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Background: Outdoor air pollution is a ubiquitous exposure that includes endocrine-disrupting and carcinogenic compounds that may contribute to the risk of hormone-sensitive outcomes such as uterine cancer. However, there is limited evidence about the relationship between outdoor air pollution and uterine cancer incidence., Methods: We investigated the associations of residential exposure to particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5) and nitrogen dioxide (NO2) with uterine cancer among 33 417 Sister Study participants with an intact uterus at baseline (2003-2009). Annual average air pollutant concentrations were estimated at participants' geocoded primary residential addresses using validated spatiotemporal models. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for the association between time-varying 12-month PM2.5 (µg/m3) and NO2 (parts per billion; ppb) averages and uterine cancer incidence., Results: Over a median follow-up period of 9.8 years, 319 incident uterine cancer cases were identified. A 5-ppb increase in NO2 was associated with a 23% higher incidence of uterine cancer (hazard ratio = 1.23, 95% confidence interval = 1.04 to 1.46), especially among participants living in urban areas (hazard ratio = 1.53, 95% confidence interval = 1.13 to 2.07), but  PM2.5 was not associated with increased uterine cancer incidence., Conclusion: In this large US cohort, NO2, a marker of vehicular traffic exposure, was associated with a higher incidence of uterine cancer. These findings expand the scope of health effects associated with air pollution, supporting the need for policy and other interventions designed to reduce air pollutant exposure., (Published by Oxford University Press 2024.)

Background: Fine particulate matter (PM2.5) has been inconsistently associated with breast cancer incidence, however, few studies have considered historic exposure when levels were higher., Methods: Outdoor residential PM2.5 concentrations were estimated using a nationwide spatiotemporal model for women in the National Institutes of Health-AARP Diet and Health Study, a prospective cohort located in 6 states (California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania) and 2 metropolitan areas (Atlanta, GA, and Detroit, MI) and enrolled in 1995-1996 (n = 196 905). Annual average PM2.5 concentrations were estimated for a 5-year historical period 10 years prior to enrollment (1980-1984). We used Cox regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between a 10 µg/m3 increase in PM2.5 and breast cancer incidence overall and by estrogen receptor status and catchment area., Results: With follow-up of participants through 2017, a total of 15 870 breast cancer cases were identified. A 10 ug/m3 increase in PM2.5 was statistically significantly associated with overall breast cancer incidence (HR = 1.08, 95% CI = 1.02 to 1.13). The association was evident for estrogen receptor-positive (HR = 1.10, 95% CI = 1.04 to 1.17) but not estrogen receptor-negative tumors (HR = 0.97, 95% CI = 0.84 to 1.13; Pheterogeneity = .3). Overall breast cancer hazard ratios were more than 1 across the catchment areas, ranging from a hazard ratio of 1.26 (95% CI = 0.96 to 1.64) for North Carolina to a hazard ratio of 1.04 (95% CI = 0.68 to 1.57) for Louisiana (Pheterogeneity = .9)., Conclusions: In this large US cohort with historical air pollutant exposure estimates, PM2.5 was associated with risk of estrogen receptor-positive breast cancer. State-specific estimates were imprecise but suggest that future work should consider region-specific associations and the potential contribution of PM2.5 chemical constituency in modifying the observed association., (Published by Oxford University Press 2023.)

Study Objectives: Sleep is an important dimension in the care of chronic obstructive pulmonary disease (COPD), but its relevance to exacerbations is unclear. We wanted to assess whether sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) is associated with an increased risk of COPD exacerbations and does this differ by socio-environmental exposures., Methods: We included 1647 current and former smokers with spirometrically confirmed COPD from the SPIROMICS cohort. We assessed incidence rate ratios for exacerbation using zero-inflated negative binomial regression adjusting for demographics, medical comorbidities, and multiple metrics of disease severity, including respiratory medications, airflow obstruction, and symptom burden. Our final model adjusted for socio-environmental exposures using the Area Deprivation Index, a composite measure of contemporary neighborhood quality, and Adversity-Opportunity Index, a composite measure of individual-level historic and current socioeconomic indicators. We used a pre-determined threshold of 20% missingness to undertake multiple imputation by chained equations. As sensitivity analyses, we repeated models in those with complete data and after controlling for prior exacerbations. As an exploratory analysis, we considered an interaction between socio-environmental condition and sleep quality., Results: After adjustment for all co-variates, increasing PSQI scores (range 0-21) were associated with a 5% increased risk for exacerbation per point (p = .001) in the imputed dataset. Sensitivity analyses using complete cases and after controlling for prior exacerbation history were similar. Exploratory analysis suggested less effect among those who lived in poor-quality neighborhoods (p-for-interaction = .035)., Conclusions: Poor sleep quality may contribute to future exacerbations among patients with COPD. This represents one target for improving disease control., Clinical Trial Registration: Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). ClinicalTrials.gov Identifier# NCT01969344. Registry URL: https://clinicaltrials.gov/ct2/show/., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Objectives: To quantify the gender-specific associations between insomnia symptoms and subclinical atherosclerosis, measured by coronary artery calcium (CAC) scores, which has strong predictive value for incident cardiovascular disease., Methods: We analyzed data from 1,429 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants completed standardized questionnaires and underwent polysomnography (PSG) and 7-day actigraphy. Insomnia symptoms were defined as: self-reported trouble falling, staying or returning to sleep, early-morning awakenings, or hypnotic use, for ≥5 nights/week. MESA assessed CAC using computed tomography. We employed multivariable linear regression to model the probability of CAC >0 overall and to model the linear continuous effect among those with nonzero CAC., Results: Our sample was a mean age of 68.1 ± 9.1 years, 53.9% female, and 36.2% white, 28.0% black, 24.2% Hispanic, and 11.5% Chinese-American. Insomnia symptoms were present in 49.7% of men and 47.2% of women. In multivariable-adjusted analyses, insomnia symptoms was associated with an 18% higher prevalence of CAC (PR 1.18, 95% CI 1.04, 1.33) among females, but no association was observed among males (PR 1.00, 95% CI 0.91, 1.08). There was no evidence that the association between insomnia symptoms and prevalence of CAC >0 differed by objective sleep duration status (by single-night PSG or multi-night actigraphy) in females or males., Conclusions: We found that among women, insomnia symptoms were associated with an 18% higher prevalence of CAC compared to no insomnia. Insomnia symptoms were not associated with CAC prevalence in men. Additionally, there was no evidence that the association between insomnia symptoms and CAC score >0 differed by objective short sleep duration status., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Cigarette smoking is inversely associated with DNA methylation of the aryl hydrocarbon receptor repressor (AHRR; cg05575921). However, the association between secondhand tobacco smoke (SHS) exposure and AHRR methylation is unknown., Methods: DNA methylation of AHRR cg05575921 in CD14+ monocyte samples, from 495 never-smokers and 411 former smokers (having quit smoking ≥15 years) from the Multi-Ethnic Study of Atherosclerosis (MESA), was cross-sectionally compared with concomitantly ascertained self-reported SHS exposure, urine cotinine concentrations, and estimates of air pollutants at participants' homes. Linear regression was used to test for associations, and covariates included age, sex, race, education, study site, and previous smoking exposure (smoking status, time since quitting, and pack-years)., Results: Recent indoor SHS exposure (hours per week) was inversely associated with cg05575921 methylation (β ± SE = -0.009 ± 0.003, p = .007). The inverse effect direction was consistent (but did not reach significance) in the majority of stratified analyses (by smoking status, sex, and race). Categorical analysis revealed high levels of recent SHS exposure (≥10 hours per week) inversely associated with cg05575921 methylation (β ± SE = -0.28 ± 0.09, p = .003), which remained significant (p < .05) in the majority of stratified analyses. cg05575921 methylation did not significantly (p < .05) associate with low to moderate levels of recent SHS exposure (1-9 hours per week), urine cotinine concentrations, years spent living with people smoking, years spent indoors (not at home) with people smoking, or estimated levels of air pollutants., Conclusions: High levels of recent indoor SHS exposure may be inversely associated with DNA methylation of AHRR in human monocytes., Implications: DNA methylation is a biochemical alteration that can occur in response to cigarette smoking; however, little is known about the effect of SHS on human DNA methylation. In the present study, we evaluated the association between SHS exposure and DNA methylation in human monocytes, at a site (AHRR cg05575921) known to have methylation inversely associated with current and former cigarette smoking compared to never smoking. Results from this study suggest high levels of recent SHS exposure inversely associate with DNA methylation of AHRR cg05575921 in monocytes from nonsmokers, albeit with weaker effects than active cigarette smoking., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Economic, social, technical, and political drivers are fundamentally changing the nature of work and work environments, with profound implications for the field of occupational health. Nevertheless, researchers and practitioners entering the field are largely being trained to assess and control exposures using approaches developed under old models of work and risks., Methods: A speaker series and symposium were organized to broadly explore current challenges and future directions for the occupational health field. Broad themes identified throughout these discussions are characterized and discussed to highlight important future directions of occupational health., Findings: Despite the relatively diverse group of presenters and topics addressed, some important cross-cutting themes emerged. Changes in work organization and the resulting insecurity and precarious employment arrangements change the nature of risk to a large fraction of the workforce. Workforce demographics are changing, and economic disparities among working groups are growing. Globalization exacerbates the 'race to the bottom' for cheap labor, poor regulatory oversight, and limited labor rights. Largely, as a result of these phenomena, the historical distinction between work and non-work exposures has become largely artificial and less useful in understanding risks and developing effective public health intervention models. Additional changes related to climate change, governmental and regulatory limitations, and inadequate surveillance systems challenge and frustrate occupational health progress, while new biomedical and information technologies expand the opportunities for understanding and intervening to improve worker health., Conclusion: The ideas and evidences discussed during this project suggest that occupational health training, professional practice, and research evolve towards a more holistic, public health-oriented model of worker health. This will require engagement with a wide network of stakeholders. Research and training portfolios need to be broadened to better align with the current realities of work and health and to prepare practitioners for the changing array of occupational health challenges., (© The Author 2017. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.)

Arterial dysfunction has been linked to decline in cardiac function and increased risk of cardiovascular disease events. We calculated the value of arterial function, measured at baseline (2000-2002), in predicting time to first coronary heart disease (CHD) event (median follow-up, 10.2 years) among participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Measures included the following: C 1 and C 2 , derived from diastolic pulse contour analysis from the radial artery blood pressure waveform obtained by tonometry (n = 6,336); carotid distensibility and Young's elastic modulus at the carotid artery, derived from carotid artery ultrasonography (n = 6,531 and 6,528); and aortic distensibility, measured using cardiac magnetic resonance imaging (n = 3,677). After adjustment, the hazard ratio for a CHD event per standard-deviation increment in arterial function was 0.97 (95% confidence interval (CI): 0.86, 1.10) for C 1 , 0.73 (95% CI: 0.63, 0.86) for C 2 , 0.98 (95% CI: 0.86, 1.11) for carotid distensibility, 0.99 (95% CI: 0.90, 1.09) for Young's modulus, and 0.90 (95% CI: 0.74, 1.10) for aortic distensibility. We examined the area under the receiver operating characteristic curve for the model with full adjustment plus the addition of each measure individually. C 2 provided additional discrimination for the prediction of CHD (area under the curve = 0.736 vs. 0.743; P = 0.04). Lower C 2 was associated with a higher risk of future CHD events., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Air pollution epidemiology studies are trending towards a multi-pollutant approach. In these studies, exposures at subject locations are unobserved and must be predicted using observed exposures at misaligned monitoring locations. This induces measurement error, which can bias the estimated health effects and affect standard error estimates. We characterize this measurement error and develop an analytic bias correction when using penalized regression splines to predict exposure. Our simulations show bias from multi-pollutant measurement error can be severe, and in opposite directions or simultaneously positive or negative. Our analytic bias correction combined with a non-parametric bootstrap yields accurate coverage of 95% confidence intervals. We apply our methodology to analyze the association of systolic blood pressure with PM 2.5 and NO 2 in the NIEHS Sister Study. We find that NO 2 confounds the association of systolic blood pressure with PM 2.5 and vice versa. Elevated systolic blood pressure was significantly associated with increased PM 2.5 and decreased NO 2 . Correcting for measurement error bias strengthened these associations and widened 95% confidence intervals.

The sum of urinary inorganic arsenic (iAs) and methylated arsenic (monomethylarsonate and dimethylarsinate (DMA)) species is the main biomarker of iAs exposure. Assessing iAs exposure, however, is difficult in populations with moderate-to-high seafood intakes. In the present study, we used subsamples from the Multi-Ethnic Study of Atherosclerosis (2000-2002) (n = 310) and the 2003-2006 National Health and Nutrition Examination Survey (n = 1,175). We calibrated urinary concentrations of non-seafood-derived iAs, DMA, and methylarsonate, as well as the sum of inorganic and methylated arsenic species, in the Multi-Ethnic Study of Atherosclerosis and of DMA in the National Health and Nutrition Examination Survey by regressing their original concentrations by arsenobetaine and extracting model residuals. To confirm that calibrated biomarkers reflected iAs exposure but not seafood intake, we compared urinary arsenic concentrations by levels of seafood and rice intakes. Self-reported seafood intakes, estimated n-3 polyunsaturated fatty acid levels, and measured n-3 polyunsaturated fatty acid levels were positively associated with the original urinary arsenic biomarkers. Using the calibrated arsenic biomarkers, we found a marked attenuation of the associations with self-reported seafood intake and estimated or measured n-3 fatty acids, whereas associations with self-reported rice intake remained similar. Our residual-based method provides estimates of iAs exposure and metabolism for each participant that no longer reflect seafood intake and can facilitate research about low-to-moderate levels of iAs exposure in populations with high seafood intakes., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although air pollution has been suggested as a possible risk factor for type 2 diabetes mellitus (DM), results from existing epidemiologic studies have been inconsistent. We investigated the associations of prevalence and incidence of DM with long-term exposure to air pollution as estimated using annual average concentrations of particulate matter with an aerodynamic diameter of 2.5 μm or less (PM₂.₅) and nitrogen oxides at baseline (2000) in the Multi-Ethnic Study of Atherosclerosis. All participants were aged 45-84 years at baseline and were recruited from 6 US sites. There were 5,839 participants included in the study of prevalent DM and 5,135 participants without DM at baseline in whom we studied incident DM. After adjustment for potential confounders, we found significant associations of prevalent DM with PM₂.₅ (odds ratio (OR) = 1.09, 95% confidence interval (CI): 1.00, 1.17) and nitrogen oxides (OR = 1.18, 95% CI: 1.01, 1.38) per each interquartile-range increase (2.43 µg/m(3) and 47.1 ppb, respectively). Larger but nonsignificant associations were observed after further adjustment for study site (for PM₂.₅, OR = 1.16, 95% CI: 0.94, 1.42; for nitrogen oxides, OR = 1.29, 95% CI: 0.94, 1.76). No air pollution measures were significantly associated with incident DM over the course of the 9-year follow-up period. Results were partly consistent with a link between long-term exposure to air pollution and the risk of type 2 DM. Additional studies with a longer follow-up time and a greater range of air pollution exposures, including high levels, are warranted to evaluate the hypothesized association., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Long-term exposure to outdoor particulate matter with an aerodynamic diameter less than or equal to 2.5 µm (PM2.5) has been associated with cardiovascular morbidity and mortality. The chemical composition of PM2.5 that may be most responsible for producing these associations has not been identified. We assessed cross-sectional associations between long-term concentrations of PM2.5 and 4 of its chemical components (sulfur, silicon, elemental carbon, and organic carbon (OC)) and subclinical atherosclerosis, measured as carotid intima-media thickness (CIMT) and coronary artery calcium, between 2000 and 2002 among 5,488 Multi-Ethnic Study of Atherosclerosis participants residing in 6 US metropolitan areas. Long-term concentrations of PM2.5 components at participants' homes were predicted using both city-specific spatiotemporal models and a national spatial model. The estimated differences in CIMT associated with interquartile-range increases in sulfur, silicon, and OC predictions from the spatiotemporal model were 0.022 mm (95% confidence interval (CI): 0.014, 0.031), 0.006 mm (95% CI: 0.000, 0.012), and 0.026 mm (95% CI: 0.019, 0.034), respectively. Findings were generally similar using the national spatial model predictions but were often sensitive to adjustment for city. We did not find strong evidence of associations with coronary artery calcium. Long-term concentrations of sulfur and OC, and possibly silicon, were associated with CIMT using 2 distinct exposure prediction modeling approaches., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Researchers have theorized that social and psychosocial factors increase vulnerability to the deleterious health effects of environmental hazards. We used baseline examination data (2000-2002) from the Multi-Ethnic Study of Atherosclerosis. Participants were 45-84 years of age and free of clinical cardiovascular disease at enrollment (n = 6814). The modifying role of social and psychosocial factors on the association between exposure to air pollution comprising particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5) and blood pressure measures were examined using linear regression models. There was no evidence of synergistic effects of higher PM2.5 and adverse social/psychosocial factors on blood pressure. In contrast, there was weak evidence of stronger associations of PM2.5 with blood pressure in higher socioeconomic status groups. For example, those in the 10th percentile of the income distribution (i.e., low income) showed no association between PM2.5 and diastolic blood pressure (b = -0.41 mmHg; 95% confidence interval: -1.40, 0.61), whereas those in the 90th percentile of the income distribution (i.e., high income) showed a 1.52-mmHg increase in diastolic blood pressure for each 10-µg/m(3) increase in PM2.5 (95% confidence interval: 0.22, 2.83). Our results are not consistent with the hypothesis that there are stronger associations between PM2.5 exposures and blood pressure in persons of lower socioeconomic status or those with greater psychosocial adversity.

The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45-84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.

The isolated ribonuclease (RNase) H domain of human immunodeficiency virus type 1 (HIV-1) is enzymatically inactive. The incorporation of the putative substrate binding site of Escherichia coli RNase HI (amino acid residues 76-102, the alpha c-helix and adjacent loop region) into the equivalent position of the RNase H domain of HIV-1 resulted in a highly active hybrid protein dependent on Mn2+. Similar restoration of RNase H activity has been observed when histidine residues are added to either the N- or C-terminus of the HIV-1 RNase H domain. The hybrid HIV-1/E. coli RNase H protein is approximately 10-fold more active than HIV-1 reverse transcriptase and 30-fold more active than the histidine-tagged proteins, indicating that the alpha c-helix and adjacent loop region of E. coli RNase HI is an excellent substrate binding region because of its sequence and/or location. The RNase H hybrid produced the same specific cleavage in the model tRNA(Lys3) primer removal assay as HIV-1 reverse transcriptase, showing that substrate binding and specificity are separable and that the specificity determinants are at least partially, if not totally, contained in the amino acid sequence of the hybrid protein derived from HIV-1 reverse transcriptase.