ .   
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 O n _ I I   t h e _ A T   o t h e r _ J J   h a n d _ N N 1   , _ ,   d u r a t i o n _ N N 1   d i s c r i m i n a t i o n _ N N 1   r e f e r s _ V V Z   t o _ I I   t h e _ A T   a b i l i t y _ N N 1   t o _ T O   d i s c r i m i n a t e _ V V I   t h e _ A T   s m a l l e s t _ J J T   p o s s i b l e _ J J   d i f f e r e n c e _ N N 1   i n _ I I   d u r a t i o n _ N N 1   ( _ (   d i f f e r e n c e _ N N 1   l i m e n _ N N 2   ) _ )   w h i c h _ D D Q   u s u a l l y _ R R   h a s _ V H Z   a _ A T 1   d u r a t i o n _ N N 1   s i m i l a r _ J J   t o _ I I   t h a t _ D D 1   r e p o r t e d _ V V D   f o r _ I F   T O J _ N P 1   , _ ,   t h u s _ R R   o f _ I O   c a _ V M   . _ .   
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 A c c o r d i n g _ I I 2 1   t o _ I I 2 2   t h e _ A T   O f f i c e _ N N 1   o f _ I O   t h e _ A T   N a t i o n a l _ J J   C o o r d i n a t o r _ N N 1   f o r _ I F   H e a l t h _ N N 1   I n f o r m a t i o n _ N N 1   T e c h n o l o g y _ N N 1   , _ ,   c u r r e n t l y _ R R   t h e r e _ E X   a r e _ V B R   3 _ M C   k e y _ J J   f o r m s _ N N 2   o f _ I O   h e a l t h _ N N 1   i n f o r m a t i o n _ N N 1   e x c h a n g e _ N N 1   . _ .   
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 T h e _ A T   c h i - s q u a r e d _ J J   t e s t _ N N 1   w a s _ V B D Z   u s e d _ V V N   f o r _ I F   g r o u p _ N N 1   c o m p a r i s o n s _ N N 2   o f _ I O   p r o p o r t i o n s _ N N 2   ( _ (   s e x _ N N 1   , _ ,   r a c e _ N N 1   , _ ,   A O N _ N P 1   h i s t o r y _ N N 1   ) _ )   . _ .   
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 A l t h o u g h _ C S   m o d e l s _ N N 2   o f _ I O   h o w _ R G Q   m a m m a l i a n _ J J   R I B E Y E _ N N 1   a s s e m b l e s _ V V Z   h a v e _ V H 0   b e e n _ V B N   p r o p o s e d _ V V N   b a s e d _ V V N   o n _ I I   y e a s t _ N N 1   t w o - h y b r i d _ N N 1   i n t e r a c t i o n s _ N N 2   ( _ (   M a g u p a l l i _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 , _ ,   2 0 0 8 _ M C   ) _ )   , _ ,   t h e _ A T   i n _ J J 2 1   v i v o _ J J 2 2   o r i e n t a t i o n _ N N 1   o f _ I O   R I B E Y E _ N N 1   w i t h i n _ I I   t h e _ A T   s p h e r i c a l _ J J   s t r u c t u r e _ N N 1   o f _ I O   h a i r _ N N 1   c e l l _ N N 1   r i b b o n s _ N N 2   i s _ V B Z   n o t _ X X   k n o w n _ V V N   . _ .   
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 T h e _ A T   p r o f i l e _ N N 1   o f _ I O   C Y P _ N P 1   e x p r e s s i o n _ N N 1   a n d _ C C   c h o l e s t e r o l _ N N 1   m e t a b o l i t e _ N N 1   c o n t e n t _ N N 1   i n _ I I   t h e _ A T   b r a i n _ N N 1   ( _ (   g r a y _ J J   m a t t e r _ N N 1   o f _ I O   t e m p o r a l _ J J   l o b e _ N N 1   ) _ )   w a s _ V B D Z   t h e _ A T   o p p o s i t e _ J J   , _ ,   c o n s i s t e n t _ J J   w i t h _ I W   t h e _ A T   r o l e _ N N 1   o f _ I O   C Y P 4 6 A 1 _ F O   a s _ I I   t h e _ A T   e n z y m e _ N N 1   r e s p o n s i b l e _ J J   f o r _ I F   t h e _ A T   m a j o r i t y _ N N 1   o f _ I O   c h o l e s t e r o l _ N N 1   e l i m i n a t i o n _ N N 1   f r o m _ I I   t h i s _ D D 1   o r g a n _ N N 1   ( _ (   B j o r k h e m _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 9 9 8 _ M C   ) _ )   . _ .   
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 I t s _ A P P G E   f i r s t _ M D   h y p o t h e s i s _ N N 1   p o s t u l a t e s _ V V Z   t h a t _ C S T   C M - P S T _ N P 1   i s _ V B Z   m o r e _ R G R   e f f e c t i v e _ J J   t h a n _ C S N   C M _ N N U   i n _ I I   r e d u c i n g _ V V G   d e p r e s s i v e _ N N 1   s y m p t o m s _ N N 2   o v e r _ R G   1 2 _ M C   w e e k s _ N N T 2   . _ .   
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 M a n y _ D A 2   s t u d i e s _ N N 2   s u p p o r t _ V V 0   t h e _ A T   f i n d i n g _ N N 1   t h a t _ C S T   a b o u t _ I I   o n e _ M C 1   t h i r d _ M D   o f _ I O   c h i l d r e n w h o _ N N 1   s t u t t e r _ N N 1   a l s o _ R R   e x h i b i t _ V V 0   a _ A T 1   c o n c o m i t a n t _ J J   p h o n o l o g i c a l _ J J   d i s o r d e r _ N N 1   ( _ (   B y r d _ N P 1   , _ ,   W o l k _ N P 1   , _ ,   & ; _ N U L L   D a v i s _ N P 1   , _ ,   2 0 0 7 _ M C   ; _ ;   W o l k _ N P 1   , _ ,   E d w a r d s _ N P 1   , _ ,   & C o n t u r e , ; _ N U L L   1 9 9 3 _ M C   ) _ )   , _ ,   a n d _ C C   a p p r o x i m a t e l y _ R R   1 0 % _ N N U   e x h i b i t _ V V 0   a _ A T 1   c o n c o m i t a n t _ J J   l a n g u a g e _ N N 1   d i s o r d e r _ N N 1   ( _ (   A r n d t _ N P 1   & ; _ N U L L   H e a l e y _ N P 1   , _ ,   2 0 0 1 _ M C   ; _ ;   B l o o d _ N N 1   & ; _ N U L L   S e i d e r _ N N 1   , _ ,   1 9 8 1 _ M C   ) _ )   . _ .   
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 D e s i g n _ N N 1   a n d _ C C   S e t t i n g _ N N 1   : _ :   A _ Z Z 1   p r o s p e c t i v e _ J J   c o h o r t _ N N 1   s t u d y _ N N 1   o f _ I O   B r i t i s h _ J J   c i v i l _ J J   s e r v a n t s _ N N 2   w h o _ P N Q S   r e s p o n d e d _ V V D   t o _ I I   a _ A T 1   s e l f - a d m i n i s t e r e d _ J J   q u e s t i o n n a i r e _ N N 1   i n _ I I   m i d d l e - a g e _ N N 1   a n d _ C C   a t _ I I   o l d e r _ J J R   a g e s _ N N 2   , _ ,   2 1 _ M C   y e a r s _ N N T 2   l a t e r _ R R R   . _ .   
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 E x c l u s i o n _ N N 1   c r i t e r i a _ N N 2   i n c l u d e d _ V V N   ( _ (   1 _ M C 1   ) _ )   l u m b a r _ N N 1   s p i n e _ N N 1   s t e n o s i s _ N N 1   o n _ I I   m a g n e t i c _ J J   r e s o n a n c e _ N N 1   i m a g i n g _ N N 1   ; _ ;   ( _ (   2 _ M C   ) _ )   u s e _ N N 1   o f _ I O   e x o g e n o u s _ J J   s t e r o i d _ N N 1   , _ ,   i n c l u d i n g _ I I   i n h a l e d _ J J   s t e r o i d s _ N N 2   , _ ,   w i t h i n _ I I   t h e _ A T   p a s t _ J J   6 _ M C   m o n t h s _ N N T 2   ; _ ;   ( _ (   3 _ M C   ) _ )   h i s t o r y _ N N 1   o f _ I O   a n y _ D D   l u m b a r _ N N 1   s p i n e _ N N 1   s u r g e r y _ N N 1   i n c l u d i n g _ I I   f u s i o n _ N N 1   a n d _ C C   d e c o m p r e s s i v e _ J J   l a m i n e c t o m y _ N N 1   ; _ ;   ( _ (   4 _ M C   ) _ )   a d r e n a l _ J J   d i s e a s e _ N N 1   , _ ,   p i t u i t a r y _ J J   d i s e a s e _ N N 1   , _ ,   o r _ C C   o t h e r _ J J   e n d o c r i n o p a t h y _ N N 1   k n o w n _ V V N   t o _ T O   i m p a i r _ V V I   t h e _ A T   H P A _ N N 1   a x i s _ N N 1   ; _ ;   ( _ (   5 _ M C   ) _ )   e n d - s t a g e _ J J   l i v e r _ N N 1   ( _ (   C h i l d - P u g h _ N P 1   c l a s s i f i c a t i o n _ N N 1   A _ Z Z 1   o r _ C C   g r e a t e r _ J J R   ) _ )   o r _ C C   k i d n e y _ N N 1   d i s e a s e _ N N 1   ( _ (   c r e a t i n i n e _ N N 1   c l e a r a n c e _ N N 1   l e s s _ D A R   t h a n _ C S N   3 0 _ M C   m L / m i n _ N N U   ) _ )   ; _ ;   ( _ (   6 _ M C   ) _ )   u s e _ N N 1   o f _ I O   a n y _ D D   m e d i c a t i o n _ N N 1   k n o w n _ V V N   t o _ T O   i n t e r f e r e _ V V I   w i t h _ I W   t h e _ A T   m e t a b o l i s m _ N N 1   o f _ I O   t r i a m c i n _ N N 1   l o n e _ J J   a c e t o n i d e _ N N 1   , _ ,   i n c l u d i n g _ V V G   , _ ,   b u t _ C C B   n o t _ X X   l i m i t e d _ V V N   t o _ I I   , _ ,   p h e n o b a r b i t a l _ N N 1   , _ ,   p h e n y t o i n _ N N 1   , _ ,   i t r a c o n a z o l e _ N N 1   , _ ,   r i f a m p i n _ N N 1   , _ ,   a n d _ C C   s e l e c t e d _ J J   a n t i r e t r o v i r a l _ J J   a g e n t s _ N N 2   ; _ ;   ( _ (   7 _ M C   ) _ )   p r e s e n c e _ N N 1   o f _ I O   a _ A T 1   p s y c h i a t r i c _ J J   d i s o r d e r _ N N 1   t h a t _ C S T   w o u l d _ V M   l i m i t _ V V I   o b t a i n i n g _ V V G   i n f o r m e d _ J J   c o n s e n t _ N N 1   o r _ C C   i m p a i r _ V V 0   f u n c t i o n i n g _ V V G   i n _ I I   a n _ A T 1   a m b u l a t o r y _ J J   c a r e _ N N 1   e n v i r o n m e n t _ N N 1   ( _ (   e g _ R E X   , _ ,   d e m e n t i a _ N N 1   , _ ,   s c h i z o p h r e n i a _ N N 1   , _ ,   s e v e r e _ J J   d e p r e s s i o n _ N N 1   ) _ )   ; _ ;   a n d _ C C   ( _ (   8 _ M C   ) _ )   p r e g n a n c y _ N N 1   . _ .   
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 T h e _ A T   g r a n d - m e a n _ J J   p e a k _ N N 1   M M N _ N P 1   l a t e n c i e s _ N N 2   w e r e _ V B D R   i d e n t i f i e d _ V V N   f r o m _ I I   t h e _ A T   d i f f e r e n c e _ N N 1   w a v e f o r m s _ N N 2   a t _ I I   F 4 _ F O   a t _ I I   1 6 0 _ M C   - _ -   3 0 0 _ M C   m s _ N N 1   f r o m _ I I   t h e _ A T   d e v i a n t - s t i m u l u s _ J J   o n s e t _ N N 1   s e p a r a t e l y _ R R   f o r _ I F   e a c h _ D D 1   g r o u p _ N N 1   a n d _ C C   d e v i a n t s _ N N 2   ( _ (   T a b l e _ N N 1   1 _ M C 1   ) _ )   . _ .   
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 N o t a b l y _ R R   , _ ,   t h e _ A T   f i b r o n e c t i n - n e g a t i v e _ J J   g r o u p _ N N 1   r e c r u i t e d _ V V N   u n d e r _ I I   t h e _ A T   e x t e n d e d _ J J   c r i t e r i a _ N N 2   , _ ,   h a d _ V H D   r a t e s _ N N 2   o f _ I O   t h e _ A T   p r i m a r y _ J J   o u t c o m e _ N N 1   ( _ (   d e a t h _ N N 1   o r _ C C   p r e t e r m _ V V 0   b i r t h _ N N 1   b e f o r e _ I I   3 4 _ M C   w e e k s _ N N T 2   ) _ )   o f _ I O   1 3 % _ N N U   ( _ (   a p p e n d i x _ N N 1   ) _ )   , _ ,   s o m e _ D D   t h r e e _ M C   t i m e s _ I I   t h o s e _ D D 2   o f _ I O   t h e _ A T   b a c k g r o u n d _ N N 1   p o p u l a t i o n _ N N 1   o f _ I O   p r e g n a n t _ J J   w o m e n _ N N 2   i n _ I I   t h e _ A T   U K _ N P 1   . _ .   
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 W e _ P P I S 2   s o u g h t _ V V D   t o _ T O   i d e n t i f y _ V V I   a l l _ D B   t r i a l s _ N N 2   , _ ,   i r r e s p e c t i v e _ I I 2 1   o f _ I I 2 2   w h e t h e r _ C S W   a _ A T 1   t r i a l _ N N 1   w a s _ V B D Z   o n g o i n g _ J J   o r _ C C   c o m p l e t e d _ V V D   , _ ,   p u b l i s h e d _ V V N   o r _ C C   u n p u b l i s h e d _ J J   , _ ,   w i t h _ I W   n o _ A T   l a n g u a g e _ N N 1   r e s t r i c t i o n s _ N N 2   . _ .   
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 A _ A T 1   m i n i m u m _ N N 1   o f _ I O   t h r e e _ M C   s c a n s _ N N 2   o f _ I O   t h e _ A T   c e n t r a l _ J J   c o r n e a _ N N 1   a n d _ C C   o f _ I O   t h e _ A T   s u p e r i o r _ J J   , _ ,   n a s a l _ J J   , _ ,   i n f e r i o r _ J J   , _ ,   a n d _ C C   t e m p o r a l _ J J   l i m b u s _ N N 1   w e r e _ V B D R   c o l l e c t e d _ V V N   . _ .   
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 M o r e o v e r _ R R   , _ ,   N R P 1 _ F O   p r o m o t e s _ V V Z   f i b r o n e c t i n _ N N 1   f i b r i l l o g e n e s i s _ N N 1   i n _ I I   a r t e r i a l _ J J   e n d o t h e l i a l _ J J   c e l l s _ N N 2   i n _ R R 2 1   v i t r o _ R R 2 2   b y _ I I   r e g u l a t i n g _ V V G   i n t r a c e l l u l a r _ J J   t r a f f i c k i n g _ N N 1   o f _ I O   a c t i v a t e d _ J J   a 5 p 1 _ F O   i n _ I I   a _ A T 1   m e c h a n i s m _ N N 1   t h a t _ C S T   r e q u i r e s _ V V Z   t h e _ A T   N R P 1 _ F O   c y t o p l a s m i c _ J J   d o m a i n _ N N 1   ( _ (   V a l d e m b r i _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 9 _ M C   ) _ )   . _ .   
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 A g e _ N N 1   w a s _ V B D Z   e v a l u a t e d _ V V N   a s _ I I   a n _ A T 1   a d d i t i o n a l _ J J   p r e d i c t o r _ N N 1   i n _ I I   e a c h _ D D 1   m u l t i v a r i a t e _ J J   m o d e l _ N N 1   t o _ T O   a d j u s t _ V V I   f o r _ I F   t h e _ A T   i n f l u e n c e _ N N 1   o f _ I O   a g e _ N N 1   o n _ I I   T 1 _ F O   a n d _ C C   T 2 _ F O   . _ .   
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 T h e s e _ D D 2   s t u d i e s _ N N 2   s h o u l d _ V M   i n c l u d e _ V V I   a n _ A T 1   e a r l y _ J J   a n d _ C C   p r o s p e c t i v e _ J J   a s s e s s m e n t _ N N 1   o f _ I O   C S F _ N P 1   a n t i b o d y _ N N 1   t i t e r s _ N N 2   a s _ I I   a _ A T 1   p o s s i b l e _ J J   p r o g n o s t i c _ J J   b i o m a r k e r _ N N 1   . _ .   
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 T h e y _ P P H S 2   f i r s t _ M D   s h o w e d _ V V D   i n _ I I   h e a l t h y _ J J   v o l u n t e e r s _ N N 2   t h a t _ C S T   t h e _ A T   d e g r e e _ N N 1   o f _ I O   l e f t _ J J   I F G _ N N 1   a c t i v i t y _ N N 1   i n _ I I   f M R I _ N N 2   c o u l d _ V M   b e _ V B I   m o d u l a t e d _ V V N   b y _ I I   t h e _ A T   s e l e c t i o n _ N N 1   d e m a n d s _ N N 2   o f _ I O   t h e _ A T   s e m a n t i c _ J J   t a s k _ N N 1   w i t h _ I W   a _ A T 1   h i g h e r _ J J R   a c t i v a t i o n _ N N 1   o f _ I O   t h e _ A T   I F G _ N N 1   f o r _ I F   s e l e c t i v e _ J J   t a s k s _ N N 2   . _ .   
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 F o u r t h _ M D   , _ ,   n o t _ X X   a l l _ D B   p a t i e n t s _ N N 2   u n d e r w e n t _ V V D   p r e o p e r a t i v e _ J J   M R _ N N B   i m a g i n g _ N N 1   . _ .   
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 F o r _ I F   " _ "   c l i n i c a l _ J J   i n f e r e n c e _ N N 1   " _ "   , _ ,   w e _ P P I S 2   h a v e _ V H 0   t o _ T O   s p e c i f y _ V V I   t h e _ A T   " _ "   m i n i m u m _ J J   c h a n c e _ N N 1   o f _ I O   b e n e f i t _ N N 1   " _ "   ( _ (   d e f a u l t _ N N 1   i n _ I I   E 3 7 _ F O   ) _ )   a n d _ C C   t h e _ A T   " _ "   m a x i m u m _ J J   r i s k _ N N 1   o f _ I O   h a r m _ N N 1   " _ "   ( _ (   d e f a u l t _ N N 1   i n _ I I   E 3 6 _ F O   ) _ )   . _ .   
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 H o w e v e r _ R R   , _ ,   e v e n _ C S 2 1   t h o u g h _ C S 2 2   i t _ P P H 1   h a s _ V H Z   b e e n _ V B N   d e m o n s t r a t e d _ V V N   t h a t _ C S T   c a r b a m y l a t e d _ V V D   a l b u m i n _ N N 1   m a y _ V M   p r e d i c t _ V V I   m o r t a l i t y _ N N 1   i n _ I I   p a t i e n t s _ N N 2   w i t h _ I W   k i d n e y _ N N 1   f a i l u r e _ N N 1   , _ ,   n o _ A T   m o l e c u l a r _ J J   m e c h a n i s m _ N N 1   i n v o l v i n g _ V V G   c a r b a m y l a t e d _ J J   a l b u m i n _ N N 1   h a s _ V H Z   b e e n _ V B N   y e t _ R R   p r o p o s e d _ V V N   . _ .   
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 G e n e r a l _ J J   u s e _ N N 1   o f _ I O   i n p a t i e n t _ N N 1   a d m i n i s t r a t i v e _ J J   d a t a _ N N   t o _ T O   d e t e r m i n e _ V V I   e p i d e m i o l o g y _ N N 1   o f _ I O   a n y _ D D   d i s e a s e _ N N 1   i s _ V B Z   l i k e l y _ J J   t o _ T O   p r o v i d e _ V V I   a _ A T 1   l o w e r _ J J R   e s t i m a t e _ N N 1   ; _ ;   h o w e v e r _ R R   , _ ,   w e _ P P I S 2   w e r e _ V B D R   a b l e _ J K   t o _ T O   v a l i d a t e _ V V I   e s t i m a t e s _ N N 2   o f _ I O   r e c u r r e n t _ J J   r e s p i r a t o r y _ J J   p a p i l l o m a t o s i s _ N N 1   a n d _ C C   f r e q u e n c y _ N N 1   o f _ I O   u s e _ N N 1   o f _ I O   C o b l a - t i o n _ N N 1   o b t a i n e d _ V V N   f r o m _ I I   o u r _ A P P G E   s u r v e y _ N N 1   u s i n g _ V V G   H o s p i t a l _ N N 1   E p i s o d e _ N N 1   S t a t i s t i c s _ N N   i n p a t i e n t _ N N 1   d a t a _ N N   d u e _ I I 2 1   t o _ I I 2 2   h i g h _ J J   a d m i s s i o n / i n t e r v e n t i o n _ N N 1   r a t e _ N N 1   a s s o c i a t e d _ V V N   w i t h _ I W   t h e _ A T   r e c u r r e n t _ J J   r e s p i r a t o r y _ J J   p a p i l l o m a t o s i s _ N N 1   c o n d i t i o n _ N N 1   . _ .   
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 T h e r e f o r e _ R R   , _ ,   a _ A T 1   b r e a k _ N N 1   o f _ I O   a t _ R R 2 1   l e a s t _ R R 2 2   4 _ M C   w e e k s _ N N T 2   w a s _ V B D Z   c o m p l e t e d _ V V N   a f t e r _ I I   e v a l u a t i o n _ N N 1   o f _ I O   S R s _ N P 1   t o _ T O   a v o i d _ V V I   r e c a l l _ N N 1   b i a s _ N N 1   f o r _ I F   t h e _ A T   a s s e s s m e n t _ N N 1   o f _ I O   F T _ N N U   r e p o r t s _ N N 2   . _ .   
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 I n _ I I   t h a t _ D D 1   r e t r o s p e c t i v e _ J J   , _ ,   s i n g l e - c e n t e r _ J J   s t u d y _ N N 1   o n _ I I   1 1 2 9 _ M C   p a t i e n t s _ N N 2   w h o _ P N Q S   u n d e r w e n t _ V V D   l u n g _ N N 1   r e s e c t i o n _ N N 1   s u r g e r y _ N N 1   , _ ,   m u l t i v a r i a t e _ J J   a n a l y s i s _ N N 1   d e m o n s t r a t e d _ V V D   a n _ A T 1   i n d e p e n d e n t _ J J   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   p o s t o p e r a t i v e _ J J   A K I _ N N 2   a n d _ C C   H E _ P P H S 1   S _ V B Z   u s e _ N N 1   ( _ (   O R _ C C   , _ ,   1 . 5 _ M C   ; _ ;   9 5 % _ N N U   C I _ F O   , _ ,   1 . 1 _ M C   ' _ N U L L   2 . 1 _ M C   ) _ )   a n d _ C C   o p e n _ J J   p r o c e d u r e s _ N N 2   . _ .   
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 I f _ C S   t h i s _ D D 1   i s _ V B Z   t h e _ A T   c a s e _ N N 1   , _ ,   t h e n _ R T   g i v e n _ V V N   t h e _ A T   e a r l y _ J J   o n s e t _ N N 1   o f _ I O   m o s t _ D A T   m e n t a l _ J J   d i s o r d e r s _ N N 2   a n d _ C C   t h e _ A T   s i m i l a r l y _ R R   e a r l y _ J J   e t i o p a t h o g e n e s i s _ N N 1   o f _ I O   m a n y _ D A 2   c h r o n i c _ J J   p h y s i c a l _ J J   c o n d i t i o n s _ N N 2   , _ ,   2 9 _ M C   t r e a t m e n t _ N N 1   o f _ I O   a l l _ D B   m e n t a l _ J J   d i s o r d e r s _ N N 2   s h o u l d _ V M   o p t i m a l l y _ R R   i n c o r p o r a t e _ V V I   a t t e n t i o n _ N N 1   t o _ I I   p h y s i c a l _ J J   h e a l t h _ N N 1   a n d _ C C   h e a l t h _ N N 1   b e h a v i o r s _ N N 2   , _ ,   w i t h _ I W   t h i s _ D D 1   p a r a l l e l _ J J   f o c u s _ N N 1   o n _ I I   p h y s i c a l _ J J   h e a l t h _ N N 1   b e g i n n i n g _ V V G   a s _ R G   e a r l y _ R R   i n _ I I   t h e _ A T   c o u r s e _ N N 1   o f _ I O   t h e _ A T   m e n t a l _ J J   d i s o r d e r _ N N 1   a s _ C S A   p o s s i b l e _ J J   . _ .   
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 I t _ P P H 1   i s _ V B Z   p o s s i b l e _ J J   t h a t _ C S T   s o m e _ D D   o f _ I O   t h e _ A T   c h i l d r e n _ N N 2   w h o _ P N Q S   c o m p l e t e d _ V V D   S t a g e _ N N 1   1 _ M C 1   d i d _ V D D   s o _ R G   n a t u r a l l y _ R R   . _ .   
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 N P C 1 _ F O   l o s s _ N N 1   i m p a i r e d _ V V D   v i s u a l _ J J   f u n c t i o n _ N N 1   a n d _ C C   c a u s e d _ V V D   d e g e n e r a t i o n _ N N 1   o f _ I O   O S _ N P 2   , _ ,   d i s r u p t i o n _ N N 1   o f _ I O   s y n a p t i c _ J J   l a y e r s _ N N 2   , _ ,   a n d _ C C   a c c u m u l a t i o n _ N N 1   o f _ I O   c h o l e s t e r o l _ N N 1   i n _ I I   t h e _ A T   R P E _ N N 1   . _ .   
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 T h e _ A T   e x p r e s s i o n _ N N 1   o f _ I O   D r p 1 _ F O   i n _ I I   t h e _ A T   g p 1 2 0 _ F O   + _ F O   A S - D r p 1 _ J J   g r o u p _ N N 1   w a s _ V B D Z   l o w e r _ J J R   t h a n _ C S N   t h a t _ D D 1   i n _ I I   t h e _ A T   g p 1 2 0 _ F O   + _ F O   M M - D r p 1 _ J J   g r o u p _ N N 1   ( _ (   P _ Z Z 1   = _ F O   0 . 0 0 0 9 _ M C   , _ ,   1 - w a y _ J J   A N O V A _ N N 1   , _ ,   n _ Z Z 1   = _ F O   4 _ M C   ' _ N U L L   5 _ M C   ; _ ;   F i g . _ N N 1   4 _ M C   ) _ )   . _ .   
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 T h e _ A T   A n t i a l l o d y n i c _ J J   E f f e c t _ N N 1   o f _ I O   I n t r a t h e c a l _ N P 1   R O S _ N P 1   S c a v e n g e r _ N N 1   i n _ I I   R a t s _ N N 2   w i t h _ I W   P e r i n e u r a l _ N P 1   g p 1 2 0 _ F O   N e u r o p a t h i c _ J J   P a i n _ N N 1   P r e v i o u s _ J J   e v i d e n c e _ N N 1   s h o w s _ V V Z   t h a t _ C S T   s p i n a l _ J J   R O S _ N P 1   s c a v e n g e r _ N N 1   , _ ,   P B N _ N P 1   , _ ,   r e d u c e s _ V V Z   c h r o n i c _ J J   p a i n _ N N 1   i n _ I I   a n i m a l s _ N N 2   . _ .   
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 F i n a l l y _ R R   , _ ,   t h e _ A T   c u r r e n t _ J J   s t u d y _ N N 1   f o c u s e d _ V V N   o n _ I I   a d u l t s _ N N 2   , _ ,   w h o _ P N Q S   m a y _ V M   h a v e _ V H I   a _ A T 1   l o n g _ J J   h i s t o r y _ N N 1   o f _ I O   a n t i c i p a t i o n _ N N 1   o f _ I O   s t u t t e r i n g _ V V G   w h i c h _ D D Q   m a y _ V M   h a v e _ V H I   c h a n g e d _ V V N   a n d _ C C   e v o l v e d _ V V N   t h r o u g h o u t _ I I   t h e _ A T   p r o g r e s s i o n _ N N 1   o f _ I O   s t u t t e r i n g _ V V G   . _ .   
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 T h e _ A T   s u g g e s t e d _ J J   m a i n t e n a n c e _ N N 1   r a t e _ N N 1   i s _ V B Z   0 . 2 5 _ M C   m L / k g _ N N U   p e r _ I I   m i n u t e _ N N T 1   , _ ,   w h i c h _ D D Q   e q u a l s _ V V Z   1 0 5 0 _ M C   m L _ N N U   p e r _ I I   h o u r _ N N T 1   f o r _ I F   a _ A T 1   7 0 - k g _ J J   p a t i e n t _ N N 1   , _ ,   w i t h _ I W   s u b s e q u e n t _ J J   d i r e c t i v e _ N N 1   t o _ T O   d o u b l e _ V V I   t h e _ A T   m a i n t e n a n c e _ N N 1   ( _ (   g r e a t e r _ J J R   t h a n _ C S N   2 0 0 0 _ M C   m L / h _ F U   ) _ )   a s _ C S A   n e e d e d _ V V N   . _ .   
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 H o w e v e r _ R R   , _ ,   o n e _ M C 1   o f _ I O   t h e _ A T   d i f f i c u l t i e s _ N N 2   i n _ I I   d e s c r i b i n g _ V V G   t h e _ A T   r e l e v a n c e _ N N 1   o f _ I O   t h e _ A T   d i f f e r e n t _ J J   c o n s t r a i n t s _ N N 2   o n _ I I   R A E s _ N P 2   i s _ V B Z   t h e _ A T   o b v i o u s _ J J   i n t e r a c t i o n _ N N 1   b e t w e e n _ I I   t h e _ A T   d i f f e r e n t _ J J   c o n s t r a i n t s _ N N 2   . _ .   
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 H g _ F O   f r o m _ I I   b a s e l i n e _ N N 1   w a s _ V B D Z   t h e _ A T   r e s p i r a t o r y _ J J   d e p r e s s i o n _ N N 1   c r i t e r i o n _ N N 1   a s s o c i a t e d _ V V N   w i t h _ I W   t h e _ A T   l a r g e s t _ J J T   r e l a t i v e _ J J   d r o p _ N N 1   i n _ I I   S t O 2 _ F O   ( _ (   1 7 . 1 % _ F O   ) _ )   . _ .   
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 F i n a l l y _ R R   , _ ,   a s _ C S A   a _ A T 1   s t a n d a r d _ N N 1   o f _ I O   c a r e _ N N 1   f o r _ I F   n o n - c a n c e r _ J J   S C S _ N P 1   , _ ,   a l l _ D B   s u b j e c t s _ N N 2   h a d _ V H D   a _ A T 1   p s y c h o l o g i c a l _ J J   e v a l u a t i o n _ N N 1   t o _ T O   d e t e r m i n e _ V V I   e l i g i b i l i t y _ N N 1   p r i o r _ I I 2 1   t o _ I I 2 2   e n r o l l m e n t _ N N 1   . _ .   
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 A l l _ D B   p a r t i c i p a n t s _ N N 2   p r o v i d e d _ C S   w r i t t e n _ V V N   i n f o r m e d _ J J   c o n s e n t _ N N 1   . _ .   
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 S e v e r a l _ D A 2   d i f f e r e n t _ J J   g e n e t i c a l l y _ R R   e n g i n e e r e d _ J J   m o u s e _ N N 1   m u t a n t s _ N N 2   h a v e _ V H 0   b e e n _ V B N   r e p o r t e d _ V V N   t o _ T O   i n c r e a s e _ V V I   t h e _ A T   f r e q u e n c y _ N N 1   o f _ I O   a r t e r i o v e n o u s _ J J   c r o s s i n g s _ N N 2   i n _ I I   t h e _ A T   r e t i n a _ N N 1   , _ ,   i n c l u d i n g _ I I   s o m e _ D D   a f f e c t i n g _ V V G   N R P 1 _ F O   ( _ (   s e e _ V V 0   s e c t i o n _ N N 1   4 . 4 . 1 _ M C   ) _ )   . _ .   
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 T h e r e _ E X   w a s _ V B D Z   n o _ A T   d i f f e r e n c e _ N N 1   o n _ I I   o t h e r _ J J   c o v a r i a t e s _ N N 2   i n c l u d i n g _ I I   s p e c i m e n _ N N 1   w e i g h t _ N N 1   a n d _ C C   a d h e s i o n _ N N 1   s e v e r i t y _ N N 1   . _ .   
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 I n _ I I   c o n c l u s i o n _ N N 1   , _ ,   o u r _ A P P G E   d a t a _ N N   i n d i c a t e _ V V 0   t h a t _ C S T   a _ A T 1   p r e g n a n c y _ N N 1   a f t e r _ I I   p r i m a r y _ J J   h e r n i a _ N N 1   r e p a i r _ N N 1   i s _ V B Z   a s s o c i a t e d _ V V N   w i t h _ I W   a n _ A T 1   i n c r e a s e d _ J J   r i s k _ N N 1   o f _ I O   h e r n i a _ N N 1   r e c u r r e n c e _ N N 1   r e q u i r i n g _ V V G   r e o p e r a t i o n _ N N 1   . _ .   
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 T h u s _ R R   , _ ,   t h i s _ D D 1   i s _ V B Z   t h e _ A T   f i r s t _ M D   a d e q u a t e l y _ R R   p o w e r e d _ J J   r a n d o m i z e d _ J J   c l i n i c a l _ J J   t r i a l _ N N 1   t o _ T O   t e s t _ V V I   i n _ I I   n o n o b e s e _ N N 1   h u m a n s _ N N 2   t h e _ A T   l o n g - t e r m _ J J   e f f e c t s _ N N 2   o f _ I O   C R _ N P 1   o n _ I I   t h e _ A T   I G F - 1 _ M C 1   a x i s _ N N 1   a n d _ C C   o t h e r _ J J   g r o w t h _ N N 1   f a c t o r s _ N N 2   i m p l i c a t e d _ V V D   i n _ I I   t h e _ A T   p a t h o g e n e s i s _ N N 1   o f _ I O   c a n c e r _ N N 1   . _ .   
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 T h i s _ D D 1   i s _ V B Z   a _ A T 1   r e a s o n a b l e _ J J   w a y _ N N 1   t o _ T O   d e c r e a s e _ V V I   c o s t s _ N N 2   i n _ I I   p a t i e n t s _ N N 2   w h o _ P N Q S   p r e s e n t _ V V 0   f o r _ I F   r o u t i n e _ N N 1   c a n c e r _ N N 1   d e t e c t i o n _ N N 1   u s i n g _ V V G   M R I _ N N 2   a s _ I I   a _ A T 1   c o m p l e m e n t _ N N 1   t o _ I I   b i o p s y _ N N 1   ; _ ;   h o w e v e r _ R R   , _ ,   i n _ I I   p a t i e n t s _ N N 2   w h o _ P N Q S   a r e _ V B R   p o s t p r o s t a t e c t o m y _ N N 1   o r _ C C   p o s t r a d i a t i o n _ N N 1   , _ ,   D C E _ N P 1   M R I _ N P 1   s h o u l d _ V M   b e _ V B I   u s e d _ V V N   , _ ,   b e c a u s e _ C S   i t _ P P H 1   m a y _ V M   b e _ V B I   t h e _ A T   o n l y _ J J   w a y _ N N 1   t o _ T O   d e t e c t _ V V I   r e c u r r e n t _ J J   d i s e a s e _ N N 1   i n _ I I   t h e s e _ D D 2   p a t i e n t s _ N N 2   w i t h _ I W   a l t e r e d _ J J   a n a t o m y _ N N 1   i n _ I I   t h e _ A T   f o r m _ N N 1   o f _ I O   e n h a n c e m e n t _ N N 1   w i t h i n _ I I   s c a r _ N N 1   t i s s u e _ N N 1   . _ .   
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 O u r _ A P P G E   h y p o t h e s i s _ N N 1   w a s _ V B D Z   t h a t _ C S T   t h e _ A T   e x t e n t _ N N 1   a n d _ C C   d e g r e e _ N N 1   o f _ I O   S I _ F W   i n c r e a s e s _ V V Z   w i t h _ I W   s C J D _ N N U   p r o g r e s s i o n _ N N 1   . _ .   
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 T h i s _ D D 1   t i m e _ N N T 1   d i f f e r e n c e _ N N 1   f r o m _ I I   M C _ N N 1   d e t e c t i o n _ N N 1   t o _ T O   r e l a p s e _ V V I   r e a c h e d _ V V N   s t a t i s t i c a l _ J J   s i g n i f i c a n c e _ N N 1   ( _ (   p _ Z Z 1   = _ F O   0 . 0 1 9 1 _ M C   ) _ )   . _ .   
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 W e _ P P I S 2   a l s o _ R R   r e v i e w e d _ V V D   t h e _ A T   r e c o v e r y _ N N 1   d a t a _ N N   f o r _ I F   x e n o n _ N N 1   v e r s u s _ I I   p r o p o f o l _ N N 1   . _ .   
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 S e l f - a s s e s s m e n t _ N N 1   o f _ I O   s k i l l s _ N N 2   a n d _ C C   i d e n t i f i c a t i o n _ N N 1   o f _ I O   s u p p l e m e n t a l _ J J   s e s s i o n s _ N N T 2   ; _ ;   p l a n n i n g _ V V G   f o r _ I F   t h e _ A T   f u t u r e _ N N 1   w i t h _ I W   t h e _ A T   f o l l o w i n g _ J J   s u p p l e m e n t a l _ J J   s e s s i o n s _ N N T 2   : _ :   T a l k i n g _ V V G   w i t h _ I W   y o u r _ A P P G E   t e e n a g e r _ N N 1   T a k i n g _ V V G   c a r e _ N N 1   o f _ I O   y o u / m a r i t a l _ F U   c o m m u n i c a t i o n / g u i l t _ N N 1   , _ ,   g r i e f _ N N 1   , _ ,   a n d _ C C   c a r e g i v e r _ V V 0   S o c i a l _ J J   s k i l l s _ N N 2   A f t e r _ I I   h i g h _ J J   s c h o o l _ N N 1   S i b l i n g _ N N 1   i s s u e s _ N N 2   P a i n _ N N 1   m a n a g e m e n t _ N N 1   S l e e p _ N N 1   s e s s i o n _ N N T 1   M e m o r y _ N N 1   s e s s i o n _ N N T 1   T h e _ A T   8 _ M C   c o r e _ N N 1   s e s s i o n s _ N N T 2   a n d _ C C   a s _ R G   m a n y _ D A 2   a s _ C S A   4 _ M C   s u p p l e m e n t a l _ J J   s e s s i o n s _ N N T 2   p e r _ I I   f a m i l y _ N N 1   w e r e _ V B D R   p r o v i d e d _ V V N   t h r o u g h o u t _ I I   t h e _ A T   6 - m o n t h _ J J   i n t e r v e n t i o n _ N N 1   p e r i o d _ N N 1   . _ .   
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 T h e _ A T   s h o r t _ J J   a n d _ C C   l o n g _ J J   d u r a t i o n _ N N 1   e x e r c i s e _ N N 1   t e s t _ N N 1   t o _ T O   d o c u m e n t _ V V I   c h a n n e l o p a t h y _ N N 1   a s _ C S A   c a u s e _ N N 1   o f _ I O   h y p o k a l e m i a _ N N 1   w a s _ V B D Z   p l a n n e d _ V V N   , _ ,   b u t _ C C B   p a t i e n t _ N N 1   d i d _ V D D   n o t _ X X   g i v e _ V V I   c o n s e n t _ N N 1   f o r _ I F   t h e _ A T   s a m e _ D A   . _ .   
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 A t _ I I   i n i t i a l _ J J   v i s i t _ N N 1   , _ ,   t h e _ A T   f o l l o w i n g _ J J   v a r i a b l e s _ N N 2   w e r e _ V B D R   c o l l e c t e d _ V V N   : _ :   d e m o g r a p h i c _ J J   d e t a i l s _ N N 2   , _ ,   s y m p t o m _ N N 1   d u r a t i o n _ N N 1   , _ ,   s i t e _ N N 1   o f _ I O   o n s e t _ N N 1   , _ ,   p h e n o t y p e _ N N 1   , _ ,   r i l u z o l e _ N N 1   u s e _ N N 1   a n d _ C C   A m y o t r o p h i c _ J J   L a t e r a l _ J J   S c l e r o s i s _ N N 1   F u n c t i o n a l _ J J   R a t i n g _ N N 1   S c a l e - R e v i s e d _ N N 1   ( _ (   A L S F R S - R _ N P 1   ) _ )   s c o r e s _ N N 2   . _ .   
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 T h e _ A T   m o s t _ R G T   c o m m o n _ J J   o t h e r _ J J   d i a g n o s e s _ N N 2   i n _ I I   t h e _ A T   r u l e - i n _ N N 1   z o n e _ N N 1   w e r e _ V B D R   m y o c a r d i t i s _ N N 1   ( _ (   n = 4 _ F O   ) _ )   , _ ,   u n s t a b l e _ J J   a n g i n a _ N N 1   ( _ (   n = 4 _ F O   ) _ )   , _ ,   t a k o t s u b o _ N N 1   c a r d i o m y o p a t h y _ N N 1   ( _ (   n = 3 _ F O   ) _ )   , _ ,   h e a r t _ N N 1   f a i l u r e _ N N 1   ( _ (   n = 3 _ F O   ) _ )   , _ ,   a r r h y t h m i a _ N N 1   ( _ (   n = 3 _ F O   ) _ )   , _ ,   a n d _ C C   s y m p t o m s _ N N 2   o f _ I O   u n k n o w n _ J J   o r i g i n _ N N 1   ( _ (   n = 1 6 _ F O   ) _ )   . _ .   
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 P a r t i c i p a n t s _ N N 2   w e r e _ V B D R   e x c l u d e d _ V V N   i f _ C S   t h e y _ P P H S 2   h a d _ V H D   a _ A T 1   t e m p e r a t u r e _ N N 1   g r e a t e r _ J J R   t h a n _ C S N   3 8 _ M C   . _ .   
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 F _ Z Z 1   ) _ )   , _ ,   a n _ A T 1   e s t i m a t e d _ J J   g l o m e r u l a r _ J J   f i l t r a t i o n _ N N 1   r a t e _ N N 1   l e s s _ D A R   t h a n _ C S N   6 0 _ M C   m L / m i n u t e _ F U   p e r _ I I   1 . 7 3 _ M C   m 2 _ F O   , _ ,   a _ A T 1   c a l c u l u s _ N N 1   g r e a t e r _ J J R   t h a n _ C S N   1 0 _ M C   m m _ N N U   , _ ,   s o l i t a r y _ J J   k i d n e y _ N N 1   , _ ,   t r a n s p l a n t e d _ V V D   k i d n e y _ N N 1   , _ ,   h i s t o r y _ N N 1   o f _ I O   u r e t e r a l _ J J   s t r i c t u r e _ N N 1   , _ ,   k n o w n _ V V N   a l l e r g i c _ J J   r e a c t i o n _ N N 1   t o _ I I   t h e _ A T   s t u d y _ N N 1   m e d i c a t i o n _ N N 1   , _ ,   o r _ C C   c u r r e n t _ J J   c a l c i u m _ N N 1   c h a n n e l _ N N 1   b l o c k e r _ N N 1   o r _ C C   a - b l o c k e r _ N N 1   u s e _ N N 1   o r _ C C   h y p o t e n s i o n _ N N 1   ( _ (   s y s t o l i c _ J J   b l o o d _ N N 1   p r e s s u r e _ N N 1   l e s s _ D A R   t h a n _ C S N   1 0 0 _ M C   m m _ N N U   H g _ F O   ) _ )   , _ ,   o r _ C C   i f _ C S   t h e y _ P P H S 2   w e r e _ V B D R   p r e g n a n t _ J J   o r _ C C   p l a n n i n g _ V V G   p r e g n a n c y _ N N 1   . _ .   
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 C o l l e c t i v e l y _ R R   , _ ,   t h e s e _ D D 2   e n c o u r a g i n g _ J J   n e w _ J J   f i n d i n g s _ N N 2   a c c e n t u a t e _ V V 0   a n _ A T 1   i m p o r t a n t _ J J   r o l e _ N N 1   o f _ I O   E R _ N P 1   s t r e s s _ N N 1   a n d _ C C   t h e _ A T   U P R _ N N 1   i n _ I I   g o v e r n i n g _ V V G   t h e _ A T   l o n g e v i t y _ N N 1   a n d _ C C   f u n c t i o n _ N N 1   o f _ I O   h e m a t o p o i e t i c _ J J   p r o g e n i t o r / s t e m _ N N 1   c e l l s _ N N 2   . _ .   
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 U s i n g _ V V G   t h i s _ D D 1   m o d e l _ N N 1   , _ ,   t h e _ A T   p r e d i c t e d _ J J   r i s k _ N N 1   o f _ I O   c o n v e r s i o n _ N N 1   t o _ I I   l a p a r o t o m y _ N N 1   w i t h _ I W   t r a d i t i o n a l _ J J   l a p a r o s c o p y _ N N 1   c o m p a r e d _ V V N   w i t h _ I W   r o b o t i c - a s s i s t e d _ J J   l a p a r o s c o p y _ N N 1   w a s _ V B D Z   5 . 4 % _ F O   c o m p a r e d _ V V N   w i t h _ I W   0 . 8 % _ F O   ( _ (   P _ N N U   l e s s _ D A R   t h a n _ C S N   . 0 0 1 _ M C   ) _ )   a f t e r _ I I   a d j u s t i n g _ V V G   f o r _ I F   a l l _ D B   o t h e r _ J J   v a r i a b l e s _ N N 2   i n _ I I   t h e _ A T   m o d e l _ N N 1   . _ .   
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 W e _ P P I S 2   w e r e _ V B D R   a l s o _ R R   i n t r i g u e d _ V V N   b y _ I I   t h e _ A T   v e r y _ J J   r a p i d _ J J   D i M _ J J   i n _ I I   c e l l s _ N N 2   l a c k i n g _ V V G   B c l - x L _ J J   a n d _ C C   M c l 1 _ F O   ( _ (   F i g u r e _ N N 1   S 3 F _ F O   ) _ )   . _ .   
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 F u n c t i o n a l _ J J   O r a l _ J J   I n t a k e _ N N 1   S c a l e _ N N 1   ( _ (   F O I S _ N P 1   ) _ )   s c o r e s _ N N 2   a n d _ C C   p e r c u t a n e o u s _ J J   e n d o s c o p i c _ J J   g a s t r o s t o m y _ N N 1   ( _ (   P E G _ N P 1   ) _ )   p l a c e m e n t s _ N N 2   w e r e _ V B D R   c o m p a r e d _ V V N   a t _ I I   p o s t t r e a t m e n t _ N N 1   a n d _ C C   a t _ I I   3 _ M C   m o n t h s _ N N T 2   . _ .   
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 A _ A T 1   t o t a l _ N N 1   o f _ I O   5 5 6 9 _ M C   t h y r o i d _ J J   n o d u l e s _ N N 2   t h a t _ C S T   w e r e _ V B D R   1 0 - 1 9 _ M C M C   m m _ N N U   o n _ I I   U S _ N P 1   i m a g e s _ N N 2   w e r e _ V B D R   a s p i r a t e d _ V V N   . _ .   
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 R e c e n t _ J J   T 2 _ F O   i n t e n s i t y _ N N 1   s t u d i e s _ N N 2   i n v o l v i n g _ V V G   e a r l y _ J J   a n d _ C C   m i l d e r _ J J R   f o r m s _ N N 2   o f _ I O   M S _ N N 1   ( _ (   C e c c a r e l l i _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 9 _ M C   , _ ,   2 0 1 0 _ M C   , _ ,   2 0 1 1 _ M C   ) _ )   h a v e _ V H 0   b e g u n _ V V N   t o _ T O   b r i d g e _ V V I   g a p s _ N N 2   i n _ I I   k n o w l e d g e _ N N 1   r e g a r d i n g _ I I   t h e _ A T   r o l e _ N N 1   o f _ I O   i r o n _ N N 1   d e p o s i t i o n _ N N 1   i n _ I I   t h e _ A T   p a t h o p h y s i o l o g y _ N N 1   o f _ I O   t h e _ A T   d i s e a s e _ N N 1   . _ .   
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 W e _ P P I S 2   h y p o t h e s i z e d _ V V D   t h a t _ C S T   t h e _ A T   r e a s o n _ N N 1   f o r _ I F   t h e _ A T   r e s t o r a t i o n _ N N 1   s e e n _ V V N   i n _ I I   m i R - 7 _ M C   i n h i b i t o r y _ J J   e x p e r i m e n t s _ N N 2   w a s _ V B D Z   d u e _ I I 2 1   t o _ I I 2 2   a n _ A T 1   u p r e g u l a t e d _ J J   t h e _ A T   p r e s e n c e _ N N 1   o f _ I O   H A S 2 - p r o d u c e d _ N N 1   H A _ U H   . _ .   
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 O v e r _ I I   t h e _ A T   l a s t _ M D   1 0 _ M C   y e a r s _ N N T 2   w e _ P P I S 2   h a v e _ V H 0   s e e n _ V V N   a n d _ C C   t r e a t e d _ V V N   s e v e n _ M C   p a t i e n t s _ N N 2   w i t h _ I W   m e s h _ N N 1   e r o s i o n s _ N N 2   i n t o _ I I   t h e _ A T   b l a d d e r _ N N 1   w i t h _ I W   p a r t i a l _ J J   r e m o v a l _ N N 1   o f _ I O   t h e _ A T   m e s h _ N N 1   v i a _ I I   a _ A T 1   t r a n s v e s i c a l _ J J   l a p a r o s c o p i c _ J J   a p p r o a c h _ N N 1   . _ .   
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 C o m p a r i s o n s _ N N 2   i n _ I I   e l i g i b l e _ J J   s t u d i e s _ N N 2   w e r e _ V B D R   b e t w e e n _ I I   t h e _ A T   i n t e r v e n t i o n _ N N 1   g r o u p _ N N 1   a n d _ C C   e i t h e r _ R R   a _ A T 1   u s u a l _ J J   c a r e _ N N 1   o r _ C C   c o n t r o l _ N N 1   g r o u p _ N N 1   , _ ,   a n d _ C C   s t u d i e s _ N N 2   w i t h _ I W   f a c t o r i a l _ J J   d e s i g n s _ N N 2   c o m p a r i n g _ V V G   m o r e _ D A R   t h a n _ C S N   o n e _ M C 1   i n t e r v e n t i o n _ N N 1   w e r e _ V B D R   a l s o _ R R   i n c l u d e d _ V V N   . _ .   
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 A _ A T 1   p a i n _ N N 1   p s y c h o l o g i s t _ N N 1   i s _ V B Z   a _ A T 1   t h e r a p i s t _ N N 1   w i t h _ I W   v e r y _ R G   s p e c i f i c _ J J   t r a i n i n g _ N N 1   a n d _ C C   e x p e r i e n c e _ N N 1   i n _ I I   t h e _ A T   t r e a t m e n t _ N N 1   o f _ I O   p a i n _ N N 1   . _ .   
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 I n h i b i t i o n _ N N 1   o f _ I O   C o m p l e x _ N N 1   I _ P P I S 1   l e a d s _ V V Z   t o _ I I   i n c r e a s e d _ J J   g e n e r a t i o n _ N N 1   o f _ I O   R O S _ N P 1   , _ ,   d e c r e a s e d _ V V D   A T P _ N N 1   l e v e l s _ N N 2   , _ ,   a n d _ C C   i n d u c t i o n _ N N 1   o f _ I O   a p o p t o s i s _ N N 1   ( _ (   L a n g s t o n _ N P 1   a n d _ C C   B a l l a r d _ N P 1   , _ ,   1 9 8 3 _ M C   , _ ,   L i _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 0 3 _ M C   a n d _ C C   R a m s a y _ N P 1   a n d _ C C   S i n g e r _ N P 1   , _ ,   1 9 8 6 _ M C   ) _ )   , _ ,   a l l _ D B   o f _ I O   w h i c h _ D D Q   p l a y _ V V 0   a _ A T 1   m a j o r _ J J   r o l e _ N N 1   i n _ I I   n e u r o d e g e n e r a t i o n _ N N 1   . _ .   
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 A p p l i c a t i o n _ N N 1   o f _ I O   a p p r o p r i a t e _ J J   s e l e c t i o n _ N N 1   c r i t e r i a _ N N 2   w o u l d _ V M   b e _ V B I   r e q u i r e d _ V V N   . _ .   
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 H o w e v e r _ R R   , _ ,   t h e _ A T   a d d i t i o n a l _ J J   a d v a n t a g e s _ N N 2   o f _ I O   W G S _ N P 1   o v e r _ I I   c u r r e n t _ J J   g e n o m i c _ J J   d i a g n o s t i c _ J J   t e c h n o l o g i e s _ N N 2   ( _ (   t a r g e t e d _ V V D   N G S _ N P 1   ) _ )   f o r _ I F   o p h t h a l m i c _ J J   d i s o r d e r s _ N N 2   a r e _ V B R   n o t _ X X   y e t _ R R   f u l l y _ R R   q u a n t i f i e d _ V V N   , _ ,   b e c a u s e _ C S   f o r m a l _ J J   c o m p a r a t i v e _ J J   a n a l y s e s _ N N 2   o f _ I O   t h e _ A T   2 _ M C   t e c h n i q u e s _ N N 2   h a v e _ V H 0   n o t _ X X   b e e n _ V B N   u n d e r t a k e n _ V V N   . _ .   
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 H e n c e _ R R   i n _ I I   I t a l y _ N P 1   t h e _ A T   o v e r a l l _ J J   i n c i d e n c e _ N N 1   r a t e _ N N 1   o f _ I O   A N _ A T 1   i n c l u d i n g _ V V G   l e s s _ R G R   s e v e r e _ J J   f o r m s _ N N 2   m i g h t _ V M   b e _ V B I   h i g h e r _ J J R   . _ .   
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 T w o _ M C   r e p r e s e n t a t i v e _ J J   c a s e s _ N N 2   w i t h _ I W   h i g h _ J J   a n d _ C C   l o w _ J J   s t a i n i n g _ J J   i n t e n s i t y _ N N 1   o f _ I O   S Y K _ N P 1   , _ ,   p h o s p h o - S Y K _ N P 1   , _ ,   a n d _ C C   p h o s p h o - a - t u b u l i n _ N N 1   a r e _ V B R   s h o w n _ V V N   i n _ I I   F i g u r e _ N N 1   5 H . E x p r e s s i o n _ F O   o f _ I O   A c t i v e _ J J   S Y K _ N N 1   C o n f e r s _ V V Z   P a c l i t a x e l _ N P 1   R e s i s t a n c e _ N N 1   a n d _ C C   I n c r e a s e s _ V V Z   M A P 1 B _ F O   a n d _ C C   M A P 4 _ F O   T y r o s i n e _ N P 1   P h o s p h o r y l a t i o n _ N N 1   T o _ T O   d e m o n s t r a t e _ V V I   w h e t h e r _ C S W   a c t i v a t i n g _ V V G   t h e _ A T   S Y K _ N N 1   p a t h w a y _ N N 1   i s _ V B Z   s u f f i c i e n t _ J J   t o _ T O   c o n f e r _ V V I   p a c l i t a x e l _ N N 1   r e s i s t a n c e _ N N 1   , _ ,   w e _ P P I S 2   g e n e r a t e d _ V V D   t e t r a c y c l i n e - i n d u c - i b l e _ J J   S K O V 3 _ F O   c e l l s _ N N 2   t o _ T O   e c t o p i c a l l y _ R R   e x p r e s s _ V V I   w i l d - t y p e _ J J   o r _ C C   a c t i v e _ J J   S Y K _ N N 1   m u t a n t _ N N 1   ( _ (   S Y K - 1 3 0 E _ F O   ) _ )   , _ ,   w h i c h _ D D Q   h a s _ V H Z   b e e n _ V B N   s h o w n _ V V N   t o _ T O   h a v e _ V H I   a _ A T 1   h i g h _ J J   b a s a l _ J J   k i n a s e _ N N 1   a c t i v i t y _ N N 1   ( _ (   K e s h v a r a _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 9 9 7 _ M C   ) _ )   . _ .   
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 A _ A T 1   w e a k n e s s _ N N 1   c o n c e r n i n g _ I I   t h e _ A T   d o s e - r e s p o n s e _ J J   a n a l y s i s _ N N 1   o f _ I O   e x c i s e d _ J J   t i s s u e _ N N 1   w a s _ V B D Z   t h a t _ D D 1   c o n e _ N N 1   s i z e _ N N 1   i n f o r m a t i o n _ N N 1   w a s _ V B D Z   o n l y _ R R   a v a i l a b l e _ J J   f o r _ I F   3 7 % _ N N U   o f _ I O   t r e a t m e n t s _ N N 2   , _ ,   a n d _ C C   w e _ P P I S 2   d i d _ V D D   n o t _ X X   h a v e _ V H I   i n f o r m a t i o n _ N N 1   o n _ I I   t h e _ A T   p o s s i b l y _ R R   m o r e _ R G R   d e s c r i p t i v e _ J J   m e a s u r e _ N N 1   o f _ I O   e x c i s i o n _ N N 1   d e p t h _ N N 1   a n d _ C C   l e n g t h _ N N 1   . _ .   
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 T h e r e b y _ R R   , _ ,   t h e _ A T   h s - c T n T _ J J   0 - h o u r / 1 - h o u r _ J J   a l g o r i t h m _ N N 1   s e e m e d _ V V D   t o _ T O   b e _ V B I   e v e n _ R R   m o r e _ R G R   c o m p l e t e _ J J   a n d _ C C   m o r e _ R G R   e f f e c t i v e _ J J   i n _ I I   t h e _ A T   e a r l y _ J J   t r i a g e _ N N 1   o f _ I O   a c u t e _ J J   c h e s t _ N N 1   p a i n _ N N 1   p a t i e n t s _ N N 2   t h a n _ C S N   o t h e r _ J J   i m p o r t a n t _ J J   e m e r g i n g _ J J   e a r l y _ J J   t r i a g e _ N N 1   s t r a t e g i e s _ N N 2   i n _ I I   s i m i l a r _ J J   s t u d y _ N N 1   p o p u l a t i o n s _ N N 2   . _ .   
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 N e g a t i v e _ J J   v a l e n c e _ N N 1   e m o t i o n a l _ J J   a u d i t o r y _ J J   s t i m u l i _ N N 2   l e d _ V V N   t o _ I I   h i g h e r _ J J R   t i n n i t u s _ J J   l o u d n e s s _ N N 1   r a t i n g s _ N N 2   i n _ I I   m a l e s _ N N 2   a n d _ C C   f e m a l e s _ N N 2   a n d _ C C   h i g h e r _ J J R   a n n o y a n c e _ N N 1   r a t i n g s _ N N 2   i n _ I I   m a l e s _ N N 2   o n l y _ R R   ; _ ;   l o u d n e s s _ N N 1   m a t c h e s _ N N 2   o f _ I O   t i n n i t u s _ N N 1   r e m a i n e d _ V V D   u n c h a n g e d _ J J   . _ .   
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 T h e _ A T   t e m p o r a l _ J J   i n c r e a s e _ N N 1   i n _ I I   e a r l y - o n s e t _ J J   d i s e a s e _ N N 1   i s _ V B Z   a l s o _ R R   c o n s i s t e n t _ J J   w i t h _ I W   t h e _ A T   t e m p o r a l _ J J   i n c r e a s e _ N N 1   i n _ I I   c h r o n i c _ J J   h y p e r t e n s i o n _ N N 1   a m o n g _ I I   p r e g n a n t _ J J   w o m e n _ N N 2   , _ ,   w h i c h _ D D Q   i s _ V B Z   m o r e _ R G R   s t r o n g l y _ R R   a s s o c i a t e d _ V V N   w i t h _ I W   e a r l y - o n s e t _ N N 1   a s _ I I 3 1   o p p o s e d _ I I 3 2   t o _ I I 3 3   l a t e - o n s e t _ J J   d i s e a s e _ N N 1   . _ .   
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 T h i s _ D D 1   r o l e _ N N 1   t h a t _ C S T   w e _ P P I S 2   o b s e r v e d _ V V D   f o r _ I F   D C E _ N P 1   i n _ I I   t h e _ A T   T Z _ N P 1   m a y _ V M   r e l a t e _ V V I   t o _ I I   o u r _ A P P G E   i n c o r p o r a t i o n _ N N 1   o f _ I O   m o r p h o l o g i c _ J J   c r i t e r i a _ N N 2   f o r _ I F   a s s e s s i n g _ V V G   D C E _ N P 1   i n _ I I   t h e _ A T   T Z _ N P 1   l e s i o n _ N N 1   t h a t _ C S T   a r e _ V B R   n o t _ X X   a _ A T 1   c o m p o n e n t _ N N 1   o f _ I O   P I - R A D S V 2 _ N N 1   . _ .   
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 C a s e _ N N 1   f a m i l i e s _ N N 2   w e r e _ V B D R   a s k e d _ V V N   t o _ T O   n o m i n a t e _ V V I   1 _ M C 1   o r _ C C   m o r e _ D A R   f r i e n d s _ N N 2   o r _ C C   n o n b i o l o g i c a l _ J J   r e l a t i v e s _ N N 2   w i t h _ I W   a _ A T 1   c h i l d _ N N 1   i n _ I I   t h e _ A T   s a m e _ D A   a g e _ N N 1   r a n g e _ N N 1   a s _ C S A   t h e _ A T   i n d e x _ N N 1   c h i l d _ N N 1   ( _ (   0 - 1 _ M C M C   , _ ,   2 - 3 _ M C M C   , _ ,   4 - 5 _ M C M C   , _ ,   6 - 7 _ M C M C   , _ ,   8 - 9 _ M C M C   , _ ,   1 0 - 1 1 _ M C M C   , _ ,   1 2 - 1 3 _ M C M C   , _ ,   o r _ C C   1 4 - 1 5 _ M C M C   y e a r s _ N N T 2   ) _ )   a s _ C S A   p o t e n t i a l _ J J   c o n t r o l s _ N N 2   . _ .   
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 A l t h o u g h _ C S   x - r a y _ J J   m a m m o g r a p h y _ N N 1   i s _ V B Z   w e l l _ R R   e s t a b l i s h e d _ V V N   i n _ I I   b o t h _ D B 2   c u r a t i v e _ J J   m a m m o g r a p h y _ N N 1   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   i n _ I I   x - r a y _ J J   m a m m o g r a p h y _ N N 1   s c r e e n i n g _ N N 1   , _ ,   i t _ P P H 1   h a s _ V H Z   k n o w n _ V V N   d i a g n o s t i c a l _ J J   l i m i t a t i o n s _ N N 2   , _ ,   e s p e c i a l l y _ R R   r e g a r d i n g _ I I   t h e _ A T   s e n s i t i v i t y _ N N 1   o f _ I O   t u m o r _ N N 1   d e t e c t i o n _ N N 1   i n _ I I   d e n s e _ J J   b r e a s t s _ N N 2   . _ .   
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 P r o p o n e n t s _ N N 2   o f _ I O   m a r i j u a n a _ N N 1   s u g g e s t _ V V 0   t h a t _ C S T   i t _ P P H 1   i s _ V B Z   s a f e r _ J J R   t h a n _ C S N   e t h a n o l _ N N 1   . _ .   
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 K e y _ J J   W o r d s _ N N 2   : _ :   a u t o l o g o u s _ J J   c h o n d r o c y t e _ N N 1   i m p l a n t a t i o n _ N N 1   , _ ,   a r t i c u l a r _ J J   c a r t i l a g e _ N N 1   , _ ,   c a r t i l a g e _ N N 1   d e f e c t _ N N 1   , _ ,   r e g e n e r a t i o n _ N N 1   t e c h n i q u e s _ N N 2   F o c a l _ J J   c a r t i l a g e _ N N 1   d e f e c t s _ N N 2   o f _ I O   t h e _ A T   k n e e _ N N 1   a r e _ V B R   r e l a t i v e l y _ R R   c o m m o n _ J J   a n d _ C C   m a y _ V M   i n c r e a s e _ V V I   t h e _ A T   r i s k _ N N 1   o f _ I O   d e v e l o p i n g _ J J   o s t e o a r t h r i t i s _ N N 1   . _ .   
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 T h e s e _ D D 2   y i e l d e d _ V V N   s i m i l a r _ J J   r e s u l t s _ N N 2   , _ ,   e x c e p t _ I I 2 1   f o r _ I I 2 2   t h e _ A T   E Q - 5 D _ J J   t h e r m o m e t e r _ N N 1   i n _ I I   c o g n i t i v e l y _ R R   i m p a i r e d _ V V D   o l d e r _ J J R   p e r s o n s _ N N 2   : _ :   A _ A T 1   c u t - o f f _ N N 1   s c o r e _ V V 0   l e s s _ D A R   t h a n _ C S N   7 0 _ M C   a n d _ C C   e x c l u d i n g _ V V G   m i s s i n g _ J J   v a l u e s _ N N 2   s h o w e d _ V V D   a _ A T 1   l o w e r _ J J R   q u a l i t y _ N N 1   o f _ I O   l i f e _ N N 1   i n _ I I   t h e _ A T   s u b g r o u p _ N N 1   w i t h _ I W   a p a t h y _ N N 1   c o m p a r e d _ V V N   w i t h _ I W   t h e _ A T   s u b g r o u p _ N N 1   w i t h o u t _ I W   a p a t h y _ N N 1   . _ .   
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 T h e _ A T   r a t e _ N N 1   o f _ I O   a d h e r e n c e _ N N 1   t o _ I I   t h e _ A T   m a n u a l _ N N 1   w a s _ V B D Z   9 4 % _ N N U   a s _ C S A   m e a s u r e d _ V V N   b y _ I I   t h e r a p i s t _ N N 1   r e p o r t _ N N 1   a n d _ C C   w a s _ V B D Z   9 3 % _ N N U   a s _ C S A   m e a s u r e d _ V V N   b y _ I I   i n d e p e n d e n t _ J J   a u d i t _ N N 1   . _ .   
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 I n d e e d _ R R   , _ ,   p a t i e n t s _ N N 2   w i t h _ I W   n o d e - n e g a t i v e _ J J   s t a g e _ N N 1   I _ Z Z 1   H E R 2 - p o s i t i v e _ J J   d i s e a s e _ N N 1   c o u l d _ V M   b e _ V B I   t r e a t e d _ V V N   w i t h _ I W   a d j u v a n t _ J J   c h e m o t h e r a p y _ N N 1   c o n t a i n i n g _ V V G   p a c l i t a x e l _ N N 1   a n d _ C C   t r a s t u z u m a b _ V V 0   w i t h o u t _ I W   a n t h r a c y c l i n e _ N N 1   , _ ,   t h a n k s _ N N 2   t o _ I I   a _ A T 1   l o w e r _ J J R   u n d e r l y i n g _ J J   r i s k _ N N 1   o f _ I O   r e c u r r e n c e _ N N 1   t h a n _ C S N   w o m e n _ N N 2   w i t h _ I W   m o r e _ R G R   a d v a n c e d _ J J   s t a g e _ N N 1   o f _ I O   d i s e a s e _ N N 1   & l s q b ; _ (   8 5 _ M C   & r s q b ; _ )   . _ .   
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 O u r _ A P P G E   b e h a v i o r a l _ J J   t e s t s _ N N 2   r e v e a l e d _ V V D   t h a t _ C S T   t h e _ A T   m e c h a n i c a l _ J J   P W T _ N P 1   v a l u e s _ N N 2   o f _ I O   R - t r e a t e d _ J J   a n i m a l s _ N N 2   a t _ I I   0 . 5 _ M C   a n d _ C C   2 _ M C   h o u r s _ N N T 2   p o s t i n f u s i o n _ N N 1   w e r e _ V B D R   s i g n i f i c a n t l y _ R R   l o w e r _ J J R   t h a n _ C S N   t h e _ A T   b a s a l _ J J   l e v e l _ N N 1   a n d _ C C   w e r e _ V B D R   c l e a r l y _ R R   l o w e r _ J J R   t h a n _ C S N   t h e _ A T   c o r r e s p o n d i n g _ J J   l e v e l s _ N N 2   i n _ I I   t h e _ A T   L _ Z Z 1   a n d _ C C   R L _ N P 1   g r o u p s _ N N 2   . _ .   
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 P u l m o n a r y _ J J   e m b o l i s m _ N N 1   a n d _ C C   v e n o u s _ J J   t h r o m b o s i s _ N N 1   a r e _ V B R   i n c i d e n t a l _ J J   f i n d i n g s _ N N 2   i n _ I I   u p _ R G 2 1   t o _ R G 2 2   2 6 % _ N N U   o f _ I O   o n c o l o g i c _ J J   p a t i e n t s _ N N 2   u n d e r g o i n g _ V V G   i m a g i n g _ V V G   s u r - v e i l l a n c e . 7 _ J J   A s _ C S A   C T _ N N 1   p r o t o c o l s _ N N 2   i n _ I I   s u c h _ D A   p a t i e n t s _ N N 2   a r e _ V B R   o p t i m i z e d _ J J   f o r t h e _ N N 1   d e t e c t i o n _ N N 1   a n d _ C C   m o n i t o r i n g _ N N 1   o f _ I O   n e o p l a s t i c _ J J   d i s e a s e s _ N N 2   , _ ,   t h e y _ P P H S 2   a r e _ V B R   o f t e n _ R R   s u b o p t i m a l _ J J   f o r _ I F   d e t e c t i n g _ V V G   p u l m o n a r y _ J J   e m b o l i s m _ N N 1   o r _ C C   d e e p _ R R   v e n o u s _ J J   t h r o m b o s i s _ N N 1   . _ .   
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 U n i v e r s a l l y _ R R   d i r e c t i n g _ V V G   a l l _ D B   i n j u r e d _ J J   p a t i e n t s _ N N 2   t o _ I I   n o n t r a u m a _ N N 1   h o s p i t a l s _ N N 2   r i s k s _ V V Z   l i m i t i n g _ J J   a c c e s s _ N N 1   t o _ I I   m a j o r _ J J   t r a u m a _ N N 1   c e n t e r s _ N N 2   f o r _ I F   t h o s e _ D D 2   m o s t _ R R T   l i k e l y _ J J   t o _ T O   b e n e f i t _ V V I   f r o m _ I I   s u c h _ D A   c a r e _ N N 1   . _ .   
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 F o l l o w i n g _ V V G   s e l e c t i o n _ N N 1   o f _ I O   o p e r a t i v e _ J J   c a s e s _ N N 2   i n _ I I   a d u l t s _ N N 2   w i t h i n _ I I   4 8 _ M C   ? _ ?   h o u r s _ N N T 2   , _ ,   w h e r e _ C S   p u p i l _ N N 1   r e a c t i v i t y _ N N 1   d a t a _ N N   w e r e _ V B D R   m i s s i n g _ V V G   b u t _ C C B   G C S _ N P 1   w a s _ V B D Z   1 4 _ M C   o r _ C C   1 5 _ M C   , _ ,   w e _ P P I S 2   a s s u m e d _ V V D   t h a t _ C S T   n o _ A T   s i g n i f i c a n t _ J J   b r a i n s t e m _ N N 1   c o m p r e s s i o n / u n c a l _ N N 1   h e r n i a t i o n _ N N 1   w o u l d _ V M   e x i s t _ V V I   a n d _ C C   p u p i l s _ N N 2   w e r e _ V B D R   c o n s i d e r e d _ V V N   t o _ T O   b e _ V B I   b o t h _ R R   r e a c t i v e _ J J   . _ .   
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 A l b e i t _ C S   t h e _ A T   u n d e n i a b l e _ J J   i m p o r t a n c e _ N N 1   o f _ I O   a _ A T 1   s t u d y _ N N 1   r e p o r t i n g _ V V G   t h a t _ D D 1   n u t r i t i o n a l _ J J   i n t a k e _ N N 1   c a n _ V M   m o d i f y _ V V I   t h e _ A T   r a t e _ N N 1   o f _ I O   d e c l i n e _ N N 1   o f _ I O   v i s u a l _ J J   a c u i t y _ N N 1   i n _ I I   R P _ N P 1   , _ ,   t h e _ A T   A u t h o r s _ N N 2   t h e m s e l v e s _ P P X 2   e x p r e s s _ V V 0   c a u t i o n _ N N 1   i n _ I I   e v a l u a t i n g _ V V G   t h e _ A T   r e s u l t s _ N N 2   o b t a i n e d _ V V N   . _ .   
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 S o m e _ D D   r e s t o r a t i o n _ N N 1   o f _ I O   t h e _ A T   E Z _ N N 1   l i n e _ N N 1   c a n _ V M   o c c u r _ V V I   i n _ I I   o t h e r _ J J   r e t i n a l d i s o r d e r s _ N N 2   , _ ,   1 4 , 1 5 _ M C   b u t _ C C B   m o r e _ D A R   h y d r o x y c h l o r o q u i n e _ N N 1   c a s e s _ N N 2   n e e d _ V V 0   t o _ T O   b e _ V B I   m o n i t o r e d _ V V N   w i t h _ I W   r e p e t i t i v e _ J J   s t u d i e s _ N N 2   t o _ T O   v e r i f y _ V V I   t h e _ A T   p o t e n t i a l _ N N 1   f o r _ I F   r e c o v e r y _ N N 1   . _ .   
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 I d e n t i f i c a t i o n _ N N 1   o f _ I O   c o m p o u n d s _ N N 2   t h a t _ C S T   i n t e r a c t _ V V 0   s p e c i f i c a l l y _ R R   w i t h _ I W   S C _ F O   c e l l s _ N N 2   a n d _ C C   d e c r e a s e _ V V 0   o u t f l o w _ N N 1   r e s i s t a n c e _ N N 1   w i l l _ V M   a l s o _ R R   g i v e _ V V I   i m p o r t a n t _ J J   i n s i g h t s _ N N 2   i n t o _ I I   c e l l u l a r _ J J   c o n t r o l _ N N 1   o f _ I O   a q u e o u s _ J J   o u t f l o w _ N N 1   a n d _ C C   a i d _ N N 1   i n _ I I   t h e _ A T   u n d e r s t a n d i n g _ N N 1   o f _ I O   i t s _ A P P G E   d y s f u n c t i o n _ N N 1   i n _ I I   g l a u c o m a _ N N 1   . _ .   
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 T h e _ A T   r e m a i n i n g _ J J   p a r t i c i p a n t _ N N 1   , _ ,   w h o _ P N Q S   p r e s e n t e d _ V V D   w i t h _ I W   s e v e r e _ J J   s t u t t e r i n g _ N N 1   , _ ,   c o m p l e t e d _ V V D   S t a g e _ N N 1   1 _ M C 1   b u t _ C C B   h a d _ V H D   s o m e _ D D   r e l a p s e _ N N 1   i n _ I I   S t a g e _ N N 1   2 _ M C   a n d _ C C   d e m o n s t r a t e d _ V V D   m i l d _ J J   s t u t t e r i n g _ V V G   1 2 _ M C   m o n t h s _ N N T 2   p o s t - S t a g e _ N N 1   1 _ M C 1   . _ .   
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 L E M D 1 _ F O   i s _ V B Z   o v e r e x p r e s s e d _ V V N   i n _ I I   p r o s t a t e _ N N 1   c a n c e r _ N N 1   ( _ (   G h a f o u r i - F a r d _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 0 _ M C   ) _ )   a n d _ C C   a n a p l a s t i c _ J J   c e l l _ N N 1   l y m p h o m a _ N N 1   ( _ (   M a t s u y a m a _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 1 _ M C   ) _ )   . _ .   
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 T h e _ A T   d e f i n i t i o n _ N N 1   o f _ I O   o p e n - a n g l e _ J J   g l a u c o m a _ N N 1   ' _ N U L L   t h e _ A T   m o s t _ R G T   c o m m o n _ J J   f o r m _ N N 1   o f _ I O   t h e _ A T   n e u r o p a t h y _ N N 1   ' _ N U L L   i s _ V B Z   d e g e n e r a t i o n _ N N 1   a n d _ C C   l o s s _ N N 1   o f _ I O   r e t i n a l _ J J   g a n g l i o n _ N N 1   c e l l s _ N N 2   ( _ (   R G C s _ N P 1   ) _ )   a n d _ C C   t h e i r _ A P P G E   a x o n s _ N N 2   w i t h _ I W   c h a r a c t e r i s t i c _ J J   c h a n g e s _ N N 2   i n _ I I   t h e _ A T   o p t i c _ N N 1   n e r v e _ N N 1   h e a d _ N N 1   a n d _ C C   t h e _ A T   v i s u a l _ J J   f i e l d _ N N 1   ( _ (   K e r r i g a n - B a u m r i n d _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   ' _ N U L L   
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 T h e _ A T   l a r g e r _ J J R   c u r r e n t _ N N 1   e v o k e d _ V V N   b y _ I I   e t o m i d a t e _ N N 1   p l u s _ I I   G A B A _ N P 1   i n _ I I   I L - 1 m i u - t r e a t e d _ J J   n e u r o n s _ N N 2   c o u l d _ V M   r e s u l t _ V V I   f r o m _ I I   e i t h e r _ R R   a n _ A T 1   i n c r e a s e _ N N 1   i n _ I I   t h e _ A T   n u m b e r _ N N 1   o f _ I O   G A B A A _ N N 1   r e c e p t o r s _ N N 2   o r _ C C   a n _ A T 1   i n c r e a s e _ N N 1   i n _ I I   t h e _ A T   p h a r m a c o l o g i c a l _ J J   s e n s i t i v i t y _ N N 1   o f _ I O   t h e _ A T   r e c e p t o r s _ N N 2   . _ .   
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 I n _ I I   c o n t r a s t _ N N 1   , _ ,   c r i t i c a l _ J J   a c c e s s _ N N 1   h o s p i t a l s _ N N 2   h a d _ V H D   h i g h e r _ J J R   r a t e s _ N N 2   o f _ I O   r e a d m i s s i o n _ N N 1   w i t h i n _ I I   3 0 _ M C   d a y s _ N N T 2   t h a n _ C S N   n o n _ F U   ' _ N U L L   c r i t i c a l _ J J   a c c e s s _ N N 1   h o s p i t a l s _ N N 2   ( _ (   1 4 . 7 % _ F O   v s _ I I   1 3 . 3 % _ F O   ; _ ;   O R _ C C   , _ ,   1 . 1 3 _ M C   ; _ ;   9 5 % _ N N U   C I _ F O   , _ ,   1 . 0 8 - 1 . 1 8 _ M C M C   ; _ ;   P _ N P 1   l e s s _ D A R   t h a n _ C S N   . 0 0 1 _ M C   ) _ )   . _ .   
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 T o _ T O   f u r t h e r _ R R R   d e t e r m i n e _ V V I   w h e t h e r _ C S W   t h e _ A T   p r e s y n a p t i c _ J J   a n d _ C C   p o s t - s y n a p t i c _ J J   t r a n s m i s s i o n s _ N N 2   w e r e _ V B D R   d e c r e a s e d _ V V N   b y _ I I   M e f l o _ N P 1   , _ ,   p a i r e d - p u l s e _ J J   f a c i l i t a t i o n _ N N 1   ( _ (   P P F _ N P 1   ) _ )   a n d _ C C   i n w a r d _ J J   r e c t i f i c a t i o n _ N N 1   w e r e _ V B D R   e x a m i n e d _ V V N   i n _ I I   A C C _ N P 1   n e u r o n s _ N N 2   i n _ I I   t h e _ A T   c u r r e n t _ J J   s t u d y _ N N 1   . _ .   
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 F u r t h e r _ J J R   d e v e l o p m e n t _ N N 1   o f _ I O   f a m i l y _ N N 1   a n d _ C C   c o m m u n i t y - b a s e d _ J J   i n t e r v e n t i o n s _ N N 2   t h a t _ C S T   c o u l d _ V M   b e t t e r _ R R R   t a r g e t _ V V I   b e h a v i o u r _ N N 1   d u r i n g _ I I   w e e k e n d s _ N N T 2   m a y _ V M   b e _ V B I   e s p e c i a l l y _ R R   i m p o r t a n t _ J J   . _ .   
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 A s _ I I   s u c h _ D A   , _ ,   i t _ P P H 1   m a y _ V M   b e _ V B I   t h a t _ C S T   t h e _ A T   s i g n a l _ N N 1   c h a r a c t e r i s t i c s _ N N 2   n e e d _ V V 0   t o _ T O   b e _ V B I   i n d i v i d u a l i s e d _ V V N   t o _ T O   a c c o u n t _ V V I   f o r _ I F   t h e _ A T   v a r i a n c e _ N N 1   i n _ I I   d i s e a s e _ N N 1   a n d _ C C   t h e _ A T   s t a t e _ N N 1   o f _ I O   t h e _ A T   p a t i e n t _ N N 1   ' _ N U L L   s _ Z Z 1   r e s i d u a l _ J J   r e t i n a _ N N 1   . _ .   
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 H e _ P P H S 1   w a s _ V B D Z   n o t _ X X   o n _ I I   s y s t e m i c _ J J   i m m u n o s u p p r e s s i v e _ J J   m e d i c a t i o n s _ N N 2   a n d _ C C   p a i n _ N N 1   w a s _ V B D Z   n o t _ X X   a _ A T 1   m a j o r _ J J   c o m p l a i n t _ N N 1   f o r _ I F   h i m _ P P H O 1   . _ .   
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 R e s u l t s _ N N 2   ' _ N U L L   L i f e t i m e _ N N T 1   a n d _ C C   1 2 - m o n t h _ J J   p r e v a l e n c e _ N N 1   o f _ I O   M D D _ N P 1   w e r e _ V B D R   1 1 . 0 % _ F O   a n d _ C C   7 . 5 % _ F O   , _ ,   r e s p e c t i v e l y _ R R   . _ .   
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 I n t e r - a s s a y _ J J   c o e f f i c i e n t _ N N 1   o f _ I O   v a r i a t i o n _ N N 1   f o r _ I F   t h i s _ D D 1   s e t _ N N 1   o f _ I O   a s s a y s _ N N 2   i s _ V B Z   1 2 . 9 8 % _ F O   . _ .   
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 A l t h o u g h _ C S   t h e _ A T   s t u d y _ N N 1   w a s _ V B D Z   n o t _ X X   d e s i g n e d _ V V N   t o _ T O   d e t e c t _ V V I   e f f i c a c y _ N N 1   ' _ N U L L   s o m e _ D D   i m p r o v e m e n t _ N N 1   i n _ I I   v i s u a l _ J J   f u n c t i o n _ N N 1   w a s _ V B D Z   n o t e d _ V V N   o n _ I I   m i c r o p e r i m e t r y _ N N 1   ' _ N U L L   p e r i m e t r y _ N N 1   ' _ N U L L   a n d / o r _ C C   E R G _ V V 0   i n _ I I   m o s t _ D A T   o f _ I O   t h e _ A T   s t u d y _ N N 1   e y e s _ N N 2   f o l l o w i n g _ V V G   C D 3 4 + _ F O   c e l l _ N N 1   i n j e c t i o n _ N N 1   . _ .   
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 T h e _ A T   s c a l e s _ N N 2   a r e _ V B R   , _ ,   h o w e v e r _ R R   , _ ,   i n t e n d e d _ V V D   t o _ T O   b e _ V B I   i n t e r p r e t e d _ V V N   i n d e p e n d e n t l y . 1 8 _ F O   T h e _ A T   S e l f _ N N 1   C a r e _ N N 1   I n v e n t o r y _ N N 1   h a s _ V H Z   r e c e n t l y _ R R   b e e n _ V B N   v a l i d a t e d _ V V N   f o r _ I F   m e d i c a l _ J J   t r a i n e e s _ N N 2   . _ .   
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 W h e r e a s _ C S   t h e _ A T   g r o u p s _ N N 2   d i d _ V D D   n o t _ X X   d i f f e r _ V V I   w i t h _ I I 3 1   r e s p e c t _ I I 3 2   t o _ I I 3 3   d i s e a s e _ N N 1   d u r a t i o n _ N N 1   , _ ,   t h e r e _ E X   w a s _ V B D Z   a _ A T 1   s t r o n g _ J J   m a l e _ J J   p r e d o m i n a n c e _ N N 1   i n _ I I   t h e _ A T   b e n i g n _ J J   b v F T D _ N N U   p h e n o c o p y _ N N 1   s y n d r o m e _ N N 1   g r o u p _ N N 1   o n l y _ R R   a n d _ C C   t h e _ A T   p a t i e n t s _ N N 2   i n _ I I   t h i s _ D D 1   g r o u p _ N N 1   w e r e _ V B D R   s i g n i f i c a n t l y _ R R   y o u n g e r _ J J R   . _ .   
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 T h e _ A T   d e m o g r a p h i c s _ N N 1   ( _ (   e . g . _ R E X   , _ ,   m a l e - t o - f e m a l e _ J J   r a t i o _ N N 1   ) _ )   a n d _ C C   b a s e l i n e _ N N 1   c h a r a c t e r i s t i c s _ N N 2   o f _ I O   p a t i e n t s _ N N 2   i n c l u d e d _ V V N   i n _ I I   t h e _ A T   C R Y S T A L _ N N 1   s t u d y _ N N 1   a r e _ V B R   m o r e _ R G R   r e p r e s e n t a t i v e _ J J   o f _ I O   t h o s e _ D D 2   w i t h _ I W   C R V O _ N N 1   i n _ I I   t h e _ A T   g e n e r a l _ N N 1   p o p u l a t i o n . 1 5 , 1 6 _ F O   I n _ I I   t h e _ A T   C R Y S T A L _ N N 1   s t u d y _ N N 1   , _ ,   p a t i e n t s _ N N 2   h a d _ V H D   a _ A T 1   h i g h e r _ J J R   m e a n _ J J   B C V A _ N N 1   s c o r e _ N N 1   t h a n _ C S N   i n _ I I   C R U I S E _ N N 1   ( _ (   5 3 . 0 _ M C   v s . _ I I   4 8 . 1 _ M C   l e t t e r s _ N N 2   ) _ )   . _ .   
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 P o t e n t i a l _ J J   r e a s o n s _ N N 2   f o r _ I F   a n _ A T 1   a b s e n c e _ N N 1   o f _ I O   t h i s _ D D 1   t o _ T O   b e _ V B I   e x p e c t e d _ V V N   n e g a t i v e _ J J   r e l a t i o n s h i p _ N N 1   w i t h _ I W   t i m e _ N N T 1   i n t e r v a l _ N N 1   m i g h t _ V M   b e _ V B I   t h a t _ C S T   t h e _ A T   d e c r e a s e _ N N 1   o v e r a l l _ N N 1   i s _ V B Z   r a t h e r _ R G   s m a l l _ J J   ( _ (   a n d _ C C   h e n c e _ R R   v a r i a t i o n s _ N N 2   t h e r e i n _ R R   a r e _ V B R   h a r d e r _ J J R   t o _ T O   p r e d i c t _ V V I   ) _ )   a n d _ C C   t h a t _ C S T   t h e _ A T   v a r i a t i o n s _ N N 2   o f _ I O   t h e _ A T   t o t a l _ J J   t i m e _ N N T 1   i n t e r v a l s _ N N 2   i n _ I I   t h e _ A T   c u r r e n t _ J J   s t u d y _ N N 1   w e r e _ V B D R   n o t _ X X   l a r g e _ J J   e n o u g h _ R R   t o _ T O   m a k e _ V V I   a n _ A T 1   e f f e c t _ N N 1   o n _ I I   t h e _ A T   d e c r e a s e _ N N 1   v i s i b l e _ J J   . _ .   
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 R a t h e r _ R R   , _ ,   a d a p t a t i o n _ N N 1   f a c i l i t a t e s _ V V Z   a _ A T 1   r o b u s t _ J J   , _ ,   t e m p o r a r y _ J J   i m p r o v e m e n t _ N N 1   i n _ I I   S L S _ N P 1   t i m e _ N N T 1   s y m m e t r y _ N N 1   e i t h e r _ R R   a t _ I I   t h e _ A T   e n d _ N N 1   o f _ I O   A d a p t a t i o n _ N N 1   o r _ C C   t h e _ A T   b e g i n n i n g _ N N 1   o f _ I O   P o s t a d a p t a t i o n _ N N 1   ( _ (   a f t e r e f f e c t _ N N 1   ) _ )   , _ ,   d e p e n d i n g _ I I 2 1   o n _ I I 2 2   w h e t h e r _ C S W   t h e _ A T   p a r e t i c _ J J   o r _ C C   n o n p a r e t i c _ J J   l e g _ N N 1   i s _ V B Z   p e r t u r b e d _ V V N   . _ .   
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 C h a n g e s _ N N 2   o f _ I O   t h e _ A T   o p t i c _ N N 1   n e r v e _ N N 1   h e a d _ N N 1   v e s s e l _ N N 1   s t r u c t u r e _ N N 1   a r e _ V B R   f u r t h e r m o r e _ R R   c o m m o n _ J J   f o r _ I F   c e n t r a l _ J J   n e u r o p a t h i e s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   m u l t i p l e _ J J   s c l e r o s i s _ N N 1   . _ .   
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 F o r _ I F   t h i s _ D D 1   r e a s o n _ N N 1   , _ ,   a _ A T 1   n e w _ J J   p a t e n t e d _ J J   m e t h o d _ N N 1   f o r _ I F   d i r e c t _ J J   n o n - C p _ N N 1   C u _ F O   d e t e c t i o n _ N N 1   i n _ I I   s e r u m _ N N 1   t h r o u g h _ I I   a _ A T 1   f l u o r e s c e n t _ J J   p r o b e _ N N 1   h a s _ V H Z   b e e n _ V B N   s e t - u p _ N N 1   . _ .   
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 H o w e v e r _ R R   , _ ,   e c h o c a r d i o g r a p h i c _ J J   a n d _ C C   M R _ N N B   i m a g e s _ N N 2   w e r e _ V B D R   a n a l y z e d _ V V N   a n d _ C C   r e p o r t e d _ V V N   b y _ I I   s i t e s _ N N 2   a n d _ C C   n o t _ X X   b y _ I I   i n d e p e n d e n t _ J J   c o r e _ N N 1   l a b o r a t o r i e s _ N N 2   . _ .   
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 R e l e a s e d _ J J   A M C _ N N 1   w a s _ V B D Z   m e a s u r e d _ V V N   u s i n g _ V V G   a _ A T 1   F l u o r o s k a n _ J J   A s c e n t _ N N 1   f l u o r o m e t e r _ N N 1   ( _ (   T h e r m o _ N P 1   E l e c t r o n _ N N 1   , _ ,   W a l t h a m _ N P 1   , _ ,   M A _ N N A   , _ ,   U S A _ N P 1   ) _ )   a t _ I I   a n _ A T 1   e x c i t a t i o n _ N N 1   w a v e l e n g t h _ N N 1   o f _ I O   3 9 0 _ M C   n m _ F U   a n d _ C C   a n _ A T 1   e m i s s i o n _ N N 1   w a v e l e n g t h _ N N 1   o f _ I O   4 6 0 _ M C   n m _ F U   . _ .   
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 I n s i g h t s _ N N 2   i n t o _ I I   p o s t - E D _ J J   c l i n i c a l _ J J   p r o g r e s s _ N N 1   a r e _ V B R   , _ ,   i n _ R R 2 1   g e n e r a l _ R R 2 2   , _ ,   o f _ I O   v a l u e _ N N 1   f o r _ I F   p r a c t i c e - b a s e d _ J J   l e a r n i n g _ N N 1   a n d _ C C   i m p r o v e m e n t _ N N 1   , _ ,   w h e t h e r _ C S W   f o r _ I F   i n t e r n s _ N N 2   a n d _ C C   r e s i d e n t s _ N N 2   , _ ,   o r _ C C   f o r _ I F   t h o s e _ D D 2   w h o _ P N Q S   a r e _ V B R   a l r e a d y _ R R   a t t e n d i n g _ V V G   p h y s i c i a n s _ N N 2   . _ .   
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 L i p o p o l y s a c c h a r i d e _ N N 1   w a s _ V B D Z   u s e d _ V V N   t o _ T O   i n d u c e _ V V I   m i c r o g l i a l _ J J   a c t i v a t i o n _ N N 1   , _ ,   a _ A T 1   c r i t i c a l _ J J   c o m p o n e n t _ N N 1   o f _ I O   n e u r o i n f l a m m a t i o n _ N N 1   . _ .   
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 N o w _ R T   , _ ,   m a n y _ D A 2   s t a t e s _ N N 2   a r e _ V B R   e x p a n d i n g _ V V G   M e d i c a i d _ J J   c o v e r a g e _ N N 1   t o _ T O   i n c l u d e _ V V I   p r e v i o u s l y _ R R   i n e l i g i b l e _ J J   a d u l t s _ N N 2   . _ .   
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 C r o s s - s e c t i o n a l _ J J   a n a l y s i s _ N N 1   a t _ I I   2 4 _ M C   m o n t h s _ N N T 2   s h o w e d _ V V D   n o _ A T   s i g n i f i c a n t _ J J   d i f f e r e n c e s _ N N 2   i n _ I I   o v e r a l l _ J J   b o w e l _ N N 1   b o t h e r _ V V 0   b e t w e e n _ I I   t h e _ A T   t r e a t m e n t _ N N 1   g r o u p s _ N N 2   ( _ (   7 4 _ M C   G y _ J J   v s _ I I   6 0 _ M C   G y _ N P 1   , _ ,   p t r e n d = 0 - 6 4 _ F O   ; _ ;   7 4 _ M C   G y _ J J   v s _ I I   5 7 _ M C   G y _ N P 1   , _ ,   p t r e n d = 0 * 5 9 _ F O   ; _ ;   a p p e n d i x _ N N 1   p _ Z Z 1   3 _ M C   ) _ )   . _ .   
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 N o _ A T   e v i d e n c e _ N N 1   o f _ I O   e f f e c t _ N N 1   m o d i f i c a t i o n _ N N 1   ( _ (   n o n s i g n i f i c a n t _ J J   i n t e r a c t i o n s _ N N 2   , _ ,   d a t a _ N N   n o t _ X X   s h o w n _ V V N   ) _ )   w a s _ V B D Z   f o u n d _ V V N   a n d _ C C   s o _ R R   e f f e c t _ V V 0   m o d i f i e r s _ N N 2   w e r e _ V B D R   n o t _ X X   c o n s i d e r e d _ V V N   f u r t h e r _ R R R   . _ .   
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 A d j u s t e d _ J J   m o d e l _ N N 1   2 _ M C   i n c l u d e d _ V V D   v a r i a b l e s _ N N 2   f r o m _ I I   t h e _ A T   f i r s t _ M D   m o d e l _ N N 1   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   l i f e s t y l e _ N N 1   v a r i a b l e s _ N N 2   o f _ I O   s m o k i n g _ J J   s t a t u s _ N N 1   & l s q b ; _ (   3 3 _ M C   & r s q b ; _ )   , _ ,   a l c o h o l _ N N 1   i n t a k e _ N N 1   & l s q b ; _ (   3 4 _ M C   & r s q b ; _ )   , _ ,   e m p l o y m e n t _ N N 1   s t a t u s _ N N 1   & l s q b ; _ (   3 5 _ M C   & r s q b ; _ )   , _ ,   a n d _ C C   p h y s i c a l _ J J   a c t i v i t y _ N N 1   & l s q b ; _ (   3 6 _ M C   & r s q b ; _ )   . _ .   
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 I n c i d e n t _ N N 1   P D _ N P 1   c a s e s _ N N 2   w e r e _ V B D R   i d e n t i f i e d _ V V N   e i t h e r _ R R   t h r o u g h _ I I   f o l l o w - u p _ J J   i n t e r v i e w s _ N N 2   o r _ C C   r e c o r d _ N N 1   l i n k a g e _ N N 1   a n a l y s i s _ N N 1   w i t h _ I W   h o s p i t a l _ N N 1   d i s c h a r g e _ N N 1   a n d _ C C   P D _ N P 1   o u t p a t i e n t _ N N 1   r e g i s t r i e s _ N N 2   . _ .   
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 I n d e e d _ R R   , _ ,   U 4 6 6 1 9 _ F O   c a u s e d _ V V N   a _ A T 1   d o s e - _ N N 1   a n d _ C C   t i m e - d e p e n d e n t _ J J   s t i m u l a t i o n _ N N 1   o f _ I O   E R K _ N P 1   p h o s p h o r y l a t i o n _ N N 1   ( _ (   F i g u r e s _ V V Z   6 A _ F O   , _ ,   B _ Z Z 1   ) _ )   . _ .   
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 I n _ R R 2 1   a d d i t i o n _ R R 2 2   , _ ,   t h e s e _ D D 2   f i n d i n g s _ N N 2   s u g g e s t _ V V 0   C S P _ N P 1   d u r a t i o n _ N N 1   m a y _ V M   b e _ V B I   u s e d _ V V N   t o _ T O   a s s i s t _ V V I   i n _ I I   t h e _ A T   d i f f e r e n t i a l _ J J   d i a g n o s i s _ N N 1   o f _ I O   A d S D _ N P 1   , _ ,   a n d _ C C   p r o v i d e s _ V V Z   t h e _ A T   f o u n d a t i o n _ N N 1   f o r _ I F   f u t u r e _ J J   s t u d i e s _ N N 2   i n _ I I   c o r t i c a l _ J J   e x c i t a b i l i t y _ N N 1   i n _ I I   t h i s _ D D 1   p o p u l a t i o n _ N N 1   w h i c h _ D D Q   m a y _ V M   l e a d _ V V I   t o _ I I   n o v e l _ J J   t r e a t m e n t _ N N 1   p r o t o c o l s _ N N 2   t h a t _ C S T   t a r g e t _ N N 1   a n d _ C C   f a c i l i t a t e _ V V 0   b a l a n c e _ N N 1   i n _ I I   c o r t i c a l _ J J   e x c i t a b i l i t y _ N N 1   . _ .   
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 S a m p l e s _ N N 2   w e r e _ V B D R   d r a w n _ V V N   i m m e d i a t e l y _ R R   a f t e r _ I I   m o v i n g _ V V G   t h e _ A T   c a g e _ N N 1   ( _ (   w i t h i n _ I I   2 0 _ M C   s e c _ N N U   ) _ )   t o _ T O   m i n i m i z e _ V V I   t h e _ A T   e f f e c t _ N N 1   o f _ I O   s t r e s s _ N N 1   . _ .   
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 C l a s s _ N N 1   m e m b e r s h i p _ N N 1   p r o b a b i l i t i e s _ N N 2   f r o m _ I I   s u b j e c t s _ N N 2   d i s p l a y i n g _ V V G   v 1 . 0 _ F O   q u i t _ V V 0   s u c c e s s _ N N 1   s c o r e s _ N N 2   i n _ I I   t h e _ A T   t o p _ J J   t e r c i l e _ N N 1   w e r e _ V B D R   c o m p a r e d _ V V N   t o _ I I   t h o s e _ D D 2   o f _ I O   s u b j e c t s _ N N 2   d i s p l a y i n g _ V V G   v 1 . 0 _ F O   s c o r e s _ V V Z   i n _ I I   t h e _ A T   l o w e s t _ J J T   t e r c i l e _ N N 1   b y _ I I   t _ Z Z 1   t e s t _ N N 1   . _ .   
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 W e _ P P I S 2   h a v e _ V H 0   a n _ A T 1   i m p o r t a n t _ J J   r o l e _ N N 1   i n _ I I   e d u c a t i n g _ V V G   a l l _ D B   m e d i c a l _ J J   s t u d e n t s _ N N 2   a s _ I I 3 1   w e l l _ I I 3 2   a s _ I I 3 3   t h e _ A T   f u t u r e _ J J   p e d i a t r i c _ J J   c l i n i c a l _ J J   a n d _ C C   r e s e a r c h _ N N 1   w o r k f o r c e _ N N 1   . _ .   
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 A l l _ D B   a n a l y s e s _ N N 2   w e r e _ V B D R   c a r r i e d _ V V N   o u t _ R P   b y _ I I   a p p l y i n g _ V V G   t h e _ A T   s e l e c t e d _ J J   a n d _ C C   f i x e d _ J J   s c a n n i n g _ N N 1   s e t t i n g s _ N N 2   o b t a i n e d _ V V N   f r o m _ I I   t h e _ A T   p r i m a r y _ J J   e v a l u a t i o n _ N N 1   r e s u l t s _ N N 2   . _ .   
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 R e g i o n a l _ J J   T o p o l o g i c _ J J   O r g a n i z a t i o n _ N N 1   o f _ I O   t h e _ A T   S t r u c t u r a l _ J J   C o n n e c t o m e _ N N 1   W e _ P P I S 2   i d e n t i f i e d _ V V D   t h e _ A T   b r a i n _ N N 1   r e g i o n s _ N N 2   t h a t _ C S T   s h o w e d _ V V D   s i g n i f i c a n t _ J J   b e t w e e n - g r o u p _ J J   d i f f e r e n c e s _ N N 2   i n _ I I   a t _ R R 2 1   l e a s t _ R R 2 2   o n e _ M C 1   n o d a l _ J J   m e t r i c _ J J   ( _ (   P _ N N U   l e s s _ D A R   t h a n _ C S N   . 0 5 _ M C   , _ ,   c o r r e c t e d _ V V N   f o r _ I F   f a l s e - d i s c o v e r y _ J J   r a t e _ N N 1   ) _ )   . _ .   
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 T h e _ A T   o t h e r _ J J   s t u d y _ N N 1   d i d _ V D D   n o t _ X X   f i n d _ V V I   a n y _ D D   s t e r o i d _ N N 1   a n d _ C C   l o w e s t _ R R T   i n _ I I   t h e _ A T   g r o u p _ N N 1   r e c e i v i n g _ V V G   t h e _ A T   l e a s t _ R G T   p o t e n t _ J J   s t e r o i d _ N N 1   , _ ,   r e s p o n d e r s _ N N 2   . _ .   
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 U n a d j u s t e d _ J J   A s s o c i a t i o n s _ N N 2   B e t w e e n _ I I   S c h o o l _ N N 1   M o b i l i t y _ N N 1   a n d _ C C   S u b s e q u e n t _ J J   P e e r _ N N 1   D i f f i c u l t i e s _ N N 2   S c h o o l _ N N 1   m o b i l i t y _ N N 1   w a s _ V B D Z   s i g n i f i c a n t l y _ R R   a s s o c i a t e d _ V V N   w i t h _ I W   b u l l y _ N N 1   s t a t u s _ N N 1   ( _ (   O R _ C C   = _ F O   1 . 4 7 _ M C   ; _ ;   9 5 % _ N N U   C I _ F O   = _ F O   1 . 0 2 - 2 . 1 4 _ M C M C   ) _ )   , _ ,   b u l l y _ V V 0   v i c t i m i z a t i o n _ N N 1   ( _ (   O R _ C C   = _ F O   1 . 2 6 _ M C   ; _ ;   9 5 % _ N N U   C I _ F O   = _ F O   1 . 0 1 - 1 . 5 9 _ M C M C   ) _ )   a n d _ C C   n e g a t i v e _ J J   f r i e n d s h i p _ N N 1   s c o r e _ N N 1   ( _ (   b _ Z Z 1   = _ F O   0 . 5 0 _ M C   ; _ ;   9 5 % _ N N U   C I _ F O   = _ F O   0 . 2 9 - 0 . 7 2 _ M C M C   ) _ )   . _ .   
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 I f _ C S   t h e r e _ E X   w a s _ V B D Z   a _ A T 1   p a t t e r n _ N N 1   i n _ I I   n u m b e r _ N N 1   o f _ I O   i n t e r v a l _ N N 1   c a n c e r s _ N N 2   w i t h _ I W   t i m e _ N N T 1   o n _ I I   t a s k _ N N 1   , _ ,   t h e n _ R T   t h i s _ D D 1   m a y _ V M   p r o v i d e _ V V I   e v i d e n c e _ N N 1   o f _ I O   a _ A T 1   v i g i l a n c e _ N N 1   d e c r e m e n t _ N N 1   . _ .   
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 O u r _ A P P G E   r e s u l t s _ N N 2   i n _ I I   b o t h _ D B 2   g r o u p s _ N N 2   c o m p a r e _ V V 0   f a v o u r a b l y _ R R   w i t h _ I W   a _ A T 1   m e t a - a n a l y s i s _ N N 1   o f _ I O   t h e _ A T   e f f e c t s _ N N 2   o f _ I O   C B T _ N P 1   t h a t _ D D 1   e s t i m a t e _ N N 1   p r o p o r t i o n s _ N N 2   o f _ I O   p a t i e n t s _ N N 2   w i t h _ I W   r e m i s s i o n s _ N N 2   o f _ I O   a r o u n d _ R G   5 0 % _ N N U   . _ .   
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 T h e _ A T   r e c u r r e n c e - f r e e _ J J   i n t e r v a l _ N N 1   w a s _ V B D Z   r e c o r d e d _ V V N   a s _ I I   t h e _ A T   t i m e _ N N T 1   b e t w e e n _ I I   m e t a s t a s e c t o m y _ N N 1   a n d _ C C   s u b s e q u e n t _ J J   t u m o r _ N N 1   r e c u r r e n c e _ N N 1   o r _ C C   t h e _ A T   d a t e _ N N 1   o f _ I O   l a s t _ M D   f o l l o w - u p _ N N 1   . _ .   
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 T h e _ A T   p r i m a r y _ J J   g o a l _ N N 1   o f _ I O   t h i s _ D D 1   s t u d y _ N N 1   w a s _ V B D Z   t o _ T O   c o m p a r e _ V V I   t h e _ A T   f r e q u e n c y _ N N 1   w i t h _ I W   w h i c h _ D D Q   S S E P s _ N N 2   w e r e _ V B D R   o b t a i n e d _ V V N   w i t h _ I W   t h a t _ D D 1   f o r _ I F   T c M E P s _ N N 2   i n _ I I   c h i l d r e n _ N N 2   y o u n g e r _ J J R   t h a n _ C S N   6 _ M C   y e a r s _ N N T 2   . _ .   
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 I n t e r m o l e c u l a r _ J J   d i s u l f i d e _ N N 1   b r i d g e s _ N N 2   c a n _ V M   f o r m _ V V I   b e t w e e n _ I I   a _ A T 1   c h a i n s _ N N 2   o f _ I O   e a c h _ D D 1   m o n o m e r _ N N 1   , _ ,   c r e a t i n g _ V V G   H p _ N N 1   p o l y m e r s _ N N 2   . _ .   
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 M e t h o d s _ N N 2   W e _ P P I S 2   c o n d u c t e d _ V V D   a _ A T 1   s e c o n d a r y _ J J   a n a l y s i s _ N N 1   o f _ I O   n a t i o n a l _ J J   D H S _ N P 2   d a t a _ N N   f r o m _ I I   n i n e _ M C   c o u n t r i e s _ N N 2   o n _ I I   t h e _ A T   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   p l a c e _ N N 1   a n d _ C C   a t t e n d a n c e _ N N 1   a t _ I I   b i r t h _ N N 1   , _ ,   a n d _ C C   m a t e r n a l _ J J   c o m p l i c a t i o n s _ N N 2   d u r i n g _ I I   d e l i v e r y _ N N 1   w i t h _ I W   r e p o r t e d _ J J   e a r l y _ J J   n e o n a t a l _ J J   m o r t a l i t y _ N N 1   . _ .   
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 T h e r e f o r e _ R R   , _ ,   t h e r a p e u t i c _ J J   i n t e r v e n t i o n _ N N 1   t h r o u g h _ I I   d i e t a r y _ J J   s u p p l e m e n t a t i o n _ N N 1   o f _ I O   D H A _ N P 1   h a s _ V H Z   p o t e n t i a l _ J J   t o _ T O   i m p r o v e _ V V I   t h e _ A T   r e c o v e r y _ N N 1   p r o c e s s _ N N 1   i n _ I I   p a t i e n t - a t h l e t e s _ N N 2   a f t e r _ I I   b r a i n _ N N 1   i n j u r y _ N N 1   . _ .   
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 C o n t r o l _ V V 0   c o n n e c t i v i t y _ N N 1   w a s _ V B D Z   g r e a t e r _ J J R   b e t w e e n _ I I   t h e _ A T   m i d c i n g u l a t e _ N N 1   s e e d _ N N 1   p o i n t _ N N 1   a n d _ C C   t h e _ A T   v e n t r a l _ J J   a t t e n t i o n _ N N 1   n e t w o r k _ N N 1   , _ ,   a _ A T 1   ' _ N U L L   b o t t o m - u p _ J J   ' _ N U L L   a t t e n t i o n a l _ J J   n e t w o r k _ N N 1   . _ .   
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 F i r s t _ M D   , _ ,   w e _ P P I S 2   u s e d _ V V D   t h e _ A T   w e i g h t s _ N N 2   t h a t _ C S T   w e r e _ V B D R   c o m p u t e d _ V V N   t o _ T O   b e _ V B I   o p t i m a l _ J J   f o r _ I F   p r e d i c t i n g _ V V G   l i f e s p a n _ N N 1   a t _ I I   e x a m _ N N 1   1 _ M C 1   , _ ,   w h e n _ C S   t h e _ A T   m e a n _ J J   a g e _ N N 1   o f _ I O   t h e _ A T   c o h o r t _ N N 1   w a s _ V B D Z   3 4 . 5 _ M C   y e a r s _ N N T 2   ( _ (   F i g . _ N N 1   1 _ M C 1   , _ ,   b o t t o m _ N N 1   ) _ )   . _ .   
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 W h e n _ C S   a n a l y z i n g _ V V G   m i R - 2 2 3 _ M C   , _ ,   t h e y _ P P H S 2   d e m o n s t r a t e d _ V V D   t h a t _ C S T   t h e _ A T   u s e _ N N 1   o f _ I O   e i t h e r _ R R   E D T A _ N P 1   o r _ C C   c i t r a t e _ J J   t u b e s _ N N 2   r e s u l t e d _ V V N   i n _ I I   s l i g h t l y _ R R   e l e v a t e d _ J J   m i R N A _ N N 1   l e v e l s _ N N 2   . _ .   
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 S i x _ M C   m a l e _ J J   p i g l e t s _ N N 2   ( _ (   m e a n _ J J   a g e _ N N 1   o f _ I O   1 3 _ M C   w e e k s _ N N T 2   a n d _ C C   m e a n _ J J   w e i g h t _ N N 1   o f _ I O   3 9 _ M C   k g _ N N U   ) _ )   u n d e r w e n t _ V V D   e x p e r i m e n t s _ N N 2   u n d e r _ I I   g e n e r a l _ J J   a n e s t h e s i a _ N N 1   i n _ I I   a _ A T 1   s u p i n e _ J J   p o s i t i o n _ N N 1   . _ .   
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 F o r _ I F   D C E - M R I _ N N 1   , _ ,   n o _ A T   e l e v a t e d _ J J   p a r a m e t r i c _ J J   m a p s _ N N 2   o f _ I O   p e r m e a b i l i t y _ N N 1   w e r e _ V B D R   f o u n d _ V V N   i n _ I I   h u m a n _ J J   i s c h e m i c _ J J   s t r o k e . 2 9 _ F O   T h e _ A T   d i f f e r e n c e _ N N 1   b e t w e e n _ I I   o u r _ A P P G E   r e s u l t s _ N N 2   a n d _ C C   t h o s e _ D D 2   o f _ I O   p r e v i o u s _ J J   s t u d i e s _ N N 2   c a n _ V M   n o t _ X X   b e _ V B I   e x p l a i n e d _ V V N   b y _ I I   e i t h e r _ R R   t h e _ A T   d i f f e r e n t _ J J   t i m e _ N N T 1   o f _ I O   o n s e t _ N N 1   o r _ C C   d i f f e r e n c e s _ N N 2   i n _ I I   t h e _ A T   e m p l o y e d _ J J   k i n e t i c _ J J   m o d e l _ N N 1   s i n c e _ C S   w e _ P P I S 2   d i d _ V D D   n o t _ X X   f i n d _ V V I   a n _ A T 1   a s s o c i a t i o n _ N N 1   b e t w e e n _ I I   t i m e _ N N T 1   o f _ I O   o n s e t _ N N 1   a n d _ C C   s t r o k e _ V V 0   K t r a n s _ N N 2   v a l u e s _ N N 2   a n d _ C C   u s e d _ V V D   a _ A T 1   u n i d i r e c t i o n a l _ J J   2 - c o m p a r t m e n t _ J J   m o d e l _ N N 1   a s _ R R 2 1   w e l l _ R R 2 2   . _ .   
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 T h e _ A T   c a l i b r a t i o n _ N N 1   p h a s e _ N N 1   , _ ,   p e r f o r m e d _ V V N   a t _ I I   b o t h _ R R   s e s s i o n s _ N N T 2   , _ ,   c o n s i s t e d _ V V N   i n _ I I   f i x a t i n g _ V V G   9 _ M C   p o s i t i o n s _ N N 2   o n _ I I   t h e _ A T   s c r e e n _ N N 1   l o c a t e d _ V V N   i n _ I I   t h e _ A T   c o r n e r s _ N N 2   , _ ,   t h e _ A T   c e n t e r _ N N 1   , _ ,   a n d _ C C   t h e _ A T   e x t r e m i t i e s _ N N 2   o n _ I I   t h e _ A T   h o r i z o n t a l _ J J   a n d _ C C   v e r t i c a l _ J J   m i d d l e _ J J   l i n e s _ N N 2   . _ .   
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 A l s o _ R R   , _ ,   i n _ I I   t h e _ A T   s t u d y _ N N 1   b y _ I I   H o _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   a b o u t _ I I   o n e - t h i r d _ M F   o f _ I O   t h e _ A T   p a t i e n t s _ N N 2   h a d _ V H D   g e n e r a l _ J J   a n e s t h e s i a _ N N 1   , _ ,   w h e r e a s _ C S   a l l _ D B   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   c u r r e n t _ J J   s t u d y _ N N 1   h a d _ V H D   r e g i o n a l _ J J   a n e s t h e s i a _ N N 1   . _ .   
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 T h i s _ D D 1   s u g g e s t s _ V V Z   t h a t _ C S T   n e u r o m u s c u l a r _ J J   e x e r c i s e _ N N 1   m a y _ V M   b e _ V B I   t h e _ A T   b e s t _ J J T   t y p e _ N N 1   o f _ I O   e x e r c i s e _ N N 1   f o r _ I F   p a i n _ N N 1   r e l i e f _ N N 1   i n _ I I   t h o s e _ D D 2   w i t h _ I W   v a r u s _ N N 1   t h r u s t _ N N 1   ( _ (   4 _ M C   ) _ )   . _ .   
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 E V A L U A T I O N _ N N 1   T O O L S _ N N 2   A N D _ C C   O U T C O M E S _ N N 2   I N _ I I   N E U R O M U S C U L A R _ J J   E X E R C I S E _ N N 1   T R I A L S _ N N 2   F r o m _ I I   t h e _ A T   p a t i e n t _ N N 1   ' _ N U L L   s _ Z Z 1   p e r s p e c t i v e _ N N 1   , _ ,   i t _ P P H 1   i s _ V B Z   m o s t _ R G T   i m p o r t a n t _ J J   t o _ T O   e v a l u a t e _ V V I   t h e _ A T   e f f e c t _ N N 1   f r o m _ I I   e x e r c i s e _ N N 1   o n _ I I   p e r c e i v e d _ J J   p a i n _ N N 1   a n d _ C C   f u n c t i o n a l _ J J   l i m i t a t i o n s _ N N 2   . _ .   
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 C A F _ N P 1   w a s _ V B D Z   s i g n i f i c a n t l y _ R R   s u p e r i o r _ J J   t o _ I I   B U N _ N N 1   a n d _ C C   e G F R _ N N 1   , _ ,   s i n c e _ C S   t h e _ A T   l a t t e r _ D A   o n e s _ N N 2   w e r e _ V B D R   n o _ A T   m o r e _ R G R   a s s o c i a t e d _ J J   w i t h _ I W   G L _ N P 1   w h e n _ C S   a d j u s t e d _ V V N   f o r _ I F   C A F _ N N 1   l e v e l s _ N N 2   . _ .   
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 W e s t e r n _ J J   p e r i o p e r a t i v e _ J J   n e u r o l o g i c _ J J   s c a l e _ N N 1   T h e _ A T   W e s t e r n _ J J   p e r i o p e r a t i v e _ J J   n e u r o l o g i c _ J J   s c a l e _ N N 1   w a s _ V B D Z   d e s i g n e d _ V V N   t o _ T O   d e t e c t _ V V I   n e u r o l o g i c _ J J   d e f i c i t s _ N N 2   a f t e r _ I I   c a r d i a c _ J J   s u r g e r y _ N N 1   . _ .   
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 F o r _ R E X 2 1   e x a m p l e _ R E X 2 2   , _ ,   i f _ C S   w e _ P P I S 2   i n c r e a s e _ V V 0   f r o m _ I I   0 . 0 0 5 _ M C   t o _ I I   0 . 0 5 _ M C   ( _ (   b y _ I I   c h a n g i n g _ V V G   E 3 6 _ F O   t o _ I I   5 _ M C   ) _ )   , _ ,   t h e _ A T   " _ "   c l i n i c a l _ J J   i n f e r e n c e _ N N 1   " _ "   c h a n g e s _ N N 2   t o _ I I   " _ "   p o s s i b l y _ R R   b e n e f i c i a l _ J J   " _ "   . _ .   
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 F o r _ I F   p e r s i s t e n t _ J J   t h r o m b o c y t o p e n i a _ N N 1   , _ ,   t h e _ A T   n e x t _ M D   c y c l e _ N N 1   w a s _ V B D Z   d e l a y e d _ V V N   u n t i l _ C S   p l a t e l e t s _ N N 2   h a d _ V H D   r e c o v e r e d _ V V N   t o _ I I   a t _ R R 2 1   l e a s t _ R R 2 2   1 0 0 _ M C   x _ Z Z 1   1 0 9 _ M C   c e l l s _ N N 2   p e r _ I I   L _ Z Z 1   a n d _ C C   c h e m o t h e r a p y _ N N 1   d o s e s _ N N 2   w e r e _ V B D R   r e d u c e d _ V V N   t o _ I I   8 0 % _ N N U   , _ ,   m a i n t a i n i n g _ V V G   t h i s _ D D 1   d o s e _ N N 1   r e d u c t i o n _ N N 1   f o r _ I F   s u b s e q u e n t _ J J   c y c l e s _ N N 2   . _ .   
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 T h e _ A T   f o u r _ M C   p a t i e n t s _ N N 2   w i t h _ I W   a _ A T 1   B R C A 2 _ F O   g e n e _ N N 1   m u t a t i o n _ N N 1   u n d e r w e n t _ V V D   M R _ N N B   m a m m o g r a p h y _ N N 1   f o r _ I F   e a r l y _ J J   d e t e c t i o n _ N N 1   i n _ I I   h i g h - r i s k _ J J   p a t i e n t s _ N N 2   ( _ (   n = 2 _ F O   ) _ )   , _ ,   s u s p e c t e d _ J J   r e c u r r e n c e _ N N 1   ( _ (   n = 1 _ F O   ) _ )   a n d _ C C   p r o v e n _ J J   b r e a s t _ N N 1   c a n c e r _ N N 1   ( _ (   n = 1 _ F O   ) _ )   . _ .   
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 T h e y _ P P H S 2   r e a s o n e d _ V V D   , _ ,   m a i n l y _ R R   b y _ I I   l i n k i n g _ V V G   s y m p t o m s _ N N 2   t o _ I I   l e s i o n s _ N N 2   i d e n t i f i e d _ V V N   b y _ I I   d i s s e c t i o n _ N N 1   , _ ,   t h a t _ C S T   d i s o r d e r s _ N N 2   c o u l d _ V M   b e _ V B I   c a u s e d _ V V N   b y _ I I   f o c a l _ J J   l e s i o n s _ N N 2   t o _ I I   c o r t i c a l _ J J   n e t w o r k _ N N 1   n o d e s _ N N 2   o r _ C C   t h e _ A T   w h i t e _ J J   m a t t e r _ N N 1   l i n k s _ V V Z   b e t w e e n _ I I   t h e m _ P P H O 2   . _ .   
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 T h i s _ D D 1   l e n d s _ V V Z   c r e d e n c e _ N N 1   t o _ I I   o u r _ A P P G E   f i n d i n g s _ N N 2   t h a t _ C S T   1 _ M C 1   m M _ N N U   p r o p o f o l - f e d _ J J   f l i e s _ N N 2   a r e _ V B R   n o t _ X X   m e r e l y _ R R   s l e e p i n g _ J J   a n d _ C C   s h o u l d _ V M   n o t _ X X   b e _ V B I   r o u s e d _ V V N   b y _ I I   v i b r a t o r y _ J J   s t i m u l i _ N N 2   a s _ C S A   t h e s e _ D D 2   t i s s u e _ N N 1   l e v e l s _ N N 2   a r e _ V B R   p r e d i c t e d _ V V N   t o _ T O   p r o d u c e _ V V I   s u r g i c a l _ J J   p l a n e _ N N 1   o f _ I O   p r o p o f o l _ N N 1   a n e s t h e s i a _ N N 1   . _ .   
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 W e _ P P I S 2   n o t e _ V V 0   t h a t _ C S T   t h e s e _ D D 2   f i n d i n g s _ N N 2   a p p l y _ V V 0   t o _ I I   o p t i m i z a t i o n _ N N 1   o f _ I O   c a r e _ N N 1   f o r _ I F   t h e _ A T   e n t i r e _ J J   r e g i o n _ N N 1   a n d _ C C   d o _ V D 0   n o t _ X X   f o c u s _ V V I   o n _ I I   t h e _ A T   p e r f o r m a n c e _ N N 1   o f _ I O   i s o l a t e d _ J J   h o s p i t a l s _ N N 2   i n _ I I   t h e _ A T   r e g i o n _ N N 1   . _ .   
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 D i s c u s s i o n _ N N 1   D a t a _ N N   t h a t _ C S T   h a v e _ V H 0   t h e _ A T   p o t e n t i a l _ J J   t o _ T O   i n f o r m _ V V I   o u r _ A P P G E   k n o w l e d g e _ N N 1   b a s e _ N N 1   a b o u t _ I I   h o w _ R G Q   s c h o o l - a g e _ J J   c h i l d r e n _ N N 2   a n d _ C C   a d o l e s c e n t s _ N N 2   w h o _ P N Q S   s t u t t e r _ V V 0   ( _ (   S - O n l y _ J J   ) _ )   d i f f e r _ V V 0   f r o m _ I I   S t u t t e r i n g _ V V G   p l u s _ I I   L a n g u a g e _ N N 1   D i s o r d e r e d _ J J   ( _ (   S _ Z Z 1   + _ F O   L D _ N P 1   ) _ )   p e e r s _ N N 2   a r e _ V B R   p r e s e n t e d _ V V N   i n _ I I   t h e _ A T   c u r r e n t _ J J   s t u d y _ N N 1   . _ .   
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 D e l i r i u m _ N N 1   o c c u r s _ V V Z   i n _ R P   a l m o s t _ R R   h a l f _ D B   o f _ I O   s u r g i c a l _ J J   p a t i e n t s _ N N 2   o v e r _ I I   t h e _ A T   a g e _ N N 1   o f _ I O   6 5 . 3 _ M C   S u r g e r y _ N N 1   h a s _ V H Z   a l s o _ R R   b e e n _ V B N   o b s e r v e d _ V V N   t o _ T O   i n c r e a s e _ V V I   r i s k _ N N 1   o f _ I O   p e r s i s t e n t _ J J   a n d / o r _ C C   p r o g r e s s i v e _ J J   c o g n i t i v e _ J J   i m p a i r m e n t _ N N 1   , _ ,   h o w e v e r _ R R   . _ .   
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 A g r e e m e n t _ N N 1   b e t w e e n _ I I   r e s p o n d e n t s _ N N 2   a n d _ C C   t h e _ A T   d i f f e r e n t _ J J   s c a l e s _ N N 2   w a s _ V B D Z   a s s e s s e d _ V V N   u s i n g _ V V G   k a p p a _ N N 1   ( _ (   k _ Z Z 1   ) _ )   s t a t i s t i c s _ N N   . _ .   
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 S o _ R G   f a r _ R R   o n l y _ R R   s o m e _ D D   r e c e n t _ J J   r e t r o s p e c t i v e _ J J   o r _ C C   s m a l l _ J J   p r o s p e c t i v e _ J J   s t u d i e s _ N N 2   h a v e _ V H 0   c a l l e d _ V V N   a t t e n t i o n _ N N 1   t o _ I I   t h e _ A T   h i g h _ J J   p r e v a l e n c e _ N N 1   o f _ I O   p o s t o p e r a t i v e _ J J   p a i n _ N N 1   a f t e r _ I I   o t o r h i n o l a r y n g o l o g i c _ J J   s u r g e r y _ N N 1   . _ .   
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 T h i s _ D D 1   a d d s _ V V Z   t o _ I I   t h e _ A T   e v i d e n c e _ N N 1   p r e v i o u s l y _ R R   o f f e r e d _ V V N   , _ ,   d e m o n s t r a t i n g _ V V G   t h a t _ D D 1   p r i m a r y _ J J   c o n s e r v a t i v e _ J J   m a n a g e m e n t _ N N 1   o f _ I O   t u m o u r s _ N N 2   o f _ I O   t h i s _ D D 1   s i z e _ N N 1   l e a d s _ V V Z   t o _ I I   s u p e r i o r _ J J   c l i n i c a l _ J J   o u t c o m e s _ N N 2   i n _ I I 3 1   t e r m s _ I I 3 2   o f _ I I 3 3   f a c i a l _ J J   n e r v e _ N N 1   a n d _ C C   h e a r i n g _ V V G   p r e s e r v a t i o n _ N N 1   . _ .   
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 A l l o d y n i a _ N N 1   t o _ T O   b r u s h _ V V I   : _ :   s c o r e d _ V V N   n i l _ P N 1   , _ ,   m i l d _ J J   , _ ,   m o d e r a t e _ J J   , _ ,   o r _ C C   s e v e r e _ J J   . _ .   
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 T h a t _ R E X 2 1   i s _ R E X 2 2   , _ ,   r e s p o n d e n t s _ N N 2   w h o _ P N Q S   o n l y _ R R   k n e w P W S _ V V Z   a s _ C S A   a c q u a i n t a n c e s _ N N 2   w e r e _ V B D R   n o t _ X X   s i g n i f i c a n t l y _ R R   d i f f e r e n t _ J J   i n _ I I   r e p o r t e d _ J J   a f f e c t i v e _ J J   r e a c t i o n s _ N N 2   f r o m _ I I   t h o s e _ D D 2   w i t h o u t _ I W   f a m i l i a r i t y _ N N 1   w i t h P W S _ N N 2   . _ .   
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 C o n c l u s i o n s _ N N 2   G i v e n _ V V N   t h e _ A T   h i g h _ J J   p r e v a l e n c e _ N N 1   a n d _ C C   i m p a c t _ N N 1   o f _ I O   t r a u m a _ N N 1   o n _ I I   p e d i a t r i c _ J J   p a t i e n t s _ N N 2   , _ ,   f a m i l i e s _ N N 2   , _ ,   a n d _ C C   p r o v i d e r s _ N N 2   , _ ,   i t _ P P H 1   i s _ V B Z   e s s e n t i a l _ J J   t h a t _ C S T   p e d i a t r i c _ J J   h e a l t h c a r e _ N N 1   n e t w o r k s _ N N 2   i n t e g r a t e _ V V 0   a _ A T 1   t r a u m a - i n f o r m e d _ J J   c a r e _ N N 1   a p p r o a c h _ N N 1   i n t o _ I I   d e l i v e r y _ N N 1   o f _ I O   m e d i c a l _ J J   c a r e _ N N 1   . _ .   
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 Q u a n t i f i c a t i o n _ N N 1   o f _ I O   t h e _ A T   t o t a l _ J J   a m o u n t _ N N 1   o f _ I O   N C X 3 _ F O   ( _ (   i n t a c t _ J J   p l u s _ I I   f r a g m e n t e d _ J J   ) _ )   s h o w e d _ V V D   t h a t _ C S T   t h e r e _ E X   w e r e _ V B D R   n o _ A T   s i g n i f i c a n t _ J J   d i f f e r e n c e s _ N N 2   b e t w e e n _ I I   a n y _ D D   t a u o p a t h y _ N N 1   a n d _ C C   c o n t r o l _ N N 1   b r a i n _ N N 1   f o l l o w i n g _ V V G   n o r m a l i z a t i o n _ N N 1   t o _ T O   N S E _ V V I   ( _ (   F i g . _ N N 1   3 B _ F O   ) _ )   . _ .   
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 I I I _ M C   , _ ,   r e s p i r a t o r y _ J J   f a i l u r e _ N N 1   p r i o r _ I I 2 1   t o _ I I 2 2   p r i m a r y _ J J   P C I _ N P 1   , _ ,   t h e _ A T   a v e r a g e _ N N 1   o f _ I O   T I M I _ J J   r i s k _ N N 1   s c o r e _ N N 1   , _ ,   a n d _ C C   t h e _ A T   i n c i d e n c e _ N N 1   o f _ I O   h i g h _ J J   T I M I _ J J   r i s k _ N N 1   s c o r e _ N N 1   w e r e _ V B D R   s i m i l a r _ J J   b e t w e e n _ I I   g r o u p s _ N N 2   . _ .   
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 A C R _ N P 1   A p p r o p r i a t e n e s s _ N N 1   C r i t e r i a _ N N 2   N a s a l _ J J   C a v i t y _ N N 1   a n d _ C C   P a r a n a s a l _ N P 1   S i n u s _ N P 1   C a n c e r s _ N N 2   S u p p o r t i n g _ V V G   d o c u m e n t s _ N N 2   F o r _ I F   a d d i t i o n a l _ J J   i n f o r m a t i o n _ N N 1   o n _ I I   t h e _ A T   A p p r o p r i a t e n e s s _ N N 1   C r i t e r i a _ N N 2   m e t h o d o l o g y _ N N 1   a n d _ C C   o t h e r _ J J   s u p p o r t i n g _ J J   d o c u m e n t s _ N N 2   g o _ V V 0   t o _ I I   w w w _ N N U   . _ .   
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 A d v a n c e s _ N N 2   i n _ I I   C T _ N N 1   i n _ I I   r e c e n t _ J J   y e a r s _ N N T 2   h a v e _ V H 0   f o c u s e d _ V V N   i n _ R R 2 1   p a r t _ R R 2 2   o n _ I I   r e d u c e d _ J J   r a d i a t i o n _ N N 1   d o s e _ N N 1   , _ ,   a n _ A T 1   i m p o r t a n t _ J J   t o p i c _ N N 1   f o r _ I F   t h e _ A T   y e a r s _ N N T 2   t o _ T O   c o m e _ V V I   . _ .   
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 D B T _ N P 1   w o r k e d _ V V D   w i t h _ I W   c o n t i n u o u s _ J J   x - r a y _ J J   t u b e _ N N 1   m o t i o n _ N N 1   , _ ,   t a k i n g _ V V G   1 5 _ M C   p r o j e c t i o n s _ N N 2   o v e r _ I I   a _ A T 1   1 5 - d e g r e e _ J J   a n g u l a r _ J J   r a n g e _ N N 1   . _ .   
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 I n _ I I   t h e _ A T   B o g a l u s a _ N P 1   H e a r t _ N N 1   S t u d y _ N N 1   o f _ I O   5 - t o _ M C   1 0 - y r - o l d _ J J   o b e s e _ J J   c h i l d r e n _ N N 2   , _ ,   5 8 % _ N N U   o f _ I O   t h e _ A T   p o p u l a t i o n _ N N 1   h a d _ V H D   o n e _ M C 1   r i s k _ N N 1   f a c t o r _ N N 1   f o r _ I F   c a r d i o v a s c u l a r _ J J   d i s e a s e _ N N 1   a n d _ C C   2 5 % _ N N U   h a d _ V H D   t w o _ M C   o r _ C C   m o r e _ R R R   . _ .   
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 A M O S S _ N P 1   w a s _ V B D Z   a p p r o v e d _ V V N   b y _ I I   t h e _ A T   H u m a n _ J J   R e s e a r c h _ N N 1   E t h i c s _ N N   C o m m i t t e e _ N N 1   o f _ I O   T h e _ A T   U n i v e r s i t y _ N N 1   o f _ I O   N e w _ N P 1   S o u t h _ N P 1   W a l e s _ N P 1   , _ ,   A u s t r a l i a _ N P 1   ( _ (   R e f e r e n c e _ N N 1   0 7 3 1 3 _ M C   ) _ )   a n d _ C C   m u l t i p l e _ J J   o t h e r _ J J   e t h i c a l _ J J   a n d _ C C   s i t e _ N N 1   g o v e r n a n c e _ N N 1   r e v i e w s _ N N 2   . _ .   
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 M i R N A s _ N N 2   w i t h _ I W   c y c l e _ N N 1   t h r e s h o l d s _ N N 2   ( _ (   C T s _ N N 2   ) _ )   g r e a t e r _ J J R   t h a n _ C S N   3 5 _ M C   w e r e _ V B D R   e x c l u d e d _ V V N   f r o m _ I I   f u r t h e r _ J J R   a n a l y s i s _ N N 1   . _ .   
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 R e s u l t s _ N N 2   W e _ P P I S 2   o b t a i n e d _ V V D   a g g r e g a t e d _ J J   s c r e e n i n g _ N N 1   d a t a _ N N   f o r _ I F   5 _ M C   2 4 3 _ M C   6 5 8 _ M C   w o m e n _ N N 2   s c r e e n e d _ V V N   b e t w e e n _ I I   A p r i l _ N P M 1   1 _ M C 1   , _ ,   2 0 0 3 _ M C   , _ ,   a n d _ C C   M a r c h _ N P M 1   3 1 _ M C   , _ ,   2 0 0 7 _ M C   . _ .   
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 F u r t h e r _ J J R   i n v e s t i g a t i o n s _ N N 2   a r e _ V B R   n e e d e d _ V V N   t o _ T O   e s t a b l i s h _ V V I   t h e _ A T   l i n k _ N N 1   b e t w e e n _ I I   i n c r e a s e d _ J J   h i p p o c a m p a l _ J J   z i n c _ N N 1   l e v e l s _ N N 2   a n d _ C C   t h e _ A T   a g e - a s s o c i a t e d _ J J   m e m o r y _ N N 1   d e f i c i t s _ N N 2   a n d _ C C   h o w _ R G Q   d i e t a r y _ J J   z i n c _ N N 1   s u p p l e m e n t a t i o n _ N N 1   a f f e c t s _ V V Z   t h e _ A T   h i p p o c a m p a l _ J J   z i n c _ N N 1   l e v e l s _ N N 2   a n d _ C C   p l a s t i c i t y _ N N 1   . _ .   
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 T h e _ A T   m e a n _ J J   ( _ (   S D _ N P 1   ) _ )   d i f f e r e n c e _ N N 1   b e t w e e n _ I I   t h e _ A T   t w o _ M C   m e t h o d s _ N N 2   w a s _ V B D Z   0 . 0 0 3 _ M C   ( _ (   0 . 8 6 _ M C   ) _ )   , _ ,   a n d _ C C   T a b l e _ N N 1   2 _ M C   a n d _ C C   F i g u r e _ N N 1   1 D _ N N U   s h o w _ V V 0   a _ A T 1   g o o d _ J J   l i n e a r i t y _ N N 1   f i t _ N N 1   . _ .   
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 T o _ T O   d e t e r m i n e _ V V I   w h e t h e r _ C S W   t h e s e _ D D 2   c h a n g e s _ N N 2   w e r e _ V B D R   a s s o c i a t e d _ V V N   w i t h _ I W   a l t e r e d _ J J   c o l l a g e n _ N N 1   c o n t e n t _ N N 1   , _ ,   w e _ P P I S 2   u n d e r t o o k _ V V D   c i r c u l a r _ J J   p o l a r i z a t i o n _ N N 1   m i c r o s c o p i c _ J J   i m a g i n g _ N N 1   o f _ I O   t h e _ A T   a o r t i c _ J J   w a l l _ N N 1   o f _ I O   1 5 - m o n t h - o l d _ J J   m i c e _ N N 2   . _ .   
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 T h e r e s a _ N P 1   A . _ N P 1   G u i s e _ N N 1   1 D i v i s i o n _ F O   o f _ I O   E n d o c r i n o l o g y _ N P 1   , _ ,   I n d i a n a _ N P 1   U n i v e r s i t y _ N N 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   , _ ,   I n d i a n a p o l i s _ N P 1   , _ ,   I N _ I I   4 6 2 0 2 _ M C   , _ ,   U S A _ N P 1   2 D i v i s i o n _ F O   o f _ I O   E n d o c r i n o l o g y _ N P 1   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   V i r g i n i a _ N P 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   , _ ,   C h a r l o t t e s v i l l e _ N P 1   , _ ,   V A _ F W   2 2 9 0 3 _ M C   , _ ,   U S A _ N P 1   3 C e n t e r _ F O   f o r _ I F   C o m p u t a t i o n a l _ J J   B i o l o g y _ N N 1   a n d _ C C   B i o i n f o r m a t i c s _ N P 1   , _ ,   I n d i a n a _ N P 1   U n i v e r s i t y _ N N 1   , _ ,   I n d i a n a p o l i s _ N P 1   , _ ,   I N _ I I   4 6 2 0 2 _ M C   , _ ,   U S A _ N P 1   4 D i v i s i o n _ F O   o f _ I O   M e t a b o l i s m _ N N 1   , _ ,   E n d o c r i n o l o g y _ N P 1   a n d _ C C   D i a b e t e s _ N N 1   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   M i c h i g a n _ N P 1   , _ ,   A n n _ N P 1   A r b o r _ N P 1   , _ ,   M I _ N P 1   4 8 1 0 5 _ M C   , _ ,   U S A _ N P 1   5 D e p a r t m e n t _ F O   o f _ I O   B i o c h e m i s t r y _ N P 1   a n d _ C C   M o l e c u l a r _ J J   B i o l o g y _ N N 1   , _ ,   I n d i a n a _ N P 1   U n i v e r s i t y _ N N 1   S c h o o l _ N N 1   o f _ I O   M e d i c i n e _ N N 1   , _ ,   I n d i a n a p o l i s _ N P 1   , _ ,   I N _ I I   4 6 2 0 2 _ M C   , _ ,   U S A _ N P 1   6 R i c h a r d _ F O   L . _ N P 1   R o u d e b u s h _ N P 1   V A _ F W   M e d i c a l _ J J   C e n t e r _ N N 1   , _ ,   I n d i a n a p o l i s _ N P 1   , _ ,   I N _ I I   4 6 2 0 2 _ M C   , _ ,   U S A _ N P 1   C o r r e s p o n d e n c e _ N N 1   : _ :   t g u i s e @ i u . e d u _ F O   h t t p _ N N U   : _ :   H i g h l i g h t s _ V V Z   T G F - b _ N N 1   i n h i b i t i o n _ N N 1   d e c r e a s e s _ V V Z   p r o m e t a s t a t i c _ J J   g e n e s _ N N 2   a n d _ C C   P M E P A 1 _ F O   i n h i b i t s _ V V Z   T G F - b _ N N 1   s i g n a l i n g _ V V G   b y _ I I   a _ A T 1   n o n - p r o t e a s o m a l _ J J   m e c h a n i s m _ N N 1   C l i n i c a l l y _ R R   , _ ,   l o w _ J J   P M E P A 1 _ F O   c o r r e l a t e s _ V V Z   w i t h _ I W   p o o r _ J J   m e t a s t a s i s - f r e e _ J J   s u r v i v a l _ N N 1   P M E P A 1 _ F O   k n o c k d o w n _ N N 1   i n c r e a s e s _ V V Z   p r o s t a t e _ N N 1   c a n c e r _ N N 1   b o n e _ N N 1   m e t a s t a s e s _ V V Z   i n _ I I   a _ A T 1   m o u s e _ N N 1   m o d e l _ N N 1   S U M M A R Y _ N N 1   T r a n s f o r m i n g _ V V G   g r o w t h _ N N 1   f a c t o r - b _ N N 1   ( _ (   T G F - b _ N P 1   ) _ )   r e g u l a t e s _ V V Z   t h e _ A T   e x p r e s s i o n _ N N 1   o f _ I O   g e n e s _ N N 2   s u p p o r t i n g _ V V G   b r e a s t _ N N 1   c a n c e r _ N N 1   c e l l s _ N N 2   i n _ I I   b o n e _ N N 1   , _ ,   b u t _ C C B   l i t t l e _ D A 1   i s _ V B Z   k n o w n _ V V N   a b o u t _ I I   p r o s t a t e _ N N 1   c a n c e r _ N N 1   b o n e _ N N 1   m e t a s t a s e s _ N N 2   a n d _ C C   T G F - b _ N P 1   . _ .   
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 B e c a u s e _ C S   t h e _ A T   o n l y _ R R   t w o _ M C   c a s e s _ N N 2   o f _ I O   E b o l a _ N P 1   v i r u s _ N N 1   - _ -   i n f e c t e d _ J J   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   U n i t e d _ N P 1   S t a t e s _ N P 1   w e r e _ V B D R   t h e _ A T   r e s u l t _ N N 1   o f _ I O   e v a c u a t i o n _ N N 1   e f f o r t s _ N N 2   , _ ,   t h i s _ D D 1   r e p r e s e n t s _ V V Z   a _ A T 1   v e r y _ R G   r a r e _ J J   s i t u a t i o n _ N N 1   . _ .   
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 I n _ I I   V E _ N P 1   , _ ,   K P _ N P 1   r e s u l t e d _ V V D   i n _ I I   i n c r e a s e d _ J J   e l b o w _ N N 1   e x t e n s i o n _ N N 1   w i t h o u t _ I W   c o m p e n s a t o r y _ J J   t r u n k _ N N 1   m o v e m e n t _ N N 1   i n _ I I   t h e _ A T   m i l d _ J J   s u b g r o u p _ N N 1   . _ .   
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 I n _ I I   t h i r d - g e n e r a t i o n _ J J   A C I _ N N 2   , _ ,   s c a f f o l d s _ N N 2   a r e _ V B R   b i o d e g r a d a b l e _ J J   , _ ,   n o n c y t o t o x i c _ J J   , _ ,   a n d _ C C   m e c h a n i c a l l y _ R R   p l i a b l e _ J J   . _ .   
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 T h e s e _ D D 2   f a c i l i t i e s _ N N 2   a l s o _ R R   i n c l u d e _ V V 0   4 3 _ M C   s p e c i a l i s t _ J J   e a t i n g _ N N 1   d i s o r d e r s _ N N 2   s e r v i c e s _ N N 2   w i t h _ I W   d e d i c a t e d _ J J   i n p a t i e n t s _ N N 2   b e d s _ N N 2   , _ ,   a l s o _ R R   l o c a t e d _ V V N   i n _ I I   g e n e r a l _ J J   h o s p i t a l s _ N N 2   . _ .   
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 T h e _ A T   f i r s t _ M D   g r o u p _ N N 1   o f _ I O   1 7 7 _ M C   p a t i e n t s _ N N 2   ( _ (   J u l y _ N P M 1   2 0 0 2 _ M C   t o _ I I   J u n e _ N P M 1   2 0 0 3 _ M C   ) _ )   d i d _ V D D   n o t _ X X   r e c e i v e _ V V I   v i t a m i n _ N N 1   C _ Z Z 1   s u p p l e m e n t a t i o n _ N N 1   , _ ,   w h e r e a s _ C S   t h e _ A T   s e c o n d _ M D   g r o u p _ N N 1   o f _ I O   2 1 5 _ M C   p a t i e n t s _ N N 2   ( _ (   J u l y _ N P M 1   2 0 0 3 _ M C   t o _ I I   J u n e _ N P M 1   2 0 0 4 _ M C   ) _ )   r e c e i v e d _ V V D   v i t a m i n _ N N 1   C _ Z Z 1   s u p p l e m e n t a t i o n _ N N 1   . _ .   
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 A _ A T 1   t h i r d _ M D   q u e s t i o n _ N N 1   i s _ V B Z   w h e t h e r _ C S W   s u i c i d e _ N N 1   i s _ V B Z   s u f f i c i e n t l y _ R R   c o m m o n _ J J   i n _ I I   t h e _ A T   h i g h e s t - r i s k _ J J   s t r a t u m _ N N 1   a n d _ C C   a v a i l a b l e _ J J   i n t e r v e n t i o n s _ N N 2   s u f f i c i e n t l y _ R R   p o w e r f u l _ J J   t o _ T O   m a k e _ V V I   t a r g e t e d _ V V N   p o s t - h o s p i t a l _ J J   i n t e r v e n t i o n s _ N N 2   e f f i c i e n t _ J J   c o m p a r e d _ V V N   t o _ I I   a l t e r n a t i v e _ J J   w a y s _ N N 2   o f _ I O   d e p l o y i n g _ V V G   t h e _ A T   s a m e _ D A   c l i n i c a l _ J J   r e s o u r c e s _ N N 2   . _ .   
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 A u t h o r _ N N 1   c o n t r i b u t i o n s _ N N 2   w e r e _ V B D R   a s _ C S A   f o l l o w s _ V V Z   : _ :   S t u d y _ N N 1   c o n c e p t _ N N 1   a n d _ C C   d e s i g n _ N N 1   : _ :   D e _ N P 1   W a a l _ N P 1   , _ ,   G u s s e k l o o _ N P 1   , _ ,   V a n _ N P 1   d e r _ N P 1   M a s t _ N P 1   . _ .   
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 S t a i n e d _ J J   t i s s u e s _ N N 2   w e r e _ V B D R   m o u n t e d _ V V N   o n _ I I   g l a s s _ N N 1   s l i d e s _ V V Z   w i t h _ I W   F l u o r o - G e l _ N P 1   m o u n t i n g _ V V G   m e d i a _ N N   ( _ (   E l e c t r o n _ N N 1   M i c r o s c o p y _ N N 1   S c i e n c e s _ N N 2   , _ ,   H a t f i e l d _ N P 1   , _ ,   P A _ N P 1   ) _ )   . _ .   
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 T h e _ A T   m e c h a n i s m _ N N 1   o f _ I O   t h i s _ D D 1   n e u r o l o g i c _ J J   d e t e r i o r a t i o n _ N N 1   i s _ V B Z   n o t _ X X   f u l l y _ R R   u n d e r s t o o d _ V V N   , _ ,   b u t _ C C B   a p p e a r s _ V V Z   t o _ T O   b e _ V B I   r e l a t e d _ V V N   t o _ T O   d o s a g e _ V V I   s i n c e _ C S   a _ A T 1   h i g h _ J J   s t a r t i n g _ N N 1   d o s e _ N N 1   c o u l d _ V M   i n c r e a s e _ V V I   t h e _ A T   r i s k _ N N 1   o f _ I O   r a p i d _ J J   c h e l a t o r - i n d u c e d _ J J   p a r a d o x i c a l _ J J   w o r s e n i n g _ J J   . _ .   
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 B y _ I I   t h e _ A T   e n d _ N N 1   o f _ I O   t h e _ A T   4 2 - m o n t h _ J J   f o l l o w - u p _ J J   p e r i o d _ N N 1   , _ ,   t h e _ A T   r e d u c e d _ J J   m o r t a l i t y _ N N 1   i n _ I I   t h e _ A T   p a r t i c i p a t i n g _ J J   h o s p i t a l s _ N N 2   w a s _ V B D Z   n o _ R R 2 1   l o n g e r _ R R 2 2   s i g n i f i c a n t _ J J   ( _ (   . 0 . 1 _ M C   p e r c e n t a g e _ N N 1   p o i n t s _ N N 2   ; _ ;   9 5 % _ N N U   C I _ F O   , _ ,   . 0 . 6 _ M C   t o _ I I   0 . 3 _ M C   ) _ )   . _ .   
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 I t _ P P H 1   i s _ V B Z   a l s o _ R R   a p p r o p r i a t e _ J J   f o r _ I F   t h e _ A T   s p e c i a l i s t _ N N 1   t o _ T O   f o r g o _ V V I   o r _ C C   d e l a y _ V V I   t h e _ A T   i n t e r n a l _ J J   g y n e c o l o g i c _ J J   c o m p o n e n t _ N N 1   o f _ I O   t h e _ A T   e x a m i n a t i o n _ N N 1   o f _ I O   a n _ A T 1   a d o l e s c e n t _ J J   p a t i e n t _ N N 1   ( _ (   a s _ C S A   d e s c r i b e d _ V V N   i n _ I I   f u r t h e r _ J J R   d e t a i l _ N N 1   b e l o w _ R L   ) _ )   o r _ C C   i n _ I I   c a s e s _ N N 2   w h e r e _ R R Q   t h e _ A T   p a t i e n t _ N N 1   m a k e s _ V V Z   i n f o r m e d _ J J   r e f u s a l _ N N 1   , _ ,   c a n _ V M   n o t _ X X   t o l e r a t e _ V V I   t h e _ A T   e x a m i n a t i o n _ N N 1   , _ ,   o r _ C C   i s _ V B Z   n e a r _ I I   t h e _ A T   e n d _ N N 1   o f l i f e _ N N 1   . _ .   
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 A l l _ D B   s t a t i s t i c a l _ J J   a n a l y s e s _ N N 2   w e r e _ V B D R   c o m p l e t e d _ V V N   u s i n g _ V V G   S A S _ N P 1   E n t e r p r i s e _ N N 1   G u i d e _ N N 1   7 . 1 _ M C   s o f t w a r e _ N N 1   . _ .   
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 C o r t i c a l _ J J   S t i m u l a t i o n _ N N 1   P r o g r a m m i n g _ N N 1   T h r e e _ M C   e l e c t r o d e _ N N 1   c o n t a c t s _ N N 2   a l o n g _ I I   o n e _ M C 1   e d g e _ N N 1   o f _ I O   t h e _ A T   l e a d _ N N 1   w e r e _ V B D R   c o n f i g u r e d _ V V N   a s _ C S A   a n o d e s _ N N 2   , _ ,   a n d _ C C   3 _ M C   c o n t a c t s _ N N 2   o n _ I I   t h e _ A T   o p p o s i t e _ J J   e d g e _ N N 1   w e r e _ V B D R   p r o g r a m m e d _ V V N   a s _ C S A   c a t h o d e s _ N N 2   . _ .   
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 O f _ I O   n o t e _ N N 1   , _ ,   f u r t h e r _ J J R   s u b s e t _ N N 1   a n a l y s i s _ N N 1   o f _ I O   t h e _ A T   l e s s _ D A R   t h a n _ C S N   3 5 % _ N N U   a n d _ C C   m o r e _ D A R   t h a n _ C S N   8 5 % _ N N U   p e r f u s i o n _ N N 1   r e d u c t i o n _ N N 1   c a t e g o r i e s _ N N 2   i n t o _ I I   i n d i v i d u a l _ J J   g r o u p s _ N N 2   w a s _ V B D Z   l i m i t e d _ V V N   b y _ I I   s m a l l _ J J   s a m p l e _ N N 1   s i z e s _ N N 2   ( _ (   1 1 _ M C   p a t i e n t s _ N N 2   i n _ I I   t h e _ A T   , _ ,   3 5 % _ N N U   g r o u p _ N N 1   a n d _ C C   s e v e n _ M C   i n _ I I   t h e _ A T   . 8 5 % _ F O   g r o u p _ N N 1   ) _ )   . _ .   
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 T h e s e _ D D 2   f i n d i n g s _ N N 2   t a k e n _ V V N   t o g e t h e r _ R L   s u g g e s t _ V V 0   t h a t _ C S T   t h e _ A T   C A T _ N N 1   a s s e s s _ V V 0   s o m e _ D D   u n d e r l y i n g _ J J   d i m e n s i o n s _ N N 2   o f _ I O   t h e _ A T   c o n s t r u c t _ N N 1   c o m m u n i c a t i o n _ N N 1   a t t i t u d e s _ N N 2   t h a t _ C S T   i s _ V B Z   n o t _ X X   a s s e s s e d _ V V N   i n _ I I   t h e _ A T   K i d d y C A T _ N N 1   . _ .   
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 I n _ I I   o u r _ A P P G E   s t u d y _ N N 1   , _ ,   n e a r l y _ R R   4 0 % _ N N U   o f _ I O   p a t i e n t s _ N N 2   l o s t _ V V D   c o n s c i o u s n e s s _ N N 1   f o r _ I F   l e s s _ D A R   t h a n _ C S N   1 0 _ M C   m i n u t e s _ N N T 2   , _ ,   a n d _ C C   a n o t h e r _ D D 1   2 1 . 0 % _ F O   l o s t _ J J   c o n s c i o u s n e s s _ N N 1   f o r _ I F   1 0 _ M C   t o _ I I   6 0 _ M C   m i n u t e s _ N N T 2   , _ ,   w i t h _ I W   s u b s e q u e n t _ J J   w i t n e s s e d _ V V D   r e c o v e r y _ N N 1   o f _ I O   a l e r t n e s s _ N N 1   d u r i n g _ I I   t h e _ A T   p r e h o s p i t a l _ J J   p h a s e _ N N 1   . _ .   
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 I n _ I I   m a n y _ D A 2   o t h e r _ J J   a s s a y s _ N N 2   , _ ,   t h i s _ D D 1   i n f o r m a t i o n _ N N 1   w o u l d _ V M   b e _ V B I   l o s t _ V V N   t o _ I I   t h e _ A T   d o m i n a n t _ J J   s i g n a l _ N N 1   o f _ I O   t h e _ A T   c l o n a l _ J J   e x p a n s i o n s _ N N 2   . _ .   
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 W e _ P P I S 2   t h a n k _ V V 0   D r . _ N N B   P h i l i p p _ N P 1   E l b e r t _ N P 1   a n d _ C C   D r . _ N N B   R i c h a r d _ N P 1   D a h l e r _ N P 1   f o r _ I F   p r o o f r e a d i n g _ V V G   t h e _ A T   m a n u s c r i p t _ N N 1   . _ .   
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 T h e _ A T   b r a i n s t e m s _ N N 2   w e r e _ V B D R   s e c t i o n e d _ V V N   t h r o u g h _ I I   t h e i r _ A P P G E   e n t i r e _ J J   r o s t r o c a u d a l _ J J   a x i s _ N N 1   a t _ I I   5 0 - m _ N N U   o n _ I I   a _ A T 1   c r y o s t a t _ N N 1   a n d _ C C   1 6 _ M C   s p a c e d _ J J   s e r i e s _ N N   o f _ I O   s e c t i o n s _ N N 2   w e r e _ V B D R   o b t a i n e d _ V V N   ( _ (   s e c t i o n s _ N N 2   s a m p l e d _ V V D   e v e r y _ A T 1   8 0 0 _ M C   m _ N N U   ) _ )   . _ .   
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 s i m i l a r l y _ R R   c o m p a r e d _ V V N   a _ A T 1   G P C _ N P 1   m e t h o d _ N N 1   t o _ I I   t h e _ A T   H i g h _ J J   P u r e _ J J   R N A _ N N 1   P a r a f f i n _ N N 1   K i t _ N N 1   ( _ (   R o c h e _ N P 1   ) _ )   a n d _ C C   d e m o n s t r a t e d _ V V D   l o w e r _ J J R   C t _ N N 1   v a l u e s _ N N 2   o f _ I O   b e t a - 2 _ M C   m i c r o g l o b u l i n _ N N 1   ( _ (   B 2 M _ F O   ) _ )   w h e n _ R R Q   m i R N A _ N N 1   w a s _ V B D Z   e x t r a c t e d _ V V N   f r o m _ I I   f o r m a l i n - f i x e d _ J J   p a r a f f i n - e m b e d d e d _ J J   t i s s u e _ N N 1   ( _ (   F F P E _ N P 1   ) _ )   b y _ I I   t h e _ A T   c o m m e r c i a l _ J J   k i t _ N N 1   . _ .   
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 A l t h o u g h _ C S   f l u c t u a t i o n s _ N N 2   i n _ I I   c h o r o i d a l _ J J   t h i c k n e s s _ N N 1   m a y _ V M   n o t _ X X   b e _ V B I   m e c h a n i s t i c _ J J   i n _ I I 3 1   t e r m s _ I I 3 2   o f _ I I 3 3   t h e _ A T   c a u s e _ N N 1   o f _ I O   v i s i o n _ N N 1   l o s s _ N N 1   i n _ I I   m i g r a i n e _ N N 1   ( _ (   s e e _ V V 0   S e c t i o n s _ N N 2   5 . _ M C   1 _ M C 1   a n d _ C C   5 . _ M C   2 _ M C   ) _ )   , _ ,   i t _ P P H 1   m a y _ V M   r e f l e c t _ V V I   a _ A T 1   v a s c u l a r _ J J   d y s r e g u l a t i o n _ N N 1   i n _ I I   m i g r a i n e _ N N 1   t h a t _ C S T   c o u l d _ V M   e x p l a i n _ V V I   w h y _ R R Q   t h e _ A T   r e t i n a _ N N 1   i s _ V B Z   s u s c e p t i b l e _ J J   t o _ I I   g l a u c o m a _ N N 1   d e v e l o p m e n t _ N N 1   i n _ I I   s o m e _ D D   m i g r a i n e _ N N 1   s u f f e r e r s _ N N 2   . _ .   
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 F i g u r e _ N N 1   3 _ M C   g i v e s _ V V Z   a _ A T 1   f u r t h e r _ J J R   b r e a k d o w n _ N N 1   o f _ I O   t h e s e _ D D 2   4 7 _ M C   a r t i c l e s _ N N 2   i n _ I I 3 1   t e r m s _ I I 3 2   o f _ I I 3 3   y e a r _ N N T 1   , _ ,   t o p i c _ N N 1   , _ ,   a n d _ C C   j o u r n a l _ N N 1   . _ .   
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 I n t e r e s t i n g l y _ R R   , _ ,   2 _ M C   m a c r o c y c l i c _ J J   G B C A s - g a d o t e r a t e _ J J   m e g l u m i n e _ N N 1   a n d _ C C   g a d o t e r i d o l _ V V 0   ' _ N U L L   p r e s e n t _ V V 0   a _ A T 1   m u c h _ R R   f a s t e r _ J J R   c l e a r a n c e _ N N 1   ( _ (   2 0 - 3 0 _ M C M C   d a y s _ N N T 2   ) _ )   . _ .   
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 B e c a u s e _ I I 2 1   o f _ I I 2 2   t h e _ A T   r e l a t i v e l y _ R R   s m a l l _ J J   p e r c e n t a g e _ N N 1   o f _ I O   n o n w h i t e _ N N 1   s t u d e n t s _ N N 2   i n _ I I   V e r m o n t _ N P 1   d u r i n g _ I I   t h e _ A T   t i m e _ N N T 1   p e r i o d _ N N 1   o f _ I O   t h i s _ D D 1   s t u d y _ N N 1   , _ ,   t h e _ A T   m i n i m u m _ J J   c e l l _ N N 1   s i z e _ N N 1   r e s t r i c t i o n _ N N 1   o f _ I O   1 0 _ M C   p r e v e n t e d _ V V D   u s _ P P I O 2   f r o m _ I I   s e a r c h i n g _ V V G   f o r _ I F   e f f e c t s _ N N 2   o f _ I O   r a c e _ N N 1   . _ .   
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 T h e _ A T   t w i t c h _ N N 1   f o r c e _ N N 1   e l i c i t e d _ V V N   b y _ I I   t h e _ A T   M m a x _ N N 1   s t i m u l u s _ N N 1   w a s _ V B D Z   g r e a t e r _ J J R   i m m e d i a t e l y _ R R   a f t e r _ I I   t h e _ A T   p r o t o c o l _ N N 1   b u t _ C C B   w a s _ V B D Z   t h e n _ R T   r e d u c e d _ V V N   . _ .   
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 T h e _ A T   m e c h a n i s m s _ N N 2   u n d e r l y i n g _ V V G   t h e _ A T   i n c r e a s e d _ J J   r i s k _ N N 1   o f _ I O   h y p o n a t r e m i a _ N N 1   i n _ I I   s o m e _ D D   T B I _ J J   p a t i e n t s _ N N 2   r e m a i n _ V V 0   u n c l e a r _ J J   t o _ I I   d a t e _ N N 1   . _ .   
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 G a s t r o e s o p h a g e a l _ J J   r e f l u x _ N N 1   d i s e a s e _ N N 1   ( _ (   G E R D _ N P 1   ) _ )   w a s _ V B D Z   o n e _ M C 1   o f _ I O   t h e _ A T   m o s t _ R G T   c o m m o n _ J J   g a s t r o i n t e s t i n a l _ J J   d i s e a s e s _ N N 2   i n _ I I   E u r o p e _ N P 1   a n d _ C C   t h e _ A T   U n i t e d _ N P 1   S t a t e s _ N P 1   w i t h _ I W   p r e v a l e n c e _ N N 1   r a t e s _ N N 2   o f _ I O   1 0 % _ N N U   t o _ I I   2 5 % _ N N U   i n _ I I   p o p u l a t i o n - b a s e d _ N N 1   s t u d i e s . 9 , 1 0 _ F O   R e p o r t s _ V V Z   f r o m _ I I   m a n y _ D A 2   o t h e r _ J J   r e g i o n s _ N N 2   h a v e _ V H 0   a l s o _ R R   d e m o n s t r a t e d _ V V N   a n _ A T 1   i n c r e a s e _ N N 1   i n _ I I   t h e _ A T   p r e v a l e n c e _ N N 1   o f _ I O   G E R D _ N N 1   . _ .   
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 W a l c o t t _ N P 1   e t _ N P 1   a l 1 1 _ F O   i d e n t i f i e d _ V V N   a _ A T 1   g r e a t e r _ J J R   m o r t a l i t y _ N N 1   a s s o c i a t e d _ V V N   w i t h _ I W   f a s t e r _ J J R   t i m e _ N N T 1   t o _ I I   s u r g e r y _ N N 1   , _ ,   b u t _ C C B   t h e _ A T   s t u d y _ N N 1   w a s _ V B D Z   l i m i t e d _ V V N   t o _ I I   p a t i e n t s _ N N 2   w i t h _ I W   A S D H _ N N 1   b u t _ C C B   l i m i t e d _ J J   a d d i t i o n a l _ J J   s t r u c t u r a l _ J J   b r a i n _ N N 1   i n j u r y _ N N 1   . _ .   
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 T a b l e _ N N 1   5 _ M C   p r e s e n t s _ V V Z   t h e _ A T   s t a n d a r d i z e d _ J J   a n d _ C C   u n s t a n d a r d i z e d _ J J   c o e f f i c i e n t s _ N N 2   o f _ I O   b e l i e f s _ N N 2   a b o u t _ I I   P W S _ N P 2   a n d _ C C   t h e _ A T   c o n t r o l _ N N 1   v a r i a b l e s _ N N 2   f r o m _ I I   t h e _ A T   S U R _ N P 1   r e s u l t s _ N N 2   f o r _ C S   s y m p a t h y / s o c i a l _ F U   d i s t a n c i n g _ N N 1   . _ .   
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 A t _ I I   1 2 _ M C   m o n t h s _ N N T 2   f o l l o w i n g _ R A   t h e _ A T   o r i g i n a l _ J J   I D M _ N P 1   + _ F O   C M M _ N P 1   t r e a t m e n t _ N N 1   , _ ,   p r i m a r y _ J J   o u t c o m e _ N N 1   d a t a _ N N   o n _ I I   2 2 _ M C   o f _ I O   t h e _ A T   o r i g i n a l _ J J   2 9 _ M C   ( _ (   7 6 % _ N N U   ) _ )   s u b j e c t s _ N N 2   i n _ I I   t h i s _ D D 1   c o h o r t _ N N 1   w e r e _ V B D R   a v a i l a b l e _ J J   . _ .   
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 P r o t e i n s _ N N 2   w e r e _ V B D R   t r a n s f e r r e d _ V V N   e l e c t r i c a l l y _ R R   f r o m _ I I   t h e _ A T   g e l _ N N 1   o n t o _ I I   a _ A T 1   0 . 4 5 _ M C   | _ N U L L   x m _ N N U   n i t r o c e l l u l o s e _ N N 1   m e m b r a n e _ N N 1   ( _ (   M i l l i p o r e _ N P 1   , _ ,   T e m e c u l a _ N P 1   , _ ,   C A _ N P 1   , _ ,   U S A _ N P 1   ) _ )   b y _ I I   t h e _ A T   s e m i d r y _ J J   e l e c t r o - t r a n s f e r _ J J   m e t h o d _ N N 1   . _ .   
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 C u r r e n t l y _ R R   , _ ,   t h e _ A T   d o m i n a n t _ J J   m o d e _ N N 1   o f _ I O   P A _ N N 1   a n d _ C C   S B _ N P 1   e n v i r o n m e n t a l _ J J   a s s e s s m e n t _ N N 1   i s _ V B Z   c e n t e r e d _ V V N   o n _ I I   c o m b i n i n g _ V V G   G I S _ N N 2   a n d _ C C   a c c e l e r o m e t e r _ J J R   d a t a _ N N   - _ -   f o c u s i n g _ V V G   o n _ I I   s p e c i f i c _ J J   a _ J J 2 1   p r i o r i _ J J 2 2   l o c a t i o n s _ N N 2   s u c h _ I I 2 1   a s _ I I 2 2   t h e _ A T   h o m e _ N N 1   o r _ C C   w o r k _ V V 0   a d d r e s s _ N N 1   a n d _ C C   e x t r a c t i n g _ V V G   e n v i r o n m e n t a l _ J J   v a r i a b l e s _ N N 2   f r o m _ I I   G I S _ N N 2   f o r _ I F   t h o s e _ D D 2   l o c a t i o n s _ N N 2   u s i n g _ V V G   a _ A T 1   b u f f e r _ N N 1   ( _ (   3 _ M C   ) _ )   . _ .   
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 W r i t t e n _ V V N   i n f o r m e d _ J J   c o n s e n t _ N N 1   w a s _ V B D Z   o b t a i n e d _ V V N   f r o m _ I I   a l l _ D B   p a r e n t s _ N N 2   a n d _ C C   p a r t i c i p a n t s _ N N 2   m o r e _ D A R   t h a n _ C S N   1 6 _ M C   y e a r s _ N N T 2   o f _ I O   a g e _ N N 1   , _ ,   a n d _ C C   i n f o r m e d _ J J   a s s e n t _ N N 1   f r o m _ I I   p a r t i c i p a n t s _ N N 2   l e s s _ D A R   t h a n _ C S N   1 6 _ M C   y e a r s _ N N T 2   o f _ I O   a g e _ N N 1   , _ ,   a f t e r _ C S   a _ A T 1   d e t a i l e d _ J J   d e s c r i p t i o n _ N N 1   o f _ I O   t h e _ A T   s t u d y _ N N 1   h a d _ V H D   b e e n _ V B N   g i v e n _ V V N   . _ .   
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 W e _ P P I S 2   f o u n d _ V V D   t h a t _ C S T   p e r c e i v e d _ V V D   t r u s t w o r t h i n e s s _ N N 1   i s _ V B Z   i m p o r t a n t _ J J   i n _ I I   t h e r a p e u t i c _ J J   e n c o u n t e r s _ N N 2   a s _ C S A   i t _ P P H 1   h e l p s _ V V Z   t o _ T O   n e g o t i a t e _ V V I   t e n s i o n s _ N N 2   w i t h _ I I 3 1   r e s p e c t _ I I 3 2   t o _ I I 3 3   s u b j e c t i v e _ J J   p a i n _ N N 1   s y m p t o m s _ N N 2   , _ ,   a d d i c t i o n _ N N 1   , _ ,   a n d _ C C   p r e s c r i p t i o n _ N N 1   o p i o i d _ N N 1   u s e _ N N 1   . _ .   
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 I t _ P P H 1   i s _ V B Z   i m p o r t a n t _ J J   t o _ T O   u n d e r s t a n d _ V V I   , _ ,   h o w e v e r _ R R Q V   t h a t _ C S T   t h e _ A T   r e l a t i v e _ J J   i m p o r t a n c e _ N N 1   , _ ,   m e c h a n i s m s _ N N 2   a n d _ C C   f u n c t i o n s _ N N 2   o f _ I O   t h e _ A T   v a r i o u s _ J J   P R P H 2 / R D S _ F U   o l i g o m e r s _ N N 2   a r e _ V B R   n o t _ X X   u n d e r s t o o d _ V V N   , _ ,   a n d _ C C   g i v e n _ V V N   t h e _ A T   d i f f e r e n c e s _ N N 2   i n _ I I   d i s t r i b u t i o n _ N N 1   o f _ I O   c o m p l e x _ J J   t y p e _ N N 1   b e t w e e n _ I I   r o d s _ N N 2   a n d _ C C   c o n e s _ N N 2   , _ ,   t h e _ A T   f u n c t i o n _ N N 1   o f _ I O   i n d i v i d u a l _ J J   t y p e s _ N N 2   o f _ I O   P R P H 2 / R D S _ F U   c o m p l e x e s _ N N 2   r e m a i n s _ V V Z   o f _ I O   g r e a t _ J J   i n t e r e s t _ N N 1   . _ .   
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 A l t h o u g h _ C S   t h e _ A T   p r e s e n t _ J J   r e s u l t s _ N N 2   s h o w e d _ V V D   t h a t _ C S T   s t i m u l u s - p r e s e n t a t i o n _ J J   c o n d i t i o n _ N N 1   h a d _ V H D   a n _ A T 1   i m p a c t _ N N 1   o n _ I I   t h e _ A T   E R P _ N N 1   a m p l i t u d e s _ N N 2   , _ ,   t h e y _ P P H S 2   d i d _ V D D   n o t _ X X   f u l l y _ R R   c o n t r a d i c t _ V V I   t h e _ A T   f i n d i n g _ N N 1   b y _ I I   A m e n e d o _ N P 1   a n d _ C C   E s c e r a _ N P 1   ( _ (   2 0 0 0 _ M C   ) _ )   w h o _ P N Q S   f o u n d _ V V D   t h a t _ C S T   t h e _ A T   m a g n i t u d e _ N N 1   o f _ I O   t h e _ A T   M M N _ N P 1   w a s _ V B D Z   p r o p o r t i o n a l _ J J   t o _ I I   a _ A T 1   d i f f e r e n c e _ N N 1   b e t w e e n _ I I   s t a n d a r d s _ N N 2   a n d _ C C   d e v i a n t s _ N N 2   . _ .   
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 T h e _ A T   S M O G _ N N 1   a n d _ C C   G F O G _ V V 0   s c o r e s _ N N 2   w e r e _ V B D R   c o n s i s t e n t l y _ R R   h i g h e r _ J J R   t h a n _ C S N   t h e _ A T   F K G L _ N P 1   s c o r e _ N N 1   , _ ,   i n _ I I 3 1   k e e p i n g _ I I 3 2   w i t h _ I I 3 3   p r e v i o u s _ J J   r e p o r t s _ N N 2   . _ .   
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 F o r _ I F   t h a t _ D D 1   p u r p o s e _ N N 1   l i g a n d - b a s e d _ N N 1   a f f i n i t y _ N N 1   c h r o m a t o g r a p h y _ N N 1   c a n _ V M   b e _ V B I   e x p l o i t e d _ V V N   , _ ,   w h i c h _ D D Q   a l s o _ R R   c a n _ V M   b e _ V B I   e m p l o y e d _ V V N   t o _ T O   p u r i f y _ V V I   G P C R s _ N P 1   f r o m _ I I   n a t i v e _ J J   s o u r c e s _ N N 2   ( _ (   R e i l a n d e r _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   1 9 9 1 _ M C   ) _ )   . _ .   
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 I n _ I I   f a c t _ N N 1   , _ ,   o n l y _ R R   t h e _ A T   p r o v i s i o n _ N N 1   o f _ I O   v e r b a l _ J J   c o n t i n g e n c i e s _ N N 2   f o r _ I F   u n a m b i g u o u s _ J J   s t u t t e r i n g _ V V G   d u r i n g _ I I   p r a c t i c e _ N N 1   s e s s i o n s _ N N T 2   w a s _ V B D Z   a s s o c i a t e d _ V V N   w i t h _ I W   t r e a t m e n t _ N N 1   d u r a t i o n _ N N 1   a n d _ C C   t h i s _ D D 1   w a s _ V B D Z   i n _ I I   t h e _ A T   o p p o s i t e _ J J   d i r e c t i o n _ N N 1   t o _ I I   e x p e c t a t i o n s _ N N 2   . _ .   
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 F i n a l l y _ R R   , _ ,   a _ A T 1   t o t a l _ N N 1   o f _ I O   2 3 8 0 _ M C   p r e g n a n t _ J J   w o m e n _ N N 2   a g e d _ I I   2 1 _ M C   - _ -   3 8 _ M C   y e a r s _ N N T 2   w e r e _ V B D R   r e c r u i t e d _ V V N   f r o m _ I I   h o s p i t a l i z e d _ J J   a n d _ C C   o u t p a t i e n t _ N N 1   w o m e n _ N N 2   i n _ I I   o u r _ A P P G E   h o s p i t a l _ N N 1   . _ .   
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 W e _ P P I S 2   d i d _ V D D   n o t _ X X   a d d r e s s _ V V I   t e s t _ N N 1   p e r f o r m a n c e _ N N 1   f o r _ I F   d i f f e r e n t i a t i n g _ V V G   p e r f o r a t e d _ J J   f r o m _ I I   n o n p e r f o r a t e d _ J J   a p p e n d i c i t i s _ N N 1   , _ ,   n o r _ C C   d i d _ V D D   w e _ P P I S 2   l o o k _ V V I   a t _ I I   s p e c i f i c _ J J   U S _ N P 1   f e a t u r e s _ N N 2   . _ .   
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 A _ A T 1   c u r s o r y _ J J   r e v i e w _ N N 1   o f _ I O   t h e _ A T   p a s t _ J J   3 0 _ M C   y e a r s _ N N T 2   o f _ I O   l i t e r a t u r e _ N N 1   d e m o n s t r a t e s _ V V Z   s e v e r a l _ D A 2   d i s c r e t e _ J J   e v o l u t i o n s _ N N 2   i n _ I I   t h e _ A T   o p e r a t i v e _ J J   t r e a t m e n t _ N N 1   o f _ I O   h e r n i a _ N N 1   . _ .   
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 O v e r _ I I   t h e _ A T   s a m e _ D A   p e r i o d _ N N 1   , _ ,   a g e - s t a n d a r d i s e d _ J J   a d u l t _ N N 1   p r e v a l e n c e _ N N 1   o f _ I O   d i a b e t e s _ N N 1   a t _ R R 2 1   l e a s t _ R R 2 2   d o u b l e d _ V V N   f o r _ I F   m e n _ N N 2   i n _ I I   1 2 0 _ M C   c o u n t r i e s _ N N 2   a n d _ C C   f o r _ I F   w o m e n _ N N 2   i n _ I I   8 7 _ M C   c o u n t r i e s _ N N 2   , _ ,   w i t h _ I W   a _ A T 1   p o s t e r i o r _ J J   p r o b a b i l i t y _ N N 1   o f _ I O   0 . 8 8 7 _ M C   o r _ C C   h i g h e r _ J J R   . _ .   
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 S i m i l a r l y _ R R   , _ ,   w e _ P P I S 2   f o u n d _ V V D   t h e _ A T   l e v e l _ N N 1   o f _ I O   N R 1 _ F O   p r o t e i n _ N N 1   t o _ T O   b e _ V B I   s i g n i f i c a n t l y _ R R   r e d u c e d _ V V N   i n _ I I   C _ N P 1   c a r r i e r s _ N N 2   w i t h _ I W   s c h i z o p h r e n i a _ N N 1   r e l a t i v e _ I I 2 1   t o _ I I 2 2   C _ N P 1   c a r r i e r _ N N 1   c o n t r o l s _ N N 2   ( _ (   P = 0 . 0 2 5 _ F O   ; _ ;   F i g u r e _ N N 1   3 c _ F O   ) _ )   . _ .   
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 M a r c o _ N P 1   L e z z e r i n i _ N P 1   a n d _ C C   Y e l e n a _ N P 1   B u d o v s k a y a _ N P 1   S w a m m e r d a m _ N P 1   I n s t i t u t e _ N N 1   f o r _ I F   L i f e _ N N 1   S c i e n c e s _ N N 2   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   A m s t e r d a m _ N P 1   , _ ,   A m s t e r d a m _ N P 1   , _ ,   T h e _ A T   N e t h e r l a n d s _ N P 1   C o r r e s p o n d e n c e _ N N 1   Y e l e n a _ N P 1   B u d o v s k a y a _ N P 1   , _ ,   S w a m m e r d a m _ N P 1   I n s t i t u t e _ N N 1   f o r _ I F   L i f e _ N N 1   S c i e n c e s _ N N 2   , _ ,   U n i v e r s i t y _ N N 1   o f _ I O   A m s t e r d a m _ N P 1   , _ ,   S c i e n c e _ N N 1   P a r k _ N N 1   9 0 4 _ M C   , _ ,   A m s t e r d a m _ N P 1   1 0 9 8 _ M C   X H _ N P 1   , _ ,   T h e _ A T   N e t h e r l a n d s _ N P 1   . _ .   
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 S i m i l a r l y _ R R   , _ ,   0 1 5 _ M C   , _ ,   a n _ A T 1   i n v e s t i g a t i o n a l _ J J   p a r t i c i p a n t _ N N 1   w i t h _ I W   m o d e r a t e _ J J   a p h a s i a _ N N 1   r e t u r n e d _ V V N   a t _ I I   8 _ M C   m o n t h s _ N N T 2   p o s t t r e a t m e n t _ N N 1   , _ ,   w h e r e a s _ C S   t h e _ A T   c o n t r o l _ N N 1   p a r t i c i p a n t _ N N 1   0 0 5 _ M C   r e t u r n e d _ V V D   a t _ I I   2 0 _ M C   m o n t h s _ N N T 2   p o s t t r e a t m e n t _ N N 1   . _ .   
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 O b e s i t y _ N N 1   c a u s e s _ V V Z   a d v e r s e _ J J   e f f e c t s _ N N 2   o n _ I I   h e a l t h _ N N 1   i n _ I I   c h i l d h o o d _ N N 1   , _ ,   w h i c h _ D D Q   p e r p e t u a t e _ V V 0   a n d _ C C   a m p l i f y _ V V 0   t h e _ A T   m e t a b o l i c _ J J   d i s t u r b a n c e s _ N N 2   i n _ I I   a d u l t h o o d _ N N 1   , _ ,   t h e r e b y _ R R   l e a d i n g _ V V G   t o _ I I   a _ A T 1   h i g h _ J J   r i s k _ N N 1   o f _ I O   m o r t a l i t y _ N N 1   . _ .   
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 A t _ I I   t h e _ A T   h e a r t _ N N 1   o f _ I O   t h i s _ D D 1   d e b a t e _ N N 1   a r e _ V B R   t h e _ A T   p r o p o n e n t s _ N N 2   a n d _ C C   c r i t i c s _ N N 2   o f _ I O   t h e _ A T   c o m p e t e n c y - b a s e d _ J J   e d u c a t i o n _ N N 1   m o v e m e n t _ N N 1   , _ ,   w i t h _ I W   p r o v o c a t i v e _ J J   a r g u m e n t s _ N N 2   f o r _ I F   b o t h _ D B 2   b r e a k i n g _ V V G   d o w n _ R P   p e r f o r m a n c e _ N N 1   i n t o _ I I   o b s e r v a b l e _ J J   c o m p e t e n c i e s _ N N 2   a n d _ C C   c o n s i d e r i n g _ V V G   p e r f o r m a n c e _ N N 1   a s _ I I   a _ A T 1   g l o b a l _ J J   p h e n o m e n o n _ N N 1   o r _ C C   s u m _ N N 1   t h a t _ C S T   m a y _ V M   b e _ V B I   i n c o m p l e t e l y _ R R   m e a s u r e d _ V V N   e v e n _ R R   b y _ I I   a c c u r a t e l y _ R R   a s s e s s i n g _ V V G   i t s _ A P P G E   p a r t s _ N N 2   . _ .   
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 N o t a b l y _ R R   , _ ,   w h i l e _ C S   g e n o m e _ N N 1   s e q u e n c i n g _ N N 1   o f _ I O   2 0 _ M C   t r e a t e d _ V V D   M M _ N N U   t u m o r s _ N N 2   d i d _ V D D   n o t _ X X   i d e n t i f y _ V V I   a n y _ D D   p r o t e a s o m e _ J J   P S M B 5 _ F O   m u t a t i o n s _ N N 2   , _ ,   t h i s _ D D 1   i n i t i a l _ J J   g e n o m i c _ J J   a n a l y s i s _ N N 1   o f _ I O   M M _ N N U   d i d _ V D D   i d e n t i f y _ V V I   t w o _ M C   m u t a t i o n s _ N N 2   i n _ I I   X B P 1 _ F O   ( _ (   C h a p m a n _ N P 1   e t _ R A 2 1   a l . _ R A 2 2   , _ ,   2 0 1 1 _ M C   ) _ )   , _ ,   b o t h _ R R   i n _ I I   t r e a t m e n t - r e f r a c t o r y _ J J   t u m o r s _ N N 2   ( _ (   F i g u r e _ N N 1   2 F _ R A   ) _ )   . _ .   
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 T h e _ A T   m a x i l l a r y _ J J   s i n u s _ N N 1   c a n _ V M   b e _ V B I   d i v i d e d _ V V N   i n t o _ I I   2 _ M C   p o r t i o n s _ N N 2   b y _ I I   t h e _ A T   i m a g i n a r y _ J J   O h n g r e n _ N N 1   l i n e _ N N 1   , _ ,   d r a w n _ V V N   f r o m _ I I   t h e _ A T   m e d i a l _ J J   c a n t h u s _ N N 1   t o _ I I   t h e _ A T   a n g l e _ N N 1   o f _ I O   t h e _ A T   m a n d i b l e _ N N 1   . _ .   
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 T h e n _ R T   , _ ,   t h e _ A T   s c o r e s _ N N 2   o b t a i n e d _ V V N   b y _ I I   t h e _ A T   p a r e n t s _ N N 2   i n _ I I   t h e _ A T   C I S S _ N N 1   q u e s t i o n n a i r e _ N N 1   w e r e _ V B D R   c o r r e l a t e d _ V V N   w i t h _ I W   t h o s e _ D D 2   i n _ I I   t h e _ A T   R S D S _ N P 1   . _ .   
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 S S _ N P 1   , _ ,   R D M _ N P 1   , _ ,   R A S _ N P 2   , _ ,   P L H _ N P 1   , _ ,   D A P _ N P 1   , _ ,   N K R _ N P 1   , _ ,   J S J _ N P 1   , _ ,   a n d _ C C   D C L _ M C   c o n t r i b u t e d _ V V D   t o _ I I   t h e _ A T   a c q u i s i t i o n _ N N 1   o f _ I O   d a t a _ N N   a n d _ C C   r e v i e w e d _ V V D   t h e _ A T   m a n u s c r i p t _ N N 1   . _ .   
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 I n s t e a d _ R R   , _ ,   m u l t i p l e _ J J   a s s e s s m e n t _ N N 1   m e t h o d s _ N N 2   t h a t _ C S T   a r e _ V B R   w e l l _ R R   i n t e g r a t e d _ V V N   i n t o _ I I   e d u c a t i o n _ N N 1   c u r r i c u l a _ N N 2   p r o v i d e _ V V 0   t h e _ A T   m o s t _ R G T   v a l i d _ J J   i n f o r m a t i o n _ N N 1   . _ .   
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 S t a t i s t i c a l _ J J   A n a l y s e s _ N N 2   B o t h _ D B 2   s t u d i e s _ N N 2   w e r e _ V B D R   d e s i g n e d _ V V N   t o _ T O   u s e _ V V I   a _ J J 2 1   p r i o r i _ J J 2 2   p l a n n e d _ J J   c o m p a r i s o n s _ N N 2   f o r _ I F   t h e _ A T   p r i m a r y _ J J   a n a l y s e s _ N N 2   , _ ,   u s i n g _ V V G   S P S S _ N P 1   ( _ (   S P S S _ N P 1   , _ ,   I n c . _ J J   ) _ )   o r _ C C   S A S _ N P 1   ( _ (   S A S _ N P 1   I n s t i t u t e _ N N 1   , _ ,   I n c _ J J   , _ ,   C a r y _ N P 1   , _ ,   N C _ N P 1   ) _ )   g e n e r a l _ J J   l i n e a r _ J J   m o d e l s _ N N 2   p r o c e d u r e s _ N N 2   f o r _ I F   a n a l y s i s _ N N 1   o f _ I O   v a r i a n c e _ N N 1   ( _ (   A N O V A _ N P 1   ) _ )   , _ ,   w i t h _ I W   p o s t _ J J 2 1   h o c _ J J 2 2   T _ Z Z 1   t e s t s _ N N 2   a s _ C S A   w a r r a n t e d _ V V N   b y _ I I   A N O V A _ N P 1   . _ .   
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 A n t i c o a g u l a t i o n _ N N 1   w a s _ V B D Z   r e c o m m e n d e d _ V V N   t o _ T O   b e _ V B I   c o n t i n u e d _ V V N   f o r _ I F   6 0 _ M C   d a y s _ N N T 2   , _ ,   u n l e s s _ C S   c o m p l i c a t i o n s _ N N 2   o c c u r r e d _ V V D   . _ .   
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 W i t h _ I W   t h i s _ D D 1   t e c h n i q u e _ N N 1   , _ ,   y o u _ P P Y   c a n _ V M   r e d u c e _ V V I   t h e _ A T   w o u n d - h e a l i n g _ J J   p r o c e s s _ N N 1   a n d _ C C   m i n i m i s e _ V V I   t h e _ A T   p o s t o p e r a t i v e _ J J   s i d e - e f f e c t s _ N N 2   , _ ,   w h i c h _ D D Q   m a k e s _ V V Z   i t _ P P H 1   p o s s i b l e _ J J   f o r _ I F   t h e _ A T   w o u n d _ N N 1   t o _ T O   h e a l _ V V I   f u l l y _ R R   a n d _ C C   f o r _ I F   t h e _ A T   p a t i e n t _ J J   t o _ T O   w e a r _ V V I   t h e _ A T   s o u n d _ N N 1   p r o c e s s o r _ N N 1   o v e r _ I I   t h e _ A T   w o u n d _ N N 1   w i t h o u t _ I W   p r o b l e m s _ N N 2   . _ .   
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 T h e _ A T   " _ "   n e e d _ N N 1   f o r _ I F   t r a n s p l a n t a t i o n _ N N 1   " _ "   w a s _ V B D Z   r e c o r d e d _ V V N   a s _ I I   a _ A T 1   b i n a r y _ J J   v a r i a b l e _ N N 1   , _ ,   w h e r e _ C S   0 _ M C   = l o w _ F O   a n d _ C C   1 _ M C 1   = m e d i u m _ F O   , _ ,   h i g h _ J J   . _ .   
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 A l t h o u g h _ C S   t h e _ A T   f i n d i n g s _ N N 2   o f _ I O   t h i s _ D D 1   s t u d y _ N N 1   s u g g e s t _ V V 0   a _ A T 1   s i g n i f i c a n t _ J J   r e l a t i o n s h i p _ N N 1   a m o n g _ I I   t h e _ A T   r o b o t i c _ J J   p l a t f o r m _ N N 1   , _ ,   h i g h - v o l u m e _ J J   s u r g e o n s _ N N 2   , _ ,   a n d _ C C   l o w e r _ J J R   o d d s _ N N 2   o f _ I O   c o n v e r s i o n _ N N 1   t o _ I I   l a p a r o t o m y _ N N 1   , _ ,   t h e s e _ D D 2   r e s u l t s _ N N 2   a r e _ V B R   n o t _ X X   i n t e n d e d _ V V N   t o _ T O   d e f i n e _ V V I   m e d i c a l _ J J   p o l i c i e s _ N N 2   o r _ C C   s u r g i c a l _ J J   p r i v i l e g i n g _ N N 1   . _ .   
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 T h e _ A T   p r i m a r y _ J J   a i m _ N N 1   o f _ I O   t h e _ A T   p r e s e n t _ J J   r e v i e w _ N N 1   w a s _ V B D Z   t h e r e f o r e _ R R   t o _ T O   e v a l u a t e _ V V I   e v i d e n c e _ N N 1   r e g a r d i n g _ I I   t h e _ A T   p o t e n t i a l _ J J   i m p a c t _ N N 1   o f _ I O   t h e _ A T   7 - d a y _ J J   H F I _ N N 2   o n _ I I   o v a r i a n _ J J   a c t i v i t y _ N N 1   , _ ,   c o n t r a c e p t i v e _ J J   e f f e c t i v e n e s s _ N N 1   , _ ,   a n d _ C C   a d v e r s e _ J J   e f f e c t s _ N N 2   . _ .   
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 A _ A T 1   r a n d o m _ J J   s a m p l e _ N N 1   o f _ I O   2 2 5 _ M C   r e c o r d e d _ J J   s e s s i o n s _ N N T 2   ( _ (   2 5 % _ N N U   ) _ )   w e r e _ V B D R   t h e n _ R T   a u d i t e d _ V V N   a n d _ C C   i n d e p e n d e n t l y _ R R   r a t e d _ V V N   f o r _ I F   i n t e g r i t y _ N N 1   t o _ I I   p r o t o c o l _ N N 1   b y _ I I   a _ A T 1   d o c t o r a t e - l e v e l _ J J   t r a i n e e _ N N 1   i n _ I I   c l i n i c a l _ J J   p s y c h o l o g y _ N N 1   . _ .   
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 A _ A T 1   s e n s i t i v i t y _ N N 1   a n a l y s i s _ N N 1   e x c l u d i n g _ I I   s u b j e c t s _ N N 2   w i t h _ I W   g r e a t e s t _ J J T   p r o g r e s s i o n _ N N 1   ( _ (   g r e a t e r _ J J R   t h a n _ C S N   1 0 0 _ M C   u n i t s _ N N 2   o f _ I O   c h a n g e _ N N 1   ) _ )   d i d _ V D D   n o t _ X X   a l t e r _ V V I   t h e _ A T   r e s u l t _ N N 1   . _ .   
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 T h e _ A T   a v e r a g e _ J J   P P T _ N P 1   a c r o s s _ I I   t h e _ A T   2 _ M C   r e p e t i t i o n s _ N N 2   a n d _ C C   4 _ M C   s i t e s _ N N 2   w a s _ V B D Z   u s e d _ V V N   f o r _ I F   f u r t h e r _ J J R   a n a l y s i s _ N N 1   a s _ I I   a _ A T 1   m e a s u r e _ N N 1   o f _ I O   w i d e s p r e a d _ J J   P P T _ N P 1   . _ .   
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 T h i s _ D D 1   a p p r o a c h _ N N 1   e n t a i l s _ V V Z   s e r i a l _ J J   C P X _ N P 1   t e s t i n g _ N N 1   b e f o r e _ I I   a n d _ C C   a f t e r _ C S   t h e _ A T   i m p l e m e n t a t i o n _ N N 1   o f _ I O   a _ A T 1   g i v e n _ J J   i n t e r v e n t i o n _ N N 1   . _ .   
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 I n _ I I   p a t i e n t s _ N N 2   w h o _ P N Q S   u n d e r w e n t _ V V D   p r e o p e r a t i v e _ J J   s t a n d a r d _ J J   b r e a s t _ N N 1   M R I _ N N 2   , _ ,   a x i l l a r y _ J J   u l t r a s o u n d _ N N 1   i s _ V B Z   o n l y _ R R   r e q u i r e d _ V V N   i n _ I I 3 1   c a s e _ I I 3 2   o f _ I I 3 3   s u s p i c i o u s _ J J   n o d a l _ J J   f i n d i n g s _ N N 2   o n _ I I   M R I _ N P 1   . _ .   
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 P u b l i c a t i o n _ N N 1   b i a s _ N N 1   T h e r e _ E X   w a s _ V B D Z   a _ A T 1   m o d e r a t e _ J J   v i s u a l _ J J   a s y m m e t r y _ N N 1   i n _ I I   t h e _ A T   f u n n e l _ N N 1   p l o t _ N N 1   , _ ,   a s _ C S A   s h o w n _ V V N   i n _ I I   F i g . _ N N 1   4 _ M C   . _ .   
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 O n _ I I   t h e _ A T   o t h e r _ J J   h a n d _ N N 1   , _ ,   t h e r e _ E X   a r e _ V B R   n u m e r o u s _ J J   s t u d i e s _ N N 2   s u g g e s t i n g _ V V G   t h a t _ D D 1   a d a p t a t i o n _ N N 1   t o _ I I   s t a n d a r d _ J J   f r e q u e n c y _ N N 1   a l l o c a t i o n _ N N 1   t a b l e s _ N N 2   m a y _ V M   t a k e _ V V I   a _ A T 1   l o n g _ J J   t i m e _ N N T 1   o r _ C C   m a y _ V M   e v e n _ R R   b e _ V B I   i n c o m p l e t e _ J J   d e s p i t e _ I I   m o n t h s _ N N T 2   o r _ C C   y e a r s _ N N T 2   o f _ I O   e x p e r i e n c e _ N N 1   ( _ (   F u _ N P 1   e t _ R A 2 1   a l _ R A 2 2   . _ .   
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 A _ A T 1   c o m p a r i s o n _ N N 1   b e t w e e n _ I I   t h e _ A T   w t _ N N 1   h o m i n g e n d o n u c l e a s e _ N N 1   I - A n i I _ N N 1   ( _ (   i n d u c i n g _ V V G   a _ A T 1   D S B _ N P 1   ) _ )   a n d _ C C   a _ A T 1   n i c k i n g _ J J   v a r i a n t _ N N 1   o f _ I O   I - A n i l _ N P 1   s h o w e d _ V V D   l o w e r _ J J R   H R _ N N U   r a t i o s _ N N 2   f o r _ I F   t h e _ A T   n i c k i n g _ J J   n u c l e a s e _ N N 1   b y _ I I   a _ A T 1   f a c t o r _ N N 1   4 _ M C   t o _ I I   6 _ M C   a n d _ C C   a l s o _ R R   l o w e r _ J J R   m u t a t i o n _ N N 1   r a t e _ N N 1   b y _ I I   a _ A T 1   f a c t o r _ N N 1   o f _ I O   1 5 0 _ M C   . _ .   
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 I t _ P P H 1   i s _ V B Z   n o t a b l e _ J J   t h a t _ C S T   t h e _ A T   2 _ M C   g e n e s _ N N 2   i m p l i c a t e d _ V V D   b y _ I I   o u r _ A P P G E   s t u d i e s _ N N 2   , _ ,   T N K 2 _ F O   a n d _ C C   T N R _ N P 1   , _ ,   w e r e _ V B D R   e a c h _ D D 1   m o r e _ D A R   t h a n _ C S N   1 0 0 0 _ M C   a m i n o _ N N 1   a c i d s _ N N 2   i n _ I I   l e n g t h _ N N 1   , _ ,   r a i s i n g _ V V G   p o t e n t i a l _ J J   c o n c e r n _ N N 1   t h a t _ C S T   t h e y _ P P H S 2   w o u l d _ V M   b e _ V B I   d i s c o v e r e d _ V V N   t o _ T O   h a r b o r _ V V I   r a r e _ J J   d a m a g i n g _ J J   v a r i a t i o n _ N N 1   b y _ I I   c h a n c e _ N N 1   b e c a u s e _ I I 2 1   o f _ I I 2 2   t h e i r _ A P P G E   l a r g e _ J J   s i z e _ N N 1   . _ .   
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 I N T R O D U C T I O N _ N N 1   B a c k g r o u n d _ N N 1   M a s s _ N N 1   m e t h a n o l _ N N 1   p o i s o n i n g s _ N N 2   r e p r e s e n t _ V V 0   a _ A T 1   c h a l l e n g e _ N N 1   f o r _ I F   h e a l t h _ N N 1   c a r e _ N N 1   p r o v i d e r s _ N N 2   t h r o u g h o u t _ I I   t h e _ A T   w o r l d _ N N 1   b e c a u s e _ I I 2 1   o f _ I I 2 2   t h e _ A T   d i s t i l l a t i o n _ N N 1   a n d _ C C   c o n s u m p t i o n _ N N 1   o f _ I O   i l l i c i t _ J J   a l c o h o l _ N N 1   . _ .   
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 T h i s _ D D 1   i n t e r p r e t a t i o n _ N N 1   r e c e i v e s _ V V Z   s o m e _ D D   s u p p o r t _ N N 1   f r o m _ I I   t h e _ A T   r e l a t i v e l y _ R R   p o o r _ J J   e a r l y _ J J   p e r f o r m a n c e _ N N 1   o f _ I O   t h e _ A T   t r a n s g e n i c _ J J   g r o u p s _ N N 2   o n _ I I   t h e _ A T   s p a t i a l _ J J   m e m o r y _ N N 1   a n d _ C C   N M T S _ N P 1   t a s k s _ N N 2   . _ .   
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 D i s c u s s i o n _ N N 1   C r i c o i d _ N N 1   p r e s s u r e _ N N 1   i s _ V B Z   a _ A T 1   t e c h n i q u e _ N N 1   u s e d _ V M K   t o _ T O   o c c l u d e _ V V I   t h e _ A T   o e s o p h a g u s _ N N 1   b y _ I I   c o m p r e s s i n g _ V V G   i t _ P P H 1   b e t w e e n _ I I   t h e _ A T   c r i c o i d _ J J   c a r t i l a g e _ N N 1   a n d _ C C   c e r v i c a l _ J J   v e r t e b r a e _ N N 2   . _ .   
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 D a t a _ N N   w e r e _ V B D R   e x t r a c t e d _ V V N   f o r _ I F   a l l _ D B   c a s e s _ N N 2   a n d _ C C   c o n t r o l s _ V V Z   o n _ I I   a l l _ D B   i n p a t i e n t _ N N 1   a n d _ C C   o u t p a t i e n t _ N N 1   d i a g n o s e s _ V V Z   w i t h _ I W   p r i n c i p a l _ J J   o r _ C C   c o m o r b i d _ J J   d i a g n o s e s _ N N 2   o f _ I O   a l c o h o l _ N N 1   o r _ C C   d r u g _ N N 1   a b u s e _ N N 1   o r _ C C   d e p e n d e n c e _ N N 1   , _ ,   d e p r e s s i o n _ N N 1   a n d _ C C   r e l a t e d _ J J   m o o d _ N N 1   d i s o r d e r s _ N N 2   , _ ,   a n d _ C C   a n y _ D D   p s y c h i a t r i c _ J J   d i s o r d e r _ N N 1   ( _ (   A u t h o r _ N N 1   T a b l e _ N N 1   1 _ M C 1   ) _ )   . _ .   
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 E v e n _ C S 2 1   t h o u g h _ C S 2 2   a _ A T 1   l a r g e _ J J   v o l u m e _ N N 1   o f _ I O   i n f o r m a t i o n _ N N 1   h a s _ V H Z   b e e n _ V B N   c o l l e c t e d _ V V N   a b o u t _ I I   m a n a g i n g _ N N 1   a n d _ C C   t r e a t i n g _ V V G   s e p t i c _ J J   p a t i e n t _ N N 1   , _ ,   t h e _ A T   l a c k _ N N 1   o f _ I O   k n o w l e d g e _ N N 1   a b o u t _ I I   t h e _ A T   d i a g n o s t i c _ J J   c r i t e r i a _ N N 2   f o r _ I F   s e p s i s _ N N 1   b y _ I I   e m e r g e n c y _ N N 1   t e a m s _ N N 2   i s _ V B Z   o n e _ M C 1   o f _ I O   t h e _ A T   g r e a t e s t _ J J T   f a c t o r s _ N N 2   l i m i t i n g _ V V G   i t s _ A P P G E   a d e q u a t e _ J J   t r e a t m e n t _ N N 1   . _ .   
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 F r o m _ I I   3 _ M C   y e a r s _ N N T 2   o f _ I O   a g e _ N N 1   , _ ,   d u r i n g _ I I   t h e _ A T   w i n t e r _ N N T 1   m o n t h s _ N N T 2   , _ ,   p a p u l a r _ J J   l e s i o n s _ N N 2   w e r e _ V B D R   n o t i c e d _ V V N   o n _ I I   t h e _ A T   l e g s _ N N 2   , _ ,   w h i c h _ D D Q   r e s o l v e d _ V V D   l e a v i n g _ V V G   a t r o p h i c _ J J   s c a r s _ N N 2   ( _ (   F i g . _ N N 1   3 d _ N N U   ) _ )   . _ .   
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 W e _ P P I S 2   d o _ V D 0   n o t _ X X   e x p e c t _ V V I   t h e _ A T   r i s e _ N N 1   i n _ I I   t h e _ A T   u s e _ N N 1   o f _ I O   p o r t a b l e _ J J   d e v i c e s _ N N 2   t o _ T O   a f f e c t _ V V I   t h e _ A T   e s t i m a t e d _ J J   l e v e l s _ N N 2   a n d _ C C   t r e n d s _ N N 2   b e c a u s e _ C S   t h e i r _ A P P G E   h i g h e r _ J J R   u s e _ N N 1   i n _ I I   p o p u l a t i o n - b a s e d _ J J   r e s e a r c h _ N N 1   i s _ V B Z   p a r t l y _ R R   d u e _ I I 2 1   t o _ I I 2 2   i n c r e a s i n g _ J J   s i m i l a r i t y _ N N 1   b e t w e e n _ I I   t h e i r _ A P P G E   m e a s u r e m e n t s _ N N 2   a n d _ C C   t h o s e _ D D 2   i n _ I I   l a b o r a t o r y - b a s e d _ J J   t e s t s _ N N 2   , _ ,   4 7 _ M C   , _ ,   4 8 _ M C   f a c i l i t a t e d _ V V D   b y _ I I   m o r e _ R G R   a d v a n c e d _ J J   t e c h n o l o g i e s _ N N 2   a n d _ C C   b e t t e r _ J J R   s t a n d a r d i s a t i o n _ N N 1   . _ .   
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 N e x t _ M D   , _ ,   t h e _ A T   c o m m i t t e e _ N N 1   w o u l d _ V M   d i s c o v e r _ V V I   i f _ C S W   a _ A T 1   c o n s e n s u s _ N N 1   e x i s t e d _ V V D   , _ ,   t h r o u g h _ I I   a _ A T 1   q u i c k _ J J   v e r b a l _ J J   p o l l i n g _ N N 1   o f _ I O   a l l _ D B   c o m m i t t e e _ N N 1   m e m b e r s _ N N 2   p r e s e n t _ N N 1   . _ .   
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 T h e _ A T   r e o p e r a t i o n _ N N 1   r a t e _ N N 1   w a s _ V B D Z   1 5 . 2 % _ F O   w i t h _ I W   a d j u s t a b l e _ J J   s u t u r e _ N N 1   a n d _ C C   1 0 . 4 % _ F O   w i t h _ I W   c o n v e n t i o n a l _ J J   s u t u r e _ N N 1   t e c h n i q u e _ N N 1   ( _ (   p = 0 . 0 4 5 _ F O   , _ ,   T a b l e _ N N 1   4 _ M C   , _ ,   F i g u r e _ N N 1   1 _ M C 1   ) _ )   . _ .   
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