Search

Objective: To identify factors associated with declining beta-cell compensation for insulin resistance.Research Design and Methods: In a cohort of Hispanic women with recent gestational diabetes mellitus, oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and bioelectrical impedance measurements were performed at 15-month intervals for up to 5 years, or until fasting plasma glucose exceeded 140 mg/dl (7.8 mmol/l). Data were analyzed to identify predictors of declining beta-cell compensation for insulin resistance (the disposition index [DI]) and to examine the mechanism of weight gain and changes in circulating levels of selected adipokines and inflammatory markers on beta-cell compensation decline.Results: A total of 60 nondiabetic women had a median of four sets of OGTT + IVGTT during a median follow-up of 52 months. Fourteen of the women developed diabetes. None of the baseline characteristics were significantly predictive of a decline in DI. There were significant univariate associations between declining DI and weight gain (specifically fat gain), declining adiponectin and rising C-reactive protein. Multivariate analysis showed that the weight gain was the most significant factor associated with declining DI. The amount of association between weight gain and declining DI was explained 31% by changes in adiponectin and C-reactive protein and 40% by changes in insulin resistance.Conclusions: These results identify weight gain as the strongest factor associated with declining beta-cell compensation for insulin resistance in Hispanic women at high risk for type 2 diabetes. Such effect may be mediated through at least two effects: alterations in adipokine levels and increasing insulin resistance. [ABSTRACT FROM AUTHOR]

Unlabelled: Because of skeletal muscle's density and vascularity, its transection with standard electrocautery can be tedious. In a pilot study we asked whether a linear cutting stapling device decreased surgical time, blood loss, transfusion rates, and complications in patients undergoing above-knee amputation when compared to traditional electrocautery. We retrospectively reviewed 11 patients with above-knee amputation cases using a linear cutting stapling device over a 10-year period and compared those to 13 patients in whom we used electrocautery. The patients treated with the linear cutting stapling device had an average of 97 minutes of surgical time, 302 cc blood loss, and 1.55 units transfusion, compared to an average 119 minutes, 510 cc, and 2.15 units, respectively, with the electrocautery cases. Despite the trends, these parameters, as well as major complications, were similar in these two small groups. In skeletal muscle transection, we believe the linear cutting stapler is a reasonable and potentially cost-effective technical alternative to electrocautery, possibly resulting in less blood loss and shorter surgical time with similar rates of complications.Level Of Evidence: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine longitudinally the relationship among glucose levels, pancreatic beta-cell function, and insulin resistance in women at high risk for type 2 diabetes. Oral glucose tolerance tests (OGTTs) and intravenous glucose tolerance tests (IVGTTs) were performed at 15-month intervals for up to 5 years or until fasting plasma glucose exceeded 140 mg/dl in Hispanic women with recent gestational diabetes. Data were analyzed 1) to compare changes in insulin sensitivity, beta-cell function, and glucose levels between women who had diabetes at one or more visits and women who remained diabetes free and 2) to determine longitudinal patterns of change in glucose levels and acute beta-cell compensation for insulin resistance. Seventy-one women provided data from a total of 280 paired OGTTs and IVGTTs during a median follow-up of 46 months. Compared with the 47 women who remained free of diabetes, the 24 who either had diabetes (n = 9) or developed it during follow-up (n = 15) had higher baseline glucose levels and lower acute beta-cell compensation for insulin resistance. Baseline insulin sensitivity was low in both groups and did not change significantly during follow-up. Fasting and 2-h glucose levels increased more rapidly in the diabetic group despite a decline in acute beta-cell compensation that was significantly slower than the decline in women who did not develop diabetes. This paradox was explained by an accelerated rise in glucose levels for any decline in beta-cell compensation when beta-cell compensation reached approximately 10% of normal, a level that was reached in the women who had or developed diabetes but not in the women who remained diabetes free. These findings define a pathogenesis for type 2 diabetes in one high-risk group that is characterized by a relatively long-term decline in acute beta-cell compensation for chronic insulin resistance that is attended by slowly rising glucose levels. Only relatively late in this process do glucose levels rise rapidly and into the diabetic range. [ABSTRACT FROM AUTHOR]

The Pioglitazone In Prevention Of Diabetes (PIPOD) study was conducted to evaluate beta-cell function, insulin resistance, and the incidence of diabetes during treatment with pioglitazone in Hispanic women with prior gestational diabetes who had completed participation in the Troglitazone In Prevention Of Diabetes (TRIPOD) study. Women who completed the TRIPOD study were offered participation in the PIPOD study for a planned 3 years of drug treatment and 6 months of postdrug washout. Oral glucose tolerance tests were performed annually on pioglitazone and at the end of the postdrug washout. Intravenous glucose tolerance tests (IVGTTs) for assessment of insulin sensitivity and beta-cell function were conducted at baseline, after 1 year on pioglitazone, and at the end of the postdrug washout. Of 95 women who were not diabetic at the end of the TRIPOD study, 89 enrolled in the PIPOD study, 86 completed at least one follow-up visit, and 65 completed all study visits, including the postdrug tests. Comparison of changes in beta-cell compensation for insulin resistance across the TRIPOD and PIPOD studies revealed that pioglitazone stopped the decline in beta-cell function that occurred during placebo treatment in the TRIPOD study and maintained the stability of beta-cell function that had occurred during troglitazone treatment in the TRIPOD study. The risk of diabetes, which occurred at an average rate of 4.6% per year, was lowest in women with the largest reduction in total IVGTT insulin area after 1 year of treatment. The similarity of findings between the PIPOD and TRIPOD studies support a class effect of thiazolidinedione drugs to enhance insulin sensitivity, reduce insulin secretory demands, and preserve pancreatic beta-cell function, all in association with a relatively low rate of type 2 diabetes, in Hispanic women with prior gestational diabetes. [ABSTRACT FROM AUTHOR]

Objective: We have tested whether the Pro12Ala variant of the peroxisome proliferator-activated receptor (PPAR)-gamma nuclear receptor involved in thiazolidinedione (TZD) action accounted for the failure of troglitazone to increase insulin sensitivity in nondiabetic Hispanic women with previous gestational diabetes treated in the Troglitazone in Prevention of Diabetes (TRIPOD) study.Research Design and Methods: Ninety-three women assigned to troglitazone had intravenous glucose tolerance tests at randomization and after 3 months of treatment with troglitazone, 400 mg/day, and were genotyped for the Pro12Ala variant of the PPAR-gamma gene. Subjects were divided into tertiles based on their change in minimal model insulin sensitivity (S(i)) during the first 3 months of troglitazone treatment.Results: The mean changes in S(i) in the bottom, middle, and top tertiles of S(i) response were -0.21 +/- 0.57, 0.91 +/- 0.26, and 2.58 +/- 1.32 min(-1) per microU/ml. 10(-4), respectively. Frequencies of the Ala/- genotype were 30, 22, and 26% in the same three tertiles (P = 0.77). Analysis of phenotypes by genotype revealed only small differences between the Pro/Pro and Ala/- groups, respectively, in baseline S(i) (2.76 +/- 0.19 vs. 2.33 +/- 0.33 x 10(-4) min(-1) per microU/ml; P = 0.27), the change in S(i) after 3 months of troglitazone treatment (1.19 +/- 0.17 vs. 0.93 +/- 0.30; P = 0.46), and the cumulative incidence of diabetes during a median follow-up of 30 months (13 vs. 17%; P = 0.66).Conclusions: Among young Hispanic women at high risk for type 2 diabetes, the Pro12Ala variant of the PPAR-gamma receptor gene did not explain the failure of approximately 1/3 of subjects to increase their insulin sensitivity when placed on troglitazone at a dose of 400 mg/day. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a developmental disorder with symptoms that range from social and communication impairments to restricted interests and repetitive behavior and is the 4th most disabling condition for children aged 5-14. Risk factors of ASD are not fully understood. Environmental risk factors are believed to play a significant role in the ASD epidemic. Research focusing on air pollution exposure as an early-life risk factor of autism is growing, with numerous studies finding associations of traffic and industrial emissions with an increased risk of ASD. One of the possible mechanisms linking autism and air pollution exposure is metabolic dysfunction. However, there were no consensus about the key metabolic pathways and corresponding metabolite signatures in mothers and children that are altered by air pollution exposure and cause the ASD. Therefore, we performed a review of published papers examining the metabolomic signatures and metabolic pathways that are associated with either air pollution exposure or ASD risk in human studies. In conclusion, we found that dysregulated lipid, fatty acid, amino acid, neurotransmitter, and microbiome metabolisms are associated with both short-term and long-term air pollution exposure and the risk of ASD. These dysregulated metabolisms may provide insights into ASD etiology related to air pollution exposure, particularly during the perinatal period in which neurodevelopment is highly susceptible to damage from oxidative stress and inflammation., 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. Published by Elsevier Ltd.)

In this study, associations between prenatal exposure to fine particulate matter (PM2.5) from 9 sources and development of autism spectrum disorder (ASD) were assessed in a population-based retrospective pregnancy cohort in southern California. The cohort included 318,750 mother-child singleton pairs. ASD cases ( N = 4559) were identified by ICD codes. Source-specific PM2.5 concentrations were estimated from a chemical transport model with a 4 × 4 km 2 resolution and assigned to maternal pregnancy residential addresses. Cox proportional hazard models were used to estimate the hazard ratios (HR) of ASD development for each individual source. We also adjusted for total PM2.5 mass and in a separate model for all other sources simultaneously. Increased ASD risk was observed with on-road gasoline (HR [CI]: 1.18 [1.13, 1.24]), off-road gasoline (1.15 [1.12, 1.19]), off-road diesel (1.08 [1.05, 1.10]), food cooking (1.05 [1.02, 1.08]), aircraft (1.04 [1.01, 1.06]), and natural gas combustion (1.09 [1.06, 1.11]), each scaled to standard deviation increases in concentration. On-road gasoline and off-road gasoline were robust for other pollutant groups. PM2.5 emitted from different sources may have different impacts on ASD. The results also identify PM source mixtures for toxicological investigations that may provide evidence for future public health policies.

Importance: Data from surveys show increased mental health disorders in youths. However, little is known about clinical diagnosis over time., Objective: To assess the incidence, prevalence, and changes from 2017 to 2021 for depression and anxiety diagnosed clinically among children, adolescents, and young adults and to identify potential disparities., Design, Setting, and Participants: This cohort study included approximately 1.7 million individuals aged 5 to 22 years in Southern California. Data were extracted from electronic medical records; International Statistical Classification of Diseases, Tenth Revision (ICD-10), codes were used to identify depression and/or anxiety diagnosis for each study year from January 1, 2017, to December 31, 2021. Rates were stratified by age, gender, race and ethnicity, estimated household income, weight status, and comorbidity history. Changes over time and association with these variables were assessed using Poisson regression. Data were analyzed between June 1, 2022, and November 29, 2023., Main Outcomes and Measures: Clinical diagnosis of (1) depression and (2) anxiety without a depression diagnosis using ICD-10 codes., Results: Among the 1.7 million participants, mean (SD) age was approximately 14 (5) years, and 51% were male. In terms of race and ethnicity for each study year, approximately 50% of participants were Hispanic; 8%, non-Hispanic Asian; 8%, non-Hispanic Black; and 23%, non-Hispanic White. From 2017 to 2021, depression diagnosis increased by 55.6% (from 1.35% to 2.10%) for incidence and 60.0% (from 2.55% to 4.08%) for prevalence; anxiety without depression diagnosis increased by 31.1% (from 1.77% to 2.32%) for incidence and 35.2% (from 3.13% to 4.22%) for prevalence (P < .001 for trend). The increases in rates were higher during the COVID-19 pandemic (2020-2021) than before the pandemic (2017-2019), except for depression incidence. Rates increased across all subgroups. Rates were highest for subgroups aged 14 to 17 and 18 to 22 years; female participants; those of non-Hispanic American Indian or Alaska Native, non-Hispanic White, or multiple races or ethnicities; and subgroups with higher household income, obesity (and underweight for anxiety without depression), or comorbidities. Among these factors, age was the most important factor for depression diagnosis, whereas weight status was the most important factor for anxiety without depression diagnosis., Conclusions and Relevance: This cohort study, using electronic medical record data from a large integrated health care system, found an increase in clinically diagnosed depression from 2017 to 2021, with a higher increase during the COVID-19 pandemic and higher rates in some subgroups. Equally important, this study identified high rates and an increase in clinical diagnosis of anxiety without a depression diagnosis. These results support the increased need in public health and health care effort to combat the mental health crisis in youths.

While fine particulate matter (PM 2.5 ) has been associated with autism spectrum disorder (ASD), few studies focused on ultrafine particles (PM 0.1 ). Given that fine and ultrafine particles can be highly correlated due to shared emission sources, challenges remain to distinguish their health effects. In a retrospective cohort of 318,371 mother-child pairs (4549 ASD cases before age 5) in Southern California, pregnancy average PM 2.5 and PM 0.1 were estimated using a California-based chemical transport model and assigned to residential addresses. The correlation between PM 2.5 and PM 0.1 was 0.87. We applied a two-step variance decomposition approach: first, decomposing PM 2.5 and PM 0.1 into the shared and unique variances using ordinary least squares linear regression (OLS) and Deming regression considering errors in both exposures; then assessing associations between decomposed PM 2.5 and PM 0.1 and ASD using Cox proportional hazard models adjusted for covariates. Prenatal PM 2.5 and PM 0.1 each was associated with increased ASD risk. OLS decomposition showed that associations were driven mainly by their shared variance, not by their unique variance. Results from Deming regression considering assumptions of measurement errors were consistent with those from OLS. This decomposition approach has potential to disentangle health effects of correlated exposures, such as PM 2.5 and PM 0.1 from common emissions sources., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anny Xiang reports financial support was provided by National Institutes of Environmental Health Sciences. Rob McConnell reports financial support was provided by National Institute of Environmental Health Sciences. Joel Schwartz reports financial support was provided by US Environmental Protection Agency. Joel Schwartz has testified on behalf of the U.S. Department of Justice in a case involving a Clean Air Act violation If there are other authors, they 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.)

Purpose: Little is known about changes in depression screening outcomes among adolescents in primary healthcare across the COVID-19 pandemic. We describe trends in depression screening outcomes within a large integrated health care system in Southern California., Methods: Retrospective electronic health record data from preventative healthcare visits of 11-12-year-olds and 13-17-year-olds screened for depression from March 1, 2017, to August 31, 2022, were extracted in 6-month blocks. The percentages of screens meeting "threshold depression" were reported overall, and by sex, race or ethnicity, and median household income quintiles. We used Poisson regression to estimate rate ratios of threshold depression in 3 winter blocks (September to February) comparing lockdown (2020), reopening (2021) to a pre-COVID (2019) period, and reopening relative to lockdown. Disparities in trends by sex, race, or ethnicity and household income were tested using interaction terms., Results: Of 735,333 visits with complete screening (183,550 for 11-12-year-olds and 551,783 for 13-17-year-olds), 4.6%, 6.5%, and 7.4% of 11-12-year-olds had "threshold depression" during winter blocks of pre-COVID, lockdown and reopening, respectively. The corresponding rates were 5.8%, 8.5%, and 9.8% for 13-17-year-olds. The rates were higher during lockdown and reopening relative to pre-COVID and higher during reopening relative to lockdown for both age groups (all p-values <.001). Trends differed by sex in both age groups (p-values <.001) and by race or ethnicity (p = .001) in the 13-17-year age group., Discussion: Californian adolescents demonstrated an increase in threshold depression since COVID lockdown starting March 2020 with further increase observed during reopening in September 2021. Future studies are needed to determine the long-term trends., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: Intrauterine exposure to gestational diabetes mellitus (GDM) increases the risk of obesity in the offspring, but little is known about the underlying neural mechanisms. The hippocampus is crucial for food intake regulation and is vulnerable to the effects of obesity. The purpose of the study was to investigate whether GDM exposure affects hippocampal functional connectivity during exposure to food cues using functional magnetic resonance imaging (fMRI)., Methods: Participants were 90 children age 7-11 years (53 females) who underwent an fMRI-based visual food cue task in the fasted state. Hippocampal functional connectivity (FC) was examined using generalized psychophysiological interaction in response to food versus non-food cues. Hippocampal FC was compared between children with and without GDM exposure, while controlling for possible confounding effects of age, sex and waist-to-hip ratio. In addition, the influence of childhood and maternal obesity were investigated using multiple regression models., Results: While viewing high caloric food cues compared to non-food cure, children with GDM exposure exhibited higher hippocampal FC to the insula and striatum (i.e., putamen, pallidum and nucleus accumbens) compared to unexposed children. With increasing BMI, children with GDM exposure had lower hippocampal FC to the somatosensory cortex (i.e., postcentral gyrus)., Conclusions: Intrauterine exposure to GDM was associated with higher food-cue induced hippocampal FC especially to reward processing regions. Future studies with longitudinal measurements are needed to clarify whether altered hippocampal FC may raise the risk of the development of metabolic diseases later in life., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Maternal preeclampsia is associated with a risk of autism spectrum disorders (ASD) in offspring. However, it is unknown whether the increased ASD risk associated with preeclampsia is due to preeclampsia onset or clinical management of preeclampsia after onset, as clinical expectant management of preeclampsia allows pregnant women with this complication to remain pregnant for potentially weeks depending on the onset and severity. Identifying the risk associated with preeclampsia onset and exposure provides evidence to support the care of high-risk pregnancies and reduce adverse effects on offspring., Objective: This study aimed to fill the knowledge gap by assessing the ASD risk in children associated with the gestational age of preeclampsia onset and the number of days from preeclampsia onset to delivery., Methods: This retrospective population-based clinical cohort study included 364,588 mother-child pairs of singleton births between 2001 and 2014 in a large integrated health care system in Southern California. Maternal social demographic and pregnancy health data, as well as ASD diagnosis in children by the age of 5 years, were extracted from electronic medical records. Cox regression models were used to assess hazard ratios (HRs) of ASD risk in children associated with gestational age of the first occurrence of preeclampsia and the number of days from first occurrence to delivery., Results: Preeclampsia occurred in 16,205 (4.4%) out of 364,588 pregnancies; among the 16,205 pregnancies, 2727 (16.8%) first occurred at <34 weeks gestation, 4466 (27.6%) first occurred between 34 and 37 weeks, and 9012 (55.6%) first occurred at ≥37 weeks. Median days from preeclampsia onset to delivery were 4 (IQR 2,16) days, 1 (IQR 1,3) day, and 1 (IQR 0,1) day for those first occurring at <34, 34-37, and ≥37 weeks, respectively. Early preeclampsia onset was associated with greater ASD risk (P=.003); HRs were 1.62 (95% CI 1.33-1.98), 1.43 (95% CI 1.20-1.69), and 1.23 (95% CI 1.08-1.41), respectively, for onset at <34, 34-37, and ≥37 weeks, relative to the unexposed group. Within the preeclampsia group, the number of days from preeclampsia onset to delivery was not associated with ASD risk in children; the HR was 0.995 (95% CI 0.986-1.004) after adjusting for gestational age of preeclampsia onset., Conclusions: Preeclampsia during pregnancy was associated with ASD risk in children, and the risk was greater with earlier onset. However, the number of days from first preeclampsia onset to delivery was not associated with ASD risk in children. Our study suggests that ASD risk in children associated with preeclampsia is not increased by expectant management of preeclampsia in standard clinical practice. Our results emphasize the need to identify effective approaches to preventing the onset of preeclampsia, especially during early pregnancy. Further research is needed to confirm if this finding applies across different populations and clinical settings., (©Sarah Carter, Jane C Lin, Ting Chow, Mayra P Martinez, Chunyuan Qiu, R Klara Feldman, Rob McConnell, Anny H Xiang. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 17.04.2024.)

Lay Abstract: Early intervention and treatment can help reduce disability in children diagnosed with autism spectrum disorder. Screening for autism spectrum disorder in young children identifies those at increased likelihood of diagnosis who may need further support. Previous research has reported that exposure to maternal obesity and diabetes during pregnancy is associated with higher likelihood of autism spectrum disorder diagnosis in children. However, little is known about whether these maternal conditions are associated with how very young children score on autism spectrum disorder screening tools. This study examined associations between exposure to maternal obesity and diabetes during pregnancy and offspring scores on the Quantitative Checklist for Autism in Toddlers, an autism spectrum disorder screening questionnaire administered between 18-24 months at well-child visits. A higher score on the Quantitative Checklist for Autism in Toddlers suggests a higher likelihood of autism spectrum disorder; children with scores 3 or greater are referred to developmental pediatricians for evaluation. Our study found that children of mothers with obesity or diabetes during pregnancy had higher scores than children whose mothers did not have these conditions. Associations with maternal obesity and gestational diabetes diagnosed at or before 26 weeks of pregnancy were also present in children who did not have later autism spectrum disorder diagnoses, suggesting that exposure to these conditions during early pregnancy may be associated with a broad range of social and behavioral abilities. Identifying associations between maternal health conditions and early Quantitative Checklist for Autism in Toddlers screening scores could influence future screening and provision of support for children of mothers with these conditions., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes 1,2 and molecular mechanisms that are often specific to cell type 3,4 . Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10 -8 ) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores 5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care., (© 2024. The Author(s).)

Importance: Family socioeconomic status has been associated with autism spectrum disorder (ASD) diagnoses. Less is known regarding the role of neighborhood disadvantage in the United States, particularly when children have similar access to health insurance., Objective: To evaluate the association between neighborhood disadvantage and the diagnosis of ASD and potential effect modification by maternal and child demographic characteristics., Design, Setting, and Participants: This cohort study examined a retrospective birth cohort from Kaiser Permanente Southern California (KPSC), an integrated health care system. Children born in 2001 to 2014 at KPSC were followed up through KPSC membership records. Electronic medical records were used to obtain an ASD diagnosis up to December 31, 2019, or the last follow-up. Data were analyzed from February 2022 to September 2023., Exposure: Socioeconomic disadvantage at the neighborhood level, an index derived from 7 US census tract characteristics using principal component analysis., Main Outcomes and Measures: Clinical ASD diagnosis based on electronic medical records. Associations between neighborhood disadvantage and ASD diagnosis were determined by hazard ratios (HRs) from Cox regression models adjusted for birth year, child sex, maternal age at delivery, parity, severe prepregnancy health conditions, maternal race and ethnicity, and maternal education. Effect modification by maternal race and ethnicity, maternal education, and child sex was assessed., Results: Among 318 372 mothers with singleton deliveries during the study period, 6357 children had ASD diagnoses during follow-up; their median age at diagnosis was 3.53 years (IQR, 2.57-5.34 years). Neighborhood disadvantage was associated with a higher likelihood of ASD diagnosis (HR, 1.07; 95% CI, 1.02-1.11, per IQR = 2.70 increase). Children of mothers from minoritized racial and ethnic groups (African American or Black, Asian or Pacific Islander, Hispanic or Latinx groups) had increased likelihood of ASD diagnosis compared with children of White mothers. There was an interaction between maternal race and ethnicity and neighborhood disadvantage (difference in log-likelihood = 21.88; P < .001 for interaction under χ24); neighborhood disadvantage was only associated with ASD among children of White mothers (HR, 1.17; 95% CI, 1.09-1.26, per IQR = 2.00 increase). Maternal education and child sex did not significantly modify the neighborhood-ASD association., Conclusions and Relevance: In this study, children residing in more disadvantaged neighborhoods at birth had higher likelihood of ASD diagnosis among a population with health insurance. Future research is warranted to investigate the mechanisms behind the neighborhood-related disparities in ASD diagnosis, alongside efforts to provide resources for early intervention and family support in communities with a higher likelihood of ASD.

Aims: To assess maternal pre-existing type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM) during pregnancy and risk of depression and anxiety from childhood to young adulthood in offspring., Materials and Methods: This birth cohort included singletons born during 1995-2015, followed using electronic medical records through 2020. Cox regression was used to estimate hazard ratio (HR) of depression or anxiety diagnosis during follow-up associated with in-utero exposure to maternal diabetes., Results: Among 439 590 offspring, 29 891 (6.8%) had depression and 51 918 (11.8%) had anxiety. T1D, followed by T2D and GDM requiring antidiabetes medication were associated with risk of depression and anxiety in offspring. Compared with no diabetes during pregnancy, the adjusted HRs (95% confidence interval) of depression in offspring associated with T1D, T2D or GDM requiring medications were 1.44 (1.09-1.91), 1.30 (1.15-1.47) and 1.18 (1.11-1.26) respectively; conversely, HRs were 0.97 (0.82-1.15) for T2D and 0.99 (0.94-1.04) for GDM without medications. The associations with anxiety followed similar patterns. The significant associations were observed for offspring ages 5-12 and >12-18 years and attenuated for 18-25 years., Conclusion: These data suggest that the severity of diabetes (T1D vs. T2D requiring medications vs. GDM requiring medications) during pregnancy may increase the vulnerability of offspring for depression or anxiety., (© 2023 John Wiley & Sons Ltd.)

Objective: To review the status of comparative effectiveness studies for kidney stone disease with focus on study outcome, type, population, time trends, and patient-centered approaches., Methods: A systematic scoping review was performed for articles published between January 1, 2005, and March 30, 2021, using keywords relevant to kidney stone disease. Studies published in English that compared two or more alternative methods for prevention, diagnosis, treatment, monitoring, or care delivery were included. Two reviewers independently reviewed abstracts and an arbitrator resolved discrepancies. Nine reviewers abstracted information from full-length studies. Descriptive statistics were summarized, and linear regression was performed to evaluate temporal trends of study characteristics., Results: We reviewed 1773 abstracts and 707 full-length manuscripts focused on surgical intervention (440); medical expulsive therapy (MET) (152); analgesic control (80); and homeopathic, diagnostics, and/or prophylaxis (84). Randomized controlled trials were common across all outcome categories, including surgery (41.6%), MET (60.2%), analgesic control (81.3%), homeopathic (41.2%), diagnostic (47.6%), and prophylaxis (49.1%). Patient-reported outcomes were utilized in 71.7% and 95% of MET and analgesic control studies, respectively, but in the minority of all other study themes. Over time, meta-analyses and multicenter studies increased [P < .001]., Conclusion: Surgical and MET themes dominate published comparative literature in kidney stone disease. There is substantial variation in use of patient-reported outcomes across surgical themes. Multicentered studies and those generating higher level evidence have increased over time but opportunities exist to improve collaborative, high-quality, and patient-centered research in kidney stone disease., Competing Interests: Declaration of Competing Interest Jonathan S. Ellison: paid consultant for Alnylam Pharmaceuticals (not active, but present w/in past 24 months); paid contributor for UpToDate (active). Gregory Tasian: Gregory Tasian is on the Scientific Advisory Board of, is a consultant for, and receives research funding from Dicerna Pharmaceuticals and Alnylam Pharmaceuticals. David I. Chu: This work is supported in part by a research grant from the National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK125670) to Dr David I. Chu. Ryan Spiardi: This work is supported in part by a research grant from NIH T32 research grants supporting Dr Ryan Spiardi (NIH 5T32DK7006-48 &NIH 5T32DK7006-49). None of the other authors have any financial interests to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Previous work found poor reproducibility for measures of glycemia in individuals at risk for dysglycemia. Differences between youth and adults have not been assessed. Using youth and adults in the Restoring Insulin Secretion Study, we tested variability and classification concordance for hemoglobin A1C (HbA1c), fasting and 2-hour glucose from oral glucose tolerance tests (OGTTs)., Methods: HbA1c and glucose on repeated samples obtained ∼6 weeks apart were compared in 66 youth (mean age 14.2 years) and 354 adults (52.7 years). Changes, coefficient of variation (CV), and concordance of diagnostic categories between the 2 visits were compared., Results: Mean difference between the 2 visits in HbA1c was higher in youth than adults (P < .001), while fasting glucose was similar and 2-hour glucose was lower in youth (P = .051). CV was smallest for HbA1c compared to fasting and 2-hour glucose. For HbA1c, youth had higher CV (P < .001); whereas CV for 2-hour glucose was lower for youth (P = .041). Classification concordance by HbA1c was lower in youth (P = .004). Using OGTT or HbA1c for classification, intervisit variability produced discordant classification in 20% of youth and 28% of adults. Using both fasting glucose and HbA1c, intervisit variability reduced discordant classification to 16% of adults while not improving classification in youth., Conclusions: Poor reproducibility and lack of classification concordance highlight the limitations of one-time testing, with important implications for assessing eligibility in clinical trials. Consideration should be given to using more than a single parameter for screening and diagnosis, especially when classification category is important., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Autism Spectrum Disorder (ASD) risk is highly heritable, with potential additional non-genetic factors, such as prenatal exposure to ambient particulate matter with aerodynamic diameter < 2.5 µm (PM 2.5 ) and maternal immune activation (MIA) conditions. Because these exposures may share common biological effect pathways, we hypothesized that synergistic associations of prenatal air pollution and MIA-related conditions would increase ASD risk in children., Objectives: This study examined interactions between MIA-related conditions and prenatal PM 2.5 or major PM 2.5 components on ASD risk., Methods: In a population-based pregnancy cohort of children born between 2001 and 2014 in Southern California, 318,751 mother-child pairs were followed through electronic medical records (EMR); 4,559 children were diagnosed with ASD before age 5. Four broad categories of MIA-related conditions were classified, including infection, hypertension, maternal asthma, and autoimmune conditions. Average exposures to PM 2.5 and four PM 2.5 components, black carbon (BC), organic matter (OM), nitrate (NO 3 - ), and sulfate (SO 4 2- ), were estimated at maternal residential addresses during pregnancy. We estimated the ASD risk associated with MIA-related conditions, air pollution, and their interactions, using Cox regression models to adjust for covariates., Results: ASD risk was associated with MIA-related conditions [infection (hazard ratio 1.11; 95% confidence interval 1.05-1.18), hypertension (1.30; 1.19-1.42), maternal asthma (1.22; 1.08-1.38), autoimmune disease (1.19; 1.09-1.30)], with higher pregnancy PM 2.5 [1.07; 1.03-1.12 per interquartile (3.73 μg/m 3 ) increase] and with all four PM 2.5 components. However, there were no interactions of each category of MIA-related conditions with PM 2.5 or its components on either multiplicative or additive scales., Conclusions: MIA-related conditions and pregnancy PM 2.5 were independently associations with ASD risk. There were no statistically significant interactions of MIA conditions and prenatal PM 2.5 exposure with ASD risk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: There is increasing evidence for adverse health effects associated with aircraft-emitted particulate matter (PM) exposures, which are largely in the ultrafine (PM 0.1 ) size fraction, but no previous study has examined neurodevelopmental outcomes., Objective: To assess associations between maternal exposure to aircraft ultrafine particles (UFP) during pregnancy and offspring autism spectrum disorder (ASD) diagnosis., Methods: This large, representative cohort study included 370,723 singletons born in a single healthcare system. Demographic data, maternal health information, and child's ASD diagnosis by age 5 were extracted from electronic medical records. Aircraft exposure estimates for PM 0.1 were generated by the University of California Davis/California Institute of Technology Source Oriented Chemical Transport model. Cox proportional hazard models were used to assess associations between maternal exposure to aircraft PM 0·1 in pregnancy and ASD diagnosis, controlling for covariates., Results: Over the course of follow-up, 4,554 children (1.4 %) were diagnosed with ASD. Increased risk of ASD was associated with maternal exposure to aircraft PM 0.1 [hazard ratio, HR: 1.02, (95 % confidence interval (CI): 1.01-1.03) per IQR = 0.02 µg/m 3 increase during pregnancy. Associations were robust to adjustment for total PM 0.1 and fine particulate matter (PM 2.5 ), near-roadway air pollution, and other covariates. Noise adjustment modestly attenuated estimates of UFP effects, which remained statistically significant., Discussion: The results strengthen the emerging evidence that maternal particulate matter exposure during pregnancy is associated with offspring ASD diagnosis and identify aircraft-derived PM 0.1 as novel targets for further study and potential regulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Maternal labor epidural analgesia (LEA) and oxytocin use for labor and delivery have been reported to be associated with child autism spectrum disorders (ASD). However, it remains unclear whether these 2 common medications used during labor and delivery have synergistic associations with ASD risk in children., Objective: To assess the independent associations of LEA and oxytocin during labor and delivery with ASD, as well as outcome modification associated with the concurrent use of both interventions., Design, Setting, and Participants: Data for this cohort study included 205 994 singleton births with vaginal deliveries in a single integrated health care system in Southern California from calendar years 2008 to 2017. Children were followed up to December 31, 2021. Data on use of LEA and oxytocin, covariates, and ASD outcome in children were obtained from electronic medical records. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) adjusting for covariates., Exposures: Labor epidural analgesia and/or oxytocin use during labor and delivery., Main Outcomes and Measures: A child's clinical diagnosis of ASD during follow-up and at age of diagnosis., Results: Among the cohort, 153 880 children (74.7%) were exposed to maternal LEA and 117 808 children (57.2%) were exposed to oxytocin during labor and delivery. The population of children was approximately half boys and half girls. The median (IQR) age of the mothers was 30.8 (26.8-34.5) years for those not exposed to LEA, 30.0 (25.9-33.8) years for those exposed to LEA, 30.4 (26.5-34.1) years for those unexposed to oxytocin, and 30.0 (25.9-33.9) years for those exposed to oxytocin during labor and delivery. A total of 5146 children (2.5%) had ASD diagnosed during follow-up. Oxytocin exposure was higher among LEA-exposed (67.7%) than -unexposed (26.1%) children. The ASD risk associated with LEA was independent of oxytocin exposure (HR, 1.28; 95% CI, 1.18-1.38); however, the ASD risk associated with oxytocin was not significant after adjusting for LEA exposure (HR, 1.05; 95% CI, 0.99-1.12). A significant interaction of LEA and oxytocin on child ASD risk was found (P = .02 for interaction). Compared with no exposure, HRs were 1.20 (95% CI, 1.09-1.32) for LEA alone, 1.30 (95% CI, 1.20-1.42) for both LEA and oxytocin, and 0.90 (95% CI, 0.78-1.04) for oxytocin alone., Conclusions and Relevance: The findings of this cohort study suggest an association between maternal LEA and ASD risk in children, and the risk appeared to be further increased if oxytocin was also administered. Oxytocin exposure without LEA exposure was not associated with ASD risk in children. These findings must be interpreted with caution. Further studies are needed to replicate or refute the study results and examine biological plausibility.

Exposure to intrapartum antibiotic prophylaxis to reduce perinatal group B streptococcal disease was associated with increased childhood body mass index (BMI) persisting to age 10 years compared to no exposure (Δ BMI at 10 years: vaginal delivery 0.14 kg/m 2 , caesarean 0.40 kg/m 2 )., (© 2023 World Obesity Federation.)

Objective: The study aimed to examine the association between neonatal sepsis and autism risk among children and whether the risk varied with the timing of exposure, child's sex, and race/ethnicity., Study Design: We conducted a retrospective cohort study using electronic health records (EHR) extracted from Kaiser Permanente Southern California Health Care System. Mother-child dyads were constructed by linking records of children born to member mothers and continuing to receive care through the system during the follow-up period with those of their biological mothers ( n  = 469,789). Clinical health records were used to define neonatal sepsis. Diagnosis of autism was made by medical specialists. Potential confounders included maternal sociodemographic factors, obstetrical history, child's age, sex, race/ethnicity, and maternal and child medical history. Incident rates and adjusted hazard ratios (aHR) were used to estimate the associations., Results: Compared with children without the diagnosis of autism, children with the condition were more likely to be from Asian/Pacific Islander descent and male sex. Exposed children showed higher rates of autism as compared with unexposed children (3.43 vs. 1.73 per 1,000 person-years, aHR: 1.67-95% confidence interval [CI]: 1.39-2.00). Both preterm (aHR: 1.47; 95% CI: 1.09-1.98) and term (aHR: 1.63; 95% CI: 1.29-2.06) births were associated with increased risk for autism. Although the magnitude of the HRs and incidence ratios for neonatal sepsis to increase autism risk varied between race ethnicities, neonatal sepsis was associated with significantly increased likelihood of autism diagnosis for all race-ethic groups except for Asian/Pacific Islanders. Although neonatal sepsis was associated with significantly increased autism risk for both boys and girls, incident rates and HR point estimates suggested that the effect may be stronger in girls., Conclusion: Neonatal sepsis is associated with increased risk of autism diagnosis in preterm- and term-born children. The association was significant for both girls and boys and all race ethnicities except for Asian-Pacific Islanders., Key Points: · Neonatal sepsis is associated with increased risk of autism diagnosis.. · The association was significant in preterm- and term-born children.. · The association was significant for all race/ethnicities except for Asian-Pacific Islanders.., Competing Interests: None declared., (Thieme. All rights reserved.)

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10 -8 ) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Lay Abstract: Autism spectrum disorder is heterogeneous and often accompanied by co-occurring conditions. Previous studies have shown that maternal health conditions during pregnancy including obesity, diabetes, preeclampsia, and asthma were associated with increased likelihood of autism. However, little has been done examining the likelihood associated with autism with co-occurring conditions. This study assessed these maternal health conditions in relationship to autism and gastrointestinal disturbances, a common co-occurring condition in children diagnosed with autism. Data included 308,536 mother-child pairs from one integrated health care system with comprehensive electronic medical records. Among the study cohort, 5,131 (1.7%) children had a diagnosis of autism by age 5. Gastrointestinal disturbances were present in 35.4% of children diagnosed with autism and 25.1% of children without autism diagnoses. Our results showed that each of the four maternal health conditions during pregnancy was associated with increased likelihood of gastrointestinal disturbances, autism without gastrointestinal disturbances, and autism with gastrointestinal disturbances. For all four maternal health conditions, the association was greatest for likelihood of autism with gastrointestinal disturbances. Given that children diagnosed with autism are more likely to have gastrointestinal disturbances and over 80% of gastrointestinal disturbances in this cohort were diagnosed prior to autism diagnosis, this study suggests that there may be common biological pathways between autism and gastrointestinal disturbances impacted by these maternal exposures. Future studies are warranted to assess associations between different exposures and autism with other co-occurring conditions to increase our understanding of autism heterogeneity.

Hyperglycemia during pregnancy is a double-edged sword, affecting both mothers and their offspring and creating a vicious cycle that can affect multiple generations. Research in this field over the past 30 years has greatly improved our understanding of this disease and formed the basis of improved strategies to improve the health of mothers and their babies. Despite this progress, gestational and preexisting diabetes continue to have significant effects on both short- and long-term health of mothers and their offspring. In this article, I provide an overview of the work that my colleagues and I have done to advance the knowledge base around diabetes and pregnancy in four areas: 1) diabetes risk after gestational diabetes mellitus (GDM), including racial and ethnic disparities; 2) the pathophysiology of GDM and subsequent diabetes in Hispanic women; 3) diabetes prevention and β-cell preservation following GDM; and 4) evidence for multiple potential developmental effects in offspring that vary according to the timing of exposure and severity of maternal diabetes during pregnancy. This research continues the legacy of Norbert Freinkel and the concepts that he contributed to the field of diabetes and pregnancy. With the epidemic of obesity, increasing rates of type 1 and type 2 diabetes in youth, and rising prevalence of GDM across all racial and ethnic groups, we have a lot more work to do to combat this disease to break the vicious cycle., (© 2023 by the American Diabetes Association.)

This retrospective cohort study examined associations of autism spectrum disorder (ASD) with prenatal exposure to major fine particulate matter (PM 2.5 ) components estimated using two independent exposure models. The cohort included 318 750 mother-child pairs with singleton deliveries in Kaiser Permanente Southern California hospitals from 2001 to 2014 and followed until age five. ASD cases during follow-up ( N = 4559) were identified by ICD codes. Prenatal exposures to PM 2.5 , elemental (EC) and black carbon (BC), organic matter (OM), nitrate (NO 3 - ), and sulfate (SO 4 2- ) were constructed using (i) a source-oriented chemical transport model and (ii) a hybrid model. Exposures were assigned to each maternal address during the entire pregnancy, first, second, and third trimester. In single-pollutant models, ASD was associated with pregnancy-average PM 2.5 , EC/BC, OM, and SO 4 2- exposures from both exposure models, after adjustment for covariates. The direction of effect estimates was consistent for EC/BC and OM and least consistent for NO 3 - . EC/BC, OM, and SO 4 2- were generally robust to adjustment for other components and for PM 2.5 . EC/BC and OM effect estimates were generally larger and more consistent in the first and second trimester and SO 4 2- in the third trimester. Future PM 2.5 composition health effect studies might consider using multiple exposure models and a weight of evidence approach when interpreting effect estimates.

Background: Traffic-related air pollution exposure is associated with increased risk of autism spectrum disorder (ASD). It is unknown whether carbonaceous material from vehicular tailpipe emissions or redox-active non-tailpipe metals, eg. from tire and brake wear, are responsible. We assessed ASD associations with fine particulate matter (PM 2.5 ) tracers of tailpipe (elemental carbon [EC] and organic carbon [OC]) and non-tailpipe (copper [Cu]; iron [Fe] and manganese [Mn]) sources during pregnancy in a large cohort., Methods: This retrospective cohort study included 318,750 children born in Kaiser Permanente Southern California (KPSC) hospitals during 2001-2014, followed until age 5. ASD cases were identified by ICD codes. Monthly estimates of PM 2.5 and PM 2.5 constituents EC, OC, Cu, Fe, and Mn with 4 km spatial resolution were obtained from a source-oriented chemical transport model. These exposures and NO 2 were assigned to each maternal address during pregnancy, and associations with ASD were assessed using Cox regression models adjusted for covariates. PM constituent effect estimates were adjusted for PM 2.5 and NO 2 to assess independent effects. To distinguish ASD risk associated with non-tailpipe from tailpipe sources, the associations with Cu, Fe, and Mn were adjusted for EC and OC, and vice versa., Results: There were 4559 children diagnosed with ASD. In single-pollutant models, increased ASD risk was associated with gestational exposures to tracers of both tailpipe and non-tailpipe emissions. The ASD hazard ratios (HRs) per inter-quartile increment of exposure) for EC, OC, Cu, Fe, and Mn were 1.11 (95% CI: 1.06-1.16), 1.09 (95% CI: 1.04-1.15), 1.09 (95% CI: 1.04-1.13), 1.14 (95% CI: 1.09-1.20), and 1.17 (95% CI: 1.12-1.22), respectively. Estimated effects of Cu, Fe, and Mn (reflecting non-tailpipe sources) were largely unchanged in two-pollutant models adjusting for PM 2.5 , NO 2 , EC or OC. In contrast, ASD associations with EC and OC were markedly attenuated by adjustment for non-tailpipe sources., Conclusion: Results suggest that non-tailpipe emissions may contribute to ASD. Implications are that reducing tailpipe emissions, especially from vehicles with internal combustion engines, may not eliminate ASD associations with traffic-related air pollution., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Prior neuroimaging studies have shown associations between healthy lifestyle factors and cortical thickness; however, results on the direction of this association have been inconsistent. While the majority of studies were performed in older adults within specific weight status categories, little has been reported in younger populations with a range of adiposity, including groups with healthy-weight, overweight, and obesity. Here we investigated relationships between indices of physical activity (PA) and healthy eating with cortical thickness in children and youth/young adults and examined whether these relationships differed by weight status and age groups. Study participants included 119 youth/young adults and 159 children. We hypothesized that greater levels of PA and/or healthy eating index (HEI) composite scores would be positively associated with cortical thickness, and that this association would differ in overweight or obese groups versus normal weight groups, as well as youth/young adults vs. child cohorts. Overall PA (minutes/day) was assessed using 24-hour PA recalls. HEI was calculated to assess diet quality. A structural MRI was performed, and FreeSurfer 6.0 was used to assess cortical thickness in 68 regions of interest (ROI). Mixed effects modeling was performed to investigate associations of PA or HEI with cortical thickness. FDR corrections were applied for multiple ROIs. PA was positively associated with cortical thickness in the caudal middle frontal cortex (FDR adjusted p = 0.042) and cuneus cortex (FDR adjusted p = 0.017) after controlling for sex, age group, and weight status. When stratified by age, in youth/young adults, higher time spent in PA was associated with greater cortical thickness in the frontal, temporal, parietal and occipital cortex, after adjusting for sex and weight group (FDR adjusted ps < 0.05). No significant associations between PA and cortical thickness were observed in children. No significant associations between PA and cortical thickness were observed when stratified by weight group. No significant associations between HEI and cortical thickness were observed. These results indicate that higher time spent in PA is associated with greater cortical thickness, a relationship that appears to be stronger during youth/young adulthood and may be related to more favorable brain health outcomes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Context: Growing evidence suggests an important role for sleep for the metabolic health of children., Objective: We aimed to determine how sleep is related to insulin sensitivity, insulin secretion, beta-cell function, and adiposity (BMI z-scores, body fat %, waist to height ratio) using objectively measured sleep and oral glucose tolerance test (OGTT)-derived measures., Methods: Sixty-two children aged 7-11 years, born at Kaiser Permanente Southern California, wore wrist accelerometers for 7 days to objectively measure sleep, completed an OGTT, and had anthropometric measures (height [cm], weight [kg], waist [cm], body fat [%]) collected. Using linear regression, associations between Matsuda insulin sensitivity index (ISI), insulinogenic index (IGI), disposition index (DI), BMI z-score, waist to height ratio, and body fat % with sleep parameters [total sleep time (TST; min), sleep efficiency (SE; %), time in bed (TIB; min), wake after sleep onset (WASO; min), and sleep latency (SL; min)] were assessed. Body fat % was tested as a mediator of the relationship between TST and ISI., Results: Longer TST was associated with better insulin sensitivity ( P  = 0.02), but not after adjusting for body fat %. Sleep parameters were not associated with IGI or DI. Longer TST was associated with lower % body fat ( P  = 0.01) and lower waist-to-height-ratios ( P  = 0.05). Body fat % explained 62% ( P  = 0.01) of the relationship between TST and ISI. Longer TIB was associated with lower adiposity measures ( P  < 0.05). There were no associations between SE, WASO, or SL and metabolic outcomes., Conclusion: Objectively measured sleep duration was associated with lower adiposity, and the relationship between sleep duration and ISI appeared partly through adiposity levels in preadolescent children. Longer sleep duration may be important for metabolic health., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Rationale: Ecological studies have shown air pollution associations with coronavirus disease (COVID-19) outcomes. However, few cohort studies have been conducted. Objectives: To conduct a cohort study investigating the association between air pollution and COVID-19 severity using individual-level data from the electronic medical record. Methods: This cohort included all individuals who received diagnoses of COVID-19 from Kaiser Permanente Southern California between March 1 and August 31, 2020. One-year and 1-month averaged ambient air pollutant (particulate matter ⩽2.5 μm in aerodynamic diameter [PM 2.5 ], NO 2 , and O 3 ) exposures before COVID-19 diagnosis were estimated on the basis of residential address history. Outcomes included COVID-19-related hospitalizations, intensive respiratory support (IRS), and ICU admissions within 30 days and mortality within 60 days after COVID-19 diagnosis. Covariates included socioeconomic characteristics and comorbidities. Measurements and Main Results: Among 74,915 individuals (mean age, 42.5 years; 54% women; 66% Hispanic), rates of hospitalization, IRS, ICU admission, and mortality were 6.3%, 2.4%, 1.5%, and 1.5%, respectively. Using multipollutant models adjusted for covariates, 1-year PM 2.5 and 1-month NO 2 average exposures were associated with COVID-19 severity. The odds ratios associated with a 1-SD increase in 1-year PM 2.5 (SD, 1.5 μg/m 3 ) were 1.24 (95% confidence interval [CI], 1.16-1.32) for COVID-19-related hospitalization, 1.33 (95% CI, 1.20-1.47) for IRS, and 1.32 (95% CI, 1.16-1.51) for ICU admission; the corresponding odds ratios associated with 1-month NO 2 (SD, 3.3 ppb) were 1.12 (95% CI, 1.06-1.17) for hospitalization, 1.18 (95% CI, 1.10-1.27) for IRS, and 1.21 (95% CI, 1.11-1.33) for ICU admission. The hazard ratios for mortality were 1.14 (95% CI, 1.02-1.27) for 1-year PM 2.5 and 1.07 (95% CI, 0.98-1.16) for 1-month NO 2 . No significant interactions with age, sex or ethnicity were observed. Conclusions: Ambient PM 2.5 and NO 2 exposures may affect COVID-19 severity and mortality.

(1) Background: The developmental origins of health and disease (DOHaD) hypothesis links adverse fetal exposures with developmental mal-adaptations and morbidity later in life. Short- and long-term exposures to air pollutants are known contributors to health outcomes; however, the potential for developmental health effects of air pollution exposures during gestation or early-childhood have yet to be reviewed and synthesized from a DOHaD lens. The objective of this study is to summarize the literature on cardiovascular and metabolic, respiratory, allergic, and neuropsychological health outcomes, from prenatal development through early childhood, associated with early-life exposures to outdoor air pollutants, including traffic-related and wildfire-generated air pollutants. (2) Methods: We conducted a search using PubMed and the references of articles previously known to the authors. We selected papers that investigated health outcomes during fetal or childhood development in association with early-life ambient or source-specific air pollution exposure. (3) Results: The current literature reports that prenatal and early-childhood exposures to ambient and traffic-related air pollutants are associated with a range of adverse outcomes in early life, including cardiovascular and metabolic, respiratory and allergic, and neurodevelopmental outcomes. Very few studies have investigated associations between wildfire-related air pollution exposure and health outcomes during prenatal, postnatal, or childhood development. (4) Conclusion: Evidence from January 2000 to January 2022 supports a role for prenatal and early-childhood air pollution exposures adversely affecting health outcomes during development. Future studies are needed to identify both detrimental air pollutants from the exposure mixture and critical exposure time periods, investigate emerging exposure sources such as wildfire, and develop feasible interventional tools.

Objective: The extent to which weight loss contributes to increases in insulin sensitivity (IS) and β-cell function after surgical or medical intervention has not been directly compared in individuals with impaired glucose tolerance or newly diagnosed type 2 diabetes., Methods: The Restoring Insulin Secretion (RISE) Study included adults in the Beta-Cell Restoration Through Fat Mitigation Study (n = 88 randomized to laparoscopic gastric banding or metformin [MET]) and the Adult Medication Study (n = 267 randomized to placebo, MET, insulin glargine/MET, or liraglutide + MET [L + M]). IS and β-cell responses were measured at baseline and after 12 months by modeling of oral glucose tolerance tests and during arginine-stimulated hyperglycemic clamps. Linear regression models assessed differences between and within treatments over time., Results: BMI decreased in all treatment groups, except placebo, at 12 months. IS increased in all arms except placebo and was inversely correlated with changes in BMI. L + M was the only treatment arm that enhanced multiple measures of β-cell function independent of weight loss. Insulin secretion decreased in the laparoscopic gastric banding arm proportional to increases in IS, with no net benefit on β-cell function., Conclusions: Reducing demand on the β-cell by improving IS through weight loss does not reverse β-cell dysfunction. L + M was the only treatment that enhanced β-cell function., (© 2022 The Obesity Society.)

Background: Air pollution exposure may make people more vulnerable to COVID-19 infection. However, previous studies in this area mostly focused on infection before May 2020 and long-term exposure., Objective: To assess both long-term and short-term exposure to air pollution and COVID-19 incidence across four case surges from 03/1/2020 to 02/28/2021., Methods: The cohort included 4.6 million members from a large integrated health care system in southern California with comprehensive electronic medical records (EMR). COVID-19 cases were identified from EMR. Incidence of COVID-19 was computed at the census tract-level among members. Prior 1-month and 1-year averaged air pollutant levels (PM 2.5 , NO 2 , and O 3 ) at the census tract-level were estimated based on hourly and daily air quality data. Data analyses were conducted by each wave: 3/1/2020-5/31/2020, 6/1/202-9/30/2020, 10/1/2020-12/31/2020, and 1/1/2021-2/28/2021 and pooled across waves using meta-analysis. Generalized linear mixed effects models with Poisson distribution and spatial autocorrelation were used with adjustment for meteorological factors and census tract-level social and health characteristics. Results were expressed as relative risk (RR) per 1 standard deviation., Results: The cohort included 446,440 COVID-19 cases covering 4609 census tracts. The pooled RRs (95% CI) of COVID-19 incidence associated with 1-year exposures to PM 2.5 , NO 2 , and O 3 were 1.11 (1.04, 1.18) per 2.3 μg/m 3 ,1.09 (1.02, 1.17) per 3.2 ppb, and 1.06 (1.00, 1.12) per 5.5 ppb respectively. The corresponding RRs (95% CI) associated with prior 1-month exposures were 1.11 (1.03, 1.20) per 5.2 μg/m 3 for PM 2.5 , 1.09 (1.01, 1.17) per 6.0 ppb for NO 2 and 0.96 (0.85, 1.08) per 12.0 ppb for O 3 ., Conclusion: Long-term PM 2.5 and NO 2 exposures were associated with increased risk of COVID-19 incidence across all case surges before February 2021. Short-term PM 2.5 and NO 2 exposures were also associated. Our findings suggest that air pollution may play a role in increasing the risk of COVID-19 infection., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many studies have found associations between early life air pollution exposure and subsequent onset of autism spectrum disorder (ASD). However, characteristics that affect susceptibility remain unclear., Objective: This systematic review examined epidemiologic studies on the modifying roles of social, child, genetic and maternal characteristics in associations between prenatal and early postnatal air pollution exposure and ASD., Methods: A systematic literature search in PubMed and Embase was conducted. Studies that examined modifiers of the association between air pollution and ASD were included., Results: A total of 19 publications examined modifiers of the associations between early life air pollution exposures and ASD. In general, estimates of effects on risk of ASD in boys were larger than in girls (based on 11 studies). Results from studies of effects of family education (2 studies) and neighborhood deprivation (2 studies) on air pollution-ASD associations were inconsistent. Limited data (1 study) suggest pregnant women with insufficient folic acid intake might be more susceptible to ambient particulate matter less than 2.5 μm (PM 2.5 ) and 10 μm (PM 10 ) in aerodynamic diameter, and to nitrogen dioxide (NO 2 ). Children of mothers with gestational diabetes had increased risk of ozone-associated ASD (1 study). Two genetic studies reported that copy number variations may amplify the effect of ozone, and MET rs1858830 CC genotype may augment effects of PM and near-roadway pollutants on ASD., Conclusions: Child's sex, maternal nutrition or diabetes, socioeconomic factors, and child risk genotypes were reported to modify the effect of early-life air pollutants on ASD risk in the epidemiologic literature. However, the sparsity of studies on comparable modifying hypotheses precludes conclusive findings. Further research is needed to identify susceptible populations and potential targets for preventive intervention., (Copyright © 2021. Published by Elsevier Inc.)

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10 -9 ), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification., Competing Interests: S.M.G. and A.M.S. receive funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. All others authors declare no competing interests., (© 2022 The Author(s).)

Background: Studies have shown that air pollution exposures during pregnancy are associated with an increased risk of autism spectrum disorder (ASD) in children, and the risk appears to be greater for boys. However, studies assessing gestational windows of susceptibility have been mostly limited by trimesters., Objective: We identified sensitive windows of exposure to regional air pollution and risk of ASD and examined sex differences in a large birth cohort., Methods: This population-based retrospective cohort study included 294,937 mother-child pairs with singleton deliveries in Kaiser Permanente Southern California (KPSC) hospitals from 2001 to 2014. Children were followed using electronic medical records until clinical ASD diagnosis, non-KPSC membership, death, or 31 December 2019, whichever came first. Weekly mean fine particulate matter [PM with an aerodynamic diameter of ≤ 2.5 μ m ( PM 2.5 )], nitrogen dioxide ( NO 2 ), and ozone ( O 3 ) pregnancy exposures were estimated using spatiotemporal prediction models. Cox proportional hazard models with distributed lags were used to estimate weekly pollutant exposure associations with ASD risk for the entire cohort, and separately for boys and for girls. Models were adjusted for child sex (for full cohort), maternal race/ethnicity, maternal age at delivery, parity, maternal education, maternal comorbidities, medical center, census tract median household income, birth year, and season., Results: There were 5,694 ASD diagnoses (4,636 boys, 1,058 girls). Sensitive PM 2.5 exposure windows associated with ASD were found early in pregnancy, statistically significant throughout the first two trimesters [1-27 wk of gestation, cumulative hazard ratio  ( HR ) = 1.14 [95% confidence interval (CI): 1.06, 1.23] per interquartile range (IQR) ( 7.4 - μ g / m 3 ) increase]. O 3 exposure during 34-37 wk of gestation was associated with increased risk [ HR = 1.06 (95% CI: 1.01, 1.11) per IQR ( 17.4  ppb ) increase] but with reduced risk during 20-28 wk of gestation [ HR = 0.93 (95% CI: 0.89, 0.98)]. No associations were observed with NO 2 . Sex-stratified early gestational PM 2.5 associations were stronger among boys [boys HR = 1.16 (95% CI: 1.08, 1.26); girls HR = 1.06 (95% CI: 0.89, 1.26)]. O 3 associations in later gestation were observed only in boys [boys HR = 1.10 (95% CI: 1.04, 1.16); girls HR = 0.94 (95% CI: 0.84, 1.05)]., Conclusions: Exposures to PM 2.5 in the first two gestational trimesters were associated with increased ASD risk in children, with stronger associations observed for boys. The role of O 3 exposure on ASD risk merits further investigation. https://doi.org/10.1289/EHP9509.

Importance: Previous studies have reported associations between in utero exposure to regional air pollution and autism spectrum disorders (ASD). In utero exposure to components of near-roadway air pollution (NRAP) has been linked to adverse neurodevelopment in animal models, but few studies have investigated NRAP association with ASD risk., Objective: To identify ASD risk associated with in utero exposure to NRAP in a large, representative birth cohort., Design, Setting, and Participants: This retrospective pregnancy cohort study included 314,391 mother-child pairs of singletons born between 2001 and 2014 at Kaiser Permanente Southern California (KPSC) hospitals. Maternal and child data were extracted from KPSC electronic medical records. Children were followed until: clinical diagnosis of ASD, non-KPSC membership, death, or December 31, 2019, whichever came first. Exposure to the complex NRAP mixture during pregnancy was assessed using line-source dispersion models to estimate fresh vehicle emissions from freeway and non-freeway sources at maternal addresses during pregnancy. Vehicular traffic load exposure was characterized using advanced telematic models combining traditional traffic counts and travel-demand models with cell phone and vehicle GPS data. Cox proportional-hazard models estimated hazard ratios (HR) of ASD associated with near-roadway traffic load and dispersion-modeled NRAP during pregnancy, adjusted for covariates. Non-freeway NRAP was analyzed using quintile distribution due to nonlinear associations with ASD., Exposures: Average NRAP and traffic load exposure during pregnancy at maternal residential addresses., Main Outcomes: Clinical diagnosis of ASD., Results: A total of 6,291 children (5,114 boys, 1,177 girls) were diagnosed with ASD. The risk of ASD was associated with pregnancy-average exposure to total NRAP [HR(95% CI): 1.03(1.00,1.05) per 5 ppb increase in dispersion-modeled NOx] and to non-freeway NRAP [HR(95% CI) comparing the highest to the lowest quintile: 1.19(1.11, 1.27)]. Total NRAP had a stronger association in boys than in girls, but the association with non-freeway NRAP did not differ by sex. The association of freeway NRAP with ASD risk was not statistically significant. Non-freeway traffic load exposure demonstrated associations with ASD consistent with those of NRAP and ASD., Conclusions: In utero exposure to near-roadway air pollution, particularly from non-freeway sources, may increase ASD risk in children., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Increasing evidence suggests that exposure to air pollution during pregnancy is associated with adverse pregnancy outcomes. However, biomarkers associated with air pollution exposure are widely lacking and often transient. In addition, ascertaining biospecimens during pregnacy to assess the prenatal environment remains largely infeasible. Objectives: To address these challenges, we investigated relationships between air pollution exposure during pregnancy and human serum albumin Cys 34 (HSA-Cys 34 ) adducts in newborn dried blood spots (DBS) samples, which captures an integration of perinatal exposures to small reactive molecules in circulating blood. Methods: Newborn DBS were obtained from a state archive for a cohort of 120 children born at one Kaiser Permanente Southern California (KPSC) hospitals in 2007. These children were selected to maximize the range of residential air pollution exposure during the entire pregnancy to PM 2.5 , PM 10 , NO 2 , O 3 , based on monthly estimates interpolated from regulatory monitoring sites. HSA-Cys 34 adducts were selected based on previously reported relationships with air pollution exposure and oxidative stress. Results: Six adducts measured in newborn DBS samples were associated with air pollution exposures during pregnancy; these included direct oxidation products, adducts formed with small thiol compounds, and adducts formed with reactive aldehydes. Two general trends were identified: Exposure to air pollution late in pregnancy (i.e., in the last 30 days) was associated with increased oxidative stress, and exposure to air pollution earlier in pregnancy (i.e., not in the last 30 days) was associated with decreased oxidative stress around the time of birth. Discussion: Air pollution exposure occurring during pregnancy can alter biology and leave measurable impacts on the developing infant captured in the newborn DBS adductome, which represents a promising tool for investigating adverse birth outcomes in population-based studies., Competing Interests: FL was employed by company Sonoma Technology, Inc. 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., (Copyright © 2021 Funk, Montgomery, Bae, Chen, Chow, Martinez, Lurmann, Eckel, McConnell and Xiang.)