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Introduction Type 2 diabetes mellitus (T2DM) is a powerful risk factor for cardiovascular disease (CVD), conferring a greater relative risk in women than men. We sought to examine sex differences in cardiometabolic risk factors and management in the contemporary cohort represented by the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).Research design and methods GRADE enrolled 5047 participants (1837 women, 3210 men) with T2DM on metformin monotherapy at baseline. The current report is a cross-sectional analysis of baseline data collected July 2013 to August 2017.Results Compared with men, women had a higher mean body mass index (BMI), greater prevalence of severe obesity (BMI≥40 kg/m2), higher mean LDL cholesterol, greater prevalence of low HDL cholesterol, and were less likely to receive statin treatment and achieve target LDL, with a generally greater prevalence of these risk factors in younger women. Women with hypertension were equally likely to achieve blood pressure targets as men; however, women were less likely to receive ACE inhibitors or angiotensin receptor blockers. Women were more likely to be divorced, separated or widowed, and had fewer years of education and lower incomes.Conclusions This contemporary cohort demonstrates that women with T2DM continue to have a greater burden of cardiometabolic and socioeconomic risk factors than men, particularly younger women. Attention to these persisting disparities is needed to reduce the burden of CVD in women.Trial registration number ClinicalTrials.gov (NCT01794143)

Introduction The shape of the glucose curve during an oral glucose tolerance test (OGTT) reflects β-cell function in populations without diabetes but has not been as well studied in those with diabetes. A monophasic shape has been associated with higher risk of diabetes, while a biphasic pattern has been associated with lower risk. We sought to determine if phenotypic or metabolic characteristics were associated with glucose response curve shape in adults with type 2 diabetes treated with metformin alone.Research design and methods This is a cross-sectional analysis of 3108 metformin-treated adults with type 2 diabetes diagnosed

Objective: To determine whether the relationship between average glucose (AG) levels and hemoglobin A1c (HbA1c) differs across racial/ethnic groups., Research Design and Methods: We performed a prospective substudy of GRADE, a comparative effectiveness randomized trial conducted in 36 centers in the U.S. A total of 1,454 of the 5,047 participants in the GRADE cohort, including 534 non-Hispanic White (NHW), 389 non-Hispanic Black (NHB), and 327 Hispanic White patients and 204 patients of other racial/ethnic backgrounds, were included in the substudy. Continuous glucose monitoring (CGM) performed for 10 days was used to calculate AG10. Immediately after CGM, HbA1c and glycated albumin were measured. Fasting plasma glucose (FPG) and glucose area under the curve (AUC) were derived from a 75-g oral glucose tolerance test., Results: The relationship between AG10 and HbA1c was significantly different for NHB compared with NHW patients and those of other racial/ethnic groups. HbA1c levels were 0.2-0.6 percentage points higher in NHB than in NHW patients for AG10 levels from 100 to 250 mg/dL. For an HbA1c of 7%, AG10 was 11 mg/dL higher for NHW than for NHB patients. Similar findings were observed across races for relationships of FPG and AUC with HbA1c and for glucose measurements with glycated albumin levels. Differences in the relationship between AG10 and HbA1c across racial groups remained after adjustments for any demographic or other differences between racial/ethnic subgroups., Conclusions: The relationship between several measures of glucose with HbA1c and glycated albumin consistently differed across races. These findings should be considered in setting treatment goals and diagnostic levels., (© 2024 by the American Diabetes Association.)

Objective: Hypoglycemia is a major concern in type 2 diabetes (T2DM), but little is known about its likelihood compared across common therapies. We compared the likelihood of hypoglycemia among metformin-treated patients with T2DM randomized to the addition of one of 4 common therapies., Research Design & Methods: Randomized, controlled trial of 5,047 participants with T2DM of <10 years' duration, hemoglobin A1c (HbA1c) 6.8-8.5% (50.8-69.4 mmol/mol). Randomization to addition of glargine U100, glimepiride, liraglutide, or sitagliptin over 5.0 ± 1.3 (mean ± SD) years. HbA1c was measured quarterly; if a level >7.5% (>58.5 mmol/mol) was confirmed, rescue glargine and/or aspart insulin was added. We conducted a per-protocol analysis of 4,830, who attended at least one post-baseline visit and took at least one dose of assigned study medication. We assessed severe hypoglycemia events reported throughout the entire study. At quarterly visits, all participants were asked about hypoglycemic symptoms within the last 30 days, and those in the glargine and glimepiride groups were asked for any measured glucose <70 mg/dL (3.9 mmol/L) within this time period., Results: While participants were taking their assigned medications, severe hypoglycemia occurred in 10 (0.8%), 16 (1.3%), 6 (0.5%), and 4 (0.3%), (p<0.05) and hypoglycemic symptoms in 659 (54.2%), 833 (68.3%), 375 (32.4%), and 361 (29.1%) of participants following randomization to glargine, glimepiride, liraglutide, and sitagliptin, respectively (p<0.001)., Conclusions: In metformin-treated patients with T2DM who add a second medication, hypoglycemia is most likely with addition of glimepiride, less with glargine, and least likely with liraglutide and sitagliptin., Trial Registration: ClinicalTrials.gov Identifier: NCT01794143., Competing Interests: Outside the submitted work, Dr. Elizabeth Seaquist reports grants or contracts from JDRF to her institution; consulting fees from Lily, NovoNordisk, Sanofi, and Zucara; honoraria from International Hypoglycemia study group; board membership with the American Diabetes Association; and receipt of sensors from Dexcom to her institution. Dr. Lawrence Phillips reports salary support from the Veterans Health Administration during the conduct of the study; grants from Janssen Pharmaceuticals, grants from Merck, Amylin, Eli Lilly, Novo Nordisk, Sanofi, PhaseBio, Roche, AbbVie, Vascular Pharmaceuticals, GlaxoSmithKline, Pfizer, AstraZeneca, Kowa, and Cystic Fibrosis Foundation; other support from DIASYST, outside the submitted work. Outside the submitted work, Dr. Richard M. Bergenstal reports consulting fees from Abbot Diabetes Care, Ascencia, Bigfoot Biomedical, Inc., DexCom, MannKind, Medtronic, Novo Nordisk, Sanofi, and United Health Care made to HealthPartners Institute; payments or honoraria from Sanofi and Vertex Pharmaceuticals made to Health Partners Institute; support for meetings or travel from Abbott Diabetes Care, Ascensia, CeQur, Eli Lilly, Embecta, MannKind, Novo Nordisk, Roche GmbH, Sanofi, Vertex Pharmaceuticals, and Zealand Pharma made to Health Partners Institute, and participation on a data safety monitoring or advisory board from Abbott Diabetes Care, CeQur, Eli Lilly, Embecta, Hygieia, Roche GmbH, and Zealand Pharma with payments made to HealthPartners Institute. Outside the submitted work, Dr. Jill Crandall reports non-financial support from Abbott. Outside the submitted work, Mary L Johnson reports research grants paid to Health Partners Institute from Sanofi, Novo Nordisk, and Lilly. Dr. Alokananda Ghosh, Dr. Naji Younes, Dr. John Lachin, Chelsea Baker, Dr. Robin S. Goland, Michaela R Gramzinski, Dr. Daniel S Hsia, Dr. Sophia H Hox, Dr. Philip Raskin, Dr. Willy M Valencia, and Andrea H Waltje have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Anti-obesity medications (AOMs) have emerged as one element of comprehensive obesity clinical care intended to improve long-term health outcomes for children and adolescents. The number of pediatric AOM clinical trials has burgeoned in recent years as new pharmacotherapeutics have been developed. Factors related to growth and development in children and adolescents can present unique challenges in terms of designing and conducting clinical trials investigating the safety and efficacy of AOMs. These barriers can delay the AOM development and evaluation process, increase the cost of performing trials, create challenges in the interpretation of results, influence the generalizability of the findings and present ethical dilemmas. In an effort to address these issues and provide guidance to streamline the process of designing and conducting pediatric AOM clinical trials, relevant key stakeholders convened a series of roundtable meetings to discuss, debate and achieve harmonization on design features. Stakeholder participants included a multidisciplinary group of international pediatric obesity experts, patient (parent) representatives and representatives from academic medicine, key regulatory agencies and industry. Topics of discussion included primary efficacy end-points, secondary end-points, eligibility criteria, trial run-in and follow-up phases, use of active comparators and guidelines for down-titration and/or stopping rules for excessive weight reduction. Consensus recommendations were agreed upon. Regarding end-points, emphasis was placed on moving away from BMI z-score as a primary outcome, incorporating multiple alternative BMI-related outcomes and measuring adiposity/body fat as a prominent secondary end-point. Trial eligibility criteria were carefully considered to maximize generalizability while maintaining safety. The limited value of trial run-in phases was discussed. It was also underscored that designing trials with extended follow-up periods after AOM withdrawal should be avoided owing to ethical issues (including possible psychological harm) related to weight regain without providing the opportunity to access other treatments. The panel emphasized the value of the randomized, placebo-controlled trial but recommended the thoughtful consideration of the use of active comparators in addition to, or instead of, placebo to achieve clinical equipoise when appropriate. Finally, the panel recommended that clinical trial protocols should include clear guidance regarding AOM down-titration to avoid excessive weight reduction when applicable., (© 2024 The Author(s). Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Recent advancements in immunology and islet biology have unveiled remarkable prospects for the postponement of Type 1 diabetes (T1D) through the strategic modulation of the immune system. In this Perspective, we discuss the pharmaceutical strides achieved, traversing from pre-clinical validation to the execution of impactful clinical trials. We begin with the initial investigations involving cyclosporine and glucocorticoids in rodent models, such as the non-obese diabetic (NOD) mouse, which guided early clinical trials. We then discuss the pre-clinical studies using suitable mouse models that eventually led to contemporary clinical trials targeting immune cell functionality and cytokine signaling pathways. Collectively, these discoveries promote the exciting paradigm of immune system modulation to mitigate autoimmunity, which continues to broaden. Notably, the use of baricitinib, a potent JAK1/2 inhibitor, and teplizumab, an anti-CD3 monoclonal antibody, represent discrete methodologies converging upon a singular outcome: the preservation of islet beta-cell functionality. The latter interventional strategies build on the original idea that tempering specific facets of the immune system will generate therapeutic benefit. Enthusiasm from these discoveries stems from efficacy with reduced side effects when compared with past approaches. The success of therapeutic intervention(s) in pre-clinical studies, combined with knowledge about stages of progression to clinical T1D, have ultimately encouraged the design of more successful clinical trials targeting highly specific populations at risk. Collectively, these findings instill a profound sense of optimism, suggesting that the prevention and even reversal of T1D may soon be within reach., Competing Interests: Declaration of Competing Interest The authors are unaware of any affiliations, memberships, or financial holdings that might be perceived as affecting the objectivity of this review., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment., Objective: To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC., Design, Setting, and Participants: Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history., Exposure: SARS-CoV-2 infection., Main Outcomes and Measures: PASC and 89 prolonged symptoms across 9 symptom domains., Results: A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents., Conclusions and Relevance: This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

The proposed glucosylamine oxidation pathway (GOP) is a two-step, intraerythrocyte, thermodynamically favorable nonenzymatic reaction that first binds glucose to the N-terminal valine of beta globin (βVal1) to form a closed-chain glucosylamine that can spontaneously reduce oxidized vitamin C to its antioxidant form. This review summarizes analytical, biochemical and clinical research supporting the existence of the GOP and the surprising hypothesis that βVal1 glucosylamine is a reducing agent that works cooperatively with reduced glutathione to dynamically regulate vitamin C recycling during naturally occurring periods of transiently or chronically elevated blood glucose and oxidant production. Rationale for the existence of the GOP is presented from the perspective of the hemoglobin glycation index, a clinically practical biomarker of risk for chronic vascular disease that we propose is mechanistically explained by person-to-person variation in GOP activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Early age at menarche (AAM) is a risk factor for type 2 diabetes later in life, but the pathogenic pathways that confer increased risk remain unknown., Objective: We examined the associations between AAM and inflammatory and glucose metabolism biomarkers among U.S. adult women who were free of diabetes., Methods: Using the National Health and Nutrition Examination Survey (NHANES) 1999-2018, 19,228 women over 20 years old who were free of self-reported cancer and diabetes were included in this cross-sectional analysis. AAM was the self-reported age at first menstruation. CRP, fasting glucose, fasting insulin, and ferritin levels were measured as biomarkers of inflammation and glucose metabolism in adult blood samples using latex-enhanced nephelometry, enzymatic, and immunoassay methods. Multiple linear regression was used to relate AAM to the biomarkers., Results: The median age at the time of blood sample collection was 44 years (IQR, 33-62). After age adjustment, there was an association between a lower AAM and higher CRP (P-trend=0.006); fasting glucose (P-trend<0.0001); fasting insulin (P-trend <0.0001); and ferritin (p-trend<0.0001). These remained significant after additional adjustment for demographic, reproductive, lifestyle, and adiposity variables, except for ferritin. Smoking modified the effect of AAM on CRP (p-interaction = 0.014), fasting insulin (p-interaction <0.001), and fasting glucose (p-interaction<0.001). In stratified analysis, the observed associations became more pronounced in non-smokers, while they were attenuated to non-significance in active smokers., Conclusion: Earlier age at menarche is associated with an unfavorable inflammatory and glucose metabolic biomarker profile in a nationally representative sample of adult women free of diabetes, especially among non-smokers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults., Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science., Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions., Clinical Trials.gov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Brett Anderson reported receiving direct support for work not related to RECOVER work/publications from Genentech and the National Institute of Allergy and Immunology. Walter Dehority reported receiving grant support from Merck and participating in research for the Moderna COVID-19 pediatric vaccine trial and the Pfizer Paxlovid trial. Alex Fiks reported receiving support from NJM insurance and personal consulting fees not related to this paper from Rutgers University and the American Academy of Pediatrics. Ashraf Harahsheh reported serving as a scientific advisory board member unrelated to this paper for OP2 DRUGS. Lawrence Kleinman reported serving as an unpaid member of the Board of Directors for the DARTNet Institute, as a principle investigator at Quality Matters, Inc., and as the Vice Chair for the Borough of Metuchen Board of Health. Dr. Kleinman also reported grant support for work not related to RECOVER work/publications from NIH, HRSA, and the Robert Wood Johnson Foundation. Dr. Kleinman also reported minority individual stock ownership in Apple Computer, Sanofi SA, Experion, GlaxoSmithKline, Magyar Bank, Regeneron Pharmaceuticals, JP Morgan Chase, and Amgen Inc. Torri Metz reported participating as a Principle Investigator in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She is also a principle investigator for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Joshua Milner reported serving as a member of the Scientific Advisory Board for Blueprint Medicines, in a capacity unrelated to RECOVER work/publications. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Gross et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: In Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (5,047 participants, mean follow-up 5.0 years), differences in glycemic control were demonstrated over time among four randomized therapies added to metformin. Weight gain and hypoglycemia are also important outcomes for people with type 2 diabetes. We compared the effects of the four randomized GRADE medications on a composite outcome incorporating glycemic deterioration, weight gain, and hypoglycemia., Research Design and Methods: The composite outcome was time to first occurrence of any of the following: HbA1c >7.5%, confirmed; ≥5% weight gain; or severe or recurrent nonsevere hypoglycemia. Secondary analyses included examination of individual components of the composite outcome, subgroup effects and potential mediators, and treatment satisfaction. Cumulative incidence was estimated with the Kaplan-Meier estimator. Cox proportional hazards models were used to assess pairwise group differences in risk of an outcome., Results: Risk of reaching the composite outcome (events per 100 participants per treatment year [PTYs]) was lowest with liraglutide (19 per 100 PTYs) followed by sitagliptin (26 per 100 PTYs), glargine (29 per 100 PTYs), and glimepiride (40 per 100 PTYs); all pairwise comparisons were statistically significant. The order was the same for risk of weight gain and hypoglycemia, but risk of glycemic deterioration was lowest with glargine, followed by liraglutide, glimepiride, and sitagliptin. No significant heterogeneity in risk of composite outcome was detected across prespecified covariates. Participants who reached the composite outcome had modestly but significantly lower treatment satisfaction., Conclusions: Among participants treated with common second-line drug classes for type 2 diabetes, the liraglutide group had the lowest and glimepiride the highest risk of reaching a composite outcome encompassing glycemic deterioration, weight gain, and hypoglycemia. These findings may inform decision-making regarding type 2 diabetes therapy., (© 2024 by the American Diabetes Association.)

Objectives: Insulin resistance is associated with elevations in plasma branched-chain amino acids (BCAAs). BCAAs compete with aromatic amino acids including tryptophan for uptake into β cells. To explore relationships between BCAAs and tryptophan metabolism, adiposity, and glucose tolerance, we compared urine metabolites in overweight/obese youth with type 2 diabetes (T2D) with those in nondiabetic overweight/obese and lean youth., Methods: Metabolites were measured in 24-hour and first-morning urine samples of 56 nondiabetic adolescents with overweight/obesity, 42 adolescents with T2D, and 43 lean controls, aged 12 to 21 years. Group differences were assessed by Kruskal Wallis or ANOVA., Results: Groups were comparable for age, pubertal status, and ethnicity. Youth with T2D were predominantly female and had highest percent body fat. BCAAs, branched-chain ketoacids (BCKAs), tryptophan, and kynurenine were higher in urine of subjects with T2D. There were no differences between lean controls and nondiabetic youth with overweight/obesity. T2D was associated with diversion of tryptophan from the serotonin to the kynurenine pathway, with higher urinary kynurenine/serotonin ratio and lower serotonin/tryptophan and 5-HIAA/kynurenine ratios. Urinary BCAAs, BCKAs, tryptophan, and ratios reflecting diversion to the kynurenine pathway correlated positively with metrics of body fat and hemoglobin A1c. Increases in these metabolites in the obese T2D group were more pronounced and statistically significant only in adolescent girls., Conclusion: Increases in urinary BCAAs and BCKAs in adolescent females with T2D are accompanied by diversion of tryptophan metabolism from the serotonin to the kynurenine pathway. These adaptations associate with higher risks of T2D in obese adolescent females than adolescent males., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of end-stage liver disease. NAFLD diagnosis and follow-up relies on a combination of clinical data, liver imaging, and/or liver biopsy. However, intersite imaging differences impede diagnostic consistency and reduce the repeatability of the multisite clinical trials necessary to develop effective treatments., Purpose/hypothesis: The goal of this pilot study was to harmonize commercially available 3 T magnetic resonance imaging (MRI) measurements of liver fat and stiffness in human participants across academic sites and MRI vendors., Study Type: Cohort., Subjects: Four community-dwelling adults with obesity., Field Strength/sequence: 1.5 and 3 T, multiecho 3D imaging, PRESS, and GRE., Assessment: Harmonized proton density fat fraction (PDFF) and magnetic resonance spectroscopy (MRS) protocols were used to quantify the FF of synthetic phantoms and human participants with obesity using standard acquisition parameters at four sites that had four different 3 T MRI instruments. In addition, a harmonized magnetic resonance elastography (MRE) protocol was used to quantify liver stiffness among participants at two different sites at 1.5 and 3 T field strengths. Data were sent to a single data coordinating site for postprocessing., Statistical Tests: Linear regression in MATLAB, ICC analyses using SAS 9.4, one-sided 95% confidence intervals for the ICC., Results: PDFF and MRS FF measurements were highly repeatable among sites in both humans and phantoms. MRE measurements of liver stiffness in three individuals at two sites using one 1.5 T and one 3 T instrument showed repeatability that was high although lower than that of MRS and PDFF., Conclusions: We demonstrated harmonization of PDFF, MRS, and MRE-based quantification of liver fat and stiffness through synthetic phantoms, traveling participants, and standardization of postprocessing analysis. Multisite MRI harmonization could contribute to multisite clinical trials assessing the efficacy of interventions and therapy for NAFLD., Level of Evidence: 2 TECHNICAL EFFICACY STAGE: 2., (© 2023 International Society for Magnetic Resonance in Medicine.)

Based on self-report in the GRADE diabetes study, cumulative incidence of retinopathy was low over 5 years (3.7 %; 184 of 4098 participants) and did not differ among the 4 treatment groups (glargine 4.0 %, glimepiride 3.2 %, liraglutide 3.7 %, sitagliptin 3.8 %). There were no differences in retinopathy with specific therapies in GRADE. Clinicaltrials.gov identifier: NCT01794143., Competing Interests: Declaration of competing interest DH, LSK, HKS and NY have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Context: Exercise can decrease central adiposity, but the effect of exercise dose and the relationship between central adiposity and exercise-induced compensation is unclear., Objective: Test the effect of exercise dose on central adiposity change and the association between central adiposity and exercise-induced weight compensation., Methods: In this ancillary analysis of a 6-month randomized controlled trial, 170 participants with overweight or obesity (mean ± SD body mass index: 31.5 ± 4.7 kg/m2) were randomized to a control group or exercise groups that reflected exercise recommendations for health (8 kcal/kg/week [KKW]) or weight loss and weight maintenance (20 KKW). Waist circumference was measured, and dual-energy X-ray absorptiometry assessed central adiposity. Predicted weight change was estimated and weight compensation (weight change - predicted weight change) was calculated., Results: Between-group change in waist circumference (control: .0 cm [95% CI, -1.0 to 1.0], 8 KKW: -.7 cm [95% CI, -1.7 to .4], 20 KKW: -1.3 cm [95% CI, -2.4 to -.2]) and visceral adipose tissue (VAT; control: -.02 kg [95% CI, -.07 to .04], 8 KKW: -.01 kg [95% CI, -.07 to .04], 20 KKW: -.04 kg [95% CI, -.10 to .02]) was similar (P ≥ .23). Most exercisers (82.6%) compensated (weight loss less than expected). Exercisers who compensated exhibited a 2.5-cm (95% CI, .8 to 4.2) and .23-kg (95% CI, .14 to .31) increase in waist circumference and VAT, respectively, vs those who did not (P < .01). Desire to eat predicted VAT change during exercise (β = .21; P = .03)., Conclusion: In the presence of significant weight compensation, exercise at doses recommended for health and weight loss and weight maintenance leads to negligible changes in central adiposity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Understanding how race may influence the association between A1c and glycemia can improve diabetes screening. We sought to determine whether, for a given A1c level, glucose levels during an oral glucose tolerance test (OGTT) differed by race., Research Design and Methods: From data collected at 22 US clinical sites, we conducted a cross-sectional study of concurrently measured A1c and OGTT and observational longitudinal follow-up of the subset with high-risk pre-diabetes. Numerical integration methods were used to calculate area under the glycemic curve (AUC glu ) during OGTT and least squares regression model to estimate A1c for a given AUC glu by race, controlling for potential confounders., Results: 1016 black, 2658 white, and 193 Asian persons at risk of diabetes were included in cross-sectional analysis. Of these, 2154 with high-risk pre-diabetes were followed for 2.5 years. For a given A1c level, AUC glu was lower in black versus white participants. After adjustment for potential confounders, A1c levels for a given AUC glu quintile were 0.15-0.20 and 0.02-0.19 percentage points higher in black and Asian compared with white participants, respectively (p<0.05). In longitudinal analyses, black participants were more likely to be diagnosed with diabetes by A1c than white participants (28% vs 10%, respectively; p<0.01). Black and Asian participants were less likely to be diagnosed by fasting glucose than white participants (16% vs 15% vs 37%, respectively; p<0.05). Black participants with A1c levels in the lower-level quintiles had greater increase in A1c over time compared with white participants., Conclusions: Use of additional testing beyond A1c to screen for diabetes may better stratify diabetes risk in the diverse US population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A fixed-dose combination of phentermine and extended-release topiramate (PHEN/TPM - approved for weight management) has demonstrated in-clinic reduction of blood pressure (BP). Ambulatory BP monitoring (ABPM) may be a better predictor of cardiovascular disease risk than in-clinic BP., Methods: This randomized, multicenter, double-blind study enrolled 565 adults with overweight/obesity. Inclusion criteria included participants willing to wear ABPM device for 24 h. Exclusion criteria included screening blood pressure >140/90 mmHg and antihypertensive medications not stable for 3 months prior to randomization. Participants received placebo (n = 184), phentermine 30 mg; (n = 191), or PHEN 15 mg/TPM 92 mg; (n = 190). 24-hour ABPM was performed at baseline and at week 8. The primary endpoint was mean 24-h systolic BP (SBP) as measured by ABPM, in the per protocol population., Results: Participants were mostly female (73.5 ​%) and White (81.6 ​%), with a mean age of 53.4 years; 32.4 ​% had no hypertension diagnosis or treatment, 62.5 ​% had hypertension using 0 to 2 antihypertensive medications, and 5.1 ​% had hypertension using ≥ 3 antihypertensive medications. Baseline mean SBP/diastolic BP (DBP) was 123.9/77.6 ​mmHg. At week 8, mean SBP change was -0.1 ​mmHg (placebo), +1.4 ​mmHg (phentermine 30 ​mg), and -3.3 ​mmHg (PHEN/TPM). Between-group difference for PHEN/TPM versus placebo was -3.2 ​mmHg (95 ​% CI: -5.48, -0.93 ​mmHg; p ​= ​0.0059). The between-group difference for PHEN/TPM versus phentermine 30 ​mg was -4.7 ​mmHg (95 ​% CI: -6.96, -2.45 ​mmHg; p ​< ​0.0001). Common (>2 ​% in any treatment group) adverse events (i.e., dry mouth, constipation, nausea, dizziness, paresthesia, dysgeusia, headache, COVID-19, urinary tract infection, insomnia, and anxiety) were mostly mild or moderate., Conclusions: In this randomized, multicenter, double-blind ABPM study, PHEN/ TPM reduced SBP compared to either placebo or phentermine 30 mg (Funding: Vivus LLC; ClinicalTrials.gov: NCT05215418)., Competing Interests: HEB's research site institution has received research grants from 89Bio, Alon Medtech/Epitomee, Altimmune, Amgen, Boehringer Ingelheim, Eli Lilly, Kallyope, Novartis, NovoNordisk, Pfizer, Shionogi, Viking, and Vivus. HEB has served as a consultant/advisor for 89Bio, Altimmune, Amgen, Boehringer Ingelheim, and Lilly. DSH served as a site principal investigator for this study, which was conducted through a contract with his institution. DSH did not receive any funds directly from the sponsor. LTN is a full-time employee of VIVUS LLC, which markets the PHEN/TPM product evaluated in this study. At the time of this study her work on this study was done as part of her employment. CAP is a full-time employee of VIVUS LLC, which markets the PHEN/TPM product evaluated in this study. At the time of this study, his work on this study was done as part of his employment. STV is a full-time employee of VIVUS LLC, which markets the PHEN/TPM product evaluated in this study. At the time of this study, his work on this study was done as part of his employment and role as an officer in the company., (© 2024 The Authors.)

Background: Food insecurity is a risk factor for multiple chronic diseases, including obesity. Importantly, both food insecurity and obesity are more prevalent in African American women than in other groups. Furthermore, food insecurity is considered a cyclic phenomenon, with episodes of food adequacy (ie, enough food to eat) and food shortage (ie, not enough food to eat). More research is needed to better understand why food insecurity is linked to obesity, including acknowledging the episodic nature of food insecurity as a stressor and identifying underlying mechanisms., Objective: The objective of this study is to investigate the episodic nature of food insecurity as a stressor via responses in body weight and psychological and physiological parameters longitudinally and do so in a health-disparate population-African American women., Methods: We enrolled 60 African American women (food-insecure cohort: n=30, 50%; food-secure cohort: n=30, 50%) aged 18-65 years with obesity (BMI 30-50 kg/m 2 ) to measure (1) daily body weight remotely over 22 weeks and (2) psychological and physiological parameters via clinic assessments at the beginning and end of the 22-week study. Furthermore, we are assessing episodes of food insecurity, stress, hedonic eating, and appetite on a weekly basis. We hypothesize that food-insecure African American women with obesity will demonstrate increased body weight and changes in psychological and physiological end points, whereas food-secure African American women with obesity will not. We are also examining associations between changes in psychological and physiological parameters and changes in body weight and performing a mediation analysis on the psychological parameters assessed at the study midpoint. Psychological questionnaires are used to assess stress; executive function, decision-making, and motivation; and affect and nonhomeostatic eating. Physiological measurements are used to evaluate the levels of cortisol, dehydroepiandrosterone-sulfate (DHEA-S), C-reactive protein, thyroid hormones, blood glucose, glycated hemoglobin, and insulin, as well as allostatic load., Results: This study has completed participant recruitment (n=60). At the time of study enrollment, the mean age of the participants was almost 47 (SD 10.8) years, and they had a mean BMI of 39.6 (SD 5.31) kg/m 2 . All data are anticipated to be collected by the end of 2023., Conclusions: We believe that this is the first study to examine changes in body weight and psychological and physiological factors in food-insecure African American women with obesity. This study has significant public health implications because it addresses the cyclic nature of food insecurity to identify underlying mechanisms that can be targeted to mitigate the adverse relationship between food insecurity and obesity and reduce health disparities in minority populations., Trial Registration: ClinicalTrials.gov NCT05076487; https://clinicaltrials.gov/study/NCT05076487., International Registered Report Identifier (irrid): DERR1-10.2196/52193., (©Candice A Myers, Robbie A Beyl, Daniel S Hsia, Melissa N Harris, Isabella J Reed, Danielle D Eliser, Lauren Bagneris, John W Apolzan. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 20.12.2023.)

Observation studies suggest differences in myelination in relation to differences in early life nutrition. This two-center randomized controlled trial investigates the effect of a 12-month nutritional intervention on longitudinal changes in myelination, cognition, and behavior. Eighty-one full-term, neurotypical infants were randomized into an investigational (N = 42) or a control group (N = 39), receiving higher versus lower levels of a blend of nutrients. Non-randomized breastfed infants (N = 108) served as a reference group. Main outcomes were myelination (MRI), neurodevelopment (Bayley-III), social-emotional development (ASQ:SE-2), infant and toddler behavior (IBQ-R and TBAQ), and infant sleep (BISQ) during the first 2 years of life. The full analysis set comprised N = 67 infants from the randomized groups, with 81 myelin-sensitive MRI sequences. Significantly higher myelination was observed in the investigational compared to the control group at 6, 12, 18, and 24 months of life, as well as significantly higher gray matter volume at 24 months, a reduced number of night awakenings at 6 months, increased day sleep at 12 months, and reduced social fearfulness at 24 months. The results suggest that brain development may be modifiable with brain- and age-relevant nutritional approaches in healthy infants and young children, which may be foundational for later learning outcomes.

There is evidence suggesting that infection with SARS-CoV-2 can lead to several long-term sequelae including diabetes. This mini-review examines the rapidly evolving and conflicting literature on new-onset diabetes after COVID-19, which we term NODAC. We searched PubMed, MEDLINE, and medRxiv from inception until December 1, 2022, using Medical Subject Headings (MeSH) terms and free text words including "COVID-19," "SARS-CoV-2," "diabetes," "hyperglycemia," "insulin resistance," and "pancreatic β-cell." We also supplemented searches by examining reference lists from retrieved articles. Current evidence suggests that COVID-19 increases the risk of developing diabetes, but the attributable risk is uncertain because of limitations of study designs and the evolving nature of the pandemic, including new variants, widespread population exposure to the virus, diagnostic options for COVID-19, and vaccination status. The etiology of diabetes after COVID-19 is likely multifactorial and includes factors associated with host characteristics (eg, age), social determinants of health (eg, deprivation index), and pandemic-related effects both at the personal (eg, psychosocial stress) and the societal-community level (eg, containment measures). COVID-19 may have direct and indirect effects on pancreatic β-cell function and insulin sensitivity related to the acute infection and its treatment (eg, glucocorticoids); autoimmunity; persistent viral residency in multiple organs including adipose tissue; endothelial dysfunction; and hyperinflammatory state. While our understanding of NODAC continues to evolve, consideration should be given for diabetes to be classified as a post-COVID syndrome, in addition to traditional classifications of diabetes (eg, type 1 or type 2), so that the pathophysiology, natural history, and optimal management can be studied., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: People with a low or high haemoglobin glycation index (HGI) have lower or higher HbA1c than other people with the same FPG. This study compared the prevalence of prediabetes based on FPG, 2hOGTT and HbA1c in people with low, moderate or high HGI., Methods: Prediabetes was diagnosed based on ADA cutpoints in 10,488 NHANES participants without self-reported diabetes. HGI was calculated as the difference between a participant's observed HbA1c and a predicted HbA1c where predicted HbA1c = 0.024 FPG + 3.1. Participants were divided into low (HGI < -0.15%), moderate (HGI -0.15% to +0.15%) and high (HGI > +0.15%) HGI subgroups., Results: The prevalence of prediabetes was 42.4% based on FPG, 27.2% based on HbA1c and 17.2% based on 2hOGTT. FPG and HbA1c thus overdiagnosed prediabetes by 25.2% and 10.0%, respectively, compared to the OGTT gold standard. Prevalence was (1) similar in low, moderate and high HGI participants based on 2hOGTT, (2) highest in low HGI participants based on FPG, and (3) highest in high HGI participants based on HbA1c. Among participants with mismatched FPG and HbA1c, OGTT was normal in (1) 79.5% of participants with normal FPG but prediabetic HbA1c (mean HGI = +0.53%), and (2) 75.2% of participants with normal HbA1c but prediabetic FPG (mean HGI = -0.30%)., Conclusions: FPG overdiagnosed prediabetes in people with low HGI. HbA1c overdiagnosed prediabetes in people with high HGI. Clinical use of HGI could improve prediabetes diagnosis and help health care providers avoid inappropriate or delayed treatment of people with extremes of HGI., (© 2023 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Aims: To examine the effect of vitamin D on regression to normal glucose regulation (NGR) and individual glycemic measures in the D2d study., Methods: In per-protocol analyses, we examined time to new-onset diabetes; time to new-onset NGR defined as first occurrence of: 2-or-3 glycemic criteria in the normal range (NGR-1) or fasting plasma glucose (FPG) and 2-hour post-load-glucose (2hPG) in the normal range (NGR-2); proportion meeting NGR at the last study visit; and change in FPG, 2hPG, and HbA1c., Results: Among 2423 participants, hazard ratio [HR] for diabetes was 0.84 [95%CI, 0.71, 0.99]). HR (95%CI) was 1.16 (0.99, 1.36) for new-onset NGR-1 and 1.06 (0.87, 1.30) for NGR-2. At the last visit, NGR-1 occurred in 12.4% vs. 9.5% participants in the vitamin D vs. placebo group (rate ratio for vitamin D 1.31 [1.02, 1.70]); whereas, NGR-2 occurred in 8.7% vs. 6.0% (rate ratio for vitamin D 1.45 [1.05, 2.00]). During follow-up, FPG, HbA1c, and 2hPG increased in both groups. Mean difference in FPG favored vitamin D (-0.80 mg/dL; 95%CI, -1.26, -0.33)., Conclusions: In secondary analyses among participants adherent to the trial protocol, vitamin D lowered risk of developing diabetes and increased likelihood of NGR at the end of the study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: This study aimed to examine the effects of substituting sedentary time with sleep or physical activity on adiposity in a longitudinal sample of adolescents., Methods: Adolescents (10-16 yr) were recruited for a prospective observational cohort. Parents and adolescents reported demographic characteristics and pubertal development. Accelerometry was used to measure sleep, physical activity, and sedentary time. Adiposity was quantified with imaging techniques. Isotemporal substitution modeling was conducted to examine the effect of substituting 10 min of sedentary time with sleep or differing intensities of physical activity. Results were stratified by sex and race and adjusted for covariates., Results: A total of 217 adolescents provided complete measures at both baseline and 2 yr later (58.1% White, 51.8% girls; 12.9 ± 1.9 yr at baseline). Sleep was negatively related to adiposity 2 yr later when considering other movement behaviors, but substituting baseline sedentary time with sleep was not related to future adiposity ( P > 0.05). In boys and non-White adolescents, substituting sedentary time with vigorous-intensity physical activity was related to lower adiposity 2 yr later ( P < 0.05). Substituting sedentary time for moderate- to vigorous-intensity physical activity was not associated with future adiposity., Conclusions: Substituting sedentary time with vigorous-intensity physical activity was related to lower adiposity in later adolescence in certain groups. Opportunities to promote an adequate balance of sleep, sedentary time, and physical activity in all adolescents are encouraged for optimal development., (Copyright © 2022 by the American College of Sports Medicine.)

Context: Blood pressure and plasma catecholamines normally decline during sleep and rapidly increase in early morning. This is blunted in adults with type 2 diabetes (T2D)., Objective: We hypothesize that increased sympatho-adrenal activity during sleep differentiates youth with T2D from nondiabetic obese youth and lean youth., Methods: Fasting spot morning and 24-hour urines were collected in obese adolescents with and without T2D, and normal-weight controls. Fractionated free urine catecholamines (epinephrine, norepinephrine, and dopamine) were measured, and the ratio of fasting spot morning to 24-hour catecholamines was calculated., Results: Urinary 24-hour catecholamine levels were comparable across the 3 groups. Fasting morning epinephrine and the ratio of fasting morning/24-hour epinephrine were higher in youth with T2D ( P = 0.004 and P = 0.035, respectively). In males, the ratio of fasting morning/24-hour epinephrine was also higher in youth with T2D ( P = 0.005). In females, fasting morning norepinephrine and the ratio of fasting morning/24-hour dopamine were lower in obese youth with and without T2D ( P = 0.013 and P = 0.005, respectively) compared with lean youth. Systolic blood pressure was higher in diabetic participants than other groups; males trended higher than females., Conclusion: Circadian rhythm in catecholamines is disrupted in youth-onset T2D, with a blunted overnight fall in urinary epinephrine in males. Conversely, fasting morning norepinephrine and dopamine levels were lower in obese females with or without T2D. Higher nocturnal catecholamines in males with T2D might associate with, or predispose to, hypertension and cardiovascular complications. Lower catecholamine excretion in females with obesity might serve an adaptive, protective role., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Objectives: To evaluate the frequency and severity of new cases of youth-onset type 2 diabetes in the US during the first year of the pandemic compared with the mean of the previous 2 years., Study Design: Multicenter (n = 24 centers), hospital-based, retrospective chart review. Youth aged ≤21 years with newly diagnosed type 2 diabetes between March 2018 and February 2021, body mass index ≥85th percentile, and negative pancreatic autoantibodies were included. Demographic and clinical data, including case numbers and frequency of metabolic decompensation, were compared between groups., Results: A total of 3113 youth (mean [SD] 14.4 [2.4] years, 50.5% female, 40.4% Hispanic, 32.7% Black, 14.5% non-Hispanic White) were assessed. New cases of type 2 diabetes increased by 77.2% in the year during the pandemic (n = 1463) compared with the mean of the previous 2 years, 2019 (n = 886) and 2018 (n = 765). The likelihood of presenting with metabolic decompensation and severe diabetic ketoacidosis also increased significantly during the pandemic., Conclusions: The burden of newly diagnosed youth-onset type 2 diabetes increased significantly during the coronavirus disease 2019 pandemic, resulting in enormous strain on pediatric diabetes health care providers, patients, and families. Whether the increase was caused by coronavirus disease 2019 infection, or just associated with environmental changes and stressors during the pandemic is unclear. Further studies are needed to determine whether this rise is limited to the US and whether it will persist over time., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to investigate the pharmacokinetic, pharmacodynamic and safety profile of the glucagon-like peptide-1 receptor agonist, lixisenatide, for the treatment of type 2 diabetes (T2D) in pediatric individuals., Materials and Methods: In this Phase 1, multicenter, randomized, double-blind, placebo-controlled, parallel-group, ascending repeated dose study (NCT02803918), participants aged ≥10 and < 18 years were randomized 3:1 to receive once-daily lixisenatide in 2-week increments of 5, 10, and 20 μg (n = 18) or placebo (n = 5) for 6 weeks., Results: Mean lixisenatide concentrations generally increased with increasing doses irrespective of anti-drug antibody (ADA) status; however, mean lixisenatide concentrations and inter-subject variability were higher for participants with positive ADA status. Improvements in fasting plasma glucose, post-prandial glucose, AUC 0-4.5 , HbA 1c , and body weight were observed with lixisenatide. Overall, the safety profile was consistent with the known profile in adults, with no unexpected side effects and no treatment-emergent adverse events resulting in death or discontinuation. The most common events in the lixisenatide group were vomiting (11.1%) and nausea (11.1%). No symptomatic hypoglycemia was reported in either group. No clinically significant hematologic, biochemical or vital sign abnormalities were observed., Conclusions: Mean lixisenatide concentrations generally increased with increasing dose, irrespective of ADA status. Lixisenatide was associated with improved glycemic control and a trend in body weight reduction compared with placebo. The safety and tolerability profile of repeated lixisenatide doses of up to 20 μg per day in children and adolescents with T2D was reflective of the established safety profile of lixisenatide in adults., (© 2022 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

A high hemoglobin glycation index (HGI) has been repeatedly associated with greater risk for hypoglycemia in people with diabetes and greater risk for chronic vascular disease in people with or without diabetes. This review explores how different sources of analytical and biological variation in HbA1c and blood glucose individually and collectively affect the clinical information value of HGI. We conclude that HGI is a complex quantitative trait that is a clinically practical biomarker of risk for both hypoglycemia and chronic vascular disease., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Antiobesity medication may be useful for the treatment of pediatric obesity, yet few safe and effective options exist. We evaluated phentermine/topiramate (PHEN/TPM) for weight management in adolescents with obesity., Methods: This 56-week, randomized, double-blind trial enrolled adolescents 12 to less than 17 years of age with obesity. Participants were randomly assigned 1:1:2 to receive either placebo (n=56), mid-dose PHEN/TPM (7.5 mg/46 mg; n=54), or top-dose PHEN/TPM (15 mg/92 mg; n=113), respectively. All participants received lifestyle therapy. The primary end point was mean percent change in body-mass index (BMI) from randomization to week 56., Results: Participants had a mean (±SD) age of 14.0±1.4 years and a mean (±SD) BMI of 37.8±7.1 kg/m 2 ; 54.3% were female. The primary end point of percent change in BMI at week 56 showed differences from placebo of -10.44 percentage points (95% CI, -13.89 to -6.99; P<0.001) and -8.11 percentage points (95% CI, -11.92 to -4.31; P<0.001) for the top and mid doses of PHEN/TPM, respectively. Differences from placebo in percent change in triglycerides nominally favored PHEN/TPM (mid dose, -21%; 95% CI, -40 to -2; and top dose, -21%; 95% CI, -38 to -4), as did differences in percent change in high-density lipoprotein cholesterol (HDL-C) (mid dose, 10%; 95% CI, 3 to 18; and top dose, 9%; 95% CI, 2 to 15). The incidence of participants reporting at least one adverse event was 51.8%, 37.0%, and 52.2% in the placebo, mid-dose, and top-dose groups, respectively. Serious adverse events were reported for two participants in the top-dose group., Conclusions: PHEN/TPM at both the mid and top doses offered a statistically significant reduction in BMI and favorably impacted triglyceride and HDL-C levels in adolescents with obesity. (Funded by VIVUS LLC, with project support provided by Covance LLC; ClinicalTrials.gov number, NCT03922945.).

Background: Accuracy and participant burden are two key considerations in the selection of a dietary assessment tool for assessing children's full-day dietary intake., Objective: The aim of this study was to identify barriers experienced by parents and burden when using two technology-based measures of dietary intake to report their child's intake: the Remote Food Photography Method (RFPM) and the Automated Self-Administered 24-hour Dietary Assessment Tool (ASA24)., Design: Qualitative, semistructured, focus groups were conducted with parents who served as proxy reporters of their child's dietary intake using the two different dietary assessment methods (ie, RFPM and ASA24) 1 week apart., Participants/setting: This study was conducted in 2019 and included 32 parents of children aged 7 to 8 years in Colorado and Louisiana., Main Outcome Measures: Barriers adhering to the protocol and burden with the RFPM and ASA24., Qualitative Analyses: Qualitative content analysis and Atlas.ti software were used to analyze and interpret focus group data., Results: For the RFPM, parents described missing photos due to unobserved intake, forgetting to capture images, disruption of mealtimes, and child embarrassment when meals were photographed at school. For the ASA24, parents described the time commitment as the main source of burden and the need to expand the food database to include additional ethnic foods and restaurant items. The main strengths were ease of use for the RFPM and the consolidated workload for the ASA24., Conclusions: The barriers experienced by parents and burden differed by method, highlighting the importance of considering the unique characteristics of each assessment tool when designing a pediatric dietary assessment study and interpreting findings., (Copyright © 2022 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

The limitations of self-report measures of dietary intake are well-known. Novel, technology-based measures of dietary intake may provide a more accurate, less burdensome alternative to existing tools. The first objective of this study was to compare participant burden for two technology-based measures of dietary intake among school-age children: the Automated-Self-Administered 24-hour Dietary Assessment Tool-2018 (ASA24-2018) and the Remote Food Photography Method (RFPM). The second objective was to compare reported energy intake for each method to the Estimated Energy Requirement for each child, as a benchmark for actual intake. Forty parent-child dyads participated in two, 3-d dietary assessments: a parent proxy-reported version of the ASA24 and the RFPM. A parent survey was subsequently administered to compare satisfaction, ease of use and burden with each method. A linear mixed model examined differences in total daily energy intake between assessments, and between each assessment method and the Estimated Energy Requirement (EER). Reported energy intake was 379 kcal higher with the ASA24 than the RFPM (P = 0·0002). Reported energy intake with the ASA24 was 231 kcal higher than the EER (P = 0·008). Reported energy intake with the RFPM did not differ significantly from the EER (difference in predicted means = -148 kcal, P = 0·09). Median satisfaction and ease of use scores were five out of six for both methods. A higher proportion of parents reported that the ASA24 was more time-consuming than the RFPM (74·4 % v. 25·6 %, P = 0·002). Utilisation of both methods is warranted given their high satisfaction among parents.

Background: The coronavirus disease 2019 (COVID-19) pandemic caused a shutdown of clinical research but offered a unique opportunity to understand attitudes and motivations around contributing to clinical research and resuming in-person visits during a pandemic., Methods: We conducted an anonymous survey study at Pennington Biomedical Research Center (PBRC) in participants returning for in-person visits from May 26, 2020 to August 11, 2020 and in people who previously expressed interest in research via an online Research Electronic Data Capture (REDCap) survey from August 6, 2020 to September 11, 2020. The survey gathered demographic information and presented statements that required answers on a scale of 1 (absolutely disagree) to 10 (absolutely agree). Two hundred fifty-one people completed paper surveys in-person while 1,537 people completed the survey online., Results: Online participants were more likely to be female (75.2% vs. 56.8%), more likely to have had COVID-19 symptoms (19.6% vs. 5.2%), and more likely to know someone with COVID-19 (72.7% vs. 49.4%). More people who came in-person thought they were low risk for severe COVID-19 compared to those who filled out the survey online (52.2% vs. 38.4%, P = 0.0002). More people who completed the survey online preferred to do as many study visits over the phone or internet as possible (37.8% vs. 22.7%, P < 0.0001). More people who came in-person agreed that clinical research is even more important than before COVID-19 (54.2% vs. 44.3%, P = 0.0035)., Conclusions: The majority of people felt that clinical research is important because of the health benefits received and because it may help others. These data may provide important considerations in the planning of future studies in the era of COVID-19., Competing Interests: The authors report no conflict of interest., (Copyright 2022, Hsia et al.)

Background: Prior studies of early antibiotic use and growth have shown mixed results, primarily on cross-sectional outcomes. This study examined the effect of oral antibiotics before age 24 months on growth trajectory at age 2-5 years., Methods: We captured oral antibiotic prescriptions and anthropometrics from electronic health records through PCORnet, for children with ≥1 height and weight at 0-12 months of age, ≥1 at 12-30 months, and ≥2 between 25 and 72 months. Prescriptions were grouped into episodes by time and by antimicrobial spectrum. Longitudinal rate regression was used to assess differences in growth rate from 25 to 72 months of age. Models were adjusted for sex, race/ethnicity, steroid use, diagnosed asthma, complex chronic conditions, and infections., Results: 430,376 children from 29 health U.S. systems were included, with 58% receiving antibiotics before 24 months. Exposure to any antibiotic was associated with an average 0.7% (95% CI 0.5, 0.9, p < 0.0001) greater rate of weight gain, corresponding to 0.05 kg additional weight. The estimated effect was slightly greater for narrow-spectrum (0.8% [0.6, 1.1]) than broad-spectrum (0.6% [0.3, 0.8], p < 0.0001) drugs. There was a small dose response relationship between the number of antibiotic episodes and weight gain., Conclusion: Oral antibiotic use prior to 24 months of age was associated with very small changes in average growth rate at ages 2-5 years. The small effect size is unlikely to affect individual prescribing decisions, though it may reflect a biologic effect that can combine with others., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

A successful randomized clinical trial of the effect of dietary supplements on a chosen endpoint begins with developing supporting data in preclinical studies while paying attention to easily overlooked details when planning the related clinical trial. In this perspective, we draw on our experience studying the effect of an ethanolic extract from Artemisia dracunculus L. (termed PMI-5011) on glucose homeostasis as a potential therapeutic option in providing resilience to metabolic syndrome (MetS). Decisions on experimental design related to issues ranging from choice of mouse model to dosing levels and route of administration in the preclinical studies will be discussed in terms of translation to the eventual human studies. The more complex considerations in planning the clinical studies present different challenges as these studies progress from testing the safety of the dietary supplement to assessing the effect of the dietary supplement on a predetermined clinical outcome. From the vantage point of hindsight, we will outline potential pitfalls when translating preclinical studies to clinical studies and point out details to address when designing clinical studies of dietary supplements., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Floyd, Ribnicky, Raskin, Hsia, Rood and Gurley.)

Exercise may sensitize individuals with overweight and obesity to appetitive signals (e.g., hunger and fullness cues), overriding trait eating behaviors that contribute to overeating and obesity, such as uncontrolled eating. The objective of the current study was to measure predictors of objective ad libitum energy intake at a laboratory-based, post-exercise test-meal in adolescents ranging in weight status from overweight to severe obesity. We hypothesized that appetitive states, rather than appetitive traits, would be the strongest predictors of energy intake at a post-exercise test-meal, after controlling for body size. At Baseline, 30 adolescents (ages 10-16 years, 50% female (F), 43% non-Hispanic white (NHW), 83% with obesity (OB)) completed state and trait appetite measures and an ad libitum dinner meal following intensive exercise. Nineteen of those participants (47% F, 32% NHW, 79% OB) completed identical assessments two years later (Year 2). Energy intake (kcal) at each time point was adjusted for fat-free mass index (i.e., body size). Adjusted energy intake was reliable from Baseline to Year 2 (ICC = 0.84). Multiple pre-meal appetite ratings were associated with test-meal energy intake. In stepwise linear regression models, pre-meal prospective food consumption was the strongest and only significant predictor of test-meal energy intake at both Baseline (R 2 = 0.25, p = 0.005) and Year 2 (R 2 = 0.41, p = 0.003). Baseline post-exercise energy intake was associated with weight change over two years (R 2 = 0.24, p = 0.04), but not with change in fat mass ( p = 0.11). Appetitive traits were not associated with weight or body composition change ( p > 0.22). State appetite cues were the strongest predictors of post-exercise energy intake, independent of body size. Future studies should examine whether long-term exercise programs enhance responsiveness to homeostatic appetite signals in youth with overweight and obesity, with a goal to reduce excess energy intake and risk for weight gain over time.

Aims: A high haemoglobin glycation index (HGI) is associated with greater risk for hypoglycaemia and chronic vascular disease. Standardizing how the HGI is calculated would normalize results between research studies and hospital laboratories and facilitate the clinical use of HGI for assessing risk., Methods: The HGI is the difference between an observed HbA1c and a predicted HbA1c obtained by inserting fasting plasma glucose (FPG) into a regression equation describing the linear relationship between FPG and HbA1c in a reference population. We used data from the 2005-2016 U.S. National Health and Nutrition Examination Survey (NHANES) to identify a reference population of 18,675 diabetes treatment-naïve adults without self-reported diabetes. The reference population regression equation (predicted HbA1c = 0.024 FPG + 3.1) was then used to calculate the HGI and divide participants into low (<-0.150), moderate (-0.150 to <0.150) and high (≥0.150) HGI subgroups. Diabetes status was classified by OGTTs., Results: As previously reported in multiple studies, a high HGI was associated with black race independent of diabetes status, and with older age, higher BMI and higher CRP in normal and prediabetic but not diabetic participants. The mean HGI was 0.6% higher in self-reported diabetic adults. The HGI was not associated with plasma insulin, HOMA-IR or 2 h OGTT in participants classified as normal, prediabetic or diabetic., Conclusions: The regression equation derived from this demographically diverse diabetes treatment-naïve adult NHANES reference population is suitable for standardizing how the HGI is calculated for both clinical use and in research to mechanistically explain population variation in the HGI and why a high HGI is associated with greater risk for chronic vascular disease., (© 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Introduction: Our primary aim was to investigate the association between initial weight change and longer-term changes in weight and compensation (predicted weight loss-observed weight loss) during exercise. As secondary aims, we investigated if initial weight change was related to change in cardiometabolic risk markers and energy balance modulators., Methods: Two 6-month randomized controlled exercise trials conducted in individuals with overweight or obesity were analyzed (study 1, n = 312; study 2, n = 102). In both studies, participants in an exercise condition (4 kcal·kg-1·wk-1 [KKW], 8 KKW, 12 KKW, or 20 KKW) were split into tertiles based on percent weight change from baseline to week 4. Tertiles 1 and 3 exhibited the least and most initial weight loss, respectively. Changes in end points were compared between tertiles., Results: At month 6, weight loss was lower in tertile 1 than tertile 3 (study 1: -3.6%, 95% confidence interval [CI] = -4.6 to -2.6; study 2: -1.8%, 95% CI = -3.1 to -0.4; P ≤ 0.034). Tertile 1 also showed greater compensation than tertile 3 in study 1 (3.0 kg, 95% CI = 2.2 to 3.9) and study 2 (1.5 kg, 95% CI = 0.3 to 2.6; P ≤ 0.048). Changes in triglycerides and, in study 1, HDL cholesterol were less favorable in tertile 1 versus tertile 3 (P ≤ 0.043); however, changes in other cardiometabolic markers were similar (P ≥ 0.209). In study 2, tertile 1 increased energy intake and exhibited maladaptive changes in eating behaviors relative to tertile 3 (P < 0.050). No between-tertile differences in cumulative exercise energy expenditure and physical activity were evident (P ≥ 0.321)., Conclusions: Less initial weight loss was associated with longer-term attenuated weight loss and greater compensation during aerobic exercise training. Individuals who display less initial weight loss during exercise may require early interventions to decrease compensation and facilitate weight loss., (Copyright © 2021 by the American College of Sports Medicine.)

Objective: We previously found that antibiotic use at <24 months of age was associated with slightly higher body weight at 5 years of age. In this study, we examine associations of early life antibiotic prescriptions with weight outcomes at 108 to 132 months of age ("10 years")., Methods: We used electronic health record data from 2009 through 2016 from 10 health systems in PCORnet, a national distributed clinical research network. We examined associations of any (vs no) antibiotics at <24 months of age with body mass index z-score (BMI-z) at 10 years adjusted for confounders selected a priori. We further examined dose response (number of antibiotic episodes) and antibiotic spectrum (narrow and broad)., Results: Among 56,727 included children, 57% received any antibiotics at <24 months; at 10 years, mean (standard deviation) BMI-z was 0.54 (1.14), and 36% had overweight or obesity. Any versus no antibiotic use at <24 months was associated with a slightly higher BMI-z at 10 years among children without a complex chronic condition (β 0.03; 95% confidence interval [CI] 0.01, 0.05) or with a complex chronic condition (β 0.09; 95% CI 0.03, 0.15). Any versus no antibiotic use was not associated with odds of overweight or obesity at 10 years among children without (odds ratio 1.02; 95% CI 0.97, 1.07) or with a complex chronic condition (odds ratio 1.07; 95% CI 0.96, 1.19)., Conclusions: The small and likely clinically insignificant associations in this study are consistent with our previous 5-year follow-up results, suggesting that, if this relationship is indeed causal, early increases in weight are small but maintained over time., (Copyright © 2020 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To discuss selected endocrine causes of hypertension and to provide practical clinical recommendations regarding the evaluation and treatment of these disorders., Recent Findings: More than 15 endocrine disorders with varying rates of prevalence can cause hypertension. For example, primary aldosteronism may exist in up to 20% of patients with resistant hypertension. Recognition of these important secondary causes of hypertension is essential to provide contemporary targeted therapies in order to improve long-term disease outcomes. Clinicians must have a broad understanding of the prevalence, clinical presentation, and current diagnostic modalities for endocrine causes of hypertension to facilitate prompt referral, identification, and optimal management of these disorders. Endocrine causes of hypertension are multifactorial and, in some cases, widely prevalent. It is important for clinicians considering secondary causes of hypertension to be knowledgeable about the underlying pathophysiology of these disorders and to understand when additional evaluation and treatment may be needed.

The National Institutes of Health's Environmental Influences on Child Health Outcomes (ECHO) program aims to study high-priority and high-impact pediatric conditions. This broad-based health initiative is unique in the National Institutes of Health research portfolio and involves 2 research components: (1) a large group of established centers with pediatric cohorts combining data to support longitudinal studies (ECHO cohorts) and (2) pediatric trials program for institutions within Institutional Development Awards states, known as the ECHO Institutional Development Awards States Pediatric Clinical Trials Network (ISPCTN). In the current presentation, we provide a broad overview of the ISPCTN and, particularly, its importance in enhancing clinical trials capabilities of pediatrician scientists through the support of research infrastructure, while at the same time implementing clinical trials that inform future health care for children. The ISPCTN research mission is aligned with the health priority conditions emphasized in the ECHO program, with a commitment to bringing state-of-the-science trials to children residing in underserved and rural communities. ISPCTN site infrastructure is critical to successful trial implementation and includes research training for pediatric faculty and coordinators. Network sites exist in settings that have historically had limited National Institutes of Health funding success and lacked pediatric research infrastructure, with the initial funding directed to considerable efforts in professional development, implementation of regulatory procedures, and engagement of communities and families. The Network has made considerable headway with these objectives, opening two large research studies during its initial 18 months as well as producing findings that serve as markers of success that will optimize sustainability., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Cranberries are high in polyphenols, and epidemiological studies have shown that a high-polyphenol diet may reduce risk factors for diabetes and CVD. The present study aimed to determine if short-term cranberry beverage consumption would improve insulin sensitivity and other cardiovascular risk factors. Thirty-five individuals with obesity and with elevated fasting glucose or impaired glucose tolerance participated in a randomised, double-blind, placebo-controlled, parallel-designed pilot trial. Participants consumed 450 ml of low-energy cranberry beverage or placebo daily for 8 weeks. Changes in insulin sensitivity and cardiovascular risk factors including vascular reactivity, blood pressure, RMR, glucose tolerance, lipid profiles and oxidative stress biomarkers were evaluated. Change in insulin sensitivity via hyperinsulinaemic-euglycaemic clamp was not different between the two groups. Levels of 8-isoprostane (biomarker of lipid peroxidation) decreased in the cranberry group but increased in the placebo group (-2·18 v. +20·81 pg/ml; P = 0·02). When stratified by baseline C-reactive protein (CRP) levels, participants with high CRP levels (>4 mg/l) benefited more from cranberry consumption. In this group, significant differences in the mean change from baseline between the cranberry (n 10) and the placebo groups (n 7) in levels of TAG (-13·75 v. +10·32 %; P = 0·04), nitrate (+3·26 v. -6·28 µmol/l; P = 0·02) and 8-isoprostane (+0·32 v. +30·8 pg/ml; P = 0·05) were observed. These findings indicate that 8 weeks of daily cranberry beverage consumption may not impact insulin sensitivity but may be helpful in lowering TAG and changing certain oxidative stress biomarkers in individuals with obesity and a proinflammatory state.

Background: Less than one-third of women gain an appropriate amount of weight during pregnancy, which can influence the long-term health of both the mother and the child. Economically disadvantaged women are the most vulnerable to maternal obesity, excessive weight gain during pregnancy, and poor birth outcomes. Effective and scalable health care strategies to promote healthy weight gain during pregnancy specifically tailored for these women are lacking., Objective: This paper presents the design and protocol of a biphasic, community-based eHealth trial, SmartMoms in WIC, to increase the adherence to healthy gestational weight gain (GWG) recommendations in low-income mothers receiving women, infant, and children (WIC) benefits., Methods: Phase 1 of the trial included using feedback from WIC mothers and staff and participants from 2 community peer advisory groups to adapt an existing eHealth gestational weight management intervention to meet the needs of women receiving WIC benefits. The health curriculum, the format of delivery, and incentive strategies were adapted to be culturally relevant and at an appropriate level of health literacy. Phase 2 included a pragmatic randomized controlled trial across the 9 health care regions in Louisiana with the goal of enrolling 432 women. The SmartMoms in WIC intervention is an intensive 24-week behavioral intervention, which includes nutrition education and exercise strategies, and provides the technology to assist with weight management, delivered through a professionally produced website application., Results: Phase 1 of this trial was completed in July 2019, and recruitment for phase 2 began immediately thereafter. All data are anticipated to be collected by Spring 2023., Conclusions: The SmartMoms in WIC curriculum was methodically developed using feedback from community-based peer advisory groups to create a culturally relevant, mobile behavioral intervention for mothers receiving WIC benefits. The randomized clinical trial is underway to test the effectiveness of a sustainable eHealth program on the incidence rates of appropriate GWG. SmartMoms in WIC may be able to offer an innovative, cost-effective, and scalable solution for GWG management in women served by WIC., Trial Registration: ClinicalTrials.gov NCT04028843; https://clinicaltrials.gov/ct2/show/NCT04028843., International Registered Report Identifier (irrid): DERR1-10.2196/18211., (©Emily W Flanagan, Abby D Altazan, Natalie R Comardelle, L Anne Gilmore, John W Apolzan, Jessica St. Romain, Julie C Hardee, Renee S Puyau, Christy L Mayet, Robbie A Beyl, S Ariel Barlow, Sarah Surber Bounds, Kelsey N Olson, Betty M Kennedy, Daniel S Hsia, Leanne M Redman. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 10.09.2020.)

Background: High levels of sedentary behavior and low physical activity are associated with poor health, and the cognitive determinants of these behaviors in children and adolescents are not well understood. To address this gap, we developed a novel, non-verbal, computer-based assessment to quantify the degree to which youth prefer to be sedentary relative to physically active in their leisure time., Methods: The Activity Preference Assessment (APA) uses a forced-choice paradigm to understand implicit decision-making processes when presented with common sedentary and physical activities. The APA bias score ranges from - 100 to + 100, with positive scores indicating a relative preference for sedentary activities, and negative scores representing a preference for physical activities. In 60 children ages 8-17 years, we assessed the validity of this behavioral task against a free-choice play observation, accelerometry-measured activity, anthropometrics and body composition, and cardiorespiratory fitness. We explored neighborhood, family, and individual-level factors that may influence implicit activity preferences. Test-retest reliability was assessed over one week., Results: The majority of children (67%) preferred sedentary relative to physical activities. APA bias scores were positively associated with sedentary time during free-choice play. In girls, bias scores were negatively associated with average daily MVPA. APA bias scores were positively associated with body fat and negatively associated with cardiorespiratory fitness. These findings were independent of age, sex, and race/ethnicity. Neighborhood access to physical activity spaces, the number of people in the home, perceived physical self-competence (e.g., coordination, strength), and self-reported depressive symptoms were associated with activity preferences. The intra-class correlation for test-retest reliability was r = 0.59., Conclusions: The APA shows promise as a novel tool for quantifying children's relative preference for sedentary versus physical activities. Implicit bias scores from the APA are clinically meaningful, as shown by significant associations with adiposity and cardiorespiratory fitness. Future longitudinal studies should examine the directionality of the association between preferences and health markers, and the degree to which implicit activity preferences are modifiable. Importantly, the task only takes an average of 10 min to complete, highlighting a potential role as an efficient screening tool for the propensity to be sedentary versus physically active., Trial Registration: ClinicalTrials.gov NCT03624582 .

Purpose: The aim of the study was to assess the associations of meeting physical activity (PA), sleep, and dietary guidelines with cardiometabolic risk factors and adiposity in adolescents., Methods: The sample included adolescents aged 10-16 years. Accelerometry was used to measure PA and sleep over 7 days, 24 h/d. The PA guideline was defined as ≥60 min/d of moderate-to-vigorous PA. The sleep guideline was 9-11 hours (10-13 years) or 8-10 hours (14-16 years) per night. The dietary guideline was based on the Healthy Eating Index calculated from dietary recalls. Cardiometabolic risk factors and adiposity were assessed in an in-patient setting. Linear regression was used to examine the association between meeting each guideline and cardiometabolic risk factors/adiposity, adjusted for confounders and meeting other guidelines., Results: Of the 342 participants, 251 (73%) provided complete measurements. Adolescents were 12.5 ± 1.9 years (African American [37%] and white [57%], girls [54%], and overweight or obesity [48%]). Half met the sleep guideline (52%), few met the PA guideline (11%), and the top quintile was preselected as meeting the diet guideline (20%). Most met one (47%) or no guidelines (35%), and few met multiple guidelines (18%). Meeting the PA guideline was associated with lower cardiometabolic risk factors and adiposity (p < .05 for all). Compared with meeting no guidelines, those who met multiple guidelines had lower cardiometabolic risk factors and adiposity (p < .05 for all)., Conclusions: Few met the PA or multiple guidelines, and those not meeting guidelines were associated with adverse cardiometabolic factors and adiposity. Multidisciplinary strategies for improving multiple behaviors are needed to improve adolescent health., (Copyright © 2020 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

While there are eight medications/combinations approved for the treatment of obesity in adults, the options for the treatment of obesity in adolescents remain limited. Evidence for obesity medication use in adolescents is limited due to the relatively small number of clinical trials that have been completed and the few adolescents that have been included in many of the trials. The goal of this review will be to present the current evidence for the medications approved for adolescents, medications not approved for adolescents but have adolescent data, and medications approved for adults with the prospect for use in adolescents. We will also discuss current limitations and next steps in the exploration of future treatment options., Competing Interests: Conflict of interest statement: DSH has served as site principal investigator for clinical trials funded by Novo Nordisk and Vivus, Inc., with funds paid directly to his institution. No conflicts of interest exist for any of the authors., (© The Author(s), 2020.)

Objective: This study aimed to determine whether different measures of habitual physical activity (PA) at baseline predict weight change, weight compensation, and changes in energy intake (EI) during a 24-week supervised aerobic exercise intervention., Methods: Data from 108 participants (78 women; 48.7 [SD: 11.6] years; BMI 31.4 [SD: 4.6] kg/m 2 ), randomly assigned to either the moderate-dose exercise group (8 kcal/kg of body weight per week) or the high-dose exercise group (20 kcal/kg of body weight per week) of the Examination of Mechanisms of Exercise-induced Weight Compensation (E-MECHANIC) trial, were analyzed. Moderate-to-vigorous PA (MVPA), steps per day, and PA energy expenditure (PAEE) were measured with SenseWear armbands (BodyMedia, Pittsburgh, Pennsylvania), and total activity energy expenditure and EI were estimated with doubly labeled water, all over 2 weeks, before and toward the end of the intervention. Multiple linear regression models, adjusted for sex, exercise group, and baseline value of the outcome, were used., Results: Baseline habitual MVPA levels predicted weight change (β = -0.275; P = 0.020), weight compensation (β = -0.238; P = 0.043), and change in EI (β = -0.318; P = 0.001). Associations between baseline PAEE and outcomes were comparable, whereas steps per day and, importantly, total activity energy expenditure (via doubly labeled water) did not significantly predict change in weight-related outcomes., Conclusions: While acknowledging substantial variability in the data, on average, lower baseline habitual MVPA and PAEE levels were associated with less weight loss from exercise, higher compensation, and increased EI., (© 2020 The Obesity Society.)

Objective: To conduct a preliminary assessment of the relationships between cardiorespiratory fitness, adiposity, and cardiometabolic health using gold standard measures in diverse youth ranging from overweight to severe obesity., Methods: Twenty of 30 participants (mean [SD]; age 13.2 [1.8] y, 55% female, 45% African American) met the criteria for VO2peak during a graded cycle ergometer test to volitional fatigue. The body composition was measured by dual-energy X-ray absorptiometry (percentage of body fat, fat mass index, and fat-free mass) and magnetic resonance imaging (abdominal visceral and subcutaneous [SAT] adipose tissue). The VO2peak was expressed relative to fat-free mass. Fasting lipid levels, glycemic biomarkers, and vital signs were examined individually and used in a composite cardiometabolic risk score. Accelerometer-measured physical activity and sedentary time were included as covariates., Results: VO2peak was negatively associated with abdominal SAT (r = -.49, P < .05), but not visceral adipose tissue or markers of cardiometabolic health. The association between SAT and VO2peak was partly explained by habitual sedentary time., Conclusions: We demonstrated a significant negative association between cardiorespiratory fitness and SAT in a diverse group of high-risk youth. The inclusion of rigorous, laboratory-based measures and youth with severe obesity extends the previous work in pediatric populations.

Aims: To assess the pharmacokinetic (PK) and pharmacodynamic characteristics of VI-0521, a fixed-dose combination of immediate-release phentermine (PHEN) and extended-release topiramate (TPM) in adolescents aged 12 to 17 years with obesity, and to report weight loss and adverse events using this drug combination., Materials and Methods: This was a multicentre, randomized, double-blind, parallel-design, placebo-controlled study in adolescents with obesity. A total of 42 adolescents were randomly assigned in a 1:1:1 ratio to placebo, or to a mid-dose (PHEN/TPM 7.5 mg/46 mg), or a top-dose (PHEN/TPM 15 mg/92 mg) of VI-0521. A total of 26 adolescents were included in the PK analysis (14 from the mid-dose group and 12 from the top-dose group)., Results: On day 56, arithmetic means of terminal elimination half-life, apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) were consistent across dose levels for both PHEN and TPM. Arithmetic means of CL/F and Vc/F for PHEN and TPM administered as a combination in adolescents with obesity were within 10% to 30% of those previously assessed in adults with obesity enrolled in phase II and III studies. A higher proportion of adolescents in both the mid- and top-dose groups (13.3% and 50.0%, respectively) compared with placebo (0.0%) reached ≥5% weight loss at day 56. The least squares (LS) mean change in systolic blood pressure from baseline to day 56 was -5.2 mmHg for the placebo group, -2.5 mmHg for the mid-dose group, and - 5.5 mmHg for the top-dose group. The LS mean change in diastolic blood pressure from baseline to day 56 was -2.4 mmHg for the placebo group, +3.8 mmHg for the mid-dose group, and + 2.0 mmHg for the top-dose group. Participants in the top-dose group had increases in heart rate from baseline of 4.1 bpm, while participants in the mid-dose group experienced a mean decrease in heart rate of 4.5 bpm at day 56. Both PHEN/TPM dose combinations were safe and well tolerated., Conclusions: Treatment of adolescents with obesity using a fixed-dose combination of PHEN/TPM for 8 weeks resulted in exposure to PHEN and TPM that was comparable to that observed in adults, statistically significant weight loss, and a tolerable safety profile. These data indicate that both mid- and top-dose levels are appropriate for longer-term safety and efficacy studies in adolescents., (© 2019 John Wiley & Sons Ltd.)

Objective: Fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG) from a 75-g oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) can lead to different results when diagnosing prediabetes and diabetes. The Hemoglobin Glycation Index (HGI) quantifies the interindividual variation in glycation resulting in discrepancies between FPG and HbA1c. We used data from the Vitamin D and Type 2 Diabetes (D2d) study to calculate HGI, to identify HGI-associated variables, and to determine how HGI affects prediabetes and diabetes diagnosis., Measurements: A linear regression equation [HbA1c (%) = 0.0164 × FPG (mg/dL) + 4.2] was derived using the screening cohort (n = 6829) and applied to calculate predicted HbA1c. This was subtracted from the observed HbA1c to determine HGI in the baseline cohort with 2hPG data (n = 3945). Baseline variables plus prediabetes and diabetes diagnosis by FPG, HbA1c, and 2hPG were compared among low, moderate, and high HGI subgroups., Results: The proportion of women and Black/African American individuals increased from low to high HGI subgroups. Mean FPG decreased and mean HbA1c increased from low to high HGI subgroups, consistent with the HGI calculation; however, mean 2hPG was not significantly different among HGI subgroups., Conclusions: High HGI was associated with Black race and female sex as reported previously. The observation that 2hPG was not different across HGI subgroups suggests that variation in postprandial glucose is not a significant source of population variation in HGI. Exclusive use of HbA1c for diagnosis will classify more Black individuals and women as having prediabetes compared with using FPG or 2hPG., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: This study aimed to compare the proinsulin to C-peptide (PI:C) ratio in those with recent-onset type 1 diabetes versus those with no diabetes and to explore the effect of age on PI:C ratio., Methods: Nineteen participants (n=9 with type 1 diabetes and n=10 with no diabetes) between 10 and 19 years of age were enrolled in a single-visit cross-sectional study and underwent blood collection after 10 hours fasting to measure proinsulin and C-peptide levels as well as other glycemic parameters., Results: The median PI:C ratio was significantly different between type 1 diabetes and nondiabetes groups (6.24% vs. 1.46%, P&lt;0.01). A significant negative correlation was seen between PI:C ratio and patient age after adjustment for duration of diabetes (r2=0.61, P=0.02) in the type 1 diabetes group., Conclusion: Even in this narrow age window, a higher degree of β-cell dysfunction indicated by a higher PI:C ratio was seen in younger children.