Endocrine System Diseases Commons^™

Metabolic Cell Death In Cancer: Ferroptosis, Cuproptosis, Disulfidptosis, And Beyond, Chao Mao, Min Wang, Li Zhuang, Boyi Gan

Faculty, Staff and Student Publications

Cell death resistance represents a hallmark of cancer. Recent studies have identified metabolic cell death as unique forms of regulated cell death resulting from an imbalance in the cellular metabolism. This review discusses the mechanisms of metabolic cell death-ferroptosis, cuproptosis, disulfidptosis, lysozincrosis, and alkaliptosis-and explores their potential in cancer therapy. Our review underscores the complexity of the metabolic cell death pathways and offers insights into innovative therapeutic avenues for cancer treatment.

Safety Of Treating Acute Pulmonary Embolism At Home: An Individual Patient Data Meta-Analysis, Dieuwke Luijten, Delphine Douillet, Kim Luijken, Cecile Tromeur, Andrea Penaloza, Olivier Hugli, Drahomir Aujesky, Stefano Barco, Joseph R Bledsoe, Kyle E Chang, Francis Couturaud, Paul L Den Exter, Carme Font, Menno V Huisman, David Jimenez, Christopher Kabrhel, Jeffrey A Kline, Stavros Konstantinides, Thijs Van Mens, Remedios Otero, W Frank Peacock, Olivier Sanchez, William B Stubblefield, Luca Valerio, David R Vinson, Philip Wells, Maarten Van Smeden, Pierre-Marie Roy, Frederikus A Klok

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Home treatment is considered safe in acute pulmonary embolism (PE) patients selected by a validated triage tool (e.g. simplified PE severity index score or Hestia rule), but there is uncertainty regarding the applicability in underrepresented subgroups. The aim was to evaluate the safety of home treatment by performing an individual patient-level data meta-analysis.

METHODS: Ten prospective cohort studies or randomized controlled trials were identified in a systematic search, totalling 2694 PE patients treated at home (discharged within 24 h) and identified by a predefined triage tool. The 14- and 30-day incidences of all-cause mortality and adverse events …

Junctophilin-2 Regulates Mitochondrial Metabolism, Sasha Z Prisco, Lynn M Hartweck, Felipe Kazmirczak, Jenna B Mendelson, Stephanie L Deng, Madelyn Blake, Satadru K Lahiri, Xander H T Wehrens, Kurt W Prins

Faculty, Staff and Students Publications

No abstract provided.

Population-Level Trends In Self-Reported Healthcare Utilization Among Older Adults In Mexico With And Without Cognitive Impairment, José Eduardo Cabrero Castro, Rebeca Wong, Rafael Samper Ternent, Brian Downer

Faculty, Staff and Student Publications

BACKGROUND: Older adults with cognitive impairment exhibit different patterns of healthcare utilization compared to their cognitively healthy counterparts. Despite extensive research in high-income countries, similar studies in low- and middle-income countries are lacking. This study aims to investigate the population-level patterns in healthcare utilization among older adults with and without cognitive impairment in Mexico.

METHODS: Data came from five waves (2001-2018) of the Mexican Health and Aging Study. We used self-reported measures for one or more over-night hospital stays, doctor visits, visits to homeopathic doctors, and dental visits in the past year; seeing a pharmacist in the past year; and …

Lipid Droplet-Associated Hydrolase Mobilizes Stores Of Liver X Receptor Sterol Ligands And Protects Against Atherosclerosis, Young-Hwa Goo, Janeesh Plakkal Ayyappan, Francis D Cheeran, Sushant Bangru, Pradip K Saha, Paula Baar, Sabine Schulz, Todd A Lydic, Bernhard Spengler, Andreas H Wagner, Auinash Kalsotra, Vijay K Yechoor, Antoni Paul

Faculty, Staff and Students Publications

Foam cells in atheroma are engorged with lipid droplets (LDs) that contain esters of regulatory lipids whose metabolism remains poorly understood. LD-associated hydrolase (LDAH) has a lipase structure and high affinity for LDs of foam cells. Using knockout and transgenic mice of both sexes, here we show that LDAH inhibits atherosclerosis development and promotes stable lesion architectures. Broad and targeted lipidomic analyzes of primary macrophages and comparative lipid profiling of atheroma identified a broad impact of LDAH on esterified sterols, including natural liver X receptor (LXR) sterol ligands. Transcriptomic analyzes coupled with rescue experiments show that LDAH modulates the expression …

Effect Of Semaglutide On Regression And Progression Of Glycemia In People With Overweight Or Obesity But Without Diabetes In The Select Trial, Steven E Kahn, John E Deanfield, Ole Kleist Jeppesen, Scott S Emerson, Trine Welløv Boesgaard, Helen M Colhoun, Robert F Kushner, Ildiko Lingvay, Bartolome Burguera, Grzegorz Gajos, Deborah Bade Horn, Irene M Hramiak, Ania M Jastreboff, Alexander Kokkinos, Michael Maeng, Ana Laura S A Matos, Francisco J Tinahones, A Michael Lincoff, Donna H Ryan, Select Trial Investigators

Faculty, Staff and Student Publications

OBJECTIVE: To determine whether semaglutide slows progression of glycemia in people with cardiovascular disease and overweight or obesity but without diabetes.

RESEARCH DESIGN AND METHODS: In a multicenter, double-blind trial, participants aged ≥45 years, with BMI ≥27 kg/m2, and with preexisting cardiovascular disease but without diabetes (HbA1c

RESULTS: Of 17,604 participants, 8,803 were assigned to semaglutide and 8,801 to placebo. Mean ± SD intervention exposure was 152 ± 56 weeks and follow-up 176 ± 40 weeks. In both treatment arms mean nadir HbA1c for participants was at 20 weeks. Thereafter, HbA1c increased similarly in both arms, with a mean difference …

Voices Of Wisdom: Geriatric Interviews On Self-Management Of Type 2 Diabetes In The United States-A Systematic Review And Metasynthesis, David F Lo, Ahmed Gawash, Kunal P Shah, Jasmine Emanuel, Brandon Goodwin, Don D Shamilov, Gaurav Kumar, Nathan Jean, Christian P White

Rowan-Virtua School of Osteopathic Medicine Departmental Research

This review is aimed at unraveling the intricacies of diabetic self-management among geriatric people, drawing on current insights and understanding the complex paths geriatric people navigate. A wide search was conducted in health-oriented databases, including CINAHL, Embase, PsycINFO, MEDLINE, PubMed, Web of Science, and Cochrane Library, while gray literature was excluded. The search combined keywords and subject headings, focusing on the geriatric population, diabetes, self-management, and qualitative research. A three-tiered screening process was employed, with titles and then abstracts initially reviewed. Full-text analysis followed, with disagreements resolved among reviewers. In total, there were 248 participants included across these eight studies. …

Depressive Symptoms Are Associated With C-Reactive Protein In Older Adults With Obesity, Henry D Heisey, Clifford Qualls, Dennis T Villareal, Martha Belen Segoviano-Escobar, Maria Liza Duremdes Nava, Jennifer R Gatchel, Mark E Kunik

Faculty, Staff and Students Publications

OBJECTIVES: To test the hypothesis that depressive symptoms vary with high-sensitivity C-reactive protein (hs-CRP), among older adults with obesity.

METHODS: This was a cross-sectional, secondary analysis of baseline data from two related lifestyle intervention trials. The study sample comprises 148 consecutively recruited, community-dwelling older adults (age >=65 years) without severe psychiatric illness and with body mass index >=30 kg/m

RESULTS: Sample mean GDS score was 2.7 (SD 3.0, range 0 - 14). A significant multivariate model of GDS scores (R

CONCLUSIONS: In older adults with obese BMI, male sex and higher hs-CRP are associated with depression, even in a group …

Long-Term Weight Loss Effects Of Semaglutide In Obesity Without Diabetes In The Select Trial, Donna H Ryan, Ildiko Lingvay, John Deanfield, Steven E Kahn, Eric Barros, Bartolome Burguera, Helen M Colhoun, Cintia Cercato, Dror Dicker, Deborah B Horn, G Kees Hovingh, Ole Kleist Jeppesen, Alexander Kokkinos, A Michael Lincoff, Sebastian M Meyhöfer, Tugce Kalayci Oral, Jorge Plutzky, André P Van Beek, John P H Wilding, Robert F Kushner

Faculty, Staff and Student Publications

In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (-10.2%), waist circumference (-7.7 cm) and waist-to-height ratio (-6.9%) versus placebo (-1.5%, -1.3 cm and -1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events. For each BMI category (

Spatiotemporal Analysis Of Hpv Vaccination And Associated Neighborhood-Level Disparities In Texas-An Ecological Study, Ryan Ramphul, Abigail S Zamorano, Saswati Upadhyay, Manali Desai, Cici Bauer

Faculty, Staff and Student Publications

BACKGROUND: HPV is responsible for most cervical, oropharyngeal, anal, vaginal, and vulvar cancers. The HPV vaccine has decreased cervical cancer incidence, but only 49% of Texas adolescents have initiated the vaccine. Texas shows great variation in HPV vaccination rates. We used geospatial analysis to identify areas with high and low vaccination rates and explored differences in neighborhood characteristics.

METHODS: Using Anselin's Local Moran's I statistic, we conducted an ecological analysis of hot and cold spots of adolescent HPV vaccination coverage in Texas from 2017 to 2021. Next, we utilized a Mann-Whitney U test to compare neighborhood characteristics of vaccination coverage …

Time-To-Event Genome-Wide Association Study For Incident Cardiovascular Disease In People With Type 2 Diabetes, Soo Heon Kwak, Ryan B Hernandez-Cancela, Daniel A Dicorpo, David E Condon, Jordi Merino, Peitao Wu, Jennifer A Brody, Jie Yao, Xiuqing Guo, Fariba Ahmadizar, Mariah Meyer, Murat Sincan, Josep M Mercader, Sujin Lee, Jeffrey Haessler, Ha My T Vy, Zhaotong Lin, Nicole D Armstrong, Shaopeng Gu, Noah L Tsao, Leslie A Lange, Ningyuan Wang, Kerri L Wiggins, Stella Trompet, Simin Liu, Ruth J F Loos, Renae Judy, Philip H Schroeder, Natalie R Hasbani, Maxime M Bos, Alanna C Morrison, Rebecca D Jackson, Alexander P Reiner, Joann E Manson, Ninad S Chaudhary, Lynn K Carmichael, Yii-Der Ida Chen, Kent D Taylor, Mohsen Ghanbari, Joyce Van Meurs, Achilleas N Pitsillides, Bruce M Psaty, Raymond Noordam, Ron Do, Kyong Soo Park, J Wouter Jukema, Maryam Kavousi, Adolfo Correa, Stephen S Rich, Scott M Damrauer, Catherine Hajek, Nam H Cho, Marguerite R Irvin, James S Pankow, Girish N Nadkarni, Robert Sladek, Mark O Goodarzi, Jose C Florez, Daniel I Chasman, Susan R Heckbert, Charles Kooperberg, Josée Dupuis, Rajeev Malhotra, Paul S De Vries, Ching-Ti Liu, Jerome I Rotter, James B Meigs

Faculty, Staff and Student Publications

Objective: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D).

Research design and methods: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD.

Results: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near …

The Long-Term Effects Of Blood Urea Nitrogen Levels On Cardiovascular Disease And All-Cause Mortality In Diabetes: A Prospective Cohort Study, Hongfang Liu, Xiaoqin Xin, Jinghui Gan, Jungao Huang

Faculty, Staff and Student Publications

BACKGROUND: The long-term effects of blood urea nitrogen(BUN) in patients with diabetes remain unknown. Current studies reporting the target BUN level in patients with diabetes are also limited. Hence, this prospective study aimed to explore the relationship of BUN with all-cause and cardiovascular mortalities in patients with diabetes.

METHODS: In total, 10,507 participants with diabetes from the National Health and Nutrition Examination Survey (1999-2018) were enrolled. The causes and numbers of deaths were determined based on the National Death Index mortality data from the date of NHANES interview until follow-up (December 31, 2019). Multivariate Cox proportional hazard regression models were …

High All-Cause Mortality And Increasing Proportion Of Older Adults With Tuberculosis In Texas, 2008–2020, Belinda A Medrano, Miryoung Lee, Gretchen Gemeinhardt, Lana Yamba, Blanca I Restrepo

Faculty, Staff and Student Publications

Pulmonary tuberculosis (PTB) elimination efforts must consider the global growth of the ageing population. Here we used TB surveillance data from Texas, United States (2008-2020; total n = 10656) to identify unique characteristics and outcomes in older adults (OA, ≥65 years) with PTB, compared to young adults (YA, 18-39 years) or middle-aged adults (40-64 years). We found that the proportion of OA with PTB increased from 15% in 2008 to 24% in 2020 (trend p < 0.05). Diabetes was highly prevalent in OA (32%) but not associated with adverse outcomes. Death was 13-fold higher in OA compared to YA and was 7% at the time of diagnosis which suggests diagnostic delays. However, once TB was suspected, we found no differences in culture, smear, or nucleic acid detection of mycobacteria (although less lung cavitations) in OA. During treatment, OA had less drug-resistant TB, few adverse reactions and adhered with TB treatment. We recommend training healthcare workers to 'think TB' in OA, for prompt treatment initiation to diminish deaths. Furthermore, OA should be added as a priority group to the latent TB treatment guidelines by the World Health Organization, to prevent TB disease in this highly vulnerable group.

Towards A Remote Patient Monitoring Platform For Comprehensive Risk Evaluations For People With Diabetic Foot Ulcers, Gozde Cay, M G Finco, Jason Garcia, Jill L Mcnitt-Gray, David G Armstrong, Bijan Najafi

Center on Aging Staff Publications

Diabetic foot ulcers (DFUs) significantly affect the lives of patients and increase the risk of hospital stays and amputation. We suggest a remote monitoring platform for better DFU care. This system uses digital health metrics (scaled from 0 to 10, where higher scores indicate a greater risk of slow healing) to provide a comprehensive overview through a visual interface. The platform features smart offloading devices that capture behavioral metrics such as offloading adherence, daily steps, and cadence. Coupled with remotely measurable frailty and phenotypic metrics, it offers an in-depth patient profile. Additional demographic data, characteristics of the wound, and clinical …

Endotrophin, A Key Marker And Driver For Fibroinflammatory Disease, Kim Henriksen, Federica Genovese, Alexander Reese-Petersen, Laurent P Audoly, Kai Sun, Morten A Karsdal, Philipp E Scherer

Faculty, Staff and Student Publications

Our overview covers several key areas related to recent results obtained for collagen type VI and endotrophin (ETP). (1) An introduction to the history of ETP, including how it was identified, how it is released, and its function and potential receptors. (2) An introduction to the collagen family, with a focus on what differentiates collagen type VI from an evolutionary standpoint. (3) An overview of collagen type VI, the 6 individual chains (COL6A1, A2, A3, A4, A5, and A6), their differences and similarities, as well as their expression profiles and function. (4) A detailed analysis of COL6A3, including the cleaved …

Maternal Diabetes And Intrapartum Fetal Electrocardiogram, Beth A Plunkett, Steven J Weiner, George R Saade, Michael A Belfort, Sean C Blackwell, John M Thorp, Alan T N Tita, Russell S Miller, David S Mckenna, Edward K S Chien, Dwight J Rouse, Yasser Y El-Sayed, Yoram Sorokin, Steve N Caritis, Eunice Kennedy Shriver National Institute Of Child Health And Human Development Maternal-Fetal Medicine Units (Mfmu) Network

Faculty, Staff and Student Publications

Objective:

Fetal electrocardiogram (ECG) ST-changes are associated with fetal cardiac hypoxia. Our objective was to evaluate ST-changes by maternal diabetic status and stage of labor.

Methods:

Secondary analysis of a multi-centered randomized-controlled trial in which laboring patients with singleton gestations underwent fetal ECG scalp electrode placement and were randomly assigned to masked or unmasked ST-segment readings. Our primary outcome was the frequency of fetal ECG tracings with ST-changes by stage of labor. ECG tracings were categorized into mutually exclusive groups (ST-depression, ST-elevation without ST-depression or no ST-changes). We compared participants with pre-gestational diabetes mellitus (DM), gestational DM (GDM), and no …

An Estrogen Receptor Α-Derived Peptide Improves Glucose Homeostasis During Obesity, Wanbao Yang, Wen Jiang, Wang Liao, Hui Yan, Weiqi Ai, Quan Pan, Wesley A Brashear, Yong Xu, Ling He, Shaodong Guo

Faculty, Staff and Students Publications

Estrogen receptor α (ERα) plays a crucial role in regulating glucose and energy homeostasis during type 2 diabetes mellitus (T2DM). However, the underlying mechanisms remain incompletely understood. Here we find a ligand-independent effect of ERα on the regulation of glucose homeostasis. Deficiency of ERα in the liver impairs glucose homeostasis in male, female, and ovariectomized (OVX) female mice. Mechanistic studies reveal that ERα promotes hepatic insulin sensitivity by suppressing ubiquitination-induced IRS1 degradation. The ERα 1-280 domain mediates the ligand-independent effect of ERα on insulin sensitivity. Furthermore, we identify a peptide based on ERα 1-280 domain and find that ERα-derived peptide …

Inaccurate Diagnosis Of Diabetes Type In Youth: Prevalence, Characteristics, And Implications, Mustafa Tosur, Xiaofan Huang, Audrey S Inglis, Rebecca Schneider Aguirre, Maria J Redondo

Faculty, Staff and Students Publications

Classifying diabetes at diagnosis is crucial for disease management but increasingly difficult due to overlaps in characteristics between the commonly encountered diabetes types. We evaluated the prevalence and characteristics of youth with diabetes type that was unknown at diagnosis or was revised over time. We studied 2073 youth with new-onset diabetes (median age [IQR] = 11.4 [6.2] years; 50% male; 75% White, 21% Black, 4% other race; overall, 37% Hispanic) and compared youth with unknown versus known diabetes type, per pediatric endocrinologist diagnosis. In a longitudinal subcohort of patients with data for ≥ 3 years post-diabetes diagnosis (n = 1019), …

Combined Deletion Of Men1, Atrx And Pten Triggers Development Of High-Grade Pancreatic Neuroendocrine Tumors In Mice, Mary Esmeralda Fuentes, Xiaoyin Lu, Natasha M Flores, Simone Hausmann, Pawel K Mazur

Faculty, Staff and Student Publications

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of tumors that exhibit an unpredictable and broad spectrum of clinical presentations and biological aggressiveness. Surgical resection is still the only curative therapeutic option for localized PanNET, but the majority of patients are diagnosed at an advanced and metastatic stage with limited therapeutic options. Key factors limiting the development of new therapeutics are the extensive heterogeneity of PanNETs and the lack of appropriate clinically relevant models. In that context, genomic sequencing of human PanNETs revealed recurrent mutations and structural alterations in several tumor suppressors. Here, we demonstrated that combined loss of MEN1, …

The Stress Of Measuring Plantar Tissue Stress In People With Diabetes-Related Foot Ulcers: Biomechanical And Feasibility Findings From Two Prospective Cohort Studies, Chantal M Hulshof, Madelyn Page, Sjef G Van Baal, Sicco A Bus, Malindu E Fernando, Lisette Van Gemert-Pijnen, Kilian D R Kappert, Scott Lucadou-Wells, Bijan Najafi, Jaap J Van Netten, Peter A Lazzarini

Center on Aging Staff Publications

Reducing high mechanical stress is imperative to heal diabetes-related foot ulcers. We explored the association of cumulative plantar tissue stress (CPTS) and plantar foot ulcer healing, and the feasibility of measuring CPTS, in two prospective cohort studies (Australia (AU) and The Netherlands (NL)). Both studies used multiple sensors to measure factors to determine CPTS: plantar pressures, weight-bearing activities, and adherence to offloading treatments, with thermal stress response also measured to estimate shear stress in the AU-study. The primary outcome was ulcer healing at 12 weeks. Twenty-five participants were recruited: 13 in the AU-study and 12 in the NL-study. CPTS data …

Cardiovascular Disease Management With Sodium-Glucose Cotransporter-2 Inhibitors In Patients With Type 2 Diabetes: A Cardiology Primer, Allan Zhang, Ramsey Kalil, Alexander Marzec, Stephanie A Coulter, Salim Virani, Kershaw V Patel, Matthew W Segar

Faculty, Staff and Students Publications

Patients with type 2 diabetes face an elevated risk of cardiovascular disease. This review centers on sodium-glucose cotransporter-2 (SGLT2) inhibitors, a class of drugs that, according to a growing body of evidence, may have major potential for managing cardiovascular disease in patients with type 2 diabetes. This review presents findings from multiple clinical trials suggesting that SGLT2 inhibitors can not only serve as preventive therapeutic agents but also play a role in the active management of heart failure. The discussion includes the mechanism of action of SGLT2 inhibitors, emphasizing that they enhance urinary glucose excretion, which could lead to improved …

Single-Cell Analysis Of Age-Related Changes In Leukocytes Of Diabetic Mouse Hindpaws, James M Nichols, Hoang Vu Pham, Eric F Lee, Rajasekaran Mahalingam, Andrew J Shepherd

Faculty, Staff and Student Publications

Complications associated with Type 1 and Type 2 diabetes, such as diabetic peripheral neuropathy and diabetic foot ulcers, are a growing health-care concern. In addition, this concern increases as diabetic patients age due to their increased susceptibility to complications. To address this growing problem, it is important to understand fluctuations in physiology which lead to pathological changes associated with the metabolic disturbances of diabetes. Our study explores dysregulation of immune cell populations in the hindpaws of healthy and diabetic mice at 12 and 21 weeks of age using single-cell RNA sequencing to provide insight into immune disruptions occurring in the …

Adipose Tissue Dysfunction And Energy Balance Paradigms In People Living With Hiv, Claudia E Ramirez Bustamante, Neeti Agarwal, Aaron R Cox, Sean M Hartig, Jordan E Lake, Ashok Balasubramanyam

Faculty, Staff and Students Publications

Over the past 4 decades, the clinical care of people living with HIV (PLWH) evolved from treatment of acute opportunistic infections to the management of chronic, noncommunicable comorbidities. Concurrently, our understanding of adipose tissue function matured to acknowledge its important endocrine contributions to energy balance. PLWH experience changes in the mass and composition of adipose tissue depots before and after initiating antiretroviral therapy, including regional loss (lipoatrophy), gain (lipohypertrophy), or mixed lipodystrophy. These conditions may coexist with generalized obesity in PLWH and reflect disturbances of energy balance regulation caused by HIV persistence and antiretroviral therapy drugs. Adipocyte hypertrophy characterizes visceral …

Diabetes Study Of Children Of Diverse Ethnicity And Race: Study Design, Maria J Redondo, Kylie K Harrall, Deborah H Glueck, Mustafa Tosur, Serife Uysal, Andrew Muir, Elizabeth G Atkinson, Melanie R Shapiro, Liping Yu, William E Winter, Michael Weedon, Todd M Brusko, Richard Oram, Kendra Vehik, William Hagopian, Mark A Atkinson, Dana Dabelea, Discover Study Group

Faculty, Staff and Students Publications

AIMS: Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)-supported multicenter, prospective, observational study that enrols children and adolescents with non-secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth.

MATERIALS AND METHODS: The proposed models will evaluate the utility of three existing T1D genetic risk scores in combination with data on …

Efficacy Of A Primary Care Ehealth Obesity Treatment Pilot Intervention Developed For Vulnerable Pediatric Patients, Joshua S Yudkin, Marlyn A Allicock, Folefac D Atem, Carol A Galeener, Sarah E Messiah, Sarah E Barlow

Faculty, Staff and Student Publications

Background:

Challenges to treat excess weight in primary care settings include time constraints during encounters and barriers to multiple visits for patient families, especially those from vulnerable backgrounds. Dynamo Kids! (DK), a bilingual (English/Spanish) e-health intervention, was created to address these system-level challenges. This pilot study assessed the effect of DK use on parent-reported healthy habits and child BMI.

Methods:

In this 3-month, quasi-experimental cohort design, DK was offered to parents with children aged 6–12 years with BMI ≥85th percentile in three public primary care sites in Dallas, Texas. DK included three educational modules, one tracking tool, recipes, and links …

Genetic Drivers Of Heterogeneity In Type 2 Diabetes Pathophysiology, Ken Suzuki, Konstantinos Hatzikotoulas, Lorraine Southam, Henry J Taylor, Xianyong Yin, Kim M Lorenz, Ravi Mandla, Alicia Huerta-Chagoya, Giorgio E M Melloni, Stavroula Kanoni, Nigel W Rayner, Ozvan Bocher, Ana Luiza Arruda, Kyuto Sonehara, Shinichi Namba, Simon S K Lee, Michael H Preuss, Lauren E Petty, Philip Schroeder, Brett Vanderwerff, Mart Kals, Fiona Bragg, Kuang Lin, Xiuqing Guo, Weihua Zhang, Jie Yao, Young Jin Kim, Mariaelisa Graff, Fumihiko Takeuchi, Jana Nano, Amel Lamri, Masahiro Nakatochi, Sanghoon Moon, Robert A Scott, James P Cook, Jung-Jin Lee, Ian Pan, Daniel Taliun, Esteban J Parra, Jin-Fang Chai, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Gudmar Thorleifsson, Niels Grarup, Tamar Sofer, Matthias Wuttke, Chloé Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Soo-Heon Kwak, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Suraj S Nongmaithem, Raymond Noordam, Victor J Y Lim, Claudia H T Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Jennifer A Brody, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, K Alaine Broadaway, Alice Williamson, Zoha Kamali, Jinrui Cui, Manonanthini Thangam, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Tarunveer S Ahluwalia, Sonia S Anand, Alain Bertoni, Jette Bork-Jensen, Ivan Brandslund, Thomas A Buchanan, Charles F Burant, Adam S Butterworth, Mickaël Canouil, Juliana C N Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, John Danesh, Swapan K Das, H Janaka De Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Penny Gordon-Larsen, Myron Gross, Lindsay A Guare, Sophie Hackinger, Liisa Hakaste, Sohee Han, Andrew T Hattersley, Christian Herder, Momoko Horikoshi, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Torben Jørgensen, Frederick K Kamanu, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Kyung Min Lee, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian'an Luan, Andrea O Luk, Xi Luo, Jun Lv, Julie A Lynch, Valeriya Lyssenko, Shiro Maeda, Vasiliki Mamakou, Sohail Rafik Mansuri, Koichi Matsuda, Thomas Meitinger, Olle Melander, Andres Metspalu, Huan Mo, Andrew D Morris, Filipe A Moura, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Snehal Patil, Pei Pei, Mark A Pereira, Annette Peters, Fraser J Pirie, Hannah G Polikowsky, Bianca Porneala, Gauri Prasad, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Kevin Sandow, Alagu Sankareswaran, Naveed Sattar, Sebastian Schönherr, Mohammad Shahriar, Botong Shen, Jinxiu Shi, Dong Mun Shin, Nobuhiro Shojima, Jennifer A Smith, Wing Yee So, Alena Stančáková, Valgerdur Steinthorsdottir, Adrienne M Stilp, Konstantin Strauch, Kent D Taylor, Barbara Thorand, Unnur Thorsteinsdottir, Brian Tomlinson, Tam C Tran, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M Van Dam, Jan B Van Klinken, Rohit Varma, Niels Wacher-Rodarte, Eleanor Wheeler, Ananda R Wickremasinghe, Ko Willems Van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Kenichi Yamamoto, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Matthew Zawistowski, Liang Zhang, Wei Zheng, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Myriam Fornage, Craig L Hanis, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Mitsuhiro Yokota, Sharon L R Kardia, Patricia A Peyser, James S Pankow, James C Engert, Amélie Bonnefond, Philippe Froguel, James G Wilson, Wayne H H Sheu, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald C W Ma, Tien-Yin Wong, Dennis O Mook-Kanamori, Tiinamaija Tuomi, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Yii-Der Ida Chen, Stephen S Rich, Roberta Mckean-Cowdin, Harald Grallert, Ching-Yu Cheng, Mohsen Ghanbari, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Donald W Bowden, Colin N A Palmer, Jaspal S Kooner, Charles Kooperberg, Simin Liu, Kari E North, Danish Saleheen, Torben Hansen, Oluf Pedersen, Nicholas J Wareham, Juyoung Lee, Bong-Jo Kim, Iona Y Millwood, Robin G Walters, Kari Stefansson, Emma Ahlqvist, Mark O Goodarzi, Karen L Mohlke, Claudia Langenberg, Christopher A Haiman, Ruth J F Loos, Jose C Florez, Daniel J Rader, Marylyn D Ritchie, Sebastian Zöllner, Reedik Mägi, Nicholas A Marston, Christian T Ruff, David A Van Heel, Sarah Finer, Joshua C Denny, Toshimasa Yamauchi, Takashi Kadowaki, John C Chambers, Maggie C Y Ng, Xueling Sim, Jennifer E Below, Philip S Tsao, Kyong-Mi Chang, Mark I Mccarthy, James B Meigs, Anubha Mahajan, Cassandra N Spracklen, Josep M Mercader, Michael Boehnke, Jerome I Rotter, Marijana Vujkovic, Benjamin F Voight, Andrew P Morris, Eleftheria Zeggini

Faculty, Staff and Student Publications

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Endocrine-Sensitive Disease Rate In Postmenopausal Patients With Estrogen Receptor-Rich/Erbb2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, Or Their Combination: A Phase 3 Randomized Clinical Trial, Cynthia X Ma, Vera J Suman, Souzan Sanati, Kiran Vij, Meenakshi Anurag, A Marilyn Leitch, Gary W Unzeitig, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard A Gibbs, Mark A Watson, Travis J Dockter, Olwen Hahn, Joseph M Guenther, Abigail Caudle, Erika Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Mothaffar F Rimawi, Anna Weiss, Eric P Winer, Kelly K Hunt, Charles M Perou, Matthew J Ellis, Ann H Partridge, Lisa A Carey

Faculty, Staff and Students Publications

IMPORTANCE: Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)-positive/ERBB2 (formerly HER2)-negative breast cancer. However, the combination has not been tested in early-stage disease.

OBJECTIVE: To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone.

DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or …

Fluvoxamine Inhibits Th1 And Th17 Polarization And Function By Repressing Glycolysis To Attenuate Autoimmune Progression In Type 1 Diabetes, Yuan Zou, Jing Zhang, Fei Sun, Qianqian Xu, Longmin Chen, Xi Luo, Ting Wang, Qing Zhou, Shu Zhang, Fei Xiong, Wen Kong, Ping Yang, Qilin Yu, Shiwei Liu, Cong-Yi Wang

Faculty, Staff and Student Publications

BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed.

METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune …

Gestational Diabetes Augments Group B Streptococcus Infection By Disrupting Maternal Immunity And The Vaginal Microbiota, Vicki Mercado-Evans, Marlyd E Mejia, Jacob J Zulk, Samantha Ottinger, Zainab A Hameed, Camille Serchejian, Madelynn G Marunde, Clare M Robertson, Mallory B Ballard, Simone H Ruano, Natalia Korotkova, Anthony R Flores, Kathleen A Pennington, Kathryn A Patras

Faculty, Staff and Student Publications

Group B Streptococcus (GBS) is a pervasive perinatal pathogen, yet factors driving GBS dissemination in utero are poorly defined. Gestational diabetes mellitus (GDM), a complication marked by dysregulated immunity and maternal microbial dysbiosis, increases risk for GBS perinatal disease. Using a murine GDM model of GBS colonization and perinatal transmission, we find that GDM mice display greater GBS in utero dissemination and subsequently worse neonatal outcomes. Dual-RNA sequencing reveals differential GBS adaptation to the GDM reproductive tract, including a putative glycosyltransferase (yfhO), and altered host responses. GDM immune disruptions include reduced uterine natural killer cell activation, impaired recruitment to placentae, …

Preparing Community Health Workers To Empower Latino(A)S With Diabetes: A Real-World Implementation Study, Laura Porterfield, Zuleica Santiago Delgado, Premal G Patel, Michael L Goodman, Kendall M Campbell, Elizabeth M Vaughan

Faculty, Staff and Students Publications

Purpose: The purpose of the study was to evaluate the delivery of diabetes self-management education (DSME) to Latino(a) adults by community health workers (CHWs).

Methods: Investigators developed an evidence-based, bilingual (Spanish/English) diabetes education curriculum and trained 10 CHWs on its content. CHWs then implemented the curriculum in 6-month diabetes group visit programs for low-income Latino(a)s with type 2 diabetes in nonacademic 501(c)3 community clinics. Investigators evaluated efficacy of the training through successful implementation, measured by participant group visit acceptance and attendance.

Results: Participants (n = 70) reported high levels of program satisfaction (3.8/4.0), improvement in quality of life (9.7/10), meeting …