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BACKGROUND: Procedures utilized to address the flatfoot in this study included medializing calcaneal osteotomy, posterior tibial tendon reconstruction with flexor digitorum longus tendon transfer, and in patients with more severe deformity, lateral column lengthening. We evaluated patients age 50 and less at the time of surgery, who underwent surgical reconstruction for Stage 2 posterior tibial tendon dysfunction. Pre- and postoperative activity levels were evaluated to assess the effect of surgical reconstruction in the younger patient. MATERIALS AND METHOD: Thirty-four feet in 30 patients (11 male, 19 female) with an average age of 41.2 (range, 17 to 50) years had surgery between 1997 and 2004. All feet were examined at an average followup of 44.5 (range, 24 to 65) months and were evaluated with the American-Orthopaedic-Foot and Ankle Society (AOFAS) Hindfoot-Score and SF-36 score. RESULTS: The average preoperative AOFAS-Score was 53.1 +/- 14.5 points and 83.2 +/- 12.2 points at final postoperative followup. The mean improvement was 29.5. The difference between the preoperative and postoperative AOFAS score was significant (p < 0.0001) using a two-tailed t-test. The difference in the AOFAS pain and alignment subscales was also significant (p < 0.0001). The function subscale improvement was also significant (p = 0.018). The mean physical function component of the postoperative SF-36 score was 79.2. A correlation was found between the SF-36 physical component score and the post operative AOFAS score (r(2) = 0.754). CONCLUSION: While some lateral discomfort or pain occurred in patients with or without a lateral column lengthening, the posterior tibial tendon reconstruction utilizing medial calcaneal displacement osteotomy with flexor digitorum longus transfer and a lateral column lengthening with more deformity was successful in the higher-functioning, younger patients. [ABSTRACT FROM AUTHOR]

This study explored the efficacy of a behavioral pain management treatment package implemented in a primary-care pediatric clinic as an intervention for recurrent pediatric headache. This study used a multiple baseline design with 7 children (ages 8 to 16), who had regular tension or migraine activity. Treatment was implemented by a master's level behavioral health clinician following a behavioral treatment protocol. The clinician did not have specific expertise in biofeedback or pain management. The children participated in 5 sessions of thermal biofeedback training supplemented with independent pain management guidelines for parents. Each child kept a daily pain diary of frequency, duration, and intensity of headache activity. Six of the 7 children demonstrated significant reductions in 1 or more self-reported headache parameters (frequency, duration, intensity) following treatment. The efficacy of the behavioral pain management treatment package implemented in a primary-care clinic is supported as a treatment for recurrent pediatric headache sufferers. [ABSTRACT FROM AUTHOR]

Endothelial cells (ECs) display organ- and tissue-specific heterogeneity. In the eye, the retinal and choroidal vascular beds are distinct networks with different molecular and morphological properties that serve location-specific functions, i.e., the former maintaining a tight barrier and the latter, a permeable fenestrated vasculature. Given that retinal health critically relies on the function of these vascular beds and that their dysfunction is implicated in a variety of retinal diseases, a molecular understanding of both physiological and pathophysiological characteristics of these distinct vasculatures is critical. Given their interspersed anatomic distribution among parenchymal cells, the study of EC gene expression, in vivo, has been hampered by the challenge of isolating pure populations of ocular ECs in sufficient quantities for large-scale transcriptomics. To address this challenge, we present a methodological and analytical workflow to facilitate inter-tissue comparisons of the in vivo EC translatome isolated from choroid, retina, and brain using the Cre-inducible NuTRAP flox construct and two widely-used endothelial Cre mouse lines: constitutive Tie2-Cre and tamoxifen-inducible Cdh5-CreERT2. For each Cre line, inter-tissue comparison of TRAP-RNAseq enrichment (TRAP-isolated translatome vs input transcriptome) showed tissue-specific gene enrichments with differential pathway representation. For each mouse model, inter-tissue comparison of the EC translatome (choroid vs brain, choroid vs retina, and brain vs retina) showed over 50% overlap of differentially expressed genes (DEGs) between the three paired comparisons, with differential pathway representation for each tissue. Pathway analysis of DEGs in the Cdh5-NuTRAP vs Tie2-NuTRAP comparison for retina, choroid, and brain predicted inhibition of processes related to myeloid cell function and activation, consistent with more specific targeting of ECs in the Cdh5-NuTRAP than in the Tie2-NuTRAP model which also targets hematopoietic progenitors giving rise to immune cells. Indeed, while TRAP enriches for EC transcripts in both models, myeloid transcripts were also captured in the Tie2-NuTRAP model which was confirmed using cell sorting. We suggest experimental/analytical considerations should be taken when selecting Cre-lines to target ECs., Competing Interests: Declaration of competing interest Ana J. Chucair-Elliott: none, Kevin Pham: none, Audrey C.A. Cleuren: none, Christopher M. Schafer: none, Courtney T. Griffin: none, Sarah R. Ocanas: none, Willard M. Freeman: none. Michael H. Elliott: none., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A growing body of literature links prenatal mood and substance use to children's cognitive and behavioral development. The relative contribution of these risk factors on children's executive function (EF) in the context of socioeconomic adversities needs further evaluation. To address this gap, we investigated the role of prenatal maternal anxiety and depression on childhood EF, specifically inhibitory control and working memory, within the context of socioeconomic adversities and prenatal substance use. We hypothesized that higher maternal mood symptoms, higher persistent prenatal drinking and smoking, and lower socioeconomic status would be associated with lower EF skills during early childhood., Methods: We used data from 334 mother-child dyads followed prospectively through pregnancy and the offspring's childhood. Prenatal maternal depression and anxiety were assessed via standardized questionnaires. Prenatal alcohol and tobacco consumption were assessed via a timeline follow-back interview. The EF touch battery assessed child inhibitory control and working memory at 3-5 years of age (4.76 ± 0.58 years, 171 females). Separate linear regression models were used to estimate the association of prenatal tobacco, alcohol, anxiety, and depression exposure with our two components of child EF, inhibitory control and working memory, while adjusting for gestational age, sex, and age at assessment. The following variables were also included as covariates: maternal educational achievement, employment status, parity, and household crowding index., Results: Children of mothers with high trait anxiety scores had reduced inhibitory control compared to children of mothers without trait anxiety or depression (β = -0.12, 95% CI:-0.22,-0.01). Children of mothers in the moderate to high continuous smoking group showed lower inhibitory control (β = - 0.19, 95% CI:-0.38,-0.01) compared to children of mothers in the none smoking group. Additionally, lower maternal education and higher household crowding were each associated with reduced inhibitory control. We found no significant association between prenatal maternal depression, anxiety, or socioeconomic factors with working memory., Conclusions: These results underscore the need for comprehensive context-specific intervention packages, including mental health support for women to promote healthy inhibitory control development in children., (© 2024. The Author(s).)

Background: Childhood sleep quality is associated with physical, cognitive, and behavioral health and predicts later sleep quality; it has many determinants, including developmental exposures., Objectives: To examine associations between maternal stress during pregnancy and childhood sleep quality and determine whether postnatal stress mediates the association., Method: Data from the Environmental Influences on Child Health Outcomes cohort were used. Perceived Stress Scale (PSS) T-scores were the exposure measure. Outcome measures were preschool Child Behavior Checklist (CBCL) sleep syndrome scale and Patient-Reported Outcomes Measurement Information System Sleep Disturbance Parent Proxy short form 4a (PSD4a) T-scores at ages 4-8 years. Linear mixed-effects regression modeling was performed for each sleep outcome, adjusting for maternal age at delivery and education and child sex, gestational age at birth, and age at outcome ascertainment, with random intercepts for cohorts., Results: Prenatal PSS score was associated with both CBCL (B = 0.09, 95% confidence interval [CI]: 0.06, 0.11; p < 0.01) and PSD4a (B = 0.07, 95% CI: 0.03, 0.12; p < 0.01) scores. Postnatal perceived stress mediated a proportion of the total effect of prenatal stress in both CBCL (66.3%) and PSD4a (95.9%) samples., Conclusions: Both pre- and postnatal maternal perceived stress appear to influence sleep quality during early life., Impact: Prenatal stress significantly associates with child sleep problems and disturbances at ages 4-8 years; postnatal maternal stress is a significant mediator of these associations. Research suggests a range of prenatal affective/distress exposures associated with child sleep problems, but the conclusions remain in doubt due to the mixture of exposures and outcomes employed. Ours is the first US-based effort to explore associations between perceived maternal stress during pregnancy and child sleep problems and disturbance in early and middle childhood. Even a small effect of a prevalent issue like psychosocial stress may have important public health implications at the population level., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified as a selective and potent SOS1 inhibitor that disrupts the KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS and translates into an anti-proliferative effect in cancer cell lines with genetic alterations of the KRAS-MAPK pathway. MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of 12 KRAS G12C-mutant human non-small cell lung cancer and colorectal cancer xenograft models. Pharmacogenomic profiling in preclinical models identified cell cycle genes and the SOS2 homolog as genetic co-dependencies and implicated tumor suppressor genes (NF1 and PTEN) in resistance following combination treatment. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Prenatal fish intake is a key source of omega-3 (ω-3) polyunsaturated fatty acids needed for brain development, yet intake is generally low, and studies addressing associations with autism spectrum disorder (ASD) and related traits are lacking., Objective: This study aimed to examine associations of prenatal fish intake and ω-3 supplement use with both autism diagnosis and broader autism-related traits., Methods: Participants were drawn from 32 cohorts in the Environmental influences on Child Health Outcomes Cohort Consortium. Children were born between 1999 and 2019 and part of ongoing follow-up with data available for analysis by August 2022. Exposures included self-reported maternal fish intake and ω-3/fish oil supplement use during pregnancy. Outcome measures included parent report of clinician-diagnosed ASD and parent-reported autism-related traits measured by the Social Responsiveness Scale (SRS)-second edition (n = 3939 and v3609 for fish intake analyses, respectively; n = 4537 and n = 3925 for supplement intake analyses, respectively)., Results: In adjusted regression models, relative to no fish intake, fish intake during pregnancy was associated with reduced odds of autism diagnosis (odds ratio: 0.84; 95% confidence interval [CI]: 0.77, 0.92), and a modest reduction in raw total SRS scores (β: -1.69; 95% CI: -3.3, -0.08). Estimates were similar across categories of fish consumption from "any" or "less than once per week" to "more than twice per week." For ω-3 supplement use, relative to no use, no significant associations with autism diagnosis were identified, whereas a modest relation with SRS score was suggested (β: 1.98; 95% CI: 0.33, 3.64)., Conclusions: These results extend previous work by suggesting that prenatal fish intake, but not ω-3 supplement use, may be associated with lower likelihood of both autism diagnosis and related traits. Given the low-fish intake in the United States general population and the rising autism prevalence, these findings suggest the need for better public health messaging regarding guidelines on fish intake for pregnant individuals., Competing Interests: Conflicts of interest The authors report no conflicts of interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment., Objective: To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC., Design, Setting, and Participants: Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history., Exposure: SARS-CoV-2 infection., Main Outcomes and Measures: PASC and 89 prolonged symptoms across 9 symptom domains., Results: A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents., Conclusions and Relevance: This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

Background: Empirical evidence has demonstrated associations between pre-pregnancy obesity and perinatal maternal depressive symptoms. Omega-3 is an essential fatty acid derived from dietary sources that is critical for fetal brain development. Pre-pregnancy obesity is associated with higher omega-3 intake, but a weaker association between dietary intake and respective maternal and cord blood omega-3 levels. Further, lower intake of omega-3 during pregnancy has been linked to higher depressive symptoms. Yet, prior studies have not examined the interactive effects of pre-pregnancy overweight or obesity (OWOB) and prenatal maternal mental health symptoms on infant cord blood omega-3 levels., Methods: Participants included 394 maternal-infant dyads from the NIH Environmental influences on Child Health Outcomes (ECHO) - Safe Passage Study in South Dakota. A pre-pregnancy body mass index (BMI) > 25 was used to dichotomize participants as OWOB (54%) vs. non-OWOB (46%). Prenatal maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS) and prenatal maternal anxiety symptoms were measured using the State-Trait Anxiety Inventory (STAI). We implemented linear regression models to examine the interaction term between pre-pregnancy BMI category and prenatal maternal mental health symptoms on cord blood omega-3 levels. Secondary analyses were stratified by pre-pregnancy BMI category., Results: We observed a significant interaction between pre-pregnancy BMI category and prenatal maternal depressive symptoms with cord blood omega-3 (F(4,379) = 6.21, p < .0001, adj. R 2  = 0.05). Stratified models revealed an association between prenatal maternal depressive symptoms with lower cord blood omega-3 levels only among individuals with pre-pregnancy OWOB (β = -0.06, 95% CI = -0.11, -0.02; F (2,208) = 4.00, p < .05, adj R 2  = 0.03). No associations were observed among non-OWOB participants., Conclusions: Findings suggest maternal-placental transfer of omega-3 may represent one pathway by which maternal metabolic and mental health impacts infant development., (© 2024. The Author(s).)

Aging is the main risk factor for age-related macular degeneration (AMD), a retinal neurodegenerative disease that leads to irreversible blindness, particularly in people over 60 years old. Retinal pigmented epithelium (RPE) atrophy is an AMD hallmark. Genome-wide chromatin accessibility, DNA methylation, and gene expression studies of AMD and control RPE demonstrate epigenomic/transcriptomic changes occur during AMD onset and progression. However, mechanisms by which molecular alterations of normal aging impair RPE function and contribute to AMD pathogenesis are unclear. Here, we specifically interrogate the RPE translatome with advanced age and across sexes in a novel RPE reporter mouse model. We find differential age- and sex- associated transcript expression with overrepresentation of pathways related to inflammation in the RPE. Concordant with impaired RPE function, the phenotypic changes in the aged translatome suggest that aged RPE becomes immunologically active, in both males and females, with some sex-specific signatures, which supports the need for sex representation for in vivo studies., Competing Interests: Declaration of interest Ana J. Chucair-Elliott: none, Sarah R. Ocañas: none, Kevin Pham: none, Adeline Machalinski: none, Scott Plafker: none, Michael B. Stout: none, Michael H. Elliott: none, Willard M. Freeman: none., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The corona virus disease (COVID-19) pandemic disrupted daily life worldwide, and its impact on child well-being remains a major concern. Neighborhood characteristics affect child well-being, but how these associations were affected by the pandemic is not well understood. We analyzed data from 1039 children enrolled in the Environmental influences on Child Health Outcomes Program whose well-being was assessed using the Patient-Reported Outcomes Measurement Information System Global Health questionnaire and linked these data to American Community Survey (ACS) data to evaluate the impacts of neighborhood characteristics on child well-being before and during the pandemic. We estimated the associations between more than 400 ACS variables and child well-being t-scores stratified by race/ethnicity (non-Hispanic white vs. all other races and ethnicities) and the timing of outcome data assessment (pre-vs. during the pandemic). Network graphs were used to visualize the associations between ACS variables and child well-being t-scores. The number of ACS variables associated with well-being t-scores decreased during the pandemic period. Comparing non-Hispanic white with other racial/ethnic groups during the pandemic, different ACS variables were associated with child well-being. Multiple ACS variables representing census tract-level housing conditions and neighborhood racial composition were associated with lower well-being t-scores among non-Hispanic white children during the pandemic, while higher percentage of Hispanic residents and higher percentage of adults working as essential workers in census tracts were associated with lower well-being t-scores among non-white children during the same study period. Our study provides insights into the associations between neighborhood characteristics and child well-being, and how the COVID-19 pandemic affected this relationship., 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 Inc.)

Background: Sleep problems are reported for up to 80% of autistic individuals. We examined whether parsimonious sets of items derived from the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) and the Brief Infant Sleep Questionnaire (BISQ) are superior to the standard M-CHAT-R in predicting subsequent autism spectrum disorder (ASD) diagnoses., Methods: Participants from 11 Environmental influences on Child Health Outcomes (ECHO) cohorts were included. We performed logistic LASSO regression models with 10-fold cross-validation to identify whether a combination of items derived from the M-CHAT-R and BISQ are superior to the standard M-CHAT-R in predicting ASD diagnoses., Results: The final sample comprised 1552 children. The standard M-CHAT-R had a sensitivity of 44% (95% CI: 34, 55), specificity of 92% (95% CI: 91, 94), and AUROC of 0.726 (95% CI: 0.663, 0.790). A higher proportion of children with ASD had difficulty falling asleep or resisted bedtime during infancy/toddlerhood. However, LASSO models revealed parental reports of sleep problems did not improve the accuracy of the M-CHAT-R in predicting ASD diagnosis., Conclusion: While children with ASD had higher rates of sleep problems during infancy/toddlerhood, there was no improvement in ASD developmental screening through the incorporation of parent-report sleep metrics., Impact: Parental-reported sleep problems are common in autism spectrum disorder (ASD). We investigated whether the inclusion of parental-reports of infant/toddler sleep patterns enhanced the effectiveness of developmental screening for autism. We reported higher rates of difficulty falling asleep and resisting bedtime during infancy and toddlerhood among children later diagnosed with ASD; however, we did not find an improvement in ASD developmental screening through the incorporation of parent-report sleep metrics. In our sample, the standard M-CHAT-R had a sensitivity of 39% among children of mothers with government insurance compared with a sensitivity of 53% among children of mothers with employer-based insurance., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

A large body of research has established a relation between maternal education and children's neurocognitive functions, such as executive function and language. However, most studies have focused on early childhood and relatively few studies have examined associations with changes in maternal education over time. Consequently, it remains unclear if early maternal education is longitudinally related to neurocognitive functions in children, adolescents, and young adults. In addition, the associations between changes in maternal education across development and more broadly defined neurocognitive outcomes remain relatively untested. The current study leveraged a large multicohort sample to examine the longitudinal relations between perinatal maternal education and changes in maternal education during development with children's, adolescents', and young adults' neurocognitive functions ( N = 2,688; M age = 10.32 years; SD age = 4.26; range = 3-20 years). Moreover, we examined the differential effects of perinatal maternal education and changes in maternal education across development on executive function and language performance. Perinatal maternal education was positively associated with children's later overall neurocognitive function. This longitudinal relation was stronger for language than executive function. In addition, increases in maternal education were related to improved language performance but were not associated with executive functioning performance. Our findings support perinatal maternal education as an important predictor of neurocognitive outcomes later in development. Moreover, our results suggest that examining how maternal education changes across development can provide important insights that can help inform policies and interventions designed to foster neurocognitive development. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults., Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science., Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions., Clinical Trials.gov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Brett Anderson reported receiving direct support for work not related to RECOVER work/publications from Genentech and the National Institute of Allergy and Immunology. Walter Dehority reported receiving grant support from Merck and participating in research for the Moderna COVID-19 pediatric vaccine trial and the Pfizer Paxlovid trial. Alex Fiks reported receiving support from NJM insurance and personal consulting fees not related to this paper from Rutgers University and the American Academy of Pediatrics. Ashraf Harahsheh reported serving as a scientific advisory board member unrelated to this paper for OP2 DRUGS. Lawrence Kleinman reported serving as an unpaid member of the Board of Directors for the DARTNet Institute, as a principle investigator at Quality Matters, Inc., and as the Vice Chair for the Borough of Metuchen Board of Health. Dr. Kleinman also reported grant support for work not related to RECOVER work/publications from NIH, HRSA, and the Robert Wood Johnson Foundation. Dr. Kleinman also reported minority individual stock ownership in Apple Computer, Sanofi SA, Experion, GlaxoSmithKline, Magyar Bank, Regeneron Pharmaceuticals, JP Morgan Chase, and Amgen Inc. Torri Metz reported participating as a Principle Investigator in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She is also a principle investigator for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Joshua Milner reported serving as a member of the Scientific Advisory Board for Blueprint Medicines, in a capacity unrelated to RECOVER work/publications. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Gross et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To examine the additive or moderating influences of caregiver COVID-19-related stress, social support, and discrimination on children's behavior problems across racially diverse populations., Method: In this Environmental influences on Child Health Outcomes (ECHO) cohort study (N = 1,999 caregiver/child pairs), we operationalized caregiver COVID-19-related stress in 2 ways: first, as the number of stressors (eg, financial concerns, social distancing); and second, as the level of pandemic-related traumatic stress symptoms reported via questionnaires administered between April 2020 and August 2022. At the same assessment visit, caregivers also reported their current levels of discrimination, and a subsample (n = 968) reported their emotional and instrumental support. Either concurrently or at a later assessment visit, caregivers reported on their children's internalizing and externalizing behavior problems using the Child Behavior Checklist for Ages 6-18 (CBCL/6-18)., Results: Multivariable analyses controlling for maternal education, marital status, child age, and child sex revealed that COVID-19-related stress (caregiver stressors and symptoms) and discrimination were positively associated, and that perceived support was negatively associated with child internalizing and externalizing behavior problems. Unexpectedly, neither emotional nor instrumental support attenuated the relationship between caregiver COVID-19-related stressors nor traumatic stress symptoms and child behavior problems. In the subset of Black American participants, caregiver perceived discrimination moderated the relationship between caregiver COVID-19 traumatic stress symptoms and child internalizing problems, such that the association was stronger at higher levels of discrimination., Conclusion: Our findings highlight the potential importance of relieving caregiver stress and increasing caregiver social support to optimize children's behavioral outcomes., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: We sought to evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on perinatal outcomes while accounting for maternal depression or perceived stress and to describe COVID-specific stressors, including changes in prenatal care, across specific time periods of the pandemic., Study Design: Data of dyads from 41 cohorts from the National Institutes of Health Environmental influences on Child Health Outcomes Program ( N  = 2,983) were used to compare birth outcomes before and during the pandemic ( n  = 2,355), and a partially overlapping sample ( n  = 1,490) responded to a COVID-19 questionnaire. Psychosocial stress was defined using prenatal screening for depression and perceived stress. Propensity-score matching and general estimating equations with robust variance estimation were used to estimate the pandemic's effect on birth outcomes., Results: Symptoms of depression and perceived stress during pregnancy were similar prior to and during the pandemic, with nearly 40% of participants reporting mild to severe stress, and 24% reporting mild depression to severe depression. Gestations were shorter during the pandemic ( B  =  - 0.33 weeks, p  = 0.025), and depression was significantly associated with shortened gestation ( B  =  - 0.02 weeks, p  = 0.015) after adjustment. Birth weights were similar ( B  =  - 28.14 g, p  = 0.568), but infants born during the pandemic had slightly larger birth weights for gestational age at delivery than those born before the pandemic ( B  = 0.15 z-score units, p  = 0.041). More women who gave birth early in the pandemic reported being moderately or extremely distressed about changes to their prenatal care and delivery (45%) compared with those who delivered later in the pandemic. A majority (72%) reported somewhat to extremely negative views of the impact of COVID-19 on their life., Conclusion: In this national cohort, we detected no effect of COVID-19 on prenatal depression or perceived stress. However, experiencing the COVID-19 pandemic in pregnancy was associated with decreases in gestational age at birth, as well as distress about changes in prenatal care early in the pandemic., Key Points: · COVID-19 was associated with shortened gestations.. · Depression was associated with shortened gestations.. · However, stress during the pandemic remained unchanged.. · Most women reported negative impacts of the pandemic.., Competing Interests: C.M. served as Chair of the Data Safety Monitoring Board (DSMB) for an Aerogen-supported trial: A Partially-Blind, Randomized, Controlled, Parallel-Group Dose Ranging Study to Determine the Efficacy, Safety and Tolerability of AeroFactTM (SF-RI 1 surfactant for inhalation combined with a dedicated drug delivery system) in Preterm Infants at Risk for Worsening Respiratory Distress Syndrome; Chair of the DSMB for the NIH RCT evaluating Sildenafil in Preterm Infants with Pulmonary Hypertension. J.N. served on the Advisory Board for the Twin Life Study (Germany); received royalties or licenses from Macmillan and consulting fees from the University of Southern California. J.H. served on the New York State Drinking Water Quality Council. The other authors have no conflicts of interest to disclose., (Thieme. All rights reserved.)

Inhibitory control plays an important role in children's cognitive and socioemotional development, including their psychopathology. It has been established that contextual factors such as socioeconomic status (SES) and parents' psychopathology are associated with children's inhibitory control. However, the relations between the neural correlates of inhibitory control and contextual factors have been rarely examined in longitudinal studies. In the present study, we used both event-related potential (ERP) components and time-frequency measures of inhibitory control to evaluate the neural pathways between contextual factors, including prenatal SES and maternal psychopathology, and children's behavioral and emotional problems in a large sample of children ( N = 560; 51.75% females; M age = 7.13 years; Range age = 4-11 years). Results showed that theta power, which was positively predicted by prenatal SES and was negatively related to children's externalizing problems, mediated the longitudinal and negative relation between them. ERP amplitudes and latencies did not mediate the longitudinal association between prenatal risk factors (i.e., prenatal SES and maternal psychopathology) and children's internalizing and externalizing problems. Our findings increase our understanding of the neural pathways linking early risk factors to children's psychopathology.

Prenatal maternal internalizing psychopathology (depression and anxiety) and socioeconomic status (SES) have been independently associated with higher risk for internalizing and externalizing problems in children. However, the pathways behind these associations are not well understood. Numerous studies have linked greater right frontal alpha asymmetry to internalizing problems; however, findings have been mixed. Several studies have also linked maternal internalizing psychopathology to children's frontal alpha asymmetry. Additionally, emerging studies have linked SES to children's frontal alpha asymmetry. To date, only a limited number of studies have examined these associations within a longitudinal design, and the majority have utilized relatively small samples. The current preregistered study utilizes data from a large prospective study of young children (N = 415; Mean age  = 7.27 years; Range age  = 5-11 years) to examine the association between prenatal maternal internalizing symptoms, children's frontal alpha asymmetry, and behavior problems. Prenatal maternal internalizing symptoms did not predict children's frontal alpha asymmetry, and there was no association between frontal alpha asymmetry and behavior problems. However, mothers' internalizing symptoms during pregnancy predicted children's internalizing and externalizing outcomes. Non-preregistered analyses showed that lower prenatal maternal SES predicted greater child right frontal alpha asymmetry and internalizing problems. Additional non-preregistered analyses did not find evidence for frontal alpha asymmetry as a moderator of the relation between prenatal maternal internalizing psychopathology and SES to children's behavior problems. Future research should examine the impact of SES on children's frontal alpha asymmetry in high-risk samples., (© 2024 Wiley Periodicals LLC.)

Objectives. To examine whether a previously reported association between airborne lead exposure and children's cognitive function replicates across a geographically diverse sample of the United States. Methods. Residential addresses of children (< 5 years) were spatially joined to the Risk-Screening Environmental Indicators model of relative airborne lead toxicity. Cognitive outcomes for children younger than 8 years were available for 1629 children with IQ data and 1476 with measures of executive function (EF; inhibitory control, cognitive flexibility). We used generalized linear models using generalized estimating equations to examine the associations of lead, scaled by interquartile range (IQR), accounting for individual- and area-level confounders. Results. An IQR increase in airborne lead was associated with a 0.74-point lower mean IQ score (b = -0.74; 95% confidence interval = -1.00, -0.48). The association between lead and EF was nonlinear and was modeled with a knot at the 97.5th percentile of lead in our sample. Lead was significantly associated with lower mean inhibitory control but not with cognitive flexibility. This effect was stronger among males for both IQ and inhibitory control. Conclusions. Early-life exposure to airborne lead is associated with lower cognitive functioning. ( Am J Public Health. 2024;114(3):309-318. https://doi.org/10.2105/AJPH.2023.307519).

Importance: Prenatal alcohol exposure (PAE) and prenatal tobacco exposure (PTE) are risk factors associated with adverse neurobehavioral and cognitive outcomes., Objective: To quantify long-term associations of PAE and PTE with brain activity in early and middle childhood via electroencephalography (EEG)., Design, Setting, and Participants: This cohort study included participants enrolled in the Safe Passage Study (August 2007 to January 2015), from which a subset of 649 participants were followed up in the Environmental Influences on Child Health Outcomes Program. From September 2018 through November 2022, EEG recordings were obtained at ages 4, 5, 7, 9, or 11 years. Data were analyzed from November 2022 to November 2023., Exposures: Maternal self-reported consumptions of alcohol and tobacco during pregnancy were captured at the recruitment interview and at up to 3 visits during pregnancy (20-24, 28-32, and ≥34 weeks' gestation). Classifications of PAE (continuous drinking, quit-early drinking, and nondrinking) and PTE (continuous smoking, quit-early smoking, and nonsmoking) were previously obtained., Main Outcomes and Measures: EEG band powers (theta, alpha, beta, gamma) were extracted from the EEG recordings. Linear regression models were used to estimate the associations of PAE and PTE with EEG estimates., Results: The final sample included 649 participants (333 [51.3%] female) aged 4, 5, 7, 9, or 11 years. Children whose mothers were in the quit-early drinking cluster had increased alpha power (0.116 [95% CI, 0.023 to 0.209] μV2; P = .02) compared with individuals without PAE. The magnitude of this increase was approximately double for children exposed to continuous drinking (0.211 [95% CI, 0.005 to 0.417] μV2; P = .04). Children whose mothers were in the continuous smoking cluster had decreased beta power (-0.031 [95% CI, -0.059 to -0.003] μV2; P = .03) and gamma power (-0.020 [95% CI, -0.039 to -0.000] μV2; P = .04) compared with the nonsmoking cluster. In exploratory sex-stratified models, male participants in the quit-early PAE cluster had greater EEG power in the alpha band (0.159 [95% CI, 0.003 to 0.315] μV2; P = .04) compared with those with no PAE, and the difference was approximately double for male participants with continuous PAE (0.354 [95% CI, 0.041 to 0.667] μV2; P = .03). Male participants in the continuous PTE cluster had decreased beta (-0.048 [95% CI, -0.090 to - 0.007] μV2; P = .02) and gamma (-0.032 [95% CI, -0.061 - 0.002] μV2; P = .04) power compared with those with no PTE., Conclusions and Relevance: These findings suggest that even low levels of PAE and PTE were associated with long-term alterations of brain activity.

Background: Economic hardships imposed by the pandemic could have implications for children's experiences of adversity in the home, or Adverse Childhood Experiences (ACEs)., Objective: This observational cohort study examined associations between COVID-19-related hardships and distress (e.g., job loss, caregiver stress) and the cumulative number of child ACEs reported by caregivers during the pandemic (i.e., March 1, 2020-February 28, 2022)., Participants and Setting: The study included children (N = 4345; median age = 6.0 years, interquartile range = 4-9 years) and their parents/caregivers who participated in the NIH-funded Environmental influences in Child Health Outcomes (ECHO) Program., Methods: We described socio-demographic characteristics and pandemic-related family hardships/distress and cumulative child ACE scores reported during pre-pandemic and pandemic periods. We used negative binomial regression models to evaluate associations between pandemic-related family hardships and cumulative child ACE scores reported during the pandemic., Results: Each caregiver-reported hardship/distress was associated with higher child ACE scores reported during the pandemic. After accounting for pre-pandemic child ACE scores, moderate and severe symptoms of pandemic-related traumatic stress among caregivers were associated with 108 % and 141 % higher child ACE scores reported during the pandemic, respectively, compared with no or low caregiver symptoms. In addition, finance-related stress during the pandemic was associated with 47 % higher child ACE scores. After adjusting for pre-pandemic child experiences of neglect, most sources of stress remained significantly associated with higher child ACE scores reported during the pandemic, particularly severe/very severe symptoms of pandemic-related traumatic stress among caregivers. Findings held for children with no known pre-pandemic ACEs., Conclusions: This research suggests that caregivers experiencing financial hardships and those with severe pandemic-related traumatic stress may require additional support systems during stressful events., Competing Interests: Declaration of competing interest Courtney Blackwell, Amy Elliott, Jody Ganiban, Thomas O'Connor, Allison Hipwell, Carlos Camargo Jr., Sarah Comstock, Dana Dabelea, Leslie Leve, Amy Margolis, Cindy McEvoy, Elizabeth McGowan, Aruna Chandran, Christine Hockett, and Karen Thierry received support from the NIH for the research reported in this manuscript. Amy Margolis received support from the NIEHS for the research reported in this manuscript. Cindy McEvoy received royalties for peer review from UptoDate, payment for participation in the Vanderbilt Neonatology Symposium, and participated in a DSMB for Aerogen Pharma and 2 DSMBs for the NIH. Christine Hockett received grants from the NIH, USDA, HRSA, and the JDRF & Helmsley Charitable Trust. Karen Thierry received grant support from the JDRF & Helmsley Charitable Trust., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In the United States, disparities in gestational age at birth by maternal race, ethnicity, and geography are theorized to be related, in part, to differences in individual- and neighborhood-level socioeconomic status (SES). Yet, few studies have examined their combined effects or whether associations vary by maternal race and ethnicity and United States Census region., Methods: We assembled data from 34 cohorts in the Environmental influences on Child Health Outcomes (ECHO) program representing 10,304 participants who delivered a liveborn, singleton infant from 2000 through 2019. We investigated the combined associations of maternal education level, neighborhood deprivation index (NDI), and Index of Concentration at the Extremes for racial residential segregation (ICE Race ) on gestational weeks at birth using linear regression and on gestational age at birth categories (preterm, early term, post-late term relative to full term) using multinomial logistic regression., Results: After adjustment for NDI and ICE Race , gestational weeks at birth was significantly lower among those with a high school diploma or less (-0.31 weeks, 95% CI: -0.44, -0.18), and some college (-0.30 weeks, 95% CI: -0.42, -0.18) relative to a master's degree or higher. Those with a high school diploma or less also had an increased odds of preterm (aOR 1.59, 95% CI: 1.20, 2.10) and early term birth (aOR 1.26, 95% CI: 1.05, 1.51). In adjusted models, NDI quartile and ICE Race quartile were not associated with gestational weeks at birth. However, higher NDI quartile (most deprived) associated with an increased odds of early term and late term birth, and lower ICE Race quartile (least racially privileged) associated with a decreased odds of late or post-term birth. When stratifying by region, gestational weeks at birth was lower among those with a high school education or less and some college only among those living in the Northeast or Midwest. When stratifying by race and ethnicity, gestational weeks at birth was lower among those with a high school education or less only for the non-Hispanic White category., Conclusion: In this study, maternal education was consistently associated with shorter duration of pregnancy and increased odds of preterm birth, including in models adjusted for NDI and ICE Race ., 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., (Copyright © 2023 Dunlop, Burjak, Dean, Alshawabkeh, Avalos, Aschner, Breton, Charifson, Cordero, Dabelea, D’Sa, Duarte, Elliott, Eick, Ferrara, Fichorova, Ganiban, Gern, Hedderson, Herbstman, Hipwell, Huddleston, Karagas, Karr, Kerver, Koinis-Mitchell, Lyall, Madan, Marsit, McEvoy, Meeker, Oken, O’Shea, Padula, Sathyanarayana, Schantz, Schmidt, Snowden, Stanford, Weiss, Wright, Wright, Zhang and McGrath.)

Introduction: The effect of prenatal cannabis exposure (PCE) on childhood neurodevelopment remains poorly understood. There is a paucity of studies describing the neurodevelopment impact of PCE in infancy. The Mullen Scale of Early Learning (MSEL) is a cognitive screening tool that can be used from birth to 68 months and includes language and motor domains. Here we aim to explore the association between PCE during pregnancy and neurodevelopmental outcomes at 12 months of age., Methods: Participants were pregnant persons/infant pairs enrolled in The Safe Passage Study, a large prospective cohort study. Inclusion criteria included data available on PCE with associated MSEL scores at 12 months of age. Exposed participants were defined as early exposure (1st trimester only) or late exposure (2nd or 3rd trimester) and were randomly matched with unexposed participants. Multiple linear regression models were performed to test associations between prenatal cannabis exposure and the five Mullen subscales: gross motor, fine motor, expressive language, receptive language, and visual reception., Results: Sixty-nine exposed and 138 randomly matched unexposed infants were included in the analyses. Mothers of children with PCE were younger with the mean age 23.7 years for early exposure ( n  = 51) and 22.8 years for late exposure ( n  = 18). Maternal characteristics with prenatal cannabis use include a high-school education, American Indian or Alaska Native descent, lower socioeconomic status and co-use of tobacco. There were no gestational age or sex difference among the groups. Expressive (95% CI: 2.54-12.76; p  = 0.0036,) and receptive language scores (95% CI: 0.39-8.72; p  = 0.0322) were significantly increased between late-exposed infants compared to unexposed infants following adjustment for covariates. Gross motor scores (95% CI: 1.75-13; p  = 0.0105) were also significantly increased for early-exposed infants with no difference in visual reception scores., Conclusion: Preclinical studies have shown abnormal brain connectivity in offspring exposed to cannabis affecting emotional regulation, hyperactivity, and language development. Results from this study link PCE to altered early language development within the first year of life. Exposed infants demonstrated increased expressive and receptive language scores at 12 months of age, which can translate to better performance in school. However, further research is needed to determine the implications of these results later in childhood., 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., (© 2023 Talavera-Barber, Morehead, Ziegler, Hockett and Elliott.)

Background: Cellular identity is determined partly by cell type-specific epigenomic profiles that regulate gene expression. In neuroscience, there is a pressing need to isolate and characterize the epigenomes of specific CNS cell types in health and disease. In this study, we developed an in vivo tagging mouse model (Camk2a-NuTRAP) for paired isolation of neuronal DNA and RNA without cell sorting and then used this model to assess epigenomic regulation, DNA modifications in particular, of gene expression between neurons and glia., Results: After validating the cell-specificity of the Camk2a-NuTRAP model, we performed TRAP-RNA-Seq and INTACT-whole genome oxidative bisulfite sequencing (WGoxBS) to assess the neuronal translatome and epigenome in the hippocampus of young mice (4 months old). WGoxBS findings were validated with enzymatic methyl-Seq (EM-Seq) and nanopore sequencing. Comparing neuronal data to microglial and astrocytic data from NuTRAP models, microglia had the highest global mCG levels followed by astrocytes and then neurons, with the opposite pattern observed for hmCG and mCH. Differentially modified regions between cell types were predominantly found within gene bodies and distal intergenic regions, rather than proximal promoters. Across cell types there was a negative correlation between DNA modifications (mCG, mCH, hmCG) and gene expression at proximal promoters. In contrast, a negative correlation of gene body mCG and a positive relationship between distal promoter and gene body hmCG with gene expression was observed. Furthermore, we identified a neuron-specific inverse relationship between mCH and gene expression across promoter and gene body regions., Conclusions: Neurons, astrocytes, and microglia demonstrate different genome-wide levels of mCG, hmCG, and mCH that are reproducible across analytical methods. However, modification-gene expression relationships are conserved across cell types. Enrichment of differential modifications across cell types in gene bodies and distal regulatory elements, but not proximal promoters, highlights epigenomic patterning in these regions as potentially greater determinants of cell identity. These findings also demonstrate the importance of differentiating between mC and hmC in neuroepigenomic analyses, as up to 30% of what is conventionally interpreted as mCG can be hmCG, which often has a different relationship to gene expression than mCG., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Temporally controlling Cre recombination through tamoxifen (Tam) induction has many advantages for biomedical research. Most studies report early post-natal/juvenile (<2 m.o.) Tam induction, but age-related neurodegeneration and aging studies can require Cre induction in older mice (>12 m.o.). While anecdotally reported as problematic, there are no published comparisons of Tam-mediated Cre induction at early and late ages. Here, microglial-specific Cx3cr1 creERT2 mice were crossed to a floxed NuTRAP reporter to compare Cre induction at early (3-6 m.o.) and late (20 m.o.) ages. Specificity and efficiency of microglial labeling at 21-22 m.o. were identical in mice induced with Tam at early and late ages. Age-related microglial translatomic changes were also similar regardless of Tam induction age. Each Cre and flox mouse line should be independently validated, however, these findings demonstrate that Tam-mediated Cre induction can be performed even into older mouse ages and should be generalizable to other inducible Cre models., Competing Interests: The authors declare they have no financial or non-financial interests directly or indirectly related to this work.

Background: Drinking water is a common source of exposure to inorganic arsenic. In the US, the Safe Drinking Water Act (SDWA) was enacted to protect consumers from exposure to contaminants, including arsenic, in public water systems (PWS). The reproductive effects of preconception and prenatal arsenic exposure in regions with low to moderate arsenic concentrations are not well understood., Objectives: This study examined associations between preconception and prenatal exposure to arsenic violations in water, measured via residence in a county with an arsenic violation in a regulated PWS during pregnancy, and five birth outcomes: birth weight, gestational age at birth, preterm birth, small for gestational age (SGA), and large for gestational age (LGA)., Methods: Data for arsenic violations in PWS, defined as concentrations exceeding 10 parts per billion, were obtained from the Safe Drinking Water Information System. Participants of the Environmental influences on Child Health Outcomes Cohort Study were matched to arsenic violations by time and location based on residential history data. Multivariable, mixed effects regression models were used to assess the relationship between preconception and prenatal exposure to arsenic violations in drinking water and birth outcomes., Results: Compared to unexposed infants, continuous exposure to arsenic from three months prior to conception through birth was associated with 88.8 g higher mean birth weight (95% CI: 8.2, 169.5), after adjusting for individual-level confounders. No statistically significant associations were observed between any preconception or prenatal violations exposure and gestational age at birth, preterm birth, SGA, or LGA., Conclusions: Our study did not identify associations between preconception and prenatal arsenic exposure, defined by drinking water exceedances, and adverse birth outcomes. Exposure to arsenic violations in drinking water was associated with higher birth weight. Future studies would benefit from more precise geodata of water system service areas, direct household drinking water measurements, and exposure biomarkers., 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 Inc. All rights reserved.)

To assess the public health impact of the COVID-19 pandemic on mental health, investigators from the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) research program developed the Pandemic-Related Traumatic Stress Scale (PTSS). Based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) acute stress disorder symptom criteria, the PTSS is designed for adolescent (13-21 years) and adult self-report and caregiver-report on 3-12-year-olds. To evaluate psychometric properties, we used PTSS data collected between April 2020 and August 2021 from non-pregnant adult caregivers ( n = 11,483), pregnant/postpartum individuals ( n = 1,656), adolescents ( n = 1,795), and caregivers reporting on 3-12-year-olds ( n = 2,896). We used Mokken scale analysis to examine unidimensionality and reliability, Pearson correlations to evaluate relationships with other relevant variables, and analyses of variance to identify regional, age, and sex differences. Mokken analysis resulted in a moderately strong, unidimensional scale that retained nine of the original 10 items. We detected small to moderate positive associations with depression, anxiety, and general stress, and negative associations with life satisfaction. Adult caregivers had the highest PTSS scores, followed by adolescents, pregnant/postpartum individuals, and children. Caregivers of younger children, females, and older youth had higher PTSS scores compared to caregivers of older children, males, and younger youth, respectively. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Major histocompatibility complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses, but the cellular localization was undetermined. Neuronal MHC-I is proposed to regulate developmental synapse elimination and tau pathology in Alzheimer's disease (AD). Here, we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia are the primary source of classical and non-classical MHC-I in mice and humans. Translating ribosome affinity purification-qPCR analysis of 3-6- and 18-22-month-old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genes B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 but not in astrocytes and neurons. Across a timecourse (12-23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I-binding leukocyte immunoglobulin-like (Lilrs) and paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell -autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in multiple AD mouse models and human AD data across methods and studies. MHC-I expression correlated with p16INK4A, suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The extent to which physical and social attributes of neighborhoods play a role in childhood asthma remains understudied., Objective: To examine associations of neighborhood-level opportunity and social vulnerability measures with childhood asthma incidence., Design, Setting, and Participants: This cohort study used data from children in 46 cohorts participating in the Environmental Influences on Child Health Outcomes (ECHO) Program between January 1, 1995, and August 31, 2022. Participant inclusion required at least 1 geocoded residential address from birth and parent or caregiver report of a physician's diagnosis of asthma. Participants were followed up to the date of asthma diagnosis, date of last visit or loss to follow-up, or age 20 years., Exposures: Census tract-level Child Opportunity Index (COI) and Social Vulnerability Index (SVI) at birth, infancy, or early childhood, grouped into very low (<20th percentile), low (20th to <40th percentile), moderate (40th to <60th percentile), high (60th to <80th percentile), or very high (≥80th percentile) COI or SVI., Main Outcomes and Measures: The main outcome was parent or caregiver report of a physician's diagnosis of childhood asthma (yes or no). Poisson regression models estimated asthma incidence rate ratios (IRRs) associated with COI and SVI scores at each life stage., Results: The study included 10 516 children (median age at follow-up, 9.1 years [IQR, 7.0-11.6 years]; 52.2% male), of whom 20.6% lived in neighborhoods with very high COI and very low SVI. The overall asthma incidence rate was 23.3 cases per 1000 child-years (median age at asthma diagnosis, 6.6 years [IQR, 4.1-9.9 years]). High and very high (vs very low) COI at birth, infancy, or early childhood were associated with lower subsequent asthma incidence independent of sociodemographic characteristics, parental asthma history, and parity. For example, compared with very low COI, the adjusted IRR for asthma was 0.87 (95% CI, 0.75-1.00) for high COI at birth and 0.83 (95% CI, 0.71-0.98) for very high COI at birth. These associations appeared to be attributable to the health and environmental and the social and economic domains of the COI. The SVI during early life was not significantly associated with asthma incidence. For example, compared with a very high SVI, the adjusted IRR for asthma was 0.88 (95% CI, 0.75-1.02) for low SVI at birth and 0.89 (95% CI, 0.76-1.03) for very low SVI at birth., Conclusions: In this cohort study, high and very high neighborhood opportunity during early life compared with very low neighborhood opportunity were associated with lower childhood asthma incidence. These findings suggest the need for future studies examining whether investing in health and environmental or social and economic resources in early life would promote health equity in pediatric asthma.

Background: Research and clinical practice rely heavily on caregiver-report measures, such as the Child Behavior Checklist 1.5-5 (CBCL/1.5-5), to gather information about early childhood behavior problems and to screen for child psychopathology. While studies have shown that demographic variables influence caregiver ratings of behavior problems, the extent to which the CBCL/1.5-5 functions equivalently at the item level across diverse samples is unknown., Methods: Item-level data of CBCL/1.5-5 from a large sample of young children ( N  = 9087) were drawn from 26 cohorts in the Environmental influences on Child Health Outcomes program. Factor analyses and the alignment method were applied to examine measurement invariance (MI) and differential item functioning (DIF) across child (age, sex, bilingual status, and neurodevelopmental disorders), and caregiver (sex, education level, household income level, depression, and language version administered) characteristics. Child race was examined in sensitivity analyses., Results: Items with the most impactful DIF across child and caregiver groupings were identified for Internalizing, Externalizing, and Total Problems. The robust item sets, excluding the high DIF items, showed good reliability and high correlation with the original Internalizing and Total Problems scales, with lower reliability for Externalizing. Language version of CBCL administration, education level and sex of the caregiver respondent showed the most significant impact on MI, followed by child age. Sensitivity analyses revealed that child race has a unique impact on DIF over and above socioeconomic status., Conclusions: The CBCL/1.5-5, a caregiver-report measure of early childhood behavior problems, showed bias across demographic groups. Robust item sets with less DIF can measure Internalizing and Total Problems equally as well as the full item sets, with slightly lower reliability for Externalizing, and can be crosswalked to the metric of the full item set, enabling calculation of normed T scores based on more robust item sets., Competing Interests: The authors have declared that they have no competing or potential conflicts of interest., (© 2023 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia., Methods: Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic and translatomic findings., Results: There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally and autosomally encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Normalized gene expression values can be accessed through a searchable web interface ( https://neuroepigenomics.omrf.org/ ). Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP., Conclusions: These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children's health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-Wide Cohort Data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7-11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in 5 main outcome areas: pre-, peri-, and postnatal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include factors at the level of place (e.g., air pollution, neighborhood socioeconomic status), family (e.g., parental mental health), and individuals (e.g., diet, genomics)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Importance: Few population-based studies in the US collected individual-level data from families during the COVID-19 pandemic., Objective: To examine differences in COVID-19 pandemic-related experiences in a large sociodemographically diverse sample of children and caregivers., Design, Setting, and Participants: The Environmental influences on Child Health Outcomes (ECHO) multi-cohort consortium is an ongoing study that brings together 64 individual cohorts with participants (24 757 children and 31 700 caregivers in this study) in all 50 US states and Puerto Rico. Participants who completed the ECHO COVID-19 survey between April 2020 and March 2022 were included in this cross-sectional analysis. Data were analyzed from July 2021 to September 2022., Main Outcomes and Measures: Exposures of interest were caregiver education level, child life stage (infant, preschool, middle childhood, and adolescent), and urban or rural (population <50 000) residence. Dependent variables included COVID-19 infection status and testing; disruptions to school, child care, and health care; financial hardships; and remote work. Outcomes were examined separately in logistic regression models mutually adjusted for exposures of interest and race, ethnicity, US Census division, sex, and survey administration date., Results: Analyses included 14 646 children (mean [SD] age, 7.1 [4.4] years; 7120 [49%] female) and 13 644 caregivers (mean [SD] age, 37.6 [7.2] years; 13 381 [98%] female). Caregivers were racially (3% Asian; 16% Black; 12% multiple race; 63% White) and ethnically (19% Hispanic) diverse and comparable with the US population. Less than high school education (vs master's degree or more) was associated with more challenges accessing COVID-19 tests (adjusted odds ratio [aOR], 1.88; 95% CI, 1.06-1.58), lower odds of working remotely (aOR, 0.04; 95% CI, 0.03-0.07), and more food access concerns (aOR, 4.14; 95% CI, 3.20-5.36). Compared with other age groups, young children (age 1 to 5 years) were least likely to receive support from schools during school closures, and their caregivers were most likely to have challenges arranging childcare and concerns about work impacts. Rural caregivers were less likely to rank health concerns (aOR, 0.77; 95% CI, 0.69-0.86) and social distancing (aOR, 0.82; 95% CI, 0.73-0.91) as top stressors compared with urban caregivers., Conclusions: Findings in this cohort study of US families highlighted pandemic-related burdens faced by families with lower socioeconomic status and young children. Populations more vulnerable to public health crises should be prioritized in recovery efforts and future planning.

Background: Breast cancer is the most common cancer in the United States and the second leading cause of death for American Indian women. American Indian women have lower rates of breast cancer screening than other racial groups, and disparities in breast cancer mortality and survival rates persist among them. To address this critical need, a culturally appropriate, accessible, and personalized intervention is necessary to promote breast cancer screening among American Indian women. This study used mobile health principles to develop a mobile web app-based mammogram intervention (wMammogram) for American Indian women in a remote, rural community in the Northern Plains., Objective: This study aimed to assess the feasibility and efficacy of the wMammogram intervention, which was designed to motivate American Indian women to undergo breast cancer screening, as compared with the control group, who received an educational brochure., Methods: Using community-based participatory research (CBPR) principles and a multipronged recruitment strategy in a randomized controlled trial design, we developed the wMammogram intervention. This study involved 122 American Indian women aged between 40 and 70 years, who were randomly assigned to either the intervention group (n=62) or the control group (n=60). Those in the intervention group received personalized and culturally appropriate messages through a mobile web app, while those in the control group received an educational brochure. We measured outcomes such as mammogram receipt, intention to receive breast cancer screening after the intervention, and participants' satisfaction with and acceptance of the intervention., Results: A significantly higher proportion of women who received the wMammogram intervention (26/62, 42%; P=.009) completed mammograms by the 6-month follow-up than the control group (12/60, 20%). The wMammogram intervention group, compared with the control group, reported significantly higher ratings on perceived effectiveness of the intervention (t 120 =-5.22; P<.001), increase in knowledge (t 120 =-4.75; P<.001), and satisfaction with the intervention (t 120 =-3.61; P<.001). Moreover, compared with the brochure group, the intervention group expressed greater intention to receive a mammogram in the future when it is due (62/62, 100% vs 51/60, 85%) and were more willing to recommend the intervention they received to their friends (61/62, 98.4% vs 54/60, 90%) with statistically significant differences., Conclusions: This study shows the feasibility and efficacy of the wMammogram intervention to promote breast cancer screening for American Indian women in a remote, rural community-based setting. Findings suggest that, with advancements in technology and the ubiquity of mobile devices, mobile web apps could serve as a valuable health intervention tool that builds upon low-cost technology and enhances accessibility and sustainability of preventive care to help reduce breast health disparities experienced in hard-to-reach American Indian populations., Trial Registration: ClinicalTrials.gov NCT05530603; https://clinicaltrials.gov/ct2/show/NCT05530603., (©Soonhee Roh, Yeon-Shim Lee, DenYelle B Kenyon, Amy J Elliott, Daniel G Petereit, Anu Gaba, Hee Yun Lee. Originally published in JMIR Formative Research (https://formative.jmir.org), 20.07.2023.)

Background: There is increasing evidence linking infant rhinorrhea to school-age exercise-induced wheeze (EIW) via a parasympathetic nervous system pathway. The ratio of the root mean square of successive differences in heart beats (RMSSD) measured in quiet sleep versus active sleep (RMSSD QS:AS ) is a novel biomarker in asthma., Objective: We tested the hypotheses that (1) neonatal rhinorrhea predicts childhood EIW independent of other neonatal respiratory symptoms, (2) neonatal RMSSD QS:AS predicts childhood EIW, and (3) RMSSD QS:AS mediates the association between neonatal rhinorrhea and childhood EIW., Methods: Participants from the Safe Passage/Environmental Influences on Child Health Outcomes (PASS/ECHO) prospective birth cohort had heart rate variability extracted from electrocardiogram traces acquired in the first month of life. Parents reported on rhinorrhea in their child at age 1 month and on EIW in their child at ages 4 to 11 years., Results: In models (N = 831) adjusted for potential confounders and covariates, including neonatal wheeze, cough and fever, neonatal rhinorrhea-predicted childhood EIW (relative risk [RR] = 2.22; P  = .040), specifically, among females (RR = 3.38; P  = .018) but not males (RR = 1.39; P  = .61). Among participants contributing data in both active and quiet sleep (n = 231), RMSSD QS:AS predicted EIW (RR = 2.36; P  = .003) and mediated the effect estimate of neonatal rhinorrhea predicting EIW among females. Half of the females with a higher RMSSD QS:AS and neonatal rhinorrhea (n = 5 of 10) developed EIW as compared with 1.8% of the other females (n = 2 of 109) ( P  < .001)., Conclusions: Our findings support dysregulation of the parasympathetic nervous system in infancy as one of the possible underlying mechanisms for the development of EIW later in childhood among females, which could aid in the development of future interventions., (© 2023 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.)

The last decade has witnessed growing calls for the return of individual research results. Prior work in genetic studies has shown that individual, contextual, and cultural factors influence participants' preferences for individual research results. There is a gap in knowledge about participants' views about other types of results, specifically those lacking clinical significance. This study investigates the perspectives of 1587 mothers enrolled in the Northern Plains Environmental Influences on Child Health Outcomes (ECHO) Program. Participants were presented with hypothetical scenarios to determine their perceived value of individual research results based on result type and the ability to interpret them within a normative context. Irrespective of the result type, participants attributed higher perceived value to results that were well understood than results of unknown significance.

Objective: Ongoing pediatric cohort studies offer opportunities to investigate the impact of the COVID-19 pandemic on children's health. With well-characterized data from tens of thousands of US children, the Environmental influences on Child Health Outcomes (ECHO) Program offers such an opportunity., Methods: ECHO enrolled children and their caregivers from community- and clinic-based pediatric cohort studies. Extant data from each of the cohorts were pooled and harmonized. In 2019, cohorts began collecting data under a common protocol, and data collection is ongoing with a focus on early life environmental exposures and five child health domains: birth outcomes, neurodevelopment, obesity, respiratory, and positive health. In April of 2020, ECHO began collecting a questionnaire designed to assess COVID-19 infection and the pandemic's impact on families. We describe and summarize the characteristics of children who participated in the ECHO Program during the COVID-19 pandemic and novel opportunities for scientific advancement., Results: This sample ( n  = 13,725) was diverse by child age (31% early childhood, 41% middle childhood, and 16% adolescence up to age 21), sex (49% female), race (64% White, 15% Black, 3% Asian, 2% American Indian or Alaska Native, <1% Native Hawaiian or Pacific Islander, 10% Multiple race and 2% Other race), Hispanic ethnicity (22% Hispanic), and were similarly distributed across the four United States Census regions and Puerto Rico., Conclusion: ECHO data collected during the pandemic can be used to conduct solution-oriented research to inform the development of programs and policies to support child health during the pandemic and in the post-pandemic era., Competing Interests: All authors report funding from the National Institutes of Health., (© 2023 Bekelman, Trasande, Law, Blackwell, Jacobson, Bastain, Breton, Elliott, Ferrara, Karagas, Aschner, Bornkamp, Camargo, Comstock, Dunlop, Ganiban, Gern, Karr, Kelly, Lyall, O'Shea, Schweitzer and LeWinn.)