Sleep measures as a predictor of suicidal ideation among high-risk adolescents.

Suicide is the second leading cause of death among youth aged 15-24 years. Identifying modifiable risk factors relevant to adolescents is crucial for suicide prevention. Sleep patterns have been linked to suicidality in adults, but lack sufficient study in youth. This ecological momentary assessment (EMA) study aimed to explore the relationship between objectively and subjectively measured sleep characteristics and next-day suicidal ideation in high-risk youth. We included 29 adolescents (12-18 years old) admitted to the inpatient psychiatric ward post-suicide attempt or due to suicidal intent within the previous month. We conducted objective (actigraphy) and subjective (sleep diary) sleep pattern assessments over ten consecutive days. Daily suicidal ideation was evaluated using a questionnaire based on the validated C-SSRS interview. A significant positive association was observed between sleep onset latency (SOL) and expressing a "death wish" the following day (OR = 1.06, 95% CI [1-1.11], p = .04), with each minute of longer SOL increased the risk for a death wish the following day by 6%. In addition, a marginally significant negative association was observed between total sleep time (TST) and expressing a "death wish" the following day (OR = 0.57, 95% CI [0.3-1.11], p = 0.1), with each one-hour decrease in objectively measured TST increasing the odds of a death wish by 43%. Our study highlights the interplay between sleep patterns and suicidal ideation, with SOL and TST playing a significant role that may function as proximal risk factors for suicidality and as a target for intervention while treating suicidal youth.

A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System.

The circadian clock, which drives a wide range of bodily rhythms in synchrony with the day-night cycle, is based on a molecular oscillator that ticks with a period of approximately 24 h. Timed proteasomal degradation of clock components is central to the fine-tuning of the oscillator's period. FBXL3 is a protein that functions as a substrate-recognition factor in the E3 ubiquitin ligase complex, and was originally shown in mice to mediate degradation of CRY proteins and thus contribute to the mammalian circadian clock mechanism. By exome sequencing, we have identified a FBXL3 mutation in patients with syndromic developmental delay accompanied by morphological abnormalities and intellectual disability, albeit with a normal sleep pattern. We have investigated the function of FBXL3 in the zebrafish, an excellent model to study both vertebrate development and circadian clock function and, like humans, a diurnal species. Loss of fbxl3a function in zebrafish led to disruption of circadian rhythms of promoter activity and mRNA expression as well as locomotor activity and sleep-wake cycles. However, unlike humans, no morphological effects were evident. These findings point to an evolutionary conserved role for FBXL3 in the circadian clock system across vertebrates and to the acquisition of developmental roles in humans.

Acute and chronic sleep deprivation in residents: Cognition and stress biomarkers.

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.

Herpes Simplex Virus Pneumonia in an Immunocompetent Child on Corticosteroids for Acute Wheezing.

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.

[APNEA OF PREMATURITY - PATHOPHYSIOLOGY, TREATMENT & PROGNOSIS].

INTRODUCTION: Apnea of prematurity affects the majority of infants born before 34 weeks of complete gestation. Significant recurrent apnea of prematurity is associated with both short and long term complications and is a risk factor for increased mortality and neurodevelopmental disability. The current review discusses the recent advances in the understanding of the pathophysiology of apnea of prematurity, as well as the clinical questions relevant to physicians and staff treating infants with apnea of prematurity. Finally, we discuss monitoring and discharge decisions, and present recommendations following discharge from the neonatal intensive care unit.

Respiratory manifestations in LPS-responsive beige-like anchor (LRBA) protein-deficient patients.

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. CONCLUSION: 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.

Stromal derived factor-1 mediates the lung regenerative effects of mesenchymal stem cells in a rodent model of bronchopulmonary dysplasia.

BACKGROUND: Mesenchymal stem cells (MSCs) attenuate lung injury in experimental models of bronchopulmonary dysplasia (BPD). Stromal derived factor-1 (SDF-1), a chemokine secreted by MSCs, modulates angiogenesis and stem cell recruitment. Here we tested the hypothesis that SDF-1 mediates MSC protective effects in experimental BPD by modulating angiogenesis. METHODS: SDF-1 was knocked down in MSCs using lentiviral vectors carrying anti-SDF-1 short hairpin RNA (MSC-SDF KD). Non-silencing short hairpin RNA was used as control (MSC-NS control). Newborn rats exposed to normoxia or hyperoxia (FiO2 = 0.85) for 3 weeks, were randomly assigned to receive a single intra-tracheal injection (IT) of MSC-NS control or MSC-SDF KD (1 × 106 cells/50 µl) or placebo on postnatal day 7. The degree of alveolarization, lung angiogenesis, inflammation, and pulmonary hypertension (PH) were assessed at postnatal day 21. RESULTS: Administration of IT MSC-NS control improved lung alveolarization, angiogenesis and inflammation, and attenuated PH in newborn rats with hyperoxia-induced lung injury (HILI). In contrast, knockdown of SDF-1 in MSCs significantly reduced their beneficial effects on alveolarization, angiogenesis, inflammation and PH. CONCLUSIONS: The therapeutic benefits of MSCs in neonatal HILI are in part mediated by SDF-1, through anti-inflammatory and angiogenesis promoting mechanisms. Therapies directly targeting this chemokine may provide a novel strategy for the treatment of BPD.

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

The diagnosis and management of common sleep disorders in adolescents.

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.

The association of obstructive sleep apnea and behavioral insomnia in children ages 10 and under.

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.

Long-term therapy with CFTR modulators consistently improves glucose metabolism in adolescents and adults with cystic fibrosis.

BACKGROUND: Impaired glycemic control and the subsequent development of Cystic fibrosis Related Diabetes (CFRD) are prevalent complications, affecting up to 50 % of adults with cystic fibrosis (CF). CFTR modulator (CFTRm) therapies improve pulmonary functions, reduce exacerbation rates, increase survival in people with CF (pwCF) and appear to have a positive effect on extrapulmonary manifestations, such as nutritional state, improvements in upper respiratory symptoms, and quality of life. Initial findings indicate that CFTRm may have a positive impact on short-term glycemic control; however, long-term effects remain uncertain at present. METHODS: In this retrospective study, data were collected and analyzed on 15 pwCF, ages 13-37 years, started on CFTRm therapy. Oral Glucose Tolerance Test (OGTT) results were compared pre- and post-CFTRm therapy. RESULTS: The 120-min OGTT value decreased from 159.7 mg/dL to 130.4 mg/dL post-CFTRm (p = 0.047). The average time elapsed between the two OGTTs was 49.87 months (ranging 9-157 months, median 38 months). Glycemic status improved in six pwCF (two CFRD to normal (NGT)/indeterminate (INDET) glucose tolerance; two impaired glucose tolerance (IGT) to INDET; two INDET to NGT) and worsened in one (IGT to CFRD). Six pwCF and NGT remained stable with no changes in glycemic status throughout the follow-up period. CONCLUSIONS: CFTRm therapy may decelerate the glycemic control deterioration in pwCF over an extended period. These findings indicate the need for periodic OGTTs following the initiation of CFTRm therapy to appropriately adjust insulin requirements and prevent hypoglycemia. Further larger cohorts are required to authenticate and substantiate these findings.

Clinical efficacy of CFTR modulator therapy in people with cystic fibrosis carrying the I1234V mutation.

BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) mutation I1234V (I1234V, p.Ile1234Val, c.3700A>G), is a missense-mutation that creates a cryptic splice site, with the formation of a protein lacking 6 amino acids, that is misfolded and misprocessed. The in vitro effects of CFTR modulator (CFTRm) therapies on human bronchial cell models and intestinal organoids carrying this mutation are conflicting. The aim of this study was therefore to explore the clinical efficacy of CFTRm in people with cystic fibrosis (pwCF) carrying this mutation. METHODS: This was a retrospective descriptive study of the clinical records of homozygous and compound heterozygous (none F508del) pwCF, for the I1234V mutation, that received CFTRm. Parameters explored were body mass index (BMI), forced expiratory volume in one second percent predicted (FEV1%), lung clearance index (LCI) and quantitative sweat chloride measurements. RESULTS: Mean age was 38.6 ± 14 years (range 21-60). Two subjects were homozygous and five compound heterozygous, with minimal function mutations. Four were pancreatic insufficient and three pancreatic sufficient. The two homozygous subjects received Tezacaftor/Ivacaftor, the remaining Elexacaftor/Tezacaftor/Ivacaftor (ETI); treatment ranged from 6 to 12 months. Mean BMI score increased from 21.7 ± 1.3 to 23.6 ± 2.1 kg/m2 (p = 0.04); FEV1(%pred) increased by 20.14±10.2while mean change in FEV1 in the year prior to CFTRm initiation was -0.14±1.18 (p = 0.0001). Additionally, LCI 2.5% decreased from 18.7 to 14.5 (p = 0.07); sweat chloride decreased from 116±10 to 90±17 mEq/L (p = 0.017) and chronic pseudomonas airway infection was eradicated in one subject. CONCLUSIONS: This study supports a clinical benefit for CFTRm therapy in pwCF carrying the I1234V mutation.

Maternal and fetal outcomes in multiparous women with Cystic Fibrosis.

BACKGROUND: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown. METHODS: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy. RESULTS: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications. CONCLUSIONS: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies.

Changes in Sleep in Children and Adults with Cystic Fibrosis and Primary Ciliary Dyskinesia over Time and after CFTR Modulator Therapy.

Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are associated with sleep disturbances affecting quality of life (QOL) in both children and adults. However, little is known about the progression of these complaints over time, and the effect of CFTR modulator (CFTRm) therapies. Participants completed sleep quality (SDSC, PSQI) and quality of life questionnaires (PedQL, QOL-BE) as well as the Epworth sleepiness scale (ESS) at baseline and after 4 years. Medical records were reviewed for clinical data and correlations were sought between sleep, QOL, and clinical parameters. A total of 67 patients (33 pediatric), 37 pancreatic insufficient CF (CF-PI), 15 pancreatic sufficient CF (CF-PS), and 15 PCD patients, completed the study. In adults, global sleep quality decreased from 85.8% (76.2-90.5) to 80.9% (71.4-85.7); (p = 0.009). Analysis by disease cohort showed a significant deterioration only in the CF-PS group. In adults off CFTRm, sleep quality decreased from 85.7% (78.6-88.2) to 80.9% (71.4-87.3); (p = 0.021) and from 85.8% (76.2-92.9) to 76.2% (71.4-85.8); (p = 0.078) in people on CFTRm. Changes in sleep quality and changes in QOL over time were strongly associated with each other. In conclusion sleep quality deteriorates over time, correlates with QOL, and is driven primarily by adults and CF-PS patients. CFTRm has a possible effect on sleep initiation; however, results are mixed, and further long-term studies are required.

Sleep disorders in children with celiac disease: a prospective study.

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.

Ovarian reserve in women with cystic fibrosis: is this a cause of sub-fertility?

BACKGROUND: Over the past two decades, increasing number of people with cystic fibrosis (CF) survive into adulthood. Compared to the general population, sub-fertility is an obstacle for many women with CF (wwCF). Decreased ovarian reserve has been proposed as a possible cause, but limited data is available to support this. The aim of this study was to evaluate the ovarian reserve in wwCF and to correlate this with patients' demographic and clinical data. METHODS: Reproductive-aged wwCF were enrolled during their routine medical appointments. Assessment included Anti-Mullerian hormone (AMH) levels, routine blood tests and antral follicular count (AFC) evaluation. Additionally, demographic, and clinical information were collected. RESULTS: A total of wenty-three wwCF were enrolled, with ages ranging from 19 to 40 years (median 27 years). Among the fourteen wwCF who were considering pregnancy, five (35.7%) disclosed undergoing an infertility assessment and receiving fertility treatments. All but one patient had an Anti-Mullerian hormone (AMH) level between the 5th and 95th % for age. Measurement of the antral follicular count (AFC) was possible in 12 of the 23 patients and was ranging 8-40 with a median of 17. The proportion of wwCF presenting below median AMH values was not different in sub-fertile as compared to fertile wwCF (P value 0.54). There were no correlations between AMH levels and disease severity parameters. AMH seemed to be relatively higher in wwCF with mild class mutations, but this was not shown to have statistical significance. CONCLUSIONS: Our results, in contrast with the limited available published data, do not support the hypothesis that decreased ovarian reserve plays a major role in infertility in wwCF.

The clinical yield of bronchoscopy in the management of cystic fibrosis: A retrospective multicenter study.

BACKGROUND: Pulmonary disease is the leading cause of morbidity and mortality in people with cystic fibrosis (pwCF). Several studies have shown no benefit for bronchoscopy and bronchoalveolar lavage (BAL) over sputum to obtain microbiological cultures, hence the role of bronchoscopy in pwCF is unclear. AIM: To analyze how bronchoscopy results affected clinical decision-making in pwCF and assess safety. METHODS: A retrospective analysis of all charts of pwCF from three CF centers in Israel, between the years 2008 and 2019. We collected BAL culture results as well as sputum cultures obtained within 1 month of the BAL sample. A meaningful yield was defined as a decision to start antibiotics, change the antibiotic regimen, hospitalize the patient for treatment, or the resolution of the problem that led to bronchoscopy (e.g., atelectasis or hemoptysis). RESULTS: During the study years, of the 428 consecutive patient charts screened, 72 patients had 154 bronchoscopies (2.14 bronchoscopies/patient). Forty-five percent of the bronchoscopies had a meaningful clinical yield. The finding of copious sputum on bronchoscopy was strongly associated with a change in treatment (OR: 5.25, 95%CI: 2.1-13.07, p < 0.001). BAL culture results were strongly associated with a meaningful yield, specifically isolation of Aspergillus spp. (p = 0.003), Haemophilus influenza (p = 0.001). Eight minor adverse events following bronchoscopy were recorded. CONCLUSIONS: In this multicenter retrospective analysis of bronchoscopy procedures from three CF centers, we have shown that a significant proportion of bronchoscopies led to a change in treatment, with no serious adverse events. Our findings suggest that bronchoscopy is a safe procedure that may assist in guiding treatment in some pwCF. Future studies should evaluate whether BAL-guided decision-making may also lead to a change in clinical outcomes in pwCF.

The association between Attention-Deficit-Hyperactivity-Disorder (ADHD) symptoms and disease severity in people with Cystic Fibrosis (pwCF).

BACKGROUND: The hallmarks of Cystic fibrosis (CF), chronic infection and inflammation, require intensive daily treatment to maintain and improve quality of life and outcome. The incidence of Attention Deficit/Hyperactivity Disorder (ADHD) is increased in chronic inflammatory diseases. Previous studies suggested that the prevalence of ADHD in people with CF (pwCF) is higher than in the general population. The objective of this study was to evaluate the association between ADHD symptoms and parameters of CF disease severity, measured by demographic and clinical data. METHODS: Based on our previous study, the results of ADHD questionnaires and the MOXOCPT (continuous performance task) from 143 pwCF (7-68 years old) were analyzed and linked to patient data such as forced expiratory volume in 1 second (FEV1)%predicted, body mass index (BMI), number of pulmonary exacerbations, days of antibiotic (Abx) treatment and serum inflammatory markers. RESULTS: A positive correlation between FEV1 and ADHD questionnaire's score (p = 0.046) was observed in the children's group. Furthermore, BMI, white blood cells (WBC) count, and days of Abx treatment showed a positive correlation with some of the MOXOCPT parameters. CONCLUSION: There is an association between ADHD symptoms and some parameters of CF disease severity. These results highlight the need for an early diagnosis of ADHD in pwCF, which have the potential to improve their ability to deal with the burden of their disease and consequently their quality of life. Additional research is needed to understand the full spectrum of ADHD pathophysiology and the relationship with chronic inflammatory diseases such as CF.

Clinical and functional efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis carrying the N1303K mutation.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA. METHODS: Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment. RESULTS: Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m2, and mean lung clearance index decreased by 3.6 points and 22.2%. There was no significant change in sweat chloride. Nasal potential difference normalized in four patients and remained abnormal in three. Results in 3D intestinal organoids and 2D nasal epithelial cultures showed a response in CFTR channel activity. CONCLUSIONS: This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment.

The new face of cystic fibrosis in the era of population genetic carrier screening.

BACKGROUND: Population genetic carrier screening (PGCS) for cystic fibrosis (CF) has been offered to couples in Israel since 1999 and was included in a fully subsidized national program in 2008. We evaluated the impact of PGCS on CF incidence, genetic and clinical features. METHODS: This was a retrospective national study. Demographic and clinical characteristics of children with CF born in Israel between 2008 and 2018 were obtained from the national CF registry and from patients' medical records. Data on CF births, preimplantation genetic testing (PGT), pregnancy termination and de-identified data from the PGCS program were collected. RESULTS: CF births per 100,000 live births decreased from 8.29 in 2008 to 0.54 in 2018 (IRR = 0.84, p < 0.001). The CF pregnancy termination rate did not change (IRR = 1, p=  0.9) while the CF-related PGT rate increased markedly (IRR = 1.33, p < 0.001). One hundred and two children were born with CF between 2008 and 2018 with a median age at diagnosis of 4.8 months, range 0-111 months. Unlike the generally high uptake nationally, 65/102 had not performed PGCS. Even if all had utilized PGCS, only 51 would have been detected by the existing genetic screening panel. Clinically, 34 % of children were pancreatic sufficient compared to 23 % before 2008 (p = 0.04). CONCLUSIONS: Since institution of a nationwide PGCS program, the birth of children with CF decreased markedly. Residual function variants and pancreatic sufficiency were more common. A broader genetic screening panel and increased PGCS utilization may further decrease the birth of children with CF.