Associations of street-view greenspace with Parkinson's disease hospitalizations in an open cohort of elderly US Medicare beneficiaries.

INTRODUCTION: Protective associations of greenspace with Parkinson's disease (PD) have been observed in some studies. Visual exposure to greenspace seems to be important for some of the proposed pathways underlying these associations. However, most studies use overhead-view measures (e.g., satellite imagery, land-classification data) that do not capture street-view greenspace and cannot distinguish between specific greenspace types. We aimed to evaluate associations of street-view greenspace measures with hospitalizations with a PD diagnosis code (PD-involved hospitalization). METHODS: We created an open cohort of about 45.6 million Medicare fee-for-service beneficiaries aged 65 + years living in core based statistical areas (i.e. non-rural areas) in the contiguous US (2007-2016). We obtained 350 million Google Street View images across the US and applied deep learning algorithms to identify percentages of specific greenspace features in each image, including trees, grass, and other green features (i.e., plants, flowers, fields). We assessed yearly average street-view greenspace features for each ZIP code. A Cox-equivalent re-parameterized Poisson model adjusted for potential confounders (i.e. age, race/ethnicity, socioeconomic status) was used to evaluate associations with first PD-involved hospitalization. RESULTS: There were 506,899 first PD-involved hospitalizations over 254,917,192 person-years of follow-up. We found a hazard ratio (95% confidence interval) of 0.96 (0.95, 0.96) per interquartile range (IQR) increase for trees and a HR of 0.97 (0.96, 0.97) per IQR increase for other green features. In contrast, we found a HR of 1.06 (1.04, 1.07) per IQR increase for grass. Associations of trees were generally stronger for low-income (i.e. Medicaid eligible) individuals, Black individuals, and in areas with a lower median household income and a higher population density. CONCLUSION: Increasing exposure to trees and other green features may reduce PD-involved hospitalizations, while increasing exposure to grass may increase hospitalizations. The protective associations may be stronger for marginalized individuals and individuals living in densely populated areas.

Food, nutrition, and autism: from soil to fork.

Food and nutrition-related factors have the potential to impact development of autism spectrum disorder (ASD) and quality of life for people with ASD, but gaps in evidence exist. On 10 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships of food and nutrition with ASD. This meeting report summarizes the presentations and deliberations from the meeting. Topics addressed included prenatal and child dietary intake, the microbiome, obesity, food-related environmental exposures, mechanisms and biological processes linking these factors and ASD, food-related social factors, and data sources for future research. Presentations highlighted evidence for protective associations with prenatal folic acid supplementation and ASD development, increases in risk of ASD with maternal gestational obesity, and the potential for exposure to environmental contaminants in foods and food packaging to influence ASD development. The importance of the maternal and child microbiome in ASD development or ASD-related behaviors in the child was reviewed, as was the role of discrimination in leading to disparities in environmental exposures and psychosocial factors that may influence ASD. The role of child diet and high prevalence of food selectivity in children with ASD and its association with adverse outcomes were also discussed. Priority evidence gaps identified by participants include further clarifying ASD development, including biomarkers and key mechanisms; interactions among psychosocial, social, and biological determinants; interventions addressing diet, supplementation, and the microbiome to prevent and improve quality of life for people with ASD; and mechanisms of action of diet-related factors associated with ASD. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and ASD.

Trends of Antihypertensive Prescription Among US Adults From 2010 to 2019 and Changes Following Treatment Guidelines: Analysis of Multicenter Electronic Health Records.

BACKGROUND: Guidelines for the use of antihypertensives changed in 2014 and 2017. To understand the effect of these guidelines, we examined trends in antihypertensive prescriptions in the United States from 2010 to 2019 using a repeated cross-sectional design. METHODS AND RESULTS: Using electronic health records from 15 health care institutions for adults (20-85 years old) who had ≥1 antihypertensive prescription, we assessed whether (1) prescriptions of beta blockers decreased after the 2014 Eighth Joint National Committee (JNC 8) report discouraged use for first-line treatment, (2) prescriptions for calcium channel blockers and thiazide diuretics increased among Black patients after the JNC 8 report encouraged use as first-line therapy, and (3) prescriptions for dual therapy and fixed-dose combination among patients with blood pressure ≥140/90 mm Hg increased after recommendations in the 2017 Hypertension Clinical Practice Guidelines. The study included 1 074 314 patients with 2 133 158 prescription episodes. After publication of the JNC 8 report, prescriptions for beta blockers decreased (3% lower in 2018-2019 compared to 2010-2014), and calcium channel blockers increased among Black patients (20% higher in 2015-2017 and 41% higher in 2018-2019, compared to 2010-2014), in accordance with guideline recommendations. However, contrary to guidelines, dual therapy and fixed-dose combination decreased after publication of the 2017 Hypertension Clinical Practice Guidelines (9% and 11% decrease in 2018-2019 for dual therapy and fixed-dose combination, respectively, compared to 2015-2017), and thiazide diuretics decreased among Black patients after the JNC 8 report (6% lower in 2018-2019 compared to 2010-2014). CONCLUSIONS: Adherence to guidelines on prescribing antihypertensive medication was inconsistent, presenting an opportunity for interventions to achieve better blood pressure control in the US population.

Associations of Prenatal Per- and Polyfluoroalkyl Substance (PFAS) Exposures with Offspring Adiposity and Body Composition at 16-20 Years of Age: Project Viva.

BACKGROUND: Findings on the associations between prenatal PFAS exposures and offspring adiposity are inconsistent. Whether such associations may extend to adolescence is especially understudied. OBJECTIVES: We investigated associations of prenatal PFAS exposures with offspring adiposity and body composition at 16-20 years of age. METHODS: We studied 545 mother-child pairs in the prospective prebirth cohort Project Viva (Boston, Massachusetts). We measured six PFAS (PFOA, PFOS, PFNA, PFHxS, EtFOSAA, and MeFOSAA) in maternal early pregnancy (median age=9.6wk, range: 5.7-19.6 wk) plasma samples. At the late adolescence visit (median age=17.4 y, range: 15.9-20.0 y), we obtained anthropometric measures and assessed body composition using bioelectrical impedance analysis and dual-energy X-ray absorptiometry. We examined associations of individual PFAS with obesity [i.e., age- and sex-specific body mass index (BMI) ≥95th percentile] and adiposity and body composition using multivariable Poisson and linear regression models, respectively. We assessed PFAS mixture effects using Bayesian kernel machine regression (BKMR) and quantile g-computation. We used fractional-polynomial models to assess BMI trajectories (at 3-20 years of age) by prenatal PFAS levels. RESULTS: Thirteen percent (n=73) of the children had obesity in late adolescence. After multivariable adjustment, higher prenatal PFAS concentrations were associated with higher obesity risk [e.g., 1.59 (95% CI: 1.19, 2.12), 1.24 (95% CI: 0.98, 1.57), and 1.49 (95% CI: 1.11, 1.99) times the obesity risk per doubling of PFOS, PFOA, and PFNA, respectively]. BKMR showed an interaction between PFOA and PFOS, where the positive association between PFOS and obesity was stronger when PFOA levels were lower. Each quartile increment of the PFAS mixture was associated with 1.52 (95% CI: 1.03, 2.25) times the obesity risk and 0.52 (95% CI: -0.02, 1.06) kg/m2 higher BMI. Children with higher prenatal PFOS, EtFOSAA, and MeFOSAA concentrations had higher rates of BMI increase starting from 9-11 years of age. DISCUSSION: Prenatal PFAS exposures may have obesogenic effects into late adolescence. https://doi.org/10.1289/EHP12597.

Prenatal and Childhood Per- and Polyfluoroalkyl Substance (PFAS) Exposures and Blood Pressure Trajectories From Birth to Late Adolescence in a Prospective US Prebirth Cohort.

Background Evidence is limited regarding the associations of prenatal and childhood per- and polyfluoroalkyl substance (PFAS) exposures with blood pressure (BP) trajectories in children. Methods and Results Participants are from Project Viva, a prospective prebirth cohort in eastern Massachusetts. We measured PFAS in early-pregnancy maternal (median, 9.6 weeks) and midchildhood (median, 7.7 years) plasma samples. We conducted standardized BP measurements at 6 research visits: birth, infancy (median, 6.3 months), early childhood (median, 3.2 years), midchildhood (median, 7.7 years), early adolescence (median, 12.9 years), and late adolescence (median, 17.5 years). We used linear regression to examine associations of individual PFASs with BP at each visit, linear spline mixed-effects regression to model BP trajectories, and a mixture approach to estimate PFAS exposure burden. We included 9036 BP measures from 1506 participants. We observed associations between particular individual prenatal PFASs and child BP at specific time points, for example, prenatal 2-(N-ethyl-perfluorooctane sulfonamido) acetate (EtFOSAA) and 2-(N-methyl-perfluorooctane sulfonamido) acetate (MeFOSAA) with higher systolic BP at birth; prenatal perfluorooctane sulfonate (PFOS) and EtFOSAA with lower diastolic BP in infancy; and prenatal PFOS, perfluorooctanoate (PFOA), and EtFOSAA with higher systolic BP at midchildhood. No prenatal or childhood PFAS was consistently associated with BP across all visits. Diastolic BP trajectories from 0 to 20 years differed slightly by prenatal PFOA, perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA) (P values 0.01-0.09). Diastolic BP trajectories from 6 to 20 years differed slightly by midchildhood PFHxS and MeFOSAA (P-values 0.03-0.08). Prenatal or childhood PFAS mixture burden scores were not associated with BP. Conclusions We found associations of prenatal and childhood PFAS exposures with BP at specific time points between birth and late adolescence but no consistent associations across all time points or PFAS types.

A Cross-validated Ensemble Approach to Robust Hypothesis Testing of Continuous Nonlinear Interactions: Application to Nutrition-Environment Studies.

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.

Changes in obesity and BMI among children and adolescents with selected chronic conditions during the COVID-19 pandemic.

OBJECTIVE: The aim of this study was to examine COVID-19 pandemic-related changes in obesity and BMI among patients aged 5 to <20 years with selected chronic conditions. METHODS: A longitudinal study in 293,341 patients aged 5 to <20 years who were prescribed one of five medication classes (for depression, psychosis, hypertension, diabetes, or epilepsy) and who had BMI measures from January 2019 to March 2021 was conducted. Generalized estimating equations and linear mixed-effects models were used, accounting for within-child repeated measures and stratified by age, race, ethnicity, gender, and class of medication prescribed, to compare obesity and BMI z score during the pandemic (June through December 2020) versus pre-pandemic (June through December 2019). RESULTS: Obesity prevalence increased from 23.8% before the pandemic to 25.5% during the pandemic; mean (SD) BMI z score increased from 0.62 (1.26) to 0.65 (1.29). Obesity prevalence during the pandemic increased at a faster rate compared with pre-pandemic among children aged 5 to <13 years (0.27% per month; 95% CI: 0.11%-0.44%) and 13 to <18 years (0.24% per month; 95% CI: 0.09%-0.40%), with the largest increases among children aged 5 to <13 years who were male (0.42% per month), Black (0.35% per month), or Hispanic (0.59% per month) or who were prescribed antihypertensives (0.28% per month). CONCLUSIONS: The COVID-19 pandemic has exacerbated the obesity epidemic and widened disparities among children with selected chronic conditions. These findings highlight the importance of continuing efforts to specifically help high-risk populations who are experiencing weight gain from the pandemic.

Comparison of Rates of Type 2 Diabetes in Adults and Children Treated With Anticonvulsant Mood Stabilizers.

Importance: Anticonvulsant mood stabilizer treatment is associated with an increased risk of weight gain, but little is known about the risk of developing type 2 diabetes (T2D). Objective: To evaluate the comparative safety of anticonvulsant mood stabilizers on risk of T2D in adults and children by emulating a target trial. Design, Setting, and Participants: This observational cohort study used data from IBM MarketScan (2010-2019), with a 5-year follow-up period. The nationwide sample of US commercially insured patients included children (aged 10-19 years) and adults (aged 20-65 years) who initiated anticonvulsant mood stabilizer treatment. Data were analyzed from August 2020 to May 2021. Exposures: Initiation and continuation of carbamazepine, lamotrigine, oxcarbazepine, or valproate. Main Outcomes and Measures: Onset of T2D during follow-up. Weighted pooled logistic regression was used to estimate the association of initiation and continuation of carbamazepine, lamotrigine, oxcarbazepine, or valproate with the risk of developing T2D. Inverse probability weights were used to control for confounding and loss to follow-up by measured baseline and time-varying covariates. Results: The analysis included 274 206 adults (159 428 women [58%]; mean [SD] age, 39.9 [13.2] years) and 74 005 children (38 672 girls [52%]; mean [SD] age, 15.6 [2.6] years) who initiated an anticonvulsant mood stabilizer. In adults, initiation of valproate was associated with an increased risk of developing T2D compared with initiation of lamotrigine (5-year risk difference [RD], 1.17%; 95% CI, 0.66% to 1.76%). The number needed to harm was 87 patients initiating valproate for 1 patient to develop T2D within 5 years compared with initiation of lamotrigine. Point estimates were similar when evaluating the association of treatment continuation (5-year RD, 1.99%; 95% CI, -0.64% to 5.31%). The estimated association was smaller and more variable comparing carbamazepine and oxcarbazepine to lamotrigine. In children, RDs were much smaller and more variable (5-year RD for initiation of oxcarbazepine vs lamotrigine, 0.29%; 95% CI, -0.12% to 0.69%; 5-year RD for initiation of valproate vs lamotrigine, 0.18%; 95% CI, -0.09% to 0.49%). Conclusions and Relevance: In this cohort study, valproate was associated with the highest risk of developing T2D in adults. The comparative safety was generally similar in children, but estimates were small and variable. In the absence of randomized trials, emulating target trials within health care databases can generate the age-specific drug safety data needed to inform treatment decision-making.

Early pregnancy essential and non-essential metal mixtures and gestational glucose concentrations in the 2nd trimester: Results from project viva.

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.

Early Life Antibiotic Prescriptions and Weight Outcomes in Children 10 Years of Age.

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

The Patient-Centered Outcomes Research Network Antibiotics and Childhood Growth Study: Implementing Patient Data Linkage.

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.

Gender differences and lung cancer risk in occupational chefs: analyzing more than 350,000 chefs in Taiwan, 1984-2011.

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.