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Ram Jagannathan,1 João Sérgio Neves,2,3 Brenda Dorcely,4 Stephanie T Chung,5 Kosuke Tamura,6 Mary Rhee,7 Michael Bergman8 1Division of Hospital Medicine, Emory University School of Medicine, Atlanta, GA, USA; 2Department of Surgery and Physiology, Cardiovascular Research and Development Center, Faculty of Medicine, University of Porto, Porto, Portugal; 3Department of Endocrinology, Diabetes and Metabolism, Sa&uppertilde;o Joa&uppertilde; o University Hospital Center, Porto, Portugal; 4NYU Grossman School of Medicine, Division of Endocrinology, Diabetes, Metabolism, New York, NY 10016, USA; 5Diabetes, Obesity, and Endocrinology Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; 6Social Determinants of Obesity and Cardiovascular Risk Laboratory, Cardiovascular Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; 7Emory University School of Medicine, Department of Medicine, Division of Endocrinology, Metabolism, and Lipids, Atlanta VA Health Care System, Atlanta, GA 30322, USA; 8NYU Grossman School of Medicine, NYU Diabetes Prevention Program, Endocrinology, Diabetes, Metabolism, VA New York Harbor Healthcare System, Manhattan Campus, New York, NY 10010, USACorrespondence: Ram JagannathanDivision of Hospital Medicine, Emory University School of Medicine, Atlanta, GA 30322, USAEmail ram.jagannathan@emory.eduAbstract: For over 100 years, the oral glucose tolerance test (OGTT) has been the cornerstone for detecting prediabetes and type 2 diabetes (T2DM). In recent decades, controversies have arisen identifying internationally acceptable cut points using fasting plasma glucose (FPG), 2-h post-load glucose (2-h PG), and/or HbA1c for defining intermediate hyperglycemia (prediabetes). Despite this, there has been a steadfast global consensus of the 2-h PG for defining dysglycemic states during the OGTT. This article reviews the history of the OGTT and recent advances in its application, including the glucose challenge test and mathematical modeling for determining the shape of the glucose curve. Pitfalls of the FPG, 2-h PG during the OGTT, and HbA1c are considered as well. Finally, the associations between the 30-minute and 1-hour plasma glucose (1-h PG) levels derived from the OGTT and incidence of diabetes and its complications will be reviewed. The considerable evidence base supports modifying current screening and diagnostic recommendations with the use of the 1‐h PG. Measurement of the 1‐h PG level could increase the likelihood of identifying high-risk individuals when the pancreatic ß-cell function is substantially more intact with the added practical advantage of potentially replacing the conventional 2‐h OGTT making it more acceptable in the clinical setting.Keywords: OGTT history, OGTT, glycated hemoglobin, diabetes, gestational diabetes, pathophysiology, 1-h post-load glucose, prediction, shape index

Previous studies have shown that the spatial extent of crowding in peripheral vision is reduced when a target letter and its flanking letters have opposite contrast polarity. We have examined if this reduction in crowding leads to improved reading performance. We compared the spatial extent of crowding, visual-span profiles (plots of letter-recognition accuracy versus letter position), and reading speed at 10 degrees inferior visual field, using white letters, black letters, or mixtures of white and black letters, presented on a mid-gray background. Consistent with previous studies, the spatial extent of crowding was reduced when the target and flanking letters had opposite contrast polarity. However, using mixed contrast polarity did not lead to improvements in visual-span profiles or reading speed. [ABSTRACT FROM AUTHOR]

Accurate reading of words and text relies on reliable identification of letters in left-to-right order. Previous studies have shown that people often make letter-reversal errors when identifying strings of letters away from fixation. These errors contribute to a decline in letter identification performance away from fixation. This study tests the hypothesis that these errors are due to decreased precision (increased position noise) in the coding of letter position in the periphery. To test our hypothesis, we measured observers' performance for identifying pairs of adjacent letters presented within eight letter positions left and right of fixation. The task was to name the two letters of each pair, from left to right. Responses were scored in two ways for each letter position: (1) letters were identified correctly and in the correct position, and (2) letters were identified correctly but in the wrong position. The ratio of these two scores, when subtracted from 1, gives the empirical rate of mislocation errors. Our primary finding shows that the coding of letter position becomes increasingly imprecise with distance from fixation. A model in which the encoded position of each letter is independent and Gaussian distributed, and in which the spread of the distribution governs the precision of localizing the letter accounts for the empirical rate of mislocation errors. We also found that precision of letter position coding scales with letter size but the precision does not improve with the use of a pre-cue. [ABSTRACT FROM AUTHOR]

Abstract Background Pancreatic ductal adenocarcinoma is a lethal disease with a 5-year survival rate of 4% and typically presents in an advanced stage. In this setting, prognostic markers identifying the more agrressive tumors could aid in managment decisions. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3, also known as IMP3 or KOC) is an oncofetal RNA-binding protein that regulates targets such as insulin-like growth factor-2 (IGF-2) and ACTB (beta-actin). Methods We evaluated the expression of IGF2BP3 by immunohistochemistry using a tissue microarray of 127 pancreatic ductal adenocarcinomas with tumor grade 1, 2 and 3 according to WHO criteria, and the prognostic value of IGF2BP3 expression. Results IGF2BP3 was found to be selectively overexpressed in pancreatic ductal adenocarcinoma tissues but not in benign pancreatic tissues. Nine (38%) patient samples of tumor grade 1 (n = 24) and 27 (44%) of tumor grade 2 (n = 61) showed expression of IGF2BP3. The highest rate of expression was seen in poorly differentiated specimen (grade 3, n = 42) with 26 (62%) positive samples. Overall survival was found to be significantly shorter in patients with IGF2BP3 expressing tumors (P = 0.024; RR 2.3, 95% CI 1.2-4.8). Conclusions Our data suggest that IGF2BP3 overexpression identifies a subset of pancreatic ductal adenocarcinomas with an extremely poor outcome and supports the rationale for developing therapies to target the IGF pathway in this cancer.

Sustained stress, assessed as a high allostatic load score (ALS), is an independent cardiovascular disease (CVD) risk factor in older adults but its associations in young people are undefined. Since neurological maturation impacts stress adaptation and CVD risk, we assessed the relationship of ALS with CVD profile using a tiered approach stratified by age (emerging adults 20-24y, EA vs. young adults 25-30y, YA) and ALS (high vs. low). In 1054 healthy African-PREDICT participants, we determined: 1) ALS in EA vs. YA; 2) the relationship between ALS with cardiovascular health; and 3) the odds of high ALS>4 to identify masked hypertension and prediabetes as cardiometabolic outcomes. A 9-component four-domain ALS was compiled: neuro-endocrine (dehydroepiandrosterone, cortisol), inflammatory (interleukin-6, C-reactive protein), cardiovascular (systolic and diastolic-blood pressure), and metabolic (total cholesterol, HDL-cholesterol, body mass index). Retinal vessel caliber, pulse wave velocity (PWV), cardiac structure and function were assessed. Median ALS was 3 (range:1-9). A high-ALS>4 was more common in YA vs. EA (47%vs.35%, P =0.032). Higher ALS associated with narrower retinal arteries (P<0.01), greater PWV ( P =<0.01), lower diastolic ( P <0.01) and left ventricular function ( P <0.01). High-ALS increased the odds of having masked hypertension, prediabetes, narrower retinal arteries, higher LV mass, poorer diastolic and ventricular function (all P ≤0.01) in EA and YA independent of traditional CVD risk factors. The composite ALS identified early stress dysregulation in cardiometabolic health and higher odds for prediabetes and masked hypertension in young adults. Cumulative stress may be a modifiable independent cardiometabolic risk factor in younger populations that needs further investigation.

Aims: Because one-hour post-load plasma glucose (1h-PG) ≥ 155 mg/dL (8.6 mmol/L) has been proposed as an early marker for future diabetes but lacks sufficient longitudinal confirmation of its risk, we aimed to evaluate the risk of T2D based on 1h-PG and track changes of insulin sensitivity and β-cell function over time by 1h-PG in a longitudinal cohort., Methods: OGTTs were conducted every 2 years in the 10-year longitudinal Korean Genome Epidemiology study (n = 6144) with three groups characterized at baseline: Low 1h-PG (< 155 mg/dL) with Normal Glucose Tolerance (NGT), High 1h-PG (≥155 mg/dL) with NGT, and prediabetes (PreDM)., Results: T2D risk was higher in people with High 1h-PG with NGT and PreDM than those with Low 1h-PG with NGT. Baseline insulin sensitivity in Low 1h-PG as measured by the insulin sensitivity and secretion (ISS) model and Matsuda insulin sensitivity index (ISI) was higher than in High 1h-PG, which was comparable to PreDM. β-cell function as assessed by ISS and the insulinogenic index decreased from Low 1h-PG to High 1h-PG to PreDM. Over time, insulin sensitivity decreased in the three groups. Time from High 1h-PG to T2D was 0.9 years shorter than from Low 1h-PG. All participants passed the 1h-PG threshold for T2D (209 mg/dL, 11.6 mmol/L) first, and 74 % passed the 1h-PG threshold for impaired glucose tolerance (IGT; 155 mg/dL) first., Conclusions: High 1h-PG NGT is an intermediate risk category between Low 1h-PG NGT and PreDM and may provide an opportunity for early intervention to prese rve ß-cell function., 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 Elsevier B.V. All rights reserved.)

Background: CaO-SiO 2 -P 2 O 5 -B 2 O 3 bioactive glass-ceramics7 (BGS-7) are known for their strong integration with bone and stability and are commonly used in spinal fusions., Purpose: This study aimed to compare fusion rates and radiological and clinical outcomes between BGS-7 and allograft spacers with iliac bone grafts (IBG) in multilevel anterior cervical discectomy and fusion (ACDF) surgeries., Study Design/setting: This retrospective study was conducted at BRM Medical Center., Patient Sample: We included patients who underwent multilevel ACDF at BRM Medical Center between January 2012 and December 2023. The patients had symptoms such as cervical radiculopathy and myelopathy due to cervical disc herniation, stenosis, and spondylosis., Outcome Measures: We evaluated the preoperative and postoperative Japanese Orthopedic Association (JOA) scores, neck disability index (NDI), functional rating index (FRI), and visual analog scale (VAS) scores for the neck, shoulder, and upper extremities at 6 months and 1 year after surgery., Methods: Fusion rates were assessed using dynamic radiography and computed tomography (CT) scans at 1 year postoperatively. Radiological measurements were obtained from preoperative and postoperative plain radiographs., Results: At the 1-year follow-up, the fusion rates were 89.5% for BGS-7 and 92.2% for the allograft cage on dynamic radiographs (p=0.156) and 93.4% and 90.4%, respectively, on CT scans (p=0.319), confirming both internal and external osseointegration. Subsidence rates were 4% for BGS-7 and 10% for the allograft spacer group. Both groups showed increased cervical lordosis (CL), segmental lordosis (SL), and segmental height postoperatively, with maintained lower segmental height (LSH) in the BGS-7 group than in the allograft spacer group at postoperatively 1 year. No adjacent segmental disease (ASD) occurred in either group. The JOA, NDI, and FRI showed significant improvements in both groups. The VAS scores decreased significantly in both groups, indicating improved clinical outcomes., Conclusions: In multilevel ACDF, BGS-7 demonstrated fusion rates comparable to those of the allograft spacer with IBG, experiencing fewer instances of subsidence and cage fracture. Therefore, BGS-7 spacer can be safely utilized in multilevel ACDF as a substitute for traditional allograft spacers, without the need for additional IBG., Competing Interests: Declarations. Competing interests: The authors declare that they have no affiliations or involvement with any organization or entity with any competing interests or funding on the subject matter or materials discussed in this manuscript., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Thermally activated delayed fluorescence (TADF)-based electroluminescence (EL) devices adopting a host/guest strategy in their emitting layer (EML) are capable of realizing high efficiency. However, TADF emitters composed of donor and acceptor moieties as guests dispersed in organic host materials containing a donor and/or an acceptor are subject to donor-acceptor (D-A) interactions. In addition, electron delocalization between neighboring emitter molecules could form different species of aggregates. Here, we investigate the effects of intermolecular interacting emission species on the optoelectronic properties of sky-blue/green/red (sB/G/R) TADF emitters as guests using poly(biphenyl-Si/Ge) grafted with various donor moieties as hosts. We found the presence of guest/guest exciplex (D g /A g )*, host/guest exciplexes (D h /A g )*, and aggregates through the exploration of interactions between neighboring TADF guest molecules and between host and TADF-guest molecules. The nonradiative 3 (D h /A g )* (Δ E ST ≈ 0.5 eV) could increase the internal conversion rate (k IC ) and reduce delayed luminescence, and both of them could cause a decrease in PLQY. The luminescence of 3 (D h /A g )* may have a positive or negative effect on PLQY depending on its triplet energy. As the singlet and triplet energies of (aggregate)* are lower than those of (ICT)*, energy transfer from (ICT)* to (aggregate)* could occur. The low PLQY nature of (aggregate)* means that it is more likely to cause quenching in device emission. The emissions from (D h /A g )* and (aggregate)* are found to have increased full width at half-maximum and lead to lower emission color purity. Such intermolecular interactions should also occur in host/guest (TADF) systems and nondoped TADF emitter systems and thus are important factors for the molecular design of the TADF emitter and/or its accompanying host for high device efficiency and emission color purity.

Background: Up to 50% of adolescents who undergo metabolic and bariatric surgery (MBS) have obesity 3 years post-MBS, placing them at continued risk for the consequences of obesity., Objectives: We conducted an open-label, 16-week pilot study of liraglutide in adolescents with obesity after sleeve gastrectomy (SG) to investigate liraglutide effects on weight and body mass index (BMI) post-SG., Methods: Adolescents aged 12-20.99 years with obesity and a history of SG ≥1 year prior were enrolled. Liraglutide was initiated at 0.6 mg/day, escalated weekly to a maximum of 3 mg/day, with treatment duration 16 weeks. Fasting laboratory assessments and an oral glucose tolerance test were performed at baseline and end-treatment., Results: A total of 43 participants were screened, 34 initiated liraglutide (baseline BMI 41.2 ± 7.7 kg/m 2 ), and 31 (91%) attended the end-treatment visit. BMI decreased by 4.3% (p < 0.001) with liraglutide. Adolescents who had poor initial response to SG (<20% BMI reduction at BMI nadir) had less weight loss with liraglutide. Fasting glucose and haemoglobin A1C concentrations significantly decreased. There were no serious treatment-emergent adverse events reported., Conclusions: Liraglutide treatment was feasible and associated with a BMI reduction of 4.3% in adolescents who had previously undergone SG, quantitatively similar to results obtained in adolescents with obesity who have not undergone MBS., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings., Methods: Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate., Results: Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; P =0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P <0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P =0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells., Conclusions: Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385., Competing Interests: None.

Aims: The gold standard clamp measurements for insulin sensitivity (cSI), β-cell function (cBCF) and disposition index (cDI = cSI*cBCF), are not practical in large-scale studies. We sought to: 1) validate a mathematical model-derived DI from oral glucose tolerance tests (OGTT) with insulin (mDI) and without (mDI-woI) against cDI and oral disposition index (oDI) evaluate the ability of the novel indices to detect prediabetes and type 2 diabetes., Methods: We carried out a secondary analysis of previously reported cross-sectional observational studies. The Insulin Sensitivity and Secretion mathematical model for glucose-insulin dynamics was applied to five-point and three-point OGTTs synchronized with hyperinsulinemic-euglycemic and hyperglycemic clamps from 130 youth with obesity (68 NGT, 33 IGT, 29 T2D)., Results: Model-derived DI correlated well with clamp DI (R = 0.76 (logged)). Between NGT and IGT, mDI and mDI-woI decreased more than oDI and cDI, (60 and 59% vs 29 and 27%), and by receiver operating characteristic (ROC) analysis were superior at detecting IGT than oDI and cDI (AUC 0.88, 0.87 vs 0.68, 0.65), as was mean glucose (AUC 0.87)., Conclusions: mDI-woI is better than oDI or the labor-intensive cDI for detecting dysglycemia in obese youth. Bypassing insulin measurements with mDI-woI from the OGTT provides a cost-effective approach for large-scale epidemiological studies of dysglycemia in youth., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)

Background: Whole-food, plant-based vegan diets, low in oils, and Mediterranean diets, rich in extra virgin olive oil (EVOO), reduce cardiovascular disease risk factors. Optimal quantity of dietary fat, particularly EVOO, is unclear., Methods and Results: In a randomized crossover trial with weekly cooking classes, adults with ≥5% cardiovascular disease risk followed a high (4 tablespoons/day) to low (<1 teaspoon/day) or low to high EVOO whole-food, plant-based diet for 4 weeks each, separated by a 1-week washout. The primary outcome was difference in low-density lipoprotein cholesterol (LDL-C) from baseline. Secondary measures were changes in additional cardiometabolic markers. Linear mixed models assessed changes from baseline between phases, with age, sex, and body weight change as covariates. In 40 participants, fat intake comprised 48% and 32% of energy during high and low EVOO phases, respectively. Both diets resulted in comparable reductions in LDL-C, total cholesterol, apolipoprotein B, high-density lipoprotein cholesterol, glucose, and high-sensitivity C-reactive protein (all P <0.05). With diet-sequence interactions for LDL-C, differences were detected between diets by diet order (mean±SEM high to low: Δ-12.7[5.9] mg/dL, P =0.04 versus low to high: Δ+15.8[6.8] mg/dL, P =0.02). Similarly, low to high order led to increased glucose, total cholesterol, and high-density lipoprotein cholesterol (all P <0.05). Over period 1, LDL-C reductions were -25.5(5.1) post-low versus -16.7(4.2) mg/dL post-high EVOO, P =0.162, which diminished over period 2., Conclusions: Both plant-based diet patterns improved cardiometabolic risk profiles compared with baseline diets, with more pronounced decreases in LDL-C after the low EVOO diet. Addition of EVOO after following a low intake pattern may impede further lipid reductions., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04828447.

The Caregiver Strain Questionnaire assesses the three dimensions of caregiver strain, namely the objective, subjective externalized and subjective internalized strain. It was validated among caregivers of children with Autism Spectrum Disorder (ASD) in the United States and Mainland China with promising psychometric properties.This study aimed to develop and validate the Chinese (traditional script) version of the Caregiver Strain Questionnaire (C-CGSQ) among 198 caregivers of children with ASD in Hong Kong. The C-CGSQ showed excellent internal consistency (α = 0.958) and test-retest reliability (Spearman's r = 0.966). Concurrent, convergent, divergent validity and a three-factor structure (consistent with previous studies) were established. The C-CGSQ demonstrated promising psychometric properties in measuring caregiver strain among caregivers of Chinese ASD children in Hong Kong., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Resting energy expenditure (REE) assessments can help inform clinical treatment decisions in adolescents with elevated body mass index (BMI), but current equations are suboptimal for severe obesity. We developed a predictive REE equation for youth with severe obesity and obesity-related comorbidities and compared results to previously published predictive equations., Methods: Data from indirect calorimetry, clinical measures, and body composition per Dual x-ray absorptiometry (DXA) were collected from five sites. Data were randomly divided into development (N = 438) and validation (N = 118) cohorts. A predictive equation was developed using Elastic Net regression, using sex, race, ethnicity, weight, height, BMI percent of the 95th%ile (BMIp95), waist circumference, hip circumference, waist/hip ratio, age, Tanner stage, fat and fat-free mass. This equation was verified in the validation cohort and compared with 11 prior equations., Results: Data from the total cohort (n = 556, age 15 ± 1.7 years, 77% female, BMIp95 3.3 ± 0.94) were utilized. The best fit equation was REE = -2048 + 18.17 × (Height in cm) - 2.57 × (Weight in kg) + 7.88 × (BMIp95) + 189 × (1 = male, 0 = female), R 2  = 0.466, and mean bias of 23 kcal/day., Conclusion: This new equation provides an updated REE prediction that accounts for severe obesity and metabolic complications frequently observed in contemporary youth., (© 2024 World Obesity Federation.)

Ultra-processed foods high in fat and sugar may be addictive, in part, due to their purported ability to induce an exaggerated postingestive brain dopamine response akin to drugs of abuse. Using standard [ 11 C]raclopride positron emission tomography (PET) displacement methods used to measure brain dopamine responses to addictive drugs, we measured postingestive striatal dopamine responses to an ultra-processed milkshake high in fat and sugar in 50 young, healthy adults over a wide body mass index range (BMI 20-45 kg/m 2 ). Surprisingly, milkshake consumption did not result in significant postingestive dopamine response in the striatum ( p =0.62) nor any striatal subregion (p>0.33) and the highly variable interindividual responses were not significantly related to adiposity (BMI: r =0.076, p =0.51; %body fat: r =0.16, p =0.28). Thus, postingestive striatal dopamine responses to an ultra-processed milkshake were likely substantially smaller than many addictive drugs and below the limits of detection using standard PET methods.

Objective: Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and β-cell function after therapy in AA Y-T2D., Methods: In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. β-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test., Results: At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 ± 1.3 vs -0.6 ± 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 ± 0.68 vs -0.05 ± 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P = .9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P = .003) but not gluconeogenesis or mSI., Conclusion: Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance β-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed., (Published by Oxford University Press on behalf of the Endocrine Society 2023.)

Background: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD)., Objective: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG)., Methods: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity., Results: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups., Conclusions: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease., Trial Registration: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022., (© 2024. The Author(s).)

Efficient and accurate methods to estimate insulin sensitivity ( S I ) and β-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes (T2D). Existing methods range in sensitivity, input data, and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological than intravenous methods. However, current analytical methods for OGTT-derived S I and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic surrogate indices (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new insulin secretion and sensitivity (ISS) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. This model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. This model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including postchallenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts across the lifespan. The new model had a strong correlation with gold-standard estimates from intravenous glucose tolerance tests and insulin clamps. The ISS model has broad applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk. NEW & NOTEWORTHY The pathogenesis of type 2 diabetes (T2D) is determined by a balance between insulin sensitivity ( S I ) and β-cell function (BCF), which can be determined by gold standard direct measurements or estimated by fitting differential equation models to oral glucose tolerance tests (OGTTs). We propose and validate a new differential equation model that is simpler to use than current models and requires less data while maintaining good correlation and agreement with gold standards. Matlab and Python code is freely available.

The prevalence of youth-onset type 2 diabetes is growing worldwide and current first-line treatment with metformin and intensive behavior and lifestyle changes are suboptimal in over 50% of youth within 2 years of diagnosis. This perspective article is a call to action for reevaluation of existing strategies and critical appraisal of metformin as first-line therapy in youth-onset type 2 diabetes. Increased attention should be given to novel therapeutics approved in youth, including glucagon-like 1 receptor agonists, sodium glucose cotransporter-2, and sociocultural interventions that will promote diabetes self-management., (Published by Oxford University Press on behalf of the Endocrine Society 2023.)

Introduction: Cases and severity of presentation of youth-onset type 2 diabetes (Y-T2D) increased during the COVID-19 pandemic, yet the potential drivers of this rise remain unknown. During this time public health mandates paused in-person education and limited social interactions, resulting in radical lifestyle changes. We hypothesized that the incidence and severity of presentation of Y-T2D increased during virtual learning amidst the COVID-19 pandemic., Materials and Methods: We conducted a single-center retrospective chart review to identify all newly diagnosed cases of Y-T2D (n = 387) at a pediatric tertiary care center in Washington, DC during three predetermined learning periods as defined by learning modality in Washington, DC Public Schools: pre-pandemic in-person learning (March 11, 2018-March 13, 2020), pandemic virtual learning (March 14, 2020-August 29, 2021), and pandemic in-person learning (August 30, 2021-March 10, 2022) periods., Results: Incident cases were stable during pre-pandemic in-person learning (3.9 cases/month, 95% CI: 2.8-5.4 cases/month), increased to a peak during virtual learning (18.7 cases/month, 95% CI: 15.9-22.1 cases/month), and declined with return to in-person learning (4.3 cases/month, 95% CI: 2.8-6.8 cases/month). Y-T2D incidence was 16.9 (95% CI: 9.8-29.1, p &lt; 0.001) and 5.1-fold higher (95% CI: 2.9-9.1, p &lt; 0.001) among non-Hispanic Black and Latinx youth, respectively, throughout the study period. Overall COVID-19 infection rates at diagnosis were low (2.5%) and were not associated with diabetes incidence (p = 0.26)., Conclusions: This study provides timely insights into an important and modifiable correlate of Y-T2D incidence, its disproportionate impact on underserved communities, and the need to consider the effects on long-term health outcomes and preexisting healthcare inequities when designing public policy., (© 2023 S. Karger AG, Basel.)

Objective: Ribonuclease P RNA component H1 (RPPH1) is a long non-coding RNA (lncRNA) associated with cancer progression. Higher RPPH1 expression in breast and cervical cancer samples than that in normal tissues were observed through the lncRNASNP2 database; therefore, silencing RPPH1 expression might be a potential strategy for cancer treatments, even though RPPH1 is also an RNA subunit of ribonuclease P involved in processing transfer RNA (tRNA) precursors and the effect of RPPH1 knockdown is not yet fully understood., Methods: Differentially expressed genes (DEGs) were identified through RNA sequencing in each shRNA-transfected RPPH1 knockdown MDA-MB-231, RPPH1 knockdown HeLa cell, and respective control cells, then the gene ontology enrichment analysis was performed by IPA and MetaCore database according to these DEGs, with further in vitro experiments validating the effect of RPPH1 silencing in MDA-MB-231 and HeLa cells., Results: Hundreds of down-regulated DEGs were identified in RPPH1 knockdown MDA-MB-231 and HeLa cells while bioinformatics analysis revealed that these genes were involved in pathways related to immune response and cancerogenesis. Compared to mock- and vector-transfected cells, the production of mature tRNAs, cell proliferation and migration capacity were inhibited in RPPH1-silenced HeLa and MDA-MB-231 cells. Additionally, RPPH1 knockdown promoted G1 cell cycle arrest mainly through the down-regulation of cyclin D1, although glycolytic pathways were only affected in RPPH1 knockdown HeLa cells but not MDA-MB-231 cells., Conclusion: This study demonstrated that knockdown RPPH1 affected tRNA production, cell proliferation and metabolism. Our findings might provide insight into the role of RPPH1 in tumor development., Competing Interests: None., (AJTR Copyright © 2023.)

The relationship between adiposity and dopamine type-2 receptor binding potential (D2BP) in the human brain has been repeatedly studied for >20 years with highly discrepant results, likely due to variable methodologies and differing study populations. We conducted a controlled inpatient feeding study to measure D2BP in the striatum using positron emission tomography with both [ 18 F]fallypride and [ 11 C]raclopride in pseudo-random order in 54 young adults with a wide range of body mass index (BMI 20-44 kg/m 2 ). Within-subject D2BP measurements using the two tracers were moderately correlated (r=0.47, p<0.001). D2BP was negatively correlated with BMI as measured by [ 11 C]raclopride (r= -0.51; p<0.0001) but not [ 18 F]fallypride (r=-0.01; p=0.92) and these correlation coefficients were significantly different from each other (p<0.001). Given that [ 18 F]fallypride has greater binding affinity to dopamine type-2 receptors than [ 11 C]raclopride, which is more easily displaced by endogenous dopamine, our results suggest that adiposity is positively associated with increased striatal dopamine tone., Competing Interests: Conflict of Interest The authors have declared no conflicts of interest.

Aims: The timing of increase in 1-hour PG and its utility as an earlier predictor of both prediabetes (PreDM) and type 2 diabetes (T2D) compared to 2-hour PG (2 h-PG) are unknown. To evaluate the timing of crossing of the 1 h-PG ≥ 155 mg/dl (8.6 mmol/L) for PreDM and 209 mg/dl (11.6 mmol/L) for T2D and respective current 2 h-PG thresholds of 140 mg/dl (7.8 mmol/L) and 200 mg/dl (11.1 mmol/L)., Methods: Secondary analysis of 201 Southwest Native Americans who were followed longitudinally for 6-10 years and had at least 3 OGTTs., Results: We identified a subset of 43 individuals who first developed PreDM by both 1 h-PG and 2 h-PG criteria during the study. For most (32/43,74%), 1 h-PG ≥ 155 mg/dl was observed before 2 h-PG reached 140 mg/dl (median [IQR]: 1.7 [-0.25, 4.59] y; mean ± SEM: 5.3 ± 1.9 y). We also identified a subset of 33 individuals who first developed T2D during the study. For most (25/33, 75%), 1 h-PG reached 209 mg/dl earlier (median 1.0 [-0.56, 2.02] y; mean ± SEM: 1.6 ± 0.8 y) than 2 h-PG reached 200 mg/dl, diagnostic of T2D., Conclusions: 1 h-PG ≥ 155 mg/dl is an earlier marker of elevated risk for PreDM and T2D than 2 h-PG ≥ 140 mg/dl., 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., (Published by Elsevier B.V.)

Background: Objective markers of ultraprocessed foods (UPF) may improve the assessment of UPF intake and provide insight into how UPF influences health., Objectives: To identify metabolites that differed between dietary patterns (DPs) high in or void of UPF according to Nova classification., Methods: In a randomized, crossover, controlled-feeding trial (clinicaltrials.govNCT03407053), 20 domiciled healthy participants (mean ± standard deviation: age 31 ± 7 y, body mass index [kg/m 2 ] 22 ± 11.6) consumed ad libitum a UPF-DP (80% UPF) and an unprocessed DP (UN-DP; 0% UPF) for 2 wk each. Metabolites were measured using liquid chromatography with tandem mass spectrometry in ethylenediaminetetraacetic acid plasma, collected at week 2 and 24-h, and spot urine, collected at weeks 1 and 2, of each DP. Linear mixed models, adjusted for energy intake, were used to identify metabolites that differed between DPs., Results: After multiple comparisons correction, 257 out of 993 plasma and 606 out of 1279 24-h urine metabolites differed between UPF-DP and UN-DP. Overall, 21 known and 9 unknown metabolites differed between DPs across all time points and biospecimen types. Six metabolites were higher (4-hydroxy-L-glutamic acid, N-acetylaminooctanoic acid, 2-methoxyhydroquinone sulfate, 4-ethylphenylsulfate, 4-vinylphenol sulfate, and acesulfame) and 14 were lower following the UPF-DP; pimelic acid, was lower in plasma but higher in urine following the UPF-DP., Conclusions: Consuming a DP high in, compared with 1 void of, UPF has a measurable impact on the short-term human metabolome. Observed differential metabolites could serve as candidate biomarkers of UPF intake or metabolic response in larger samples with varying UPF-DPs. This trial was registered at clinicaltrials.gov as NCT03407053 and NCT03878108., (Published by Elsevier Inc.)

Purpose of Review: The global epidemic of youth-onset obesity is tightly linked to the rising burden of cardiometabolic disease across the lifespan. While the link between childhood obesity and cardiovascular disease is established, this contemporary review summarizes recent and novel advances in this field that elucidate the mechanisms and impact of this public health issue., Recent Findings: The review highlights the emerging data supporting the relationship between childhood adverse events, social determinants of health, and systemic and institutional systems as etiological factors. We also provide updates on new screening and treatment approaches including updated nutrition and dietary guidelines and benchmarks for pediatric obesity screening, novel pharmacological agents for pediatric obesity and type 2 diabetes such as glucagon-like 1 peptide receptor agonists, and we discuss the long-term safety and efficacy data on surgical management of pediatric obesity. The global burden of pediatric obesity continues to rise and is associated with accelerated and early vascular aging especially in youth with obesity and type 2 diabetes. Socio-ecological determinants of risk mediate and moderate the relationship of childhood obesity with cardiometabolic disease. Recognizing the importance of neighborhood level influences as etiological factors in the development of cardiovascular disease is critical for designing effective policies and interventions. Novel surgical and pharmacological interventions are effective pediatric weight-loss interventions, but future research is needed to assess whether these agents, within a socio-ecological framework, will be associated with abatement of the pediatric obesity epidemic and related increased cardiovascular disease risk., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Efficient and accurate methods to estimate insulin sensitivity (S I ) and beta-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes. Many methods exist, ranging in input data and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological. However, current analytical methods for OGTT-derived S I and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic models (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new ISS (Insulin Secretion and Sensitivity) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. The model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. The model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including post-challenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts including individuals at high risk of prediabetes (adult women with a wide range of BMI and adolescents with obesity). The new model had strong correlation with gold-standard estimates from intravenous glucose tolerance tests and hyperinsulinemic-euglycemic clamp. The ISS model has broad clinical applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.

In this work, we demonstrated Ga 2 O 3 -based power MOSFETs grown on c-plane sapphire substrates using in-situ TEOS doping for the first time. The β-Ga 2 O 3 :Si epitaxial layers were formed by the metalorganic chemical vapor deposition (MOCVD) with a TEOS as a dopant source. The depletion-mode Ga 2 O 3 power MOSFETs are fabricated and characterized, showing the increase of the current, transconductance, and breakdown voltage at 150 °C. In addition, the sample with the TEOS flow rate of 20 sccm exhibited a breakdown voltage of more than 400 V at RT and 150 °C, indicating that the in-situ Si doping by TEOS in MOCVD is a promising method for Ga 2 O 3 power MOSFETs., (© 2023. The Author(s).)

The thermal warpage of a server-computer-used DIMM socket-PCB assembly after the solder reflow process is studied experimentally, theoretically, and numerically, especially along the socket lines and over the entire assembly. Strain gauge and shadow moiré are used for determining the coefficients of thermal expansion of the PCB and DIMM sockets and for measuring the thermal warpages of the socket-PCB assembly, respectively, while a newly proposed theory and a finite element method (FEM) simulation are used to calculate the thermal warpage of the socket-PCB assembly in order to understand its thermo-mechanical behavior and then further identify some important parameters. The results show that the theoretical solution validated by the FEM simulation provides the mechanics with the critical parameters. In addition, the cylindrical-like thermal deformation and warpage, measured by the moiré experiment, are also consistent with the theory and FEM simulation. Moreover, the results of the thermal warpage of the socket-PCB assembly from the strain gauge suggest a warpage dependence on the cooling rate during the solder reflow process, due to the nature of the creep behavior in the solder material. Finally, the thermal warpages of the socket-PCB assemblies after the solder reflow processes are provided through a validated FEM simulation for future designs and verification.

Disclosure Summary: Dr. Yadav is Chief Scientific Officer and Co-Founder of Postbiotics Inc and has no conflict of interest with this work. All other authors have no conflicts of interest to disclose., Background: Metformin is the only approved first-line oral glucose lowering agent for youth with type 2 diabetes mellitus (Y-T2DM) but often causes gastrointestinal (GI) side effects, which may contribute to reduced treatment adherence and efficacy. Prebiotic intake may reduce metformin's side effects by shifting microbiota composition and activity., Objective: The aims of this study were to determine the feasibility and tolerability of a prebiotic supplement to improve metformin-induced GI symptoms and explore the changes in glycemia and shifts in the microbiota diversity., Methods: In a two-phase pilot clinical trial, we compared, stool frequency and stool form every 1-2 days, and composite lower GI symptoms (weekly) at initiation of daily metformin combined with either a daily prebiotic or a placebo shake in a 1-week randomized double-blind crossover design (Phase 1), followed by a 1-month open-labeled extension (Phase 2). Plasma glycemic markers and stool samples were collected before and after each phase., Results: Six Y-T2DM (17.2 ± 1.7y (mean ± SD), 67% male, BMI (42 ± 9 kg/m 2 ), HbA1c (6.4 ± 0.6%)) completed the intervention. Stool frequency, stool composition, and GI symptom scores did not differ by group or study phase. There were no serious or severe adverse events reported, and no differences in metabolic or glycemic markers. After one week Phase 1metformin/placebo Proteobacteria , Enterobacteriaceae , and Enterobacteriales were identified as candidate biomarkers of metformin effects. Principle coordinate analyses of beta diversity suggested that the metformin/prebiotic intervention was associated with distinct shifts in the microbiome signatures at one week and one month., Conclusion: Administration of a prebiotic fiber supplement during short-term metformin therapy was well tolerated in Y-T2DM and associated with modest shifts in microbial composition. This study provides a proof-of-concept for feasibility exploring prebiotic-metformin-microbiome interactions as a basis for adjunctive metformin therapy., Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04209075., Competing Interests: HY is Chief Scientific Officer and Co-Founder of Postbiotics Inc and has no conflict of interest with this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Dixon, Mishra, Dietsche, Jain, Mabundo, Stagliano, Krenek, Courville, Yang, Turner, Meyers, Estrada, Yadav and Chung.)

Objectives: Despite the development of various cancer treatment methods, chemotherapy remains the most common approach for treating cancer. The risk of tumors acquiring resistance to chemotherapy remains a significant hurdle to the successful treatment of various types of cancer. Therefore, overcoming or predicting multidrug resistance in clinical treatment is essential. The detection of circulating tumor cells (CTCs) is an important component of liquid biopsy and the diagnosis of cancer. This study aims to test the feasibility of single-cell bioanalyzer (SCB) and microfluidic chip technology in identifying patients with cancer resistant to chemotherapy and propose new methods to provide clinicians with new choices. Methods: In this study, we used rapidly isolated viable CTCs from the patient blood samples method combined with SCB technology and a novel microfluidic chip, to predict whether patients with cancer are resistant to chemotherapy. SCB and microfluidic chip were used to select single CTCs, and the accumulation of chemotherapy drug was fluorescently measured in real time on these cells in the absence and presence of permeability-glycoprotein inhibitors. Results: Initially, we successfully isolated viable CTCs from the blood samples of patients. Additionally, the present study accurately predicted the response of 4 lung cancer patients to chemotherapeutic drugs. In addition, the CTCs of 17 patients with breast cancer diagnosed at Zhuhai Hospital of Traditional Chinese and Western Medicine were assessed. The results indicated that 9 patients were sensitive to chemotherapeutic drugs, 8 patients were resistant to a certain degree, and only 1 was completely resistant to chemotherapy. Conclusion: The present study indicated that the SCB technology could be used as a prognostic assay to evaluate the CTCs response to available drugs and guide physicians to treatment options that are most likely to be effective.

Developing an effective host for highly efficient full-color electroluminescence devices through a solution-process is still a challenge at present. Here, we use the σ-π conjugated polymer, poly(acridan grafted biphenyl germanium) P(DMAC-Ge), having the highest triplet energy ( E T ) 2.86 eV among conjugated polymers as the host in sky-blue phosphorescence, TADFs (blue (B), green (G), and red (R)), and hybrid white (W) PLEDs. Upon doping with a sky-blue phosphor-emitter (Firpic), the resulting device gives the high EQE max 19.7% with B max 24,918 cd/m 2 . The Ge-containing polymer backbone can provide as a channel for electron transport and charge trap into the guest as manifested by the electroluminescence dynamics. Further introducing the bipolar material DCzPPy as cohost, the devices with a sky-blue phosphor (Firpic) and each of the TADF-guests─B (DMAC-TRZ), G (DACT-II), and R (TPA-DCPP) in the EML─achieve the high maximum EQEs as 19.7%, 19.4%, 21.5% and 3.82% with the emission peaks at 470, 485, 508, and 630 nm, respectively. As the three guests (DMAC-TRZ, Ir-O, Ir-R) are doped together into the emitting layer, we obtain a TADF-phosphor (T-P) hybrid white PLED giving a record-high EQE 22.5% among the solution processed hybrid OLED with CIE (0.34, 0.40) and B max 28,945 cd/m 2 . These results manifest that P(DMAC-Ge) is a potential polymer host for full-color TADF and hybrid white light PLEDs with high performance.

Introduction: The transition from paediatric to adult diabetes care in youth-onset diabetes (type 1 diabetes mellitus, Y-T1DM and type 2 diabetes mellitus, Y-T2DM) is associated with worsening glycaemic control, missed clinical visits, decreased medication adherence and the emergence of cardiometabolic complications. The socio-ecological challenges that influence transitioning to adult diabetes care may be distinct between Y-T1DM and Y-T2DM. The goal of this scoping review is to map the state of the literature on transitioning care in Y-T2DM compared with Y-T1DM and to identify the main sources and types of evidence available. The objectives are : (1) to identify the factors within the socio-ecological framework (individual, relationship, community, societal) associated with transitioning to adult care in Y-T2DM compared with Y- T1DM, and (2) to identify knowledge gaps related to transitioning to adult care., Methods: The scoping review protocol and reporting will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews guidelines. A systematic search of scientific databases (PubMed, Embase, Cumulative Index to Nursing and Allied Health, Scopus and APA PsycNet will be undertaken for articles between 1 January 1990 and 30 September 2022. Study designs will include peer-reviewed experimental and quasi-experimental published studies without language or country-specific restrictions. We will exclude articles on other diabetes subtypes and will exclude non-peer reviewed articles such as opinion papers, anecdotal reports or supplementary commentaries., Analysis: References will be collated, sorted and extracted using Covidence. Factors associated with transition from paediatric to adult diabetes care in Y-T1DM and Y-T2DM will be identified using the socio-ecological framework and results will be presented in narrative format, tables, and summary graphs., Ethics and Dissemination: Ethical approval will not be applicable for this review., Trial Registration Number: https://osf.io/k2pwc., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Youth with obesity and abnormal glucose tolerance have an increased risk for atherosclerosis but the relative contributions of insulin resistance and hyperglycemia to dyslipidemia and the development of subclinical atherosclerosis are unknown., Objective: This work aims to determine the association between insulin resistance, dyslipidemia, and carotid intimal thickness (cIMT) in adolescents with normal and abnormal glucose tolerance., Methods: An observational cohort study in 155 youth: 44 obese insulin sensitive (OIS; fasting insulin ≤ 20 µM/mL, body mass index [BMI] ≥ 95th percentile), 35 obese insulin resistant (OIR; fasting insulin > 20 µM/mL, BMI ≥ 95th percentile), 34 obese abnormal glucose tolerant (AGT; BMI ≥ 95th percentile), and 42 Lean (BMI 5th-85th percentile). Lipids, lipoprotein particle size and concentration (-P), insulin sensitivity (SI an intravenous glucose test), and CMIT were compared using linear models adjusted for age, race/ethnicity, biological sex, and Tanner stage. Lipid/lipoprotein profile and CMIT were reevaluated in a subset after 2 years., Results: Compared to OIS and Lean, OIR and AGT had elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) but similar total cholesterol and low-density lipoprotein cholesterol (LDL-C). Among OIS, OIR, AGT, lower SI was associated with atherogenic lipids (higher triglycerides, LDL-C, non-HDL-C, and lower HDL-C) and lipoproteins (higher total LDL-P and small HDL-P, and lower large HDL-P). There was a steeper decline in the association of SI with HDL-C and large HDL-P in AGT compared with OIR and OIS. cIMT was comparable across groups and inversely correlated with SI, with no change after 2 years., Conclusion: Among youth with obesity, insulin resistance was associated with an atherogenic lipoprotein/lipid profile and cIMT, regardless of glucose tolerance status. Insulin resistance in AGT youth was associated with a shift to smaller HDL-P compared to normoglycemic youth with obesity. Alterations in HDL-P metabolism may be early adverse manifestations of hyperglycemia in youth with obesity., (Published by Oxford University Press on behalf of the Endocrine Society 2022.)

Nonalcoholic fatty liver disease (NAFLD) in children resulting from the obesity epidemic is widespread and increasing. Although the complexities of pediatric NAFLD are recognized, screening and therapies in children remain limited. Moreover, pediatric NAFLD diagnosis fails to consider insulin resistance and metabolic dysfunction as important determinants. In this issue of the JCI, Cohen et al. explored the contribution of dietary factors to the pathogenesis of NAFLD in adolescent boys with biopsy-proven NAFLD and control participants. Notably, dietary sugar restriction over 8 weeks decreased de novo lipogenesis (DNL) and hepatic fat. The change in DNL correlated with changes in insulin and weight, but not with changes in hepatic fat, supporting the relevance of metabolic dysfunction to NAFLD. These results confirm the pathological link between excessive dietary sugar intake and NAFLD in children and support recent recommendations to change the nomenclature of NAFLD to metabolic associated fatty liver disease (MAFLD).

Gluconeogenesis (GNG), the formation of glucose from noncarbohydrate precursors, requires adenosine triphosphate (ATP). Previous studies have estimated the energetic cost of GNG in humans based on theoretical calculations of rates of GNG, moles of oxygen consumption by GNG, and average oxygen consumption. Few human studies have measured the energy expenditure (EE) due to GNG. We estimated EE attributable to GNG in patients with three insulin resistance conditions and high GNG rates (insulin receptor pathogenic variants, lipodystrophy, and type 2 diabetes) and obesity without diabetes. Fractional GNG was measured by incorporation of deuterium from body water into newly formed glucose, endogenous glucose production (EGP) as glucose appearance following administration of [6,6- 2 H 2 ]glucose, and total GNG as fractional GNG × EGP. EE was measured by indirect calorimetry and compared with predicted EE from the Mifflin St. Jeor equation. EE attributable to GNG was estimated using linear regression after accounting for age and fat-free mass (FFM). EE in patients with insulin resistance was significantly higher than predicted by the Mifflin St. Jeor equation. GNG correlated with resting EE (REE). EE attributable to GNG in patients with insulin resistance was almost one-third of REE, substantially higher than theorized in healthy subjects. Our findings demonstrate that GNG is a significant contributor to EE in insulin-resistant states. Prediction equations may underestimate caloric needs in patients with insulin resistance. Therefore, targeting caloric needs to account for higher EE due to increased GNG should be considered in energy balance studies in patients with insulin resistance. NEW & NOTEWORTHY Gluconeogenesis is an energy-requiring process that is upregulated in diabetes, contributing to hyperglycemia. Previous studies have estimated that gluconeogenesis accounts for less than 10% of resting energy expenditure. This study estimates the energy expenditure attributable to gluconeogenesis in uncommon and severe forms of insulin resistance and common, milder forms of insulin resistance. In these populations, gluconeogenesis accounts for almost one-third of resting energy expenditure, substantially higher than previously theorized in the literature.

Objectives: Examine the association of patient perceptions of care with hemoglobin A1c (HbA1c), medication adherence, and missed appointments in non-Hispanic Black (NHB) and White (NHW) patients with type 2 diabetes (T2DM)., Methods: We used linear and logistic regression models to analyze the association of the Interpersonal Processes of Care survey (IPC) with HbA1c, medication adherence, and missed appointments. We then examined how these associations differed by race., Results: There was no overall association between IPC subdomains and HbA1c in our sample (N = 221). NHB patients perceiving their provider always explained results and medications had a HbA1c on average 0.59 (-1.13, -0.04; p = 0.04) points lower than those perceiving their provider sometimes explained results and medications. No effect was observed in NHWs. Never perceiving disrespect from office staff was associated with an average 0.67 (-1.1, -0.24; p = 0.002) point improvement in medication adherence for all patients. Never perceiving discrimination from providers was associated with a 0.44 (-0.63, -0.25; p < 0.0001) decrease in the probability of missing an appointment for NHB patients., Conclusions: These results demonstrate that particular aspects of communication in the patient-provider interaction may contribute to racial disparities in T2DM., Practice Implications: Communication training for both providers and staff may reduce disparities in T2DM., Competing Interests: Declaration of Competing Interest None, (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Research suggests that providers contribute to racial disparities in health outcomes. Identifying modifiable provider perspectives that are associated with decreased racial disparities will help in the design of effective educational interventions for providers. Methods: This cross-sectional study investigated the association between primary care provider (PCP) perspectives on race and racial disparities with patient outcomes. Results: Study participants included 40 PCPs (70% White, 30% racial minority) caring for 55 patients (45% White, 55% Black) with type 2 diabetes mellitus. Associations of provider perspectives on race and racial disparities with patient variables (Interpersonal Processes of Care [IPC] Survey, which measures patient's ratings of their provider's interpersonal skills; medication adherence; glycemic control) were measured using Spearman correlation coefficients. Results suggest that Black patients of providers who reported greater skill in caring for Black patients had more positive perceptions of care in three of four IPC subdomains (Spearman correlation coefficients of -0.43, 0.44, 0.46, all with p <0.05); however, Black patients of providers who believe that racial disparities are highly prevalent had more negative perceptions of care in three of four IPC subdomains (Spearman correlation coefficients of 0.38, -0.53, -0.51, all with p <0.05). These same provider characteristics had no correlation with outcomes of medication adherence and hemoglobin A1c (HbA1c) or among White patients. Conclusion: Findings suggest that Black patients of providers who felt better equipped to take care of Black patients had a better experience. Therefore, educational interventions for providers may be most effective if they focus on skill development rather than increasing awareness about racial disparities alone., Competing Interests: No competing financial interests exist., (© Olivia M. Lin et al., 2021; Published by Mary Ann Liebert, Inc.)

Youth with obesity have an increased risk for cardiometabolic disease, but identifying those at highest risk remains a challenge. Four biomarkers that might serve this purpose are "by products" of clinical NMR LipoProfile ® lipid testing: LPIR (Lipoprotein Insulin Resistance Index), GlycA (inflammation marker), BCAA (total branched-chain amino acids), and glycine. All are strongly related to insulin resistance and type 2 diabetes (T2DM) in adults (glycine inversely) and are independent of biological and methodological variations in insulin assays. However, their clinical utility in youth is unclear. We compared fasting levels of these biomarkers in 186 youth (42 lean normal glucose tolerant (NGT), 88 obese NGT, 23 with prediabetes (PreDM), and 33 with T2DM. All four biomarkers were associated with obesity and glycemia in youth. LPIR and GlycA were highest in youth with PreDM and T2DM, whereas glycine was lowest in youth with T2DM. While all four were correlated with HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), LPIR had the strongest correlation (LPIR: r = 0.6; GlycA: r = 0.4, glycine: r = -0.4, BCAA: r = 0.2, all P < 0.01). All four markers correlated with HbA1c (LPIR, GlycA, BCAA: r ≥ 0.3 and glycine: r = -0.3, all P < 0.001). In multi-variable regression models, LPIR, GlycA, and glycine were independently associated with HOMA-IR (Adjusted R 2 = 0.473, P < 0.001) and LPIR, glycine, and BCAA were independently associated with HbA1c (Adjusted R 2 = 0.33, P < 0.001). An LPIR index of >44 was associated with elevated blood pressure, BMI, and dyslipidemia. Plasma NMR-derived markers were related to adverse markers of cardiometabolic risk in youth. LPIR, either alone or in combination with GlycA, should be explored as a non-insulin dependent predictive tool for development of insulin resistance and diabetes in youth., Clinical Trial Registration: Clinicaltrials.gov, identifier NCT:02960659., Competing Interests: JO was employed by the company Laboratory Corporation of America Holdings (LabCorp), Morrisville, NC, USA. The remaining 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., (At least a portion of this work is authored by Stephanie T. Chung on behalf of the U.S. Government and, as regards Dr. Chung and the U.S. Government, is not subject to copyright protection in the United States.)

Due to the increasing incidence of malignant gliomas, particularly glioblastoma multiforme (GBM), a simple and reliable GBM diagnosis is needed to screen early the death-threaten patients. This study aimed to identify a protein that can be used to discriminate GBM from low-grade astrocytoma and elucidate further that it has a functional role during malignant glioma progressions. To identify proteins that display low or no expression in low-grade astrocytoma but elevated levels in GBM, glycoprotein fibronectin (FN) was particularly examined according to the mining of the Human Protein Atlas. Web-based open megadata minings revealed that FN was mainly mutated in the cBio Cancer Genomic Portal but dominantly overexpressed in the ONCOMINE (a cancer microarray database and integrated data-mining platform) in distinct tumor types. Furthermore, numerous different cancer patients with high FN indeed exhibited a poor prognosis in the PrognoScan mining, indicating that FN involves in tumor malignancy. To investigate further the significance of FN expression in glioma progression, tumor specimens from five malignant gliomas with recurrences that received at least two surgeries were enrolled and examined. The immunohistochemical staining showed that FN expression indeed determined the distinct progressions of malignant gliomas. Furthermore, the expression of vimentin (VIM), a mesenchymal protein that is strongly expressed in malignant cancers, was similar to the FN pattern. Moreover, the level of epithelial-mesenchymal transition (EMT) inducer transforming growth factor-beta (TGF-β) was almost recapitulated with the FN expression. Together, this study identifies a protein FN that can be used to diagnose GBM from low-grade astrocytoma; moreover, its expression functionally determines the malignant glioma progressions via TGF-β-induced EMT pathway.