Modification of the PM2.5- and extreme heat-mortality relationships by historical redlining: a case-crossover study in thirteen U.S. states.

BACKGROUND: Redlining has been associated with worse health outcomes and various environmental disparities, separately, but little is known of the interaction between these two factors, if any. We aimed to estimate whether living in a historically-redlined area modifies the effects of exposures to ambient PM2.5 and extreme heat on mortality by non-external causes. METHODS: We merged 8,884,733 adult mortality records from thirteen state departments of public health with scanned and georeferenced Home Owners Loan Corporation (HOLC) maps from the University of Richmond, daily average PM2.5 from a sophisticated prediction model on a 1-km grid, and daily temperature and vapor pressure from the Daymet V4 1-km grid. A case-crossover approach was used to assess modification of the effects of ambient PM2.5 and extreme heat exposures by redlining and control for all fixed and slow-varying factors by design. Multiple moving averages of PM2.5 and duration-aware analyses of extreme heat were used to assess the most vulnerable time windows. RESULTS: We found significant statistical interactions between living in a redlined area and exposures to both ambient PM2.5 and extreme heat. Individuals who lived in redlined areas had an interaction odds ratio for mortality of 1.0093 (95% confidence interval [CI]: 1.0084, 1.0101) for each 10 µg m-3 increase in same-day ambient PM2.5 compared to individuals who did not live in redlined areas. For extreme heat, the interaction odds ratio was 1.0218 (95% CI 1.0031, 1.0408). CONCLUSIONS: Living in areas that were historically-redlined in the 1930's increases the effects of exposures to both PM2.5 and extreme heat on mortality by non-external causes, suggesting that interventions to reduce environmental health disparities can be more effective by also considering the social context of an area and how to reduce disparities there. Further study is required to ascertain the specific pathways through which this effect modification operates and to develop interventions that can contribute to health equity for individuals living in these areas.

Long-term noise exposures and cardiovascular diseases mortality: A study in 5 U.S. states.

BACKGROUND: Previous studies have linked noise exposure with adverse cardiovascular events. However, evidence remains inconsistent, and most previous studies only focused on traffic noise, excluding other anthropogenic sources like constructions, industrial process and commercial activities. Additionally, few studies have been conducted in the U.S. or evaluated the non-linear exposure-response relationships. METHODS: We conducted a relative incidence analysis study using all cardiovascular diseases mortality as cases (n = 936,019) and external causes mortality (n = 232,491) as contrast outcomes. Mortality records geocoded at residential addresses were obtained from five U.S. states (Indiana, 2007; Kansas, 2007-2009, Missouri, 2010-2019, Ohio, 2007-2013, Texas, 2007-2016). Time-invariant long-term noise exposure was obtained from a validated model developed based on acoustical measurements across 2000-2014. Noises from both natural sources (natural activities, including animals, insects, winds, water flows, thunder, etc.) and anthropogenic sources (human activities, including transportation, industrial activities, community facilities & infrastructures, commercial activities, entertainments, etc.) were included. We used daytime and nighttime total anthropogenic noise & day-night average sound pressure level combining natural and anthropogenic sources as exposures. Logistic regression models were fit controlling for Census tract-level & individual-level characteristics. We examined potential modification by sex by interaction terms and potential non-linear associations by thin plate spline terms. RESULTS: We observed positive associations for daytime anthropogenic L50 (sound level exceeded 50% of time) noise (10-dBA OR = 1.047, 95%CI 1.025-1.069), nighttime anthropogenic L50 noise (10-dBA OR = 1.061, 95%CI 1.033-1.091) in a two-exposure-term model, and overall Ldn (day-night average) sound pressure level (10-dBA OR = 1.064, 95%CI 1.040-1.089) in single-exposure-term model. Females were more susceptible to all three exposures. All exposures showed monotonic positive associations with cardiovascular mortality up to certain thresholds around 45-55 dBA, with a generally flattened or decreasing trend beyond those thresholds. CONCLUSIONS: Both daytime anthropogenic and nighttime anthropogenic noises were associated with cardiovascular disease mortality, and associations were stronger in females.

Psychological Stress and Epigenetic Aging in Older Men: The VA Normative Aging Study.

Psychological stress remains an important risk factor for morbidity and mortality throughout the life course. However, there have been counterintuitive findings reported in previous studies of older persons that examine the relationships of perceived psychological stress with DNA methylation-based markers of aging, which also serve as predictors of morbidity and mortality (epigenetic age/clocks). We aimed to replicate and expand findings from existing work by examining relationships of self-reported stress with nine epigenetic clocks: Hannum, Horvath, Intrinsic, Extrinsic, SkinBloodClock, PhenoAge, GrimAge, DNAm Telomere Length, and Pace of Aging. We analyzed data from 607 male participants (mean age 73.2 years) of the VA Normative Aging Study with one to two study visits from 1999 to 2007 (observations = 956). Stress was assessed via the 14-item Perceived Stress Scale (PSS). Epigenetic age was calculated from DNA methylation measured in leukocytes with the HumanMethylation450 BeadChip. In linear mixed effects models adjusted for demographic/lifestyle/health factors, a standard deviation (sd) increase in PSS was associated with Horvath (ß = -0.35-years, 95%CI: -0.61, -0.09, P=0.008) and Intrinsic (ß = -0.40-years, 95%CI: -0.67, -0.13, P=0.004) epigenetic age deceleration. However, in models limited to participants with the highest levels of stress (≥ 75th-percentile), Horvath (ß = 2.29-years, 95%CI: 0.16, 4.41, P=0.04) and Intrinsic (ß = 2.06-years, 95%CI: -0.17, 4.28, P=0.07) age acceleration associations were observed. Our results reinforce the complexity of psychological stress and epigenetic aging relationships and lay a foundation for future studies that explore longitudinal relationships with other adult stress metrics and factors that can influence stress such as resilience measures.

Long-term exposure to ambient fine particulate components and leukocyte epigenome-wide DNA Methylation in older men: the Normative Aging Study.

BACKGROUND: Epigenome-wide association studies of ambient fine particulate matter (PM2.5) have been reported. However, few have examined PM2.5 components (PMCs) and sources or included repeated measures. The lack of high-resolution exposure measurements is the key limitation. We hypothesized that significant changes in DNA methylation might vary by PMCs and the sources. METHODS: We predicted the annual average of 14 PMCs using novel high-resolution exposure models across the contiguous U.S., between 2000-2018. The resolution was 50 m × 50 m in the Greater Boston Area. We also identified PM2.5 sources using positive matrix factorization. We repeatedly collected blood samples and measured leukocyte DNAm with the Illumina HumanMethylation450K BeadChip in the Normative Aging Study. We then used median regression with subject-specific intercepts to estimate the associations between long-term (one-year) exposure to PMCs / PM2.5 sources and DNA methylation at individual cytosine-phosphate-guanine CpG sites. Significant probes were identified by the number of independent degrees of freedom approach, using the number of principal components explaining > 95% of the variation of the DNA methylation data. We also performed regional and pathway analyses to identify significant regions and pathways. RESULTS: We included 669 men with 1,178 visits between 2000-2013. The subjects had a mean age of 75 years. The identified probes, regions, and pathways varied by PMCs and their sources. For example, iron was associated with 6 probes and 6 regions, whereas nitrate was associated with 15 probes and 3 regions. The identified pathways from biomass burning, coal burning, and heavy fuel oil combustion sources were associated with cancer, inflammation, and cardiovascular diseases, whereas there were no pathways associated with all traffic. CONCLUSIONS: Our findings showed that the effects of PM2.5 on DNAm varied by its PMCs and sources.

Intermediate and long-term exposure to air pollution and temperature and the extracellular microRNA profile of participants in the normative aging study (NAS).

BACKGROUND: The molecular effects of intermediate and long-term exposure to air pollution and temperature, such as those on extracellular microRNA (ex-miRNA) are not well understood but may have clinical consequences. OBJECTIVES: To assess the association between exposure to ambient air pollution and temperature and ex-miRNA profiles. METHODS: Our study population consisted of 734 participants in the Normative Aging Study (NAS) between 1999 and 2015. We used high-resolution models to estimate four-week, eight-week, twelve-week, six-month, and one-year moving averages of PM2.5, O3, NO2, and ambient temperature based on geo-coded residential addresses. The outcome of interest was the extracellular microRNA (ex-miRNA) profile of each participant over time. We used a longitudinal quantile regression approach to estimate the association between the exposures and each ex-miRNA. Results were corrected for multiple comparisons and ex-miRNAs that were still significantly associated with the exposures were further analyzed using KEGG pathway analysis and Ingenuity Pathway Analysis. RESULTS: We found 151 significant associations between levels of PM2.5, O3, NO2, and ambient temperature and 82 unique ex-miRNAs across multiple quantiles. Most of the significant results were associations with intermediate-term exposure to O3, long-term exposure to PM2.5, and both intermediate and long-term exposure to ambient temperature. The exposures were most often associated with the 75th and 90th percentile of the outcomes. Pathway analyses of significant ex-miRNAs revealed their involvement in biological pathways involving cell function and communication as well as clinical diseases such as cardiovascular disease, respiratory disease, and neurological disease. CONCLUSION: Our results show that intermediate and long-term exposure to all our exposures of interest were associated with changes in the ex-miRNA profile of study participants. Further studies on environmental risk factors and ex-miRNAs are warranted.

Short-term air pollution and temperature exposure and changes in the extracellular microRNA profile of Normative Aging Study (NAS) participants.

BACKGROUND: While the health effects of air pollution and temperature are widely studied, the molecular effects are poorly understood. Extracellular microRNAs (ex-miRNAs) have the potential to serve as diagnostic or prognostic biomarkers and/or to act as intercellular signaling molecules that mediate the effects of environmental exposures on health outcomes. METHODS: We examined the relationship between short-term exposure to air pollution and ambient temperature and the ex-miRNA profiles of participants in the Normative Aging Study (NAS) from 1999 to 2015. Our exposures were defined as same-day, two-day, three-day, one-week, two-week, and three-week moving averages of PM2.5, NO2, O3, and temperature which were derived from high-resolution spatio-temporal models. The ex-miRNA profiles of the subjects were obtained during follow-up visits. We analyzed the data using a longitudinal quantile regression model adjusted for individual covariates, batch effects, and time trends. We adjusted for multiple comparisons using a false discovery rate (FDR) correction. Ex-miRNAs that were significantly associated with exposures were further investigated using pathway analyses. RESULTS: We found that all the examined exposures were associated with changes in ex-miRNA profiles in our study, particularly PM2.5 which was responsible for most of the statistically significant results. We found 110 statistically significant exposure-outcome relationships that revealed associations with the levels of 52 unique ex-miRNAs. Pathway analyses showed these ex-miRNAs have been linked to target mRNAs, genes, and biological mechanisms that could affect virtually every organ system, and as such may be linked to multiple clinical disease presentations such as cardiovascular disease, respiratory disease, and neurological disease. CONCLUSIONS: Air pollution and temperature exposures were significantly associated with alterations in the ex-miRNA profiles of NAS subjects with possible biological consequences.

Epigenome-wide DNA methylation in leukocytes and toenail metals: The normative aging study.

BACKGROUND: Environmental metal exposures have been associated with multiple deleterious health endpoints. DNA methylation (DNAm) may provide insight into the mechanisms underlying these relationships. Toenail metals are non-invasive biomarkers, reflecting a medium-term time exposure window. OBJECTIVES: This study examined variation in leukocyte DNAm and toenail arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg) among elderly men in the Normative Aging Study, a longitudinal cohort. METHODS: We repeatedly collected samples of blood and toenail clippings. We measured DNAm in leukocytes with the Illumina HumanMethylation450 K BeadChip. We first performed median regression to evaluate the effects of each individual toenail metal on DNAm at three levels: individual cytosine-phosphate-guanine (CpG) sites, regions, and pathways. Then, we applied a Bayesian kernel machine regression (BKMR) to assess the joint and individual effects of metal mixtures on DNAm. Significant CpGs were identified using a multiple testing correction based on the independent degrees of freedom approach for correlated outcomes. The approach considers the effective degrees of freedom in the DNAm data using the principal components that explain >95% variation of the data. RESULTS: We included 564 subjects (754 visits) between 1999 and 2013. The numbers of significantly differentially methylated CpG sites, regions, and pathways varied by metals. For example, we found six significant pathways for As, three for Cd, and one for Mn. The As-associated pathways were associated with cancer (e.g., skin cancer) and cardiovascular disease, whereas the Cd-associated pathways were related to lung cancer. Metal mixtures were also associated with 47 significant CpG sites, as well as pathways, mainly related to cancer and cardiovascular disease. CONCLUSIONS: This study provides an approach to understanding the potential epigenetic mechanisms underlying observed relations between toenail metals and adverse health endpoints.

Associations between long-term exposures to airborne PM2.5 components and mortality in Massachusetts: mixture analysis exploration.

BACKGROUND: Numerous studies have documented PM2.5's links with adverse health outcomes. Comparatively fewer studies have evaluated specific PM2.5 components. The lack of exposure measurements and high correlation among different PM2.5 components are two limitations. METHODS: We applied a novel exposure prediction model to obtain annual Census tract-level concentrations of 15 PM2.5 components (Zn, V, Si, Pb, Ni, K, Fe, Cu, Ca, Br, SO42-, NO3-, NH4+, OC, EC) in Massachusetts from 2000 to 2015, to which we matched geocoded deaths. All non-accidental mortality, cardiovascular mortality, and respiratory mortality were examined for the population aged 18 or over. Weighted quantile sum (WQS) regression models were used to examine the cumulative associations between PM2.5 components mixture and outcomes and each component's contributions to the cumulative associations. We have fit WQS models on 15 PM2.5 components and a priori identified source groups (heavy fuel oil combustion, biomass burning, crustal matter, non-tailpipe traffic source, tailpipe traffic source, secondary particles from power plants, secondary particles from agriculture, unclear source) for the 15 PM2.5 components. Total PM2.5 mass analysis and single component associations were also conducted through quasi-Poisson regression models. RESULTS: Positive cumulative associations between the components mixture and all three outcomes were observed from the WQS models. Components with large contribution to the cumulative associations included K, OC, and Fe. Biomass burning, traffic emissions, and secondary particles from power plants were identified as important source contributing to the cumulative associations. Mortality rate ratios for cardiovascular mortality were of greater magnitude than all non-accidental mortality and respiratory mortality, which is also observed in cumulative associations estimated from WQS, total PM2.5 mass analysis, and single component associations. CONCLUSION: We have found positive associations between the mixture of 15 PM2.5 components and all non-accidental mortality, cardiovascular mortality, and respiratory mortality. Among these components, Fe, K, and OC have been identified as having important contribution to the cumulative associations. The WQS results also suggests potential source effects from biomass burning, traffic emissions, and secondary particles from power plants.

Synergistic Effects of Particle Radioactivity (Gross ß Activity) and Particulate Matter ≤2.5 µm Aerodynamic Diameter on Cardiovascular Disease Mortality.

Background Although the effects of fine particulate matter (particulate matter ≤2.5 µm aerodynamic diameter [PM2.5]) on cardiovascular disease (CVD) morbidity and mortality are well established, little is known about the CVD health effects of particle radioactivity. In addition, there are still questions about which of the PM2.5 physical, chemical, or biological properties are mostly responsible for its toxicity. Methods and Results We investigated the association between particle radioactivity, measured as gross ß activity from highly resolved spatiotemporal predictions, and mortality for CVD, myocardial infarction, stroke, and all-cause nonaccidental mortality in Massachusetts (2001-2015). Within both difference-in-differences model and generalized linear mixed model frameworks, we fit both single-exposure and 2-exposure models adjusting for PM2.5 and examined the interaction between PM2.5 and gross ß activity. We found significant associations between gross ß activity and PM2.5 and each mortality cause. Using difference-in-differences and adjusting for PM2.5, we found the highest associations with myocardial infarction (rate ratio, 1.16 [95% CI, 1.08-1.24]) and stroke (rate ratio, 1.11 [95% CI, 1.04-1.18]) for an interquartile range increase (0.055 millibecquerels per cubic meter) in gross ß activity. We found a significant positive interaction between PM2.5 and gross ß activity, with higher associations between PM2.5 and mortality at a higher level of gross ß activity. We also observed that the associations varied across age groups. The results were comparable between the 2 statistical methods also with and without adjusting for PM2.5. Conclusions This is the first study that, using highly spatiotemporal predictions of gross ß-activity, provides evidence that particle radioactivity increases CVD mortality and enhances PM2.5 CVD mortality. Therefore, particle radioactivity can be an important property of PM2.5 that must be further investigated. Addressing this important question can lead to cost-effective air-quality regulations.

Short term exposure to air pollution and mortality in the US: a double negative control analysis.

RATIONALE: Studies examining the association of short-term air pollution exposure and daily deaths have typically been limited to cities and used citywide average exposures, with few using causal models. OBJECTIVES: To estimate the associations between short-term exposures to fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2) and all-cause and cause-specific mortality in multiple US states using census tract or address exposure and including rural areas, using a double negative control analysis. METHODS: We conducted a time-stratified case-crossover study examining the entire population of seven US states from 2000-2015, with over 3 million non-accidental deaths. Daily predictions of PM2.5, O3, and NO2 at 1x1 km grid cells were linked to mortality based on census track or residential address. For each pollutant, we used conditional logistic regression to quantify the association between exposure and the relative risk of mortality conditioning on meteorological variables, other pollutants, and using double negative controls. RESULTS: A 10 µg/m3 increase in PM2.5 exposure at the moving average of lag 0-2 day was significantly associated with a 0.67% (95%CI: 0.34-1.01%) increase in all-cause mortality. 10 ppb increases in NO2 or O3 exposure at lag 0-2 day were marginally associated with and 0.19% (95%CI: -0.01-0.38%) and 0.20 (95% CI-0.01, 0.40), respectively. The adverse effects of PM2.5 persisted when pollution levels were restricted to below the current global air pollution standards. Negative control models indicated little likelihood of omitted confounders for PM2.5, and mixed results for the gases. PM2.5 was also significantly associated with respiratory mortality and cardiovascular mortality. CONCLUSIONS: Short-term exposure to PM2.5 and possibly O3 and NO2 are associated with increased risks for all-cause mortality. Our findings delivered evidence that risks of death persisted at levels below currently permissible.

Associations between Air Pollution and Psychiatric Symptoms in The Normative Aging Study.

Background: Environmental risk factors for psychiatric health are poorly identified. We examined the association between air pollution and psychiatric symptoms, which are often precursors to the development of psychiatric disorders. Methods: This study included 570 participants in the US Veterans Administration (VA) Normative Aging Study and 1,114 visits (defined as an onsite follow-up at the VA with physical examination and questionnaires) from 2000-2014 with information on the Brief Symptom Inventory (BSI) to assess their psychiatric symptom levels. Differences in the three BSI global measures (Global Severity Index - GSI, Positive Symptom Distress Index - PSDI and Positive Symptom Total - PST) were reported per interquartile (IQR) increase of residential address-specific air pollutants levels (fine particulate matter - PM2.5, ozone - O3, nitrogen dioxide - NO2) at averages of 1 week, 4 weeks, 8 weeks and 1 year prior to the visit using generalized additive mixed effects models. We also evaluated modification by neighborhood factors. Results: On average, among the NAS sample (average age, 72.4 yrs. (standard deviation: 6.7 yrs.)), an IQR increase in 1- and 4- week averages of NO2 before visit was associated with a PSDI T score (indicator for psychiatric symptom intensity) increase of 1.60 (95% Confidence Interval (CI): 0.31, 2.89), 1.71 (95% CI: 0.18, 3.23), respectively. Similarly, for each IQR increase in 1- and 4-week averages of ozone before visit, PSDI T-score increased by 1.66 (95% CI: 0.68, 2.65), and 1.36 (95% CI: 0.23, 2.49), respectively. Stronger associations were observed for ozone and PSDI in low house value and low household income areas. No associations were found for PM2.5. Conclusions: Exposure to gaseous air pollutants was associated with higher intensity of psychiatric symptoms among a cohort of older men, particularly in communities with lower socio-economic or housing conditions.

Maternal exposure to black carbon and nitrogen dioxide during pregnancy and birth weight: Using machine-learning methods to achieve balance in inverse-probability weights.

BACKGROUND: Low birth weight is associated with increased risks of health problems in infancy and later life. Among the epidemiological analyses suggesting an association between air pollution and birth weight, few have estimated the effects of black carbon (BC) or together with nitrogen dioxide (NO2), and even fewer studies have used causal modelling. METHODS: We examined 1,119,011 birth records between 2001/01/01 and 2015/12/31 from the Massachusetts Birth Registry to investigate causal associations between prenatal exposure to BC and NO2 and birth weight. We calculated mean residential BC and NO2 exposures 0-30, and 31-280 days prior to birth from validated spatial-temporal models. We fit generalized propensity score models with gradient boosting tuned by a new algorithm to achieve covariate balance, then fit marginal structural models with stabilized inverse-probability weights. RESULTS: Throughout pregnancy, the average birth weight would drop by 17.0 g (95% CI: 15.4, 18.6) for an IQR increase of 0.14 µg/m3 in BC and would independently drop by 19.9 g (95% CI: 18.6, 21.3) for an IQR increase of 9.8 ppb in NO2. Most of the negative effects of BC on birth weight are from 0 to 30 days before the delivery date. The estimated odds ratio of low birth weight for every IQR increase during the entire pregnancy was 1.131 (95% CI: 1.106, 1.156) for BC and 1.082 (95% CI: 1.062, 1.103) for NO2. CONCLUSIONS: We found that prenatal exposures to both BC and NO2 were associated with lower birth weight.

PRACTICAL ASPECTS AND RESULTS OF COGNITIVE THERAPY IN THE EARLY RECOVERY PERIOD OF ISCHEMIC STROKE.

OBJECTIVE: The aim: To determine the impact of cognitive training on the degree of cognitive functions recovery and quality of life in the early recovery period of ischemic stroke. PATIENTS AND METHODS: Materials and methods: 108 patients with cerebral infarction were examined outpatiently, follow-up from 1 to 3 months from the onset of the disease. Basic assessment methods: screening index of cognitive disorders according to the Montreal Cognitive Assessment Scale (MoCA), SF-36 questionnaire. RESULTS: Results and Conclusions: Comprehensive rehabilitation measures for the early recovery period of ischemic stroke achieve improvement of the cognitive sphere: a significant increase in the average score on the Montreal scale of cognitive functions assessment (MoCA scale) in both observation groups.

Short- and intermediate-term exposure to ambient fine particulate elements and leukocyte epigenome-wide DNA methylation in older men: the Normative Aging Study.

BACKGROUND: Several epigenome-wide association studies (EWAS) of ambient particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) have been reported. However, EWAS of PM2.5 elements (PEs), reflecting different emission sources, are very limited. OBJECTIVES: We performed EWAS of short- and intermediate-term exposure to PM2.5 and 13 PEs. We hypothesized that significant changes in DNAm may vary by PM2.5 mass and its elements. METHODS: We repeatedly collected blood samples in the Normative Aging Study and measured leukocyte DNA methylation (DNAm) with the Illumina HumanMethylation450K BeadChip. We collected daily PM2.5 and 13 PEs at a fixed central site. To estimate the associations between each PE and DNAm at individual cytosine-phosphate-guanine (CpG) sites, we incorporated a distributed-lag (0-27 d) term in the setting of median regression with subject-specific intercept and examined cumulative lag associations. We also accounted for selection bias due to loss to follow-up and mortality prior to enrollment. Significantly differentially methylated probes (DMPs) were identified using Bonferroni correction for multiple testing. We further conducted regional and pathway analyses to identify significantly differentially methylated regions (DMRs) and pathways. RESULTS: We included 695 men with 1,266 visits between 1999 and 2013. The subjects had a mean age of 75 years. The significant DMPs, DMRs, and pathways varied by to PM2.5 total mass and PEs. For example, PM2.5 total mass was associated with 2,717 DMPs and 10,470 DMRs whereas Pb was associated with 3,173 DMPs and 637 DMRs. The identified pathways by PM2.5 mass were mostly involved in mood disorders, neuroplasticity, immunity, and inflammation, whereas the pathways associated with motor vehicles (BC, Cu, Pb, and Zn) were related with cardiovascular disease and cancer (e.g., "PPARs signaling"). CONCLUSIONS: PM2.5 and PE were associated with methylation changes at multiple probes and along multiple pathways, in ways that varied by particle components.

The Surplus Effect in Adaptive Behaviour in Down Syndrome: What Can Promote It?

BACKGROUND: In Down syndrome (DS), adaptive behaviour often shows a "surplus effect" (i.e., higher adaptive abilities than expected from cognitive skills). As inclusive schooling has become mandatory in Italy, we studied the impact of school inclusion on the surplus effect of adaptive behaviour in adult DS, considering potential confounding factors such as parental education. METHODS: All consecutive DS individuals from three different sites were queried prospectively regarding type of schooling (inclusive and non-inclusive). Demographic data were documented; cognitive abilities and adaptive behaviour were assessed (Coloured Progressive Matrices and Vineland Adaptive Behaviour Scales). The aim was to establish the presence of a surplus effect in adaptive behaviour, primarily in the overall level and secondarily in the main domains and subdomains. A multivariable-adjusted logistic regression model was used for the association of schooling, and parental education. RESULTS: The majority (65%) showed a surplus effect in adaptive behaviour and had attended inclusive schools (85%). Higher adaptive skills as well as early and longer functional treatment programmes were more readily available for younger individuals. In the group of inclusive schooling, the surplus effect on overall adaptive behaviour was present in 70% as opposed to 38% in the group without inclusive schooling, significant when adjusted for gender and maternal education. This was also observed in socialisation, written, and community, and after adjustment in playing and leisure time. CONCLUSIONS: Adaptive behaviour showed a surplus effect in the majority of DS adults, even more so after inclusive schooling. Younger adults showed higher adaptive skills. Moreover, female gender and higher maternal educational level significantly enhanced this surplus effect.

Metabolomic signatures of the long-term exposure to air pollution and temperature.

BACKGROUND: Long-term exposures to air pollution has been reported to be associated with inflammation and oxidative stress. However, the underlying metabolic mechanisms remain poorly understood. OBJECTIVES: We aimed to determine the changes in the blood metabolome and thus the metabolic pathways associated with long-term exposure to outdoor air pollution and ambient temperature. METHODS: We quantified metabolites using mass-spectrometry based global untargeted metabolomic profiling of plasma samples among men from the Normative Aging Study (NAS). We estimated the association between long-term exposure to PM2.5, NO2, O3, and temperature (annual average of central site monitors) with metabolites and their associated metabolic pathways. We used multivariable linear mixed-effect regression models (LMEM) while simultaneously adjusting for the four exposures and potential confounding and correcting for multiple testing. As a reduction method for the intercorrelated metabolites (outcome), we further used an independent component analysis (ICA) and conducted LMEM with the same exposures. RESULTS: Men (N = 456) provided 648 blood samples between 2000 and 2016 in which 1158 metabolites were quantified. On average, men were 75.0 years and had an average body mass index of 27.7 kg/m2. Almost all men (97%) were not current smokers. The adjusted analysis showed statistically significant associations with several metabolites (58 metabolites with PM2.5, 15 metabolites with NO2, and 6 metabolites with temperature) while no metabolites were associated with O3. One out of five ICA factors (factor 2) was significantly associated with PM2.5. We identified eight perturbed metabolic pathways with long-term exposure to PM2.5 and temperature: glycerophospholipid, sphingolipid, glutathione, beta-alanine, propanoate, and purine metabolism, biosynthesis of unsaturated fatty acids, and taurine and hypotaurine metabolism. These pathways are related to inflammation, oxidative stress, immunity, and nucleic acid damage and repair. CONCLUSIONS: Using a global untargeted metabolomic approach, we identified several significant metabolites and metabolic pathways associated with long-term exposure to PM2.5, NO2 and temperature. This study is the largest metabolomics study of long-term air pollution, to date, the first study to report a metabolomic signature of long-term temperature exposure, and the first to use ICA in the analysis of both.

DNA methylation-based biomarkers of age acceleration and all-cause death, myocardial infarction, stroke, and cancer in two cohorts: The NAS, and KORA F4.

BACKGROUND: DNA methylation (DNAm) may play a role in age-related outcomes. It is not yet known which DNAm-based biomarkers of age acceleration (BoAA) has the strongest association with age-related endpoints. METHODS: We collected the blood samples from two independent cohorts: the Normative Ageing Study, and the Cooperative Health Research in the Region of Augsburg cohort. We measured epigenome-wide DNAm level, and generated five DNAm BoAA at baseline. We used Cox proportional hazards model to analyze the relationships between BoAA and all-cause death. We applied the Fine and Gray competing risk model to estimate the risk of BoAA on myocardial infarction (MI), stroke, and cancer, accounting for death of other reasons as the competing risks. We used random-effects meta-analyses to pool the individual results, with adjustment for multiple testing. FINDINGS: The mean chronological ages in the two cohorts were 74, and 61, respectively. Baseline GrimAgeAccel, and DNAm-related mortality risk score (DNAmRS) both had strong associations with all-cause death, MI, and stroke, independent from chronological age. For example, a one standard deviation (SD) increment in GrimAgeAccel was significantly associated with increased risk of all-cause death [hazard ratio (HR): 2.01; 95% confidence interval (CI), 1.15, 3.50], higher risk of MI (HR: 1.44; 95% CI, 1.16, 1.79), and elevated risk of stroke (HR: 1.42; 95% CI, 1.06, 1.91). There were no associations between any BoAA and cancer. INTERPRETATION: From the public health perspective, GrimAgeAccel is the most useful tool for identifying at-risk elderly, and evaluating the efficacy of anti-aging interventions. FUNDING: National Institute of Environmental Health Sciences of U.S., Harvard Chan-NIEHS Center for Environmental Health, German Federal Ministry of Education and Research, and the State of Bavaria in Germany.

Prenatal exposure to particulate air pollution and gestational age at delivery in Massachusetts neonates 2001-2015: A perspective of causal modeling and health disparities.

There is a lack of evidence on causal effects of air pollution on gestational age (GA) at delivery. METHODS: Inverse probability weighting (IPW) quantile regression was applied to derive causal marginal population-level GA reduction for GA percentiles associated with increased ambient particulate matter with diameter <2.5 µm (PM2.5) levels at maternal residential address for each trimester and the month preceding delivery using Massachusetts birth registry 2001 to 2015. Stratified analyses were conducted for neonatal sex, maternal age/race/education, and extreme ambient temperature conditions. RESULTS: For neonates at 2.5th, 10th, 25th, 50th, 75th, and 97.5th percentiles of GA at delivery, we estimated an adjusted GA reduction of 4.2 days (95% confidence interval [CI] = 3.4, 5.0), 1.9 days (1.6, 2.1), 1.2 days (1.0, 1.4), 0.82 days (0.72, 0.92), 0.74 days (0.54, 0.94), and 0.54 days (0.15, 0.93) for each 5 µg/m3 increment in third trimester average PM2.5 levels. Final gestational month average exposure yielded a similar effect with greater magnitude. Male neonates and neonates of younger (younger than 35 years) and African American mothers as well as with high/low extreme temperature exposure in third trimester were more affected. Estimates were consistently higher at lower GA percentiles, indicating preterm/early-term births being more affected. Low-exposure analyses yielded similar results, restricting to areas with PM2.5 levels under US ambient annual standard of 12 µg/m3. CONCLUSIONS: Prenatal exposure to PM2.5 in late pregnancy reduced GA at delivery among Massachusetts neonates, especially among preterm/early-term births, male neonates, and neonates of younger and African American mothers. Exposure to extremely high/low temperature amplifies the effect of PM2.5 on GA.

A Structural Model of Social Determinants of the Metabolic Syndrome.

Objectives: The metabolic syndrome (MetS) refers to a cluster of interrelated physiological characteristics that are associated with an increased risk of cardiovascular disease and diabetes. While the clinical usefulness of the MetS has been the subject of controversy for years, increasingly sophisticated methods are being used to measure the concept. Participants: Study of community health center patients who were not diabetic; study group was evenly divided between Black and White adults. Main Outcome Measures: Latent MetS score and MetS status based on the five-point scale developed by the National Cholesterol Education Panel (NCEP). Methods: Structural equation modeling of MetS incorporating the effects of race/ethnicity, racial discrimination, socioeconomic position (SEP), and selected mediating variables. Results: The largest influences on latent MetS scores were SEP (negative relationship) and male gender (higher scores for men). Two mediating variables, physical activity and stress-related eating, had smaller impacts. Self-reported racial discrimination was associated with cynical hostility but did not influence the MetS level among nondiabetics. Despite higher NCEP scores and MetS prevalence rates for Blacks compared with Whites, race did not have direct effect on MetS levels when adjusted for the other characteristics in our model. Conclusions: Neither race nor self-reported racial discrimination had direct effects on MetS level in our structural model. The large effects of socioeconomic position and male gender were not mediated by the other variables in the model.