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Childhood exposure to nitrogen oxides (NOx) is considered a risk factor for the onset of asthma. However, associations of this exposure with other atopic diseases and factors that modify this association are less clear. We aimed to study associations between exposure to NOx and the prevalence of atopic diseases in Israeli adolescents using a cross-sectional design. The study population comprised all Israeli-born adolescents whose medical status was evaluated for mandatory military recruitment during 1967-2017 (n = 2,523,745), of whom 5.9% had prevalent asthma. We based the exposure assessments on a land-use regression model and estimated associations using multivariable logistic regression models. Across all periods, mean exposure to NOx from birth to adolescence was associated with prevalent asthma at the examination in a dose-response manner, with an odds ratio for the upper quintile of 1.61 (95% CI: 1.56-1.67), in comparison to the lowest quintile. Associations were stronger in males and in lower socioeconomic strata. We found the strongest associations for asthma with comorbid rhinitis, with an almost twofold increase in the odds of upper versus lower quintile of exposure (odds ratio = 1.96, 95% CI: 1.82-2.11). Rhino-conjunctivitis and allergic atopic dermatitis suggested a possible threshold level with NOx. Capsule Summary: Research indicates that half of the global population will suffer from an allergic condition at some point in life. Childhood exposure to nitrogen oxides is a risk factor for the onset of asthma. The association between exposure and allergic diseases other than asthma is unclear. We demonstrate a strong, dose-response relationship between exposure and a group of allergic outcomes, using data comprising 2.5 million subjects over 50 years. The large health benefits from clean air should motivate governments to prioritize mitigation measures. [ABSTRACT FROM AUTHOR]

Rationale: Ivacaftor's clinical effects in the residual function mutations 3849 + 10kb C→T and D1152H warrant further characterization.Objectives: To evaluate ivacaftor's effect in people with cystic fibrosis aged ≥6 years with 3849 + 10kb C→T or D1152H residual function mutations and to explore the correlation between ivacaftor-induced organoid-based cystic fibrosis transmembrane conductance regulator function measurements and clinical response to ivacaftor.Methods: Participants were randomized (1:1) in this placebo-controlled crossover study; each treatment sequence included two 8-week treatments with an 8-week washout period. The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 8. Additional endpoints included lung function, patient-reported outcomes, and in vitro intestinal organoid-based measurements of ivacaftor-induced cystic fibrosis transmembrane conductance regulator function.Results: Of 38 participants, 37 completed the study. The primary endpoint was met; the Bayesian posterior probability of improvement in lung clearance index2.5 with ivacaftor versus placebo was >99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor's known safety profile. Dose-dependent swelling was observed in 23 of 25 viable organoid cultures with ivacaftor treatment. Correlations between ivacaftor-induced organoid swelling and clinical endpoints were negligible to low.Conclusions: In people with cystic fibrosis aged ≥6 years with a 3849 + 10kb C→T or D1152H mutation, ivacaftor treatment improved clinical endpoints compared with placebo; however, there was no correlation between organoid swelling and change in clinical endpoints. The organoid assay may assist in identification of ivacaftor-responsive mutations but in this study did not predict magnitude of clinical benefit for individual people with cystic fibrosis with these two mutations.Clinical trial registered with ClinicalTrials.gov (NCT03068312). [ABSTRACT FROM AUTHOR]

Objectives: Insufficient sleep affects circadian hormonal profiles and inflammatory markers and may modulate attention, executive functioning and decision‐making. Medical professionals and specifically resident physicians, who are involved in long‐term nightshift schedules during their post‐graduate training, are prone to acute and chronic sleep deprivation and disruption, putting them at risk for making medical errors. The aim of the study was to evaluate the impact of chronic and acute‐on‐chronic sleep deprivation and disruption among residents on selected physiological and cognitive measures. Methods: Thirty‐three medical and surgical residents were evaluated twice ‐ at baseline and after a 26‐hour shift. Eighteen young attending physicians who did not engage in nightshift schedules served as controls and were evaluated once. Measures included morning cortisol and high‐sensitivity C‐reactive protein (hs‐CRP), computerised tests of attention and behaviour, the Behaviour Rating Inventory of Executive Function, a risk‐taking questionnaire and the Pittsburgh Sleep Quality Index. Results: Residents, but not attendings, reported chronic sleep disruption and deprivation. Residents at baseline exhibited reduced morning cortisol levels and elevated hs‐CRP levels, compared to attendings. Residents at baseline had impaired global executive function compared to attendings. A nightshift with acute sleep deprivation further reduced residents' executive function. Residents at baseline and after a nightshift demonstrated increased impulsivity and slower processing time than attendings. Residents and attendings did not differ in risk‐taking tendencies which were assessed in a separate cohort. Conclusions: In a real‐life setting, resident physicians exhibit increased low‐grade systemic inflammation (hs‐CRP) and impaired HPA‐axis function. Their chronic sleep curtailment is associated with greater impulsivity, slower cognitive processing, and impaired executive function. Future research is warranted to understand how improving working schedule by increasing sleep duration may minimise the short‐term and potential long‐term risks to physicians in training. The authors demonstrate that not only does chronic sleep deprivation impair a variety of mental and physical functions, but some effects are further aggravated by the acute sleep restriction of night calls. [ABSTRACT FROM AUTHOR]

Haifa Bay Area (HBA) contains Israel's principal industrial area, and there are substantial public concerns about health effects from its emissions. We aimed to examine associations between exposure to air pollution from HBA industrial area with prevalent asthma and other atopic diseases at age 17. This is a cross-sectional study. The study population included all adolescents born in Israel and whose medical status was evaluated for mandatory military recruitment by the Israeli medical corps during 1967–2017. We analyzed prevalent asthma, allergic rhinitis, atopic dermatitis, and rhinoconjunctivitis. We estimated exposure to industrial air pollution by a kriging interpolation of historical SO2 observations and adjusted the associations to the year of birth, SES, school orientation, and traffic pollution. The study population included n = 2,523,745 adolescents, among which 5.9% had prevalent asthma and 4.6% had allergic rhinitis. Residency in HBA was associated with a higher adjusted risk of asthma, compared with non-HBA residency. Still, this association was limited to the three lowest exposure categories, while the highest exposure group had the lowest adjusted risk. Sensitivity analyses and other atopic diseases presented similar results. These results do not provide support for causal relationships between HBA industry-related emissions and prevalent atopic diseases. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxic environments at the cellular level and is an independent risk factor for the development of cardiovascular disease. Endothelial cell (EC) dysfunction precedes the development of cardiovascular disease; however, the mechanisms by which ECs respond to these intermittent hypoxic events are poorly understood. To better understand EC responses to hypoxia, we examined the effects of sustained hypoxia (SH) and intermittent hypoxia (IH) on the activation of HIF-1α in ECs. While SH stabilized HIF-1α and led to its nuclear localization, IH did not activate HIF-1α and the expression of its target genes. Using RNA-sequencing, we evaluated transcriptional responses of ECs to hypoxia. SH induced the expression of HIF-1α and hypoxia response genes, while IH affected cell-cycle regulation genes. A cytoscape protein-protein interaction network for EC response to hypoxia was created with differentially expressed genes. The network comprises cell-cycle regulation, inflammatory signaling via NF-κB and response to VEGF stimulus subnetworks on which SH and IH had distinct activities. As OSA is associated with elevated catecholamines, we investigated the effect of epinephrine on the EC response to SH and IH. Transcriptomic responses under IH and epinephrine revealed protein-protein interaction networks emphasizing distinct subnetworks, including cytokine-mediated TNFα signaling via NF-κB, Wnt/LRP/DKK signaling and cell cycle regulation. This study reveals differential transcriptomic responses under SH and IH characterised by HIF-1α transcriptional response induced only by SH, but not by IH. The study also features the potential molecular events that may occur at the vascular level in OSA.

Background: Preterm infants suffer from significant respiratory morbidity during the first years of life, but the underlying lung pathophysiology is not fully understood. This study aimed to comprehensively characterize the pulmonary functions of preterm infants using full infant pulmonary function testing (iPFT)., Methods: Between 2008 and 2019, we recruited 150 infants (M age 10.5 ± 6 months) of them 104 preterm infants (median gestational age [GA] = 34 weeks (28-36), n = 23 with bronchopulmonary disease [BPD]) and 46 controls born at term. We compared full iPFT parameters of preterm infants to a control group of term infants. Subanalysis included a comparison of preterm infants by BPD status and GA., Results: Preterm infants had impaired flow parameters, reduced compliance, and air trapping, compared to term infants. Only 15% (n = 14) of the preterm group had normal iPFT, compared to 69% (n = 31) of the term group. The majority of the impaired iPFT in preterm infants were obstructive and 72% (n = 69) had no response to bronchodilators. Reduced maximal flow at the functional residual capacity point (V' max FRC) was associated with low birth weight and GA. There were no major differences between preterm infants with or without BPD., Conclusions: Preterm infants in the first year of life, demonstrated a high prevalence of obstructive iPFT unresponsive to bronchodilators. BPD status did not add to the degree of pulmonary impairment. These data reveal an airway-predominant pathology of the modern-era prematurity-associated lung disease. Pulmonary function screening tests at an early age may be of value in determining the presence and severity of lung disease in the preterm population. V' max FRC may provide a good assessment of pulmonary impairment in preterm infants., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Study Objectives: Behavioral insomnia of childhood (BIC) and obstructive sleep apnea (OSA) are highly prevalent conditions affecting 10%-20% and 1%-5% of children, respectively. Studies in adults and adolescents have suggested that comorbid insomnia and OSA may have distinct clinical characteristics. The association between the two conditions in the pediatric population has not been thoroughly investigated. This study aimed to examine the association between BIC and OSA in young children., Methods: Children, 6 months to 10 years old, referred to a sleep specialist and polysomnography at the Hadassah Medical Center between 2018 and 2021 were included in this retrospective analysis. We excluded children with chromosomal and craniofacial abnormalities, posttonsillectomy, or neurological impairment. BIC diagnosis was extracted from the electronic health records in accordance with the International Classification of Sleep Disorders , third edition criteria. OSA was diagnosed by polysomnography (apnea-hypopnea index > 2 events/h)., Results: Of 312 children (age 4.42 ± 2.42 years), 126 (40.4%) were non-OSA non-BIC, 125 (40.1%) OSA non-BIC, 34 (10.9%) BIC non-OSA, and 27 (8.7%) comorbid insomnia and OSA. OSA and non-OSA children had a similar prevalence of BIC. Children in the comorbid insomnia and OSA group were significantly younger (2.22 ± 1.21 years). Younger age at polysomnography, premature birth, and increased periodic leg movements on polysomnography were independently associated with OSA in a multivariable analysis. Lower body mass index, regardless of OSA, was associated with BIC., Conclusions: Current findings do not support an association between behavioral insomnia of childhood and obstructive sleep apnea in children. Healthcare providers should consider each of these sleep disorders in children presenting with sleep difficulties since each has distinct diagnostic and therapeutic options., Citation: Yelov L, Reiter J, Meira E Cruz M, Gileles-Hillel A. The association of obstructive sleep apnea and behavioral insomnia in children ages 10 and under. J Clin Sleep Med . 2024;20(2):245-251., (© 2024 American Academy of Sleep Medicine.)

Study Objectives: Celiac disease (CD), an immune-mediated enteropathy, has a clinical spectrum that is remarkably wide and includes neuropsychiatric manifestations. While studies of adults have shown sleep disturbances, there is limited data in children. Our objectives were to assess the association between sleep disturbances and CD in children, and the effect of a gluten-free diet., Methods: Parents of children 3-12 years old referred for endoscopy completed the Sleep Disturbance Scale for Children and modified Epworth Sleepiness Scale. Children with CD were compared with healthy controls and children with abdominal pain but no definitive findings on investigation. Parents of children with CD and abdominal pain were contacted after 6 months for follow-up., Results: We enrolled 101 patients, mean age 6.5 (2.8), 51% female, 38 with CD, 18 abdominal pain, and 45 healthy. Sleep Disturbance Scale for Children scores were 37.4 (8.7), 41.3 (11.3), and 45.4 (13.7) in healthy controls, CD, and abdominal pain, respectively ( P = .024). There was a significant difference in the disorders of arousal domain ( P = .044). There were no significant differences on the modified Epworth Sleepiness Scale. A trend toward improvement in Sleep Disturbance Scale for Children scores was seen in children with CD presenting with abdominal pain after 6 months on a gluten-free diet ( P = .07)., Conclusions: In this first prospective study of sleep disturbances in children with CD, we show high rates of disturbed sleep compared with healthy children. Sleep disturbances did not improve on a gluten-free diet and may be driven by abdominal pain., Citation: Reiter J, Abuelhija H, Slae M, et al. Sleep disorders in children with celiac disease: a prospective study. J Clin Sleep Med . 2023;19(3):591-594., (© 2023 American Academy of Sleep Medicine.)

Rationale: Ivacaftor's clinical effects in the residual function mutations 3849 + 10kb C→T and D1152H warrant further characterization. Objectives: To evaluate ivacaftor's effect in people with cystic fibrosis aged ≥6 years with 3849 + 10kb C→T or D1152H residual function mutations and to explore the correlation between ivacaftor-induced organoid-based cystic fibrosis transmembrane conductance regulator function measurements and clinical response to ivacaftor. Methods: Participants were randomized (1:1) in this placebo-controlled crossover study; each treatment sequence included two 8-week treatments with an 8-week washout period. The primary endpoint was absolute change in lung clearance index 2.5 from baseline through Week 8. Additional endpoints included lung function, patient-reported outcomes, and in vitro intestinal organoid-based measurements of ivacaftor-induced cystic fibrosis transmembrane conductance regulator function. Results: Of 38 participants, 37 completed the study. The primary endpoint was met; the Bayesian posterior probability of improvement in lung clearance index 2.5 with ivacaftor versus placebo was >99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor's known safety profile. Dose-dependent swelling was observed in 23 of 25 viable organoid cultures with ivacaftor treatment. Correlations between ivacaftor-induced organoid swelling and clinical endpoints were negligible to low. Conclusions: In people with cystic fibrosis aged ≥6 years with a 3849 + 10kb C→T or D1152H mutation, ivacaftor treatment improved clinical endpoints compared with placebo; however, there was no correlation between organoid swelling and change in clinical endpoints. The organoid assay may assist in identification of ivacaftor-responsive mutations but in this study did not predict magnitude of clinical benefit for individual people with cystic fibrosis with these two mutations.Clinical trial registered with ClinicalTrials.gov (NCT03068312).