Pharmacotherapy guideline concordance for major depressive disorder and its link to functioning via symptom change.

Introduction: Alleviation of symptom severity for major depressive disorder (MDD) is known to be associated with a lagged improvement of functioning. Pharmacotherapy guidelines support algorithms for MDD treatment. However, it is currently unclear whether concordance with guidelines influences functional recovery. A guideline concordance algorithm (GCA-8) was used to measure this pathway in a naturalistic clinical setting. Methods: Data from 1403 adults (67% female, 84% non-Hispanic/Latino White, mean age of 43 years) with nonpsychotic MDD from the Penn State Psychiatry Clinical Assessment and Rating Evaluation System registry (visits from 02/01/2015 to 04/13/2021) were evaluated. Multivariable linear regression measured associations between GCA-8 and World Health Organization Disability Assessment Schedule 2.0 (WHODAS) scores. Mediation by MDD symptom severity using the Patient Health Questionnaire depression module (PHQ-9) was also evaluated. Results: This study found a statistically significant improvement in WHODAS scores (functioning) between baseline and final measures (-2 points, P < .001) within one year. A one standard deviation increase in the GCA-8 score was associated with a 0.48-point reduction in mean disability score (total effect; P = .02) with significant mediation by the change in MDD symptom severity (coefficient = -0.51, P < .001) and a nonsignificant natural direct effect of the GCA-8 independent of PHQ-9 change (coefficient = -0.02, P = .92). Conclusions: Higher pharmacotherapy guideline concordance is associated with better functioning for MDD patients; this association likely occurs through improvement in MDD symptom severity rather than directly.

Effects of ACE inhibitor/ARB therapy and long COVID on kidney disease: a retrospective cohort study using real-world data.

Background: The association between angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and severe acute respiratory syndrome coronavirus 2 susceptibility, particularly via ACE-2 receptor upregulation in the kidneys, raises concerns about potential kidney disease risks in long coronavirus disease (COVID) patients. This study explores the association of ACEI/ARB therapy on acute kidney injury (AKI), chronic kidney disease (CKD) and all-cause mortality in patients with and without long COVID. Methods: A retrospective cohort study using TriNetX datasets was conducted, with diagnoses of long COVID via International Classification of Diseases, Tenth Revision (ICD-10) codes and prescription for ACEI/ARB as the classification of four cohorts: long COVID ACEI/ARB users (LCAUs), long COVID ACEI/ARB non-users (LCANs), non-long COVID ACEI/ARB users (NLCAUs) and non-long COVID ACEI/ARB non-users (NLCANs). Multivariable stratified Cox proportional hazards regression models assessed the adjusted hazard ratios (aHRs) across groups. Additional analyses were conducted, including time-dependent exposure analysis and comparison with an active comparator, calcium channel blockers. Results: Our study included 18 168 long COVID and 181 680 propensity score-matched non-long COVID patients from October 2021 to October 2023. ACEI/ARB use did not significantly affect the risk of AKI or CKD when comparing LCAUs with LCANs and NLCAUs with NLCANs. However, a protective effect against all-cause mortality was observed {aHR 0.79 [95% confidence interval (CI) 0.65-0.93]} in the NLCAU group compared with the NLCAN group. Conversely, long COVID was associated with increased risks of CKD [aHR 1.49 (95% CI 1.03-2.14)] and all-cause mortality [aHR 1.49 (95% CI 1.00-2.23)] when comparing LCANs with NLCANs. The additional analyses support the primary findings. Conclusions: ACEI/ARB treatment does not increase the incidence of CKD or AKI, regardless of long COVID status. However, long COVID itself is associated with increasing risks of kidney diseases and all-cause mortality.

Association of Gaseous Ambient Air Pollution and Dementia-Related Neuroimaging Markers in the ARIC Cohort, Comparing Exposure Estimation Methods and Confounding by Study Site.

BACKGROUND: Evidence linking gaseous air pollution to late-life brain health is mixed. OBJECTIVE: We explored associations between exposure to gaseous pollutants and brain magnetic resonance imaging (MRI) markers among Atherosclerosis Risk in Communities (ARIC) Study participants, with attention to the influence of exposure estimation method and confounding by site. METHODS: We considered data from 1,665 eligible ARIC participants recruited from four US sites in the period 1987-1989 with valid brain MRI data from Visit 5 (2011-2013). We estimated 10-y (2001-2010) mean carbon monoxide (CO), nitrogen dioxide (NO2), nitrogen oxides (NOx), and 8- and 24-h ozone (O3) concentrations at participant addresses, using multiple exposure estimation methods. We estimated site-specific associations between pollutant exposures and brain MRI outcomes (total and regional volumes; presence of microhemorrhages, infarcts, lacunes, and severe white matter hyperintensities), using adjusted linear and logistic regression models. We compared meta-analytically combined site-specific associations to analyses that did not account for site. RESULTS: Within-site exposure distributions varied across exposure estimation methods. Meta-analytic associations were generally not statistically significant regardless of exposure, outcome, or exposure estimation method; point estimates often suggested associations between higher NO2 and NOx and smaller temporal lobe, deep gray, hippocampal, frontal lobe, and Alzheimer disease signature region of interest volumes and between higher CO and smaller temporal and frontal lobe volumes. Analyses that did not account for study site more often yielded significant associations and sometimes different direction of associations. DISCUSSION: Patterns of local variation in estimated air pollution concentrations differ by estimation method. Although we did not find strong evidence supporting impact of gaseous pollutants on brain changes detectable by MRI, point estimates suggested associations between higher exposure to CO, NOx, and NO2 and smaller regional brain volumes. Analyses of air pollution and dementia-related outcomes that do not adjust for location likely underestimate uncertainty and may be susceptible to confounding bias. https://doi.org/10.1289/EHP13906.

A comparison of PM2.5 exposure estimates from different estimation methods and their associations with cognitive testing and brain MRI outcomes.

BACKGROUND: Reported associations between particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5) and cognitive outcomes remain mixed. Differences in exposure estimation method may contribute to this heterogeneity. OBJECTIVES: To assess agreement between PM2.5 exposure concentrations across 11 exposure estimation methods and to compare resulting associations between PM2.5 and cognitive or MRI outcomes. METHODS: We used Visit 5 (2011-2013) cognitive testing and brain MRI data from the Atherosclerosis Risk in Communities (ARIC) Study. We derived address-linked average 2000-2007 PM2.5 exposure concentrations in areas immediately surrounding the four ARIC recruitment sites (Forsyth County, NC; Jackson, MS; suburbs of Minneapolis, MN; Washington County, MD) using 11 estimation methods. We assessed agreement between method-specific PM2.5 concentrations using descriptive statistics and plots, overall and by site. We used adjusted linear regression to estimate associations of method-specific PM2.5 exposure estimates with cognitive scores (n = 4678) and MRI outcomes (n = 1518) stratified by study site and combined site-specific estimates using meta-analyses to derive overall estimates. We explored the potential impact of unmeasured confounding by spatially patterned factors. RESULTS: Exposure estimates from most methods had high agreement across sites, but low agreement within sites. Within-site exposure variation was limited for some methods. Consistently null findings for the PM2.5-cognitive outcome associations regardless of method precluded empirical conclusions about the potential impact of method on study findings in contexts where positive associations are observed. Not accounting for study site led to consistent, adverse associations, regardless of exposure estimation method, suggesting the potential for substantial bias due to residual confounding by spatially patterned factors. DISCUSSION: PM2.5 estimation methods agreed across sites but not within sites. Choice of estimation method may impact findings when participants are concentrated in small geographic areas. Understanding unmeasured confounding by factors that are spatially patterned may be particularly important in studies of air pollution and cognitive or brain health.

The Effects of Heart Rhythm Meditation on Vagal Tone and Well-being: A Mixed Methods Research Study.

Many studies have examined the effects of meditation practice focused on the normal breath on vagal tone with mixed results. Heart Rhythm Meditation (HRM) is a unique meditation form that engages in the deep slow full breath, and puts the focus of attention on the heart. This form of breathing likely stimulates the vagus nerve with greater intensity. The purpose of this study was (a) to examine how the practice of HRM affects vagal activity as measured by heart rate variability (HRV); and (b) to examine how it affects participants' well-being. 74 participants signed consent agreeing to: (a) take a six-week course to learn the practice of HRM; (b) engage in a daily practice for 10 weeks; (c) have their heart rate variability read through ECG technology and to take two validated well-being instruments at the beginning and end of the 10 weeks; and (d) participate in a focus group interview examining their perceptions of how the practice affected their well-being. 48 participants completed the study. Quantitative findings show the effect of the practice of HRM approached significance for multiple measures of HRV and vagal tone. An increase in well-being scores for those who did the meditation more than 10-minutes per day did meet statistical significance. Qualitative data indicate: (a) the positive effects of HRM on stress and well-being; (b) the development of a more expanded sense of self; and (c) an increased awareness of the interconnection of the body-heart-emotions and HRM's role in emotion regulation.

Short-term air pollution levels and sickle cell disease hospital encounters in South Carolina: A case-crossover analysis.

BACKGROUND: Sickle cell disease (SCD) is a genetic disorder and symptoms may be sensitive to environmental stressors. Although it has been hypothesized that exposure to outdoor air pollution could trigger acute SCD events, evidence is limited. METHODS: We obtained SCD administrative data on hospital encounters in South Carolina from 2002 to 2019. We estimated outdoor air pollutant (particulate matter<2.5 µm (PM2.5), ozone (O3), and PM2.5 elemental carbon (EC) concentrations at residential zip codes using spatio-temporal models. Using a random bi-directional, fixed-interval case-crossover study design, we investigated the relationship between air pollution exposure over 1-, 3-, 5-, 9-, and14-day periods with SCD hospital encounters. RESULTS: We studied 8410 patients with 144,129 hospital encounters. We did not observe associations among all patients with SCD and adults for PM2.5, O3, and EC. We observed positive associations among children for 9- and 14-day EC (OR: 1.05 (95% confidence interval (CI): 1.02, 1.08) and OR: 1.05 (95% CI: 1.02, 1.09), respectively) and 9- and 14-day O3 (OR: 1.04 (95%CI: 1.00, 1.08)) for both. CONCLUSIONS: Our findings suggest that short-term (within two-weeks) levels of EC and O3 and may be associated with SCD hospital encounters among children. Two-pollutant model results suggest that EC is more likely responsible for effects on SCD than O3. More research is needed to confirm our findings.

Racial/ethnic disparities in the trajectories of insomnia symptoms from childhood to young adulthood.

STUDY OBJECTIVES: To examine differences in the longitudinal prevalence of childhood insomnia symptoms across black/African American, Hispanic/Latinx, and non-Hispanic white groups. METHODS: Participants were 519 children from the Penn State Child Cohort (baseline [V1] from 2000-2005) who were followed up 8 years later as adolescents (V2) and 15 years later as young adults (S3). Mean age at S3 was 24.1 ±â€…2.7 years. Approximately, 76.5% identified as non-Hispanic white, 12.9% as black/African American, 7.1% as Hispanic/Latinx, and 3.5% as "other" race/ethnicity. Insomnia symptoms were defined as parent-reported (childhood) or self-reported (adolescence and young adulthood) moderate-to-severe difficulties initiating/maintaining sleep. Longitudinal trajectories of insomnia symptoms were identified across three-time points and the odds of each trajectory were compared between racial/ethnic groups, adjusting for sex, age, overweight, sleep apnea, periodic limb movements, psychiatric/behavioral disorders, and psychotropic medication use. RESULTS: Black/African Americans compared to non-Hispanic whites were at significantly higher odds of having a childhood-onset persistent trajectory through young adulthood (OR = 2.58, 95% CI [1.29, 5.14]), while Hispanics/Latinx were at nonsignificantly higher odds to have the same trajectory (OR = 1.81, 95% CI [0.77, 4.25]). No significant racial/ethnic differences were observed for remitted and waxing-and-waning trajectories since childhood or incident/new-onset trajectories in young adulthood. CONCLUSIONS: The results indicate that disparities in insomnia symptoms among black/African American and, to a lesser extent, Hispanic/Latinx groups start early in childhood and persist into young adulthood. Identifying and intervening upon upstream determinants of racial/ethnic insomnia disparities are warranted to directly address these disparities and to prevent their adverse health sequelae. CLINICAL TRIAL INFORMATION: N/A; Not a clinical trial.

Comparison of PM2.5 Air Pollution Exposures and Health Effects Associations Using 11 Different Modeling Approaches in the Women's Health Initiative Memory Study (WHIMS).

BACKGROUND: Many approaches to quantifying air pollution exposures have been developed. However, the impact of choice of approach on air pollution estimates and health-effects associations remains unclear. OBJECTIVES: Our objective is to compare particulate matter with aerodynamic diameter ≤2.5µm (PM2.5) concentrations and resulting health effects associations using multiple estimation approaches previously used in epidemiologic analyses. METHODS: We assigned annual PM2.5 exposure estimates from 1999 to 2004 derived from 11 different approaches to Women's Health Initiative Memory Study (WHIMS) participant addresses within the contiguous US. Approaches included geostatistical interpolation approaches, land-use regression or spatiotemporal models, satellite-derived approaches, air dispersion and chemical transport models, and hybrid models. We used descriptive statistics and plots to assess relative and absolute agreement among exposure estimates and examined the impact of approach on associations between PM2.5 and death due to natural causes, cardiovascular disease (CVD) mortality, and incident CVD events, adjusting for individual-level covariates and climate-based region. RESULTS: With a few exceptions, relative agreement of approach-specific PM2.5 exposure estimates was high for PM2.5 concentrations across the contiguous US. Agreement among approach-specific exposure estimates was stronger near PM2.5 monitors, in certain regions of the country, and in 2004 vs. 1999. Collectively, our results suggest but do not quantify lower agreement at local spatial scales for PM2.5. There was no evidence of large differences in health effects associations with PM2.5 among estimation approaches in analyses adjusted for climate region. CONCLUSIONS: Different estimation approaches produced similar spatial patterns of PM2.5 concentrations across the contiguous US and in areas with dense monitoring data, and PM2.5-health effects associations were similar among estimation approaches. PM2.5 estimates and PM2.5-health effects associations may differ more in samples drawn from smaller areas or areas without substantial monitoring data, or in analyses with finer adjustment for participant location. Our results can inform decisions about PM2.5 estimation approach in epidemiologic studies, as investigators balance concerns about bias, efficiency, and resource allocation. Future work is needed to understand whether these conclusions also apply in the context of other air pollutants of interest. https://doi.org/10.1289/EHP12995.

Novel Quality Control Metric for the Pharmacotherapy of Major Depressive Disorder: Measuring Guideline Concordance and Its Impact on Symptom Severity.

Objective: Studies suggest that people with major depressive disorder (MDD) often receive treatment that is not concordant with practice guidelines. To evaluate this, we (1) developed a guideline concordance algorithm for MDD pharmacotherapy (GCA-8), (2) scored it using clinical data, and (3) compared its explanation of patient-reported symptom severity to a traditional concordance measure.Methods: This study evaluated 1,403 adults (67% female, 85% non-Hispanic/Latino White, mean age 43 years) with non-psychotic MDD (per ICD-10 codes), from the Penn State Psychiatry Clinical Assessment and Rating Evaluation System (PCARES) registry (visits from February 1, 2015, to April 13, 2021). We (1) scored 1-year concordance using the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines and deviation from 8 pharmacotherapy-related criteria and (2) examined associations between concordance and Patient Health Questionnaire depression module (PHQ-9) scores.Results: The mean GCA-8 score was 6.37 (standard deviation [SD] = 1.30; 8.00 = perfect concordance). Among those who switched drugs (n = 671), 81% (n = 542) did not have their dose increased to the recommended maximum before switching. In our adjusted analyses, we found that a 1 SD increase in the GCA-8 was associated with a 0.78 improvement in the mean PHQ-9 score (P < .001). The comparison concordance measure was not associated with the mean PHQ-9 score (ß = -0.20; P = .20; R2 = 0.53), and adding the GCA-8 score significantly improved the model (R2 = 0.54; Vuong test P = .008).Conclusions: By measuring naturalistic MDD pharmacotherapy guideline concordance with the GCA-8, we revealed potential treatment gaps and an inverse association between guideline concordance and MDD symptom severity.

Circadian misalignment impacts the association of visceral adiposity with metabolic syndrome in adolescents.

STUDY OBJECTIVES: Although insufficient sleep is a risk factor for metabolic syndrome (MetS), the circadian timing of sleep (CTS) is also involved in cardiac and metabolic regulation. We examined whether delays and deviations in the sleep midpoint (SM), a measure of CTS, modify the association between visceral adipose tissue (VAT) and MetS in adolescents. METHODS: We evaluated 277 adolescents (median 16 years) who had at least 5 nights of at-home actigraphy (ACT), in-lab polysomnography (PSG), dual-energy X-ray absorptiometry (DXA) scan, and MetS score data. Sleep midpoint (SM), sleep irregularity (SI), and social jetlag (SJL) were examined as effect modifiers of the association between VAT and MetS, including waist circumference, blood pressure, insulin resistance, triglycerides, and cholesterol. Linear regression models adjusted for demographics, ACT-sleep duration, ACT-sleep variability, and PSG-apnea-hypopnea index. RESULTS: The association between VAT and MetS was significantly stronger (p-values for interactions < 0.001) among adolescents with a schooldays SM later than 4:00 (2.66 [0.30] points increase in MetS score), a SI higher than 1 hour (2.49 [0.30]) or a SJL greater than 1.5 hours (2.15 [0.36]), than in those with an earlier SM (<3:00; 1.76 [0.28]), lower SI (<30 minutes; 0.98 [0.70]), or optimal SJL (<30 minutes; 1.08 [0.45]). CONCLUSIONS: A delayed sleep phase, an irregular sleep-wake cycle, and greater social jetlag on schooldays identified adolescents in whom VAT had a stronger association with MetS. Circadian misalignment is a risk factor that enhances the impact of visceral obesity on cardiometabolic morbidity and should be a target of preventative strategies in adolescents.

Gender differences in transdiagnostic domains and function of adults measured by DSM-5 assessment scales at the first clinical visit: a cohort study.

BACKGROUND: Measurement-based care has been called for as best practice in psychiatric care and learning health systems and use of transdiagnostic measures was suggested as part of the DSM-5. Our objective is to examine gender differences in first visit socioeconomic, transdiagnostic, and functional characteristics of a dynamic, real-world measurement-based care cohort. METHODS: Transdiagnostic, functional, and clinical measures were collected from 3,556 patients at first visit in an ambulatory psychiatric clinic. All patients were evaluated at the first visit by board-certified psychiatrists or licensed clinical psychologists. Demographic variables and clinical diagnoses were collected from the Electronic Medical Record. Self-report measures were collected that assessed transdiagnostic symptoms (DSM-5 Level 1 Cross-cutting Measure and Level 2 symptom scales), disability, alcohol use, attention deficit hyperactivity disorder (ADHD) symptoms, depression, anxiety, mania, suicidal thoughts and behaviors, and trauma exposure. RESULTS: Men and women did not differ in age, BMI, household income, high school graduation rate, race, or ethnicity, but women were more likely to be formerly married and less likely to have commercial insurance. Compared to men, women reported significantly higher overall psychopathology on the transdiagnostic Level 1 Cross-cutting measure and had higher depression, anxiety, sleep, anger, ADHD combined presentation, and suicidality severity. Women also had higher disability scores than men. However, men reported higher alcohol, tobacco and substance use, and more risky behavior than women. Trauma exposure differed significantly by gender; men reported more exposure to accidents, war-related trauma, serious accidents, and major disasters and women reported more unwanted sexual contact. CONCLUSIONS: This cross-sectional study of a transdiagnostic, ecologically-valid real-word measurement-based care cohort demonstrates gender differences in socioeconomic factors, trauma exposure, transdiagnostic symptoms, and functioning.

Urban vs. rural differences in psychiatric diagnoses, symptom severity, and functioning in a psychiatric sample.

OBJECTIVE: Identifying whether certain groups of people experience elevated rates or severities of psychiatric symptoms provides information to guide healthcare allocation. People living in urban areas have higher rates of some psychiatric disorders relative to people living in rural settings, however, it is unclear if psychiatric severity is more elevated in urban vs. rural settings. This study investigates the urban vs. rural differences in rates of psychiatric disorders and severity of psychiatric symptoms. METHOD: A cohort of patients (63% women, 85% White) presenting to an outpatient psychiatric treatment center in the U.S. completed patient-reported outcomes at all clinic visits as part of standard care. Rurality was determined by municipality population density. Sociodemographic characteristics, psychiatric diagnoses, trauma exposure, psychiatric symptom severity, functioning, and suicidality were compared by rural vs. urban municipality. RESULTS: There were virtually no differences between patients living in rural vs. urban municipalities on rates of psychiatric disorders, severity of psychiatric symptoms, functional impairment, and suicidality (ps≥.09). The only difference was that patients living in rural municipalities had higher exposure to serious accidents than patients living in urban municipalities (p < .01); exposure to nine other traumatic events did not differ between groups (p≥.07). CONCLUSIONS: People living in urban and rural municipalities have a similar need for mental health treatment. Access to care may be one explanatory factor for the occasional rural-urban differences in rates of psychiatric disorders. In other words, if people living in rural areas can access care, their symptom presentations appear unlikely to differ from those of people living in urban areas.

The association of long-term exposure to criteria air pollutants, fine particulate matter components, and airborne trace metals with late-life brain amyloid burden in the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Studies suggest associations between long-term ambient air pollution exposure and outcomes related to Alzheimer's disease (AD). Whether a link exists between pollutants and brain amyloid accumulation, a biomarker of AD, is unclear. We assessed whether long-term air pollutant exposures are associated with late-life brain amyloid deposition in Atherosclerosis Risk in Communities (ARIC) study participants. METHODS: We used a chemical transport model with data fusion to estimate ambient concentrations of PM2.5 and its components, NO2, NOx, O3 (24-hour and 8-hour), CO, and airborne trace metals. We linked concentrations to geocoded participant addresses and calculated 10-year mean exposures (2002 to 2011). Brain amyloid deposition was measured using florbetapir amyloid positron emission tomography (PET) scans in 346 participants without dementia in 2012-2014, and we defined amyloid positivity as a global cortical standardized uptake value ratio ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and each air pollutant, adjusting for putative confounders. In sensitivity analyses, we considered whether use of alternate air pollution estimation approaches impacted findings for PM2.5, NO2, NOx, and 24-hour O3. RESULTS: At PET imaging, eligible participants (N = 318) had a mean age of 78 years, 56% were female, 43% were Black, and 27% had mild cognitive impairment. We did not find evidence of associations between long-term exposure to any pollutant and brain amyloid positivity in adjusted models. Findings were materially unchanged in sensitivity analyses using alternate air pollution estimation approaches for PM2.5, NO2, NOx, and 24-hour O3. CONCLUSIONS: Air pollution may impact cognition and dementia independent of amyloid accumulation, though whether air pollution influences AD pathogenesis later in the disease course or at higher exposure levels deserves further consideration.

Objective and subjective measures of sleep initiation are differentially associated with DNA methylation in adolescents.

INTRODUCTION: The onset of puberty is associated with a shift in the circadian timing of sleep, leading to delayed sleep initiation [i.e., later sleep onset time (SOT)] due to later bedtimes and/or longer sleep onset latency (SOL). Several genome-wide association studies (GWAS) have identified genes that may be involved in the etiology of sleep phenotypes. However, circadian rhythms are also epigenetically regulated; therefore, epigenetic biomarkers may provide insight into the physiology of the pubertal sleep onset shift and the pathophysiology of prolonged or delayed sleep initiation. RESULTS: The gene-wide analysis indicated differential methylation within or around 1818 unique genes across the sleep initiation measurements using self-report, actigraphy (ACT), and polysomnography (PSG), while GWAS-informed analysis yielded 67 genes. Gene hits were identified for bedtime (PSG), SOL (subjective, ACT and PSG) and SOT (subjective and PSG). DNA methylation within 12 genes was associated with both subjective and PSG-measured SOL, 31 with both ACT- and PSG-measured SOL, 19 with both subjective and ACT-measured SOL, and one gene (SMG1P2) had methylation sites associated with subjective, ACT- and PSG-measured SOL. CONCLUSIONS: Objective and subjective sleep initiation in adolescents is associated with altered DNA methylation in genes previously identified in adult GWAS of sleep and circadian phenotypes. Additionally, our data provide evidence for a potential epigenetic link between habitual (subjective and ACT) SOL and in-lab SOT and DNA methylation in and around genes involved in circadian regulation (i.e., RASD1, RAI1), cardiometabolic disorders (i.e., FADS1, WNK1, SLC5A6), and neuropsychiatric disorders (i.e., PRR7, SDK1, FAM172A). If validated, these sites may provide valuable targets for early detection and prevention of disorders involving prolonged or delayed SOT, such as insomnia, delayed sleep phase, and their comorbidity.

Metabolomic Evaluation of Air Pollution-related Bone Damage and Potential Mediation.

Ambient air pollution has been associated with bone damage. However, no studies have evaluated the metabolomic response to air pollutants and its potential influence on bone health in postmenopausal women. We analyzed data from WHI participants with plasma samples. Whole-body, total hip, femoral neck, and spine BMD at enrollment and follow-up (Y1, Y3, Y6). Daily particulate matter NO, NO2, PM10 and SO2 were averaged over 1-, 3-, and 5-year periods before metabolomic assessments. Statistical analyses included multivariable-adjusted linear mixed models, pathways analyses, and mediation modeling. NO, NO2, and SO2, but not PM10, were associated with taurine, inosine, and C38:4 phosphatidylethanolamine (PE), at all averaging periods. We found a partial mediation of C38:4 PE in the association between 1-year average NO and lumbar spine BMD (p-value: 0.032). This is the first study suggesting that a PE may partially mediate air pollution-related bone damage in postmenopausal women.

Circadian Misalignment Impacts the Association of Visceral Adiposity With Elevated Blood Pressure in Adolescents.

BACKGROUND: Although insufficient sleep has been shown to contribute to obesity-related elevated blood pressure, the circadian timing of sleep has emerged as a novel risk factor. We hypothesized that deviations in sleep midpoint, a measure of circadian timing of sleep, modify the association between visceral adiposity and elevated blood pressure in adolescents. METHODS: We studied 303 subjects from the Penn State Child Cohort (16.2±2.2 years; 47.5% female; 21.5% racial/ethnic minority). Actigraphy-measured sleep duration, midpoint, variability, and regularity were calculated across a 7-night period. Visceral adipose tissue (VAT) was measured with dual-energy X-ray absorptiometry. Systolic blood pressure (SBP) and diastolic blood pressure levels were measured in the seated position. Multivariable linear regression models tested sleep midpoint and its regularity as effect modifiers of VAT on SBP/diastolic blood pressure levels, while adjusting for demographic and sleep covariables. These associations were also examined as a function of being in-school or on-break. RESULTS: Significant interactions were found between VAT and sleep irregularity, but not sleep midpoint, on SBP (P interaction=0.007) and diastolic blood pressure (P interaction=0.022). Additionally, significant interactions were found between VAT and schooldays sleep midpoint on SBP (P interaction=0.026) and diastolic blood pressure (P interaction=0.043), whereas significant interactions were found between VAT and on-break weekdays sleep irregularity on SBP (P interaction=0.034). CONCLUSIONS: A delayed and an irregular sleep midpoint during school and during free-days, respectively, increase the impact of VAT on elevated blood pressure in adolescents. These data suggest that deviations in the circadian timing of sleep contribute to the increased cardiovascular sequelae associated with obesity and that its distinct metrics require measurement under different entrainment conditions in adolescents.

Short-term and intermediate-term fine particulate air pollution are synergistically associated with habitual sleep variability in adolescents - A cross-sectional study.

BACKGROUND: Both air pollution and poor sleep have been associated with increased risk of cardiovascular diseases. However, the association between air pollution and sleep health, especially among adolescents, is rarely investigated. METHODS: To investigate the association between fine particulate (PM2.5) air pollution and habitual sleep patterns, we analyzed data obtained from 246 adolescents who participated in the Penn State Child Cohort follow-up examination. We collected their individual-level 24-h (short-term) PM2.5 concentration by using a portable monitor. We estimated their residential-level PM2.5 concentration during the 60-day period prior to the examination (intermediate-term) using a kriging approach. Actigraphy was used to measure participants' sleep durations for seven consecutive nights. Habitual sleep duration (HSD) and sleep variability (HSV) were calculated as the mean and SD of the seven-night sleep duration. Multivariable-adjusted linear regression models were used to assess the association between PM2.5 exposures and HSD/HSV. An interaction between short-term and intermediate-term PM2.5 was created to explore their synergistic associations with HSD/HSV. RESULTS: Elevated short-term and intermediate-term PM2.5 exposure were significantly (p < 0.05) associated with higher HSV, but not HSD. Specifically, the mean (95% CI) increase in HSV associated with 1 SD higher 24-h (26.3 µg/m3) and 60-day average (2.2 µg/m3) PM2.5 were 14.6 (9.4, 14.8) and 4.9 (0.5, 9.2) minutes, respectively. In addition, there was a synergistic interaction (p = 0.08) between short-term and intermediate-term PM2.5 exposure on HSV, indicative that the association between intermediate-term PM2.5 and HSV became stronger as short-term PM2.5 increases, and vice versa. CONCLUSION: Short-term individual-level and intermediate-term residential-level PM2.5 exposures are adversely and synergistically associated with increased sleep variability, an indicator of instability of sleep quantity, in adolescents. Through such an association with sleep pattern, PM2.5 air pollution may increase long-term cardiometabolic risks.

Short-term Air Pollution Levels and Blood Pressure in Older Women.

BACKGROUND: Evidence of associations between daily variation in air pollution and blood pressure (BP) is varied and few prior longitudinal studies adjusted for calendar time. METHODS: We studied 143,658 postmenopausal women 50 to 79 years of age from the Women's Health Initiative (1993-2005). We estimated daily atmospheric particulate matter (PM) (in three size fractions: PM2.5, PM2.5-10, and PM10) and nitrogen dioxide (NO2) concentrations at participants' residential addresses using validated lognormal kriging models. We used linear mixed-effects models to estimate the association between air pollution concentrations and repeated measures of systolic and diastolic BP (SBP, DBP) adjusting for confounders and calendar time. RESULTS: Short-term PM2.5 and NO2 were each positively associated with DBP {0.10 mmHg [95% confidence interval (CI): 0.04, 0.15]; 0.13 mmHg (95% CI: 0.09, 0.18), respectively} for interquartile range changes in lag 3-5 day PM2.5 and NO2. Short-term NO2 was negatively associated with SBP [-0.21 mmHg (95%CI: -0.30, -0.13)]. In two-pollutant models, the NO2-DBP association was slightly stronger, but for PM2.5 was attenuated to null, compared with single-pollutant models. Associations between short-term NO2 and DBP were more pronounced among those with higher body mass index, lower neighborhood socioeconomic position, and diabetes. When long-term (annual) and lag 3-5 day PM2.5 were in the same model, associations with long-term PM2.5 were stronger than for lag 3-5 day. CONCLUSIONS: We observed that short-term PM2.5 and NO2 levels were associated with increased DBP, although two-pollutant model results suggest NO2 was more likely responsible for observed associations. Long-term PM2.5 effects were larger than short-term.

Air pollution and decreased bone mineral density among Women's Health Initiative participants.

Background: Osteoporosis heavily affects postmenopausal women and is influenced by environmental exposures. Determining the impact of criteria air pollutants and their mixtures on bone mineral density (BMD) in postmenopausal women is an urgent priority. Methods: We conducted a prospective observational study using data from the ethnically diverse Women's Health Initiative Study (WHI) (enrollment, September 1994-December 1998; data analysis, January 2020 to August 2022). We used log-normal, ordinary kriging to estimate daily mean concentrations of PM10, NO, NO2, and SO2 at participants' geocoded addresses (1-, 3-, and 5-year averages before BMD assessments). We measured whole-body, total hip, femoral neck, and lumbar spine BMD at enrollment and follow-up (Y1, Y3, Y6) via dual-energy X-ray absorptiometry. We estimated associations using multivariable linear and linear mixed-effects models and mixture effects using Bayesian kernel machine regression (BKMR) models. Findings: In cross-sectional and longitudinal analyses, mean PM10, NO, NO2, and SO2 averaged over 1, 3, and 5 years before the visit were negatively associated with whole-body, total hip, femoral neck, and lumbar spine BMD. For example, lumbar spine BMD decreased 0.026 (95% CI: 0.016, 0.036) g/cm2/year per a 10% increase in 3-year mean NO2 concentration. BKMR suggested that nitrogen oxides exposure was inversely associated with whole-body and lumbar spine BMD. Interpretation: In this cohort study, higher levels of air pollutants were associated with bone damage, particularly on lumbar spine, among postmenopausal women. These findings highlight nitrogen oxides exposure as a leading contributor to bone loss in postmenopausal women, expanding previous findings of air pollution-related bone damage. Funding: US National Institutes of Health.

Long-term air pollution and risk of amyotrophic lateral sclerosis mortality in the Women's Health Initiative cohort.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure. Although the etiology of sporadic ALS is largely unknown, environmental exposures may affect ALS risk. OBJECTIVE: We investigated relationships between exposure to long-term ambient particulate matter (PM) and gaseous air pollution (AP) and ALS mortality. METHODS: Within the Women's Health Initiative (WHI) cohort of 161,808 postmenopausal women aged 50-79 years at baseline (1993-1998), we performed a nested case-control study of 256 ALS deaths and 2486 matched controls with emphasis on PM constituents (PM2.5, PM10, and coarse PM [PM10-2.5]) and gaseous pollutants (NOx, NO2, SO2, and ozone). Time-varying AP exposures estimates were averaged 5, 7.5, and 10 years prior to ALS death using both a GIS-based spatiotemporal generalized additive mixed model and ordinary kriging (empirical and multiple imputation, MI). Conditional logistic regression was used to estimate the relative risk of ALS death. RESULTS: In general, PM2.5 and PM10-related risks were not significantly elevated using either method. However, for PM10-2.5, odds ratios (ORs) were >1.0 for both methods at all time periods using MI and empirical data for PM10-2.5 (coarse) except for 5 and 7.5 years using the kriging method with covariate adjustment. CONCLUSION: This investigation adds to the body of information on long-term ambient AP exposure and ALS mortality. Specifically, the 2019 US Environmental Protection Agency (EPA) Integrated Science Assessment summarized the neurotoxic effects of PM2.5, PM10, and PM10-2.5. The conclusion was that evidence of an effect of coarse PM is suggestive but the data is presently not sufficient to infer a causal relationship. Further research on AP and ALS is warranted. As time from symptom onset to death in ALS is ∼2-4 years, earlier AP measures may also be of interest to ALS development. This is the first study of ALS and AP in postmenopausal women controlling for individual-level confounders.