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Nadirah Damseh,1 Nada Quercia,1,2 Nisreen Rumman,3 Sharon D Dell,4 Raymond H Kim5 1Division of Clinical and Metabolic Genetics, 2Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; 3Pediatric Department, Makassed Hospital, Jerusalem, Palestine; 4Division of Respiratory Medicine, Department of Pediatrics, Child Health Evaluative Sciences, Hospital for Sick Children, 5Fred A Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Department of Medicine, University of Toronto, Toronto, ON, Canada Abstract: Primary ciliary dyskinesia is a genetically heterogeneous disorder of motile cilia that is predominantly inherited in an autosomal-recessive fashion. It is associated with abnormal ciliary structure and/or function leading to chronic upper and lower respiratory tract infections, male infertility, and situs inversus. The estimated prevalence of primary ciliary dyskinesia is approximately one in 10,000–40,000 live births. Diagnosis depends on clinical presentation, nasal nitric oxide, high-speed video-microscopy analysis, transmission electron microscopy, genetic testing, and immunofluorescence. Here, we review its clinical features, diagnostic methods, molecular basis, and available therapies. Keywords: genetic testing, Kartagener’s syndrome, primary ciliary dyskinesia

Background: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterised by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes., Methods: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, forced expiratory volume in 1 s (FEV 1 )) were collected from 19 countries using the European Reference Network's ERN-LUNG international PCD Registry. Genetic data were evaluated according to American College of Medical Genetics and Genomics guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV 1 ., Results: The study included 1236 individuals carrying 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%, range 47-100%) and laterality defects (mean 42%, range 28-69%) varied widely among countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV 1 z-score (-1.66). Median FEV 1 z-scores were significantly lower in CCNO (-3.26), CCDC39 (-2.49) and CCDC40 (-2.96) variant groups, while the FEV 1 z-score reductions were significantly milder in DNAH11 (-0.83) and ODAD1 (-0.85) variant groups compared to the whole PCD cohort., Conclusion: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of the genetic epidemiology of PCD and indicates that the genetic variant can predict diagnostic and phenotypic features such as the course of lung function., Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Ciliopathies are inherited disorders caused by defective cilia. Mutations affecting motile cilia usually cause the chronic muco-obstructive sinopulmonary disease primary ciliary dyskinesia (PCD) and are associated with laterality defects, while a broad spectrum of early developmental as well as degenerative syndromes arise from mutations affecting signalling of primary (non-motile) cilia. Cilia assembly and functioning requires intraflagellar transport (IFT) of cargos assisted by IFT-B and IFT-A adaptor complexes. Within IFT-B, the N-termini of partner proteins IFT74 and IFT81 govern tubulin transport to build the ciliary microtubular cytoskeleton. We detected a homozygous 3-kb intragenic IFT74 deletion removing the exon 2 initiation codon and 40 N-terminal amino acids in two affected siblings. Both had clinical features of PCD with bronchiectasis, but no laterality defects. They also had retinal dysplasia and abnormal bone growth, with a narrowed thorax and short ribs, shortened long bones and digits, and abnormal skull shape. This resembles short-rib thoracic dysplasia, a skeletal ciliopathy previously linked to IFT defects in primary cilia, not motile cilia. Ciliated nasal epithelial cells collected from affected individuals had reduced numbers of shortened motile cilia with disarranged microtubules, some misorientation of the basal feet, and disrupted cilia structural and IFT protein distributions. No full-length IFT74 was expressed, only truncated forms that were consistent with N-terminal deletion and inframe translation from downstream initiation codons. In affinity purification mass spectrometry, exon 2-deleted IFT74 initiated from the nearest inframe downstream methionine 41 still interacts as part of the IFT-B complex, but only with reduced interaction levels and not with all its usual IFT-B partners. We propose that this is a hypomorphic mutation with some residual protein function retained, which gives rise to a primary skeletal ciliopathy combined with defective motile cilia and PCD., (© The Author(s) 2023. Published by Oxford University Press.)

Background: The majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year., Method: Over a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly., Results: At the end of the observation period, median age was 6.3 years (IQR: 2.8-11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p = 0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss -1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, the ABCA3 sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function., Conclusion: The natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: It has become apparent that the endoscopic surgeries are rapidly developing, and they have become an essential part of every specialty of surgery. Single port thoracoscopic surgery is developing, enhancing the advantages of muti-portal video-assisted thoracoscopic surgery (VATS). Although becoming a well-recognised approach for adult patients, extremely limited literature exists concerning uniportal VATS among pediatric cases. This study aims to present our initial experience with this approach in a single tertiary hospital and extrapolate its feasibility and safety in this specific context., Methods: Perioperative parameters and surgical outcomes for all pediatric patients who underwent an intercostal or subxiphoid uniportal VATS surgery in our department in 2 years retrospectively reviewed. The median length of follow-up was 8 months., Results: Sixty-eight pediatric patients underwent different uniportal VATS operation for different types of pathology. The median age was (3.5 years). Median operating time was 116 minutes. Three cases converted to open. The mortality rate was zero. The median length of stay was 5 days. Three patients presented complications. Three patients lost from follow-up., Conclusions: Despite literature data heterogeneity, these results provide support to the feasibility and applicability of uniportal VATS in the pediatric population. Further studies are required to explore the benefit of uniportal over multi-portal VATS (including chest wall deformities, cosmesis and quality of life)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-216/coif). The authors have no conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

Objective: To assess the clinical characteristics and outcomes of cystic fibrosis in Palestine by studying the quality of life (QoL) of participants., Method: This cross-sectional study involved the application of Cystic Fibrosis Questionnaire-Revised (CFQ-R) to participants attending the pediatric pulmonology clinic at Caritas Baby Hospital between January and May 2017. Health status was assessed by measuring pulmonary function test (FEV 1 ), body mass index (BMI), age of CF diagnosis, and presence of other affected siblings or deaths in the family., Results: There were 77 participants from 58 families: 46.8% (36/77) were males, and 53.3% (41/77) were females. The mean age was 10.7 years (range: 0.5-36 years). The participants were divided into three groups by age in years: group I ( < 6), II (6-13), and III (≥ 14). The highest and lowest CFQ scores were for the eating domain in group III (55.6 ± 22.5) and the body domain in group II (14.5 ± 17.7), respectively. Mean illness severity was 69.6% (range: 33%-111%). The mean BMI was 15.9 (range: 9.6-23.1). The mean age at the time of diagnosis was 4.2 years (± 6.3). The study showed that 1.7% of the families (1/58) had four affected siblings, and 21% (12/58) had death cases related to CF, of which 58.3% (7/12) were from the Hebron district. Finally, all parameters for CF participants in West Bank, Palestine were noticeably lower than those reported in other countries., Conclusions: This study illustrates the need for new therapies for CF participants in Palestine to improve QoL, health status, and longevity., (© 2023 Wiley Periodicals LLC.)

Background: Paediatric diffuse alveolar haemorrhage (DAH) is a rare heterogeneous condition with limited knowledge on clinical presentation, treatment and outcome., Methods: A retrospective, descriptive multicentre follow-up study initiated from the European network for translational research in children's and adult interstitial lung disease (Cost Action CA16125) and chILD-EU CRC (the European Research Collaboration for Children's Interstitial Lung Disease). Inclusion criteria were DAH of any cause diagnosed before the age of 18 years., Results: Data of 124 patients from 26 centres (15 counties) were submitted, of whom 117 patients fulfilled the inclusion criteria. Diagnoses were idiopathic pulmonary haemosiderosis (n=35), DAH associated with autoimmune features (n=20), systemic and collagen disorders (n=18), immuno-allergic conditions (n=10), other childhood interstitial lung diseases (chILD) (n=5), autoinflammatory diseases (n=3), DAH secondary to other conditions (n=21) and nonspecified DAH (n=5). Median (IQR) age at onset was 5 (2.0-12.9) years. Most frequent clinical presentations were anaemia (87%), haemoptysis (42%), dyspnoea (35%) and cough (32%). Respiratory symptoms were absent in 23%. The most frequent medical treatment was systemic corticosteroids (93%), hydroxychloroquine (35%) and azathioprine (27%). Overall mortality was 13%. Long-term data demonstrated persistent abnormal radiology and a limited improvement in lung function., Conclusions: Paediatric DAH is highly heterogeneous regarding underlying causes and clinical presentation. The high mortality rate and number of patients with ongoing treatment years after onset of disease underline that DAH is a severe and often chronic condition. This large international study paves the way for further prospective clinical trials that will in the long term allow evidence-based treatment and follow-up recommendations to be determined., Competing Interests: Conflicts of interest: T. Bandeira reports personal fees from Sanofi and other support from Boehringer Ingelheim, outside the submitted work. Conflicts of interest: E.D. Manali reports other from Boehringer Ingelheim, other from Bering, other from Hoffman la Roche, outside the submitted work. Conflicts of interest: S. Papiris reports grants and other support from Boehringer Ingelheim and Hoffman la Roche, and other support from Savara, outside the submitted work. Conflicts of interest: M. Griese reports grants, personal fees and nonfinancial support from Boehringer Ingelheim for an advisory board on nintedanib, outside the submitted work. Conflicts of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Nasal nitric oxide (nNO) is extremely low in most people with primary ciliary dyskinesia (PCD) and its measurement is an important contributor to making the diagnosis. Existing guidelines and technical standards focus on nNO measurements in older, cooperative children using chemiluminescence analysers. However, measurements of nNO in pre-school-age children (age 2-5 years) may facilitate early diagnosis and electrochemical rather than chemiluminescence analysers are widely used. Pre-schoolers often need different methods to be employed when measuring nNO. Hence, a European Respiratory Society Task Force has developed this technical standard as the first step towards standardising sampling, analysis and reporting of nNO measured as part of the diagnostic testing for PCD in all age groups, including pre-school-age children. Furthermore, we considered both chemiluminescence and electrochemical analysers that are in use worldwide. There was a paucity of quality evidence for electrochemical analysers and sampling methods used in young children, and the Task Force proposes future research priorities to allow updates of this technical standard., Competing Interests: Conflict of interest: N. Beydon reports educational writing payments as a member of the HERMES examination committee for paediatric respiratory medicine of the European Respiratory Society, and a leadership role as Chair of Group 07.01 of the European Respiratory Society (Paediatric respiratory physiology and sleep), outside the submitted work. P. Latzin reports grants from Vertex and OM Pharma, lecture honoraria from Vertex, Vifor and OM Pharma, and advisory board participation from Polyphor, Santhera (DMC), Vertex, Vifor, OM Pharma and Sanofi Aventis, outside the submitted work. S.D. Davis reports grants from the National Institutes of Health/National Heart, Lung, and Blood Institute, to support the present manuscript, and consulting fees from Parion Sciences and ReCode Therapeutics, and advisory board participation for the PCD Foundation, outside the submitted work. T. Ferkol reports grants from the National Institutes of Health (HL096458) to support the present manuscript, and grants from the National Institutes of Health (HL116211, HL125241, AI146999), National Health and Medical Research Council (NHMRC1043768) and Parion Sciences, advisory board participation for the PCD Foundation, Parion Sciences and Translate Bio, and is past president and executive board member of the American Thoracic Society, outside the submitted work. J.S. Lucas reports grants from AAIR Charity and NIHR Research for patient benefit, and consulting fees from Translate Bio, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Diagnostic testing for primary ciliary dyskinesia (PCD) started in 2013 in Palestine. We aimed to describe the diagnostic, genetic and clinical spectrum of the Palestinian PCD population., Methods: Individuals with symptoms suggestive of PCD were opportunistically considered for diagnostic testing: nasal nitric oxide (nNO) measurement, transmission electron microscopy (TEM) and/or PCD genetic panel or whole-exome testing. Clinical characteristics of those with a positive diagnosis were collected close to testing including forced expiratory volume in 1 s (FEV 1 ) Global Lung Index z-scores and body mass index z-scores., Results: 68 individuals had a definite positive PCD diagnosis, 31 confirmed by genetic and TEM results, 23 by TEM results alone, and 14 by genetic variants alone. 45 individuals from 40 families had 17 clinically actionable variants and four had variants of unknown significance in 14 PCD genes . CCDC39 , DNAH11 and DNAAF11 were the most commonly mutated genes. 100% of variants were homozygous. Patients had a median age of 10.0 years at diagnosis, were highly consanguineous (93%) and 100% were of Arabic descent. Clinical features included persistent wet cough (99%), neonatal respiratory distress (84%) and situs inversus (43%). Lung function at diagnosis was already impaired (FEV 1 z-score median -1.90 (-5.0-1.32)) and growth was mostly within the normal range (z-score mean -0.36 (-3.03-2.57). 19% individuals had finger clubbing., Conclusions: Despite limited local resources in Palestine, detailed geno- and phenotyping forms the basis of one of the largest national PCD populations globally. There was notable familial homozygosity within the context of significant population heterogeneity., Competing Interests: Conflict of interest: N. Rumman received support for the present manuscript from two NIOX MINO devices from Circassia (previously called Aerocrine) to perform nasal nitric oxide testing and AAIR Charity funded whole-exome sequencing testing, and support for attending meetings and/or travel from the European Respiratory Society for a short term research training fellowship (3 months at Southampton University) (STRTF 2014-6816), outside the submitted work. M.R. Fassad received support for the present manuscript from a Wellcome Trust Collaborative Award in Science (210585/Z/18/Z). C. Driessens received support for the present manuscript from NHS England: work for this manuscript was performed while working for the National PCD Diagnostic Service at University Hospital Southampton; this service is commissioned and funded by NHS England. R. Pengelly received support for the present manuscript from Asthma Allergy and Inflammation Research. G. Wheway received support for the present manuscript from Asthma Allergy and Inflammation Research Trust; grants or contracts from UKRI COVID-19 Agile Response Fund, Wessex Medical Research/Rosetrees Trust PhD studentship, and Asthma Allergy and Inflammation Research Trust, outside the submitted work; stock or stock options for Illumina Inc., outside the submitted work; and receipt of equipment, materials, medical writing, gifts or other services from Synthego, outside the submitted work. H.M. Mitchison received support for the present manuscript from Great Ormond Street Children's Charity, NIHR Biomedical Research Centre at Great Ormond Street Hospital, and British Council Newton-Mosharafa Fund and Ministry of Higher Education in Egypt. J.S. Lucas received grants or contracts from NIHR, AAIR Charity, and NHS England, outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

We present a scoring-based genetic algorithm (SBGA) for wavefront shaping to optimize multiple objectives at a time. The algorithm is able to find one feasible solution despite having to optimize multiple objectives. We employ the algorithm to generate multiple focus points simultaneously and allocate their intensities as desired. We then introduce a third objective to confine light focusing only to desired targets and prevent irradiation in neighboring regions. Through simulations and experiments, we demonstrate the algorithm's ease of implementation and flexibility to control the search direction. This algorithm can potentially be applied to improve biomedical imaging, optogenetics, and optical trapping.

Nasal nitric oxide (nNO) measurements are used in the assessment of patients suspected of having primary ciliary dyskinesia (PCD), but recommendations for performing such measurements have not focused on children and do not include all current practices. To guide the development of a European Respiratory Society-supported technical standard for nNO measurement in children, an international online survey was conducted to better understand current measurement practices among providers involved in PCD diagnostics. 78 professionals responded, representing 65 centres across 18 countries, mainly in Europe and North America. Nearly all centres measured nNO in children and more than half performed measurements before 5 years of age. The test was often postponed in children with signs of acute airway infection. In Europe, the electrochemical technique was more frequently used than chemiluminescence. A similar proportion of centres performed measurements during exhalation against a resistance (49 out of 65) or during tidal breathing (50 out of 65); 15 centres used only exhalation against a resistance and 15 used only tidal breathing. The cut-off values used to discriminate PCD were consistent across centres using chemiluminescence analysers; these centres reported results as an output (nL·min -1 ). Cut-off values were highly variable across centres using electrochemical devices, and nNO concentrations were typically reported as ppb. This survey is the first to determine real-world use of nNO measurements globally and revealed remarkable variability in methodology, equipment and interpretation. These findings will help standardise methods and training., Competing Interests: Conflict of interest: N. Beydon declares no competing interests. Conflict of interest: T. Ferkol declares no competing interests. Conflict of interest: A.L. Harris declares no competing interests. Conflict of interest: M. Colas declares no competing interests. Conflict of interest: S.D. Davis declares grant NIH U54 HL09640958 funded by the Office of Rare Diseases Research (NCATS) in the 36 months prior to manuscript submission, and membership of the PCD Foundation Medical and Scientific Advisory Council. Conflict of interest: E. Haarman declares no competing interests. Conflict of interest: C. Hogg declares no competing interests. Conflict of interest: E. Kilbride declares no competing interests. Conflict of interest: P. Kouis declares no competing interests. Conflict of interest: C.E. Kuehni declares no competing interests. Conflict of interest: P. Latzin declares grants to their institution from Vertex and Vifor; payment to their institution and themself for lectures, presentations, speaker bureaus, manuscript writing or educational events from Vertex, Vifor and OM Pharma; and paid (to their institution and/or themself) participation on data safety monitoring or advisory boards for Polyphor, Santhera (DMC), Vertex, OM Pharma, Vifor and Sanofi Aventis, all in the 36 months prior to manuscript submission. Conflict of interest: D. Marangu declares no competing interests. Conflict of interest: J. Marthin declares no competing interests. Conflict of interest: K.G. Nielsen declares no competing interests. Conflict of interest: P. Robinson declares no competing interests. Conflict of interest: N. Rumman declares no competing interests. Conflict of interest: M. Rutter declares no competing interests. Conflict of interest: W. Walker declares no competing interests. Conflict of interest: J.S. Lucas declares no competing interests., (Copyright ©The authors 2022.)

Primary ciliary dyskinesia (PCD) is an inherited ciliopathy leading to chronic suppurative lung disease, chronic rhinosinusitis, middle ear disease, sub-fertility and situs abnormalities. As PCD is rare, it is important that scientists and clinicians foster international collaborations to share expertise in order to provide the best possible diagnostic and management strategies. 'Better Experimental Approaches to Treat Primary Ciliary Dyskinesia' (BEAT-PCD) is a multidisciplinary network funded by EU COST Action (BM1407) to coordinate innovative basic science and clinical research from across the world to drive advances in the field. The fourth and final BEAT-PCD Conference and fifth PCD Training School were held jointly in March 2019 in Poznan, Poland. The varied program of plenaries, workshops, break-out sessions, oral and poster presentations were aimed to enhance the knowledge and skills of delegates, whilst also providing a collaborative platform to exchange ideas. In this final BEAT-PCD conference we were able to build upon programmes developed throughout the lifetime of the COST Action. These proceedings report on the conference, highlighting some of the successes of the BEAT-PCD programme., Competing Interests: Competing interestsCircassia provided funding support., (© The Author(s) 2020.)

Background: Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests., Methods: The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries., Results: Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results., Conclusions: This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although rare in the Western world, the incidence of hydatid disease is still prevalent and strikingly endemic among the Palestinians. Until 2017, surgical treatment of lung pathologies was performed through the traditional incision (open thoracotomy). Uniportal video-assisted thoracoscopic surgery (VATS) approach has recently been applied in the cases of the pulmonary hydatid cysts with very satisfactory results., Methods: Between January 2010 and January 2019, 39 patients with pulmonary HC disease have been surgically treated. The cases divided into two cohorts: operations performed by thoracotomy classified as group A, (n=16). Operations performed by uniportal VATS classified as group B, (n=23). Prospectively collected data was analysed retrospectively, and the results compared between both groups., Results: No significant statistical differences were noticed in terms of demographics and comorbidity. Laboratory tests were similar except haemoglobin level, which was higher in group A (P=0.001). Despite that, blood transfusion was higher in group A (P=0.016). Moreover, operation time was longer in group A (P=0.000). Chest drainage remained longer in group A (P=0.077). The level of postoperative pain was significantly higher in group A certainly in POD 1 (P=0.000). Patients in group B discharged earlier from the hospital (P=0.011) and experienced lower complications (P=0.060). No significant difference in length of ICU stay. Neither recurrence nor 30-day mortality recorded in either group., Conclusions: Uniportal VATS can be safely applied for pulmonary hydatidosis. It also seems to have a preference in several aspects compared to open Thoracotomy approach., Competing Interests: Conflicts of Interest: D Gonzalez-Rivas and M Ismail serve as the unpaid editorial board member of Journal of Thoracic Disease from Dec 2019 to Nov 2021 and from Aug 2019 to Jul 2021 respectively. The other authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Clinical data on primary ciliary dyskinesia (PCD) are limited, heterogeneous and mostly derived from retrospective chart reviews, leading to missing data and unreliable symptoms and results of physical examinations. We need standardised prospective data collection to study phenotypes, severity and prognosis and improve standards of care. A large, international and multidisciplinary group of PCD experts developed FOLLOW-PCD, a standardised clinical PCD form and patient questionnaire. We identified existing forms for clinical data collection via the Better Experimental Approaches to Treat PCD (BEAT-PCD) COST Action network and a literature review. We selected and revised the content items with the working group and patient representatives. We then revised several drafts in an adapted Delphi process, refining the content and structure. FOLLOW-PCD has a modular structure, to allow flexible use based on local practice and research focus. It includes patient-completed versions for the modules on symptoms and lifestyle. The form allows a comprehensive standardised clinical assessment at baseline and for annual reviews and a short documentation for routine follow-up. It can either be completed using printable paper forms or using an online REDCap database. Data collected in FOLLOW-PCD version 1.0 is available in real-time for national and international monitoring and research. The form will be adapted in the future after extensive piloting in different settings and we encourage the translation of the patient questionnaires to multiple languages. FOLLOW-PCD will facilitate quality research based on prospective standardised data from routine care, which can be pooled between centres, to provide first-line and real-time evidence for clinical decision-making., Competing Interests: Conflict of interest: M. Goutaki has nothing to disclose. Conflict of interest: J-F. Papon has nothing to disclose. Conflict of interest: M. Boon reports COST BEAT-PCD Action (BM 1407) during the conduct of the study, and Postdoc KOOR funding from the University Hospital Leuven and MyCyFAPP Horizon 2020 EU funding outside the submitted work. Conflict of interest: C. Casaulta has nothing to disclose. Conflict of interest: E. Eber has nothing to disclose. Conflict of interest: E. Escudier has nothing to disclose. Conflict of interest: F.S. Halbeisen has nothing to disclose. Conflict of interest: A. Harris has nothing to disclose. Conflict of interest: C. Hogg has nothing to disclose. Conflict of interest: I. Honore has nothing to disclose. Conflict of interest: A. Jung has nothing to disclose. Conflict of interest: B. Karadag has nothing to disclose. Conflict of interest: C. Koerner-Rettberg has nothing to disclose. Conflict of interest: M. Legendre has nothing to disclose. Conflict of interest: B. Maitre has nothing to disclose. Conflict of interest: K.G. Nielsen has nothing to disclose. Conflict of interest: B. Rubbo has nothing to disclose. Conflict of interest: N. Rumman has nothing to disclose. Conflict of interest: L. Schofield has nothing to disclose. Conflict of interest: A. Shoemark has nothing to disclose. Conflict of interest: G. Thouvenin has nothing to disclose. Conflict of interest: H. Wilkins has nothing to disclose. Conflict of interest: J.S. Lucas reports COST Action BM1407 BEAT-PCD during the conduct of the study. Conflict of interest: C.E. Kuehni has nothing to disclose., (Copyright ©ERS 2020.)

Purpose: All reported patients with hypomorphic X-linked severe combined immunodeficiency (X-SCID) due to c.664C>T (p.R222C) mutations in the gene (IL2RG) encoding the common γ chain (γc) have presented with opportunistic infections within the first year of life, despite the presence of nearly normal NK and T cell numbers. Reporting five children of one extended family with hemizygous mutations in IL2RG, we explore potential diagnostic clues and extend our comprehension of the functional impact of this mutation., Methods: Whole exome sequencing (WES); detailed immune phenotyping; cytokine-induced STAT phosphorylation; B, T, and NK cell activation; and quantification of sjTRECs in five Arab children with c.664C>T (p.R222C) IL2RG mutation., Results: The mean age at clinical presentation with respiratory tract infection or diarrhea was 6.8 (range: 2-12) months. None of the children presented with opportunistic infections. Diagnostic clues were early onset in the first year of life, and a suggestive family history associated with reduced naïve CD4 T cells and absent switched memory B cells. Number and phenotype of NK cells and innate-like lymphocytes were normal. The diagnosis was made by WES and corroborated by absent STAT phosphorylation and reduced functional response after IL-2 and IL-21 stimulation. Four patients underwent successful hematopoietic stem cell transplantation., Conclusions: As early diagnosis and treatment are important, a high index of suspicion in the diagnosis of c.664C>T (p.R222C) X-SCID is needed. This requires prompt genetic testing by next generation sequencing in order to avoid unnecessary delays in the definite diagnosis since immunological work up may not be discriminating. Assays directly testing cytokine signaling or cytokine-dependent functions are helpful in confirming the functional impact of the identified hypomorphic variants.

Primary ciliary dyskinesia is a genetic disease of ciliary function leading to chronic upper and lower respiratory tract symptoms. The diagnosis is frequently overlooked because the symptoms are nonspecific and the knowledge about the disease in the primary care setting is poor. Additionally, none of the available tests is accurate enough to be used in isolation. These tests are expensive, and need sophisticated equipment and expertise to analyse and interpret results; diagnosis is therefore only available at highly specialised centres. The diagnosis is particularly challenging in countries with limited resources due to the lack of such costly equipment and expertise.In this review, we discuss the importance of early and accurate diagnosis especially for countries where the disease is clinically prevalent but diagnostic tests are lacking. We review the diagnostic tests available in specialised centres (nasal nitric oxide, high-speed video microscopy, transmission electron microscopy, immunofluorescence and genetics). We then consider modifications that might be considered in less well-resourced countries whilst maintaining acceptable accuracy., (Copyright ©ERS 2017.)

Severe combined immune deficiency (SCID) is a group of genetically heterogeneous diseases caused by an early block in T cell differentiation and present with life threatening infections, often within the first year of life. Janus kinase (JAK)3 gene mutations have been found to cause autosomal recessive T-B+ SCID phenotype. In this study we describe three patients with a novel deep intronic mis-splicing mutation in JAK3 as a cause of T-B+NK- SCID highlighting the need for careful evaluation of intronic regulatory elements of known genes associated with clearly defined clinical phenotypes. We present the cases and discuss the current literature., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Cystic fibrosis (CF) is an autosomal recessive inherited life-threatening disorder that causes severe damage to the lungs and the digestive system. In Palestine, mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) that contributes to the clinical presentation of CF are ill defined. A cohort of thirty three clinically diagnosed CF patients from twenty one different Palestinian families residing in the central and southern part of Palestine were incorporated in this study. Sweat chloride testing was performed using the Sweat Chek Conductivity Analyzer (ELITECH Group, France) to confirm the clinical diagnosis of CF. In addition, nucleic acid from the patients' blood samples was extracted and the CFTR mutation profiles were assessed by direct sequencing of the CFTR 27 exons and the intron-exon boundaries. For patient's DNA samples where no homozygous or two heterozygous CFTR mutations were identified by exon sequencing, DNA samples were tested for deletions or duplications using SALSA MLPA probemix P091-D1 CFTR assay. Sweat chloride testing confirmed the clinical diagnosis of CF in those patients. All patients had NaCl conductivity >60 mmol/l. In addition, nine different CFTR mutations were identified in all 21 different families evaluated. These mutations were c.1393-1G>A, F508del, W1282X, G85E, c.313delA, N1303K, deletion exons 17a-17b-18, deletion exons 17a-17b and Q1100P. c.1393-1G>A was shown to be the most frequent occurring mutation among tested families. We have profiled the underling mutations in the CFTR gene of a cohort of 21 different families affected by CF. Unlike other studies from the Arab countries where F508del was reported to be the most common mutation, in southern/central Palestine, the c.1393-1G>A appeared to be the most common. Further studies are needed per sample size and geographic distribution to account for other possible CFTR genetic alterations and their frequencies. Genotype/phenotype assessments are also recommended and finally carrier frequency should be ascertained.

Screening for cystic fibrosis (CF) is suggested in patients with rectal prolapse (RP). Little is known about the association between CF and RP in the era of newborn screening for CF. Our retrospective review showed that 3.6% of patients with RP had CF, and 3.5% of patients with CF had RP. No demographic or clinical factors appear to predict the likelihood of RP in patients with CF. Sweat chloride testing for patients with RP has a low yield in the era of newborn screening but may still need to be considered in children with RP to avoid missing the rare child with CF.

Background: Severe tracheobronchomalacia significantly complicates the postoperative course of infants and children with congenital heart disease, tracheoesophageal fistula, and tracheal stenosis. We have found that traditional approaches, including aortopexy, have been inconsistent in preventing acute life threatening events (ALTEs). In order to directly support the anterior tracheal wall, we have adopted the use of direct anterior tracheal suspension (ATS)., Methods: Twenty-one children, median age 5 months (35 days to 11 years) and weight 5.0 (2.3 to 28.0) kg have undergone anterior tracheal suspension for severe tracheobronchomalacia through median sternotomy; 15 for inability to ventilate despite mechanical respiratory support, 3 for intermittent ALTEs without mechanical respiratory support, and 3 for recurrent respiratory admissions. Nine procedures were performed as isolated ATS and 12 procedures were combined with at least 1 of the following: repair of ventricular septal defect; vascular ring; atrioventricular canal; tracheal reconstruction or arterial-pexy. Level of respiratory support was graded at preoperative (preop), discharge, and follow-up, and respiratory clinical status was graded at preop and follow-up. Median follow-up was 30.0 months (2.0 to 57.0 months)., Results: There was no mortality. Both level of respiratory support and the clinical status improved at all time points studied compared with preoperative score (p < 0.001) after ATS. Whether ATS was performed in isolation or combined with other procedures did not impact these findings., Conclusions: Anterior tracheal suspension is feasible and appears effective in dramatically improving respiratory clinical status. Tracheal suspension is applicable to a wide range of anatomic variants. Additional study is needed to characterize long-term functional outcomes., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: There is increasing evidence that intestinal inflammation plays a major role in gastrointestinal symptoms in cystic fibrosis (CF). Fecal calprotectin is a marker that is elevated in several gastrointestinal inflammatory diseases, but little is known about its value in CF. We aimed to look for associations of elevated fecal calprotectin among CF patients and whether its level correlates with the clinical manifestations of CF., Methods: A single stool specimen was collected from 62 patients with CF. Fecal calprotectin was measured using the commercially available ELISA kits (PhiCal™ test). Clinical data were collected from patients' records and CF registry., Results: There were no significant differences between CF patients with normal and abnormal fecal calprotectin levels. However, patients who were not receiving inhaled antibiotics had higher fecal calprotectin levels than those who were., Conclusion: Elevated fecal calprotectin may not accurately predict intestinal inflammation in CF. However, the fact that it was elevated in both pancreatic sufficient and insufficient groups supports the concept of "cystic fibrosis enteropathy" regardless of the pancreatic status.

Mesenteric panniculitis is a chronic inflammatory process involving the adipose tissue of the mesentery. The etiology is unknown, and it is rare in children. We report a 5 year old girl who presented with abdominal symptoms and was misdiagnosed as appendicular mass. The correct diagnosis was established after surgical resection.