Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease.

BACKGROUND: Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD. METHODS: Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE-/-) mouse model of atherosclerosis. RESULTS: A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic. CONCLUSIONS: Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

Depression, loneliness, and lower social activity as partial mediators of the association between visual impairment and cognitive decline.

OBJECTIVES: Sensory impairment is a hypothesized risk factor for cognitive decline; however, the psychosocial pathways are not well understood. We evaluated whether the association between visual impairment (VI) and cognitive decline was partially mediated via depressive symptoms, loneliness, or social activity. METHODS: We used data from 2601 older adults enrolled in the Memory and Aging Project in 1997 and the Minority Aging Research Study in 2004 with neuropsychological tests across five domains measured annually for up to 16 years. VI was assessed with the Rosenbaum Pocket Vision Screener. Depressive symptoms, loneliness, and social activity were self-reported using validated scales. We used structural equation models to estimate the associations of VI with baseline and change in cognitive function, directly and indirectly through each mediator (depressive symptoms, loneliness, and social activity). We evaluated mediation via "psychological distress" using a latent variable combining depressive symptoms and loneliness. RESULTS: The association between VI and global cognitive decline was mediated via lower social activity (indirect effect) [95% confidence interval (CI)] of linear slope: -0.025 (-0.048, -0.011), via loneliness (-0.011 [95% CI: -0.028, -0.002]), and via psychological distress (-0.017 [95% CI: -0.042, -0.003]). We did not find sufficient evidence for mediation via depressive symptoms alone. CONCLUSIONS: The harmful effect of VI on cognitive decline may be partially mediated through loneliness and lower social activity.

Fifty million years of beetle evolution along the Antarctic Polar Front.

Global cooling and glacial-interglacial cycles since Antarctica's isolation have been responsible for the diversification of the region's marine fauna. By contrast, these same Earth system processes are thought to have played little role terrestrially, other than driving widespread extinctions. Here, we show that on islands along the Antarctic Polar Front, paleoclimatic processes have been key to diversification of one of the world's most geographically isolated and unique groups of herbivorous beetles-Ectemnorhinini weevils. Combining phylogenomic, phylogenetic, and phylogeographic approaches, we demonstrate that these weevils colonized the sub-Antarctic islands from Africa at least 50 Ma ago and repeatedly dispersed among them. As the climate cooled from the mid-Miocene, diversification of the beetles accelerated, resulting in two species-rich clades. One of these clades specialized to feed on cryptogams, typical of the polar habitats that came to prevail under Miocene conditions yet remarkable as a food source for any beetle. This clade's most unusual representative is a marine weevil currently undergoing further speciation. The other clade retained the more common weevil habit of feeding on angiosperms, which likely survived glaciation in isolated refugia. Diversification of Ectemnorhinini weevils occurred in synchrony with many other Antarctic radiations, including penguins and notothenioid fishes, and coincided with major environmental changes. Our results thus indicate that geo-climatically driven diversification has progressed similarly for Antarctic marine and terrestrial organisms since the Miocene, potentially constituting a general biodiversity paradigm that should be sought broadly for the region's taxa.

Urban-Rural Differences in Health Care Utilization and COVID-19 Outcomes in Patients With Type 2 Diabetes.

INTRODUCTION: Two studies in Pennsylvania aimed to determine whether community type and community socioeconomic deprivation (CSD) 1) modified associations between type 2 diabetes (hereinafter, diabetes) and COVID-19 hospitalization outcomes, and 2) influenced health care utilization among individuals with diabetes during the COVID-19 pandemic. METHODS: The hospitalization study evaluated a retrospective cohort of patients hospitalized with COVID-19 through 2020 for COVID-19 outcomes: death, intensive care unit (ICU) admission, mechanical ventilation, elevated D-dimer, and elevated troponin level. We used adjusted logistic regression models, adding interaction terms to evaluate effect modification by community type (township, borough, or city census tract) and CSD. The utilization study included patients with diabetes and a clinical encounter between 2017 and 2020. Autoregressive integrated moving average time-series models evaluated changes in weekly rates of emergency department and outpatient visits, hemoglobin A1c (HbA1c) laboratory tests, and antihyperglycemic medication orders from 2018 to 2020. RESULTS: In the hospitalization study, of 2,751 patients hospitalized for COVID-19, 1,020 had diabetes, which was associated with ICU admission and elevated troponin. Associations did not differ by community type or CSD. In the utilization study, among 93,401 patients with diabetes, utilization measures decreased in March 2020. Utilization increased in July, and then began to stabilize or decline through the end of 2020. Changes in HbA1c tests and medication order trends during the pandemic differed by community type and CSD. CONCLUSION: Diabetes was associated with selected outcomes among individuals hospitalized for COVID-19, but these did not differ by community features. Utilization trajectories among individuals with diabetes during the pandemic were influenced by community type and CSD and could be used to identify individuals at risk of gaps in diabetes care.

Risk factors for Lyme disease stage and manifestation using electronic health records.

BACKGROUND: Little is known about risk factors for early (e.g., erythema migrans) and disseminated Lyme disease manifestations, such as arthritis, neurological complications, and carditis. No study has used both diagnoses and free text to classify Lyme disease by disease stage and manifestation. METHODS: We identified Lyme disease cases in 2012-2016 in the electronic health record (EHR) of a large, integrated health system in Pennsylvania. We developed a rule-based text-matching algorithm using regular expressions to extract clinical data from free text. Lyme disease cases were then classified by stage and manifestation using data from both diagnoses and free text. Among cases classified by stage, we evaluated individual, community, and health care variables as predictors of disseminated stage (vs. early) disease using Poisson regression models with robust errors. Final models adjusted for sociodemographic factors, receipt of Medical Assistance (i.e., Medicaid, a proxy for low socioeconomic status), primary care contact, setting of diagnosis, season of diagnosis, and urban/rural status. RESULTS: Among 7310 cases of Lyme disease, we classified 62% by stage. Overall, 23% were classified using both diagnoses and text, 26% were classified using diagnoses only, and 13% were classified using text only. Among the staged diagnoses (n = 4530), 30% were disseminated stage (762 arthritis, 426 neurological manifestations, 76 carditis, 95 secondary erythema migrans, and 76 other manifestations). In adjusted models, we found that persons on Medical Assistance at least 50% of time under observation, compared to never users, had a higher risk (risk ratio [95% confidence interval]) of disseminated Lyme disease (1.20 [1.05, 1.37]). Primary care contact (0.59 [0.54, 0.64]) and diagnosis in the urgent care (0.22 [0.17, 0.29]), compared to the outpatient setting, were associated with lower risk of disseminated Lyme disease. CONCLUSIONS: The associations between insurance payor, primary care status, and diagnostic setting with disseminated Lyme disease suggest that lower socioeconomic status and less health care access could be linked with disseminated stage Lyme disease. Intervening on these factors could reduce the individual and health care burden of disseminated Lyme disease. Our findings demonstrate the value of both diagnostic and narrative text data to identify Lyme disease manifestations in the EHR.

The changing form of Antarctic biodiversity.

Antarctic biodiversity is much more extensive, ecologically diverse and biogeographically structured than previously thought. Understanding of how this diversity is distributed in marine and terrestrial systems, the mechanisms underlying its spatial variation, and the significance of the microbiota is growing rapidly. Broadly recognizable drivers of diversity variation include energy availability and historical refugia. The impacts of local human activities and global environmental change nonetheless pose challenges to the current and future understanding of Antarctic biodiversity. Life in the Antarctic and the Southern Ocean is surprisingly rich, and as much at risk from environmental change as it is elsewhere.

Urinary arsenic and heart disease mortality in NHANES 2003-2014.

BACKGROUND: Evidence evaluating the prospective association between low-to moderate-inorganic arsenic (iAs) exposure and cardiovascular disease in the general US population is limited. We evaluated the association between urinary arsenic concentrations in National Health and Nutrition Examination Survey (NHANES) 2003-2014 and heart disease mortality linked from the National Death Index through 2015. METHODS: We modeled iAs exposure as urinary total arsenic and dimethylarsinate among participants with low seafood intake, based on low arsenobetaine levels (N = 4990). We estimated multivariable adjusted hazard ratios (HRs) for heart disease mortality per interquartile range (IQR) increase in urinary arsenic levels using survey-weighted, Cox proportional hazards models, and evaluated flexible dose-response analyses using restricted quadratic spline models. We updated a previously published relative risk of coronary heart disease mortality from a dose-response meta-analysis per a doubling of water iAs (e.g., from 10 to 20 µg/L) with our results from NHANES 2003-2014, assuming all iAs exposure came from drinking water. RESULTS: A total of 77 fatal heart disease events occurred (median follow-up time 75 months). The adjusted HRs (95% CI) of heart disease mortality for an increase in urinary total arsenic and DMA corresponding to the interquartile range were 1.20 (0.83, 1.74) and 1.18 (0.68, 2.05), respectively. Restricted quadratic splines indicate a significant association between increasing urinary total arsenic and the HR of fatal heart disease for all participants at the lowest exposure levels <4.5 µg/L. The updated pooled relative risk of coronary heart disease mortality per doubling of water iAs (µg/L) was 1.16 (95% CI 1.07, 1.25). CONCLUSIONS: Despite a small number of events, relatively short follow-up time, and high analytical limits of detection for urinary arsenic species, iAs exposure at low-to moderate-levels is consistent with increased heart disease mortality in NHANES 2003-2014 although the associations were only significant in flexible dose-response models.

Peridomestic and community-wide landscape risk factors for Lyme disease across a range of community contexts in Pennsylvania.

Land use and forest fragmentation are thought to be major drivers of Lyme disease incidence and its geographic distribution. We examined the association between landscape composition and configuration and Lyme disease in a population-based case control study in the Geisinger health system in Pennsylvania. Lyme disease cases (n = 9657) were identified using a combination of diagnosis codes, laboratory codes, and antibiotic orders from electronic health records (EHRs). Controls (5:1) were randomly selected and frequency matched on year, age, and sex. We measured six landscape variables based on prior literature, derived from the National Land Cover Database and MODIS satellite imagery: greenness (normalized difference vegetation index), percent forest, percent herbaceous, forest edge density, percent forest-herbaceous edge, and mean forest patch size. We assigned landscape variables within two spatial contexts (community and ½-mile [805 m] Euclidian residential buffer). In models stratified by community type, landscape variables were modeled as tertiles and flexible splines and associations were adjusted for demographic and clinical covariates. In general, we observed positive associations between landscape metrics and Lyme disease, except for percent herbaceous, where associations differed by community type. For example, compared to the lowest tertile, individuals with highest tertile of greenness in residential buffers had higher odds of Lyme disease (odds ratio: 95% confidence interval [CI]) in townships (1.73: 1.55, 1.93), boroughs (1.70: 1.40, 2.07), and cities (3.71: 1.74, 7.92). Similarly, corresponding odds ratios (95% CI) for forest edge density were 1.34 (1.22, 1.47), 1.56 (1.33, 1.82), and 1.90 (1.13, 3.18). Associations were generally higher in residential buffers, compared to community, and in cities, compared to boroughs or townships. Our results reinforce the importance of peridomestic landscape in Lyme disease risk, particularly measures that reflect human interaction with tick habitat. Linkage of EHR data to public data on residential and community context may lead to new health system-based approaches for improving Lyme disease diagnosis, treatment, and prevention.

Biomarkers of Secondhand Smoke Exposure in Waterpipe Tobacco Venue Employees in Istanbul, Moscow, and Cairo.

Background: Most smoke-free legislation to reduce secondhand smoke (SHS) exposure exempts waterpipe (hookah) smoking venues. Few studies have examined SHS exposure in waterpipe venues and their employees. Methods: We surveyed 276 employees of 46 waterpipe tobacco venues in Istanbul, Moscow, and Cairo. We interviewed venue managers and employees and collected biological samples from employees to measure exhaled carbon monoxide (CO), hair nicotine, saliva cotinine, urine cotinine, urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and urine 1-hydroxypyrene glucuronide (1-OHPG). We estimated adjusted geometric mean ratios (GMR) of each SHS biomarker by employee characteristics and indoor air SHS measures. Results: There were 73 nonsmoking employees and 203 current smokers of cigarettes or waterpipe. In nonsmokers, the median (interquartile) range concentrations of SHS biomarkers were 1.1 (0.2, 40.9) µg/g creatinine urine cotinine, 5.5 (2, 15) ng/mL saliva cotinine, 0.95 (0.36, 5.02) ng/mg hair nicotine, 1.48 (0.98, 3.97) pg/mg creatinine urine NNAL, 0.54 (0.25, 0.97) pmol/mg creatinine urine 1-OHPG, and 1.67 (1.33, 2.33) ppm exhaled CO. An 8-hour increase in work hours was associated with higher urine cotinine (GMR: 1.68, 95% CI: 1.20, 2.37) and hair nicotine (GMR: 1.22, 95% CI: 1.05, 1.43). Lighting waterpipes was associated with higher saliva cotinine (GMR: 2.83, 95% CI: 1.05, 7.62). Conclusions: Nonsmoking employees of waterpipe tobacco venues were exposed to high levels of SHS, including measurable levels of carcinogenic biomarkers (tobacco-specific nitrosamines and PAHs). Implications: Smoke-free regulation should be extended to waterpipe venues to protect nonsmoking employees and patrons from the adverse health effects of SHS.

Chronic arsenic exposure and risk of carotid artery disease: The Strong Heart Study.

BACKGROUND: Inorganic arsenic exposure from naturally contaminated groundwater is related to vascular disease. No prospective studies have evaluated the association between arsenic and carotid atherosclerosis at low-moderate levels. We examined the association of long-term, low-moderate inorganic arsenic exposure with carotid arterial disease. METHODS: American Indians, 45-74 years old, in Arizona, Oklahoma, and North and South Dakota had arsenic concentrations (sum of inorganic and methylated species, µg/g urine creatinine) measured from baseline urine samples (1989-1991). Carotid artery ultrasound was performed in 1998-1999. Vascular disease was assessed by the carotid intima media thickness (CIMT), the presence of atherosclerotic plaque in the carotid, and by the number of segments containing plaque (plaque score). RESULTS: 2402 participants (mean age 55.3 years, 63.1% female, mean body mass index 31.0kg/m2, diabetes 45.7%, hypertension 34.2%) had a median (interquintile range) urine arsenic concentration of 9.2 (5.00, 17.06) µg/g creatinine. The mean CIMT was 0.75mm. 64.7% had carotid artery plaque (3% with >50% stenosis). In fully adjusted models comparing participants in the 80th vs. 20th percentile in arsenic concentrations, the mean difference in CIMT was 0.01 (95% confidence interval (95%CI): 0.00, 0.02) mm, the relative risk of plaque presence was 1.04 (95%CI: 0.99, 1.09), and the geometric mean ratio of plaque score was 1.05 (95%CI: 1.01, 1.09). CONCLUSIONS: Urine arsenic was positively associated with CIMT and increased plaque score later in life although the association was small. The relationship between urinary arsenic and the presence of plaque was not statistically significant when adjusted for other risk factors. Arsenic exposure may play a role in increasing the severity of carotid vascular disease.

Secondhand smoke in waterpipe tobacco venues in Istanbul, Moscow, and Cairo.

OBJECTIVE: The prevalence of waterpipe tobacco smoking has risen in recent decades. Controlled studies suggest that waterpipe secondhand smoke (SHS) contains similar or greater quantities of toxicants than cigarette SHS, which causes significant morbidity and mortality. Few studies have examined SHS from waterpipe tobacco in real-world settings. The purpose of this study was to quantify SHS exposure levels and describe the characteristics of waterpipe tobacco venues. METHODS: In 2012-2014, we conducted cross-sectional surveys of 46 waterpipe tobacco venues (9 in Istanbul, 17 in Moscow, and 20 in Cairo). We administered venue questionnaires, conducted venue observations, and sampled indoor air particulate matter (PM2.5) (N=35), carbon monoxide (CO) (N=23), particle-bound polycyclic aromatic hydrocarbons (p-PAHs) (N=31), 4-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (N=43), and air nicotine (N=46). RESULTS: Venue characteristics and SHS concentrations were highly variable within and between cities. Overall, we observed a mean (standard deviation (SD)) of 5 (5) waterpipe smokers and 5 (3) cigarette smokers per venue. The overall median (25th percentile, 75th percentile) of venue mean air concentrations was 136 (82, 213) µg/m(3) for PM2.5, 3.9 (1.7, 22) ppm for CO, 68 (33, 121) ng/m(3) for p-PAHs, 1.0 (0.5, 1.9) ng/m(3) for NNK, and 5.3 (0.7, 14) µg/m(3) for nicotine. PM2.5, CO, and p-PAHs concentrations were generally higher in venues with more waterpipe smokers and cigarette smokers, although associations were not statistically significant. CONCLUSION: High concentrations of SHS constituents known to cause health effects indicate that indoor air quality in waterpipe tobacco venues may adversely affect the health of employees and customers.

Association between exposure to low to moderate arsenic levels and incident cardiovascular disease. A prospective cohort study.

BACKGROUND: Long-term exposure to high levels of arsenic is associated with increased risk for cardiovascular disease, whereas risk from long-term exposure to low to moderate arsenic levels (< 100µg/L in drinking water) is unclear. OBJECTIVE: To evaluate the association between long-term exposure to low to moderate arsenic levels and incident cardiovascular disease. DESIGN: Prospective cohort study. SETTING: The Strong Heart Study baseline visit between 1989 and 1991, with follow-up through 2008. PATIENTS: 3575 American Indian men and women aged 45 to 74 years living in Arizona, Oklahoma, and North and South Dakota. MEASUREMENTS: The sum of inorganic and methylated arsenic species in urine at baseline was used as a biomarker of long-term arsenic exposure. Outcomes were incident fatal and nonfatal cardiovascular disease. RESULTS: A total of 1184 participants developed fatal and nonfatal cardiovascular disease. When the highest and lowest quartiles of arsenic concentrations (> 15.7 vs. < 5.8 µg/g creatinine) were compared,the hazard ratios for cardiovascular disease, coronary heart disease, and stroke mortality after adjustment for sociodemographic factors, smoking, body mass index, and lipid levels were 1.65 (95%CI, 1.20 to 2.27; P for trend < 0.001), 1.71 (CI, 1.19 to 2.44; P for trend < 0.001), and 3.03 (CI, 1.08 to 8.50; P for trend = 0.061),respectively. The corresponding hazard ratios for incident cardiovascular disease, coronary heart disease, and stroke were 1.32 (CI,1.09 to 1.59; P for trend = 0.002), 1.30 (CI, 1.04 to 1.62; P for trend = 0.006), and 1.47 (CI, 0.97 to 2.21; P for trend = 0.032).These associations varied by study region and were attenuated after further adjustment for diabetes, hypertension, and kidney disease measures. LIMITATION: Direct measurement of individual arsenic levels in drinking water was unavailable. CONCLUSION: Long-term exposure to low to moderate arsenic levels was associated with cardiovascular disease incidence and mortality.

Community profiles in northeastern and central Pennsylvania characterized by distinct social, natural, food, and physical activity environments and their relation to type 2 diabetes.

Background: Understanding geographic disparities in type 2 diabetes (T2D) requires approaches that account for communities' multidimensional nature. Methods: In an electronic health record nested case-control study, we identified 15,884 cases of new-onset T2D from 2008 to 2016, defined using encounter diagnoses, medication orders, and laboratory test results, and frequency-matched controls without T2D (79,400; 65,069 unique persons). We used finite mixture models to construct community profiles from social, natural, physical activity, and food environment measures. We estimated T2D odds ratios (OR) with 95% confidence intervals (CI) using logistic generalized estimating equation models, adjusted for sociodemographic variables. We examined associations with the profiles alone and combined them with either community type based on administrative boundaries or Census-based urban/rural status. Results: We identified four profiles in 1069 communities in central and northeastern Pennsylvania along a rural-urban gradient: "sparse rural," "developed rural," "inner suburb," and "deprived urban core." Urban areas were densely populated with high physical activity resources and food outlets; however, they also had high socioeconomic deprivation and low greenness. Compared with "developed rural," T2D onset odds were higher in "deprived urban core" (1.24, CI = 1.16-1.33) and "inner suburb" (1.10, CI = 1.04-1.17). These associations with model-based community profiles were weaker than when combined with administrative boundaries or urban/rural status. Conclusions: Our findings suggest that in urban areas, diabetogenic features overwhelm T2D-protective features. The community profiles support the construct validity of administrative-community type and urban/rural status, previously reported, to evaluate geographic disparities in T2D onset in this geography.

Extant and extinct bilby genomes combined with Indigenous knowledge improve conservation of a unique Australian marsupial.

Ninu (greater bilby, Macrotis lagotis) are desert-dwelling, culturally and ecologically important marsupials. In collaboration with Indigenous rangers and conservation managers, we generated the Ninu chromosome-level genome assembly (3.66 Gbp) and genome sequences for the extinct Yallara (lesser bilby, Macrotis leucura). We developed and tested a scat single-nucleotide polymorphism panel to inform current and future conservation actions, undertake ecological assessments and improve our understanding of Ninu genetic diversity in managed and wild populations. We also assessed the beneficial impact of translocations in the metapopulation (N = 363 Ninu). Resequenced genomes (temperate Ninu, 6; semi-arid Ninu, 6; and Yallara, 4) revealed two major population crashes during global cooling events for both species and differences in Ninu genes involved in anatomical and metabolic pathways. Despite their 45-year captive history, Ninu have fewer long runs of homozygosity than other larger mammals, which may be attributable to their boom-bust life history. Here we investigated the unique Ninu biology using 12 tissue transcriptomes revealing expression of all 115 conserved eutherian chorioallantoic placentation genes in the uterus, an XY1Y2 sex chromosome system and olfactory receptor gene expansions. Together, we demonstrate the holistic value of genomics in improving key conservation actions, understanding unique biological traits and developing tools for Indigenous rangers to monitor remote wild populations.

Environmental chemicals and type 2 diabetes: an updated systematic review of the epidemiologic evidence.

The burden of diabetes is increasing globally. Identifying novel preventable risk factors is an urgent need. In 2011, the U.S. National Toxicological Program (NTP) conducted a workshop to evaluate the epidemiologic and experimental evidence on the relationship of environmental chemicals with obesity, diabetes, and metabolic syndrome. Although the evidence was insufficient to establish causality, the NTP workshop review identified an overall positive association between some environmental chemicals and diabetes. In the present systematic review, our objective was to summarize the epidemiological research published since the NTP workshop. We identified a total of 29 articles (7 on arsenic, 3 on cadmium, 2 on mercury, 11 on persistent organic pollutants, 3 on phthalates, and 4 on bisphenol A), including 7 prospective studies. Considering consistency, temporality, strength, dose-response relationship, and biological plausibility (confounding), we concluded that the evidence is suggestive but not sufficient for a relationship between arsenic and persistent organic pollutants and is insufficient for mercury, phthalates, and bisphenol A. For cadmium, the epidemiologic evidence does not seem to suggest an association with diabetes. Important research questions include the need for additional prospective studies and the evaluation of the dose-response relationship, the role of joint exposures, and effect modification with other comorbidities and genetic variants.

Machine learning identifies T cell receptor repertoire signatures associated with COVID-19 severity.

T cell receptor (TCR) repertoires are critical for antiviral immunity. Determining the TCR repertoire composition, diversity, and dynamics and how they change during viral infection can inform the molecular specificity of host responses to viruses such as SARS-CoV-2. To determine signatures associated with COVID-19 disease severity, here we perform a large-scale analysis of over 4.7 billion sequences across 2130 TCR repertoires from COVID-19 patients and healthy donors. TCR repertoire analyses from these data identify and characterize convergent COVID-19-associated CDR3 gene usages, specificity groups, and sequence patterns. Here we show that T cell clonal expansion is associated with the upregulation of T cell effector function, TCR signaling, NF-kB signaling, and interferon-gamma signaling pathways. We also demonstrate that machine learning approaches accurately predict COVID-19 infection based on TCR sequence features, with certain high-power models reaching near-perfect AUROC scores. These analyses provide a systems immunology view of T cell adaptive immune responses to COVID-19.

Five questions on how biochemistry can combat climate change.

Global warming is caused by human activity, such as the burning of fossil fuels, which produces high levels of greenhouse gasses. As a consequence, climate change impacts all organisms and the greater ecosystem through changing conditions from weather patterns to the temperature, pH and salt concentrations found in waterways and soil. These environmental changes fundamentally alter many parameters of the living world, from the kinetics of chemical reactions and cellular signaling pathways to the accumulation of unforeseen chemicals in the environment, the appearance and dispersal of new diseases, and the availability of traditional foods. Some organisms adapt to extremes, while others cannot. This article asks five questions that prompt us to consider the foundational knowledge that biochemistry can bring to the table as we meet the challenge of climate change. We approach climate change from the molecular point of view, identifying how cells and organisms - from microbes to plants and animals - respond to changing environmental conditions. To embrace the concept of "one health" for all life on the planet, we argue that we must leverage biochemistry, cell biology, molecular biophysics and genetics to fully understand the impact of climate change on the living world and to bring positive change.

​Comparative genomics of Balto, a famous historic dog, captures lost diversity of 1920s sled dogs.

We reconstruct the phenotype of Balto, the heroic sled dog renowned for transporting diphtheria antitoxin to Nome, Alaska, in 1925, using evolutionary constraint estimates from the Zoonomia alignment of 240 mammals and 682 genomes from dogs and wolves of the 21st century. Balto shares just part of his diverse ancestry with the eponymous Siberian husky breed. Balto's genotype predicts a combination of coat features atypical for modern sled dog breeds, and a slightly smaller stature. He had enhanced starch digestion compared with Greenland sled dogs and a compendium of derived homozygous coding variants at constrained positions in genes connected to bone and skin development. We propose that Balto's population of origin, which was less inbred and genetically healthier than that of modern breeds, was adapted to the extreme environment of 1920s Alaska.

Mediation of an association between neighborhood socioeconomic environment and type 2 diabetes through the leisure-time physical activity environment in an analysis of three independent samples.

INTRODUCTION: Inequitable access to leisure-time physical activity (LTPA) resources may explain geographic disparities in type 2 diabetes (T2D). We evaluated whether the neighborhood socioeconomic environment (NSEE) affects T2D through the LTPA environment. RESEARCH DESIGN AND METHODS: We conducted analyses in three study samples: the national Veterans Administration Diabetes Risk (VADR) cohort comprising electronic health records (EHR) of 4.1 million T2D-free veterans, the national prospective cohort REasons for Geographic and Racial Differences in Stroke (REGARDS) (11 208 T2D free), and a case-control study of Geisinger EHR in Pennsylvania (15 888 T2D cases). New-onset T2D was defined using diagnoses, laboratory and medication data. We harmonized neighborhood-level variables, including exposure, confounders, and effect modifiers. We measured NSEE with a summary index of six census tract indicators. The LTPA environment was measured by physical activity (PA) facility (gyms and other commercial facilities) density within street network buffers and population-weighted distance to parks. We estimated natural direct and indirect effects for each mediator stratified by community type. RESULTS: The magnitudes of the indirect effects were generally small, and the direction of the indirect effects differed by community type and study sample. The most consistent findings were for mediation via PA facility density in rural communities, where we observed positive indirect effects (differences in T2D incidence rates (95% CI) comparing the highest versus lowest quartiles of NSEE, multiplied by 100) of 1.53 (0.25, 3.05) in REGARDS and 0.0066 (0.0038, 0.0099) in VADR. No mediation was evident in Geisinger. CONCLUSIONS: PA facility density and distance to parks did not substantially mediate the relation between NSEE and T2D. Our heterogeneous results suggest that approaches to reduce T2D through changes to the LTPA environment require local tailoring.

Arsenic exposure and cardiovascular disease: an updated systematic review.

In epidemiologic studies, high-chronic arsenic exposure has been associated with cardiovascular disease, despite methodological limitations. At low-moderate arsenic levels, the evidence was inconclusive. Here, we update a previous systematic review (Am J Epidemiol 2005;162:1037-49) examining the association between arsenic exposure and cardiovascular disease. Eighteen studies published since 2005 were combined with 13 studies from the previous review. We calculated pooled relative risks by comparing the highest versus the lowest exposure category across studies. For high exposure (arsenic in drinking water > 50 µg/L), the pooled relative risks (95 % confidence interval) for cardiovascular disease, coronary heart disease, stroke, and peripheral arterial disease were 1.32 (95 % CI:1.05-1.67), 1.89 (95 % CI:1.33-2.69), 1.08 (95 % CI:0.98-1.19), and 2.17 (95 % CI:1.47-3.20), respectively. At low-moderate arsenic levels, the evidence was inconclusive. Our review strengthens the evidence for a causal association between high-chronic arsenic exposure and clinical cardiovascular endpoints. Additional high quality studies are needed at low-moderate arsenic levels.