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1.  Association of Type 1 Diabetes vs Type 2 Diabetes Diagnosed During Childhood and Adolescence With Complications During Teenage Years and Young Adulthood 
JAMA  2017;317(8):825-835.
IMPORTANCE
The burden and determinants of complications and comorbidities in contemporary youth-onset diabetes are unknown.
OBJECTIVE
To determine the prevalence of and risk factors for complications related to type 1 diabetes vs type 2 diabetes among teenagers and young adults who had been diagnosed with diabetes during childhood and adolescence.
DESIGN, SETTING, AND PARTICIPANTS
Observational study from 2002 to 2015 in 5 US locations, including 2018 participants with type 1 and type 2 diabetes diagnosed at younger than 20 years, with single outcome measures between 2011 and 2015.
EXPOSURES
Type 1 and type 2 diabetes and established risk factors (hemoglobin A1c level, body mass index, waist-height ratio, and mean arterial blood pressure).
MAIN OUTCOMES AND MEASURES
Diabetic kidney disease, retinopathy, peripheral neuropathy, cardiovascular autonomic neuropathy, arterial stiffness, and hypertension.
RESULTS
Of 2018 participants, 1746 had type 1 diabetes (mean age, 17.9 years [SD 4.1]; 1327 non-Hispanic white [76.0%]; 867 female patients [49.7%]), and 272 had type 2 (mean age, 22.1 years [SD 3.5]; 72 non-Hispanic white [26.5%]; 181 female patients [66.5%]). Mean diabetes duration was 7.9 years (both groups). Patients with type 2 diabetes vs those with type 1 had higher age-adjusted prevalence of all measured complications except cardiovascular autonomic neuropathy. After adjustment for established risk factors measured over time, participants with type 2 diabetes vs those with type 1 had significantly higher odds of diabetic kidney disease, retinopathy, and peripheral neuropathy but no significant difference in the odds of arterial stiffness and hypertension.
CONCLUSIONS AND RELEVANCE
Among teenagers and young adults who had been diagnosed with diabetes during childhood or adolescence, the prevalence of complications and comorbidities was higher among those with type 2 diabetes compared with type 1, but frequent in both groups. These findings support early monitoring of youth with diabetes for development of complications.
doi:10.1001/jama.2017.0686
PMCID: PMC5483855  PMID: 28245334
2.  Isolation and characterization of an HLA-DPB1*04:01-restricted MAGE-A3 T cell receptor for cancer immunotherapy 
Summary
Long-term tumor regressions have been observed in patients following the adoptive transfer of autologous tumor infiltrating lymphocytes (TILs) or genetically-modified T cells expressing MHC class I-restricted T cell receptors (TCRs), but clinical trials have not evaluated responses to genetically-modified T cells expressing anti-tumor MHC class II-restricted TCRs. Since studies carried out in a murine tumor model system have demonstrated that the adoptive transfer of CD4+ T cells could lead to the regression of established tumors, we plan to test the hypothesis that CD4+ T cells can also induce tumor regressions in cancer patients. In this study, two MAGE-A3-specific TCRs were isolated from a regulatory T cell clone (6F9) and an effector clone (R12C9), generated from the peripheral blood of two melanoma patients after MAGE-A3 vaccination. The results indicated that T cells transduced with 6F9 TCR mediated stronger effector functions than R12C9 TCR. The 6F9 TCR specifically recognized MAGE-A3 and the closely related MAGE-A6 gene product, but not other members of the MAGE-A family in the context of HLA-DPB1*04:01. To test the feasibility of a potential clinical trial using this TCR, a clinical-scale procedure was developed to obtain a large number of purified CD4+ T cells transduced with 6F9 TCR. Because HLA-DPB1*04:01 is present in ~60% of the Caucasian population and MAGE-A3 is frequently expressed in a variety of cancer types, this TCR immunotherapy could potentially be applicable for a significant portion of cancer patients.
doi:10.1097/CJI.0000000000000123
PMCID: PMC4947411  PMID: 27163739
3.  Health Literacy and Awareness of Atrial Fibrillation 
Background
Atrial fibrillation (AF) is the most common clinically significant arrhythmia in adults and a major risk factor for ischemic stroke. Nonetheless, previous research suggests that many individuals diagnosed with AF lack awareness about their diagnosis and inadequate health literacy may be an important contributing factor to this finding.
Methods and Results
We examined the association between health literacy and awareness of an AF diagnosis in a large, ethnically diverse cohort of Kaiser Permanente Northern and Southern California adults diagnosed with AF between January 1, 2006 and June 30, 2009. Using self‐reported questionnaire data completed between May 1, 2010 and September 30, 2010, awareness of an AF diagnosis was evaluated using the question “Have you ever been told by a doctor or other health professional that you have a heart rhythm problem called atrial fibrillation or atrial flutter?” and health literacy was assessed using a validated 3‐item instrument examining problems because of reading, understanding, and filling out medical forms. Of the 12 517 patients diagnosed with AF, 14.5% were not aware of their AF diagnosis and 20.4% had inadequate health literacy. Patients with inadequate health literacy were less likely to be aware of their AF diagnosis compared with patients with adequate health literacy (prevalence ratio=0.96; 95% CI [0.94, 0.98]), adjusting for sociodemographics, health behaviors, and clinical characteristics.
Conclusions
Lower health literacy is independently associated with less awareness of AF diagnosis. Strategies designed to increase patient awareness of AF and its complications are warranted among individuals with limited health literacy.
doi:10.1161/JAHA.116.005128
PMCID: PMC5533014  PMID: 28400367
arrhythmia; atrial fibrillation; awareness; health literacy; Arrhythmias; Catheter Ablation and Implantable Cardioverter-Defibrillator; Health Services
4.  31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one 
Lundqvist, Andreas | van Hoef, Vincent | Zhang, Xiaonan | Wennerberg, Erik | Lorent, Julie | Witt, Kristina | Sanz, Laia Masvidal | Liang, Shuo | Murray, Shannon | Larsson, Ola | Kiessling, Rolf | Mao, Yumeng | Sidhom, John-William | Bessell, Catherine A. | Havel, Jonathan | Schneck, Jonathan | Chan, Timothy A. | Sachsenmeier, Eliot | Woods, David | Berglund, Anders | Ramakrishnan, Rupal | Sodre, Andressa | Weber, Jeffrey | Zappasodi, Roberta | Li, Yanyun | Qi, Jingjing | Wong, Philip | Sirard, Cynthia | Postow, Michael | Newman, Walter | Koon, Henry | Velcheti, Vamsidhar | Callahan, Margaret K. | Wolchok, Jedd D. | Merghoub, Taha | Lum, Lawrence G. | Choi, Minsig | Thakur, Archana | Deol, Abhinav | Dyson, Gregory | Shields, Anthony | Haymaker, Cara | Uemura, Marc | Murthy, Ravi | James, Marihella | Wang, Daqing | Brevard, Julie | Monaghan, Catherine | Swann, Suzanne | Geib, James | Cornfeld, Mark | Chunduru, Srinivas | Agrawal, Sudhir | Yee, Cassian | Wargo, Jennifer | Patel, Sapna P. | Amaria, Rodabe | Tawbi, Hussein | Glitza, Isabella | Woodman, Scott | Hwu, Wen-Jen | Davies, Michael A. | Hwu, Patrick | Overwijk, Willem W. | Bernatchez, Chantale | Diab, Adi | Massarelli, Erminia | Segal, Neil H. | Ribrag, Vincent | Melero, Ignacio | Gangadhar, Tara C. | Urba, Walter | Schadendorf, Dirk | Ferris, Robert L. | Houot, Roch | Morschhauser, Franck | Logan, Theodore | Luke, Jason J. | Sharfman, William | Barlesi, Fabrice | Ott, Patrick A. | Mansi, Laura | Kummar, Shivaani | Salles, Gilles | Carpio, Cecilia | Meier, Roland | Krishnan, Suba | McDonald, Dan | Maurer, Matthew | Gu, Xuemin | Neely, Jaclyn | Suryawanshi, Satyendra | Levy, Ronald | Khushalani, Nikhil | Wu, Jennifer | Zhang, Jinyu | Basher, Fahmin | Rubinstein, Mark | Bucsek, Mark | Qiao, Guanxi | MacDonald, Cameron | Hylander, Bonnie | Repasky, Elizabeth | Chatterjee, Shilpak | Daenthanasanmak, Anusara | Chakraborty, Paramita | Toth, Kyle | Meek, Megan | Garrett-Mayer, Elizabeth | Nishimura, Michael | Paulos, Chrystal | Beeson, Craig | Yu, Xuezhong | Mehrotra, Shikhar | Zhao, Fei | Evans, Kathy | Xiao, Christine | Holtzhausen, Alisha | Hanks, Brent A. | Scharping, Nicole | Menk, Ashley V. | Moreci, Rebecca | Whetstone, Ryan | Dadey, Rebekah | Watkins, Simon | Ferris, Robert | Delgoffe, Greg M. | Peled, Jonathan | Devlin, Sean | Staffas, Anna | Lumish, Melissa | Rodriguez, Kori Porosnicu | Ahr, Katya | Perales, Miguel | Giralt, Sergio | Taur, Ying | Pamer, Eric | van den Brink, Marcel R. M. | Jenq, Robert | Annels, Nicola | Pandha, Hardev | Simpson, Guy | Mostafid, Hugh | Harrington, Kevin | Melcher, Alan | Grose, Mark | Davies, Bronwyn | Au, Gough | Karpathy, Roberta | Shafren, Darren | Ricca, Jacob | Merghoub, Taha | Wolchok, Jedd D. | Zamarin, Dmitriy | Batista, Luciana | Marliot, Florence | Vasaturo, Angela | Carpentier, Sabrina | Poggionovo, Cécile | Frayssinet, Véronique | Fieschi, Jacques | Van den Eynde, Marc | Pagès, Franck | Galon, Jérôme | Hermitte, Fabienne | Smith, Sean G. | Nguyen, Khue | Ravindranathan, Sruthi | Koppolu, Bhanu | Zaharoff, David | Schvartsman, Gustavo | Bassett, Roland | McQuade, Jennifer L. | Haydu, Lauren E. | Davies, Michael A. | Tawbi, Hussein | Glitza, Isabella | Kline, Douglas | Chen, Xiufen | Fosco, Dominick | Kline, Justin | Overacre, Abigail | Chikina, Maria | Brunazzi, Erin | Shayan, Gulidanna | Horne, William | Kolls, Jay | Ferris, Robert L. | Delgoffe, Greg M. | Bruno, Tullia C. | Workman, Creg | Vignali, Dario | Adusumilli, Prasad S. | Ansa-Addo, Ephraim A | Li, Zihai | Gerry, Andrew | Sanderson, Joseph P. | Howe, Karen | Docta, Roslin | Gao, Qian | Bagg, Eleanor A. L. | Tribble, Nicholas | Maroto, Miguel | Betts, Gareth | Bath, Natalie | Melchiori, Luca | Lowther, Daniel E. | Ramachandran, Indu | Kari, Gabor | Basu, Samik | Binder-Scholl, Gwendolyn | Chagin, Karen | Pandite, Lini | Holdich, Tom | Amado, Rafael | Zhang, Hua | Glod, John | Bernstein, Donna | Jakobsen, Bent | Mackall, Crystal | Wong, Ryan | Silk, Jonathan D. | Adams, Katherine | Hamilton, Garth | Bennett, Alan D. | Brett, Sara | Jing, Junping | Quattrini, Adriano | Saini, Manoj | Wiedermann, Guy | Gerry, Andrew | Jakobsen, Bent | Binder-Scholl, Gwendolyn | Brewer, Joanna | Duong, MyLinh | Lu, An | Chang, Peter | Mahendravada, Aruna | Shinners, Nicholas | Slawin, Kevin | Spencer, David M. | Foster, Aaron E. | Bayle, J. Henri | Bergamaschi, Cristina | Ng, Sinnie Sin Man | Nagy, Bethany | Jensen, Shawn | Hu, Xintao | Alicea, Candido | Fox, Bernard | Felber, Barbara | Pavlakis, George | Chacon, Jessica | Yamamoto, Tori | Garrabrant, Thomas | Cortina, Luis | Powell, Daniel J. | Donia, Marco | Kjeldsen, Julie Westerlin | Andersen, Rikke | Westergaard, Marie Christine Wulff | Bianchi, Valentina | Legut, Mateusz | Attaf, Meriem | Dolton, Garry | Szomolay, Barbara | Ott, Sascha | Lyngaa, Rikke | Hadrup, Sine Reker | Sewell, Andrew Kelvin | Svane, Inge Marie | Fan, Aaron | Kumai, Takumi | Celis, Esteban | Frank, Ian | Stramer, Amanda | Blaskovich, Michelle A. | Wardell, Seth | Fardis, Maria | Bender, James | Lotze, Michael T. | Goff, Stephanie L. | Zacharakis, Nikolaos | Assadipour, Yasmine | Prickett, Todd D. | Gartner, Jared J. | Somerville, Robert | Black, Mary | Xu, Hui | Chinnasamy, Harshini | Kriley, Isaac | Lu, Lily | Wunderlich, John | Robbins, Paul F. | Rosenberg, Steven | Feldman, Steven A. | Trebska-McGowan, Kasia | Kriley, Isaac | Malekzadeh, Parisa | Payabyab, Eden | Sherry, Richard | Rosenberg, Steven | Goff, Stephanie L. | Gokuldass, Aishwarya | Blaskovich, Michelle A. | Kopits, Charlene | Rabinovich, Brian | Lotze, Michael T. | Green, Daniel S. | Kamenyeva, Olena | Zoon, Kathryn C. | Annunziata, Christina M. | Hammill, Joanne | Helsen, Christopher | Aarts, Craig | Bramson, Jonathan | Harada, Yui | Yonemitsu, Yoshikazu | Helsen, Christopher | Hammill, Joanne | Mwawasi, Kenneth | Denisova, Galina | Bramson, Jonathan | Giri, Rajanish | Jin, Benjamin | Campbell, Tracy | Draper, Lindsey M. | Stevanovic, Sanja | Yu, Zhiya | Weissbrich, Bianca | Restifo, Nicholas P. | Trimble, Cornelia L. | Rosenberg, Steven | Hinrichs, Christian S. | Tsang, Kwong | Fantini, Massimo | Hodge, James W. | Fujii, Rika | Fernando, Ingrid | Jochems, Caroline | Heery, Christopher | Gulley, James | Soon-Shiong, Patrick | Schlom, Jeffrey | Jing, Weiqing | Gershan, Jill | Blitzer, Grace | Weber, James | McOlash, Laura | Johnson, Bryon D. | Kiany, Simin | Gangxiong, Huang | Kleinerman, Eugenie S. | Klichinsky, Michael | Ruella, Marco | Shestova, Olga | Kenderian, Saad | Kim, Miriam | Scholler, John | June, Carl H. | Gill, Saar | Moogk, Duane | Zhong, Shi | Yu, Zhiya | Liadi, Ivan | Rittase, William | Fang, Victoria | Dougherty, Janna | Perez-Garcia, Arianne | Osman, Iman | Zhu, Cheng | Varadarajan, Navin | Restifo, Nicholas P. | Frey, Alan | Krogsgaard, Michelle | Landi, Daniel | Fousek, Kristen | Mukherjee, Malini | Shree, Ankita | Joseph, Sujith | Bielamowicz, Kevin | Byrd, Tiara | Ahmed, Nabil | Hegde, Meenakshi | Lee, Sylvia | Byrd, David | Thompson, John | Bhatia, Shailender | Tykodi, Scott | Delismon, Judy | Chu, Liz | Abdul-Alim, Siddiq | Ohanian, Arpy | DeVito, Anna Marie | Riddell, Stanley | Margolin, Kim | Magalhaes, Isabelle | Mattsson, Jonas | Uhlin, Michael | Nemoto, Satoshi | Villarroel, Patricio Pérez | Nakagawa, Ryosuke | Mule, James J. | Mailloux, Adam W. | Mata, Melinda | Nguyen, Phuong | Gerken, Claudia | DeRenzo, Christopher | Spencer, David M. | Gottschalk, Stephen | Mathieu, Mélissa | Pelletier, Sandy | Stagg, John | Turcotte, Simon | Minutolo, Nicholas | Sharma, Prannda | Tsourkas, Andrew | Powell, Daniel J. | Mockel-Tenbrinck, Nadine | Mauer, Daniela | Drechsel, Katharina | Barth, Carola | Freese, Katharina | Kolrep, Ulrike | Schult, Silke | Assenmacher, Mario | Kaiser, Andrew | Mullinax, John | Hall, MacLean | Le, Julie | Kodumudi, Krithika | Royster, Erica | Richards, Allison | Gonzalez, Ricardo | Sarnaik, Amod | Pilon-Thomas, Shari | Nielsen, Morten | Krarup-Hansen, Anders | Hovgaard, Dorrit | Petersen, Michael Mørk | Loya, Anand Chainsukh | Junker, Niels | Svane, Inge Marie | Rivas, Charlotte | Parihar, Robin | Gottschalk, Stephen | Rooney, Cliona M. | Qin, Haiying | Nguyen, Sang | Su, Paul | Burk, Chad | Duncan, Brynn | Kim, Bong-Hyun | Kohler, M. Eric | Fry, Terry | Rao, Arjun A. | Teyssier, Noam | Pfeil, Jacob | Sgourakis, Nikolaos | Salama, Sofie | Haussler, David | Richman, Sarah A. | Nunez-Cruz, Selene | Gershenson, Zack | Mourelatos, Zissimos | Barrett, David | Grupp, Stephan | Milone, Michael | Rodriguez-Garcia, Alba | Robinson, Matthew K. | Adams, Gregory P. | Powell, Daniel J. | Santos, João | Havunen, Riikka | Siurala, Mikko | Cervera-Carrascón, Víctor | Parviainen, Suvi | Antilla, Marjukka | Hemminki, Akseli | Sethuraman, Jyothi | Santiago, Laurelis | Chen, Jie Qing | Dai, Zhimin | Wardell, Seth | Bender, James | Lotze, Michael T. | Sha, Huizi | Su, Shu | Ding, Naiqing | Liu, Baorui | Stevanovic, Sanja | Pasetto, Anna | Helman, Sarah R. | Gartner, Jared J. | Prickett, Todd D. | Robbins, Paul F. | Rosenberg, Steven A. | Hinrichs, Christian S. | Bhatia, Shailender | Burgess, Melissa | Zhang, Hui | Lee, Tien | Klingemann, Hans | Soon-Shiong, Patrick | Nghiem, Paul | Kirkwood, John M. | Rossi, John M. | Sherman, Marika | Xue, Allen | Shen, Yueh-wei | Navale, Lynn | Rosenberg, Steven A. | Kochenderfer, James N. | Bot, Adrian | Veerapathran, Anandaraman | Gokuldass, Aishwarya | Stramer, Amanda | Sethuraman, Jyothi | Blaskovich, Michelle A. | Wiener, Doris | Frank, Ian | Santiago, Laurelis | Rabinovich, Brian | Fardis, Maria | Bender, James | Lotze, Michael T. | Waller, Edmund K. | Li, Jian-Ming | Petersen, Christopher | Blazar, Bruce R. | Li, Jingxia | Giver, Cynthia R. | Wang, Ziming | Grossenbacher, Steven K. | Sturgill, Ian | Canter, Robert J. | Murphy, William J. | Zhang, Congcong | Burger, Michael C. | Jennewein, Lukas | Waldmann, Anja | Mittelbronn, Michel | Tonn, Torsten | Steinbach, Joachim P. | Wels, Winfried S. | Williams, Jason B. | Zha, Yuanyuan | Gajewski, Thomas F. | Williams, LaTerrica C. | Krenciute, Giedre | Kalra, Mamta | Louis, Chrystal | Gottschalk, Stephen | Xin, Gang | Schauder, David | Jiang, Aimin | Joshi, Nikhil | Cui, Weiguo | Zeng, Xue | Menk, Ashley V. | Scharping, Nicole | Delgoffe, Greg M. | Zhao, Zeguo | Hamieh, Mohamad | Eyquem, Justin | Gunset, Gertrude | Bander, Neil | Sadelain, Michel | Askmyr, David | Abolhalaj, Milad | Lundberg, Kristina | Greiff, Lennart | Lindstedt, Malin | Angell, Helen K. | Kim, Kyoung-Mee | Kim, Seung-Tae | Kim, Sung | Sharpe, Alan D. | Ogden, Julia | Davenport, Anna | Hodgson, Darren R. | Barrett, Carl | Lee, Jeeyun | Kilgour, Elaine | Hanson, Jodi | Caspell, Richard | Karulin, Alexey | Lehmann, Paul | Ansari, Tameem | Schiller, Annemarie | Sundararaman, Srividya | Lehmann, Paul | Hanson, Jodi | Roen, Diana | Karulin, Alexey | Lehmann, Paul | Ayers, Mark | Levitan, Diane | Arreaza, Gladys | Liu, Fang | Mogg, Robin | Bang, Yung-Jue | O’Neil, Bert | Cristescu, Razvan | Friedlander, Philip | Wassman, Karl | Kyi, Chrisann | Oh, William | Bhardwaj, Nina | Bornschlegl, Svetlana | Gustafson, Michael P. | Gastineau, Dennis A. | Parney, Ian F. | Dietz, Allan B. | Carvajal-Hausdorf, Daniel | Mani, Nikita | Velcheti, Vamsidhar | Schalper, Kurt | Rimm, David | Chang, Serena | Levy, Ronald | Kurland, John | Krishnan, Suba | Ahlers, Christoph Matthias | Jure-Kunkel, Maria | Cohen, Lewis | Maecker, Holden | Kohrt, Holbrook | Chen, Shuming | Crabill, George | Pritchard, Theresa | McMiller, Tracee | Pardoll, Drew | Pan, Fan | Topalian, Suzanne | Danaher, Patrick | Warren, Sarah | Dennis, Lucas | White, Andrew M. | D’Amico, Leonard | Geller, Melissa | Disis, Mary L. | Beechem, Joseph | Odunsi, Kunle | Fling, Steven | Derakhshandeh, Roshanak | Webb, Tonya J. | Dubois, Sigrid | Conlon, Kevin | Bryant, Bonita | Hsu, Jennifer | Beltran, Nancy | Müller, Jürgen | Waldmann, Thomas | Duhen, Rebekka | Duhen, Thomas | Thompson, Lucas | Montler, Ryan | Weinberg, Andrew | Kates, Max | Early, Brandon | Yusko, Erik | Schreiber, Taylor H. | Bivalacqua, Trinity J. | Ayers, Mark | Lunceford, Jared | Nebozhyn, Michael | Murphy, Erin | Loboda, Andrey | Kaufman, David R. | Albright, Andrew | Cheng, Jonathan | Kang, S. Peter | Shankaran, Veena | Piha-Paul, Sarina A. | Yearley, Jennifer | Seiwert, Tanguy | Ribas, Antoni | McClanahan, Terrill K. | Cristescu, Razvan | Mogg, Robin | Ayers, Mark | Albright, Andrew | Murphy, Erin | Yearley, Jennifer | Sher, Xinwei | Liu, Xiao Qiao | Nebozhyn, Michael | Lunceford, Jared | Joe, Andrew | Cheng, Jonathan | Plimack, Elizabeth | Ott, Patrick A. | McClanahan, Terrill K. | Loboda, Andrey | Kaufman, David R. | Forrest-Hay, Alex | Guyre, Cheryl A. | Narumiya, Kohei | Delcommenne, Marc | Hirsch, Heather A. | Deshpande, Amit | Reeves, Jason | Shu, Jenny | Zi, Tong | Michaelson, Jennifer | Law, Debbie | Trehu, Elizabeth | Sathyanaryanan, Sriram | Hodkinson, Brendan P. | Hutnick, Natalie A. | Schaffer, Michael E. | Gormley, Michael | Hulett, Tyler | Jensen, Shawn | Ballesteros-Merino, Carmen | Dubay, Christopher | Afentoulis, Michael | Reddy, Ashok | David, Larry | Fox, Bernard | Jayant, Kumar | Agrawal, Swati | Agrawal, Rajendra | Jeyakumar, Ghayathri | Kim, Seongho | Kim, Heejin | Silski, Cynthia | Suisham, Stacey | Heath, Elisabeth | Vaishampayan, Ulka | Vandeven, Natalie | Viller, Natasja Nielsen | O’Connor, Alison | Chen, Hui | Bossen, Bolette | Sievers, Eric | Uger, Robert | Nghiem, Paul | Johnson, Lisa | Kao, Hsiang-Fong | Hsiao, Chin-Fu | Lai, Shu-Chuan | Wang, Chun-Wei | Ko, Jenq-Yuh | Lou, Pei-Jen | Lee, Tsai-Jan | Liu, Tsang-Wu | Hong, Ruey-Long | Kearney, Staci J. | Black, Joshua C. | Landis, Benjamin J. | Koegler, Sally | Hirsch, Brooke | Gianani, Roberto | Kim, Jeffrey | He, Ming-Xiao | Zhang, Bingqing | Su, Nan | Luo, Yuling | Ma, Xiao-Jun | Park, Emily | Kim, Dae Won | Copploa, Domenico | Kothari, Nishi | doo Chang, Young | Kim, Richard | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Knaus, Hanna A. | Berglund, Sofia | Hackl, Hubert | Karp, Judith E. | Gojo, Ivana | Luznik, Leo | Hong, Henoch S. | Koch, Sven D. | Scheel, Birgit | Gnad-Vogt, Ulrike | Kallen, Karl-Josef | Wiegand, Volker | Backert, Linus | Kohlbacher, Oliver | Hoerr, Ingmar | Fotin-Mleczek, Mariola | Billingsley, James M. | Koguchi, Yoshinobu | Conrad, Valerie | Miller, William | Gonzalez, Iliana | Poplonski, Tomasz | Meeuwsen, Tanisha | Howells-Ferreira, Ana | Rattray, Rogan | Campbell, Mary | Bifulco, Carlo | Dubay, Christopher | Bahjat, Keith | Curti, Brendan | Urba, Walter | Vetsika, E-K | Kallergi, G. | Aggouraki, Despoina | Lyristi, Z. | Katsarlinos, P. | Koinis, Filippos | Georgoulias, V. | Kotsakis, Athanasios | Martin, Nathan T. | Aeffner, Famke | Kearney, Staci J. | Black, Joshua C. | Cerkovnik, Logan | Pratte, Luke | Kim, Rebecca | Hirsch, Brooke | Krueger, Joseph | Gianani, Roberto | Martínez-Usatorre, Amaia | Jandus, Camilla | Donda, Alena | Carretero-Iglesia, Laura | Speiser, Daniel E. | Zehn, Dietmar | Rufer, Nathalie | Romero, Pedro | Panda, Anshuman | Mehnert, Janice | Hirshfield, Kim M. | Riedlinger, Greg | Damare, Sherri | Saunders, Tracie | Sokol, Levi | Stein, Mark | Poplin, Elizabeth | Rodriguez-Rodriguez, Lorna | Silk, Ann | Chan, Nancy | Frankel, Melissa | Kane, Michael | Malhotra, Jyoti | Aisner, Joseph | Kaufman, Howard L. | Ali, Siraj | Ross, Jeffrey | White, Eileen | Bhanot, Gyan | Ganesan, Shridar | Monette, Anne | Bergeron, Derek | Amor, Amira Ben | Meunier, Liliane | Caron, Christine | Morou, Antigoni | Kaufmann, Daniel | Liberman, Moishe | Jurisica, Igor | Mes-Masson, Anne-Marie | Hamzaoui, Kamel | Lapointe, Rejean | Mongan, Ann | Ku, Yuan-Chieh | Tom, Warren | Sun, Yongming | Pankov, Alex | Looney, Tim | Au-Young, Janice | Hyland, Fiona | Conroy, Jeff | Morrison, Carl | Glenn, Sean | Burgher, Blake | Ji, He | Gardner, Mark | Mongan, Ann | Omilian, Angela R. | Conroy, Jeff | Bshara, Wiam | Angela, Omilian | Burgher, Blake | Ji, He | Glenn, Sean | Morrison, Carl | Mongan, Ann | Obeid, Joseph M. | Erdag, Gulsun | Smolkin, Mark E. | Deacon, Donna H. | Patterson, James W. | Chen, Lieping | Bullock, Timothy N. | Slingluff, Craig L. | Obeid, Joseph M. | Erdag, Gulsun | Deacon, Donna H. | Slingluff, Craig L. | Bullock, Timothy N. | Loffredo, John T. | Vuyyuru, Raja | Beyer, Sophie | Spires, Vanessa M. | Fox, Maxine | Ehrmann, Jon M. | Taylor, Katrina A. | Korman, Alan J. | Graziano, Robert F. | Page, David | Sanchez, Katherine | Ballesteros-Merino, Carmen | Martel, Maritza | Bifulco, Carlo | Urba, Walter | Fox, Bernard | Patel, Sapna P. | De Macedo, Mariana Petaccia | Qin, Yong | Reuben, Alex | Spencer, Christine | Guindani, Michele | Bassett, Roland | Wargo, Jennifer | Racolta, Adriana | Kelly, Brian | Jones, Tobin | Polaske, Nathan | Theiss, Noah | Robida, Mark | Meridew, Jeffrey | Habensus, Iva | Zhang, Liping | Pestic-Dragovich, Lidija | Tang, Lei | Sullivan, Ryan J. | Logan, Theodore | Khushalani, Nikhil | Margolin, Kim | Koon, Henry | Olencki, Thomas | Hutson, Thomas | Curti, Brendan | Roder, Joanna | Blackmon, Shauna | Roder, Heinrich | Stewart, John | Amin, Asim | Ernstoff, Marc S. | Clark, Joseph I. | Atkins, Michael B. | Kaufman, Howard L. | Sosman, Jeffrey | Weber, Jeffrey | McDermott, David F. | Weber, Jeffrey | Kluger, Harriet | Halaban, Ruth | Snzol, Mario | Roder, Heinrich | Roder, Joanna | Asmellash, Senait | Steingrimsson, Arni | Blackmon, Shauna | Sullivan, Ryan J. | Wang, Chichung | Roman, Kristin | Clement, Amanda | Downing, Sean | Hoyt, Clifford | Harder, Nathalie | Schmidt, Guenter | Schoenmeyer, Ralf | Brieu, Nicolas | Yigitsoy, Mehmet | Madonna, Gabriele | Botti, Gerardo | Grimaldi, Antonio | Ascierto, Paolo A. | Huss, Ralf | Athelogou, Maria | Hessel, Harald | Harder, Nathalie | Buchner, Alexander | Schmidt, Guenter | Stief, Christian | Huss, Ralf | Binnig, Gerd | Kirchner, Thomas | Sellappan, Shankar | Thyparambil, Sheeno | Schwartz, Sarit | Cecchi, Fabiola | Nguyen, Andrew | Vaske, Charles | Hembrough, Todd
Journal for Immunotherapy of Cancer  2016;4(Suppl 1):1-106.
doi:10.1186/s40425-016-0172-7
PMCID: PMC5123387
5.  GENOME WIDE IDENTIFICATION OF NEW GENES AND PATHWAYS IN PATIENTS WITH BOTH AUTOIMMUNE THYROIDITIS AND TYPE 1 DIABETES 
Journal of autoimmunity  2015;60:32-39.
Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the cooccurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D+AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340 controls. Association analyses were performed using the PLINK program, and pathway analyses were performed using the MAGENTA software. We identified multiple signals within the HLA region and conditioning studies suggested that a few of them contributed independently to the strong association of the HLA locus with APS3v. Outside the HLA region, variants in GPR103, a gene not suggested by previous studies of APS3v, T1D, or AITD, showed genome-wide significance (p<5×10−8). In addition, a locus on 1p13 containing the PTPN22 gene showed genome-wide significant associations. Pathway analysis demonstrated that cell cycle, B-cell development, CD40, and CTLA-4 signaling were the major pathways contributing to the pathogenesis of APS3v. These findings suggest that complex mechanisms involving T-cell and B-cell pathways are involved in the strong genetic association between AITD and T1D.
doi:10.1016/j.jaut.2015.03.006
PMCID: PMC4457545  PMID: 25936594
Type 1 diabetes; Graves’ disease; Hashimoto’s thyroiditis; Gene; HLA
6.  Three-dimensional direct measurement of cardiomyocyte volume, nuclearity, and ploidy in thick histological sections 
Scientific Reports  2016;6:23756.
Quantitative assessment of myocardial development and disease requires accurate measurement of cardiomyocyte volume, nuclearity (nuclei per cell), and ploidy (genome copies per cell). Current methods require enzymatically isolating cells, which excludes the use of archived tissue, or serial sectioning. We describe a method of analysis that permits the direct simultaneous measurement of cardiomyocyte volume, nuclearity, and ploidy in thick histological sections. To demonstrate the utility of our technique, heart tissue was obtained from four species (rat, mouse, rabbit, sheep) at up to three life stages: prenatal, weaning and adulthood. Thick (40 μm) paraffin sections were stained with Wheat Germ Agglutinin-Alexa Fluor 488 to visualise cell membranes, and DAPI (4′,6-diamidino-2-phenylindole) to visualise nuclei and measure ploidy. Previous methods have been restricted to thin sections (2–10 μm) and offer an incomplete picture of cardiomyocytes. Using confocal microscopy and three-dimensional image analysis software (Imaris Version 8.2, Bitplane AG, Switzerland), cardiomyocyte volume, nuclearity, and ploidy were measured. This method of staining and analysis of cardiomyocytes enables accurate morphometric measurements in thick histological sections, thus unlocking the potential of archived tissue. Our novel time-efficient method permits the entire cardiomyocyte to be visualised directly in 3D, eliminating the need for precise alignment of serial sections.
doi:10.1038/srep23756
PMCID: PMC4822151  PMID: 27048757
8.  Calibrated integrated backscatter and myocardial fibrosis in patients undergoing cardiac surgery 
Open Heart  2015;2(1):e000278.
Objective
The reported association between calibrated integrated backscatter (cIB) and myocardial fibrosis is based on study of patients with dilated or hypertrophic cardiomyopathy and extensive (mean 15–34%) fibrosis. Its association with lesser degrees of fibrosis is unknown. We examined the relationship between cIB and myocardial fibrosis in patients with coronary artery disease.
Methods
Myocardial histology was examined in left ventricular epicardial biopsies from 40 patients (29 men and 11 women) undergoing coronary artery bypass graft surgery, who had preoperative echocardiography with cIB measurement.
Results
Total fibrosis (picrosirius red staining) varied from 0.7% to 4%, and in contrast to previous reports, cIB showed weak inverse associations with total fibrosis (r=−0.32, p=0.047) and interstitial fibrosis (r=−0.34, p=0.03). However, cIB was not significantly associated with other histological parameters, including immunostaining for collagens I and III, the advanced glycation end product (AGE) Nε-(carboxymethyl)lysine (CML) and the receptor for AGEs (RAGE). When biomarkers were examined, cIB was weakly associated with log plasma levels of amino-terminal pro-B-type natriuretic peptide (r=0.34, p=0.03), creatinine (r=0.33, p=0.04) and glomerular filtration rate (r=−0.33, p=0.04), and was more strongly associated with log plasma levels of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) (r=0.44, p=0.01) and soluble RAGE (r=0.53, p=0.002).
Conclusions
Higher cIB was not a marker of increased myocardial fibrosis in patients with coronary artery disease, but was associated with higher plasma levels of sVEGFR-1 and soluble RAGE. The role of cIB as a non-invasive index of fibrosis in clinical studies of patients without extensive fibrosis is, therefore, questionable.
doi:10.1136/openhrt-2015-000278
PMCID: PMC4555070  PMID: 26339497
9.  Use of the piggyBac Transposon to Create Stable Packaging Cell Lines for the Production of Clinical-Grade Self-Inactivating γ-Retroviral Vectors 
Human Gene Therapy Methods  2014;25(4):253-260.
Abstract
Efforts to improve the biosafety of γ-retroviral-mediated gene therapy have resulted in a shift toward the use of self-inactivating (SIN) γ-retroviral vectors. However, scale-up and manufacturing of such vectors requires significant optimization of transient transfection-based processes or development of novel platforms for the generation of stable producer cell clones. To that end, we describe the use of the piggybac transposon to generate stable producer cell clones for the production of SIN γ-retroviral vectors. The piggybac transposon is a universal tool allowing for the stable integration of SIN γ-retroviral constructs into murine (PG13) and human 293-based Phoenix (GALV and RD114, respectively) packaging cell lines without reverse transcription. Following transposition, a high-titer clone is selected for manufacture of a master cell bank and subsequent γ-retroviral vector supernatant production. Packaging cell clones created using the piggybac transposon have comparable titers to non-SIN vectors generated via conventional methods. We describe herein the use of the piggybac transposon for the production of stable packaging cell clones for the manufacture of clinical-grade SIN γ-retroviral vectors for ex vivo gene therapy clinical trials.
doi:10.1089/hgtb.2014.071
PMCID: PMC4142856  PMID: 25072603
10.  Demographic and Clinical Correlates of Diabetes-Related Quality of Life among Youth with Type 1 Diabetes 
The Journal of pediatrics  2012;161(2):201-7.e2.
Objectives
To evaluate the reliability and cluster structure of the Pediatric Quality of Life Inventory Type 1 Diabetes Module 3.0 (PedsQL-T1DM) and associated subscales and to explore the associations between PedsQL-T1DM total score and demographic and clinical characteristics and clinical indicators among a large racially/ethnically diverse cohort of youth with type 1 diabetes.
Study design
Principal components analysis was conducted on responses from the PedsQL-T1DM child self-report forms completed by SEARCH for Diabetes in Youth study participants aged ≥5 years. Multivariate linear regression models were fit to examine the associations among PedsQL-T1DM total score, demographic and clinical characteristics, and clinical indicators.
Results
The sample comprised 2602 youth with a mean age of 13.6 ± 4.1 years and a mean T1DM duration of 62.1 ± 47.0 months. Principal components analysis did not support the 5 existing PedsQL-T1DM subscales. In multivariate analyses, the PedsQL-T1DM total score was negatively and significantly associated with younger age (5–7 years), female sex, receiving insulin by injection (vs pump), having parents without a college degree, Medic-aid/Medicare insurance, and having a comorbid medical condition. Youth with poor glycemic control based on their age-specific hemoglobin A1c target values and those with depressive symptoms had significantly lower PedsQL-T1DM scores than their counterparts with good control and no or limited depressive symptoms.
Conclusion
This study has identified sociodemographic and clinical characteristics of youth with T1DM more likely to experience poor diabetes-specific quality of life. The association of lower PedsQL-T1DM scores with depressive symptoms and poor glycemic control is especially concerning and may be the focus of future interventions and studies.
doi:10.1016/j.jpeds.2012.01.016
PMCID: PMC4503360  PMID: 22361221
11.  Associations of dietary intake patterns identified using reduced rank regression with markers of arterial stiffness among youth with type 1 diabetes 
European journal of clinical nutrition  2014;68(12):1327-1333.
BACKGROUND/OBJECTIVES
Youth with type 1 diabetes (T1DM) are at substantially increased risk for adverse vascular outcomes, but little is known about the influence of dietary behavior on cardiovascular disease (CVD) risk profile. We aimed to identify dietary intake patterns associated with CVD risk factors and evaluate their impact on arterial stiffness (AS) measures collected thereafter in a cohort of youth with T1DM.
SUBJECTS/METHODS
Baseline diet data from a food frequency questionnaire and CVD risk factors (triglycerides, LDL-cholesterol, systolic BP, HbA1c, C-reactive protein and waist circumference) were available for 1,153 youth aged ≥10 years with T1DM from the SEARCH for Diabetes in Youth Study. A dietary intake pattern was identified using 33 food-groups as predictors and six CVD risk factors as responses in reduced rank regression (RRR) analysis. Associations of this RRR-derived dietary pattern with AS measures [augmentation index(AIx75), n=229; pulse wave velocity(PWV), n=237; and brachial distensibility(BrachD), n=228] were then assessed using linear regression.
RESULTS
The RRR-derived pattern was characterized by high intakes of sugar-sweetened beverages (SSB) and diet soda, eggs, potatoes and high-fat meats, and low intakes of sweets/desserts and low-fat dairy; major contributors were SSB and diet soda. This pattern captured the largest variability in adverse CVD risk profile and was subsequently associated with AIx75 (β=0.47; p<0.01). The mean difference in AIx75 concentration between the highest and the lowest dietary pattern quartiles was 4.3% in fully adjusted model.
CONCLUSIONS
Intervention strategies to reduce consumption of unhealthful foods and beverages among youth with T1DM may significantly improve CVD risk profile and ultimately reduce the risk for AS.
doi:10.1038/ejcn.2014.96
PMCID: PMC4247344  PMID: 24865480
type 1 diabetes; arterial stiffness; CVD risk factors; dietary intake pattern; reduced rank regression
12.  Evidence of Interaction Between PPARG2 and HNF4A Contributing to Variation in Insulin Sensitivity in Mexican Americans 
Diabetes  2007;57(4):1048-1056.
OBJECTIVE
We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are associated with type 2 diabetes–related quantitative traits in Mexican-American families of a proband with previous gestational diabetes.
RESEARCH DESIGN AND METHODS
The BetaGene project genotyped PPARG2 Pro12Ala and nine HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose <126 mg/dl and were phenotyped by oral and intravenous glucose tolerance tests.
RESULTS
Neither PPARG2 Pro12Ala nor any of the nine HNF4A SNPs were independently associated with type 2 diabetes–related quantitative traits. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (SI) (Bonferroni P = 0.0006) and 2-h insulin (Bonferroni P = 0.039). Subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had 40% higher SI compared with individuals with at least one G allele. SI did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for SI was replicated by the Insulin Resistance Atherosclerosis Family Study (P = 0.018) in their San Antonio sample (n = 484) where subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had a 29% higher SI compared with individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n = 496; P = 0.401).
CONCLUSIONS
Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican Americans at risk for type 2 diabetes.
doi:10.2337/db07-0848
PMCID: PMC4447520  PMID: 18162503
13.  Longitudinal changes in insulin sensitivity and beta cell function between women with and without a history of gestational diabetes mellitus 
Diabetologia  2013;56(12):2753-2760.
Aims/hypothesis
The aim of the study was to compare longitudinal changes in insulin sensitivity (SI) and beta cell function between women with and without a history of gestational diabetes mellitus (GDM).
Methods
The prospective follow-up cohort included 235 parous non-diabetic Mexican-American women, 93 with and 142 without a history of GDM. The participants underwent dual-energy x-ray absorptiometry, OGTTs and IVGTTs at baseline and at a median of 4.1 years follow-up. The baseline values and rates of change of metabolic measures were compared between groups.
Results
At baseline, women with prior GDM (mean age 36.3 years) had similar values of SI but higher percentages of body fat and trunk fat (p≤0.02), a lower acute insulin response and poorer beta cell compensation (disposition index [DI]) (p<0.0001) than women without GDM (mean age 37.9 years). During the follow-up, women with GDM had a faster decline in SI (p=0.02) and DI (p=0.02) than their counterparts without GDM, with no significant differences in changes of weight or fat (p>0.50). Adjustment for baseline age, adiposity, calorie intake, physical activity, age at first pregnancy, additional pregnancies and changes in adiposity during follow-up increased the between-group differences in the rates of change of SI and DI (p≤0.003).
Conclusions/interpretation
Mexican-American women with recent GDM had a faster deterioration in insulin sensitivity and beta cell compensation than their parous counterparts without GDM. The differences were not explained by differences in adiposity, suggesting more deleterious effects of existing fat and/or reduced beta cell robustness in women with GDM.
doi:10.1007/s00125-013-3048-0
PMCID: PMC4139094  PMID: 24030069
Beta cell function; Gestational diabetes mellitus; Longitudinal change; Insulin sensitivity
15.  High Blood Pressure in Overweight and Obese Youth: ok Implications for Screening 
In the absence of evidence-based guidelines for high blood pressure screening in asymptomatic youth, a reasonable strategy is to screen those who are high risk. The present study aimed to identify optimal body mass index (BMI) thresholds as a marker for high-risk youth to predict hypertension prevalence. In a cross-sectional study, youth aged 6–17 years (n=237,248) enrolled in an integrated prepaid health plan in 2007–2009 were classified according to their BMI and hypertension status. In moderately and extremely obese youth, the prevalence of hypertension was 3.8% and 9.2%, respectively, compared to 0.9% in normal weight youth. The adjusted prevalence ratios (95% CIs) of hypertension for normal weight, overweight, moderate obesity and extreme obesity were 1.00 (Reference), 2.27 (2.08–2.47), 4.43 (4.10–4.79), and 10.76 (9.99–11.59), respectively. The prevalence of hypertension was best predicted by a BMI-forage ≥94th percentile. Our results suggest that all obese youth should be screened for hypertension.
doi:10.1111/jch.12199
PMCID: PMC3849231  PMID: 24119024
Children; adolescents; hypertension; prehypertension; disparities
16.  THE PREVALENCE OF PRIMARY PEDIATRIC PREHYPERTENSION AND HYPERTENSION IN A REAL-WORLD MANAGED-CARE SYSTEM 
To assess the burden associated with hypertension, reliable estimates for the prevalence of pediatric hypertension are vital. For this cross-sectional study of 237,248 youths aged 6–17 years without indication of secondary hypertension, blood pressure (BP) was classified according to age, gender, and height using standards from the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents as prehypertension with at least 1 BP ≥90th percentile and as hypertension with 3 BPs ≥95th. The prevalence of prehypertension and hypertension were 31.4% and 2.1%, respectively. An additional 21.4% had either one (16.6%) or two (4.8%) BPs ≥95th percentile. Based on this large population-based study using routinely measured BP from clinical care, a remarkable proportion of youth (6.9%) has hypertension or nearly meets the definition of hypertension with two documented BPs in the hypertensive range.
doi:10.1111/jch.12173
PMCID: PMC3844934  PMID: 24283596
Children; Hypertension; Prehypertension; Disparities; Managed care setting
17.  Increased Asthma Risk and Asthma-Related Health Care Complications Associated With Childhood Obesity 
American Journal of Epidemiology  2013;178(7):1120-1128.
Asthma is the most common chronic condition of childhood, yet the relationship between obesity and asthma risk and the impact of obesity on clinical asthma outcomes are not well understood. For this population-based, longitudinal study, demographic and clinical data were extracted from administrative and electronic health records of 623,358 patients aged 6–19 years who were enrolled in the Kaiser Permanente Southern California health plan in 2007–2011. Crude asthma incidence ranged from 16.9 per 1,000 person-years among normal-weight youth to 22.3 per 1,000 person-years among extremely obese youth. The adjusted risks of asthma for overweight, moderately obese, and extremely obese youth relative to those of normal weight youth were 1.16 (95% confidence interval: 1.13, 1.20), 1.23 (95% confidence interval: 1.19, 1.28), and 1.37 (95% confidence interval: 1.32, 1.42), respectively (Ptrend < 0.0001). The relationship between obesity and asthma risk was strongest in Asian/Pacific Islanders and in the youngest girls (aged 6–10 years), compared with other groups. Among youth who developed asthma, those who were moderately or extremely obese had more frequent asthma exacerbations requiring emergency department services and/or treatment with oral corticosteroids. In conclusion, obese youth are not only more likely to develop asthma, but they may be more likely to have severe asthma, resulting in a greater need for health care utilization and aggressive asthma treatment.
doi:10.1093/aje/kwt093
PMCID: PMC3857927  PMID: 23924576
asthma; body mass index; cohort studies; obesity; overweight; severe asthma
18.  The prevalence of polycystic ovary syndrome in adolescents 
Fertility and sterility  2013;100(2):10.1016/j.fertnstert.2013.04.001.
Objective
To investigate the prevalence of polycystic ovary syndrome (PCOS) in adolescents and its association with obesity.
Design
Cross-sectional study using electronic medical records.
Setting
Integrated health care delivery system in Southern California.
Patients
Adolescents aged 15–19 years (n= 137,502).
Interventions
None.
Main Outcome Measures
PCOS diagnosed or defined according to NIH criteria.
Results
The prevalence of a confirmed diagnosis of PCOS was 0.56%, and increased to 1.14% when undiagnosed cases with documented symptoms qualifying for PCOS according to NIH criteria were included. Compared to normal/underweight girls, the ORs (95% CI) for confirmed PCOS diagnosis were 3.85 (3.04–4.88), 10.25 (8.16–12.84) and 23.10 (18.66–28.61) for overweight, moderately obese, and extremely obese adolescents, respectively (P-trend<0.001) after adjusting for potential confounders. When adolescents with two or more supportive diagnoses were included (diagnosed and undiagnosed PCOS-NIH) the ORs (95% CI) for PCOS-NIH by weight class were significantly attenuated to 2.95 (2.53–3.44), 6.73 (5.78–7.83), and 14.65 (12.73–16.86) for overweight, moderately obese, and extremely obese adolescents, respectively.
Conclusions
Overweight and obesity were associated with higher odds of PCOS in adolescents. Studies based solely on diagnosis codes may underestimate the prevalence of PCOS and overestimate the magnitude of the association between obesity and PCOS.
doi:10.1016/j.fertnstert.2013.04.001
PMCID: PMC3813299  PMID: 23756098
Obesity; epidemiology; body weight; childhood; adolescence; polycystic ovary syndrome
20.  Low‐dose maternal alcohol consumption: effects in the hearts of offspring in early life and adulthood 
Physiological Reports  2014;2(7):e12087.
Abstract
High alcohol consumption during pregnancy leads to deleterious effects on fetal cardiac structure and it also affects cardiomyocyte growth and maturation. This study aimed to determine whether low levels of maternal alcohol consumption are also detrimental to cardiomyocyte and cardiac growth in the early life of offspring and whether cardiac structure and function in adulthood is affected. Pregnant Sprague–Dawley rat dams were fed a control or 6% (volume/volume) liquid‐based ethanol supplemented (isocaloric) diet throughout gestation. At embryonic day 20, the expression of genes involved in cardiac development was analyzed using Real‐time PCR. At postnatal day 30, cardiomyocyte number, size, and nuclearity in the left ventricle (LV) were determined stereologically. In 8‐month‐old offspring, LV fibrosis and cardiac function (by echocardiography) were examined. Maternal ethanol consumption did not alter gene expression of the cardiac growth factors in the fetus or cardiomyocyte number in weanling offspring. However, at 8 months, there were significant increases in LV anterior and posterior wall thickness during diastole in ethanol‐exposed offspring (P = 0.037 and P = 0.024, respectively), indicative of left ventricular hypertrophy; this was accompanied by a significant increase in fibrosis. Additionally, maximal aortic flow velocity was significantly decreased in ethanol‐exposed offspring (P = 0.035). In conclusion, although there were no detectable early‐life differences in cardiac and cardiomyocyte growth in animals exposed to a chronic low dose of ethanol during gestation, there were clearly deleterious outcomes by adulthood. This suggests that even relatively low doses of alcohol consumed during pregnancy can be detrimental to long‐term cardiac health in the offspring.
Low dose alcohol consumption during gestation in rats illustrated no differences in cardiomyocyte and cardiac growth in the offspring in early life. However, in adulthood, induction of left ventricular hypertrophy was observed suggesting low doses of alcohol during pregnancy can be detrimental to long‐term cardiac health in offspring.
doi:10.14814/phy2.12087
PMCID: PMC4187541  PMID: 25077510
Cardiomyocyte; ethanol; heart; prenatal; rat
21.  Permanent Neonatal Diabetes Mellitus: Prevalence and Genetic Diagnosis in the SEARCH for Diabetes in Youth Study 
Pediatric diabetes  2012;14(3):174-180.
Background
Neonatal diabetes mellitus (NDM) is defined as diabetes with onset before 6 months of age. Nearly half of individuals with NDM are affected by permanent neonatal diabetes mellitus (PNDM). Mutations in KATP channel genes (KCNJ11, ABCC8) and the insulin gene (INS) are the most common causes of PNDM.
Objective
To estimate the prevalence of PNDM among SEARCH for Diabetes in Youth (SEARCH) study participants (2001-2008) and to identify the genetic mutations causing PNDM.
Methods
SEARCH is a multi-center population-based study of diabetes in youth < 20 years of age. Participants diagnosed with diabetes before 6 months of age were invited for genetic testing for mutations in the KCNJ11, ABCC8 and INS genes.
Results
Of the 15,829 SEARCH participants with diabetes, 39 were diagnosed before 6 months of age. Thirty five of them had PNDM (0.22% of all diabetes cases in SEARCH), 3 had transient neonatal diabetes that had remitted by 18 months and one was unknown. The majority of them (66.7%) had a clinical diagnosis of type1 diabetes by their health care provider. Population prevalence of PNDM in youth <20 years was estimated at 1 in 252,000. Seven participants underwent genetic testing; mutations causing PNDM were identified in five (71%), (two KCNJ11, three INS).
Conclusions
We report the first population-based frequency of PNDM in the US based on the frequency of PNDM in SEARCH. Patients with NDM are often misclassified as having type1 diabetes. Widespread education is essential to encourage appropriate genetic testing and treatment of NDM.
doi:10.1111/pedi.12003
PMCID: PMC4101463  PMID: 23050777
neonatal diabetes; KCNJ11; INS; ABCC8; infant
22.  Associations between childhood obesity and upper and lower extremity injuries 
Objectives
To estimate the overall and age-specific associations between obesity and extremity musculoskeletal injuries and pain in children.
Methods
This cross-sectional study used information from electronic medical records of 913 178 patients aged 2–19 years enrolled in an integrated health plan in the period 2007–2009. Children were classified as underweight, normal weight, overweight, or moderately/extremely obese and, using multivariable logistic regression methods, the associations between weight class and diagnosis of upper or lower extremity fractures, sprains, dislocations and pain were calculated.
Results
Overweight (OR 1.18, 95% CI 1.15 to 1.20), moderately obese (OR 1.24, 95% CI 1.20 to 1.27) and extremely obese (OR 1.34, 95% CI 1.30 to 1.39) children had statistically significantly higher odds of lower extremity injuries/pain compared to normal weight, adjusted for sex, age, race/ethnicity and insurance status. Age-stratified analyses yielded similar results. No consistent association was observed between body mass index and injuries/pain of the upper extremities.
Conclusions
Greater body mass index is associated with increased odds of lower extremity injuries and pain issues. Because the benefits of physical activity may still outweigh the risk of injury, attention should be paid to injury prevention strategies for these children at greater risk for lower extremity injuries.
doi:10.1136/injuryprev-2012-040341
PMCID: PMC3747966  PMID: 22789612
23.  Self-Reported Physical Activity Is Associated With β-Cell Function in Mexican American Adults 
Diabetes Care  2013;36(3):638-644.
OBJECTIVE
To examine the association between self-reported physical activity (PA) and diabetes-related quantitative traits.
RESEARCH DESIGN AND METHODS
The observational cohort was 1,152 Mexican American adults with dual-energy X-ray absorptiometry, oral and intravenous glucose tolerance tests, and self-reported dietary and PA questionnaires. PA was categorized into three mutually exclusive groups according to the U.S. Department of Health and Human Services PA guidelines for Americans: low (vigorous <75 min/week and moderate <150 min/week), moderate (vigorous ≥75 min/week or moderate ≥150 min/week), and high (vigorous ≥75 min/week and moderate ≥150 min/week). Trends in PA groups were tested for association with metabolic traits in a cross-sectional analysis.
RESULTS
The participants’ mean age was 35 years (range, 18–66 years), mean BMI was 29.6 kg/m2, and 73% were female. Among them, 501 (43%), 448 (39%), and 203 (18%) were classified as having low, moderate, and high PA, respectively. After adjustment for age, a higher PA was significantly associated with lower 2-h glucose, fasting insulin, and 2-h insulin and greater β-cell function (P = 0.001, 0.0003, 0.0001, and 0.004, respectively). The association did not differ significantly by sex. Results were similar after further adjustment for age, sex, BMI, or percent body fat.
CONCLUSIONS
An increasing level of PA is associated with a better glucose and insulin profile and enhanced β-cell function that is not explained by differences in BMI or percent body fat. Our results suggest that PA can be beneficial to β-cell function and glucose regulation independent of obesity.
doi:10.2337/dc12-1485
PMCID: PMC3579363  PMID: 23223346
24.  HLA-Associated Phenotypes in Youth with Autoimmune Diabetes 
Pediatric diabetes  2012;14(2):121-128.
Objectives
To examine HLA DRB1-DQB1 haplotypes within a multi-ethnic cohort and assess their association with characteristics of diabetes onset.
Methods
The sample included 1,662 participants from the SEARCH for Diabetes in Youth Study who tested positive for GADA and/or IA-2A autoantibodies. Blood drawn at the study visit was used to measure fasting C-peptide and genotype HLA DRB1 and DQB1 loci. Diabetic ketoacidosis (DKA) at diagnosis was determined from medical records. Multivariable linear and logistic regression models stratified by race/ethnicity were used to assess associations with DRB1-DQB1 haplotypes.
Results
The frequency of DRB1*03 susceptibility haplotypes ranged 27.5–28.9% in all racial/ethnic groups. The frequency of susceptibility DRB1*04-DQB1*0302 was higher in non-Hispanic white (NHW; 34.1%) and Hispanic (38.9%) compared to non-Hispanic black (NHB; 20.8%) youth. Neutral and protective haplotypes were low frequency in all groups. DBR1*03 haplotypes were associated with younger age at diagnosis in NHW and positivity for multiple autoantibodies in Hispanics. DRB1*04-DQB1*0302 haplotypes were associated with multiple autoantibody positivity in NHW and Hispanics, and lower fasting C-peptide and higher odds of DKA in Hispanics only. Although protective DRB1*04-DQB1*0301 haplotypes were associated with older age at diagnosis in NHW, they were also associated with multiple autoantibody positivity in these youth. Protective DRB1*13 haplotypes were associated with decreased odds of multiple autoantibody positivity in NHB youth.
Conclusions
The distribution of DRB1-DQB1 haplotypes and their association with onset-related characteristics of autoimmune diabetes varies across major racial/ethnic groups in the United States. This may contribute to variation in clinical presentation of autoimmune diabetes by race/ethnicity.
doi:10.1111/j.1399-5448.2012.00905.x
PMCID: PMC3932799  PMID: 22913598
HLA; type 1 diabetes; autoantibodies; diabetic ketoacidosis; fasting C-peptide
25.  The Relative Contribution of Prepregnancy Overweight and Obesity, Gestational Weight Gain, and IADPSG-Defined Gestational Diabetes Mellitus to Fetal Overgrowth 
Diabetes Care  2012;36(1):56-62.
OBJECTIVE
The International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria for diagnosis of gestational diabetes mellitus (GDM) identifies women and infants at risk for adverse outcomes, which are also strongly associated with maternal overweight, obesity, and excess gestational weight gain.
RESEARCH DESIGN AND METHODS
We conducted a retrospective study of 9,835 women who delivered at ≥20 weeks’ gestation; had a prenatal, 2-h, 75-g oral glucose tolerance test; and were not treated with diet, exercise, or antidiabetic medications during pregnancy. Women were classified as having GDM based on IADPSG criteria and were categorized into six mutually exclusive prepregnancy BMI/GDM groups: normal weight ± GDM, overweight ± GDM, and obese ± GDM.
RESULTS
Overall, 5,851 (59.5%) women were overweight or obese and 1,892 (19.2%) had GDM. Of those with GDM, 1,443 (76.3%) were overweight or obese. The prevalence of large-for-gestational-age (LGA) infants was significantly higher for overweight and obese women without GDM compared with their normal-weight counterparts. Among women without GDM, 21.6% of LGA infants were attributable to maternal overweight and obesity, and the combination of being overweight or obese and having GDM accounted for 23.3% of LGA infants. Increasing gestational weight gain was associated with a higher prevalence of LGA in all groups.
CONCLUSIONS
Prepregnancy overweight and obesity account for a high proportion of LGA, even in the absence of GDM. Interventions that focus on maternal overweight/obesity and gestational weight gain, regardless of GDM status, have the potential to reach far more women at risk for having an LGA infant.
doi:10.2337/dc12-0741
PMCID: PMC3526206  PMID: 22891256

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