Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition.

BACKGROUND: Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy. METHODS: The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay. RESULTS: Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib. CONCLUSIONS: Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies. IMPACT: This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation. Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies. We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis. Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.

Advanced Lung Disease in Patients with Cystic Fibrosis Is Associated with Low Diffusion capacity.

BACKGROUND: The single-breath diffusing capacity of the lungs (DLCOSB) test measures the extent to which carbon monoxide (CO) passes from the lung air sacs into the blood. The accessible alveolar volume (VASB) is measured by inert gas during a 10-second period. The single-breath transfer coefficient of the lung for carbon monoxide (KCOSB) is the DLCOSB divided by VASB. Cystic fibrosis (CF) disease comprises progressive airway obstruction with bronchiectasis and parenchyma fibrosis. Yet, the KCOSB appears insignificant in the assessment of pulmonary function in CF. OBJECTIVES: To challenge the precision of normal KCOSB in CF. METHODS: The authors collected pulmonary function tests (PFT) data from 74 confirmed CF patients (mean age 26 ± 10 years) with various levels of pulmonary disease severity. Tests included spirometry, DLCOBP, and body plethysmography (BP). Anatomical dead space was calculated by deducting anatomical dead space from total lung capacity TLC(BP) to establish alveolar volume (VABP) and to determine KCOBP. We also included individual data of arterial pCO2 blood-gas level. RESULTS: KCOSB values were normal or higher in most patients, regardless of patient FEV1 value (R2 = 0.2204; P < 0.02). In contrast, the measurements of KCOBP were low corresponding with low FEV1 values, and negatively correlated with the elevation of trapped air and pCO2 levels (R2 = 0.1383; P = 0.0133, P > 0.05, respectively). CONCLUSIONS: The 10- second perfusion time of the inert gas during DLCOSB represent the communicative alveolar volume in CF patients with advanced pulmonary disease. The findings justify the use of DLCOSB with the deterioration of FEV1 and elevation of pCO2 levels.

Resting Energy Expenditure in Patients With Familial Dysautonomia: A Preliminary Study.

OBJECTIVES: Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy characterized by chronic lung disease and cyclic vomiting due to hyper-adrenergic crises. Most FD patients are in a depleted nutritional state; however, the phenotype of the disease is quite different between patients, as for the severity of lung disease and the intensity and frequency of these pathognomonic crises. In this study we wanted to investigate whether resting energy expenditure (REE) levels are increased in this population, and if correlations exist between REE levels and phenotype severity. METHODS: Data was collected from 12 FD patients (6/6 m/f). REE measurements were conducted by indirect calorimeter. Measured REE % predicted were correlated with pulmonary function, severity of the scoliosis, serum C-reactive protein, yearly frequency of hyperadrenergic crisis, hospital admissions and the use of nocturnal noninvasive positive pressure ventilation. RESULTS: Mean REE was 112 ±13% predicted with 50% being in a hypermetabolic state (REE/HB > 110%). Body mass index (BMI) was below normal range in 75% of patients, and reduced energy intake was also decreased in 75%. No significant correlations to disease severity factors were found. When dividing the subjects to REE levels above or below 125% predicted, Patients with REE above 125% predicted presented with significantly lower inspiratory capacity (42.7% predicted vs 62.8% predicted; P = 0.04). CONCLUSIONS: Hypermetabolic state was described in 50% of FD patients. The Low BMI is explained by combination of relative anorexia and increased REE. The REE levels are related to the underling respiratory disease.

[DIAGNOSIS AND TREATMENT OF BRONCHIECTASIS: POSITION PAPER OF THE ISRAELI PULMONOLOGY SOCIETY AND THE ISRAELI PEDIATRIC PULMONOLOGY SOCIETY].

INTRODUCTION: Bronchiectasis is anatomically defined by irreversible distortion of the bronchi. Clinically, its manifestations are cough with sputum production and a predisposition to pulmonary infections. Unlike asthma and COPD, where ample clinical data are present regarding the course and effective treatment, knowledge of bronchiectasis has yet to evolve. Lately, bronchiectasis is gaining renewed attention among the medical community, with growing basic and clinical research-based data. In Israel, no registered treatments exist for bronchiectasis, which makes it difficult to treat these patients. This paper is a summary of the position of the Israeli Pulmonology Association and the Israeli Pediatric Pulmonology Association for diagnosis and treatment of bronchiectasis.

Religiosity as a Substance Use Protective Factor Among Female College Students.

Research exists about religiosity as a substance use protective factor. However, there is little attention of this issue regarding Israeli female college students. Undergraduate religious and secular students were studied. Religious students reported lower last month tobacco, alcohol, cannabis and non-medical prescription drug use. Secular females who smoked, missed class because of party habits and reported easy access to cannabis had a higher probability of binge drinking. This study contributes to knowledge about religiosity and college student substance use, and it provides useful information for their mental health and well-being.

Bone mineral density utilization in patients with newly diagnosed multiple myeloma.

Bone disease is a major cause for morbidity in multiple myeloma (MM), with the main focus concerning the manifestation as osteolytic lesions. Bone mineral loss is another reflection of myeloma bone involvement. Recently, osteoporosis has been omitted as a defining criterion for symptomatic disease in MM. We conducted a retrospective study to evaluate the use of bone mineral density (BMD) exams by dual-energy X-ray absorptiometry (DXA) among MM patients in a tertiary medical care centre. One-hundred seventy three patients were included. The T-scores of lumbar spine (LS), left femur neck (FN) and left total hip (TH) were obtained and analysed. The extent of osteolytic disease was categorized based on six bony areas. There was a strong correlation between spine and femur's T-scores (r = 0.56-0.61, p < 0.0001), although different sets of variables were correlated with LS and femur's T-scores. There was no correlation between BMD measurements and osteolytic disease extent. Patients with vertebral fracture(s) had significant lower T-scores of the spine in comparison to patients without vertebral fractures. Sixty-three patients (36.4% of the cohort) had follow-up DXA exam. In general, there was an increase in the LS T-scores, while femoral values decreased. However, in patients who achieved complete response (CR) and in those who retained CR during follow-up, femoral BMD increased as well. Because correlation between BMD and the extent of osteolytic lesions was not seen, our data support the recent exclusion of BMD assessment from the definition of symptomatic myeloma. Still, its use should be considered for evaluation of age- or therapy-related osteoporosis. Copyright © 2016 John Wiley & Sons, Ltd.

Nocardia Colonization: A Risk Factor for Lung Deterioration in Cystic Fibrosis Patients?

BACKGROUND: Cystic fibrosis (CF) patients are predisposed to infection and colonization with different microbes. Some cause deterioration of lung functions, while others are colonizers without clear pathogenic effects. Our aim was to understand the effects of Nocardia species in sputum cultures on the course of lung disease in CF patients. MATERIAL AND METHODS: A retrospective study analyzing the impact of positive Nocardia spp. in sputum of 19 CF patients over a period of 10 years, comparing them with similar status patients without Nocardia growth. Pulmonary function tests (PFTs) are used as indicators of lung disease severity and decline rate in functions per year is calculated. RESULTS: No significant difference in PFTs of CF patients with positive Nocardia in sputum was found in different sub-groups according to number of episodes of growth, background variables, or treatment plans. The yearly decline in PFTs was similar to that recognized in CF patients. The control group patients showed similar background data. However, a small difference was found in the rate of decline of their PFTs, which implies a possibly slower rate of progression of lung disease. CONCLUSIONS: The prognosis of lung disease in CF patients colonized with Nocardia does not seem to differ based on the persistence of growth on cultures, different treatment plans or risk factors. Apparently, Nocardia does not cause a deterioration of lung functions with time. However, it may show a trend to faster decline in PFTs compared to similar status CF patients without isolation of this microorganism in their sputum.

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.

COVID-19 Fear Impact on Israeli and Maltese Female "Help" Profession Students.

BACKGROUND: The aim of this cross-sectional study was to examine the impact of COVID-19 fear on the well-being of Israeli and Maltese female "help" profession (e.g., social work and psychology) undergraduate students. This cross-national comparison includes factors of depression, anxiety, anger, loneliness, nervousness, substance use, eating behavior, burnout, and resilience. The study hypothesis is that country status, even with different social-cultural characteristics including religiosity, is not a significant factor associated with COVID-19 fear impact on select behavioral characteristics of female university students. METHODS: A total of 453 female "help" profession students completed an online survey from January to July 2021. Various statistical methods of analysis including regression were used for this study. RESULTS: The mean COVID-19 fear scores were the same among Israeli and Maltese students. Resilience was found to be higher among Israeli females; burnout was found to be higher among those from Malta. Substance use (i.e., tobacco, alcohol, cannabis, stimulants, or prescription drugs) in the last month was reported by 77.2% of the respondents. No significant differences were found for previous-month substance use based on country status. Regardless of country, respondents who reported more previous-month substance use had higher COVID-19 fear and burnout scores, as well as lower resilience. Due to COVID-19, most respondents (74.3%) reported deterioration of their psycho-emotional well-being in the last month; however, no significant differences were found based on country and religiosity statuses. Furthermore, no significant differences were found for eating behavior changes and weight increase based on country and religiosity statuses. CONCLUSION: Study findings showed the impact of COVID-19 fear on the well-being of Israeli and Maltese female "help" profession undergraduate students. This study examined only female students; however, additional research is needed to address male students and their experiences. Prevention and treatment intervention measures aimed to increase resilience and decrease burnout, including those that can be made available on campus, should be thought about by university administration personnel and student association leaders in consultation with mental health professionals.

Treatment effects of Elexacaftor/Tezacaftor/Ivacaftor in people with CF carrying non-F508del mutations.

BACKGROUND: In vitro studies have demonstrated rescue of CFTR function with Elexacaftor/Tezacaftor/Ivacaftor (ETI) in several mutations other than F508del. However, clinical efficacy was not tested in vivo in people with CF (pwCF) carrying mutations other than F508del. We report effects of treatment with ETI in pwCF with non-F508del mutations. METHODS: We retrospectively analyzed pwCF with non-F508del mutations who received treatment with ETI. We evaluated sweat chloride, nutritional status, spirometry, antibiotic treatment, and pulmonary exacerbations (PEx), at baseline and 3-6 months after commencing treatment with ETI. RESULTS: We included 16 pwCF, including eight without previous use of CFTR modulators. Median time on treatment was 5.3 (range, 1.8-7.7) months. Compared to baseline, in the "naïve" group sweat chloride concentration was reduced from 113.0 (98-129) to 64.0 (32-97) mEq/L (n=7; median (IQR), p=0.018), and rate of pulmonary exacerbations declined from a median of 1.5 (IQR 1, 2.75) in the previous year to 0 (0,0) (p= 0.019) with a significant decline in annualized days with antibiotics (oral + parenteral) per year: 36 (17.5; 42) in the year before to 0 (0,0) (median (IQR), p= 0.027). Mean FEV1% changed from 66.3±25 to 72.4±29 % (mean ± SD, p=0.058). In the group of patients previously treated with Ivacaftor or Tezacaftor/Ivacaftor, we didn't observe significant improvements in any of the parameters. CONCLUSIONS: We demonstrate the clinical efficacy of ETI in pwCF carrying CFTR processing non-F508del mutations which are predicted to respond by in vitro studies. Our results support routine clinical use of ETI in this patient group.

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.

The role of inspiratory capacity and tidal flow in diagnosing exercise ventilatory limitation in Cystic Fibrosis.

BACKGROUND: Exercise ventilatory limitation conventionally defined by reduced breathing reserve (BR) may underestimate the effect of lung disease on exercise capacity in patients with mild to moderate obstructive lung diseases. OBJECTIVE: To investigate whether ventilatory limitation may be present despite a normal BR in Cystic Fibrosis (CF). METHODS: Twenty adult CF patients (age 16-58y) with a wide range of pulmonary obstruction severity completed a symptom-limited incremental exercise test on a cycle ergometer. Operating lung volumes were derived from inspiratory capacity (IC) measurement during exercise and exercise tidal flow volume loop analysis. RESULTS: six patients had a severe airway obstruction (FEV1<45% predicted) and conventional evidence of ventilatory limitation (low BR). Fourteen patients had mild to moderate-severe airway obstructive (FEV1 46-103% predicted), and a normal BR [12-62 L/min, BR% (17-40)]. However, dynamic respiratory mechanics demonstrated that even CF patients with mild to moderate-severe lung disease had clear evidence of ventilatory limitation during exercise. IC was decreased by (median) 580 ml (range 90-1180 ml) during exercise, indicating dynamic hyperinflation. Inspiratory reserve volume at peak exercise was 445 ml (241-1350 ml) indicating mechanical constraint on the respiratory system. The exercise tidal flow met or exceeded the expiratory boundary of the maximal flow volume loop over 72% of the expiratory volume (range 40-90%), indicating expiratory flow limitation. CONCLUSION: Reduced BR as a sole criterion underestimates ventilatory limitation during exercise in mild to moderate-severe CF patients. Assessment of dynamic respiratory mechanics during exercise revealed ventilatory limitation, present even in patients with mild obstruction.

Gaming Disorder and Psycho-Emotional Wellbeing among Male University Students and Other Young Adults in Israel.

The aim of this cross-sectional study was to examine the impact of gaming and gaming disorder on the wellbeing of Israeli male university students and other adults. Gaming disorder (i.e., persistent, and recurrent gaming activity associated with a lack of control that may be clinically diagnosed) was determined using the Internet Gaming Disorder Scale-Short-Form (IGDS9-SF). Survey participants were recruited from gaming associations, clubs and the gaming community using Facebook. Data were collected in June 2022. A total of 526 males completed the survey (30.9% university students and 69.1% other young adults). Various statistical methods of analysis including regression were used for this study. Significant study group differences revealed university students with more indications of gaming disorder, more burnout, less loneliness, more stimulant (i.e., Ritalin) use, a greater consumption of salt- and/or sugar-loaded foods and lower economic wellbeing. The levels of resilience (i.e., the ability to recover from stress), substance use (e.g., tobacco and alcohol) and weight gain were similar for the two groups. Regression analysis showed gaming disorder as a key predictor of burnout, economic wellbeing and resilience. This study examined only male gamers because of the small number of female respondents. However, additional research is needed about female internet gamers, including their possible exposure to online harassment and sexual degradation. Additionally, additional research should be considered to verify the present study's findings about gamers based on demographic factors and gaming disorder levels. Prevention and treatment intervention measures, including those that can be made available on campus, should be thought about by university administration personnel and student association leaders in consultation with professionals who are experienced in reducing gaming disorder and other harmful behaviors among students.

Medical cannabis for the treatment of comorbid symptoms in children with autism spectrum disorder: An interim analysis of biochemical safety.

Background: Autistic Spectrum Disorder (ASD) is a common neurodevelopmental disorder and no effective treatment for the core symptoms is currently available. The present study is part of a larger clinical trial assessing the effects of cannabis oil on autism co-morbidities. Objectives: The aim of the present study was to assess the safety of a CBD-rich oil treatment in children and adolescents with ASD. Methods: Data from 59 children and young adults (ages 5-25 years) from a single-arm, ongoing, prospective, open-label, one center, phase III study was analyzed. Participants received the Nitzan Spectrum® Oil, with cannabis extracts infused in medium chain triglyceride (MCT) oil with a cannabidiol:THC ratio of 20:1, for 6 months. Blood analysis was performed before treatment initiation, and after 3 months. Complete blood count, glucose, urea, creatinine, electrolytes, liver enzymes (AST, ALT, gamma glutamyl transferase), bilirubin, lipid profile, TSH, FT4, thyroid antibodies, prolactin, and testosterone measurements were performed at baseline, prior to starting treatment and at study midpoint, after 3 months of treatment. Results: 59 children (85% male and 15% female) were followed for 18 ± 8 weeks (mean ±SD). The mean total daily dose was 7.88 ± 4.24 mg/kg body weight. No clinically significant differences were found in any of the analytes between baseline and 3 months follow up. Lactate dehydrogenase was significantly higher before treatment (505.36 ± 95.1 IU/l) as compared to its level after 3 months of treatment (470.55 ± 84.22 IU/L) (p = 0.003). FT4 was significantly higher after 3 months of treatment (15.54 ± 1.9) as compared to its level before treatment (15.07 ± 1.88) (p = 0.03), as was TSH [(2.34 ± 1.17) and (2.05 ± 1.02)] before and after 3 months of treatment, respectively (p = 0.01). However, all these values were within normal range. A comparison of the group with additional medications (n = 14) to those who received solely medical cannabis (n = 45) showed no difference in biochemical analysis, including liver enzymes, which remained stable, except for change in potassium level which was significantly higher in the group that did not receive additional medications (0.04 ± 0.37) compared to the group receiving concomitant drug therapy (-0.2 ± 0.33) (p = 0.04). A comparison of patients who received a high dose of the cannabis oil (upper quartile-16 patients), with those receiving a low dose (lower quartile-14 patients) showed no significant difference between the two groups, except for the mean change of total protein, which was significantly higher among patients receiving high dose of CBD (0.19 ± 2.74) compared to those receiving a low dose of CBD (1.71 ± 2.46 (p = 0.01), and mean change in number of platelets, that was significantly lower among patients who received high dose of CBD (13.46 ± 31.38) as compared to those who received low dose of CBD (29.64 ± 26.2) (p = 0.0007). However, both of these changes lack clinical significance. Conclusion: CBD-rich cannabis oil (CBD: THC 20:1), appears to have a good safety profile. Long-term monitoring with a larger number of participants is warranted.

Clinical impact of exome sequencing in the setting of a general pediatric ward for hospitalized children with suspected genetic disorders.

Background: Genetic conditions contribute a significant portion of disease etiologies in children admitted to general pediatric wards worldwide. While exome sequencing (ES) has improved clinical diagnosis and management over a variety of pediatric subspecialties, it is not yet routinely used by general pediatric hospitalists. We aim to investigate the impact of exome sequencing in sequencing-naive children suspected of having monogenic disorders while receiving inpatient care. Methods: We prospectively employed exome sequencing in children admitted to the general pediatric inpatient service at a large tertiary medical center in Israel. Genetic analysis was triggered by general and/or subspecialist pediatricians who were part of the primary inpatient team. We determined the diagnostic yield among children who were referred for exome sequencing and observed the effects of genetic diagnosis on medical care. Results: A total of fifty probands were evaluated and exome sequenced during the study period. The most common phenotypes included were neurodevelopmental (56%), gastrointestinal (34%), and congenital cardiac anomalies (24%). A molecular diagnosis was reached in 38% of patients. Among seven patients (37%), the molecular genetic diagnosis influenced subsequent clinical management already during admission or shortly following discharge. Conclusion: We identified a significant fraction of genetic etiologies among undiagnosed children admitted to the general pediatric ward. Our results support that early application of exome sequencing may be maximized by pediatric hospitalists' high index of suspicion for an underlying genetic etiology, prompting an in-house genetic evaluation. This framework should include a multidisciplinary co-management approach of the primary care team working alongside with subspecialties, geneticists and bioinformaticians.

Adrenal insufficiency during physiological stress in children after kidney or liver transplantation.

The aim of this study was to assess the prevalence and risk factors of AI in pediatric recipients of kidney or liver transplantation admitted because of a physiological stress episode and to identify patients that might be at risk of adrenal crises by clinical and laboratory parameters at admission. Adrenal function was prospectively evaluated by a standard (250 µg) adrenocorticotropin test in 48 recipients. Data on clinical and laboratory parameters were collected. AI was diagnosed in 11 patients: 10/32 (31.3%) children on long-term steroid treatment and 1/16 (6.25%) untreated. The only risk factor for AI was corticosteroids cumulative dose of >0.15 mg/kg/day during the last six months (p = 0.02, OR 6.67; 95% CI: 0.97-45.79). No correlation was found between clinical or laboratory signs of adrenal crisis on admission and the presence of AI. None of the patients with AI who did not receive stress dose (n = 8) developed adrenal crisis. AI is relatively common in children receiving prolonged corticosteroid treatment after kidney or liver transplantation. Clinical parameters on admission could not reliably identify patients with AI. Universal administration of a stress dose during physiological stress might not be required. However, at this point, the only method to identify patients that will benefit from a stress dose is through the ACTH test.

Spontaneous pneumothorax-When do we need to intervene?

BACKGROUND: Pneumothorax can be classified as traumatic, iatrogenic or spontaneous (SP), which can be subdivided into primary spontaneous pneumothorax (PSP), a condition without preexisting lung disease, or secondary spontaneous pneumothorax (SSP) a complication of a preexisting lung disease. Recurrence rate of PSP is 30% whereas for SSP rate is unknown. This article explores the experience of a tertiary center over 20 years. METHODS: A retrospective case review of patients hospitalized with pneumothorax to investigate the natural history and treatment of SP in a young population in a single tertiary center was conducted. A search of the digital archive (going back to 01/01/1995) of Sheba Medical Center identified hospitalized patients below the age of 40. RESULTS: The database was composed of the records of 750 patients (612 males, 138 females) who were hospitalized. The recurrence risk for SP after nonoperative treatment was significantly higher. Women were found to have an increased risk of SSP when having SP (OR 2.78). Asthma was the most prevalent disease causing SSP in young people. CONCLUSIONS: In this large cohort, we found that operative procedure has clear protective effect from recurrence in SP, so surgery should be positively considered when treating SP in hospitalized patients. Among young people and particularly in pediatric patients, when females have a SP, we strongly recommend looking for primary lung disease. More studies are needed to determine the risk factors and produce clear guidelines regarding surgery as first treatment.

Phenotypic and molecular characteristics of CF patients carrying the I1234V mutation.

BACKGROUND: The Mutation I1234V is a CF causing mutation; however the mechanisms leading to loss of function are not fully understood. In this study, we aimed to characterize phenotypically individuals with the I1234V variant, and to gain a structural point of view of the mutant CFTR using computational studies. METHODS: We conducted a retrospective descriptive study, reviewing the clinical records of 9 Israeli patients. The study was designed to include patients either homozygous or compound heterozygous for the I1234V mutation. For a comparison we analyzed clinical data of 12 patients homozygous for the F508del mutation. Computer models were constructed for I1234V, 1234-1239del and wild type CFTR. RESULTS: Mean FEV1 was 73.8 ± 21% predicted with an average annual rate of decline of 1%. When compared to patients homozygous for F508del the mean annual values of FEV1% predicted during the 6 years of data collection ranged from 51 to 58 ± 22-30 in the F508del group versus 76-82 ± 14-19 in the I1234V group (p < 0.05). Structural models did not demonstrate noticeable differences between the three simulated constructs. Although the mutation resides in the NBD2, no interference with ATP binding was detected. DISCUSSION: This study describes phenotypically patients carrying the I1234V mutation. Compared to patients homozygous for F508del, these patients present with more favorable outcome. Structural models show high similarity between the static and dynamics pictures obtained for both the mutated and the WT-CFTR; however this model does not explore the folding process and therefore may strengthen the notion of a misfolding mutation.