Chronic loneliness and the risk of incident stroke in middle and late adulthood: a longitudinal cohort study of U.S. older adults.

Background: Loneliness has been implicated as a stroke risk factor, yet studies have examined loneliness at only one time point. The association of loneliness changes and risk of incident stroke remains understudied. Our aim was to examine the association of loneliness with incident stroke, particularly the role of loneliness chronicity. Methods: This prospective cohort study examined data from the Health and Retirement Study during 2006-2018. For analyses examining baseline loneliness only, we included U.S. adults aged 50 years or older and stroke-free at baseline and excluded individuals missing data on loneliness and those who experienced death at baseline. For analyses examining loneliness changes over two time points, we included those aged 50 years or older at baseline and stroke-free through the exposure measurement period. Individuals missing a loneliness scale measure or those who experienced death during the exposure measurement period were excluded. Loneliness was measured with the 3-item Revised UCLA Loneliness Scale. We constructed loneliness scores (range 3-9), dichotomized loneliness measures (high vs low using a >6 cutoff), and loneliness patterns across two time points (consistently low, remitting, recent onset, consistently high). Cox regression models estimated associations of baseline loneliness (N = 12,161) with incident stroke over a 10-12-year period, and loneliness change patterns (N = 8936) with incident stroke over a subsequent 6-8-year period, adjusting for demographics, health behaviors and health conditions. Findings: Higher loneliness scores at baseline were associated with incident stroke for continuous (hazard ratio [HR]: 1.05, 95% confidence interval [CI]: 1.01-1.08) and dichotomized (HR: 1.25, 95% CI: 1.06-1.47) loneliness measures, and persisted after adjustment for social isolation but not depressive symptoms. Only individuals with a consistently high loneliness pattern over time (vs consistently low) had significantly higher incident stroke risk (HR: 1.56, 95% CI: 1.11-2.18) after adjusting for depressive symptoms and social isolation. Interpretation: Chronic loneliness was associated with higher stroke risk independent of depressive symptoms or social isolation. Addressing loneliness may have an important role in stroke prevention, and repeated assessments of loneliness over time may help identify those particularly at risk. Funding: National Institute on Aging (NIA U01AG009740).

Epigenome-wide meta-analysis of prenatal vitamin D insufficiency and cord blood DNA methylation.

Low maternal vitamin D concentrations during pregnancy have been associated with a range of offspring health outcomes. DNA methylation is one mechanism by which the maternal vitamin D status during pregnancy could impact offspring's health in later life. We aimed to evaluate whether maternal vitamin D insufficiency during pregnancy was conditionally associated with DNA methylation in the offspring cord blood. Maternal vitamin D insufficiency (plasma 25-hydroxy vitamin D ≤ 75 nmol/L) during pregnancy and offspring cord blood DNA methylation, assessed using Illumina Infinium 450k or Illumina EPIC Beadchip, was collected for 3738 mother-child pairs in 7 cohorts as part of the Pregnancy and Childhood Epigenetics (PACE) consortium. Associations between maternal vitamin D and offspring DNA methylation, adjusted for fetal sex, maternal smoking, maternal age, maternal pre-pregnancy or early pregnancy BMI, maternal education, gestational age at measurement of 25(OH)D, parity, and cell type composition, were estimated using robust linear regression in each cohort, and a fixed-effects meta-analysis was conducted. The prevalence of vitamin D insufficiency ranged from 44.3% to 78.5% across cohorts. Across 364,678 CpG sites, none were associated with maternal vitamin D insufficiency at an epigenome-wide significant level after correcting for multiple testing using Bonferroni correction or a less conservative Benjamini-Hochberg False Discovery Rate approach (FDR, p > 0.05). In this epigenome-wide association study, we did not find convincing evidence of a conditional association of vitamin D insufficiency with offspring DNA methylation at any measured CpG site.

Early childhood family threat and longitudinal amygdala-mPFC circuit development: Examining cortical thickness and gray matter-white matter contrast.

Early threat-associated cortical thinning may be interpreted as accelerated cortical development. However, non-adaptive processes may show similar macrostructural changes. Examining cortical thickness (CT) together with grey/white-matter contrast (GWC), a proxy for intracortical myelination, may enhance the interpretation of CT findings. In this prospective study, we examined associations between early life family-related threat (harsh parenting, family conflict, and neighborhood safety) and CT and GWC development from late childhood to middle adolescence. MRI was acquired from 4200 children (2069 boys) from the Generation R study at ages 8, 10 and 14 years (in total 6114 scans), of whom 1697 children had >1 scans. Linear mixed effect models were used to examine family factor-by-age interactions on amygdala volume, caudal and rostral anterior cingulate (ACC) and medial orbitofrontal cortex (mOFC) CT and GWC. A neighborhood safety-by-age-interaction was found for rostral ACC GWC, suggesting less developmental change in children from unsafe neighborhoods. Moreover, after more stringent correction for motion, family conflict was associated with greater developmental change in CT but less developmental change in GWC. Results suggest that early threat may blunt ACC GWC development. Our results, therefore, do not provide evidence for accelerated threat-associated structural development of the amygdala-mPFC circuit between ages 8-14 years.

Association of maternal thyroglobulin with gestational thyroid function and offspring IQ and brain morphology.

BACKGROUND: Low maternal urinary iodine concentration (UIC) during pregnancy is associated with adverse offspring neurodevelopment. Thyroglobulin (Tg) has been suggested as a more sensitive biomarker than UIC of long-term iodine status, but associations of Tg with neurodevelopment and the possible mediating role of thyroid function remain unknown. AIM: To study whether maternal Tg is associated with i) maternal and newborn thyroid function and ii) offspring IQ and brain morphology. METHODS: Participants were selected from two population-based prospective cohorts: Generation R (the Netherlands, iodine-sufficient) and INfancia y Medio Ambiente (Spain, mildly iodine-deficient) with maternal Tg and thyroid function data in the first half of pregnancy or in cord blood, early childhood IQ (age 4.5 and 6 years), late childhood IQ (age 9 and 13), or brain morphology at 10 years. Associations of Tg with TSH, FT4, IQ and brain morphology were studied with multivariable linear regression. RESULTS: i) Tg was associated with lower TSH (-0.12[-0.16; -0.08]) and higher FT4 (0.08[0.05;0.12]) in pregnancy (N=4,367), but not with cord blood TSH or FT4 (N=2,008). ii) Tg was associated with lower IQ in early childhood (ß[95% CI]:-0.06 [-0.10; -0.01], N=2,919), but not with IQ (N=2,503) or brain morphology (N=1,180) in later childhood. None of the associations of Tg with the studied outcomes differed by the iodine-to-creatinine ratio (i.e. effect modification) or changed when adjusted for thyroid function. CONCLUSIONS: Higher Tg is associated with lower IQ in early childhood and higher thyroid function during pregnancy, but not with IQ or brain morphology in later childhood. Further research should determine the value of Tg in addition to UIC for defining iodine status.

"When I hold my daughter, she quiets, no need [for]any verbal conversation": A qualitative understanding of responsive caregiving in rural, Sindh Pakistan.

Responsive caregiving is associated with secure attachment and positive child developmental outcomes. However, there is some debate on whether responsive caregiving is a universal construct. Few studies have researched responsive caregiving in diverse cultural settings, particularly in low- and middle-income countries. In this study, we explore if and how responsive caregiving is conceptualized among mothers of children under 3-years-old in rural, Sindh Pakistan. A phenomenological qualitative study was implemented in Naushahro Feroze through in-depth interviews with twenty mothers. Mothers were asked about their aspirations for their children and how they would respond in a variety of different scenarios. Data were analyzed using thematic content analysis with an inductive-deductive coding scheme. There was substantial variation in mothers' described responsive behaviors and beliefs. Almost all mothers described using some form of responsive parenting. Responding to children's demands while the mother was preoccupied, using verbal responses to console children, and if mothers believed that children should be praised, lacked consensus. Most mothers described using breastfeeding for consolation and highlighted the importance of immediately consoling their crying child. The results suggest that there is a need for a more nuanced approach to understand caregiver behaviors across contexts.

Una sensible prestación de cuidado se asocia con una afectividad segura y con resultados positivos en el desarrollo del niño. Sin embargo, se da un debate sobre si la sensible prestación de cuidado es una estructura universal. Pocos estudios han investigado la sensible prestación de cuidado en diversos escenarios culturales, particularmente en países de bajas y medias entradas económicas. En este estudio, exploramos si la sensible prestación de cuidado está conceptualizada entre las madres de niños menores de 3 años en el área rural de Sindh en Pakistán y cómo lo está. Un estudio fenomenológico cualitativo se implementó usando datos de Naushahro Feroze (ciudad en la provincia de Sindh), por medio de entrevistas profundas con veinte madres. A las madres se les preguntó acerca de sus aspiraciones con respecto a sus niños y cómo ellas responderían en una variedad de diferentes escenarios. Se analizaron los datos usando un análisis de contenido temático con un esquema de codificación inductivo­deductivo. Hubo variación sustancial en las descripciones de las madres acerca de sus conductas y creencias sensibles. Casi todas las madres hicieron las descripciones usando alguna forma de crianza sensible. Faltó el consenso en el caso de responder a las peticiones de los niños mientras la madre estaba preocupada, en el uso de respuestas verbales para consolar a los niños, así como en el caso de si las madres creían que los niños debían ser elogiados. La mayoría de las madres hizo sus descripciones usando el amamantar como manera de consolar y subrayó la importancia de consolar inmediatamente al niño que llora. Los resultados sugieren que hay una necesidad de un acercamiento más matizado para comprender las conductas de prestación de cuidado a través de los contextos.

Limited generalizability of multivariate brain-based dimensions of child psychiatric symptoms.

Multivariate machine learning techniques are a promising set of tools for identifying complex brain-behavior associations. However, failure to replicate results from these methods across samples has hampered their clinical relevance. Here we aimed to delineate dimensions of brain functional connectivity that are associated with child psychiatric symptoms in two large and independent cohorts: the Adolescent Brain Cognitive Development (ABCD) Study and the Generation R Study (total n = 6935). Using sparse canonical correlations analysis, we identified two brain-behavior dimensions in ABCD: attention problems and aggression/rule-breaking behaviors. Importantly, out-of-sample generalizability of these dimensions was consistently observed in ABCD, suggesting robust multivariate brain-behavior associations. Despite this, out-of-study generalizability in Generation R was limited. These results highlight that the degrees of generalizability can vary depending on the external validation methods employed as well as the datasets used, emphasizing that biomarkers will remain elusive until models generalize better in true external settings.

Genome-wide meta-analysis of ascertainment and symptom structures of major depression in case-enriched and community cohorts.

BACKGROUND: Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and etiological subtypes. There are several challenges to integrating symptom data from genetically informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data. METHODS: We conducted genome-wide association studies of major depressive symptoms in three cohorts that were enriched for participants with a diagnosis of depression (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts who were not recruited on the basis of diagnosis (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors. RESULTS: The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for the skip-structure in community cohorts (use of Depression and Anhedonia as gating symptoms). CONCLUSION: The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analyzing genetic association data.

Residential ambient air pollution exposure and the development of white matter microstructure throughout adolescence.

BACKGROUND: Recent evidence suggests an association of air pollution exposure with brain development, but evidence on white matter microstructure in children is scarce. We investigated how air pollution exposure during pregnancy and childhood impacts longitudinal development of white matter microstructure throughout adolescence. METHODS: Our study population consisted of 4108 participants of Generation R, a large population-based birth cohort from Rotterdam, the Netherlands. Residential air pollution exposure to 14 air pollutants during pregnancy and childhood was estimated with land-use regression models. Diffusion tensor images were obtained around age 10 and 14, resulting in a total of 5422 useable scans (n = 3082 for wave 1 and n = 2340 for wave 2; n = 1314 for participants with data on both waves). We calculated whole-brain fractional anisotropy (FA) and mean diffusivity (MD) and performed single- and multi-pollutant analyses using mixed effects models adjusted for life-style and socioeconomic status variables. RESULTS: Higher exposure to PM2.5 during pregnancy, and PM10, PM2.5, PM2.5-10, and NOX during childhood was associated with a consistently lower whole-brain FA throughout adolescence (e.g. - 0.07 × 10-2 FA [95%CI -0.12; -0.02] per 1 standard deviation higher PM2.5 exposure during pregnancy). Higher exposure to silicon (Si) in PM2.5 and oxidative potential of PM2.5 during pregnancy, and PM2.5 during childhood was associated with an initial higher MD followed by a faster decrease in MD throughout adolescence (e.g. - 0.02 × 10-5 mm2/s MD [95%CI -0.03; -0.00] per year of age per 1 standard deviation higher Si exposure during pregnancy). Results were comparable when performing the analysis in children with complete data on the outcome for both neuroimaging assessments. CONCLUSIONS: Exposure to several pollutants was associated with a consistently lower whole-brain FA throughout adolescence. The association of few pollutants with whole-brain MD at baseline attenuated throughout adolescence. These findings suggest both persistent and age-limited associations of air pollution exposure with white matter microstructure.

Intergenerational transmission of psychopathology across three generations: the role of social support.

Psychopathology runs in families and affects functioning of individuals and their family members. This study assessed the intergenerational transmission of psychopathology risk across three generations, and the extent to which social support factors may protect against this transmission from parents to their offspring. This study was embedded in Generation R, a multi-ethnic population-based cohort from fetal life onwards. Lifetime psychiatric disorders of grandparents were assessed with the Family Informant Schedule Criteria- updated for DSM-IV. Parental psychopathology was repeatedly measured by the Brief Symptom Inventory. Offspring psychopathology (ages 10 and 14) was assessed with the Brief Problem Monitor. Maternal and child social factors were assessed using questionnaire measures and a computerized peer nomination assessment. Our results show that the estimated additive interaction effect for the risk transmission of grandparental and pre- and postnatal parental psychopathology to offspring psychopathology was 23% (95% CI 19; 27). The joint effect of grandparental and parental psychopathology combined with maternal and child social support factors was 13% (95% CI 08; 17)], suggesting that social support factors diminished the intergenerational transmission of psychopathology from (grand)parents (G1 and G2) to offspring (G3). Transmission of psychopathology risk may have long-lasting developmental effects across generations. Social support factors reduced the vulnerability to the effects of psychopathology risk, underscoring the importance of the identification of buffering factors associated with good mental health in adolescents who are at high familial risk.

Different concepts of neighborhood safety and child internalizing and externalizing behaviors.

Neighborhood safety is defined inconsistently across epidemiologic studies - a conceptual problem that results in incomparable measurements, hampering the design of health interventions. Using child behavior problems (measured via the Child Behavior Checklist) as the outcome of interest, this study directly compared four measures of neighborhood safety: two of experienced safety and two of perceived safety, with each one measured at family and community levels. These included children's direct experience of harm, parental perceptions, community crime statistics, and community perceptions. In a sample of 3291 ten-year-olds from the Generation R cohort (living in municipal Rotterdam, Netherlands, 2013), all four measures were correlated (χ2 ≥ 9.2, P < 0.002 in pairwise chi-square comparisons), but ultimately identified different levels of risk for behavioral health. Direct experiences of harm, parental perceptions, and community crime statistics were all associated with increased child internalizing behaviors (ß = 3.12, ß = 2.10, and ß = 1.77, respectively), while only experiences of harm and parental perceptions were associated with increased externalizing behaviors (ß = 2.75 and ß = 1.31, respectively). These results provide novel evidence that the conceptual distinctions underlying different measures of neighborhood safety are meaningful for child mental health and should be considered in intervention design.

Prenatal exposure to common infections and newborn DNA methylation: A prospective, population-based study.

BACKGROUND: Infections during pregnancy have been robustly associated with adverse mental and physical health outcomes in offspring, yet the underlying molecular pathways remain largely unknown. Here, we examined whether exposure to common infections in utero associates with DNA methylation (DNAm) patterns at birth and whether this in turn relates to offspring health outcomes in the general population. METHODS: Using data from 2,367 children from the Dutch population-based Generation R Study, we first performed an epigenome-wide association study to identify differentially methylated sites and regions at birth associated with prenatal infection exposure. We also examined the influence of infection timing by using self-reported cumulative infection scores for each trimester. Second, we sought to develop an aggregate methylation profile score (MPS) based on cord blood DNAm as an epigenetic proxy of prenatal infection exposure and tested whether this MPS prospectively associates with offspring health outcomes, including psychiatric symptoms, BMI, and asthma at ages 13-16 years. Third, we investigated whether prenatal infection exposure associates with offspring epigenetic age acceleration - a marker of biological aging. Across all analysis steps, we tested whether our findings replicate in 864 participants from an independent population-based cohort (ALSPAC, UK). RESULTS: We observed no differentially methylated sites or regions in cord blood in relation to prenatal infection exposure, after multiple testing correction. 33 DNAm sites showed suggestive associations (p < 5e10 - 5; of which one was also nominally associated in ALSPAC), indicating potential links to genes associated with immune, neurodevelopmental, and cardiovascular pathways. While the MPS of prenatal infections associated with maternal reports of infections in the internal hold out sample in the Generation R Study (R2incremental = 0.049), it did not replicate in ALSPAC (R2incremental = 0.001), and it did not prospectively associate with offspring health outcomes in either cohort. Moreover, we observed no association between prenatal exposure to infections and epigenetic age acceleration across cohorts and clocks. CONCLUSION: In contrast to prior studies, which reported DNAm differences in offspring exposed to severe infections in utero, we do not find evidence for associations between self-reported clinically evident common infections during pregnancy and DNAm or epigenetic aging in cord blood within the general pediatric population. Future studies are needed to establish whether associations exist but are too subtle to be statistically meaningful with present sample sizes, whether they replicate in a cohort with a more similar infection score as our discovery cohort, whether they occur in different tissues than cord blood, and whether other biological pathways may be more relevant for mediating the effect of prenatal common infection exposure on downstream offspring health outcomes.

Prenatal exposure to non-persistent chemicals and fetal-to-childhood growth trajectories.

INTRODUCTION: Prenatal exposure to non-persistent chemicals, including organophosphate pesticides, phthalates, and bisphenols, is associated with altered fetal and childhood growth. Few studies have examined these associations using longitudinal growth trajectories or considering exposure to chemical mixtures. METHODS: Among 777 participants from the Generation R Study, we used growth mixture models to identify weight and body mass index (BMI) trajectories using weight and height measures collected from the prenatal period to age 13. We measured exposure biomarkers for organophosphate pesticides, phthalates, and bisphenols in maternal urine at three timepoints during pregnancy. Multinomial logistic regression was used to estimate associations between averaged exposure biomarker concentrations and growth trajectories. We used quantile g-computation to estimate joint associations with growth trajectories. RESULTS: Phthalic acid (OR: 1.4, 95% CI: 1.01, 1.9) and bisphenol A (BPA; OR: 1.5, 95% CI: 1.0, 2.2) were associated with higher odds of a growth trajectory characterized by smaller prenatal and larger childhood weight relative to a referent trajectory of larger prenatal and average childhood weight. Biomarkers of organophosphate pesticides, individually and jointly, were associated with lower odds of a growth trajectory characterized by average prenatal and lower childhood weight. CONCLUSIONS: Exposure to phthalates and BPA was positively associated with a weight trajectory characterized by lower prenatal and higher childhood weight, while exposure to organophosphate pesticides was negatively associated with a trajectory of average prenatal and lower childhood weight. This study is consistent with the hypothesis that non-persistent chemical exposures disrupt growth trajectories from the prenatal period through childhood.

Gratitude and Mortality Among Older US Female Nurses.

Importance: Supporting healthy aging is a US public health priority, and gratitude is a potentially modifiable psychological factor that may enhance health and well-being in older adults. However, the association between gratitude and mortality has not been studied. Objective: To examine the association of gratitude with all-cause and cause-specific mortality in later life. Design, Setting, and Participants: This population-based prospective cohort study used data from self-reported questionnaires and medical records of 49 275 US older female registered nurses who participated in the Nurses' Health Study (2016 questionnaire wave to December 2019). Cox proportional hazards regression models estimated the hazard ratio (HR) of deaths by self-reported levels of gratitude at baseline. These models adjusted for baseline sociodemographic characteristics, social participation, physical health, lifestyle factors, cognitive function, and mental health. Data analysis was conducted from December 2022 to April 2024. Exposure: Gratitude was assessed with the 6-item Gratitude Questionnaire, a validated and widely used measure of one's tendency to experience grateful affect. Main Outcomes and Measures: Deaths were identified from the National Death Index, state statistics records, reports by next of kin, and the postal system. Causes of death were ascertained by physicians through reviewing death certificates and medical records. Results: Among the 49 275 participants (all female; mean [SD] age at baseline, 79 [6.16] years), 4608 incident deaths were identified over 151 496 person-years of follow-up. Greater gratitude at baseline was associated with a lower hazard of mortality in a monotonic fashion. For instance, the highest tertile of gratitude, compared with the lowest tertile, was associated with a lower hazard of all-cause deaths (HR, 0.91; 95% CI, 0.84-0.99) after adjusting for baseline sociodemographic characteristics, social participation, religious involvement, physical health, lifestyle factors, cognitive function, and mental health. When considering cause-specific deaths, death from cardiovascular disease was inversely associated with gratitude (HR, 0.85; 95% CI, 0.73-0.995). Conclusions and Relevance: This study provides the first empirical evidence suggesting that experiencing grateful affect is associated with increased longevity among older adults. The findings will need to be replicated in future studies with more representative samples.

Longitudinal relationships between early-life homelessness and school-aged asthma and wheezing.

BACKGROUND: Homelessness is a disruptive life event with profound impacts on children's health. It remains unclear, however, whether homelessness in early life has an enduring association with asthma and wheezing among school-aged children. OBJECTIVE: To test whether early-life homelessness is prospectively associated with asthma and wheezing during school-aged years. METHODS: We draw on data from 9242 children from the Avon Longitudinal Study of Parents and Children. Children were categorised as 'ever' or 'never' homeless based on maternal reports from the prenatal period through age 5 years. Children were assigned a binary indicator of asthma/wheezing based on maternal reports of asthma and wheezing at ages 6.8, 7.6 and 8.6 years. We used multilevel logistic regression models to test the association of interest in both bivariate analyses and models adjusted for a broad set of potential confounders. We conducted sensitivity analyses using generalised estimating equations and considering asthma and wheezing separately to test the robustness of the results. RESULTS: Between 12.1% and 14.3% of children had asthma or wheezing at ages 6.8, 7.6 and 8.6 years, and these conditions were more common among ever homeless participants. Ever-homeless children displayed higher odds of asthma or wheezing than never-homeless children (OR: 1.59, 95% CI 1.02 to 2.48) after adjustment for child, maternal and household risk factors. Sensitivity analyses yielded similar results. CONCLUSION: Early-life homelessness is prospectively associated with asthma and wheezing among school-aged children and should be prioritised by interventions promoting healthy child development.

Prenatal stress and gestational epigenetic age: No evidence of associations based on a large prospective multi-cohort study.

Psychological stress during pregnancy is known to have a range of long-lasting negative consequences on the development and health of offspring. Here, we tested whether a measure of prenatal early-life stress was associated with a biomarker of physiological development at birth, namely epigenetic gestational age, using foetal cord-blood DNA-methylation data. Longitudinal cohorts from the Netherlands (Generation R Study [Generation R], n = 1,396), the UK (British Avon Longitudinal Study of Parents and Children [ALSPAC], n = 642), and Norway (Mother, Father and Child Cohort Study [MoBa], n1 = 1,212 and n2 = 678) provided data on prenatal maternal stress and genome-wide DNA methylation from cord blood and were meta-analysed (pooled n = 3,928). Measures of epigenetic age acceleration were calculated using three different gestational epigenetic clocks: "Bohlin", "EPIC overlap" and "Knight". Prenatal stress exposure, examined as an overall cumulative score, was not significantly associated with epigenetically-estimated gestational age acceleration or deceleration in any of the clocks, based on the results of the pooled meta-analysis or those of the individual cohorts. No significant associations were identified with specific domains of prenatal stress exposure, including negative life events, contextual (socio-economic) stressors, parental risks (e.g., maternal psychopathology) and interpersonal risks (e.g., family conflict). Further, no significant associations were identified when analyses were stratified by sex. Overall, we find little support that prenatal psychosocial stress is associated with variation in epigenetic age at birth within the general paediatric population.

Associations of gestational exposure to air pollution with maternal vitamin D levels: a meta-analysis.

OBJECTIVE: Maternal vitamin D level is an important determinant of pregnancy and child health outcomes. Exposure to air pollution is suspected to increase the risk of vitamin D deficiency, but the evidence is scarce. We investigated the association between air pollution during pregnancy and maternal vitamin D levels. METHODS: A total of 15,935 pregnant women from 5 birth cohorts in Europe and U.S were included. Averaged concentrations of nitrogen oxides, fine and coarse particles, and composition of fine particles from conception until vitamin D measurement were estimated at participants' residential addresses using land-use regression or other spatiotemporal models. Cohorts measured vitamin D as 25(OH)D or 25(OH)D3 levels in serum or plasma at early or mid-pregnancy. We defined suboptimal vitamin D levels as levels below 20 ng/mL. We performed logistic regression models for each cohort to estimate the association between air pollution exposure and suboptimal vitamin D levels and pooled cohort-specific estimates in a random-effect meta-analysis. Models were adjusted for sociodemographic and lifestyle characteristics and month of conception. RESULTS: We found an association between PM2.5 and higher odds of suboptimal vitamin D levels (i.e., below 20 ng/mL) (odds ratio per 5 µg/m3 increase in PM2.5, 1.43 95%CI: 1.02, 1.99). There was no association between other air pollutant exposure and vitamin D levels. CONCLUSIONS: PM2.5 exposure might contribute to suboptimal levels of vitamin D in pregnancy. Reducing air pollution exposure should be a priority because vitamin D deficiency may adversely influence offspring development.

Delaying high school start times impacts depressed mood among students: evidence from a natural experiment.

PURPOSE: Delaying high school start times prolongs weekday sleep. However, it is not clear if longer sleep reduces depression symptoms and if the impact of such policy change is the same across groups of adolescents. METHODS: We examined how gains in weekday sleep impact depression symptoms in 2,134 high school students (mean age 15.16 ± 0.35 years) from the Minneapolis metropolitan area. Leveraging a natural experiment design, we used the policy change to delay school start times as an instrument to estimate the effect of a sustained gain in weekday sleep on repeatedly measured Kandel-Davies depression symptoms. We also evaluated whether allocating the policy change to subgroups with expected benefit could improve the impact of the policy. RESULTS: Over 2 years, a sustained half-hour gain in weekday sleep expected as a result of the policy change to delay start times decreased depression symptoms by 0.78 points, 95%CI (-1.32,-0.28), or 15.6% of a standard deviation. The benefit was driven by a decrease in fatigue and sleep-related symptoms. While symptoms of low mood, hopelessness, and worry were not affected by the policy on average, older students with greater daily screen use and higher BMI experienced greater improvements in mood symptoms than would be expected on average, signaling heterogeneity. Nevertheless, universal implementation outperformed prescriptive strategies. CONCLUSION: High school start time delays are likely to universally decrease fatigue and overall depression symptoms in adolescents. Students who benefit most with respect to mood are older, spend more time on screens and have higher BMI.

The biological embedding of social adversity: How adolescent housing insecurity impacts inflammation over time.

BACKGROUND & PURPOSE: Adolescent housing insecurity is a dynamic form of social adversity that impacts child health outcomes worldwide. However, the means by which adolescent housing insecurity may become biologically embedded to influence health outcomes over the life course remain unclear. Therefore, we aimed to utilize life course perspectives and advanced causal inference methods to evaluate the potential for inflammation to contribute to the biological embedding of adolescent housing insecurity. MATERIALS AND METHODS: Using prospective data from the Great Smoky Mountains Study, we investigated the relationship between adolescent housing insecurity and whole-blood spot samples assayed for C-reactive protein (CRP). Adolescent housing insecurity was created based on annual measures of frequent residential moves, reduced standard of living, forced separation from the home, and foster care. Annual measures of CRP ranged from 0.001 mg/L to 13.6 mg/L (median = 0.427 mg/L) and were log10 transformed to account for positively skewed values. We used g-estimation of structural nested mean models to estimate a series of conditional average causal effects of adolescent housing insecurity on CRP levels from ages 11 to 16 years and interpreted the results within life course frameworks of accumulation, recency, and sensitive periods. PRINCIPAL RESULTS: Of the 1,334 participants, 427 [44.3 %] were female. Based on the conditional average causal effect, one exposure to adolescent housing insecurity from ages 11 to 16 years led to a 6.4 % (95 % CI = 0.69 - 12.4) increase in later CRP levels. Exposure at 14 years of age led to a 27.9 % increase in CRP levels at age 15 (95 % CI = 6.5 - 53.5). Recent exposures to adolescent housing insecurity (<3 years) suggested stronger associations with CRP levels than distant exposures (>3 years), but limited statistical power prevented causal conclusions regarding recency effects at the risk of a Type II Error. MAJOR CONCLUSIONS: These findings highlight inflammation-as indicated by increased CRP levels-as one potential mechanism for the biological embedding of adolescent housing insecurity. The results also suggest that adolescent housing insecurity-particularly recent, repeated, and mid-adolescent exposures-may increase the risk of poor health outcomes and should be considered a key intervention target.