Reduced generation of multiple motile cilia (RGMC) is a rare mucociliary clearance disorder. Affected persons suffer from recurrent infections of upper and lower airways because of highly reduced numbers of multiple motile respiratory cilia. Here we report recessive loss-of-function and missense mutations in MCIDAS-encoding Multicilin, which was shown to promote the early steps of multiciliated cell differentiation in Xenopus. MCIDAS mutant respiratory epithelial cells carry only one or two cilia per cell, which lack ciliary motility-related proteins (DNAH5; CCDC39) as seen in primary ciliary dyskinesia. Consistent with this finding, FOXJ1-regulating axonemal motor protein expression is absent in respiratory cells of MCIDAS mutant individuals. CCNO, when mutated known to cause RGMC, is also absent in MCIDAS mutant respiratory cells, consistent with its downstream activity. Thus, our findings identify Multicilin as a key regulator of CCNO/FOXJ1 for human multiciliated cell differentiation, and highlight the 5q11 region containing CCNO and MCIDAS as a locus underlying RGMC.

The prevalence of A. xylosoxidans infection or colonisation is probably underestimated. Colonised patients are mostly older, with more pronounced lung damage and lower lung function values. Although there was more need for intravenous antibiotic treatment courses, no faster decline in lung function was observed in A. xylosoxidans positive patients.

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRβ repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.

Exercise-induced asthma (EIA) is a possible cause of poor physical performance in children. No data are available on the value of respiratory symptoms to discriminate children with bad physical fitness from children with EIA. We evaluated respiratory symptoms in school-age children during and after exercise in relation to EIA. The population of 149 primary schools (849 classes with 15,241 children) was enrolled in the study. EIB was assessed using the 6-min free-running-test (6MFRT) in 15,241 children. At the end or at premature arrest of the 6MFRT, signs reported by the children and clinical symptoms observed by supervising physicians were recorded. Peak flow measurements were obtained before and 5 and 10 min after the 6MFRT, a decrease of 15% or more being defined as significant. The 6MFRT was positive in 7.4% of primary schoolchildren. Girls were more likely to have a positive test than boys (8.5% vs. 6.4%, P < 0.001), and children living in urban areas more than those living in rural areas (8.9% vs. 7.0%, P < 0.01). Premature arrest was seen in 3.5% (i.e., n = 353) of the children. The main reasons for premature arrest were dyspnea and chest pain. Among them, only 21% had a positive 6MFRT, while 89% with a positive 6MFRT could terminate the test. Premature arrest, breathlessness, chest tightness, wheezing, and cough had a positive predictive value to detect a EIA of 21.9%, 20.8%, 36.4%, 41.2%, and 28.3%, respectively, and a sensitivity of 10.8%, 29.5%, 14.9%, 4.8%, and 13.0%, respectively. In conclusion, EIA was detected in 7.4% of schoolchildren. A slightly higher incidence was observed in girls and children from an urban area. Neither premature arrest nor clinical signs and symptoms were good predictors of EIA in primary schoolchildren.

The combination of m-CIMT with an intensive therapy program on distal hand function and strength enhances the effects of m-CIMT alone for improving bimanual performance.