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1.  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.
doi:10.1038/sdata.2015.36
PMCID: PMC4508823  PMID: 26217490
2.  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.
doi:10.1093/aje/kwu115
PMCID: PMC4070938  PMID: 24872350
age; air pollution; effect modifiers; hospitalization; mortality; ozone; sex
3.  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.
doi:10.1136/jech-2014-203939
PMCID: PMC4451447  PMID: 25452456
4.  Relationship between Outdoor Temperature and Blood Pressure 
Objectives
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1136/oem.2010.056507
PMCID: PMC4437584  PMID: 20864465
Cardiovascular; Blood pressure; Climate; Epidemiology; Temperature
5.  Outdoor temperature is associated with serum HDL and LDL 
Environmental research  2010;111(2):281-287.
Background
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.
Methods
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.
Results
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.
Conclusions
Changes in HDL and LDL levels associated with an increase in ambient temperature may be among the underlying mechanisms of temperature-related cardiovascular mortality.
doi:10.1016/j.envres.2010.12.001
PMCID: PMC4437587  PMID: 21172696
cardiovascular; cholesterol; cohort; high-density lipoprotein; low-density lipoprotein; temperature
6.  Effects of airborne fine particles (PM2.5) on Deep Vein Thrombosis Admissions in North Eastern United States 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1111/jth.12873
PMCID: PMC4424156  PMID: 25678264
Air Pollution; Public health; Epidemiology; Environment; Venous Thrombosis; Deep-Venous Thrombosis
7.  Health effects of multi-pollutant profiles 
Environment international  2014;71:13-19.
Background
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.
Objectives
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.envint.2014.05.023
PMCID: PMC4383187  PMID: 24950160
Total mortality; fine particulate air pollution; pollutant mixtures
8.  Prenatal Air Pollution Exposure and Newborn Blood Pressure 
Environmental Health Perspectives  2015;123(4):353-359.
Background
Air pollution exposure has been associated with increased blood pressure in adults.
Objective:
We examined associations of antenatal exposure to ambient air pollution with newborn systolic blood pressure (SBP).
Methods:
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.
Results:
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).
Conclusions:
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.
Citation:
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; http://dx.doi.org/10.1289/ehp.1307419
doi:10.1289/ehp.1307419
PMCID: PMC4384198  PMID: 25625652
9.  Associations between arrhythmia episodes and temporally and spatially resolved black carbon and particulate matter in elderly patients 
Objectives
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.
Methods
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.
Results
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).
Conclusion
Increased levels of short-term traffic related pollutants may increase the risk of ventricular arrhythmia in elderly subjects.
doi:10.1136/oemed-2013-101526
PMCID: PMC4371778  PMID: 24142987
arrhythmia episodes; spatially-resolved black carbon and particulate matter; traffic pollution; elderly
10.  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.
doi:10.4161/epi.27584
PMCID: PMC4053463  PMID: 24385016
air pollution; traffic; gene-specific DNA methylation; effect modification; mediation analysis; elderly
11.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
We identified several subgroups of the population who are particularly susceptible to temperature extremes, including persons with atrial fibrillation.
doi:10.1097/01.ede.0000434432.06765.91
PMCID: PMC4304207  PMID: 24045717
12.  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.
doi:10.1093/aje/kwt271
PMCID: PMC3873113  PMID: 24227017
air pollution; particulate matter; pulse wave analysis
13.  Effects of Temperature and Relative Humidity on DNA Methylation 
Epidemiology (Cambridge, Mass.)  2014;25(4):561-569.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/EDE.0000000000000120
PMCID: PMC4224120  PMID: 24809956
14.  Cardiac Autonomic Dysfunction: Particulate Air Pollution Effects Are Modulated by Epigenetic Immunoregulation of Toll‐like Receptor 2 and Dietary Flavonoid Intake 
Background
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.
Conclusions
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.
doi:10.1161/JAHA.114.001423
PMCID: PMC4330067  PMID: 25628407
epidemiology; epigenetics; heart rate variability; inflammation; nutrition
15.  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; http://dx.doi.org/10.1289/ehp.1206132
doi:10.1289/ehp.1206132
PMCID: PMC4216145  PMID: 24905551
16.  Acclimatization across space and time in the effects of temperature on mortality: a time-series analysis 
Environmental Health  2014;13:89.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1476-069X-13-89
PMCID: PMC4271464  PMID: 25352015
Temperature and mortality; Acclimation; Acclimatization; Climate change; Global warming
17.  Isolated and synergistic effects of PM10 and average temperature on cardiovascular and respiratory mortality 
Revista de Saúde Pública  2014;48(6):881-888.
OBJECTIVE
To analyze the effect of air pollution and temperature on mortality due to cardiovascular and respiratory diseases.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1590/S0034-8910.2014048005218
PMCID: PMC4285836  PMID: 26039390
Particulate Matter, adverse effects; Temperature; Cardiovascular Diseases, mortality; Respiratory Tract Diseases, mortality; Air Pollution; Time Series Studies
18.  Associations between Changes in City and Address Specific Temperature and QT Interval - The VA Normative Aging Study 
PLoS ONE  2014;9(9):e106258.
Background
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.
Methods
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.
Results
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.
Conclusion/Significance
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.
doi:10.1371/journal.pone.0106258
PMCID: PMC4169528  PMID: 25238150
19.  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.
doi:10.1093/aje/kwt090
PMCID: PMC3775545  PMID: 23887042
age; effect modifiers; hospital admissions; mortality; particulate matter; PM10; PM2.5; socioeconomic status
20.  A framework to spatially cluster air pollution monitoring sites in US based on the PM2.5 composition 
Environment international  2013;59:10.1016/j.envint.2013.06.003.
Background
Heterogeneity in the response to PM2.5 is hypothesized to be related to differences in particle composition across monitoring sites which reflect differences in source types as well as climatic and topographic conditions impacting different geographic locations. Identifying spatial patterns in particle composition is a multivariate problem that requires novel methodologies.
Objectives
Use cluster analysis methods to identify spatial patterns in PM2.5 composition. Verify that the resulting clusters are distinct and informative.
Methods
109 monitoring sites with 75% reported speciation data during the period 2003–2008 were selected. These sites were categorized based on their average PM2.5 composition over the study period using k-means cluster analysis. The obtained clusters were validated and characterized based on their physico-chemical characteristics, geographic locations, emissions profiles, population density and proximity to major emission sources.
Results
Overall 31 clusters were identified. These include 21 clusters with 2 or more sites which were further grouped into 4 main types using hierarchical clustering. The resulting groupings are chemically meaningful and represent broad differences in emissions. The remaining clusters, encompassing single sites, were characterized based on their particle composition and geographic location.
Conclusions
The framework presented here provides a novel tool which can be used to identify and further classify sites based on their PM2.5 composition. The solution presented is fairly robust and yielded groupings that were meaningful in the context of air-pollution research.
doi:10.1016/j.envint.2013.06.003
PMCID: PMC3878877  PMID: 23850585
Multi-pollutant mixtures; Cluster analysis; Effect modification; Air pollution profiles; k-Means
21.  Associations of Fine Particulate Matter Species with Mortality in the United States: A Multicity Time-Series Analysis 
Environmental Health Perspectives  2014;122(8):837-842.
Background: Epidemiological studies have examined the association between PM2.5 and mortality, but uncertainty remains about the seasonal variations in PM2.5-related effects and the relative importance of species.
Objectives: We estimated the effects of PM2.5 species on mortality and how infiltration rates may modify the association.
Methods: Using city–season specific Poisson regression, we estimated PM2.5 effects on approximately 4.5 million deaths for all causes, cardiovascular disease (CVD), myocardial infarction (MI), stroke, and respiratory diseases in 75 U.S. cities for 2000–2006. We added interaction terms between PM2.5 and monthly average species-to-PM2.5 proportions of individual species to determine the relative toxicity of each species. We combined results across cities using multivariate meta-regression, and controlled for infiltration.
Results: We estimated a 1.18% (95% CI: 0.93, 1.44%) increase in all-cause mortality, a 1.03% (95% CI: 0.65, 1.41%) increase in CVD, a 1.22% (95% CI: 0.62, 1.82%) increase in MI, a 1.76% (95% CI: 1.01, 2.52%) increase in stroke, and a 1.71% (95% CI: 1.06, 2.35%) increase in respiratory deaths in association with a 10-μg/m3 increase in 2-day averaged PM2.5 concentration. The associations were largest in the spring. Silicon, calcium, and sulfur were associated with more all-cause mortality, whereas sulfur was related to more respiratory deaths. County-level smoking and alcohol were associated with larger estimated PM2.5 effects.
Conclusions: Our study showed an increased risk of mortality associated with PM2.5, which varied with seasons and species. The results suggest that mass alone might not be sufficient to evaluate the health effects of particles.
Citation: Dai L, Zanobetti A, Koutrakis P, Schwartz JD. 2014. Associations of fine particulate matter species with mortality in the United States: a multicity time-series analysis. Environ Health Perspect 122:837–842; http://dx.doi.org/10.1289/ehp.1307568
doi:10.1289/ehp.1307568
PMCID: PMC4123030  PMID: 24800826
22.  A national case-crossover analysis of the short-term effect of PM2.5 on hospitalizations and mortality in subjects with diabetes and neurological disorders 
Environmental Health  2014;13:38.
Background
Diabetes and neurological disorders are a growing burden among the elderly, and may also make them more susceptible to particulate air matter with aerodynamic diameter less than 2.5 μg (PM2.5). The same biological responses thought to effect cardiovascular disease through air pollution-mediated systemic oxidative stress, inflammation and cerebrovascular dysfunction could also be relevant for diabetes and neurodegenerative diseases.
Methods
We conducted multi-site case-crossover analyses of all-cause deaths and of hospitalizations for diabetes or neurological disorders among Medicare enrollees (>65 years) during the period 1999 to 2010 in 121 US communities. We examined whether 1) short-term exposure to PM2.5 increases the risk of hospitalization for diabetes or neurological disorders, and 2) the association between short-term exposure to PM2.5 and all-cause mortality is modified by having a previous hospitalization of diabetes or neurological disorders.
Results
We found that short term exposure to PM2.5 is significantly associated with an increase in hospitalization risks for diabetes (1.14% increase, 95% CI: 0.56, 1.73 for a 10 μg/m3 increase in the 2 days average), and for Parkinson’s disease (3.23%, 1.08, 5.43); we also found an increase in all-cause mortality risks (0.64%, 95% CI: 0.42, 0.85), but we didn’t find that hospitalization for diabetes and neurodegenerative diseases modifies the association between short term exposure to PM2.5 and all-cause mortality.
Conclusion
We found that short-term exposure to fine particles increased the risk of hospitalizations for Parkinson’s disease and diabetes, and of all-cause mortality. While the association between short term exposure to PM2.5 and mortality was higher among Medicare enrollees that had a previous admission for diabetes and neurological disorders than among Medicare enrollees that did not had a prior admission for these diseases, the effect modification was not statistically significant. We believe that these results provide useful insights regarding the mechanisms by which particles may affect the brain. A better understanding of the mechanisms will enable the development of new strategies to protect individuals at risk and to reduce detrimental effects of air pollution on the nervous system.
doi:10.1186/1476-069X-13-38
PMCID: PMC4064518  PMID: 24886318
PM2.5; Diabetes; Neurological disorders; Mortality risk; Hospitalizations
23.  Ambient particulate air pollution and microRNAs in elderly men 
Background
Ambient particulate matter (PM) has been associated with mortality and morbidity for cardiovascular disease (CVD). MicroRNAs control gene expression at a post-transcriptional level. Altered microRNA expression has been reported in processes related to CVD and PM exposure, e.g. systemic inflammation, endothelial dysfunction and atherosclerosis. Polymorphisms in microRNA-related genes could influence response to PM.
Methods
We investigated the association of exposure to ambient particles in several time windows (4-hours to 28-days moving averages) and blood-leukocyte expression changes in fourteen candidate microRNAs, in 153 elderly males from the Normative Aging Study (examined 2005–2009). Potential effect modification by six single nucleotide polymorphisms (SNPs) in three microRNA-related genes was investigated. Fine PM (PM2.5), black carbon, organic carbon and sulfates were measured at a stationary ambient monitoring site. Linear regression models, adjusted for potential confounders, were used to assess effects of particles and SNP-by-pollutant interaction. An in silico pathways analysis was performed on target genes of miRNAs associated with the pollutants.
Results
We found a negative association for pollutants in all moving averages and miR-1, -126, -135a, -146a, -155, -21, -222 and -9. The strongest associations were observed with the 7-day moving averages for PM2.5 and black carbon and with the 48-hour moving averages for organic carbon. The association with sulfates was stable across the moving averages. The in silico pathway analysis identified 18 pathways related to immune response shared by at least two miRNAs; in particular, the “HMGB1/RAGE signaling pathway” was shared by miR-126, -146a, -155, -21 and -222.
No important associations were observed for miR-125a-5p, -125b, -128, -147, -218 and -96. We found significant SNP-by-pollutant interactions for rs7813, rs910925 and rs1062923 in GEMIN4 and black carbon and PM2.5 for miR-1, -126, -146a, -222 and -9, and for rs1640299 in DGCR8 and SO42− for miR-1 and -135a.
Conclusions
Exposure to ambient particles could cause a downregulation of microRNAs involved in processes related to PM exposure. Polymorphisms in GEMIN4 and DGCR8 could modify these associations.
doi:10.1097/EDE.0000000000000026
PMCID: PMC3977338  PMID: 24257509
24.  Air Pollution Exposure and Abnormal Glucose Tolerance during Pregnancy: The Project Viva Cohort 
Environmental Health Perspectives  2014;122(4):378-383.
Background: Exposure to fine particulate matter (PM with diameter ≤ 2.5 μm; PM2.5) has been linked to type 2 diabetes mellitus, but associations with hyperglycemia in pregnancy have not been well studied.
Methods: We studied Boston, Massachusetts–area pregnant women without known diabetes. We identified impaired glucose tolerance (IGT) and gestational diabetes mellitus (GDM) during pregnancy from clinical glucose tolerance tests at median 28.1 weeks gestation. We used residential addresses to estimate second-trimester PM2.5 and black carbon exposure via a central monitoring site and spatiotemporal models. We estimated residential traffic density and roadway proximity as surrogates for exposure to traffic-related air pollution. We performed multinomial logistic regression analyses adjusted for sociodemographic covariates, and used multiple imputation to account for missing data.
Results: Of 2,093 women, 65 (3%) had IGT and 118 (6%) had GDM. Second-trimester spatiotemporal exposures ranged from 8.5 to 15.9 μg/m3 for PM2.5 and from 0.1 to 1.7 μg/m3 for black carbon. Traffic density was 0–30,860 vehicles/day × length of road (kilometers) within 100 m; 281 (13%) women lived ≤ 200 m from a major road. The prevalence of IGT was elevated in the highest (vs. lowest) quartile of exposure to spatiotemporal PM2.5 [odds ratio (OR) = 2.63; 95% CI: 1.15, 6.01] and traffic density (OR = 2.66; 95% CI: 1.24, 5.71). IGT also was positively associated with other exposure measures, although associations were not statistically significant. No pollutant exposures were positively associated with GDM.
Conclusions: Greater exposure to PM2.5 and other traffic-related pollutants during pregnancy was associated with IGT but not GDM. Air pollution may contribute to abnormal glycemia in pregnancy.
Citation: Fleisch AF, Gold DR, Rifas-Shiman SL, Koutrakis P, Schwartz JD, Kloog I, Melly S, Coull BA, Zanobetti A, Gillman MW, Oken E. 2014. Air pollution exposure and abnormal glucose tolerance during pregnancy: the Project Viva Cohort. Environ Health Perspect 122:378–383; http://dx.doi.org/10.1289/ehp.1307065
doi:10.1289/ehp.1307065
PMCID: PMC3984217  PMID: 24508979
25.  Brachial Artery Responses to Ambient Pollution, Temperature, and Humidity in People with Type 2 Diabetes: A Repeated-Measures Study 
Environmental Health Perspectives  2014;122(3):242-248.
Background: Extreme weather and air pollution are associated with increased cardiovascular risk in people with diabetes.
Objectives: In a population with diabetes, we conducted a novel assessment of vascular brachial artery responses both to ambient pollution and to weather (temperature and water vapor pressure, a measure of humidity).
Methods: Sixty-four 49- to 85-year-old Boston residents with type 2 diabetes completed up to five study visits (279 repeated measures). Brachial artery diameter (BAD) was measured by ultrasound before and after brachial artery occlusion [i.e., flow-mediated dilation (FMD)] and before and after nitroglycerin-mediated dilation (NMD). Ambient concentrations of fine particulate mass (PM2.5), black carbon (BC), organic carbon (OC), elemental carbon, particle number, and sulfate were measured at our monitoring site; ambient concentrations of carbon monoxide, nitrogen dioxide, and ozone were obtained from state monitors. Particle exposure in the home and during each trip to the clinic (home/trip exposure) was measured continuously and as a 5-day integrated sample. We used linear models with fixed effects for participants, adjusting for date, season, temperature, and water vapor pressure on the day of each visit, to estimate associations between our outcomes and interquartile range increases in exposure.
Results: Baseline BAD was negatively associated with particle pollution, including home/trip–integrated BC (–0.02 mm; 95% CI: –0.04, –0.003, for a 0.28 μg/m3 increase in BC), OC (–0.08 mm; 95% CI: –0.14, –0.03, for a 1.61 μg/m3 increase) as well as PM2.5, 5-day average ambient PM2.5, and BC. BAD was positively associated with ambient temperature and water vapor pressure. However, exposures were not consistently associated with FMD or NMD.
Conclusion: Brachial artery diameter, a predictor of cardiovascular risk, decreased in association with particle pollution and increased in association with ambient temperature in our study population of adults with type 2 diabetes.
Citation: Zanobetti A, Luttmann-Gibson H, Horton ES, Cohen A, Coull BA, Hoffmann B, Schwartz JD, Mittleman MA, Li Y, Stone PH, de Souza C, Lamparello B, Koutrakis P, Gold DR. 2014. Brachial artery responses to ambient pollution, temperature, and humidity in people with type 2 diabetes: a repeated-measures study. Environ Health Perspect 122:242–248; http://dx.doi.org/10.1289/ehp.1206136
doi:10.1289/ehp.1206136
PMCID: PMC3948021  PMID: 24398072

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