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Background . Fish and rice are the main dietary sources of methylmercury (MeHg); however, rice does not contain the same beneficial nutrients as fish, and these differences can impact the observed health effects of MeHg. Hence, it is important to validate a biomarker, which can distinguish among dietary MeHg sources. Methods . Mercury (Hg) stable isotopes were analyzed in hair samples from peripartum mothers in China ( n = 265). Associations between mass dependent fractionation (MDF) ( δ 202 Hg) and mass independent fractionation (MIF) ( Δ 199 Hg) (dependent variables) and dietary MeHg intake (independent variable) were investigated using multivariable regression models. Results . In adjusted models, hair Δ 199 Hg was positively correlated with serum omega-3 fatty acids (a biomarker for fish consumption) and negatively correlated with maternal rice MeHg intake, indicating MIF recorded in hair can be used to distinguish MeHg intake predominantly from fish versus rice. Conversely, in adjusted models, hair δ 202 Hg was not correlated with measures of dietary measures of MeHg intake. Instead, hair δ 202 Hg was strongly, negatively correlated with hair Hg, which explained 27-29% of the variability in hair δ 202 Hg. Conclusions . Our results indicated that hair Δ 199 Hg can be used to distinguish MeHg intake from fish versus rice. Results also suggested that lighter isotopes were preferentially accumulated in hair, potentially reflecting Hg binding to thiols ( i.e. , cysteine); however, more research is needed to elucidate this hypothesis. Broader impacts include 1) validation of a non-invasive biomarker to distinguish MeHg intake from rice versus fish, and 2) the potential to use Hg isotopes to investigate Hg binding in tissues.

Prior studies reported excess rates (ERs) of cardiorespiratory events associated with short-term increases in PM 2.5 concentrations, despite implementation of pollution-control policies. In 2017, Federal Tier 3 light-duty vehicle regulations began, and to-date there have been no assessments of population health effects of the policy. Using the NYS Statewide Planning and Research Cooperative System (SPARCS) database, we obtained hospitalizations and ED visits with a principal diagnosis of asthma or chronic obstructive pulmonary disease (COPD) for residents living within 15 miles of six urban PM 2.5 monitoring sites in NYS (2014-2019). We used a time-stratified case-crossover design and conditional logistic regression (adjusting for ambient temperature, relative humidity, and weekday) to estimate associations between PM 2.5 , POC (primary organic carbon), SOC (secondary organic carbon), and rates of respiratory disease hospitalizations and emergency department (ED) visits from 2014 to 2019. We evaluated demographic disparities in these relative rates and compared changes in ERs before (2014-2016) and after Tier 3 implementation (2017-2019). Each interquartile range increase in PM 2.5 was associated with increased ERs of asthma or COPD hospitalizations and ED visits in the previous 7 days (ERs ranged from 1.1%-3.1%). Interquartile range increases in POC were associated with increased rates of asthma ED visits (lag days 0-6: ER = 2.1%, 95% CI = 0.7%, 3.6%). Unexpectedly, the ERs of asthma admission and ED visits associated with PM 2.5 , POC, and SOC were higher during 2017-2019 (after Tier 3) than 2014-2016 (before Tier-3). Chronic obstructive pulmonary disease analyses showed similar patterns. Excess Rates were higher in children (<18 years; asthma) and seniors (≥65 years; COPD), and Black, Hispanic, and NYC residents. In summary, unanticipated increases in asthma and COPD ERs after Tier-3 implementation were observed, and demographic disparities in asthma/COPD and PM2.5, POC, and SOC associations were also observed. Future work should confirm findings and investigate triggering of respiratory events by source-specific PM., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Air pollution exposure during pregnancy has been associated with numerous adverse pregnancy, birth, and child health outcomes. One proposed mechanism underlying these associations is maternal immune activation and dysregulation. We examined associations between PM 2.5 and NO 2 exposure during pregnancy and immune markers within immune function groups (TH1, TH2, TH17, Innate/Early Activation, Regulatory, Homeostatic, and Proinflammatory), and examined whether those associations changed across pregnancy., Methods: In a pregnancy cohort study (n = 290) in Rochester, New York, we measured immune markers (using Luminex) in maternal plasma up to 3 times during pregnancy. We estimated ambient PM 2.5 and NO 2 concentrations at participants' home addresses using a spatial-temporal model. Using mixed effects models, we estimated changes in immune marker concentrations associated with interquartile range increases in PM 2.5 (2.88 μg/m 3 ) and NO 2 (7.82 ppb) 0-6 days before blood collection, and assessed whether associations were different in early, mid, and late pregnancy., Results: Increased NO 2 concentrations were associated with higher maternal immune markers, with associations observed across TH1, TH2, TH17, Regulatory, and Homeostatic groups of immune markers. Furthermore, the largest increases in immune markers associated with each 7.82 ppb increase in NO 2 concentration were in late pregnancy (e.g., IL-23 = 0.26 pg/ml, 95% CI = 0.07, 0.46) compared to early pregnancy (e.g., IL-23 = 0.08 pg/ml, 95% CI = -0.11, 0.26)., Conclusions: Results were suggestive of NO 2 -related immune activation. Increases in effect sizes from early to mid to late pregnancy may be due to changes in immune function over the course of pregnancy. These findings provide a basis for immune activation as a mechanism for previously observed associations between air pollution exposure during pregnancy and reduced birthweight, fetal growth restriction, and pregnancy complications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Increased systemic oxidative stress, implicated in adverse pregnancy outcomes for both mothers and fetuses, has been associated with gestational exposure to air pollutants such as polycyclic aromatic hydrocarbons (PAHs), fine particulate matter (PM 2.5 ), and nitrogen dioxide (NO 2 ). However, it is unclear whether exposure to pollutants at levels below the current air quality standards can increase oxidative stress in pregnant women. In a cohort of 305 pregnant persons residing in western New York, we examined the association between exposure to PM 2.5 , NO 2 , and PAHs (measured as urinary 1-hydroxypyrene) and urinary biomarkers of oxidative stress (malondialdehyde [MDA] and 8-hydroxy-2'-deoxyguanosine [8-OHdG]) measured in each trimester. After controlling for gestational stage, maternal age, lifestyles, and socioeconomic factors, each interquartile range (IQR) increase in 1-hydroxypyrene concentration (65.8 pg/ml) was associated with a 7.73% (95%CI: 3.18%,12.3%) higher in MDA levels throughout the pregnancy and in the first and second trimester. An IQR increase in PM 2.5 concentration (3.20 μg/m 3 ) was associated with increased MDA levels in the first trimester (8.19%, 95%CI: 0.28%,16.1%), but not the 2nd (-7.99%, 95% CI: 13.8%, -2.23%) or 3rd trimester (-2.81%, 95% CI: 10.0%, 4.38%). The average cumulative PM 2.5 exposures in the 3-7 days before urine collection were associated with increased 8-OHdG levels during the second trimester, with the largest difference (22.6%; 95% CI: 3.46%, 41.7%) observed in relation to a one IQR increase in PM 2.5 concentration in the previous 7 days. In contrast, neither oxidative stress biomarker was associated with NO 2 exposure. Observed in pregnant women exposed to low-level air pollution, these findings expanded previously reported associations between systemic oxidative stress and high-level PM 2.5 and PAH concentrations. Further, the first and second trimesters may be a susceptible window during pregnancy for oxidative stress responses to air pollution exposure., 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.)

Epidemiologic evidence has emerged showing an association between exposure to air pollution and increased risks of gestational diabetes mellitus (GDM). This study examines the effect of low-level air pollution exposure on a subclinical biomarker of hyperglycemia (i.e., HbA1c) in pregnant people without diabetes before conception. We measured HbA1c in 577 samples repeatedly collected from 224 pregnant people in Rochester, NY, and estimated residential concentrations of PM 2.5 and NO 2 using high-resolution spatiotemporal models. We observed a U-shaped trajectory of HbA1c during pregnancy with average HbA1c levels of 5.13 (±0.52), 4.97 (±0.54), and 5.43 (±0.40)% in early-, mid-, and late pregnancy, respectively. After adjustment for the U-shaped trajectory and classic GDM risk factors, each interquartile range increase in 10 week NO 2 concentration (8.0 ppb) was associated with 0.09% (95% CI: 0.02 to 0.16%) and 0.18% (95% CI: 0.08 to 0.28%) increases in HbA1c over the entire pregnancy and in late pregnancy, respectively. These associations remained robust among participants without GDM. Using separate distributed lag models, we identified a period between 8th and 14th gestational weeks as critical windows responsible for increased levels of HbA1c measured at 14th, 22nd, and 30th gestational weeks. Our results suggest that low-level air pollution contributes to hyperglycemia in medically low-risk pregnant people.

Background: Influenza healthcare encounters in adults associated with specific sources of PM 2.5 is an area of active research., Objective: Following 2017 legislation requiring reductions in emissions from light-duty vehicles, we hypothesized a reduced rate of influenza healthcare encounters would be associated with concentrations of PM 2.5 from traffic sources in the early implementation period of this regulation (2017-2019)., Methods: We used the Statewide Planning and Research Cooperative System (SPARCS) to study adult patients hospitalized (N = 5328) or treated in the emergency department (N = 18,247) for influenza in New York State. Using a modified case-crossover design, we estimated the excess rate (ER) of influenza hospitalizations and emergency department visits associated with interquartile range increases in source-specific PM 2.5 concentrations (e.g., spark-ignition emissions [GAS], biomass burning [BB], diesel [DIE]) in lag day(s) 0, 0-3 and 0-6. We then evaluated whether ERs differed after Tier 3 implementation (2017-2019) compared to the period prior to implementation (2014-2016)., Results: Each interquartile range increase in DIE in lag days 0-6 was associated with a 21.3% increased rate of influenza hospitalization (95% CI: 6.9, 37.6) in the 2014-2016 period, and a 6.3% decreased rate (95% CI: -12.7, 0.5) in the 2017-2019 period. The GAS/influenza excess rates were larger in the 2017-2019 period than the 2014-2016 period for emergency department visits. We also observed a larger ER associated with increased BB in the 2017-2019 period compared to the 2014-2016 period., Impact Statement: We present an accountability study on the impact of the early implementation period of the Tier 3 vehicle emission standards on the association between specific sources of PM 2.5 air pollution on influenza healthcare encounters in New York State. We found that the association between gasoline emissions and influenza healthcare encounters did not lessen in magnitude between periods, possibly because the emissions standards were not yet fully implemented. The reduction in the rates of influenza healthcare encounters associated with diesel emissions may be reflective of past policies to reduce the toxicity of diesel emissions. Accountability studies can help policy makers and environmental scientists better understand the timing of pollution changes and associated health effects., (© 2024. The Author(s).)

Background: Previous work reported increased rates of cardiovascular hospitalizations associated with increased source-specific PM 2.5 concentrations in New York State, despite decreased PM 2.5 concentrations. We also found increased rates of ST elevation myocardial infarction (STEMI) associated with short-term increases in concentrations of ultrafine particles and other traffic-related pollutants in the 2014-2016 period, but not during 2017-2019 in Rochester. Changes in PM 2.5 composition and sources resulting from air quality policies (e.g., Tier 3 light-duty vehicles) may explain the differences. Thus, this study aimed to estimate whether rates of STEMI were associated with organic carbon and source-specific PM 2.5 concentrations., Methods: Using STEMI patients treated at the University of Rochester Medical Center, compositional and source-apportioned PM 2.5 concentrations measured in Rochester, a time-stratified case-crossover design, and conditional logistic regression models, we estimated the rate of STEMI associated with increases in mean primary organic carbon (POC), secondary organic carbon (SOC), and source-specific PM 2.5 concentrations on lag days 0, 0-3, and 0-6 during 2014-2019., Results: The associations of an increased rate of STEMI with interquartile range (IQR) increases in spark-ignition emissions (GAS) and diesel (DIE) concentrations in the previous few days were not found from 2014 to 2019. However, IQR increases in GAS concentrations were associated with an increased rate of STEMI on the same day in the 2014-2016 period (Rate ratio [RR] = 1.69; 95% CI = 0.98, 2.94; 1.73 μg/m 3 ). In addition, each IQR increase in mean SOC concentration in the previous 6 days was associated with an increased rate of STEMI, despite imprecision (RR = 1.14; 95% CI = 0.89, 1.45; 0.42 μg/m 3 )., Conclusion: Increased SOC concentrations may be associated with increased rates of STEMI, while there seems to be a declining trend in adverse effects of GAS on triggering of STEMI. These changes could be attributed to changes in PM 2.5 composition and sources following the Tier 3 vehicle introduction., Competing Interests: The 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zhao, Hopke, Utell, Croft, Thurston, Lin, Ling, Chen, Yount and Rich.)

Restricted fetal growth (RFG) is a leading contributor to perinatal mortality and has been associated with gestational exposure to air pollution, such as fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ), and polycyclic aromatic hydrocarbons (PAHs). This study examines the association between trimester-specific and weekly means of air pollution throughout gestation and placental inflammatory markers at delivery. In a prospective cohort study of 263 pregnant women in Rochester, NY, we measured interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in placental tissue and estimated gestational exposure to PM 2.5 and NO 2 using a high-resolution spatial-temporal model. Exposure to PAHs was estimated using urinary 1-hydroxypyrene (1-OHP) concentrations collected once per trimester. Using distributed lag models with a penalized spline function, each interquartile range (2.6 μg/m 3 ) increase in PM 2.5 concentration during gestational weeks 6-11 was associated with decreased placental IL-6 levels (-22.2%, 95% CI: -39.0%, -0.64%). Using multiple linear regression models, each interquartile range increase of 1-OHP was associated with an increase in TNF-α in the first trimester (58.5%, 95% CI: 20.7%, 74.2%), third trimester (22.9%, 95% CI: 0.04%, 49.5%), and entire pregnancy (29.6%, 95%CI: 3.9%,60.6%). Our results suggest gestational exposure to air pollution may alter the inflammatory environment of the placenta at delivery., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Co-published by Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, and American Chemical Society.)

Understanding health risks from methylmercury (MeHg) exposure is complicated by its link to fish consumption which may confound or modify toxicities. One solution is to include fish intake and a biomarker of MeHg exposure in the same model, but resulting estimates do not reflect the independent impact of accumulated MeHg or fish exposures. In fish-eating populations, this can be addressed by separating MeHg exposure into fish intake and average Hg content of the consumed fish. We assessed the joint association of prenatal MeHg exposure (maternal hair Hg) and fish intake (among fish-eating mothers) with neurodevelopment in 361 eight-year-olds from the New Bedford Cohort (born 1993-1998). Neurodevelopmental assessments used standardized tests of IQ, language, memory, and attention. Covariate-adjusted regression assessed the association of maternal fish consumption, stratified by tertiles of estimated average fish Hg, with neurodevelopment. Associations between maternal fish intake and child outcomes were generally beneficial for those in the lowest average fish Hg tertile, but detrimental in the highest average fish Hg tertile where, for example, each serving of fish was associated with 1.3 fewer correct responses (95% CI: -2.2, -0.4) on the Boston Naming test. Standard analyses showed no outcome associations with hair Hg or fish intake., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Medical researchers are increasingly prioritizing the inclusion of underserved communities in clinical studies. However, mere inclusion is not enough. People from underserved communities frequently experience chronic stress that may lead to accelerated biological aging and early morbidity and mortality. It is our hope and intent that the medical community come together to engineer improved health outcomes for vulnerable populations. Here, we introduce Health Equity Engineering (HEE), a comprehensive scientific framework to guide research on the development of tools to identify individuals at risk of poor health outcomes due to chronic stress, the integration of these tools within existing healthcare system infrastructures, and a robust assessment of their effectiveness and sustainability. HEE is anchored in the premise that strategic intervention at the individual level, tailored to the needs of the most at-risk people, can pave the way for achieving equitable health standards at a broader population level. HEE provides a scientific framework guiding health equity research to equip the medical community with a robust set of tools to enhance health equity for current and future generations., Competing Interests: The authors declare none., (© The Author(s) 2024.)

Background: Maternal exposure to polycyclic aromatic hydrocarbons (PAHs), ubiquitous constituents of air pollution, has been associated with adverse birth outcomes. Yet it remains unclear whether and how socioeconomic status (SES) affects gestational PAH exposure., Objective: To examine whether there are socioeconomic disparities in PAHs exposure among pregnant women from Rochester, NY, and if so, to what extent disproportionate proximity to air pollution sources, measured by residential distance to transportation-related sources, contributed to the exposure disparity., Methods: We measured 1-hydroxypyrene concentrations in 726 urine samples collected from 305 pregnant women up to three samples throughout pregnancy. Residential distances to transportation-related sources were calculated based on participants' home addresses. We used linear mixed-effects models with random intercepts of participants to examine associations between 1-hydroxypyrene, SES indicators, and distance to transportation-related sources. We used structural equation modelling to assess to what extent distance to transportation-related sources contributes to the socioeconomic disparity in 1-hydroxypyrene concentrations., Results: Reduced household income and maternal education level were both significant SES predictors of 1-hydroxypyrene concentrations, after the adjustment for other maternal demographic characteristics. Each interquartile range (IQR) increases in residential proximity to the airport (from 14.3 to 6.0 km), the railroad yard (from 22.3 to 6.0 km), and annual average daily traffic within 300 m (from 3796 to 99,933 vehicles/year) were associated with 15.0% (95%CI: 7.0-22.2%), 15.4% (95%CI: 6.5-23.5%), and 13.6% (95%CI: 4.7-23.3%) increases in 1-hydroxypyrene concentrations, respectively. Proximity to these sources jointly explained 10% (95%CI: 1.6-18.4%) of the 1-hydroxypyrene concentration change associated with decreases in SES as a latent variable defined by both household income and education level., Impact Statement: Our findings suggest that efforts to address disproportionate residential proximity to transportation-related sources may reduce the socioeconomic disparity in PAH exposure., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Consumption of fish yields many nutritional benefits, but also results in exposure to methylmercury (MeHg). The developing brain is known to be particularly susceptible to MeHg toxicity in high doses. However, the potential impact of low-level environmental exposure from fish consumption on children's neurodevelopment remains unclear., Methods: We investigated postnatal MeHg exposure at 7 years and its association with a battery of 17 neurodevelopmental outcomes in a subset of children (n = 376) from 1535 enrolled mother-child pairs in Nutrition Cohort 2 of the Seychelles Child Development Study (SCDS NC2). Each outcome was modeled in relation to postnatal MeHg exposure using linear regression, adjusting for prenatal MeHg exposure, levels of maternal polyunsaturated fatty acids (PUFA), and several other covariates known to be associated with neurodevelopmental outcomes., Results: Median postnatal MeHg exposure at 7 years was 2.5 ppm, while the median prenatal MeHg exposure was 3.5 ppm. We found no statistically significant associations between postnatal MeHg exposure and any of the 17 neurodevelopmental outcomes after adjusting for prenatal MeHg exposure and other covariates., Conclusions: These findings are consistent with previous cross-sectional analyses of the SCDS Main Cohort. Continued follow-up of the entire NC2 cohort at later ages with repeated exposure measures is needed to further confirm these findings., 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 Elsevier B.V. All rights reserved.)

Background: High concentrations of taurine are present in the developing human brain and maternal breast milk. Taurine is thought to influence fetal growth and brain development based on experimental rodent studies. As fish is an important dietary source of taurine, we investigated associations between taurine concentrations and child outcomes in a high fish consuming population., Objective: To examine associations between maternal and cord serum taurine concentrations and birth anthropometric measures and cognitive development in children at 20 months of age., Methods: Pregnant women were recruited between 2008 and 2011 as part of Nutrition Cohort 2 (NC2) of the Seychelles Child Development Study (SCDS). Maternal taurine serum concentrations were measured at 28 week's gestation and in cord serum. Child weight, length and head circumference were measured at birth and neurodevelopment was assessed using Bayley Scales of Infant Development II (BSID-II) at 20 months of age. Associations between taurine status, birth measures and neurodevelopmental outcomes were examined (n = 300) using regression models and adjusted for relevant covariates., Results: Mean (SD) maternal and cord taurine concentrations were 124.9 (39.2) µmol/L (range 28.2-253.9 µmol/L) and 187.6 (60.0) µmol/L (range 55.0-417.4 µmol/L) respectively. We found no associations between maternal taurine concentrations and child anthropometric and neurodevelopmental measures (weight β = -0.001, SE=0.001; length β = -0.006, SE=0.006; head circumference β = -0.002, SE=0.002; MDI β = -0.005, SE=0.015; PDI β = -0.004, SE=0.016; all P > 0.05), or between cord taurine concentrations and outcomes (weight β = -0.001, SE<0.000; length β = -0.001, SE=0.004; head circumference β < 0.000, SE=0.002; MDI β = 0.004, SE=0.010; PDI β = -0.015, SE=0.012; all P > 0.05)., Conclusion: The Seychellois population have high maternal and cord taurine concentrations owing to their high fish intake and may be considered taurine replete compared to individuals who consume a Westernised diet. This high taurine status may explain why there were no significant associations between maternal and cord taurine concentrations and outcomes after adjusting for covariates., 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. Conflict of Interest No conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Humans differ in the metabolism of the neurotoxicant methyl mercury (MeHg). This variation may be partially due to variation in genes encoding the transcription factor Nuclear factor E2-related factor 2 (NRF2) and its negative regulator Kelch-like ECH-Associated Protein 1 (KEAP1), which regulate glutathione and related transporter and antioxidant proteins that play a role in the metabolism and neurotoxicity of MeHg., Aim: To elucidate a potential risk from genetic variation in NFE2L2 (encoding NRF2) and KEAP1 toward prenatal mercury exposure and child neurodevelopmental outcomes at 20 months and 7 years of age in a population with variable prenatal exposure to MeHg from maternal fish consumption., Material and Methods: Nutrition Cohort 2 is a mother-child cohort in the Republic of Seychelles. Children were genotyped for NFE2L2 (rs2364723, rs13001694) and KEAP1 (rs8113472, rs9676881) polymorphisms (N = 1285 after removing siblings). Total mercury (Hg) was measured in cord blood as a biomarker for prenatal MeHg exposure. Child neurodevelopmental outcomes included the Bayley Scales of Infant Development II administered at 20 months of age, and outcomes across multiple neurodevelopmental domains from 14 tests administered in children and 3 instruments completed by parents when children were 7 years of age., Results: The mean cord blood MeHg concentration was 34 (95% CI 11, 75) µg/L. None of the four polymorphisms had a significant association (p < 0.05) with either cord MeHg or neurodevelopmental test results at 20 months. There were no significant associations between either NFE2L2 polymorphism and any developmental test scores. At 7 years, children carrying KEAP1 rs8113472 CA showed significantly worse performance on psychomotor function than children with the CC variant (finger tapping, dominant hand: β - 1.19, SE 0.34; finger tapping, non-dominant hand: β - 0.92, SE 0.31) and worse social communication (SCQ Total: β 0.65, SE 0.27). Children carrying rs8113472 AA, versus children with CC, showed significantly better performance on social communication (SRS Total: β - 8.88, SE 3.60). Children carrying KEAP1 rs9676881 AG, versus children with GG, showed significantly worse performance on psychomotor function (trailmaking A time: β 8.66, SE 3.37) and cognition (KBIT Matrices: β - 0.96, SE 0.36)., Conclusion: No associations between NFE2L2 and KEAP1 polymorphisms and MeHg concentration were identified. However, at 7 years, KEAP1 polymorphisms were associated with differences in neurodevelopmental outcomes in children from a population with high fish intake., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tanzy M. Love, Gene E. Watson, Sally W. Thurston, Alison J. Yeates, Maria S. Mulhern, Emeir M. McSorley, J.J. Strain, Conrad F. Shamlaye, G.J. Myers, Matthew D. Rand, and Edwin van Wijngaarden report financial support was provided by the National Institutes of Health. Helena Korres de Paulaa, Tanzy M. Love, Daniela Pineda, Gene E. Watson, Alison J. Yeates and, Karin Broberg report financial support was provided by The Swedish Research Council for Health, Working Life and Welfare (FORTE), the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS), and the Karolinska Institutet. Conrad Shamlaye reports in kind support from the Government of Seychelles., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We characterized mercury and selenium in the fish consumed in the Seychelles Islands to determine if their levels are similar to fish consumed in the US. A secondary aim was to examine whether fish weight and species predict mercury and selenium in fish consumed in the Seychelles. We measured total mercury (THg) and selenium (Se) content of 10 samples from each of the 19 most frequently consumed fish species in Seychelles and for each calculated the Se:Hg molar ratios and the Selenium Health Benefit Value Index (HBV Se). Linear regression models examined associations with weight and species. Average MeHg levels in fish ranged from less than 0.01 ppm (streamlined spinefoot) to 0.7 ppm (bludger trevally) with an overall mean of 0.21 ± 0.23 ppm. Average Se levels ranged from 0.34 ppm (blue-barred parrot fish) to 0.93 ppm (blue-lined large-eye bream) with a mean of 0.54 ± 0.23 ppm. All fish species had a mean Se:Hg molar ratio > 1 and positive mean HBV Se index values. Weight was strongly predictive of MeHg and Se:Hg molar ratio, both across and within most species, but was less predictive of Se and HBV Se. Our study demonstrated that fish consumed in Seychelles have mercury and selenium content similar to that of fish consumed in the US. Fish in both countries have favorable positive values for Se:Hg molar ratios and HBV Se indexes. Because mercury and selenium concentrations in fish are similar to those in the US but fish consumption is substantially higher in Seychelles, the Seychellois make an ideal population in which to determine if there are adverse effects of prenatal, postnatal, and lifetime low dose MeHg exposure from fish consumption., 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 Elsevier B.V. All rights reserved.)

Background: Ambient air pollution may be a developmental endocrine disruptor. In animal models, gestational and perinatal exposure to diesel exhaust and concentrated particulate matter alters anogenital distance (AGD), a marker of prenatal androgen activity, in both sexes. Little is known in humans., Objectives: We examined exposure to fine particulate matter ( PM 2.5 ) and nitrogen dioxide ( NO 2 ) in relation to human AGD at birth and at 1 year of age, focusing on exposures during critical windows of reproductive development: the male programming window (MPW; gestational weeks 8-14) and mini-puberty (postnatal months 1-3)., Methods: The Infant Development and Environment Study (TIDES) recruited first trimester pregnant women ( n = 687 ) at four U.S. sites (Minneapolis, Minnesota; Rochester, New York; San Francisco, California; and Seattle, Washington) from 2010 to 2012. We measured anus to clitoris (AGD-AC) and anus to fourchette (AGD-AF) in female infants at birth; in males, we measured anus to penis (AGD-AP), anus to scrotum (AGD-AS), and penile width at birth and at 1 year of age. Using advanced spatiotemporal models, we estimated maternal exposure to PM 2.5 and NO 2 in the MPW and mini-puberty. Covariate-adjusted, sex-stratified linear regression models examined associations between PM 2.5 and NO 2 and AGD., Results: In males, a 1 - μ g / m 3 increase in PM 2.5 exposure during the MPW was associated with shorter AGD at birth, but a longer AGD at 1 year of age (e.g., birth AGD-AP: β = - 0.35 mm ; 95% CI: - 0.62 , - 0.07 ; AGD-AS: β = 0.37 mm ; 95% CI: 0.02, 0.73). Mini-pubertal PM 2.5 exposure was also associated with shorter male AGD-AP ( β = - 0.50 mm ; 95% CI: - 0.89 , - 0.11 ) at 1 year of age. Although not associated with male AGD measures, 1 -ppb increases in NO 2 exposure during the MPW ( β = - 0.07 mm ; 95% CI: - 0.02 , - 0.12 ) and mini-puberty ( β = - 0.04 mm ; 95% CI: - 0.08 , 0.01) were both associated with smaller penile width at 1 year of age. Results were similar in multipollutant models, where we also observed that in females AGD-AC was inversely associated with PM 2.5 exposure, but positively associated with NO 2 exposure., Discussion: PM 2.5 and NO 2 exposures during critical pre- and postnatal windows may disrupt reproductive development. More work is needed to confirm these novel results and clarify mechanisms. https://doi.org/10.1289/EHP12627.

A Bayesian Network (BN) is a probabilistic model that represents a set of variables using a directed acyclic graph (DAG). Current algorithms for learning BN structures from data focus on estimating the edges of a specific DAG, and often lead to many 'likely' network structures. In this paper, we lay the groundwork for an approach that focuses on learning global properties of the DAG rather than exact edges. This is done by defining the structural hypergraph of a BN, which is shown to be related to the inverse-covariance matrix of the network. Spectral bounds are derived for the normalized inverse-covariance matrix, which are shown to be closely related to the maximum indegree of the associated BN., Competing Interests: Declaration of Competing Interest: There is no competing interest.

Background: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals found in drinking water and consumer products, resulting in ubiquitous human exposure. PFAS have been linked to endocrine disruption and altered weight gain across the lifespan. A limited and inconsistent body of research suggests PFAS may impact gestational weight gain (GWG) and postpartum body mass index (BMI), which are important predictors of overall infant and maternal health, respectively., Methods: In the Understanding Pregnancy Signals and Infant Development (UPSIDE/UPSIDE-MOMs) study (n = 243; Rochester, NY), we examined second trimester serum PFAS (PFOS: perfluorooctanesulfonic acid, PFOA: perfluorooctanoic acid, PFNA: perfluorononanoic acid, PFHxS: perfluorohexanesulfonic acid, PFDA: perfluorodecanoic acid) in relation to GWG (kg, and weekly rate of gain) and in the postpartum, weight retention (PPWR (kg) and total body fat percentage (measured by bioelectrical impedance)). We fit multivariable linear regression models examining these outcomes in relation to log-transformed PFAS in the whole cohort as well as stratified by maternal pre-pregnancy BMI (< 25 vs. =  > 25 kg/m 2 ), adjusting for demographics and lifestyle factors. We used weighted quantile sum regression to find the combined influence of the 5 PFAS on GWG, PPWR, and body fat percentage., Results: PFOA and PFHxS were inversely associated with total GWG (PFOA: ß = -1.54 kg, 95%CI: -2.79, -0.30; rate ß = -0.05 kg/week, 95%CI: -0.09, -0.01; PFHxS: ß = -1.59 kg, 95%CI: -3.39, 0.21; rate ß = -0.05 kg/week, 95%CI: -0.11, 0.01) and PPWR at 6 and 12 months (PFOA 6 months: ß = -2.39 kg, 95%CI: -4.17, -0.61; 12 months: ß = -4.02 kg, 95%CI: -6.58, -1.46; PFHxS 6 months: ß = -2.94 kg, 95%CI: -5.52, -0.35; 12 months: ß = -5.13 kg, 95%CI: -8.34, -1.93). PFOA was additionally associated with lower body fat percentage at 6 and 12 months (ß = -1.75, 95%CI: -3.17, -0.32; ß = -1.64, 95%CI: -3.43, 0.16, respectively) with stronger associations observed in participants with higher pre-pregnancy BMI. The PFAS mixture was inversely associated with weight retention at 12 months (ß = -2.030, 95%CI: -3.486, -0.573) amongst all participants., Conclusion: PFAS, in particular PFOA and PFHxS, in pregnancy are associated with altered patterns of GWG and postpartum adiposity with potential implications for fetal development and long-term maternal cardiometabolic health., (© 2023. BioMed Central Ltd., part of Springer Nature.)

We present a Bayesian partial membership model that estimates the associations between an outcome, a small number of latent variables, and multiple observed exposures where the number of latent variables is specified a priori . We assign one observed exposure as the sentinel marker for each latent variable. The model allows non-sentinel exposures to have complete membership in one latent group, or partial membership across two or more latent groups. MCMC sampling is used to determine latent group partial memberships for the non-sentinel exposures, and estimate all model parameters. We compare the performance of our model to competing approaches in a simulation study and apply our model to inflammatory marker data measured in a large mother-child cohort of the Seychelles Child Development Study (SCDS). In simulations, our model estimated model parameters with little bias, adequate coverage, and tighter credible intervals compared to competing approaches. Under our partial membership model with two latent groups, SCDS inflammatory marker classifications generally aligned with the scientific literature. Incorporating additional SCDS inflammatory markers and more latent groups produced similar groupings of markers that also aligned with the literature. Associations between covariates and birth weight were similar across latent variable models and were consistent with earlier work in this SCDS cohort.

Existing statistical methods can estimate a policy, or a mapping from covariates to decisions, which can then instruct decision makers (eg, whether to administer hypotension treatment based on covariates blood pressure and heart rate). There is great interest in using such data-driven policies in healthcare. However, it is often important to explain to the healthcare provider, and to the patient, how a new policy differs from the current standard of care. This end is facilitated if one can pinpoint the aspects of the policy (ie, the parameters for blood pressure and heart rate) that change when moving from the standard of care to the new, suggested policy. To this end, we adapt ideas from Trust Region Policy Optimization (TRPO). In our work, however, unlike in TRPO, the difference between the suggested policy and standard of care is required to be sparse, aiding with interpretability. This yields "relative sparsity," where, as a function of a tuning parameter, λ $$ \lambda $$ , we can approximately control the number of parameters in our suggested policy that differ from their counterparts in the standard of care (eg, heart rate only). We propose a criterion for selecting λ $$ \lambda $$ , perform simulations, and illustrate our method with a real, observational healthcare dataset, deriving a policy that is easy to explain in the context of the current standard of care. Our work promotes the adoption of data-driven decision aids, which have great potential to improve health outcomes., (© 2023 John Wiley & Sons Ltd.)

Purpose: Suicide risk is higher among violence-involved individuals. Intimate Partner Violence hotline workers are a critical source of support and can potentially be suicide prevention champions. Our primary goal was to examine the effectiveness of disseminating a free, online IPV-Suicide Prevention curriculum, via a randomized control trial, to hotline workers in ten states with the highest suicide and IPV homicide rates., Method: We divided the country into five regions and, based on criterion, chose two states in each region to randomize into the two arms of the study. We examined training participation and engagement between the two approaches: (1) 'dissemination as usual' (control) using a National Domestic Violence Hotline email and a postcard to state/county IPV directors, versus (2) 'enhanced dissemination' (intervention) using a four-point touch method (postcard, phone call, email, and letter) to 'drive' participation., Results: Participation increased in the intervention arm as approaches became more personal (i.e., email and phone calls vs. letters). Results indicate that traditional dissemination strategies such as email announcements and invitations are not as effective as varied and multiple touchpoints for IPV hotline staff., Conclusion: Successful dissemination strategies to promote digital training should consider the value added by personalized connection. Future research is needed to understand how to offer effective and efficient web-based training to those providing IPV and child abuse services., Competing Interests: Conflict of InterestsNone., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Previously, we found increased rates of ST-elevation myocardial infarction (STEMI) associated with increased ultrafine particle (UFP; <100 nm) concentrations in the previous few hours in Rochester, New York. Relative rates were higher after air quality policies and a recession reduced pollutant concentrations (2014-2016 versus 2005-2013), suggesting PM composition had changed and the same PM mass concentration had become more toxic. Tier 3 light duty vehicles, which should produce less primary organic aerosols and oxidizable gaseous compounds, likely making PM less toxic, were introduced in 2017. Thus, we hypothesized we would observe a lower relative STEMI rate in 2017-2019 than 2014-2016., Methods: Using STEMI events treated at the University of Rochester Medical Center (2014-2019), UFP and other pollutants measured in Rochester, a case-crossover design, and conditional logistic regression models, we estimated the rate of STEMI associated with increased UFP and other pollutants in the previous hours and days in the 2014-2016 and 2017-2019 periods., Results: An increased rate of STEMI was associated with each 3111 particles/cm 3 increase in UFP concentration in the previous hour in 2014-2016 (lag hour 0: OR = 1.22; 95% CI = 1.06, 1.39), but not in 2017-2019 (OR = 0.94; 95% CI = 0.80, 1.10). There were similar patterns for black carbon, UFP 11-50nm , and UFP 51-100nm . In contrast, increased rates of STEMI were associated with each 0.6 ppb increase in SO 2 concentration in the previous 120 h in both periods (2014-2016: OR = 1.26, 95% CI = 1.03, 1.55; 2017-2019: OR = 1.21, 95% CI = 0.87, 1.68)., Conclusions: Greater rates of STEMI were associated with short term increases in concentrations of UFP and other motor vehicle related pollutants before Tier 3 introduction (2014-2016), but not afterwards (2017-2019). This change may be due to changes in PM composition after Tier 3 introduction, as well as to increased exposure misclassification and greater underestimation of effects from 2017 to 2019., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David Rich reports financial support was provided by New York State Energy Research Development Authority. David Rich reports financial support was provided by National Institute of Environmental Health Sciences. David Rich reports a relationship with US Environmental Protection Agency that includes: consulting or advisory., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In many studies of the health effects of toxicants, exposure is measured once even though exposure may be continuous. However, some studies collect repeated measurements on participants over an extended time with the goal of determining a long-term metric that captures the average or cumulative exposure. This can be challenging, especially when exposure is measured at irregular intervals and has some missing values. Here we describe a method for determining a measure of long-term exposure using data on postnatal mercury (Hg) from the Seychelles Child Development Study (SCDS) Main Cohort as a model. In this cohort (n = 779), we incorporate postnatal Hg values that were measured on most study participants at seven ages, three between 6 months and 5.5 years ("childhood"), and an additional four between 17 and 24 years ("early adulthood"). We develop time-weighted measures of average exposure during the childhood and the early adulthood periods and compare the strengths and weaknesses of our metric to two standard measures: overall average and cumulative exposure. We account for missing values through an imputation method that uses information about age- and sex-specific Hg means and the participant's Hg values at similar ages to estimate subject-specific missing Hg values. We compare our method to the implicit imputation assumed by these two standard methods, and to Fully Conditional Specification (FCS), an alternative method of imputing missing data. To determine the accuracy of our imputation method we use data from participants with no missing Hg values in the relevant time window. The imputed values from our proposed method are substantially closer to the observed values on average than the average or cumulative exposure, while also performing slightly better than FCS. In conclusion, time-weighted long-term exposure appears to offer advantages over cumulative exposure in longitudinal studies with repeated measures where the follow-up period for a toxicant is similar for all participants. Additionally, our method to impute missing values maximizes the number of participants for whom the overall exposure metric can be calculated and should provide a more accurate long-term exposure metric than standard methods when exposure has missing values. Our method is applicable to any study of long-term toxicant effects when longitudinal exposure measurements are available but have missing values., 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 © 2022 Elsevier B.V. All rights reserved.)

Purpose: Methylmercury (MeHg) is a known neurodevelopmental toxicant in sufficient dosage and is universally found in fish. Current fish advisories for children are based on epidemiology studies examining prenatal exposure with a premise that MeHg exposure resulting from children eating fish could also be neurotoxic and have long-term consequences. However, the evidence that this assumption is true is limited. We investigated postnatal MeHg exposure from regular fish consumption using time weighted Hg measurements to determine if there are neurotoxic consequences., Methods: We examined 85 neurodevelopmental outcomes measured from ages 9-24 years in the Seychelles Child Development Study Main Cohort (n = 312-550) and examined their association with time-weighted measures of postnatal MeHg exposure in childhood and early adulthood. Postnatal MeHg exposure measured in the first cm of participants' hair samples collected at seven evaluations were used to create two time-weighted (TW) average MeHg exposure metrics, one for childhood (TW-C) and the other for early adulthood (TW-A). TW-C was based on Hg measures at three ages between 6 months and 5.5 years, and TW-A was based on Hg measured at up to four ages between 17 and 24 years. We examined the association between each of these exposure metrics and the neurodevelopmental outcomes using linear regression with adjustment for covariates known to influence neurodevelopmental outcomes., Results: There were 14 statistically significant associations between a postnatal metric and an endpoint. Six were associated with the TW-C and eight with the TW-A. Thirteen were adverse. Only the TW-C association at 9 years with the Bender Gestalt error score showed improvement. TW-C was adversely associated at 9 years with the Continuous Performance Task risk score, at 22 years with the Boston Naming Test (BNT) total and no cues scores, and at 24 years with the Test of Variables of Attention (TOVA) auditory response time variability and visual response time mean on the logarithmic scale. TW-A was adversely associated at 17 years with the Wisconsin Card Sorting Test % total errors, the Woodcock-Johnson passage comprehension, and the CANTAB rapid visual information processing false alarms, and at 22 years with the BNT total and no cue scores, the CANTAB rapid visual information processing false alarms and the intra-extra dimensional shift total errors and trials., Conclusion: These findings suggest that postnatal MeHg exposure may be adversely associated with neurodevelopmental outcomes in early adulthood. However, the associations are statistical and of unknown, if any, clinical significance. The results need confirmation in other cohorts., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Bisphenol A (BPA) is a polymer used in the production of polycarbonate plastics and epoxy resins. An estrogen mimic, prenatal BPA exposure has been associated with several behavioral outcomes in children; however, the impact of maternal demographic and economic factors on associations between BPA and child behavioral outcomes have not been examined. The objective of this study was to examine associations between prenatal maternal urinary BPA and behavior in 4-5 year old girls, and to assess whether socio-demographic factors modify this relationship. Mothers enrolled in The Infant Development and Environment Study (TIDES) provided a single spot urine at enrollment (median gestational age 11 weeks) and completed the Behavior Assessment System for Children-2 (BASC-2) and Social Responsiveness Scale-2 (SRS-2) when their daughters were 4-5 years of age. Mother-daughter pairs with complete phthalate, BASC-2, SRS-2, and covariate data were included in this analysis (N = 244). BPA was detectable in 93 % of urine samples. We used multivariable linear regression analyses to estimate associations between maternal urinary log 10 -transformed BPA concentration and BASC-2 subscale and composite scores and SRS-2 Total Score. To examine the role of socioeconomic and demographic factors associated with study site, we stratified by TIDES center, comparing those enrolled at University of Rochester Medical Center (URMC), a predominately lower socioeconomic population, and those enrolled elsewhere: University of Washington, University of Minnesota, and University of California San Francisco, whose populations share similar higher socioeconomic demographic characteristics. Across all centers, no associations were seen between BPA and BASC-2 or SRS-2 scores. When stratifying by center, BPA was significantly associated with greater social impairment as measured by the SRS-2 Total Score (β-coefficient [95 % confidence intervals]: 5.1 [1.0, 9.2]) in URMC participants (N = 61). In non-URMC participants (N = 183), BPA was significantly associated with lower BASC-2 Internalizing composite (-3.3 [-6.7, 0.0]) and Depression subscale scores (-3.4 [-6.7, 0.0]) while no associations were seen between BPA and SRS-2 scores. Our findings suggest that sociodemographic factors may modify the impacts of maternal prenatal BPA on developmental endpoints., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: There is emerging evidence that exposure to prenatal methylmercury (MeHg) from maternal fish consumption during pregnancy can differ between individuals due to genetic variation. In previous studies, we have reported that maternal polymorphisms in ABC-transporter genes were associated with maternal hair MeHg concentrations, and with children's early neurodevelopmental tests. In this study, we add to these findings by evaluating the contribution of genetic variation in children's ABC-transporter genes to prenatal MeHg exposure and early child neurodevelopmental tests., Methods: We genotyped six polymorphisms (rs2032582, rs10276499 and rs1202169 in ABCB1; rs11075290 and rs215088 in ABCC1; rs717620 in ABCC2) in DNA from cord blood and maternal blood of the Seychelles Child Development Study Nutrition Cohort 2. We determined prenatal MeHg exposure by measuring total mercury (Hg) in cord blood by atomic fluorescence spectrometry. We assessed neurodevelopment in children at approximately 20 months using the Bayley Scales of Infant Development (BSID-II). We used linear regression models to analyze covariate-adjusted associations of child genotype with cord MeHg and BSID-II outcomes (Mental Developmental and Psychomotor Developmental Indexes). We also evaluated interactions between genotypes, cord MeHg, and neurodevelopmental outcomes. All models were run with and without adjustment for maternal genotype., Results: Of the six evaluated polymorphisms, only ABCC1 rs11075290 was associated with cord blood MeHg; children homozygous for the T-allele had on average 29.99 µg/L MeHg in cord blood while those homozygous for the C-allele had on average 38.06 µg/L MeHg in cord blood (p < 0.001). No polymorphisms in the children were associated with either subscale of the BSID. However, the association between cord MeHg and the Mental Developmental Index (MDI) of the BSID differed significantly across the three genotypes of ABCB1 rs10276499 (2df F-test, p = 0.045). With increasing cord MeHg, the MDI decreased (slope=-0.091, p = 0.014) among children homozygous for the rare C-allele., Conclusions: These findings support the possibility that child ABC genetics might influence prenatal MeHg exposure., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The cardiovascular effects of ozone exposure are unclear. Using measurements from the 87 participants in the Multicenter Ozone Study of oldEr Subjects (MOSES), we examined whether personal and ambient pollutant exposures before the controlled exposure sessions would be associated with adverse changes in pulmonary and cardiovascular function., Methods: We used mixed effects linear regression to evaluate associations between increased personal exposures and ambient pollutant concentrations in the 96 h before the pre-exposure visit, and 1) biomarkers measured at pre-exposure, and 2) changes in biomarkers from pre-to post-exposure., Results: Decreases in pre-exposure forced expiratory volume in 1 s (FEV 1 ) were associated with interquartile-range increases in concentrations of particulate matter ≤2.5 μm (PM 2.5 ) 1 h before the pre-exposure visit (-0.022 L; 95% CI -0.037 to -0.006; p = 0.007), carbon monoxide (CO) in the prior 3 h (-0.046 L; 95% CI -0.076 to -0.016; p = 0.003), and nitrogen dioxide (NO 2 ) in the prior 72 h (-0.030 L; 95% CI -0.052 to -0.008; p = 0.007). From pre-to post-exposure, increases in FEV 1 were marginally significantly associated with increases in personal ozone exposure (0.010 L; 95% CI 0.004 to 0.026; p = 0.010), and ambient PM 2.5 and CO at all lag times. Ambient ozone concentrations in the prior 96 h were associated with both decreased pre-exposure high frequency (HF) heart rate variability (HRV) and increases in HF HRV from pre-to post-exposure., Conclusions: We observed associations between increased ambient PM 2.5 , NO 2 , and CO levels and reduced pulmonary function, and increased ambient ozone concentrations and reduced HRV. Pulmonary function and HRV increased across the exposure sessions in association with these same pollutant increases, suggesting a "recovery" during the exposure sessions. These findings support an association between short term increases in ambient PM 2.5 , NO 2 , and CO and decreased pulmonary function, and increased ambient ozone and decreased HRV., (Copyright © 2021. Published by Elsevier Inc.)

Background: Maternal fish consumption increases infant methylmercury (MeHg) exposure and polyunsaturated fatty acid (PUFA) concentrations. The n-3 PUFA are regulators of inflammation while MeHg may impact the cord cytokine profile and, subsequently, contribute to immune mediated outcomes. This study aimed to investigate associations between infant MeHg exposure and cord cytokine concentrations while adjusting for cord PUFA., Methods: We studied participants in the Seychelles Child Development Study (SCDS) Nutrition Cohort 2 (NC2), a large birth cohort in a high fish-eating population. Whole blood MeHg, serum PUFA and serum cytokine concentrations (IFN-γ, IL-1β, IL-2, IL-12p70, TNF-α, IL-4, IL-10, IL-13, IL-6 and IL-8) were measured in cord blood collected at delivery (n = 878). Linear regression examined associations between infant MeHg exposure and cord cytokines concentrations, with and without adjustment for cord PUFA. An interaction model examined cord MeHg, cytokines and tertiles of the n-6:n-3 ratio (low/medium/high)., Results: There was no overall association between cord MeHg (34.08 ± 19.98 μg/L) and cytokine concentrations, with or without adjustment for PUFA. Increased total n-3 PUFA (DHA, EPA and ALA) was significantly associated with lower IL-10 (β = -0.667; p = 0.007) and lower total Th2 (IL-4, IL-10 and IL-13) (β = -0.715; p = 0.036). In the interaction model, MeHg and IL-1β was positive and significantly different from zero in the lowest n-6:n-3 ratio tertile (β = 0.002, p = 0.03)., Conclusion: Methylmercury exposure from fish consumption does not appear to impact markers of inflammation in cord blood. The association of cord n-3 PUFA with lower IL-10 and total Th2 cytokines suggests that they may have a beneficial influence on the regulation of the inflammatory milieu. These findings are important for public health advice and deserve to be investigated in follow up studies., (Copyright © 2021. Published by Elsevier Inc.)

Research Question: Are preconception ovarian reserve markers, such as Anti-Mullerian hormone and antral follicle count, associated with preeclampsia and placenta mediated pregnancy complications among women with unexplained infertility who conceive with superovulation?, Design: This is a secondary analysis of women with unexplained infertility who had a singleton live birth after enrollment in the Analysis of Multiple Intrauterine Gestations after Ovarian Stimulation (AMIGOS) trial that randomized couples to superovulation with letrozole, clomiphene, or gonadotropins with insemination for up to 4 cycles., Results: Compared to controls (N = 156), women who developed preeclampsia (N = 17) had lower Anti-Mullerian hormone levels (2.24 ± 1.20 vs. 2.89 ± 2.32, p = 0.07) and lower antral follicle count (18 ± 7.67 vs. 21 ± 11.43, p = 0.16); though these differences were not statistically significant. There was no relationship between Anti-Mullerian hormone (OR: 1.00, 95% CI: 0.76-1.25) or antral follicle count (OR: 0.98, 95% CI 0.93-1.04) with preeclampsia and between Anti-Mullerian hormone (OR: 1.00, 95% CI: 0.83-1.17) and antral follicle count (OR: 1.00, 95% CI: 0.97-1.04) with placenta medicated pregnancy complications after adjusting for age, BMI and race., Conclusions: Preconception ovarian reserve markers are not associated with preeclampsia and placenta mediated pregnancy complications among women with unexplained infertility who conceive with superovulation with insemination., (Copyright © 2022 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Context: Phthalates may disrupt maternal-fetal-placental endocrine pathways, affecting pregnancy outcomes and child development. Placental corticotropin releasing hormone (pCRH) is critical for healthy pregnancy and child development, but understudied as a target of endocrine disruption., Objective: To examine phthalate metabolite concentrations (as mixtures and individually) in relation to pCRH., Design: Secondary data analysis from a prospective cohort study., Setting: Prenatal clinics in Tennessee, USA., Patients: 1018 pregnant women (61.4% non-Hispanic Black, 32% non-Hispanic White, 6.6% other) participated in the CANDLE study and provided data. Inclusion criteria included: low-medical-risk singleton pregnancy, age 16-40, and gestational weeks 16-29., Intervention: None., Main Outcome Measures: Plasma pCRH at two visits (mean gestational ages 23.0 and 31.8 weeks) and change in pCRH between visits (ΔpCRH)., Results: In weighted quantile sums (WQS) regression models, phthalate mixtures were associated with higher pCRH at Visit 1 (β = 0.07, 95 %CI: 0.02, 0.11) but lower pCRH at Visit 2 (β = -0.08, 95 %CI: -0.14, -0.02). In stratified analyses, among women with gestational diabetes (n = 59), phthalate mixtures were associated with lower pCRH at Visit 1 (β = -0.17, 95 %CI: -0.35, 0.0006) and Visit 2 (β = -0.35, 95 %CI: -0.50, -0.19), as well as greater ΔpCRH (β = 0.16, 95 %CI: 0.07, 0.25). Among women with gestational hypertension (n = 102), phthalate mixtures were associated with higher pCRH at Visit 1 (β = 0.20, 95 %CI: 0.03, 0.36) and Visit 2 (β = 0.42; 95 %CI: 0.19, 0.64) and lower ΔpCRH (β = -0.17, 95 %CI: -0.29, -0.06). Significant interactions between individual phthalate metabolites and pregnancy complications were observed., Conclusions: Phthalates may impact placental CRH secretion, with differing effects across pregnancy. Differences in results between women with and without gestational diabetes and gestational hypertension suggest a need for further research examining whether women with pregnancy complications may be more vulnerable to endocrine-disrupting effects of phthalates., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We propose a Bayesian latent variable model to allow estimation of the covariate-adjusted relationships between an outcome and a small number of latent exposure variables, using data from multiple observed exposures. Each latent variable is assumed to be represented by multiple exposures, where membership of the observed exposures to latent groups is unknown. Our model assumes that one measured exposure variable can be considered as a sentinel marker for each latent variable, while membership of the other measured exposures is estimated using MCMC sampling based on a classical measurement error model framework. We illustrate our model using data on multiple cytokines and birth weight from the Seychelles Child Development Study, and evaluate the performance of our model in a simulation study. Classification of cytokines into Th1 and Th2 cytokine classes in the Seychelles study revealed some differences from standard Th1/Th2 classifications. In simulations, our model correctly classified measured exposures into latent groups, and estimated model parameters with little bias and with coverage that was similar to the oracle model.

Prenatal hormones have been proposed as key factors impacting child development as well as long-term health and disease. Digit ratio (the ratio of the lengths of the second to fourth digits; 2D:4D) has been proposed as a sexually dimorphic, noninvasive marker of prenatal androgen exposure that can be reliably measured in children and adults. To date, few longitudinal pregnancy cohort studies have examined childhood digit ratio in relation to other relevant measures including prenatal hormones and androgen-sensitive outcomes. To augment the current literature on this topic, we measured right-hand digit ratio in 4-year-old children participating in The Infant Development and the Environment Study, a multicenter longitudinal cohort study that has been following mother-child dyads since the first trimester of pregnancy (n = 321). We assessed sex differences in digit ratio and fit multivariable linear regression models to examine digit ratio in relation to: (1) child sex; (2) maternal sex steroid hormone concentrations in early pregnancy; (3) newborn anogenital distance, another proposed measure of sensitivity to prenatal androgens; and (4) gender-typical play behavior as measured by the Preschool Activities Inventory (PSAI) at age 4. We observed no sex difference in digit ratio; the mean 2D:4D was 0.97 ± 0.05 mm in both sexes. Furthermore, digit ratio was not associated with maternal sex steroid concentrations in early pregnancy, anogenital distance in either sex, or PSAI scores in either sex in covariate-adjusted models. In conclusion, we observed no evidence that early childhood digit ratio was associated with child sex or hormone-sensitive measures in this cohort.

Objective: To determine if cesarean delivery is adversely associated with child neurodevelopment as measured at 20 months and 7 years., Methods: In a prospective cohort study (n = 1328) in the Republic of Seychelles, we examined the association between mode of delivery and 22 measures of child neurodevelopment spanning multiple domains: cognition, executive and psychomotor function, language development, behavior, scholastic achievement, and social communication. Using multivariable linear regression, we evaluated the relationship between delivery mode (Cesarean/vaginal delivery) and each developmental outcome, while controlling for relevant covariates including child sex and age, maternal age, maternal IQ, whether both parents lived with the child, and Hollingshead socioeconomic status., Results: At 20 months, children born via cesarean delivery had slightly higher scores (β = 0.11, 95% confidence interval: 0.00, 0.21) on the Infant Behavior Questionnaire-Revised Positive Affectivity/Surgency subtest, a measure of infant temperament, as compared to vaginal delivery. Delivery mode was not associated with any of the 7-year developmental outcomes., Conclusions for Practice: Our study does not support the notion that cesarean delivery is associated with child neurodevelopmental outcomes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Combustion related particulate matter air pollution (PM) is associated with an increased risk of respiratory infections in adults. The exact mechanism underlying this association has not been determined. We hypothesized that increased concentrations of combustion related PM would result in dysregulation of the innate immune system. This epidemiological study includes 111 adult patients hospitalized with respiratory infections who underwent transcriptional analysis of their peripheral blood. We examined the association between gene expression at the time of hospitalization and ambient measurements of particulate air pollutants in the 28 days prior to hospitalization. For each pollutant and time lag, gene-specific linear models adjusting for infection type were fit using LIMMA (Linear Models For Microarray Data), and pathway/gene set analyses were performed using the CAMERA (Correlation Adjusted Mean Rank) program. Comparing patients with viral and/or bacterial infection, the expression patterns associated with air pollution exposure differed. Adjusting for the type of infection, increased concentrations of Delta-C (a marker of biomass smoke) and other PM were associated with upregulation of iron homeostasis and protein folding. Increased concentrations of black carbon (BC) were associated with upregulation of viral related gene pathways and downregulation of pathways related to antigen presentation. The pollutant/pathway associations differed by lag time and by type of infection. This study suggests that the effect of air pollution on the pathogenesis of respiratory infection may be pollutant, timing, and infection specific., (© 2021. The Author(s).)

Multiple physiological changes occur in pregnancy as a woman's body adapts to support the growing fetus. These pregnancy-induced changes are essential for fetal growth, but the extent to which they reverse after pregnancy remains in question. For some women, physiological changes persist after pregnancy and may increase long-term cardiometabolic disease risk. The National Institutes of Health-funded study described in this protocol addresses a scientific gap by characterizing weight and biological changes during pregnancy and an extended postpartum period in relation to cardiometabolic risk. We use a longitudinal repeated measures design to prospectively examine maternal health from early pregnancy until 3 years postpartum. The aims are: (1) identify maternal weight profiles in the pregnancy-postpartum period that predict adverse cardiometabolic risk profiles three years postpartum; (2) describe immune, endocrine, and metabolic biomarker profiles in the pregnancy-postpartum period, and determine their associations with cardiometabolic risk; and (3) determine how modifiable postpartum health behaviors (diet, physical activity, breastfeeding, sleep, stress) (a) predict weight and cardiometabolic risk in the postpartum period; and (b) moderate associations between postpartum weight retention and downstream cardiometabolic risk. The proposed sample is 250 women. This study of mothers is conducted in conjunction with the Understanding Pregnancy Signals and Infant Development study, which examines child health outcomes. Biological and behavioral data are collected in each trimester and at 6, 12, 24, and 36 months postpartum. Findings will inform targeted health strategies that promote health and reduce cardiometabolic risk in childbearing women., (© 2021 Wiley Periodicals LLC.)

Background: Fish is a primary source of protein and n-3 PUFA but also contains methylmercury (MeHg), a naturally occurring neurotoxicant to which, at sufficient exposure levels, the developing fetal brain is particularly sensitive., Objectives: To examine the association between prenatal MeHg and maternal status of n-3 and n-6 PUFA with neurodevelopment, and to determine whether PUFA might modify prenatal MeHg associations with neurodevelopment., Methods: We examined the Seychelles Child Development Study Nutrition Cohort 2 (NC2) at age 7 y. We used a sophisticated and extensive neurodevelopmental test battery that addressed 17 specific outcomes in multiple neurodevelopmental domains: cognition, executive and psychomotor function, language development, behavior, scholastic achievement, and social communication. Analyses were undertaken on 1237 mother-child pairs with complete covariate data (after exclusions) and a measure of at least 1 outcome. We examined the main and interactive associations of prenatal MeHg exposure (measured as maternal hair mercury) and prenatal PUFA status (measured in maternal serum at 28 weeks' gestation) on child neurodevelopmental outcomes using linear regression models. We applied the Bonferroni correction to account for multiple comparisons and considered P values <0.0029 to be statistically significant., Results: Prenatal MeHg exposure and maternal DHA and arachidonic acid (20:4n-6) (AA) status were not significantly associated with any neurodevelopmental outcomes. Findings for 4 outcomes encompassing executive function, cognition, and linguistic skills suggested better performance with an increasing maternal n-6:n-3 PUFA ratio (P values ranging from 0.004 to 0.05), but none of these associations were significant after adjusting for multiple comparisons. No significant interaction between MeHg exposure and PUFA status was present., Conclusions: Our findings do not support an association between prenatal MeHg exposure or maternal DHA and AA status with neurodevelopmental outcomes at age 7 y. The roles of n-6 and n-3 PUFA in child neurodevelopment need further research., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Purpose: Long-term exposure to ambient fine particle (PM 2.5 ) concentrations has been associated with an increased rate or risk of neurodegenerative conditions, but individual PM sources have not been previously examined in relation to neurodegenerative diseases., Methods: Using the Statewide Planning and Research Cooperative System database, we studied 63,287 hospital admissions with a primary diagnosis of either Alzheimer's disease, dementia, or Parkinson's disease for New York State residents living within 15 miles from six PM 2.5 monitoring sites. In addition to PM 2.5 concentrations, we studied seven specific PM 2.5 sources: secondary sulfate, secondary nitrate, biomass burning, diesel, spark-ignition emissions, pyrolyzed organic rich, and road dust. We estimated the rate of neurodegenerative hospital admissions associated with increased concentration of PM 2.5 and individual PM 2.5 sources average concentrations in the previous 0-29, 0-179, and 0-364 days., Results: Increases in ambient PM 2.5 concentrations were not consistently associated with increased hospital admissions rates. Increased source-specific PM2.5 concentrations were associated with both increased (e.g., secondary sulfates and diesel emissions) and decreased rates (e.g., secondary nitrate and spark-ignition vehicular emissions) of neurodegenerative admissions., Conclusions: We did not observe clear associations between overall ambient PM 2.5 concentrations or source-apportioned ambient PM 2.5 contributions and rates of neurologic disease hospitalizations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Bayesian model-based clustering provides a powerful and flexible tool that can be incorporated into regression models to better understand the grouping of observations. Using data from the Seychelles Child Development Study, we explore the effect of prenatal methylmercury exposure on 20 neurodevelopmental outcomes measured in 9-year-old children. Rather than cluster individual subjects, we cluster the outcomes within a multiple outcomes model. By using information in the data to nest the outcomes into groups called domains, the model more accurately reflects the shared characteristics of neurodevelopmental domains and improves estimation of the overall and outcome-specific exposure effects by shrinking effects within and between domains selected by the data. The Bayesian paradigm allows for sampling from the posterior distribution of the grouping parameters; thus, inference can be made about group membership and their defining characteristics. We avoid the often difficult and highly subjective requirement of a priori identification of the total number of groups by incorporating a Dirichlet process prior to form a fully Bayesian multiple outcomes model., (© 2019 The International Biometric Society.)

Background: Maternal status of long-chain PUFAs (LC-PUFAs) may be related to fetal growth. Maternal fish consumption exposes the mother to the neurotoxicant methylmercury (MeHg), which, in contrast, may restrict fetal growth., Objective: Our aim was to examine relations between maternal LC-PUFA status at 28 wk and birth outcomes (birth weight, length, and head circumference), controlling for MeHg exposure throughout pregnancy, in the Seychelles Child Development Study Nutrition Cohort 2. Our secondary aim was to examine the influence of maternal variation in genes regulating the desaturation of LC-PUFAs [fatty acid desaturase (FADS)] on birth outcomes., Methods: From nonfasting blood samples collected at 28 wk of gestation, we measured serum total LC-PUFA concentrations and FADS1 (rs174537, rs174561), FADS1-FADS2rs3834458, and FADS2rs174575 genotypes, with hair total mercury concentrations assessed at delivery. Data were available for n = 1236 mother-child pairs. Associations of maternal LC-PUFAs, MeHg, and FADS genotype with birth outcomes were assessed by multiple linear regression models, adjusting for child sex, gestational age, maternal age, BMI, alcohol use, socioeconomic status, and parity., Results: In our cohort of healthy mothers, neither maternal LC-PUFA status nor MeHg exposure were significant determinants of birth outcomes. However, when compared with major allele homozygotes, mothers who were heterozygous for the minor allele of FADS1 (rs174537 and rs174561, GT compared with TT, β = 0.205, P = 0.03; TC compared with CC, β = 0.203, P = 0.04) and FADS1-FADS2 (rs3834458, Tdel compared with DelDel, β = 0.197, P = 0.04) had infants with a greater head circumference (all P < 0.05). Homozygosity for the minor allele of FADS2 (rs174575) was associated with a greater birth weight (GG compared with CC, β = 0.109, P = 0.04)., Conclusions: In our mother-child cohort, neither maternal LC-PUFA status nor MeHg exposure was associated with birth outcomes. The observed associations of variation in maternal FADS genotype with birth outcomes should be confirmed in other populations., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Introduction: Statistical literacy is essential in clinical and translational science (CTS). Statistical competencies have been published to guide coursework design and selection for graduate students in CTS. Here, we describe common elements of graduate curricula for CTS and identify gaps in the statistical competencies., Methods: We surveyed statistics educators using e-mail solicitation sent through four professional organizations. Respondents rated the degree to which 24 educational statistical competencies were included in required and elective coursework in doctoral-level and master's-level programs for CTS learners. We report competency results from institutions with Clinical and Translational Science Awards (CTSAs), reflecting institutions that have invested in CTS training., Results: There were 24 CTSA-funded respondents representing 13 doctoral-level programs and 23 master's-level programs. For doctoral-level programs, competencies covered extensively in required coursework for all doctoral-level programs were basic principles of probability and hypothesis testing, understanding the implications of selecting appropriate statistical methods, and computing appropriate descriptive statistics. The only competency extensively covered in required coursework for all master's-level programs was understanding the implications of selecting appropriate statistical methods. The least covered competencies included understanding the purpose of meta-analysis and the uses of early stopping rules in clinical trials. Competencies considered to be less fundamental and more specialized tended to be covered less frequently in graduate courses., Conclusion: While graduate courses in CTS tend to cover many statistical fundamentals, learning gaps exist, particularly for more specialized competencies. Educational material to fill these gaps is necessary for learners pursuing these activities., (© The Association for Clinical and Translational Science 2020.)

Rationale: In a previous trial (MOSES [Multicenter Ozone Study of oldEr Subjects]), 3 hours of controlled ozone (O 3 ) exposure caused concentration-related reductions in lung function with evidence of airway inflammation and injury, but without convincing evidence of effects on cardiovascular function. However, the subjects' exposures to indoor and outdoor air pollution in the hours and days before each controlled O 3 exposure may have modified biomarker responses to the controlled O 3 exposures. Objectives: We sought to determine whether personal measures of nitrogen dioxide (NO 2 ) and O 3 , or ambient concentrations of O 3 , particulate matter ≤2.5 μm in aerodynamic diameter, NO 2 , carbon monoxide (CO), and sulfur dioxide (SO 2 ) in the 72 and 96 hours before the exposure visit modified biomarker responses to controlled O 3 exposure. Methods: MOSES subjects were exposed for 3 hours in random order to clean air containing 0 ppb O 3 , 70 ppb O 3 , or 120 ppm O 3 , alternating 15 minutes of moderate exercise with 15 minutes of rest. Cardiovascular and pulmonary endpoints (biomarkers of autonomic function, repolarization, ST segment change, arrhythmia, prothrombotic vascular status, systemic inflammation, vascular function, pulmonary function, oxidative stress, and lung injury) were measured on the day before, the day of, and up to 22 hours after each exposure. We evaluated whether ambient pollutant concentrations in the 96 hours before the pre-exposure visit modified pre- to post-exposure lung function biomarker responses to the controlled O 3 exposures, using tertiles of passive personal exposure samplers (PES) of O 3 and NO 2 , ambient air pollutant concentrations, and mixed effects linear regression. We also similarly explored the effect modification of controlled O 3 effects on biomarkers of other MOSES outcome groups in the same way. Although we used P  < 0.01 to define statistical significance, we did not formally correct for multiple comparisons. Results: The effects of MOSES controlled O 3 exposures on forced expiratory volume in 1 second (FEV 1 ) and forced vital capacity (FVC) were modified by ambient NO 2 and CO, and PES NO 2 . Reductions in FEV 1 and FVC were observed only when these concentrations were in the "medium" or "high" tertile in the 72 hours before the pre-exposure visit. There was no such modification of the effect of controlled O 3 exposure on any other cardiopulmonary outcome group. Conclusions: Reductions in markers of lung function, but not other pathways, by the MOSES controlled O 3 exposure were modified by ambient NO 2 and CO, and PES NO 2 , and these reductions were observed only when these pollutant concentrations were elevated in the hours and days before the pre-exposure visit.Clinical trial registered with ClinicalTrials.gov (NCT01487005).

Background: Exposure to the environmental toxicant mercury (Hg) has been associated with immune dysregulation, including autoimmune disease, but few human studies have examined methylmercury (MeHg) exposure from fish consumption., Objectives: We examined associations between MeHg exposure and biological markers of autoimmunity and inflammation while adjusting for long chain polyunsaturated fatty acids (LCPUFA)., Method: At age 19 years, hair total Hg (Y19Hg), LCPUFA status, a panel of 13 antinuclear antibodies (ANA), total serum immunoglobulins (Ig) IgG, IgA, and IgM and serum markers of inflammation (IL-1, IL-2, IL-6, IL-10, C-reactive protein (CRP), IFN-γ, TNF-α) were measured in the Seychelles Child Development Study (SCDS) Main Cohort (n = 497). Multivariable regression models investigated the association between Y19Hg and biomarkers, adjusting for prenatal total hair Hg (MatHg) and other relevant covariates, and with and without adjustment for LCPUFA., Results: With each 1 ppm increase in Y19Hg (mean 10.23 (SD 6.02) ppm) we observed a 4% increased odds in a positive Combined ANA following adjustment for the n6:n3 LCPUFA ratio (β = 0.036, 95%; CI: 0.001, 0.073). IgM was negatively associated with Y19Hg (β = -0.016, 95%CI: 0.016, -0.002) in models adjusted for n-3, n-6 LCPUFA and when separately adjusted for the n-6:n-3 LCPUFA ratio. No associations were observed with MatHg. Total n-3 LCPUFA status was associated with reduced odds of a positive anti-ribonuclear protein (RNP) A. The n-3 LCPUFA were negatively associated with IL-6, IL-10, CRP, IFN-γ, TNF-α and positively with TNF-α:IL-10. There were positive associations between the n-6:n-3 ratio and IL-6, IL-10, CRP, IFN-γ, TNF-α and a negative association with TNF-α:IL-10., Discussion: The Y19Hg exposure was associated with higher ANA and lower IgM albeit only following adjustment for the n-3 LCPUFA or the n-6:n-3 LCPUFA ratio. The clinical significance of these findings is unclear, but warrant follow up at an older age to determine any relationship to the onset of autoimmune disease., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The Multicenter Ozone Study of oldEr Subjects (MOSES) was a multi-center study evaluating whether short-term controlled exposure of older, healthy individuals to low levels of ozone (O 3 ) induced acute changes in cardiovascular biomarkers. In MOSES Part 1 (MOSES 1), controlled O 3 exposure caused concentration-related reductions in lung function with evidence of airway inflammation and injury, but without convincing evidence of effects on cardiovascular function. However, subjects' prior exposures to indoor and outdoor air pollution in the few hours and days before each MOSES controlled O 3 exposure may have independently affected the study biomarkers and/or modified biomarker responses to the MOSES controlled O 3 exposures., Methods: MOSES 1 was conducted at three clinical centers (University of California San Francisco, University of North Carolina, and University of Rochester Medical Center) and included healthy volunteers 55 to 70 years of age. Consented participants who successfully completed the screening and training sessions were enrolled in the study. All three clinical centers adhered to common standard operating procedures and used common tracking and data forms. Each subject was scheduled to participate in a total of 11 visits: screening visit, training visit, and three sets of exposure visits consisting of the pre-exposure day, the exposure day, and the post-exposure day. After completing the pre-exposure day, subjects spent the night in a nearby hotel. On exposure days, the subjects were exposed for 3 hours in random order to 0 ppb O 3 (clean air), 70 ppb O 3 , and 120 ppm O 3 . During the exposure period the subjects alternated between 15 minutes of moderate exercise and 15 minutes of rest. A suite of cardiovascular and pulmonary endpoints was measured on the day before, the day of, and up to 22 hours after each exposure., In MOSES Part 2 (MOSES 2), we used a longitudinal panel study design, cardiopulmonary biomarker data from MOSES 1, passive cumulative personal exposure samples (PES) of O 3 and nitrogen dioxide (NO 2 ) in the 72 hours before the pre-exposure visit, and hourly ambient air pollution and weather measurements in the 96 hours before the pre-exposure visit. We used mixed-effects linear regression and evaluated whether PES O 3 and NO 2 and these ambient pollutant concentrations in the 96 hours before the pre-exposure visit confounded the MOSES 1 controlled O 3 exposure effects on the pre- to post-exposure biomarker changes (Aim 1), whether they modified these pre- to post-exposure biomarker responses to the controlled O 3 exposures (Aim 2), whether they were associated with changes in biomarkers measured at the pre-exposure visit or morning of the exposure session (Aim 3), and whether they were associated with differences in the pre- to post-exposure biomarker changes independently of the controlled O 3 exposures (Aim 4)., Results: Ambient pollutant concentrations at each site were low and were regularly below the National Ambient Air Quality Standard levels. In Aim 1, the controlled O 3 exposure effects on the pre- to post-exposure biomarker differences were little changed when PES or ambient pollutant concentrations in the previous 96 hours were included in the model, suggesting these were not confounders of the controlled O 3 exposure/biomarker difference associations. In Aim 2, effects of MOSES controlled O 3 exposures on forced expiratory volume in 1 second (FEV 1 ) and forced vital capacity (FVC) were modified by ambient NO 2 and carbon monoxide (CO), and PES NO 2 , with reductions in FEV 1 and FVC observed only when these concentrations were "Medium" or "High" in the 72 hours before the pre-exposure visit. There was no such effect modification of the effect of controlled O 3 exposure on any other cardiopulmonary biomarker., As hypothesized for Aim 3, increased ambient O 3 concentrations were associated with decreased pre-exposure heart rate variability (HRV). For example, high frequency (HF) HRV decreased in association with increased ambient O 3 concentrations in the 96 hours before the pre-exposure visit (-0.460 ln[ms 2 ]; 95% CI, -0.743 to -0.177 for each 10.35-ppb increase in O 3 ; P = 0.002). However, in Aim 4 these increases in ambient O 3 were also associated with increases in HF and low frequency (LF) HRV from pre- to post-exposure, likely reflecting a "recovery" of HRV during the MOSES O 3 exposure sessions. Similar patterns across Aims 3 and 4 were observed for LF (the other primary HRV marker), and standard deviation of normal-to-normal sinus beat intervals (SDNN) and root mean square of successive differences in normal-to-normal sinus beat intervals (RMSSD) (secondary HRV markers)., Similar Aim 3 and Aim 4 patterns were observed for FEV 1 and FVC in association with increases in ambient PM with an aerodynamic diameter ≤ 2.5 μm (PM 2.5 ), CO, and NO 2 in the 96 hours before the pre-exposure visit. For Aim 3, small decreases in pre-exposure FEV 1 were significantly associated with interquartile range (IQR) increases in PM 2.5 concentrations in the 1 hour before the pre-exposure visit (-0.022 L; 95% CI, -0.037 to -0.006; P = 0.007), CO in the 3 hours before the pre-exposure visit (-0.046 L; 95% CI, -0.076 to -0.016; P = 0.003), and NO 2 in the 72 hours before the pre-exposure visit (-0.030 L; 95% CI, -0.052 to -0.008; P = 0.007). However, FEV 1 was not associated with ambient O 3 or sulfur dioxide (SO 2 ), or PES O 3 or NO 2 (Aim 3). For Aim 4, increased FEV 1 across the exposure session (post-exposure minus pre-exposure) was marginally significantly associated with each 4.1-ppb increase in PES O 3 concentration (0.010 L; 95% CI, 0.004 to 0.026; P = 0.010), as well as ambient PM 2.5 and CO at all lag times. FVC showed similar associations, with patterns of decreased pre-exposure FVC associated with increased PM 2.5 , CO, and NO 2 at most lag times, and increased FVC across the exposure session also associated with increased concentrations of the same pollutants, reflecting a similar recovery. However, increased pollutant concentrations were not associated with adverse changes in pre-exposure levels or pre- to post-exposure changes in biomarkers of cardiac repolarization, ST segment, vascular function, nitrotyrosine as a measure of oxidative stress, prothrombotic state, systemic inflammation, lung injury, or sputum polymorphonuclear leukocyte (PMN) percentage as a measure of airway inflammation., Conclusions: Our previous MOSES 1 findings of controlled O 3 exposure effects on pulmonary function, but not on any cardiovascular biomarker, were not confounded by ambient or personal O 3 or other pollutant exposures in the 96 and 72 hours before the pre-exposure visit. Further, these MOSES 1 O 3 effects were generally not modified, blunted, or lessened by these same ambient and personal pollutant exposures. However, the reductions in markers of pulmonary function by the MOSES 1 controlled O 3 exposure were modified by ambient NO 2 and CO, and PES NO 2 , with reductions observed only when these pollutant concentrations were elevated in the few hours and days before the pre-exposure visit. Increased ambient O 3 concentrations were associated with reduced HRV, with "recovery" during exposure visits. Increased ambient PM 2.5 , NO 2 , and CO were associated with reduced pulmonary function, independent of the MOSES-controlled O 3 exposures. Increased pollutant concentrations were not associated with pre-exposure or pre- to post-exposure changes in other cardiopulmonary biomarkers. Future controlled exposure studies should consider the effect of ambient pollutants on pre-exposure biomarker levels and whether ambient pollutants modify any health response to a controlled pollutant exposure., (© 2020 Health Effects Institute. All rights reserved.)

Problem: Markers of maternal inflammation may determine infant birth outcomes., Method of Study: Maternal serum samples were collected at 28 weeks gestation (n = 1418) in the Seychelles Child Development Study Nutrition Cohort 2 and analyzed for immune markers by MSD multiplex assay, including cytokines from the Th1 (IFN-γ, IL-1β, IL-2 and TNF-α) and Th2 (IL-4, IL-5, IL-10) subsets, with IL-6, MCP-1, TARC, sFlt-1 and VEGF-D. Associations of log-transformed immune markers with birthweight, length, head circumference and gestational age were assessed by multiple linear regression models, which were adjusted for maternal age, BMI, parity, child sex, gestational age and socioeconomic status., Results: Neither total Th1, Th2 nor Th1:Th2 were significantly associated with any birth outcome. However, the angiogenesis marker VEGF-D was predictive of a lower birthweight, (β = -0.058, P = 0.017) and birth length (β = -0.088, P = 0.001) after adjusting for covariates. Higher concentrations of CRP were predictive of a lower birthweight (β = -0.057, P = 0.023) and IL-2 (β = 0.073, P = 0.009) and the chemokine MCP-1 (β = 0.067, P = 0.016) were predictive of a longer gestational age., Conclusions: In our cohort of healthy pregnant women, we found no evidence for associations between the Th1 or Th2 inflammatory markers with birth outcomes. However, VEGF-D and CRP appear to predict lower birthweight and IL-2 and MCP-1 a longer gestation. Greater understanding is required of the variation in these immune markers at different gestational stages, as well as the factors which may regulate their balance in healthy pregnancy. n = 233., 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 © 2019 Elsevier B.V. All rights reserved.)

Prior work found increased rates for emergency department (ED) visits for asthma and hospitalizations for chronic obstructive pulmonary disease per unit mass of PM 2.5 across New York State (NYS) during 2014-2016 after significant reductions in ambient PM 2.5 concentrations had occurred following implementation of various policy actions and major economic disruptions. The associations of source-specific PM 2.5 concentrations with these respiratory diseases were assessed with a time-stratified case-cossover design and logistic regression models to identify the changes in the PM 2.5 that have led to the apparently increased toxicity per unit mass. The rates of ED visits and hospitalizations for asthma and COPD associated with increases in source-specific PM 2.5 concentrations in the prior 1, 4, and 7 days were estimated for 6 urban sites in New York State. Overall, there were similar numbers of significantly increased (n = 9) and decreased rates (n = 8) of respiratory events (asthma and COPD hospitalizations and ED visits) associated with increased source-specific PM 2.5 concentrations in the previous 1, 4, and 7 days. Associations of source-specific PM 2.5 concentrations with excess rates of hospitalizations for COPD for spark- and compression ignition vehicles increased in the 2014-2016 period, but the values were not statistically significant. Other source types showed inconsistent patterns of excess rates. For asthma ED visits, only biomass burning and road dust showed consistent positive associations with road dust having significant values for most lag times. Secondary nitrate also showed significant positive associations with asthma ED visits in the AFTER period compared to no associations in the prior periods. These results suggest that the relationships of asthma and COPD exacerbation with source-specific PM 2.5 are not well defined and further work will be needed to determine the causes of the apparent increases in the per unit mass toxicity of PM 2.5 in New York State in the 2014-16 period., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The response of respiratory infections to source-specific particulate matter (PM) is an area of active research. Using source-specific PM 2.5 concentrations at six urban sites in New York State, a case-crossover design, and conditional logistic regression, we examined the association between source-specific PM and the rate of hospitalizations and emergency department (ED) visits for influenza or culture-negative pneumonia from 2005 to 2016. There were at most N = 14 764 influenza hospitalizations, N = 57 522 influenza ED visits, N = 274 226 culture-negative pneumonia hospitalizations, and N = 113 997 culture-negative pneumonia ED visits included in our analyses. We separately estimated the rate of respiratory infection associated with increased concentrations of source-specific PM 2.5 , including secondary sulfate (SS), secondary nitrate (SN), biomass burning (BB), pyrolyzed organic carbon (OP), road dust (RD), residual oil (RO), diesel (DIE), and spark ignition vehicle emissions (GAS). Increased rates of ED visits for influenza were associated with interquartile range increases in concentrations of GAS (excess rate [ER] = 9.2%; 95% CI: 4.3%, 14.3%) and DIE (ER = 3.9%; 95% CI: 1.1%, 6.8%) for lag days 0-3. There were similar associations between BB, SS, OP, and RO, and ED visits or hospitalizations for influenza, but not culture-negative pneumonia hospitalizations or ED visits. Short-term increases in PM 2.5 from traffic and other combustion sources appear to be a potential risk factor for increased rates of influenza hospitalizations and ED visits.