Caregiver burden and risk of epithelial ovarian cancer in the Nurses' Health Studies.

Psychosocial stress may increase ovarian cancer risk and accelerate disease progression. We examined the association between caregiver burden, a common stressor, and risk of epithelial ovarian cancer. We prospectively followed 67,724 women in the Nurses' Health Study (NHS; 1992-2012) and 70,720 women in the NHSII (2001-2009) who answered questions on informal caregiving (i.e., caregiving outside of work). Women who reported no informal caregiving were considered non-caregivers while, among women who provided care outside of work, caregiver burden was categorized by time spent caregiving and perceived stress from caregiving. For the 34% of women who provided informal care for ≥15 hours per week, 42% described caregiving as moderately to extremely stressful. Pooled multivariate analyses indicated no difference in ovarian cancer risk for women providing ≥15 hours of care per week compared to non-caregivers (hazard ratio (HR)=0.96; 95% confidence interval (CI): 0.79-1.18), and no association was evident for women who reported moderate or extreme stress from caregiving compared to non-caregivers (HR=0.96; 95% CI: 0.75-1.22). Together with prior work evaluating job strain and ovarian cancer risk, our findings suggest that, when evaluating a stressor's role in cancer risk, it is critical to consider how the stressor contributes to the overall experience of distress.

Fulfilled Mind, Healthy Gut? Relationships of Eudaimonic Psychological Well-Being With the Gut Microbiome in Postmenopausal Women.

OBJECTIVE: Eudaimonic facets of psychological well-being (PWB), like purpose in life and sense of mastery, are associated with healthy aging. Variation in the gut microbiome may be one pathway by which mental health influences age-related health outcomes. However, associations between eudaimonic PWB and the gut microbiome are understudied. We examined whether purpose in life and sense of mastery, separately, were associated with features of the gut microbiome in older women. METHODS: Participants were from the Mind-Body Study ( N = 206, mean age = 61 years), a substudy of the Nurses' Health Study II cohort. In 2013, participants completed the Life Engagement Test and the Pearlin Mastery Scale. Three months later, up to two pairs of stool samples were collected, 6 months apart. Covariates included sociodemographics, depression, health status, and health behaviors. Analyses examined associations of PWB with gut microbiome taxonomic diversity, overall community structure, and specific species/pathways. To account for multiple testing, statistical significance was established using Benjamini-Hochberg adjusted p values (i.e., q values ≤0.25). RESULTS: We found no evidence of an association between PWB and gut microbiome alpha diversity. In multivariate analysis, higher purpose levels were significantly associated with lower abundance of species previously linked with poorer health outcomes, notably Blautia hydrogenotrophica and Eubacterium ventriosum ( q values ≤0.25). No significant associations were found between PWB and metabolic pathways. CONCLUSIONS: These findings offer early evidence suggesting that eudaimonic PWB is linked with variation in the gut microbiome, and this might be one pathway by which PWB promotes healthy aging.

Pre-Pandemic Resilience to Trauma & COVID-19 Infection in Older Women.

OBJECTIVE: Prior work suggests psychological resilience to trauma may protect not only mental but also physical health. This study examined the relationship of pre-pandemic psychological resilience to lifetime trauma with self-reported COVID-19 infection and symptoms during the early years of the COVID-19 pandemic. METHODS: Data are from 18,670 longitudinal cohort participants in the Nurses' Health Study II. Based on prior evidence that trauma and subsequent distress can increase infection risk and severity, and that psychological assets may offset this risk, we hypothesized higher versus lower psychological resilience to prior trauma would be associated with lower risk for COVID-19 infection. Pre-pandemic resilience was assessed via self-report between 2017-2019 based on self-reported lifetime trauma exposure and psychological health. COVID-19 infection and symptoms were self-reported on 7 questionnaires administered between May 2020 - October 2021, from which we derived a composite outcome measure of probable COVID-19 infection, defined as having 3+ COVID-19 symptoms (out of 9) and/or a positive COVID-19 test result at any single assessment. RESULTS: Multivariable regression revealed significant associations between higher pre-pandemic resilience scores and lower risk for probable COVID-19 infection, adjusting for socio-demographic and COVID-19-related risk factors (RR = 0.90 [95% CI 0.87, 0.93]). Considering subcomponents of the composite COVID-19 infection measure separately, pre-pandemic resilience was significantly associated with lower risk of reported symptoms (RR = 0.83 [95% CI 0.79, 0.88]), but not with a positive test result alone (RR = 0.96 (95% CI 0.91, 1.01]). CONCLUSION: Identifying protective factors for infection risk may help inform psychosocial interventions to improve health outcomes.

Post-traumatic stress disorder symptom remission and cognition in a large cohort of civilian women.

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with cognitive impairments. It is unclear whether problems persist after PTSD symptoms remit. METHODS: Data came from 12 270 trauma-exposed women in the Nurses' Health Study II. Trauma and PTSD symptoms were assessed using validated scales to determine PTSD status as of 2008 (trauma/no PTSD, remitted PTSD, unresolved PTSD) and symptom severity (lifetime and past-month). Starting in 2014, cognitive function was assessed using the Cogstate Brief Battery every 6 or 12 months for up to 24 months. PTSD associations with baseline cognition and longitudinal cognitive changes were estimated by covariate-adjusted linear regression and linear mixed-effects models, respectively. RESULTS: Compared to women with trauma/no PTSD, women with remitted PTSD symptoms had a similar cognitive function at baseline, while women with unresolved PTSD symptoms had worse psychomotor speed/attention and learning/working memory. In women with unresolved PTSD symptoms, past-month PTSD symptom severity was inversely associated with baseline cognition. Over follow-up, both women with remitted and unresolved PTSD symptoms in 2008, especially those with high levels of symptoms, had a faster decline in learning/working memory than women with trauma/no PTSD. In women with remitted PTSD symptoms, higher lifetime PTSD symptom severity was associated with a faster decline in learning/working memory. Results were robust to the adjustment for sociodemographic, biobehavioral, and health factors and were partially attenuated when adjusted for depression. CONCLUSION: Unresolved but not remitted PTSD was associated with worse cognitive function assessed six years later. Accelerated cognitive decline was observed among women with either unresolved or remitted PTSD symptoms.

Psychological resilience predicting cardiometabolic conditions in adulthood in the Midlife in the United States Study.

Early adversity is associated with poor cardiometabolic health, potentially via psychological distress. However, not everyone exposed to adversity develops significant distress. Psychological resilience and positive psychological health despite adversity may protect against unfavorable cardiometabolic outcomes that are otherwise more likely. We examined early adversity, psychological resilience, and cardiometabolic risk among 3,254 adults in the Midlife in the United States Study. Psychological resilience was defined according to both early psychosocial adversity and adult psychological health (characterized by low distress and high wellbeing) at Wave 1 (1994 to 1995). Categorical resilience was derived by cross-classifying adversity (exposed versus unexposed) and psychological health (higher versus lower). We also assessed count of adversities experienced and psychological symptoms as separate variables. Incident cardiometabolic conditions (e.g., heart attack, stroke, and diabetes) were self-reported at Waves 2 (2004 to 2005) and 3 (2013 to 2014). Secondary analyses examined biological cardiometabolic risk using a composite of biomarkers available within a Wave-2 subsample. Logistic and Poisson regressions evaluated associations of resilience with cardiometabolic health across 20 follow-up y, adjusting for relevant covariates. In this initially healthy sample, nonresilient (adversity-exposed, lower psychological health) versus resilient (adversity-exposed, high psychological health) individuals had 43% higher odds of cardiometabolic conditions (95% CI 1.10 to 1.85). Odds of cardiometabolic conditions were similar among resilient versus unexposed, psychologically healthy individuals. More adversity experiences were associated with increased odds, while better psychological health with decreased odds of cardiometabolic conditions, and effects were largely independent. Patterns were similar for objectively assessed cardiometabolic risk. Psychological resilience in midlife may protect against negative cardiometabolic impacts of early adversity.

Associations of nature contact with emotional ill-being and well-being: the role of emotion regulation.

Nature contact has associations with emotional ill-being and well-being. However, the mechanisms underlying these associations are not fully understood. We hypothesised that increased adaptive and decreased maladaptive emotion regulation strategies would be a pathway linking nature contact to ill-being and well-being. Using data from a survey of 600 U.S.-based adults administered online in 2022, we conducted structural equation modelling to test our hypotheses. We found that (1) frequency of nature contact was significantly associated with lesser emotional ill-being and greater emotional well-being, (2) effective emotion regulation was significantly associated with lesser emotional ill-being and greater emotional well-being, and (3) the associations of higher frequency of nature contact with these benefits were partly explained via emotion regulation. Moreover, we found a nonlinear relationship for the associations of duration of nature contact with some outcomes, with a rise in benefits up to certain amounts of time, and a levelling off after these points. These findings support and extend previous work that demonstrates that the associations of nature contact with emotional ill-being and well-being may be partly explained by changes in emotion regulation.

Epigenome-Wide Analysis of DNA Methylation and Optimism in Women and Men.

OBJECTIVE: Higher optimism is associated with reduced mortality and a lower risk of age-related chronic diseases. DNA methylation (DNAm) may provide insight into mechanisms underlying these relationships. We hypothesized that DNAm would differ among older individuals who are more versus less optimistic. METHODS: Using cross-sectional data from two population-based cohorts of women with diverse races/ethnicities ( n = 3816) and men (only White, n = 667), we investigated the associations of optimism with epigenome-wide leukocyte DNAm. Random-effects meta-analyses were subsequently used to pool the individual results. Significantly differentially methylated cytosine-phosphate-guanines (CpGs) were identified by the "number of independent degrees of freedom" approach: effective degrees of freedom correction using the number of principal components (PCs), explaining >95% of the variation of the DNAm data (PC-correction). We performed regional analyses using comb-p and pathway analyses using the Ingenuity Pathway Analysis software. RESULTS: We found that essentially all CpGs (total probe N = 359,862) were homogeneous across sex and race/ethnicity in the DNAm-optimism association. In the single CpG site analyses based on homogeneous CpGs, we identified 13 significantly differentially methylated probes using PC-correction. We found four significantly differentially methylated regions and two significantly differentially methylated pathways. The annotated genes from the single CpG site and regional analyses are involved in psychiatric disorders, cardiovascular disease, cognitive impairment, and cancer. Identified pathways were related to cancer, and neurodevelopmental and neurodegenerative disorders. CONCLUSION: Our findings provide new insights into possible mechanisms underlying optimism and health.

Long-term associations between early-life family functioning and preadolescent white matter microstructure.

BACKGROUND: Causes of childhood behavior problems remain poorly understood. Enriched family environments and corresponding brain development may reduce the risk of their onset, but research investigating white matter neurodevelopmental pathways explaining associations between the family environment and behavior remains limited. We hypothesized that more positive prenatal and mid-childhood family functioning - a measure of a family's problem solving and supportive capacity - would be associated with two markers of preadolescent white matter neurodevelopment related to reduced behavior problems: higher global fractional anisotropy (FA) and lower global mean diffusivity (MD). METHODS: Data are from 2727 families in the Generation R Study, the Netherlands. Mothers reported family functioning (McMaster Family Assessment Device, range 1-4, higher scores indicate healthier functioning) prenatally and in mid-childhood (mean age 6.1 years). In preadolescence (mean age 10.1), the study collected diffusion-weighted scans. We computed standardized global MD and FA values by averaging metrics from 27 white matter tracts, and we fit linear models adjusting for possible confounders to examine global and tract-specific outcomes. RESULTS: Prenatal and mid-childhood family functioning scores were moderately correlated, r = 0.38. However, only prenatal family functioning - and not mid-childhood functioning - was associated with higher global FA and lower global MD in preadolescence in fully adjusted models: ßglobal FA = 0.11 (95% CI 0.00, 0.21) and ßglobal MD = -0.15 (95% CI -0.28, -0.03) per one-unit increase in functioning score. Sensitivity and tract-specific analyses supported these global findings. CONCLUSIONS: These results suggest high-functioning prenatal or perinatal family environments may confer lasting white matter neurodevelopmental benefits into preadolescence.

Depression, worry, and loneliness are associated with subsequent risk of hospitalization for COVID-19: a prospective study.

BACKGROUND: Pre-pandemic psychological distress is associated with increased susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but associations with the coronavirus disease 2019 (COVID-19) severity are not established. The authors examined the associations between distress prior to SARS-CoV-2 infection and subsequent risk of hospitalization. METHODS: Between April 2020 (baseline) and April 2021, we followed 54 781 participants from three ongoing cohorts: Nurses' Health Study II (NHSII), Nurses' Health Study 3 (NHS3), and the Growing Up Today Study (GUTS) who reported no current or prior SARS-CoV-2 infection at baseline. Chronic depression was assessed during 2010-2019. Depression, anxiety, worry about COVID-19, perceived stress, and loneliness were measured at baseline. SARS-CoV-2 infection and hospitalization due to COVID-19 was self-reported. Relative risks (RRs) were calculated by Poisson regression. RESULTS: 3663 participants reported a positive SARS-CoV-2 test (mean age = 55.0 years, standard deviation = 13.8) during follow-up. Among these participants, chronic depression prior to the pandemic [RR = 1.72; 95% confidence interval (CI) 1.20-2.46], and probable depression (RR = 1.81, 95% CI 1.08-3.03), being very worried about COVID-19 (RR = 1.79; 95% CI 1.12-2.86), and loneliness (RR = 1.81, 95% CI 1.02-3.20) reported at baseline were each associated with subsequent COVID-19 hospitalization, adjusting for demographic factors and healthcare worker status. Anxiety and perceived stress were not associated with hospitalization. Depression, worry about COVID-19, and loneliness were as strongly associated with hospitalization as were high cholesterol and hypertension, established risk factors for COVID-19 severity. CONCLUSIONS: Psychological distress may be a risk factor for hospitalization in patients with SARS-CoV-2 infection. Assessment of psychological distress may identify patients at greater risk of hospitalization. Future work should examine whether addressing distress improves physical health outcomes.

Gut feelings: associations of emotions and emotion regulation with the gut microbiome in women.

BACKGROUND: Accumulating evidence suggests that positive and negative emotions, as well as emotion regulation, play key roles in human health and disease. Recent work has shown the gut microbiome is important in modulating mental and physical health through the gut-brain axis. Yet, its association with emotions and emotion regulation are understudied. Here we examined whether positive and negative emotions, as well as two emotion regulation strategies (i.e. cognitive reappraisal and suppression), were associated with the gut microbiome composition and functional pathways in healthy women. METHODS: Participants were from the Mind-Body Study (N = 206, mean age = 61), a sub-study of the Nurses' Health Study II cohort. In 2013, participants completed measures of emotion-related factors. Two pairs of stool samples were collected, 6 months apart, 3 months after emotion-related factors measures were completed. Analyses examined associations of emotion-related factors with gut microbial diversity, overall microbiome structure, and specific species/pathways and adjusted for relevant covariates. RESULTS: Alpha diversity was negatively associated with suppression. In multivariate analysis, positive emotions were inversely associated with the relative abundance of Firmicutes bacterium CAG 94 and Ruminococcaceae bacterium D16, while negative emotions were directly correlated with the relative abundance of these same species. At the metabolic pathway level, negative emotions were inversely related to the biosynthesis of pantothenate, coenzyme A, and adenosine. CONCLUSIONS: These findings offer human evidence supporting linkages of emotions and related regulatory processes with the gut microbiome and highlight the importance of incorporating the gut microbiome in our understanding of emotion-related factors and their associations with physical health.

The link between post-traumatic stress disorder and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous, multisystem autoimmune disorder characterized by unpredictable disease flares. Although the pathogenesis of SLE is complex, an epidemiologic link between posttraumatic stress disorder (PTSD) and the development of SLE has been identified, suggesting that stress-related disorders alter the susceptibility to SLE. Despite the strong epidemiologic evidence connecting PTSD and SLE, gaps remain in our understanding of how the two may be connected. Perturbations in the autonomic nervous system, neuroendocrine system, and at the genomic level may cause and sustain immune dysregulation that could lower the threshold for the development and propagation of SLE. We first describe shared risk factors for SLE and PTSD. We then describe potential biological pathways which may facilitate excessive inflammation in the context of PTSD. Among those genetically predisposed to SLE, systemic inflammation that accompanies chronic stress may fan the flames of smoldering SLE by priming immune pathways. Further studies on the connection between trauma and inflammation will provide important data on pathogenesis, risk factors, and novel treatments for SLE.

Metabolomic profiles of chronic distress are associated with cardiovascular disease risk and inflammation-related risk factors.

BACKGROUND: Chronic psychological distress is associated with increased risk of cardiovascular disease (CVD) and investigators have posited inflammatory factors may be centrally involved in these relationships. However, mechanistic evidence and molecular underpinnings of these processes remain unclear, and data are particularly sparse among women. This study examined if a metabolite profile linked with distress was associated with increased CVD risk and inflammation-related risk factors. METHODS: A plasma metabolite-based distress score (MDS) of twenty chronic psychological distress-related metabolites was developed in cross-sectional, 1:1 matched case-control data comprised of 558 women from the Nurses' Health Study (NHS; 279 women with distress, 279 controls). This MDS was then evaluated in two other cohorts: the Women's Health Initiative Observational Cohort (WHI-OS) and the Prevención con Dieta Mediterránea (PREDIMED) trial. We tested the MDS's association with risk of future CVD in each sample and with levels of C-reactive protein (CRP) in the WHI-OS. The WHI-OS subsample included 944 postmenopausal women (472 CHD cases; mean time to event = 5.8 years); the PREDIMED subsample included 980 men and women (224 CVD cases, mean time to event = 3.1 years). RESULTS: In the WHI-OS, a 1-SD increase in the plasma MDS was associated with a 20% increased incident CHD risk (odds ratio [OR] = 1.20, 95% CI: 1.04 - 1.38), adjusting for known CVD risk factors excluding total and HDL cholesterol. This association was attenuated after including total and HDL cholesterol. CRP mediated an average 12.9% (95% CI: 4.9% - 28%, p < 10-15) of the total effect of MDS on CHD risk when adjusting for matching factors. This effect was attenuated after adjusting for known CVD risk factors. Of the metabolites in the MDS, tryptophan and threonine were inversely associated with incident CHD risk in univariate models. In PREDIMED, each one SD increase in the MDS was associated with an OR of 1.19 (95% CI: 1.00 - 1.41) for incident CVD risk, after adjusting all risk factors. Similar associations were observed in men and women. Four metabolites in the MDS were associated with incident CVD risk in PREDIMED in univariate models. Biliverdin and C36:5 phosphatidylcholine (PC) plasmalogen had inverse associations; C16:0 ceramide and C18:0 lysophosphatidylethanolamine(LPE) each had positive associations with CVD risk. CONCLUSIONS: Our study points to molecular alterations that may underlie the association between chronic distress and subsequent risk of cardiovascular disease in adults.

The relationship of lifetime history of depression on the ovarian tumor immune microenvironment.

BACKGROUND: Depression is associated with a higher ovarian cancer risk. Prior work suggests that depression can lead to systemic immune suppression, which could potentially alter the anti-tumor immune response. METHODS: We evaluated the association of pre-diagnosis depression with features of the anti-tumor immune response, including T and B cells and immunoglobulins, among women with ovarian tumor tissue collected in three studies, the Nurses' Health Study (NHS; n = 237), NHSII (n = 137) and New England Case-Control Study (NECC; n = 215). Women reporting depressive symptoms above a clinically relevant cut-point, antidepressant use, or physician diagnosis of depression at any time prior to diagnosis of ovarian cancer were considered to have pre-diagnosis depression. Multiplex immunofluorescence was performed on tumor tissue microarrays to measure immune cell infiltration. In pooled analyses, we estimated odds ratios (OR) and 95% confidence intervals (CI) for the positivity of tumor immune cells using a beta-binomial model comparing those with and without depression. We used Bonferroni corrections to adjust for multiple comparisons. RESULTS: We observed no statistically significant association between depression status and any immune markers at the Bonferroni corrected p-value of 0.0045; however, several immune markers were significant at a nominal p-value of 0.05. Specifically, there were increased odds of having recently activated cytotoxic (CD3+CD8+CD69+) and exhausted-like T cells (CD3+Lag3+) in tumors of women with vs. without depression (OR = 1.36, 95 %CI = 1.09-1.69 and OR = 1.24, 95 %CI = 1.01-1.53, respectively). Associations were comparable when considering high grade serous tumors only (comparable ORs = 1.33, 95 %CI = 1.05-1.69 and OR = 1.25, 95 %CI = 0.99-1.58, respectively). There were decreased odds of having tumor infiltrating plasma cells (CD138+) in women with vs. without depression (OR = 0.54, 95 %CI = 0.33-0.90), which was similar among high grade serous carcinomas, although not statistically significant. Depression was also related to decreased odds of having naïve and memory B cells (CD20+: OR = 0.54, 95 %CI = 0.30-0.98) and increased odds of IgG (OR = 1.22, 95 %CI = 0.97-1.53) in high grade serous carcinomas. CONCLUSION: Our results provide suggestive evidence that depression may influence ovarian cancer outcomes through changes in the tumor immune microenvironment, including increasing T cell activation and exhaustion and reducing antibody-producing B cells. Further studies with clinical measures of depression and larger samples are needed to confirm these results.

Pre-pandemic resilience to trauma and mental health outcomes during COVID-19.

PURPOSE: The stress-sensitization hypothesis posits that individuals with prior trauma are at elevated risk for poor mental health when faced with subsequent stressors. Little work has examined whether those who have demonstrated psychological resilience to prior trauma would show either increased resilience or vulnerability to subsequent stressors. We examined pre-pandemic psychological resilience to lifetime trauma in relation to mental health outcomes amid the coronavirus disease 2019 (COVID-19) pandemic, a major societal stressor. METHODS: The sample included 16,900 trauma-exposed women from the Nurses' Health Study II. Pre-pandemic resilience was defined by psychological health in 2017-2019 (characterized by levels of both distress and positive emotional well-being) relative to lifetime trauma. Resilience was defined categorically by cross-classifying unfavorable, adequate, and favorable psychological health by higher versus lower trauma burden, and continuously as the residual difference in predicted versus actual psychological health regressed on trauma burden. Mental health outcomes as of May-August 2020 included psychological distress symptoms and overall positive emotional well-being. Associations were assessed using covariate-adjusted regression models. RESULTS: Pre-pandemic resilience was associated with lower distress and higher well-being early in the COVID-19 pandemic. Relative to the women showing highest resilience (favorable psychological health despite higher trauma), only those with lower trauma and favorable prior psychological health had significantly lower distress and higher positive emotional well-being during the pandemic. Higher continuous pre-pandemic resilience was also significantly associated with lower distress and higher positive emotional well-being during the pandemic. CONCLUSION: Preventing mental health problems following trauma may contribute to protecting population well-being amid major stressors.

Social integration and risk of mortality among African-Americans: the Jackson heart study.

OBJECTIVE: Evidence suggests that greater social integration is related to lower mortality rates. However, studies among African-Americans are limited. We examined whether higher social integration was associated with lower mortality in 5306 African-Americans from the Jackson Heart Study, who completed the Berkman-Syme Social Network Index in 2000-2004 and were followed until 2018. METHODS: We estimated hazard ratios (HR) of mortality by categories of the Social Network Index (i.e., high social isolation, moderate social isolation [reference group], moderate social integration, high social integration) using Cox proportional hazard models. Covariates included baseline sociodemographics, depressive symptoms, health conditions, and health behaviors. RESULTS: Compared with moderate isolation, moderate integration was associated with an 11% lower mortality rate (HR = 0.89, 95% confidence interval [CI] 0.77, 1.03), and high integration was associated with a 25% lower mortality rate (HR = 0.75, 95% CI 0.64, 0.87), controlling for sociodemographics and depressive symptoms; compared with moderate isolation, high isolation was related to a 34% higher mortality rate (HR = 1.34, 95% CI 1.00, 1.79). Further adjustment of potential mediators (health conditions and health behaviors) only slightly attenuated HRs (e.g., HRmoderate integration = 0.90, 95% CI 0.78, 1.05; HRhigh integration = 0.77, 95% CI 0.66, 0.89). CONCLUSION: Social integration may be a psychosocial health asset with future work needed to identify biobehavioral processes underlying observed associations with mortality among African-Americans.

Behavioral and neurostructural correlates of childhood physical violence victimization: Interaction with family functioning.

Violence victimization may cause child behavior problems and neurostructural differences associated with them. Healthy family environments may buffer these effects, but neural pathways explaining these associations remain inadequately understood. We used data from 3154 children (x̅age  = 10.1) to test whether healthy family functioning moderated possible associations between violence victimization, behavior problems, and amygdala volume (a threat-responsive brain region). Researchers collected data on childhood violence victimization, family functioning (McMaster Family Assessment Device, range 0-3, higher scores indicate healthier functioning), and behavior problems (Achenbach Child Behavior Checklist [CBCL] total problem score, range 0-117), and they scanned children with magnetic resonance imaging. We standardized amygdala volumes and fit confounder-adjusted models with "victimization × family functioning" interaction terms. Family functioning moderated associations between victimization, behavior problems, and amygdala volume. Among lower functioning families (functioning score = 1.0), victimization was associated with a 26.1 (95% confidence interval [CI]: 9.9, 42.4) unit higher CBCL behavior problem score, yet victimized children from higher functioning families (score = 3.0) exhibited no such association. Unexpectedly, victimization was associated with higher standardized amygdala volume among lower functioning families (y = 0.5; 95% CI: 0.1, 1.0) but lower volume among higher functioning families (y = -0.4; 95% CI: -0.7, -0.2). Thus, healthy family environments may mitigate some neurobehavioral effects of childhood victimization.

Psychological Health, Well-Being, and the Mind-Heart-Body Connection: A Scientific Statement From the American Heart Association.

As clinicians delivering health care, we are very good at treating disease but often not as good at treating the person. The focus of our attention has been on the specific physical condition rather than the patient as a whole. Less attention has been given to psychological health and how that can contribute to physical health and disease. However, there is now an increasing appreciation of how psychological health can contribute not only in a negative way to cardiovascular disease (CVD) but also in a positive way to better cardiovascular health and reduced cardiovascular risk. This American Heart Association scientific statement was commissioned to evaluate, synthesize, and summarize for the health care community knowledge to date on the relationship between psychological health and cardiovascular health and disease and to suggest simple steps to screen for, and ultimately improve, the psychological health of patients with and at risk for CVD. Based on current study data, the following statements can be made: There are good data showing clear associations between psychological health and CVD and risk; there is increasing evidence that psychological health may be causally linked to biological processes and behaviors that contribute to and cause CVD; the preponderance of data suggest that interventions to improve psychological health can have a beneficial impact on cardiovascular health; simple screening measures can be used by health care providers for patients with or at risk for CVD to assess psychological health status; and consideration of psychological health is advisable in the evaluation and management of patients with or at risk for CVD.

Eight-Year Depressive Symptom Trajectories and Incident Stroke: A 10-Year Follow-Up of the HRS (Health and Retirement Study).

BACKGROUND: Evidence suggests a link between depressive symptoms and risk of subsequent stroke. However, most studies assess depressive symptoms at only one timepoint, with few examining this relationship using repeatedly measured depressive symptoms. This study aimed to examine the relationship between depressive symptom trajectories and risk of incident stroke. METHODS: This prospective cohort included 12 520 US individuals aged ≥50 years enrolled in the Health and Retirement Study, free of stroke at study baseline (1998). We used the 8-item Center for Epidemiologic Studies Depression scale to assess depressive symptoms (high defined as ≥3 symptoms; low <3 symptoms) at 4 consecutive, biennial timepoints from 1998 to 2004. We assigned individuals to 5 predefined trajectories based on their scores at each timepoint (consistently low, decreasing, fluctuating, increasing, and consistently high). Using self-reported doctors' diagnoses, we assessed incident stroke over a subsequent 10-year period from 2006 to 2016. Cox regression models estimated the association of depressive symptom trajectories with risk of incident stroke, adjusting for demographics, health behaviors, and health conditions. RESULTS: During follow-up, 1434 incident strokes occurred. Compared with individuals with consistently low symptoms, individuals with consistently high depressive symptoms (adjusted hazard ratio, 1.18 [95% CI, 1.02-1.36]), increasing symptoms (adjusted hazard ratio, 1.31 [95% CI, 1.10-1.57]), and fluctuating symptoms (adjusted hazard ratio, 1.21 [95% CI, 1.01-1.46]) all had higher hazards of stroke onset. Individuals in the decreasing symptom trajectory group did not show increased stroke risk. CONCLUSIONS: Depressive symptom trajectories characterized by high symptoms at multiple timepoints were associated with increased stroke risk. However, a trajectory with depressive symptoms that started high but decreased over time was not associated with higher stroke risk. Given the remitting-relapsing nature of depressive symptoms, it is important to understand the relationship between depressive symptoms and stroke risk over time through repeated assessments.

Marginal Structural Models for Life-Course Theories and Social Epidemiology: Definitions, Sources of Bias, and Simulated Illustrations.

Social epidemiology aims to identify social structural risk factors, thus informing targets and timing of interventions. Ascertaining which interventions will be most effective and when they should be implemented is challenging because social conditions vary across the life course and are subject to time-varying confounding. Marginal structural models (MSMs) may be useful but can present unique challenges when studying social epidemiologic exposures over the life course. We describe selected MSMs corresponding to common theoretical life-course models and identify key issues for consideration related to time-varying confounding and late study enrollment. Using simulated data mimicking a cohort study evaluating the effects of depression in early, mid-, and late life on late-life stroke risk, we examined whether and when specific study characteristics and analytical strategies may induce bias. In the context of time-varying confounding, inverse-probability-weighted estimation of correctly specified MSMs accurately estimated the target causal effects, while conventional regression models showed significant bias. When no measure of early-life depression was available, neither MSMs nor conventional models were unbiased, due to confounding by early-life depression. To inform interventions, researchers need to identify timing of effects and consider whether missing data regarding exposures earlier in life may lead to biased estimates.

Plasma Metabolomic Signature of Early Abuse in Middle-Aged Women.

OBJECTIVE: Metabolomic profiling may provide insights into biological mechanisms underlying the strong epidemiologic links observed between early abuse and cardiometabolic disorders in later life. METHODS: We examined the associations between early abuse and midlife plasma metabolites in two nonoverlapping subsamples from the Nurses' Health Study II, comprising 803 (mean age = 40 years) and 211 women (mean age = 61 years). Liquid chromatography-tandem mass spectrometry assays were used to measure metabolomic profiles, with 283 metabolites consistently measured in both subsamples. Physical and sexual abuse before age 18 years was retrospectively assessed by validated questions integrating type/frequency of abuse. Analyses were conducted in each sample and pooled using meta-analysis, with multiple testing adjustment using the q value approach for controlling the positive false discovery rate. RESULTS: After adjusting for age, race, menopausal status, body size at age 5 years, and childhood socioeconomic indicators, more severe early abuse was consistently associated with five metabolites at midlife (q value < 0.20 in both samples), including lower levels of serotonin and C38:3 phosphatidylethanolamine plasmalogen and higher levels of alanine, proline, and C40:6 phosphatidylethanolamine. Other metabolites potentially associated with early abuse (q value < 0.05 in the meta-analysis) included triglycerides, phosphatidylcholine plasmalogens, bile acids, tyrosine, glutamate, and cotinine. The association between early abuse and midlife metabolomic profiles was partly mediated by adulthood body mass index (32% mediated) and psychosocial distress (13%-26% mediated), but not by other life-style factors. CONCLUSIONS: Early abuse was associated with distinct metabolomic profiles of multiple amino acids and lipids in middle-aged women. Body mass index and psychosocial factors in adulthood may be important intermediates for the observed association.