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Prenatal nonessential metals may contribute to postnatal adiposity, whereas essential metals may have metabolic benefits. We evaluated joint and individual associations between prenatal metals and childhood adiposity.We measured concentrations of six nonessential (arsenic, barium, cadmium, cesium, lead, and mercury) and four essential (magnesium, manganese, selenium, and zinc) metals in first trimester maternal blood from a prebirth cohort. We collected anthropometric measures in early childhood, mid-childhood, and early adolescence including subscapular+tricep skinfold thickness (mm) (N = 715-859), waist circumference (cm) (N = 717-882), and body mass index (BMI) (z-score) (N = 716-875). We measured adiposity in mid-childhood and early adolescence using bone densitometry total- and trunk- fat mass index (kg/m 2 ) (N = 511-599). We estimated associations using adjusted quantile g-computation and linear regression.The nonessential metal mixture was associated with higher total (β = 0.07, 95% CI = 0.01, 0.12) and trunk fat mass index (β = 0.12, CI = 0.02, 0.22), waist circumference (β = 0.01, CI = 0.00, 0.01), and BMI (β = 0.24, CI = 0.07, 0.41) in mid-childhood, and total fat mass index (β = 0.07, CI = 0.01, 0.14), and BMI (β = 0.19, CI = 0.02, 0.37) in early adolescence. The essential metal mixture was associated with lower early adolescence total-(β = -0.11, CI = -0.17, -0.04) and trunk- fat mass index (β = -0.13, CI = -0.21, -0.05), subscapular+tricep skinfold thickness (β = -0.02, CI = -0.03, -0.00), waist circumference (β = -0.003, CI = -0.01, -0.00), and BMI (β = -0.16, CI = -0.28, -0.04). Cadmium and cesium were individually associated with childhood adiposity at different timepoints.Prenatal first-trimester essential metals were associated with lower childhood adiposity, whereas nonessential metals were associated with higher adiposity into adolescence.

In this work, we propose the use of molecular emission of calcium fluoride (CaF) by laser induced breakdown spectroscopy (LIBS) to obtain quantitative fluoride distribution images of teeth.

Introduction: The developing kidney is vulnerable to pre- and postnatal environmental stressors. Suboptimal environmental conditions during early life, such as exposure to toxic metals and deficiency in essential metals, can alter the risk of kidney dysfunction later in life. In this pilot study, we aimed to examine the relationship between prenatal exposure to metals and adolescent kidney function using data from Project Viva, a Boston-area prospective pre-birth cohort. Hypothesis: Prenatal exposure to higher metal concentrations, both individually and as mixtures, will be associated with altered kidney function in mid-adolescence. Methods: We assessed the following metals in erythrocyte samples collected during pregnancy: 1 st -trimester [arsenic (As), barium (Ba), cadmium (Cd), cesium (Cs), mercury (Hg), lead (Pb), copper (Cu), magnesium (Mg), manganese (Mn), selenium (Se), and Zinc (Zn)]; 2 nd -trimester (Pb, Mn, Hg, and Se). We measured plasma cystatin C and creatinine from blood samples collected in mid-adolescence (mean age 18 years) in a sub-sample of Project Viva participants. We calculated the estimated glomerular filtrate rate (eGFR) using a cystatin C-based equation for children. We examined associations of prenatal metal exposure and mid-adolescent eGFR using linear regression for single metal analyses, and Bayesian kernel machine regression and quantile-based g-computation for mixture analyses. In all models, we adjusted for maternal education level, annual household income, race/ethnicity, child sex, and age at eGFR assessment. Results: A total of 146 participants had complete data for 1 st -trimester erythrocyte metals and mid-adolescent eGFR, and 105 participants had complete data for 2 nd -trimester blood metals and mid-adolescent eGFR. All children had eGFR values in the normal range (i.e., >60 mL/min/1.73m 2 ); the mean (SD) eGFR was 92.0 (13.7) mL/min/1.73m 2 . Most pairwise metal-eGFR relationships were statistically null; however, a 2-fold increase in 1 st -trimester Zn was associated with higher eGFR (β 7.25 mL/min/1.73m 2 ; 95% CI 0.33, 14.16), while a 2-fold increase in 2 nd -trimester Pb was associated with lower eGFR (β -4.90 mL/min/1.73m 2 ; 95% CI -8.32, -1.48). Mixture analyses did not identify statistically significant findings but suggested some non-linear associations and interactions between metals. Conclusions: Preliminary evidence suggests that prenatal Zn exposure is associated with higher kidney function while prenatal Pb exposure is associated with lower kidney function in mid-adolescence. We plan to assess eGFR in additional participants to increase the power of the analyses.

Prenatal antidepressant exposure has been associated with increased risk for neurodevelopmental disorders in childhood, including autism spectrum disorder (ASD). The current study utilized multi-cohort data from the Environmental influences on Child Health Outcomes (ECHO) program (N = 3129) to test for this association, and determine whether the association remained after adjusting for maternal prenatal depression and other potential confounders. Antidepressants and a subset of selective serotonin reuptake inhibitors (SSRIs) were examined in relation to binary (e.g., diagnostic) and continuous measures of ASD and ASD related traits (e.g., social difficulties, behavior problems) in children 1.5 to 12 years of age. Child sex was tested as an effect modifier. While prenatal antidepressant exposure was associated with ASD related traits in univariate analyses, these associations were statistically non-significant in models that adjusted for prenatal maternal depression and other maternal and child characteristics. Sex assigned at birth was not an effect modifier for the prenatal antidepressant and child ASD relationship. Overall, we found no association between prenatal antidepressant exposures and ASD diagnoses or traits. Discontinuation of antidepressants in pregnancy does not appear to be warranted on the basis of increased risk for offspring ASD.

Objective To demonstrate the utility of growthcleanr, an anthropometric data cleaning method designed for electronic health records (EHR). Materials and Methods We used all available pediatric and adult height and weight data from an ongoing observational study that includes EHR data from 15 healthcare systems and applied growthcleanr to identify outliers and errors and compared its performance in pediatric data with 2 other pediatric data cleaning methods: (1) conditional percentile (cp) and (2) PaEdiatric ANthropometric measurement Outlier Flagging pipeline (peanof). Results 687 226 children ( Conclusion growthcleanr is useful for cleaning pediatric and adult height and weight data. It is the only method with the ability to clean adult data and identify carried-forward and duplicates, which are prevalent in EHR. Findings of this study can be used to improve the growthcleanr algorithm.

Gene-environment and nutrition-environment studies often involve testing of high-dimensional interactions between two sets of variables, each having potentially complex nonlinear main effects on an outcome. Construction of a valid and powerful hypothesis test for such an interaction is challenging, due to the difficulty in constructing an efficient and unbiased estimator for the complex, nonlinear main effects. In this work we address this problem by proposing a Cross-validated Ensemble of Kernels (CVEK) that learns the space of appropriate functions for the main effects using a cross-validated ensemble approach. With a carefully chosen library of base kernels, CVEK flexibly estimates the form of the main-effect functions from the data, and encourages test power by guarding against over-fitting under the alternative. The method is motivated by a study on the interaction between metal exposures in utero and maternal nutrition on children’s neurodevelopment in rural Bangladesh. The proposed tests identified evidence of an interaction between minerals and vitamins intake and arsenic and manganese exposures. Results suggest that the detrimental effects of these metals are most pronounced at low intake levels of the nutrients, suggesting nutritional interventions in pregnant women could mitigate the adverse impacts of in utero metal exposures on children’s neurodevelopment.

Background Dietary sources of metals are not well established among pregnant women in the United States. Objective We aimed to perform a diet-wide association study (DWAS) of metals during the first trimester of pregnancy. Methods In early pregnancy (11.3 ± 2.8 weeks of gestation), 1196 women from Project Viva (recruited 1999-2002 in eastern Massachusetts) completed a validated FFQ (135 food items) and underwent measurements of erythrocyte metals [arsenic (As), barium, cadmium, cesium (Cs), copper, mercury (Hg), magnesium, manganese, lead (Pb), selenium (Se), zinc]. The DWAS involved a systematic evaluation and visualization of all bivariate relations for each food-metal combination. For dietary items with strong associations with erythrocyte metals, we applied targeted maximum likelihood estimations and substitution models to evaluate how hypothetical dietary interventions would influence metals' concentrations. Results Participants' mean ± SD age was 32.5 ± 4.5 y and prepregnancy BMI was 24.8 ± 5.4 kg/m2; they were mostly white (75.9%), college graduates (72.4%), married or cohabitating (94.6%), had a household income >$70,000/y (63.5%), and had never smoked (67.1%). Compared with other US-based cohorts, the overall diet quality of participants was above average, and concentrations of erythrocyte metals were lower. The DWAS identified significant associations of several food items with As, Hg, Pb, Cs, and Se; for example, As was higher for each SD increment in fresh fruit (11.5%; 95% CI: 4.9%, 18.4%), white rice (17.9%; 95% CI: 9.4%, 26.9%), and seafood (50.9%; 95% CI: 42.8%, 59.3%). Following the guidelines for pregnant women to consume ≤3 servings/wk of seafood was associated with lower As (-0.55 ng/g; 95% CI: -0.82, -0.28 ng/g) and lower Hg (-2.67 ng/g; 95% CI: -3.55, -1.80 ng/g). Substituting white rice with bread, pasta, tortilla, and potato was also associated with lower As (35%-50%) and Hg (35%-70%). Conclusions Our DWAS provides a systematic evaluation of diet-metals relations. Prenatal diet may be an important source of exposures to metals.

We previously found that antibiotic use at24 months of age was associated with slightly higher body weight at 5 years of age. In this study, we examine associations of early life antibiotic prescriptions with weight outcomes at 108 to 132 months of age ("10 years").We used electronic health record data from 2009 through 2016 from 10 health systems in PCORnet, a national distributed clinical research network. We examined associations of any (vs no) antibiotics at24 months of age with body mass index z-score (BMI-z) at 10 years adjusted for confounders selected a priori. We further examined dose response (number of antibiotic episodes) and antibiotic spectrum (narrow and broad).Among 56,727 included children, 57% received any antibiotics at24 months; at 10 years, mean (standard deviation) BMI-z was 0.54 (1.14), and 36% had overweight or obesity. Any versus no antibiotic use at24 months was associated with a slightly higher BMI-z at 10 years among children without a complex chronic condition (β 0.03; 95% confidence interval [CI] 0.01, 0.05) or with a complex chronic condition (β 0.09; 95% CI 0.03, 0.15). Any versus no antibiotic use was not associated with odds of overweight or obesity at 10 years among children without (odds ratio 1.02; 95% CI 0.97, 1.07) or with a complex chronic condition (odds ratio 1.07; 95% CI 0.96, 1.19).The small and likely clinically insignificant associations in this study are consistent with our previous 5-year follow-up results, suggesting that, if this relationship is indeed causal, early increases in weight are small but maintained over time.

PCORnet, the Patient-Centered Outcomes Research Network, is comprised of health systems and health plans that transform electronic health records (EHRs) and claims data to a common data model (CDM) to facilitate real-world clinical research. Because patients receive health care in multiple care delivery settings, linking health records across systems and health plan claims would provide a more comprehensive and accurate picture of health care for patients. The current study expanded on a PCORnet Antibiotics and Childhood Growth (ABX) study to (1) identify and implement a privacy-preserving patient linkage solution among a clinical data research network and a health plan network within the ABX Study, and (2) assess overlap in prescribed and dispensed antibiotics and additional data gained from claims among the linked patients. This manuscript describes the linkage process and resulting overlap analysis. The authors identified 549 patients from the EHR record study cohort who had claims records with the health plan. Sixty percent (n = 329) of patients had consistent antibiotic exposure data across the 2 sources, indicating antibiotic exposure (44.3%) or nonexposure (15.7%). Among total antibiotic prescribing records, 43.1% had a matched claims record for dispensing within 60 days. Among antibiotic dispense records 26.5% were not associated with a prescribing record in the linked health systems. These findings showcase the feasibility of linking health plan claims data to PCORnet CDM in a privacy-preserving manner while also demonstrating continued gaps in data that may occur. The study highlights the importance of combining multiple health data sources for comprehensive clinical research.

Background: Metal exposure during pregnancy influences maternal and child health. Oxidative stress and inflammation may mediate adverse effects of heavy metals, whereas essential metals may act as antioxidants. Mitochondrial DNA is a prime target for metal-induced oxidative damage. Telomere dysfunction is attributed to imbalances between reactive oxidant species and antioxidants. Objectives: We evaluated individual and joint associations of prenatal metals with mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) in maternal and cord blood as biomarkers of inflammation and oxidative stress. Methods: We measured six nonessential metals (arsenic, barium, cadmium, cesium, lead, mercury) and four essential metals (magnesium, manganese, selenium, zinc) in first-trimester maternal red blood cells in Project Viva, a U.S. prebirth cohort. We measured relative mtDNAcn (n=898) and TL (n=893) in second-trimester maternal blood and mtDNAcn (n=419) and TL (n=408) in cord blood. We used multivariable linear regression and quantile g-computation to estimate associations between prenatal metals and the biomarkers. We used generalized additive models and Bayesian kernel machine regression to examine nonlinearity and interactions. Results: A 2-fold increase in maternal magnesium was associated with lower maternal [β=−0.07, 95% confidence interval (CI): −0.10, −0.01] and cord blood (β=−0.08, 95% CI: −0.20, −0.01) mtDNAcn. Lead was associated with higher maternal mtDNAcn (β=0.04, 95% CI: 0.01, 0.06). Selenium was associated with longer cord blood TL (β=0.30, 95% CI: 0.01 0.50). An association was observed between the nonessential metal mixture and higher maternal mtDNAcn (β=0.04, 95% CI: 0.01, 0.07). There was a nonlinear relationship between cord blood mtDNAcn and magnesium; maternal mtDNAcn and barium, lead, and mercury; and maternal TL and barium. Discussion: Maternal exposure to metals such as lead, magnesium, and selenium was associated with mtDNAcn and TL in maternal second trimester and cord blood. Future work will evaluate whether these biomarkers are associated with child health. https://doi.org/10.1289/EHP9294

BackgroundPrenatal inorganic arsenic (iAs) exposure is associated with pregnancy outcomes. Maternal capabilities of arsenic biotransformation and elimination may influence the susceptibility of arsenic toxicity. Therefore, we examined the determinants of arsenic metabolism of pregnant women in Bangladesh who are exposed to high levels of arsenic.MethodsIn a prospective birth cohort, we followed 1613 pregnant women in Bangladesh and collected urine samples at two prenatal visits: one at 4–16 weeks, and the second at 21–37 weeks of pregnancy. We measured major arsenic species in urine, including iAs (iAs%) and methylated forms. The proportions of each species over the sum of all arsenic species were used as biomarkers of arsenic methylation efficiency. We examined the difference in arsenic methylation using a paired t-test between first and second visits. Using linear regression, we examined determinants of arsenic metabolism, including age, BMI at enrollment, education, financial provider income, arsenic exposure level, and dietary folate and protein intake, adjusted for daily energy intake.ResultsComparing visit 2 to visit 1, iAs% decreased 1.1% (p p 50 μg/g-creatinine) gestational age at measurement was strongly associated with DMA% (β = 0.38, p ConclusionsOur findings indicate that arsenic metabolism and adjusted U-As level increase during pregnancy. We have identified determinants of arsenic methylation efficiency at visit 1.

BACKGROUND Privacy-protecting analytic approaches without centralized pooling of individual-level data, such as distributed regression, are particularly important for vulnerable populations, such as children, but these methods have not yet been tested in multi-center pediatric studies. METHODS Using the electronic health data from 34 healthcare institutions in the National Patient-Centered Clinical Research Network (PCORnet), we fit 12 multivariable-adjusted linear regression models to assess the associations of antibiotic use

Exposure to per- and polyfluoroalkyl substances (PFASs) may interfere with lipid regulation. However, most previous studies were cross-sectional with the risk of reverse causation, suggesting a need for long-term prospective studies. We examined the relationship of baseline plasma PFAS concentrations with repeated measures of blood lipids. We included 888 prediabetic adults from the Diabetes Prevention Program (DPP) and DPP Outcomes Study, who had measurements of 6 plasma PFAS concentrations at baseline (1996–1999) and repeated measures of blood lipids over 15 years of follow-up, and were initially randomized to placebo or a lifestyle intervention. We used linear regression to examine cross-sectional associations of PFAS concentrations and lipid levels at baseline, and evaluated prospective risks of hypercholesterolemia and hypertriglyceridemia using Cox proportional hazard models, and tested for effect modification by study arm. Participants (65.9% female, 57.0% White, 65.9% aged 40–59 years) had comparable PFAS concentrations [e.g., median (IQR) perfluorooctanoic acid (PFOA) 4.9 ng/mL (3.2)] with the general U.S. population in 1999–2000. We observed higher total cholesterol at baseline per doubling of PFOA (β: 6.1 mg/dL, 95% CI: 3.1, 9.04), perfluorohexane sulfonic acid (PFHxS, β: 2.2 mg/dL, 95% CI: 0.2, 4.3), and perfluorononanoic acid (PFNA, β: 2.9 mg/dL, 95% CI: 0.7, 5.0). Prospectively, baseline concentrations of several PFASs, including PFOA, PFOS, PFHxS and PFNA, predicted higher risks of incident hypercholesterolemia and hypertriglyceridemia, but only in the placebo group and not the lifestyle intervention group. For example, participants in the placebo group with PFOA concentration > median (4.9 ng/mL) were almost twice as likely (HR: 1.90, 95% CI: 1.25, 2.88) to develop hypertriglyceridemia compared to those ≤median. Findings suggest adverse effects of some PFASs on lipid profiles in prediabetic adults. However, the detrimental effect was attenuated with a lifestyle intervention. Keywords: Lipid and cholesterol, Hyperlipidemia, Per- and polyfluoroalkyl substances, Environmental epidemiology, Lifestyle intervention, Prospective assessment

OBJECTIVE Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are suspected endocrine disruptors widely detected across populations. We examine the extent to which PFASs are associated with diabetes incidence and microvascular disease. Secondarily, we tested whether a lifestyle intervention modifies associations and decreases concentrations. RESEARCH DESIGN AND METHODS We analyzed data from a prospective cohort of 957 participants from the Diabetes Prevention Program (DPP) trial and Diabetes Prevention Program Outcomes Study (DPPOS). At baseline, participants were randomized to an intensive lifestyle intervention of diet, physical activity, and behavior modification or a placebo medication. We quantified plasma concentrations of six PFASs at baseline and 2 years after randomization. Participants were monitored for ∼15 years, repeatedly tested for diabetes, and evaluated for microvascular disease at the end of the follow-up. RESULTS A doubling in baseline branched perfluorooctanoic acid concentration was associated with a 14% increase in diabetes risk for the placebo (hazard ratio [HR] 1.14, 95% CI 1.04, 1.25) but not in the lifestyle intervention group (HR 1.01, 95% CI 0.92, 1.11, Pinteraction = 0.11). Mean change in plasma baseline branched perfluorooctanoic acid concentration was greater for the placebo (0.96 ng/mL; 95% CI 0.71, 1.22) compared with the lifestyle intervention group (0.31 ng/mL; 95% CI 0.14, 0.48) 2 years after randomization. Each doubling in N-ethyl-perfluorooctane sulfonamido acetic acid was associated with 17% greater odds of prevalent microvascular disease (OR 1.17, 95% CI 1.05, 1.31), and a similar association was observed for perfluorodimethylhexane sulfonic acid (OR 1.18, 95% CI 1.04, 1.35), regardless of treatment. CONCLUSIONS Some plasma PFASs were associated with diabetes and microvascular disease. Our results suggest that exercise and diet may attenuate the diabetogenic association of PFASs.

BACKGROUND AND AIM: Exposure to neurotoxicant metals, hypothesized to alter dopaminergic function, have not been sufficiently explored as a risk factor for maternal depression. We evaluated the ext...

Background Diet is thought to account for most adult human exposure to per- and polyfluoroalkyl substances (PFAS). Children are particularly vulnerable to adverse health effects of PFAS and may have different eating habits than adults. However, studies of dietary patterns and PFAS in children are limited. Methods We studied 548 Boston-area children with food frequency questionnaire data (89 food items) in early childhood (median age 3.3 years) and plasma concentrations of 6 PFAS quantified in mid-childhood (median age 7.7 years). We used univariate linear regression to examine associations between each food item and PFAS, accounting for multiple comparisons. We next used reduced rank regression (RRR) to estimate overall percent variation in PFAS explained by diet and identify dietary patterns most correlated with PFAS. All models were adjusted for race/ethnicity, maternal education, and household income. Results In univariate analyses, 2-(N-methyl-perfluorooctane sulfonamide) acetate (MeFOSAA) plasma concentrations were 17.8% (95% CI: 7.2, 29.5) and 17.0% (95% CI: 6.4, 28.7) higher per SD increment in intake of ice cream and soda, respectively. RRR identified 6 dietary patterns that together explained 18% variation in the plasma concentrations of the 6 PFAS, of which 50% was explained by a dietary pattern consisting of primarily packaged foods (including ice cream and soda) and fish. Children with higher intake of the packaged foods and fish dietary pattern had higher plasma concentrations of all PFAS, particularly MeFOSAA and PFOS. Conclusions Our analysis examined food intake in association with several PFAS in children and identified dietary determinants that may be sources of PFAS exposure or reflect correlated lifestyle or toxicokinetic factors. Further investigation may help inform measures to modify childhood PFAS exposure.

BackgroundPer- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals that have been associated with cardiovascular risk factors including elevated body weight and hypercholesterolemia. Therefore, PFAS may contribute to the development of atherosclerosis and cardiovascular disease (CVD). However, no previous study has evaluated associations between PFAS exposure and arterial calcification.Methods and resultsThis study used data from 666 prediabetic adults enrolled in the Diabetes Prevention Program trial who had six PFAS quantified in plasma at baseline and two years after randomization, as well as measurements of coronary artery calcium (CAC) and ascending (AsAC) and descending (DAC) thoracic aortic calcification 13-14years after baseline. We performed multinomial regression to test associations between PFAS and CAC categorized according to Agatston score [low (400)]. We used logistic regression to assess associations between PFAS and presence of AsAC and DAC. We adjusted models for baseline sex, age, BMI, race/ethnicity, cigarette smoking, education, treatment assignment (placebo or lifestyle intervention), and statin use. PFAS concentrations were similar to national means; 53.9% of participants had CAC>11, 7.7% had AsAC, and 42.6% had DAC. Each doubling of the mean sum of plasma concentrations of linear and branched isomers of perfluorooctane sulfonic acid (PFOS) was associated with 1.49-fold greater odds (95% CI: 1.01, 2.21) of severe versus low CAC. This association was driven mainly by the linear (n-PFOS) isomer [1.54 (95% CI: 1.05, 2.25) greater odds of severe versus low CAC]. Each doubling of mean plasma N-ethyl-perfluorooctane sulfonamido acetic acid concentration was associated with greater odds of CAC in a dose-dependent manner [OR=1.26 (95% CI:1.08, 1.47) for moderate CAC and OR=1.37 (95% CI:1.07, 1.74) for severe CAC, compared to low CAC)]. Mean plasma PFOS and n-PFOS were also associated with greater odds of AsAC [OR=1.67 (95% CI:1.10, 2.54) and OR=1.70 (95% CI:1.13, 2.56), respectively], but not DAC. Other PFAS were not associated with outcomes.ConclusionsPrediabetic adults with higher plasma concentrations of select PFAS had higher risk of coronary and thoracic aorta calcification. PFAS exposure may be a risk factor for adverse cardiovascular health among high-risk populations.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitously detected in populations worldwide and may hinder kidney function. The objective of the study was to determine longitudinal associations of plasma PFAS concentrations with estimated glomerular filtration rate (eGFR) and evaluate whether a lifestyle intervention modify the associations. We studied 875 participants initially randomized to the lifestyle or placebo arms in the Diabetes Prevention Program (DPP, 1996–2002) trial and Outcomes Study (DPPOS, 2002–2014). We ran generalized linear mixed models accounting a priori covariates to evaluate the associations between baseline PFAS concentrations and repeated measures of eGFR, separately, for six PFAS (PFOS, PFOA, PFHxS, EtFOSAA, MeFOSAA, PFNA); then used quantile-based g-computation to evaluate the effects of the six PFAS chemicals as a mixture. The cohort was 64.9% female; 73.4% 40–64 years-old; 29.4% with hypertension; 50.5% randomized to lifestyle intervention and 49.5% to placebo and had similar plasma PFAS concentrations as the general U.S. population in 1999–2000. Most participants had normal kidney function (eGFR > 90 mL/min/1.73 m2) over the approximately 14 years of follow-up. We found that plasma PFAS concentrations during DPP were inversely associated with eGFR during DPPOS follow-up. Each quartile increase in baseline plasma concentration of the 6 PFAS as a mixture was associated with 2.26 mL/min/1.73 m2 lower eGFR (95% CI: −4.12, −0.39) at DPPOS Year 5, approximately 9 years since DPP randomization and PFAS measurements. The lifestyle intervention did not modify associations, but inverse associations were stronger among participants with hypertension at baseline. Among prediabetic adults, we found inverse associations between baseline plasma PFAS concentrations and measures of eGFR throughout 14 years of follow-up. The lifestyle intervention of diet, exercise and behavioral changes did not modify the associations, but persons with hypertension may have heightened susceptibility.

BACKGROUND: Many studies have identified early-life risk factors for childhood overweight/obesity (OwOb), but few have evaluated how they combine to influence later cardiometabolic health. OBJECTIVES: We aimed to examine the association of risk factors in the first 1000 d with adiposity and cardiometabolic risk in early adolescence. METHODS: We studied 1038 mother–child pairs in Project Viva. We chose 6 modifiable early-life risk factors previously associated with child adiposity or metabolic health in the cohort: smoking during pregnancy (yes compared with no); gestational weight gain (excessive compared with nonexcessive); sugar-sweetened beverage consumption during pregnancy (≥0.5 compared with 1 early-life risk factor. In covariate-adjusted models, we observed positive monotonic increases in BMI, FMI, TFMI, and MetS z scores with increasing risk factor score. Children with 5‒6 risk factors (compared with 0–1 risk factors) had the highest risk of OwOb [risk ratio (RR): 2.53; 95% CI: 1.63, 3.91] and being in the highest MetS quartile (RR: 2.46; 95% CI: 1.43, 4.21). The predicted probability of OwOb in adolescence varied from 9.4% (favorable levels for all factors) to 63.6% (adverse levels for all factors), and for being in the highest MetS quartile from 9.6% to 56.6%. CONCLUSIONS: Early-life risk factors in the first 1000 d cumulatively predicted higher adiposity and cardiometabolic risk in early adolescence. Intervention strategies to prevent later obesity and cardiometabolic risk may be more effective if they concurrently target multiple modifiable factors.

OBJECTIVES: To identify foods associated with blood metal concentrations during the 1(st) trimester of pregnancy. METHODS: In early pregnancy (11.3 ± 2.8 gestational week), 1206 women from Project Viva completed food frequency questionnaire and provided a blood sample to measure essential and non-essential metals. This analysis included 135 food items and 14 metals (As, Cd, Hg, Pb, Co, Cu, Mg, Mn, Se, Zn, Ba, Cs, Sb, Sn) in red blood cells (RBC). We perform a diet-wide association study (DWAS) of all bivariate relationships between each food-metal combination. Additionally, we used machine learning models with elastic-net regularization to estimate the % variation in metal concentrations explained by diet. RESULTS: Mean (standard deviation [SD]) age was 32.5 (4.5) years and pre-pregnancy BMI was 24.8 (5.4) kg/m(2). Most participants were white (76.0%), not current smokers (88.5%), completed a college degree (75.5%), and had a household income >$70 K/year (66.8%). Compared to other US-based cohorts, the overall diet quality of participants was higher, and levels of toxic metals were lower. DWAS identified significant associations between several food items with As, Hg, Pb, Cs and Se; among the positives associations, for example, each SD increase in fresh fruit, white rice, and seafood was associated with 4%, 8%, and 18% higher median concentrations of As, respectively; and fresh fruits (12%), eggs (12%), white rice (15%), green vegetables (17%), and seafood (64%) was associated with Hg. Elastic net models identified significant positive and negative dietary predictors of As, Cs, and Hg, but not other metals. The % variation explained by the selected dietary variables was 21% for As, 7% for Cs, and 11% for Hg. CONCLUSIONS: DWAS provides systematic evaluation of diet-metal relationship and can uncover potential dietary sources of prenatal metal exposure. In this population, we found positive associations between fruit, green vegetable, white rice and seafood consumption with As and Hg. Prenatal diet may be an important source of metals exposures, including As, Hg, and Cs. FUNDING SOURCES: This work was supported by the US National Institutes of Health grants R01HD034568, UH3OD023286, U2CES026561and U2CES026555, and metal analysis was conducted by the Children's Health Exposure Analysis Resource (CHEAR award #2017–1740).

The relationship of plasma concentration of per- and polyfluoroalkyl substances (PFAS) with blood pressure (BP) is uncertain. This study examined cross-sectional and prospective associations of PFAS with BP and hypertension. We quantified plasma PFAS concentrations from 957 participants enrolled in the lifestyle and placebo arms of the Diabetes Prevention Program (DPP), a randomized controlled trial with approximately 15 years of follow-up. We used multivariable linear and logistic regressions to test cross-sectional associations of six PFAS, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA), N-methyl-perfluorooctane sulfonamido acetic acid (MeFOSAA), and perfluorononanoic acid (PFNA), with BP and hypertension prevalence, respectively, at baseline. We used generalized linear mixed models to estimate longitudinal associations between baseline PFAS and the rate of BP changes, and Cox-Proportional hazard models to estimate risk of developing hypertension relative to baseline PFAS. Models were adjusted for baseline age, sex, race/ethnicity, treatment arm, educational attainment, income, marital status, smoking habit, alcohol drinking, and diet. We tested for effect modification by the treatment arm and sex, and accounted for multiple comparisons using the False-Discovery Rate (FDR). PFAS concentrations and hypertension prevalence within the study population (65.3% female, 57.7% White, 65.3% aged 40–59 years) were comparable to the general U.S. population. Cross-sectionally, we found small but statistically significant associations of baseline plasma concentrations of PFOA with systolic BP (β per doubling: 1.49 mmHg, 95% CI: 0.29, 2.70); and MeFOSAA with hypertension (RR = 1.09 per doubling, 95% CI: 1.01, 1.19). Estimates were not statistically significant after FDR adjustment. Longitudinally, we observed null associations in the placebo arm, but some inverse associations of baseline PFOS and MeFOSAA with systolic BP in the lifestyle arm, perhaps due to regression toward the mean. Baseline PFAS concentrations also were not prospectively associated with hypertension risk. Overall, there were modest and mostly null associations of plasma PFAS concentrations with BP and hypertension. Keywords: Per- and polyfluoroalkyl substances, Blood pressure, Hypertension, Prediabetic adults, Longitudinal study, Diabetes Prevention Program

Arsenic crosses the placenta, possibly increasing the risk of adverse reproductive outcomes. We aimed to examine the association between maternal arsenic exposure and fetal/neonatal survival using data from a prospective cohort study of 1,616 maternal-infant pairs recruited at a gestational age of ≤16 weeks in Bangladesh (2008–2011). Arsenic concentration in maternal drinking water was measured at enrollment. Extended Cox regression (both time-dependent coefficients and step functions) was used to estimate the time-varying association between maternal arsenic exposure and fetal/neonatal death (all mortality between enrollment and 1 month after birth). In a sensitivity analysis, we assessed gestational arsenic exposure using maternal urine samples taken at enrollment. We observed 203 fetal losses and 20 neonatal deaths. Higher arsenic exposure was associated with a slightly decreased mortality rate up to the middle of the second trimester, and then the mortality rate switched directions around 20 weeks’ gestation. In the step function model, the hazard ratios for combined mortality (fetal loss and neonatal death) per unit increase in the natural log of drinking water arsenic concentration (μg/L) ranged from 1.35 (95% CI: 1.08, 1.69) in weeks 25–28 to 0.81 (95% CI: 0.65, 1.02) in weeks 9–12. This nonlinear association suggests that arsenic may exert survival pressure on developing fetuses, potentially contributing to survival bias, and may also indicate that arsenic toxicity differs by fetal developmental stage.

Objectives Cooking oil fumes (COFs) contain many carcinogens. We investigated the association between COFs and incidence risk of any cancer and lung cancer in chefs. Methods We identified Chinese food chefs and non-Chinese food chefs from Taiwan’s national database of certified chefs in 1984–2007. Of them, 379,275 had not been diagnosed as having any cancer before chef certification. We followed them in Taiwan’s Cancer Registry Database (1979–2010) and Taiwan’s National Death Statistics Database (1985–2011) for any newly diagnosed cancer or lung cancer. Results 378,126 and 379,215 chefs were included for risk analysis of cancer and lung cancer, respectively. 6099 chefs developed cancer and 339 developed lung cancer over the follow-up periods of 4,183,550 and 4,220,163 person-years, respectively. Compared to non-Chinese food chefs, the adjusted IRR of cancer for Chinese food chefs was 1.69 (95% CI 1.51–1.89). For lung cancer, the risk was significantly higher among Chinese food chefs who had been certified for more than 5 years (adjusted IRR 2.12, 95% CI 1.32–3.40). This increased risk was pronounced in female chefs (adjusted IRR 4.73, 95% CI 1.74–12.86). Conclusions Chinese food chefs had an increased risk of cancer and lung cancer, particularly in females. Electronic supplementary material The online version of this article (10.1007/s00420-018-1358-8) contains supplementary material, which is available to authorized users.

Metals are involved in glucose metabolism, and some may alter glycemic regulation. However, joint effects of essential and non-essential metals on glucose concentrations during pregnancy are unclear. This study explored the joint associations of pregnancy exposures to essential (copper, magnesium, manganese, selenium, zinc) and non-essential (arsenic, barium, cadmium, cesium, lead, mercury) metals with gestational glucose concentrations using 1,311 women enrolled 1999–2002 in Project Viva, a Boston, MA-area pregnancy cohort. The study measured erythrocyte metal concentrations from 1st trimester blood samples and used glucose concentrations measured 1 h after non-fasting 50-gram glucose challenge tests (GCT) from clinical gestational diabetes screening at 26–28 weeks gestation. Bayesian Kernel Machine Regression (BKMR) and quantile-based g-computation were applied to model the associations of metal mixtures—including their interactions—with glucose concentrations post-GCT. We tested for reproducibility of BKMR results using generalized additive models. The BKMR model showed an inverse U-shaped association for barium and a linear inverse association for mercury. Specifically, estimated mean glucose concentrations were highest around 75th percentile of barium concentrations [2.1 (95% confidence interval: −0.2, 4.4) mg/dL higher comparing to the 25th percentile], and each interquartile range increase of erythrocyte mercury was associated with 1.9 mg/dL lower mean glucose concentrations (95% credible interval: −4.2, 0.4). Quantile g-computation showed joint associations of all metals, essential-metals, and non-essential metals on gestational glucose concentrations were all null, however, we observed evidences of interaction for barium and lead. Overall, we found early pregnancy barium and mercury erythrocytic concentrations were associated with altered post-load glucose concentrations in later pregnancy, with potential interactions between barium and lead.

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

OBJECTIVES: To identify dietary characteristics associated with variation in plasma per- and polyfluoroalkyl substances (PFAS) concentrations among pre-diabetic adults in the US. METHODS: We evaluated cross-sectional associations between diet and plasma PFAS concentrations among pre-diabetic adults in the US enrolled in the Diabetic Prevention Program 1996–1999. Participants reported their diet over the previous year using a 117-item food frequency questionnaire. Plasma concentrations of 6 PFASs were measured using SPE-LC/MS/MS. We calculated daily intake for major food groups and characterized dietary patterns using principal component analysis (PCA). We estimated differences in plasma PFAS concentrations relative to diet using multivariate linear regression models adjusting for age, sex, race, marital status, education, income, smoking, waist circumference and total caloric intake. RESULTS: Participants (N = 941, 65% female , 58% Caucasian, 68% married, 75% with higher education, 95% nonsmoker) had similar plasma PFAS concentrations compared to the general US population measured in 1999–2000. Mean (SD) daily energy intake was 2091 (975) kcal. Using single food group approach, the strongest predictor for plasma PFAS concentrations was fried fish; each SD increase (0.1 serving/day) was associated with 13.6% (95% CI: 7.7, 19.9) and 6.9% (95% CI: 2.2, 11.8) higher median plasma concentration of perfluorononanoic acid (PFNA) and straight-chain perfluorooctanesulfonic acid (n-PFOS), respectively. Some food groups had inverse associations, with the strongest predictor being cruciferous vegetable [11.5% (95% CI: −16.1, −6.6) decrease in median concentration of plasma 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA) per SD (0.3 serving/day) increase in intake]. PCA showed a vegetable diet to be associated with lower plasma PFAS concentrations, and diet patterns of high-fat meat diet and high-fat and low-fiber grains to be associated with higher PFAS concentrations. CONCLUSIONS: Dietary patterns may influence PFAS exposures and/or excretion and absorption pathways. Studies of PFASs with diet-sensitive disease outcomes should account for confounding by diet. FUNDING SOURCES: This work was supported by the US National Institutes of Health grant R01ES024765.

Rationale Organophosphate pesticides (OPPs) are the most commonly used insecticides around the world in various agricultural and domestic practices, and humans are frequently exposed to these hazardous insecticides that can lead to several chronic health effects. Therefore, a fast and sensitive analytical method is required for biomonitoring the markers of OPPs in humans for exposure estimation. In this study, a fast and sensitive analytical procedure was developed for the determination of the metabolites of OPPs in human urine samples. Methods Metabolites of OPPs were extracted from 2 mL of urine sample using a novel vortex-assisted salt-induced liquid-liquid microextraction (VA-SI-LLME) technique, and the preconcentrated metabolites were analyzed by ultra-high-performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS). Various factors affecting the efficiency of VA-SI-LLME were thoroughly investigated. Results The metabolites of OPPs exhibited very good linearity over the concentration range between 0.05 and 50 ng mL-1 with coefficient (r2 ) values ranging between 0.9986 and 0.9999. The method showed excellent sensitivity with detection limits ranging from 0.01 to 0.03 ng mL-1 and quantification limits from 0.03 to 0.05 ng mL-1 . The developed method was applied to the analysis of real samples and the recoveries ranged between 85.0 and 114.1% with related standard deviations Conclusions The results showed the VA-SI-LLME/UHPLC/MS/MS method to be a simple, rapid, sensitive, and selective analytical procedure for the biomonitoring of the metabolites of OPPs in humans. This efficient and cost-effective analytical method could be a potential alternative method for the biomonitoring of the metabolites of pesticides in humans.

Literature on maternal dietary patterns during pregnancy and offspring weight status have been largely equivocal. We aimed to investigate the association of maternal dietary patterns with infant weight status among 937 mother–infant dyads in a Chinese birth cohort. We assessed maternal diet during pregnancy using food frequency questionnaires (FFQ) and three-day food diaries (TFD) and examined infants’ body weight and length at birth, 1, 3, 6, 8 and 12 months. Maternal adherence to the “protein-rich pattern (FFQ)” was associated with lower infant body mass index z-scores (BMIZ) at birth, 3 and 6 months and lower odds of overweight and obesity (OwOb) across infancy (quartile 3 (Q3) vs. quartile 1 (Q1): odds ratio (OR): 0.50, (95% confidence interval: 0.27, 0.93)). Maternal adherence to the “vegetable–fruit–rice pattern (FFQ)” was associated with higher BMIZ at birth, 3 and 6 months and higher odds of OwOb across infancy (Q3 vs. Q1: OR: 1.79, (1.03, 3.12)). Maternal adherence to the “fried food–bean–dairy pattern (TFD)” was associated with lower BMIZ at 3, 6, 8 and 12 months and lower odds of OwOb (Q3 vs. Q1: OR: 0.54, (0.31, 0.95)). The study results may help to develop interventions and to better define target populations for childhood obesity prevention.

Dietary patterns during pregnancy have been shown to influence the development of gestational diabetes mellitus (GDM). However, evidence from Asian populations is limited and inconsistent. We conducted a prospective cohort study in China to assess the relationship between dietary patterns and GDM. We administered three-day food diaries (TFD) and food frequency questionnaires (FFQ) at the second trimester. GDM was diagnosed with a 75 g 2-h oral glucose tolerance test at 24&ndash, 28 weeks of gestation. We identified dietary patterns using principal components analysis and used multivariable logistic regression to investigate associations of dietary patterns with GDM. Of the 1014 participants, 23.5% were diagnosed with GDM. Both the TFD and FFQ identified a &ldquo, traditional pattern&rdquo, consisting of high vegetable, fruit, and rice intake, which was associated with a lower GDM risk (odds ratio (OR) for quartile 4 versus quartile 1: 0.40, 95% CI: 0.23&ndash, 0.71 for traditional pattern (TFD), OR: 0.44, CI: 0.27&ndash, 0.70 for traditional pattern (FFQ)). The protective associations were more pronounced among women &ge, 35 years old. A whole grain&ndash, seafood TFD pattern was associated with higher risk of GDM (OR: 1.73, 95% CI: 1.10&ndash, 2.74). These findings may provide evidence for making dietary guidelines among pregnant women in Chinese populations to prevent GDM.

Per- and polyfluoroalkyl substances (PFASs) may interfere with lipid regulation but most previous studies examined occupational cohorts or general populations but not those with high metabolic risk...

Background: Per- and polyfluoroalkyl substances (PFASs) are ubiquitous synthetic chemicals, widely detected across populations and suspected endocrine disruptors. We sought to determine the extent ...

Researchers often use prescribing data from electronic health records (EHR) or dispensing data from medication or medical claims to determine medication utilization. However, neither source has complete information on medication use. We compared antibiotic prescribing and dispensing records for 200,395 patients in the National Patient-Centered Clinical Research Network (PCORnet) Antibiotics and Childhood Growth Study. We stratified analyses by delivery system type [closed integrated (cIDS) and non-cIDS]; 90.5 percent and 39.4 percent of prescribing records had matching dispensing records, and 92.7 percent and 64.0 percent of dispensing records had matching prescribing records at cIDS and non-cIDS, respectively. Most of the dispensings without a matching prescription did not have same-day encounters in the EHR, suggesting they were medications given outside the institution providing data, such as those from urgent care or retail clinics. The sensitivity of prescriptions in the EHR, using dispensings as a gold standard, was 99.1 percent and 89.9 percent for cIDS and non-cIDS, respectively. Only 0.7 percent and 6.1 percent of patients at cIDS and non-cIDS, respectively, were classified as false-negative, i.e. entirely unexposed to antibiotics when they in fact had dispensings. These patients were more likely to have a complex chronic condition or asthma. Overall, prescription records worked well to identify exposure to antibiotics. EHR data, such as the data available in PCORnet, is a unique and vital resource for clinical research. Closing data gaps by understanding why prescriptions may not be captured can improve this type of data, making it more robust for observational research.

This prospective study evaluated the relationship between long-term dietary habits and total arsenic (As) concentration in toenail clippings in a cohort of 1616 pregnant women in the Bangladeshi administrative regions of Sirajdikhan and Pabna Sadar. Diet was assessed at Gestation Week 28 and at Postpartum Month 1, using a locally-validated dish-based semi-quantitative food-frequency questionnaire. Toenail As concentration was analyzed by microwave-assisted acid digestion and inductively coupled plasma mass spectrometry. Associations between natural log-transformed consumption of individual food items and temporally matched natural log-transformed toenail As concentration were quantified using general linear models that accounted for As concentration in the primary drinking water source and other potential confounders. The analysis was stratified by As in drinking water (≤50 μg/L versus >50 μg/L) and the time of dietary assessment (Gestation Week 28 versus Postpartum Week 1). Interestingly, toenail As was not significantly associated with consumption of plain rice as hypothesized. However, toenail As was positively associated with consumption of several vegetable, fish and meat items and was negatively associated with consumption of rice, cereal, fruits, and milk based food items. Further studies in pregnant women are needed to compare As metabolism at different levels of As exposure and the interaction between dietary composition and As absorption.

Importance Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are ubiquitous synthetic chemicals that are suspected endocrine disruptors. Objectives To determine the extent to which PFASs are associated with increases in weight and body size and evaluate whether a lifestyle intervention modifies this association. Design, Setting, and Participants This prospective cohort study included 957 individuals who participated in the Diabetes Prevention Program trial, conducted from July 1996 to May 2001, and the Diabetes Prevention Program Outcomes Study, conducted from September 2002 to January 2014. Statistical analysis was conducted from September 1, 2017, to May 25, 2018. Interventions and Exposures The initial lifestyle intervention consisted of training in diet, physical activity, and behavior modification, with the major goals of achieving 7% weight loss with subsequent maintenance and a minimum of 150 minutes per week of physical activity. Participants randomized to placebo received standard information about diet and exercise. A total of 6 plasma PFASs were quantified at baseline and 2 years after randomization, means were calculated from baseline and year 2 concentrations, and means were summed to assess total PFAS burden. Main Outcomes and Measures Weight, waist circumference, and hip girth were measured at baseline and at scheduled visits. Results Of the 957 participants, 625 (65.3%) were women and 731 participants (76.4%) were between 40 and 64 years of age; 481 participants were randomized to the lifestyle intervention and 476 participants were randomized to the placebo arm. The PFAS concentrations were not different by treatment arm and were similar to concentrations reported for the US population in 1999-2000. The association of PFAS and weight change differed by treatment. Each doubling in total PFAS concentration was associated with an increase of 1.80 kg (95% CI, 0.43-3.17 kg; P = .01) from baseline to 9 years after randomization for the placebo group but not the lifestyle intervention group (−0.59 kg; 95% CI, –1.80 to 0.62 kg; P = .34). Similarly, each doubling in PFAS was associated with a 1.03-cm increase in hip girth in the Diabetes Prevention Program trial for the placebo group (95% CI, 0.18-1.88 cm; P = .02) but not the lifestyle intervention group (−0.09 cm; 95% CI, −0.82 to 0.63 cm; P = .80). No associations were observed for changes in mean waist circumference. Conclusions and Relevance Among adults at high risk for diabetes, higher plasma PFAS concentration was associated with increases in weight and hip girth over time, but a lifestyle intervention attenuated these associations. Diet and exercise may mitigate the obesogenic effects of environmental chemicals. Trial Registration ClinicalTrials.gov Identifier: NCT00004992 and NCT00038727, This cohort study from the Diabetes Prevention Program trial and Outcomes Study determines the extent to which perfluoroalkyl and polyfluoroalkyl substances are associated with increases in body weight and size and evaluates whether a lifestyle intervention modifies this association., Key Points Question Are synthetic perfluoroalkyl and polyfluoroalkyl substances associated with changes in weight, body size, and adiposity in adults? Findings In this follow-up cohort study of 957 participants in the the Diabetes Prevention Program Outcomes Study for 15 years, plasma concentrations of perfluoroalkyl and polyfluoroalkyl substances were associated with increases in weight gain and body size among individuals initially randomized to placebo. However, for participants randomized to a lifestyle intervention of exercise and diet, no detrimental associations were observed. Meaning Plasma concentration of perfluoroalkyl and polyfluoroalkyl substances is associated with increases in weight and body size in adults; however, exercise and diet may modify and attenuate the obesogenic effects of perfluoroalkyl and polyfluoroalkyl substances.