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PURPOSE OF REVIEW: Allergic disorders are the result of complex interactions between genetic predisposition and environmental exposures. Elucidating how specific environmental exposures contribute to allergic diseases in adults is crucial, especially as the world population ages in a rapidly changing environment. RECENT FINDINGS: The effects of environmental exposures on allergic diseases remain understudied in adults. While epidemiological studies suggest various environmental exposures are associated with the development and exacerbation of allergic diseases, further longitudinal studies are needed across various age groups in adults to pinpoint the exposures of concerns and the time windows of susceptibility. Mechanistic studies in adults are few. A multi-component strategy targeting several allergens has been conditionally recommended for asthma, but recent findings on mitigation strategies remain limited. SUMMARY: Further research on how environmental exposures cause and exacerbate allergic disorders is needed in adults, particularly across disease phenotypes. The effects of mitigation strategies against environmentally-induced adult allergic diseases remain large research gaps. A better understanding of how and which environmental exposures contribute to allergic disorders is necessary to identify patients who are at higher risk and would benefit from specific interventions.

RATIONALE Asthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset. OBJECTIVES To determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association. METHODS We studied 8,716 children between ages 6 and 18.5 years who were nonobese at study entry participating in 18 US cohorts of the Environmental influences on Child Health Outcomes program (among 7,299 children with complete covariate data mean [SD] study entry age = 7.2 [1.6] years and follow up = 5.3 [3.1] years). MEASUREMENTS AND MAIN RESULTS We defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95% confidence intervals [CI] = 4, 44) higher risk for subsequently developing obesity compared with those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess hazard ratios = 0.64; 95% CI = -1.05, -0.23). CONCLUSIONS This nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma.

Background: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12–21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12–21 locus. Methods: We first did a genetic association study and meta-analysis using 17q12–21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12–21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12–21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). Findings: 17q12–21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p

Rationale: Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated...

Growing evidence links adolescent exposures to cancer risk later in life, particularly for common cancers like breast. The adolescent time period is also important for cancer risk reduction as many individual lifestyle behaviors are initiated including smoking and alcohol use. We developed a cancer risk-reduction educational tool tailored for adolescents that focused on five modifiable cancer risk factors. To contextualize risk factors in adolescents' social and physical environments, the intervention also focused on structural barriers to individual- and community-level change, with an emphasis on environmental justice or the fair treatment and meaningful involvement of all people regardless of race, color, national origin, or income with respect to the development, implementation, and enforcement of environmental laws, regulations, and policies. The educational tool consisted of a 50-min module that included an introduction to cancer biology including genetic susceptibility and environmental interactions, cancer burden in the local community, and risk reduction strategies. The module also included an interactive activity in which adolescent students identify cancer risk factors and brainstorm strategies for risk reduction at both the individual and community level. We administered the module to 12 classes of over 280 high school and college students in New York City. Cancer risk reduction strategies identified by the students included family- or peer-level strategies such as team physical activity and community-level action including improving parks and taxing sugary foods. We developed a novel and interactive cancer risk-reduction education tool focused on multiple cancers that can be adopted by other communities and educational institutions.

Although short-duration elevated exposures (peak exposures) to pollutants may trigger adverse acute effects, epidemiological studies to understand their influence on different health effects are hampered by lack of methods for objectively identifying peaks. Secondhand smoke from cigarettes (SHS) in the residential environment can lead to peak exposures. The aim of this study was to explore whether peaks in continuous PM2.5 data can indicate SHS exposure. A total of 41 children (21 with and 20 without SHS exposure based on self-report) from 28 families in New York City (NY, USA) were recruited. Both personal and residential continuous PM2.5 monitoring were performed for five consecutive days using MicroPEM sensors (RTI International, USA). A threshold detection method based on cumulative distribution function was developed to identify peaks. When children were home, the mean accumulated peak area (APA) for peak exposures was 297 ± 325 hour*µg/m3 for children from smoking families and six times that of the APA from non-smoking families (~50 ± 54 hour*µg/m3 ). Average PM2.5 mass concentrations for SHS exposed and unexposed children were 24 ± 15 µg/m3 and 15 ± 9 µg/m3 , respectively. The average SHS exposure duration represents ~5% of total exposure time, but ~13% of children's total PM2.5 exposure dose, equivalent to an additional 2.6 µg/m3 per day. This study demonstrated the feasibility of peak analysis for quantifying SHS exposure. The developed method can be adopted more widely to support epidemiology studies on impacts of short-term exposures.

Asthma in children poses a significant clinical and public health burden. We examined the association between reported neighborhood traffic (a proxy for traffic-related air pollution) and asthma among 855 multi-racial children aged 4&ndash, 8 years old who participated in the Environmental Influences on Child Health Outcomes (ECHO) cohort. We hypothesized that high neighborhood traffic density would be associated with the prevalence of asthma. Asthma/asthma-like symptoms (defined as current and/or past physician diagnosed asthma, past wheezing, or nighttime cough or wheezing in the past 12 months) was assessed by parental report. The relationship between neighborhood traffic and asthma/asthma-like symptoms was assessed using logistic regression. The prevalence of asthma/asthma-like symptoms among study participants was 23%, and 15% had high neighborhood traffic. Children with significant neighborhood traffic had a higher odds of having asthma/asthma-like symptoms than children without neighborhood traffic [adjusted OR = 2.01 (95% CI: 1.12, 3.62)] after controlling for child&rsquo, s race-ethnicity, age, sex, maternal education, family history of asthma, play equipment in the home environment, public parks, obesity and prescribed asthma medication. Further characterization of neighborhood traffic is needed since many children live near high traffic zones and significant racial/ethnic disparities exist.

Breast cancer risk remains incompletely explained, and higher incidence rates of breast cancer over recent times and in urban and industrialized areas suggest environmental causes. Polycyclic aromatic hydrocarbons (PAH) are ubiquitous in the environment and epidemiological and rodent studies have shown associations between exposure to PAH and breast cancer incidence as well as mammary tumorigenesis. In addition, in vitro and rodent studies have implicated alterations in estrogen receptor alpha (Erα) signaling pathways following PAH exposure in limited experimental studies. However, our understanding of these mechanisms is incomplete. Sahay et al. addressed this gap by examining the effect of PAH exposure on epigenetic and transcriptional regulation of genes in the Erα pathway in a mouse cohort exposed to aerosolized PAH at proportions measured in urban air. In addition to alterations in the Erα signaling pathway in the pregnant mice and in their offspring and grandoffspring, the investigators observed higher body weights in mice exposed to PAH compared to the control. Given that associations between mammary tissue adiposity, systemic adiposity, and breast cancer risk have been observed previously, the finding of higher body weight in the PAH exposure group raises the possibility that body weight might influence the association between PAH exposure and breast cancer risk. Along with new analyses, we discuss the possibility that body weight may modify the association between PAH exposure, mammary cellular proliferation, and mammary gland ductal hyperplasia in offspring and grandoffspring mice and future research that may be needed to delineate these associations.

The last 2 years yielded a proliferation of high-quality asthma research. These include new understandings of the incidence and natural history of asthma, findings on the effects of exposure to air pollution, allergens, and intake of acetaminophen, soy isoflavones, and polyunsaturated fatty acids, and exposure to microbial products. The past 2 years have benefited from great strides in determining potential mechanisms of asthma development and asthma exacerbations. These novel understandings led to identification and development of exciting new avenues for potential therapeutic intervention. Finally, there has been significant progress made in the development of tools to facilitate the diagnosis of asthma and measurement of airway physiology and in precision diagnostic approaches. Asthma guidelines were updated and new insights into the pharmacologic management of patients, including biologics, were reported. We review the most notable advances in the natural history of asthma, risk factors for the development of asthma, underlying mechanisms, diagnostic approaches, and treatments. Although greater knowledge of the mechanisms underlying responses and nonresponses to novel therapeutics and across asthma phenotypes would be beneficial, the progress over just the past 2 years has been immense and impactful.

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.

Laura A Conrad,1 Natalie Buchinsky,2 Luis M Acosta,2 J David Nugent,3 Khalil W Savary,4 Rachel L Miller,5 Nurdant Emanet,6 Julie Herbstman,2 Beatrice Beebe,6 Michael M Myers,3 William P Fifer,3 Matthew S Perzanowski2 1Division of Respiratory and Sleep Medicine, Albert Einstein College of Medicine, New York, NY, USA; 2Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA; 3Division of Developmental Neuroscience, Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA; 4Department of Pediatrics, Rutgers University, Newark, NJ, USA; 5Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USACorrespondence: Matthew S PerzanowskiDepartment of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 West 168th St, 11th Floor, New York, NY, 10032, USATel +1 212-305-3465Fax +1 212-305-4012Email mp2217@cumc.columbia.eduIntroduction: Previously, we found that reported infant rhinorrhea and watery eyes without a cold (RWWC) predicted school age exercise-induced wheeze, emergency department visits, and hospitalizations. These findings were independent of allergic sensitization, and we theorized that increased parasympathetic tone underlay the association. We also reported that increased heart-rate variability (HRV) in infants predicted wheeze in 2– 3 year-olds. In a convenience sample of children participating in a birth cohort study, we tested the hypothesis that infants with RWWC would have elevated HRV, indicating increased parasympathetic tone.Methods: RWWC symptoms since birth were queried for 3-month-old children. At 4-months, HRV was assessed (root mean square of successive differences [RMSSD]) during a standardized infant–mother still-face paradigm, which included 2 minutes of mother/child play immediately followed by 2 minutes of the mother maintaining a still-face.Results: Among participants (n=38), RWWC was common for girls (32%) and boys (21%). The children with the greatest decrease in RMSSD between play and still-face challenge (lowest tertile) had a higher prevalence of RWWC as compared with children in the higher tertiles (50% vs 16%, P=0.045). In a logistic regression model controlling for sex, age and time between HRV and RWWC assessment, children with greater decrease in HRV between play and still-face (lowest tertile) had greater odds of having RWWC (odds ratio=6.0, P=0.029).Conclusion: In this relatively small study, we demonstrated greater decreases in HRV in response to a stressor among children with reported RWWC, suggesting that these children might have increased parasympathetic tone and/or overall greater vagal reactivity.Keywords: watery eyes, still-face challenge, rhinitis, exercise-induced asthma, autonomic nervous system, heart rate variability

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.

Background Few studies have examined longitudinal asthma incidence rates (IRs) from a public health surveillance perspective. Objective Our aim was to calculate descriptive asthma IRs in children over time with consideration for demographics and parental asthma history. Methods Data from 9 US birth cohorts were pooled into 1 population covering the period from 1980 to 2017. The outcome was earliest parental report of a doctor diagnosis of asthma. IRs per 1,000 person-years were calculated. Results The racial/ethnic backgrounds of the 6,283 children studied were as follows: 55% European American (EA), 25.5% African American (AA), 9.5% Mexican-Hispanic American (MA) and 8.5% Caribbean-Hispanic American (CA). The average follow-up was 10.4 years (SD = 8.5 years; median = 8.4 years), totaling 65,291 person-years, with 1789 asthma diagnoses yielding a crude IR of 27.5 per 1,000 person-years (95% CI = 26.3-28.8). Age-specific rates were highest among children aged 0 to 4 years, notably from 1995 to 1999, with a decline in EA and MA children in 2000 to 2004 followed by a decline in AA and CA children in 2010 to 2014. Parental asthma history was associated with statistically significantly increased rates. IRs were similar and higher in AA and CA children versus lower but similar in EA and MA children. The differential rates by sex from birth through adolescence principally resulted from a decline in rates among males but relatively stable rates among females. Conclusions US childhood asthma IRs varied dramatically by age, sex, parental asthma history, race/ethnicity, and calendar year. Higher rates in the 0- to 4-year-olds group, particularly among AA/CA males with a parental history of asthma, as well as changes in rates over time and by demographic factors, suggest that asthma is driven by complex interactions between genetic susceptibility and variation in time-dependent environmental and social factors.

Rationale: Physical activity while being exposed to high concentrations of air pollution may lead to greater inhalation of pollutant particles and gases. Thus, owing to features of the built city environment, specific locations where physical activity take place may put individuals at increased risk for harmful inhaled exposures leading to decrements in lung function. Objectives: The objectives were to determine locations throughout an urban landscape where children engage in moderate to vigorous activity (MVA). We hypothesized that outdoor activity would be associated with increased exposure to air pollution and reduced lung function. Methods: Children aged 9–14 years living in New York City (NYC) (n = 151) wore global positioning system devices and wrist accelerometers for two 24-hour periods. Time-stamped global positioning system points and accelerometer data were aggregated and mapped using ArcGIS to determine locations where children engaged in MVA. Location-specific particulate matter 0.05), and a formal test for interaction (MVA time × season) was significant (P value for interaction = 0.01 and 0.03 for FEV(1)/FVC and FEF(25–75), respectively). Conclusions: Children in NYC spent less time active outdoors compared with indoors. Outdoor activity was greatest near traffic sources and associated with higher annual average concentrations of NO(2). In warmer months, outdoor activity was associated with lower lung function, but this association did not appear to be mediated by higher exposure to outdoor pollution during exercise.

Objectives To provide accessible, uniform, comprehensive, and balanced information to families deciding whether to initiate long-term ventilation (LTV) for their child, we sought to develop and validate a novel informational resource. Methods The Ottawa Decision Support Framework was followed. Previous interviews with 44 lay and 15 professional stakeholders and published literature provided content for a booklet. Iterative versions were cognitive tested with six parents facing decisions and five pediatric intensivists. Ten parents facing decisions evaluated the booklet using the Preparation for Decision Making Scale and reported their decisional conflict, which was juxtaposed to the conflict of 21 parents who did not read it, using the Decisional Conflict Scale. Twelve home ventilation program directors evaluated the booklet's clinical sensibility and sensitivity, using a self-designed six-item questionnaire. Data presented using summary statistics. Results The illustrated booklet (6th-grade reading level) has nine topical sections on chronic respiratory failure and invasive and noninvasive LTV, including the option to forgo LTV. Ten parents who read the booklet rated it as helping "Quite a bit" or more on all items of the Preparation for Decision Making Scale and had seemingly less decisional conflict than 21 parents who did not. Twelve directors rated it highly for clinical sensibility and sensitivity. Conclusions The LTV booklet was rigorously developed and favorably evaluated. It offers a resource to improve patient/family knowledge, supplement shared decision-making, and reduce decisional conflict around LTV decisions. Future studies should validate it in other settings and further study its effectiveness.

Personal air pollution monitoring in research studies should not interfere with usual patterns of behavior and bias results. In an urban pediatric cohort study we tested whether wearing an air monitor impacted activity time based on continuous watch-based accelerometry. The majority (71%) reported that activity while wearing the monitor mimicked normal activity. Correspondingly, variation in activity while wearing versus not wearing the monitor did not differ greatly from baseline variation in activity (P = 0.84).

Background: Social and environmental stressors, may modify associations between environmental pollutants and asthma symptoms. We examined if neighborhood asthma prevalence (higher: HAPN vs. lower: LAPN), a surrogate for underlying risk factors for asthma, modified the relationship between pollutants and urgent asthma visits. Methods: Through zip code, home addresses were linked to New York City Community Air Survey’s land use regression model for street-level, annual average nitrogen dioxide (NO2), particulate matter (PM2.5), elemental carbon (EC); summer average ozone (O3); winter average sulfur dioxide (SO2) concentrations. Poisson regression models were fit to estimate the association (prevalence ratio, PR) between pollutant exposures and seeking urgent asthma care. Results: All pollutants, except O3 were higher in HAPN than LAPN (P0.05). Conclusions: Relationships between modeled street-level pollutants and urgent asthma were stronger in LAPN compared to HAPN. Social stressors that may be more prevalent in HAPN than LAPN, could play a greater role in asthma exacerbations in HAPN versus pollutant exposure alone.

Polycyclic aromatic hydrocarbons (PAH) are carcinogenic and neurotoxic combustion by-products commonly found in urban air. Exposure to PAH is disproportionately high in low income communities of color who also experience chronic economic stress.In a prospective cohort study in New York City (NYC) we previously found a significant association between prenatal PAH exposure and Attention Deficit Hyperactivity Disorder (ADHD) behavior problems at age 9. Here, we have evaluated the joint effects of prenatal exposure to PAH and prenatal/childhood material hardship on ADHD behavior problems.We enrolled nonsmoking African-American and Dominican pregnant women in New York City between 1998 and 2006 and followed their children through 9 years of age. As a biomarker of prenatal PAH exposure, PAH-DNA adducts were measured in maternal blood at delivery and were dichotomized at the limit of detection (to indicate high vs. low exposure). Maternal material hardship (lack of adequate food, housing, utilities, and clothing) was self-reported prenatally and at multiple time points through child age 9. Latent variable analysis identified four distinct patterns of hardship. ADHD behavior problems were assessed using the Conners Parent Rating Scale- Revised. Analyses adjusted for relevant covariates.Among 351 children in our sample, across all hardship groups, children with high prenatal PAH exposure (high adducts) generally had more symptoms of ADHD (higher scores) compared to those with low PAH exposure. The greatest difference was seen among the children with hardship persisting from pregnancy through childhood. Although the interactions between high PAH exposure and hardship experienced at either period ("persistent" hardship or "any" hardship) were not significant, we observed significant differences in the number of ADHD symptoms between children with high prenatal PAH exposure and either persistent hardship or any hardship compared to the others. These differences were most significant for combined high PAH and persistent hardship: ADHD Index (p0.008), DSM-IV Inattentive (p = 0.006), DSM-IV Hyperactive Impulsive problems (p = 0.033), and DSM-IV Index Total (p = 0.009).The present findings add to existing evidence that co-exposure to socioeconomic disadvantage and air pollution in early life significantly increases the risk of adverse neurodevelopmental outcomes. They suggest the need for multifaceted interventions to protect pregnant mothers and their children.

BackgroundDNA 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 2years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures.ResultsAsthma 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 (90days 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 2years 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).ConclusionsShort-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.

Background Whether concomitant home exposures modify the effectiveness of mouse allergen reduction among mouse-sensitized children with asthma is unknown. Objective To determine whether a lower baseline home mouse allergen level, lower particulate matter 10 μ or less (PM10), and the absence of sensitization and exposure to other indoor allergens are associated with greater improvements in asthma associated with mouse allergen reduction. Methods A secondary analysis of a randomized clinical trial of a home mouse allergen intervention was performed to examine the effect of 3 indoor factors on the relationship between mouse allergen reduction and a range of asthma outcomes. Results Participants (N = 297) were predominantly minority (78% African American, 22% Hispanic) and publicly insured (88%). Higher baseline mouse allergen levels were associated with a greater response to mouse allergen reduction for several symptom and exacerbation outcomes. Lower indoor PM10 levels were associated with a greater response to mouse allergen reduction for several symptom outcomes, but not exacerbation outcomes. Overall, sensitization and exposure to other indoor allergens did not appear to modify the effect of mouse allergen reduction. Conclusions In this population of predominantly low-income children with persistent asthma and mouse sensitization, mouse allergen reduction was associated with improvements in asthma, especially among those with high baseline mouse allergen exposure. Lower indoor PM10 was associated with greater improvements in asthma symptoms.

Rationale: The decision whether to initiate or forgo long-term ventilation for children can be difficult and impactful. However, little has been published on the informational and decisional needs ...

Many notable advances in drug allergy, urticaria, angioedema, and anaphylaxis were reported in 2018. Broad-spectrum antibiotic use and, consequently, antibiotic resistance are widespread, and algorithms to clarify β-lactam allergy and optimize antibiotic use were described. Meaningful data emerged on the pathogenesis of delayed drug hypersensitivity reactions. Progress not only in defining biomarkers but also in understanding the effect on quality of life and developing better treatments has been made for patients with chronic idiopathic urticaria. Patients with hereditary angioedema (HAE) have gained additional access to highly efficacious therapies, with associated improvements in quality of life, and some progress was made in our understanding of recurrent angioedema in patients with normal laboratory results. Guidelines have defined clear goals to help providers optimize therapies in patients with HAE. The epidemiology and triggers of anaphylaxis and the mechanisms underlying anaphylaxis were elucidated further. In summary, these disorders (and labels) cause substantial burdens for individual persons and even society. Fortunately, publications in 2018 have informed on advancements in diagnosis and management and have provided better understanding of mechanisms that potentially could yield new therapies. This progress should lead to better health outcomes and paths forward in patients with drug allergy, urticaria, HAE, and anaphylaxis.

Background Single birth cohort studies have been the basis for many discoveries about early life risk factors for childhood asthma but are limited in scope by sample size and characteristics of the local environment and population. The Children’s Respiratory and Environmental Workgroup (CREW) was established to integrate multiple established asthma birth cohorts and to investigate asthma phenotypes and associated causal pathways (endotypes), focusing on how they are influenced by interactions between genetics, lifestyle, and environmental exposures during the prenatal period and early childhood. Methods and results CREW is funded by the NIH Environmental influences on Child Health Outcomes (ECHO) program, and consists of 12 individual cohorts and three additional scientific centers. The CREW study population is diverse in terms of race, ethnicity, geographical distribution, and year of recruitment. We hypothesize that there are phenotypes in childhood asthma that differ based on clinical characteristics and underlying molecular mechanisms. Furthermore, we propose that asthma endotypes and their defining biomarkers can be identified based on personal and early life environmental risk factors. CREW has three phases: 1) to pool and harmonize existing data from each cohort, 2) to collect new data using standardized procedures, and 3) to enroll new families during the prenatal period to supplement and enrich extant data and enable unified systems approaches for identifying asthma phenotypes and endotypes. Conclusions The overall goal of CREW program is to develop a better understanding of how early life environmental exposures and host factors interact to promote the development of specific asthma endotypes.

Background Air pollution exposure is ubiquitous with demonstrated effects on morbidity and mortality. A growing literature suggests that prenatal air pollution exposure impacts neurodevelopment. We posit that the Environmental influences on Child Health Outcomes (ECHO) program will provide unique opportunities to fill critical knowledge gaps given the wide spatial and temporal variability of ECHO participants. Objectives We briefly describe current methods for air pollution exposure assessment, summarize existing studies of air pollution and neurodevelopment, and synthesize this information as a basis for recommendations, or a blueprint, for evaluating air pollution effects on neurodevelopmental outcomes in ECHO. Methods We review peer-reviewed literature on prenatal air pollution exposure and neurodevelopmental outcomes, including autism spectrum disorder, attention deficit hyperactivity disorder, intelligence, general cognition, mood, and imaging measures. ECHO meta-data were compiled and evaluated to assess frequency of neurodevelopmental assessments and prenatal and infancy residential address locations. Cohort recruitment locations and enrollment years were summarized to examine potential spatial and temporal variation present in ECHO. Discussion While the literature provides compelling evidence that prenatal air pollution affects neurodevelopment, limitations in spatial and temporal exposure variation exist for current published studies. As >90% of the ECHO cohorts have collected a prenatal or infancy address, application of advanced geographic information systems-based models for common air pollutant exposures may be ideal to address limitations of published research. Conclusions In ECHO we have the opportunity to pioneer unifying exposure assessment and evaluate effects across multiple periods of development and neurodevelopmental outcomes, setting the standard for evaluation of prenatal air pollution exposures with the goal of improving children's health.

Background While animal data support an association between prenatal exposure to endocrine disrupting chemicals (EDCs) and altered mammary gland development and tumorigenesis, epidemiologic studies have only considered a few classes of EDCs in association with pubertal growth and development in girls. Polycyclic aromatic hydrocarbons (PAH) are a class of EDCs that have not been rigorously evaluated in terms of prenatal exposure and pubertal growth and development in girls. Objective In a New York City birth cohort of Black and Hispanic girls (n = 196; recruited 1998–2006), we examined associations of prenatal PAH exposure with self-reported age at growth spurt onset, breast development onset and menarche, and clinical measures of adolescent body composition including body mass index, waist-to-hip ratio, and body fat measured at ages 11–20 years. Methods We measured prenatal exposure to PAH using personal air monitoring data collected from backpacks worn by mothers during the third trimester of pregnancy (data available for all 196 girls) and biomarkers of benzo[α]pyrene-DNA adducts in umbilical cord blood (data available for 106 girls). We examined associations of prenatal PAH with the timing of pubertal milestones and adolescent body composition (11–20 years) using multivariable linear regression models adjusted for race/ethnicity, household public assistance status at birth, and age at outcome assessment. We also fit models further adjusted for potential mediators, including birthweight and childhood body size (BMI-for-age z-score measured at 6–8 years). Results Girls in the highest versus lowest tertile of ambient exposure to PAH, based on a summary measure of eight carcinogenic higher-molecular weight non-volatile PAH compounds (Σ8 PAH), had a 0.90 year delay in growth spurt onset (95% confidence interval (CI) = 0.25, 1.55; n = 196), a 0.35 year delay in breast development onset (95% CI = −0.26, 0.95; n = 193), and a 0.59 year delay in menarche (95% CI = 0.06, 1.11; n = 191) in models adjusted for race/ethnicity and household public assistance at birth. The statistically significant associations for age at growth spurt onset and menarche were not impacted by adjustment for birthweight or childhood body size. No differences in BMI-for-age z-score, waist-to-hip ratio, or percent body fat were found between girls in the highest versus lowest tertile of ambient Σ8 PAH. Results were similar when we evaluated benzo[α]pyrene-DNA adduct levels. Discussion Our results suggest that prenatal exposure to PAH might delay pubertal milestones in girls, but findings need to be replicated in other cohorts using prospectively collected data on pubertal outcomes.

Background Specific patterns of allergic sensitization to common allergens may provide relevant clinical insight into asthma risk. Objective To identify patterns of allergic sensitization based on multiple individual allergens and link these to current and persistent asthma using baseline and 3-year follow-up data. Methods Children 7 to 8 years old with (n = 196) and without (n = 136) asthma from the New York City Neighborhood Asthma and Allergy Study were studied. IgE against a panel of 112 antigens was measured using the ISAC multiplex panel array. Latent class analysis (LCA) was used to identify patterns of allergic sensitization among the 26 most common allergens against which children had measurable IgE. The association between patterns of allergic sensitization and risk of asthma and other allergic diseases was examined. Results LCA identified 4 patterns of allergic sensitization as follows: low risk of sensitization (prevalence of 53% in children with asthma and 76% in children without asthma), indoor (prevalence of 23% in children with asthma and 15% in children without asthma), pollen and indoor group 1 (prevalence of 16% in children with asthma and 5% in children without asthma), and pollen and indoor group 2 (prevalence of 9% in children with asthma and 4% in children without asthma). Compared with the low risk of sensitization pattern, children belonging to the 3 sensitized patterns had significantly higher risk of asthma at ages 7 to 8 years and 3 years later, with the highest risk for children in the pollen and indoor group 1 pattern. Conclusions LCA facilitates the study of sensitization profiles to a large number of common allergens. Analyzing patterns of allergic sensitization from multiple allergens reveals additional relevant associations with asthma than the study of a single allergen or total IgE.

BACKGROUND: Previously, we found that reported infant rhinorrhea and watery eyes without a cold (RWWC) predicted school age exercise-induced wheezing, emergency department visits, and respiratory-related hospitalizations for asthma. These findings appeared independent of infant wheezing and allergy. Overall, we theorize that prenatal material hardship and psychosocial distress can induce infant dysregulation in the autonomic nervous system leading to infant RWWC and school age exercise-induced wheezing. OBJECTIVE: To test the hypotheses that indicators of prenatal stress and measures of maternal demoralization, which can alter infant autonomic nervous system responses, would predict infant RWWC. METHODS: In a prospective birth cohort of urban children (n = 578), pregnant women were queried in the third trimester about material hardship and maternal demoralization using validated instruments. Child RWWC was queried every 3 months in infancy. RESULTS: Notably, 44% of the mothers reported not being able to afford at least one of the basic needs of daily living during pregnancy, and children of those mothers were more likely to have infant RWWC (P < .001). The children had an increased risk of RWWC with increasing maternal demoralization during pregnancy (P < .001). In models controlling for sex, race/ethnicity, maternal asthma, maternal allergy, smoker in the home (pre- or postnatal), prenatal pesticide exposure, and older siblings, RWWC was predicted by mother’s report of material hardship (relative risk, 1.22; P = .021) and maternal demoralization (relative risk, 1.14; P = .030). CONCLUSION: These results suggest an association between material hardship and psychological distress during pregnancy and RWWC in infancy, further supporting a link between infant autonomic dysregulation and RWWC.

Polycyclic aromatic hydrocarbons (PAH) are common environmental pollutants that result from incomplete combustion of biomass and fossil fuels. PAH have endocrine-disrupting properties and are known animal carcinogens. Evidence from case-control studies suggests an association between PAH and breast cancer risk, but longitudinal research on PAH exposure during critical windows of susceptibility, such as prenatally and in early life, is limited. The purpose of this study was to prospectively examine whether prenatal exposure to PAH is associated with breast tissue composition, an intermediate marker of breast cancer risk, in adolescent girls. We studied 105 adolescent girls in the Columbia Center for Children’s Environmental Health (CCCEH) birth cohort, which recruited nonsmoking African American and Dominican American pregnant women living in three low-income neighborhoods in New York City from 1998-2006. Women wore a small backpack holding a personal air monitor for 2 consecutive days during the 3rd trimester of pregnancy, which measured concentrations of pyrene and 8 other carcinogenic PAH (summed and categorized into tertiles for analysis). Girls completed a follow-up clinic visit in adolescence (ages 11.2-19.6 years, median=15.8), at which time breast tissue composition was measured by optical spectroscopy (OS). OS is a novel and noninvasive tool that provides a broad compositional view of the breast by capturing variation in the amount of water, lipid, oxy-hemoglobin, deoxy-hemoglobin, and collagen, as well as overall cellular and connective tissue density. OS measured red and near-infrared light transmission of 7 wavelengths (650-1060 nm) at 4 source-detector distances in each breast quadrant, resulting in 16 overlapping tissue volumes. Principal component analysis was used to reduce spectral data and generate principal component (PC) scores for each participant, which were averaged over both breasts. We used multivariable linear regression to examine associations of prenatal PAH measures (pyrene and Σ8 PAH) with each of the first 4 OS PCs, which explained >99% of the spectral variation in the sample. Models were adjusted for age, ethnicity, body mass index (BMI) at time of OS measurement, age at breast development, and mothers’ prepregnancy BMI. After adjusting for covariates, PC1 scores were significantly lower on average in the highest compared to lowest tertile of prenatal ambient Σ8 PAH (β = -0.42, 95% CI = -0.81 to -0.02, p = 0.04). PC1 covered 91.8% of the spectral variations and represents overall light attenuation from higher scattering due to higher cellularity and connective tissues. PC1 also mapped to multiple chromophores including hemoglobin and collagen. No associations were found between prenatal ambient Σ8 PAH and PCs 2-4, and no associations with OS PCs were found for pyrene. To conclude, we found evidence suggesting that prenatal exposure to PAH is associated with breast tissue composition in adolescent girls. Citation Format: Rebecca D. Kehm, Lothar Lilge, E. Jane Walter, Nur Zeinomar, Jasmine A. McDonald, Parisa Tehranifar, Julie B. Herbstman, Rachel L. Miller, Mary Beth Terry. Prenatal exposure to polycyclic aromatic hydrocarbons and breast tissue composition in adolescent girls [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A15.

Background: Reduced access to treatment advances in rural populations contributes to increased cancer mortality. Rural Appalachian Kentucky is a geographically isolated population with a unique carcinogen exposure and a low frequency guideline-recommended germline testing. To improve testing rates, a return of germline results program for patients enrolled in the Total Cancer Care (TCC) protocol at Markey Cancer Center (MCC) was initiated. Methods: Pre-intervention testing rates were obtained from the electronic health record. Patient and physician focus groups were conducted to assess barriers to germline testing. Whole exome germline data from TCC patients enrolled in the Avatar subset is analyzed using standard bioinformatics pipeline for known, clinically significant mutations in the 59 American College of Medical Genetics (ACMG) genes where return of incidental germline findings is recommended and 21 pharmacogenetic genes. Results are reviewed by our Molecular Tumor Board and a recommendation for confirmatory clinical testing, if needed, is made to the treating physician. Results: Baseline rates of guideline recommended germline testing at MCC in 2018 was 20% of ovarian, 15% of breast, 9% of colon, 3% of pancreas and no metastatic prostate patients. Testing was infrequent in rural communities. Almost all patients who had testing recommended by their physician, had testing performed. Unaffected family members were also rarely tested. Physician focus groups at MCC identified lack of time and low perceived value of the testing as barriers. Rural physicians also identified lack of access to genetic counselors. Patient focus groups in the Appalachian region demonstrated poor quality internet and low knowledge and self- efficacy as major barriers to patients discussing genetic testing with family members. To overcome patient barriers, a preloaded audio card was developed to facilitate discussion with family members. The preloaded audio card was tested in a rural Appalachian community, demonstrating significantly improved knowledge and self-efficacy. To overcome physician barriers, a genetic counselor telemedicine clinic and standing order were initiated. To improve physician perception of test value, the ORIEN return of germline results project was initiated. Of the more than 2000 patients enrolled on TCC at MCC, approximately 40% are from Appalachia, 173 have appropriate consent and specimen availability for germline sequencing and 5 have had results returned. Data describing the first 3 months of this initiative, including frequency of mutations in patients and unaffected family members and acceptance of genetic counselor referrals by physicians, patients and family members will be presented. Conclusion: Rural Appalachian communities identified significant barriers to guideline recommended germline testing, however, ORIEN and the TCC protocol are novel methods to reduce these barriers and improve the rates of testing in both patients and their family members. Citation Format: Jill Kolesar, Micheal Cavnar, Rachel Miller, Justine Pickarski, Shulin Zhang, Kannabiran Nandakumar, Marissa Schuh, Elizabeth Belcher, Eric Durbin, Ming Poi, Fred Ueland, Isaac Hands, Therese Bocklage, JC Jeong, Susanne Arnold, Mark Evers. Improving cancer germline testing in rural Appalachian populations with ORIEN [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A001.

Exposome research can improve the understanding of the mechanistic connections between exposures and health to help mitigate adverse health outcomes across the life span. The exposomic approach provides a risk profile instead of single predictors and thus is particularly applicable to allergic diseases and asthma. Under the PRACTALL collaboration between the European Academy of Allergy and Clinical Immunology (EAACI) and the American Academy of Allergy, Asthma, and Immunology (AAAAI), we evaluated the current concepts and the unmet needs on the role of the exposome in allergic diseases and asthma. ispartof: ALLERGY vol:74 issue:3 pages:449-463 ispartof: location:Denmark status: published

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.

A common explanation for the origins and rising prevalence of asthma is that they involve complex interactions between hereditary predispositions and environmental exposures that are incompletely understood. Yet, emerging evidence substantiates the paradigm that environmental exposures prenatally and during very early childhood induce epigenetic alterations that affect the expression of asthma genes and, thereby, asthma itself. Here, we review much of the key evidence supporting this paradigm. First, we describe evidence that the prenatal and early postnatal periods are key time windows of susceptibility to environmental exposures that may trigger asthma. Second, we explain how environmental epigenetic regulation may explain the immunopathology underlying asthma. Third, we outline specific evidence that environmental exposures induce epigenetic regulation, both from animal models and robust human epidemiological research. Finally, we review some emerging topics, including the importance of coexposures, population divergence, and how epigenetic regulation may change over time. Despite all the inherent complexity, great progress has been made toward understanding what we still consider reversible asthma risk factors. These, in time, may impact patient care.

The dramatic rise in the prevalence of food allergy and food allergy-associated anaphylaxis in the past few decades has fueled investigative interest into understanding this puzzling trend. Here, we review the question as to whether important external environmental determinants beyond dietary habits and exposure to food allergens are involved. This review will summarize our current understanding of these environment determinants, derived from the latest experimental and epidemiological research. Specifically, we will review the role of exposures that affect skin barrier function, development of a diverse microbiome, and food processing. Additional exposures of concern are insufficient sunlight, endocrine disrupting chemicals and pesticides, and use of specific pharmaceutical agents that may drive or modify the risk for food allergy. Despite limitations in the quantity and quality of research to date, many new epidemiological associations and experimental data in support of this paradigm have emerged.

OBJECTIVE The aim of this study was to investigate the presence and correlates of clinically relevant cognitive impairment in middle-aged adults with childhood-onset type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS During 2010–2013, 97 adults diagnosed with T1D and aged RESULTS The prevalence of clinically relevant cognitive impairment was five times higher among participants with than without T1D (28% vs. 5%; P < 0.0001), independent of education, age, or blood pressure. Effect sizes were large (Cohen d 0.6–0.9; P < 0.0001) for psychomotor speed and visuoconstruction tasks and were modest (d 0.3–0.6; P < 0.05) for measures of executive function. Among participants with T1D, prevalent cognitive impairment was related to 14-year average A1c >7.5% (58 mmol/mol) (odds ratio [OR] 3.0; P = 0.009), proliferative retinopathy (OR 2.8; P = 0.01), and distal symmetric polyneuropathy (OR 2.6; P = 0.03) measured 5 years earlier; higher BMI (OR 1.1; P = 0.03); and ankle-brachial index ≥1.3 (OR 4.2; P = 0.01) measured 20 years earlier, independent of education. CONCLUSIONS Clinically relevant cognitive impairment is highly prevalent among these middle-aged adults with childhood-onset T1D. In this aging cohort, chronic hyperglycemia and prevalent microvascular disease were associated with cognitive impairment, relationships shown previously in younger populations with T1D. Two additional potentially modifiable risk factors for T1D-related cognitive impairment, vascular health and BMI, deserve further study.

Prior studies have shown that vinyl flooring as well as the vinyl-softening plasticizers butylbenzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) are associated with asthma and airway inflammation. Although DEHP exposure is primarily dietary, whether home vinyl flooring contributes to indoor air and urinary metabolite concentrations for these two phthalates is unclear. Exposures to BBzP and DEHP were examined in a prospective birth cohort of New York City children (n=239) using: (i) visual observation of potential phthalate containing flooring, (ii) a 2-week home indoor air sample, and (iii) concurrent urinary metabolites in a subset (n=193). The category "vinyl or linoleum" flooring was observed in 135 (56%) of monitored rooms; these rooms had statistically significantly higher indoor air geometric mean concentrations of BBzP (23.9 ng/m(3)) than rooms with wood or carpet flooring (10.6 ng/m(3)). Children from homes with "vinyl or linoleum" flooring also had significantly higher urinary BBzP metabolite concentrations than other children. Indoor air BBzP and urinary metabolite concentrations were correlated positively (Spearman's rho 0.40). By contrast, indoor air DEHP was not associated with flooring type nor with its urinary metabolite concentrations. Vinyl flooring in the home may be an important source of children's exposure to BBzP via indoor air.