229 results on '"Neil H. White"'
Search Results
2. Retinal Thickness and Morphology Changes on OCT in Youth with Type 2 Diabetes
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Mihai Mititelu, MD, MPH, Diane Uschner, PhD, Lindsay Doherty, PhD, Petter Bjornstad, MD, Amitha Domalpally, MD, PhD, Kimberly L. Drews, PhD, Rose Gubitosi-Klug, MD, PhD, Lynne L. Levitsky, MD, Jeong W. Pak, PhD, Neil H. White, MD, and Barbara A. Blodi, MD
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Glycemic control ,Macular morphology ,Posterior vitreous detachment ,Retinal thickening ,Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study ,Ophthalmology ,RE1-994 - Abstract
Objective: To evaluate changes in retinal thickness and morphology using OCT in youth with type 2 diabetes (T2D) and to identify systemic biomarkers correlating with these changes. Design: Retrospective subgroup analysis of a prospective study. Participants: Participants who underwent OCT imaging in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial and its follow-up study TODAY2. Methods: In 2010–2011 (TODAY) and 2017–2018 (TODAY2), 6 × 6-mm macular volume OCT scans were acquired, segmented, and analyzed to generate total retinal thickness, inner retinal thickness, and outer retinal thickness. The main retinal morphologies graded were intraretinal cystoid spaces, subretinal fluid, and posterior vitreous detachment (PVD). Main Outcome Measures: Changes in total and individual retinal layer thickness and development of abnormal vitreomacular morphology between TODAY and TODAY2. Results: Participants had a mean age of 17.9 ± 2.4 years and glycated hemoglobin (HbA1c) of 8.2 ± 2.8% in TODAY and a mean age of 25.0 ± 2.4 years and mean HbA1c of 9.5 ± 2.8% in TODAY2. Longitudinally between assessments, there were overall decreases in outer retinal thickness from 167.2 ± 11.5 microns to 158.4 ± 12.8 microns (P
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- 2022
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3. A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome
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Damien Abreu, Stephen I. Stone, Toni S. Pearson, Robert C. Bucelli, Ashley N. Simpson, Stacy Hurst, Cris M. Brown, Kelly Kries, Chinyere Onwumere, Hongjie Gu, James Hoekel, Lawrence Tychsen, Gregory P. Van Stavern, Neil H. White, Bess A. Marshall, Tamara Hershey, and Fumihiko Urano
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Endocrinology ,Genetics ,Medicine - Abstract
BACKGROUND Wolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODS Based on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTS Dantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSION This study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02829268FUNDING NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.
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- 2021
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4. Circulating sex hormone binding globulin levels are modified with intensive lifestyle intervention, but their changes did not independently predict diabetes risk in the Diabetes Prevention Program
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Mike Reidy, Christine Lee, Michael Brändle, Sherita Hill Golden, Samuel Dagogo-Jack, David Kessler, Elizabeth Barrett-Connor, Steve Jones, Ling Chen, Judith Wylie-Rosett, Ping Zhang, Paula Williamson, Carlos Lorenzo, Leigh Perreault, Dana Dabelea, Santica Marcovina, Rachel Williams, Marie Smith, Carmen Pal, Patricia Katz, William H. Herman, Sharon L Edelstein, Yong Ma, Vanita R Aroda, Costas A Christophi, Catherine Kim, Sherita H Golden, Edward Horton, Kieren J Mather, George A. Bray, Kishore Gadde, Iris W. Culbert, Jennifer Arceneaux, Annie Chatellier, Amber Dragg, Catherine M. Champagne, Crystal Duncan, Barbara Eberhardt, Frank Greenway, Fonda G. Guillory, April A. Herbert, Michael L. Jeffirs, Betty M. Kennedy, Erma Levy, Monica Lockett, Jennifer C. Lovejoy, Laura H. Morris, Lee E. Melancon, Donna H. Ryan, Deborah A. Sanford, Kenneth G. Smith, Lisa L. Smith, Julia A. St, Richard T. Tulley Amant, Paula C. Vicknair, Donald Williamson, Jeffery J. Zachwieja, Kenneth S. Polonsky, Janet Tobian, David A. Ehrmann, Margaret J. Matulik, Bart Clark, Kirsten Czech, Catherine DeSandre, Ruthanne Hilbrich, Wylie McNabb, Ann R. Semenske, Jose F. Caro, Kevin Furlong, Barry J. Goldstein, Pamela G. Watson, Kellie A. Smith, Jewel Mendoza, Wendi Wildman, Renee Liberoni, John Spandorfer, Constance Pepe, Richard P. Donahue, Ronald B. Goldberg, Ronald Prineas, Jeanette Calles, Juliet Ojito, Patricia Rowe, Paul Cassanova-Romero, Sumaya Castillo-Florez, Hermes J. Florez, Anna Giannella, Lascelles Kirby, Carmen Larreal, Olga Lara, Valerie McLymont, Jadell Mendez, Arlette Perry, Patrice Saab, Beth Veciana, Steven M. Haffner, Helen P. Hazuda, Maria G. Montez, Kathy Hattaway, Arlene Martinez, Tatiana Walker, Richard F. Hamman, Patricia V. Nash, Sheila C. Steinke, Lisa Testaverde, Denise R. Anderson, Larry B. Ballonoff, Alexis Bouffard, Brian Bucca, B. Ned Calonge, Lynne Delve, Martha Farago, James O. Hill, Shelley R. Hoyer, Tonya Jenkins, Bonnie T. Jortberg, Dione Lenz, Marsha Miller, David W. Price, Judith G. Regensteiner, Helen Seagle, Carissa M. Smith, Brent VanDorsten, Edward S. Horton, Kathleen E. Lawton, Catherine S. Poirier, Kati Swift, Ronald A. Arky, Marybeth Bryant, Jacqueline P. Burke, Enrique Caballero, Karen M. Callaphan, Barbara Fargnoli, Therese Franklin, Om P. Ganda, Ashley Guidi, Mathew Guido, Sharon D. Jackson, Alan M. Jacobsen, Lori Lambert, Sarah Ledbury, Margaret Kocal, Lyn M. Kula, Maureen A. Malloy, Maryanne Nicosia, Cathryn F. Oldmixon, Jocelyn Pan, Marizel Quitingon, Stacy Rubtchinsky, Jessica Sansoucy, Dana Schweizer, Ellen W. Seely, Donald Simonson, Fannie Smith, Caren G. Solomon, Jeanne Spellman, James Warram, Steven E. Kahn, Brenda K. Montgomery, Wilfred Fujimoto, Robert H. Knopp, Edward W. Lipkin, Michelle Marr, Ivy Morgan-Taggart, Anne Murillo, Dace Trence, Lonnese Taylor, April Thomas, Elaine C. Tsai, Abbas E. Kitabchi, Mary E. Murphy, Laura Taylor, Jennifer Dolgoff, William B. Applegate, Michael Bryer-Ash, Debra Clark, Sandra L. Frieson, Uzoma Ibebuogu, Raed Imseis, Helen Lambeth, Lynne C. Lichtermann, Hooman Oktaei, Harriet Ricks, Lily M.K. Rutledge, Amy R. Sherman, Clara M. Smith, Judith E. Soberman, Beverly Williams-Cleaves, Boyd E. Metzger, Mark E. Molitch, Mariana K. Johnson, Daphne T. Adelman, Catherine Behrends, Michelle Cook, Marian Fitzgibbon, Mimi M. Giles, Deloris Heard, Cheryl K.H. Johnson, Diane Larsen, Anne Lowe, Megan Lyman, David McPherson, Samsam C. Penn, Thomas Pitts, Renee Reinhart, Susan Roston, Pamela A. Schinleber, David M. Nathan, Charles McKitrick, Heather Turgeon, Mary Larkin, Kathy Abbott, Ellen Anderson, Laurie Bissett, Kristy Bondi, Enrico Cagliero, Jose C. Florez, Kali D’Anna, Linda Delahanty, Valerie Goldman, Peter Lou, Alexandra Poulos, Elyse Raymond, Christine Stevens, Beverly Tseng, Jerrold M. Olefsky, Mary Lou Carrion-Petersen, Madeline Beltran, Lauren N. Claravall, Jonalle M. Dowden, Steven V. Edelman, Robert R. Henry, Javiva Horne, Marycie Lamkin, Simona Szerdi Janesch, Diana Leos, Sunder Mudaliar, William Polonsky, Jean Smith, Jennifer Torio-Hurley, Karen Vejvoda, F. Xavier Pi-Sunyer, Jane E. Lee, David B. Allison, Nnenna Agharanya, Nancy J. Aronoff, Maria Baldo, Jill P. Crandall, Sandra T. Foo, Susan Hagamen, Jose A. Luchsinger, Kathy Parkes, Mary Beth Pena, Ellen S. Rooney, Gretchen E.H. Van Wye, Kristine A. Viscovich, David G. Marrero, Kieren J. Mather, Melvin J. Prince, Susie M. Kelly, Marcia A. Jackson, Gina McAtee, Paula Putenney, Ronald T. Ackermann, Carolyn M. Cantrell, Yolanda F. Dotson, Edwin S. Fineberg, Megan Fultz, John C. Guare, Angela Hadden, James M. Ignaut, Marion S. Kirkman, Erin O’Kelly Phillips, Beverly D. Porter, Paris J. Roach, Nancy D. Rowland, Madelyn L. Wheeler, Vanita Aroda, Robert E. Ratner, Gretchen Youssef, Sue Shapiro, Catherine Bavido-Arrage, Geraldine Boggs, Marjorie Bronsord, Ernestine Brown, Wayman W. Cheatham, Susan Cola, Cindy Evans, Peggy Gibbs, Tracy Kellum, Renee Wiggins, Milvia Lagarda, Lilia Leon, Claresa Levatan, Milajurine Lindsay, Asha K. Nair, Maureen Passaro, Angela Silverman, Gabriel Uwaifo, Debra Wells-Thayer, Mohammed F. Saad, Karol Watson, Maria Budget, Sujata Jinagouda, Medhat Botrous, Khan Akbar, Claudia Conzues, Perpetua Magpuri, Kathy Ngo, Amer Rassam, Debra Waters, Kathy Xapthalamous, Julio V. Santiago, Neil H. White, Angela L. Brown, Samia Das, Prajakta Khare-Ranade, Tamara Stich, Ana Santiago, Edwin Fisher, Emma Hurt, Tracy Jones, Michelle Kerr, Lucy Ryder, Cormarie Wernimont, Christopher D. Saudek, Vanessa Bradley, Emily Sullivan, Tracy Whittington, Caroline Abbas, Adrienne Allen, Frederick L. Brancati, Sharon Cappelli, Jeanne M. Clark, Jeanne B. Charleston, Janice Freel, Katherine Horak, Alicia Greene, Dawn Jiggetts, Deloris Johnson, Hope Joseph, Kimberly Loman, Henry Mosley, John Reusing, Richard R. Rubin, Alafia Samuels, Thomas Shields, Shawne Stephens, Kerry J. Stewart, LeeLana Thomas, Evonne Utsey, David S. Schade, Karwyn S. Adams, Janene L. Canady, Carolyn Johannes, Claire Hemphill, Penny Hyde, Leslie F. Atler, Patrick J. Boyle, Mark R. Burge, Lisa Chai, Kathleen Colleran, Ysela Gonzales, Doris A. Hernandez-McGinnis, Carolyn King, Sofya Rubinchik, Willette Senter, Jill Crandall, Harry Shamoon, Janet O. Brown, Gilda Trandafirescu, Elsie Adorno, Liane Cox, Helena Duffy, Samuel Engel, Allison Friedler, Angela Goldstein, Crystal J. Howard-Century, Jennifer Lukin, Stacey Kloiber, Nadege Longchamp, Helen Martinez, Dorothy Pompi, Jonathan Scheindlin, Elissa Violino, Elizabeth A. Walker, Elise Zimmerman, Joel Zonszein, Trevor Orchard, Rena R. Wing, Susan Jeffries, Gaye Koenning, M. Kaye Kramer, Susan Barr, Catherine Benchoff, Miriam Boraz, Lisa Clifford, Rebecca Culyba, Marlene Frazier, Ryan Gilligan, Stephanie Guimond, Susan Harrier, Louann Harris, Andrea Kriska, Bonny Rockette-Wagner, Qurashia Manjoo, Monica Mullen, Alicia Noel, Amy Otto, Jessica Pettigrew, Debra Rubinstein, Linda Semler, Cheryl F. Smith, Elizabeth Venditti, Valarie Weinzierl, Katherine V. Williams, Tara Wilson, Richard F. Arakaki, Renee W. Latimer, Narleen K. Baker-Ladao, Mae K. Isonaga, Ralph Beddow, Nina E. Bermudez, Lorna Dias, Jillian Inouye, Marjorie K. Mau, John S. Melish, Kathy Mikami, Pharis Mohideen, Sharon K. Odom, Raynette U. Perry, Robin E. Yamamoto, William C. Knowler, Norman Cooeyate, Mary A. Hoskin, Carol A. Percy, Alvera Enote, Camille Natewa, Kelly J. Acton, Vickie L. Andre, Rosalyn Barber, Shandiin Begay, Peter H. Bennett, Mary Beth Benson, Evelyn C. Bird, Brenda A. Broussard, Brian C. Bucca, Marcella Chavez, Sherron Cook, Jeff Curtis, Tara Dacawyma, Matthew S. Doughty, Roberta Duncan, Charlotte Dodge, Cyndy Edgerton, Jacqueline M. Ghahate, Justin Glass, Martia Glass, Dorothy Gohdes, Wendy Grant, Robert L. Hanson, Ellie Horse, Louise E. Ingraham, Merry Jackson, Priscilla Jay, Roylen S. Kaskalla, Kathleen M. Kobus, Jonathan Krakoff, Jason Kurland, Catherine Manus, Cherie McCabe, Sara Michaels, Tina Morgan, Yolanda Nashboo, Julie A. Nelson, Steven Poirier, Evette Polczynski, Christopher Piromalli, Jeanine Roumain, Debra Rowse, Robert J. Roy, Sandra Sangster, Janet Sewenemewa, Miranda Smart, Darryl Tonemah, Charlton Wilson, Michelle Yazzie, Raymond Bain, Sarah Fowler, Marinella Temprosa, Michael D. Larsen, Tina Brenneman, Sharon L. Edelstein, Solome Abebe, Julie Bamdad, Melanie Barkalow, Joel Bethepu, Tsedenia Bezabeh, Nicole Butler, Jackie Callaghan, Caitlin E. Carter, Costas Christophi, Gregory M. Dwyer, Mary Foulkes, Yuping Gao, Robert Gooding, Adrienne Gottlieb, Kristina L. Grimes, Nisha Grover-Fairchild, Lori Haffner, Heather Hoffman, Kathleen Jablonski, Tara L. Jones, Richard Katz, Preethy Kolinjivadi, John M. Lachin, Pamela Mucik, Robert Orlosky, Qing Pan, Susan Reamer, James Rochon, Alla Sapozhnikova, Hanna Sherif, Charlotte Stimpson, Ashley Hogan Tjaden, Fredricka Walker-Murray, Elizabeth M. Venditti, Andrea M. Kriska, Valerie Weinzierl, Jessica Harting, F. Alan Aldrich, John Albers, Greg Strylewicz, R. Eastman, Judith Fradkin, Sanford Garfield, Edward Gregg, Morton B. Brown, David Altshuler, Liana K. Billings, Maegan Harden, Toni I. Pollin, Alan R. Shuldiner, Paul W. Franks, and Marie-France Hivert
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Introduction Sex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methods This is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.Results ILS resulted in significantly higher increases (postmenopausal women: p
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- 2020
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5. The Impact of Behavior Change Counseling Delivered via a Digital Health Tool Versus Routine Care Among Adolescents With Obesity: Pilot Randomized Feasibility Study
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Maura Kepper, Callie Walsh-Bailey, Zoe M Miller, Min Zhao, Kianna Zucker, Angeline Gacad, Cynthia Herrick, Neil H White, Ross C Brownson, and Randi E Foraker
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Medicine - Abstract
BackgroundYouth overweight and obesity is a public health crisis and increases the risk of poor cardiovascular health (CVH) and chronic disease. Health care providers play a key role in weight management, yet few tools exist to support providers in delivering tailored evidence-based behavior change interventions to patients. ObjectiveThe goal of this pilot randomized feasibility study was to determine the feasibility of implementing the Patient-Centered Real-Time Intervention (PREVENT) tool in clinical settings, generate implementation data to inform scale-up, and gather preliminary effectiveness data. MethodsA pilot randomized clinical trial was conducted to examine the feasibility, implementation, and preliminary impact of PREVENT on patient knowledge, motivation, behaviors, and CVH outcomes. The study took place in a multidisciplinary obesity management clinic at a children’s hospital within an academic medical center. A total of 36 patients aged 12 to 18 years were randomized to use PREVENT during their routine visit (n=18, 50%) or usual care control (n=18, 50%). PREVENT is a digital health tool designed for use by providers to engage patients in behavior change education and goal setting and provides resources to support change. Patient electronic health record and self-report behavior data were collected at baseline and 3 months after the intervention. Implementation data were collected via PREVENT, direct observation, surveys, and interviews. We conducted quantitative, qualitative, and mixed methods analyses to evaluate pretest-posttest patient changes and implementation data. ResultsPREVENT was feasible, acceptable, easy to understand, and helpful to patients. Although not statistically significant, only PREVENT patients increased their motivation to change their behaviors as well as their knowledge of ways to improve heart health and of resources. Compared to the control group, PREVENT patients significantly improved their overall CVH and blood pressure (P
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- 2024
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6. Case of Hypercalcemia Secondary to Hypervitaminosis A in a 6-Year-Old Boy with Autism
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Arpita Kalla Vyas and Neil H. White
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Vitamin A intoxication secondary to over-the-counter nutritional supplements and from its use in acne treatment has been described. However, there have been very few case reports of chronic hypervitaminosis A leading to hypercalcemia in the pediatric population. This paper describes a boy with hypercalcemia secondary to chronic vitamin A intoxication in the context of vitamin A usage for therapy of autism. In addition to discontinuation of vitamin A, hyperhydration, and furosemide, the hypercalcemia in this patient required the use of prednisone and pamidronate to normalize the calcium.
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- 2011
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7. Clinical and Laboratory Predictors of Dehydration Severity in Children With Diabetic Ketoacidosis
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Jennifer L. Trainor, Nicole S. Glaser, Leah Tzimenatos, Michael J. Stoner, Kathleen M. Brown, Julie K. McManemy, Jeffrey E. Schunk, Kimberly S. Quayle, Lise E. Nigrovic, Arleta Rewers, Sage R. Myers, Jonathan E. Bennett, Maria Y. Kwok, Cody S. Olsen, T. Charles Casper, Simona Ghetti, Nathan Kuppermann, Clinton S. Perry, James P. Marcin, Mary Murray, Jared Henricksen, Brad Poss, J. Michael Dean, Bema Bonsu, Tensing Maa, Justin Indyk, Marian Rewers, Peter Mourani, Jake A. Kushner, Laura L. Loftis, Monika Goyal, Rakesh Mistry, Vijay Srinivasan, Andrew Palladino, Colin Hawkes, Joseph I. Wolfsdorf, Michael S. Agus, Linda Snelling, Charlotte Boney, Fran R. Cogen, Sonali Basu, Neil H. White, Nikoleta S. Kolovos, Donald Zimmerman, Denise Goodman, Andrew D. DePiero, Daniel A. Doyle, Meg A. Frizzola, Scott Baird, and David Schnadower
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Emergency Medicine - Published
- 2023
8. Deterioration of Glycemic Control in Youth-Onset Type 2 Diabetes: What Are the Early and Late Predictors?
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Philip Zeitler, Laure El Ghormli, Silva Arslanian, Sonia Caprio, Elvira Isganaitis, Megan K Kelsey, Ruth S Weinstock, Neil H White, and Kimberly Drews
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Blood Glucose ,Glycated Hemoglobin ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Biochemistry (medical) ,Clinical Biochemistry ,Glycemic Control ,Biochemistry ,Endocrinology ,Diabetes Mellitus, Type 2 ,Humans ,Treatment Failure ,Age of Onset ,Online Only Articles ,Proinsulin - Abstract
Objective We examined predictors of early and late loss of glycemic control in individuals with youth-onset type 2 diabetes, as well as predictors of short-term deterioration in youth from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. Methods Demographic, physical, and biochemical measures at baseline and 48 months, and change over time, were examined in 584 participants separated into those with loss of glycemic control (sustained HbA1c ≥ 8%) before 48 months or at 48 months or later, and those who remained in control until the end of the study (median 6.8 years). Univariate and multivariate models, and receiver operating characteristic curve analyses were performed. Results Approximately 45% of youth remained in control at 48 months; of these, 30% subsequently lost glycemic control prior to the end of follow-up. Predictors of early loss of glycemic control included baseline HbA1c, C-peptide index, oral disposition index, proinsulin, and proinsulin to insulin ratio. Predictors of late loss included baseline measures of insulin secretion and change in HbA1c and insulin processing at 48 months. A baseline HbA1c cutoff of ≥ 6.2% was optimally predictive of loss of glycemic control at any time, while an absolute rise in HbA1c > 0.5% related to loss of glycemic control within 3 to 6 months. Conclusion This analysis demonstrates that youth with type 2 diabetes at risk for loss of glycemic control, including impending rapid deterioration, can be identified using available clinical measures, allowing for closer monitoring of at-risk youth, and facilitating the design of research on better therapeutic options.
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- 2022
9. Longitudinal progression of diabetes mellitus in Wolfram syndrome: The Washington University Wolfram Research Clinic experience
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Ling Chen, Neil H. White, Mary Katherine Ray, Bess A. Marshall, Richard Ni, and Tamara Hershey
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Male ,Washington ,Pediatrics ,medicine.medical_specialty ,Adolescent ,endocrine system diseases ,Wolfram syndrome ,Endocrinology, Diabetes and Metabolism ,Ambulatory Care Facilities ,Article ,chemistry.chemical_compound ,Break point ,Diabetes mellitus ,Diabetes Mellitus ,Internal Medicine ,Humans ,Medicine ,Medical history ,Longitudinal Studies ,Intervention trial ,Child ,Chi-Square Distribution ,C-peptide ,business.industry ,nutritional and metabolic diseases ,Wolfram Syndrome ,medicine.disease ,chemistry ,Pediatrics, Perinatology and Child Health ,Disease Progression ,Female ,Observational study ,business ,Blood sampling - Abstract
OBJECTIVE 1) Describe the progression of diabetes mellitus over time in an observational study of Wolfram syndrome, a rare, genetic, neurodegenerative disorder which often includes diabetes mellitus and is typically diagnosed during childhood or adolescence. 2) Determine whether C-peptide could be used as a marker of diabetes progression in interventional trials for Wolfram syndrome. METHODS N=44 (25F/19M) participants with genetically-confirmed Wolfram syndrome attended the Washington University Wolfram Research Clinic annually from 2010-2019. Medical history, physical examinations, blood sampling, and questionnaires were used to collect data about diabetes mellitus and other components of Wolfram syndrome. Beta-cell function was assessed by determination of C-peptide during a mixed meal tolerance test. Random coefficients models evaluated the rate of progression of C-peptide over time, and power analyses were used to estimate the number of subjects needed to detect a change in C-peptide decline during an intervention trial. RESULTS 93.2% of patients had diabetes mellitus. Mean HbA1c across all study visits was 7.9%. C-peptide significantly decreased with increasing duration of diabetes mellitus (p
- Published
- 2021
10. Association of Metformin With the Development of Age-Related Macular Degeneration
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Amitha, Domalpally, Samuel A, Whittier, Qing, Pan, Dana M, Dabelea, Christine H, Darwin, William C, Knowler, Christine G, Lee, Jose A, Luchsinger, Neil H, White, Emily Y, Chew, and Marie-France, Hivert
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Age-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD.To investigate the association between metformin use and age-related macular degeneration (AMD).The Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022.Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo.Prevalence of AMD in the treatment arms.Of 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49 [9] years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02).These data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.
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- 2022
11. Retinopathy during the First 5 Years of Type 1 Diabetes and Subsequent Risk of Advanced Retinopathy
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Ionut Bebu, Lloyd P Aiello, Amisha Wallia, William Tamborlane, Arup Das, Dean P. Hainsworth, Neil H. White, Philip Raskin, Xiaoyu Gao, and John I. Malone
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Objectives: To determine whether individuals with type 1 diabetes (T1D) who develop any retinopathy at any time prior to five years of diabetes duration have an increased subsequent risk for further progression of retinopathy or onset of proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), diabetes-related retinal photocoagulation or anti-VEGF injections. Additionally, to determine the influence of HbA1c and other risk factors in these individuals. Methods: Diabetic retinopathy (DR) was assessed longitudinally using standardized stereoscopic seven-field fundus photography at time intervals of six months to four years. Early onset DR (EDR) was defined as onset prior to 5 years of T1D duration. Cox models assessed the associations of EDR with subsequent risk of outcomes. Results: In unadjusted models, individuals with EDR (n=484) had an increased subsequent risk of PDR (hazard ratio HR=1.51, 95%CI [1.12,2.02], P=0.006), CSME (HR=1.44, [1.10,1.88], P=0.008) and diabetes-related retinal photocoagulation (HR=1.48, [1.12,1.96], P=0.006) compared to individuals without EDR (n=369). These associations remained significant adjusted for HbA1c, but only the association with PDR remained significant after adjustment for age, duration of T1D, HbA1c, sex, systolic/diastolic blood pressure, pulse, use of ACE inhibitors, albumin excretion rate, and eGFR (HR=1.47, [1.04,2.06], P=0.028). Conclusions: These data suggest that individuals with any sign of retinopathy within the first 5 years of T1D onset may be at higher risk of long-term development of advanced DR, especially PDR. Identification of early onset DR may influence prognosis and help guide therapeutic management to reduce the risk of future visual loss in these individuals.
- Published
- 2022
12. Utility of using electrocardiogram measures of heart rate variability as a measure of cardiovascular autonomic neuropathy in type 1 diabetes patients
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Dcct, Elsayed Z. Soliman, Ionut Bebu, Neil H. White, John M. Lachin, Jye-Yu C. Backlund, Barbara H. Braffett, Rodica Pop-Busui, and Gayle M. Lorenzi
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Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Cardiovascular autonomic neuropathy ,Sensitivity and Specificity ,Diseases of the endocrine glands. Clinical endocrinology ,Standard deviation ,Electrocardiography ,Cohen's kappa ,Diabetic Neuropathies ,Heart Rate ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,Humans ,Medicine ,Heart rate variability ,Randomized Controlled Trials as Topic ,Type 1 diabetes ,business.industry ,fungi ,Area under the curve ,Reproducibility of Results ,food and beverages ,Articles ,General Medicine ,Gold standard (test) ,Middle Aged ,RC648-665 ,medicine.disease ,Cardiovascular reflex tests ,Confidence interval ,Diabetes Mellitus, Type 1 ,Clinical Science and Care ,Autonomic Nervous System Diseases ,Cardiovascular Diseases ,Cardiology ,Female ,Original Article ,business ,Diabetic Angiopathies - Abstract
Aims/Introduction Cardiovascular autonomic neuropathy (CAN) is a predictor of cardiovascular disease and mortality. Cardiovascular reflex tests (CARTs) are the gold standard for the diagnosis of CAN, but might not be feasible in large research cohorts or in clinical care. We investigated whether measures of heart rate variability obtained from standard electrocardiogram (ECG) recordings provide a reliable measure of CAN. Materials and Methods Standardized CARTs (R‐R response to paced breathing, Valsalva, postural changes) and digitized 12‐lead resting ECGs were obtained concomitantly in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications participants (n = 311). Standard deviation of normally conducted R‐R intervals (SDNN) and the root mean square of successive differences between normal‐to‐normal R‐R intervals (rMSSD) were measured from ECG. Sensitivity, specificity, probability of correct classification and Kappa statistics evaluated the agreement between ECG‐derived CAN and CARTs‐defined CAN. Results Participants with CARTs‐defined CAN had significantly lower SDNN and rMSSD compared with those without CAN (P, Participants with cardiovascular reflex tests‐defined cardiovascular autonomic neuropathy (CAN) had significantly lower standard deviation of normally conducted R‐R intervals and root mean square of successive differences between normal‐to‐normal R‐R intervals compared to those without CAN (P
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- 2021
13. Retinopathy During the First 5 Years of Type 1 Diabetes and Subsequent Risk of Advanced Retinopathy
- Author
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John I, Malone, Xiaoyu, Gao, Gayle M, Lorenzi, Philip, Raskin, Neil H, White, Dean P, Hainsworth, Arup, Das, William, Tamborlane, Amisha, Wallia, Lloyd P, Aiello, and Ionut, Bebu
- Abstract
To determine whether individuals with type 1 diabetes (T1D) who develop any retinopathy at any time prior to 5 years of diabetes duration have an increased subsequent risk for further progression of retinopathy or onset of proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), diabetes-related retinal photocoagulation, or anti-vascular endothelial growth factor injections. Additionally, to determine the influence of HbA1c and other risk factors in these individuals.Diabetic retinopathy (DR) was assessed longitudinally using standardized stereoscopic seven-field fundus photography at time intervals of 6 months to 4 years. Early-onset DR (EDR) was defined as onset prior to 5 years of T1D duration. Cox models assessed the associations of EDR with subsequent risk of outcomes.In unadjusted models, individuals with EDR (n = 484) had an increased subsequent risk of PDR (hazard ratio [HR] 1.51 [95% CI 1.12, 2.02], P = 0.006), CSME (HR 1.44 [1.10, 1.88], P = 0.008), and diabetes-related retinal photocoagulation (HR 1.48 [1.12, 1.96], P = 0.006) compared with individuals without EDR (n = 369). These associations remained significant when adjusted for HbA1c, but only the association with PDR remained significant after adjustment for age, duration of T1D, HbA1c, sex, systolic/diastolic blood pressure, pulse, use of ACE inhibitors, albumin excretion rate, and estimated glomerular filtration rate (HR 1.47 [95% CI 1.04, 2.06], P = 0.028).These data suggest that individuals with any sign of retinopathy within the first 5 years of T1D onset may be at higher risk of long-term development of advanced DR, especially PDR. Identification of early-onset DR may influence prognosis and help guide therapeutic management to reduce the risk of future visual loss in these individuals.
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- 2022
14. Implementation of School Diabetes Care in the United States: A Scoping Review
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Neil H. White, Danyi Li, Marjorie Cole, Ruopeng An, Katherine Park, and Aaron R. Lyon
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Parents ,Schools ,Nursing (miscellaneous) ,business.industry ,Health Personnel ,education ,medicine.disease ,United States ,Article ,Nursing ,Diabetes management ,Diabetes mellitus ,Health care ,Diabetes Mellitus ,Humans ,Medicine ,Students ,business - Abstract
Diabetes management at school demands close collaboration of multiple stakeholders, including students with diabetes and parents, school nurses, teachers/staff, and local health care providers. This scoping review identified and synthesized evidence concerning factors that contributed to the quality and effectiveness of diabetes care implementation in U.S. K-12 schools. Forty-six studies met the eligibility criteria and were included. Five common factors emerged surrounding training and experiences, communications, parent engagement, resource allocations, and school environment. Complex interactions between multiple stakeholders jointly determined the quality of school diabetes care. A conceptual model was established to elucidate the complex interactions between multiple stakeholders and the relevant facilitators and barriers. Future research should improve sample representativeness, contrast school diabetes care practices to the national guidelines, and assess the impact of the social, economic, and political environment at federal, state, local/district levels on school diabetes care implementation.
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- 2021
15. The Effect of Interventions to Prevent Type 2 Diabetes on the Development of Diabetic Retinopathy: The DPP/DPPOS Experience
- Author
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the Diabetes Prevention Program Research Group, David M. Nathan, Mathias Schlögl, Christine Darwin, Xavier Pi-Sunyer, Ronald B. Goldberg, Barbara Blodi, Emily Y. Chew, Dana Dabelea, Emily B. Schroeder, William C. Knowler, Qing Pan, and Neil H. White
- Abstract
OBJECTIVE: To determine whether interventions that slow or prevent the development of type 2 diabetes mellitus in those at risk reduce the subsequent prevalence of diabetic retinopathy. RESEARCH DESIGN AND METHODS: The Diabetes Prevention Program (DPP) randomized subjects at risk for developing type 2 diabetes because of overweight/obesity and dysglycemia to either metformin (MET), intensive lifestyle intervention (ILS) or placebo (PLB) to assess the prevention of diabetes. During the DPP and DPP Outcome Study (DPPOS), we performed fundus photography over time on study participants, regardless of their diabetes status. Fundus photographs were graded using the ETDRS grading system with diabetic retinopathy defined as typical lesions of diabetic retinopathy (microaneurysms, exudates or hemorrhage, or worse) in either eye. RESULTS: Despite reduced progression to diabetes in the ILS and MET groups compared to PLB, there was no difference in the prevalence of diabetic retinopathy between treatment groups after 1, 5, 11 or 16 years of follow up. No treatment group differences in retinopathy were found within prespecified subgroups (baseline age, sex, race/ethnicity, baseline BMI). In addition, there was no difference in the prevalence of diabetic retinopathy between those exposed to metformin and those not exposed to metformin regardless of treatment group assignment. CONCLUSION: Interventions that delay or prevent the onset of type 2 diabetes in overweight/obese subjects with dysglycemia who are at risk for diabetes do not reduce the development of diabetic retinopathy for up to 20 years.
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- 2022
16. Risk Factors for the Development of Retinopathy in Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Experience
- Author
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Neil H, White, Qing, Pan, William C, Knowler, Emily B, Schroeder, Dana, Dabelea, Emily Y, Chew, Barbara, Blodi, Ronald B, Goldberg, Xavier, Pi-Sunyer, Christine, Darwin, Mathias, Schlögl, David M, Nathan, and Morton B, Brown
- Subjects
Advanced and Specialized Nursing ,Adult ,Prediabetic State ,Glycated Hemoglobin ,Blood Glucose ,Diabetic Retinopathy ,Diabetes Mellitus, Type 2 ,Risk Factors ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,Humans - Abstract
OBJECTIVE To determine glycemic and nonglycemic risk factors that contribute to the presence of diabetic retinopathy (DR) before and after the onset of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS During the Diabetes Prevention Program (DPP) and DPP Outcome Study (DPPOS), we performed fundus photography over time in adults at high risk for developing T2D, including after they developed diabetes. Fundus photographs were graded using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading system, with DR defined as typical lesions of DR (microaneurysms, exudates, hemorrhage, or worse) in either eye. RESULTS By DPPOS year 16 (∼20 years after random assignment into DPP), 24% of 1,614 participants who had developed T2D and 14% of 885 who remained without diabetes had DR. In univariate analyses, using results from across the entire duration of follow-up, American Indian race was associated with less frequent DR compared with non-Hispanic White (NHW) race, and higher HbA1c, fasting and 2-h plasma glucose levels during an oral glucose tolerance test, weight, and history of hypertension, dyslipidemia, and smoking, but not treatment group assignment, were associated with more frequent DR. On multivariate analysis, American Indian race was associated with less DR compared with NHW (odds ratio [OR] 0.36, 95% CI 0.20–0.66), and average HbA1c was associated with more DR (OR 1.92, 95% CI 1.46–1.74 per SD [0.7%] increase in HbA1c). CONCLUSIONS DR may occur in adults with prediabetes and early in the course of T2D. HbA1c was an important risk factor for the development of DR across the entire glycemic range from prediabetes to T2D.
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- 2022
17. Impact of Type 1 Diabetes in the Developing Brain in Children: A Longitudinal Study
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Hanyang Shen, Ana Maria Arbelaez, Michael Tansey, Allison Cato, Paul K. Mazaika, Lara C. Foland-Ross, Kimberly Englert, William V. Tamborlane, Allan L. Reiss, Tamara Hershey, Nelly Mauras, Matthew J. Marzelli, Stuart A. Weinzimer, Eva Tsalikian, Tandy Aye, Booil Jo, Neil H. White, Bruce A. Buckingham, and Larry A. Fox
- Subjects
Blood Glucose ,Male ,Research design ,Pediatrics ,medicine.medical_specialty ,Longitudinal study ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,White matter ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Humans ,Longitudinal Studies ,030212 general & internal medicine ,Child ,Pathophysiology/Complications ,Advanced and Specialized Nursing ,Type 1 diabetes ,business.industry ,Blood Glucose Self-Monitoring ,Brain ,Cognition ,medicine.disease ,Verbal reasoning ,Magnetic Resonance Imaging ,Cognitive test ,Diabetes Mellitus, Type 1 ,medicine.anatomical_structure ,Child, Preschool ,Female ,business - Abstract
OBJECTIVE To assess whether previously observed brain and cognitive differences between children with type 1 diabetes and control subjects without diabetes persist, worsen, or improve as children grow into puberty and whether differences are associated with hyperglycemia. RESEARCH DESIGN AND METHODS One hundred forty-four children with type 1 diabetes and 72 age-matched control subjects without diabetes (mean ± SD age at baseline 7.0 ± 1.7 years, 46% female) had unsedated MRI and cognitive testing up to four times over 6.4 ± 0.4 (range 5.3–7.8) years; HbA1c and continuous glucose monitoring were done quarterly. FreeSurfer-derived brain volumes and cognitive metrics assessed longitudinally were compared between groups using mixed-effects models at 6, 8, 10, and 12 years. Correlations with glycemia were performed. RESULTS Total brain, gray, and white matter volumes and full-scale and verbal intelligence quotients (IQs) were lower in the diabetes group at 6, 8, 10, and 12 years, with estimated group differences in full-scale IQ of −4.15, −3.81, −3.46, and −3.11, respectively (P < 0.05), and total brain volume differences of −15,410, −21,159, −25,548, and −28,577 mm3 at 6, 8, 10, and 12 years, respectively (P < 0.05). Differences at baseline persisted or increased over time, and brain volumes and cognitive scores negatively correlated with a life-long HbA1c index and higher sensor glucose in diabetes. CONCLUSIONS Detectable changes in brain volumes and cognitive scores persist over time in children with early-onset type 1 diabetes followed longitudinally; these differences are associated with metrics of hyperglycemia. Whether these changes can be reversed with scrupulous diabetes control requires further study. These longitudinal data support the hypothesis that the brain is a target of diabetes complications in young children.
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- 2021
18. Brain Function Differences in Children With Type 1 Diabetes: A Functional MRI Study of Working Memory
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Paul K. Mazaika, Michael Tansey, Hanyang Shen, Kimberly Englert, Lara C. Foland-Ross, Stuart A. Weinzimer, Allan L. Reiss, Gabby Tong, Nelly Mauras, Neil H. White, Tandy Aye, and Allison Cato
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Cerebellum ,Future studies ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Audiology ,Pathophysiology ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Diabetes mellitus ,Cortex (anatomy) ,Internal Medicine ,Humans ,Medicine ,Child ,Brain function ,Glycemic ,Type 1 diabetes ,business.industry ,Working memory ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,Diabetes Mellitus, Type 1 ,Memory, Short-Term ,030104 developmental biology ,medicine.anatomical_structure ,Female ,business - Abstract
Glucose is a primary fuel source to the brain, yet the influence of dysglycemia on neurodevelopment in children with type 1 diabetes remains unclear. We examined brain activation using functional MRI in 80 children with type 1 diabetes (mean ± SD age 11.5 ± 1.8 years; 46% female) and 47 children without diabetes (control group) (age 11.8 ± 1.5 years; 51% female) as they performed a visuospatial working memory (N-back) task. Results indicated that in both groups, activation scaled positively with increasing working memory load across many areas, including the frontoparietal cortex, caudate, and cerebellum. Between groups, children with diabetes exhibited reduced performance on the N-back task relative to children in the control group, as well as greater modulation of activation (i.e., showed greater increase in activation with higher working memory load). Post hoc analyses indicated that greater modulation was associated in the diabetes group with better working memory function and with an earlier age of diagnosis. These findings suggest that increased modulation may occur as a compensatory mechanism, helping in part to preserve working memory ability, and further, that children with an earlier onset require additional compensation. Future studies that test whether these patterns change as a function of improved glycemic control are warranted.
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- 2020
19. Comparison of ETDRS 7-Field to 4-Widefield Digital Imaging in the Evaluation of Diabetic Retinopathy Severity
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Barbara A. Blodi, Amitha Domalpally, Ashley H. Tjaden, Nancy Barrett, Emily Y. Chew, William C. Knowler, Christine G. Lee, Xavier Pi-Sunyer, Amisha Wallia, Neil H. White, and Marinella Temprosa
- Subjects
Ophthalmology ,diabetic retinopathy ,ETDRS grading ,Fundus Oculi ,digital imaging ,Biomedical Engineering ,Diabetes Mellitus ,Photography ,Humans ,Prospective Studies ,Article ,Retina - Abstract
Purpose To compare Early Treatment Diabetic Retinopathy Study (ETDRS) severity levels between two digital fundus imaging protocols for research studies of diabetic retinopathy: the gold standard 7-field (7F) imaging and the more recent 4-widefield (4W) imaging. Methods Two hundred twenty-two participants enrolled in the Diabetes Prevention Program Outcomes Study underwent concurrent 7F and 4W imaging. The ETDRS levels from 220 paired gradable images were determined by masked graders. Each image was graded by two independent graders with adjudication by a senior grader, if necessary. Percent agreement between graders and between imaging protocols was evaluated with kappa statistics and weighted kappa statistics. Results Of 220 gradable eyes, diabetic retinopathy was seen in 11.8%; this was mild in 10.4% and more than mild in 1.4% using 7F imaging. The ETDRS levels showed exact agreement of 95% between 7F and 4W imaging (weighted kappa 0.86). Intergrader agreement for each modality had exact agreement of 89% (weighted kappa of 0.73) for 7F and 91% (weighted kappa 0.77) for 4W. Conclusions There is substantial agreement in the ETDRS severity level between the 7F and 4W digital imaging protocols, demonstrating that the two imaging protocols are interchangeable. Both 4W and 7F digital imaging protocols can be used for assessing ETDRS levels, even in populations with minimal diabetic retinopathy. Translational Relevance The 4W protocol requires fewer images than the 7F, is more comfortable for the patients, is easier for photographic capture, and provides diabetic retinopathy data that is equivalent to the 7F imaging protocol.
- Published
- 2022
20. Risk Factors for Diabetic Peripheral Neuropathy in Adolescents and Young Adults With Type 2 Diabetes: Results From the TODAY Study
- Author
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the TODAY Study Group, Philip Zeitler, Marsha D. Marcus, Terri H. Lipman, Kenneth C. Copeland, Christine L. Chan, Laure El ghormli, Neil H. White, and Lorraine E. Levitt Katz
- Abstract
Objective: Data related to diabetic neuropathy in youth with type 2 diabetes are limited. We examined the relationship of glycemic control, sex, race-ethnicity, BMI, and other type 2 diabetes-associated factors with the development of diabetic peripheral neuropathy (DPN) in type 2 diabetes youth enrolled in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. Research Design and Methods: The Michigan Neuropathy Screening Instrument (MNSI) and a 10-gram monofilament exam were performed annually. DPN was defined as a score (>2) on the MNSI-exam or combined MNSI-exam and MNSI-survey scores (exam >2 and/or survey ≥4), or monofilament ( Results: 674 participants (35% male), with mean age 14 years and diabetes duration Conclusions: DPN was evident early in the course of youth-onset type 2 diabetes and increased over time. It was higher in males and related to glycemic control. These findings raise concern for long-term development of neuropathy-related morbidity in youth with type 2 diabetes and the need to achieve improved glycemic control.
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- 2021
21. Development and Progression of Diabetic Retinopathy in Adolescents and Young Adults With Type 2 Diabetes: Results From the TODAY Study
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Phil Zeitler, Neil H. White, Steven M. Willi, Mihai Mititelu, Lynne L. Levitsky, Lori Laffel, Barbara A. Blodi, Diane Uschner, Kimberly L. Drews, Ingrid Libman, and Rose Gubitosi-Klug
- Abstract
Objective: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial reported a 13.9% prevalence of diabetic retinopathy (DR) in youth with an average 4.9 ± 1.5 years of type 2 diabetes duration. After seven years of additional follow up, we report the risk factors for progression of DR in the TODAY cohort. Research Design and Methods: Retinal photographs (n = 517) were obtained in 2010-2011 and again in 2017-18 (n = 420) with seven standard stereoscopic field digital fundus photography. Photographs were graded centrally using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Three hundred sixty-seven patients with gradable fundus photographs in at least one eye at both assessments were included in analyses of progression of diabetic retinopathy, defined as an increase of three or more steps on the ETDRS scale. Results: With mean age of 25.4 ± 2.5 years and diabetes duration of 12.0 ± 1.5 years, participants had a 49% prevalence of any diabetic retinopathy. Prevalence by DR stage included: 39% very mild or mild non-proliferative diabetic retinopathy (NPDR); 6% moderate to severe NPDR; and 3.8% proliferative diabetic retinopathy. Compared with non-progressors, participants who progressed three or more steps had significantly lower BMI, higher HbA1c, higher blood pressure, increased triglycerides, decreased C-peptide, and higher prevalence of other comorbidities. Multivariate analysis demonstrated that HbA1c was the dominant factor impacting DR progression. Conclusions: Poor glycemic control of youth-onset type 2 diabetes imparts a high risk for progression of DR, including advanced, sight-threatening disease by young adulthood.
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- 2021
22. Long-Term Complications in Youth-Onset Type 2 Diabetes
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Petter Bjornstad, Kimberly L Drews, Rose A. Gubitosi-Klug, Neil H. White, Bereket Tesfaldet, Sonia Caprio, Philip Zeitler, Jeanie Tryggestad, and David M. Nathan
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,General Medicine ,Type 2 diabetes ,medicine.disease ,Article ,Metformin ,Clinical trial ,Diabetes mellitus ,Medicine ,Cumulative incidence ,Young adult ,business ,General Economics, Econometrics and Finance ,Dyslipidemia ,medicine.drug - Abstract
Background The prevalence of type 2 diabetes in youth is increasing, but little is known regarding the occurrence of related complications as these youths transition to adulthood. Methods We previously conducted a multicenter clinical trial (from 2004 to 2011) to evaluate the effects of one of three treatments (metformin, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention) on the time to loss of glycemic control in participants who had onset of type 2 diabetes in youth. After completion of the trial, participants were transitioned to metformin with or without insulin and were enrolled in an observational follow-up study (performed from 2011 to 2020), which was conducted in two phases; the results of this follow-up study are reported here. Assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease were performed annually, and assessments for retinal disease were performed twice. Complications related to diabetes identified outside the study were confirmed and adjudicated. Results At the end of the second phase of the follow-up study (January 2020), the mean (±SD) age of the 500 participants who were included in the analyses was 26.4±2.8 years, and the mean time since the diagnosis of diabetes was 13.3±1.8 years. The cumulative incidence of hypertension was 67.5%, the incidence of dyslipidemia was 51.6%, the incidence of diabetic kidney disease was 54.8%, and the incidence of nerve disease was 32.4%. The prevalence of retinal disease, including more advanced stages, was 13.7% in the period from 2010 to 2011 and 51.0% in the period from 2017 to 2018. At least one complication occurred in 60.1% of the participants, and at least two complications occurred in 28.4%. Risk factors for the development of complications included minority race or ethnic group, hyperglycemia, hypertension, and dyslipidemia. No adverse events were recorded during follow-up. Conclusions Among participants who had onset of type 2 diabetes in youth, the risk of complications, including microvascular complications, increased steadily over time and affected most participants by the time of young adulthood. Complications were more common among participants of minority race and ethnic group and among those with hyperglycemia, hypertension, and dyslipidemia. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01364350 and NCT02310724.).
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- 2021
23. A phase 1b/2a clinical trial of dantrolene sodium in patients with Wolfram syndrome
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Ashley N Simpson, Damien Abreu, Toni S. Pearson, Hongjie Gu, Tamara Hershey, Neil H. White, Gregory P. Van Stavern, James Hoekel, Stacy Hurst, Robert C. Bucelli, Chinyere Onwumere, Cris M. Brown, Bess A. Marshall, Stephen I. Stone, Fumihiko Urano, Kelly Kries, and Lawrence Tychsen
- Subjects
Oncology ,medicine.medical_specialty ,Visual acuity ,Wolfram syndrome ,business.industry ,medicine.medical_treatment ,General Medicine ,Immunotherapy ,medicine.disease ,Dantrolene Sodium ,Dantrolene ,Clinical trial ,Tolerability ,Internal medicine ,Diabetes mellitus ,medicine ,medicine.symptom ,business ,medicine.drug - Abstract
BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.
- Published
- 2021
24. Heart Rate Variability and Cardiac Autonomic Dysfunction: Prevalence, Risk Factors, and Relationship to Arterial Stiffness in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study
- Author
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Fida Bacha, Lorraine E. Levitt Katz, Mary Ellen Vajravelu, Neil H. White, Elaine M. Urbina, Amy S. Shah, Ryan M. Farrell, Jeanie B. Tryggestad, Laure El Ghormli, and Samuel S. Gidding
- Subjects
Male ,Research design ,Cardiovascular and Metabolic Risk ,medicine.medical_specialty ,Randomization ,Adolescent ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Type 2 diabetes ,Pulse Wave Analysis ,Autonomic Nervous System ,Young Adult ,03 medical and health sciences ,Vascular Stiffness ,0302 clinical medicine ,Heart Rate ,Risk Factors ,Internal medicine ,Diabetes mellitus ,Prevalence ,Internal Medicine ,Humans ,Hypoglycemic Agents ,Medicine ,Heart rate variability ,030212 general & internal medicine ,Young adult ,Child ,Glycemic ,Glycated Hemoglobin ,Advanced and Specialized Nursing ,business.industry ,Arrhythmias, Cardiac ,Heart ,medicine.disease ,Autonomic Nervous System Diseases ,Diabetes Mellitus, Type 2 ,Cardiology ,Arterial stiffness ,Female ,business ,Follow-Up Studies - Abstract
OBJECTIVE To determine whether prior type 2 diabetes (T2D) treatment or glycemic control over time are independently associated with heart rate variability (HRV) and whether the presence of cardiac autonomic dysfunction is associated with arterial stiffness in young adults with youth-onset T2D enrolled in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. RESEARCH DESIGN AND METHODS Heartbeats over 10 min were measured to derive the normal R-Rs (NN intervals). Outcomes included the standard deviation of the NN intervals (SDNN), the root mean square differences of successive NN intervals (RMSSD), percent of NN beats that differ by more than 50 ms (PNN50), and the low-frequency (LF) power domain, high-frequency (HF) power domain, and their ratio (LF:HF). Autonomic dysfunction was defined as ≥3 of 5 abnormal HRV indices compared with obese controls from a separate study. RESULTS A total of 397 TODAY participants were evaluated 7 years after randomization. TODAY participants had reduced HRV (SDNN 58.1 ± 29.6 ms vs. controls 67.1 ± 25.4 ms; P < 0.0001) with parasympathetic loss (RMSSD 53.2 ± 36.7 ms vs. controls 67.9 ± 35.2 ms; P < 0.0001) with sympathetic overdrive (LF:HF ratio 1.4 ± 1.7 vs. controls 1.0 ± 1.1; P < 0.0001). Cardiac autonomic dysfunction was present in 8% of TODAY participants, and these participants had greater pulse wave velocity compared with those without dysfunction (P = 0.0001). HRV did not differ by randomized treatment, but higher hemoglobin A1c (HbA1c) over time was independently associated with lower SDNN and RMSSD and higher LF:HF ratio after adjustment for age, race-ethnicity, sex, and BMI. CONCLUSIONS Young adults with youth-onset T2D show evidence of cardiac autonomic dysfunction with both parasympathetic and sympathetic impairments that are associated with higher HbA1c.
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- 2019
25. Regression From Prediabetes to Normal Glucose Regulation and Prevalence of Microvascular Disease in the Diabetes Prevention Program Outcomes Study (DPPOS)
- Author
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Samuel Dagogo-Jack, Dana Dabelea, Steven E. Kahn, Leigh Perreault, William C. Knowler, Nestoras Mathioudakis, Qing Pan, Neil H. White, Rita R. Kalyani, Emily B. Schroeder, George A. Bray, and Ronald B. Goldberg
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Cardiovascular and Metabolic Risk ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Logistic regression ,Nephropathy ,Prediabetic State ,03 medical and health sciences ,0302 clinical medicine ,Retinal Diseases ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Odds Ratio ,Prevalence ,Humans ,030212 general & internal medicine ,Prediabetes ,Generalized estimating equation ,Advanced and Specialized Nursing ,Peripheral Vascular Diseases ,business.industry ,Incidence (epidemiology) ,Odds ratio ,Middle Aged ,medicine.disease ,Logistic Models ,Diabetes Mellitus, Type 2 ,Microvessels ,Female ,Kidney Diseases ,business ,Retinopathy - Abstract
OBJECTIVE Regression from prediabetes to normal glucose regulation (NGR) was associated with reduced incidence of diabetes by 56% over 10 years in participants in the Diabetes Prevention Program Outcomes Study (DPPOS). In an observational analysis, we examined whether regression to NGR also reduced risk for microvascular disease (MVD). RESEARCH DESIGN AND METHODS Generalized estimating equations were used to examine the prevalence of aggregate MVD at DPPOS year 11 in people who regressed to NGR at least once (vs. never) during the Diabetes Prevention Program (DPP). Logistic regression assessed the relationship of NGR with retinopathy, nephropathy, and neuropathy, individually. Generalized additive models fit smoothing splines to describe the relationship between average A1C during follow-up and MVD (and its subtypes) at the end of follow-up. RESULTS Regression to NGR was associated with lower prevalence of aggregate MVD in models adjusted for age, sex, race/ethnicity, baseline A1C, and treatment arm (odds ratio [OR] 0.78, 95% CI 0.65–0.78, P = 0.011). However, this association was lost in models that included average A1C during follow-up (OR 0.95, 95% CI 0.78–1.16, P = 0.63) or diabetes status at the end of follow-up (OR 0.92, 95% CI 0.75–1.12, P = 0.40). Similar results were observed in examination of the association between regression to NGR and prevalence of nephropathy and retinopathy, individually. Risk for aggregate MVD, nephropathy, and retinopathy increased across the A1C range. CONCLUSIONS Regression to NGR is associated with a lower prevalence of aggregate MVD, nephropathy, and retinopathy, primarily due to lower glycemic exposure over time. Differential risk for the MVD subtypes begins in the prediabetes A1C range.
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- 2019
26. Does diabetes prevention translate into reduced long-term vascular complications of diabetes?
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Sharon L. Edelstein, Jill P. Crandall, Marinella Temprosa, Peter H. Bennett, David M. Nathan, Steven E. Kahn, William C. Knowler, Neil H. White, Sunder Mudaliar, Trevor J. Orchard, Kieren J. Mather, and Ronald B. Goldberg
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cost-Benefit Analysis ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Type 2 diabetes ,Disease ,Diabetes Complications ,Rosiglitazone ,Impaired glucose tolerance ,03 medical and health sciences ,0302 clinical medicine ,Ramipril ,Risk Factors ,Diabetes mellitus ,Glucose Intolerance ,Internal Medicine ,medicine ,Humans ,Hypoglycemic Agents ,Intensive care medicine ,Life Style ,Preventive healthcare ,Clinical Trials as Topic ,business.industry ,Microcirculation ,Atherosclerosis ,medicine.disease ,Metformin ,Clinical trial ,Treatment Outcome ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Preventive Medicine ,business ,Follow-Up Studies ,medicine.drug - Abstract
The global epidemic of type 2 diabetes has prompted numerous studies and public health efforts to reduce its development. A variety of interventions, including lifestyle modifications and pharmacological agents directed at ameliorating the major risk factors for type 2 diabetes, are of proven efficacy in reducing the development of type 2 diabetes in people with impaired glucose tolerance. While prevention of the hyperglycaemia characteristic of diabetes is arguably an important, clinically relevant outcome, a more compelling outcome with greater clinical significance is the prevention or reduction of the relatively diabetes-specific microvascular and less-specific cardiovascular disease (CVD) complications associated with diabetes. These complications cause the majority of morbidity and excess mortality associated with diabetes. Any reduction in diabetes should, logically, also reduce the occurrence of its long-term complications; however, most diabetes prevention trials have not been of sufficient duration to allow such an evaluation. The limited long-term data, largely from the Da Qing Diabetes Prevention Study (DQDPS) and the Diabetes Prevention Program (DPP) and their respective follow-up studies (DQDPOS and DPPOS), suggest a reduction in microvascular complications and amelioration of CVD risk factors. Only the DQDPOS and Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) studies have shown a reduction in CVD events and only DQDPOS has demonstrated a decrease in CVD and overall mortality. While these limited data are promising, whether diabetes prevention directly reduces complication-related morbidity and mortality remains unclear. Longer follow-up of prevention studies is needed to supplement the limited current clinical trial data, to help differentiate the effects of diabetes prevention itself from the means used to reduce diabetes development and to understand the balance among benefits, risks and costs of prevention.
- Published
- 2019
27. Risk Factors for Retinopathy in Type 1 Diabetes: The DCCT/EDIC Study
- Author
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Rose Gubitosi-Klug, Andrew J. Barkmeier, Ionut Bebu, John M. Lachin, Ronald P. Danis, Thomas W. Gardner, Arup Das, William I. Sivitz, Amisha Wallia, Xiaoyu Gao, Neil H. White, John I. Malone, Dean P. Hainsworth, Lloyd Paul Aiello, and Shriji Patel
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Time Factors ,Adolescent ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,Humans ,Medicine ,030212 general & internal medicine ,Epidemiology/Health Services Research ,Risk factor ,Randomized Controlled Trials as Topic ,Glycemic ,Glycated Hemoglobin ,Advanced and Specialized Nursing ,Type 1 diabetes ,Diabetic Retinopathy ,business.industry ,Proportional hazards model ,nutritional and metabolic diseases ,Diabetic retinopathy ,medicine.disease ,Diabetes Mellitus, Type 1 ,Blood pressure ,Disease Progression ,Female ,business ,Follow-Up Studies ,Retinopathy - Abstract
OBJECTIVE The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC. RESEARCH DESIGN AND METHODS The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward- and backward-selection approaches determined the multivariable models. RESULTS Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA1c, longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA1c, longer duration of T1D, and greater age and DBP and, for ocular surgeries, were higher mean HbA1c, older age, and longer duration of T1D. CONCLUSIONS Mean HbA1c was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy.
- Published
- 2019
28. Risk Factors for Kidney Disease in Type 1 Diabetes
- Author
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William V. Tamborlane, Catherine C. Cowie, John M. Lachin, Mark E. Molitch, Andrew D. Paterson, Bruce A. Perkins, Gayle M. Lorenzi, Ian H. de Boer, Ionut Bebu, Trevor J. Orchard, William H. Herman, Neil H. White, and Rodica Pop-Busui
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Time Factors ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Renal function ,030209 endocrinology & metabolism ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Albuminuria ,Humans ,Diabetic Nephropathies ,030212 general & internal medicine ,Epidemiology/Health Services Research ,Randomized Controlled Trials as Topic ,Glycemic ,Advanced and Specialized Nursing ,Type 1 diabetes ,business.industry ,Proportional hazards model ,Hazard ratio ,medicine.disease ,Diabetes Mellitus, Type 1 ,Hyperglycemia ,Female ,Kidney Diseases ,Microalbuminuria ,business ,Follow-Up Studies ,Glomerular Filtration Rate ,Kidney disease - Abstract
OBJECTIVE In type 1 diabetes (T1D), the course of microalbuminuria is unpredictable and timing of glomerular filtration rate (GFR) loss is uncertain. Thus, there is a need to identify the risk factors associated with the development of more advanced stages of kidney disease through large, long-term systematic analysis. RESEARCH DESIGN AND METHODS Multivariable Cox proportional hazards models assessed the association of baseline and time-dependent glycemic and nonglycemic risk factors for incident macroalbuminuria and reduced estimated GFR (eGFR; defined as RESULTS Higher mean HbA1c (hazard ratio [HR] 1.969 per 1% higher level [95% CI 1.671–2.319]) and male sex (HR 2.767 [95% CI 1.951–3.923]) were the most significant factors independently associated with incident macroalbuminuria, whereas higher mean triglycerides, higher pulse, higher systolic blood pressure (BP), longer diabetes duration, higher current HbA1c, and lower mean weight had lower magnitude associations. For incident reduced eGFR, higher mean HbA1c (HR 1.952 per 1% higher level [95% CI 1.714–2.223]) followed by higher mean triglycerides, older age, and higher systolic BP were the most significant factors. CONCLUSIONS Although several risk factors associated with macroalbuminuria and reduced eGFR were identified, higher mean glycemic exposure was the strongest determinant of kidney disease among the modifiable risk factors. These findings may inform targeted clinical strategies for the frequency of screening, prevention, and treatment of kidney disease in T1D.
- Published
- 2019
29. Impact of Early Diabetic Ketoacidosis on the Developing Brain
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Booil Jo, Allison Cato, Allan L. Reiss, Matthew J. Marzelli, Paul K. Mazaika, Tandy Aye, Neil H. White, Hanyang Shen, Nelly Mauras, Stuart A. Weinzimer, Tamara Hershey, and Eva Tsalikian
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,endocrine system diseases ,Diabetic ketoacidosis ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Severity of Illness Index ,Diabetic Ketoacidosis ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Diabetes mellitus ,Severity of illness ,Internal Medicine ,medicine ,Humans ,030212 general & internal medicine ,Effects of sleep deprivation on cognitive performance ,Age of Onset ,Pathophysiology/Complications ,Child ,Advanced and Specialized Nursing ,Type 1 diabetes ,Intelligence quotient ,business.industry ,Functional Neuroimaging ,nutritional and metabolic diseases ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,Ketoacidosis ,Diabetes Mellitus, Type 1 ,Case-Control Studies ,Child, Preschool ,Female ,Age of onset ,Cognition Disorders ,business - Abstract
OBJECTIVE This study examined whether a history of diabetic ketoacidosis (DKA) is associated with changes in longitudinal cognitive and brain development in young children with type 1 diabetes. RESEARCH DESIGN AND METHODS Cognitive and brain imaging data were analyzed from 144 children with type 1 diabetes, ages 4 to RESULTS In 48 of 51 subjects, the DKA event occurred at the time of onset, at an average of 2.9 years before study entry. The moderate/severe DKA group gained more total and regional white and gray matter volume over the observed 18 months compared with the none/mild group. When matched by age at time of enrollment and average HbA1c during the 18-month interval, participants who had a history of moderate/severe DKA compared with none/mild DKA were observed to have significantly lower Full Scale Intelligence Quotient scores and cognitive performance on the Detectability and Commission subtests of the Conners’ Continuous Performance Test II and the Dot Locations subtest of the Children’s Memory Scale. CONCLUSIONS A single episode of moderate/severe DKA in young children at diagnosis is associated with lower cognitive scores and altered brain growth. Further studies are needed to assess whether earlier diagnosis of type 1 diabetes and prevention of DKA may reduce the long-term effect of ketoacidosis on the developing brain.
- Published
- 2018
30. Efficacy and Safety of Inhaled Human Insulin (Exu hera
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Neil H, White, Teresa, Quattrin, Lisa B St, Aubin, William T, Duggan, Richard D, England, and Julie S, Fryburg
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Blood Glucose ,Male ,Injections, Subcutaneous ,Insulin Antibodies ,Prognosis ,Diabetes Mellitus, Type 1 ,Administration, Inhalation ,Humans ,Hypoglycemic Agents ,Insulin ,Female ,Child ,Biomarkers ,Follow-Up Studies - Abstract
To compare the efficacy and safety of Exubera121 children were randomized to receive EXU or SC insulin, plus intermediate/ long-acting insulin for 12 weeks. Change in HbADecreases from baseline HbAThe efficacy and safety profiles shown in this study are the foundation for further investigation of EXU in this population.
- Published
- 2021
31. Impact of Type 1 Diabetes in the Developing Brain in Children: A Longitudinal Study
- Author
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the Diabetes Research in Children Network (DirecNet), Allan L. Reiss, Matthew Marzelli, Paul Mazaika, Kimberly Englert, Hanyang Shen, Lara C. Foland-Ross, William Tamborlane, Michael Tansey, Tamara Hershey, Ana Maria Arbelaez, Tandy Aye, Larry A. Fox, Allison Cato, Booil Jo, Stuart A. Weinzimer, Eva Tsalikian, Neil H. White, Bruce Buckingham, and Nelly Mauras
- Abstract
Objective: To assess whether previously observed brain and cognitive differences between children with type 1 diabetes and non-diabetic controls persist, worsen or improve as children grow into puberty, and whether differences are associated with hyperglycemia. Research Design & Methods: 144 children with type 1 diabetes and 72 non-diabetic age-matched controls, mean±SD age 7.0±1.7 years at baseline, 46% female, had unsedated magnetic resonance imaging and cognitive testing up to 4 times over 6.4±0.4 years (5.3-7.8); HbA1C and continuous glucose monitoring were done quarterly. FreeSurfer-derived brain volumes and cognitive metrics assessed longitudinally were compared between groups using mixed effects models at 6, 8, 10 and 12 years. Correlations with glycemia were performed. Results: Total brain, gray and white matter volumes, full-scale and verbal IQ were lower in the diabetes group [at 6, 8, 10 and 12 years estimate group differences in full-scale IQ respectively: -4.15, -3.81, -3.46, -3.11, p 3x103, -21159, -25548, -28577, p C index and higher sensor glucose in diabetes. Conclusions: Detectable changes in brain volumes and cognitive scores persist over time in children with early-onset type 1 diabetes followed longitudinally; these differences are associated with metrics of hyperglycemia. Whether these changes can be reversed with scrupulous diabetes control requires further study. These longitudinal data support the hypothesis that the brain is a target of diabetes complications in young children.
- Published
- 2021
32. Post-intervention Effects of Varying Treatment Arms on Glycemic Failure and Beta-Cell Function in the TODAY Study
- Author
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The TODAY Study Group, Silva Arslanian, Kristen J. Nadeau, Siripoom McKay, Sonia Caprio, Mitchell E. Geffner, Jeanie B. Tryggestad, Neil H. White, Lorraine E. Levitt Katz, Barbara H. Braffett, and Rachelle Gandica
- Abstract
Objective: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that glycemic failure rates were significantly lower in youth randomized to metformin plus rosiglitazone treatment compared to metformin alone or metformin plus intensive lifestyle intervention. At end of study, rosiglitazone was permanently discontinued, and routine diabetes care resumed. Herein, we report post-intervention glycemic failure rates in TODAY participants over an additional 36 months of follow-up for the three original treatment arms and describe insulin sensitivity and beta-cell function outcomes. Research Design and Methods: A total of 699 participants were randomized during TODAY, of whom 572 enrolled in the TODAY2 observational follow-up. Glycemic failure was defined as HbA1c ≥8% over a 6-month period or inability to wean from temporary insulin therapy within 3 months after acute metabolic decompensation during TODAY or a sustained HbA1c ≥8% over two consecutive visits during TODAY2. Oral glucose tolerance tests were conducted and insulin sensitivity, insulinogenic index, and oral disposition index (oDI) were calculated. Results: During the 36 months of TODAY2, glycemic failure rates did not differ among participants by original treatment group assignment. Insulin sensitivity and beta-cell function deteriorated rapidly during the 36 months of TODAY2 routine diabetes care, but did not differ by treatment group assignment. Conclusions: The added benefit of preventing glycemic failure by using rosiglitazone as a second agent in youth-onset type 2 diabetes did not persist after its discontinuation. More work is needed to address this rapid progression to avoid long-term diabetes complications.
- Published
- 2020
33. Erratum. Risk of Severe Hypoglycemia in Type 1 Diabetes Over 30 Years of Follow-up in the DCCT/EDIC Study. Diabetes Care 2017;40:1010-1016
- Author
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Rose Gubitosi-Klug, Robert S. Sherwin, William V. Tamborlane, Barbara H. Braffett, John M. Lachin, Neil H. White, and Complications Trial
- Subjects
Advanced and Specialized Nursing ,Pediatrics ,medicine.medical_specialty ,Type 1 diabetes ,endocrine system diseases ,business.industry ,Endocrinology, Diabetes and Metabolism ,Intensive treatment ,MEDLINE ,Conventional treatment ,Clinical Care/Education/Nutrition/Psychosocial Research ,nutritional and metabolic diseases ,macromolecular substances ,medicine.disease ,Severe hypoglycemia ,Diabetes mellitus ,Internal Medicine ,medicine ,business - Abstract
OBJECTIVE During the Diabetes Control and Complications Trial (DCCT), intensive diabetes therapy achieving a mean HbA1c of ∼7% was associated with a threefold increase in the rate of severe hypoglycemia (defined as requiring assistance) compared with conventional diabetes therapy with a mean HbA1c of 9% (61.2 vs. 18.7 per 100 patient-years). After ∼30 years of follow-up, we investigated the rates of severe hypoglycemia in the DCCT/Epidemiology of Diabetes Inverventions and Complications (EDIC) cohort. RESEARCH DESIGN AND METHODS Rates of severe hypoglycemia were reported quarterly during DCCT and annually during EDIC (i.e., patient recall of episodes in the preceding 3 months). Risk factors influencing the rate of severe hypoglycemia over time were investigated. RESULTS One-half of the DCCT/EDIC cohort reported episodes of severe hypoglycemia. During EDIC, rates of severe hypoglycemia fell in the former DCCT intensive treatment group but rose in the former conventional treatment group, resulting in similar rates (36.6 vs. 40.8 episodes per 100 patient-years, respectively) with a relative risk of 1.12 (95% CI 0.91–1.37). A preceding episode of severe hypoglycemia was the most powerful predictor of subsequent episodes. Entry into the DCCT study as an adolescent was associated with an increased risk of severe hypoglycemia, whereas insulin pump use was associated with a lower risk. Severe hypoglycemia rates increased with lower HbA1c similarly among participants in both treatment groups. CONCLUSIONS Rates of severe hypoglycemia have equilibrated over time between the two DCCT/EDIC treatment groups in association with advancing duration of diabetes and similar HbA1c levels. Severe hypoglycemia persists and remains a challenge for patients with type 1 diabetes across their life span.
- Published
- 2020
34. A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome
- Author
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Damien, Abreu, Stephen I, Stone, Toni S, Pearson, Robert C, Bucelli, Ashley N, Simpson, Stacy, Hurst, Cris M, Brown, Kelly, Kries, Chinyere, Onwumere, Hongjie, Gu, James, Hoekel, Lawrence, Tychsen, Gregory P, Van Stavern, Neil H, White, Bess A, Marshall, Tamara, Hershey, and Fumihiko, Urano
- Subjects
Adult ,Neurologic Examination ,Adolescent ,Dose-Response Relationship, Drug ,Muscle Relaxants, Central ,Interleukin-1beta ,Diabetes ,Interleukin-18 ,Visual Acuity ,Biological Availability ,Wolfram Syndrome ,Cell stress ,Dantrolene ,Treatment Outcome ,Endocrinology ,Insulin-Secreting Cells ,Quality of Life ,Genetics ,Humans ,Calcium Signaling ,Molecular Targeted Therapy ,Drug Monitoring ,Clinical Medicine ,Child ,Genetic diseases - Abstract
BACKGROUND Wolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial. METHODS Based on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions. RESULTS Dantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects. CONCLUSION This study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02829268 FUNDING NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.
- Published
- 2020
35. A Phase 1b/2a Clinical Trial of Dantrolene Sodium in Patients with Wolfram Syndrome
- Author
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Neil H. White, Toni S. Pearson, Stacy Hurst, Hongjie Gu, Tamara Hershey, Ashley N Simpson, Lawrence Tychsen, Cris M. Brown, Kelly Kries, James Hoekel, Damien Abreu, Bess A. Marshall, Stephen I. Stone, Fumihiko Urano, Robert C. Bucelli, and Gregory P. Van Stavern
- Subjects
medicine.medical_specialty ,Visual acuity ,business.industry ,Wolfram syndrome ,medicine.disease ,Dantrolene ,Dantrolene Sodium ,Clinical trial ,Quality of life ,Tolerability ,Diabetes mellitus ,Internal medicine ,Medicine ,medicine.symptom ,business ,medicine.drug - Abstract
BackgroundWolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, may be beneficial.MethodsBased on the results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, our group put together the first-ever clinical trial in pediatric and adult patients with Wolfram syndrome. An open-label phase 1b/2a trial design was chosen. The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.ResultsThe results indicate that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.ConclusionThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.Trial registrationClinicalTrials.gov Identifier NCT02829268Key PointsQuestionIs dantrolene sodium safe and effective for the treatment of adult and pediatric patients with Wolfram syndrome?FindingsThe results of this open-label clinical trial show that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.MeaningDantrolene sodium is well tolerated by patients with Wolfram syndrome. Some patients may experience an increase in β cell function when taking dantrolene.ImportanceWolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, is an emerging therapeutic strategy.ObjectiveThe primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric subjects with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.DesignOpen-label phase 1b/2a trial of dantrolene sodium over a 6-month treatment period.SettingSingle site, academic medical center.ParticipantsAdult and pediatric subjects with a genetically confirmed diagnosis of Wolfram syndrome.InterventionsAll subjects received increasing doses of dantrolene sodium.Main Outcomes and MeasuresThe safety and tolerability of dantrolene sodium administered orally at the upper end of therapeutic dose range for 6 months, and the efficacy of dantrolene sodium on residual pancreatic β-cell functions using a mixed-meal tolerance test, visual acuity using LogMar scores, quality of life measures related to vision using Visual Functioning Questionnaire – 25, and neurological functions using the Wolfram Unified Rating Scale (WURS) and standard neurological assessments.ResultsThe results indicate that dantrolene sodium is well tolerated by subjects with Wolfram syndrome. Although the study was small, a select few subjects seemed to have improvements in β-cell function, which might be correlated with a positive trend in visual acuity.Conclusions and RelevanceThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.Trial RegistrationRegistered with clinicaltrials.gov, NCT02829268, (https://clinicaltrials.gov/ct2/show/NCT02829268?term=NCT02829268&draw=2&rank=1)
- Published
- 2020
36. Brain function differences in children with type 1 diabetes: An fMRI study of working memory
- Author
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Diabetes Research in Children Network (DirecNet), Allan L. Reiss, Paul K. Mazaika, Hanyang Shen, Kimberly Englert, Stuart A. Weinzimer, Neil H. White, Michael Tansey, Tandy Aye, Allison Cato, Nelly Mauras, Gabby Tong, Lara C. Foland-Ross, and Ada Admin
- Abstract
Glucose is a primary fuel source to the brain, yet the influence of dysglycemia on neurodevelopment in children with type 1 diabetes remains unclear. We examined brain activation using functional MRI in 80 children with type 1 diabetes (mean age ± SD, 11.5±1.8 years; 46% female) and 47 children without diabetes (“control”, mean age 11.8±1.5 years; 51% female) as they performed a visuospatial working memory (N-back) task. Results indicated that in both groups, activation scaled positively with increasing working memory load across many areas, including the frontoparietal cortex, caudate and cerebellum. Between groups, children with diabetes exhibited reduced performance on the N-back task relative to control children, as well as greater modulation of activation (i.e., showed greater a increase in activation with higher working memory load). Post-hoc analyses indicated that greater modulation was associated in the diabetes group with better working memory function and with an earlier age of diagnosis. These findings suggest that increased modulation may occur as a compensatory mechanism, helping in part to preserve working memory ability, and further, that children with an earlier onset require additional compensation. Future studies that test whether these patterns change as a function of improved glycemic control are warranted.
- Published
- 2020
37. 2278-PUB: Longitudinal Progression of Diabetes Mellitus in Wolfram Syndrome
- Author
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Mary Katherine Ray, Tamara Hershey, Neil H. White, Ling Chen, and Bess A. Marshall
- Subjects
Pediatrics ,medicine.medical_specialty ,business.operation ,Wolfram syndrome ,business.industry ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,Beta-cell Function ,Mallinckrodt ,medicine.disease ,Substance abuse ,Atrophy ,Diabetes mellitus ,Diabetes insipidus ,Internal Medicine ,medicine ,business - Abstract
Wolfram Syndrome (WFS) is a rare, genetic, neurodegenerative disorder with associated features of diabetes mellitus (DM), diabetes insipidus, deafness, and optic atrophy. In order to design intervention studies, concrete markers of disease progression are required. DM in WFS is believed to be due to endoplasmic reticulum stress-induced failure of insulin secretion. Therefore, progressive loss of insulin production may be a viable marker of disease progression. The purpose of this study was to examine progression of DM, measured by beta-cell function, in WFS patients over time. N=44 (25F/19M) participants with genetically confirmed WFS attended the Washington University Wolfram Research Clinic from 2010-2019. A mixed meal tolerance test was administered to assess beta cell function (i.e., C-peptide). A hierarchical random coefficients model was used to relate C-peptide as a function of DM duration. Most patients (91%) had DM at time of study enrollment (N=39) or developed DM during the study (N=1). There was a significant association between C-peptide and DM duration, such that C-peptide decreased over time (F= 39.44, p= Disclosure M. Ray: None. T. Hershey: None. L. Chen: None. N.H. White: None. B.A. Marshall: None. Funding Washington University (HD070855, U54HD087011); Clinical and Translational Science Award (UL1RR024992); National Institute on Drug Abuse (5T32DA007261-27); Diabetes Research Center (DK020579); Snow Foundation, George Decker and Julio V. Santiago Pediatric Diabetes Research Fund; Mallinckrodt Institute of Radiology; McDonnell Center for Systems Neuroscience
- Published
- 2020
38. Review for 'Challenges in the Diagnosis of Diabetes Type in Pediatrics'
- Author
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Neil H. White
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Diabetes mellitus ,Medicine ,business ,medicine.disease - Published
- 2020
39. DNA methylation age calculators reveal association with diabetic neuropathy in type 1 diabetes
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Thomas Donner, P. Rezaeian, John I. Malone, Sharon B. Schwartz, Xiaoyu Gao, Szilard Kiss, Matthew J. Budoff, David R. Sell, A. Dwoskin, Ronald J. Prineas, C. Pittman, M. Reid, C. McDonald, S. Caulder, M. Szpiech, Oscar B. Crofford, Rachel G. Miller, Louis A. Lobes, M. Patronas, C. Canny, M. E. Lackaye, Sandra R. Montezuma, Richard M. Bergenstal, Patricia Gatcomb, Julie A. Stoner, H. Pan, James L. Kinyoun, J. Mortenson, Osama Hamdy, Connie Fountain, David D. Moore, Kusiel Perlman, R. Trail, David A. Lee, J. Sheindlin, Samuel Dagogo-Jack, Jeffrey L. Mahon, Jill P. Crandall, L. Gill, T. Thompson, Lee M. Jampol, K. Koushan, David S. Schade, J. Brown-Friday, M. Basco, S. Dunnigan, J. Bylsma, R. Birk, L. H. Ketai, J. Hotaling, Stephen W. Scherer, W. Mestrezat, Stephan Villavicencio, R. Lyon, M. Carney, John Kramer, Sunder Mudaliar, David M. Nathan, M. Moran, F. Leandre, James W. Albers, L. Survant, Joseph F. Polak, Manjot K. Gill, Anton Orlin, M. Prince, Pamela A. Silver, Amy K. Saenger, John D. Brunzell, Kathleen E. Bainbridge, L. Babbione, Amisha Wallia, J. Vaccaro-Kish, Bradley D. Jones, M. Hebdon, L. McKenzie, Richard M. Hoffman, S. Chang, C. Siebert, George S. Sharuk, D. Counts, A. Lucas, P. Ramos, N. Burkhart, N. Bakshi, N. Flaherty, D. Kenny, M. Driscoll, Harjit Chahal, Ronald K. Mayfield, S. Hensley, E. Weimann, M. Franz, Martin J. Stevens, N. S. Gregory, Christopher J. O'Donnell, J. Laechelt, Pamela Ossorio, Jerry P. Palmer, Rama Natarajan, G. Ziegler, K. Martin, R. Beaser, C. Beck, L. Zhang, T. J. Declue, David M. Kendall, H. Solc, A. Vella, H. Martinez, Cormac T. Taylor, S. Neill, Douglas A. Greene, P. Lee, D. Norman, Andrew J. Barkmeier, Dean P. Hainsworth, Alka Jain, Sapna Gangaputra, N. Thangthaeng, Lorraine Thomas, Michael H. Brent, M. Bracey, Philip Raskin, Q. Clemens, Barbara H. Braffett, Mark S. Mandelcorn, Lloyd Paul Aiello, John E. Godine, T. Speigelberg, R. Chan, R. Hanna, Shelley B. Bull, William I. Sivitz, R. Sussman, C. Kwong, S. Cercone, P. Hollander, N. Leloudes, Joseph M. Terry, J. Wesche, E. A. Tanaka, D. Rosenberg, Wanjie Sun, L. Sun, Tom Clark, Deborah K. Schlossman, Louis M. Luttrell, R. Dunn, A. Farr, K. McVary, Gayle M. Lorenzi, A. Joseph, Catherine C. Cowie, M. Barr, D. Zimbler, S. Mendley, S. Schussler, N. Grove, Matthew D. Davis, Jong Mu Sun, Sophie Rogers, John P. Bantle, Brandy N. Rutledge, Senda Ajroud-Driss, Vincent M. Monnier, Cladd E. Stevens, Y. G. He, M. Phillips, C. Williams, J. MacIndoe, Kaleigh Farrell, Helen Lambeth, Ayad A. Jaffa, J. Quin, Morey W. Haymond, R. Kirby, D. Steinberg, William H. Herman, M. Mech, Arup Das, Robert Detrano, J. Brown, D. McMillan, Linda Snetselaar, Mark W. Johnson, R. Zeitler, T. Taylor, Peter R. Pavan, Michael H. Goldbaum, Bruce A. Perkins, R. G. Campbell, David A. Nicolle, R. J. van der Geest, Irene Hramiak, D. Freking, Lucy A. Levandoski, S. Colson, Charles Campbell, Victoria R. Trapani, Lawrence J. Singerman, D. Meyer, W. Tang, J. Soule, Anita Harrington, Julie A. Nelson, John A. Colwell, Naji Younes, P. Salemi, K. Hansen, Trevor J. Orchard, S. Huddleston, L. Steranchak, C. Sommer, G. Castle, J. Ginsberg, Paula McGee, V. Gama, John Dupre, Z. Strugula, M. Swenson, N. Wong, David A. Bluemke, M. Nutaitis, Anita Agarwal, M. Lin, K. Nickander, Elsayed Z. Soliman, Joao A. Lima, M. L. Schluter, Fred W. Whitehouse, Lisa Diminick, C. Cornish, M. Spencer, Daniel T. Lackland, Ionut Bebu, Hunter Wessells, S. Yacoub-Wasef, A. Determan, L. Van Ottingham, Howard Wolpert, R. Ehrlich, A. Blevins, L. Jovanovic, D. Finegold, Davida F. Kruger, Jye-Yu C. Backlund, K. Chan, Timothy J. Murtha, R. K. Mayfield, Robert W. Cavicchi, Maria F. Lopes-Virella, Thomas A. Weingeist, K. Lee, Mary E. Larkin, B. Blodi, J. Gott, Timothy J. Lyons, J. Selby, Chris Ryan, J. Harth, P. Pugsley, L. Keasler, John D. Maynard, Paul G. Arrigg, Amy B. Karger, P. Colby, J. Farquhar, Mark H. Schutta, Murk-Hein Heinemann, Kathie L. Hermayer, B. Bosco, C. Lovell, A. Bhan, A. Galprin, M. Cayford, M. Schumer, John E. Chapin, D. Rubinstein, F. Miao, V. Asuquo, Catherine L. Martin, Rodney A. Lorenz, Samuel S. Engel, L. Funk, Cyndi F. Liu, Barbara J. Maschak-Carey, Stephen S. Feman, P. Lindsey, M. Giotta, Philip A. Low, S. Kwon, R. Fahlstrom, A. Iannacone, B. French, H. Remtema, L. Cimino, S. Barron, J. McConnell, Jane L. Lynch, L. Kim, T. Williams, A. Degillio, Blanche M. Chavers, M. Novak, Julio V. Santiago, Ronald P. Danis, P. Gaston, Tae Sup Lee, T. Woodfill, R. Cuddihy, Scott M. Steidl, Alanna C. Morrison, E. Ryan, D. Lawrence, D. Cros, T. Adkins, D. Adelman, L. Dews, Patricia A. Cleary, J. Parker, L. Olmos De Koo, C. Kim, Mark R. Palmert, P. Astelford, Stefan Fritz, B. Olson, Kelvin C. Fong, Alan M. Jacobson, Stanley L. Hazen, D. Hornbeck, K. Folino, M. L. Bernal, Gabriel Virella, William V. Tamborlane, Neil H. White, Daniel L. McGee, Denis Daneman, H. Shamoon, William Dahms, S. Elsing, S. Brink, J. Ahern, Delnaz Roshandel, John M. Pach, N. W. Rodger, E. Cupelli, Dara D. Koozekanani, Abbas E. Kitabchi, K. Stoessel, B. Petty, Jamie R. Wood, J. Seegmiller, T. Strand, Y. Li, Eva L. Feldman, Larry Rand, Robert C. Colligan, T. Smith, A. Carlson, David J. Brillon, Margaret L. Bayless, M. Ong, S. Darabian, W. Hsu, Janet E. Olson, B. Rogness, N. Silvers, M. Pfiefer, B. Schaefer, E. Mendelson, S. Braunstein, Maren Nowicki, R. Reed, James S. Floyd, Z. M. Zhang, T. Sandford, R. B. Avery, A. Pratt, Paolo S. Silva, H. Bode, Alexander J. Brucker, Nikhil D. Patel, Alexander R. Lyon, M. Jenner, N. Wimmergren, L. Tuason, J. Rosenzwieg, D. J. Becker, C. Gauthier-Kelly, M. Richardson, Richard S. Crow, Andrew D. Paterson, Mark E. Molitch, Suzanne M. Strowig, S. Pendegast, M. Burger, Ramzi K. Hemady, J. Dingledine, I. H. de Boer, L. Mayer, F. Perdikaris, Om P. Ganda, F. Thoma, Karen J. Cruickshanks, Abraham Thomas, K. Klumpp, Jerry D. Cavallerano, D. Zheng, Annette Barnie, J. L. Canady, C. Wigley, David G. Miller, Sheila Smith-Brewer, D. Ostrowski, P. Crawford, K. Kelly, Robert G. Devenyi, B. Zimmerman, Susan M. Hitt, C. Johnson, L. Gurry, R. Jarboe, E. Angus, David E. Goldstein, A. Killeen, H. Schrott, Orville G. Kolterman, Mark R. Burge, Michael Rubin, J. Lipps Hagan, Alicia J. Jenkins, Hugh D. Wabers, R. Warhol, Edward Chaum, Karen L. Jones, L. Spillers, C. Miao, J. K. Jones, Angelo J. Canty, Rickey E. Carter, Evrim B. Turkbey, B. Burzuk, R. Woodwick, Evica Simjanoski, Michael W. Steffes, S. Crowell, Suresh D. Shah, H. Ricks, J. D. Carey, Paul A. Edwards, S. Holt, W. F. Schwenk, Ronald J. Oudiz, E. Brown, J. Heier, R. L. Ufret-Vincenty, L. M. Aiello, Robert A. Rizza, Karen L. Anderson, Valerie L. Arends, J. Giangiacomo, R. Liss, Aruna V. Sarma, B. Levy, Ellen J. Anderson, S. Catton, P. Callahan, Rodica Pop-Busui, S. Debrabandere, S. Moser, Bernard H. Doft, A. Malayeri, C. Johannes, R. Ramker, J. Rich, M. Fox, Rukhsana G. Mirza, Katherine A. Morgan, Thomas J. Songer, C. Shah, H. Engel, Saul M. Genuth, S. Ferguson, Anushka Patel, C. Haggan, P. Lou, J. Gordon, M. B. Murphy, D. Sandstrom, Dawn M. Ryan, Daniel H. O'Leary, B. Gloeb, Lois E. Schmidt, H. Zegarra, D. Dalton, W. Brown, Tom G. Sheidow, Margaret E. Stockman, Shyam M. Thomas, Charles McKitrick, Jyotika K. Fernandes, P. A. Bourne, L. Baker, G. Friedenberg, Allan Gordon, Allan L. Drash, S. Yoser, D. Wood, S. Johnsonbaugh, A. De Manbey, L. Kaminski, M. May, L. Bestourous, A. Kowarski, M. Geckle, M. Hartmuller, Michael Bryer-Ash, S. List, F. Goetz, V. Reppucci, D. Etzwiler, Rose A. Gubitosi-Klug, M. Brabham, E. Golden, A. Nayate, J. Hu, M. McLellan, Ronald Klein, N. Rude, B. Vittetoe, John M. Lachin, M. Christofi, Zhuo Chen, Isaac Boniuk, C. Strauch, K. Gunyou, L. Delahanty, W. T. Garvey, Andrew P. Boright, Larry D. Hubbard, D. Weiss, Igor Grant, Jonathan Q. Purnell, Jean M. Bucksa, N. Olson, and B. Zinman
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Diabetic neuropathy ,Adolescent ,030209 endocrinology & metabolism ,Gastroenterology ,Nephropathy ,Epigenesis, Genetic ,Diabetic complications ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Diabetic Neuropathies ,Internal medicine ,Diabetes mellitus ,Albumins ,Genetics ,Medicine ,Humans ,Molecular Biology ,Genetics (clinical) ,Whole blood ,Oligonucleotide Array Sequence Analysis ,Type 1 diabetes ,business.industry ,Research ,dNaM ,DNA methylation age ,DNA Methylation ,medicine.disease ,030104 developmental biology ,Blood pressure ,Peripheral neuropathy ,Diabetes Mellitus, Type 1 ,CpG Islands ,Female ,business ,Developmental Biology ,Genome-Wide Association Study - Abstract
Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.
- Published
- 2020
40. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial
- Author
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Morey W. Haymond, Lynne L. Levitsky, Kenneth C. Copeland, Barbara Linder, Neil H. White, Alan R. Shuldiner, Toni I. Pollin, Jeffrey W. Kleinberger, Rachelle Gandica, and Sherida E. Tollefsen
- Subjects
Male ,obesity ,Pediatrics ,medicine.medical_specialty ,Adolescent ,030209 endocrinology & metabolism ,Type 2 diabetes ,Protein Serine-Threonine Kinases ,Overweight ,Article ,Body Mass Index ,Germinal Center Kinases ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,medicine ,Humans ,Hepatocyte Nuclear Factor 1-alpha ,030212 general & internal medicine ,Child ,Genetics (clinical) ,2. Zero hunger ,youth ,business.industry ,clinical trial ,medicine.disease ,Obesity ,3. Good health ,HNF1A ,Diabetes Mellitus, Type 2 ,Hepatocyte Nuclear Factor 4 ,monogenic diabetes ,Cohort ,Female ,type 2 diabetes ,medicine.symptom ,business ,Body mass index ,Cohort study - Abstract
PurposeMonogenic diabetes accounts for 1-2% of diabetes cases. It is often undiagnosed, which may lead to inappropriate treatment. This study was performed to estimate the prevalence of monogenic diabetes in a cohort of overweight/obese adolescents diagnosed with type 2 diabetes (T2D).MethodsSequencing using a custom monogenic diabetes gene panel was performed on a racially/ethnically diverse cohort of 488 overweight/obese adolescents with T2D in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial. Associations between having a monogenic diabetes variant and clinical characteristics and time to treatment failure were analyzed.ResultsMore than 4% (22/488) had genetic variants causing monogenic diabetes (seven GCK, seven HNF4A, five HNF1A, two INS, and one KLF11). Patients with monogenic diabetes had a statistically, but not clinically, significant lower body mass index (BMI) z-score, lower fasting insulin, and higher fasting glucose. Most (6/7) patients with HNF4A variants rapidly failed TODAY treatment across study arms (hazard ratio = 5.03, P = 0.0002), while none with GCK variants failed treatment.ConclusionThe finding of 4.5% of patients with monogenic diabetes in an overweight/obese cohort of children and adolescents with T2D suggests that monogenic diabetes diagnosis should be considered in children and adolescents without diabetes-associated autoantibodies and maintained C-peptide, regardless of BMI, as it may direct appropriate clinical management.
- Published
- 2018
41. Longitudinal assessment of hippocampus structure in children with type 1 diabetes
- Author
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Nelly Mauras, Lara C. Foland-Ross, Neil H. White, Paul K. Mazaika, Allan L. Reiss, Stuart A. Weinzimer, Tandy Aye, and Michael Tansey
- Subjects
Pediatrics ,medicine.medical_specialty ,Type 1 diabetes ,endocrine system diseases ,business.industry ,Endocrinology, Diabetes and Metabolism ,nutritional and metabolic diseases ,Hippocampus ,030209 endocrinology & metabolism ,Cognition ,Hypoglycemia ,medicine.disease ,Control subjects ,Article ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Pediatrics, Perinatology and Child Health ,Internal Medicine ,medicine ,Cognitive development ,business ,030217 neurology & neurosurgery ,Glycemic - Abstract
The extant literature finds that children with type 1 diabetes mellitus (T1D) experience mild cognitive alterations compared to healthy age-matched controls. The neural basis of these cognitive differences is unclear but may relate in part to the effects of dysglycemia on the developing brain. We investigated longitudinal changes in hippocampus volume in young children with early-onset T1D. Structural magnetic resonance imaging data were acquired from 142 children with T1D and 65 age-matched control subjects (4-10 years of age at study entry) at 2 time points, 18 months apart. The effects of diabetes and glycemic exposure on hippocampal volume and growth were examined. Results indicated that although longitudinal hippocampus growth did not differ between children with T1D and healthy control children, slower growth of the hippocampus was associated with both increased exposure to hyperglycemia (interval HbA1c) and greater glycemic variability (MAGE) in T1D. These observations indicate that the current practice of tolerating some hyperglycemia to minimize the risk of hypoglycemia in young children with T1D may not be optimal for the developing brain. Efforts that continue to assess the factors influencing neural and cognitive development in children with T1D will be critical in minimizing the deleterious effects of diabetes.
- Published
- 2018
42. Risk of Severe Hypoglycemia in Type 1 Diabetes Over 30 Years of Follow-up in the DCCT/EDIC Study
- Author
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Rose A, Gubitosi-Klug, Barbara H, Braffett, Neil H, White, Robert S, Sherwin, F John, Service, John M, Lachin, and William V, Tamborlane
- Subjects
Adult ,Male ,Insulin pump ,medicine.medical_specialty ,Pediatrics ,Adolescent ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Hypoglycemia ,Lower risk ,Diabetes Therapy ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Diabetes mellitus ,Internal Medicine ,medicine ,Humans ,Insulin ,Glycated Hemoglobin ,Advanced and Specialized Nursing ,Type 1 diabetes ,Errata ,business.industry ,nutritional and metabolic diseases ,medicine.disease ,3. Good health ,Surgery ,Diabetes Mellitus, Type 1 ,Relative risk ,Cohort ,Female ,business ,Follow-Up Studies - Abstract
OBJECTIVE During the Diabetes Control and Complications Trial (DCCT), intensive diabetes therapy achieving a mean HbA1c of ∼7% was associated with a threefold increase in the rate of severe hypoglycemia (defined as requiring assistance) compared with conventional diabetes therapy with a mean HbA1c of 9% (61.2 vs. 18.7 per 100 patient-years). After ∼30 years of follow-up, we investigated the rates of severe hypoglycemia in the DCCT/Epidemiology of Diabetes Inverventions and Complications (EDIC) cohort. RESEARCH DESIGN AND METHODS Rates of severe hypoglycemia were reported quarterly during DCCT and annually during EDIC (i.e., patient recall of episodes in the preceding 3 months). Risk factors influencing the rate of severe hypoglycemia over time were investigated. RESULTS One-half of the DCCT/EDIC cohort reported episodes of severe hypoglycemia. During EDIC, rates of severe hypoglycemia fell in the former DCCT intensive treatment group but rose in the former conventional treatment group, resulting in similar rates (40.8 vs. 36.6 episodes per 100 patient-years, respectively) with a relative risk of 1.12 (95% CI 0.91–1.37). A preceding episode of severe hypoglycemia was the most powerful predictor of subsequent episodes. Entry into the DCCT study as an adolescent was associated with an increased risk of severe hypoglycemia, whereas insulin pump use was associated with a lower risk. Severe hypoglycemia rates increased with lower HbA1c similarly among participants in both treatment groups. CONCLUSIONS Rates of severe hypoglycemia have equilibrated over time between the two DCCT/EDIC treatment groups in association with advancing duration of diabetes and similar HbA1c levels. Severe hypoglycemia persists and remains a challenge for patients with type 1 diabetes across their life span.
- Published
- 2017
43. Adiponectin, Insulin Sensitivity, β-Cell Function, and Racial/Ethnic Disparity in Treatment Failure Rates in TODAY
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Sonia Caprio, Steven M. Willi, Fida Bacha, Laure El Ghormli, Robin Goland, Kristen J. Nadeau, Lynne L. Levitsky, Silva A. Arslanian, Morey W. Haymond, and Neil H. White
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Black People ,030209 endocrinology & metabolism ,Type 2 diabetes ,030204 cardiovascular system & hematology ,White People ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,Ethnicity ,Humans ,Hypoglycemic Agents ,Treatment Failure ,Pathophysiology/Complications ,Child ,Life Style ,Glycemic ,Advanced and Specialized Nursing ,Glucose tolerance test ,medicine.diagnostic_test ,Adiponectin ,C-Peptide ,business.industry ,Hazard ratio ,Health Status Disparities ,Hispanic or Latino ,Glucose Tolerance Test ,medicine.disease ,Metformin ,Drug Combinations ,Thiazoles ,Endocrinology ,Diabetes Mellitus, Type 2 ,Female ,Insulin Resistance ,Rosiglitazone ,business ,medicine.drug - Abstract
OBJECTIVE The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study demonstrated that glycemic failure rates in the three treatments combined—metformin plus rosiglitazone, metformin alone, and metformin plus lifestyle—were higher in non-Hispanic blacks (NHB; 52.8%) versus non-Hispanic whites (NHW; 36.6%) and Hispanics (H; 45.0%). Moreover, metformin alone was less effective in NHB versus NHW versus H youth. This study describes treatment-associated changes in adiponectin, insulin sensitivity, and β-cell function over time among the three racial/ethnic groups to understand potential mechanism(s) responsible for this racial/ethnic disparity. RESEARCH DESIGN AND METHODS TODAY participants underwent periodic oral glucose tolerance tests to determine insulin sensitivity, C-peptide index, and oral disposition index (oDI), with measurements of total and high-molecular-weight adiponectin (HMWA). RESULTS At baseline NHB had significantly lower HMWA than NHW and H and exhibited a significantly smaller increase (17.3% vs. 33.7% vs. 29.9%, respectively) during the first 6 months overall. Increases in HMWA were associated with reductions in glycemic failure in the three racial/ethnic groups combined (hazard ratio 0.61, P < 0.0001) and in each race/ethnicity separately. Over time, HMWA was significantly lower in those who failed versus did not fail treatment, irrespective of race/ethnicity. There were no differences in treatment-associated temporal changes in insulin sensitivity, C-peptide index, and oDI among the three racial/ethnic groups. CONCLUSIONS HMWA is a reliable biomarker of treatment response in youth with type 2 diabetes. The diminutive treatment-associated increase in HMWA in NHB (∼50% lower) compared with NHW and H may explain the observed racial/ethnic disparity with higher therapeutic failure rates in NHB in TODAY.
- Published
- 2016
44. Cardiovascular Autonomic Neuropathy and Cardiovascular Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study
- Author
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B. Zinman, Barbara H. Braffett, Catherine L. Martin, Rose Gubitosi-Klug, Rodica Pop-Busui, William H. Herman, Neil H. White, and Saul Genuth
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,endocrine system diseases ,Valsalva Maneuver ,Endocrinology, Diabetes and Metabolism ,Blood Pressure ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Cardiovascular System ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Diabetic Neuropathies ,Randomized controlled trial ,Risk Factors ,law ,Internal medicine ,Internal Medicine ,medicine ,Autonomic reflex ,Humans ,Hypoglycemic Agents ,Cumulative incidence ,Risk factor ,Pathophysiology/Complications ,Proportional Hazards Models ,Advanced and Specialized Nursing ,Type 1 diabetes ,Proportional hazards model ,business.industry ,Incidence ,Hazard ratio ,nutritional and metabolic diseases ,Middle Aged ,medicine.disease ,Diabetes Mellitus, Type 1 ,Treatment Outcome ,Autonomic Nervous System Diseases ,Cardiovascular Diseases ,Cohort ,Physical therapy ,Female ,business ,Follow-Up Studies - Abstract
OBJECTIVE To examine whether cardiovascular autonomic neuropathy (CAN) is an independent risk factor of cardiovascular disease (CVD) events during DCCT/EDIC. RESEARCH DESIGN AND METHODS Standardized cardiovascular autonomic reflex tests (R-R response to paced breathing, Valsalva maneuver, postural changes in blood pressure) were performed at DCCT baseline, every 2 years throughout DCCT, and at two time points in EDIC. CVD events were ascertained throughout the study and adjudicated by a review committee. Cox proportional hazards models were used to estimate the effect of CAN at DCCT closeout on subsequent CVD risk. RESULTS There were 299 adjudicated CVD events in 165 participants following the DCCT closeout assessment: 132 of 1,262 subjects (10%) without CAN at DCCT closeout who experienced 244 CVD events versus 33 of 131 subjects (25%) with CAN at DCCT closeout who experienced 55 events (hazard ratio 2.79, 95% CI 1.91–4.09 for time to first CVD event). The cumulative incidence of the first occurrence of any CVD event during EDIC was significantly higher in participants with CAN at DCCT closeout compared with those without CAN. The association remained marginally significant after adjustment for multiple risk factors, including the EDIC updated mean HbA1c. When analyzed as a continuous variable, R-R variation was significantly lower at DCCT closeout in participants who experienced a CVD event compared with those who did not (P = 0.0012). CONCLUSIONS In the DCCT/EDIC cohort, individuals diagnosed with CAN at DCCT closeout experienced a higher long-term risk of CVD events during follow-up in EDIC. This association was not independent of historic glycemic exposure and its metabolic memory effect, the principal determinant of both long-term CVD risk and CAN in type 1 diabetes.
- Published
- 2016
45. Posaconazole-induced hypertension and hypokalemia due to inhibition of the 11β-hydroxylase enzyme
- Author
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Neil H. White, Kevin T. Barton, Bess A. Marshall, Alexis Elward, and T. Keefe Davis
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Posaconazole ,hypertension ,030106 microbiology ,mineralocorticoid excess ,03 medical and health sciences ,Mineralocorticoid receptor ,Internal medicine ,hypokalemia ,medicine ,Congenital adrenal hyperplasia ,Nephrotoxicity ,Immunodeficiency ,Transplantation ,business.industry ,Activator (genetics) ,Hypertensive urgency ,Adrenal crisis ,medicine.disease ,posaconazole ,Hypokalemia ,030104 developmental biology ,Endocrinology ,11β-hydroxylase ,Nephrology ,adrenal hyperplasia ,medicine.symptom ,business ,medicine.drug - Abstract
Posaconazole is an antifungal therapy reported to cause incident hypertension. Hypokalemia is also a known side effect. The combination of hypertension and hypokalemia suggests mineralocorticoid excess. We present the case of a 15-year-old adolescent male with hypertensive urgency while on prophylactic posaconazole therapy for a combined immunodeficiency. We identify the mechanism of posaconazole-induced hypertension to be inhibition of the 11β-hydroxylase enzyme, resulting in elevated levels of the mineralocorticoid receptor activator deoxycorticosterone. Loss of function of the 11β-hydroxylase enzyme is responsible for a rare form of congenital adrenal hyperplasia and can be associated with life-threatening adrenal crisis.
- Published
- 2018
46. Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study
- Author
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John M. Lachin, Neil H. White, Rose Gubitosi-Klug, Barbara H. Braffett, Eva L. Feldman, Catherine L. Martin, James W. Albers, Rodica Pop-Busui, Trevor J. Orchard, and Maria F. Lopes-Virella
- Subjects
0301 basic medicine ,Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Diabetic neuropathy ,Complications ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Autonomic Nervous System ,Cohort Studies ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Diabetic Neuropathies ,Risk Factors ,Diabetes mellitus ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Longitudinal Studies ,Glycated Hemoglobin ,Type 1 diabetes ,business.industry ,medicine.disease ,030104 developmental biology ,Blood pressure ,Peripheral neuropathy ,Diabetes Mellitus, Type 1 ,Cardiovascular Diseases ,Cohort ,Multivariate Analysis ,Albuminuria ,Female ,medicine.symptom ,business ,Cohort study - Abstract
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive glucose control reduced the risk of developing diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). We evaluated multiple risk factors and phenotypes associated with DPN and CAN in this large, well-characterized cohort of participants with type 1 diabetes, followed for >23 years. DPN was defined by symptoms, signs, and nerve conduction study abnormalities in ≥2 nerves; CAN was assessed using standardized cardiovascular reflex tests. Generalized estimating equation models assessed the association of DPN and CAN with individual risk factors measured repeatedly. During DCCT/EDIC, 33% of participants developed DPN and 44% CAN. Higher mean HbA1c was the most significant risk factor for DPN, followed by older age, longer duration, greater height, macroalbuminuria, higher mean pulse rate, β-blocker use, and sustained albuminuria. The most significant risk factor for CAN was older age, followed by higher mean HbA1c, sustained albuminuria, longer duration of type 1 diabetes, higher mean pulse rate, higher mean systolic blood pressure, β-blocker use, estimated glomerular filtration rate
- Published
- 2019
47. 322-OR: Risk Factors for Peripheral and Cardiovascular Autonomic Neuropathy in Type 1 Diabetes: Thirty Years of Follow-Up in DCCT/EDIC
- Author
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Rose Gubitosi-Klug, Eva L. Feldman, James W. Albers, Rodica Pop-Busui, Maria F. Lopes-Virella, Barbara H. Braffett, Philip Raskin, Trevor J. Orchard, Neil H. White, and Catherine L. Martin
- Subjects
medicine.medical_specialty ,Type 1 diabetes ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.disease ,Blood pressure ,Peripheral neuropathy ,Internal medicine ,Diabetes mellitus ,Epidemiology ,Cohort ,Internal Medicine ,Medicine ,Microalbuminuria ,business ,Stroke - Abstract
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study reported that intensive glucose control as assessed by hemoglobin A1c (HbA1c) reduced the risk of diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) in type 1 diabetes (T1D), with long lasting benefits. We evaluated additional clinical parameters and risk factors that could contribute to the development of DPN and CAN in this cohort. DPN was assessed at three different times and defined as a composite of symptoms, signs, and abnormal nerve conduction studies in ≥2 nerves; CAN was assessed seven different times and defined based on R-R variation, Valsalva maneuver, and postural changes in blood pressure. Generalized estimating equation models were used to evaluate the association of DPN and CAN with individual risk factors over repeated time points spanning 30 years. Among 1,441 DCCT/EDIC participants, 32% developed DPN and 44% developed CAN. Higher mean HbA1c was the most significant risk factor for DPN (OR=1.56 per 1%, 95% CI 1.41,1.72). DPN was also associated with older age (1.43 per 5 years, 95% CI 1.31,1.55), longer duration of T1D, higher albuminuria, β-blocker use, higher mean diastolic blood pressure, and higher HbA1c at DCCT eligibility. CAN was associated (in order) with older age (1.51 per 5 years, 95% CI 1.40,1.63), longer duration of T1D (1.07 per 1 year, 95% CI 1.05,1.10), any sustained microalbuminuria (AER ≥30 mg/24 hour on two consecutive visits), higher mean HbA1c, higher mean and current pulse rate (likely as an indirect measure of CAN), higher mean systolic blood pressure, β-blocker use, any eGFR Disclosure B. Braffett: None. R. Gubitosi-Klug: None. J.W. Albers: Consultant; Self; Eli Lilly and Company. E.L. Feldman: None. C. Martin: None. N.H. White: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. M.F. Lopes-Virella: None. P. Raskin: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Gan & Lee Pharmaceuticals, Novo Nordisk A/S. R. Pop-Busui: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association. Funding Division of Diabetes Endocrinology & Metabolic Diseases (U01DK094176, U01DK094157); National Eye Institute; National Institute of Neurologic Disorders and Stroke; General Clinical Research Centers Program; Clinical Translational Science Center
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- 2019
48. 1321-P: Reduced Heart Rate Variability (HRV) in Young Adults with Youth-Onset Type 2 Diabetes (T2D) Is Related to Glycemic Control: The TODAY Study
- Author
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Neil H. White, Fida Bacha, Samuel S. Gidding, Amy S. Shah, Jeanie B. Tryggestad, Laure El Ghormli, Lorraine E. Katz, Ryan M. Farrell, Elaine M. Urbina, and Mary Ellen Vajravelu
- Subjects
medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Type 2 diabetes ,medicine.disease ,Metformin ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Heart rate variability ,Young adult ,Rosiglitazone ,business ,Complication ,medicine.drug ,Glycemic - Abstract
Cardiovascular autonomic neuropathy (CAN), a complication of T2D, affects the autonomic nerves innervating the heart and can adversely affect cardiac performance. Reduction in HRV is an early manifestation of CAN with parasympathetic loss preceding sympathetic dysfunction. Whether HRV is influenced by prior diabetes treatment or glycemic control in young adults with youth-onset T2D is not known. Heart beats over 10 minutes from an ECG were measured by Sphygmocor to derive the normal R-R intervals (NN intervals). HRV outcomes included: the standard deviation of the NN intervals (SDNN), the root mean square differences of the NN intervals (RMSSD), and the frequency domain low to high (LF:HF) power. TODAY participants (n=400) 7 y post-randomization (T2D duration 7.7±1.5 y) were compared to 133 obese controls without T2D. We assessed whether prior randomized treatment (metformin alone, metformin+ rosiglitazone or metformin+ intensive lifestyle) or glycemic control over time (time-weighted HbA1c) were associated with HRV. Compared to obese controls, TODAY subjects were younger (mean age 20.7±2.5 vs. 22.6±3.7 y) but not different by sex or BMI (35% male, BMI 36.6±8.1 kg/m2). TODAY participants had reduced overall HRV (SDNN; 57.9±29.6 vs. controls 67.1±25.4, p Young adults with youth-onset T2D show early manifestations of CAN with both parasympathetic and sympathetic impairments that are associated with higher HbA1c. Disclosure A.S. Shah: None. L. El Ghormli: None. F. Bacha: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, Pediatric Diabetes Consortium. Other Relationship; Self; AstraZeneca, Jaeb Center for Health Research. R.M. Farrell: Stock/Shareholder; Self; Tandem Diabetes Care. S. Gidding: Research Support; Self; Color Genomics. L.E. Katz: None. J.B. Tryggestad: None. M. Vajravelu: None. N.H. White: None. E.M. Urbina: None. Funding National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases
- Published
- 2019
49. 85-LB: A Phase 1b/2 Clinical Trial of Dantrolene Sodium in Patients with Wolfram Syndrome
- Author
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Kelly Kries, Stephen I. Stone, Gregory P. Van Stavern, Ashley N Simpson, Cris M. Brown, Bess A. Marshall, Robert C. Bucelli, Fumihiko Urano, Neil H. White, Damien Abreu, Toni S. Pearson, Lawrence Tychsen, Hongjie Gu, and Tamara Hershey
- Subjects
medicine.medical_specialty ,business.industry ,Wolfram syndrome ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Muscle relaxant ,Hypoglycemia ,medicine.disease ,Dantrolene Sodium ,Dantrolene ,Clinical trial ,Tolerability ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,business ,medicine.drug - Abstract
Wolfram syndrome is a rare, progressive neurodegenerative disorder characterized by juvenile-onset diabetes, optic nerve atrophy and mutation of the WFS1 gene. Calcium dyshomeostasis is a key mechanism underlying neuronal and pancreatic β-cell death and dysfunction in this endoplasmic reticulum (ER) disorder. Dantrolene sodium is an FDA-approved muscle relaxant that preserves ER calcium through inhibition of ryanodine receptor (RyR) activity. We therefore hypothesized that dantrolene could have therapeutic potential for Wolfram syndrome. Our preclinical studies showed that dantrolene improves β-cell and neuronal cell survival in mouse and induced pluripotent stem (iPS) cell models of Wolfram syndrome. To translate these findings to humans, we conducted the first clinical trial in 19 Wolfram syndrome patients through a 6-month phase 1b/2 study of dantrolene sodium with an optional extension phase up to 24-months (NCT02829268). The endpoints of this study were to assess: (1) dantrolene safety and tolerability in pediatric and adult Wolfram syndrome patients and (2) its effects on remaining β-cell, visual and neurologic functions and quality of life measures. Among pediatric subjects, dantrolene was well-tolerated at a daily dose of 0.5mg/kg in those < 50kg and 2mg/kg in those > 50kg. Adults tolerated dantrolene well at 50mg - 100mg daily. Common adverse events included mild fatigue, diarrhea, headache and hypoglycemia. A mild increase in 30-minute mixed-meal-stimulated C-peptide was observed in subjects after 6- and 12-months of dantrolene treatment. No significant changes were observed in visual or neurological functions or quality of life measures, although mild improvement in disease severity was noted by the Wolfram Unified Rating Scale. These findings suggest that dantrolene is safe for use in Wolfram syndrome at the specified doses and support further study of dantrolene in a randomized, placebo-controlled trial. Disclosure D. Abreu: None. T.S. Pearson: None. R.C. Bucelli: None. A. Simpson: None. C.M. Brown: None. K. Kries: None. H. Gu: None. S.I. Stone: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Speaker’s Bureau; Self; AbbVie Inc. L. Tychsen: None. G. Van Stavern: None. N.H. White: None. B.A. Marshall: None. T. Hershey: Research Support; Spouse/Partner; Sage Pharmaceuticals. F. Urano: Board Member; Self; Healthbeat. Research Support; Self; Aetas, Amylyx, JDRF, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Stock/Shareholder; Self; CytRx. Other Relationship; Self; Novus Biologicals. Funding National Institutes of Health (R21DK113487-02)
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- 2019
50. 1382-P: Impaired Default Mode Network Suppression and Compensatory Hyperactivation in Children with Type 1 Diabetes
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Michael Tansey, Kimberly Englert, Stuart A. Weinzimer, Gabby Tong, William V. Tamborlane, Paul K. Mazaika, Lara C. Foland-Ross, Allison Cato, Allan L. Reiss, Tandy Aye, Neil H. White, Tamara Hershey, Ana Maria Arbelaez, Darrell M. Wilson, Larry A. Fox, Bruce A. Buckingham, Eva Tsalikian, and Nelly Mauras
- Subjects
Brain activation ,Dorsum ,Type 1 diabetes ,medicine.medical_specialty ,Brain development ,business.industry ,Endocrinology, Diabetes and Metabolism ,Mean age ,medicine.disease ,Child health ,Spouse ,Internal Medicine ,medicine ,business ,Psychiatry ,Default mode network - Abstract
Background: The effect of dysglycemia on brain development and cognition is not well understood. Methods: In a multi-site study, we examined brain activation in 93 children with T1D (mean age 11.5 ± 1.8 years) and 57 nondiabetic children (mean age 11.8 ± 1.5 years) as they performed a classic executive function paradigm, the Go/No-Go task. Participants responded to letters flashed on a screen by a key press (Go) but not to the letter X (No-Go). Results: Despite similar task performance between the groups, children with T1D exhibited greater activation in executive control regions (dorsal anterior cingulate cortex, inferior frontal gyri, cerebellum and supramarginal gyri; p=0.010) and less suppression in the posterior node of the default mode network (DMN) compared to controls (p=0.006). Secondary analyses showed greater activation in executive control regions was associated in T1D with shorter response times and better parent-reported measures of executive function (ps Conclusion: These findings suggest that compensatory recruitment of executive control areas may act to offset T1D-related impairments in the DMN and, at least transiently, allow behavioral performance on Go/No-Go to be equivalent to that of nondiabetic controls. Disclosure L.C. Foland-Ross: None. B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Novo Nordisk Inc., Profusa, Inc. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Beta Bionics, ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Other Relationship; Self; Insulet Corporation, Tandem Diabetes Care. N. Mauras: Consultant; Self; Novo Nordisk Inc., PicoLife. Research Support; Self; Medtronic MiniMed, Inc. A. Arbelaez: None. N.H. White: None. T. Aye: None. D.M. Wilson: Advisory Panel; Self; Tolerion, Inc. Research Support; Self; Beta Bionics, Dexcom, Inc., Medtronic. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. S.A. Weinzimer: Consultant; Self; Eli Lilly and Company, Sanofi. Consultant; Spouse/Partner; Tandem Diabetes Care. Consultant; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Insulet Corporation, Medtronic MiniMed, Inc., Tandem Diabetes Care. Stock/Shareholder; Self; InsuLine Medical Ltd. E. Tsalikian: None. M. Tansey: Advisory Panel; Self; Daiichi Sankyo Company, Limited. A. Cato: None. T. Hershey: Research Support; Spouse/Partner; Sage Pharmaceuticals. L.A. Fox: None. G. Tong: None. K.A. Englert: Consultant; Self; PicoLife Technologies, LLC. P. Mazaika: None. A.L. Reiss: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (DIRECNET: U01HD-41906, HD-41908, HD-41915, HD-41918, HD-56526, R01HD078463, U54HD087011; National Center for Advancing Translational Sciences (UL1TR000448)
- Published
- 2019
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