Inhibiting CFTR through inh-172 in primary neutrophils reveals CFTR-specific functional defects.

The lungs of people with cystic fibrosis (PwCF) are characterized by recurrent bacterial infections and inflammation. Infections in cystic fibrosis (CF) are left unresolved despite excessive neutrophil infiltration. The role of CFTR in neutrophils is not fully understood.

Airway Remodeling in Cystic Fibrosis Is Heterogeneous.

RATIONALE+OBJECTIVE/ Cystic fibrosis (CF) is characterized by bronchiectasis on imaging, while functionally evolving towards obstructive impairment. Despite its assumed importance in CF, small airway remodeling and its relation to bronchiectasis, is still poorly understood. METHOD/ On high-resolution computed tomography (HRCT, 600µm, CF=21, control=6) and micro-computed tomography (µCT, 150µm, CF=3, control=1) scans of inflated explant lungs, AV% (airway/total lung volume) was calculated as marker for bronchiectasis, while airway segmentation was used for generation analysis.

Pseudo-Bartter syndrome: A CFTR-related disorder?

This case report presents a 14-month-old boy with a history of cystic fibrosis (CF) carrier status, diagnosed following a positive newborn screening for CF (CF-NBS), who developed symptoms suggestive of Pseudo-Bartter syndrome (PBS). Despite initial evaluations not meeting CF diagnostic criteria, subsequent investigations revealed an intermediate sweat chloride concentration, a second CFTR mutation, and CFTR dysfunction through rectal organoid morphology analysis (ROMA) consistent with CFTR-related disorder (CFTR-RD). This case raises important considerations regarding the diagnosis and management of CFTR-RD.

Understanding disciplinary perspectives: a framework to develop skills for interdisciplinary research collaborations of medical experts and engineers.

Background: Health professionals need to be prepared for interdisciplinary research collaborations aimed at the development and implementation of medical technology. Expertise is highly domain-specific, and learned by being immersed in professional practice. Therefore, the approaches and results from one domain are not easily understood by experts from another domain.

Rectal organoid morphology analysis (ROMA) as a novel physiological assay for diagnostic classification in cystic fibrosis.

Background: Diagnosing cystic fibrosis (CF) is not always straightforward, in particular when sweat chloride concentration (SCC) is intermediate and <2 CF-causing variants are identified. The physiological CFTR assays proposed in the guidelines, nasal potential difference and intestinal current measurement, are not readily available nor feasible at all ages. Rectal organoid morphology analysis (ROMA) was previously shown to discriminate between organoids from subjects with and without CF based on a distinct phenotypical difference: compared with non-CF organoids, CF organoids have an irregular shape and lack a visible lumen.

Single-cell RNA sequencing of cystic fibrosis liver disease explants reveals endothelial complement activation.

Background & Aims: Cystic fibrosis (CF) is considered a multisystemic disorder in which CF-associated liver disease (CFLD) is the third most common cause of mortality. Currently, no effective treatment is available for CFLD because its pathophysiology is still unclear. Interestingly, CFLD exhibits identical vascular characteristics as non-cirrhotic portal hypertension, recently classified as porto-sinusoidal vascular disorders (PSVD).

Respiratory morbidity in patients with spinal muscular atrophy-a changing world in the light of disease-modifying therapies.

Respiratory complications are common in spinal muscular atrophy (SMA) and significantly contribute to morbidity and mortality in these patients. Generalized respiratory and bulbar muscle weakness translates into diverse and complex clinical consequences necessitating strict follow-up and specialized care. The natural history of SMA has evolved drastically in recent years as a result of the introduction of novel, disease-modifying therapies.

Association between upper and lower respiratory disease among patients with primary ciliary dyskinesia: an international study.

Introduction: Nearly all patients with primary ciliary dyskinesia (PCD) report ear-nose-throat (ENT) symptoms. However, scarce evidence exists about how ENT symptoms relate to pulmonary disease in PCD. We explored possible associations between upper and lower respiratory disease among patients with PCD in a multicentre study.

Long-term evaluation of faecal calprotectin levels in a European cohort of children with cystic fibrosis.

Objective: Intestinal inflammation with contradictory data on faecal calprotectin (fCP) levels is documented in patients with cystic fibrosis (CF). The aim of this study was to longitudinally evaluate fCP in a cohort of children with CF and their relationship with clinical variables.

Design: Prospective observational study to assess evolution of fCP levels, primary aimed at improving fat absorption.

Sinonasal disease among patients with primary ciliary dyskinesia: an international study.

Background: Sinonasal symptoms are a common feature of primary ciliary dyskinesia (PCD); however, literature about their severity and frequency, particularly during the life course, is scarce. Using baseline data from the Ear, nose and throat (ENT) Prospective International Cohort of PCD patients, we describe sinonasal disease in PCD.

Methods: We included participants who had a routine sinonasal examination during which they completed a symptoms questionnaire.

Post-operative Outcomes for Vascular Rings: A Systematic Review and Meta-analysis.

Objectives: Vascular rings may cause tracheal and/or oesophageal compression. For many patients, symptoms/signs have been present for a long period before diagnosis. However, in the era of prenatal diagnosis, some units advocate universal early surgery.

Understanding and managing respiratory infections in children and young adults with neurological impairment.

Introduction: Patients with neurocognitive impairment (NI) have multiple medical needs, with respiratory problems leading to an important reduction in quality of life and life expectancy. We aimed to explain that the origin of chronic respiratory symptoms in patients with NI is multifactorial.

Areas Covered: In people with NI there is a high prevalence of swallowing dysfunction and hypersalivation inducing aspiration; cough efficacy is decreased resulting in chronic lung infection; sleep-disordered breathing is frequent and muscle mass is abnormal due to malnutrition.

The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity.

Severity of the S1251N allele in cystic fibrosis is affected by the presence of the F508C variant in cis.

Background: In cystic fibrosis (CF), genotype-phenotype correlation is complicated by the large number of CFTR variants, the influence of modifier genes, environmental effects, and the existence of complex alleles. We document the importance of complex alleles, in particular the F508C variant present in cis with the S1251N disease-causing variant, by detailed analysis of a patient with CF, with the [S1251N;F508]/G542X genotype and a very mild phenotype, contrasting it to that of four subjects with the [S1251N;F508C]/F508del genotype and classical CF presentation.

Methods: Genetic differences were identified by Sanger sequencing and CFTR function was quantified using rectal organoids in rectal organoid morphology analysis (ROMA) and forskolin-induced swelling (FIS) assays.

The Short Term Influence of Chest Physiotherapy on Lung Function Parameters in Children With Cystic Fibrosis and Primary Ciliary Dyskinesia.

Airway clearance therapy (ACT) is one of the cornerstone treatment modalities to improve mucociliary clearance for patients with bronchiectasis. The progression of lung disease in patients with bronchiectasis can be evaluated by spirometry and multiple breath washout (MBW) and it is advised to monitor these on a regular basis. However, the short term effect of ACT on spirometry and MBW parameters is insufficiently clear and this variability may impact standardization.

Microbial Community Composition in Explanted Cystic Fibrosis and Control Donor Lungs.

To date, investigations of the microbiota in the lungs of people with Cystic Fibrosis (PWCF) have primarily focused on microbial community composition in luminal mucus, with fewer studies observing the microbiota in tissue samples from explanted lung tissue. Here, we analysed both tissue and airway luminal mucus samples extracted from whole explanted lungs of PWCF and unused donor lungs. We determined if the lung microbiota in end-stage CF varied within and between patients, was spatially heterogeneous and related to localized structural damage.

Lung function from school age to adulthood in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the International PCD Cohort and calculated z-scores for forced expiratory volume in 1 s (FEV), forced vital capacity (FVC) and FEV/FVC ratio using the Global Lung Function Initiative 2012 references.

Assays of CFTR Function In Vitro, Ex Vivo and In Vivo.

Cystic fibrosis, a multi-organ genetic disease, is characterized by abnormal function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel at the apical membrane of several epithelia. In recent years, therapeutic strategies have been developed to correct the CFTR defect. To evaluate CFTR function at baseline for diagnosis, or the efficacy of CFTR-restoring therapy, reliable tests are needed to measure CFTR function, in vitro, ex vivo and in vivo.