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Short-term elevations in ambient fine particulate matter (PM(2.5)) may increase resting systolic (SBP) and diastolic (DBP) blood pressures, but whether PM(2.5) alters hemodynamic responses to orthostatic challenge has not been studied in detail. We repeatedly measured SBP and DBP during supine rest and 1 and 3 minutes after standing among 747 elderly (aged 78.3±5.3 years, mean±SD) participants from a prospective cohort study. We used linear mixed models to assess the association between change in SBP (ΔSBP=standing SBP-supine SBP) and DBP (ΔDBP) on standing and mean PM(2.5) levels over the preceding 1 to 28 days, adjusting for meteorologic covariates, temporal trends, and medical history. We observed a 1.4-mm Hg (95% CI: 0.0-2.8 mm Hg; P=0.046) higher ΔSBP and a 0.7-mm Hg (95% CI: 0.0-1.4 mm Hg; P=0.053) higher ΔDBP at 1 minute of standing per interquartile range increase (3.8 μg/m(3)) in mean PM(2.5) levels in the past 7 days. ΔSBP and ΔDBP measured 3 minutes after standing were not associated with PM(2.5). Resting DBP (but not SBP or pulse pressure) was positively associated with PM(2.5) at longer averaging periods. Responses were more strongly associated with black carbon than sulfate levels. These associations did not differ significantly according to hypertension status, obesity, diabetes mellitus, or sex. These results suggest that ambient particles can increase resting DBP and exaggerate blood pressure responses to postural changes in elderly people. Increased vasoreactivity during posture change may be responsible, in part, for the adverse effect of ambient particles on cardiovascular health. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of air pollutants in risk of dementia, considering differences by study factors that could influence findings., Design: Systematic review and meta-analysis., Data Sources: EMBASE, PubMed, Web of Science, Psycinfo, and OVID Medline from database inception through July 2022., Eligibility Criteria for Selecting Studies: Studies that included adults (≥18 years), a longitudinal follow-up, considered US Environmental Protection Agency criteria air pollutants and proxies of traffic pollution, averaged exposure over a year or more, and reported associations between ambient pollutants and clinical dementia. Two authors independently extracted data using a predefined data extraction form and assessed risk of bias using the Risk of Bias In Non-randomised Studies of Exposures (ROBINS-E) tool. A meta-analysis with Knapp-Hartung standard errors was done when at least three studies for a given pollutant used comparable approaches., Results: 2080 records identified 51 studies for inclusion. Most studies were at high risk of bias, although in many cases bias was towards the null. 14 studies could be meta-analysed for particulate matter <2.5 µm in diameter (PM 2.5 ). The overall hazard ratio per 2 μg/m 3 PM 2.5 was 1.04 (95% confidence interval 0.99 to 1.09). The hazard ratio among seven studies that used active case ascertainment was 1.42 (1.00 to 2.02) and among seven studies that used passive case ascertainment was 1.03 (0.98 to 1.07). The overall hazard ratio per 10 μg/m 3 nitrogen dioxide was 1.02 ((0.98 to 1.06); nine studies) and per 10 μg/m 3 nitrogen oxide was 1.05 ((0.98 to 1.13); five studies). Ozone had no clear association with dementia (hazard ratio per 5 μg/m 3 was 1.00 (0.98 to 1.05); four studies)., Conclusion: PM 2.5 might be a risk factor for dementia, as well as nitrogen dioxide and nitrogen oxide, although with more limited data. The meta-analysed hazard ratios are subject to limitations that require interpretation with caution. Outcome ascertainment approaches differ across studies and each exposure assessment approach likely is only a proxy for causally relevant exposure in relation to clinical dementia outcomes. Studies that evaluate critical periods of exposure and pollutants other than PM 2.5 , and studies that actively assess all participants for outcomes are needed. Nonetheless, our results can provide current best estimates for use in burden of disease and regulatory setting efforts., Systematic Review Registration: PROSPERO CRD42021277083., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from National Institutes of Health and Biogen for the submitted work; MGW served on the Healthy Climate, Healthy Lives Advisory Board for Biogen and EHW received salary support from Alexion, and Moderna Tx; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: When emergency physicians see new patients in an ad libitum system, they see fewer patients as the shift progresses. However, it is unclear if this reflects a decreasing workload, as patient assessments often span many hours. We sought to investigate whether the size of a physician's queue of active patients similarly declines over a shift., Methods: Retrospective cohort study, conducted over two years in three community hospitals in the Northeastern United States, with 8 and 9-h shifts. Timestamps of all encounters were recorded electronically. Generalized estimating equations were constructed to predict the number of active patients a physician concurrently managed per hour., Results: We evaluated 64 physicians over a two-year period, with 9822 physician-shifts. Across all sites, physicians managed an increasing queue of active patients in the first several hours. This queue plateaued in the middle of the shift, declining in the final hours, independently of other factors. Physicians' queues of active patients increased slightly with greater volume and acuity, but did not affect the overall pattern of work. Similarly, working alone or with colleagues had little effect on the number of active patients managed., Conclusions: Emergency physicians in an ad libitum system tend to see new patients until reaching a stable roster of active patients. This pattern may help explain why physicians see fewer new patients over the course of a shift, should be factored into models of throughput, and suggests new avenues for evaluating relationships between physician workload, patient safety, physicians' well-being, and the quality of care., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The association between particulate pollution and cardiovascular morbidity and mortality is well established. While the cardiovascular effects of nationally regulated criteria pollutants (e.g., fine particulate matter [PM 2.5 ] and nitrogen dioxide) have been well documented, there are fewer studies on particulate pollutants that are more specific for traffic, such as black carbon (BC) and particle number (PN). In this paper, we synthesized studies conducted in the Greater Boston Area on cardiovascular health effects of traffic exposure, specifically defined by BC or PN exposure or proximity to major roadways. Large cohort studies demonstrate that exposure to traffic-related particles adversely affect cardiac autonomic function, increase systemic cytokine-mediated inflammation and pro-thrombotic activity, and elevate the risk of hypertension and ischemic stroke. Key patterns emerged when directly comparing studies with overlapping exposure metrics and population cohorts. Most notably, cardiovascular risk estimates of PN and BC exposures were larger in magnitude or more often statistically significant compared to those of PM 2.5 exposures. Across multiple exposure metrics (e.g., short-term vs. long-term; observed vs. modeled) and different population cohorts (e.g., elderly, individuals with co-morbidities, young healthy individuals), there is compelling evidence that BC and PN represent traffic-related particles that are especially harmful to cardiovascular health. Further research is needed to validate these findings in other geographic locations, characterize exposure errors associated with using monitored and modeled traffic pollutant levels, and elucidate pathophysiological mechanisms underlying the cardiovascular effects of traffic-related particulate pollutants. Implications : Traffic emissions are an important source of particles harmful to cardiovascular health. Traffic-related particles, specifically BC and PN, adversely affect cardiac autonomic function, increase systemic inflammation and thrombotic activity, elevate BP, and increase the risk of ischemic stroke. There is evidence that BC and PN are associated with greater cardiovascular risk compared to PM 2.5 . Further research is needed to elucidate other health effects of traffic-related particles and assess the feasibility of regulating BC and PN or their regional and local sources.

Background: Short-term exposure to air pollution has been associated with cardiovascular events, potentially by promoting endothelial cell activation and inflammation. A few large-scale studies have examined the associations and have had mixed results., Methods: We included 3820 non-current smoking participants (mean age 56 years, 54% women) from the Framingham Offspring cohort examinations 7 (1998-2001) and 8 (2005-2008), and Third Generation cohort examination 1 (2002-2005), who lived within 50 km of a central monitoring station. We calculated the 1- to 7-day moving averages of fine particulate matter (PM 2.5 ), black carbon (BC), sulfate (SO 4 2- ), nitrogen oxides (NO x ), and ozone before examination visits. We used linear mixed effect models for P-selectin, monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1, lipoprotein-associated phospholipase A2 activity and mass, and osteoprotegerin that were measured up to twice, and linear regression models for CD40 ligand and interleukin-18 that were measured once, adjusting for demographics, life style and clinical factors, socioeconomic position, time, and meteorology., Results: We found negative associations of PM 2.5 and BC with P-selectin, of ozone with MCP-1, and of SO 4 2- and NO x with osteoprotegerin. At the 5-day moving average, a 5 µg/m 3 higher PM 2.5 was associated with 1.6% (95% CI: - 2.8, - 0.3) lower levels of P-selectin; a 10 ppb higher ozone was associated with 1.7% (95% CI: - 3.2, - 0.1) lower levels of MCP-1; and a 20 ppb higher NO x was associated with 2.0% (95% CI: - 3.6, - 0.4) lower levels of osteoprotegerin., Conclusions: We did not find evidence of positive associations between short-term air pollution exposure and endothelial cell activation. On the contrary, short-term exposure to higher levels of ambient pollutants were associated with lower levels of P-selectin, MCP-1, and osteoprotegerin in the Framingham Heart Study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Acute exposure to cold dry air is a trigger of bronchoconstriction, but little is known about how daily outdoor temperature influences lung function.We investigated associations of temperature from a model using satellite remote sensing data with repeated measures of lung function among 5896 participants of the Framingham Heart Study Offspring and Third Generation cohorts residing in the Northeastern US. We further tested if temperature modified previously reported associations between pollution and lung function. We constructed linear mixed-effects models, and assessed departures from linearity using penalised splines.In fully adjusted linear models, 1-, 2- and 7-day average temperatures were all associated with lower lung function: each 5°C higher previous-week temperature was associated with a 20 mL lower (95% CI -34---6) forced expiratory volume in 1 s. There was significant effect modification by season: negative associations of temperature and lung function were present in winter and spring only. Negative associations between previous-day fine particulate matter and lung function were present during unseasonably warm but not unseasonably cool days, with a similar pattern for other pollutants.We speculate that temperature-related differences in lung function may be explained by behavioural changes on relatively warm days, which may increase outdoor exposures., Competing Interests: Conflict of interest: M.B. Rice reports grants from the American Thoracic Society Foundation, American Lung Association and National Institutes of Environmental Health Sciences, during the conduct of the study; and she is the vice chair of the American Thoracic Society's Environmental Health Policy Committee. Conflict of interest: W. Li has nothing to disclose. Conflict of interest: E.H. Wilker reports grants from the National Institutes of Health and US Environmental Protection Agency, during the conduct of the study. Conflict of interest: D.R. Gold reports grants from the National Institutes of Health and US Environmental Protection Agency, during the conduct of the study. Conflict of interest: J. Schwartz has nothing to disclose. Conflict of interest: A. Zanobetti reports grants from the National Institutes of Health, US Environmental Protection Agency and Health Effect Institute, during the conduct of the study. Conflict of interest: P. Koutrakis reports a grant from US Environmental Protection Agency (RD-835872-01), during the conduct of the study. Conflict of interest: I. Kloog has nothing to disclose. Conflict of interest: G.R. Washko reports grants from the National Institutes of Health and BTG Interventional Medicine, grants and other support from Boehringer Ingelheim and Janssen Pharmaceuticals, other support from Genentech, Quantitative Imaging Solutions, PulmonX, Regeneron, ModoSpira, Toshiba and GlaxoSmithKline, outside the submitted work; G.R. Washko's spouse works for Biogen, which is focused on developing therapies for fibrotic lung disease. Conflict of interest: G.T. O'Connor reports personal fees from AstraZeneca and grants from Janssen Pharmaceuticals, outside the submitted work. Conflict of interest: M.A. Mittleman reports grants from the National Institutes of Health and US Environmental Protection Agency, during the conduct of the study., (Copyright ©ERS 2019.)

Background: Decay products of radioactive materials may attach to ambient fine particles and form radioactive aerosol. Internal ionizing radiation source from inhaled radioactive aerosol may contribute to the fine particulate matter (PM 2.5 )-inflammation pathway. However, few studies in humans have examined the associations., Objectives: To examine the associations between particle radioactivity and biomarkers of oxidative stress and inflammation among participants from the Framingham Offspring and Third Generation cohorts., Methods: We included 3996 participants who were not current smokers and lived within 50 km from our central air pollution monitoring station. We estimated regional mean gross beta radioactivity from monitors in the northeastern U.S. as a surrogate for ambient radioactive particles, and calculated the 1- to 28-day moving averages. We used linear regression models for fibrinogen, tumor necrosis factor α, interleukin-6, and myeloperoxidase which were measured once, and linear mixed effect models for 8-epi-prostaglandin F 2α , C-reactive protein, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), P-selectin, and tumor necrosis factor receptor-2 that were measured up to twice, adjusting for demographics, individual- and area-level socioeconomic positions, time, meteorology, and PM 2.5 . We also examined whether the associations differed by median age, sex, diabetes status, PM 2.5 levels, and black carbon levels., Results: The mean age was 54 years and 54% were women. An interquartile range (3 × 10 -3  pCi/m 3 ) higher beta radioactivity level at the 7-day moving average was associated with 5.09% (95% CI: 0.92, 9.43), 2.65% (1.10, 4.22), and 4.71% (95% CI: 3.01, 6.44) higher levels of interleukin-6, MCP-1, and P-selectin, but with 7.01% (95% CI: -11.64, -2.15) and 2.70% (95% CI: -3.97, -1.42) lower levels of 8-epi-prostaglandin F 2α and ICAM-1, respectively., Conclusions: Regional mean particle radioactivity was positively associated with interleukin-6, MCP-1, and P-selectin, but negatively with ICAM-1 and 8-epi-prostaglandin F 2α among our study participants., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Studies of air pollution exposure and arterial stiffness have reported inconsistent results and large studies employing the reference standard of arterial stiffness, carotid-femoral pulse-wave velocity (CFPWV), have not been conducted., Aim: To study long-term exposure to ambient fine particles (PM 2.5 ), proximity to roadway, and short-term air pollution exposures in relation to multiple measures of arterial stiffness in the Framingham Heart Study., Methods: We assessed central arterial stiffness using CFPWV, forward pressure wave amplitude, mean arterial pressure and augmentation index. We investigated long-and short-term air pollution exposure associations with arterial stiffness with linear regressions using long-term residential PM 2.5 (2003 average from a spatiotemporal model using satellite data) and proximity to roadway in addition to short-term averages of PM 2.5 , black carbon, particle number, sulfate, nitrogen oxides, and ozone from stationary monitors., Results: We examined 5842 participants (mean age 51 ± 16, 54% women). Living closer to a major roadway was associated with higher arterial stiffness (0.11 m/s higher CFPWV [95% CI: 0.01, 0.22] living <50 m vs 400 ≤ 1000 m). We did not observe association between arterial stiffness measures and long-term PM 2.5 or short-term levels of PM 2.5 , particle number, sulfate or ozone. Higher levels of black carbon and nitrogen oxides in the previous days were unexpectedly associated with lower arterial stiffness., Conclusions: Long-term exposure to PM 2.5 was not associated with arterial stiffness but positive associations with living close to a major road may suggest that pollutant mixtures very nearby major roads, rather than PM 2.5 , may affect arterial stiffness. Furthermore, short-term air pollution exposures were not associated with higher arterial stiffness., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Purpose- Associations between exposures to ambient air pollution and spontaneous intracerebral hemorrhage (ICH) have been inconsistent, and data on stroke subtypes are currently limited. Methods- We obtained information on all cases of deep or lobar hematomas from ICH patients who were admitted to the Massachusetts General Hospital in Boston, MA, between 2006 and 2011. We linked the date of admission with 1- to 7-day moving averages of fine particulate matter (PM 2.5 ), black carbon, nitrogen dioxide, and ozone from area monitors. We conducted time-stratified bidirectional case-crossover analyses to assess associations between pollutants and stroke. We also investigated whether associations differed by hemorrhage location and type. Results- There were 577 cases of ICH (295 deep, 282 lobar). Overall, there was no evidence of elevated ICH risk after increases in PM 2.5 , black carbon, or nitrogen dioxide in the whole population. However, there was suggestion of heightened risk with higher levels of ozone for averages longer than 1 day although CIs were wide. In models stratified by ICH location, associations with ozone remained positive for patients with lobar (3-day moving average odds ratio, 1.62; 95% CI, 1.18-2.22) but not deep ICH (odds ratio, 0.88; 95% CI, 0.65-1.20). Larger estimates were observed among participants with a probable diagnosis of cerebral amyloid angiopathy (odds ratio, 2.23; 95% CI, 1.25-3.96). Conclusions- Exposure to ozone may be associated with incidence of lobar ICH, especially among those who have confirmed or probable cerebral amyloid angiopathy.

Rationale & Objective: Mesoamerican nephropathy (MeN), a form of chronic kidney disease (CKD) of unknown cause in Central America, affects young individuals working in physically strenuous occupations. Repeated episodes of work-related kidney injury may lead to CKD in this setting. We aimed to better understand the burden and natural history of acute kidney injury (AKI) in workers at risk for MeN., Study Design: Cross-sectional study of active sugarcane workers, followed by prospective follow-up of individuals with AKI., Setting & Participants: 326 sugarcane workers with normal preharvest serum creatinine (Scr) values and no history of CKD in an MeN hotspot in Nicaragua near the end of the harvest, and prospective follow-up of workers with AKI., Predictor: AKI during the harvest, as defined by Scr level increase ≥ 0.3mg/dL over baseline to a level ≥ 1.3mg/dL., Outcomes: Kidney function trajectory and development of CKD over 12 months., Analytical Approach: Linear regression models were used to analyze the association between job category and kidney function. For workers with AKI, the effect of time on Scr level was evaluated using linear mixed effects., Results: 34 of 326 participants were found to have AKI, with a median late-harvest Scr level of 1.64mg/dL in the AKI group. Workers without AKI had a median Scr level of 0.88mg/dL. AKI was more common among cane cutters compared with other field workers. Participants with AKI had variable degrees of kidney function recovery, with median 6- and 12-month Scr values of 1.25 and 1.27mg/dL, respectively (P < 0.001 for each follow-up value compared to late-harvest Scr). When we compared workers' kidney function before the AKI episode to their kidney function at last follow-up, 10 participants with AKI developed de novo estimated glomerular filtration rate < 60mL/min/1.73m 2 and 11 had a >30% decrease in estimated glomerular filtration rate., Limitations: Follow-up limited to 1 year and some loss to follow-up in the prospective component of the study. Broad definition of AKI that includes both acute and subacute kidney injury., Conclusions: In a group of sugarcane workers with normal preharvest kidney function, newly decreased kidney function developing during the harvest season was common. Of those with kidney injury, nearly half had established CKD 12 months later., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Exposure to ambient air pollution has been associated with lower lung function in adults, but few studies have investigated associations with radiographic lung and airway measures., Methods: We ascertained lung volume, mass, density, visual emphysema, airway size, and airway wall area by computed tomography (CT) among 2,545 nonsmoking Framingham CT substudy participants. We examined associations of home distance to major road and PM2.5 (2008 average from a spatiotemporal model using satellite data) with these outcomes using linear and logistic regression models adjusted for age, sex, height, weight, census tract median household value and population density, education, pack-years of smoking, household tobacco exposure, cohort, and date. We tested for differential susceptibility by sex, smoking status (former vs. never), and cohort., Results: The mean participant age was 60.1 years (standard deviation 11.9 years). Median PM2.5 level was 9.7 µg/m (interquartile range, 1.6). Living <100 m from a major road was associated with a 108 ml (95% CI = 8, 207) higher lung volume compared with ≥400 m away. There was also a log-linear association between proximity to road and higher lung volume. There were no convincing associations of proximity to major road or PM2.5 with the other pulmonary CT measures. In subgroup analyses, road proximity was associated with lower lung density among men and higher odds of emphysema among former smokers., Conclusions: Living near a major road was associated with higher average lung volume, but otherwise, we found no association between ambient pollution and radiographic measures of emphysema or airway disease.

Objectives: Emergency physician productivity, often defined as new patients evaluated per hour, is essential to planning clinical operations. Prior research in this area considered this a static quantity; however, our group's study of resident physicians demonstrated significant decreases in hourly productivity throughout shifts. We now examine attending physicians' productivity to determine if it is also dynamic., Methods: This is a retrospective cohort study, conducted from 2014 to 2016 across three community hospitals in the north-eastern USA, with different schedules and coverage. Timestamps of all patient encounters were automatically logged by the sites' electronic health record. Generalised estimating equations were constructed to predict productivity in terms of new patients per shift hour., Results: 207 169 patients were seen by 64 physicians over 2 years, comprising 9822 physician shifts. Physicians saw an average of 15.0 (SD 4.7), 20.9 (SD 6.4) and 13.2 (SD 3.8) patients per shift at the three sites, with 2.97 (SD 0.22), 2.95 (SD 0.24) and 2.17 (SD 0.09) in the first hour. Across all sites, physicians saw significantly fewer new patients after the first hour, with more gradual decreases subsequently. Additional patient arrivals were associated with greater productivity; however, this attenuates substantially late in the shift. The presence of other physicians was also associated with slightly decreased productivity., Conclusions: Physician productivity over a single shift follows a predictable pattern that decreases significantly on an hourly basis, even if there are new patients to be seen. Estimating productivity as a simple average substantially underestimates physicians' capacity early in a shift and overestimates it later. This pattern of productivity should be factored into hospitals' staffing plans, with shifts aligned to start with the greatest volumes of patient arrivals., Competing Interests: Competing interests: SD and OL are employees of LogixHealth, which provides billing, coding and analytics services for EDs throughout the USA., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To examine associations of proximity to major roadways, sustained exposure to fine particulate matter (PM 2.5 ), and acute exposure to ambient air pollutants with adipokines and measures of glucose homeostasis among participants living in the northeastern United States., Methods: We included 5958 participants from the Framingham Offspring cohort examination cycle 7 (1998-2001) and 8 (2005-2008) and Third Generation cohort examination cycle 1 (2002-2005) and 2 (2008-2011), who did not have type 2 diabetes at the time of examination visit. We calculated 2003 annual average PM 2.5 at participants' home address, residential distance to the nearest major roadway, and daily PM 2.5 , black carbon (BC), sulfate, nitrogen oxides (NO x ), and ozone concentrations. We used linear mixed effects models for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) which were measured up to twice, and used linear regression models for adiponectin, resistin, leptin, and hemoglobin A1c (HbA1c) which were measured only once, adjusting for demographics, socioeconomic position, lifestyle, time, and seasonality., Results: The mean age was 51years and 55% were women. Participants who lived 64m (25th percentile) from a major roadway had 0.28% (95% CI: 0.05%, 0.51%) higher fasting plasma glucose than participants who lived 413m (75th percentile) away, and the association appeared to be driven by participants who lived within 50m from a major roadway. Higher exposures to 3- to 7-day moving averages of BC and NO x were associated with higher glucose whereas the associations for ozone were negative. The associations otherwise were generally null and did not differ by median age, sex, educational attainment, obesity status, or prediabetes status., Conclusions: Living closer to a major roadway or acute exposure to traffic-related air pollutants were associated with dysregulated glucose homeostasis but not with adipokines among participants from the Framingham Offspring and Third Generation cohorts., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We examined associations between ambient air pollution and hepatic steatosis among 2,513 participants from the Framingham (Massachusetts) Offspring Study and Third Generation Cohort who underwent a computed tomography scan (2002-2005), after excluding men who reported >21 drinks/week and women who reported >14 drinks/week. We calculated each participant's residential-based distance to a major roadway and used a spatiotemporal model to estimate the annual mean concentrations of fine particulate matter. Liver attenuation was measured by computed tomography, and liver-to-phantom ratio (LPR) was calculated. Lower values of LPR represent more liver fat. We estimated differences in continuous LPR using linear regression models and prevalence ratios for presence of hepatic steatosis (LPR ≤ 0.33) using generalized linear models, adjusting for demographics, individual and area-level measures of socioeconomic position, and clinical and lifestyle factors. Participants who lived 58 m (25th percentile) from major roadways had lower LPR (β = -0.003, 95% confidence interval: -0.006, -0.001) and higher prevalence of hepatic steatosis (prevalence ratio = 1.16, 95% confidence interval: 1.05, 1.28) than those who lived 416 m (75th percentile) away. The 2003 annual average fine particulate matter concentration was not associated with liver-fat measurements. Our findings suggest that living closer to major roadways was associated with more liver fat., (© The Author(s) 2017. 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.)

Objective: The objective of this study is to examine associations between short-term exposure to ambient air pollution and circulating biomarkers of systemic inflammation in participants from the Framingham Offspring and Third Generation cohorts in the greater Boston area., Approach and Results: We included 3996 noncurrent smoking participants (mean age, 53.6 years; 54% women) who lived within 50 km from a central air pollution monitoring site in Boston, MA, and calculated the 1- to 7-day moving averages of fine particulate matter (diameter<2.5 µm), black carbon, sulfate, nitrogen oxides, and ozone before the examination visits. We used linear mixed effects models for C-reactive protein and tumor necrosis factor receptor 2, which were measured up to twice for each participant; we used linear regression models for interleukin-6, fibrinogen, and tumor necrosis factor α, which were measured once. We adjusted for demographics, socioeconomic position, lifestyle, time, and weather. The 3- to 7-day moving averages of fine particulate matter (diameter<2.5 µm) and sulfate were positively associated with C-reactive protein concentrations. A 5 µg/m 3 higher 5-day moving average fine particulate matter (diameter<2.5 µm) was associated with 4.2% (95% confidence interval: 0.8, 7.6) higher circulating C-reactive protein. Positive associations were also observed for nitrogen oxides with interleukin-6 and for black carbon, sulfate, and ozone with tumor necrosis factor receptor 2. However, black carbon, sulfate, and nitrogen oxides were negatively associated with fibrinogen, and sulfate was negatively associated with tumor necrosis factor α., Conclusions: Higher short-term exposure to relatively low levels of ambient air pollution was associated with higher levels of C-reactive protein, interleukin-6, and tumor necrosis factor receptor 2 but not fibrinogen or tumor necrosis factor α in individuals residing in the greater Boston area., (© 2017 American Heart Association, Inc.)

Few studies have examined rates and causes of short-term readmissions among adults across age and insurance types. We compared rates, characteristics, and costs of 30-day readmission after all-cause hospitalizations across insurance types in the US. We retrospectively evaluated alive patients ≥18 years old, discharged for any cause, 1/1/13-11/31/13, 2006 non-federal hospitals in 21 states in the Nationwide Readmissions Database. The primary stratification variable of interest was primary insurance. Comorbid conditions were assessed based on Elixhauser comorbidities, as defined by administrative billing codes. Additional measures included diagnoses for index hospitalizations leading to rehospitalization. Hierarchical multivariable logistic regression models, with hospital site as a random effect, were used to calculate the adjusted odds of 30-day readmissions by age group and insurance categories. Cost and discharge estimates were weighted per NRD procedures to reflect a nationally representative sample. Diagnoses for index hospitalizations leading to rehospitalization were determined. Among 12,533,551 discharges, 1,818,093 (14.5%) resulted in readmission within 30 days. Medicaid insurance was associated with the highest adjusted odds ratio (AOR) for readmission both in those ≥65 years old (AOR 1.12, 95%CI 1.10-1.14; p <0.001), and 45-64 (AOR 1.67, 95% CI 1.66-1.69; p < 0.001), and Medicare in the 18-44 group (Medicare vs. private insurance: AOR 1.99, 95% CI 1.96-2.01; p <0.001). Discharges for psychiatric or substance abuse disorders, septicemia, and heart failure accounted for the largest numbers of readmissions, with readmission rates of 24.0%, 17.9%, 22.9% respectively. Total costs for readmissions were 50.7 billion USD, highest for Medicare (29.6 billion USD), with non-Medicare costs exceeding 21 billion USD. While Medicare readmissions account for more than half of the total burden of readmissions, costs of non-Medicare readmissions are nonetheless substantial. Medicaid patients have the highest odds of readmission in individuals older than age 44, commonly due to hospitalizations for psychiatric illness and substance abuse disorders. Medicaid patients represent a population at uniquely high risk for readmission.

Objectives: Traffic and ambient air pollution exposure are positively associated with cardiovascular disease, potentially through atherosclerosis promotion. Few studies have assessed associations of these exposures with thoracic aortic calcium Agatston score (TAC) or abdominal aortic calcium Agatston score (AAC), systemic atherosclerosis correlates. We assessed whether living close to a major road and residential fine particulate matter (PM 2.5 ) exposure were associated with TAC and AAC in a Northeastern US cohort., Design: Cohort study., Setting: Framingham Offspring and Third Generation participants residing in the Northeastern USA., Participants and Outcome Measures: Among 3506 participants, mean age was 55.8 years; 50% female. TAC was measured from 2002 to 2005 and AAC up to two times (2002-2005; 2008-2011) among participants from the Framingham Offspring or Third Generation cohorts. We first assessed associations with detectable TAC (logistic regression) and AAC (generalised estimating equation regression, logit link). As aortic calcium scores were right skewed, we used linear regression models and mixed-effects models to assess associations with natural log-transformed TAC and AAC, respectively, among participants with detectable aortic calcium. We also assessed associations with AAC progression. Models were adjusted for demographic variables, socioeconomic position indicators and time., Results: There were no consistent associations of major roadway proximity or PM 2.5 with the presence or extent of TAC or AAC, or with AAC progression. Some estimates were in the opposite direction than expected., Conclusions: In this cohort from a region with relatively low levels of and variation in PM 2.5 , there were no strong associations of proximity to a major road or PM 2.5 with the presence or extent of aortic calcification, or with AAC progression., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Individually, heart failure (HF) and Alzheimer's disease (AD) are severe threats to population health, and their potential coexistence is an alarming prospect. In addition to sharing analogous epidemiological and genetic profiles, biochemical characteristics, and common triggers, the authors recently recognized common molecular and pathological features between the 2 conditions. Whereas cognitive impairment has been linked to HF through perfusion defects, angiopathy, and inflammation, whether patients with AD present with myocardial dysfunction, and if the 2 conditions bear a common pathogenesis as neglected siblings are unknown., Objectives: Here, the authors investigated whether amyloid beta (Aβ) protein aggregates are present in the hearts of patients with a primary diagnosis of AD, affecting myocardial function., Methods: The authors examined myocardial function in a retrospective cross-sectional study from a cohort of AD patients and age-matched controls. Imaging and proteomics approaches were used to identify and quantify Aβ deposits in AD heart and brain specimens compared with controls. Cell shortening and calcium transients were measured on isolated adult cardiomyocytes., Results: Echocardiographic measurements of myocardial function suggest that patients with AD present with an anticipated diastolic dysfunction. As in the brain, Aβ 40 and Aβ 42 are present in the heart, and their expression is increased in AD., Conclusions: Here, the authors provide the first report of the presence of compromised myocardial function and intramyocardial deposits of Aβ in AD patients. The findings depict a novel biological framework in which AD may be viewed either as a systemic disease or as a metastatic disorder leading to heart, and possibly multiorgan failure. AD and HF are both debilitating and life-threatening conditions, affecting enormous patient populations. Our findings underline a previously dismissed problem of a magnitude that will require new diagnostic approaches and treatments for brain and heart disease, and their combination., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Higher traffic-related air pollution has been associated with higher body mass index (BMI) among children. However, few studies have assessed the associations among adults., Methods: Participants (N = 2,372) from the Framingham Offspring and Third Generation cohorts who underwent multidetector-computed tomography scans (2002-2005) were included. Residential-based proximity to the nearest major roadway and 1-year average levels of fine particulate matter (PM 2.5 ) air pollution were estimated. BMI was measured at Offspring examination 7 (1998-2001) and Third Generation examination 1 (2002-2005); subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured using multidetector-computed tomography. Linear regression models were used for continuous BMI, SAT, and VAT and logistic models for the binary indicator of obesity (BMI ≥30 kg/m 2 ), adjusting for demographic variables, individual- and area-level measures of socioeconomic position, and clinical and lifestyle factors., Results: Participants who lived 60 m from a major roadway had 0.37 kg/m 2 higher BMI (95% CI: 0.10 to 0.65 kg/m 2 ), 78.4 cm 3 higher SAT (95% CI: 4.5 to 152.3 cm 3 ), and 41.8 cm 3 higher VAT (95% CI: -4.7 to 88.2 cm 3 ) than those who lived 440 m away., Conclusions: Living closer to a major roadway was associated with higher overall and abdominal adiposity., (© 2016 The Obesity Society.)

Objective: Long-term exposure to traffic and particulate matter air pollution is associated with a higher risk of cardiovascular disease, potentially via atherosclerosis promotion. Prior research on associations of traffic and particulate matter with coronary artery calcium Agatston score (CAC), an atherosclerosis correlate, has yielded inconsistent findings. Given this background, we assessed whether residential proximity to major roadway or fine particulate matter were associated with CAC in a Northeastern US study., Approach and Results: We measured CAC ≤2 times from 2002 to 2005 and 2008 to 2011 among Framingham Offspring or Third-Generation Cohort participants. We assessed associations of residential distance to major roadway and residential fine particulate matter (2003 average; spatiotemporal model) with detectable CAC, using generalized estimating equation regression. We used linear mixed effects models to assess associations with loge(CAC). We also assessed associations with CAC progression. Models were adjusted for demographic variables, socioeconomic position markers, and time. Among 3399 participants, 51% had CAC measured twice. CAC was detectable in 47% of observations. At first scan, mean age was 52.2 years (standard deviation 11.7); 51% male. There were no consistent associations with detectable CAC, continuous CAC, or CAC progression. We observed heterogeneous associations of distance to major roadway with odds of detectable CAC by hypertensive status; interpretation of these findings is questionable., Conclusions: Our findings add to prior work and support evidence against strong associations of traffic or fine particulate matter with the presence, extent, or progression of CAC in a region with relatively low levels of and little variation in fine particulate matter., (© 2016 American Heart Association, Inc.)

Background: Long-term exposure to ambient air pollution has been associated with impaired cognitive function and vascular disease in older adults, but little is known about these associations among people with concerns about memory loss., Objective: To examine associations between exposures to fine particulate matter and residential proximity to major roads and markers of small vessel disease., Methods: From 2004-2010, 236 participants in the Massachusetts Alzheimer's Disease Research Center Longitudinal Cohort participated in neuroimaging studies. Residential proximity to major roads and estimated 2003 residential annual average of fine particulate air pollution (PM2.5) were linked to measures of brain parenchymal fraction (BPF), white matter hyperintensities (WMH), and cerebral microbleeds. Associations were modeled using linear and logistic regression and adjusted for clinical and lifestyle factors., Results: In this population (median age [interquartile range] = 74 [12], 57% female) living in a region with median 2003 PM2.5 annual average below the current Environmental Protection Agency (EPA) standard, there were no associations between living closer to a major roadway or for a 2μg/m3 increment in PM2.5 and smaller BPF, greater WMH volume, or a higher odds of microbleeds. However, a 2μg/m3 increment in PM2.5 was associated with -0.19 (95% Confidence Interval (CI): -0.37, -0.005) lower natural log-transformed WMH volume. Other associations had wide confidence intervals., Conclusions: In this population, where median 2003 estimated PM2.5 levels were below the current EPA standard, we observed no pattern of association between residential proximity to major roads or 2003 average PM2.5 and greater burden of small vessel disease or neurodegeneration.

Background: Short-term exposure to elevated air pollution has been associated with higher risk of acute cardiovascular diseases, with systemic oxidative stress induced by air pollution hypothesized as an important underlying mechanism. However, few community-based studies have assessed this association., Methods and Results: Two thousand thirty-five Framingham Offspring Cohort participants living within 50 km of the Harvard Boston Supersite who were not current smokers were included. We assessed circulating biomarkers of oxidative stress including blood myeloperoxidase at the seventh examination (1998-2001) and urinary creatinine-indexed 8-epi-prostaglandin F2α (8-epi-PGF2α) at the seventh and eighth (2005-2008) examinations. We measured fine particulate matter (PM2.5), black carbon, sulfate, nitrogen oxides, and ozone at the Supersite and calculated 1-, 2-, 3-, 5-, and 7-day moving averages of each pollutant. Measured myeloperoxidase and 8-epi-PGF2α were loge transformed. We used linear regression models and linear mixed-effects models with random intercepts for myeloperoxidase and indexed 8-epi-PGF2α, respectively. Models were adjusted for demographic variables, individual- and area-level measures of socioeconomic position, clinical and lifestyle factors, weather, and temporal trend. We found positive associations of PM2.5 and black carbon with myeloperoxidase across multiple moving averages. Additionally, 2- to 7-day moving averages of PM2.5 and sulfate were consistently positively associated with 8-epi-PGF2α. Stronger positive associations of black carbon and sulfate with myeloperoxidase were observed among participants with diabetes than in those without., Conclusions: Our community-based investigation supports an association of select markers of ambient air pollution with circulating biomarkers of oxidative stress., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Prior studies including the Framingham Heart Study have suggested associations between single components of air pollution and vascular function; however, underlying mixtures of air pollution may have distinct associations with vascular function., Methods: We used a k-means approach to construct five distinct pollution mixtures from elemental analyses of particle filters, air pollution monitoring data, and meteorology. Exposure was modeled as an interaction between fine particle mass (PM2.5), and concurrent pollution cluster. Outcome variables were two measures of microvascular function in the fingertip in the Framingham Offspring and Third Generation cohorts from 2003 to 2008., Results: In 1,720 participants, associations between PM2.5 and baseline pulse amplitude tonometry differed by air pollution cluster (interaction P value 0.009). Higher PM2.5 on days with low mass concentrations but high proportion of ultrafine particles from traffic was associated with 18% (95% confidence interval: 4.6%, 33%) higher baseline pulse amplitude per 5 μg/m and days with high contributions of oil and wood combustion with 16% (95% confidence interval: 0.2%, 34%) higher baseline pulse amplitude. We observed no variation in associations of PM2.5 with hyperemic response to ischemia observed across air pollution clusters., Conclusions: PM2.5 exposure from air pollution mixtures with large contributions of local ultrafine particles from traffic, heating oil, and wood combustion was associated with higher baseline pulse amplitude but not hyperemic response. Our findings suggest little association between acute exposure to air pollution clusters reflective of select sources and hyperemic response to ischemia, but possible associations with excessive small artery pulsatility with potentially deleterious microvascular consequences.

Introduction: Air pollution exposure has been linked to impaired cognitive aging, but little is known about biomarkers modifying this association. MicroRNAs (miRNAs) control gene expression and neuronal programming. miRNA levels vary due to single nucleotide polymorphisms (SNPs) in genes processing miRNAs from precursor molecules., Objectives: To investigate whether SNPs in miRNA-processing genes are associated with cognition and modify the relationship between black carbon (BC), marker of traffic-related pollution, and cognitive functions., Methods: 533 Normative Aging Study men (mean±SD 72±7years) were tested ≤4 times (mean=1.7 times) using seven cognitive tests between 1995 and 2007. We tested interactions of 16 miRNA-related SNPs with 1-year average BC from a validated land-use-regression model. We used covariate-adjusted logistic regression for low (≤25) Mini-Mental tate Examination (MMSE) and mixed-effect regression for a global cognitive score combining six other tests., Results: Global cognition was negatively associated with the homozygous minor variant of rs595961 AGO1 (-0.42SD; 95%CI: (-0.71, -0.13)) relative to the major variant. BC-MMSE association was stronger in heterozygous carriers of rs11077 XPO5 (OR=1.99; 95%CI: (1.39, 2.85)) and minor variant carriers of GEMIN4 rs2740348 (OR=1.34; 95%CI: (1.05, 1.7)), compared to their major variant. The BC-global-cognition association was stronger in heterozygous carriers of GEMIN4 rs4968104 (-0.10SD; 95%CI: (-0.18, -0.02)), and GEMIN4 rs910924 (-0.09SD; 95%CI: (-0.17, -0.02)) relative to the major variant. Blood miRNA expression analyses showed associations only of XPO5 rs11077 with miR-9 and miR-96., Conclusions: Carriers of particular miRNA-processing SNPs had higher susceptibility to BC in BC-cognition associations, possibly due to influences on miRNA expression., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Early and late readmissions may have different causal factors, requiring different prevention strategies., Objective: To determine whether predictors of readmission change within 30 days after discharge., Design: Retrospective cohort study., Setting: Academic medical center., Participants: Patients admitted between 1 January 2009 and 31 December 2010., Measurements: Factors related to the index hospitalization (acute illness burden, inpatient care process factors, and clinical indicators of instability at discharge) and unrelated factors (chronic illness burden and social determinants of health) and how they affect early readmissions (0 to 7 days after discharge) and late readmissions (8 to 30 days after discharge)., Results: 13 334 admissions, representing 8078 patients, were included in the analysis. Early readmissions were associated with markers of acute illness burden, including length of hospital stay (odds ratio [OR], 1.02 [95% CI, 1.00 to 1.03]) and whether a rapid response team was called for assessment (OR, 1.48 [CI, 1.15 to 1.89]); markers of chronic illness burden, including receiving a medication indicating organ failure (OR, 1.19 [CI, 1.02 to 1.40]); and social determinants of health, including barriers to learning (OR, 1.18 [CI, 1.01 to 1.38]). Early readmissions were less likely if a patient was discharged between 8:00 a.m. and 12:59 p.m. (OR, 0.76 [CI, 0.58 to 0.99]). Late readmissions were associated with markers of chronic illness burden, including receiving a medication indicating organ failure (OR, 1.24 [CI, 1.08 to 1.41]) or hemodialysis (OR, 1.61 [CI, 1.12 to 2.17]), and social determinants of health, including barriers to learning (OR, 1.24 [CI, 1.09 to 1.42]) and having unsupplemented Medicare or Medicaid (OR, 1.16 [CI, 1.01 to 1.33])., Limitation: Readmissions were ascertained at 1 institution., Conclusion: The time frame of 30 days after hospital discharge may not be homogeneous. Causal factors and readmission prevention strategies may differ for the early versus late periods., Primary Funding Source: Health Resources and Services Administration, National Institute on Aging, National Institutes of Health, Harvard Catalyst, and Harvard University.

Background and Purpose: Long-term exposure to ambient air pollution is associated with cerebrovascular disease and cognitive impairment, but whether it is related to structural changes in the brain is not clear. We examined the associations between residential long-term exposure to ambient air pollution and markers of brain aging using magnetic resonance imaging., Methods: Framingham Offspring Study participants who attended the seventh examination were at least 60 years old and free of dementia and stroke were included. We evaluated associations between exposures (fine particulate matter [PM2.5] and residential proximity to major roadways) and measures of total cerebral brain volume, hippocampal volume, white matter hyperintensity volume (log-transformed and extensive white matter hyperintensity volume for age), and covert brain infarcts. Models were adjusted for age, clinical covariates, indicators of socioeconomic position, and temporal trends., Results: A 2-μg/m(3) increase in PM2.5 was associated with -0.32% (95% confidence interval, -0.59 to -0.05) smaller total cerebral brain volume and 1.46 (95% confidence interval, 1.10 to 1.94) higher odds of covert brain infarcts. Living further away from a major roadway was associated with 0.10 (95% confidence interval, 0.01 to 0.19) greater log-transformed white matter hyperintensity volume for an interquartile range difference in distance, but no clear pattern of association was observed for extensive white matter., Conclusions: Exposure to elevated levels of PM2.5 was associated with smaller total cerebral brain volume, a marker of age-associated brain atrophy, and with higher odds of covert brain infarcts. These findings suggest that air pollution is associated with insidious effects on structural brain aging even in dementia- and stroke-free persons., (© 2015 American Heart Association, Inc.)

Rationale: Few studies have examined associations between long-term exposure to fine particulate matter (PM2.5) and lung function decline in adults., Objectives: To determine if exposure to traffic and PM2.5 is associated with longitudinal changes in lung function in a population-based cohort in the Northeastern United States, where pollution levels are relatively low., Methods: FEV1 and FVC were measured up to two times between 1995 and 2011 among 6,339 participants of the Framingham Offspring or Third Generation studies. We tested associations between residential proximity to a major roadway and PM2.5 exposure in 2001 (estimated by a land-use model using satellite measurements of aerosol optical thickness) and lung function. We examined differences in average lung function using mixed-effects models and differences in lung function decline using linear regression models. Current smokers were excluded. Models were adjusted for age, sex, height, weight, pack-years, socioeconomic status indicators, cohort, time, season, and weather., Measurements and Main Results: Living less than 100 m from a major roadway was associated with a 23.2 ml (95% confidence interval [CI], -44.4 to -1.9) lower FEV1 and a 5.0 ml/yr (95% CI, -9.0 to -0.9) faster decline in FEV1 compared with more than 400 m. Each 2 μg/m(3) increase in average of PM2.5 was associated with a 13.5 ml (95% CI, -26.6 to -0.3) lower FEV1 and a 2.1 ml/yr (95% CI, -4.1 to -0.2) faster decline in FEV1. There were similar associations with FVC. Associations with FEV1/FVC ratio were weak or absent., Conclusions: Long-term exposure to traffic and PM2.5, at relatively low levels, was associated with lower FEV1 and FVC and an accelerated rate of lung function decline.

We investigated associations between ambient air pollution and microvessel function measured by peripheral arterial tonometry between 2003 and 2008 in the Framingham Heart Study Offspring and Third Generation Cohorts. We measured particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), black carbon, sulfates, particle number, nitrogen oxides, and ozone by using fixed monitors, and we determined moving averages for 1-7 days preceding vascular testing. We examined associations between these exposures and hyperemic response to ischemia and baseline pulse amplitude, a measure of arterial tone (n = 2,369). Higher short-term exposure to air pollutants, including PM2.5, black carbon, and particle number was associated with higher baseline pulse amplitude. For example, higher 3-day average PM2.5 exposure was associated with 6.3% higher baseline pulse amplitude (95% confidence interval: 2.0, 10.9). However, there were no consistent associations between the air pollution exposures assessed and hyperemic response. Our findings in a community-based sample exposed to relatively low pollution levels suggest that short-term exposure to ambient particulate pollution is not associated with vasodilator response, but that particulate air pollution is associated with baseline pulse amplitude, suggesting potentially adverse alterations in baseline vascular tone or compliance., (© 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.)

Background: Residential proximity to green space has been associated with physical and mental health benefits, but whether green space is associated with post-stroke survival has not been studied., Methods: Patients ≥ 21 years of age admitted to the Beth Israel Deaconess Medical Center (BIDMC) between 1999 and 2008 with acute ischemic stroke were identified. Demographics, presenting symptoms, medical history and imaging results were abstracted from medical records at the time of hospitalization for stroke onset. Addresses were linked to average Normalized Difference Vegetation Index, distance to roadways with more than 10,000 cars/day, and US census block group. Deaths were identified through June 2012 using the Social Security Death Index., Results: There were 929 deaths among 1645 patients with complete data (median follow up: 5 years). In multivariable Cox models adjusted for indicators of medical history, demographic and socioeconomic factors, the hazard ratio for patients living in locations in the highest quartile of green space compared to the lowest quartile was 0.78 (95% Confidence Interval: 0.63-0.97) (p-trend = 0.009). This association remained statistically significant after adjustment for residential proximity to a high traffic road., Conclusions: Residential proximity to green space is associated with higher survival rates after ischemic stroke in multivariable adjusted models. Further work is necessary to elucidate the underlying mechanisms for this association, and to better understand the exposure-response relationships and susceptibility factors that may contribute to higher mortality in low green space areas., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Long-term exposure to ambient air pollution has been associated with cardiovascular morbidity and mortality. Impaired vascular responses may, in part, explain these findings, but the association of such long-term exposure with measures of both conduit artery and microvascular function has not been widely reported. We evaluated the association between residential proximity to a major roadway (primary or secondary highway) and spatially resolved average fine particulate matter (PM2.5) and baseline brachial artery diameter and mean flow velocity, flow-mediated dilation%, and hyperemic flow velocity, in the Framingham Offspring and Third Generation Cohorts. We examined 5,112 participants (2,731 [53%] women, mean age 49 ± 14 years). Spatially resolved average PM2.5 was associated with lower flow-mediated dilation% and hyperemic flow velocity. An interquartile range difference in PM2.5 (1.99 μg/m(3)) was associated with -0.16% (95% confidence interval [CI] -0.27%, -0.05%) lower flow-mediated dilation% and -0.72 (95% CI -1.38, -0.06) cm/s lower hyperemic flow velocity%. Residential proximity to a major roadway was negatively associated with flow-mediated dilation%. Compared with living ≥400 m away, living <50 m from a major roadway was associated with 0.32% lower flow-mediated dilation (95% CI -0.58%, -0.06%), but results for hyperemic flow velocity had wide confidence intervals -0.68 cm/s (95% CI -2.29, 0.93). In conclusion, residential proximity to a major roadway and higher levels of spatially resolved estimates of PM2.5 at participant residences are associated with impaired conduit artery and microvascular function in this large community-based cohort of middle-aged and elderly adults., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Differences in methylation across tissues are critical to cell differentiation and are key to understanding the role of epigenetics in complex diseases. In this investigation, we found that locus-specific methylation differences between tissues are highly consistent across individuals. We developed a novel statistical model to predict locus-specific methylation in target tissue based on methylation in surrogate tissue. The method was evaluated in publicly available data and in two studies using the latest IlluminaBeadChips: a childhood asthma study with methylation measured in both peripheral blood leukocytes (PBL) and lymphoblastoid cell lines; and a study of postoperative atrial fibrillation with methylation in PBL, atrium and artery. We found that our method can greatly improve accuracy of cross-tissue prediction at CpG sites that are variable in the target tissue [R(2) increases from 0.38 (original R(2) between tissues) to 0.89 for PBL-to-artery prediction; from 0.39 to 0.95 for PBL-to-atrium; and from 0.81 to 0.98 for lymphoblastoid cell line-to-PBL based on cross-validation, and confirmed using cross-study prediction]. An extended model with multiple CpGs further improved performance. Our results suggest that large-scale epidemiology studies using easy-to-access surrogate tissues (e.g. blood) could be recalibrated to improve understanding of epigenetics in hard-to-access tissues (e.g. atrium) and might enable non-invasive disease screening using epigenetic profiles.

Background: Despite consistent evidence of a higher short-term risk of cardiovascular mortality associated with ambient temperature, there have been discrepant findings on the association between temperature and ischemic stroke. Moreover, few studies have considered potential confounding by ambient fine particulate matter air pollution <2.5 μm in diameter (PM2.5) and none have examined the impact of temperature changes on stroke in the subsequent hours rather than days. The aim of this study was to evaluate whether changes in temperature trigger an ischemic stroke in the following hours and days and whether humid days are particularly harmful., Methods: We reviewed the medical records of 1,705 patients residing in the metropolitan region of Boston, Mass., USA, who were hospitalized with neurologist-confirmed ischemic stroke, and we abstracted data on the time of symptom onset and clinical characteristics. We obtained hourly meteorological data from the National Weather Service station and hourly PM2.5 data from the Harvard ambient monitoring station. We used the time-stratified case-crossover design to assess the association between ischemic stroke and apparent temperature averaged over 1-7 days prior to stroke onset adjusting for PM2.5. We assessed whether differences in apparent temperature trigger a stroke within shorter time periods by examining the association between stroke onset and apparent temperature levels averaged in 2-hour increments prior to stroke onset (0-2 h through 36-38 h). We tested whether the association varied by health characteristics or by PM2.5, ozone or relative humidity., Results: The incidence rate ratio of ischemic stroke was 1.09 (95% confidence interval 1.01-1.18) following a 5°C decrement in average apparent temperature over the 2 days preceding symptom onset. The higher risk associated with cooler temperatures peaked in the first 14-34 h. There was no statistically significant difference in the association between temperature and ischemic stroke across seasons. The risk of ischemic stroke was not meaningfully different across subgroups of patients defined by health characteristics. The association between ischemic stroke and ambient temperature was stronger on days with higher levels of relative humidity., Conclusions: Lower temperatures are associated with a higher risk of ischemic stroke onset in both warm and cool seasons, and the risk is higher on days with higher levels of relative humidity. Based on this study and the body of literature on ambient temperature and cardiovascular events, identifying methods for mitigating cardiovascular risk may be warranted.

Rationale: Short-term exposure to ambient air pollution has been associated with lower lung function. Few studies have examined whether these associations are detectable at relatively low levels of pollution within current U.S. Environmental Protection Agency (EPA) standards., Objectives: To examine exposure to ambient air pollutants within EPA standards and lung function in a large cohort study., Methods: We included 3,262 participants of the Framingham Offspring and Third Generation cohorts living within 40 km of the Harvard Supersite monitor in Boston, Massachusetts (5,358 examinations, 1995-2011) who were not current smokers, with previous-day pollutant levels in compliance with EPA standards. We compared lung function (FEV1 and FVC) after previous-day exposure to particulate matter less than 2.5 μm in diameter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) in the "moderate" range of the EPA Air Quality Index to exposure in the "good" range. We also examined linear relationships between moving averages of pollutant concentrations 1, 2, 3, 5, and 7 days before spirometry and lung function., Measurements and Main Results: Exposure to pollutant concentrations in the "moderate" range of the EPA Air Quality Index was associated with a 20.1-ml lower FEV1 for PM2.5 (95% confidence interval [CI], -33.4, -6.9), a 30.6-ml lower FEV1 for NO2 (95% CI, -60.9, -0.2), and a 55.7-ml lower FEV1 for O3 (95% CI, -100.7, -10.8) compared with the "good" range. The 1- and 2-day moving averages of PM2.5, NO2, and O3 before testing were negatively associated with FEV1 and FVC., Conclusions: Short-term exposure to PM2.5, NO2, and O3 within current EPA standards was associated with lower lung function in this cohort of adults.

Background: Living in areas with higher levels of ambient air pollution has been associated with a higher incidence of ischemic stroke and all-cause mortality but less is known about the relationship between traffic-related pollution and long-term survival after stroke., Methods: We identified consecutive patients admitted to Beth Israel Deaconess Medical Center with ischemic stroke between 1999 and 2008 and determined the distance to the nearest roadway with an average daily traffic count of more than 10,000 vehicles/day. Categories of residential proximity were defined as 100 m or less, 100-200 m, 200-400 m or less, or more than 400 m from a busy roadway. We identified deaths through June 2012 using the Social Security Death Index and used Cox proportional hazards models adjusted for medical history and socioeconomic factors to calculate hazard ratios for the association between residential proximity to a high-traffic roadway and all-cause mortality., Results: Among 1683 stroke patients with complete data, there were 950 deaths (median follow-up=4.6 years). We observed higher poststroke mortality among people living closer to high-traffic roadways. Patients living 100 m or less from high-traffic roadways had a 20% (95% confidence interval: 1%, 43%) higher rate of poststroke mortality than patients living more than 400 m away (P trend=.02)., Conclusions: In this study, living close to a high-traffic roadway was associated with an elevated mortality rate. This relationship remained statistically significant after adjustment for individual- and neighborhood-level factors, providing evidence that traffic-related pollution is associated with a higher mortality rate among stroke survivors., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Evidence suggests that air pollution is associated with atherosclerosis and that traffic-related particles are a particularly important contributor to the association., Objectives: We investigated the association between long-term exposure to black carbon, a correlate of traffic particles, and intima-media thickness of the common carotid artery (CIMT) in elderly men residing in the greater Boston, Massachusetts, area., Methods: We estimated 1-year average exposures to black carbon at the home addresses of Normative Aging Study participants before their first CIMT measurement. The association between estimated black carbon levels and CIMT was estimated using mixed effects models to account for repeated outcome measures. In secondary analyses, we examined whether living close to a major road or average daily traffic within 100 m of residence was associated with CIMT., Results: There were 380 participants (97% self-reported white race) with an initial visit between 2004 and 2008. Two or three follow-up CIMT measurements 1.5 years apart were available for 340 (89%) and 260 (68%) men, respectively. At first examination, the average ± SD age was 76 ± 6.4 years and the mean ± SD CIMT was 0.99 ± 0.18 mm. A one-interquartile range increase in 1-year average black carbon (0.26 µg/m3) was associated with a 1.1% higher CIMT (95% CI: 0.4, 1.7%) based on a fully adjusted model., Conclusions: Annual mean black carbon concentration based on spatially resolved exposure estimates was associated with CIMT in a population of elderly men. These findings support an association between long-term air pollution exposure and atherosclerosis.

Background: Living near major roadways has been associated with increased risk of cardiovascular events, but little is known about its impact on renal function., Methods: We calculated the estimated glomerular filtration rate (eGFR) for 1103 consecutive Boston-area patients hospitalised with confirmed acute ischaemic stroke between 1999 and 2004. We used linear regression to evaluate the association between eGFR and categories of residential distance to major roadway (0 to ≤50, >50 to ≤100, >100 to ≤200, >200 to ≤400, >400 to ≤1000 and >1000 m) adjusting for age, sex, race, smoking, comorbid conditions, treatment with ACE inhibitor and neighbourhood-level socioeconomic characteristics. In a second analysis, we considered the log of distance to major roadway as a continuous variable., Results: Patients living closer to a major roadway had lower eGFR than patients living farther away (Ptrend=0.01). Comparing patients living 50 m versus 1000 m from a major roadway was associated with a 3.9 ml/min/1.73 m(2) lower eGFR (95% CI 1.0 to 6.7; p=0.007): a difference comparable in magnitude to the reduction in eGFR observed for a 4-year increase in age in population-based studies. The magnitude of this association did not differ significantly across categories of age, sex, race, history of hypertension, diabetes or socioeconomic status., Conclusions: Living near a major roadway is associated with lower eGFR in a cohort of patients presenting with acute ischaemic stroke. If causal, these results imply that exposures associated with living near a major roadway contribute to reduced renal function, an important risk factor for cardiovascular events.

Background and Purpose: Short-term elevations in fine particulate matter air pollution (PM2.5) are associated with increased risk of acute cerebrovascular events. Evidence from the peripheral circulation suggests that vascular dysfunction may be a central mechanism. However, the effects of PM2.5 on cerebrovascular function and hemodynamics are unknown., Methods: We used transcranial Doppler ultrasound to measure beat-to-beat blood flow velocity in the middle cerebral artery at rest and in response to changes in end-tidal CO2 (cerebral vasoreactivity) and arterial blood pressure (cerebral autoregulation) in 482 participants from the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) of Boston study. We used linear mixed effects models with random subject intercepts to evaluate the association between cerebrovascular hemodynamic parameters and mean PM2.5 levels 1 to 28 days earlier adjusting for age, race, medical history, meteorologic covariates, day of week, temporal trends, and season., Results: An interquartile range increase (3.0 µg/m(3)) in mean PM2.5 levels during the previous 28 days was associated with an 8.6% (95% confidence interval, 3.7%-13.8%; P<0.001) higher cerebral vascular resistance and a 7.5% (95% confidence interval, 4.2%-10.6%; P<0.001) lower blood flow velocity at rest. Measures of cerebral vasoreactivity and autoregulation were not associated with PM2.5 levels., Conclusions: In this cohort of community-dwelling seniors, exposure to PM2.5 was associated with higher resting cerebrovascular resistance and lower cerebral blood flow velocity. If replicated, these findings suggest that alterations in cerebrovascular hemodynamics may underlie the increased risk of particle-related acute cerebrovascular events.

Background: Extreme temperatures have been associated with hospitalization and death among individuals with heart failure, but few studies have explored the underlying mechanisms., Objectives: We hypothesized that outdoor temperature in the Boston, Massachusetts, area (1- to 4-day moving averages) would be associated with higher levels of biomarkers of inflammation and myocyte injury in a repeated-measures study of individuals with stable heart failure., Methods: We analyzed data from a completed clinical trial that randomized 100 patients to 12 weeks of tai chi classes or to time-matched education control. B-type natriuretic peptide (BNP), C-reactive protein (CRP), and tumor necrosis factor (TNF) were measured at baseline, 6 weeks, and 12 weeks. Endothelin-1 was measured at baseline and 12 weeks. We used fixed effects models to evaluate associations with measures of temperature that were adjusted for time-varying covariates., Results: Higher apparent temperature was associated with higher levels of BNP beginning with 2-day moving averages and reached statistical significance for 3- and 4-day moving averages. CRP results followed a similar pattern but were delayed by 1 day. A 5°C change in 3- and 4-day moving averages of apparent temperature was associated with 11.3% [95% confidence interval (CI): 1.1, 22.5; p = 0.03) and 11.4% (95% CI: 1.2, 22.5; p = 0.03) higher BNP. A 5°C change in the 4-day moving average of apparent temperature was associated with 21.6% (95% CI: 2.5, 44.2; p = 0.03) higher CRP. No clear associations with TNF or endothelin-1 were observed., Conclusions: Among patients undergoing treatment for heart failure, we observed positive associations between temperature and both BNP and CRP-predictors of heart failure prognosis and severity.

Background: The relationship between residential proximity to roadway and long-term survival after acute myocardial infarction (AMI) is unknown. We investigated the association between distance from residence and major roadway and 10-year all-cause mortality after AMI in the Determinants of Myocardial Infarction Onset Study (Onset Study), hypothesizing that living closer to a major roadway at the time of AMI would be associated with increased risk of mortality., Methods and Results: The Onset Study enrolled 3886 individuals hospitalized for AMI in 64 centers across the United States from 1989 to 1996. Institutionalized patients, those providing only post office boxes, and those whose addresses could not be geocoded were excluded, leaving 3547 patients eligible for analysis. Addresses were geocoded, and distance to the nearest major roadway was assigned. Cox regression was used to calculate hazard ratios, with adjustment for personal characteristics (age, sex, race, education, marital status, distance to nearest acute care hospital), clinical characteristics (smoking, body mass index, comorbidities, medications), and neighborhood-level characteristics derived from US Census block group data (household income, education, urbanicity). There were 1071 deaths after 10 years of follow-up. In the fully adjusted model, compared with living >1000 m, hazard ratios (95% confidence interval) for living ≤100 m were 1.27 (1.01-1.60), for 100 to ≤200 m were 1.19 (0.93-1.60), and for 200 to ≤1000 m were 1.13 (0.99-1.30) (P(trend)=0.016)., Conclusions: In this multicenter study, living close to a major roadway at the time of AMI was associated with increased risk of all-cause 10-year mortality; this relationship persisted after adjustment for individual and neighborhood-level covariates.

Background: Particulate air pollution has been associated with cardiovascular morbidity and mortality, but it remains unclear which time windows and pollutant sources are most critical. MicroRNA (miRNA) is thought to be involved in cardiovascular regulation. However, little is known about whether polymorphisms in genes that process microRNAs influence response to pollutant exposure. We hypothesized that averaging times longer than routinely measured one or two day moving averages are associated with higher soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) levels, and that stationary and mobile sources contribute differently to these effects. We also investigated whether single nucleotide polymorphisms (SNPs) in miRNA-processing genes modify these associations., Methods: sICAM-1 and sVCAM-1 were measured from 1999-2008 and matched to air pollution monitoring for fine particulate matter (PM2.5) black carbon, and sulfates (SO42-). We selected 17 SNPs in five miRNA-processing genes. Mixed-effects models were used to assess effects of pollutants, SNPs, and interactions under recessive inheritance models using repeated measures., Results: 723 participants with 1652 observations and 1-5 visits were included in our analyses for black carbon and PM2.5. Sulfate data was available for 672 participants with 1390 observations. An interquartile range change in seven day moving average of PM2.5 (4.27 μg/m3) was associated with 3.1% (95%CI: 1.6, 4.6) and 2.5% (95%CI: 0.6, 4.5) higher sICAM-1 and sVCAM-1. Interquartile range changes in sulfates (1.39 μg/m3) were associated with 1.4% higher (95%CI: 0.04, 2.7) and 1.6% (95%CI: -0.4, 3.7) higher sICAM-1 and sVCAM-1 respectively. No significant associations were observed for black carbon. In interaction models with PM2.5, both sICAM-1 and sVCAM-1 levels were lower in rs1062923 homozygous carriers. These interactions remained significant after multiple comparisons adjustment., Conclusions: PM2.5 seven day moving averages are associated with higher sICAM-1 and sVCAM-1 levels. SO4-2 seven day moving averages are associated with higher sICAM-1 and a suggestive association was observed with sVCAM-1 in aging men. SNPs in miRNA-processing genes may modify associations between ambient pollution and sICAM-1 and sVCAM-1, which are correlates of atherosclerosis and cardiovascular disease.

Background: Black carbon (BC) is a marker of traffic pollution that has been associated with blood pressure (BP), but findings have been inconsistent. MicroRNAs (miRNAs) are emerging as key regulators of gene expression, but whether polymorphisms in genes involved in processing of miRNAs to maturity influence susceptibility to BC has not been elucidated., Objectives: We investigated the association between BC and BP, as well as potential effect modification by single nucleotide polymorphisms (SNPs) in miRNA processing genes., Methods: Repeated measures analyses were performed using data from the VA Normative Aging Study. Complete covariate data were available for 789 participants with one to six study visits between 1995 and 2008. In models of systolic and diastolic BP, we examined SNP-by-BC interactions with 19 miRNA-related variants under recessive models of inheritance. Mixed-effects models were adjusted for potential confounders including clinical characteristics, lifestyle, and meteorologic factors., Results: A 1-SD increase in BC (0.415 microg/m(3)) was associated with 3.04 mmHg higher systolic (95% confidence interval (CI), 2.29-3.79) and 2.28 mmHg higher diastolic BP (95% CI, 1.88-2.67). Interactions modifying BC associations were observed with SNPs in the DICER, GEMIN4, and DiGeorge critical region-8 (DGCR8) genes, and in GEMIN3 and GEMIN4, predicting diastolic and systolic BP, respectively., Conclusions: We observed evidence of effect modification of the association between BP and 7-day BC moving averages by SNPs associated with miRNA processing. Although the mechanisms underlying these associations are not well understood, they suggest a role for miRNA genesis and processing in influencing BC effects.

Background: Inflammation and endothelial dysfunction are important risk factors for cardiovascular disease (CVD). We hypothesized that candidate genes selected for a study of asthma and chronic obstructive pulmonary disorder (COPD) are associated with markers of systemic inflammation and endothelial dysfunction in an aging population., Methods: Plasma levels of circulating C-reactive protein (CRP), fibrinogen, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were obtained from 679 elderly male participants in the Normative Aging Study. Blood samples were analyzed for 202 single nucleotide polymorphisms (SNPs) in 25 candidate genes and included both haplotype tagSNPs and functional SNPs based on literature review. Data were stratified into discovery and replication cohorts for 2-stage analysis. In the discovery cohort, the relationship between biomarker level and genotype was analyzed using linear mixed effects with random intercepts for each subject and models were adjusted for age and BMI. A positive outcome in the discovery cohort was defined as a p-value <0.1 for the SNP. SNPs that met this criterion were analyzed in the replication cohort and confirmed for those which met a criterion of significance (p<0.025)., Results: In our analyses, SNPs in the CRHR1, ITPR2, and VDR genes met significance criteria., Conclusions: Our results suggest that genes thought to play a role in the pathogenesis of asthma and COPD may influence levels of serum markers of inflammation and endothelial dysfunction via novel SNP associations which have not previously been associated with cardiovascular disease.

The aim of this study was to assess the reliability of salivary cortisol as a measure of hypothalmic-pituitary-adrenal (HPA) axis function in cocaine dependent individuals. Saliva and total plasma samples were collected from 49 abusers on 3 testing days in the morning, across eight time points per day. Significant associations between saliva and plasma cortisol were observed across all time points collapsed across 3 days in both men and women. These moderately significant correlations suggest that salivary measurements represent a stable, non-invasive and broad indicator of HPA axis functioning in cocaine dependent individuals.