Social Susceptibility to Multiple Air Pollutants in Cardiovascular Disease.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death in the United States, and substantial research has linked ambient air pollution to elevated rates of CVD etiology and events. Much of this research identified increased effects of air pollution in lower socioeconomic position (SEP) communities, where pollution exposures are also often higher. The complex spatial confounding between air pollution and SEP makes it very challenging, however, to disentangle the impacts of these very different exposure types and to accurately assess their interactions. The specific causal components (i.e., specific social stressors) underlying this SEP-related susceptibility remain unknown, because there are myriad pathways through which poverty and/or lower-SEP conditions may influence pollution susceptibility - including diet, smoking, coexposures in the home and occupational environments, health behaviors, and healthcare access. Growing evidence suggests that a substantial portion of SEP-related susceptibility may be due to chronic psychosocial stress - given the known wide-ranging impacts of chronic stress on immune, endocrine, and metabolic function - and to a higher prevalence of unpredictable chronic stressors in many lower-SEP communities, including violence, job insecurity, and housing instability. As such, elucidating susceptibility to pollution in the etiology of CVD, and in the risk of CVD events, has been identified as a research priority. This interplay among social and environmental conditions may be particularly relevant for CVD, because pollution and chronic stress both impact inflammation, metabolic function, oxidative stress, hypertension, atherosclerosis, and other processes relevant to CVD etiology. Because pollution exposures are often spatially patterned by SEP, disentangling their effects - and quantifying any interplay - is especially challenging. Doing so, however, would help to improve our ability to identify and characterize susceptible populations and to improve our understanding of how community stressors may alter responses to multiple air pollutants. More clearly characterizing susceptible populations will improve our ability to design and target interventions more effectively (and cost-effectively) and may reveal greater benefits of pollution reduction in susceptible communities, strengthening cost-benefit and accountability analyses, ultimately reducing the disproportionate burden of CVD and reducing health disparities. METHODS: In the current study, we aimed to quantify combined effects of multiple pollutants and stressor exposures on CVD events, using a number of unique datasets we have compiled and verified, including the following. 1. Poverty metrics, violent crime rates, a composite socioeconomic deprivation index (SDI), an index of racial and economic segregation, noise disturbance metrics, and three composite spatial factors produced from a factor analysis of 27 community stressors. All indicators have citywide coverage and were verified against individual reports of stress and stressor exposure, in citywide focus groups and surveys. 2. Spatial surfaces for multiple pollutants from the New York City (NYC) Community Air Survey (NYCCAS), which monitored multiple pollutants year-round at 150 sites and used land use regression (LUR) modeling to estimate fine-scale (100-m) intra-urban spatial variance in fine particles (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O3). 3. Daily data and time-trends derived from all U.S. Environmental Protection Agency (EPA) Air Quality System (AQS) monitors in NYC for 2005-2011, which we combined with NYCCAS surfaces to create residence- and day-specific spatiotemporal exposure estimates. 4. Complete data on in- and out-patient unscheduled CVD events presented in NYC hospitals for 2005-2011 (n = 1,113,185) from the New York State (NYS) Department of Health's Statewide Planning and Research Cooperative System (SPARCS). In the study, we quantified relationships between multiple pollutant exposures and both community CVD event rates and individual risk of CVD events in NYC and tested whether pollution-CVD associations varied by community SEP and social stressor exposures. We hypothesized (1) that greater chronic community-level SEP, stressor, and pollution exposures would be associated with higher community CVD rates; (2) that spatiotemporal variations in multiple pollutants would be associated with excess risk of CVD events; and (3) that pollution-CVD associations would be stronger in communities of lower SEP or higher stressor exposures. RESULTS: To first understand the separate and combined associations with CVD for both stressors and pollutants measured at the same spatial and temporal scale of resolution, we used ecological cross-sectional models to examine spatial relationships between multiple chronic pollutant and stressor exposures and age-adjusted community CVD rates. Using census-tract-level annual averages (n = 2,167), we compared associations with CVD rates for multiple pollutant concentrations and social stressors. We found that associations with community CVD rates were consistently stronger for social stressors than for pollutants, in terms of both magnitude and significance. We note, however, that this result may be driven by the relatively greater variation (on a proportional basis) for stressors than for pollutants in NYC. We also tested effect modification of pollutant-CVD associations by each social stressor and found evidence of stronger associations for NO2, PM2.5, and wintertime SO2 with CVD rates, particularly across quintiles of increasing community violence or assault rates (P trend < 0.0001). To examine individual-level associations between spatiotemporal exposures to multiple pollutants and the risk of CVD events, across multiple lag days, we examined the combined effects of multiple pollutant exposures, using spatiotemporal (day- and residence-specific) pollution exposure estimates and hospital data on individual CVD events in case-crossover models, which inherently adjust for nontime-varying individual confounders (e.g., sex and race) and comorbidities. We found consistent significant relationships only for same-day pollutant exposures and the risk of CVD events, suggesting very acute impacts of pollution on CVD risk. Associations with CVD were positive for NO2, PM2.5, and SO2, as hypothesized, and we found inverse associations for O3 (a secondary pollutant chemically decreased ["scavenged"] by fresh emissions that, in NYC, displays spatial and temporal patterns opposite those of NO2). Finally, to test effect modification by chronic community social stressors on the relationships between spatiotemporal pollution measures and the risk of CVD events, we used individual-level case-crossover models, adding interaction terms with categorical versions of each social stressor. We found that associations between NO2 and the risk of CVD events were significantly elevated only in communities with the highest exposures to social stressors (i.e., in the highest quintiles of poverty, socioeconomic deprivation, violence, or assault). The largest positive associations for PM2.5 and winter SO2 were generally found in the highest-stressor communities but were not significant in any quintile. We again found inverse associations for O3, which were likewise stronger for individuals living in communities with greater stressor exposures. CONCLUSIONS: In ecological models, we found stronger relationships with community CVD rates for social stressors than for pollutant exposures. In case-crossover analyses, higher exposures to NO2, PM2.5, and SO2 were associated with greater excess risk of CVD events but only on the case day (there were no consistent significant lagged-day effects). In effect-modification analyses at both the community and individual level, we found evidence of stronger pollution-CVD associations in communities with higher stressor exposures. Given substantial spatial confounding across multiple social stressors, further research is needed to disentangle these effects in order to identify the predominant social stressors driving this observed differential susceptibility.

An experimental and computational study of 1,2-hydrogen migrations in 2-hydroxycyclopentylidene and its conjugate base.

Thermal decomposition of alpha-hydroxydiazirine 2 gives primarily cyclopentanone and some allylic alcohol, in similar amounts as the known cyclohexyl analogue 1. Calculations (B3LYP/6-31+G) also show cyclopentanone to be the major product of this carbene rearrangement. Diazirine 2 and the lithium salt of the corresponding conjugate base 3 were decomposed by photolysis. The proportion of ketone formed increases with deprotonation, a trend also found computationally. In comparison, the base-induced isomerization of cyclopentene oxide, which proceeds via alpha-elimination to a carbenoid intermediate similar to that obtained from 3, yields primarily allylic alcohol rather than ketone; neither ring size nor charge thus accounts for the unusual product distribution observed. Interestingly, the calculations reveal that in the gas phase with no counterion, the singlet, oxyanionic carbene, and the alpha-deprotonated epoxide are the same, rather than discrete structures. This intramolecular complexation stablilizes the oxyanionic carbene by 20-25 kcal/mol.

Neonatal deaths in Alabama. III. Out-of-hospital births, 1940-1980.

Out-of-hospital births in Alabama are characterized with special emphasis on the period from 1970 to 1980. Women having an out-of-hospital birth were more likely to be nonwhite, aged greater than or equal to 35, and multiparous and to have little or no prenatal care. However, within the group of women having out-of-hospital delivery, characteristics which predicted neonatal death included being white, aged less than 20, primiparous, and unmarried and having little or no prenatal care. Both the risk factors for and outcomes of out-of-hospital birth differed markedly by race. In all, out-of-hospital births, which declined from 25% to 0.5% of all births from 1940 to 1980, were associated with a twofold increase in neonatal mortality. The major care provider for out-of-hospital births, the "granny" midwife, was found to have little knowledge about, or ability to provide, modern obstetric care. High-risk status of the patients, limited capability of the care-givers, and lack of appropriate medical resources are suggested as the likely reasons for the excess neonatal mortality in out-of-hospital births.

Lethal congenital anomalies as a cause of birth-weight-specific neonatal mortality.

The percentage of neonatal mortality caused by lethal congenital anomalies and the distribution of specific anomalies in various birth-weight groups are presented. State vital statistics data and autopsy-confirmed data from a single hospital are compared. Of neonates who died, less than 5% who were born weighing between 500 and 999 g died of a congenital anomaly, and nearly 45% who were born weighing more than 2,500 g died of a congenital anomaly. Most deaths associated with congenital anomalies in infants born weighing more than 2,500 g are cardiac in origin. Twenty-three percent of all neonatal deaths in Alabama are attributed to a lethal congenital anomaly. Use of these data to define limits to future improvements in neonatal mortality by standard medical care is discussed.

Neonatal deaths in Alabama. II. Policy and research implications derived from a comparison of birth weight-specific state and medical center neonatal mortality rates.

An analysis of Alabama's recent neonatal mortality rate was performed to answer questions pertaining to projected changes in the neonatal mortality rate in the next decade. With current technology these questions include: (1) Can the current decline in the neonatal mortality rate continue? (2) Which infants not now surviving are potentially able to be saved? (3) What types of new programs may further reduce the neonatal mortality rate? (4) For which infants may research provide technology leading to further reductions in the neonatal mortality rate? In this analysis, birth weight-specific neonatal mortality rates for Alabama were compared with the lowest birth rate-specific neonatal mortality rates achieved in perinatal centers. Specific causes of neonatal death for each birth weight group were determined. Data suggest that 20% of current neonatal deaths would be preventable with available technology through expanded regionalization of perinatal care for infants born weighing less than 2,500 gm. Since lethal congenital anomalies cause the majority of neonatal deaths in infants born weighing greater than 2,499 gm, there is apparently little room for an improved neonatal mortality rate in this group. Without successful research leading to a reduction in preterm delivery rates, a reduction in lethal congenital anomalies or better survival of low-birth weight infants. Alabama's neonatal mortality rate is likely to level off at five to six per 1,000.

Neonatal deaths in Alabama, 1970-1980: an analysis of birth weight- and race-specific neonatal mortality rates.

Alabama birth and death certificate tapes for the years 1970-1980 were linked and analyzed to determine race-specific birth weight and neonatal mortality rate distributions. Changes which occurred over time were evaluated. Our analyses demonstrated that there were no substantial changes in birth weight distributions which could account for the nearly 50% reduction in the neonatal mortality rate in Alabama during this period. Birth weight changes did result in a 12% decrease in the white neonatal mortality rate but resulted in no decrease in the nonwhite neonatal mortality rate. All other improvement in the neonatal mortality rate is attributed to better survival within birth weight groups. Eighty percent of the reduction in the neonatal mortality rate during this period of time occurred in low-birth weight infants with most of the reduction found in infants weighing between 1,000 and 2,000 gm. Improvements in the quality of medical care and better access to medical care through regionalization of perinatal services, especially for low-birth weight infants, are suggested as the major reasons for this improvement.