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1.  Prenatal Exposure to Traffic Pollution: Associations with Reduced Fetal Growth and Rapid Infant Weight Gain 
Prenatal air pollution exposure inhibits fetal growth, but implications for postnatal growth are unknown.
We assessed weights and lengths of US infants in the Project Viva cohort at birth and 6 months. We estimated third-trimester residential air pollution exposures using spatiotemporal models. We estimated neighborhood traffic density and roadway proximity at birth address using geographic information systems. We performed linear and logistic regression adjusted for sociodemographic variables, fetal growth, and gestational age at birth.
Mean birth weight-for-gestational age z-score (fetal growth) was 0.17 (SD = 0.97; n=2,114), 0-6 month weight-for-length gain was 0.23 z-units (SD = 1.11; n=689), and 17% had weight-for-length ≥95th percentile at 6 months of age. Infants exposed to the highest (vs. lowest) quartile of neighborhood traffic density had lower fetal growth (−0.13 units [95% confidence interval (CI) = −0.25 to −0.01]), more rapid 0-6 month weight-for-length gain (0.25 units [95% CI = 0.01 to 0.49]), and higher odds of weight-for-length ≥95th percentile at 6 months (1.84 [95% CI = 1.11 to 3.05]). Neighborhood traffic density was additionally associated with an infant being in both the lowest quartile of fetal growth and highest quartile of 0-6 month weight-for-length gain (Q4 vs. Q1, OR = 3.01 [95% CI = 1.08 to 8.44]). Roadway proximity and third-trimester black carbon exposure were similarly associated with growth outcomes. For third-trimester PM2.5, effect estimates were in the same direction, but smaller and imprecise.
Infants exposed to higher traffic-related pollution in early life may exhibit more rapid postnatal weight gain in addition to reduced fetal growth.
PMCID: PMC4285344  PMID: 25437317
2.  Low-Concentration PM2.5 and Mortality: Estimating Acute and Chronic Effects in a Population-Based Study 
Both short- and long-term exposures to fine particulate matter (≤ 2.5 μm; PM2.5) are associated with mortality. However, whether the associations exist at levels below the new U.S. Environmental Protection Agency (EPA) standards (12 μg/m3 of annual average PM2.5, 35 μg/m3 daily) is unclear. In addition, it is not clear whether results from previous time series studies (fit in larger cities) and cohort studies (fit in convenience samples) are generalizable.
We estimated the effects of low-concentration PM2.5 on mortality.
High resolution (1 km × 1 km) daily PM2.5 predictions, derived from satellite aerosol optical depth retrievals, were used. Poisson regressions were applied to a Medicare population (≥ 65 years of age) in New England to simultaneously estimate the acute and chronic effects of exposure to PM2.5, with mutual adjustment for short- and long-term exposure, as well as for area-based confounders. Models were also restricted to annual concentrations < 10 μg/m3 or daily concentrations < 30 μg/m3.
PM2.5 was associated with increased mortality. In the study cohort, 2.14% (95% CI: 1.38, 2.89%) and 7.52% (95% CI: 1.95, 13.40%) increases were estimated for each 10-μg/m3 increase in short- (2 day) and long-term (1 year) exposure, respectively. The associations held for analyses restricted to low-concentration PM2.5 exposure, and the corresponding estimates were 2.14% (95% CI: 1.34, 2.95%) and 9.28% (95% CI: 0.76, 18.52%). Penalized spline models of long-term exposure indicated a larger effect for mortality in association with exposures ≥ 6 μg/m3 versus those < 6 μg/m3. In contrast, the association between short-term exposure and mortality appeared to be linear across the entire exposure distribution.
Using a mutually adjusted model, we estimated significant acute and chronic effects of PM2.5 exposure below the current U.S. EPA standards. These findings suggest that improving air quality with even lower PM2.5 than currently allowed by U.S. EPA standards may benefit public health.
Shi L, Zanobetti A, Kloog I, Coull BA, Koutrakis P, Melly SJ, Schwartz JD. 2016. Low-concentration PM2.5 and mortality: estimating acute and chronic effects in a population-based study. Environ Health Perspect 124:46–52;
PMCID: PMC4710600  PMID: 26038801
3.  Temporal Variation in Heat–Mortality Associations: A Multicountry Study 
Environmental Health Perspectives  2015;123(11):1200-1207.
Recent investigations have reported a decline in the heat-related mortality risk during the last decades. However, these studies are frequently based on modeling approaches that do not fully characterize the complex temperature–mortality relationship, and are limited to single cities or countries.
We assessed the temporal variation in heat–mortality associations in a multi-country data set using flexible modelling techniques.
We collected data for 272 locations in Australia, Canada, Japan, South Korea, Spain, the United Kingdom, and the United States, with a total 20,203,690 deaths occurring in summer months between 1985 and 2012. The analysis was based on two-stage time-series models. The temporal variation in heat–mortality relationships was estimated in each location with time-varying distributed lag nonlinear models, expressed through an interaction between the transformed temperature variables and time. The estimates were pooled by country through multivariate meta-analysis.
Mortality risk due to heat appeared to decrease over time in several countries, with relative risks associated to high temperatures significantly lower in 2006 compared with 1993 in the United States, Japan, and Spain, and a nonsignificant decrease in Canada. Temporal changes are difficult to assess in Australia and South Korea due to low statistical power, and we found little evidence of variation in the United Kingdom. In the United States, the risk seems to be completely abated in 2006 for summer temperatures below their 99th percentile, but some significant excess persists for higher temperatures in all the countries.
We estimated a statistically significant decrease in the relative risk for heat-related mortality in 2006 compared with 1993 in the majority of countries included in the analysis.
Gasparrini A, Guo Y, Hashizume M, Kinney PL, Petkova EP, Lavigne E, Zanobetti A, Schwartz JD, Tobias A, Leone M, Tong S, Honda Y, Kim H, Armstrong BG. 2015. Temporal variation in heat–mortality associations: a multicountry study. Environ Health Perspect 123:1200–1207;
PMCID: PMC4629745  PMID: 25933359
4.  Prenatal and Childhood Traffic-Related Pollution Exposure and Childhood Cognition in the Project Viva Cohort (Massachusetts, USA) 
Environmental Health Perspectives  2015;123(10):1072-1078.
Influences of prenatal and early-life exposures to air pollution on cognition are not well understood.
We examined associations of gestational and childhood exposure to traffic-related pollution with childhood cognition.
We studied 1,109 mother–child pairs in Project Viva, a prospective birth cohort study in eastern Massachusetts (USA). In mid-childhood (mean age, 8.0 years), we measured verbal and nonverbal intelligence, visual motor abilities, and visual memory. For periods in late pregnancy and childhood, we estimated spatially and temporally resolved black carbon (BC) and fine particulate matter (PM2.5) exposures, residential proximity to major roadways, and near-residence traffic density. We used linear regression models to examine associations of exposures with cognitive assessment scores, adjusted for potential confounders.
Compared with children living ≥ 200 m from a major roadway at birth, those living < 50 m away had lower nonverbal IQ [–7.5 points; 95% confidence interval (CI): –13.1, –1.9], and somewhat lower verbal IQ (–3.8 points; 95% CI: –8.2, 0.6) and visual motor abilities (–5.3 points; 95% CI: –11.0, 0.4). Cross-sectional associations of major roadway proximity and cognition at mid-childhood were weaker. Prenatal and childhood exposure to traffic density and PM2.5 did not appear to be associated with poorer cognitive performance. Third-trimester and childhood BC exposures were associated with lower verbal IQ in minimally adjusted models; but after adjustment for socioeconomic covariates, associations were attenuated or reversed.
Residential proximity to major roadways during gestation and early life may affect cognitive development. Influences of pollutants and socioeconomic conditions on cognition may be difficult to disentangle.
Harris MH, Gold DR, Rifas-Shiman SL, Melly SJ, Zanobetti A, Coull BA, Schwartz JD, Gryparis A, Kloog I, Koutrakis P, Bellinger DC, White RF, Sagiv SK, Oken E. 2015. Prenatal and childhood traffic-related pollution exposure and childhood cognition in the Project Viva cohort (Massachusetts, USA). Environ Health Perspect 123:1072–1078;
PMCID: PMC4590752  PMID: 25839914
5.  Exposure to Traffic and Early Life Respiratory Infection: A Cohort Study 
Pediatric pulmonology  2014;10.1002/ppul.23029.
We examined whether proximity to a major roadway and traffic density around the home during pregnancy are associated with risk of early life respiratory infection in a pre-birth cohort in the Boston area. We geocoded addresses for 1,263 mother-child pairs enrolled during the first trimester of pregnancy in Project Viva during 1999-2002. We calculated distance from home to nearest major roadway and traffic density in a 100 m buffer around the home. We defined respiratory infection as maternal report of >1 doctor-diagnosed pneumonia, bronchiolitis, croup or other respiratory infection from birth until the early childhood visit (median age 3.3). We used relative risk regression models adjusting for potential confounders to estimate associations between traffic exposures and risk of respiratory infection. Distance to roadway during pregnancy was associated with risk of respiratory infection. In fully adjusted models, relative risks (95% CI) for respiratory infection were: 1.30 (1.08, 1.55) for <100 m, 1.15 (0.93, 1.41) for 100 to <200 m, and 0.95 (0.84, 1.07) for 200 to <1000 m compared with living ≥1000 m away from a major roadway. Each interquartile range increase in distance to roadway was associated with an 8% (95% CI 0.87, 0.98) lower risk, and each interquartile range increase in traffic density was associated with a 5% (95% CI 0.98, 1.13) higher risk of respiratory infection. Our findings suggest that living close to a major roadway during pregnancy may predispose the developing lung to infection in early life.
PMCID: PMC4177521  PMID: 24678045
Epidemiology; Environmental Lung Disease; Air pollution; Traffic; Prenatal exposures; Respiratory Infection
6.  Mortality risk attributable to high and low ambient temperature: a multicountry observational study 
Lancet (London, England)  2015;386(9991):369-375.
Although studies have provided estimates of premature deaths attributable to either heat or cold in selected countries, none has so far offered a systematic assessment across the whole temperature range in populations exposed to different climates. We aimed to quantify the total mortality burden attributable to non-optimum ambient temperature, and the relative contributions from heat and cold and from moderate and extreme temperatures.
We collected data for 384 locations in Australia, Brazil, Canada, China, Italy, Japan, South Korea, Spain, Sweden, Taiwan, Thailand, UK, and USA. We fitted a standard time-series Poisson model for each location, controlling for trends and day of the week. We estimated temperature–mortality associations with a distributed lag non-linear model with 21 days of lag, and then pooled them in a multivariate metaregression that included country indicators and temperature average and range. We calculated attributable deaths for heat and cold, defined as temperatures above and below the optimum temperature, which corresponded to the point of minimum mortality, and for moderate and extreme temperatures, defined using cutoffs at the 2·5th and 97·5th temperature percentiles.
We analysed 74 225 200 deaths in various periods between 1985 and 2012. In total, 7·71% (95% empirical CI 7·43–7·91) of mortality was attributable to non-optimum temperature in the selected countries within the study period, with substantial differences between countries, ranging from 3·37% (3·06 to 3·63) in Thailand to 11·00% (9·29 to 12·47) in China. The temperature percentile of minimum mortality varied from roughly the 60th percentile in tropical areas to about the 80–90th percentile in temperate regions. More temperature-attributable deaths were caused by cold (7·29%, 7·02–7·49) than by heat (0·42%, 0·39–0·44). Extreme cold and hot temperatures were responsible for 0·86% (0·84–0·87) of total mortality.
Most of the temperature-related mortality burden was attributable to the contribution of cold. The effect of days of extreme temperature was substantially less than that attributable to milder but non-optimum weather. This evidence has important implications for the planning of public-health interventions to minimise the health consequences of adverse temperatures, and for predictions of future effect in climate-change scenarios.
UK Medical Research Council.
PMCID: PMC4521077  PMID: 26003380
7.  Impacts of elevated atmospheric CO2 on nutrient content of important food crops 
Scientific Data  2015;2:150036.
One of the many ways that climate change may affect human health is by altering the nutrient content of food crops. However, previous attempts to study the effects of increased atmospheric CO2 on crop nutrition have been limited by small sample sizes and/or artificial growing conditions. Here we present data from a meta-analysis of the nutritional contents of the edible portions of 41 cultivars of six major crop species grown using free-air CO2 enrichment (FACE) technology to expose crops to ambient and elevated CO2 concentrations in otherwise normal field cultivation conditions. This data, collected across three continents, represents over ten times more data on the nutrient content of crops grown in FACE experiments than was previously available. We expect it to be deeply useful to future studies, such as efforts to understand the impacts of elevated atmospheric CO2 on crop macro- and micronutrient concentrations, or attempts to alleviate harmful effects of these changes for the billions of people who depend on these crops for essential nutrients.
PMCID: PMC4508823  PMID: 26217490
Environmental health; Risk factors; Plant physiology; Plant breeding
8.  Who is More Affected by Ozone Pollution? A Systematic Review and Meta-Analysis 
American Journal of Epidemiology  2014;180(1):15-28.
Ozone is associated with adverse health; however, less is known about vulnerable/sensitive populations, which we refer to as sensitive populations. We systematically reviewed epidemiologic evidence (1988–2013) regarding sensitivity to mortality or hospital admission from short-term ozone exposure. We performed meta-analysis for overall associations by age and sex; assessed publication bias; and qualitatively assessed sensitivity to socioeconomic indicators, race/ethnicity, and air conditioning. The search identified 2,091 unique papers, with 167 meeting inclusion criteria (73 on mortality and 96 on hospitalizations and emergency department visits, including 2 examining both mortality and hospitalizations). The strongest evidence for ozone sensitivity was for age. Per 10-parts per billion increase in daily 8-hour ozone concentration, mortality risk for younger persons, at 0.60% (95% confidence interval (CI): 0.40, 0.80), was statistically lower than that for older persons, at 1.27% (95% CI: 0.76, 1.78). Findings adjusted for publication bias were similar. Limited/suggestive evidence was found for higher associations among women; mortality risks were 0.39% (95% CI: −0.22, 1.00) higher than those for men. We identified strong evidence for higher associations with unemployment or lower occupational status and weak evidence of sensitivity for racial/ethnic minorities and persons with low education, in poverty, or without central air conditioning. Findings show that some populations, especially the elderly, are particularly sensitive to short-term ozone exposure.
PMCID: PMC4070938  PMID: 24872350
age; air pollution; effect modifiers; hospitalization; mortality; ozone; sex
9.  Disentangling interactions between atmospheric pollution and weather 
The association between short-term exposure to extreme weather events and health has been well established. In addition, there is a large body of epidemiological literature on the short and long-term effects of ambient exposure to PM2.5.
We hypothesize that the health impact associated with exposure to air pollution and weather is larger than the risk estimated based on the health effects of air pollution and weather alone. Not much work has been done to estimate the acute and chronic effects associated with simultaneous exposure to multiple environmental agents such as weather and particulate matter.
In this editorial we highlight challenges in addressing these interactions. Around the globe, exposure to weather parameters, composition of gaseous and particulate air pollution, and the ventilation rates vary by season. Furthermore, weather and pollution mixtures exhibit different exposure-response function and act through different pathophysiological mechanisms. The synergistic analysis of ambient air pollution and weather require studies collecting appropriate data and advancing methodological approaches. Due to large variation in space and time, carefully designed multi-center studies will be important to address these challenges and provide novel stimuli for promoting measures to slow climate change and improve air pollution in urban areas and in cities around the world.
PMCID: PMC4451447  PMID: 25452456
10.  Relationship between Outdoor Temperature and Blood Pressure 
Cardiovascular mortality has been linked to changes in outdoor temperature. However, the mechanisms behind these effects are not well established. We aimed to study the effect of outdoor temperature on blood pressure (BP), as increased BP is a risk factor of cardiovascular deaths.
The study population consisted of men aged 53–100 years living in the Boston area. We used a mixed effects model to estimate the effect of three temperature variables: ambient, apparent, and dew point temperature (DPT), on repeated measures (every 3–5 years) of diastolic and systolic blood pressure. Random intercepts for subjects and several possible confounders were used in the models, including black carbon (BC) and barometric pressure.
We found modest associations between diastolic BP and ambient temperature, and apparent temperature. In the basic models, increases in diastolic BP in association with a 5°C decrease in 7-day moving averages of temperatures were 1.01% (95% CI: −0.06 – 2.09), and 1.55% (95%, CI: 0.61 – 2.49) for ambient and apparent temperature, respectively. Excluding extreme temperatures made these associations stronger (2.13%, 95% CI: 0.66 – 3.63, and 1.65%, 95% CI: 0.41 – 2.90, for ambient and apparent temperature, respectively). Effect estimates for dew point temperature were close to null. The effect of apparent temperature on systolic BP was similar (1.30% increase (95% CI: 0.32 – 2.29) for a 5°C decrease in 7-day moving average).
Cumulative exposure to decreasing ambient and apparent temperature may increase BP. These findings suggest that increase in BP could be a mechanism behind cold-, but not heat-related cardiovascular mortality.
PMCID: PMC4437584  PMID: 20864465
Cardiovascular; Blood pressure; Climate; Epidemiology; Temperature
11.  Outdoor temperature is associated with serum HDL and LDL 
Environmental research  2010;111(2):281-287.
While exposures to high and low air temperatures are associated with cardiovascular mortality, the underlying mechanisms are poorly understood. The risk factors for cardiovascular disease include high levels of total cholesterol and low-density lipoprotein (LDL), and low levels of high-density lipoprotein (HDL). We investigated whether temperature was associated with changes in circulating lipid levels, and whether this might explain part of the association with increased cardiovascular events.
The study cohort consisted of 478 men in the greater Boston area with a mean age of 74.2 years. They visited the clinic every 3–5 years between 1995–2008 for physical examination and to complete questionnaires. We excluded from analyses all men taking statin medication and all days with missing data, resulting in a total of 862 visits. Associations between three temperature variables (ambient, apparent, and dew point temperature) and serum lipid levels (total cholesterol, HDL, LDL, and triglycerides) were studied with linear mixed models that included possible confounders such as air pollution and a random intercept for each subject.
We found that HDL decreased −1.76% (95% CI: −3.17 – −0.32, lag 2 days), and −5.58% (95% CI: −8.87 – −2.16, moving average of 4 weeks) for each 5°C increase in mean ambient temperature. For the same increase in mean ambient temperature, LDL increased by 1.74% (95% CI: 0.07 – 3.44, lag 1 day) and 1.87% (95% CI: 0.14 – 3.63, lag 2 days). These results were also similar for apparent and dew point temperatures. No changes were found in total cholesterol or triglycerides in relation to temperature increase.
Changes in HDL and LDL levels associated with an increase in ambient temperature may be among the underlying mechanisms of temperature-related cardiovascular mortality.
PMCID: PMC4437587  PMID: 21172696
cardiovascular; cholesterol; cohort; high-density lipoprotein; low-density lipoprotein; temperature
12.  Effects of airborne fine particles (PM2.5) on Deep Vein Thrombosis Admissions in North Eastern United States 
Literature relating air pollution exposure to DVT and pulmonary embolism (PE), in spite of biological plausibility, is sparse. No comprehensive study examining associations between both short and long term exposure to Particulate matter (PM)2.5 and DVT or PE has been published to date. Using a novel PM2.5 prediction model we study whether long and short term PM2.5 exposure is associated with DVT and PE admissions among elderly across the northeastern USA.
We estimated daily exposure of PM2.5 in each zipcode. We investigated long and short-term effects of PM2.5 on DVT and PE hospital admissions. There were 453,413 DVT and 151,829 PE admissions in the study. For short term exposure, we performed a case crossover analysis matching on month and year and defined the hazard period as lag 01 (exposure of day of admission and previous day). For the long term association, we used a Poisson regression.
A 10-µg/m3 increase in short term exposure was associated with a 0.63 % increase in DVT admissions (95% CI = 0.03 to 1.25) and a 6.98 % (95% CI = 5.65 to 8.33) increase in long term exposure admissions. For PE, the associated risks were 0.38 (95% CI = −0.68 to 1.25) and 2.67 % (95% CI = 5.65 to 8.33). These results persisted when analyses were restricted to location-periods meeting the current EPA annual standard of 12-µg/m3.
Our findings showed that PM2.5 exposure was associated with DVT and PE hospital admissions, and that current standards are not protective of this result.
PMCID: PMC4424156  PMID: 25678264
Air Pollution; Public health; Epidemiology; Environment; Venous Thrombosis; Deep-Venous Thrombosis
13.  Health effects of multi-pollutant profiles 
Environment international  2014;71:13-19.
The association between exposure to particle mass and mortality is well established; however, there are still uncertainties as to whether certain chemical components are more harmful than others. Moreover, understanding the health effects associated with exposure to pollutants mixtures may lead to new regulatory strategies.
Recently we have introduced a new approach that uses cluster analysis to identify distinct air pollutant mixtures by classifying days into groups based on their pollutant concentration profiles. In Boston during the years 1999–2009, we examined whether the effect of PM2.5 on total mortality differed by distinct pollution mixtures.
We applied a time series analysis to examine the association of PM2.5 with daily deaths. Subsequently, we included an interaction term between PM2.5 and the pollution mixture clusters.
We found a 1.1 % increase (95% CI: 0.0, 2.2) and 2.3% increase (95% CI: 0.9–3.7) in total mortality for a 10 µg/m3 increase in the same day and the two-day average of PM2.5 respectively. The association is larger in a cluster characterized by high concentrations of the elements related to primary traffic pollution and oil combustion emissions with a 3.7% increase (95% CI: 0.4, 7.1) in total mortality, per 10 µg/m3 increase in the same day average of PM2.5.
Our study shows a higher association of PM2.5 on total mortality during days with a strong contribution of traffic emissions, and fuel oil combustion. Our proposed method to create multi-pollutant profiles is robust, and provides a promising tool to identify multi-pollutant mixtures which can be linked to the health effects.
PMCID: PMC4383187  PMID: 24950160
Total mortality; fine particulate air pollution; pollutant mixtures
14.  Prenatal Air Pollution Exposure and Newborn Blood Pressure 
Environmental Health Perspectives  2015;123(4):353-359.
Air pollution exposure has been associated with increased blood pressure in adults.
We examined associations of antenatal exposure to ambient air pollution with newborn systolic blood pressure (SBP).
We studied 1,131 mother–infant pairs in a Boston, Massachusetts, area pre-birth cohort. We calculated average exposures by trimester and during the 2 to 90 days before birth for temporally resolved fine particulate matter (≤ 2.5 μm; PM2.5), black carbon (BC), nitrogen oxides, nitrogen dioxide, ozone (O3), and carbon monoxide measured at stationary monitoring sites, and for spatiotemporally resolved estimates of PM2.5 and BC at the residence level. We measured SBP at a mean age of 30 ± 18 hr with an automated device. We used mixed-effects models to examine associations between air pollutant exposures and SBP, taking into account measurement circumstances; child’s birth weight; mother’s age, race/ethnicity, socioeconomic position, and third-trimester BP; and time trend. Estimates represent differences in SBP associated with an interquartile range (IQR) increase in each pollutant.
Higher mean PM2.5 and BC exposures during the third trimester were associated with higher SBP (e.g., 1.0 mmHg; 95% CI: 0.1, 1.8 for a 0.32-μg/m3 increase in mean 90-day residential BC). In contrast, O3 was negatively associated with SBP (e.g., –2.3 mmHg; 95% CI: –4.4, –0.2 for a 13.5-ppb increase during the 90 days before birth).
Exposures to PM2.5 and BC in late pregnancy were positively associated with newborn SBP, whereas O3 was negatively associated with SBP. Longitudinal follow-up will enable us to assess the implications of these findings for health during later childhood and adulthood.
van Rossem L, Rifas-Shiman SL, Melly SJ, Kloog I, Luttmann-Gibson H, Zanobetti A, Coull BA, Schwartz JD, Mittleman MA, Oken E, Gillman MW, Koutrakis P, Gold DR. 2015. Prenatal air pollution exposure and newborn blood pressure. Environ Health Perspect 123:353–359;
PMCID: PMC4384198  PMID: 25625652
15.  Associations between arrhythmia episodes and temporally and spatially resolved black carbon and particulate matter in elderly patients 
Ambient air pollution has been associated with sudden deaths, some of which are likely due to ventricular arrhythmias. Defibrillator discharge studies have examined the association of air pollution with arrhythmias in sensitive populations. No studies have assessed this association using residence-specific estimates of air pollution exposure.
In the Normative Aging Study, we investigated the association between temporally-and spatially-resolved black carbon (BC) and PM2.5 and arrhythmia episodes (bigeminy, trigeminy or couplets episodes) measured as ventricular ectopy (VE) by 4-min electrocardiogram (ECG) monitoring in repeated measures of 701 subjects, during the years 2000 to 2010.
We used a binomial distribution (having or not a VE episode) in a mixed effect model with a random intercept for subject, controlling for seasonality, temperature, day of the week, medication use, smoking, having diabetes, BMI and age. We also examined whether these associations were modified by genotype or phenotype.
We found significant increases in VE with both pollutants and lags; for the estimated concentration averaged over the three days prior to the health assessment we found increases in the odds of having VE with an OR of 1.52 (95% CI: 1.19–1.94) for an IQR (0.30 μg/m3) increase in BC and an OR of 1.39 (95% CI: 1.12–1.71) for an IQR (5.63 μg/m3) increase in PM2.5. We also found higher effects in subjects with the GSTT1 and GSTM1 variants and in obese (P-values<0.05).
Increased levels of short-term traffic related pollutants may increase the risk of ventricular arrhythmia in elderly subjects.
PMCID: PMC4371778  PMID: 24142987
arrhythmia episodes; spatially-resolved black carbon and particulate matter; traffic pollution; elderly
16.  Air pollution and gene-specific methylation in the Normative Aging Study 
Epigenetics  2014;9(3):448-458.
The mechanisms by which air pollution has multiple systemic effects in humans are not fully elucidated, but appear to include inflammation and thrombosis. This study examines whether concentrations of ozone and components of fine particle mass are associated with changes in methylation on tissue factor (F3), interferon gamma (IFN-γ), interleukin 6 (IL-6), toll-like receptor 2 (TLR-2), and intercellular adhesion molecule 1 (ICAM-1). We investigated associations between air pollution exposure and gene-specific methylation in 777 elderly men participating in the Normative Aging Study (1999–2009). We repeatedly measured methylation at multiple CpG sites within each gene’s promoter region and calculated the mean of the position-specific measurements. We examined intermediate-term associations between primary and secondary air pollutants and mean methylation and methylation at each position with distributed-lag models. Increase in air pollutants concentrations was significantly associated with F3, ICAM-1, and TLR-2 hypomethylation, and IFN-γ and IL-6 hypermethylation. An interquartile range increase in black carbon concentration averaged over the four weeks prior to assessment was associated with a 12% reduction in F3 methylation (95% CI: -17% to -6%). For some genes, the change in methylation was observed only at specific locations within the promoter region. DNA methylation may reflect biological impact of air pollution. We found some significant mediated effects of black carbon on fibrinogen through a decrease in F3 methylation, and of sulfate and ozone on ICAM-1 protein through a decrease in ICAM-1 methylation.
PMCID: PMC4053463  PMID: 24385016
air pollution; traffic; gene-specific DNA methylation; effect modification; mediation analysis; elderly
17.  Susceptibility to Mortality in Weather Extremes: Effect Modification by Personal and Small Area Characteristics In a Multi-City Case-Only Analysis 
Epidemiology (Cambridge, Mass.)  2013;24(6):809-819.
Extremes of temperature have been associated with short-term increases in daily mortality. We identified subpopulations with increased susceptibility to dying during temperature extremes, based on personal demographics, small-area characteristics and preexisting medical conditions.
We examined Medicare participants in 135 U.S. cities and identified preexisting conditions based on hospitalization records prior to their deaths, from 1985–2006. Personal characteristics were obtained from the Medicare records, and area characteristics were assigned based on zip-code of residence. We conducted a case-only analysis of over 11 million deaths, and evaluated modification of the risk of dying associated with extremely hot days and extremely cold days, continuous temperatures, and water-vapor pressure. Modifiers included preexisting conditions, personal characteristics, zip-code-level population characteristics, and land-cover characteristics. For each effect modifier, a city-specific logistic regression model was fitted and then an overall national estimate was calculated using meta-analysis.
People with certain preexisting conditions were more susceptible to extreme heat, with an additional 6% (95% confidence interval= 4% – 8%) increase in the risk of dying on an extremely hot day in subjects with previous admission for atrial fibrillation, an additional 8% (4%–12%) in subjects with Alzheimer disease, and an additional 6% (3%–9%) in subjects with dementia. Zip-code level and personal characteristics were also associated with increased susceptibility to temperature.
We identified several subgroups of the population who are particularly susceptible to temperature extremes, including persons with atrial fibrillation.
PMCID: PMC4304207  PMID: 24045717
18.  Associations Between Short-term Changes in Air Pollution and Correlates of Arterial Stiffness: The Veterans Affairs Normative Aging Study, 2007–2011 
American Journal of Epidemiology  2013;179(2):192-199.
We investigated associations between short-term exposure to air pollution and central augmentation index and augmentation pressure, correlates of arterial stiffness, in a cohort of elderly men in the Boston, Massachusetts, metropolitan area. This longitudinal analysis included 370 participants from the Veterans Affairs Normative Aging Study with up to 2 visits between 2007 and 2011 (n = 445). Augmentation index (as %) and augmentation pressure (in mmHg) were measured at each visit by using radial artery applanation tonometry for pulse wave analysis and modeled in a mixed effects regression model as continuous functions of moving averages of air pollution exposures (over 4 hours and 1, 3, 7, and 14 days). The results suggest that short-term changes in air pollution were associated with augmentation index and augmentation pressure at several moving averages. Interquartile range (IQR) increases in 3-day average exposure to particles with aerodynamic diameter less than 2.5 μm (3.6-μg/m3 IQR increase) and sulfate (1.4-μg/m3 IQR increase) and 1-day average exposure to particle number counts (8,741-counts/cm3 IQR increase) were associated with augmentation index values that were 0.8% (95% confidence interval (CI): 0.2, 1.4), 0.6% (95% CI: 0.1, 1.2), and 1.7% (95% CI: 0.4, 2.9) higher, respectively. Overall, the findings were similar for augmentation pressure. The findings support the hypothesis that exposure to air pollution may affect vascular function.
PMCID: PMC3873113  PMID: 24227017
air pollution; particulate matter; pulse wave analysis
19.  Effects of Temperature and Relative Humidity on DNA Methylation 
Epidemiology (Cambridge, Mass.)  2014;25(4):561-569.
Previous studies have found relationships between DNA methylation and various environmental contaminant exposures. Associations with weather have not been examined. Because temperature and humidity are related to mortality even on non-extreme days, we hypothesized that temperature and relative humidity may affect methylation.
We repeatedly measured methylation on long interspersed nuclear elements (LINE-1), Alu, and 9 candidate genes in blood samples from 777 elderly men participating in the normative aging Study (1999–2009). We assessed whether ambient temperature and relative humidity are related to methylation on LINE-1 and Alu, as well as on genes controlling coagulation, inflammation, cortisol, DNA repair, and metabolic pathway. We examined intermediate-term associations of temperature, relative humidity, and their interaction with methylation, using distributed lag models.
Temperature or relative humidity levels were associated with methylation on tissue factor (F3), intercellular adhesion molecule 1 (ICAM-1), toll-like receptor 2 (TRL-2), carnitine O-acetyltransferase (CRAT), interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS), and glucocorticoid receptor, LINE-1, and Alu. For instance, a 5°c increase in 3-week average temperature in ICAM-1 methylation was associated with a 9% increase (95% confidence interval: 3% to 15%), whereas a 10% increase in 3-week average relative humidity was associated with a 5% decrease (−8% to −1%). The relative humidity association with ICAM-1 methylation was stronger on hot days than mild days.
DNA methylation in blood cells may reflect biological effects of temperature and relative humidity. Temperature and relative humidity may also interact to produce stronger effects.
PMCID: PMC4224120  PMID: 24809956
20.  Cardiac Autonomic Dysfunction: Particulate Air Pollution Effects Are Modulated by Epigenetic Immunoregulation of Toll‐like Receptor 2 and Dietary Flavonoid Intake 
Short‐term fine particles (PM2.5) exposure is associated with reduced heart rate variability, a strong predictor of cardiac mortality among older people. Identifying modifiable factors that confer susceptibility is essential for intervention. We evaluated whether Toll‐like receptor 2 (TLR2) methylation, a reversible immune‐epigenetic process, and its dietary modulation by flavonoids and methyl nutrients, modify susceptibility to heart rate variability effects following PM2.5 exposure.
Methods and Results
We measured heart rate variability and PM2.5 repeatedly over 11 years (1275 total observations) among 573 elderly men from the Normative Aging Study. Blood TLR2 methylation was analyzed using pyrosequencing. Daily flavonoid and methyl nutrients intakes were assessed through the Food Frequency Questionnaire (FFQ). Every 10 μg/m3 increase in 48‐hour PM2.5 moving average was associated with 7.74% (95% CI: −1.21% to 15.90%; P=0.09), 7.46% (95% CI: 0.99% to 13.50%; P=0.02), 14.18% (95% CI: 1.14% to 25.49%; P=0.03), and 12.94% (95% CI: −2.36% to 25.96%; P=0.09) reductions in root mean square of successive differences, standard deviation of normal‐to‐normal intervals, low‐frequency power, and high‐frequency power, respectively. Higher TLR2 methylation exacerbated the root mean square of successive differences, standard deviation of normal‐to‐normal intervals, low‐frequency, and high‐frequency reductions associated with heightened PM2.5 (Pinteraction=0.006, 0.03, 0.05, 0.04, respectively). Every interquartile‐range increase in flavonoid intake was associated with 5.09% reduction in mean TLR2 methylation (95% CI: 0.12% to 10.06%; P=0.05) and counteracted the effects of PM2.5 on low frequency (Pinteraction=0.05). No significant effect of methyl nutrients on TLR2 methylation was observed.
Higher TLR2 methylation may confer susceptibility to adverse cardiac autonomic effects of PM2.5 exposure in older individuals. Higher flavonoid intake may attenuate these effects, possibly by decreasing TLR2 methylation.
PMCID: PMC4330067  PMID: 25628407
epidemiology; epigenetics; heart rate variability; inflammation; nutrition
21.  Heat, Heat Waves, and Hospital Admissions among the Elderly in the United States, 1992–2006 
Environmental Health Perspectives  2014;122(11):1187-1192.
Background: Heat-wave frequency, intensity, and duration are increasing with global climate change. The association between heat and mortality in the elderly is well documented, but less is known regarding associations with hospital admissions.
Objectives: Our goal was to determine associations between moderate and extreme heat, heat waves, and hospital admissions for nonaccidental causes among Medicare beneficiaries ≥ 65 years of age in 114 cities across five U.S. climate zones.
Methods: We used Medicare inpatient billing records and city-specific data on temperature, humidity, and ozone from 1992 through 2006 in a time-stratified case-crossover design to estimate the association between hospitalization and moderate [90th percentile of apparent temperature (AT)] and extreme (99th percentile of AT) heat and heat waves (AT above the 95th percentile over 2–8 days). In sensitivity analyses, we additionally considered confounding by ozone and holidays, different temperature metrics, and alternate models of the exposure–response relationship.
Results: Associations between moderate heat and hospital admissions were minimal, but extreme heat was associated with a 3% (95% CI: 2%, 4%) increase in all-cause hospital admissions over the subsequent 8 days. In cause-specific analyses, extreme heat was associated with increased hospitalizations for renal (15%; 95% CI: 9%, 21%) and respiratory (4%; 95% CI: 2%, 7%) diseases, but not for cardiovascular diseases. An added heat-wave effect was observed for renal and respiratory admissions.
Conclusion: Extreme heat is associated with increased hospital admissions, particularly for renal causes, among the elderly in the United States.
Citation: Gronlund CJ, Zanobetti A, Schwartz JD, Wellenius GA, O’Neill MS. 2014. Heat, heat waves, and hospital admissions among the elderly in the United States, 1992–2006. Environ Health Perspect 122:1187–1192;
PMCID: PMC4216145  PMID: 24905551
22.  Acclimatization across space and time in the effects of temperature on mortality: a time-series analysis 
Environmental Health  2014;13:89.
Climate change has increased the days of unseasonal temperature. Although many studies have examined the association between temperature and mortality, few have examined the timing of exposure where whether this association varies depending on the exposure month even at the same temperature. Therefore, we investigated monthly differences in the effects of temperature on mortality in a study comprising a wide range of weather and years, and we also investigated heterogeneity among regions.
We analyzed 38,005,616 deaths from 148 cities in the U.S. from 1973 through 2006. We fit city specific Poisson regressions to examine the effect of temperature on mortality separately for each month of the year, using penalized splines. We used cluster analysis to group cities with similar weather patterns, and combined results across cities within clusters using meta-smoothing.
There was substantial variation in the effects of the same temperature by month. Heat effects were larger in the spring and early summer and cold effects were larger in late fall. In addition, heat effects were larger in clusters where high temperatures were less common, and vice versa for cold effects.
The effects of a given temperature on mortality vary spatially and temporally based on how unusual it is for that time and location. This suggests changes in variability of temperature may be more important for health as climate changes than changes of mean temperature. More emphasis should be placed on warnings targeted to early heat/cold temperature for the season or month rather than focusing only on the extremes.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-069X-13-89) contains supplementary material, which is available to authorized users.
PMCID: PMC4271464  PMID: 25352015
Temperature and mortality; Acclimation; Acclimatization; Climate change; Global warming
23.  Isolated and synergistic effects of PM10 and average temperature on cardiovascular and respiratory mortality 
Revista de Saúde Pública  2014;48(6):881-888.
To analyze the effect of air pollution and temperature on mortality due to cardiovascular and respiratory diseases.
We evaluated the isolated and synergistic effects of temperature and particulate matter with aerodynamic diameter < 10 µm (PM10) on the mortality of individuals > 40 years old due to cardiovascular disease and that of individuals > 60 years old due to respiratory diseases in Sao Paulo, SP, Southeastern Brazil, between 1998 and 2008. Three methodologies were used to evaluate the isolated association: time-series analysis using Poisson regression model, bidirectional case-crossover analysis matched by period, and case-crossover analysis matched by the confounding factor, i.e., average temperature or pollutant concentration. The graphical representation of the response surface, generated by the interaction term between these factors added to the Poisson regression model, was interpreted to evaluate the synergistic effect of the risk factors.
No differences were observed between the results of the case-crossover and time-series analyses. The percentage change in the relative risk of cardiovascular and respiratory mortality was 0.85% (0.45;1.25) and 1.60% (0.74;2.46), respectively, due to an increase of 10 μg/m3 in the PM10 concentration. The pattern of correlation of the temperature with cardiovascular mortality was U-shaped and that with respiratory mortality was J-shaped, indicating an increased relative risk at high temperatures. The values for the interaction term indicated a higher relative risk for cardiovascular and respiratory mortalities at low temperatures and high temperatures, respectively, when the pollution levels reached approximately 60 μg/m3.
The positive association standardized in the Poisson regression model for pollutant concentration is not confounded by temperature, and the effect of temperature is not confounded by the pollutant levels in the time-series analysis. The simultaneous exposure to different levels of environmental factors can create synergistic effects that are as disturbing as those caused by extreme concentrations.
PMCID: PMC4285836  PMID: 26039390
Particulate Matter, adverse effects; Temperature; Cardiovascular Diseases, mortality; Respiratory Tract Diseases, mortality; Air Pollution; Time Series Studies
24.  Associations between Changes in City and Address Specific Temperature and QT Interval - The VA Normative Aging Study 
PLoS ONE  2014;9(9):e106258.
The underlying mechanisms of the association between ambient temperature and cardiovascular morbidity and mortality are not well understood, particularly for daily temperature variability. We evaluated if daily mean temperature and standard deviation of temperature was associated with heart rate-corrected QT interval (QTc) duration, a marker of ventricular repolarization in a prospective cohort of older men.
This longitudinal analysis included 487 older men participating in the VA Normative Aging Study with up to three visits between 2000–2008 (n = 743). We analyzed associations between QTc and moving averages (1–7, 14, 21, and 28 days) of the 24-hour mean and standard deviation of temperature as measured from a local weather monitor, and the 24-hour mean temperature estimated from a spatiotemporal prediction model, in time-varying linear mixed-effect regression. Effect modification by season, diabetes, coronary heart disease, obesity, and age was also evaluated.
Higher mean temperature as measured from the local monitor, and estimated from the prediction model, was associated with longer QTc at moving averages of 21 and 28 days. Increased 24-hr standard deviation of temperature was associated with longer QTc at moving averages from 4 and up to 28 days; a 1.9°C interquartile range increase in 4-day moving average standard deviation of temperature was associated with a 2.8 msec (95%CI: 0.4, 5.2) longer QTc. Associations between 24-hr standard deviation of temperature and QTc were stronger in colder months, and in participants with diabetes and coronary heart disease.
In this sample of older men, elevated mean temperature was associated with longer QTc, and increased variability of temperature was associated with longer QTc, particularly during colder months and among individuals with diabetes and coronary heart disease. These findings may offer insight of an important underlying mechanism of temperature-related cardiovascular morbidity and mortality in an older population.
PMCID: PMC4169528  PMID: 25238150
25.  Evidence on Vulnerability and Susceptibility to Health Risks Associated With Short-Term Exposure to Particulate Matter: A Systematic Review and Meta-Analysis 
American Journal of Epidemiology  2013;178(6):865-876.
Although there is strong evidence that short-term exposure to particulate matter is associated with health risks, less is known about whether some subpopulations face higher risks. We identified 108 papers published after 1995 and summarized the scientific evidence regarding effect modification of associations between short-term exposure to particulate matter and the risk of death or hospitalization. We performed a meta-analysis of estimated mortality associations by age and sex. We found strong, consistent evidence that the elderly experience higher risk of particular matter­–associated hospitalization and death, weak evidence that women have higher risks of hospitalization and death, and suggestive evidence that those with lower education, income, or employment status have higher risk of death. Meta-analysis showed a statistically higher risk of death of 0.64% (95% confidence interval (CI): 0.50, 0.78) for older populations compared with 0.34% (95% CI: 0.25, 0.42) for younger populations per 10 μg/m3 increase of particulate matter with aerodynamic diameter ≤10 μm. Women had a slightly higher risk of death of 0.55% (95% CI: 0.41, 0.70) compared with 0.50% (95% CI: 0.34, 0.54) for men, but these 2 risks were not statistically different. Our synthesis on modifiers for risks associated with particulate matter can aid the design of air quality policies and suggest directions for future research. Studies of biological mechanisms could be informed by evidence of differential risks by population, such as by sex and preexisting conditions.
PMCID: PMC3775545  PMID: 23887042
age; effect modifiers; hospital admissions; mortality; particulate matter; PM10; PM2.5; socioeconomic status

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