Peak Flow Feedback Intervention Improves Under-Perception of Airflow Limitation in Pediatric Asthma: A Randomized Clinical Trial.

RATIONALE: Under-perception of asthma symptoms is associated with poor asthma outcomes. OBJECTIVE: We assessed the effects of a behavioral intervention for improving perception of airflow limitation and asthma outcomes. METHODS: A two-arm randomized controlled trial compared peak expiratory flow (PEF) feedback versus supportive counseling. Latino and Black adolescents with asthma ages 10-17 years old and caregivers were recruited from hospitals in the Bronx, NY. PEF feedback sessions reviewed accuracy of PEF guesses and medication adherence data, and targeted behavior change using motivational interviewing and problem-solving skills training. Supportive counseling received emotional support related to asthma. Both groups received 3 sessions across 6 weeks. All participants were blinded to PEF while guessing PEF during pre-intervention, 1, 6, and 12-month follow-up. Children in PEF feedback saw actual PEF after guesses were locked in during the 6-week intervention. Participants and assessors were blinded to group assignment. MEASUREMENTS: The primary outcome was under-perception of airflow limitation (divergence between actual PEF and guesses) on home spirometers. Secondary outcomes included daily PEF and forced expiratory volume in 1 second (FEV1), inhaled corticosteroid adherence measured by electronic monitors, Asthma Control Test, and emergency healthcare use for asthma. RESULTS: The sample comprised 354 children (M = 13.2±2.2 years; 62% Latino, 38% Black) and caregivers. PEF feedback (N = 153 analyzed) demonstrated greater improvements at 1-month follow-up on under-perception of airflow limitation (difference-in-differences, -12.64; 95% CI, -17.54 to -7.74), % personal best PEF (9.89; 95% CI, 7.13 to 12.65), % predicted FEV1 (4.93; 95% CI, 0.95 to 8.90) and ICS adherence (16.02; 95% CI, 7.15 to 24.89) compared with supportive counseling (N = 152 analyzed). At 12-month follow-up PEF feedback maintained improvements on under-perception of airflow limitation (-13.87; 95% CI, -19.03 to -8.71), higher PEF (14.23; 95% CI, 11.37 to 17.08) and %FEV1 (5.62; 95% CI, 1.56 to 9.67), and had smaller declines in ICS adherence (17.51; 95% CI, 7.12 to 27.89) versus pre-intervention than supportive counseling. No between-group differences existed for asthma control or healthcare use. CONCLUSION: The efficacy and sustainability of PEF feedback was established in improving children's perception of airflow limitation, pulmonary function, and medication adherence. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT02702687.

A clinician's guide to effects of obesity on childhood asthma and into adulthood.

INTRODUCTION: Obesity, one of the most common chronic conditions affecting the human race globally, affects several organ systems, including the respiratory system, where it contributes to onset and high burden of asthma. Childhood onset of obesity-related asthma is associated with high persistent morbidity into adulthood. AREAS COVERED: In this review, we discuss the disease burden in children and adults to highlight the overlap between symptoms and pulmonary function deficits associated with obesity-related asthma in both age ranges, and then discuss the potential role of three distinct mechanisms, that of mechanical fat load, immune perturbations, and of metabolic perturbations on the disease burden. We also discuss interventions, including medical interventions for weight loss such as diet modification, that of antibiotics and anti-inflammatory therapies, as well as that of surgical intervention on amelioration of burden of obesity-related asthma. EXPERT OPINION: With increase in obesity-related asthma due to increasing burden of obesity, it is evident that it is a disease entity distinct from asthma among lean individuals. The time is ripe to investigate the underlying mechanisms, focusing on identifying novel therapeutic targets as well as consideration to repurpose medications effective for other obesity-mediated complications, such as insulin resistance, dyslipidemia and systemic inflammation.

Real-world phenotyping and risk assessment of childhood asthma burden using national registries.

BACKGROUND: Phenotype classification contributes to risk assessment of asthma. Previous studies have applied this concept primarily to adult populations and in the setting of research protocol assessments which may not be applicable to clinical settings. OBJECTIVE: Exploring the value of routinely collected clinical data for phenotype classification and risk assessment of childhood asthma. METHODS: Using hospital and laboratory data, 29,851 children in a Danish nationwide database aged 2-17 years with ICS-treated asthma in 2015 followed for two years (730 days) were classified to have T2 (elevated blood eosinophils (>300 cells/µL) and/or elevated total- or specific-IgE), and/or non-T2 risk factors (in utero tobacco exposure and/or severe viral infections). Logistic regression was applied to quantify associations of risk factors with asthma severity, control, and exacerbation risk. RESULTS: In a complete case analysis, 85.8 % children had at least one T2 risk factor and 29.3 % had mixed T2/non-T2 risk factors. Elevated blood eosinophils and total/specific IgE were associated with exacerbations (ORs 1.55 (1.38-1.73) and 1.41 (1.20-1.66) and higher asthma severity (1.42 (1.24-1.63) and 1.31 (1.08-1.60)), respectively. Dose-dependency was observed between blood eosinophil counts, total IgE levels, and risk of adverse outcomes. Furthermore, accumulation of risk factors demonstrated an increasing risk, with children with all four risk factors having a high risk of any adverse asthma-related outcome (OR 3.13 (2.03-4.82) CONCLUSION: Asthma phenotypic markers defined in research protocols can be reliably applied in real-world settings by utilizing data collected during routine clinical care and enable better classification of risk of adverse asthma outcomes.

Single-cell analysis identifies distinct CD4+ T cells associated with the pathobiology of pediatric obesity-related asthma.

Pediatric obesity-related asthma is characterized by non-atopic T helper 1 (Th1) inflammation and steroid resistance. CDC42 upregulation in CD4+T cells underliesTh1 inflammation but the CD4+T cell subtype(s) with CDC42 upregulation and their contribution to steroid resistance are not known. Compared to healthy-weight asthma, obesity-alone and healthy-weight controls, single-cell transcriptomics of obese asthma CD4+T cells revealed CDC42 upregulation in 3 clusters comprised of naïve and central memory T cells, which differed from the cluster enriched for Th1 responses that was comprised of effector T cells. NR3C1, coding for glucocorticoid receptor, was downregulated, while genes coding for NLRP3 inflammasome were upregulated, in clusters with CDC42 upregulation and Th1 responses. Conserved genes in these clusters correlated with pulmonary function deficits in obese asthma. These findings suggest that several distinct CD4+T cell subtypes are programmed in obese asthma for CDC42 upregulation, Th1 inflammation, and steroid resistance, and together contribute to obese asthma phenotype. Summary: CD4+T cells from obese children with asthma are distinctly programmed for non-allergic immune responses, steroid resistance and inflammasome activation, that underlie the obese asthma phenotype.

Impact of family socioeconomic position on childhood asthma outcomes, severity, and specialist referral - a Danish nationwide study.

BACKGROUND: Asthma is the most common chronic illness in children, carrying a major burden. Socioeconomic position (SEP) affects adult asthma outcomes, but its impact on childhood asthma, particularly in primary versus specialist care, has not been studied thoroughly. METHODS: In a Danish cohort consisting of all children aged 2-17 years redeeming inhaled corticosteroids in 2015, parental SEP impact on asthma outcomes was investigated. Workforce attachment, income, education, and metropolitan residence were chosen as covariates in logistic regression. Outcomes were uncontrolled (excessive use of short-acting beta2-agonists), exacerbating (oral corticosteroid use or hospitalization), and severe asthma (according to GINA 2020). RESULTS: The cohort comprised 29,851 children (median age 8.0, 59% boys). 16% had uncontrolled asthma, 8% had ≥1 exacerbation. Lower income and metropolitan residence correlated with higher odds of poor control, exacerbations, and severe asthma. Lower education correlated with worse asthma outcomes. Education and income were protective factors in primary care, but not in specialist care. Metropolitan residence was the sole factor linked to specialist care referral for severe asthma. CONCLUSION: Low parental SEP and metropolitan residence associated with poor asthma outcomes. However, specialist care often mitigated these effects, though such care was less likely for at-risk children in non-metropolitan areas.

Asthma prevalence among US 9th-12th graders who report past 30-day cannabis use in 2019.

INTRODUCTION: Little is known about the relationship between cannabis use and asthma among youth in the US. The aims of this study were to estimate prevalence of asthma among youth who reported any cannabis use in the past 30 days, relative to those who did not, and to investigate the relationship between frequency of cannabis use and prevalence of asthma, adjusting for demographic characteristics and cigarette use. METHODS: Data were drawn from the 2019 Youth Risk Behavior Surveillance System (YRBSS), a CDC national high school survey, which collects data from students in grades 9-12 across the US bi-annually. Logistic regression was used to examine the prevalence of asthma among youth who reported any past 30-day cannabis use, relative to no use, and by frequency of cannabis use, adjusting for demographic characteristics and cigarette use. RESULTS: Asthma was more common among youth who reported any cannabis use, relative to youth who reported no use (29.07% vs. 23.62%; AOR = 1.25 (1.20, 1.30)). Asthma was greater among youth who reported more frequent cannabis use; asthma was highest among youth who reported having used cannabis "40 or more times" in the month (31.38%; AOR = 1.35 (1.25, 1.45)) CONCLUSION: Asthma is more common among youth who use cannabis, relative to those who do not, and the prevalence of asthma increases with frequency of use among 9th-12th graders in the US. More public health and clinical research is needed quickly to produce scientific data that can inform clinical guidelines and public health policy, as well as parents and youth, on the potential relationship between cannabis use and respiratory health among youth.

Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma.

BACKGROUND: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits. OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes. METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen. RESULTS: Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10-7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10-6) and PIK3R6 with eosinophil count (P = 4.10 × 10-5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge. CONCLUSIONS: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.

Immune profile of adipose tissue from youth with obesity and asthma.

BACKGROUND: Obesity is a risk factor for paediatric asthma. Obesity-mediated systemic inflammation correlates with metabolic dysregulation; both are associated with asthma burden. However, adipose tissue inflammation is not defined in obesity-related asthma. OBJECTIVE: Define adipose tissue inflammation and its association with metabolic measures in paediatric obesity-related asthma. METHODS: Cellular profile of stromal vascular fraction from visceral adipose tissue (VAT) from youth with obesity-related asthma (n = 14) and obesity without asthma (n = 23) was analyzed using flow cytometry and correlated with metabolic measures. RESULTS: Compared to youth without asthma, VAT from youth with obesity-related asthma was enriched for leukocytes and macrophages, including M1 and dual M1M2 cells, but did not differ for CD4+ lymphocytes, and endothelial cells, their progenitors, and preadipocytes. M1 macrophage counts positively correlated with glucose, while M1M2 cells, CD4+ lymphocytes, and their subsets negatively correlated with high-density lipoprotein, in youth with obesity without asthma, but not among those with obesity-related asthma. CONCLUSIONS: Enrichment of macrophage-mediated inflammation in VAT from youth with obesity-related asthma supports its role in systemic inflammation linked with asthma morbidity. Lack of correlation of VAT cells with metabolic dysregulation in youth with obesity-related asthma identifies a need to define distinguishing factors associated with VAT inflammation in obesity-related asthma.

Cannabis use and the prevalence of current asthma among adolescents and adults in the United States.

OBJECTIVES: Cannabis use has increased among adolescents and adults in the United States (US) in recent years. Few data are available on the prevalence of asthma by frequency of cannabis use. This study aimed to estimate the prevalence of asthma by frequency of past 30-day cannabis use among US individuals. METHODS: Data were drawn from the 2020 National Survey on Drug Use and Health (NSDUH), a nationally representative, annual cross-sectional survey of US individuals aged 12 and older in the United States (N = 32,893). Logistic regression models were used to examine the relationship between frequency of any cannabis and/or blunt (i.e., cannabis smoked in a hollowed-out cigar) use in the past 30 days and current asthma, adjusting for demographics and current cigarette smoking. RESULTS: Current asthma was more common among US individuals who reported cannabis use in the past 30-days, relative to those who did not (9.8% vs. 7.4%, p < 0.0001). The odds of asthma was significantly greater among individuals reporting cannabis use 20-30 days/month (Adjusted Odds Ratio [AOR] = 1.67, 95% CI:1.21, 2.31), blunt use 6-15 and 20-30 days/month (AOR = 1.9, 95% CI:1.1, 3.2; AOR = 2.2, 95% CI:1.4, 3.6), respectively, than among those without. A positive linear relationship was observed between frequency of a) cannabis use (p < 0.0001) and b) blunt use (p < 0.0001) and current asthma prevalence. CONCLUSIONS: Findings suggest a dose-response relationship between frequency of current cannabis use and the prevalence of current asthma in the US individuals.

Attention-Deficit Hyperactivity Disorder Symptoms, Underperception of Respiratory Compromise, and Illness Representations in Black and Latino Children With Asthma.

OBJECTIVE: This study examined the associations between attention-deficit/hyperactivity disorder (ADHD) symptoms, underperception of respiratory compromise, and illness representations in Black and Latino children with asthma. We hypothesized that increased child-reported ADHD symptoms, as well as parent reports for their child, would be associated with underperception of respiratory compromise, and maladaptive asthma beliefs. METHODS: Two hundred ninety-six parent-child dyads were recruited from pediatric asthma and primary care clinics in the Bronx. Participants completed demographic questionnaires, the Conners-3 ADHD Index to measure ADHD symptoms, and the Asthma Illness Representation Scale to assess asthma beliefs. Perception of respiratory compromise was assessed by programmable electronic peak flow monitors that measured the child's subjective estimates of peak expiratory flow (PEF) and actual PEF, with underperception as the primary measure. RESULTS: Child-reported ADHD symptoms were associated with greater underperception (ß = .117, p = .049) of respiratory compromise. Parent-reported ADHD symptoms were associated with greater underperception (ß = .129, p = .028) of respiratory compromise. Child-reported ADHD symptoms (ß = -.188, p < .001) were associated with more maladaptive asthma beliefs, F(1, 341) = 13.135. Parent-reported ADHD symptoms (ß = -.203, p ≤ .001) were associated with more maladaptive asthma beliefs, F(1, 341) = 15.644. CONCLUSIONS: ADHD symptoms were associated with a greater underperception of respiratory compromise and more maladaptive asthma beliefs. Deficits of attentional processes and/or hyperactivity levels might be contributing factors. We emphasize the need for psychoeducation and interventions that improve perception and health beliefs in children with comorbid ADHD and asthma.

Childhood Asthma and Parental Antidepressant Use in a Nationwide Danish Cohort.

Background: Paediatric asthma is associated with caregiver depression, which in turn is associated with poor asthma control. Although sociodemographic risk factors are associated with parental depression among children with asthma, the contribution of these factors to caregiver depression in free-to-access universal healthcare settings is unknown. Methods: The association between childhood asthma and parental antidepressant use was investigated in a Danish nationwide cohort of children aged 2-17 years that redeemed inhaled corticosteroids in 2015. The odds of antidepressant use were estimated in comparison to control families that were matched 1:1 on the number of siblings, residence, income, and education. Results: Among the families of 28,595 children with actively treated asthma, 12% of mothers and 6.2% of fathers were on antidepressant therapy, compared to 9.3% and 5.3% in controls (p<0.001). Paediatric asthma was associated with increased odds of parental antidepressant use (OR 1.29 (1.23-1.35)), even after adjusting for parental asthma. Poor asthma control, but not higher asthma severity, was associated with higher odds of antidepressant use (1.43 (1.31-1.56)). Compared with the controls, families with two or more children with asthma had higher OR (1.42 (1.29-1.56)) than those with a single child (OR 1.27 (1.21-1.34)). Low socioeconomic status was associated with parental antidepressant use. Conclusion: Caregiver depression in a Danish cohort is more prevalent among mothers than among fathers and is associated with poor asthma control in children. Antidepressant use among caregivers was associated with total family asthma burden and was independent of socioeconomic status.

Burden and unmet need for specialist care in poorly controlled and severe childhood asthma in a Danish nationwide cohort.

BACKGROUND: Asthma is a common disease in childhood and adolescence with lifelong consequences particularly among those at risk of severe disease, poor control and/or frequent exacerbations. Specialist care is recommended for at-risk children and adolescents, yet access to specialist management in free-to-access healthcare settings remains poorly understood. METHODS: A Danish nationwide cohort of children and adolescents aged 2-17 years with persistent asthma, defined as repeated redemption of inhaled corticosteroids (ICS) during 2015, were followed for two years, to identify at-risk children and adolescents comprising those with severe asthma (classified according to GINA 2020 guidelines), poor control (defined as use of 400/600 (ages 2-11/12 +) annual doses of short-acting bronchodilators), or frequent exacerbations (defined as use of oral steroids or hospitalization), and access to specialist care. The population is chosen due to detailed medical records in the setting of universal health care. RESULTS: The cohort comprised of 29,851 children and adolescents (59% boys), with a median age of 9 years. While 17% of children were on high dose ICS, 22% were on daily ICS below GINA low dose cut-off. Prevalence of severe asthma (3.0-6.5%) was lower than poor asthma control (6.4-25%); both declined from childhood to adolescence. Exacerbations occurred in 7.1-9.0% of children, with median number of exacerbations being 1 (IQR 1-1). Despite being classified as having mild-to-moderate asthma, 15% had poor asthma control and 3.8% experienced exacerbation(s), respectively. While 61% of children with severe asthma and 58% with exacerbation-prone disease were in specialist care, only 24% with uncontrolled disease were receiving specialist care. Of children and adolescents using high-dose ICS, 71% were managed in primary care, while the use of additional controllers was more common in specialist care. CONCLUSIONS: Throughout childhood and adolescence, there was a high prevalence of severe asthma and poor control, although their prevalence declined with age. We demonstrate a large unmet need for specialist care among children with at-risk asthma, particularly among those with poorly controlled asthma, even in a system with free-to-access, tax-funded healthcare.

Carnitine supplementation increases serum concentrations of free carnitine and total acylcarnitine in preterm neonates: A retrospective cohort study.

OBJECTIVE: Our goal was to determine the efficacy of the American Society for Parenteral and Enteral Nutrition's recommended carnitine dosage of 5 mg/kg/day in maintaining normal serum free carnitine and total acylcarnitine levels in preterm neonates receiving parenteral nutrition (PN). STUDY DESIGN: A retrospective cohort study was conducted on neonates born <30 weeks gestation and weighing <1250 g, comparing those who received carnitine supplementation to those without supplementation. Free carnitine and total acylcarnitine data were collected from routine newborn screens in the first days of life and on full enetral feeds. Univariate analysis was performed, and those factors that were significantly different between the two groups were adjusted for using mixed effects analysis. RESULTS: There were 108 supplemented and 45 unsupplemented neonates in the study. At baseline, free carnitine (19.8 ± 3.3 vs 18.9 ± 3.7 µmol/L, P = 0.53) and total acylcarnitine (26.6 ± 5.1 vs 22.5 ± 7.1 µmol/L, P = 0.11) were similar between the two groups. At full enteral feeds, compared with unsupplemented group, supplemented infants had significantly higher free carnitine (27.1 ± 16.4 vs 17.1 ± 8.5 µmol/L, P < 0.001) and total acylcarnitine (30.3 ± 11.5 vs 20.2 ± 10.1 µmol/L, P < 0.001). None of the supplemented neonates developed biochemical carnitine deficiency as compared with 18% in the unsupplemented group (P < 0.001). No difference was observed in time to reach full lipid provision, and there were no differences in the change in the triglyceride levels from baseline to the time on full PN lipid provision (P = 0.39). CONCLUSION: Preterm neonates routinely supplemented with parenteral carnitine at 5 mg/kg/day demonstrated higher free carnitine and total acylcarnitine levels at full feeds, with none developing biochemical carnitine deficiency.

Complications associated with incorrect use of nasal CPAP.

Nasal continuous positive airway pressure (nCPAP) is a safe, effective, non-invasive respiratory modality to deliver positive end expiratory pressure in neonates. Many studies have established its associated improved respiratory outcomes without increase in major morbidities associated with preterm neonates. In contrast, there is paucity in literature addressing complications such as nasal injury, abdominal distention, air leak syndromes (especially pneumothorax), hearing loss, heat and chemical burns, swallowing and aspiration of small components of the nasal interface and delay in escalation of respiratory support associated with the use of nCPAP, most frequently due to its incorrect use. This is a comprehensive review that seeks to address the different complications that are associated with the incorrect use of nCPAP highlighting that these are operator-related and not device-related.

The Relationship Between Pediatric Attention-Deficit/Hyperactivity Disorder Symptoms and Asthma Management.

PURPOSE: Children with comorbid Attention-Deficit/Hyperactivity Disorder (ADHD) and asthma are at an increased risk for adverse health outcomes and reduced quality of life. The objective of these analyses was to examine if self-reported ADHD symptoms in children with asthma are associated with asthma control, asthma controller medication adherence, quick relief medication use, pulmonary function, and acute healthcare utilization. METHODS: We analyzed data from a larger study testing a behavioral intervention for Black and Latinx children with asthma aged 10-17 years and their caregivers. Participants completed the Conners-3AI self-report assessment for ADHD symptoms. Asthma medication usage data were collected for 3 weeks following baseline via electronic devices fitted to participants' asthma medications. Other outcome measures included the Asthma Control Test, self-reported healthcare utilization, and pulmonary function measured by spirometry testing. RESULTS: The study sample consisted of 302 pediatric participants with an average age of 12.8 years. Increased ADHD symptoms were directly associated with reduced adherence to controller medications, but no evidence of mediation was observed. Direct effects of ADHD symptoms on quick-relief medication use, health care utilization, asthma control, or pulmonary function were not observed. However, the effect of ADHD symptoms on emergency room visits was mediated by controller medication adherence. DISCUSSION: ADHD symptoms were associated with significantly reduced asthma controller medication adherence and indirectly with emergency room visits. There are significant potential clinical implications to these findings, including the need for the development of interventions for pediatric asthma patients with ADHD.

Risk Factors for Pneumothorax and Its Association with Ventilation in Neonates.

OBJECTIVE: The mode of ventilation that is implicated in pneumothorax is the one at the time of its diagnosis. Although there is evidence that air leak starts many hours before it is clinically evident, there are no prior studies that have investigated the association of pneumothorax with the mode of ventilation few hours before rather than at the time of its diagnosis. STUDY DESIGN: A retrospective case-control study was conducted in the neonatal intensive care unit (NICU) between 2006 and 2016 where cases of neonates with pneumothorax were compared with gestational age-matched control neonates without pneumothorax. Respiratory support associated with pneumothorax was classified as the mode of ventilation 6 hours before the clinical diagnosis of pneumothorax. We investigated the factors that were different between cases and controls, and between cases of pneumothorax on bubble continuous positive airway pressure (bCPAP) and invasive mechanical ventilation (IMV). RESULT: Of the 8,029 neonates admitted in the NICU during the study period, 223 (2.8%) developed pneumothorax. Among these, 127 occurred among 2,980 (4.3%) neonates on bCPAP, 38 among 809 (4.7%) neonates on IMV, and the remaining 58 among 4,240 (1.3%) neonates on room air. Those with pneumothorax were more likely to be male, have higher body weight, require respiratory support and surfactant administration, and have bronchopulmonary dysplasia (BPD). Among those who developed pneumothorax, there were differences in the gestational age, gender, and use of antenatal steroids between those who were on bCPAP as compared to those on IMV. IMV was associated with increased odds of pneumothorax as compared to those on bCPAP in a multivariable regression analysis. Cases on IMV had higher incidence of intraventricular hemorrhage, retinopathy of prematurity, BPD, and necrotizing enterocolitis, as well as longer length of stay as compared to those on bCPAP. CONCLUSION: Neonates who require any respiratory support have higher incidence of pneumothorax. Among those on respiratory support, those on IMV had higher odds of pneumothorax and worse clinical outcomes as compared to those on bCPAP. KEY POINTS: · The process of air leak leading to pneumothorax in majority of neonates starts much before it is clinically diagnosed.. · It is possible to detect the air leak early in the process by subtle changes in the signs, symptoms and changes in lung function.. · True association of the ventilation associated with pneumothorax is not at the time of diagnosis of pneumothorax but few hours before it is diagnosed.. · There is higher incidence of pneumothorax in neonates on any respiratory support.. · There is significantly higher incidence of pneumothorax among neonates on invasive ventilations as compared to noninvasive ventilation after correction for all other clinical factors..

Metabolic Contributions to Pathobiology of Asthma.

Asthma is a heterogenous disorder driven by inflammatory mechanisms that result in multiple phenotypes. Given the complex nature of this condition, metabolomics is being used to delineate the pathobiology of asthma. Metabolomics is the study of metabolites in biology, which includes biofluids, cells, and tissues. These metabolites have a vital role in a disease as they contribute to the pathogenesis of said condition. This review describes how macrometabolic and micrometabolic studies pertaining to these metabolites have contributed to our current understanding of asthma, as well as its many phenotypes. One of the main phenotypes this review will discuss in further detail is obesity as well as diabetes. Distinct roles of metabolites in endotyping asthma and their translation to potential therapy development for asthma is also discussed in this review.

Mechanistic Links Between Obesity and Airway Pathobiology Inform Therapies for Obesity-Related Asthma.

Obesity-related asthma is associated with a high disease burden and a poor response to existent asthma therapies, suggesting that it is a distinct asthma phenotype. The proposed mechanisms that contribute to obesity-related asthma include the effects of the mechanical load of obesity, adipokine perturbations, and immune dysregulation. Each of these influences airway smooth muscle function. Mechanical fat load alters airway smooth muscle stretch affecting airway wall geometry, airway smooth muscle contractility, and agonist delivery; weight loss strategies, including medically induced weight loss, counter these effects. Among the metabolic disturbances, insulin resistance and free fatty acid receptor activation influence distinct signaling pathways in the airway smooth muscle downstream of both the M2 muscarinic receptor and the ß2 adrenergic receptor, such as phospholipase C and the extracellular signal-regulated kinase signaling cascade. Medications that decrease insulin resistance and dyslipidemia are associated with a lower asthma disease burden. Leptin resistance is best understood to modulate muscarinic receptors via the neural pathways but there are no specific therapies for leptin resistance. From the immune perspective, monocytes and T helper cells are involved in systemic pro-inflammatory profiles driven by obesity, notably associated with elevated levels of interleukin-6. Clinical trials on tocilizumab, an anti-interleukin antibody, are ongoing for obesity-related asthma. This armamentarium of therapies is distinct from standard asthma medications, and once investigated for its efficacy and safety among children, will serve as a novel therapeutic intervention for pediatric obesity-related asthma. Irrespective of the directionality of the association between asthma and obesity, airway-specific mechanistic studies are needed to identify additional novel therapeutic targets for obesity-related asthma.

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; ßz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; ß = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.