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Motile cilia are critical structures that regulate early embryonic development and tissue homeostasis through synchronized ciliary motility. The formation of motile cilia is dependent on precisely controlled sequential processes including the generation, migration, and docking of centrioles/basal bodies as well as ciliary growth. Using the published proteomics data from various organisms, we identified proliferation-associated 2G4 as a novel regulator of ciliogenesis. Loss-of-function studies using Xenopus laevis as a model system reveal that Pa2G4 is essential for proper ciliogenesis and synchronized movement of cilia in multiciliated cells (MCCs) and the gastrocoel roof plate (GRP). Pa2G4 morphant MCCs exhibit defective basal body docking to the surface as a result of compromised Rac1 activity, apical actin network formation, and immature distal appendage generation. Interestingly, the regions that include the RNA-binding domain and the C-terminus of Pa2G4 are necessary for ciliogenesis in both MCCs and GRP cells. Our findings may provide insights into motile cilia-related genetic diseases such as Primary Ciliary Dyskinesia. The study on the role of Proliferation-associated 2G4 in motile cilia formation and synchronized cilia movement offers valuable insights into research on motile cilia-related genetic diseases. [ABSTRACT FROM AUTHOR]

Background/Objectives: Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are commonly used for allergic rhinitis (AR), yet limited research has directly compared their effects on quality of life (QoL). We aimed to assess QoL differences between SLIT and SCIT recipients. As both forms of immunotherapy have reported benefits, we hypothesize that patients undergoing SLIT and SCIT will have comparable QoL improvements. Methods: A cohort study included patients with AR treated with immunotherapy from 2018 to 2022. Patients with obstructive sleep apnea, primary ciliary dyskinesia, cystic fibrosis, vasculitis, rheumatoid arthritis, sarcoidosis, or lupus were excluded. QoL was evaluated using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at multiple time points. Demographics, additional therapies, and allergen sensitivities were recorded. Data were analyzed using SPSS Statistics. Results: A total of 41 participants were eligible for inclusion. Both SLIT and SCIT groups exhibited reductions from baseline RQLQ scores. Within SLIT recipients, 5/7 RQLQ domains significantly improved. SCIT recipients showed significant QoL enhancement in 3/7 domains. The mean difference between SLIT and SCIT cohorts was −0.18 (p = 0.57, d = −0.18, 95% CI [−0.79, 0.43] at a mean treatment time of 18 months. Conclusions: SLIT and SCIT showed comparable RQLQ score reductions after 18 months of therapy, suggesting similar QoL benefits between the two treatment paradigms. Further investigation is needed to explore SLIT vs. SCIT differences in long-term QoL improvements beyond two years. [ABSTRACT FROM AUTHOR]

Digital high-speed videomicroscopy (DHSV) is a crucial tool for evaluating ciliary function in children suspected of primary ciliary dyskinesia (PCD). However, until now, samples are taken without anesthesia due to uncertainty about its effect on ciliary function and DHSV interpretation. This study aimed to investigate the impact of general anesthesia on ciliary functional analysis by DHSV in a series of three patients listed for ENT surgeries, which could improve diagnostic procedures for pediatric patients. Patient 1 (7-year-old girl) underwent adenotonsillectomy and tympanostomy placement tube, while patients 2 (17-month-old boy) and 3 (15-month-old girl) underwent adenoidectomy and tympanostomy placement tube. All patients underwent nasal brushing before general anesthesia (control sample). Experimental samples were taken in the contralateral nostril at the time of equilibration of the anesthetic agents (sevoflurane, propofol, sufentanil). Ciliary beat frequency and pattern were measured using digital high-speed videomicroscopy. Our findings highlighted the variability of respiratory ciliary function under general anesthesia among individuals. Our results emphasize the need for caution when interpreting ciliary function data obtained during general anesthesia. Further research with larger cohorts is warranted for validation. [ABSTRACT FROM AUTHOR]

The study focused on the prevalence of frailty in elderly Asian ILD patients, with 32% found to be frail, and identified predictors of frailty such as older age and female sex. Genetic counselling was offered to 11.8% of patients, mainly due to family history of ILD and young-onset idiopathic interstitial pneumonia. Additionally, P. aeruginosa strains from bronchiectasis patients with chronic infection exhibited higher innate immune activation abilities, with a specific genotype associated with worse clinical outcomes. nCPAP treatment was found to significantly reduce liver fat content and improve liver function in OSAHS patients. The study also highlighted the high diagnostic yield and safety of using Franseen core needle in combined bronchoscopy procedures for transbronchial lung biopsy. [Extracted from the article]

Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by the malfunction of motile cilia and a specific etiology of adult bronchiectasis of unknown prevalence. A better understanding of the clinical phenotype of adults with PCD is needed to identify individuals for referral to diagnostic testing. What is the frequency of PCD among adults with bronchiectasis; how do people with PCD differ from those with other etiologies; and which clinical characteristics are independently associated with PCD? We investigated the proportion of PCD among the participants of the Prospective German Non-CF-Bronchiectasis Registry (PROGNOSIS) study; applied multiple imputation to account for missing data in 64 (FEV 1), 58 (breathlessness), 26 (pulmonary exacerbations), and two patients (BMI), respectively; and identified predictive variables from baseline data using multivariate logistic regression analysis. We consecutively recruited 1,000 patients from 38 centers across all levels of the German health care system. Overall, PCD was the fifth most common etiology of bronchiectasis in 87 patients (9%) after idiopathic, postinfective, COPD, and asthma. People with PCD showed a distinct clinical phenotype. In multivariate regression analysis, the chance of PCD being the etiology of bronchiectasis increased with the presence of upper airway disease (chronic rhinosinusitis and/or nasal polyps; adjusted OR [aOR], 6.3; 95% CI, 3.3-11.9; P <.001), age < 53 years (aOR, 5.3; 95% CI, 2.7-10.4; P <.001), radiologic involvement of any middle and lower lobe (aOR, 3.7; 95% CI, 1.3-10.8; P =.016), duration of bronchiectasis > 15 years (aOR, 3.6; 95% CI, 1.9-6.9; P <.001), and a history of Pseudomonas aeruginosa isolation from respiratory specimen (aOR, 2.4; 95% CI, 1.3-4.5; P =.007). Within our nationally representative cohort, PCD was a common etiology of bronchiectasis. We identified few easy-to-assess phenotypic features, which may promote awareness for PCD among adults with bronchiectasis. ClinicalTrials.gov; No.: NCT02574143 ; URL: www.clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Data are limited on the genetic profile of primary ciliary dyskinesia (PCD) from developing countries. Here, we report one of the first study on genetic profile of patients with suspected PCD from India. In this prospective cross‐sectional study, we enrolled 162 children with suspected PCD. We recorded clinical features, relevant laboratory tests for PCD and performed whole exome sequencing (WES). We are reporting 67 patients here who had positive variant/s on WES. We had 117 variants in 40 genes among 67 patients. Among the 108 unique variants, 33 were categorized as pathogenic or likely pathogenic (P/LP). We had nine novel variants in out cohort. The 29 definite PCD cases, diagnosed by composite reference standards, had variants in 16 genes namely LRRC6/DNAAF11 (5), DNAH5 (3), CCDC39 (3), HYDIN (3), DNAH11 (2), CCDC40 (2), CCDC65 (2) and one each DNAAF3, DNAAF2, CFAP300, RPGR, CCDC103, CCDC114, SPAG1, DNAI1, and DNAH14. To conclude, we identified 108 unique variants in 40 genes among 67 patients. The common genes involved in definite cases of PCD in Indian patients were LRRC6, DNAH5, CCDC39, and HYDIN. Our findings suggest a need to develop a separate genetic panel for PCD in the Indian population. [ABSTRACT FROM AUTHOR]

ABSTRACT Primary ciliary dyskinesia (PCD; OMIM 244400) is a rare genetic disorder affecting motile cilia and is characterized by impaired mucociliary clearance in the airway epithelium that leads to chronic oto‐sinopulmonary manifestations. To date, over 50 PCD‐causing genes have been identified, with these genes and their variants varying globally across populations. We performed targeted resequencing of 42 PCD‐causative genes in 150 Japanese patients suspected of having PCD and identified pathogenic or likely pathogenic variants in 51 patients. Among these, 24 patients exhibited a homozygous deletion of DRC1 exons 1–4, the most common cause of PCD in Japan. The allele frequency of this deletion was estimated at 0.0034 (95% CI: 0.0025–0.0044), based on bioinformatic analysis of 7906 whole‐genome sequences from the general Japanese population. Additionally, RNA sequencing of nasal samples supplemented in silico variant predictions, aiding in the identification of causative variants. Considering potential ethnic differences, it is essential to accumulate global data on these variants and their functional impacts. [ABSTRACT FROM AUTHOR]

Introduction: Individuals with inborn errors of immunity (IEI) are at increased risk of respiratory infection and frequently receive prolonged broad-spectrum antibiotics, leading to antibiotic resistance. The aim of this study was to identify respiratory pathogens and antibiotic resistance patterns in IEI patients. Methods: We retrospectively studied 36 IEI patients with positive bacterial growth in sputum cultures between 2014 and 2023. Data covered hospitalizations, respiratory infections, yearly antibiotic prescriptions, past sputum cultures, and antibiotic sensitivities. Patients with primary ciliary dyskinesia (PCD) and bronchiectasis served as a control group. Results: A total of 314 sputum cultures were analyzed from patients with IEI, alongside 585 cultures from individuals with PCD and 113 cultures from patients with bronchiectasis. Patients with IEI had a median age of 23.5 years, with 61% male participants. The study compared the differences in bacterial isolates from sputum cultures and antibiotic resistance between patients with IEI and the control groups. The most common bacterial isolates across all groups were Haemophilus influenzae (159 isolates in IEI vs. 314 in PCD and 26 in bronchiectasis), Pseudomonas aeruginosa, and Streptococcus pneumoniae. In IEI patients, 992 symptomatic respiratory exacerbations and 43 pneumonia-related hospitalizations were recorded. Notably, H. influenzae in IEI patients showed high resistance rates to cefuroxime (82%), amoxicillin/clavulanic acid (66%), trimethoprim/sulfamethoxazole (59%), and ampicillin/sulbactam (49%). P. aeruginosa in IEI patients displayed significant resistance to ciprofloxacin (85%), ceftazidime (42%), and aminoglycosides (23–33%). Additionally, all S. pneumoniae isolates in IEI patients were tetracycline resistant, with high resistance rates to penicillin, clindamycin, and erythromycin. It is essential to highlight the substantial resistance of common pathogens to oral antibiotics. In contrast, the control groups exhibited lower resistance rates across all bacterial isolates. Conclusion: Antimicrobial resistance is a growing concern among vulnerable IEI patients. We suggest conducting similar investigations in other regions to address this issue. The findings should inform future infection management guidelines for IEIs. [ABSTRACT FROM AUTHOR]

The article discusses a case report of a 35-year-old woman with Kartagener's syndrome who was found to have a novel alpha-1 antitrypsin gene variant. Kartagener's syndrome is a genetic condition characterized by bronchiectasis, situs inversus, and sinusitis. The patient underwent testing for alpha-1 antitrypsin deficiency (AATD) due to her diagnosis, revealing a previously unidentified genetic variant. The significance of this variant and its impact on the patient's health remain unknown, highlighting the importance of AATD testing in patients with Kartagener's syndrome. [Extracted from the article]

Primary ciliary dyskinesia (PCD) is predominantly an autosomal recessive disorder that is characterized by recurrent respiratory infections stemming from impaired ciliary motility. Granulomatous polyangiitis is a necrotizing vasculitic disease marked by granulomatous inflammation in the vascular wall that often manifests in the lungs with cavitating nodules, masses and consolidations. A 24-year-old female patient presented to our clinic complaining of dyspnea, productive cough and pleuritic chest pain, and was diagnosed with Kartagener Syndrome based on her situs inversus, bronchiectasis and sinusitis. Subsequent genetic tests and further clinical evaluations, including thoracic CT, revealed findings of cavitating nodules, PR3-ANCA positivity and leukocytic vasculitis from a skin biopsy pathology, confirming the coexistence of PCD and granulomatous polyangiitis. [ABSTRACT FROM AUTHOR]

The article discusses the association between airway bacterial colonization and bronchial remodeling in severe preschool wheezers. Pathogenic bacteria like NTHi, Moraxella catarrhalis, and Streptococcus pneumoniae are linked to wheezing, exacerbations, and hospitalizations in preschoolers. The presence of these bacteria is associated with neutrophilic inflammation and bronchial remodeling, particularly increased bronchial smooth muscle mass. Atopy and NTHi colonization independently influence bronchial smooth muscle mass and exacerbations in preschool wheezers, highlighting the complex interplay between bacterial colonization, atopy, and airway remodeling in severe wheezing. [Extracted from the article]

This article presents the findings of a study on bronchial remodeling in preschool children with severe preschool wheezing (SPW). The study identified two distinct classes of SPWs, BR1 and BR2, based on bronchial remodeling characteristics. These classes had different disease trajectories, clinical manifestations, and treatment responses. The study suggests that quantifying and targeting multiple bronchial remodeling features can help identify and monitor these two endotypes of SPWs. The article also emphasizes the need for biomarkers and genetic characteristics to easily identify these endotypes. [Extracted from the article]

The prevalence of asthma exceeds 3% of the population. Asthma is observed to be more common in children following severe viral lower respiratory illnesses that affect ciliary function, but mechanisms linking ciliary function to asthma pathogenesis have been obscure. Recent data regarding primary ciliary dyskinesia (PCD) may help us to understand the association. Here, I will review what is known about the relationship between ciliary function and asthma. PCD is caused by pathologic variants in over 50 different genes that affect the structure and function of motile cilia. At the cellular level, a characteristic feature shared by most PCD patients is that antigens and other particles are not cleared from the epithelial surface. Poor antigen clearance results in pro-oxidant pathway activation and airway epithelial damage and may predispose PCD patients to DUOX1- and IL33-mediated asthma. Secondary ciliary dysfunction, such as that caused by viruses or by smoking, can also contribute to asthma development. Moreover, variants in genes that affect the function of cilia can be associated with poor lung function, even in the absence of PCD, and with increased asthma severity. The role of antigen stasis on the surface of dysfunctional airway cilia in the pathophysiology of asthma is a novel area for research, because specific airway clearance techniques and other therapeutic interventions, such as antioxidants, could be of value in preventing the development of asthma. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is an autosomal recessive genetic disorder characterized by ultrastructural defects in the cilia or flagella of cells, causing respiratory abnormalities, sinusitis, visceral transposition, and male infertility. DNAAF3 plays an important role in the assembly and transportation of axonemal dynein complexes in cilia or flagella and has been shown to be associated with PCD. To date, only two cases of PCD with infertility associated with DNAAF3 mutations have been reported, and no mouse models for this gene have been successfully constructed. This study was conducted on an infertile Chinese male patient with a history of bronchitis. Examination of the patient's semen revealed severe asthenozoospermia and teratospermia. Whole exome sequencing revealed a new homozygous loss‐of‐function DNAAF3 mutation. CRISPR‐Cas9 gene‐editing technology was used to construct the same mutation in C57/B6 mice, revealing that homozygous C57/B6 mice were characterized by severe hydrocephalus and early death. The results of this study expand the mutation spectrum of DNAAF3 and confirm its correlation with PCD pathogenesis. This study provides new insights on the mechanisms underlying male infertility related to DNAAF3 mutation and PCD. [ABSTRACT FROM AUTHOR]

Background: Primary ciliary dyskinesia (PCD) is a group of rare genetically heterogeneous disorders caused by defective cilia and flagella motility. The clinical phenotype of PCD patients commonly includes chronic oto-sino-pulmonary disease, infertility, and, in about half of cases, laterality defects due to randomization of left–right body asymmetry. To date, pathogenic variants in more than 50 genes responsible for motile cilia structure and assembly have been reported in such patients. While multiple population-specific mutations have been described in PCD cohorts from different countries, the data on genetic spectrum of PCD in Russian population are still extremely limited. Results: The present study provides a comprehensive clinical and genetic characterization of 21 Russian families with PCD living in various country regions. Anomalies of ciliary beating in patients' respiratory epithelial cells were confirmed by high-speed video microscopy. In the most cases, custom-designed panel sequencing allowed to uncover causative variants in well-known or rarely mentioned PCD-related genes, including DNAH5, DNAH11, CFAP300, LRRC6, ZMYND10, CCDC103, HYDIN, ODAD4, DNAL1, and OFD1. The variations comprised common mutations, as well as novel genetic variants, some of which probably specific for Russian patients. Additional targeted analysis of mRNA transcripts from ciliated cells enabled us to specify functional effects of newly identified genetic variants in DNAH5 (c.2052+3G>T, c.3599-2A>G), HYDIN (c.10949-2A>G, c.1797C>G), and ZMYND10 (c.510+1G>C) on splicing process. In particular, the splice site variant c.2052+3G>T, detected in four unrelated families, resulted in skipping of exon 14 in DNAH5 transcripts and, according to haplotype analysis of affected probands, was proposed as an ancestral founder mutation in Udmurt population. Conclusions: The reported data provide a vital insight into genetic background of primary ciliary dyskinesia in the Russian population. The findings clearly illustrate the utility of gene panel sequencing coupled with transcriptional analysis in identification and clinical interpretation of novel genetic variants. [ABSTRACT FROM AUTHOR]

Background: Primary ciliary dyskinesia (PCD) is a rare genetical disease with malfunction of the motile cilia leading to impaired muco-ciliary clearance in the respiratory tract. There is no cure for PCD, only supportive therapy aimed at minimizing the progression of the disease and improving the patient's quality of life (QoL). Physical activity (PA) is one of these recommended supportive therapies for people with PCD (pwPCD). However, there is no scientific evidence to support this recommendation. In addition, regular medical advice to increase PA remains largely ineffective in pwPCD. Methods: To test the main hypothesis, that an individualized and supported PA program leads to a better QoL 6 months after randomization (QoL-PCD questionnaire) compared to usual recommendation in pwPCD, 158 pwPCD aged 7 to 55 years are to be included in this multi-center randomized controlled trial (RCT). After the screening visit, a 1:1 randomization stratified by age group and FEV1 will be performed. A QoL-PCD questionnaire, motor test, and lung function will be carried out at regular intervals in both groups. PA is recorded in both groups using activity trackers during the study period. The main aim of the trial is to estimate the difference in the change of QoL between the groups after 6 months. Therefore, our full analysis set consists of all randomized patients and analysis is performed using the intention-to-treat principle. Statistical software R (http://www.r-project.org) is used. Ethical approvement without any reservations: RUB Bochum Ethics Committee (No. 23–7938; December 4, 2023). Recruitment start: March 2024. Discussion: Limitations result from the rarity of PCD with its broad disease spectrum and the large age range. These are reduced by stratified randomization and the measurement of the individual change in QoL as primary endpoint. In our view, only a PA program tailored to individual needs with close contact to trainers offers the chance to meet personal needs of pwPCD and to establish PA as a pillar of therapy in the long term. The study protocol explains all procedures and methods of recruitment, implementation of the study visits and intervention, measures for patient and data safety, and for minimizing risks and bias. Trial registration: German Clinical Trials Register (DRKS) 00033030. Registered on December 7, 2023. Update 10 July 2024. Study protocol version 10: Version 1.2; 12 June 2024 [ABSTRACT FROM AUTHOR]

Several chronic respiratory diseases could be risk factors for acquiring SARS-CoV-2 infection: among them, Primary Ciliary Dyskinesia (PCD) is a rare (about 1:10.000) inherited ciliopathy (MIM 242650) characterized by recurrent upper and lower respiratory tract infections due to a dysfunction of the respiratory cilia. In this study, we aimed to investigate whether PCD subjects are more susceptible to infection by SARS-CoV-2 and whether some polymorphisms of the TAS2R38 bitter taste receptor correlate with an increased prevalence of SARS-CoV-2 infection and severity of symptoms. Patients answered several questions about possible SARS-CoV-2 infection, experienced symptoms, and vaccinations; in the case of infection, they also filled out a SNOT-22 questionnaire and ARTIQ. Forty PCD adult patients (mean age, 36.6 ± 16.7 years; 23 females, 17 males) participated in this study, out of which 30% had tested positive for COVID-19 during the last four years; most of them reported a mildly symptomatic disease. We found no differences in age or sex, but a statistically significant difference (p = 0.03) was observed in body mass index (BMI), which was higher in the COVID-acquired group (23.2 ± 3.3 vs. 20.1 ± 4.1 kg/m2). Genotyping for TAS2R38 polymorphisms showed a prevalence of 28.6% PAV/PAV, 48.6% PAV/AVI, and 22.8% AVI/AVI individuals in our cohort. In contrast to our hypothesis, we did not observe a protective role of the PAV allele towards SARS-CoV-2 infection. Conclusions: Our findings suggest that subjects with PCD may not be at increased risk of severe outcomes from COVID-19 and the TAS2R38 bitter taste receptor genotype does not affect SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by alterations in motile cilia function. The diagnosis of PCD is challenging due to the lack of standardized methods in clinical practice. High-speed video microscopy analysis (HSVA) directly evaluates ciliary beat frequency (CBF) in PCD. Recently, open-source ciliary analysis software applications have shown promise in measuring CBF accurately. However, there is limited knowledge about the performance of different software applications, creating a gap in understanding their comparative effectiveness in measuring CBF in PCD. We compared two open-source software applications, CiliarMove (v219) and Cilialyzer (v1.2.1-b3098cb), against the manual count method. We used high-speed videos of nasal ciliary brush samples from PCD RSPH4A-positive (PCD (RSPH4A)) patients and healthy controls. All three methods showed lower median CBF values for patients with PCD (RSPH4A) than in healthy controls. CiliarMove and Cilialyzer identified lower CBF in patients with PCD (RSPH4A), similarly to the manual count. Cilialyzer, CiliarMove, and manual count methods demonstrated statistical significance (p-value < 0.0001) in the difference of median CBF values between patients with PCD (RSPH4A) and healthy controls. Correlation coefficients between the manual count values against both software methods demonstrated positive linear relationships. These findings support the utility of open-source software-based analysis tools. Further studies are needed to validate these findings with other genetic variants and identify the optimal software for accurate CBF measurement in patients with PCD. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is a hereditary disease caused by genes related to motile cilia. We report two male pediatric cases of PCD caused by hemizygous pathogenic variants in the OFD1 centriole and centriolar satellite protein (OFD1) gene. The variants were NM_003611.3: c.[2789_2793delTAAAA] (p.[Ile930LysfsTer8]) in Case 1 and c.[2632_2635delGAAG] (p.[Glu878LysfsTer9]) in Case 2. Both cases had characteristic recurrent respiratory infections. Neither case had symptoms of oral‐facial‐digital syndrome type I. We identified a variant (c.2632_2635delGAAG) that has not been previously reported in any case of OFD1‐PCD. [ABSTRACT FROM AUTHOR]

Though PCD usually presents after birth in term neonates, diagnosing PCD during the neonatal and infancy stages is uncommon, particularly in children who do not exhibit laterality defects. We report our recent experience with the diagnosis of PCD in the neonatal and early infantile period in a highly consanguine population. This was achieved by implementing a novel genetic-based diagnostic approach based on direct testing for recognized regional genetic variants. We conducted a retrospective analysis of children diagnosed with PCD at Soroka University Medical Center during the neonatal or early infantile period between 2020 and 2023. We included children under 3 months of age who had a genetic confirmation of PCD, as evidenced by the presence of two pathogenic variants in recognized genes. Genetic testing targeted regional genetic variants in previously identified PCD genes. Eight patients were included. The median age at diagnosis was 12.5 days. Three (38%) were born prematurely < 34 weeks gestational age. All patients were presented with respiratory distress and hypoxemia after birth. The median duration of oxygen support was 23 days, and upper lobe atelectasis was present in five patients (63%). Congenital cardiac malformation was present in four patients. Organ laterality defects were present in four patients. Genetic mutations identified were in the DNAAF5, DNAL1, DNAAF3, and DNAH1 genes. Conclusion: Neonatal diagnosis of PCD is uncommon, especially in atypical presentations such as children without laterality defects or preterms. Focusing on a genetic diagnosis of the local tribal pathogenic variants promotes a potential cost-efficient test leading to earlier diagnosis. There is a need for a standardized protocol for earlier diagnosis of PCD in high-consanguinity areas. What is Known: • Primary ciliary dyskinesia (PCD) typically presents after birth in term neonates. • Diagnosing PCD during neonatal and infancy stages is challenging, particularly in children without laterality defects. What is New: • A novel genetic-based diagnostic approach was implemented on the neonatal population in a highly consanguine community, focusing on direct testing for regional genetic variants, leading to early and rapid diagnosis of PCD. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is a rare, chronic genetic condition with variable features arising from motile cilia dysfunction, including recurrent respiratory infections, sinonasal disease, reduced hearing, infertility and situs inversus. The aim of the study was to understand the experiences of young people with PCD as they transition into adulthood and adult healthcare services. An interpretative phenomenological analytical method was applied. Semi-structured interviews were conducted with three participants aged 18–24 years. Four interconnected group experiential themes were identified: (1) reconceptualising a stigmatised identity, (2) sharing the journey to independence, (3) entering adulthood with newfound autonomy, (4) anticipating an uncertain future. Overall, we found that transition for young people with PCD presents as a complex period marked by identity-formation, creating systems of support and becoming an autonomous adult. Facilitation of personalised and integrated approaches to care should be prioritised. Our findings are important to help health professionals provide appropriate, anticipatory support. [ABSTRACT FROM AUTHOR]

Introduction: Primary ciliary dyskinesia (PCD) is caused by the dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. This study aimed to map novel PCD variants and determine their pathogenicity in PCD patients in Kuwait. Methods: Herein, we present five PCD individuals belonging to a cohort of 105 PCD individuals recruited from different hospitals in Kuwait. Genomic DNAs from the family members were analysed to screen for pathogenic PCD variants. Transmission electron microscopy (TEM) and immunofluorescence (IF) analyses were performed on the nasal biopsies to detect specific structural abnormalities within the ciliated cells. Results: Genetic screening and functional analyses confirmed that the five PCD individuals carried novel pathogenic variants of DNAH5 causing PCD in three Arabic families. Of these, one multiplex family with two affected individuals showed two novel homozygous missense variants in DNAH5 causing PCD with situs inversus; another multiplex family with two affected individuals showed two newly identified compound heterozygous variants in DNAH5 causing PCD with situs solitus. In addition, novel heterozygous variants were identified in a child with PCD and situs solitus from a singleton family with unrelated parents. TEM analysis demonstrated the lack of outer dynein arms (ODAs) in all analysed samples, and IF analysis confirmed the absence of the dynein arm component of DNAH5 from the ciliary axoneme. Conclusion: The newly identified pathogenic variants of DNAH5 are associated with PCD as well as variable pulmonary clinical manifestations in Arabic families. [ABSTRACT FROM AUTHOR]

Disease-causing bi-allelic DNA variants in CCDC39 and CCDC40 are frequent causes of the hereditary disorder of primary ciliary dyskinesia (PCD). The encoded proteins form a molecular ruler complex, crucial for maintaining the 96 nm repeat units along the ciliary axonemes. Defects of those proteins cause a stiff, rapid, and flickery ciliary beating pattern, recurrent respiratory infections, axonemal disorganization, and abnormal assembly of GAS8, CCDC39, and DNALI1. We performed molecular characterization of the defects in the 96 nm axonemal ruler due to disease-causing variants in CCDC39 and CCDC40 and analyzed the effect on additional axonemal components. We identified a cohort of 51 individuals with disease-causing variants in CCDC39 and CCDC40 via next-generation sequencing techniques and demonstrated that the IDA heavy chains DNAH1, DNAH6, and DNAH7 are conspicuously absent within the respiratory ciliary axonemes by immunofluorescence analyses. Hence, we show for the first time that the centrin2 (CETN2) containing IDAs are also affected. These findings underscore the crucial role of CCDC39 and CCDC40 in the assembly and function of IDAs in human respiratory cilia. Thus, our data improve the diagnostics of axonemal ruler defects by further characterizing the associated molecular IDA defects. [ABSTRACT FROM AUTHOR]

Background: Primary ciliary dyskinesia (PCD) is an autosomal recessive hereditary disease characterized by recurrent respiratory infections. In clinical manifestations, DNAH5 (NM_001361.3) is one of the recessive pathogenic genes. Primary familial brain calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcification in the basal ganglia and other brain regions. PFBC can be inherited in an autosomal dominant or recessive manner. A family with PCD caused by a DNAH5 compound heterozygous variant and PFBC caused by a MYORG homozygous variant was analyzed. Methods: In this study, we recruited three generations of Han families with primary ciliary dyskinesia combined with primary familial brain calcification. Their clinical phenotype data were collected, next-generation sequencing was performed to screen suspected pathogenic mutations in the proband and segregation analysis of families was carried out by Sanger sequencing. The mutant and wild-type plasmids were constructed and transfected into HEK293T cells instantaneously, and splicing patterns were detected by Minigene splicing assay. The structure and function of mutations were analyzed by bioinformatics analysis. Results: The clinical phenotypes of the proband (II10) and his sister (II8) were bronchiectasis, recurrent pulmonary infection, multiple symmetric calcifications of bilateral globus pallidus and cerebellar dentate nucleus, paranasal sinusitis in the whole group, and electron microscopy of bronchial mucosa showed that the ciliary axoneme was defective. There was also total visceral inversion in II10 but not in II8. A novel splice variant C.13,338 + 5G > C and a frameshift variant C.4314delT (p. Asn1438lysfs *10) were found in the DNAH5 gene in proband (II10) and II8. c.347_348dupCTGGCCTTCCGC homozygous insertion variation was found in the MYORG of the proband. The two pathogenic genes were co-segregated in the family. Minigene showed that DNAH5 c.13,338 + 5G > C has two abnormal splicing modes: One is that part of the intron bases where the mutation site located is translated, resulting in early translation termination of DNAH5; The other is the mutation resulting in the deletion of exon76. Conclusions: The newly identified DNAH5 splicing mutation c.13,338 + 5G > C is involved in the pathogenesis of PCD in the family, and forms a compound heterozygote with the pathogenic variant DNAH5 c.4314delT lead to the pathogenesis of PCD. [ABSTRACT FROM AUTHOR]

TTC12 is a cytoplasmic and centromere-localized protein that plays a role in the proper assembly of dynein arm complexes in motile cilia in both respiratory cells and sperm flagella. This finding underscores its significance in cellular motility and function. However, the wide role of TTC12 in human spermatogenesis-associated primary ciliary dyskinesia (PCD) still needs to be elucidated. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify potentially pathogenic variants causing PCD and multiple morphological abnormalities of sperm flagella (MMAF) in an infertile Pakistani man. Diagnostic imaging techniques were used for PCD screening in the patient. Real-time polymerase chain reaction (RT‒PCR) was performed to detect the effect of mutations on the mRNA abundance of the affected genes. Papanicolaou staining and scanning electron microscopy (SEM) were carried out to examine sperm morphology. Transmission electron microscopy (TEM) was performed to examine the ultrastructure of the sperm flagella, and the results were confirmed by immunofluorescence staining. Using WES and Sanger sequencing, a novel homozygous missense variant (c.C1069T; p.Arg357Trp) in TTC12 was identified in a patient from a consanguineous family. A computed tomography scan of the paranasal sinuses confirmed the symptoms of the PCD. RT–PCR showed a decrease in TTC12 mRNA in the patient's sperm sample. Papanicolaou staining, SEM, and TEM analysis revealed a significant change in shape and a disorganized axonemal structure in the sperm flagella of the patient. Immunostaining assays revealed that TTC12 is distributed throughout the flagella and is predominantly concentrated in the midpiece in normal spermatozoa. In contrast, spermatozoa from patient deficient in TTC12 showed minimal staining intensity for TTC12 or DNAH17 (outer dynein arms components). This could lead to MMAF and result in male infertility. This novel TTC12 variant not only illuminates the underlying genetic causes of male infertility but also paves the way for potential treatments targeting these genetic factors. This study represents a significant advancement in understanding the genetic basis of PCD-related infertility. [ABSTRACT FROM AUTHOR]

Objectives: Coronavirus disease 2019 pandemic caused many changes in the social behaviors of individuals and the provision of health systems. Many studies revealed reductions in the number of diagnoses and delays in diagnosis time during the pandemic. This study aimed to evaluate the effect of the pandemic on the time to diagnosis of major diseases of pediatric pulmonology. Materials and Methods: Newly diagnosed patients with cystic fibrosis (CF), childhood interstitial lung disease (chILD), tuberculosis (TB), and primary ciliary dyskinesia (PCD) were grouped into pandemic (group 1) and 2 consecutive pre-pandemic periods divided into equal intervals (groups 2 and 3). For each disease group, the time to diagnosis was compared between the specified periods. Results: A total number of patients were 171 in this study. In the CF group, there was no statistically difference in time to diagnosis between periods. In the chILD group, there was a statistically significant difference in time to diagnosis (P = .036) between groups (group 1: 2 months, group 2: 4 months and group 3: 10.5 months) that was not originated from pandemic period. In TB group there was no statistically significant difference between groups. In the PCD group, the impact of the pandemic on the time to diagnosis could not be clarified because the time interval to diagnosis (minimum: 2 years, maximum: 16 years) exceeded the studied periods (21 months). Conclusion: In our study, no effect found between the pandemic and age at diagnosis or time to diagnosis in patients with PCD, chILD, CF, and TB at our center. [ABSTRACT FROM AUTHOR]

Kartagener’s Syndrome, alternatively known as Primary Ciliary Dyskinesia (PCD) is a rare and intricate inherited disorder that impacts the structure and function of cilia, leading to compromised mucociliary clearance. The defining features of this condition consist of chronic sinusitis, situs inversus totalis, and bronchiectasis, forming a characteristic triad. Kartagener’s Syndrome presents numerous challenges in its diagnosis and management, and its clinical implications have significant ramifications for affected individuals. This review aims to comprehensively review and analyse the clinical impact of this syndrome, focusing on the diagnosis, treatment, and management modalities. The ciliary dysfunction in Kartagener’s Syndrome disrupts the mucus clearance and pathogens from the respiratory tract, resulting in chronic infections, progressive lung damage, and respiratory failure in severe cases. Through a narrative review of literature, reviews, and case studies, the authors have explored clinicians’ diagnostic challenges and the advances in genetic testing methods that aid in early and accurate diagnosis. The authors have discussed the multidisciplinary approach to manage Kartagener’s Syndrome, which involves respiratory therapies, antibiotics, and surgical interventions to improve the patient’s quality of life and prevent complications. The review paper also includes in-depth case studies of individuals with Kartagener’s Syndrome, highlighting the variability in clinical presentations and treatment outcomes. These case studies provide valuable insights into the diverse manifestations of this syndrome, further enhancing the existing understanding of the disease and its management. Ultimately, this review is directed to raise awareness among healthcare professionals about Kartagener’s Syndrome, its clinical implications, and its diagnostic and treatment challenges. By shedding light on this rare and intricate genetic disorder, the authors here promote early recognition and proactive management, leading to improved outcomes and better quality of life for individuals with Kartagener’s Syndrome. [ABSTRACT FROM AUTHOR]

This article explores the advancements in rhinology, focusing on the use of artificial intelligence, technology, and innovative techniques. It discusses how these advancements have improved diagnosis, treatment planning, and patient care options. The article also highlights the integration of virtual reality and augmented reality in surgical preparation, as well as the use of artificial intelligence and machine learning algorithms in decision-making and personalized patient care. Additionally, it mentions the potential of mobile health technology applications in improving patient compliance and disease management. The article concludes by discussing future innovations and emphasizes the importance of maintaining the human connection in medicine. [Extracted from the article]

STUDY QUESTION What is the prevalence of infertility and ectopic pregnancies among individuals with primary ciliary dyskinesia (PCD)? SUMMARY ANSWER We found that 39 of 50 men (78%) and 72 of 118 women (61%) with PCD were infertile and that women with PCD had an increased risk of ectopic pregnancies (7.6 per 100 pregnancies, 95% CI 4.7–12.2). WHAT IS KNOWN ALREADY PCD is a heterogeneous multiorgan disease caused by mutations in genes required for the function and structure of motile cilia. Previous studies identified a link between PCD and infertility, but original data on prevalence of infertility and risk of ectopic pregnancies, the use and efficacy of medically assisted reproduction (MAR), and the association of fertility with PCD genotype are extremely limited. STUDY DESIGN, SIZE, DURATION We performed a cross-sectional survey about fertility within the Living with PCD study (formerly COVID-PCD). Living with PCD is an international, online, participatory study that collects information directly from people with PCD. People with PCD of any age from anywhere in the world can participate in the study. At the time of the survey, 482 adults with PCD were registered within the Living with PCD study. PARTICIPANTS/MATERIALS, SETTING, METHODS We sent a questionnaire on fertility on 12 July 2022, to all participants older than 18 years enrolled in the Living with PCD study. Responses were collected until 8 March 2023. The fertility questionnaire covered topics related to pregnancy attempts, use of MAR, and pregnancy outcomes. Data were collected via the Research Electronic Data Capture (REDCap) platform. We defined infertility as failure to achieve a clinical pregnancy after 12 months or use of MAR for at least one pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE In total, 265 of 482 adult participants (55%) completed the fertility questionnaire. Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile. Of the infertile men, 28 had tried MAR, and 17 of them (61%) fathered a child with the help of MAR. Among infertile women, 59 had used MAR, and 41 of them (69%) became pregnant with the help of MAR. In our population, women with PCD showed a relatively high risk of ectopic pregnancies: 1 in 10 women who became pregnant had at least one ectopic pregnancy and 7.6% of pregnancies were ectopic (95% CI 4.7–12.2). We evaluated the association between fertility and affected PCD genes in 46 individuals (11 men, 35 women) with available genetic and fertility information, and found differences between genotypes, e.g. all five women with a mutation in CCDC40 were infertile and all five with DNAH11 were fertile. LIMITATIONS, REASONS FOR CAUTION The study has limitations, including potential selection bias as people experiencing problems with fertility might be more likely to fill in the questionnaire, which may have influenced our prevalence estimates. We were unable to validate clinical data obtained from participant self-reports owing to the anonymous study design, which is likely to lead to recall bias. WIDER IMPLICATIONS OF THE FINDINGS The study underlines the need for addressing infertility in routine PCD care, with a focus on informing individuals with PCD about their increased risk. It emphasizes the utility and efficacy of MAR in PCD-related infertility. Additionally, women attempting conception should be made aware of the increased risk of ectopic pregnancies and seek systematic early consultation to confirm an intrauterine pregnancy. Fertility, efficacy of MAR, and risk for adverse pregnancy outcomes differ between people with PCD—depending on genotypes—and close monitoring and support might be needed from fertility specialists to increase chances of successful conception. STUDY FUNDING/COMPETING INTEREST(S) Our research was funded by the Swiss National Science Foundation, Switzerland (SNSF 320030B_192804), the Swiss Lung Association, Switzerland (2021-08_Pedersen), and we also received support from the PCD Foundation, USA; the Verein Kartagener Syndrom und Primäre Ciliäre Dyskinesie, Germany; the PCD Support UK, UK; and PCD Australia, Australia. M. Goutaki received funding from the Swiss National Science Foundation, Switzerland (PZ00P3_185923). B. Maitre participates in the RaDiCo-DCP funded by INSERM France. The study authors participate in the BEAT-PCD Clinical Research Collaboration supported by the European Respiratory Society. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER ClinicalTrials.gov ID NCT04602481. [ABSTRACT FROM AUTHOR]