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1.  5th International Symposium on Focused Ultrasound 
Zaaroor, Menashe | Sinai, Alon | Goldsher, Dorit | Eran, Ayelet | Nassar, Maria | Schlesinger, Ilana | Parker, Jonathon | Ravikumar, Vinod | Ghanouni, Pejman | Stein, Sherman | Halpern, Casey | Krishna, Vibhor | Hargrove, Amelia | Agrawal, Punit | Changizi, Barbara | Bourekas, Eric | Knopp, Michael | Rezai, Ali | Mead, Brian | Kim, Namho | Mastorakos, Panagiotis | Suk, Jung Soo | Miller, Wilson | Klibanov, Alexander | Hanes, Justin | Price, Richard | Wang, Shutao | Olumolade, Oluyemi | Kugelman, Tara | Jackson-Lewis, Vernice | Karakatsani, Maria Eleni (Marilena) | Han, Yang | Przedborski, Serge | Konofagou, Elisa | Hynynen, Kullervo | Aubert, Isabelle | Leinenga, Gerhard | Nisbet, Rebecca | Hatch, Robert | Van der Jeugd, Anneke | Evans, Harrison | Götz, Jürgen | Götz, Jürgen | Nisbet, Rebecca | Van der Jeugd, Ann | Evans, Harrison | Leinenga, Gerhard | Fishman, Paul | Yarowsky, Paul | Frenkel, Victor | Wei-Bin, Shen | Nguyen, Ben | Sanchez, Carlos Sierra | Acosta, Camilo | Chen, Cherry | Wu, Shih-Ying | Karakatsani, Maria Eleni (Marilena) | Konofagou, Elisa | Aryal, Muna | Papademetriou, Iason T. | Zhang, Yong-Zhi | Power, Chanikarn | McDannold, Nathan | Porter, Tyrone | Kovacs, Zsofia | Kim, Saejeong | Jikaria, Neekita | Qureshi, Farhan | Bresler, Michele | Frank, Joseph | Odéen, Henrik | Chiou, George | Snell, John | Todd, Nick | Madore, Bruno | Parker, Dennis | Pauly, Kim Butts | Marx, Mike | Ghanouni, Pejman | Jonathan, Sumeeth | Grissom, William | Arvanitis, Costas | McDannold, Nathan | Clement, Gregory | Parker, Dennis | de Bever, Joshua | Odéen, Henrik | Payne, Allison | Christensen, Douglas | Maimbourg, Guillaume | Santin, Mathieu David | Houdouin, Alexandre | Lehericy, Stéphane | Tanter, Mickael | Aubry, Jean Francois | Pauly, Kim Butts | Federau, Christian | Werner, Beat | Halpern, Casey | Ghanouni, Pejman | Paeng, Dong-Guk | Xu, Zhiyuan | Snell, John | Quigg, Anders | Eames, Matt | Jin, Changzhu | Everstine, Ashli | Sheehan, Jason | Lopes, M. Beatriz | Kassell, Neal | Snell, John | Quigg, Anders | Drake, James | Price, Karl | Lustgarten, Lior | Sin, Vivian | Mougenot, Charles | Donner, Elizabeth | Tam, Emily | Hodaie, Mojgan | Waspe, Adam | Looi, Thomas | Pichardo, Samuel | Lee, Wonhye | Chung, Yong An | Jung, Yujin | Song, In-Uk | Yoo, Seung-Schik | Lee, Wonhye | Kim, Hyun-Chul | Jung, Yujin | Chung, Yong An | Song, In-Uk | Lee, Jong-Hwan | Yoo, Seung-Schik | Caskey, Charles | Zinke, Wolf | Cosman, Josh | Shuman, Jillian | Schall, Jeffrey | Aurup, Christian | Wang, Shutao | Chen, Hong | Acosta, Camilo | Konofagou, Elisa | Kamimura, Hermes | Carneiro, Antonio | Todd, Nick | Sun, Tao | Zhang, Yong-Zhi | Power, Chanikarn | Nazai, Navid | Patz, Sam | Livingstone, Margaret | McDannold, Nathan | Mainprize, Todd | Huang, Yuexi | Alkins, Ryan | Chapman, Martin | Perry, James | Lipsman, Nir | Bethune, Allison | Sahgal, Arjun | Trudeau, Maureen | Hynynen, Kullervo | Liu, Hao-Li | Hsu, Po-Hung | Wei, Kuo-Chen | Sun, Tao | Power, Chanikarn | Zhang, Yong-Zhi | Sutton, Jonathan | Alexander, Phillip | Aryal, Muna | Miller, Eric | McDannold, Nathan | Kobus, Thiele | Zhang, Yong-Zhi | McDannold, Nathan | Carpentier, Alexandre | Canney, Michael | Vignot, Alexandre | Beccaria, Kevin | Leclercq, Delphine | Lafon, Cyril | Chapelon, Jean Yves | Hoang-Xuan, Khe | Delattre, Jean-Yves | Idbaih, Ahmed | Xu, Zhiyuan | Moore, David | Xu, Alexis | Schmitt, Paul | Snell, John | Foley, Jessica | Eames, Matt | Sheehan, Jason | Kassell, Neal | Sukovich, Jonathan | Cain, Charles | Xu, Zhiyuan | Pandey, Aditya | Snell, John | Chaudhary, Neeraj | Camelo-Piragua, Sandra | Allen, Steven | Paeng, Dong-Guk | Cannata, Jon | Teofilovic, Dejan | Bertolina, Jim | Kassell, Neal | Hall, Timothy | Xu, Zhen | Wu, Shih-Ying | Karakatsani, Maria Eleni (Marilena) | Grondin, Julien | Sanchez, Carlos Sierra | Ferrera, Vincent | Konofagou, Elisa | ter Haar, Gail | Mouratidis, Petros | Repasky, Elizabeth | Timbie, Kelsie | Badr, Lena | Campbell, Benjamin | McMichael, John | Buckner, Andrew | Prince, Jessica | Stevens, Aaron | Bullock, Timothy | Price, Richard | Skalina, Karin | Guha, Chandan | Orsi, Franco | Bonomo, Guido | Vigna, Paolo Della | Mauri, Giovanni | Varano, Gianluca | Schade, George | Wang, Yak-Nam | Pillarisetty, Venu | Hwang, Joo Ha | Khokhlova, Vera | Bailey, Michael | Khokhlova, Tatiana | Khokhlova, Vera | Sinilshchikov, Ilya | Yuldashev, Petr | Andriyakhina, Yulia | Kreider, Wayne | Maxwell, Adam | Khokhlova, Tatiana | Sapozhnikov, Oleg | Partanen, Ari | Lundt, Jonathan | Allen, Steven | Sukovich, Jonathan | Hall, Timothy | Cain, Charles | Xu, Zhen | Preusser, Tobias | Haase, Sabrina | Bezzi, Mario | Jenne, Jürgen | Langø, Thomas | Midiri, Massimo | Mueller, Michael | Sat, Giora | Tanner, Christine | Zangos, Stephan | Guenther, Matthias | Melzer, Andreas | Menciassi, Arianna | Tognarelli, Selene | Cafarelli, Andrea | Diodato, Alessandro | Ciuti, Gastone | Rothluebbers, Sven | Schwaab, Julia | Strehlow, Jan | Mihcin, Senay | Tanner, Christine | Tretbar, Steffen | Preusser, Tobias | Guenther, Matthias | Jenne, Jürgen | Payen, Thomas | Palermo, Carmine | Sastra, Steve | Chen, Hong | Han, Yang | Olive, Kenneth | Konofagou, Elisa | Adams, Matthew | Salgaonkar, Vasant | Scott, Serena | Sommer, Graham | Diederich, Chris | Vidal-Jove, Joan | Perich, Eloi | Ruiz, Antonio | Velat, Manuela | Melodelima, David | Dupre, Aurelien | Vincenot, Jeremy | Yao, Chen | Perol, David | Rivoire, Michel | Tucci, Samantha | Mahakian, Lisa | Fite, Brett | Ingham, Elizabeth | Tam, Sarah | Hwang, Chang-il | Tuveson, David | Ferrara, Katherine | Scionti, Stephen | Chen, Lili | Cvetkovic, Dusica | Chen, Xiaoming | Gupta, Roohi | Wang, Bin | Ma, Charlie | Bader, Kenneth | Haworth, Kevin | Maxwell, Adam | Holland, Christy | Sanghvi, Narendra | Carlson, Roy | Chen, Wohsing | Chaussy, Christian | Thueroff, Stefan | Cesana, Claudio | Bellorofonte, Carlo | Wang, Qingguo | Wang, Han | Wang, Shengping | Zhang, Junhai | Bazzocchi, Alberto | Napoli, Alessandro | Staruch, Robert | Bing, Chenchen | Shaikh, Sumbul | Nofiele, Joris | Szczepanski, Debra | Staruch, Michelle Wodzak | Williams, Noelle | Laetsch, Theodore | Chopra, Rajiv | Ghanouni, Pejman | Rosenberg, Jarrett | Bitton, Rachelle | Napoli, Alessandro | LeBlang, Suzanne | Meyer, Joshua | Hurwitz, Mark | Pauly, Kim Butts | Partanen, Ari | Yarmolenko, Pavel | Partanen, Ari | Celik, Haydar | Eranki, Avinash | Beskin, Viktoriya | Santos, Domiciano | Patel, Janish | Oetgen, Matthew | Kim, AeRang | Kim, Peter | Sharma, Karun | Chisholm, Alexander | Drake, James | Aleman, Dionne | Waspe, Adam | Looi, Thomas | Pichardo, Samuel | Napoli, Alessandro | Bazzocchi, Alberto | Scipione, Roberto | Temple, Michael | Waspe, Adam | Amaral, Joao Guilherme | Huang, Yuexi | Endre, Ruby | Lamberti-Pasculli, Maria | de Ruiter, Joost | Campbell, Fiona | Stimec, Jennifer | Gupta, Samit | Singh, Manoj | Mougenot, Charles | Hopyan, Sevan | Hynynen, Kullervo | Czarnota, Gregory | Drake, James | Brenin, David | Rochman, Carrie | Kovatcheva, Roussanka | Vlahov, Jordan | Zaletel, Katja | Stoinov, Julian | Han, Yang | Wang, Shutao | Konofagou, Elisa | Bucknor, Matthew | Rieke, Viola | Shim, Jenny | Staruch, Robert | Koral, Korgun | Chopra, Rajiv | Laetsch, Theodore | Lang, Brian | Wong, Carlos | Lam, Heather | Kovatcheva, Roussanka | Vlahov, Jordan | Zaletel, Katja | Stoinov, Julian | Shinkov, Alexander | Hu, Jim | Sharma, Karun | Zhang, Xi | Macoskey, Jonathan | Ives, Kimberly | Owens, Gabe | Gurm, Hitinder | Shi, Jiaqi | Pizzuto, Matthew | Cain, Charles | Xu, Zhen | Payne, Allison | Dillon, Christopher | Christofferson, Ivy | Hilas, Elaine | Shea, Jill | Greillier, Paul | Ankou, Bénédicte | Bessière, Francis | Zorgani, Ali | Pioche, Mathieu | Kwiecinski, Wojciech | Magat, Julie | Melot-Dusseau, Sandrine | Lacoste, Romain | Quesson, Bruno | Pernot, Mathieu | Catheline, Stefan | Chevalier, Philippe | Lafon, Cyril | Marquet, Fabrice | Bour, Pierre | Vaillant, Fanny | Amraoui, Sana | Dubois, Rémi | Ritter, Philippe | Haïssaguerre, Michel | Hocini, Mélèze | Bernus, Olivier | Quesson, Bruno | Tebebi, Pamela | Burks, Scott | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Gertner, Michael | Zhang, Jimin | Wong, Andrew | Fite, Brett | Liu, Yu | Kheirolomoom, Azadeh | Seo, Jai | Watson, Katherine | Mahakian, Lisa | Tam, Sarah | Zhang, Hua | Foiret, Josquin | Borowsky, Alexander | Ferrara, Katherine | Xu, Doudou | Melzer, Andreas | Thanou, Maya | Centelles, Miguell | Wright, Mike | Amrahli, Maral | So, Po-Wah | Gedroyc, Wladyslaw | Centelles, Miguell | Wright, Mike | Gedroyc, Wladyslaw | Thanou, Maya | Kneepkens, Esther | Heijman, Edwin | Keupp, Jochen | Weiss, Steffen | Nicolay, Klaas | Grüll, Holger | Fite, Brett | Wong, Andrew | Liu, Yu | Kheirolomoom, Azadeh | Mahakian, Lisa | Tam, Sarah | Foiret, Josquin | Ferrara, Katherine | Burks, Scott | Nagle, Matthew | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Sapozhnikov, Oleg | Nikolaeva, Anastasia V. | Terzi, Marina E. | Tsysar, Sergey A. | Maxwell, Adam | Cunitz, Bryan | Bailey, Michael | Mourad, Pierre | Downs, Matthew | Yang, Georgiana | Wang, Qi | Konofagou, Elisa | Burks, Scott | Nagle, Matthew | Nguyen, Ben | Bresler, Michele | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Burks, Scott | Nagle, Matthew | Kim, Saejeong | Milo, Blerta | Frank, Joseph | Chen, Johnny | Farry, Justin | Dixon, Adam | Du, Zhongmin | Dhanaliwala, Ali | Hossack, John | Klibanov, Alexander | Ranjan, Ashish | Maples, Danny | Chopra, Rajiv | Bing, Chenchen | Staruch, Robert | Wardlow, Rachel | Staruch, Michelle Wodzak | Malayer, Jerry | Ramachandran, Akhilesh | Nofiele, Joris | Namba, Hirofumi | Kawasaki, Motohiro | Izumi, Masashi | Kiyasu, Katsuhito | Takemasa, Ryuichi | Ikeuchi, Masahiko | Ushida, Takahiro | Crake, Calum | Papademetriou, Iason T. | Zhang, Yong-Zhi | Porter, Tyrone | McDannold, Nathan | Kothapalli, Satya V. V. N. | Leighton, Wan | Wang, Zhaorui | Partanen, Ari | Gach, H. Michael | Straube, William | Altman, Michael | Chen, Hong | Kim, Young-sun | Lim, Hyo Keun | Rhim, Hyunchul | Kim, Young-sun | Lim, Hyo Keun | Rhim, Hyunchul | van Breugel, Johanna | Braat, Manon | Moonen, Chrit | van den Bosch, Maurice | Ries, Mario | Marrocchio, Cristina | Dababou, Susan | Bitton, Rachelle | Pauly, Kim Butts | Ghanouni, Pejman | Lee, Jae Young | Lee, Jae Young | Chung, Hyun Hoon | Kang, Soo Yeon | Kang, Kook Jin | Son, Keon Ho | Zhang, Dandan | Adams, Matthew | Salgaonkar, Vasant | Plata, Juan | Jones, Peter | Pascal-Tenorio, Aurea | Bouley, Donna | Sommer, Graham | Pauly, Kim Butts | Diederich, Chris | Bond, Aaron | Dallapiazza, Robert | Huss, Diane | Warren, Amy | Sperling, Scott | Gwinn, Ryder | Shah, Binit | Elias, W. Jeff | Curley, Colleen | Zhang, Ying | Negron, Karina | Miller, Wilson | Klibanov, Alexander | Abounader, Roger | Suk, Jung Soo | Hanes, Justin | Price, Richard | Karakatsani, Maria Eleni (Marilena) | Samiotaki, Gesthimani | Wang, Shutao | Kugelman, Tara | Acosta, Camilo | Konofagou, Elisa | Kovacs, Zsofia | Tu, Tsang-Wei | Papadakis, Georgios | Hammoud, Dima | Frank, Joseph | Silvestrini, Matthew | Wolfram, Frank | Güllmar, Daniel | Reichenbach, Juergen | Hofmann, Denis | Böttcher, Joachim | Schubert, Harald | Lesser, Thomas G. | Almquist, Scott | Parker, Dennis | Christensen, Douglas | Camarena, Francisco | Jiménez-Gambín, Sergio | Jiménez, Noé | Konofagou, Elisa | Chang, Jin Woo | Chaplin, Vandiver | Griesenauer, Rebekah | Miga, Michael | Caskey, Charles | Ellens, Nicholas | Airan, Raag | Quinones-Hinojosa, Alfredo | Farahani, Keyvan | Partanen, Ari | Feng, Xue | Fielden, Samuel | Zhao, Li | Miller, Wilson | Wintermark, Max | Pauly, Kim Butts | Meyer, Craig | Guo, Sijia | Lu, Xin | Zhuo, Jiachen | Xu, Su | Gullapalli, Rao | Gandhi, Dheeraj | Jin, Changzhu | Brokman, Omer | Eames, Matt | Snell, John | Paeng, Dong-Guk | Baek, Hongchae | Kim, Hyungmin | Leung, Steven | Webb, Taylor | Pauly, Kim Butts | McDannold, Nathan | Zhang, Yong-Zhi | Vykhodtseva, Natalia | Nguyen, Thai-Son | Sukovich, Jonathan | Hall, Timothy | Xu, Zhen | Cain, Charles | Park, Chang Kyu | Park, Sang Man | Jung, Na Young | Kim, Min Soo | Chang, Won Seok | Jung, Hyun Ho | Chang, Jin Woo | Pichardo, Samuel | Hynynen, Kullervo | Plaksin, Michael | Weissler, Yoni | Shoham, Shy | Kimmel, Eitan | Quigg, Anders | Snell, John | Paeng, Dong-Guk | Eames, Matt | Sapozhnikov, Oleg | Rosnitskiy, Pavel B. | Khokhlova, Vera | Shoham, Shy | Krupa, Steve | Hazan, Eilon | Naor, Omer | Levy, Yoav | Maimon, Noam | Brosh, Inbar | Kimmel, Eitan | Kahn, Itamar | Sukovich, Jonathan | Xu, Zhen | Hall, Timothy | Allen, Steven | Cain, Charles | Cahill, Jessica | Sun, Tao | Zhang, Yong-Zhi | Power, Chanikarn | Livingstone, Margaret | McDannold, Nathan | Todd, Nick | Colas, Elodie Constanciel | Wydra, Adrian | Waspe, Adam | Looi, Thomas | Maev, Roman | Pichardo, Samuel | Drake, James | Aly, Amirah | Sun, Tao | Zhang, Yong-Zhi | Sesenoglu-Laird, Ozge | Padegimas, Linas | Cooper, Mark | McDannold, Nathan | Waszczak, Barbara | Tehrani, Seruz | Miller, Wilson | Slingluff, Craig | Larner, James | Andarawewa, Kumari | Bucknor, Matthew | Ozhinsky, Eugene | Shah, Rutwik | Krug, Roland | Rieke, Viola | Deckers, Roel | Linn, Sabine | Suelmann, Britt | Braat, Manon | Witkamp, Arjen | Vaessen, Paul | van Diest, Paul | Bartels, Lambertus W. | Bos, Clemens | van den Bosch, Maurice | Borys, Nicolas | Storm, Gert | Van der Wall, Elsken | Moonen, Chrit | Farr, Navid | Alnazeer, Moez | Yarmolenko, Pavel | Katti, Prateek | Partanen, Ari | Eranki, Avinash | Kim, Peter | Wood, Bradford | Farrer, Alexis | Almquist, Scott | Dillon, Christopher | Parker, Dennis | Christensen, Douglas | Payne, Allison | Ferrer, Cyril | Bartels, Lambertus W. | de Senneville, Baudouin Denis | van Stralen, Marijn | Moonen, Chrit | Bos, Clemens | Liu, Yu | Liu, Jingfei | Fite, Brett | Foiret, Josquin | Leach, J. Kent | Ferrara, Katherine | Gupta, Roohi | Cvetkovic, Dusica | Ma, Charlie | Chen, Lili | Haase, Sabrina | Zidowitz, Stephan | Melzer, Andreas | Preusser, Tobias | Lee, Hsin-Lun | Hsu, Fang-Chi | Kuo, Chia-Chun | Jeng, Shiu-Chen | Chen, Tung-Ho | Yang, Nai-Yi | Chiou, Jeng-Fong | Jeng, Shiu-Chen | Kao, Yi-tzu | Pan, Chia-Hsin | Wu, Jing-Fu | Chen, Tung-Ho | Hsu, Fang-Chi | Lee, Hsin-Lun | Chiou, Jeng-Fong | Hsu, Fang-Chi | Tsai, Yi-Chieh | Lee, Hsin-Lun | Chiou, Jeng-Fong | Johnson, Sara | Parker, Dennis | Payne, Allison | Li, Dawei | He, Ye | Mihcin, Senay | Karakitsios, Ioannis | Strehlow, Jan | Schwenke, Michael | Haase, Sabrina | Demedts, Daniel | Levy, Yoav | Preusser, Tobias | Melzer, Andreas | Mihcin, Senay | Rothluebbers, Sven | Karakitsios, Ioannis | Xiao, Xu | Strehlow, Jan | Demedts, Daniel | Cavin, Ian | Sat, Giora | Preusser, Tobias | Melzer, Andreas | Minalga, Emilee | Payne, Allison | Merrill, Robb | Parker, Dennis | Hadley, Rock | Ramaekers, Pascal | Ries, Mario | Moonen, Chrit | de Greef, Martijn | Shahriari, Kian | Parvizi, Mohammad Hossein | Asadnia, Kiana | Chamanara, Marzieh | Kamrava, Seyed Kamran | Chabok, Hamid Reza | Schwenke, Michael | Strehlow, Jan | Demedts, Daniel | Tanner, Christine | Rothluebbers, Sven | Preusser, Tobias | Strehlow, Jan | Stein, Ruben | Demedts, Daniel | Schwenke, Michael | Rothluebbers, Sven | Preusser, Tobias | Demedts, Daniel | Haase, Sabrina | Muller, Sébastien | Strehlow, Jan | Langø, Thomas | Preusser, Tobias | Tan, Jeremy | Zachiu, Cornel | Ramaekers, Pascal | Moonen, Chrit | Ries, Mario | Wolfram, Frank | Güllmar, Daniel | Schubert, Harald | Lesser, Thomas G. | Erasmus, Hans-Peter | Colas, Elodie Constanciel | Waspe, Adam | Mougenot, Charles | Looi, Thomas | Van Arsdell, Glen | Benson, Lee | Drake, James | Jang, Kee W. | Tu, Tsang-Wei | Jikaria, Neekita | Nagle, Matthew | Angstadt, Mary | Lewis, Bobbi | Qureshi, Farhan | Burks, Scott | Frank, Joseph | McLean, Hailey | Payne, Allison | Hoogenboom, Martijn | Eikelenboom, Dylan | den Brok, Martijn | Wesseling, Pieter | Heerschap, Arend | Fütterer, Jurgen | Adema, Gosse | Wang, Kevin | Zhang, Ying | Zhong, Pei | Xiao, Xu | Joy, Joyce | McLeod, Helen | Melzer, Andreas | Bing, Chenchen | Staruch, Robert | Nofiele, Joris | Szczepanski, Debra | Staruch, Michelle Wodzak | Laetsch, Theodore | Chopra, Rajiv | Bing, Chenchen | Staruch, Robert | Yarmolenko, Pavel | Celik, Haydar | Nofiele, Joris | Szczepanski, Debra | Kim, Peter | Kim, Harry | Lewis, Matthew | Chopra, Rajiv | Shah, Rutwik | Ozhinsky, Eugene | Rieke, Viola | Bucknor, Matthew | Diederich, Chris | Salgaonkar, Vasant | Jones, Peter | Adams, Matthew | Ozilgen, Arda | Zahos, Peter | Coughlin, Dezba | Tang, Xinyan | Lotz, Jeff | Jedruszczuk, Kathleen | Gulati, Amitabh | Solomon, Stephen | Kaye, Elena | Fielden, Samuel | Mugler, John | Miller, Wilson | Pauly, Kim Butts | Meyer, Craig | Barbato, Gaetano | Scoarughi, Gian Luca | Corso, Cristiano | Gorgone, Alessandro | Migliore, Ilaria Giuseppina | Larrabee, Zachary | Hananel, Arik | Eames, Matt | Aubry, Jean-Francois | Eranki, Avinash | Farr, Navid | Partanen, Ari | Sharma, Karun | Yarmolenko, Pavel | Wood, Bradford | Kim, Peter | Farr, Navid | Kothapalli, Satya V. V. N. | Eranki, Avinash | Negussie, Ayele | Wilson, Emmanuel | Seifabadi, Reza | Kim, Peter | Chen, Hong | Wood, Bradford | Partanen, Ari | Moon, Hyungwon | Kang, Jeeun | Sim, Changbeom | Chang, Jin Ho | Kim, Hyuncheol | Lee, Hak Jong | Sasaki, Noboru | Takiguchi, Mitsuyoshi | Sebeke, Lukas | Luo, Xi | de Jager, Bram | Heemels, Maurice | Heijman, Edwin | Grüll, Holger | Strehlow, Jan | Schwenke, Michael | Demedts, Daniel | Preusser, Tobias
Journal of Therapeutic Ultrasound  2016;4(Suppl 1):1-113.
doi:10.1186/s40349-016-0076-5
PMCID: PMC5123388
2.  Associations between Anxiety and Depression Symptoms and Cognitive Testing and Neuroimaging in Type 2 Diabetes 
Structured Abstract
Aims
Anxiety, depression, accelerated cognitive decline, and increased risk of dementia are observed in individuals with type 2 diabetes. Anxiety and depression may contribute to lower performance on cognitive tests and differences in neuroimaging observed in individuals with type 2 diabetes.
Methods
These relationships were assessed in 655 European Americans with type 2 diabetes from 504 Diabetes Heart Study families. Participants completed cognitive testing, brain magnetic resonance imaging, the Brief Symptom Inventory Anxiety subscale, and the Center for Epidemiologic Studies Depression-10.
Results
In analyses adjusted for age, sex, educational attainment, and use of psychotropic medications, individuals with comorbid anxiety and depression symptoms had lower performance on all cognitive testing measures assessed (p≤0.005). Those with both anxiety and depression also had increased white matter lesion volume (p=0.015), decreased gray matter cerebral blood flow (p=4.43 × 10−6), decreased gray matter volume (p=0.002), increased white and gray matter mean diffusivity (p≤0.001), and decreased white matter fractional anisotropy (p=7.79 × 10−4). These associations were somewhat attenuated upon further adjustment for health status related covariates.
Conclusions
Comorbid anxiety and depression symptoms were associated with cognitive performance and brain structure in a European American cohort with type 2 diabetes.
doi:10.1016/j.jdiacomp.2015.09.010
PMCID: PMC4698057  PMID: 26476474
Type 2 diabetes; anxiety; depression; cognition; magnetic resonance imaging
3.  Effects of a one-year physical activity program on serum C-terminal Agrin Fragment (CAF) concentrations among mobility-limited older adults 
Objectives
C-terminal Agrin Fragment (CAF) has been proposed as a potential circulating biomarker for predicting changes in physical function among older adults. To determine the effect of a one-year PA intervention on changes in CAF concentrations and to evaluate baseline and longitudinal associations between CAF concentrations and indices of physical function.
Design
Ancillary study to the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P), a multi-site randomized clinical trial designed to evaluate the effects of chronic exercise on the physical function of older adults at risk for mobility disability.
Setting
Four academic research centers within the U.S.
Participants
Three hundred thirty three older adults aged 70 to 89 with mild to moderate impairments in physical function.
Intervention
A 12-month intervention of either structured physical activity (PA) or health education promoting successful aging (SA).
Measurements
Serum CAF concentrations and objectives measures of physical function – i.e. gait speed and performance on the Short Physical Performance Battery (SPPB).
Results
The group*time interaction was not significant for serum CAF concentrations (p=0.265), indicating that the PA intervention did not significantly reduce serum CAF levels compared to SA. Baseline gait speed was significantly correlated with baseline CAF level (r = −0.151, p= 0.006), however the association between CAF and SPPB was not significant. Additionally, neither baseline nor the change in CAF concentrations strongly predicted the change in either performance measure following the PA intervention.
Conclusion
In summary, the present study shows that a one-year structured PA program did not reduce serum CAF levels among mobility-limited older adults. However, further study is needed to definitively determine the utility of CAF as a biomarker of physical function.
doi:10.1007/s12603-015-0474-3
PMCID: PMC4682669  PMID: 26482694
Aging; Physical Function; Neuromuscular function; mobility; LIFE study
4.  Insulin Dose and Cardiovascular Mortality in the ACCORD Trial 
Diabetes Care  2015;38(11):2000-2008.
OBJECTIVE
In the ACCORD trial, intensive treatment of patients with type 2 diabetes and high cardiovascular (CV) risk was associated with higher all-cause and CV mortality. Post hoc analyses have failed to implicate rapid reduction of glucose, hypoglycemia, or specific drugs as the causes of this finding. We hypothesized that exposure to injected insulin was quantitatively associated with increased CV mortality.
RESEARCH DESIGN AND METHODS
We examined insulin exposure data from 10,163 participants with a mean follow-up of 5 years. Using Cox proportional hazards models, we explored associations between CV mortality and total, basal, and prandial insulin dose over time, adjusting for both baseline and on-treatment covariates including randomized intervention assignment.
RESULTS
More participants allocated to intensive treatment (79%) than standard treatment (62%) were ever prescribed insulin in ACCORD, with a higher mean updated total daily dose (0.41 vs. 0.30 units/kg) (P < 0.001). Before adjustment for covariates, higher insulin dose was associated with increased risk of CV death (hazard ratios [HRs] per 1 unit/kg/day 1.83 [1.45, 2.31], 2.29 [1.62, 3.23], and 3.36 [2.00, 5.66] for total, basal, and prandial insulin, respectively). However, after adjustment for baseline covariates, no significant association of insulin dose with CV death remained. Moreover, further adjustment for severe hypoglycemia, weight change, attained A1C, and randomized treatment assignment did not materially alter this observation.
CONCLUSIONS
These analyses provide no support for the hypothesis that insulin dose contributed to CV mortality in ACCORD.
doi:10.2337/dc15-0598
PMCID: PMC4876773  PMID: 26464212
5.  Multipoint association mapping for longitudinal family data: an application to hypertension phenotypes 
BMC Proceedings  2016;10(Suppl 7):315-320.
It is essential to develop adequate statistical methods to fully utilize information from longitudinal family studies. We extend our previous multipoint linkage disequilibrium approach—simultaneously accounting for correlations between markers and repeat measurements within subjects, and the correlations between subjects in families—to detect loci relevant to disease through gene-based analysis. Estimates of disease loci and their genetic effects along with their 95 % confidence intervals (or significance levels) are reported. Four different phenotypes—ever having hypertension at 4 visits, incidence of hypertension, hypertension status at baseline only, and hypertension status at 4 visits—are studied using the proposed approach. The efficiency of estimates of disease locus positions (inverse of standard error) improves when using the phenotypes from 4 visits rather than using baseline only.
doi:10.1186/s12919-016-0049-2
PMCID: PMC5133529  PMID: 27980655
6.  Inherited genetic markers discovered to date are able to identify a significant number of men at considerably elevated risk for prostate cancer 
The Prostate  2010;71(4):421-430.
BACKGROUND
Prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) are continuously being discovered. Their ability to identify men at high risk and the impact of increasing numbers of SNPs on predictive performance are not well understood.
METHODS
Absolute risk for PCa was estimated in a population-based case-control study in Sweden (2,899 cases and 1,722 controls) using family history and three sets of sequentially discovered PCa risk-associated SNPs. Their performance in predicting PCa was assessed by positive predictive values (PPV) and sensitivity.
RESULTS
SNPs and family history were able to differentiate individual risk for PCa and identify men at higher risk; ~18% and ~8% of men in the study had 20-year (55–74 years) absolute risks that were two-fold (0.24) or three-fold (0.36) greater than the population median risk (0.12), respectively. When predictive performances were compared at absolute risk cutoffs of 0.12, 0.24 or 0.36, PPV increased considerably (~20%, ~30% and ~37%, respectively) while sensitivity decreased considerably (~55%, ~20% and ~10%, respectively). In contrast, when increasing numbers of SNPs (5, 11 and 28 SNPs) were used in risk prediction, PPV approached a constant value while sensitivity increased steadily.
CONCLUSIONS
SNPs discovered to date are suitable for risk prediction while additional SNPs discovered in the future may identify more subjects at higher risk. Men identified as high-risk by SNP-based testing may be targeted for PCa screening or chemoprevention. The clinical impact on improving the effectiveness of these interventions can be and should be assessed.
doi:10.1002/pros.21256
PMCID: PMC3025084  PMID: 20878950
Absolute risk; SNPs; association; screening; chemoprevention
7.  Relationships between cognitive performance, neuroimaging, and vascular disease: the DHS-Mind Study 
Neuroepidemiology  2015;45(1):1-11.
Background
Type 2 diabetes mellitus increases risk for cognitive decline and dementia; elevated burdens of vascular disease are hypothesized to contribute to this risk. These relationships were examined in the Diabetes Heart Study-Mind using a battery of cognitive tests, neuroimaging measures, and subclinical cardiovascular disease (CVD) burden assessed by coronary artery calcified plaque (CAC). We hypothesized that CAC would attenuate the association between neuroimaging measures and cognition performance.
Methods
Associations were examined using marginal models in this family-based cohort of 572 European Americans from 263 families. All models were adjusted for age, gender, education, type 2 diabetes, and hypertension, with some neuroimaging measures additionally adjusted for intracranial volume.
Results
Higher total brain volume (TBV) was associated with better performance on the Digit Symbol Substitution Task (DSST) and Semantic Fluency (both p≤7.0 x 10−4). Higher gray matter volume (GMV) was associated with better performance on the Modified Mini-Mental State Examination and Semantic Fluency (both p≤9.0 x 10−4). Adjusting for CAC caused minimal changes to the results.
Conclusions
Relationships exist between neuroimaging measures and cognitive performance in a type 2 diabetes-enriched European American cohort. Associations were minimally attenuated after adjusting for subclinical CVD. Additional work is needed to understand how subclinical CVD burden interacts with other factors and impacts relationships between neuroimaging and cognitive testing measures.
doi:10.1159/000435775
PMCID: PMC4543571  PMID: 26185004
Cognitive testing; Neuroimaging; Coronary artery calcified plaque; Type 2 diabetes; Vascular disease
8.  A Fast Multiple-Kernel Method with Applications to Detect Gene-Environment Interaction 
Genetic epidemiology  2015;39(6):456-468.
Kernel machine (KM) models are a powerful tool for exploring associations between sets of genetic variants and complex traits. While most KM methods use a single kernel function to assess the marginal effect of a variable set, KM analyses involving multiple kernels have become increasingly popular. Multi-kernel analysis allows researchers to study more complex problems, such as assessing gene-gene or gene-environment interactions, incorporating variance-component based methods for population substructure into rare-variant association testing, and assessing the conditional effects of a variable set adjusting for other variable sets. The KM framework is robust, powerful, and provides efficient dimension reduction for multi-factor analyses, but requires the estimation of high dimensional nuisance parameters. Traditional estimation techniques, including regularization and the EM algorithm, have a large computational cost and are not scalable to large sample sizes needed for rare variant analysis. Therefore, under the context of gene-environment interaction, we propose a computationally efficient and statistically rigorous “fastKM” algorithm for multi-kernel analysis that is based on a low-rank approximation to the nuisance-effect kernel matrices. Our algorithm is applicable to various trait types (e.g., continuous, binary, and survival traits) and can be implemented using any existing single-kernel analysis software. Through extensive simulation studies, we show that our algorithm has similar performance to an EM-based KM approach for quantitative traits while running much faster. We also apply our method to the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, examining gene-by-vitamin effects on recurrent stroke risk and gene-by-age effects on change in homocysteine level.
doi:10.1002/gepi.21909
PMCID: PMC4544636  PMID: 26139508
multiple-kernel analysis; kernel machine regression; exon level association test; gene-environment interaction; gene-gene interactions
9.  Structural and functional assessment of the brain in European Americans with mild-to-moderate kidney disease: Diabetes Heart Study-MIND 
Nephrology Dialysis Transplantation  2015;30(8):1322-1329.
Background
Advanced chronic kidney disease (CKD) is associated with altered cerebral structure and function. Relationships between mild-to-moderate CKD and brain morphology and cognitive performance were evaluated in European Americans (EAs).
Methods
A total of 478 EAs with estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2 and urine albumin:creatinine ratio (UACR) < 300 mg/g, most with type 2 diabetes (T2D), were included. Measures of total intracranial volume (TICV), cerebrospinal fluid volume, total white matter volume (TWMV), total gray matter volume (TGMV), total white matter lesion volume (TWMLV), hippocampal white matter volume (HWMV) and hippocampal gray matter volume (HGMV) were obtained with magnetic resonance imaging. Cognitive testing included memory (Rey Auditory Visual Learning Test), global cognition (Modified Mini-Mental State Examination) and executive function (Stroop Task, Semantic Fluency, Digit Symbol Substitution Test). Associations with CKD were assessed using log-transformed eGFR and UACR, adjusted for age, sex, body mass index, smoking, hemoglobin A1c, blood pressure, diabetes duration, cardiovascular disease and education.
Results
Participants were 55.2% female, 78.2% had T2D; mean ± SD age 67.6 ± 9.0 years, T2D duration 16.4 ± 6.5 years, eGFR 92.0 ± 22.3 mL/min/1.73 m2 and UACR 23.8 ± 39.6 mg/g. In adjusted models, eGFR was negatively associated with TICV only in participants with T2D [parameter estimate (β): −72.2, P = 0.002]. In non-diabetic participants, inverse relationships were observed between eGFR and HGMV (β: −1.0, P = 0.03) and UACR and normalized TWMLV (β: −0.2, P = 0.03). Kidney function and albuminuria did not correlate with cognitive testing.
Conclusions
In EAs with mild CKD enriched for T2D, brain structure and cognitive performance were generally not impacted. Longitudinal studies are necessary to determine when cerebral structural changes and cognitive dysfunction develop with progressive CKD in EAs.
doi:10.1093/ndt/gfv030
PMCID: PMC4513893  PMID: 25722384
albuminuria; brain; cognitive function; kidney disease; magnetic resonance imaging
10.  Analysis of a Cardiovascular Disease Genetic Risk Score in the Diabetes Heart Study 
Acta diabetologica  2015;52(4):743-751.
Aims
It remains unclear whether the high cardiovascular disease (CVD) burden in people with type 2 diabetes (T2D) is associated with genetic variants that contribute to CVD in general populations. Recent studies have examined genetic risk scores of single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) for their cumulative contribution to CVD-related traits. Most analyses combined SNPs associated with a single phenotypic class, e.g. lipids. In the present analysis, we examined a more comprehensive risk score comprised of SNPs associated with a broad range of CVD risk phenotypes.
Methods
The composite risk score was analyzed for potential associations with subclinical CVD, self-reported CVD events, and mortality in 983 T2D-affected individuals of European descent from 466 Diabetes Heart Study (DHS) families. Genetic association was examined using marginal models with generalized estimating equations for subclinical CVD and prior CVD events and Cox proportional hazards models with sandwich-based variance estimation for mortality; analyses were adjusted for age and sex.
Results
An increase in genetic risk score was significantly associated with higher levels of coronary artery calcified plaque (p=1.23 × 10−4); however, no significant associations with self-reported myocardial infarction and CVD events and all-cause and CVD mortality were observed.
Conclusions
These results suggest that a genetic risk score of SNPs associated with CVD events and risk factors does not significantly account for CVD risk in the DHS, highlighting the limitations of applying current genetic markers for CVD in individuals with diabetes.
doi:10.1007/s00592-015-0720-5
PMCID: PMC4506855  PMID: 25700702
Type 2 diabetes; mortality; coronary artery calcification; genetic risk score
11.  Inflammation as a Mediator of the Association Between Race and Atrial Fibrillation: Results from the Health, Aging, and Body Composition Study 
JACC. Clinical electrophysiology  2015;1(4):248-255.
Background
Despite a lower prevalence of established atrial fibrillation (AF) risk factors, Whites exhibit substantially higher rates of this arrhythmia compared to Blacks. The mechanism underlying this observation is not known. Both inflammation and obesity are risk factors for AF, and adipose tissue is a known contributor to systemic inflammation.
Objectives
We sought to determine the degree to which racial differences in AF risk are explained by differences in inflammation and adiposity.
Methods
Baseline serum inflammatory biomarker concentrations and abdominal adiposity (assessed by computed tomography) were quantified in a subset of Black and White participants without prevalent AF in the Health, Aging, and Body Composition (Health ABC) Study. Participants were prospectively followed for the diagnosis of AF using study ECGs and Medicare claims data. Cox proportional hazards models were used to determine the adjusted relative hazard of incident AF between races before and after biomarker adjustment.
Results
Among 2,768 participants (43% Black), 721 developed incident AF over a median follow up of 10.9 years. White race was associated with a heightened adjusted risk of incident AF (HR 1.55, 95% CI 1.30 to 1.84, p < 0.001). Abdominal adiposity was not associated with AF when added to the adjusted model. Among the studied biomarkers, adiponectin, TNF-α, TNF-α SR I, and TNF-α SR II concentrations were each higher among Whites and independently associated with a greater risk of incident AF. Together, these inflammatory cytokines mediated 42% (95% CI 15 to 119%, p = 0.004) of the adjusted race-AF association.
Conclusions
Systemic inflammatory pathways significantly mediate the heightened risk of AF among Whites. The higher level of systemic inflammation and concomitant increased AF risk in Whites is not explained by racial differences in abdominal adiposity or the presence of other pro-inflammatory cardiovascular comorbidities.
doi:10.1016/j.jacep.2015.04.014
PMCID: PMC4613757  PMID: 26501131
atrial fibrillation; race; inflammation
12.  Genetic Moderators of the Impact of Physical Activity on Depressive Symptoms 
Background
Converging evidence suggests that physical activity is an effective intervention for both clinical depression and sub-threshold depressive symptoms; however, findings are not always consistent. These mixed results might reflect heterogeneity in response to physical activity, with some subgroups of individuals responding positively, but not others.
Objectives
1) To examine the impact of genetic variation and sex on changes in depressive symptoms in older adults after a physical activity (PA) intervention, and 2) determine if PA differentially improves particular symptom dimensions of depression.
Design
Randomized controlled trial.
Setting
Four field centers (Cooper Institute, Stanford University, University of Pittsburgh, and Wake Forest University).
Participants
396 community-dwelling adults aged 70–89 years who participated in the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P).
Intervention
12-month PA intervention compared to an education control.
Measurements
Polymorphisms in the serotonin transporter (5-HTT), brain-derived neurotrophic factor (BDNF), and apolipoprotein E (APOE) genes; 12-month change in the Center for Epidemiologic Studies Depression Scale total score, as well as scores on the depressed affect, somatic symptoms, and lack of positive affect subscales.
Results
Men randomized to the PA arm showed the greatest decreases in somatic symptoms, with a preferential benefit in male carriers of the BDNF Met allele. Symptoms of lack of positive affect decreased more in men compared to women, particularly in those possessing the 5-HTT L allele, but the effect did not differ by intervention arm. APOE status did not affect change in depressive symptoms.
Conclusions
Results of this study suggest that the impact of PA on depressive symptoms varies by genotype and sex, and that PA may mitigate somatic symptoms of depression more than other symptoms. The results suggest that a targeted approach to recommending PA therapy for treatment of depression is viable.
doi:10.14283/jfa.2016.76
PMCID: PMC4905714  PMID: 26980363
exercise intervention; depression; aging; BDNF; APOE; serotonin transporter
13.  Testing and Estimation in Marker-Set Association Study Using Semiparametric Quantile Regression Kernel Machine 
Biometrics  2015;72(2):364-371.
Summary
We consider quantile regression for partially linear models where an outcome of interest is related to covariates and a marker set (e.g., gene or pathway). The covariate effects are modeled parametrically and the marker set effect of multiple loci is modeled using kernel machine. We propose an efficient algorithm to solve the corresponding optimization problem for estimating the effects of covariates and also introduce a powerful test for detecting the overall effect of the marker set. Our test is motivated by traditional score test, and borrows the idea of permutation test. Our estimation and testing procedures are evaluated numerically and applied to assess genetic association of change in fasting homocysteine level using the Vitamin Intervention for Stroke Prevention Trial data.
doi:10.1111/biom.12438
PMCID: PMC4870165  PMID: 26575303
Bootstrap; Genetic marker-set association; Kernel machines; Permutation; Quantile regression; Semiparametric; Smoothing parameter; Testing
15.  Heritability and Genetic Association Analysis of Neuroimaging Measures in the Diabetes Heart Study 
Neurobiology of aging  2014;36(3):1602.e7-1602.e15.
Patients with type 2 diabetes are at increased risk of age-related cognitive decline and dementia. Neuroimaging measures such as white matter lesion volume, brain volume, and fractional anisotropy may reflect the pathogenesis of these cognitive declines, and genetic factors may contribute to variability in these measures. This study examined multiple neuroimaging measures in 465 participants from 238 families with extensive genotype data in the type 2 diabetes enriched Diabetes Heart Study-Mind cohort. Heritability of these phenotypes and their association with candidate single nucleotide polymorphisms (SNPs) and SNP data from genome-and exome-wide arrays was explored. All neuroimaging measures analysed were significantly heritable (ĥ2 =0.55–0.99 in unadjusted models). Seventeen candidate SNPs (from 16 genes/regions) associated with neuroimaging phenotypes in prior studies showed no significant evidence of association. A missense variant (rs150706952, A432V) in PLEKHG4B from the exome-wide array was significantly associated with white matter mean diffusivity (p=3.66×10−7) and gray matter mean diffusivity (p=2.14×10−7). This analysis suggests genetic factors contribute to variation in neuroimaging measures in a population enriched for metabolic disease and other associated comorbidities.
doi:10.1016/j.neurobiolaging.2014.11.008
PMCID: PMC4346514  PMID: 25523635
Magnetic resonance imaging; type 2 diabetes; genetics; heritability
16.  Depressive Symptoms and Physical Performance in the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) Study 
OBJECTIVES
To determine whether the presence of high depressive symptoms diminished physical performance benefits after a comprehensive physical activity intervention in older adults.
STUDY DESIGN
A post-hoc analysis of data from the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study which was a single blind randomized controlled trial comparing a moderate intensity physical activity intervention (PA) with a successful aging control (SA).
SETTING
Multi-center U.S. sites participating in the LIFE-P trial.
PARTICIPANTS
LIFE-P trial participants included 424 sedentary, non-institutionalized adults (70–89 years).
MEASUREMENTS
Depressive symptoms were assessed by the Centers for Epidemiological Studies Depression Scale (CES-D). Physical performance tests included the Short Physical Performance Battery (SPPB) and 400 meter walk time (400 mw) at baseline, 6 and 12 months.
RESULTS
Of the participants, 15.8% had high depressive symptom scores (CES-D ≥ 14). For participants with low depressive symptoms, SPPB scores improved in the PA versus the SA group over 12 months (adjusted score difference: +0.70; p = <0.001 at 6 months and +0.58; p=0.004 at 12 months) while the 400 mw times improved in the PA group at 6 months (adjusted score difference −0.41 min.; p=0.021). For those with high depressive symptoms, a trend toward statistical improvement in the SPPB was observed in the PA versus SA group (adjusted score difference +0.76 (p=0.176) at 6 months and +0.94 (p=0.116) at 12 months).
CONCLUSION
The presence of high depressive symptoms did not substantially diminish physical performance benefits realized after a PA intervention in sedentary older adults.
doi:10.1111/j.1532-5415.2011.03319.x
PMCID: PMC3086832  PMID: 21391940
17.  A Physical Activity Intervention to Treat the Frailty Syndrome in Older Persons—Results From the LIFE-P Study 
Background.
The frailty syndrome is as a well-established condition of risk for disability. Aim of the study is to explore whether a physical activity (PA) intervention can reduce prevalence and severity of frailty in a community-dwelling elders at risk of disability.
Methods.
Exploratory analyses from the Lifestyle Interventions and Independence for Elders pilot, a randomized controlled trial enrolling 424 community-dwelling persons (mean age=76.8 years) with sedentary lifestyle and at risk of mobility disability. Participants were randomized to a 12-month PA intervention versus a successful aging education group. The frailty phenotype (ie, ≥3 of the following defining criteria: involuntary weight loss, exhaustion, sedentary behavior, slow gait speed, poor handgrip strength) was measured at baseline, 6 months, and 12 months. Repeated measures generalized linear models were conducted.
Results.
A significant (p = .01) difference in frailty prevalence was observed at 12 months in the PA intervention group (10.0%; 95% confidence interval = 6.5%, 15.1%), relative to the successful aging group (19.1%; 95% confidence interval = 13.9%,15.6%). Over follow-up, in comparison to successful aging participants, the mean number of frailty criteria in the PA group was notably reduced for younger subjects, blacks, participants with frailty, and those with multimorbidity. Among the frailty criteria, the sedentary behavior was the one most affected by the intervention.
Conclusions.
Regular PA may reduce frailty, especially in individuals at higher risk of disability. Future studies should be aimed at testing the possible benefits produced by multidomain interventions on frailty.
doi:10.1093/gerona/glu099
PMCID: PMC4311184  PMID: 25387728
Frailty; Physical activity; Physical function; Successful aging; Clinical trials.
18.  Association Between Inflammatory Components and Physical Function in the Health, Aging, and Body Composition Study: A Principal Component Analysis Approach 
Background
In older adults, studies demonstrate an inverse relationship between physical function and individual inflammatory biomarkers. Given that the inflammatory response is a complex system, a combination of biomarkers may increase the strength and consistency of these associations. This study uses principal component analysis to identify inflammatory “component(s)” and evaluates associations between the identified component(s) and measures of physical function.
Methods
Principal component analysis with a varimax rotation was used to identify two components from eight inflammatory biomarkers measured in 1,269 older persons. The study sample is a subset of the Health, Aging, and Body Composition study.
Results
The two components explained 56% of the total variance in the data (34%, component 1 and 22%, component 2). Five markers (tumor necrosis factor-alpha [TNF-α], sTNFRI, sTNFRII, interleukin [IL]-6sR, IL-2sR) loaded highest on the first component (TNF-α related), whereas three markers (C-reactive protein [CRP], IL-6, plasminogen activator inhibitor-1) loaded highest on the second component (CRP related). After adjusting for age, sex, race, site, sampling indicator, total lean and fat mass, physical activity, smoking, and anti-inflammatory drug use, knee strength and a physical performance battery score were inversely related to the TNF-α-related component, but not to the CRP-related component (knee strength: β^TNFα = −2.71, p = .002; β^CRP = −0.88, p = .325; physical performance battery score: β^TNFα = −0.05, p < .001; β^CRP = −0.02, p = .171). Both components were positively associated with 400-m walk time, inversely associated with grip strength, and not associated with 20-m walking speed.
Conclusions
At least two inflammatory components can be identified in an older population, and these components have inconsistent associations with different aspects of physical performance.
doi:10.1093/gerona/glp005
PMCID: PMC2800809  PMID: 19228783
Inflammation; Physical function; Aging; Principal component analysis
19.  Contributors to Mortality in High-Risk Diabetic Patients in the Diabetes Heart Study 
Diabetes Care  2014;37(10):2798-2803.
OBJECTIVE
Not all individuals with type 2 diabetes and high coronary artery calcified plaque (CAC) experience the same risk for adverse outcomes. This study examined a subset of high-risk individuals based on CAC >1,000 mg (using a total mass score) and evaluated whether differences in a range of modifiable cardiovascular disease (CVD) risk factors provided further insights into risk for mortality.
RESEARCH DESIGN AND METHODS
We assessed contributors to all-cause mortality among 371 European American individuals with type 2 diabetes and CAC >1,000 from the Diabetes Heart Study (DHS) after 8.2 ± 3.0 years (mean ± SD) of follow-up. Differences in known CVD risk factors, including modifiable CVD risk factors, were compared between living (n = 218) and deceased (n = 153) participants. Cox proportional hazards regression models were used to quantify risk for all-cause mortality.
RESULTS
Deceased participants had a longer duration of type 2 diabetes (P = 0.02) and reduced use of cholesterol-lowering medications (P = 0.004). Adjusted analyses revealed that vascular calcified plaque scores were associated with increased risk for mortality (hazard ratio 1.31–1.63; 3.89 × 10−5 < P < 0.03). Higher HbA1c, lipids, and C-reactive protein and reduced kidney function also were associated with a 1.1- to 1.5-fold increased risk for mortality (3.45 × 10−6 < P < 0.03) after adjusting for confounding factors.
CONCLUSIONS
Even in this high-risk group, vascular calcification and known CVD risk factors provide useful information for ongoing assessment. The use of cholesterol-lowering medication seemed to be protective for mortality.
doi:10.2337/dc14-0081
PMCID: PMC4392938  PMID: 24989706
20.  COMBINED REDUCED FORCED EXPIRATORY VOLUME IN 1-SECOND (FEV1) AND PERIPHERAL ARTERY DISEASE IN SEDENTARY ELDERS WITH FUNCTIONAL LIMITATIONS 
Objectives
Because they are potentially modifiable and may coexist, we evaluated the combined occurrence of a reduced forced expiratory volume in 1-second (FEV1) and peripheral artery disease (PAD), including its association with exertional symptoms, physical inactivity, and impaired mobility, in sedentary elders with functional limitations.
Design
Cross-sectional.
Setting
Lifestyle Interventions and Independence in Elder (LIFE) Study.
Participants
1307 sedentary community-dwelling persons, mean age 78.9, with functional limitations (Short Physical Performance Battery [SPPB] <10).
Measurements
A reduced FEV1 was defined by a Z-score <-1.64 (< lower limit of normal), while PAD was defined by an ankle-brachial index <1.00. Exertional dyspnea was defined as moderate-to-severe (modified Borg index), immediately after a 400-meter walk test (400MWT). Exertional leg symptoms were established by the San Diego Claudication Questionnaire. Physical inactivity was evaluated by percent of accelerometry wear-time with activity <100 counts/min (top quartile established high sedentary-time). Mobility was evaluated by the 400MWT (gait-speed <0.8 m/s defined as slow) and SPPB (≤7 defined moderate-to-severe mobility impairment).
Results
A combined reduced FEV1 and PAD was established in 6.0% (78/1307) of participants. However, among those who had a reduced FEV1, 34.2% (78/228) also had PAD, while 20.8% (78/375) of those who had PAD also had a reduced FEV1. The two combined conditions were associated with exertional dyspnea (adjusted odds ratio [adjOR] 2.59 [1.20, 5.60]) and slow gait-speed (adjOR 3.15 [1.72, 5.75]) but not with exertional leg symptoms, high sedentary-time, and moderate-to-severe mobility impairment.
Conclusions
In sedentary community-dwelling elders with functional limitations, a reduced FEV1 and PAD frequently coexisted and, in combination, were strongly associated with exertional dyspnea and slow gait-speed (a frailty indicator that increases the risk of deleterious outcomes).
doi:10.1016/j.jamda.2014.05.008
PMCID: PMC4145029  PMID: 24973990
FEV1; peripheral artery disease; mobility; sedentary
21.  Predictors of all-cause and cardiovascular disease mortality in type 2 diabetes: Diabetes Heart Study 
Background
Many studies evaluated the best predictors for cardiovascular disease (CVD) events in individuals with type 2 diabetes (T2D), but few studies examined the factors most strongly associated with mortality in T2D. The Diabetes Heart Study (DHS), an intensively phenotyped family-based cohort enriched for T2D, provided an opportunity to address this question.
Methods
Associations with mortality were examined in 1022 European Americans affected by T2D from 476 DHS families. All-cause mortality was 31.2 % over an average 9.6 years of follow-up. Cox proportional hazards models with sandwich-based variance estimation were used to evaluate associations between all-cause and CVD mortality and 24 demographic and clinical factors, including coronary artery calcified plaque (CAC), carotid artery intima-media thickness, medications, body mass index, waist hip ratio, lipids, blood pressure, kidney function, QT interval, educational attainment, and glycemic control. Nominally significant factors (p < 0.25) from univariate analyses were included in model selection (backward elimination, forward selection, and stepwise selection). Age and sex were included in all models.
Results
The all-cause mortality model selected from the full DHS sample included age, sex, CAC, urine albumin: creatinine ratio (UACR), insulin use, current smoking, and educational attainment. The CVD mortality model selected from the full sample included age, sex, CAC, UACR, triglycerides, and history of CVD events. Beyond age, the most significant associations for both mortality models were CAC (2.03 × 10−4 ≤ p ≤ 0.001) and UACR (1.99 × 10−8 ≤ p ≤ 2.23 × 10−8). To confirm the validity of the main predictors identified with model selection using the full sample, a two-fold cross-validation approach was used, and similar results were observed.
Conclusions
This analysis highlights important demographic and clinical factors, notably CAC and albuminuria, which predict mortality in the general population of patients with T2D.
Electronic supplementary material
The online version of this article (doi:10.1186/s13098-015-0055-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13098-015-0055-y
PMCID: PMC4490739  PMID: 26146522
Type 2 diabetes; Mortality; Coronary artery calcified plaque; Urine albumin:creatinine ratio
22.  Heritability and genetic association analysis of cognition in the Diabetes Heart Study 
Neurobiology of aging  2014;35(8):1958.e3-1958.e12.
Cognitive performance is an important component of healthy aging. Type 2 diabetes (T2D) is associated with negative outcomes for the brain and cognition, although causal mechanisms have not been definitely determined. Genetic risk factors warrant further consideration in this context. This study examined the heritability of cognitive function as assessed by (1) the Digit Symbol Substitution Task; (2) the Modified Mini-Mental State Examination; (3) the Stroop Task; (4) the Rey Auditory-Verbal Learning Task; and (5) the Controlled Oral Word Association Task for Phonemic and Semantic Fluency, in the family-based, T2D-enriched, Diabetes Heart Study sample (n = 550 participants from 257 families). The genetic basis of these cognitive measures was further evaluated by association analysis with candidate single-nucleotide polymorphisms (SNPs) and genome-wide SNP data. Measures of cognitive function were significantly heritable (ĥ2 = 0.28–0.62) following adjustment for age, gender, and education. A total of 31 SNPs (from 26 genes/regions) selected to form an a priori set of candidate SNPs showed limited evidence of association with cognitive function when applying conservative metrics of significance. Genome-wide assessment of both noncoding and coding variants revealed suggestive evidence of association for several coding variants including rs139509083 in CNST (p = 4.9 × 10−9), rs199968569 in PLAA (p = 4.9 × 10−9) and rs138487371 in PCDH8 (p = 3.7 × 10−8). The identification of a heritable component to cognitive performance in T2D suggests a role for genetic contributors to cognitive performance even in the presence of metabolic disease and other associated comorbidities and is supported by the identification of genetic association signals in functionally plausible candidates.
doi:10.1016/j.neurobiolaging.2014.03.005
PMCID: PMC4418030  PMID: 24684796
Cognitive function; Heritability; Genetics; Type 2 diabetes
23.  Genome-Wide Association Study for Circulating Tissue Plasminogen Activator (tPA) Levels and Functional Follow-up Implicates Endothelial STXBP5 and STX2 
Huang, Jie | Huffman, Jennifer E. | Yamkauchi, Munekazu | Trompet, Stella | Asselbergs, Folkert W. | Sabater-Lleal, Maria | Trégouët, David-Alexandre | Chen, Wei-Min | Smith, Nicholas L. | Kleber, Marcus E. | Shin, So-Youn | Becker, Diane M. | Tang, Weihong | Dehghan, Abbas | Johnson, Andrew D. | Truong, Vinh | Folkersen, Lasse | Yang, Qiong | Oudot-Mellakh, Tiphaine | Buckley, Brendan M. | Moore, Jason H. | Williams, Frances M.K. | Campbell, Harry | Silbernagel, Günther | Vitart, Veronique | Rudan, Igor | Tofler, Geoffrey H. | Navis, Gerjan J. | DeStefano, Anita | Wright, Alan F. | Chen, Ming-Huei | de Craen, Anton J.M. | Worrall, Bradford B. | Rudnicka, Alicja R. | Rumley, Ann | Bookman, Ebony B. | Psaty, Bruce M. | Chen, Fang | Keene, Keith L. | Franco, Oscar H. | Böhm, Bernhard O. | Uitterlinden, Andre G. | Carter, Angela M. | Jukema, J. Wouter | Sattar, Naveed | Bis, Joshua C. | Ikram, Mohammad A. | Sale, Michèle M. | McKnight, Barbara | Fornage, Myriam | Ford, Ian | Taylor, Kent | Slagboom, P. Eline | McArdle, Wendy L. | Hsu, Fang-Chi | Franco-Cereceda, Anders | Goodall, Alison H. | Yanek, Lisa R. | Furie, Karen L. | Cushman, Mary | Hofman, Albert | Witteman, Jacqueline CM. | Folsom, Aaron R. | Basu, Saonli | Matijevic, Nena | van Gilst, Wiek H. | Wilson, James F. | Westendorp, Rudi G.J. | Kathiresan, Sekar | Reilly, Muredach P. | Tracy, Russell P. | Polasek, Ozren | Winkelmann, Bernhard R. | Grant, Peter J. | Hillege, Hans L. | Cambien, Francois | Stott, David J. | Lowe, Gordon D. | Spector, Timothy D. | Meigs, James B. | Marz, Winfried | Eriksson, Per | Becker, Lewis C. | Morange, Pierre-Emmanuel | Soranzo, Nicole | Williams, Scott M. | Hayward, Caroline | van der Harst, Pim | Hamsten, Anders | Lowenstein, Charles J. | Strachan, David P. | O'Donnell, Christopher J.
Objective
Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases (CVD). We conducted a meta-analysis of genome-wide association studies (GWAS) to identify novel correlates of circulating levels of tPA.
Approach and Results
Fourteen cohort studies with tPA measures (N=26,929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P <5.0×10−8). The first locus is on 6q24.3, with the lead SNP (rs9399599, P=2.9×10−14) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739, P=1.3×10−9) is intronic to POLB and less than 200kb away from the tPA encoding gene PLAT. We identified a non-synonymous SNP (rs2020921) in modest LD with rs3136739 (r2 = 0.50) within exon 5 of PLAT (P=2.0×10−8). The third locus is on 12q24.33, with the lead SNP (rs7301826, P=1.0×10−9) within intron 7 of STX2. We further found evidence for association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased release of tPA from vascular endothelial cells, while silencing of STX2 increased tPA release. Through an in-silico lookup, we found no associations of the three lead SNPs with coronary artery disease or stroke.
Conclusions
We identified three loci associated with circulating tPA levels, the PLAT region, STXBP5 and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
doi:10.1161/ATVBAHA.113.302088
PMCID: PMC4009733  PMID: 24578379
tissue plasminogen activator; genome-wide association study; meta-analysis; cardiovascular disease risk; fibrinolysis; hemostasis
24.  Genetic Risk Score Associations With Cardiovascular Disease and Mortality in the Diabetes Heart Study 
Diabetes Care  2014;37(4):1157-1164.
OBJECTIVE
Given the high rates of cardiovascular disease (CVD) and associated mortality in individuals with type 2 diabetes, identifying and understanding predictors of CVD events and mortality could help inform clinical management in this high-risk group. Recent large-scale genetic studies may provide additional tools in this regard.
RESEARCH DESIGN AND METHODS
Genetic risk scores (GRSs) were constructed in 1,175 self-identified European American (EA) individuals comprising the family-based Diabetes Heart Study based on 1) 13 single nucleotide polymorphisms (SNPs) and 2) 30 SNPs with previously documented associations with CVD in genome-wide association studies. Associations between each GRS and a self-reported history of CVD, coronary artery calcified plaque (CAC) determined by noncontrast computed tomography scan, all-cause mortality, and CVD mortality were examined using marginal models with generalized estimating equations and Cox proportional hazards models.
RESULTS
The weighted 13-SNP GRS was associated with prior CVD (odds ratio [OR] 1.51 [95% CI 1.22–1.86]; P = 0.0002), CAC (β-coefficient [β] 0.22 [0.02–0.43]; P = 0.04) and CVD mortality (hazard ratio [HR] 1.35 [1.10–1.81]; P = 0.04) when adjusting for the other known CVD risk factors: age, sex, type 2 diabetes affection status, BMI, current smoking status, hypertension, and dyslipidemia. The weighted 30-SNP GRS was also associated with prior CVD (OR 1.33 [1.08–1.65]; P = 0.008), CAC (β 0.29 [0.08–0.50]; P = 0.006), all-cause mortality (HR 1.28 [1.05–1.56]; P = 0.01), and CVD mortality (HR 1.46 [1.08–1.96]; P = 0.01).
CONCLUSIONS
These findings support the utility of two simple GRSs in examining genetic associations for adverse outcomes in EAs with type 2 diabetes.
doi:10.2337/dc13-1514
PMCID: PMC4178326  PMID: 24574349
25.  The Peroxisomal Proliferator-Activated Receptor (PPAR) α Agonist, Fenofibrate, Prevents Fractionated Whole-Brain Irradiation-Induced Cognitive Impairment 
Radiation research  2014;181(1):33-44.
We hypothesized that dietary administration of the peroxisomal proliferator-activated receptor α agonist, fenofibrate, to young adult male rats would prevent the fractionated whole-brain irradiation (fWBI)-induced reduction in cognitive function and neurogenesis and prevent the fWBI-induced increase in the total number of activated microglia. Eighty 12–14-week-old young adult male Fischer 344 × Brown Norway rats received either: (1) sham irradiation, (2) 40 Gy of fWBI delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation + dietary fenofibrate (0.2% w/w) starting 7 days prior to irradiation, or (4) fWBI + fenofibrate. Cognitive function was measured 26–29 weeks after irradiation using: (1) the perirhinal cortex (PRh)-dependent novel object recognition task; (2) the hippocampal-dependent standard Morris water maze (MWM) task; (3) the hippocampal-dependent delayed match-to-place version of the MWM task; and (4) a cue strategy preference version of the MWM to distinguish hippocampal from striatal task performance. Neurogenesis was assessed 29 weeks after fWBI in the granular cell layer and subgranular zone of the dentate gyrus using a doublecortin antibody. Microglial activation was assessed using an ED1 antibody in the dentate gyrus and hilus of the hippocampus. A significant impairment in perirhinal cortex-dependent cognitive function was measured after fWBI. In contrast, fWBI failed to alter hippocampal-dependent cognitive function, despite a significant reduction in hippocampal neurogenesis. Continuous administration of fenofibrate prevented the fWBI-induced reduction in perirhinal cortex-dependent cognitive function, but did not prevent the radiation-induced reduction in neurogenesis or the radiation-induced increase in activated microglia. These data suggest that fenofibrate may be a promising therapeutic for the prevention of some modalities of radiation-induced cognitive impairment in brain cancer patients.
doi:10.1667/RR13202.1
PMCID: PMC4144193  PMID: 24397438

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