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Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

RationaleImproved understanding of the lung microbiome in HIV-infected individuals could lead to better strategies for diagnosis, therapy, and prophylaxis of HIV-associated pneumonias. Differences in the oral and lung microbiomes in HIV-infected and HIV-uninfected individuals are not well defined. Whether highly active antiretroviral therapy influences these microbiomes is unclear.ObjectivesWe determined whether oral and lung microbiomes differed in clinically healthy groups of HIV-infected and HIV-uninfected subjects.MethodsParticipating sites in the Lung HIV Microbiome Project contributed bacterial 16S rRNA sequencing data from oral washes and bronchoalveolar lavages (BALs) obtained from HIV-uninfected individuals (n = 86), HIV-infected individuals who were treatment naive (n = 18), and HIV-infected individuals receiving antiretroviral therapy (n = 38).Measurements and main resultsMicrobial populations differed in the oral washes among the subject groups (Streptococcus, Actinomyces, Rothia, and Atopobium), but there were no individual taxa that differed among the BALs. Comparison of oral washes and BALs demonstrated similar patterns from HIV-uninfected individuals and HIV-infected individuals receiving antiretroviral therapy, with multiple taxa differing in abundance. The pattern observed from HIV-infected individuals who were treatment naive differed from the other two groups, with differences limited to Veillonella, Rothia, and Granulicatella. CD4 cell counts did not influence the oral or BAL microbiome in these relatively healthy, HIV-infected subjects.ConclusionsThe overall similarity of the microbiomes in participants with and without HIV infection was unexpected, because HIV-infected individuals with relatively preserved CD4 cell counts are at higher risk for lower respiratory tract infections, indicating impaired local immune function.

Abstract Background As concern about youth obesity continues to mount, there is increasing consideration of widespread policy changes to support improved nutritional and enhanced physical activity offerings in schools. A critical element in the success of such programs may be to involve students as spokespeople for the program. Making such a public commitment to healthy lifestyle program targets (improved nutrition and enhanced physical activity) may potentiate healthy behavior changes among such students and provide a model for their peers. This paper examines whether student's "public commitment"--voluntary participation as a peer communicator or in student-generated media opportunities--in a school-based intervention to prevent diabetes and reduce obesity predicted improved study outcomes including reduced obesity and improved health behaviors. Methods Secondary analysis of data from a 3-year randomized controlled trial conducted in 42 middle schools examining the impact of a multi-component school-based program on body mass index (BMI) and student health behaviors. A total of 4603 students were assessed at the beginning of sixth grade and the end of eighth grade. Process evaluation data were collected throughout the course of the intervention. All analyses were adjusted for students' baseline values. For this paper, the students in the schools randomized to receive the intervention were further divided into two groups: those who participated in public commitment activities and those who did not. Students from comparable schools randomized to the assessment condition constituted the control group. Results We found a lower percentage of obesity (greater than or equal to the 95th percentile for BMI) at the end of the study among the group participating in public commitment activities compared to the control group (21.5% vs. 26.6%, p = 0.02). The difference in obesity rates at the end of the study was even greater among the subgroup of students who were overweight or obese at baseline; 44.6% for the "public commitment" group, versus 53.2% for the control group (p = 0.01). There was no difference in obesity rates between the group not participating in public commitment activities and the control group (26.4% vs. 26.6%). Conclusions Participating in public commitment activities during the HEALTHY study may have potentiated the changes promoted by the behavioral, nutrition, and physical activity intervention components. Trial Registration ClinicalTrials.gov number, NCT00458029

Aims: To assess associations of psychosocial factors with medication adherence in young adults with youth‐onset type 2 diabetes in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY2) cohort. Methods: Participants (mean age 26 years) completed validated psychosocial measures. Adherence to oral hypoglycemia agents (OHAs) was assessed with 3‐monthly unannounced phone pill counts; insulin adherence by self‐report. Logistic and linear regressions identified factors associated with "low‐adherence" (<80% of pills/insulin) controlling for confounders. Results: Of 212 participants taking OHAs (67% female, 39% Hispanic, 36% non‐Hispanic Black), 69.8% were low‐adherent. After adjustment, beliefs that medicines are necessary was associated with lower odds of low‐adherence (p = 0.040, dichotomous). Less self‐management support (p = 0.008), no healthcare coverage (p = 0.001), ≥1 (p = 0.008)/≥2 (p = 0.045) need insecurities were associated with higher odds of low‐adherence. Factors associated with lower % adherence (continuous) were beliefs that medicines are harmful (p < 0.001)/overused (p = 0.007)/less necessary (p = 0.022), low self‐management support (p = 0.003), food insecurity (p = 0.036), no healthcare coverage (p < 0.001), ≥1 (p = 0.003)/≥2 (p = 0.018) need insecurities. Of 192 taking insulin (69% female, 36% Hispanic, 41% non‐Hispanic Black, 16% non‐Hispanic white), 37.0% were low‐adherent. Beliefs that medicines are overused (p = 0.009), that diabetes is not serious (p = 0.010), low diabetes self‐efficacy (p = 0.035), high distress (p = 0.027), low self‐management support (p = 0.001), food insecurity (p = 0.020), ≥1 (p = 0.011)/≥2 (p = 0.015) insecurities increased odds of insulin low‐adherence. Conclusion s : Poor medication adherence, common in young adults with youth‐onset type 2 diabetes, is associated with interfering beliefs, diabetes distress and social factors. We must address these factors to develop tailored interventions for this vulnerable group. [ABSTRACT FROM AUTHOR]

Objective: The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study reported a 13.9% prevalence of diabetic retinopathy (DR) in youth with mean ± SD type 2 diabetes duration of 4.9 ± 1.5 years. After 7 years of additional follow-up, we report the risk factors for progression of DR in the TODAY cohort.Research Design and Methods: Retinal photographs (n = 517) were obtained in 2010-2011 and again in 2017-2018 (n = 420) with standard stereoscopic seven-field digital fundus photography. Photographs were graded centrally using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. A total of 367 patients with gradable fundus photographs in at least one eye at both assessments were included in analyses of progression of DR, defined as an increase of three or more steps on the ETDRS scale.Results: With mean ± SD age of 25.4 ± 2.5 years and diabetes duration of 12.0 ± 1.5 years, there was a 49% prevalence of any DR among participants. Prevalence by DR stage was as follows: 39% for very mild or mild nonproliferative DR (NPDR), 6% moderate to severe NPDR, and 3.8% proliferative DR. Compared with nonprogressors, participants who progressed three or more steps had significantly lower BMI, higher HbA1c, higher blood pressure, increased triglycerides, decreased C-peptide, and higher prevalence of other comorbidities. Multivariate analysis demonstrated that HbA1c was the dominant factor impacting DR progression.Conclusions: Poor glycemic control of youth-onset type 2 diabetes imparts a high risk for progression of DR, including advanced, sight-threatening disease by young adulthood. [ABSTRACT FROM AUTHOR]

Abstract Background As concern about youth obesity continues to mount, there is increasing consideration of widespread policy changes to support improved nutritional and enhanced physical activity offerings in schools. A critical element in the success of such programs may be to involve students as spokespeople for the program. Making such a public commitment to healthy lifestyle program targets (improved nutrition and enhanced physical activity) may potentiate healthy behavior changes among such students and provide a model for their peers. This paper examines whether student's "public commitment"--voluntary participation as a peer communicator or in student-generated media opportunities--in a school-based intervention to prevent diabetes and reduce obesity predicted improved study outcomes including reduced obesity and improved health behaviors. Methods Secondary analysis of data from a 3-year randomized controlled trial conducted in 42 middle schools examining the impact of a multi-component school-based program on body mass index (BMI) and student health behaviors. A total of 4603 students were assessed at the beginning of sixth grade and the end of eighth grade. Process evaluation data were collected throughout the course of the intervention. All analyses were adjusted for students' baseline values. For this paper, the students in the schools randomized to receive the intervention were further divided into two groups: those who participated in public commitment activities and those who did not. Students from comparable schools randomized to the assessment condition constituted the control group. Results We found a lower percentage of obesity (greater than or equal to the 95th percentile for BMI) at the end of the study among the group participating in public commitment activities compared to the control group (21.5% vs. 26.6%, p = 0.02). The difference in obesity rates at the end of the study was even greater among the subgroup of students who were overweight or obese at baseline; 44.6% for the "public commitment" group, versus 53.2% for the control group (p = 0.01). There was no difference in obesity rates between the group not participating in public commitment activities and the control group (26.4% vs. 26.6%). Conclusions Participating in public commitment activities during the HEALTHY study may have potentiated the changes promoted by the behavioral, nutrition, and physical activity intervention components. Trial Registration ClinicalTrials.gov number, NCT00458029

This paper examined whether a two-year change in fitness, body mass index (BMI) or the additive effect of change in fitness and BMI were associated with change in cardiometabolic risk factors among youth. Cardiometabolic risk factors, BMI group (normal weight, overweight or obese) were obtained from participants at the start of 6th grade and end of 8th grade. Shuttle run laps were assessed and categorized in quintiles at both time points. Regression models were used to examine whether changes in obesity, fitness or the additive effect of change in BMI and fitness were associated with change in risk factors. There was strong evidence (p < .001) that change in BMI was associated with change in cardiometabolic risk factors. There was weaker evidence of a fitness effect, with some evidence that change in fitness was associated with change in total cholesterol, HDL-C, LDL-C and clustered risk score among boys, as well as HDL-C among girls. Male HDL-C was the only model for which there was some evidence of a BMI, fitness and additive BMI'fitness effect. Changing body mass is central to the reduction of youth cardiometabolic risk. Fitness effects were negligible once change in body mass had been taken into account [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the effects of varied lifestyle intervention programs designed to ameliorate excess gestational weight gain (GWG) in pregnant women with overweight or obesity compared with standard care, including effects on pregnancy outcomes.Methods: Seven clinical centers conducted separate randomized clinical trials to test different lifestyle intervention strategies to modify GWG in diverse populations. Eligibility criteria, specific outcome measures, and assessment procedures were standardized across trials. The results of the separate trials were combined using an individual-participant data meta-analysis.Results: For the 1,150 women randomized, the percent with excess GWG per week was significantly lower in the intervention group compared with the standard care group (61.8% vs. 75.0%; odds ratio [95% CI]: 0.52 [0.40 to 0.67]). Total GWG from enrollment to 36 weeks' gestation was also lower in the intervention group (8.1 ± 5.2 vs. 9.7 ± 5.4 kg; mean difference: -1.59 kg [95% CI:-2.18 to -0.99 kg]). The results from the individual trials were similar. The intervention and standard care groups did not differ in preeclampsia, gestational diabetes, cesarean delivery, or birth weight.Conclusions: Behavioral lifestyle interventions focusing primarily on diet and physical activity among women with overweight and obesity resulted in a significantly lower proportion of women with excess GWG. This modest beneficial effect was consistent across diverse intervention modalities in a large, racially and socioeconomically diverse US population of pregnant women. [ABSTRACT FROM AUTHOR]

Objective To examine the prevalence of metabolic syndrome (MetS) in youth-onset type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Methods Prevalence of MetS (ATP III definition) was compared at baseline ( n = 679) and at 6 ( n = 625) and 24 months ( n = 545) using chi-square tests. Laboratory data were examined between MetS classifications at each time point using ANOVA. Results Baseline prevalence of MetS was 75.8% and did not differ by treatment group or change over time. MetS was more common in females (83.1%) than males (62.3%; P < 0.0001) at baseline; this difference persisted over 24 months. Prevalence of MetS was similar between ethnic groups at baseline but greater in Hispanics (82.7%) vs. non-Hispanic Whites (67.5%; P = 0.0017) and non-Hispanic Blacks (72.7%; P = 0.0164) at 24 months. Although MetS was common in participants with hemoglobin A1c < 7.0% (74.4% at baseline; no significant change over 24 months), it was more common in those who did not maintain glycemic control at 6 months (80.3%; P = 0.0081). Elevated C-reactive protein, ALT, IL-6, and PAI-1 levels were more frequent with MetS. Conclusions Persistent high prevalence of MetS in youth-onset diabetes, even with excellent glycemic control, is of concern given the associated increased cardiovascular risk. [ABSTRACT FROM AUTHOR]

Background: The prevalence of type 2 diabetes in youth is increasing, but little is known regarding the occurrence of related complications as these youths transition to adulthood.Methods: We previously conducted a multicenter clinical trial (from 2004 to 2011) to evaluate the effects of one of three treatments (metformin, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention) on the time to loss of glycemic control in participants who had onset of type 2 diabetes in youth. After completion of the trial, participants were transitioned to metformin with or without insulin and were enrolled in an observational follow-up study (performed from 2011 to 2020), which was conducted in two phases; the results of this follow-up study are reported here. Assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease were performed annually, and assessments for retinal disease were performed twice. Complications related to diabetes identified outside the study were confirmed and adjudicated.Results: At the end of the second phase of the follow-up study (January 2020), the mean (±SD) age of the 500 participants who were included in the analyses was 26.4±2.8 years, and the mean time since the diagnosis of diabetes was 13.3±1.8 years. The cumulative incidence of hypertension was 67.5%, the incidence of dyslipidemia was 51.6%, the incidence of diabetic kidney disease was 54.8%, and the incidence of nerve disease was 32.4%. The prevalence of retinal disease, including more advanced stages, was 13.7% in the period from 2010 to 2011 and 51.0% in the period from 2017 to 2018. At least one complication occurred in 60.1% of the participants, and at least two complications occurred in 28.4%. Risk factors for the development of complications included minority race or ethnic group, hyperglycemia, hypertension, and dyslipidemia. No adverse events were recorded during follow-up.Conclusions: Among participants who had onset of type 2 diabetes in youth, the risk of complications, including microvascular complications, increased steadily over time and affected most participants by the time of young adulthood. Complications were more common among participants of minority race and ethnic group and among those with hyperglycemia, hypertension, and dyslipidemia. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01364350 and NCT02310724.). [ABSTRACT FROM AUTHOR]

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy. Multivariable logistic regression models were constructed to assess associations between sleep and circadian measures with outcomes of interest, such as loss of glycemic control and diabetes complications. A total of 421 participants (34.2% male), mean age 23.6 ± 2.5 yr, mean body mass index (BMI) of 36.1 ± 8.3 kg/m 2 , and mean diabetes duration of 10.0 ± 1.5 yr were evaluated. Self-reported short sleep duration, daytime sleepiness, and sleep quality were not associated with loss of glycemic control or diabetes complications. Late self-reported bedtime (after midnight) on work/school nights, rather than self-expressed chronotype or circadian misalignment, was independently associated with loss of glycemic control. An association was seen between late bedtimes and albuminuria but was attenuated after adjusting for depression. In conclusion, late bedtime on work/school days, rather than short sleep duration, daytime sleepiness, or poor sleep quality, was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes. NEW & NOTEWORTHY The prevalence of type 2 diabetes in youth is increasing at an alarming rate. Identifying potentially modifiable factors modulating glycemic control is critically important to reduce micro and macrovascular complications. In a large cohort of youth-onset type 2 diabetes, self-reported late bedtime on work/school days was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.

Background: The prevalence of type 2 diabetes in youth is increasing, but little is known regarding the occurrence of related complications as these youths transition to adulthood., Methods: We previously conducted a multicenter clinical trial (from 2004 to 2011) to evaluate the effects of one of three treatments (metformin, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention) on the time to loss of glycemic control in participants who had onset of type 2 diabetes in youth. After completion of the trial, participants were transitioned to metformin with or without insulin and were enrolled in an observational follow-up study (performed from 2011 to 2020), which was conducted in two phases; the results of this follow-up study are reported here. Assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease were performed annually, and assessments for retinal disease were performed twice. Complications related to diabetes identified outside the study were confirmed and adjudicated., Results: At the end of the second phase of the follow-up study (January 2020), the mean (±SD) age of the 500 participants who were included in the analyses was 26.4±2.8 years, and the mean time since the diagnosis of diabetes was 13.3±1.8 years. The cumulative incidence of hypertension was 67.5%, the incidence of dyslipidemia was 51.6%, the incidence of diabetic kidney disease was 54.8%, and the incidence of nerve disease was 32.4%. The prevalence of retinal disease, including more advanced stages, was 13.7% in the period from 2010 to 2011 and 51.0% in the period from 2017 to 2018. At least one complication occurred in 60.1% of the participants, and at least two complications occurred in 28.4%. Risk factors for the development of complications included minority race or ethnic group, hyperglycemia, hypertension, and dyslipidemia. No adverse events were recorded during follow-up., Conclusions: Among participants who had onset of type 2 diabetes in youth, the risk of complications, including microvascular complications, increased steadily over time and affected most participants by the time of young adulthood. Complications were more common among participants of minority race and ethnic group and among those with hyperglycemia, hypertension, and dyslipidemia. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01364350 and NCT02310724.)., (Copyright © 2021 Massachusetts Medical Society.)