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Robustness is a feature of regulatory pathways to ensure signal consistency in light of environmental changes or genetic polymorphisms. The retinoic acid (RA) pathway, is a central developmental and tissue homeostasis regulatory signal, strongly dependent on nutritional sources of retinoids and affected by environmental chemicals. This pathway is characterized by multiple proteins or enzymes capable of performing each step and their integration into a self-regulating network. We studied RA network robustness by transient physiological RA signaling disturbances followed by kinetic transcriptomic analysis of the recovery during embryogenesis. The RA metabolic network was identified as the main regulated module to achieve signaling robustness using an unbiased pattern analysis. We describe the network-wide responses to RA signal manipulation and found the feedback autoregulation to be sensitive to the direction of the RA perturbation: RA knockdown exhibited an upper response limit, whereas RA addition had a minimal feedback-activation threshold. Surprisingly, our robustness response analysis suggests that the RA metabolic network regulation exhibits a multi-objective optimization, known as Pareto optimization, characterized by trade-offs between competing functionalities. We observe that efficient robustness to increasing RA is accompanied by worsening robustness to reduced RA levels and vice versa. This direction-dependent trade-off in the network-wide feedback response, results in an uneven robustness capacity of the RA network during early embryogenesis, likely a significant contributor to the manifestation of developmental defects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Parihar, Bendelac-Kapon, Gur, Abbou, Belorkar, Achanta, Kinberg, Vadigepalli and Fainsod.)

Objective: Experiential phenomena (EP), such as illusions and complex hallucinations, are vivid experiences created in one's mind. They can occur spontaneously as epileptic auras or can be elicited by electrical brain stimulation (EBS) in patients undergoing presurgical evaluation for drug-resistant epilepsy. Previous work suggests that EP arise from activation of different nodes within interconnected neural networks mainly in the temporal lobes. Yet, the anatomical extent of these neural networks has not been described and the question of lateralization of EP has not been fully addressed. To this end, an extended number of brain regions in which electrical stimulation elicited EP were studied to test whether there is a lateralization propensity to EP phenomena., Methods: A total of 19 drug-resistant focal epilepsy patients who underwent EBS as part of invasive presurgical evaluation and who experienced EP during the stimulation were included. Spatial dispersion of visual and auditory illusions and complex hallucinations in each hemisphere was determined by calculation of Euclidean distances between electrodes and their centroid in common space, based on (x, y, z) Cartesian coordinates of electrode locations., Results: In total, 5857 stimulation epochs were analyzed; 917 stimulations elicited responses, out of which 130 elicited EP. Complex visual hallucinations were found to be widely dispersed in the right hemisphere, while they were tightly clustered in the occipital lobe of the left hemisphere. Visual illusions were elicited mostly in the occipital lobes bilaterally. Auditory illusions and hallucinations were evoked symmetrically in the temporal lobes., Conclusions: These findings suggest that complex visual hallucinations arise from wider spread in the right compared to the left hemisphere, possibly mirroring the asymmetry in the white matter organization of the two hemispheres. These results offer some insights into lateralized differences in functional organization and connectivity that may be important for functional mapping and planning of surgical resections in patients with epilepsy.

Background: Bronchiectasis is associated with morbidity, low exercise capacity and poor quality of life. There is a paucity of data on exercise capacity using cardiopulmonary exercise test (CPET) in non-cystic fibrosis (CF) bronchiectasis. Our aim was to compare exercise capacity using CPET in CF and non-CF bronchiectasis patients., Methods: Cross-sectional retrospective/prospective controlled study assessing CPET using cycle ergometer. Exercise parameters and computed tomography (CT) findings were compared. Results: Hundred two patients with bronchiectasis and 88 controls were evaluated; 49 CF (age 19.7 ± 9.7 y/o, FEV1%predicted 70.9 ± 20.5%) and 53 non-CF (18.6 ± 10.6 y/o, FEV1%predicted 68.7 ± 21.5%). Peak oxygen uptake (peak [Formula: see text]) was similar and relatively preserved in both groups (CF 1915.5±702.0; non-CF 1740±568; control 2111.0±748.3 mL/min). Breathing limitation was found in the two groups vs. control; low breathing reserve (49% in CF; 43% non-CF; 5% control) and increased [Formula: see text] (CF 31.4±4.1, non-CF 31.7±4.1 and control 27.2 ± 2.8). Oxygen pulse was lower in the non-CF; whereas a linear relationship between peak [Formula: see text] vs. FEV1 and vs. FVC was found only for CF. CT score correlated with [Formula: see text] and negatively correlated with [Formula: see text] and post exercise oxygen saturation (SpO2)., Conclusions: CPET parameters may differ between CF and non-CF bronchiectasis. However, normal exercise capacity may be found unrelated to the etiology of the bronchiectasis. Anatomical changes in CT are associated with functional finding of increased [Formula: see text] and decreased SpO2. Larger longitudinal studies including cardiac assessment are needed to better study exercise capacity in different etiologies of non-CF bronchiectasis., Trial Registration: ClinicalTrials.gov, registration number: NCT03147651., Competing Interests: The authors have declared that no competing interests exist.

Background: Cystic fibrosis (CF) is a chronic life-threatening disease. In patients who suffer from chronic disease, Attention Deficit Hyperactivity Disorder (ADHD) is associated with functional impairment that can affect adherence to treatment and consequently influence prognosis., Methods: CF patients filled in the ADHD Rating Scale (ADHD-RS) adapted to the DSM5 and were assessed on a continuous performance task (MOXO-CPT), a standardized-computerized test designed to evaluate several domains of attention., Results: Of the 175 patients (99 males), 18% presented ADHD symptoms, according to ADHD-RS; 16% in the younger group (<18years), and 18.9% in the adult group. The male to female ratio was 3:1 in children and 1:1 in adults., Conclusions: The occurrence of ADHD symptoms in patients with CF is substantially higher than in the general population and should be recognized as a co-morbidity of CF. As ADHD can impair adherence to therapy, further research is needed to investigate the effect of ADHD therapy on adherence., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Enzyme replacement therapy (ERT) with Myozyme improved the prospect of Pompe disease patients. Our aim was to evaluate ERT acute effect on exercise capacity in pediatric Pompe patients., Methods: Five Pompe patients (10-19 years, 4 infantile-onset and 1 diagnosed at 5 years) were evaluated before and 2 days after ERT using cardiopulmonary exercise testing (CPET), 6 min walking test (6MWT) and motor function test (GMFM-88)., Results: Preserved normal peak oxygen uptake, 6MWT and motor function were observed in the relative mild disease and impairment of these parameters in the more advanced disease. Two days following ERT, three patients demonstrated changes; one patient (relative mild disease) increased both oxygen uptake (11%) and walking distance (38%). Second patient (advanced disease) increased oxygen uptake (11%) while a small decrease in walking distance in the 6MWT (8%) was observed. Third patient (advanced disease) decreased oxygen uptake (39%) but increased walking distance (42%) and motor function score (27%)., Conclusions: CPET is safe for pediatric Pompe patients. ERT may benefit exercise capacity in patients with less advanced disease. Individualized assessment by CPET, 6MWT, and motor function may help ERT adjustment by providing precise quantification of the response to treatment. Additional studies are needed to clarify the benefit of this assessment protocol., (© 2018 Wiley Periodicals, Inc.)

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen in cystic fibrosis (CF), with increasing incidence in recent years. We examined the association between bacterial colonization in the sputum (MRSA with or without pseudomonas (PA)) and computed tomography (CT) scores in CF patients., Methods: MRSA patients were divided according to PA status based on at least three consecutive sputum cultures; controls were patients without MRSA (with or without PA), matched for gender and age at CT. Clinical data and CT scores were compared between groups., Results: Of 33 patients with MRSA, 14 had no PA (MRSA + PA-) and 19 had also PA (MRSA + PA+). MRSA + PA- and MRSA + PA+ patients had CT scores similar to their controls PA+ (38.25 ± 20.18 vs. 32.22 ± 18.74, P = .4, and 41.88 ± 18.18 vs. 45.33 ± 11.5, P = .4, respectively). Although MRSA + PA- had worse CT scores than their matched PA- controls, their mean FEV1 values were similar., Conclusions: Colonization with MRSA in CF is associated with structural CT changes at least similar to those in PA. A cause and effect relationship cannot be established. The current findings call for a larger study assessing longitudinally the impact of MRSA acquisition and eradication protocols., (© 2016 John Wiley & Sons Ltd.)

Background: Airway infections in Primary Ciliary Dyskinesia (PCD) are caused by different microorganisms, including pseudomonas aeruginosa (PA). The aim of this study was to investigate the association of PA colonization and the progression of lung disease in PCD., Methods: Data from 11PCD centers were retrospectively collected from 2008 to 2013. Patients were considered colonized if PA grew on at least two separate sputum cultures; otherwise, they were classified as non-colonized. These two groups were compared on the lung function computed tomography (CT) Brody score and other clinical parameters., Results: Data were available from 217 patients; 60 (27.6%) of whom were assigned to the colonized group. Patients colonized with PA were older and were diagnosed at a later age. Baseline forced expiratory volume at 1 s (FEV 1 ) was lower in the colonized group (72.4 ± 22.0 vs. 80.1 ± 18.9, % predicted, p = 0.015), but FEV 1 declined throughout the study period was similar in both groups. The colonized group had significantly worse CT-Brody scores (36.07 ± 24.38 vs. 25.56 ± 24.2, p = 0.034). A subgroup analysis with more stringent definitions of colonization revealed similar results., Conclusions: Lung PA colonization in PCD is associated with more severe disease as shown by the FEV 1 and CT score. However, the magnitude of decline in pulmonary function was similar in colonized and non-colonized PCD patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A 15-year old boy was referred for evaluation of fever, productive cough, and recurrent/persistent right lower lobe (RLL) pneumonia of 1-month duration. Chest computed tomography scan showed RLL consolidation, with minimal pleural effusion and a liver abscess with sharp borders, containing a solid calcification in the lower portion. History revealed acute appendicitis with laparoscopic appendectomy 6 months prior to presentation, during which a fecalith dropped to the peritoneal cavity. Following laparoscopically guided drainage of the abscess the patient improved. Herein we describe a rare case of non-resolving RLL pneumonia secondary to pyogenic liver abscess caused by dropped appendicolith., (© 2017 Wiley Periodicals, Inc.)

Hypomyelinating leukodystrophies are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. We used whole exome analysis to study the molecular basis of hypomyelinating leukodystrophy in two sibs from a consanguineous family. A homozygous mutation, c.3068+5G>A, was identified in the ATRN gene, with the consequent insertion of an intronic sequence into the patients' cDNA and a predicted premature termination of the ATRN polypeptide. ATRN encodes Attractin, which was previously shown to play a critical role in central myelination. Several spontaneous ATRN rodent mutants exhibited impaired myelination which was attributed to oxidative stress and accelerated apoptosis. ATRN can now be added to the growing list of genes associated with hypomyelinating leukodystrophy. The disease seems to be confined to the CNS; however, given the young age of our patients, longer follow-up may be required.

Introduction: Bronchiolitis obliterans (BO) is a chronic airway disease following an insult to the lower respiratory tract. Lung clearance index (LCI) measures ventilation inhomogeneity and has been studied in cystic fibrosis (CF). We aimed to evaluate LCI in BO and to compare it to LCI in CF patients., Methods: LCI was measured in BO patients, compared to CF patients, and correlated with spirometry and CT findings., Results: Twenty BO patients and 26 CF patients (with similar mean age and BMI) underwent evaluation. FEV1 % and FEF25-75 % predicted were significantly lower in the BO group (60.5 ± 17.8 vs. 72.7 ± 20.7, p = 0.041, and 42.8 ± 22.8 vs. 66.4 ± 37.4, p = 0.017, respectively). In both groups, LCI was inversely correlated with FVC %, FEV1 %, and FEF25-75 % predicted. LCI  % was slightly higher (190.4 ± 63.5 vs. 164.9 ± 39.4, p = 0.1) and FRC gas % (measured by multiple breath washout) was significantly higher in the BO group (92.5 ± 35.9 vs. 71.3 ± 18, p = 0.014). The strength of statistical association between the lower FEF25-75 % values and the higher LCI values was stronger in BO patients., Conclusions: Similar to CF, LCI may provide estimation of ventilation inhomogeneity in BO. The results indicate greater small airway involvement and air trapping in BO. Further prospective longitudinal studies evaluating the correlation of LCI measurements with multiple clinical and physiological parameters should be performed to assess the clinical benefit of LCI measurement in BO.

Eradication of Pseudomonas aeruginosa (PA) is critical in cystic fibrosis (CF) patients., Objectives: To determine eradication success rate of newly acquired PA and to identify characteristics associated with eradication failure., Methods: In an observational study, data from patients with newly acquired PA infection from 2007 to 2013 were collected. Clinical variables were compared in patients with and without successful eradication for ≥1year., Results: Of 183 patients out of 740 (25%) from 7 CF Centers that had newly acquired PA, eradication succeeded in 72%. Patients with the highest risk of failure had multi-resistant PA, fewer sputum cultures taken, were older, and were diagnosed at a later age. The risk of eradication failure increased by 1.3% with each year of delayed CF diagnosis; successful eradication increased by 17% with each additional sputum culture taken., Conclusions: Delayed detection of PA infection leading to delayed treatment and growth of multi-resistant organisms is associated with eradication failure., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact., Methods: A retrospective review of governmental databanks, the national CF registry and CF centers., Results: CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004-2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0-98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population., Conclusions: PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Haptoglobin (Hp), a heme-Iron chelator, has different isoforms which are associated with variable tendency toward infections: Hp 1-1, Hp 2-1, and Hp 2-2. Cystic fibrosis (CF) outcomes are variable and influenced by genetic and environmental factors. The aim of this study was to determine whether Hp phenotype influenced disease severity in CF. One hundred forty-two CF patients from two centers were analyzed for Haptoglobin phenotype using gel electrophoresis of hemoglobin enriched serum. Clinical and microbiological data including bacterial colonization status, lung function, presence of CF-related diabetes and liver disease, rate of exacerbation, and mortality were compared between Hp phenotype groups. We found a trend toward less mucoid PA among Hp 2-2 (20.4 %) compared with Hp 1-1 and Hp 2-1 individuals (33.3 %), p = 0.317. Hp 2-2 individuals also had less antibiotic courses, and lower inflammatory markers without statistical significance. Haptoglobin phenotype is unlikely to be an important modifier of CF phenotype.