Background Maternal psychosocial stress is associated with perturbations in biological systems, including placental alterations with implications for fetal programming. Here, we examined associations between maternal lifetime stress and placental mitochondrial DNA (mtDNA) mutational load, while considering modifying effects of maternal characteristics. Methods In 496 participants from the PRISM cohort, we profiled placental mtDNA mutational load with next-generation sequencing. We used negative binomial regression models to investigate associations between maternal lifetime stress/trauma using the Life Stressor Checklist-Revised (LSC-R), and placental mtDNA mutational load and, assessed effect modification by obesity and race/ethnicity in stratified models. Results We detected 1,357 distinct mutations, most were homoplasmies and transitions. There was moderate evidence of an association between an interquartile increase in LSC-R and mtDNA mutational load, with incident rate ratio (IRR) 1.04 (95% confidence intervals (CI) 0.99, 1.09). In stratified analyses, associations were stronger in the non-obese than the obese, although estimates were imprecise in both groups. In analyses stratified by race/ethnicity, higher stress/trauma was associated with higher mtDNA mutational load only in Black women (IRR 1.07, 95%CI, 1.01-1.14). In analyses stratified by obesity and race/ethnicity, higher stress was associated with increased mtDNA mutational load in Black women in the non-obese (IRR = 1.09, 95%CI, 1.02-1.17) subgroup, but not in the obese (IRR = 1.02, 95%CI, 0.91-1.13) subgroup. Conclusions We found associations between maternal lifetime stress/trauma and placental mtDNA mutational load with differential association by obesity and race/ethnicity. Further work exploring the role of stress-related mitochondrial pathways in maternal and birth outcomes is warranted.

BACKGROUND:The relationship between prenatal exposure to low-level air pollution and child autism spectrum disorder (ASD) is unclear. OBJECTIVE:To examine associations of prenatal air pollution exposure with autism. METHODS:We analyzed data from 8,035 mother-child pairs from 44 United States cohorts in the Environmental influences on Child Health Outcomes (ECHO) Cohort. Fine particulate matter (PM2.5), nitrogen dioxide (NO2), and 8-h-max ozone (O3) levels were estimated at residential addresses during pregnancy. Parents rated children's autism-related traits using the Social Responsiveness Scale (SRS) (mean age 9.4 years, SD = 3.6) and reported physician-diagnosed ASD. We examined associations of the three air pollutants with SRS scores (10th, 50th, and 90th quantiles) using quantile regression and with ASD diagnosis using logistic regression. Models were run within census divisions, and coefficients were pooled in a meta-analysis. RESULTS:Average (SD) pregnancy exposures were 9.3 μg/m3 (2.7) for PM2.5, 21.8 ppb (8.8) for NO2, and 40.3 ppb (5.5) for O3, with variations across census divisions. The median SRS T-score was 46 (IQR = 41 to 52), and 444 children (5.5%) had an ASD diagnosis. Higher PM2.5 was associated with higher SRS scores at the 10th quantile (β = 0.74, 95% CI: 0.09, 1.40) but not at the median or highest quantile. The association between PM2.5 and ASD diagnosis was highly heterogeneous, with associations present in the South Central, Mountain, and Pacific census divisions. Heterogeneity was also high in the association between NO2 and SRS at the median and only in the mid-Atlantic, West North Central, and South Atlantic census divisions. Higher O3 was associated with higher SRS scores at the median (β per IQR increment = 0.83, 95% CI: 0.05, 1.61) and highest quantile (β = 2.19, 95% CI: 0.06, 4.32) in the meta-analysis. Higher O3 also was associated with ASD. DISCUSSION:Associations with ASD outcomes were present even at low levels of air pollutants.

BACKGROUND:Emerging evidence suggests that per- and polyfluoroalkyl substances (PFAS) may be associated with mother's postpartum psychological symptoms. We examined such in two population-based pregnancy cohorts. METHODS:Using liquid chromatography-high resolution mass spectrometry, we measured untargeted serum PFAS at 1 month postpartum (PROGRESS cohort) and targeted plasma PFAS at 32 gestation weeks (BiSC cohort). Postpartum depression (PPD) was assessed with the Edinburgh Postnatal Depression Scale (EPDS≥10) from 1 to 24 months postpartum. Poisson regression assessed the association between PFAS and PPD (Yes/No), and negative binomial regression was used for the EPDS subscales (anhedonia, anxiety, and depression) assessed in continuous scale. Weighted Sum Quantile regression estimated the PFAS mixture effect on PPD and subscales. RESULTS:Each doubling increase in PFNA exposure was associated with 53% increase in incident PPD (RR: 1.53, 95%CI: 1.15-2.06; q-value = 0.033) at 1 month postpartum in PROGRESS. Other individual PFAS showed a weak positive association with PPD and the subscale of anhedonia at 1 month, although adjusted p-values were borderline. The PFAS mixture at 1 month postpartum was associated with increased risk of anhedonia (IRR: 1.20, 95%CI: 1.02-1.42) at 1 month postpartum. The findings in BiSC were null or toward a protective effect. CONCLUSION:Inconsistent findings were observed between PFAS exposure and postpartum psychological symptoms across the cohorts, particularly between PFNA and incident PPD, which may be explained by variation in cohort design, exposure profiles, cultural context, and sample size. More evidence is needed on the association between PFAS exposure and postpartum psychological symptoms.

Abstract Adverse childhood experiences (ACEs) are associated with maternal depression, including during the perinatal and postpartum periods when women face elevated risk. Benevolent childhood experiences (BCEs) may buffer negative effects of ACEs and promote mental health, yet evidence on their joint effects remains limited, particularly in low-resource settings. We investigated the joint effects of ACEs and BCEs on maternal depression from the third trimester of pregnancy through eight years postpartum among 804 women in rural Pakistan. Childhood experiences were characterized using both aggregated scores and latent class analysis to capture overall burden and item-level patterns. We tested the linear interaction term of ACEs and BCEs and utilized subgroup analysis to assess non-linear interactions. Overall, more than half (58.5%) of women experienced at least one ACE, and 6.2% of women experienced four or more ACEs. Commonly reported ACE domains were home violence (39.3%), neglect (19.7%) and family psychological distress (15.2%). Nearly half (45.3%) of women experienced all ten BCEs, and over half (51.5%) experienced 6-9 BCEs. Some BCE items had a very high prevalence, including liking themselves/feeling comfortable with themselves (96.6%), having at least one caregiver with whom they felt safe (96.5%), and having good neighbors (94.9%). Adjusting for ACEs, higher levels of BCEs were independently associated with fewer depressive symptoms (β = -0.25; 95% CI: -0.45, -0.05) and the promotive effects were consistent across ACE domains. Evidence of interaction suggested that BCEs buffered the adverse effects of ACEs among women with 1-3 ACEs (β = -0.56; 95% CI: -0.86, -0.26), but not among those with four or more ACEs. The associations between exposure to ACEs and depressive symptoms were weaker among women with higher levels of BCEs. Latent class analysis identified four distinct childhood experience profiles: Low-ACE/High-BCE (58.6%), High ACE/High BCE (19.5%), Low ACE/Low BCE (13.8%), High ACE/Low BCE (8.1%), with women in the High ACE/Low BCE class experiencing the greatest depressive symptom burden. Findings suggest that both adverse and benevolent childhood experiences are important for understanding maternal depression in low-resource settings, and informing interventions that reduce adversity exposure and foster positive developmental resources.

Abstract Importance Fine particulate matter (PM2.5) is a key risk factor of lung cancer incidence and mortality. However, the specific effect of PM2.5 originating from wildfire smoke, an increasingly important contributor to total PM2.5 in the US driven by climate change, on mortality of patients with lung cancer remain unclear. Objective To explore the effect of long-term exposure to wildfire smoke versus non-smoke PM2.5 on all-cause mortality of older lung cancer patients. Design, Setting, and Participants This cohort study included patients ≥65 years with primary diagnosis of lung cancer from the SEER-Medicare database from 2006 to 2019 linked with estimates of exposure to wildfire smoke and non-smoke PM2.5 based on patients’ residential zip codes. Exposures Three-year moving average exposures to wildfire smoke and non-smoke PM2.5. Main Outcomes and Measures The study outcome was all-cause mortality after primary lung cancer diagnosis. A time-varying Cox proportional hazards model was applied to estimate hazard ratios (HRs) for mortality risk. Results Among 503,409 patients with 1,542,491 person-years of follow up, each 1-μg/m3 increase in wildfire smoke PM2.5 was associated with a 9.3% increased mortality risk (HR: 1.09, 95% CI: 1.08-1.11), substantially greater than that of non-smoke PM2.5 (HR: 1.020, 95% CI: 1.018-1.022). The number of smoke days and of smoke waves, reflecting duration and frequency of wildfire smoke PM2.5 exposure, were also positively associated with mortality risk. Larger effect of wildfire smoke PM2.5 was observed among women, patients with lung cancer other than non-small cell lung cancer, patients with comorbidities, and those not receiving first course treatment after diagnosis. Conclusions Wildfire smoke posed a substantially larger risk in older lung cancer patients than non-smoke PM2.5. Under a changing climate, strengthening wildfire management and reducing wildfire smoke exposure in clinical care could improve survival of older lung cancer patients. Citation Format: Min Zhang, Juan P. Wisnivesky, Minghao Qiu, Mahdieh Danesh Yazdi, Rosalind J. Wright, Joel D. Schwartz, Christine C. Ekenga, Robert O. Wright, Yaguang Wei. Long-term exposure to wildfire smoke PM2.5 and survival of older lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6251.

RATIONALE:Air pollution in high-poverty neighborhoods contributes to disparities in asthma morbidity. Housing mobility programs help families move to better-resourced neighborhoods and improve asthma outcomes. Whether housing mobility-related improvements in asthma morbidity are explained by reductions in air pollution is unknown. OBJECTIVES:Evaluate change in concentrations of fine particulate matter and its components and associated changes in asthma morbidity among a cohort of children with asthma who moved out of high-poverty neighborhoods. MEASUREMENTS AND MAIN RESULTS:Caregiver-reported asthma exacerbations, symptoms, and asthma control test scores were examined among 123 children (age 5-17) with persistent asthma participating in the Baltimore Regional Housing Partnership housing mobility program. Exposures considered are annual average concentrations of PM2.5 and major PM2.5 components (black carbon, organic carbon, ammonium, nitrate, and sulfate). Children moved to neighborhoods with 0.64 μg/m3 [95% CI: 0.50-0.82] lower PM2.5 concentrations, with greatest reductions in black carbon and organic carbon. One standard deviation higher exposure to PM2.5 was associated with a 60% [95% CI: 21%-112%] higher odds of exacerbations and 20% [14%-27%] higher odds of symptom days/2 weeks. Reductions in PM2.5 exposure explained 77% [39% - 100%] and 22% [16%-36%] of moving-related reductions in exacerbations and symptom days, respectively. Some PM components were also associated with asthma exacerbations and symptoms and showed mediating effects. CONCLUSIONS:Moving from high-poverty neighborhoods to better-resourced neighborhoods through a housing mobility program is associated with lower air pollution exposure, contributing to moving-related asthma improvements. Housing mobility may be a useful complement to pollution-focused environmental justice interventions.

Absence of autism risk-stratification tools under 18 months hampers early intervention. In a multinational sample of 1697 participants, aged one month and older, we provide proof-of-concept that temporal molecular dynamics can stratify autism likelihood. Using laser-ablation-inductively-coupled-plasma-mass-spectrometry, we measured elemental intensities along growth increments of single hair strands at ~800 timepoints. We developed a first-stage model to stratify individuals into a lower autism probability group and applied a second-stage model to the remaining participants, stratifying them into intermediate- and high-probability groups. Models were trained, ensembled, and tuned on participants from California and Sweden, then tested on 580 participants (within- and external-population replication in New York, Mexico, and Japan). Likelihood ratios (95%CI) for autism in low-, intermediate-, and high-probability groups were 0.18(0.15-0.23), 1.09(0.99-1.20), and 2.62(1.55-4.00), respectively. Low-probability classification (first-stage) had sensitivity of 96%(0.91-0.98), and high-probability classification (second-stage) had specificity of 90%(0.86-0.92). Our data support that elemental biodynamics can objectively stratify autism likelihood. ### Competing Interest Statement Manish Arora is a founder and CEO of Linus Biotechnology Inc., a start-up company of the Mount Sinai Health System that develops hair-based biomarkers. He owns equity in the company and is listed as an inventor on patent applications, including those related to hair biomarkers of ASD. Conflicts of interest for Manish Arora are managed by Mount Sinai in accordance with institutional policy. Ghalib Bello, Louis A. Gomez, Sujeewa C. Piyankarage, Suzy Elhlou, Jyoti Chumber, Juliet Jaramilo, and Sophie Dessalle are employees of Linus Biotechnology Inc. Deborah Bennett, Rebecca Schmidt, Vishal Midya, and Manuel Ruiz Marin consult with Linus Biotechnology Inc on hair biomarker-related work. All other authors declare no other competing financial interests or personal relationships that might influence the work reported in this paper. ### Funding Statement National Institute of Environmental Health Science (R35ES030435) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This current study is approved by the Mount Sinai IRB. The CHARGE and MARBLES study protocols were approved by the University of California at Davis and the State of California Institutional Review Boards. For SEAVER and PRISM, the present study was approved by the Mount Sinai IRB, and written informed consent was obtained from all participants, their parents, or guardians. The RATSS study was approved by the Swedish Regional Ethical Review Board. The protocol for JECS was reviewed and approved by the IRB of the Japanese Ministry of the Environment on Epidemiological Studies and by the Ethics Committees of all participating institutions. All participating women provided written informed consent. The study in Mexico City was approved by the ethical review board of IberoAmericana University. For all study populations included in this manuscript, informed consent was obtained after the nature and possible consequences of the studies were explained. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Clinical data from this study cannot be posted to a publicly accessible forum, as they contain private health information. However, they will be available from authors at reasonable request, subject to appropriate clearances from research governance authorities at each participating study institution.

Background: The mesolimbic dopamine system is a critical component of the brain’s reward pathways encompassing motivation, reward processing, reinforcement learning, and goal-directed behaviors. Early execution of reward-seeking neurobehaviors may influence later childhood adiposity. We investigated performance on a reward-based operant conditioning paradigm in relation to adiposity in later childhood.Methods: Children aged 6–7 years completed five Operant Testing Battery tasks that used nickels as rewards with higher scores reflecting greater reward sensitivity and heightened responsiveness to reinforcement. Repeated BMI (body mass index) and percentage (%) body fat were assessed from ages 8 to 10. A covariate-adjusted generalized weighted quantile sum (WQS) regression was used to derive an integrated neurobehavioral index across five tasks to estimate joint association with later adiposity measures. Stratified analyses assessed male- and female-dimorphic differences.Results: The neurobehavioral index was positively associated with BMI at ages 8 and 10 (β=0.40kg/m²; 95%CI:0.12–0.68; p =0.005 and β=0.43kg/m²; 95%CI:0.14–0.72; p =0.003, respectively) and %body fat at ages 8 and 10 (β=1.09%; 95%CI:0.14–2.03; p=0.025 and β=1.45%; 95%CI:0.60–2.29; p=0.001, respectively). Among males, higher index scores were associated with greater BMI at age 8 (β=0.48kg/m²; 95%CI:0.12–0.84; p=0.01), BMI at age 10 (β=0.52kg/m²; 95%CI:0.14–0.90; p=0.007), and %body fat at age 10 (β=1.72%; 95%CI:0.61–2.84; p=0.003) and among females was positively associated with %body fat at age 8 (β=1.58%; 95%CI: 0.35–2.82; p=0.013). Temporal processing and learning behavior contributed to the highest mixture weights in most models.Conclusion: Emerging reward-driven response patterns, as captured through laboratory-based operant conditioning tasks, may contribute to adiposity later in childhood.

Although temperamental negative affectivity has been identified as a developmental mechanism mediating the link between perinatal risk and internalizing problems in early childhood, its role in predicting broader behavioral and emotional problems across childhood remains understudied. We examined the longitudinal relations among perinatal complications (i.e., prenatal maternal depression and cardiometabolic complications, preterm birth, and low birth weight), children's negative affectivity (M age = 2.76; SD = 2.32; range = 0.24-12.46 years), and children's internalizing, externalizing, and total problems (M age = 5.12; SD = 2.63; range = 1.50-16.85 years) in the Environmental influences on Child Health Outcomes (ECHO) program (N = 3070; 47% females). Results support child negative affectivity as a mechanism in the developmental pathway linking perinatal maternal depressive symptoms and preterm birth to future emotional and behavioral problems, underscoring the importance of early prevention and intervention efforts to promote psychological well-being of at-risk children.

The goal of this study was to investigate the contextual nature of prenatal depression (PND) and postpartum depression (PPD). We report an investigation of maternal PND and PPD using nonrandomly clustered data from 8,936 mothers in 16 cohorts in the Environmental influences on Child Health Outcomes (ECHO) Cohort. We used a recursive partitioning algorithm (ctree) to account for differential effects arising from predictor and effect heterogeneity across cohort to identify contexts, and the characteristics comprising these contexts, associated with PND and PPD. Consistent with Bronfenbrenner's bioecological systems framework, risk factors for PND and PPD are heterogeneously and synergistically present in context: the same variables did not consistently present as risk factors across groups. Findings from this study support the idea that the presence or absence of medical (and sociodemographic) risks do not have simple associations with perinatal depression. To that end, no univariate predictors of PND and PPD can be said to constitute risk absent the broader context of mothers' lives. Thus, a more useful research question than "which variables increase risk for PPD?" is "in what contexts, or in which subgroups, does a particular risk or set of risks contribute to perinatal depression?"

Purpose: This study evaluated associations among breastfeeding duration and combined breast/formula feeding on childhood dental caries. Methods: This was a cross-sectional study of 3- to 6-year-old children (n =1,256) in the National Health and Nutrition Examination Survey, 2015-2018. Duration of breastfeeding and breast/formula feeding were assessed through structured interviews. Caries experience was assessed as having at least 1 decayed and filled tooth. Survey-weighted logistic regression adjusted for confounders evaluated associations. Results: The average maternal age at delivery was 28 years (standard error=0.28). About half (49.7%) of the children were girls. Thirty-eight percent of the children were breastfed for no more than 6 months, 20% for more than 6 to 12 months, and approximately 9% were breastfed for more than 12 to 18 months and over 18 months, while 24% were exclusively formula-fed. Relative to children breastfed for no more than 6 months, those breastfed for longer than 18 months had a nonsignificant covariate-adjusted caries experience odds (odds ratio [OR]=1.55, 95 percent confidence interval [95% CI]=0.80 to 3.01). Relative to children who were exclusively breastfed, those who were nonconcurrently breastfed/formula-fed (ie, there was no overlap in breastfeeding and formula feeding) had higher covariate-adjusted caries experience odds (OR=3.01, 95% CI=1.18 to 7.67). Conclusions: Nonconcurrent breast/formula feeding was associated with increased dental caries prevalence. Additional studies are needed to confirm these results and evaluate underlying mechanisms.

PURPOSE:To examine factors associated with moving during pregnancy and impacts of assigning nSES at enrollment, delivery, or a time-weighted average on birth outcomes (birthweight, birthweight-for-gestational-age z-score, low birthweight, gestational age, small-for-gestational age, preterm birth). METHODS:We used data from the Environmental influences on Child Health Outcomes (ECHO) Cohort Study (2010-2019) with nSES data from the American Community Survey (ACS) matched by time and location to monthly residential histories. We used multivariable logistic models with Generalized Estimating Equations to identify factors associated with moving and quantify exposure misclassification in model estimates. RESULTS:Approximately 7 % of 15,376 participants moved at least once during pregnancy. Maternal age (OR: 0.97, 95 % CI: 0.95, 0.98) and other race vs. White (OR: 0.39, 95 % CI: 0.20, 0.80) were associated with lower odds of moving; lower neighborhood-level education (OR: 1.34, 95 % CI: 1.11, 1.62) and living in urban neighborhoods (OR: 3.03, 95 % CI: 1.39, 6.59) were associated with higher odds. Among movers, estimates between nSES and birth outcomes changed ≥ 16 % by address assignment; birthweight-for-gestational-age z-score was significant only when using nSES at delivery. CONCLUSION:Sociodemographic and nSES characteristics are associated with moving during pregnancy; movers may experience exposure misclassification and underestimated effects on birth outcomes.

BACKGROUND:The rising global prevalence of pediatric mental health problems requires the identification of preventable factors underlying their development. This study assessed whether maternal adverse childhood experiences (ACEs) and pregnancy stress were intergenerationally associated with offspring mental health. METHODS:This study used data from 34 sites in the nationwide Environmental Influences on Child Health Outcomes Cohort. Eligible parent-child dyads (child age: 1.5-18 years) provided data on at least one measure of maternal stress and at least one measure of child mental health. Study aims were evaluated using regression analyses, including interaction tests to determine potential effect modifiers. RESULTS:Participants were organized into three subsamples with data on (1) maternal ACEs (N = 2,906), (2) perceived prenatal stress (N = 4,441), and (3) both stress exposures (N = 834). After adjusting for confounders, maternal ACEs and prenatal stress were significantly associated with child mental health problems (B = 2.53 [95% confidence interval [CI]: 2.09, 2.96], p < 0.0001 and B = 2.36 [95% CI: 2.03, 2.68], p < 0.0001, respectively). Among participants with data on both stress exposures, maternal ACEs (B = 1.72, 95% CI: [0.96, 2.48], p < 0.0001) and prenatal stress (B = 2.05, 95% CI: [1.29, 2.80], p < 0.0001) were independently associated with child mental health problems. Neither maternal ACEs nor child sex modified the association between prenatal stress and child mental health problems. CONCLUSIONS:Maternal exposure to ACEs and pregnancy stress were associated with the development of child mental health problems. These findings highlight the need for policies and interventions that mitigate exposure to adversity and protect pregnant individuals and their children from the intergenerational transmission of mental health problems.

Our objective was to examine the role of structural racism and economic disadvantage in perinatal health inequities using the Environmental influences on Child Health Outcomes Cohort. Participants' addresses were linked to area-level measures of life expectancy, education, unemployment, health insurance, jail rate, segregation, and housing cost burden. We created absolute measures to represent economic disadvantage and relative measures comparing values for Black or Latinx people to White people in the same area to represent structural racism. We used quantile G-computation to estimate the effects of a one-quartile increase in all exposures simultaneously on fetal growth and gestational age measures. A one-quartile increase in economic disadvantage was associated with a reduction in birthweight [(-25.65 grams, 95% CI (-45.83, -5.48)], but not gestational age [-0.02 weeks, 95% CI (-0.13, 0.09)]. With a one-quartile increase in Latinx-White structural racism, we observed reductions in birthweight [-80.83, 95% CI (-143.42, -18.23)] among Latinx participants. A one-quartile increase in Black-White structural racism was weakly associated with lower birthweight among Black participants [-15.70, 95% CI (-82.89, 51.48)] but was associated with higher birthweight among White participants [57.47, 95% CI (13.26, 101.67)]. Our findings suggest co-occurring forms of structural inequity likely influence racialized disparities in fetal growth outcomes.

Background/Objectives: Women exposed to high psychosocial stress in pregnancy have higher risk of postpartum health conditions, but it still is unknown whether high pregnancy stress exposure alters the maternal metabolome at one-month postpartum. Methods: We analyzed data from 625 women participating in the PROGRESS study, a longitudinal pregnancy cohort. Women answered validated psychometric tests (i.e., EPDS, PSS and NLE) during the second or third trimester of pregnancy and provided serum samples at one-month postpartum for metabolomic assessment. Untargeted metabolomics were analyzed using chromatography high-resolution mass spectrometry (LC-HRMS). We used a metabolome-wide association study, using both traditional robust regressions and variance tests, to evaluate associations between pregnancy psychosocial stress and one-month postpartum serum metabolomics. Results: We found a few nominally significant associations between prenatal psychosocial stress scores and the maternal metabolome. However, these findings did not remain after adjusting for multiple testing, with the only exception of epiandrosterone glucuronide, a steroid hormone metabolite, and lithocholyltaurine, a lipid-like molecule. Conclusions: We did not find significant associations between prenatal psychosocial stress and postpartum serum metabolomic profiles, except for two metabolites showing suggestive associations warranting further investigation.

Background:Postpartum depression (PPD) is a global health issue that can lead to high levels of maternal morbidity. We previously found that ambient air pollution (PM2.5) during pregnancy is associated with PPD. However, the modifying role of psychosocial stress on this relationship is unclear. Methods:We measured pregnancy stress in the PROGRESS cohort (n = 475 mothers) using negative life events (NLE) and perceived stress score (PSS). We assessed the modifying role of NLE and PSS on the association between prenatal PM2.5 exposure and PPD at 6 months. Daily residence level PM2.5 estimates generated from a spatiotemporal model was averaged over pregnancy. PPD was assessed using the Edinburgh Postnatal Depression Scale (EPDS ≥ 13) and categorized as chronic depression (EPDS ≥ 13 during pregnancy and at 6 months), new-onset PPD (EPDS < 13 during pregnancy and EPDS ≥ 13 at 6 months), or prevalent PPD (EPDS ≥ 13 at 6 months, regardless of EPDS score during pregnancy). Modified Poisson regression evaluated the association between PM2.5 and PPD, stratified by NLE and PSS scores, dichotomized around the median (low/high). We repeated the analyses with other proposed EPDS cut-offs for Mexico (EPDS ≥ 10 and ≥ 12). Results:Each 5-μg/m3 increase in average pregnancy PM2.5 exposure was associated with 129% higher risk of prevalent PPD among mothers with low PSS (RR: 2.29, 95% CI: 1.17-4.47). The risk of new-onset PPD at 6 months per 5-μg/m3 increase in PM2.5 during pregnancy quadrupled among mothers with low PSS (RR: 4.58, 95% CI: 1.83-11.49) and high NLE (RR: 4.71, 95% CI: 1.72-12.92) scores. Similar findings were observed with an EPDS ≥ 10 or EPDS ≥ 12 cut-off. Conclusion:The risk of PPD from PM2.5 exposure was enhanced in mothers with low PSS or high NLE scores, especially new-onset PPD, regardless of the EPDS threshold used. These findings suggest that well-characterized stress phenotyping during pregnancy may help identify which women are at-risk for depression.

BACKGROUND:The National Institutes of Health initiated the Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program with the objective of implementing adaptive design strategies to test multiple new treatments in biomarker-identified patient subsets. OBJECTIVE:The PrecISE study sought to recruit a cohort of patients with severe asthma for a biomarker-stratified adaptive trial of 5 different interventions. METHODS:Patients aged 12 years and older with a clinical diagnosis of asthma who were adhering to a stable medical regimen consisting of at least medium-dose inhaled corticosteroids and a second controller were enrolled if their diagnosis could be confirmed by bronchodilator responsiveness on spirometry or airway hyperreactivity to methacholine. Protocol adaptations over the course of the study to biomarker sampling and enrichment, interventions studied, the statistical analysis plan, and sample size are described. The baseline characteristics of the cohort were analyzed. RESULTS:A total of 358 participants were randomized. The 4 predictive biomarkers used for intervention randomization assignments were blood eosinophil count (median = 180; interquartile range (IQR) = 100-290 cells/mL), fractional exhaled nitric oxide measurement (median = 18; IQR = 11-27 ppb); plasma IL-6 level (median = 2.5; IQR = 1.6-3.6 pg/mL), and ADH5 risk genotype (present in 253 participants [71%]). Blood eosinophil counts weakly correlated with fractional exhaled nitric oxide measures (Rs = 0.13; P = .02) and IL-6 levels (Rs = 0.17; P = .002); otherwise, these biomarkers were independent from each other. Specific intervention results will be reported separately. CONCLUSION:The PrecISE adaptive study design with multiperiod crossovers is an efficient and novel way to study multiple interventions simultaneously in a heterogeneous disease such as asthma.

Background:Leukocyte telomere length (LTL) from cord blood is a marker of biological aging and long-term systemic health. Exposure to essential and toxic metals has been shown to influence LTL in a sexually dimorphic manner. However, little is known about the interplay between early-life longitudinal biodynamic patterns of these elements and cord blood LTL, as well as potential sex differences. Methods:From an ongoing longitudinal birth cohort study in Mexico City, we used available tooth samples from 231 children (129 males and 102 females) to generate 16 elemental weekly time series of direct fetal intensities from the second trimester through four to five months after birth. We analyzed the dentine growth rings using Inductively Coupled Plasma Mass Spectrometry to generate time-resolved elemental intensities. The elements included were Li, Mg, Ca, Mn, Co, Ni, Cu, Zn, As, Sr, Mo, Cd, Sn, Ba, Pb, and Bi. LTL was measured in cord blood using qPCR. We used cross-recurrence quantification analysis and entropy-complexity-based measures to generate time-resolved features that quantify the synchronization of elemental biodynamics. A stability-selection approach using five-fold cross-validation of regularized ridge regression was used for feature selection, and covariate-adjusted linear models were used to estimate associations with LTL. Findings:The biodynamic interaction of Mg-Co and Mn-Sn was identified as the most stable feature among male and female children, respectively. In males, higher vertical entropy (i.e., a measure of higher variability) of Mg-Co temporal biodynamics was associated with shorter LTL (β[95%CI]: -0.9[-0.14,-0.03]; p-value<0.01), but not in females (β[95%CI]:-0.02[-0.10,0.06]; p-value=0.60); whereas higher recurrence rate (i.e., a measure of higher synchronicity) of Mn-Sn temporal biodynamics was associated with longer LTL (β[95%CI]: 0.09[0.02,0.16]; p-value=0.01), in females but not in males (β[95%CI], 0.03[-0.04, 0.09]; p-value=0.39). Interpretation:We demonstrate that time-varying multi-elemental synchronization of early-life elemental biodynamics, a potential marker of homeostatic balance, may be associated with cord blood-based telomere length in a sexual dimorphic manner.