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Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma - viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2-3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Globally, exposure to ambient air pollutants is responsible for premature mortality and is implicated in the development and exacerbation of several acute and chronic lung disease across all ages. In this article, we discuss the source apportionment of ambient pollutants and the respiratory health effects in humans. We specifically discuss the evidence supporting ambient pollution in the development of asthma and chronic obstructive pulmonary disease and acute exacerbations of each condition. Practical advice is given to health care providers in how to promote a healthy environment and advise patients with chronic conditions to avoid unsafe air quality., Competing Interests: Disclosure None of the authors have any commercial/financial conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Sparse data address the effects of nitrogen dioxide (NO 2 ) exposure in inner-city schools on obese students with asthma., Objective: We sought to evaluate relationships between classroom NO 2 exposure and asthma symptoms and morbidity by body mass index (BMI) category., Methods: The School Inner-City Asthma Study enrolled students aged 4 to 13 years with asthma from 37 inner-city schools. Students had baseline determination of BMI percentile. Asthma symptoms, morbidity, pulmonary inflammation, and lung function were monitored throughout the subsequent academic year. Classroom NO 2 data, linked to enrolled students, were collected twice per year. We determined the relationship between classroom NO 2 levels and asthma outcomes by BMI stratification., Results: A total of 271 predominantly black (35%) or Hispanic students (35%) were included in analyses. Fifty percent were normal weight (5-84th BMI percentile), 15% overweight (≥85-94th BMI percentile), and 35% obese (≥95th BMI percentile). For each 10-parts per billion increase in NO 2 , obese students had a significant increase in the odds of having an asthma symptom day (odds ratio [OR], 1.86; 95% CI, 1.15-3.02) and in days caregiver changed plans (OR, 4.24; 95% CI, 2.33-7.70), which was significantly different than normal weight students who exhibited no relationship between NO 2 exposure and symptom days (OR, 0.90; 95% CI, 0.57-1.42; pairwise interaction P = .03) and change in caregiver plans (OR, 1.37; 95% CI, 0.67-2.82; pairwise interaction P = .02). Relationships between NO 2 levels and lung function and fractional exhaled nitric oxide did not differ by BMI category. If we applied a conservative Holm-Bonferroni correction for 16 comparisons (obese vs normal weight and overweight vs normal weight for 8 outcomes), these findings would not meet statistical significance (all P > .003)., Conclusions: Obese BMI status appears to increase susceptibility to classroom NO 2 exposure effects on asthma symptoms in inner-city children. Environmental interventions targeting indoor school NO 2 levels may improve asthma health for obese children. Although our findings would not remain statistically significant after adjustment for multiple comparisons, the large effect sizes warrant future study of the interaction of obesity and pollution in pediatric asthma., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

A 17-year-old female who presented with cough, chest pain, dyspnea, and hemoptysis was found to have an intrathoracic rib. Patients who are diagnosed with intrathoracic ribs are most often asymptomatic and should undergo limited diagnostic workup. Intrathoracic ribs are rare congenital anomalies incidentally identified after chest radiography performed for another indication, as is the case with this patient. In this case, further evaluation was necessary due to persistent symptoms. Here, we used contrast-enhanced ultrasound after chest radiography and computed tomography to further evaluate the fatty intrathoracic mass and exclude vascular features suggestive of a tumor., (© 2020 Wiley Periodicals, Inc.)

Background: Traffic proximity has been associated with adverse respiratory health outcomes. Less is known about the combined impact of residential and school exposures on pediatric asthma., Objective: We sought to use spatial analysis methodology to analyze residential and school proximity to major roadways and pediatric asthma morbidity., Methods: The School Inner-City Asthma Study (n = 350) recruited school-aged children with asthma. Each participant's school and home addresses were geocoded, and distances from major roadways were measured to calculate a composite measure accounting for both home and school traffic exposure. Generalized estimating equation models were clustered by subject and adjusted for age, race/ethnicity, sex, income, environmental tobacco smoke, controller medication, upper respiratory tract infections, and seasonality., Results: The majority of participants (62%) attended schools within 100 m from major roadways, and 40% also resided within 100 m of major roadways. In multivariate analyses major roadway proximity was independently associated with increased asthma symptom days. At greater than the threshold of 100 m, children had 29% less odds of a symptom day over the past 2 weeks for each 100-m increase in distance from a major roadway (odds ratio, 0.71; 95% CI, 0.58-0.87; P < .01). Children farther from a major roadway also had significantly less reported health care use (odds ratio, 0.63; 95% CI, 0.47-0.85; P < .01) and were significantly less likely to have poor asthma control (odds ratio, 0.80; 95% CI, 0.69-0.94; P < .01). There was not a meaningful association between distance to a major roadway and lung function outcomes., Conclusions: Proximity to a major roadway, a composite measure of home and school exposure but primarily driven by home exposure, was associated with greater asthma morbidity. More studies are needed to evaluate the independent effect of school distance to a roadway on asthma morbidity., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Children spend over 6 h a day in schools and have higher asthma morbidity from school environmental exposures. The present study aims to determine indoor and outdoor possible sources affecting indoor PM 2.5 in classrooms. Weeklong indoor PM 2.5 samples were collected from 32 inner-city schools from a Northeastern U.S. community during three seasons (fall, winter and spring) during the years 2009 to 2013. Concurrently, daily outdoor PM 2.5 samples were taken at a central monitoring site located at a median distance of 4974 m (range 1065-11,592 m) from the schools. Classroom indoor concentrations of PM 2.5 (an average of 5.2 μg/m 3 ) were lower than outdoors (an average of 6.5 μg/m 3 ), and these averages were in the lower range compared to the findings in other schools' studies. The USEPA PMF model was applied to the PM 2.5 components measured simultaneously from classroom indoor and outdoor to estimate the source apportionment. The major sources (contributions) identified across all seasons of indoor PM 2.5 were secondary pollution (41%) and motor vehicles (17%), followed by Calcium (Ca)-rich particles (12%), biomass burning (15%), soil dust (6%), and marine aerosols (4%). Likewise, the major sources of outdoor PM 2.5 across all seasons were secondary pollution (41%) and motor vehicles (26%), followed by biomass burning (17%), soil dust (7%), road dust (3%), and marine aerosols (1%). Secondary pollution was the greatest contributor to indoor and outdoor PM 2.5 over all three seasons, with the highest contribution during spring with 53% to indoor PM 2.5 and 45% to outdoor PM 2.5 . Lower contributions of this source during fall and winter are most likely attributed to less infiltration indoors. In contrast, the indoor contribution of motor vehicles source was highest in the fall (29%) and winter (25%), which was presumably categorized by a local source. From the relationship between indoor-to-outdoor sulfur ratios and each source contribution, we also estimated the local and regional influence on indoor PM 2.5 concentration. Overall, the observed differences to indoor PM 2.5 are related to seasonality, and the distinct characteristics and behavior of each classroom/school., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We seek to determine how youth with chronic medical conditions experience alcohol screening and counseling., Methods: Adolescents with type I diabetes, juvenile idiopathic arthritis, moderate persistent asthma, cystic fibrosis, attention deficit hyperactivity disorder, or inflammatory bowel disease were surveyed. Descriptive statistics and regression analysis quantified rates of asking and counseling about alcohol., Results: Of 390 participants (75.1% white/non-Hispanic, 51.8% female, average age 16.4 years), 70% reported being asked about their alcohol use by a healthcare provider, and 76% reported receiving at least one message regarding alcohol and health. Of past year drinkers, 54% disclosed use to their provider. Only 2.0% of youth reported receiving the message "I should not drink.", Conclusions: Most youth with chronic medical conditions were asked and counseled about alcohol use although few heard unambiguous recommendations to avoid alcohol consumption., (Copyright © 2019 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Home fungus exposures may be associated with development or worsening of asthma. Little is known about the effects of school/classroom fungus exposures on asthma morbidity in students., Objective: To evaluate the association of school-based fungus exposures on asthma symptoms in both fungus-sensitized and nonsensitized students with asthma., Methods: In this prospective study, 280 children with asthma from 37 inner-city schools were phenotypically characterized at baseline and followed-up for 1 year. Fungal spores were collected by using a Burkard air sampler twice during the school year. Clinical outcomes were evaluated throughout the school year and linked to classroom-specific airborne spore sampling. The primary outcome was days with asthma symptoms per 2-week period., Results: Fungal spores were present in all classroom samples. The geometric mean of the total fungi was 316.9 spores/m 3 and ranged from 15.0 to 59,345.7 spores/m 3 . There was variability in total fungus quantity between schools and classrooms within the same school. Mitospores were the most commonly detected fungal grouping. Investigation of the individual mitospores revealed that exposure to Alternaria was significantly associated with asthma symptom days in students sensitized to Alternaria (OR = 3.61, CI = 1.34-9.76, P = .01), but not in children not sensitized to Alternaria (OR = 1.04, CI = 0.72-1.49, P = .85). Students sensitized to Alternaria and exposed to high levels (≥75th percentile exposure) had 3.2 more symptom days per 2-week period as compared with students sensitized but exposed to lower levels., Conclusion: Children with asthma who are sensitized to Alternaria and exposed to this fungus in their classroom may have significantly more days with asthma symptoms than those who were sensitized and not exposed., Clinical Trial Registration: Clinicaltrials.govNCT01756391., (Copyright © 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: Digital voice assistant technology provides unique opportunities to enhance clinical practice. We aimed to understand factors influencing pediatric providers' current and potential use of this technology in clinical practice., Methods: We surveyed pediatric providers regarding current use and interest in voice technology in the workplace. Regression analyses evaluated provider characteristics associated with voice technology use. Among respondents not interested in voice technology, we elicited individual concerns., Results: Among 114 respondents, 19 (16.7%) indicated current use of voice technology in clinical practice, and 51 (44.7%) indicated use of voice technology for nonclinical purposes. Fifty-four (47.4%) reported willingness to try digital voice assistant technology in the clinical setting. Providers who had longer clinic visits (odds ratio [OR], 3.11, 95% confidence interval [CI], 1.04, 9.33, p  = 0.04), fewer patient encounters per day ( p  = 0.02), and worked in hospital-based practices (OR, 2.95, 95% CI, 1.08, 8.07, p  = 0.03) were more likely to currently use voice technology in the office. Younger providers ( p  = 0.02) and those confident in the accuracy of voice technology (OR, 3.05, 95% CI, 1.38, 6.74, p  = 0.005) were more willing to trial digital voice assistants in the clinical setting. Among respondents unwilling or unsure about trying voice assistant technology, the most common reasons elicited were concerns related to its accuracy (35%), efficiency (33%), and privacy (28%)., Conclusion: This national survey evaluating use and attitudes toward digital voice assistant technology by pediatric providers found that while only one-eighth of pediatric providers currently use digital voice assistant technology in the clinical setting, almost half are interested in trying it in the future. Younger provider age and confidence in the accuracy of voice technology are associated with provider interest in using voice technology in the clinical setting. Future development of voice technology for clinical use will need to consider accuracy of information, efficiency of use, and patient privacy for successful integration into the workplace., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Corticosteroids are the most effective treatment for asthma; inhaled corticosteroids (ICSs) are the first-line treatment for children and adults with persistent symptoms. ICSs are associated with significant improvements in lung function. The anti-inflammatory effects of corticosteroids are mediated by both genomic and nongenomic factors. Variation in the response to corticosteroids has been observed. Patient characteristics, biomarkers, and genetic features may be used to predict response to ICSs. The existence of multiple mechanisms underlying glucocorticoid insensitivity raises the possibility that this might indeed reflect different diseases with a common phenotype., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The diagnosis of asthma in children under five years has been controversial due to changing concepts of what true asthma is in this age group. Previous diagnostic algorithms that used clinical indices to predict the persistence of asthma symptoms or phenotypes based on asthma triggers do not predict which children will benefit from asthma medication. A pragmatic approach to asthma diagnosis in this age group is based on identifying signs and symptoms of reversible airflow obstruction and documenting their response to asthma medication. Hopefully, this approach will provide clearer guidance to clinicians and improve asthma morbidity in these young children., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The utility of bronchodilators to treat acute chest syndrome (ACS) in patients with sickle cell disease is unknown. Our objectives were to examine the variability in bronchodilator use for ACS among pediatric hospitals contributing to a large database and to examine the relationship between bronchodilator use and length of stay (LOS) and mortality. Between 2005 and 2011, bronchodilators were used during 6812/11 328 hospitalizations (60.1%) and use varied from 0.0% to 97.0% (median = 46.0%, interquartile range = 37.0% to 74.0%). Median LOS was 4 days, and interquartile range was 2 to 6 days. Bronchodilator use was associated with a 13.2% increase in LOS (95% confidence interval = 9.2% to 17.3%, P < .001). However, in the subgroup with asthma, bronchodilator use was associated with a 17.9% decrease in LOS (95% confidence interval = 1.7% to 31.4%, P = .03). There is wide variability in bronchodilator use for ACS, and it has variable association with LOS, depending on comorbid asthma. Prospective trials are needed to evaluate bronchodilators for ACS.

Background: Ambient and home exposure to nitrogen dioxide (NO 2 ) causes asthma symptoms and decreased lung function in children with asthma. Little is known about the health effects of school classroom pollution exposure., Objective: We aimed to determine the effect of indoor classroom NO 2 on lung function and symptoms in inner-city school children with asthma., Methods: Children enrolled in the School Inner-City Asthma Study were followed for 1 academic year. Subjects performed spirometry and had fraction of exhaled nitric oxide values measured twice during the school year at school. Classroom NO 2 was collected by means of passive sampling for 1-week periods twice per year, coinciding with lung function testing. Generalized estimating equation models assessed lung function and symptom relationships with the temporally nearest classroom NO 2 level., Results: The mean NO 2 value was 11.1 ppb (range, 4.3-29.7 ppb). In total, exposure data were available for 296 subjects, 188 of whom had complete spirometric data. At greater than a threshold of 8 ppb of NO 2 and after adjusting for race and season (spirometry standardized by age, height, and sex), NO 2 levels were associated highly with airflow obstruction, such that each 10-ppb increase in NO 2 level was associated with a 5% decrease in FEV 1 /forced vital capacity ratio (β = -0.05; 95% CI, -0.08 to -0.02; P = .01). Percent predicted forced expiratory flow between the 25th and 75th percentile of forced vital capacity was also inversely associated with higher NO 2 exposure (β = -22.8; 95% CI, -36.0 to -9.7; P = .01). There was no significant association of NO 2 levels with percent predicted FEV 1 , fraction of exhaled nitric oxide, or asthma symptoms. Additionally, there was no effect modification of atopy on lung function or symptom outcomes., Conclusion: In children with asthma, indoor classroom NO 2 levels can be associated with increased airflow obstruction., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Although pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch., Methods: To examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6-18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression., Results: From pre-/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV 1 % and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV 1 %, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV 1 % and FVC %., Conclusions: These results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty., Trial Registration: ClinicalTrials.gov registration number: NCT01748175 .

Severe asthma accounts for only a small proportion of the children with asthma but a disproportionately high amount of resource utilization and morbidity. It is a heterogeneous entity and requires a step-wise, evidence-based approach to evaluation and management by pediatric subspecialists. The first step is to confirm the diagnosis by eliciting confirmatory history and objective evidence of asthma and excluding possible masquerading diagnoses. The next step is to differentiate difficult-to-treat asthma, asthma that can be controlled with appropriate management, from asthma that requires the highest level of therapy to maintain control or remains uncontrolled despite management optimization. Evaluation of difficult-to-treat asthma includes an assessment of medication delivery, the home environment, and, if possible, the school and other frequented locations, the psychosocial situation, and comorbid conditions. Once identified, aggressive management of issues related to poor adherence and drug delivery, remediation of environmental triggers, and treatment of comorbid conditions is necessary to characterize the degree of control that can be achieved with standard therapies. For the small proportion of patients whose disease remains poorly controlled with these interventions, the clinician may assess steroid responsiveness and determine the inflammatory pattern and eligibility for biologic therapies. Management of severe asthma refractory to traditional therapies involves considering the various biologic and other newly approved treatments as well as emerging therapies based on the individual patient characteristics.

Background: Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited., Methods: We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids., Results: The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06)., Conclusions: In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

Background: The effect of age on asthma severity is poorly understood., Objectives: The objective of this study was to compare the baseline features of severe and nonsevere asthma in the Severe Asthma Research Program (SARP) III cohort, and examine in cross section the effects of age on those features., Methods: SARP III is a National Institutes of Health/National Heart Lung Blood Institute multisite 3-year cohort study conducted to investigate mechanisms of severe asthma. The sample included 188 children (111 severe, 77 nonsevere) and 526 adults (313 severe, 213 nonsevere) characterized for demographic features, symptoms, health care utilization, lung function, and inflammatory markers compared by age and severity., Results: Compared with children with nonsevere asthma, children with severe asthma had more symptoms and more historical exacerbations, but no difference in body weight, post-bronchodilator lung function, or inflammatory markers. After childhood, and increasing with age, the cohort had a higher proportion of women, less allergen sensitization, and overall fewer blood eosinophils. Enrollment of participants with severe asthma was highest in middle-aged adults, who were older, more obese, with greater airflow limitation and higher blood eosinophils, but less allergen sensitization than adults with nonsevere asthma., Conclusions: The phenotypic features of asthma differ by severity and with advancing age. With advancing age, patients with severe asthma are more obese, have greater airflow limitation, less allergen sensitization, and variable type 2 inflammation. Novel mechanisms besides type 2 inflammatory pathways may inform the severe asthma phenotype with advancing age., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Despite available and effective tools for asthma self-assessment (Asthma Control Test, ACT) and self-management (Asthma Action Plan, AAP), they are underutilized in outpatient specialty clinics. We evaluated the impact of a patient-centered checklist, the Asthma Passport, on improving ACT and AAP utilization in clinic., Methods: This was a randomized, interventional quality-improvement project in which the Asthma Passport was distributed to 120 pediatric asthma patients over the duration of 16 weeks. The passport's checklist consisted of tasks to be completed by the patient/family, including completion of the ACT and AAP. We compared rates of completion of the ACT and AAP for those who received the passport versus the control group, and assessed patient/caregiver and provider satisfaction., Results: Based on electronic medical record data from 222 participants, the ACT completion rate was not significantly different between the passport and control groups, however, the AAP completion rate was significantly greater than control (30.0% vs. 17.7%, p = 0.04). When per-protocol analysis was limited to groups who completed and returned their passports, ACT and AAP completion rates were significantly greater than control (73.8% vs. 44.1% (p = 0.002) and 35.7% vs. 17.7% (p = 0.04), respectively). Nearly all participants reported high satisfaction with care, and surveyed providers viewed the passport favorably., Conclusions: A patient-centered checklist significantly improved the completion rate of the AAP. For patient's who completed and returned the asthma passport, the ACT completion rate was also improved. Participants and providers reported high satisfaction with the checklist, suggesting that it can effectively promote asthma self-management and self-assessment without burdening clinicians or clinic workflow.

In this review we highlight recent studies that advance the knowledge and understanding of the effects of various environmental factors and associated immune responses in patients with allergic diseases. This review will focus on new literature regarding allergic and immune responses to a variety of environmental factors, including aeroallergens, stinging insects, fungi, pollutants, viral respiratory tract infections, climate change, and microbial exposures., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Asthma is the most common chronic disease of childhood in the United States, causes significant morbidity, particularly in the inner-city, and accounts for billions of dollars in health care utilization. Home environments are established sources of exposure that exacerbate symptoms and home-based interventions are effective. However, elementary school children spend 7 to 12h a day in school, primarily in one classroom. From the observational School Inner-City Asthma Study we learned that student classroom-specific exposures are associated with worsening asthma symptoms and decline in lung function. We now embark on a randomized, blinded, sham-controlled school environmental intervention trial, built on our extensively established school/community partnerships, to determine the efficacy of a school-based intervention to improve asthma control. This factorial school/classroom based environmental intervention will plan to enroll 300 students with asthma from multiple classrooms in 40 northeastern inner-city elementary schools. Schools will be randomized to receive either integrated pest management versus control and classrooms within these schools to receive either air purifiers or sham control. The primary outcome is asthma symptoms during the school year. This study is an unprecedented opportunity to test whether a community of children can benefit from school or classroom environmental interventions. If effective, this will have great impact as an efficient, cost-effective intervention for inner city children with asthma and may have broad public policy implications., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Outdoor air pollution penetrates buildings and contributes to total indoor exposures. We investigated the relationship of indoor to outdoor particulate matter in inner-city school classrooms. The School Inner City Asthma Study investigates the effect of classroom-based environmental exposures on students with asthma in the northeast United States. Mixed effects linear models were used to determine the relationships between indoor PM 2.5 (particulate matter) and black carbon (BC), and their corresponding outdoor concentrations, and to develop a model for predicting exposures to these pollutants. The indoor-outdoor sulfur ratio was used as an infiltration factor of outdoor fine particles. Weeklong concentrations of PM 2.5 and BC in 199 samples from 136 classrooms (30 school buildings) were compared with those measured at a central monitoring site averaged over the same timeframe. Mixed effects regression models found significant random intercept and slope effects, which indicate that: (1) there are important PM 2.5 sources in classrooms; (2) the penetration of outdoor PM 2.5 particles varies by school and (3) the site-specific outside PM 2.5 levels (inferred by the models) differ from those observed at the central monitor site. Similar results were found for BC except for lack of indoor sources. The fitted predictions from the sulfur-adjusted models were moderately predictive of observed indoor pollutant levels (out of sample correlations: PM 2.5 : r 2 =0.68, BC; r 2 =0.61). Our results suggest that PM 2.5 has important classroom sources, which vary by school. Furthermore, using these mixed effects models, classroom exposures can be accurately predicted for dates when central site measures are available but indoor measures are not available.

Rationale: Phenotypic distinctions between severe asthma (SA) and nonsevere asthma (NONSA) may be confounded by differential adherence or incorrect use of corticosteroids., Objectives: To determine if there are persistent phenotypic distinctions between SA (as defined by 2014 American Thoracic Society/European Respiratory Society guidelines) and NONSA after intramuscular triamcinolone acetonide (TA), and to identify predictors of a corticosteroid response in these populations., Methods: A total of 526 adults age 18 years and older (315 SA) and 188 children age 6 to less than 18 years (107 SA) in the NHLBI Severe Asthma Research Program III were characterized before and 3 weeks after TA. The primary outcome for corticosteroid response was defined as greater than or equal to 10-point improvement in percent predicted FEV 1 ., Measurements and Main Results: Adult asthma groups exhibited a small but significant mean FEV 1 % predicted improvement after TA (SA group mean difference, 3.4%; 95% confidence interval, 2.2-4.7%; P = 0.001), whereas children did not. Adult SA continued to manifest lower FEV 1 and worse asthma control as compared with NONSA after TA. In children, after TA only prebronchodilator FEV 1 distinguished SA from NONSA. A total of 21% of adults with SA and 20% of children with SA achieved greater than or equal to 10% improvement after TA. Baseline bronchodilator response and fractional exhaled nitric oxide had good sensitivity and specificity for predicting response in all groups except children with NONSA., Conclusions: One in five patients with SA exhibit greater than or equal to 10% improvement in FEV 1 with parenteral corticosteroid. Those likely to respond had greater bronchodilator responsiveness and fractional exhaled nitric oxide levels. In adults, differences in airflow obstruction and symptoms between SA and NONSA persist after parenteral corticosteroids, suggesting a component of corticosteroid nonresponsive pathobiology in adults with SA that may differ in children. Clinical trial registered with www.clinicaltrials.gov (NCT 01606826).

Importance: Home aeroallergen exposure is associated with increased asthma morbidity in children, yet little is known about the contribution of school aeroallergen exposures to such morbidity., Objective: To evaluate the effect of school-specific aeroallergen exposures on asthma morbidity among students, adjusting for home exposures., Design, Setting, and Participants: The School Inner-City Asthma Study was a prospective cohort study evaluating 284 students aged 4 to 13 years with asthma who were enrolled from 37 inner-city elementary schools in the northeastern United States between March 1, 2008, and August 31, 2013. Enrolled students underwent baseline clinical evaluations before the school year started and were then observed clinically for 1 year. During that same school year, classroom and home dust samples linked to the students were collected and analyzed for common indoor aeroallergens. Associations between school aeroallergen exposure and asthma outcomes during the school year were assessed, adjusting for home exposures., Exposures: Indoor aeroallergens, including rat, mouse, cockroach, cat, dog, and dust mites, measured in dust samples collected from inner-city schools., Main Outcomes and Measures: The primary outcome was maximum days in the past 2 weeks with asthma symptoms. Secondary outcomes included well-established markers of asthma morbidity, including asthma-associated health care use and lung function, measured by forced expiratory volume in 1 second., Results: Among 284 students (median age, 8 years [interquartile range, 6-9 years]; 148 boys and 136 girls), exposure to mouse allergen was detected in 441 (99.5%) of 443 school dust samples, cat allergen in 420 samples (94.8%), and dog allergen in 366 samples (82.6%). Levels of mouse allergen in schools were significantly higher than in students' homes (median settled dust level, 0.90 vs 0.14 µg/g; P < .001). Exposure to higher levels of mouse allergen in school (comparing 75th with 25th percentile) was associated with increased odds of having an asthma symptom day (odds ratio, 1.27; 95% CI, 1.05-1.54; P = .02) and 4.0 percentage points lower predicted forced expiratory volume in 1 second (95% CI, -6.6 to -1.5; P = .002). This effect was independent of allergic sensitization. None of the other indoor aeroallergens were associated with worsening asthma outcomes., Conclusions and Relevance: In this study of inner-city students with asthma, exposure to mouse allergen in schools was associated with increased asthma symptoms and decreased lung function. These findings demonstrate that the school environment is an important contributor to childhood asthma morbidity. Future school-based environmental interventions may be beneficial for this important public health problem.

Background: Home-based interventions to improve indoor air quality have demonstrated benefits for asthma morbidity, yet little is known about the effect of environmental interventions in the school setting., Objective: We piloted the feasibility and effectiveness of a classroom-based air cleaner intervention to reduce particulate pollutants in classrooms of children with asthma., Methods: In this pilot randomized controlled trial, we assessed the effect of air cleaners on indoor air particulate pollutant concentrations in 18 classrooms (9 control, 9 intervention) in 3 urban elementary schools. We enrolled 25 children with asthma (13 control, 12 intervention) aged 6 to 10 years. Classroom air pollutant measurements and spirometry were completed once before and twice after randomization. Asthma symptoms were surveyed every 3 months., Results: Baseline classroom levels of fine particulate matter (particulate matter with diameter of <2.5 μm [PM 2.5 ]) and black carbon (BC) were 6.3 and 0.41 μg/m 3 , respectively. When comparing the intervention to the control group, classroom PM 2.5 levels were reduced by 49% and 42% and BC levels were reduced by 58% and 55% in the first and second follow-up periods, respectively (P < .05 for all comparisons). When comparing the children randomized to intervention and control classrooms, there was a modest improvement in peak flow, but no significant changes in forced expiratory volume in 1 second (FEV 1 ) and asthma symptoms., Conclusions: In this pilot study, a classroom-based air cleaner intervention led to significant reductions in PM 2.5 and BC. Future large-scale studies should comprehensively evaluate the effect of school-based environmental interventions on pediatric asthma morbidity., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Phenotypic presentations in young children with asthma are varied and might contribute to differential responses to asthma controller medications., Methods: The Individualized Therapy for Asthma in Toddlers study was a multicenter, randomized, double-blind, double-dummy clinical trial in children aged 12 to 59 months (n = 300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2- to 8-week run-in period followed by 3 crossover periods with daily inhaled corticosteroids (ICSs), daily leukotriene receptor antagonists, and as-needed ICS treatment coadministered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved 2 stages: determination of differential response and assessment of whether 3 prespecified features (aeroallergen sensitization, previous exacerbations, and sex) predicted a differential response., Results: Seventy-four percent (170/230) of children with analyzable data had a differential response to the 3 treatment strategies. Within differential responders, the probability of best response was highest for a daily ICS and was predicted by aeroallergen sensitization but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophil counts of 300/μL or greater. In these children daily ICS use was associated with more asthma control days and fewer exacerbations compared with the other treatments., Conclusions: In young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophil counts is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with a daily ICS is beneficial despite possible risks of growth suppression., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Rhinosinusitis, is defined as an inflammation of the paranasal and nasal sinus mucosae. Chronic rhinosinusitis (CRS)is a common problem in the pediatric age group and the diagnosis and treatment are challenging due to the chronicity and similarity of symptoms with allergic rhinitis and adenoid hypertrophy. Although it is less common than acute rhinosinusitis, CRS is becoming more frequent and significantly affects the quality of life in children and can substantially impair daily function. CRS is characterized by sinus symptoms lasting more than 3 months despite medical therapy. Many factors are involved in the pathogenesis of this disease and include a primary insult with a virus followed bybacterial infection and mucosal inflammation, along with predisposition to allergies. The standard treatment of pediatricacute bacterial rhinosinusitis (ABRS) is nasal irrigation and antibiotic use. Medical treatment of pediatric CRS includes avoidance of allergens in allergic patients (environmental or food) and therapy with nasal irrigation, nasal corticosteroids sprays, nasal decongestants, and antibiotics directed at the most common sinonasalorganisms (Haemophilusinfluenzae, Streptococcus pneumoniae, and Moraxella catarrhalis). Surgical therapy is rarely needed after appropriate medical therapy. Referral to an otolaryngologist and allergy specialist is recommended in case of failure of medical treatment.

Competing Interests: All authors declare no potential conflicts of interest related to this work.

Background: Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking., Methods: In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial., Results: Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events., Conclusions: Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).

Background: In an effort to reduce barriers to screening for alcohol use in pediatric primary care, the National Institute on Alcoholism and Alcohol Abuse (NIAAA) developed a two-question Youth Alcohol Screening Tool derived from population-based survey data. It is unknown whether this screening tool, designed for use with general populations, accurately identifies risk among youth with chronic medical conditions (YCMC). This growing population, which comprises nearly one in four youth in the US, faces a unique constellation of drinking-related risks., Method: To validate the NIAAA Youth Alcohol Screening Tool in a population of YCMC, we performed a cross-sectional validation study with a sample of 388 youth ages 9-18 years presenting for routine subspecialty care at a large children's hospital for type 1 diabetes, persistent asthma, cystic fibrosis, inflammatory bowel disease, or juvenile idiopathic arthritis. Participants self-administered the NIAAA Youth Alcohol Screening Tool and the Diagnostic Interview Schedule for Children as a criterion standard measure of alcohol use disorders (AUD). Receiver operating curve analysis was used to determine cut points for identifying youth at moderate and highest risk for an AUD., Results: Nearly one third of participants (n = 118; 30.4%) reported alcohol use in the past year; 86.4% (106) of past year drinkers did not endorse any AUD criteria, 6.8% (n = 8) of drinkers endorsed a single criterion, and 6.8% of drinkers met criteria for an AUD. Using the NIAAA tool, optimal cut points found to identify youth at moderate and highest risk for an AUD were ≥ 6 and ≥12 drinking days in the past year, respectively., Conclusions: The NIAAA Youth Alcohol Screening Tool is highly efficient for detecting alcohol use and discriminating disordered use among YCMC. This brief screen appears feasible for use in specialty care to ascertain alcohol-related risk that may impact adversely on health status and disease management.

Importance: Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed., Objective: To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes., Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment., Intervention: Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child's signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12- through 18-month period., Main Outcomes and Measures: The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures., Results: A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00-0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed., Conclusions and Relevance: Among young children with histories of recurrent severe LRTIs, the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy., Trial Registration: clinicaltrials.gov Identifier: NCT01272635.

Background: Endotoxin exposure is associated with airway inflammation. Children spend 6 to 8 h/d in school, yet the effect of school-specific endotoxin exposure on asthma morbidity is not well understood., Methods: In this longitudinal cohort study, 248 students with asthma, from 38 inner-city schools, underwent baseline phenotyping and follow-up. Clinical outcomes were evaluated throughout the academic school year and linked to classroom-specific dust and air endotoxin levels as well as home dust endotoxin levels. The primary outcome was maximum asthma symptom-days per 2-week period., Results: Classrooms had higher settled dust endotoxin levels compared with homes (14.3 endotoxin unit/mg vs 11.3 endotoxin unit/mg; P = .02). Airborne endotoxin levels exceeding recommended occupational exposure limits for adults were recorded in 22.0% of classrooms. Classroom air endotoxin levels were independently associated with increased maximum symptom-days in children with nonatopic asthma, but not in those with atopic asthma (interaction P = .03). Adjusting for home exposures, classroom endotoxin exposure was independently associated with a dose-dependent increase in asthma symptom-days for children with nonatopic asthma (adjusted incidence rate ratio, 1.16 [95% CI, 1.03-1.31]; P = .02). In these subjects, maximum symptom-days increased by 1.3 days for each 14-day period when comparing students in classrooms with the lowest endotoxin levels compared with average measured levels., Conclusions: Inner-city children with asthma are exposed to high levels of airborne endotoxin at school, resulting in increased asthma symptoms in children with nonatopic asthma. Mitigation of school-related exposures may represent a strategy to decrease asthma morbidity in this population., Trial Registry: ClinicalTrials.gov; No.: NCT01756391; URL: www.clinicaltrials.gov.

Aim: The aim of this study was to investigate whether neighborhood safety as perceived by primary caregivers is associated with asthma morbidity outcomes among inner-city school children with asthma., Methods: School children with asthma were recruited from 25 inner-city schools between 2009 and 2012 for the School Inner-City Asthma Study (N = 219). Primary caregivers completed a baseline questionnaire detailing their perception of neighborhood safety and their children's asthma symptoms, and the children performed baseline pulmonary function tests. In this cross-sectional analysis, asthma control was compared between children whose caregivers perceived their neighborhood to be unsafe versus safe., Results: After adjusting for potential confounders, those children whose primary caregivers perceived the neighborhood to be unsafe had twice the odds of having poorly controlled asthma (odds ratio [OR] adjusted = 2.2, 95% confidence interval [CI] = 1.2-3.9, P = 0.009), four times the odds of dyspnea and rescue medication use (OR adjusted = 4.7; 95% CI = 1.7-13.0, P = 0.003, OR adjusted = 4.0; 95% CI = 1.8-8.8, P < 0.001, respectively), three times as much limitation in activity (OR adjusted = 3.2; 95% CI = 1.4-7.7, P = 0.008), and more than twice the odds of night-time symptoms (OR adjusted = 2.2; 95% CI = 1.3-4.0, P = 0.007) compared to participants living in safe neighborhoods. There was no difference in pulmonary function test results between the two groups., Conclusions: Primary caregivers' perception of neighborhood safety is associated with childhood asthma morbidity among inner-city school children with asthma. Further study is needed to elucidate mechanisms behind this association, and future intervention studies to address social disadvantage may be important., (© 2014 Wiley Periodicals, Inc.)

Background: Previous research has found relationships between specific indoor environmental exposures and exacerbation of asthma., Objectives: In this review we provide an updated summary of knowledge from the scientific literature on indoor exposures and exacerbation of asthma., Methods: Peer-reviewed articles published from 2000 to 2013 on indoor exposures and exacerbation of asthma were identified through PubMed, from reference lists, and from authors' files. Articles that focused on modifiable indoor exposures in relation to frequency or severity of exacerbation of asthma were selected for review. Research findings were reviewed and summarized with consideration of the strength of the evidence., Results: Sixty-nine eligible articles were included. Major changed conclusions include a causal relationship with exacerbation for indoor dampness or dampness-related agents (in children); associations with exacerbation for dampness or dampness-related agents (in adults), endotoxin, and environmental tobacco smoke (in preschool children); and limited or suggestive evidence for association with exacerbation for indoor culturable Penicillium or total fungi, nitrogen dioxide, rodents (nonoccupational), feather/down pillows (protective relative to synthetic bedding), and (regardless of specific sensitization) dust mite, cockroach, dog, and dampness-related agents., Discussion: This review, incorporating evidence reported since 2000, increases the strength of evidence linking many indoor factors to the exacerbation of asthma. Conclusions should be considered provisional until all available evidence is examined more thoroughly., Conclusion: Multiple indoor exposures, especially dampness-related agents, merit increased attention to prevent exacerbation of asthma, possibly even in nonsensitized individuals. Additional research to establish causality and evaluate interventions is needed for these and other indoor exposures.

Background: The prevalence of asthma has increased dramatically over the past several decades. While hereditary factors are highly important, the rapid rise outstrips the pace of genomic variation. Great emphasis has been placed on potential modifiable early life exposures leading to childhood asthma., Methods: We reviewed the recent medical literature for important studies discussing the role of the perinatal and early childhood exposures and the inception of childhood asthma., Results and Discussion: Early life exposure to allergens (house dust mite (HDM), furred pets, cockroach, rodent and mold), air pollution (nitrogen dioxide (NO2), ozone (O3), volatile organic compounds (VOCs), and particulate matter (PM)) and viral respiratory tract infections (Respiratory syncytial virus (RSV) and human rhinovirus (hRV)) has been implicated in the development of asthma in high risk children. Conversely, exposure to microbial diversity in the perinatal period may diminish the development of atopy and asthma symptoms., (Copyright © 2014 Elsevier B.V. All rights reserved.)

This review discusses various aspects of social disadvantage and their association with poor asthma control, including socioeconomic status, exposure to psychosocial stress and violence, minority affiliation, environmental concerns such as allergens and pollution, and poverty in rural settings. Each of these elements has been linked with worsened asthma outcomes in children. Known and hypothesized mechanisms behind these associations are described in an effort to further understand the complex entity of poorly controlled asthma among socially deprived children. Intervention studies to improve asthma outcomes in these vulnerable populations are also described., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The prevalence of asthma has increased dramatically over the past several decades. While hereditary factors are highly important, the rapid rise outstrips the pace of genomic variation. Great emphasis has been placed on potential modifiable early life exposures leading to childhood asthma., Methods: We reviewed the recent medical literature for important studies discussing the role of the perinatal and early childhood exposures and the inception of childhood asthma., Results and Discussion: Early life exposure to allergens (house dust mite (HDM), furred pets, cockroach, rodent and mold), air pollution (nitrogen dioxide (NO(2)), ozone (O(3)), volatile organic compounds (VOCs), and particulate matter (PM)) and viral respiratory tract infections (Respiratory syncytial virus (RSV) and human rhinovirus (hRV)) has been implicated in the development of asthma in high risk children. Conversely, exposure to microbial diversity in the perinatal period may diminish the development of atopy and asthma symptoms., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Desktop dust has been studied as a source of food allergen, but not as a source of potential aeroallergen exposure. Thirty-six wiped samples from desktop surfaces were collected from preschools and schools. Samples were analyzed for detectable levels of common aeroallergens including Alternaria, cockroach, dog, dust mite, cat, mouse, and rat allergens by immunoassay. Mouse allergen was the most prevalent, detectable in 97.2% of samples. Cat allergen was detectable in 80.6% of samples, and dog allergen was detectable in 77.8% of samples. Other allergens were not as prevalent. Mouse was the only allergen that was highly correlated with settled floor dust collected from the same rooms (r = 0.721, P < 0.001). This is the first study to detect aeroallergens on desktop surfaces by using moist wipes. Allergens for mouse, cat, and dog were highly detectable in wipes with mouse desktop surface levels correlating with levels in vacuumed floor dust., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)