Radon Exposure and Incident Stroke Risk in the Women's Health Initiative.

BACKGROUND AND OBJECTIVES: Little is known about the role of radon in the epidemiology of stroke among women. We therefore examined the association between home radon exposure and risk of stroke among middle-aged and older women in the United States. METHODS: We conducted a prospective cohort study of postmenopausal women aged 50-79 years at baseline (1993-1998) in the Women's Health Initiative. We measured exposures as 2-day, indoor, lowest living-level average radon concentrations in picocuries per liter (pCi/L) as estimated in 1993 by the US Geological Survey and reviewed by the Association of American State Geologists under the Indoor Radon Abatement Act. We used Cox proportional hazards models to estimate risk of incident, neurologist-adjudicated stroke during follow-up through 2020 as a hazard ratio and 95% CI, adjusting for study design and participant demographic, social, behavioral, and clinical characteristics. RESULTS: Among 158,910 women without stroke at baseline (mean age 63.2 years; 83% white), 6,979 incident strokes were identified over follow-up (mean 13.4 years). Incidence rates were 333, 343, and 349 strokes per 100,000 woman-years at radon concentrations of <2, 2-4, and >4 pCi/L, respectively. Compared with women living at concentrations <2 pCi/L, those at 2-4 and >4 pCi/L had higher covariate-adjusted risks of incident stroke: hazard ratio (95% CI) 1.06 (0.99-1.13) and 1.14 (1.05-1.22). Using nonlinear spline functions to model radon, stroke risk was significantly elevated at concentrations ranging from 2 to 4 pCi/L (p = 0.0004), that is, below the United States Environmental Protection Agency Radon Action Level for mitigation (4 pCi/L). Associations were slightly stronger for ischemic (especially cardioembolic, small vessel occlusive, and large artery atherosclerotic) than hemorrhagic stroke, but otherwise robust in sensitivity analyses. DISCUSSION: Radon exposure is associated with moderately increased stroke risk among middle-aged and older women in the United States, suggesting that promulgation of a lower Radon Action Level may help reduce the domestic impact of cerebrovascular disease on public health.

Radon Exposure, Clonal Hematopoiesis, and Stroke Susceptibility in the Women's Health Initiative.

BACKGROUND AND OBJECTIVES: Studies suggest that clonal hematopoiesis of indeterminate potential (CHIP) may increase risk of hematologic malignancy and cardiovascular disease, including stroke. However, few studies have investigated plausible environmental risk factors for CHIP such as radon, despite the climate-related increases in and documented infrequency of testing for this common indoor air pollutant.The purpose of this study was to estimate the risk of CHIP related to radon, an established environmental mutagen. METHODS: We linked geocoded addresses of 10,799 Women's Health Initiative Trans-Omics for Precision Medicine (WHI TOPMed) participants to US Environmental Protection Agency-predicted, county-level, indoor average screening radon concentrations, categorized as follows: Zone 1 (>4 pCi/L), Zone 2 (2-4 pCi/L), and Zone 3 (<2 pCi/L). We defined CHIP as the presence of one or more leukemogenic driver mutations with variant allele frequency >0.02. We identified prevalent and incident ischemic and hemorrhagic strokes; subtyped ischemic stroke using Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria; and then estimated radon-related risk of CHIP as an odds ratio (OR) and 95% CI using multivariable-adjusted, design-weighted logistic regression stratified by age, race/ethnicity, smoking status, and stroke type/subtype. RESULTS: The percentages of participants with CHIP in Zones 1, 2, and 3 were 9.0%, 8.4%, and 7.7%, respectively (ptrend = 0.06). Among participants with ischemic stroke, Zones 2 and 1 were associated with higher estimated risks of CHIP relative to Zone 3: 1.39 (1.15-1.68) and 1.46 (1.15-1.87), but not among participants with hemorrhagic stroke: 0.98 (0.68-1.40) and 1.03 (0.70-1.52), or without stroke: 1.04 (0.74-1.46) and 0.95 (0.63-1.42), respectively (pinteraction = 0.03). Corresponding estimates were particularly high among TOAST-subtyped cardioembolism: 1.78 (1.30-2.47) and 1.88 (1.31-2.72), or other ischemic etiologies: 1.37 (1.06-1.78) and 1.50 (1.11-2.04), but not small vessel occlusion: 1.05 (0.74-1.49) and 1.00 (0.68-1.47), respectively (pinteraction = 0.10). Observed patterns of association among strata were insensitive to attrition weighting, ancestry adjustment, prevalent stroke exclusion, separate analysis of DNMT3A driver mutations, and substitution with 3 alternative estimates of radon exposure. DISCUSSION: The robust elevation of radon-related risk of CHIP among postmenopausal women who develop incident cardioembolic stroke is consistent with a potential role of somatic genomic mutation in this societally burdensome form of cerebrovascular disease, although the mechanism has yet to be confirmed.

Individual and Neighborhood-level Socioeconomic Status and Somatic Mutations Associated With Increased Risk of Cardiovascular Disease and Mortality: A Cross-Sectional Analysis in the Women's Health Initiative.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of leukemogenic mutations in white blood cells, has been associated with increased risk of atherosclerotic cardiovascular diseases, cancer, and mortality. OBJECTIVE: We examined the relationship between individual- and neighborhood-level socioeconomic status (SES) and CHIP and evaluated effect modification by interpersonal and intrapersonal resources. METHODS: The study population included 10,799 postmenopausal women from the Women's Health Initiative without hematologic malignancy or antineoplastic medication use. Individual- and neighborhood (Census tract)-level SES were assessed across several domains including education, income, and occupation, and a neighborhood-level SES summary z-score, which captures multiple dimensions of SES, was generated. Interpersonal and intrapersonal resources were self-reports. CHIP was ascertained based on a prespecified list of leukemogenic driver mutations. Weighted logistic regression models adjusted for covariates were used to estimate risk of CHIP as an odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: The interval-scale neighborhood-level SES summary z-score was associated with a 3% increased risk of CHIP: OR (95% CI) = 1.03 (1.00-1.05), p = .038. Optimism significantly modified that estimate, such that among women with low/medium and high levels of optimism, the corresponding ORs (95% CIs) were 1.03 (1.02-1.04) and 0.95 (0.94-0.96), pInteraction < .001. CONCLUSIONS: Our findings suggest that reduced risk of somatic mutation may represent a biological pathway by which optimism protects contextually advantaged but at-risk women against age-related chronic disease and highlight potential benefits of long-term, positive psychological interventions.

Long-term aircraft noise exposure and risk of hypertension in postmenopausal women.

BACKGROUND: Studies of the association between aircraft noise and hypertension are complicated by inadequate control for potential confounders and a lack of longitudinal assessments, and existing evidence is inconclusive. OBJECTIVES: We evaluated the association between long-term aircraft noise exposure and risk of hypertension among post-menopausal women in the Women's Health Initiative Clinical Trials, an ongoing prospective U.S. METHODS: Day-night average (DNL) and night equivalent sound levels (Lnight) were modeled for 90 U.S. airports from 1995 to 2010 in 5-year intervals using the Aviation Environmental Design Tool and linked to participant geocoded addresses from 1993 to 2010. Participants with modeled exposures ≥45 A-weighted decibels (dB [A]) were considered exposed, and those outside of 45 dB(A) who also did not live in close proximity to unmodeled airports were considered unexposed. Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mmHg or inventoried/self-reported antihypertensive medication use. Using time-varying Cox proportional hazards models, we estimated hazard ratios (HRs) for incident hypertension when exposed to DNL or Lnight ≥45 versus <45 dB(A), controlling for sociodemographic, behavioral, and environmental/contextual factors. RESULTS/DISCUSSION: There were 18,783 participants with non-missing DNL exposure and 14,443 with non-missing Lnight exposure at risk of hypertension. In adjusted models, DNL and Lnight ≥45 db(A) were associated with HRs of 1.00 (95% confidence interval [CI]: 0.93, 1.08) and 1.06 (95%CI: 0.91, 1.24), respectively. There was no evidence supporting a positive exposure-response relationship, and findings were robust in sensitivity analyses. Indications of elevated risk were seen among certain subgroups, such as those living in areas with lower population density (HRinteraction: 0.84; 95%CI: 0.72, 0.98) or nitrogen dioxide concentrations (HRinteraction: 0.82; 95%CI: 0.71, 0.95), which may indicate lower ambient/road traffic noise. Our findings do not suggest a relationship between aircraft noise and incident hypertension among older women in the U.S., though associations in lower ambient noise settings merit further investigation.

Strengthening Causal Inference in Exposomics Research: Application of Genetic Data and Methods.

Advances in technologies to measure a broad set of exposures have led to a range of exposome research efforts. Yet, these efforts have insufficiently integrated methods that incorporate genetic data to strengthen causal inference, despite evidence that many exposome-associated phenotypes are heritable. Objective: We demonstrate how integration of methods and study designs that incorporate genetic data can strengthen causal inference in exposomics research by helping address six challenges: reverse causation and unmeasured confounding, comprehensive examination of phenotypic effects, low efficiency, replication, multilevel data integration, and characterization of tissue-specific effects. Examples are drawn from studies of biomarkers and health behaviors, exposure domains where the causal inference methods we describe are most often applied. Discussion: Technological, computational, and statistical advances in genotyping, imputation, and analysis, combined with broad data sharing and cross-study collaborations, offer multiple opportunities to strengthen causal inference in exposomics research. Full application of these opportunities will require an expanded understanding of genetic variants that predict exposome phenotypes as well as an appreciation that the utility of genetic variants for causal inference will vary by exposure and may depend on large sample sizes. However, several of these challenges can be addressed through international scientific collaborations that prioritize data sharing. Ultimately, we anticipate that efforts to better integrate methods that incorporate genetic data will extend the reach of exposomics research by helping address the challenges of comprehensively measuring the exposome and its health effects across studies, the life course, and in varied contexts and diverse populations. https://doi.org/10.1289/EHP9098.

Clonal Hematopoiesis Is Associated With Higher Risk of Stroke.

BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke. RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

Obesity Progression Between Young Adulthood and Midlife and Incident Arthritis: A Retrospective Cohort Study of US Adults.

OBJECTIVE: To examine the association between weight change from young adulthood to midlife and the risk of incident arthritis. METHODS: Using data from the National Health and Nutrition Examination Survey, we categorized participants into weight-change categories based on their recalled weight during young adulthood and midlife. We estimated the association of weight change and developing an arthritis condition over 10 years using adjusted Cox models. Findings were extrapolated to the US population to determine the proportion of incident arthritis cases that could be averted if the entire population maintained a normal body mass index (BMI) in young adulthood and midlife. RESULTS: Among our sample of adults who were ages 40-69 years at their midlife weight measure (n = 13,669), 3,603 developed an arthritis condition. Compared with adults who maintained a normal-normal BMI, the normal-overweight, normal-obese, overweight-obese, and obese-obese groups had a significantly elevated risk of incident arthritis conditions. The obese-overweight group had a lower risk of incident arthritis conditions compared with the obese-obese group and a comparable risk to the overweight-overweight group. Nearly one-fourth of incident arthritis cases, corresponding to 2.7 million individuals, would have been averted under the hypothetical scenario where all individuals maintained normal weight from young adulthood to midlife. CONCLUSION: Weight loss from young adulthood to midlife was associated with a substantially reduced risk of developing an arthritis condition. We found no evidence of residual risk from having been heavier earlier in life. Our findings highlight the critical need to expand obesity treatment and prevention to achieve meaningful reductions in the burden of arthritis.

Association of Weight Loss Between Early Adulthood and Midlife With All-Cause Mortality Risk in the US.

Importance: Describing potential mortality risk reduction associated with weight loss between early adulthood and midlife is important for informing primary and secondary prevention efforts for obesity. Objective: To examine the risk of all-cause mortality among adults who lost weight between early adulthood and midlife compared with adults who were persistently obese over the same period. Design, Setting, and Participants: Combined repeated cross-sectional analysis was conducted using data from the National Health and Nutrition Examination Survey III (1988-1994) and continuous waves collected in 2-year cycles between 1999 and 2014. The data analysis was conducted from February 10, 2019, to April 20, 2020. Individuals aged 40 to 74 years at the time of survey (baseline) were included in the analyses (n = 24 205). Exposures: Weight history was assessed by self-reported weight at age 25 years, at 10 years before baseline (midlife: mean age, 44 years; interquartile range, 37-55), and measured weight at baseline. Body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) at each time was categorized as normal (18.5-24.9), overweight (25.0-29.9), and obese (≥30.0). Weight change patterns were assessed from age 25 years (early adulthood) to 10 years before baseline (midlife). Main Outcomes and Measures: Incident all-cause mortality using linked data from the National Death Index. Results: Of the 24 205 participants, 11 617 were women (49.0%) and 11 567 were non-Hispanic White (76.9%). The mean (SD) BMI was 29.0 (6.1) at baseline. During a mean (SD) follow-up of 10.7 (7.2) years, 5846 deaths occurred. Weight loss from obese to overweight was associated with a 54% (hazard ratio, 0.46; 95% CI, 0.27-0.77) reduction in mortality risk compared with individuals with stable obesity between early adulthood and midlife. An estimated 3.2% (95% CI, 1.6%-4.9%) of early deaths could have been avoided if those who maintained an obese BMI instead lost weight to an overweight BMI by midlife. Overall, an estimated 12.4% (95% CI, 8.1%-16.5%) of early deaths may be attributable to having weight in excess of the normal BMI range at any point between early and mid-adulthood. Conclusions and Relevance: In this study, weight loss from obesity to overweight between early adulthood through midlife appeared to be associated with a mortality risk reduction compared with persistent obesity. These findings support the importance of population-based approaches to preventing weight gain across the life course and a need for greater emphasis on treating obesity early in life.

The contribution of obesity to prescription opioid use in the United States.

The prevalence of obesity has grown rapidly over the past several decades and has been accompanied by an increase in the prevalence of chronic pain and prescription opioid use. Obesity, through its association with pain, may represent an important contributor to opioid use. This cross-sectional study investigated the relationship between obesity and prescription opioid use among adults aged 35 to 79 years using data from the National Health and Nutrition Examination Survey (NHANES, 2003-2016). Relative to normal weight, body mass indices in the overweight {odds ratio (OR), 1.11 (confidence interval [CI], 0.88-1.39)}, obese I (OR, 1.26 [CI, 1.01-1.57]), obese II (OR, 1.69 [CI, 1.34-2.12]), and obese III (OR, 2.33 [CI, 1.76-3.08]) categories were associated with elevated odds of prescription opioid use. The association between excess weight and opioid use was stronger for chronic opioid use than for use with a duration of less than 90 days (P-value, <0.001). We estimated that 14% (CI, 9%-19%) of prescription opioid use at the population level was attributable to obesity, suggesting there might have been 1.5 million fewer opioid users per year under the hypothetical scenario where obese individuals were instead nonobese (CI, 0.9-2.0 million users). Back pain, joint pain, and muscle/nerve pain accounted for the largest differences in self-reported reasons for prescription opioid use across obesity status. Although interpretation is limited by the cross-sectional nature of the associations, our findings suggest that the obesity epidemic may be partially responsible for the high prevalence of prescription opioid use in the United States.

E-cigarette initiation and associated changes in smoking cessation and reduction: the Population Assessment of Tobacco and Health Study, 2013-2015.

BACKGROUND: The role of electronic cigarettes (e-cigarettes) in product transitions has been debated. METHODS: We used nationally representative data from the Population Assessment of Tobacco and Health Study waves 1 (2013-2014) and 2 (2014-2015) to investigate the associations between e-cigarette initiation and cigarette cessation/reduction in the USA. We limited the sample to current cigarette smokers aged 25+ years who were not current e-cigarette users at wave 1. We modelled 30-day cigarette cessation and substantial reduction in cigarette consumption as a function of e-cigarette initiation between surveys using multivariable logistic regression. RESULTS: Between waves 1 and 2, 6.9% of cigarette smokers who were not current e-cigarette users transitioned to former smokers. After adjusting for covariates, cigarette smokers who initiated e-cigarette use between waves and reported they used e-cigarettes daily at wave 2 had 7.88 (95% CI 4.45 to 13.95) times the odds of 30-day cigarette cessation compared with non-users of e-cigarettes at wave 2. Cigarette smokers who began using e-cigarettes every day and did not achieve cessation had 5.70 (95% CI 3.47 to 9.35) times the odds of reducing their average daily cigarette use by at least 50% between waves 1 and 2 compared with e-cigarette non-users. CONCLUSIONS: Daily e-cigarette initiators were more likely to have quit smoking cigarettes or reduced use compared with non-users. However, less frequent e-cigarette use was not associated with cigarette cessation/reduction. These results suggest incorporating frequency of e-cigarette use is important for developing a more thorough understanding of the association between e-cigarette use and cigarette cessation.

Prevalence and Determinants of Engagement with Obesity Care in the United States.

OBJECTIVE: Medical management of obesity can result in significant weight loss and reduce the burden of obesity-related complications. This report employs a new conceptual model to quantify engagement with obesity care and associated determinants in the US adult population. METHODS: Engagement with obesity care was conceptualized as a cascade comprising 5 successive steps: perceiving oneself as overweight, desiring to lose weight, attempting weight loss, seeking care from a health care professional for obesity, and seeking care from a physician specifically. RESULTS: Among adults with obesity, 7.3% did not perceive themselves as overweight, 1.5% perceived themselves as overweight but had no desire to lose weight, 29.9% wanted to lose weight but did not try in the last year, 51.3% tried to lose weight but did not consult a health professional, and 6.4% sought help for weight loss from a health professional but not a physician, implying that 96.4% of the population with obesity had an unmet need for obesity care. CONCLUSIONS: This analysis provides new insight into the most common points along the cascade at which disengagement occurs and can inform efforts to improve uptake of obesity-related health care services.

Electronic Cigarette Prevalence and Patterns of Use in Adults with a History of Cardiovascular Disease in the United States.

BACKGROUND: Characterizing electronic cigarette (e-cigarette) use patterns is important for guiding tobacco regulatory policy and projecting the future burden of tobacco-related diseases. Few studies have examined patterns of e-cigarette use in individuals with cardiovascular disease (CVD). METHODS AND RESULTS: We examined e-cigarette use in adults aged 18 to 89 years with a history of CVD, using data from the 2014 National Health Interview Survey. We investigated associations between ever and current e-cigarette use and smoking with multivariable logistic regression. In a secondary analysis, we modeled the association between e-cigarette use and a quit attempt over the past year. Former smokers with CVD who quit smoking within the past year showed 1.85 (95% confidence interval, 1.03, 3.33) times the odds of having ever used e-cigarettes as compared with those who reported being "some days" current smokers. Current smokers who attempted to quit smoking within the past year showed significantly increased odds of ever having used e-cigarettes (odds ratio, 1.70; 95% confidence interval, 1.25, 2.30) and currently using e-cigarettes (odds ratio, 1.97; 95% confidence interval, 1.32, 2.95) as compared with smokers who had not attempted to quit over the past year. CONCLUSIONS: Individuals with CVD who recently quit smoking or reported a recent quit attempt were significantly more likely to use e-cigarettes than current smokers and those who did not report a quit attempt. Our findings may indicate that this population is using e-cigarettes as an aid to smoking cessation. Characterizing emerging e-cigarette use behaviors in adults with CVD may help to inform outreach activities aimed at this high-risk population.

Obesity Progression Between Young Adulthood and Midlife and Incident Diabetes: A Retrospective Cohort Study of U.S. Adults.

OBJECTIVE: Understanding how changes in weight over the life course shape risk for diabetes is critical for the prevention of diabetes. Using data from the National Health and Nutrition Examination Survey (NHANES), we investigated the association between self-reported weight change from young adulthood to midlife and incident diabetes. RESEARCH DESIGN AND METHODS: We categorized individuals into four weight-change groups: those who remained nonobese (stable nonobese), those who moved from an obese BMI to a nonobese BMI (losing), those who moved from a nonobese BMI to an obese BMI (gaining), and those who remained obese (stable obese). Diabetes status was determined by self-report of a prior diagnosis, and age at diagnosis was used to establish time of diabetes onset. Hazard ratios (HRs) relating weight change to incident diabetes over 10 years of follow-up were calculated using Cox models adjusting for covariates. RESULTS: Those who were obese and lost weight exhibited a significantly lower risk (HR 0.33; 95% CI 0.14, 0.76) of diabetes compared with those with stable obesity. We also observed lower risk among those who were stable nonobese (HR 0.22; 95% CI 0.18, 0.28) and those in the gaining category (HR 0.70; 95% CI 0.57, 0.87). Further, there was evidence of an increased incidence of diabetes among obese individuals who lost weight compared with individuals who were stable nonobese; however, weight loss was rare, and the association was not statistically significant. If those who were obese had become nonobese during the 10-year period, we estimate that 9.1% (95% CI 5.3, 12.8) of observed diabetes cases could have been averted, and if the population had maintained a normal BMI during the period, 64.2% (95% CI 59.4, 68.3) of cases could have been averted. CONCLUSIONS: The findings from this study underscore the importance of population-level approaches to the prevention and treatment of obesity across the life course of individuals.

Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.

Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.