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The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly.

CD48 is a costimulatory receptor associated with human asthma. We aimed to assess the significance of the soluble form of CD48 (sCD48) in allergic and nonallergic asthma. Volunteer patients completed an asthma and allergy questionnaire, spirometry, methacholine challenge test, a common allergen skin prick test, and a complete blood count. sCD48, IgE, IL5, IL17A, IL33, and IFNγ were quantitated in serum by ELISA. Asthma was defined as positive methacholine challenge test or a 15% increase in FEV1 post bronchodilator in symptomatic individuals. Allergy was defined as positive skin test or IgE levels > 200 IU/l in symptomatic individuals. 137 individuals participated in the study: 82 (60%) were diagnosed with asthma of which 53 (64%) was allergic asthma. sCD48 levels were significantly elevated in patients with nonallergic asthma compared to control and to the allergic asthma cohort (median (IQR) pg/ml, 1487 (1338–1758) vs. 1308 (1070–1581), p<0.01, and 1336 (1129–1591), p=0.02, respectively). IL17A, IL33, and IFNγ levels were significantly elevated in allergic and nonallergic asthmatics when compared to control. No correlation was found between sCD48 level and other disease markers. sCD48 is elevated in nonallergic asthma. Additional studies are required for understanding the role of sCD48 in airway disease.

Blood test results showed a white cell count of 23×109/L and an elevated C reactive protein level of 3.5 mg/L. Findings on physical examination of orthodeoxia (decrease in oxygen saturation by >2% when transitioning from supine to an upright position) or platypnea (dyspnoea induced by the upright position) in a patient with hypoxaemia and cyanosis suggests an intrapulmonary shunt.1 PAVMs may be complicated by paradoxical embolism with early development of cerebral abscesses and embolic strokes, and therefore, require prompt evaluation and management.2 3 PAVMs are most commonly caused by HHT, an autosomal dominant inherited disease with marked phenotypic heterogeneity and variable onset of disease manifestation.4 About 50% of HHT patients have PAVMs, while 70%–93% of patients with PAVM are diagnosed with HHT.5 The presentation in our patient highlights the physiology, clinical manifestation and consequence of PAVMs and the importance of considering intrapulmonary shunting as cause for hypoxemia. Contributors All authors met the criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), were fully responsible for all content and editorial decisions, retained full control over all content contained in this report, and were involved with all stages of report development.

Historical studies suggest that airway infection in cystic fibrosis initiates with and , with later emergence of . species are regarded as relatively infrequent, late-occurring infections. To assess the prevalence and change in prevalence of early lower airway infections in a modern cohort of children with cystic fibrosis. All infants diagnosed with cystic fibrosis after newborn screening participating in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) cohort study between 2000 and 2018 were included. Participants prospectively underwent BAL at 3-6 months, 1 year, and annually up to 6 years of age. Lower airway infection prevalence was described. Changes in prevalence patterns were assessed longitudinally using generalized estimating equations controlling for age and repeated visits. A total of 380 infants underwent 1,759 BALs. The overall prevalence and median age of first acquisition of the most common infections were as follows: , 11%, 2.5 years; , 8%, 2.4 years; species, 11%, 3.2 years; and , 9%, 3.1 years. During the study, a significant decrease in prevalence of (  < 0.001) and (  < 0.001) was observed with a significant change toward more aggressive treatment. Prevalence of infections did not significantly change (  = 0.669). species and are commonly present in the lower airways from infancy. The decrease in prevalence of and since 2000, coinciding with a more aggressive therapeutic approach, has resulted in becoming the most commonly isolated pathogen in young children. Further research is warranted to understand the implication of these findings.

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

Here, we review current available literature regarding the effect of prior antibiotic treatment on outcomes of children hospitalized for community-acquired pneumonia (CAP). To date, no prospective trial has reported information regarding morbidity or mortality in this group of patients. Retrospective studies have provided evidence for the advantage of treatment with broad-spectrum antibiotics in children who failed prior antibiotic therapy. We discuss the changing epidemiology of CAP in the post PCV13 and Hib vaccines era and its relevance to the outcome of pediatric patients hospitalized for CAP. Current studies still report Streptococcus pneumoniae as the most common typical bacterial causative agent in pediatric CAP. However, in children who fail to respond to guideline directed antibiotic therapy, a non-pneumococcal, possibly one of several β-lactam resistant causative bacterial agents should be considered thus clarifying the advantage for broad-spectrum empirical antibiotic treatment in this group of patients.

Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death, whereas each of them separately does not. Synthetic lethality can be a useful tool in personalised oncology. MLH1 is a cancer‐related gene that has a central role in DNA mismatch‐repair and TP53 is the most frequently mutated gene in cancer. To identify genetic events that can lead to tumour death once either MLH1 or TP53 is mutated, a genome‐wide genetic screening was performed. Thus, mutations in all protein‐coding genes were introduced into haploid human embryonic stem cells (hESCs) with and without loss‐of‐function mutations in the MLH1 or TP53 genes. These experiments uncovered a list of putative hits with EXO1 , NR5A2 , and PLK2 genes for MLH1, and MYH10 gene for TP53 emerging as the most promising candidates. Synthetic lethal interactions of these genes were validated genetically or chemically using small molecules that inhibit these genes. The specific effects of SR1848, which inhibits NR5A2, ON1231320 or BI2536, which inhibits PLK2, and blebbistatin, which inhibits MYH10, were further validated in cancer cell lines. Finally, animal studies with CCL xenografts showed the selective effect of the small molecule BI2536 on MLH1 ‐null tumours and of blebbistatin on TP53‐ mutated tumours. Thus, demonstrating their potential for personalised medicine, and the robustness of genetic screening in haploid hESCs in the context of cancer therapeutics.