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Abstract To understand how chemical exposure can impact health, researchers need tools that capture the complexities of personal chemical exposure. In practice, fine particulate matter (PM2.5) air quality index (AQI) data from outdoor stationary monitors and Hazard Mapping System (HMS) smoke density data from satellites are often used as proxies for personal chemical exposure, but do not capture total chemical exposure. Silicone wristbands can quantify more individualized exposure data than stationary air monitors or smoke satellites. However, it is not understood how these proxy measurements compare to chemical data measured from wristbands. In this study, participants wore daily wristbands, carried a phone that recorded locations, and answered daily questionnaires for a 7‐day period in multiple seasons. We gathered publicly available daily PM2.5 AQI data and HMS data. We analyzed wristbands for 94 organic chemicals, including 53 polycyclic aromatic hydrocarbons. Wristband chemical detections and concentrations, behavioral variables (e.g., time spent indoors), and environmental conditions (e.g., PM2.5 AQI) significantly differed between seasons. Machine learning models were fit to predict personal chemical exposure using PM2.5 AQI only, HMS only, and a multivariate feature set including PM2.5 AQI, HMS, and other environmental and behavioral information. On average, the multivariate models increased predictive accuracy by approximately 70% compared to either the AQI model or the HMS model for all chemicals modeled. This study provides evidence that PM2.5 AQI data alone or HMS data alone is insufficient to explain personal chemical exposures. Our results identify additional key predictors of personal chemical exposure.

Abstract Background Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. Methods We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. Results Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. Conclusions Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.

Abstract Background Polycyclic aromatic hydrocarbons (PAH), which are found in air pollution, have carcinogenic and endocrine disrupting properties that might increase breast cancer risk. PAH exposure might be particularly detrimental during pregnancy, as this is a time when the breast tissue of both the mother and daughter is undergoing structural and functional changes. In this study, we tested the hypothesis that ambient PAH exposure during pregnancy is associated with breast tissue composition, measured one to two decades later, in adolescent daughters and their mothers. Methods We conducted a prospective analysis using data from a New York City cohort of non-Hispanic Black and Hispanic mother–daughter dyads (recruited 1998–2006). During the third trimester of pregnancy, women wore backpacks containing a continuously operating air sampling pump for two consecutive days that measured ambient exposure to eight carcinogenic higher molecular weight nonvolatile PAH compounds (Σ8 PAH) and pyrene. When daughters (n = 186) and mothers (n = 175) reached ages 11–20 and 29–55 years, respectively, optical spectroscopy (OS) was used to evaluate measures of breast tissue composition (BTC) that positively (water content, collagen content, optical index) and negatively (lipid content) correlate with mammographic breast density, a recognized risk factor for breast cancer. Multivariable linear regression was used to evaluate associations between ambient PAH exposure and BTC, overall and by exposure to household tobacco smoke during pregnancy (yes/no). Models were adjusted for race/ethnicity, age, and percent body fat at OS. Results No overall associations were found between ambient PAH exposure (Σ8 PAH or pyrene) and BTC, but statistically significant additive interactions between Σ8 PAH and household tobacco smoke exposure were identified for water content and optical index in both daughters and mothers (interaction p values

Background: In the 1930's the United States (US) sponsored Home Owners’ Loan Corporation (HOLC) created maps that determined risk for mortgage lending based on the racial and ethnic composition of neighborhoods leading to disinvestment in “redlined” or highest risk neighborhoods. This historical practice has perpetuated racial and economic segregation, and health disparities, that persist today. Interventions near schools where children spend large portions of the day, could impact large groups of children but schools are an often-overlooked environment for exposure. Despite a declining trend of ambient pollution in New York City (NYC) between 1998 and 2012, little is known about differences in air quality improvement near schools by historical redlining neighborhood status. Our objective was to examine if recent temporal trends of air pollution near NYC public schools differed in historically redlined neighborhoods. Methods: We examined annual average street-level concentrations of combustion-related air pollutants (black carbon (BC), particulate matter (PM2.5), nitrogen dioxide (NO2), and nitric oxide (NO)), within a 250-m radius around schools using NYC Community Air Survey land-use regression models (n = 1,462). Year of monitoring, historical redlining (binary), and summer ozone were included in multivariable linear regression using generalized estimating equation models. Average annual percent change (APC) in pollutant concentration was calculated. Models were further stratified by historical redlining and a multiplicative interaction term (year of monitoring × historical redlining) was used to assess effect modification. Results: Overall, there was a decreasing trend of BC (APC = -4.40%), PM2.5 (-3.92%), NO2 (-2.76%), and NO (-6.20%) during the 10-year period. A smaller reduction of BC, PM2.5 and NO was observed in redlined neighborhoods (n = 722), compared to others (n = 740): BC (APC: −4.11% vs −4.69%; Pinteraction

Background: Asthma affects approximately 6 million children in the United States and can greatly impact quality of life and occupational engagement. Although occupational therapists are well-equipped to address participation limitations, insufficient evidence exists to support the role of occupational therapists in asthma treatment. Method: The purpose of this study was to further understand the occupational limitations experienced by children with asthma. We also explored a dual diagnosis of asthma and obesity. The participants included children with (n = 84) and without (n = 63) asthma living in New York City. The Child Behavior Checklist, Youth Self Report, Brief Respiratory Questionnaire, and accelerometer data were used to examine occupational participation. Results: Although accelerometry data demonstrated that children with asthma were equally as active as their non-asthmatic peers, the participants with asthma perceived themselves as participating more in sedentary occupations and were less likely to be members of sports teams. They also had more missed school days and nights of troubled sleep. The children with both asthma and obesity reported the highest level of activity limitations. Conclusion: This study illustrates specific limitations experienced by children with asthma and supports the need for occupational therapy intervention. Future studies are needed to design and assess interventions that will support the addition of occupational therapists to multidisciplinary asthma treatment teams.

Carrie Breton and colleagues review the literature supporting evidence for transgenerational health effects of environmental exposures by epigenetic mechanisms. This Review summarizes current knowledge based on animal and human cohort studies, and discusses the ethical, legal, and social implications of epigenetic research in humans

During events like the COVID-19 pandemic or a disaster, researchers may need to switch from collecting biological samples to personal exposure samplers that are easy and safe to transport and wear, such as silicone wristbands. Previous studies have demonstrated significant correlations between urine biomarker concentrations and chemical levels in wristbands. We build upon those studies and use a novel combination of descriptive statistics and supervised statistical learning to evaluate the relationship between polycyclic aromatic hydrocarbon (PAH) concentrations in silicone wristbands and hydroxy-PAH (OH-PAH) concentrations in urine. In New York City, 109 participants in a longitudinal birth cohort wore one wristband for 48 h and provided a spot urine sample at the end of the 48-hour period during their third trimester of pregnancy. We compared four PAHs with the corresponding seven OH-PAHs using descriptive statistics, a linear regression model, and a linear discriminant analysis model. Five of the seven PAH and OH-PAH pairs had significant correlations (Pearson’s r = 0.35–0.64, p ≤ 0.003) and significant chi-square tests of independence for exposure categories (p ≤ 0.009). For these five comparisons, the observed PAH or OH-PAH concentration could predict the other concentration within a factor of 1.47 for 50–80% of the measurements (depending on the pair). Prediction accuracies for high exposure categories were at least 1.5 times higher compared to accuracies based on random chance. These results demonstrate that wristbands and urine provide similar PAH exposure assessment information, which is critical for environmental health researchers looking for the flexibility to switch between biological sample and wristband collection.

Abstract The HIV accessory protein Nef downregulates the viral entry receptor CD4, the Human Leukocyte Antigen (HLA)-A and -B molecules, the Serine incorporator 5 (SERINC5) protein and other molecules from the infected cell surface, thereby promoting viral infectivity, replication and immune evasion. The nef locus also represents one of the most genetically variable regions in the HIV genome, and nef sequences undergo substantial evolution within a single individual over the course of infection. Few studies however have simultaneously characterized the impact of within-host nef sequence evolution on Nef protein function over prolonged timescales. Here, we isolated 50 unique Nef clones by single-genome amplification over an 11-year period from the plasma of an individual who was largely naïve to antiretroviral treatment during this time. Together, these clones harbored nonsynonymous substitutions at 13% of nef’s codons. We assessed their ability to downregulate cell-surface CD4, HLA and SERINC5 and observed that all three Nef functions declined modestly over time, where the reductions in CD4 and HLA downregulation (an average of 0.6% and 2.0% per year, respectively) achieved statistical significance. The results from this case study support all three Nef activities as being important to maintain throughout untreated HIV infection, but nevertheless suggest that, despite nef’s mutational plasticity, within-host viral evolution can compromise Nef function, albeit modestly, over prolonged periods.

ABSTRACT Curing HIV will require eliminating the reservoir of integrated, replication-competent proviruses that persist despite antiretroviral therapy (ART). Understanding the burden, genetic diversity, and longevity of persisting proviruses in diverse individuals with HIV is critical to this goal, but these characteristics remain understudied in some groups. Among them are viremic controllers—individuals who naturally suppress HIV to low levels but for whom therapy is nevertheless recommended. We reconstructed within-host HIV evolutionary histories from longitudinal single-genome amplified viral sequences in four viremic controllers who eventually initiated ART and used this information to characterize the age and diversity of proviruses persisting on therapy. We further leveraged these within-host proviral age distributions to estimate rates of proviral turnover prior to ART. This is an important yet understudied metric, since pre-ART proviral turnover dictates reservoir composition at ART initiation (and thereafter), which is when curative interventions, once developed, would be administered. Despite natural viremic control, all participants displayed significant within-host HIV evolution pretherapy, where overall on-ART proviral burden and diversity broadly reflected the extent of viral replication and diversity pre-ART. Consistent with recent studies of noncontrollers, the proviral pools of two participants were skewed toward sequences that integrated near ART initiation, suggesting dynamic proviral turnover during untreated infection. In contrast, proviruses recovered from the other two participants dated to time points that were more evenly spread throughout infection, suggesting slow or negligible proviral decay following deposition. HIV cure strategies will need to overcome within-host proviral diversity, even in individuals who naturally controlled HIV replication before therapy. IMPORTANCE HIV therapy is lifelong because integrated, replication-competent viral copies persist within long-lived cells. To cure HIV, we need to understand when these viral reservoirs form, how large and genetically diverse they are, and how long they endure. Elite controllers—individuals who naturally suppress HIV to undetectable levels—are being intensely studied as models of HIV remission, but viremic controllers, individuals who naturally suppress HIV to low levels, remain understudied even though they too may hold valuable insights. We combined phylogenetics and mathematical modeling to reconstruct proviral seeding and decay from infection to therapy-mediated suppression in four viremic controllers. We recovered diverse proviruses persisting during therapy that broadly reflected HIV’s within-host evolutionary history, where the estimated half-lives of the persistent proviral pool during untreated infection ranged from

Objective: Many studies have shown that severe (hospitalized) bronchiolitis during infancy is a risk factor for developing childhood asthma. However, the population subgroups at the highest risk remain unclear. Using large nationwide pediatric cohort data, namely the NIH Environmental influences on Child Health Outcomes (ECHO) Program, we aimed to quantify the longitudinal relationship of bronchiolitis hospitalization during infancy with asthma in a generalizable dataset and to examine potential heterogeneity in terms of major demographics and clinical factors. Methods: We analyzed data from infants (age Results: The analytic cohort consisted of 11,762 infants, 10% of whom had bronchiolitis hospitalization. Overall, 15% subsequently developed asthma. In the Cox proportional hazards model adjusting for 10 patient-level factors, compared with the no-bronchiolitis hospitalization group, the bronchiolitis hospitalization group had a significantly higher rate of asthma (14% vs. 24%, HR = 2.77, 95%CI = 2.24–3.43, p < 0.001). There was significant heterogeneity by race and ethnicity (Pinteraction = 0.02). The magnitude of the association was greater in non-Hispanic White (HR = 3.77, 95%CI = 2.74–5.18, p < 0.001) and non-Hispanic Black (HR = 2.39, 95%CI = 1.60–3.56; p < 0.001) infants, compared with Hispanic infants (HR = 1.51, 95%CI = 0.77–2.95, p = 0.23). Conclusions: According to the nationwide cohort data, infants hospitalized with bronchiolitis are at a higher risk for asthma, with quantitative heterogeneity in different racial and ethnic groups.

Abstract Protected areas are a fundamental mechanism for ensuring the persistence of biodiversity. The strategic policy objectives set by governments for protected area land acquisition are strong determinants of biodiversity outcomes. An examination of these objectives is necessary to determine those most influential in designing protected area networks and understand why Australia's extinction rates exceed those elsewhere despite actively establishing protected areas over the past several decades. To examine spatio‐temporal trends in policy objectives for protected areas, we evaluated the strategic priorities in Federal, State, and Territory policy documents across Australia between 1992 and 2019 using thematic analysis. We classified priorities into seven themes: adequacy, Indigenous and cultural values; representation of ecosystem and species types; threatened species and their habitat; social and recreational values; unique values and avoiding threatening processes. We found that the representation of ecosystem and species types was the most prevalent theme in policy documents, and the least common theme was social and recreational values. We posit several reasons for this trend and warn that emphasizing extent, in terms of area or representativeness, may diminish the effectiveness, efficiency, and impact for biodiversity outcomes. We found that policies were generally supportive of the strategic identification of particular species or communities that would quantifiably benefit from protection (referred to as avoided loss). Risked‐based approaches to the establishment of protected areas are supported by modern conservation literature to enhance the protected area network's effectiveness. To maximize limited resources, we recommend that governments continue encouraging urgency to avoid species and habitat loss in their strategic priorities. This urgency should be accompanied by clear and consistent funding for on‐the‐ground actions which facilitate the socio‐ecological outcomes that characterize modern protected area policy.

A major component of COVID-19 severe respiratory syndrome is the patient’s immune response to the SARS-CoV-2 virus and the consequential multi-organ inflammatory response. Several studies suggested a potential role of CD4+ T cells in COVID-19 severe respiratory syndrome. We first hypothesized that there is a type 2 helper (Th2)/type 1 helper (Th1) imbalance in older age, male, asthma, smokers, and high ACE2 expression phenotype in the airway of non-infected patients. Next, we hypothesized that a Th2/Th1 imbalance may predict higher mortality in COVID-19 infected hospitalized patients with and without patient reported current asthma. We first analyzed publicly available gene expression from the sputum of 118 moderate-to-severe asthma patients and 21 healthy controls, and from nasal epithelium of 26 healthy current smokers and 21 healthy never smokers. Secondly, we profiled 288 new serum proteomics samples measured at admission from patients hospitalized within the Mount Sinai Health System with positive SARS-CoV-2 infection. We first computed Th1 and Th2 pathway enrichment scores by gene set variation analysis and then compared the differences in Th2 and Th1 pathway scores between patients that died compared to those that survived, by linear regression. The level of Th2/Th1 imbalance, as determined by the enrichment score, was associated with age, sex, and ACE2 expression in sputum, and with active smoking status in nasal epithelium (p < 0.05). Th2/Th1 imbalance at hospital admission in sera of patients was not significantly associated with death from COVID-19 (p = 0.11), unless evaluated in the asthmatic strata (p = 0.01). Using a similar approach we also observed a higher Th17/Th1 cytokine imbalance in all deceased patients compared to those that survived (p < 0.001), as well as in the asthmatic strata only (p < 0.01). Th2/Th1 imbalance is higher in the sera of asthma patients at admission that do not survive COVID-19, suggesting that the Th2/Th1 interplay may affect patient outcomes in SARS-CoV2 infection. In addition, we report that Th17/Th1 imbalance is increased in all patients that die of COVID-19.

Abstract Background The long time from exposure to potentially harmful chemicals until breast cancer occurrence poses challenges for designing etiologic studies and for implementing successful prevention programs. Growing evidence from animal and human studies indicates that distinct time periods of heightened susceptibility to endocrine disruptors exist throughout the life course. The influence of environmental chemicals on breast cancer risk may be greater during several windows of susceptibility (WOS) in a woman’s life, including prenatal development, puberty, pregnancy, and the menopausal transition. These time windows are considered as specific periods of susceptibility for breast cancer because significant structural and functional changes occur in the mammary gland, as well as alterations in the mammary micro-environment and hormone signaling that may influence risk. Breast cancer research focused on these breast cancer WOS will accelerate understanding of disease etiology and prevention. Main text Despite the plausible heightened mechanistic influences of environmental chemicals on breast cancer risk during time periods of change in the mammary gland’s structure and function, most human studies of environmental chemicals are not focused on specific WOS. This article reviews studies conducted over the past few decades that have specifically addressed the effect of environmental chemicals and metals on breast cancer risk during at least one of these WOS. In addition to summarizing the broader evidence-base specific to WOS, we include discussion of the NIH-funded Breast Cancer and the Environment Research Program (BCERP) which included population-based and basic science research focused on specific WOS to evaluate associations between breast cancer risk and particular classes of endocrine-disrupting chemicals—including polycyclic aromatic hydrocarbons, perfluorinated compounds, polybrominated diphenyl ethers, and phenols—and metals. We outline ways in which ongoing transdisciplinary BCERP projects incorporate animal research and human epidemiologic studies in close partnership with community organizations and communication scientists to identify research priorities and effectively translate evidence-based findings to the public and policy makers. Conclusions An integrative model of breast cancer research is needed to determine the impact and mechanisms of action of endocrine disruptors at different WOS. By focusing on environmental chemical exposure during specific WOS, scientists and their community partners may identify when prevention efforts are likely to be most effective.

Understanding place-based contributors to health requires geographically and culturally diverse study populations, but sharing location data is a significant challenge to multisite studies. Here, we describe a standardized and reproducible method to perform geospatial analyses for multisite studies. Using census tract-level information, we created software for geocoding and geospatial data linkage that was distributed to a consortium of birth cohorts located throughout the USA. Individual sites performed geospatial linkages and returned tract-level information for 8810 children to a central site for analyses. Our generalizable approach demonstrates the feasibility of geospatial analyses across study sites to promote collaborative translational research.

Closely related HLA alleles presenting similar HIV-1 epitopes can be associated with variable clinical outcome. Here the authors report their findings on CD8+ T cell responses to the HIV-1 Gag-p24 TL9 immunodominant epitope in the context of closely related protective and less protective HLA alleles, and their differential effect on viral control

Abstract: In sickle cell disease, respiratory infection and asthma may lead to respiratory complications that are a leading cause of morbidity and mortality. Vitamin D has anti-infective and immunomodulatory effects that may decrease the risk for respiratory infections, asthma, and acute chest syndrome. We conducted a randomized double-blind active-controlled clinical trial to determine whether monthly oral vitamin D3 can reduce the rate of respiratory events in children with sickle cell disease. Seventy sickle cell subjects, ages 3-20 years, with baseline records of respiratory events over 1 year before randomization, underwent screening. Sixty-two subjects with 25-hydroxyvitamin D levels of 5-60 ng/mL were randomly assigned to oral vitamin D3 (100 000 IU or 12 000 IU, n = 31 each) under observed administration once monthly for 2 years. The primary outcome was the annual rate of respiratory events (respiratory infection, asthma exacerbation, or acute chest syndrome) ascertained by the use of a validated questionnaire administered biweekly. Analysis included 62 children (mean age of 9.9 years, 52% female, and predominantly with homozygous HbS disease [87%]) with mean baseline 25-hydroxyvitamin D of 14.3 ng/mL. The annual rates of respiratory events at baseline and intervention years 1 and 2 were 4.34 ± 0.35, 4.28 ± 0.36, and 1.49 ± 0.37 (high dose) and 3.91 ± 0.35, 3.34 ± 0.37, and 1.54 ± 0.37 (standard dose), respectively. In pediatric patients with sickle cell disease, 2-year monthly oral vitamin D3 was associated with a >50% reduction in the rate of respiratory illness during the second year (P = .0005), with similar decreases associated with high- and standard-dose treatment. This trial was registered at www.clinicaltrials.gov as #NCT01443728.

Family history, a well-established risk factor for breast cancer, can have both genetic and environmental contributions. Shared environment in families as well as epigenetic changes that also may be influenced by shared genetics and environment may also explain familial clustering of cancers. Epigenetic regulation, such as DNA methylation, can change the activity of a DNA segment without a change in the sequence; environmental exposures experienced across the life course can induce such changes. However, genetic-epigenetic interactions, detected as methylation quantitative trait loci (mQTLs; a.k.a. meQTLs) and haplotype-dependent allele-specific methylation (hap-ASM), can also contribute to inter-individual differences in DNA methylation patterns. To identify differentially methylated regions (DMRs) associated with breast cancer susceptibility, we examined differences in white blood cell DNA methylation in 29 candidate genes in 426 girls (ages 6–13 years) from the LEGACY Girls Study, 239 with and 187 without a breast cancer family history (BCFH). We measured methylation by targeted massively parallel bisulfite sequencing (bis-seq) and observed BCFH DMRs in two genes: ESR1 (Δ4.9%, P = 0.003) and SEC16B (Δ3.6%, P = 0.026), each of which has been previously implicated in breast cancer susceptibility and pubertal development. These DMRs showed high inter-individual variability in methylation, suggesting the presence of mQTLs/hap-ASM. Using single nucleotide polymorphisms data in the bis-seq amplicon, we found strong hap-ASM in SEC16B (with allele specific-differences ranging from 42% to 74%). These findings suggest that differential methylation in genes relevant to breast cancer susceptibility may be present early in life, and that inherited genetic factors underlie some of these epigenetic differences.

Abstract Background DNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Further identification of specific CpG sites and the pollutants that are associated with methylation of these CpG sites in immune cells could impact our understanding of asthma pathophysiology. In this study, we sought to identify some CpG sites in specific genes that could be associated with asthma regulation (Foxp3 and IL10) and to identify the different AAPs for which exposure prior to the blood draw is linked to methylation levels at these sites. We recruited subjects from Fresno, California, an area known for high levels of AAPs. Blood samples and responses to questionnaires were obtained (n = 188), and in a subset of subjects (n = 33), repeat samples were collected 2 years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365 days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures. Results Asthma was significantly associated with higher differentially methylated regions (DMRs) of the Foxp3 promoter region (p = 0.030) and the IL10 intronic region (p = 0.026). Additionally, at the 90-day time period (90 days prior to the blood draw), Foxp3 methylation was positively associated with NO2, CO, and PM2.5 exposures (p = 0.001, p = 0.001, and p = 0.012, respectively). In the subset of subjects retested 2 years later (n = 33), a positive association between AAP exposure and methylation was sustained. There was also a negative correlation between the average Foxp3 methylation of the promoter region and activated Treg levels (p = 0.039) and a positive correlation between the average IL10 methylation of region 3 of intron 4 and IL10 cytokine expression (p = 0.030). Conclusions Short-term and long-term exposures to high levels of CO, NO2, and PM2.5 were associated with alterations in differentially methylated regions of Foxp3. IL10 methylation showed a similar trend. For any given individual, these changes tend to be sustained over time. In addition, asthma was associated with higher differentially methylated regions of Foxp3 and IL10.

Abstract Background Physical activity is associated with improvement in lung function; however, pollution exposure during physical activity can lead to a transient reduction in lung function. This paradoxical relationship may be linked to altered T regulatory (Treg) cell activity, which increases with exercise and suppresses airway inflammation, but decreases in association with exposure to air pollution. To clarify these relationships, we investigated buccal cell DNA methylation of the forkhead box p3 (FOXP3) gene promoter, a proposed biomarker of Treg activity. We hypothesized that active urban children would have lower FOXP3 promoter methylation, associated with better lung function compared to non-active children. We also hypothesized that this relationship would be attenuated by high exposure to the air pollutant black carbon (BC). Methods We performed a cross-sectional study of 135 children ages 9–14 who live in New York City. Activity was measured across 6 days. BC exposure was assessed by personal monitors worn for two 24-h periods, followed by lung function assessment. Buccal swabs were collected for DNA methylation analysis of three regions (six CpG sites) in the FOXP3 promoter. Results In multivariable regression models, overall, there was no significant relationship between physical activity and FOXP3 promoter methylation (p > 0.05). However, in stratified analyses, among children with higher BC exposure (≥1200 ng/m3), physical activity was associated with 2.37% lower methylation in promoter 2 (CpGs −77, −65, and −58) (β estimate = −2.37%, p 0.05). Differences across strata were statistically significant (p interaction = 0.04). Among all children, after controlling for BC concentration, promoter 2 methylation was associated with reduced FEV1/FVC (β estimate = −0.40%, p

Abstract Background Asthma gene DNA methylation may underlie the effects of air pollution on airway inflammation. However, the temporality and individual susceptibility to environmental epigenetic regulation of asthma has not been fully elucidated. Our objective was to determine the timeline of black carbon (BC) exposure, measured by personal sampling, on DNA methylation of allergic asthma genes 5 days later to capture usual weather variations and differences related to changes in behavior and activities. We also sought to determine how methylation may vary by seroatopy and cockroach sensitization and by elevated fractional exhaled nitric oxide (FeNO). Methods Personal BC levels were measured during two 24-h periods over a 6-day sampling period in 163 New York City children (age 9–14 years), repeated 6 months later. During home visits, buccal cells were collected as noninvasive surrogates for lower airway epithelial cells and FeNO measured as an indicator of airway inflammation. CpG promoter loci of allergic asthma genes (e.g., interleukin 4 (IL4), interferon gamma (IFNγ), inducible nitric oxide synthase (NOS2A)), arginase 2 (ARG2)) were pyrosequenced at the start and end of each sampling period. Results Higher levels of BC were associated with lower methylation of IL4 promoter CpG−48 5 days later. The magnitude of association between BC exposure and demethylation of IL4 CpG−48 and NOS2A CpG+5099 measured 5 days later appeared to be greater among seroatopic children, especially those sensitized to cockroach allergens (RR [95% CI] 0.55 [0.37–0.82] and 0.67 [0.45–0.98] for IL4 CpG−48 and NOS2A CpG+5099, respectively), compared to non-sensitized children (RR [95% CI] 0.87 [0.65–1.17] and 0.95 [0.69–1.33] for IL4 CpG−48 and NOS2A CpG+5099, respectively); however, the difference was not statistically different. In multivariable linear regression models, lower DNA methylation of IL4 CpG−48 and NOS2A CpG+5099 were associated with increased FeNO. Conclusions Our results suggest that exposure to BC may exert asthma proinflammatory gene demethylation 5 days later that in turn may link to airway inflammation. Our results further suggest that seroatopic children, especially those sensitized to cockroach allergens, may be more susceptible to the effect of acute BC exposure on epigenetic changes.

Abstract Background Both short and long-term exposure to traffic-related air pollutants have been associated with asthma and reduced lung function. We hypothesized that short-term indoor exposure to fine particulate matter

Abstract Marine migratory species require collaborative decision‐making because individuals move across jurisdictional boundaries within and between countries. However, governance of these species is not always harmonized or truly collaborative. We analyzed the Recovery Plan for Marine Turtles in Australia 2017 (the Plan) and three of its subsidiary plans for evidence of collaborative governance using a two‐part gap analysis and interviews with environmental managers, scientists, and other stakeholders involved in the development of the Plan and in managing marine migratory species in Australia more generally. We applied existing adaptive and collaborative governance frameworks, which focused mainly on the social components of collaborative governance, and identified a need for a new, interdisciplinary framework for the collaborative governance of marine turtles in Australia. We applied our new framework to the Plan and identified that while the biological components of the Plan were well‐developed, stakeholder analysis and engagement details were largely missing. We recognize that recovery plans are inevitably silent about certain issues but suggest that plans would benefit from including better guidance on stakeholder engagement and analysis. Our framework is directly relevant to harmonizing the management of marine turtles across jurisdictions in Australia but it could also be applied to managing threats towards other migratory species that inhabit large marine jurisdictions.

Marine migratory species are difficult to manage because animal movements can span large areas and are unconstrained by jurisdictional boundaries. We reviewed policy and management plans associated with four case studies protected under the Australian Environment Protection and Biodiversity Conservation Act 1999 (EPBC Act 1999) in order to identify the coherence of policy and management plans for managing marine migratory species in Australia. Environmental policies (n = 23) and management plans (n = 115) relevant to marine turtles, dugongs, humpback whales, and migratory shorebirds were reviewed. Few of the reviewed policies (n = 7) listed protected species and even fewer (n = 4) listed protected marine migratory species. Marine turtles were most represented in the reviewed policies (n = 7), while migratory shorebirds were most represented in management plans (n = 59). Policies and management plans were much more likely to identify relationships to other policies or plans within the same jurisdiction than to different jurisdictions. The EPBC Act 1999 served as the central link between reviewed policies and plans, but the requirements of that Act were weakly integrated into the other documents. This weak integration and the biases toward specific migratory species in environmental policies and management plans are detrimental to the conservation of these Matters of National Environmental Significance in Australia. Any changes to the EPBC Act 1999 will affect all environmental policy and management plans in Australia and highlights a need for cooperative, multi-level governance of migratory species. Our findings may have relevance to the conservation of marine migratory species in a broader international context.

Dysregulation of alternative splicing of mRNA precursors is known to contribute to numerous human diseases. In this study we carried out the first systematic search for asthma-associated changes in alternative splicing events, using a model of Aspergillus fumigatus (A. fumigatus)-sensitized mice and an exon junction microarray to detect potential changes in alternative splicing. One of the sensitization-associated changes identified in the search was a shift in alternative splicing of the mRNA encoding cFLIP, a modulator of the caspase-mediated extrinsic apoptosis pathway. Expanding these studies to human asthma patients, we discovered a significant decrease in the expression of both cFLIP isoforms in severe corticosteroid-resistant asthmatics. Although it is unclear whether these changes were due solely to differences in alternative splicing, these findings provide evidence that dysregulation of the extrinsic apoptosis pathway is part of the underlying immunopathogenesis of severe refractory asthma.

Consideration of the relationship between residential floor level and concentration of traffic-related airborne pollutants may predict individual residential exposure among inner city dwellers more accurately. Our objective was to characterize the vertical gradient of residential levels of polycyclic aromatic hydrocarbons (PAH; dichotomized into Σ8PAHsemivolatile (MW 178–206), and Σ8PAHnonvolatile (MW 228–278), black carbon (BC), PM2.5 (particulate matter) by floor level (FL), season and building type. We hypothesize that PAH, BC and PM2.5 concentrations may decrease with higher FL and the vertical gradients of these compounds would be affected by heating season and building type. PAH, BC and PM2.5 were measured over a two-week period outdoor and indoor of the residences of a cohort of 5–6 year old children (n = 339) living in New York City’s Northern Manhattan and the Bronx. Airborne-pollutant levels were analyzed by three categorized FL groups (0–2nd, 3rd–5th, and 6th–32nd FL) and two building types (low-rise versus high-rise apartment building). Indoor Σ8PAHnonvolatile and BC levels declined with increasing FL. During the nonheating season, the median outdoor Σ8PAHnonvolatile, but not Σ8PAHsemivolatile, level at 6th–2nd FL was 1.5–2 times lower than levels measured at lower FL. Similarly, outdoor and indoor BC concentrations at 6th–32nd FL were significantly lower than those at lower FL only during the nonheating season (p < 0.05). In addition, living in a low-rise building was associated significantly with higher levels of Σ8PAHnonvolatile and BC. These results suggest that young inner city children may be exposed to varying levels of air pollutants depending on their FL, season, and building type.

Purpose Adolescents are often cited as having poor rates of compliance with medical regimens and research protocols. We quantified compliance in a cohort of urban adolescents participating in a complex research protocol in which measures were obtained without direct supervision by research personnel. Methods A total of 54 early adolescents ages 10-13 were asked to wear a vest containing a personal air pollutant exposure monitor for two 24-hour periods and to perform daily peak expiratory flow (PEF) for six consecutive days. Compliance with wearing the vest was measured by comparing accelerometer data from a device within the vest to one worn continuously on the child's wrist. Daily PEF data were recorded using an electronic meter. Results A priori definition of compliance was met by 85% of the adolescents by wearing the exposure monitoring vest and 72% by performing PEF. Conclusions These findings suggest that early adolescents can be compliant with complex research protocols that are needed to help bridge gaps in pediatric asthma research.

Report-back of research results (RBRR) is becoming standard practice for environmental health research studies. RBRR is thought to increase environmental health literacy (EHL), although standardized measurements are limited. For this study, we developed a report back document on exposure to air pollutants, Polycyclic Aromatic Hydrocarbons, during pregnancy through community engaged research and evaluated whether the report increased EHL. We used focus groups and surveys to gather feedback on the report document from an initial group of study participants (Group 1, n = 22) and then sent the revised report to a larger number of participants (Group 2, n = 168). We conducted focus groups among participants in Group 1 and discussed their suggested changes to the report and how those changes could be implemented. Participants in focus groups demonstrated multiple levels of EHL. While participant engagement critically informed report development, a survey comparing feedback from Group 1 (initial report) and Group 2 (revised report) did not show a significant difference in the ease of reading the report or knowledge gained about air pollutants. We acknowledge that our approach was limited by a lack of EHL tools that assess knowledge and behavior change, and a reliance on quantitative methodologies. Future approaches that merge qualitative and quantitative methodologies to evaluate RBRR and methodologies for assessing RBRR materials and subsequent changes in knowledge, attitudes, and behavior, may be necessary.

Tracking the emergence and spread of SARS-CoV-2 lineages using phylogenetics has proven critical to inform the timing and stringency of COVID-19 public health interventions. We investigated the effectiveness of international travel restrictions at reducing SARS-CoV-2 importations and transmission in Canada in the first two waves of 2020 and early 2021. Maximum likelihood phylogenetic trees were used to infer viruses’ geographic origins, enabling identification of 2263 (95% confidence interval: 2159–2366) introductions, including 680 (658–703) Canadian sublineages, which are international introductions resulting in sampled Canadian descendants, and 1582 (1501–1663) singletons, introductions with no sampled descendants. Of the sublineages seeded during the first wave, 49% (46–52%) originated from the USA and were primarily introduced into Quebec (39%) and Ontario (36%), while in the second wave, the USA was still the predominant source (43%), alongside a larger contribution from India (16%) and the UK (7%). Following implementation of restrictions on the entry of foreign nationals on 21 March 2020, importations declined from 58.5 (50.4–66.5) sublineages per week to 10.3-fold (8.3–15.0) lower within 4 weeks. Despite the drastic reduction in viral importations following travel restrictions, newly seeded sublineages in summer and fall 2020 contributed to the persistence of COVID-19 cases in the second wave, highlighting the importance of sustained interventions to reduce transmission. Importations rebounded further in November, bringing newly emergent variants of concern (VOCs). By the end of February 2021, there had been an estimated 30 (19–41) B.1.1.7 sublineages imported into Canada, which increasingly displaced previously circulating sublineages by the end of the second wave.Although viral importations are nearly inevitable when global prevalence is high, with fewer importations there are fewer opportunities for novel variants to spark outbreaks or outcompete previously circulating lineages.

BackgroundIndividuals with respiratory conditions, such as asthma, are particularly susceptible to adverse health effects associated with higher levels of ambient air pollution and temperature. This study evaluates whether hourly levels of fine particulate matter (PM2.5) and dry bulb globe temperature (DBGT) are associated with the lung function of adult participants with asthma.Methods and findingsGlobal positioning system (GPS) location, respiratory function (measured as forced expiratory volume at 1 second (FEV1)), and self-reports of asthma medication usage and symptoms were collected as part of the Exposure, Location, and Lung Function (ELF) study. Hourly ambient PM2.5 and DBGT exposures were estimated by integrating air quality and temperature public records with time-activity patterns using GPS coordinates for each participant (n = 35). The relationships between acute PM2.5, DBGT, rescue bronchodilator use, and lung function collected in one week periods and over two seasons (summer/winter) were analyzed by multivariate regression, using different exposure time frames. In separate models, increasing levels in PM2.5, but not DBGT, were associated with rescue bronchodilator use. Conversely DBGT, but not PM2.5, had a significant association with FEV1. When DBGT and PM2.5 exposures were placed in the same model, the strongest association between cumulative PM2.5 exposures and the use of rescue bronchodilator was identified at the 0-24 hours (OR = 1.030; 95% CI = 1.012-1.049; p-value = 0.001) and 0-48 hours (OR = 1.030; 95% CI = 1.013-1.057; p-value = 0.001) prior to lung function measure. Conversely, DBGT exposure at 0 hours (β = 3.257; SE = 0.879; p-value>0.001) and 0-6 hours (β = 2.885; SE = 0.903; p-value = 0.001) hours before a reading were associated with FEV1. No significant interactions between DBGT and PM2.5 were observed for rescue bronchodilator use or FEV1.ConclusionsShort-term increases in PM2.5 were associated with increased rescue bronchodilator use, while DBGT was associated with higher lung function (i.e. FEV1). Further studies are needed to continue to elucidate the mechanisms of acute exposure to PM2.5 and DBGT on lung function in asthmatics.

Case summary A male neutered Ragdoll cat aged 11 years and 9 months presented with a 6 month history of weight loss and a 1 month history of lethargy and adipsia. A thorough clinical investigation confirmed a diagnosis of primary adipsia and hypernatraemia secondary to a non-secretory neuroendocrine pituitary macroadenoma. Relevance and novel information Primary adipsia is a very rare clinical entity. This report is the first to describe primary adipsia secondary to a non-secretory pituitary macroadenoma in the cat. The veterinary literature available in this field is very limited and this report adds a new differential diagnosis for cats presenting with primary hypodipsia.

RationaleGreater levels of prenatal exposure to polycyclic aromatic hydrocarbon (PAH) have been associated with childhood obesity in epidemiological studies. However, the underlying mechanisms are unclear.ObjectivesWe hypothesized that prenatal PAH over-exposure during gestation would lead to weight gain and increased fat mass in offspring and grand-offspring mice. Further, we hypothesized that altered adipose gene expression and DNA methylation in genes important to adipocyte differentiation would be affected.Materials and methodsPregnant dams were exposed to a nebulized PAH mixture versus negative control aerosol 5 days a week, for 3 weeks. Body weight was recorded from postnatal day (PND) 21 through PND60. Body composition, adipose cell size, gene expression of peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer-binding proteins (C/EBP) α, cyclooxygenase (Cox)-2, fatty acid synthase (FAS) and adiponectin, and DNA methylation of PPAR γ, were assayed in both the offspring and grand-offspring adipose tissue.FindingsOffspring of dams exposed to greater PAH during gestation had increased weight, fat mass, as well as higher gene expression of PPAR γ, C/EBP α, Cox2, FAS and adiponectin and lower DNA methylation of PPAR γ. Similar differences in phenotype and DNA methylation extended through the grand-offspring mice.ConclusionsGreater prenatal PAH exposure was associated with increased weight, fat mass, adipose gene expression and epigenetic changes in progeny.

Polycyclic aromatic hydrocarbons are widespread urban air pollutants from combustion of fossil fuel and other organic material shown previously to be neurotoxic.In a prospective cohort study, we evaluated the relationship between Attention Deficit Hyperactivity Disorder behavior problems and prenatal polycyclic aromatic hydrocarbon exposure, adjusting for postnatal exposure.Children of nonsmoking African-American and Dominican women in New York City were followed from in utero to 9 years. Prenatal polycyclic aromatic hydrocarbon exposure was estimated by levels of polycyclic aromatic hydrocarbon- DNA adducts in maternal and cord blood collected at delivery. Postnatal exposure was estimated by the concentration of urinary polycyclic aromatic hydrocarbon metabolites at ages 3 or 5. Attention Deficit Hyperactivity Disorder behavior problems were assessed using the Child Behavior Checklist and the Conners Parent Rating Scale- Revised.High prenatal adduct exposure, measured by elevated maternal adducts was significantly associated with all Conners Parent Rating Scale-Revised subscales when the raw scores were analyzed continuously (N = 233). After dichotomizing at the threshold for moderately to markedly atypical symptoms, high maternal adducts were significantly associated with the Conners Parent Rating Scale-Revised DSM-IV Inattentive (OR = 5.06, 95% CI [1.43, 17.93]) and DSM-IV Total (OR = 3.37, 95% CI [1.10, 10.34]) subscales. High maternal adducts were positivity associated with the DSM-oriented Attention Deficit/Hyperactivity Problems scale on the Child Behavior Checklist, albeit not significant. In the smaller sample with cord adducts, the associations between outcomes and high cord adduct exposure were not statistically significant (N = 162).The results suggest that exposure to polycyclic aromatic hydrocarbons encountered in New York City air may play a role in childhood Attention Deficit Hyperactivity Disorder behavior problems.

T cells mediate the inflammatory responses observed in asthma among genetically susceptible individuals and have been suspected to be prone to epigenetic regulation. However, these relationships are not well established from past clinical studies that have had limited capacity to control for the effects of variable genetic predisposition and early environmental exposures. Relying on a cohort of monozygotic twins discordant for asthma we sought to determine if epigenetic modifications in T cells were associated with current asthma and explored whether such modifications were associated with second hand smoke exposures. Our study was conducted in a monozygotic twin cohort of adult twin pairs (n = 21) all discordant for asthma. Regulatory T cell (Treg) and effector T cell (Teff) subsets were assessed for levels of cellular function, protein expression, gene expression and CpG methylation within Forkhead box P3 (FOXP3) and interferon gamma-γ (IFNγ) loci. Comparisons by asthma and current report of exposure to second hand smoke were made. Treg from asthmatic discordant twins demonstrated decreased FOXP3 protein expression and impaired Treg function that was associated with increased levels of CpG methylation within the FOXP3 locus when compared to their non-asthmatic twin partner. In parallel, Teff from discordant asthmatic twins demonstrated increased methylation of the IFNγ locus, decreased IFNγ expression and reduced Teff function when compared to Teff from the non-asthmatic twin. Finally, report of current exposure to second hand smoke was associated with modifications in both Treg and Teff at the transcriptional level among asthmatics. The results of the current study provide evidence for differential function of T cell subsets in monozygotic twins discordant for asthma that are regulated by changes in DNA methylation. Our preliminary data suggest exposure to second hand smoke may augment the modified T cell responses associated with asthma.

Asthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations.Over the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations.This study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.