J Allergy Clin Immunol. 2024 Nov 12:S0091-6749(24)01184-9. doi: 10.1016/j.jaci.2024.11.006. Online ahead of print.

ABSTRACT

Asthma is a common respiratory condition with various phenotypes, non-specific symptoms and variable clinical course. The occurrence of other respiratory conditions with asthma, respiratory co-morbidities (RCs), is not unusual. A literature search was performed for asthma and a variety of respiratory co-morbidities using Pub-Med for the years 2019-2024. The 5 conditions with the largest number of references, other than rhinitis and rhinosinusitis addressed in another paper in this issue, or which are the most problematic in the authors' clinical experience are summarized. Others are briefly discussed. The diagnosis and treatment of both asthma and RCs are complicated by the overlap of symptoms and signs. Recognizing RCs is especially problematic in adult onset, non-type 2 asthma as there are no biomarkers to assist in confirming non-type 2 asthma. Treatment decisions in subjects with suspected asthma and RCs are complicated by the potential similarities between the symptoms or signs of the RC and asthma, the absence of a sine quo non for the diagnosis of asthma, the likelihood that many RCs improve with systemic corticosteroids, and the possibility that the manifestations of the RCs are misattributed to asthma or vice versa. Recognition of RCs is critical to the effective management of asthma, particularly severe or difficult to treat asthma.

PMID:39542142 | DOI:10.1016/j.jaci.2024.11.006

Laryngoscope. 2024 Dec;134(12):E39-E40. doi: 10.1002/lary.31597. Epub 2024 Jun 22.

NO ABSTRACT

PMID:39540572 | DOI:10.1002/lary.31597

Laryngoscope. 2024 Dec;134(12):E38. doi: 10.1002/lary.31598. Epub 2024 Jun 22.

NO ABSTRACT

PMID:39540571 | DOI:10.1002/lary.31598

Clin Transplant. 2024 Nov;38(11):e70023. doi: 10.1111/ctr.70023.

ABSTRACT

OBJECTIVE: We aimed to explore the prevalence and predictive factors of sleep-disordered breathing (SDB) in patients with cystic fibrosis (pwCF) after lung transplantation (LTX).

METHODS: We prospectively recruited adult pwCF who underwent LTX in our hospital from 2013 to 2022 and invited them for an attended overnight polysomnography (PSG) 1 year after transplantation. The apnea-hypopnea index (AHI) was the primary outcome, and SDB was defined as an AHI ≥ 5. Demographic, anthropometric, cardiometabolic, drug treatment, and pulmonary function variables were compared between pwCF with and without SDB. Multiple regression analysis was used to identify significant predictors of SDB. For a subset of participants who had available PSG before transplantation, sleep parameters were compared pre-post transplantation.

RESULTS: Sixty-two pwCF (31 females) were enrolled. Thirty participants had SDB, but only 11 of them had moderate-to-severe SDB (AHI ≥ 15). The average Epworth Sleepiness Scale (ESS) score indicated the absence of excessive daytime sleepiness. Older age (p < 0.001), male sex (p < 0.001), and smaller thoracic gas volume (p = 0.002) significantly predicted higher AHI. Comparison between pre- and post-transplantation polysomnographic data showed a significant increase in the percentage of slow wave sleep (p = 0.047), as well as a significant improvement in mean nocturnal oxygen saturation (p = 0.007). A statistically significant increase in the AHI was also observed (p = 0.047), but its clinical importance is uncertain (p = 0.476 for the increase in the ESS score).

CONCLUSIONS: We may conclude that SDB is prevalent in pwCF after LTX, but its severity is mild. Older male pwCF with greater improvement in lung hyperinflation after transplantation might be at risk for SDB and should be followed for symptoms or signs of sleep apnea.

PMID:39539123 | DOI:10.1111/ctr.70023

Disabil Rehabil. 2024 Nov 13:1-14. doi: 10.1080/09638288.2024.2420832. Online ahead of print.

ABSTRACT

PURPOSE: This study aimed to explore the experiences and perceptions of people with cystic fibrosis (PwCF) and multidisciplinary team (MDT) members on remote exercise services (RES) and to inform recommendations for future RES.

METHODS: Participants were recruited from an adult CF centre and through social media. Individual online semi-structured interviews were conducted. Interviews were recorded, transcribed verbatim, and thematically analysed.

RESULTS: Themes from MDT members: Accessibility and convenience offered by remote exercise services; Enhanced connections between MDT members and PwCF; Perceived health and wellness benefits of remote exercise services for PwCF; Barriers to engagement; and Suggested improvements for future remote exercise services. Themes from PwCF: Remote exercise enables activity with multifaceted benefits; Perceived limitations of remote exercise services; and Enhancing participation.

CONCLUSIONS: Participants' overall perceptions towards RES were positive, and perceived benefits of RES included time and cost saving, improving work efficiency, and having peer support. Perceived barriers to RES were largely technological or related to lacking visual cues. Perceived recommendations to future RES included personalising exercise options, developing user-friendly platforms, and providing funding for buying equipment.

PMID:39539020 | DOI:10.1080/09638288.2024.2420832

Ital J Pediatr. 2024 Nov 14;50(1):243. doi: 10.1186/s13052-024-01799-3.

ABSTRACT

BACKGROUND: Non-cystic fibrosis (non-CF) bronchiectasis (BE) is defined as a clinical syndrome of recurrent, persistent wet cough and abnormal bronchial dilatation on chest High Resolution Computed Tomography (HRCT) scans. The aims of this study were to characterize the pattern of the trajectories of lung function parameters and to consider the relationship between the lung function and radiological severity according to the modified Reiff score.

METHODS: The study retrospectively considered 86 children (46.5% male, median age of 4 years) with non-CF BE, admitted at the Paediatric Pneumology Unit of Buzzi Children's Hospital from January 2015 to December 2022. The diagnosis of BE was made according to the presence of a suggestive clinical history and symptoms and key features of BE evidenced on chest HRCT scans. The modified Reiff score was adapted to quantify the severity of BE. Spirometry (COSMED MicroQuark spirometer) was performed at median age of 5.78 years (baseline or T0) and after 1 and 2 years from the baseline (T1 and T2, respectively). The general trends of lung function parameters were estimated by ANOVA models for repeated measurements. For each lung function parameter, a longitudinal regression model was fitted. The analysis was performed with the software R release 4.2.3. The statistical significance was deemed when the p-value resulted lower than 0.05.

RESULTS: The general trends of lung function parameters showed a statistically significant variation of forced vital capacity (FVC%) and forced expiratory volume in 1s (FEV1%) from T0 to T1 (p = 0.0062, 0.0009) and no significant change for FVC%, FEV1% and forced expiratory flow 25-75% of VC (FEF25/75%) from T1 to T2 (p = 0.145, 0.210, 0.600, respectively). Notably, we found no correlation between the age at diagnosis and the lung function parameters at T0 (r = 0.149, 0.103 and 0.042 for FVC%, FEV1% and FEF25/75%, respectively). Instead, a poor negative correlation resulted between the Reiff score and FVC%, FEV1% e FEF25/75% at baseline (Spearman coefficients: rho=-0.156, -0.204, -0.103, respectively).

CONCLUSIONS: A stable pulmonary function is detectable within 2 years follow up from baseline spirometry. The modified Reiff score should be considered as a good tool not only to quantify the radiological lung involvement but also the degree of pulmonary function impairment.

PMID:39538243 | DOI:10.1186/s13052-024-01799-3

BMC Microbiol. 2024 Nov 13;24(1):474. doi: 10.1186/s12866-024-03617-6.

ABSTRACT

Inquilinus limosus belongs to the class of the Alphaproteobacteria and was first described in 2002. So far, the species has mainly been isolated from respiratory specimens of patients with cystic fibrosis. A main characteristic of Inquilinus limosus is the prolonged time until bacterial colony growth is detectable. As the defined incubation times in many laboratories are too short to detect the growth of Inquilinus limosus, it is likely that the species is less frequently detected in the clinical setting than it actually occurs. This also explains why there are currently only very few data on the incidence available. Furthermore, as an uncommon pathogen, Inquilinus limosus may be familiar to only a few specialised clinicians. Due to these reasons, only little research (e.g. case reports and research papers) have been published on this species to date. However, given that a clear human pathogenic significance can be deduced from the existing literature, we have decided to present the current state of knowledge in this review and to address further aspects for the future elucidation of the pathogenesis of Inquilinus limosus.

PMID:39538164 | DOI:10.1186/s12866-024-03617-6

Dig Dis Sci. 2024 Nov 13. doi: 10.1007/s10620-024-08728-8. Online ahead of print.

ABSTRACT

BACKGROUND: Dietary fat malabsorption contributes to poor nutritional status in patients with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI). Prescribing gastric acid-reducing agents such as proton-pump inhibitors (PPI) as an adjunct to pancreatic enzyme replacement therapy (PERT) to improve dietary fat absorption has been accepted in clinical practice despite limited evidence.

AIMS: This was a pilot randomized, double-blind, placebo-controlled crossover trial of subjects aged 12 and older with CF and EPI assessed on placebo and omeprazole to determine if PPI improved the efficacy of PERT as indicated by measures of dietary fat absorption.

METHODS: Fat malabsorption via stool coefficient of fat absorption (CFA) and malabsorption blood test (MBT), gastrointestinal pH (wireless motility capsule [WMC]), and quality of life (QOL) were assessed after 14 days on both placebo or PPI (omeprazole).

RESULTS: Total 19 subjects enrolled, 13 were randomized, and 9 provided paired results on placebo and PPI. The 3 subject results for CFA were as follows: 1 increased, 1 decreased, and 1 was within the reference range in both tests for fat absorption. For 9 MBT subjects, 7 decreased and 2 increased fat absorption. For the 4 WMC studies, no change in transit times, nor in pH profiles were noted. No differences were seen in the domains of the two QOL questionnaires comparing placebo and PPI.

CONCLUSIONS: These limited descriptive pilot study results in participants with CF and EPI on PERT evaluated by stool, blood, and QOL tests did not suggest improvement in fat absorption attributable to PPI.

PMID:39537890 | DOI:10.1007/s10620-024-08728-8

Biochim Biophys Acta Biomembr. 2024 Nov 11:184401. doi: 10.1016/j.bbamem.2024.184401. Online ahead of print.

ABSTRACT

ATP-binding cassette (ABC) transporters are proteins responsible for active transport of various compounds, from small ions to macromolecules, across membranes. Proteins from this superfamily also pump drugs out of the cell resulting in multidrug resistance. Based on the cellular functions of ABC-transporters they are commonly associated with diseases like cancer and cystic fibrosis. To understand the molecular mechanism of this critical family of integral membrane proteins, structural characterization is a powerful tool which in turn requires successful recombinant production of stable and functional protein in good yields. In this review we have used high resolution structures of ABC transporters as a measure of successful protein production and summarized strategies for prokaryotic and eukaryotic proteins, respectively. In general, Escherichia coli is the most frequently used host for production of prokaryotic ABC transporters while human embryonic kidney 293 (HEK293) cells are the preferred host system for eukaryotic proteins. Independent of origin, at least two-steps of purification were required after solubilization in the most used detergent DDM. The purification tag was frequently cleaved off before structural characterization using cryogenic electron microscopy, or crystallization and X-ray analysis for prokaryotic proteins.

PMID:39537006 | DOI:10.1016/j.bbamem.2024.184401

Hum Mol Genet. 2024 Nov 13:ddae164. doi: 10.1093/hmg/ddae164. Online ahead of print.

ABSTRACT

Rare genetic respiratory disease has an incidence rate of more than 1:2500 live births in Northern Europe and carries significant disease burden. Early diagnosis improves outcomes, but many individuals remain without a confident genetic diagnosis. Improved and expanded molecular testing methods are required to improve genetic diagnosis rates and thereby improve clinical outcomes. Using primary ciliary dyskinesia (PCD) as an exemplar rare genetic respiratory disease, we developed a standardized method to identify pathogenic variants using whole transcriptome RNA-sequencing (RNA-seq) of nasal epithelial cells cultured at air-liquid interface (ALI). The method was optimized using cells from healthy volunteers, and people with rhino-pulmonary disease but no diagnostic indication of PCD. We validated the method using nasal epithelial cells from PCD patients with known genetic cause. We then assessed the ability of RNA-seq to identify pathogenic variants and the disease mechanism in PCD likely patients but in whom DNA genetic testing was inconclusive. The majority of 49 targeted PCD genes were optimally identified in RNA-seq data from nasal epithelial cells grown for 21 days at ALI culture. Four PCD-likely patients without a previous genetic diagnosis received a confirmed genetic diagnosis from the findings of the RNA-seq data. We demonstrate the clinical potential of RNA-seq of nasal epithelial cells to identify variants in individuals with genetically unsolved PCD. This uplifted genetic diagnosis should improve genetic counselling, enables family cascade screening, opens the door to potential personalised treatment and care approaches. This methodology could be implemented in other rare lung diseases such as cystic fibrosis.

PMID:39536325 | DOI:10.1093/hmg/ddae164

Chemistry. 2024 Nov 13:e202403546. doi: 10.1002/chem.202403546. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a prevalent opportunistic human pathogen, particularly associated with cystic fibrosis. Among its virulence factors are the LecA and LecB lectins. Both lectins play an important role in the adhesion to the host cells and display cytotoxic activity. In this study, we successfully synthesized hardly hydrolysable carbohydrate ligands targeting these pathogenic lectins, including two bispecific glycans. The interactions between LecA/LecB lectins and synthetic glycans were evaluated using hemagglutination (yeast agglutination) inhibition assays, comparing their efficacy with corresponding monosaccharides. Additionally, the binding affinities of bispecific glycans were assessed using isothermal titration calorimetry (ITC). Structural insight into the lectin-ligand interaction was obtained by determining the crystal structures of LecA/LecB lectins in complex with one of the bispecific ligands using X ray crystallography. This comprehensive investigation into the inhibitory potential of synthetic glycosides against P. aeruginosa lectins sheds light on their potential application in antimicrobial therapy.

PMID:39535852 | DOI:10.1002/chem.202403546

Pediatr Pulmonol. 2024 Nov 13:e27393. doi: 10.1002/ppul.27393. Online ahead of print.

ABSTRACT

BACKGROUND: Research studies are conflicting regarding new highly effective modulators and the association with mental health symptoms for adults and adolescents with cystic fibrosis (CF). For younger children, small studies and case reports indicate a wide range of effects, ranging from improvement in mood to the development of neuropsychiatric symptoms. However, a large placebo-controlled study indicated no causal connection. This study evaluates the frequency and severity of mental health symptoms in children and adolescents while taking elexacaftor/tezacaftor/ivacaftor (ETI).

METHODS: The study includes 81 pediatric patients with CF followed at Nationwide Children's Hospital (NCH). Patient Reported Outcomes Measurement Information System (PROMIS)-Anxiety and Depression, Patient Health Questionnaire 8 (PHQ-8) and Generalized Anxiety Disorder Questionnaire (GAD-7) were used to screen for depression and anxiety. Age-appropriate questionnaires were completed over the first 18 months after initiating ETI.

RESULTS: At baseline, majority of participants reported mental health symptoms within normal limits (WNL). For participants with elevated baseline measures, depressive and anxiety symptoms significantly decreased throughout the study period. Depending on the metric, patients experiencing depressive and anxiety symptoms dropped to 2-3% (n = 1, on each depressive measure) and 0% (n = 0, on either anxiety measures) respectively by 18 months.

CONCLUSION: Most pediatric patients with CF did not endorse symptoms of depression or anxiety disorders at ETI initiation. Over the first 18 months of ETI usage, the percentage of patients with these symptoms decreased, suggesting that the percentage of patients experiencing severe symptoms of depression and anxiety may decrease with ongoing use of ETI.

PMID:39535851 | DOI:10.1002/ppul.27393

Int Forum Allergy Rhinol. 2024 Nov 13. doi: 10.1002/alr.23487. Online ahead of print.

ABSTRACT

BACKGROUND: Routine prescription of antibiotics to treat chronic rhinosinusitis (CRS) exacerbations may contribute to the propagation of antibiotic resistance. Hops bitter β-acids lupulone and colupulone possess potent antibacterial activities and, as T2R1, T2R14, and/or T2R40 agonists, may improve the impaired mucociliary clearance described in CRS patients. We investigated these molecules as alternative treatments to antibiotics in CRS management based on their antibacterial and T2Rs agonists properties.

METHODS: Human nasal primary cells (HNECs) and RPMI2650 cells cultures were used as study models. T2Rs expression in cell culture models and human nasal tissue was assessed using immunofluorescence, quantitative PCR, and Western blot. We performed calcium imaging and cilia beat frequency experiments to investigate T2Rs activation in study models in response to lupulone and colupulone stimulations. Finally, we studied hops β-acids cytotoxicity on cells using CellEvent, crystal violet, lactate dehydrogenase assays, immunofluorescence, and transepithelial electrical resistance assays.

RESULTS: We confirmed lupulone and colupulone potent antibacterial effect on CRS-relevant methicillin-resistant Staphylococcus aureus but found minimal impact on P. aeruginosa. We also report T2R1, T2R14 and T2R40 expression in HNECs and RPMI2650 cell cultures. Lupulone and colupulone induced an increase in cytosolic calcium that appeared dependent on T2Rs signaling. This response was accompanied by mitochondrial membrane depolarization, cellular energy stress, decreased cell proliferation, ciliostasis, and HNECs remodeling after a single exposure to lupulone at micromolar concentrations.

CONCLUSION: Our data suggest that hops β-acids may not be beneficial as treatments in CRS patients and instead contribute to the disease by impairing cell health and further deteriorating the MCC.

PMID:39533961 | DOI:10.1002/alr.23487

Adv Healthc Mater. 2024 Nov 12:e2400510. doi: 10.1002/adhm.202400510. Online ahead of print.

ABSTRACT

Airway mucus is a major barrier to the delivery of lipid-based nanoparticles in chronic airway diseases such as cystic fibrosis (CF). Receptor-Targeted Nanocomplexes (RTN), comprise mixtures of cationic lipids and bifunctional peptides with receptor-targeting and nucleic acid packaging properties. The aim of this study is to improve the mucus-penetrating properties of cationic siRNA and mRNA RTNs by combining them with low molecular weight alginate oligosaccharides, OligoG and OligoM. Cationic RTNs formulated with either alginate become strongly anionic, while PEGylated messenger RNA (mRNA) and short interfering RNA (siRNA) RTNs remain cationic. Both alginates enhance mucus diffusion rates of cationic siRNA and mRNA RTNs in a static mucus barrier diffusion model, with OligoG particularly effective. PEGylation also enhance mucus diffusion rates of siRNA RTNs but not mRNA RTNs. Electron microscopy shows that RTNs remained intact after mucosal transit. The transfection efficiency of OligoM-coated mRNA RTNs is better than those coated with OligoG or PEG, and similar to cationic RTNs. In siRNA RTN transfections, OligoM is better than OligoG although 1% PEG is slightly better than both. The combination of cationic RTNs and alginate oligosaccharides represents a promising alternative to PEGylation for epithelial delivery of genetic therapies across the mucus barrier while retaining transfection efficiency.

PMID:39533498 | DOI:10.1002/adhm.202400510

J Cyst Fibros. 2024 Nov 11:S1569-1993(24)01797-1. doi: 10.1016/j.jcf.2024.10.008. Online ahead of print.

ABSTRACT

BACKGROUND: People with cystic fibrosis carrying two nonsense alleles lack CFTR-specific treatment. Growing evidence supports the hypothesis that nonsense mutation identity affects therapeutic response, calling for mutation-specific CF models. We describe a novel W1282X mouse model and compare it to an existing G542X mouse.

METHODS: The W1282X mouse was created using CRISPR/Cas9 to edit mouse Cftr. In this model, Cftr transcription was assessed using qRT-PCR and CFTR function was measured in the airway by nasal potential difference and in the intestine by short circuit current. Growth, survival, and intestinal motility were examined as well. Correction of W1282X CFTR was assessed pharmacologically and by gene-editing using a forskolin-induced swelling (FIS) assay in small intestine-derived organoids.

RESULTS: Homozygous W1282X mice demonstrate decreased Cftr mRNA, little to no CFTR function, and reduced survival, growth, and intestinal motility. W1282X organoids treated with various combinations of pharmacologic correctors display a significantly different amount of CFTR function than that of organoids from G542X mice. Successful gene editing of W1282X to wildtype sequence in intestinal organoids was achieved leading to restoration of CFTR function.

CONCLUSIONS: The W1282X mouse model recapitulates common human manifestations of CF similar to other CFTR null mice. Despite the similarities between the congenic W1282X and G542X models, they differ meaningfully in their response to identical pharmacological treatments. This heterogeneity highlights the importance of studying therapeutics across genotypes.

PMID:39532588 | DOI:10.1016/j.jcf.2024.10.008

J Cyst Fibros. 2024 Nov 11:S1569-1993(24)01808-3. doi: 10.1016/j.jcf.2024.10.015. Online ahead of print.

ABSTRACT

BACKGROUND: New York State implemented CFTR gene sequencing into the Cystic Fibrosis newborn screening (CF NBS) algorithm on 12/1/2017 to reduce false positive screens. With addition of sequencing, infants with 2 CFTR variants but low or intermediate sweat chloride levels classified as CFTR-related metabolic syndrome/CF screen-positive, inconclusive diagnosis (CRMS/CFSPID) are identified at a higher frequency, posing challenges to clinicians and families.

METHODS: Data from 375 screen-positive newborns between 12/1/2017 and 11/30/2020 were analyzed. We summarized 1-3 years of clinical follow-up for babies with CRMS/CFSPID following implementation of the IRT-DNA-SEQ algorithm.

RESULTS: Among 375 newborns referred, 223 (59.5 %) were classified as CRMS/CFSPID. Overall, 195/223 (87.4 %) had a CF-causing/pathogenic/likely pathogenic CFTR variant and a variant of varying clinical consequence (VCC) or uncertain significance (VUS). The most common VCC or VUS was 5T-12TG [n = 90/223 (40 %)]. All initial and repeat sweat chloride test (SCT) values for this cohort were <60 mmol/L after 1-3 years follow-up. Ninety-nine infants had ≥1 repeat SCT. Forty-two (18.8 %) had ≥1 SCT in the intermediate range (30-59 mmol/L) and 181 (81.2 %) were <30 mmol/L. Twenty-nine infants had sweat chloride increasing ≥5 mmol/L per year (29.3 % of infants with repeat testing). Fecal elastase was reported for 114/223 infants; none were abnormal. There were no conversions to CF during the 3-year follow-up period, however 2 infants have subsequently converted with diagnostic SCTs.

CONCLUSIONS: The New York experience may help inform updates to clinical guidelines, which are needed to optimize care, management, counseling, and long-term follow-up of infants and children with CRMS/CFSPID.

PMID:39532587 | DOI:10.1016/j.jcf.2024.10.015

J Physiol. 2024 Nov 12. doi: 10.1113/JP287723. Online ahead of print.

NO ABSTRACT

PMID:39530401 | DOI:10.1113/JP287723

Front Endocrinol (Lausanne). 2024 Oct 28;15:1382241. doi: 10.3389/fendo.2024.1382241. eCollection 2024.

ABSTRACT

OBJECTIVE: We hypothesized that the insulin-sensitizing adipokine adiponectin (ADP) is upregulated in cystic fibrosis (CF) related diabetes (CFRD) and underweight adults with CF. We aimed to assess correlations between glucose metabolism, body composition and ADP in CF.

METHODS: We performed a cross-sectional study among adults with CF at the Copenhagen CF Center. The study included a fasting level of ADP, an oral glucose tolerance test (OGTT), and a dual energy-x-ray absorptiometry scan.

RESULTS: In total, 115 patients were included of whom 104 had an OGTT performed. Glucose intolerance was not correlated with ADP in multivariable analysis, while increased hepatic insulin resistance (i.e., HOMA-IR) was correlated with reduced ADP levels. ADP declined by 4% (eβ 0.96, 95% CI: 0.94, 0.98), 5% (eβ 0.95, 95% CI: 0.93, 0.98), 9% (eβ 0.91, 95% CI: 0.87, 0.95), and 83% (eβ 0.17, 95% CI: 0.08, 0.37) for each one unit (kg/m2) increase in body mass index, fat mass index, muscle mass index, and bone mineral content index, respectively.

CONCLUSIONS: In CF, ADP was negatively correlated with hepatic insulin resistance as well as low fat, muscle, and bone mass, but not with glucose intolerance. This suggests that malnutrition leads to higher ADP levels in CF.

PMID:39530118 | PMC:PMC11550925 | DOI:10.3389/fendo.2024.1382241

Front Genet. 2024 Oct 28;15:1383033. doi: 10.3389/fgene.2024.1383033. eCollection 2024.

ABSTRACT

Cystic fibrosis (CF) is a genetically inherited disorder characterized by a wide range of clinical manifestations and genetic variations. This study focuses on the genetic and molecular epidemiology of CF in the Russian population, utilizing data from the national CF registry. The birth prevalence of CF in Russia has been analyzed over a span of years, revealing variations in frequency. The study delves into the genetic landscape of CFTR gene variants in Russian patients, showcasing a diverse spectrum with a predominance of severe variants, some of which are rare and distinct from global populations. A total of 233 variants have been documented, exhibiting frequencies ranging from 0.01% to 51.5%, with 47 of these variants remaining uncharted within international genetic databases. As of 2021, CFTR modulator therapy has been introduced for patients under 19 years, heightening the importance of genetic diagnosis. In 2023, more than 1,850 patients under 19 received CFTR modulator therapy. Notably, the impact of complex alleles on disease progression and response to targeted therapies is gaining recognition. Comparisons with European registries highlight distinctive features of the Russian population, such as differences in age distribution among patients. Additionally, the study emphasizes the need to ascertain clinical significance and pathogenicity of newly identified genetic variants, along with exploring their suitability for targeted therapies. The integration of genetic insights into the management of CF offers potential for enhanced personalized therapeutic interventions. In conclusion, this thorough analysis provides a comprehensive understanding of the genetic nuances within the Russian CF population. By illuminating the intricate relationship between genetic variations and disease manifestation, the study underscores the essential role of genetics in shaping therapeutic strategies and improving patient outcomes. Further research and ongoing genetic exploration are crucial for optimizing the care of individuals with CF in the era of evolving therapeutic options.

PMID:39529847 | PMC:PMC11551019 | DOI:10.3389/fgene.2024.1383033

FEBS J. 2024 Nov 11. doi: 10.1111/febs.17306. Online ahead of print.

ABSTRACT

Fluid viscosity and osmolarity are among some of the underappreciated mechanical stimuli that cells can detect. Abnormal changes of multiple fluidic factors such as viscosity and osmolarity have been linked with diseases such as cystic fibrosis, cancer, and coronary heart disease. Changes in viscosity have been recently suggested as a regulator of cell locomotion. These novel studies focus on cell migration and spreading on glass substrates and through microchannels, and it remains a question whether viscosity impacts the cellular remodeling of extracellular matrices (ECMs). Here, we demonstrate that elevated viscosity induces cellular remodeling of collagen substrates and enhances cell spreading on ECM-mimetic substrates. Our results expand on recent work showing that viscosity induces increased cellular forces and demonstrates that viscosity can drive local ECM densification. Our data further show that microtubules, Ras-related C3 botulinum toxin substrate 1 (Rac1), actin-related protein 2/3 (Arp2/3) complex, Rho-associated protein kinase 1 (ROCK), and myosin are important regulators of viscosity-induced ECM remodeling. In the context of viscosity-induced cell spreading, cells cultured on glass and collagen substrates exhibit markedly different responses to pharmacological treatments, indicating that microtubules, Rac1, and Arp2/3 play distinct roles in regulating cellular spreading depending on the substrate. In addition, our results demonstrate that high osmotic pressures override viscosity-induced cell spreading by suppressing membrane ruffling. Our results demonstrate viscosity as a regulator of ECM remodeling and cell spreading in a fibrillar microenvironment. We also reveal a complex interplay between viscosity and osmolarity. We anticipate that our research can pave the way for future investigations into the crucial roles played by viscosity in both physiological and pathological conditions.

PMID:39529371 | DOI:10.1111/febs.17306