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Cystic fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Novel, highly effective, modulator therapies correcting and potentiating CFTR function are changing the course of the disease. We present an ethical dilemma involving an 11-year-old child with CF and end stage lung disease. Shortly after starting treatment with Elexacaftor-Tezacaftor-Ivacaftor, the family received notification that a matched donor lung had been allocated. Clinical decision-making in this case is challenging as definitive data to medically support one treatment option over the other is limited. A survey of CF center team members was conducted for the purpose of this manuscript. Ethical principles that may guide us in these situations are discussed. Overall, results of the survey present a lack of agreement as to the best approach in this situation. Physicians, when compared to other team members, are more likely to provide a specific recommendation vs. to present the information and let the family decide (odds ratio (95% confidence interval)=4.0 (1.2-12.8), p=0.021). A shared decision-making model, stressing our moral obligation as clinicians to respect autonomy by appreciating family values while offering to participate in the decision-making process and ensuring non-maleficence, is presented. In summary, CFTR modulators affect the outcomes of CF disease and influence clinical decision-making. Current lack of data on long-term outcomes, in young patients with CF receiving effective modulator therapy, should not preclude CF team participation in decision-making. Shared decision-making which is focused on respecting autonomy is our preferred approach in these situations.

Background Antisense oligonucleotide (ASO)-based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to develop an ASO-based splicing modulation therapy for Cystic Fibrosis (CF) patients carrying the 3849+10 kb C-to-T splicing mutation in the CFTR gene. Methods We have screened, in FRT cells expressing the 3849+10 kb C-to-T splicing mutation, ~30 2′-O-Methyl-modified phosphorothioate ASOs, targeted to prevent the recognition and inclusion of a cryptic exon generated due to the mutation. The effect of highly potent ASO candidates on the splicing pattern, protein maturation and CFTR function was further analyzed in well differentiated primary human nasal and bronchial epithelial cells, derived from patients carrying at least one 3849+10 kb C-to-T allele. Results A highly potent lead ASO, efficiently delivered by free uptake, was able to significantly increase the level of correctly spliced mRNA and completely restore the CFTR function to wild type levels in cells from a homozygote patient. This ASO led to CFTR function with an average of 43% of wild type levels in cells from various heterozygote patients. Optimized efficiency of the lead ASO was further obtained with 2′-Methoxy Ethyl modification (2′MOE). Conclusion The highly efficient splicing modulation and functional correction, achieved by free uptake of the selected lead ASO in various patients, demonstrate the ASO therapeutic potential benefit for CF patients carrying splicing mutations and is aimed to serve as the basis for our current clinical development.

Cystic fibrosis (CF) is a chronic multisystem disease with manifestations from birth. It involves the entire respiratory system, with increased cough, and recurrent pulmonary infections, and it also leads to intestinal malabsorption, all of which can have an impact on sleep. In this review, we summarize the available literature on the various sleep disturbances in children with CF. Sleep quality and sleep efficiency are often impaired in children with CF. They may be accompanied by symptoms associated with sleep-disordered breathing (SDB), and objective findings such as nocturnal hypoxemia. Importantly, a strong association has been shown between SDB and the severity of lung disease, and some studies have reported a similar association for sleep quality. Further research is needed to better characterize the association of sleep disturbances with respiratory outcomes and the impact of treatment of sleep disorders on pulmonary status in children with CF. This article is protected by copyright. All rights reserved.

Background With increasing longevity and quality of life in adults with Cystic fibrosis (CF), growing maternity rates are reported. Women with severe CF are becoming pregnant, with unpredictable maternal and fetal outcomes. Aim To determine how baseline disease severity, pancreatic insufficiency (PI) and Pseudomonas aeruginosa (PA) infection affect fertility, the pregnancy course, delivery, neonatal outcome, and subsequent disease progression. Methods A multicenter-retrospective cohort study. Data on patients that had been pregnant between 1986-2018 was collected from ten CF centers worldwide. Disease severity [mild or moderate-severe (mod-sev)] was defined according to forced expiratory volume % predicted in 1 second (FEV1) and body mass index (BMI). Three time periods were compared, 12 months prior to conception, the pregnancy itself and the 12 months thereafter. Results Data was available on 171 pregnancies in 128 patients aged 18-45 years; 55.1% with mod-sev disease, 43.1% with PI and 40.3% with PA. Women with mod-sev disease had more CF-related complications during and after pregnancy and delivered more preterm newborns. However, FEV1 and BMI decline were no different between the mild and mod-sev groups. A more rapid decline in FEV1 was observed during pregnancy in PI and PA infected patients, though stabilizing thereafter. PI was associated with increased risk for small for gestational age infants. Conclusion Baseline disease severity, PA infection and PI have an adverse impact on infant outcomes, but do not impact significantly on disease progression during and after pregnancy. Consequently, pregnancies in severe CF patients can have a good prognosis.

BACKGROUND Normal values (>80%) of Forced Expiratory Volume in one second (FEV1 ) in patients with cystic fibrosis (CF) may lead to the interpretation that there is no lung disease. This study is a comprehensive analysis of lung involvement in CF patients having normal FEV1 . METHODS Patients were recruited from two CF centers: Hadassah Medical Center, Jerusalem and Vall d' Hebron Hospital, Barcelona. Lung disease was assessed by lung clearance index (LCI), chest CT-Brody score, respiratory cultures, number of pulmonary exacerbations (PEx), and days of antibiotic treatment in the year before the assessment. RESULTS Of the 247 patients, 89 (36%) had FEV1 ≥80% and were included in the study (mean age, 17.6; range, 4.25-49 years). Chronic Pseudomonas aeruginosa infection was found in 21%, and 31% had at least one major PEx in the year before the study. Abnormally elevated LCI was found in 86% of patients, ranging between 7.52 and 18.97, and total Brody score (TBS) was abnormal in 92% (range, 5.0-96.5). Patients with chronic P. aeruginosa had significantly higher LCI (p = .01) and TBS (p = .02) which were associated with more major PEx (p

Asthma and sleep disorders are both common in childhood, and often co-exist in the same child. Moreover, studies have shown that in many children the rate of one is influenced by the other. Sleep disorders can be classified into six different groups-insomnia, hypersomnia, parasomnia, movement disorders, circadian disorders, and sleep-related breathing disorders. Children with asthma often present with complaints of insomnia with poor sleep quality, difficulty falling asleep and sleep disruptions. These complains are often associated with asthma control. They may also complain of daytime sleepiness and have higher rates of parasomnias, such as night terrors and nocturnal enuresis when compared with their healthy peers. Whether movement and circadian disorders are also more prevalent in children with asthma is less clear. Finally, there is a complex bidirectional interaction between sleep-related breathing disorders and asthma: poor sleep and sleep disorders may worsen asthma, and asthma, particularly when it is poorly controlled, may impair sleep. In the current review we examine the association of each of the sleep disorders with asthma and review the common pathophysiological pathways. We hope to convince the reader that appropriate management of asthma must include inquiries into the patient's sleep, and vice versa.

Rationale: Ivacaftor's clinical effects in the residual function mutations 3849+10kb C →T and D1152H warrant further characterization. Objectives: Evaluate ivacaftor's effect in people with cystic fibrosis aged ≥6 years with 3849+10kb C→T or D1152H residual function mutations; 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 vs placebo was >99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor's known safety profile. Dose-dependent swelling was observed in 23/25 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 vs 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).

BACKGROUND AND OBJECTIVES Wheezing is one of the most common reasons for the presentation of children to primary care or the emergency ward, before 7 years of age. Current guidelines recommend a short course of oral corticosteroids (OCS) for those children with a wheezing attack severe enough to require hospitalization. However, the optimal choice of therapy is controversial. We aimed to compare the efficacy of betamethasone to that of dexamethasone in achieving clinical response in preschool children requiring hospitalization for an acute wheezing attack. METHODS This was a retrospective study. Medical records of healthy children without significant comorbidities between 1 and 7 years of age (n = 234) admitted with a moderate-severity acute wheezing attack to two pediatric wards between 2014 and 2018 were included. All children were treated with either betamethasone or dexamethasone exclusively during the hospitalization. The primary outcome of interest was the length of hospital stay (LOS). RESULTS The demographic parameters and the clinical severity of wheezing episodes were similar in the two study groups, as was the LOS. However, the dexamethasone cumulative dose used during hospitalization was significantly larger than the betamethasone cumulative dose (3.76 (1.88-5.64) vs. 1.86 (1.24-3.1) mg/kg of prednisone-equivalent dose, p

The diagnosis of primary ciliary dyskinesia (PCD) relies on clinical features and sophisticated studies. The detection of bi-allelic disease-causing variants confirms the diagnosis. However, a standardised genetic panel is not widely available and new disease-causing genes are continuously identified. To assess the accuracy of untargeted whole-exome sequencing (WES) as a diagnostic tool for PCD, patients with symptoms highly suggestive of PCD were consecutively included. Patients underwent measurement of nasal nitric oxide (nNO) levels, ciliary transmission electron microscopy analysis (TEM) and WES. A confirmed PCD diagnosis in symptomatic patients was defined as a recognised ciliary ultrastructural defect on TEM and/or two pathogenic variants in a known PCD-causing gene. Forty-eight patients (46% male) were enrolled, with a median age of 10.0 years (range 1.0–37 years). In 36 patients (75%) a diagnosis of PCD was confirmed, of which 14 (39%) patients had normal TEM. A standalone untargeted WES had a diagnostic yield of 94%, identifying bi-allelic variants in 11 known PCD-causing genes in 34 subjects. A nNO, Untargeted whole-exome sequencing in subjects with clinical symptoms highly suggestive of PCD has an excellent diagnostic accuracy and, as prices drop, may be the genetic test of choice for confirming PCD or establishing an alternative diagnosis https://bit.ly/3j2jMbu

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.

Background Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are characterized by impaired mucociliary clearance causing sinopulmonary infections and airway inflammation. However, they differ in many aspects including multisystemic involvement and disease severity. Aim To compare sleep disorders and their correlation with quality of life (QOL) in three distinct patient populations: CF and pancreatic insufficiency (CF-PI), pancreatic sufficiency (CF-PS) and PCD. Methods Patients completed age appropriate sleep quality questionnaires (SDSC, PSQI), quality of life questionnaires (PedQL, QOL-BE) and the Epworth sleepiness scale (ESS). Medical records were reviewed for clinical data. Results Eighty patients, 33 CF-PI, 27 CF-PS, and 20 PCD; 40 females; 41 adults and 39 children completed the study. In adults, 66% slept less than 7 h per night, and sleep quality was reduced in 26.5%, 53% reported night wakings and 47% nocturnal snoring or coughing. In children 78% slept more than 8 h, SDSC scores were mostly in the normal range. A significant correlation was found between sleep quality and QOL in both age groups. Global sleep scores were correlated with hemoglobin levels. Despite differences in disease severity and QOL, there were no significant differences in sleep quality between the three groups. Conclusion Sleep disorders are common and correlate with QOL in CF and PCD. Despite differences in disease characteristics and severity, there are no differences in terms of sleep disorders between CF-PI, CF-PS and PCD patients, suggesting that they may represent indirect outcomes of disease.

Rationale Necrotizing pneumonia is characterized by destruction and liquefaction of the lung tissue and loss of the normal pulmonary parenchymal architecture. During the course of resolution areas of hyperlucency are formed, sometimes with the development of giant lung cysts that can be a field with fluid resembling lung abscess. There is no consensus on the management of these abnormalities. Objective To assess the prevalence of giant lung cysts as a complication of necrotizing pneumonia and to report our experience with conservative treatment that achieved complete resolution. Methods Medical chart reviews of all children aged 0 to 18 years hospitalized with necrotizing pneumonia in a single tertiary center from 2015 to 2017, demographic data, and clinical course during and after hospitalization as well as serial chest imaging were collected. Results During the study period, 761 children were diagnosed with community-acquired pneumonia, 16 of 761 (2.3%) had necrotizing pneumonia and 6 of 16 (37.5%) with necrotizing pneumonia complicated by a giant lung cyst or lung abscess. All were closely observed and showed complete clinical and radiographic resolution with antibiotic treatment. Conclusions Treatment of giant lung cyst formation following necrotizing pneumonia by a conservative approach with prolonged antibiotics results in complete recovery with no need for invasive procedures.

Background Asthma is a common chronic childhood illness and frequent cause of hospitalization. A decline in hospital admission rates was noted up to the 1990s, however, trends are not as clear since the turn of the century. This study aimed to assess the rates and regional differences of asthma admissions over more than two decades using the national Ministry of Health database, which registers data from all the hospitals. Methods A retrospective cohort study, analysis of all pediatric asthma admissions, for Patients 1-14 years old, between 1996 and 2017 as recorded by the National Hospital Discharge Registry, was performed. Asthma admission rates were calculated per 1000 age adjusted residents, using the number of admission cases as the numerator, and age specific population size as the denominator. Results The annual asthma hospitalization rate decreased in the entire pediatric population from 2.14 in 1996-0.89 in 2017. Children in the 1-4 year age group comprised most of the hospital admissions, and most of the decline was attributable to this age group. Significant differences in hospitalizations were found between different regions as well as differences in the rate of decline in asthma hospitalizations with the lowest admission rate in the Jerusalem district, highest in Haifa, northern and southern Israeli regions and the greatest rate of decline in the Tel-Aviv district. Conclusion This nationwide study, over more than two decades, shows clear regional differences in the rates of asthma admissions as well as regional differences in the rates of decline.

© 2021 American Academy of Sleep Medicine, Study objectives: The stress imposed by the COVID-19 pandemic and ensuing social isolation could adversely affect sleep. As sleep problems may persist and hurt health, it is important to identify which populations have experienced changes in sleeping patterns during the pandemic and their extent. Methods: In Study 1, 3,062 responders from 49 countries accessed the survey website voluntarily between March 26 and April 26, 2020, and 2,562 (84%; age: 45.2 ± 14.5, 68% women) completed the study. In Study 2, 1,022 adult US responders were recruited for pay through Mechanical Turk, and 971 (95%; age 40.4 ± 13.6, 52% women) completed the study. The survey tool included demographics and items adapted from validated sleep questionnaires on sleep duration, quality and timing, and sleeping pills consumption. Results: In Study 1, 58% of the responders were unsatisfied with their sleep. Forty percent of the responders reported a decreased sleep quality vs before COVID-19 crisis. Self-reported sleeping pill consumption increased by 20% (P < .001). Multivariable analysis indicated that female sex, being in quarantine, and 31- to 45-years age group, reduced physical activity and adverse impact on livelihood were independently associated with more severe worsening of sleep quality during the pandemic. The majority of findings were reproduced in the independent cohort of Study 2. Conclusions: Changes imposed due to the pandemic have led to a surge in individuals reporting sleep problems across the globe. The findings raise the need to screen for worsening sleep patterns and use of sleeping aids, especially in more susceptible populations, namely, women and people with insecure livelihoods subjected to social isolation.

Background Normal values (>80%) of Forced Expiratory Volume in one second (FEV1) in patients with Cystic fibrosis (CF) may lead to the interpretation that there is no lung disease. This study is a comprehensive analysis of lung involvement in CF patients having normal FEV1. Methods Patients were recruited from two CF Centers: Hadassah Medical Center, Jerusalem and Vall d’ Hebron Hospital, Barcelona. Lung disease was assessed by lung clearance index (LCI), chest CT-Brody Score, respiratory cultures, number of pulmonary exacerbations (PEx) and days of antibiotic treatment in the year prior to the assessment. Results Of the 247 patients, 89 (36%) had FEV1 ≥80% and were included in the study (mean age 17.6 range 4.25-49 years). Chronic P. aeruginosa infection was found in 21%, and 31% had at least one major PEx in the year prior to the study. Abnormally elevated LCI was found in 86% of patients, ranging between 7.52-18.97, and total Brody score (TBS) was abnormal in 92% (range 5.0-96.5). Patients with chronic P. aeruginosa had significantly higher LCI (p=0.01) and TBS (p=0.01) which were associated with more major PEx (p = 0.04 and p

Apnea of prematurity (AOP) affects the majority of infants born prematurely, before 34 weeks of gestational age. AOP is a common diagnosis in the neonatal intensive care unit and one of significant clinical importance, both immediate and long term, as it is associated with reduced survival and poorer respiratory and neurodevelopmental outcomes. In this review, we provide an up-to-date summary of recent advances in the understanding of the pathophysiology of AOP, as well as the clinical questions relevant to physicians and staff treating infants with AOP. Finally, we discuss monitoring and discharge decisions, as these are areas of significant uncertainty.

Bronchiolitis is one of the most common infectious diseases in children and the most frequent cause of hospitalization in infants. Clinical practice guidelines recommend that a chest X-ray (CXR) should not be routinely obtained in the diagnosis of bronchiolitis, as studies have shown that they do not affect clinical outcomes, but rather lead to overuse of pharmacological agents and a longer length of hospital stay.To determine whether active institution of bronchiolitis practice guidelines as part of a quality improvement project decreased the use of CXRs in the Pediatric Emergency Department (ED). Secondary outcomes included a decrease in the use of unnecessary medical interventions and a shorter mean hospital length of stay.The study was conducted at two Hadassah Medical Center Pediatric EDs. Guidelines were reviewed with the ED staff during departmental seminars by a senior pediatric pulmonologist, and posted at the physician computer stations in the ED. Prospective, post-intervention, data obtained during the study period was compared to retrospective, pre-intervention, data from the year prior to implementation of the intervention.Post-intervention, 37% of patients vs. 58% in the retrospective cohort had a CXR via ED referral (p 0.001). The use of hypertonic saline and bronchodilators decreased, while there was no significant change in antibiotic or corticosteroid use. There was a decrease in hospitalizations post-intervention (70% vs. 77%, p = 0.05).This key intervention was successful in reinforcing the AAP guidelines, promoting greater cost-effectiveness, reducing radiation exposure, and saving valuable time and resources for the ED staff and the hospital.

STUDY OBJECTIVES: Sleep-disordered breathing (SDB) is a highly prevalent condition affecting 2% to 4% of children. However, the prevalence and characteristics of SDB in children younger than 2 years and the effect of prematurity as a risk factor remains unclear. METHODS: Children younger than 24 months referred for PSG at two medical centers between the years 2014 to 2018 were included in this retrospective analysis. We excluded children with genetic syndromes. Polysomnography (PSG) was performed and scored according to American Academy of Sleep Medicine guidelines. RESULTS: Ninety-eight children were included (age 14.1 ± 6.4 [2–23] months), with 31 born prematurely (PRETERM; 24 to 34 weeks gestational age). PRETERM had increased odds of SDB (age and sex adjusted), using a cutoff of AHI ≥ 5 events/h with an odds ratio of 4.3 (95% confidence interval 1.5–12.9). Gestational age was the only significant predictor for SDB in this cohort, every additional week of gestation reducing the odds of SDB by 12.5%. PRETERM SDB was also characterized by more severe nocturnal hypoxemia, increased frequency of central apnea, and altered sleep architecture. CONCLUSIONS: Current findings underscore the importance of prematurity antecedents as a risk factor for SDB in young symptomatic children younger than 2 years referred for a PSG. Future studies focused on improved estimates of the prevalence of SDB among nonreferral young children appear warranted. CITATION: Sadras I, Reiter J, Fuchs N, Erlichman I, Gozal D, Gileles-Hillel A. Prematurity as a risk factor of sleep-disordered breathing in children younger than two years: a retrospective case-control study. J Clin Sleep Med. 2019;15(12):1731–1736.

Summary Background Heterozygous mutations in the FOXF1 transcription factor gene are implicated in alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a developmental disorder of the lungs classically presenting with pulmonary hypertension and early demise. Evidence has suggested haploinsufficiency and partial paternal imprinting. We present a family with several affected members with an extremely variable phenotype. Patients The index patient presented several hours after birth with severe pulmonary hypertension. She is now 3-years old, thriving on maximal pulmonary hypertension therapy, chronic steroids, and oxygen. One of the patient's siblings died at 16 days with pulmonary hypertension and an annular pancreas, consistent with classical ACDMPV. Methods Whole exome sequencing was performed in the index case. The identified variant was confirmed by Sanger sequencing, and tested in the remaining family members. Parental origin was determined by PCR amplification and cloning, sequencing, and identification of adjacent single nucleotide polymorphisms. Echocardiography was performed in the asymptomatic carriers. Results Whole exome analysis revealed a novel, predictably pathogenic heterozygous missense mutation, g.chr16:86544406 C>A NM_001451, c.C231A, p.F77L, in the FOXF1 gene. The mutation arose in the father, de novo, early postzygotically, with 70% somatic mosaicism in the blood, on the grandpaternal chromosome. It was also present in the proband's asymptomatic sister, found to have partial anomalous pulmonary venous return. Conclusion FOXF1 mutations may have an extremely variable phenotype, possibly as a result of somatic mosaicism and complex gene regulation including unorthodox imprinting of the gene locus. The prolonged survival of the proband suggests the need for aggressive treatment. Pediatr Pulmonol. © 2016 Wiley Periodicals, Inc.

Cystic fibrosis (CF) is a genetic disorder that leads to airway mucus accumulation, chronic inflammation, and recurrent respiratory infections – all likely impacting sleep. However, controlled studies of sleep in CF patients are limited, and have shown mixed results. We reviewed all publications on CF and sleep indexed in PubMed, CINAHL, and Scopus through April 2019. In the meta-analysis, we calculated pooled weighted mean differences for sleep quality, sleepiness, oximetry, and polysomnographic (PSG) parameters, using fixed or random-effects models as appropriate. A total of 87 manuscripts were reviewed. Compared to controls, children with CF had lower nighttime oxygen saturation nadirs, decreased sleep efficiency and a higher respiratory event index, with no differences in the percentage of REM sleep. Adults with CF had lower oxygen saturation nadirs, with a trend towards reduced sleep efficiency and no differences in REM sleep. In addition, patients with CF cough more during sleep and experience painful events that interfere with sleep. Actigraphy and questionnaires suggest disturbed sleep and daytime sleepiness. Noninvasive ventilation appears to improve gas exchange and symptoms. We conclude that when sleep is evaluated objectively or subjectively in patients with CF, perturbations are common, emphasizing the importance of their identification and treatment and inclusion as part of routine care. Additional research, with larger sample sizes and standardized outcomes, are necessary.

Herpes simplex virus (HSV) is rarely the cause of pneumonia in immunocompetent patients. We describe a previously healthy child, with no evidence of an immunodeficiency, who presented to the emergency department with severe pneumonia, wheezing, and pleural effusions with a history of orolabial HSV infection. On admission, he was started on antibiotics and systemic corticosteroids but continued to deteriorate. Oral lesions, blood, and pleural fluid tested positive for HSV, and improvement was achieved only after the addition of acyclovir and discontinuation of steroids. We suggest that steroids should be used with caution in patients presenting with lower respiratory tract symptoms and herpetic oral lesions.

Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) protein deficiency is a rare syndrome of primary immune deficiency and immune dysregulation. In this study, we sought to summarize our experience with respiratory manifestations in LRBA-deficient patients. We conducted a retrospective analysis of the medical records of LRBA-deficient patients treated at Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Data retrieved included pulmonary workup, disease course, treatment, and outcome. Ten patients were included. Mean age at presentation of LRBA deficiency-related symptoms was 4.65 years (range 3 months-14 years). Respiratory symptoms were noted in six patients and consisted of chronic cough. Computed tomography revealed consolidation in five patients, atelectasis and bronchiectasis in two patients each, and diffuse interstitial lung disease in two additional patients. Respiratory tract cultures yielded a bacterial pathogen in five patients. Seven patients required active therapy: intravenous immunoglobulins (six patients), immunosuppressive drugs (five patients), and one was successfully treated with abatacept. Two patients underwent successful bone marrow transplantation. Mean follow-up period was 4.5 (range 0.4-14.4) years. On their latest examination, seven patients had no respiratory symptoms.Pulmonary manifestations are common in LRBA deficiency. Respiratory characteristics in LRBA-deficient patients should be investigated, monitored, and treated from the time of diagnosis. What is Known: • Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a syndrome of primary immune deficiency and immune dysregulation. • Studies concerning the pulmonary characteristics of LRBA-deficient patients are lacking. What is New: • Respiratory manifestations include infections, bronchiectasis, interstitial lung disease, thoracic lymphadenopathy, and clubbing. • Awareness to pulmonary morbidity in LRBA-deficient patients and involvement of a pulmonologist in the workup and clinical decision-making is important. • Respiratory characteristics in LRBA-deficient patients should be investigated, monitored, and treated from a young age.

Pediatric community-acquired complicated pneumonia (PCACP) is characterized by a prolonged clinical course, but this may be highly variable.A multicenter observational study was conducted to develop and validate a clinical prediction tool for prolonged hospitalizations in PCACP. The derivation and validation cohorts consisted of 144 and 169 patients with PCACP, respectively, hospitalized between the years 1997 and 2017 in three tertiary care hospitals. Logistic regression analyses were used to identify parameters associated with a prolonged hospitalization and to develop and validate a prediction model for constructing a useful clinical tool.Higher levels of lactate dehydrogenase (LDH) (P .026) and lower levels of glucose (P = .018) in pleural fluid were significantly associated with prolonged hospitalization. A predictive stepwise logistic regression model was developed and applied to the validation cohort. The area under the receiver operating characteristic curve (AUROC) constructed indicated that the model retained good predictive value (AUROC for the derivation vs validation data, [0.77 (95% CI, 0.66-0.87) vs 0.82 (95% CI, 0.72-0.91)], respectively). From these data, a clinical tool was derived; the combination of pleural LDH1,000 units/L and pleural glucose levels 1 mmol/L or pleural LDH levels2,000 units/L and pleural glucose levels 2 mmol/L or pleural LDH levels3,000 units/L and pleural glucose 3 mmol/L predict prolonged hospitalization with positive and negative predictive values of 78% (95% CI, 0.71-0.85) and 73% (95% CI, 0.59-0.85), respectively.In children, pleural fluid LDH and glucose levels are useful parameters for assessing the severity of PCACP. The model developed in this study accurately predicts patients who will have prolonged hospitalization.

Suppurative complications of pneumonia such as empyema, lung abscess, pyopneumothorax, and necrotizing pneumonia (NP) are uncommon in children. Over the last decade an increasing incidence of NP has been reported. Streptococcus pneumoniae continues to be the predominant causative organism of NP, and while sporadic cases were reported prior to routine administration of heptavalent pneumococcal vaccine, a marked increase in NP appears to relate to replacement pneumococcal strains. Pleural involvement is almost universal in NP, and the course of pleural disease often determines its duration and outcome, particularly as it relates to complication of bronchopleural fistula. Cavities are formed in NP within the lung parenchyma and in the pleural space as the fibrosing pleural process organizes. The similarity of the radiologic appearance of parenchymal and pleural space cavities often makes the differentiation of pneumatocele versus residua of loculated pneumothorax challenging. The prevailing perception from most reports on childhood NP is of a favorable outcome with conservative approach. We report two pediatric cases with pneumonia who presented with prolonged fever despite antibiotic treatment, eventually diagnosed with NP. After stabilization on prolonged IV antibiotics, and weeks after discharge, they presented with unexpected acute respiratory failure due to a life-threatening tension air collection. In this article we discuss the nature of NP, its typical presentation, benign course and outcome, albeit its potential to cause serious late complications in the light of our recent experiences. Increasing awareness of such complications will result in more careful follow-up and in providing appropriate recommendations to parents of patients recovering from NP.

To report the performance of fetal bronchoscopy in a case of pulmonary sequestration.A 24 year-old female, Gravida 2, Para 1, was referred at 27.5 weeks with a large fetal left lung mass with marked right mediastinal shift and no visible normal left lung. Differential diagnosis included possible bronchial atresia.The patient underwent fetal laryngoscopy and fetal bronchoscopy at 31.5 weeks. The right lung and a portion of the left lung expanded during surgery as a result of bronchial lavage. Bronchial atresia or bronchogenic cyst were not found. Pregnancy continued uneventfully, with continuous growth of the right lung and a small amount of left lung. The patient delivered vaginally at term. The baby underwent thoracoscopic resection of a pulmonary sequestration at 10.5 months of age and did well.Fetal bronchoscopy is feasible. The procedure may prove useful in the differential diagnosis and in the potential treatment of different fetal lung lesions, as well as aid in the understanding of the role of bronchial obstruction as a common pathophysiologic mechanism for different fetal lung masses. Risks and benefits of fetal bronchoscopy warrant further experience.

To assess the frequency, severity, and determinants of residual respiratory events during continuous positive airway therapy (CPAP) for obstructive sleep apnea (OSA) as determined by device output.Subjects were consecutive OSA patients at an American Academy of Sleep Medicine accredited multidisciplinary sleep center. Inclusion criteria included CPAP use for a minimum of 3 months, and a minimum nightly use of 4 hours. Compliance metrics and waveform data from 217 subjects were analyzed retrospectively. Events were scored manually when there was a clear reduction of amplitude (≥ 30%) or flow-limitation with 2-3 larger recovery breaths. Automatically detected versus manually scored events were subjected to statistical analyses included Bland-Altman plots, correlation coefficients, and logistic regression exploring predictors of residual events.The mean patient age was 54.7 ± 14.2 years; 63% were males. All patients had a primary diagnosis of obstructive sleep apnea, 26% defined as complex sleep apnea. Residual flow measurement based apnea-hypopnea index (AHIFLOW)5, 10, and 15/h was seen in 32.3%, 9.7%, and 1.8% vs. 60.8%, 23%, and 7.8% of subjects based on automated vs. manual scoring of waveform data. Automatically detected versus manually scored average AHIFLOW was 4.4 ± 3.8 vs. 7.3 ± 5.1 per hour. In a logistic regression analysis, the only predictors for a manual AHIFLOW5/h were the absolute central apnea index (CAI), (odds ratio [OR]: 1.5, p: 0.01, CI: 1.1-2.0), or using a CAI threshold of 5/h of sleep (OR: 5.0, p:0.001, CI: 2.2-13.8). For AHIFLOW10/h, the OR was 1.14, p: 0.03 (CI: 1.1-1.3) per every CAI unit of 1/hour.Residual respiratory events are common during CPAP treatment, may be missed by automated device detection and predicted by a high central apnea index on the baseline diagnostic study. Direct visualization of flow data is generally available and improves detection.

Study objectives We investigated the diagnostic accuracy of a nocturnal sleep onset rapid eye movement sleep period (nSOREMP) for the identification of narcolepsy with cataplexy (N+C) among children and adolescents referred to the sleep laboratory for an overnight polysomnography (PSG) and multiple sleep latency test (MSLT). Design Retrospective chart review of sleep clinic notes and PSG and MSLT reports. Setting Boston Children's Hospital sleep laboratory and outpatient clinics. Patients All patients 6-18 y old, referred for consecutive PSG and MSLT for the evaluation of central hypersomnias, between January 2005 and January 2014. Measurements and results We analyzed the records of 148 patients and established diagnostic categories using the International Classification of Sleep Disorders, 2(nd) Edition. Patient diagnoses included narcolepsy with cataplexy (28.4%), narcolepsy without cataplexy (8.1%), other hypersomnia conditions (9.5%), delayed sleep phase syndrome (12.2%), behaviorally induced insufficient sleep syndrome (4.1%), other sleep disorders (obstructive sleep apnea, periodic limb movements of sleep; 6.8%), isolated cataplexy (2%), and various diagnoses (29.1%). There were 54.8% of the N+C patients who had an nSOREMP, but only 2.4% of all other patients had an nSOREMP. The specificity of an nSOREMP for detection of N+C was high at 97.3% (95% confidence interval [CI]: 92.2-99.4%), but the sensitivity was moderate at 54.8% (95% CI: 38.7-70.2%). Overall, the positive predictive value of an nSOREMP for the diagnosis of N+C was 88.5% (95% CI: 69.8-97.4%). Conclusions In children, the presence of an nocturnal sleep onset rapid eye movement sleep period is highly suggestive of narcolepsy with cataplexy and provides further evidence of rapid eye movement sleep dysregulation in this condition.

Pediatric flexible bronchoscopy as a diagnostic modality has become a standard tool in the armamentarium of the modern pediatric pulmonologist. However the feasibility of interventions through flexible bronchoscopy is emerging slowly as it is limited not only by the size of the pediatric bronchoscope and its working channel but also by the demarcation lines between flexible and rigid bronchoscopy.

Purpose of review Sleep problems in adolescents are very common and negatively impact the quality of their health and lives, yet often go undiagnosed. This review is meant to familiarize pediatricians with some of the more commonly encountered sleep disorders in this age group, and to review their diagnosis and management. Recent findings Recent findings reinforce the ubiquity of insufficient and poor-quality sleep in teens and their consequences on physical and mental health, cognition, and behavior. Increasing use of technology by teens, especially at night, plays a growing role in this. Parentally set bedtimes can be effective in increasing the sleep duration, thereby diminishing the consequences of insufficient sleep. Parasomnias, common in early childhood, usually diminish with the transition into adolescence. An almost 10-fold increase in the incidence of narcolepsy has been reported following the use of one type of vaccination against influenza H1N1 in Europe. Recent guidelines for the diagnosis and management of obstructive sleep apnea are reviewed, as are recent guidelines pertaining to the management of sleep disorders of children on the autism spectrum. Summary Sleep disorders in adolescents are both very common and underdiagnosed, adversely affecting their overall well being.

Microelectromechanical system (MEMS) technology promises to improve performance of future spacecraft components while reducing mass, cost, and manufacturing time. Arrays of microcilia actuators offer a lightweight alternative to conventional docking systems for miniature satellites. Instead of mechanical guiding structures, such a system uses a surface tiled with MEMS cilia actuators to guide the satellite to its docking site. This paper summarizes work on an experimental system for precision docking of a ‘picosatellite’ using MEMS cilia arrays. Microgravity is simulated with an aluminum puck on an airtable. A series of experiments is performed to characterize the cilia, with the goal of understanding the influence of normal force, picosatellite mass, docking velocity, cilia actuation frequency, interface material, and actuation strategy (‘gait’) on the performance of the MEMS docking system. We demonstrat ea4c m 2 cilia array capable of docking a 41.2 g picosatellite wit ha2c m 2 contact area with micrometer precision. It is concluded that current MEMS cilia arrays are effective in positioning and aligning miniature satellites for docking to a support satellite. (Some figures in this article are in colour only in the electronic version)

Background: Macrolide antibiotics, which have anti-inflammatory and immune modulatory effects, have been studied as adjuncts for the management of asthma. However, results have been contradictory and trials underpowered. We therefore sought to conduct a meta-analysis of randomized controlled trials (RCT). Methods: All RCT of prolonged macrolides (3+ weeks) for asthma treatment, published up to January 2013 in MEDLINE, Scopus, CINAHL, Highwire, and The Cochrane Collaboration Library, were included. Fixed- or random-effects models were used to calculate pooled weighted or standard mean differences (WMD or SMD, respectively). Results: A total of 12 studies were included for analysis. The pooled effect of macrolides on FEV1 (eight trials, 381 subjects) was not significant (SMD 0.05, 95% CI 0.14–0.25), but there was a significant increase in peak expiratory flow (four trials, 419 subjects; WMD 6.7, 95% CI 1.35–12.06). Pooled analysis also showed significant improvements in symptom scores (eight studies, 478 subjects; WMD 0.46, 95% CI 0.60 to 0.32), quality of life (five trials, 346 subjects; WMD 0.18, 95% CI 0.001–0.37), and airway hyper-reactivity (two trials, 131 subjects; SMD 1.99, 95% CI 0.46–3.52). Post hoc evaluation showed limited statistical power to detect significant differences in FEV1. Conclusions: Macrolide administration for asthma for three or more weeks was not associated with improvement in FEV1, but produced significant improvements in peak expiratory flow, symptoms, quality of life, and airway hyperreactivity. Macrolides may therefore be beneficial as adjunct asthma therapy. Future trials, focusing on long-term safety and effectiveness, should use standardized outcomes and procedures.

Microelectromechanical system (MEMS) technology promises to improve performance of future spacecraft components while reducing mass, cost, and manufacture time. Arrays of microcilia actuators offer a lightweight alternative to conventional docking systems for miniature satellites. Instead of mechanical guiding structures, such a system uses a surface tiled with MEMS actuators to guide the satellite to its docking site. This paper describes an experimental setup for precision docking of a “picosatellite” with the help of MEMS cilia arrays. Microgravity is simulated with an aluminum puck on an airtable. A series of experiments is performed to characterize the cilia, with the goal to understand the influence of normal force, picosat mass, docking velocity, cilia frequency, interface material, and actuation strategy (“gait”) on the performance of the MEMS docking system. We demonstrate a 4 cm2 cilia array capable of docking a 45 gram picosat with a 2 mm2 contact area at micrometer precision. It is concluded that current MEMS cilia arrays are useful to position and align miniature satellites with up to several kg of mass.

Satellites based on microelectromechanical system (MEMS) technology and tailored to low-cost space missions are investigated to determine their characteristics and feasibility. This work explores an alternative chassis formed from a stack of microfabricated silicon wafers. The outer layers contain optical sensing, micropropulsion and power generation systems whereas internal layers contain computers, RF components and mechanical sensors. This technique has the advantage of saving space and weight while allowing for easy design changes and precise tailoring to mission specifications. This concept is expanded through a design study of the MEMS control moment gyroscope which is used in satellite attitude control. In addition, a feasibility study is performed with special regard to the alternative chassis outlined above. This work (part of a Phase I NASA Institute for Advanced Concepts study) demonstrates that a wide variety of spacecraft components can be fabricated with silicon processing techniques. This approach may lead to batch- fabricated, high-volume, low cost, redundant teams of MEMS spacecraft.

Introduction: Acute Bronchiolitis is a common seasonal lower respiratory disease in infants. Syncytial respiratory virus is responsible for more than 50 percent of bronchiolitis events. The treatment is usually supportive. This study was done to examine the efficacy of nebulizer magnesium sulfate in the treatment of acute bronchiolitis. Methods: This study was a double blind clinical trial in which 60 patients admitted with acute bronchiolitis in our hospitals in Isfahan, Iran during 2010 and 2011. Patients were randomly divided into two groups, A and B. Group A were treated by nebulizer of magnesium sulfate, epinephrine and normal saline nebulizer and group B were treated only by the epinephrine and normal saline nebulizer. Severity of symptoms was estimated by measuring the temperature, SPO2, pulse rate (PR), respiratory rate (RR) and respiratory distress assessment instrument (RDAI) index, at the beginning of study to 3 days after treatment by follow-up questionnaires. Data were analyzed by Student t-test and repeated measure ANOVA. Results: The mean of temperature, SPO2, PR, RR and RDAI at admission and during hospital stay was not significantly different between two groups. After removing the confounding effect of different arrival, RDAI in second and third days in group A was significantly less than group B (P < 0.01). Conclusion: According to this study, treatment with magnesium sulfate nebulizer has no effect on symptoms of acute bronchiolitis. Magnesium sulfate can reduce RDAI only in the second and third days of hospitalization.