Introduction of Ivacaftor/Lumacaftor in Children With Cystic Fibrosis Homozygous for F508del in the Netherlands: A Nationwide Real-Life Study.

Introduction: Lumacaftor/ivacaftor (lum/iva) was introduced in the Netherlands in 2017. We investigated 1-year efficacy of lum/iva on lung function and small airway and structural lung disease evaluated by multiple breath nitrogen washout and CT scan. Additionally, we investigated effects of lum/iva on exacerbations, anthropometry, sweat chloride and safety in children with CF in the Netherlands.

Structural insights into brassinosteroid export mediated by the Arabidopsis ABC transporter ABCB1.

Brassinosteroids (BRs) are steroidal phytohormones indispensable for plant growth, development, and responses to environmental stresses. The export of bioactive BRs to the apoplast is essential for BR signaling initiation, which requires binding of a BR molecule to the extracellular domains of the plasma membrane-localized receptor complex. We have previously shown that the Arabidopsis thaliana ATP-binding cassette (ABC) transporter ABCB19 functions as a BR exporter and, together with its close homolog ABCB1, positively regulates BR signaling.

Gout diagnoses uncertain when made by general practitioners without serum uric acid testing: an observational study.

Objective: General practitioners (GPs) diagnose the majority of all gout patients. They make their diagnosis clinically. Serum uric acid (SUA) level >0.

Small Airways Disease Affects Aerosol Deposition in Children with Severe Asthma: A Functional Respiratory Imaging Study.

Small airways disease (SAD) in severe asthma (SA) is associated with high disease burden. Effective treatment of SAD could improve disease control. Reduced end-expiratory flows (forced expiratory flow [FEF] and FEF) are considered sensitive indicators of SAD.

A UPLC-MS/MS method for quantification of metabolites in the ethylene biosynthesis pathway and its biological validation in Arabidopsis.

The plant hormone ethylene is of vital importance in the regulation of plant development and stress responses. Recent studies revealed that 1-aminocyclopropane-1-carboxylic acid (ACC) plays a role beyond its function as an ethylene precursor. However, the absence of reliable methods to quantify ACC and its conjugates malonyl-ACC (MACC), glutamyl-ACC (GACC), and jasmonyl-ACC (JA-ACC) hinders related research.

Structure and function of the ABC transporter ABCB19 in brassinosteroid export.

Brassinosteroids are steroidal phytohormones that regulate plant development and physiology, including adaptation to environmental stresses. Brassinosteroids are synthesized in the cell interior but bind receptors at the cell surface, necessitating a yet to be identified export mechanism. Here, we show that a member of the ATP-binding cassette (ABC) transporter superfamily, ABCB19, functions as a brassinosteroid exporter.

Subtherapeutic triazole concentrations as result of a drug-drug interaction with lumacaftor/ivacaftor.

Lumacaftor/ivacaftor (Orkambi®, LUM/IVA) is indicated for the treatment of cystic fibrosis (CF) patients aged ≥ 2 years with homozygous F580del mutation in the CFTR gene. Triazole fungal agents are used to treat fungal disease in CF. The use of triazoles is limited by pharmacokinetic challenges, such as drug-drug interactions.

Key inflammatory markers in bronchoalveolar lavage predict bronchiectasis progression in young children with CF.

Introduction: Inflammation appears early in cystic fibrosis (CF) pathogenesis, with specific elevated inflammatory markers in bronchoalveolar lavage fluid (BALF) correlating with structural lung disease. Our aim was to identify markers of airway inflammation able to predict bronchiectasis progression over two years with high sensitivity and specificity.

Methods: Children with CF with two chest computed tomography (CT) scans and bronchoscopies at a two-year interval were included (n= 10 at 1 and 3 years and n= 27 at 3 and 5 years).

Children with severe asthma have substantial structural airway changes on computed tomography.

Background: In adults with severe asthma (SA) bronchial wall thickening, bronchiectasis and low attenuation regions (LAR) have been described on chest computed tomography (CT) scans. The extent to which these structural abnormalities are present in children with SA is largely unknown. Our aim was to study the presence and extent of airway abnormalities on chest CT of children with SA.

CFTR Function Restoration upon Elexacaftor/Tezacaftor/Ivacaftor Treatment in Patient-Derived Intestinal Organoids with Rare Genotypes.

Cystic fibrosis (CF) is caused by mutations in the () gene. The combination of the CFTR modulators elexacaftor, tezacaftor, and ivacaftor (ETI) enables the effective rescue of CFTR function in people with the most prevalent F508del mutation. However, the functional restoration of rare variants remains unclear.

Exploratory study of risk factors related to SARS-CoV-2 prevalence in nursing homes in Flanders (Belgium) during the first wave of the COVID-19 pandemic.

In a previous study in Belgian nursing homes (NH) during the first wave of the COVID-19 pandemic, we found a SARS-CoV-2 seroprevalence of 17% with a large variability (0-45%) between NH. The current exploratory study aimed to identify nursing home-specific risk factors for high SARS-CoV-2 seroprevalence. Between October 19th, 2020 and November 13th, 2020, during the second COVID-19 wave in Belgium, capillary blood was collected on dried blood spots from 60 residents and staff in each of the 20 participating NH in Flanders and Brussels.

Comparison of prone and supine positioning for breast cancer radiotherapy using REQUITE data: dosimetry, acute and two years physician and patient-reported outcomes.

Objective: Most patients receive whole breast radiotherapy in a supine position. However, two randomised trials showed lower acute toxicity in prone position. Furthermore, in most patients, prone positioning reduced doses to the organs at risk.

Airway macrophages display decreased expression of receptors mediating and regulating scavenging in early cystic fibrosis lung disease.

Background: Cystic fibrosis (CF) airway disease is characterized by chronic inflammation, featuring neutrophil influx to the lumen. Airway macrophages (AMs) can promote both inflammation and resolution, and are thus critical to maintaining and restoring homeostasis. CF AM functions, specifically scavenging activity and resolution of inflammation, have been shown to be impaired, yet underlying processes remain unknown.

16S rRNA-Based Microbiota Profiling Assists Conventional Culture Analysis of Airway Samples from Pediatric Cystic Fibrosis Patients.

16S-based sequencing provides broader information on the respiratory microbial community than conventional culturing. However, it (often) lacks species- and strain-level information. To overcome this issue, we used 16S rRNA-based sequencing results from 246 nasopharyngeal samples obtained from 20 infants with cystic fibrosis (CF) and 43 healthy infants, which were all 0 to 6 months old, and compared them to both standard (blind) diagnostic culturing and a 16S-sequencing-informed "targeted" reculturing approach.

Minimizing Aerosol Leakage from Facemasks in the COVID-19 Pandemic.

Aerosol therapies with vented facemasks are considered a risk for nosocomial transmission of viruses such as severe acute respiratory syndrome coronavirus 2. The transmission risk can be decreased by minimizing aerosol leakage and filtering the exhaled air. In this study, we determined which closed facemask designs show the least leakage.

Management of respiratory tract exacerbations in people with cystic fibrosis: Focus on imaging.

Respiratory tract exacerbations play a crucial role in progressive lung damage of people with cystic fibrosis, representing a major determinant in the loss of functional lung tissue, quality of life and patient survival. Detection and monitoring of respiratory tract exacerbations are challenging for clinicians, since under- and over-treatment convey several risks for the patient. Although various diagnostic and monitoring tools are available, their implementation is hampered by the current definition of respiratory tract exacerbation, which lacks objective "cut-offs" for clinical and lung function parameters.

Macrophage PD-1 associates with neutrophilia and reduced bacterial killing in early cystic fibrosis airway disease.

Background: Macrophages are the major resident immune cells in human airways coordinating responses to infection and injury. In cystic fibrosis (CF), neutrophils are recruited to the airways shortly after birth, and actively exocytose damaging enzymes prior to chronic infection, suggesting a potential defect in macrophage immunomodulatory function. Signaling through the exhaustion marker programmed death protein 1 (PD-1) controls macrophage function in cancer, sepsis, and airway infection.

Discovery of a Novel Class of d-Amino Acid Oxidase Inhibitors Using the Schrödinger Computational Platform.

d-Serine is a coagonist of the -methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme activity to NMDA dysfunction and schizophrenia.

Pre-vaccination SARS-CoV-2 seroprevalence among staff and residents of nursing homes in Flanders (Belgium) in fall 2020.

Seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibodies, using dried blood spots, was determined in October–November 2020, among residents and staff randomly selected from 20 nursing homes (NH) geographically distributed in Flanders, Belgium. Sociodemographic and medical data [including coronavirus disease 2019 (COVID-19) symptoms and results of RT-PCR tests] were retrieved using questionnaires. The overall seroprevalence was 17.

Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers.

Background: In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR)-dependent bicarbonate secretion precipitates the accumulation of viscous mucus in the lumen of respiratory and gastrointestinal epithelial tissues. We investigated whether the combination of elexacaftor (ELX), ivacaftor (IVA) and tezacaftor (TEZ), apart from its well-documented effect on chloride transport, also restores Phe508del-CFTR-mediated bicarbonate transport.

Methods: Epithelial monolayers were cultured from intestinal and biliary (cholangiocyte) organoids of homozygous Phe508del-CFTR patients and controls.

Small airways targeted treatment with smart nebulizer technology could improve severe asthma in children: a retrospective analysis.

Objective: Conventional inhaler devices have a low efficacy in targeting small airways. Smart nebulizers can be used to increase deposition to small airways by adjusting the flow and depth of each inhalation based on patients 'individual inspiratory capacity. We investigated whether targeting of high dose inhaled corticosteroids (ICS) to small airways with a smart nebulizer could reduce exacerbation rate in children with severe asthma (SA).