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Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biologic mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve datasets from ten pregnancy cohorts (N=5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.

Shorter gestational age (GA) is a risk factor of developmental delay. GA is usually estimated clinically from last menstrual period and ultrasound. DNA methylation (DNAm) estimates GA using sets of cytosine-guanine-sites coupled with a clock algorithm. Therefore, DNAm-estimated GA may better reflect biological maturation. A DNAm GA greater than clinical GA, known as gestational age acceleration (GAA), may indicate epigenetic maturity and holds potential as an early biomarker for developmental delay risk. We used data from the Upstate KIDS Study to examine associations of DNAm GA and developmental delay within the first 3 years based on the Ages & Stages Questionnaire® (n = 1010). We estimated DNAm GA using two clocks specific to the Illumina Methylation EPIC 850K, the Haftorn clock and one developed from the Effects of Aspirin in Gestation and Reproduction study, in which women were followed to detect pregnancy at the earliest time possible. Among singletons, each week increase in DNAm GA was protective for overall delay (odds ratio:0.74; 95% confidence interval:0.61–0.90) and delay in all domains except for problem-solving skills. Among twins, we observed similar point estimates but lower precision. Results were similar for clinical GA. GAA was largely not associated with developmental delays. In summary, either DNAm GA or clinical GA at birth, but not epigenetic maturity (i.e. GAA), was associated with decreased odds of developmental delay in early childhood. Our study does not support using DNAm GA or GAA as separate risk factors for future risk of developmental delay within the first 3 years of age.

Delirium is common in the setting of infection with severe acute respiratory syndrome coronavirus 2. Anecdotal evidence and case reports suggest that patients with delirium in the setting of Coronavirus 2019 (COVID-19) may exhibit specific features, including increased tone, abulia, and alogia.To determine whether differences exist in sociodemographic and medical characteristics, physical examination findings, and medication use in delirious patients with and without COVID-19 infection referred for psychiatric consultation.We undertook an exploratory, retrospective chart review of 486 patients seen by the psychiatry consultation service at a tertiary care hospital from March 10 to May 15, 2020. Delirious patients were diagnosed via clinical examination by a psychiatric consultant, and these patients were stratified by COVID-19 infection status. The strata were described and compared using bivariate analyses across sociodemographic, historical, objective, and treatment-related variables.A total of 109 patients were diagnosed with delirium during the study period. Thirty-six were COVID-19+. Median age was 63 years and did not differ between groups. COVID-19+ patients with delirium were more likely to present from nursing facilities (39% vs 11%; Fisher's exact test; P = 0.001) and have a history of schizophrenia (11% vs 0%; Fisher's exact test; P = 0.011). Myoclonus (28% vs 4%; P = 0.002), hypertonia (36% vs 10%; P = 0.003), withdrawal (36% vs 15%; P = 0.011), akinesia (19% vs 6%; P = 0.034), abulia (19% vs 3%; P = 0.004), and alogia (25% vs 8%; P = 0.012) were more common in COVID-19+ patients. COVID-19+ delirious patients were significantly more likely to have received ketamine (28% vs 7%; P = 0.006), alpha-adrenergic agents besides dexmedetomidine (36% vs 14%; P = 0.014), and enteral antipsychotics (92% vs 66%; P = 0.007) at some point.Patients with COVID-19 delirium referred for psychiatric consultation are more likely to reside in nursing facilities and have a history of schizophrenia than delirious patients without COVID-19. Patients with delirium in the setting of COVID-19 may exhibit features consistent with akinetic mutism. Psychiatrists must assess for such features, as they may influence management choices and the risk of side effects with agents commonly used in the setting of delirium.

Metabolic abnormalities affect the adolescent brain. For equivalent abnormalities in metabolism young people exhibit deficits in more cognitive domains than adults. We examine sex differences performance for adolescents with obesity/insulin resistance (IR) and evaluated how sex and IR effected frontal lobe structures and executive functioning. 125 adolescents underwent medical, cognitive, and brain-imaging assessments. Participants were categorized as insulin sensitive (IS) (QUICKI ≧ 0.350) or IR (QUICKI < 0.350). Degree of IR may affect brain and cognition differentially by sex. Females had positive associations between QUICKI and anterior cingulate cortex (ACC) volume, medial orbito-frontal cortex (OFC) thickness, and scores on the Stroop and Digit Symbol Substitution (DSST) tests. Females with IR tended to have thinner insular cortices. No such associations were found in males. In female adolescents, IR may negatively affect brain structure and function. No such effects were found for males. Although needing more development, hormonal effects and inflammation are potential contributors.

Poor lung function has been linked with adverse neurocognitive outcomes including dementia, but evidence from well-designed prospective studies is limited. We therefore examined the association between lung function, as measured by forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and dementia risk in 12,688 participants of the ARIC study, a prospective study of adults aged 46-70 years (at index visit, mean age =57y, 45% male, 76% White) from four US communities. Lung function was assessed in 1991-1992 (index visit, 76% normal, 16% obstructive, and 8% restrictive lung function), and dementia was ascertained through 2019 via in-person assessments, telephone interviews, and medical record surveillance, with adjudication of dementia with all in-person exams. A total of 2452 developed dementia over 30 years of follow-up. We used Cox proportional hazards model to estimate hazard ratio (HR) and 95% confidence intervals (CI), adjusting for potential confounders (socio-demographics, behavioral factors, cardiovascular risk factors, APOE ε4). Higher FEV1 and FVC were associated with reduced dementia risk [(HR: 0.86, 95%CI: 0.78-0.98, per 1L increase in FEV1) and (HR: 0.86, 95%CI: 0.80-0.93 per 1L increase in FVC)]. Compared to normal lung function, restrictive disease was associated with elevated dementia risk [(HR: 1.19, 95%CI: 1.01-1.41), n=168 dementia cases]; HR for obstructive disease, though modestly elevated (1.09, 95%CI: 0.96-1.24, n=713 dementia cases), was not statistically significant. Our findings of decreased dementia risk with better lung function may have important implications in reducing burden of dementia that is attributable to environmental exposures and associated lung function impairment.

Importance Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. Objectives To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. Design We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. Results US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. Conclusions and Relevance From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.

Abnormal lung function is associated with a heightened risk of heart failure (HF). Whether changes in lung function over time are associated with incident HF is not known. Among 10,868 participants in the Atherosclerosis Risk in Communities Study who were free of HF, we identified participants with

There is an overwhelming abundance of genetic association studies available in the literature, which can often be collectively difficult to interpret. To address this issue, the Venice interim guidelines were established for determining the credibility of the cumulative evidence. The objective of this report is to evaluate the literature on the association of common glutathione S-transferase (GST) variants (GSTM1 null, GSTT1 null and GSTP1 Ile105Val polymorphism) and lung cancer, and to assess the credibility of the associations using the newly proposed cumulative evidence guidelines.Information from the literature was enriched with an updated meta-analysis and a pooled analysis using data from the Genetic Susceptibility to Environmental Carcinogens database.There was a significant association between GSTM1 null and lung cancer for the meta-analysis (meta odds ratio=1.17, 95% confidence interval: 1.10-1.25) and pooled analysis (adjusted odds ratio=1.10, 95% confidence interval: 1.04-1.16), although substantial heterogeneity was present. No overall association between lung cancer and GSTT1 null or GSTP1 Ile105Val was found. When the Venice criteria was applied, cumulative evidence for all associations were considered 'weak', with the exception of East Asian carriers of the G allele of GSTP1 Ile105Val, which was graded as 'moderate' evidence.Despite the large amounts of studies, and several statistically significant summary estimates produced by meta-analyses, the application of the Venice criteria suggests extensive heterogeneity and susceptibility to bias for the studies on association of common genetic polymorphisms, such as with GST variants and lung cancer.

Sulfur dioxide (SO(2)) has been associated with increased mortality and morbidity, but only few studies were conducted in Asian countries. Previous studies suggest that SO(2) may have adverse health effects independent of other pollutants. In the Public Health and Air Pollution in Asia (PAPA) project, the short-term associations between ambient sulfur dioxide (SO(2)) and daily mortality were examined in Bangkok, Thailand, and three Chinese cities: Hong Kong, Shanghai, and Wuhan. Poisson regression models incorporating natural spline smoothing functions were used to adjust for seasonality and other time-varying covariates. Effect estimates were obtained for each city and then for the cities combined. The impact of alternative model specifications, such as lag structure of pollutants and degree of freedom (df) for time trend, on the estimated effects of SO(2) were also examined. In both individual-city and combined analysis, significant effects of SO(2) on total non-accidental and cardiopulmonary mortality were observed. An increase of 10 microg/m(3) of 2-day moving average concentrations of SO(2) corresponded to 1.00% [95% confidence interval (CI), 0.75-1.24], 1.09% (95% CI, 0.71-1.47), and 1.47% (95% CI, 0.85-2.08) increase of total, cardiovascular and respiratory mortality, respectively, in the combined analysis. Sensitivity analyzes suggested that these findings were generally insensitive to alternative model specifications. After adjustment for PM(10) or O(3), the effect of SO(2) remained significant in three Chinese cities. However, adjustment for NO(2) diminished the associations and rendered them statistically insignificant in all four cities. In conclusion, ambient SO(2) concentration was associated with daily mortality in these four Asian cities. These associations may be attributable to SO(2) serving as a surrogate of other substances. Our findings suggest that the role of outdoor exposure to SO(2) should be investigated further in this region.

To the Editor: In a genomewide association study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, we identified several loci as genetic determinants of spirometric measures of lung function in more than 20,000 adults from population-based cohorts.1 Moffatt et al. (Sept. 23 issue)2 attributed to us the statement that “genetic determinants of lung function influence susceptibility to asthma” and indicated that their own data “do not support this hypothesis.” Because chronic obstructive pulmonary disease (COPD) is defined on the basis of the same spirometric measures of lung function, it is not surprising that some loci . . .

An interaction between occupational carcinogens and genetic susceptibility factors in determining individual lung cancer risk is biologically plausible, but the interpretation of available studies are limited by the small number of exposed subjects. We selected from the international database on Genetic Susceptibility and Environmental Carcinogens the studies of lung cancer that included information on metabolic polymorphisms and occupational exposures. Adequate data were available for asbestos exposure and GSTM1 (five studies) and GSTT1 (three studies) polymorphisms. For GSTM1, the pooled analysis included 651 cases and 983 controls. The odds ratio (OR) of lung cancer was 2.0 [95% confidence interval (CI) 1.4-2.7] for asbestos exposure and 1.1 (95% CI 0.9-1.4) for GSTM1-null genotype. The OR of interaction between asbestos and GSTM1 polymorphism was 1.1 (95% CI 0.6-2.1) based on 54 cases and 53 controls who were asbestos exposed and GSTM1 null. The case-only approach, which was based on 869 lung cancer cases and had an 80% power to detect an OR of interaction of 1.56, also provided lack of evidence of interaction. The analysis of possible interaction between GSTT1 polymorphism and asbestos exposure in relation to lung cancer was based on 619 cases. The prevalence OR of GSTT1-null genotype and asbestos exposure was 1.1 (95% CI 0.6-2.0). Our results do not support the hypothesis that the risk of lung cancer after asbestos exposure differs according to GSTM1 genotype. The low statistical power of the pooled analysis for GSTT1 genotypes hampered any firm conclusion. No adequate data were available to assess other interactions between occupational exposures and metabolic polymorphisms.

Item does not contain fulltext Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.

We recently reported that antioxidant supplementation with vitamins C and E mitigated ozone related decline in forced expiratory flow (FEF(25-75)) in 158 asthmatic children in an area with high ozone exposure in Mexico City.A study was undertaken to determine whether deletion of glutathione S-transferase M1 (GSTM1 null genotype), a gene involved in response to oxidative stress, influences ozone related decline in FEF(25-75) and the benefit of antioxidant supplementation.GSTM1 null children receiving placebo had significant ozone related decrements in FEF(25-75) (percentage change per 50 ppb of ozone 2.9 (95% CI -5.2 to -0.6), p=0.01); GSTM1 positive children did not. Conversely, the effect of antioxidants was stronger in children with the GSTM1 null genotype.Asthmatic children with a genetic deficiency of GSTM1 may be more susceptible to the deleterious effects of ozone on the small airways and might derive greater benefit from antioxidant supplementation.