Swiss Med Wkly. 2025 Jun 5;155:4193. doi: 10.57187/s.4193.

ABSTRACT

INTRODUCTION: The use of long-term home respiratory support in children has increased dramatically worldwide in recent decades. However, no national data are available in Switzerland since the last survey in 2001. In 2022, the national prospective Swiss Paediatric Home Respiratory Support (SwissPedHRS) registry was created on behalf of the Swiss Society of Paediatric Pulmonology, involving all centres caring for children with home respiratory support. Its main goal is to prospectively describe and study the population of children requiring home respiratory support in Switzerland. This first publication aims to present the SwissPedHRS methodology and describe the current paediatric population with home respiratory support in Switzerland and its evolution from 2001 to 2023.

METHODS: Inclusion criteria in the registry are age <18 years, use of home respiratory support for ≥3 months and follow-up in Switzerland. The seven paediatric centres caring for patients with long-term home respiratory support in Switzerland participated, asking all their patients who met the criteria to participate. Each centre designated a local person to enter data collected from medical files into a dedicated database. Inclusions began in April 2022. Data from all patients included during the first year of the registry (i.e. until March 2023) were extracted, and the following data were analysed: sex; age at inclusion; underlying pathology; age, place, and context of home respiratory support initiation; decisive test leading to home respiratory support initiation; breathing disorder mechanism; and type of home respiratory support.

RESULTS: The registry included 146 patients, and the prevalence of children with home respiratory support in Switzerland was estimated at 11.9/100,000 children (59% boys, 41% girls). The most common underlying medical conditions were related to neuro-muscular (38%) and central nervous system (25%) diseases. The home respiratory support type was bilevel positive airway pressure (BPAP) for 67% of patients, continuous positive airway pressure (CPAP) for 32%, and high flow nasal cannula for 1%. Respiratory support was delivered invasively (via tracheostomy) for 14%. The median age at home respiratory support initiation was 6.6 years. Home respiratory support was initiated electively in 68% of patients and in acute situations (weaning failure after an acute respiratory exacerbation, neonatal hospitalisation, or surgery) in 32%. The place of initiation was either an outpatient clinic (19%), standard care unit (15%) or intensive/intermediate care unit (66%).

CONCLUSION: SwissPedHRS is the first national prospective registry dedicated to children with home respiratory support. It is a valuable resource for improving knowledge and, therefore, the management of children with home respiratory support. Analysis of the first year's data in the SwissPedHRS registry showed a sixfold increase in prevalence since 2001. It also highlighted a larger spectrum of underlying medical conditions and types of sleep-disordered breathing leading to home respiratory support and important changes in home respiratory support modalities, with decreased invasive and increased non-invasive respiratory support and decreased BPAP and increased CPAP ventilation.

PMID:40570248 | DOI:10.57187/s.4193

United European Gastroenterol J. 2025 Jun 26. doi: 10.1002/ueg2.70061. Online ahead of print.

ABSTRACT

INTRODUCTION: Pancreatic exocrine insufficiency (PEI) results from a reduction in pancreatic secretion of enzymes, leading to malabsorption of nutrients, intestinal symptoms, nutritional deficiencies and related comorbidities. The diagnosis of pancreatic exocrine insufficiency should be based on digestive tests, mainly the coefficient of fat absorption (CFA), based on the quantification of 72 h fecal fat excretion (FFE). However, this test is rarely performed in clinical practice. Fecal elastase-1 (FE-1) is a simple and widely used alternative. This meta-analysis evaluates the diagnostic accuracy of fecal elastase-1 for the diagnosis of PEI diagnosed by CFA or 72h-FFE.

METHODS: A systematic search of databases was performed to identify studies evaluating fecal elastase-1 and CFA/FFE for the diagnosis of pancreatic exocrine insufficiency. Inclusion criteria required original studies with data on sensitivity, specificity and other diagnostic metrics. Two independent reviewers performed data extraction and quality assessment using the QUADAS-2 tool. Pooled sensitivity, specificity, likelihood ratios and diagnostic odds ratio (DOR) were calculated and heterogeneity was assessed using I-squared tests.

RESULTS: Thirteen studies with 888 patients were included. Fecal elastase-1 at a cut-off of 200 μg/g showed a pooled sensitivity and specificity of 0.94 and 0.69, respectively, with a DOR of 35.27. Lowering the cut-off to 100 μg/g improved specificity to 0.82 but decreased sensitivity to 0.88. Subgroup analyses showed different diagnostic performance in different clinical contexts, with higher sensitivity in cystic fibrosis (0.98) and higher specificity in chronic pancreatitis (0.81). The positive and negative predictive values are limited in situations with low and high probability of pancreatic exocrine insufficiency, respectively.

CONCLUSIONS: Fecal elastase-1 is a sensitive and moderately specific diagnostic tool for pancreatic exocrine insufficiency and is suitable for initial screening in high-risk populations. However, its moderate specificity requires careful interpretation in lower risk settings.

PMID:40569793 | DOI:10.1002/ueg2.70061

Ann Am Thorac Soc. 2025 Jun 26. doi: 10.1513/AnnalsATS.202503-276RL. Online ahead of print.

NO ABSTRACT

PMID:40569183 | DOI:10.1513/AnnalsATS.202503-276RL

Pharmacol Res Perspect. 2025 Aug;13(4):e70144. doi: 10.1002/prp2.70144.

ABSTRACT

Chloride channels are involved in many cellular processes, including cell volume regulation, modulation of cell excitability, and electrolyte and water secretion. Mutations of these proteins are associated with heterogeneous diseases such as myotonia, cystic fibrosis, epilepsy, deafness, lysosomal storage disease, and various kinds of renal and ophthalmic dysfunctions, also known as channelopathies. Thus, drugs targeting chloride channels may have important therapeutic applications. In this context, fenamates, commonly used for their anti-inflammatory properties, have been explored for drug repurposing in chloride channelopathies thanks to their ability to modulate multiple chloride channels. This narrative review resumes the effects of niflumic acid (NFA), flufenamic acid (FFA), mefenamic acid (MFA), meclofenamic acid (MCFA), and tolfenamic acid (TFA) on different types of chloride channel. It emerges that fenamates have a wide spectrum of activities on these channels that vary depending on multiple factors like channel isoforms, extracellular and intracellular conditions, and cell and tissue types. They may also exhibit both activating and inhibitory effects depending on their concentration. Therefore, thanks to their variegated modulatory activity on chloride channels, fenamates might be considered promising lead compounds for the development of new drug candidates that can target these altered channels involved in channelopathies. Trial Registration: EudraCT number: 2021-000708-39; ClinicalTrials.gov identifier: NCT029930005 and NCT02429570.

PMID:40568930 | DOI:10.1002/prp2.70144

J Proteome Res. 2025 Jun 26. doi: 10.1021/acs.jproteome.5c00086. Online ahead of print.

ABSTRACT

The ubiquitin-proteasome system contributes to protein quality control, involving E3 ligases that ubiquitinate proteins and leading to their degradation. The dysregulation of protein degradation results in the abnormal accumulation of proteins and is implicated in the pathology of diverse diseases, making targeted protein degradation a promising therapeutic strategy. Here, we focus on RFFL, an endosome-associated RING E3 ligase involved in mitochondrial homeostasis and the clearance of misfolded cystic fibrosis transmembrane conductance regulator proteins. Using label-free quantitative mass spectrometry based proteomics for interactome and differential expression analyses, we systematically investigated and identified putative substrates of RFFL. For more confident identification, we performed these analyses on three cell lines that we generated: an RFFL knockout cell line generated using CRISPR/Cas9, another cell line rescuing RFFL expression when complemented with KO cells with stably expressing RFFL cDNA, and wild-type cells. We validated JMJD6 and DNAJB11 as substrates of endogenous RFFL, providing orthogonal validation and confidence in our screening approach. We demonstrated that RFFL ubiquitinates and degrades JMJD6 and DNAJB11 via the proteasomal pathway using in vivo assays. Interestingly, we also discovered a hitherto unknown role of RFFL in lipid metabolism. Collectively, this study provides the first comprehensive and unbiased analysis of RFFL substrates employing multiple complementary approaches.

PMID:40568870 | DOI:10.1021/acs.jproteome.5c00086

Mayo Clin Proc Digit Health. 2025 Mar 3;3(2):100203. doi: 10.1016/j.mcpdig.2025.100203. eCollection 2025 Jun.

ABSTRACT

OBJECTIVE: To develop a cystic fibrosis (CF)-specific patient-reported outcome measure (PROM) to measure the daily burden of gastrointestinal symptoms for people with cystic fibrosis (pwCF) aged 12 years and older and address the lack of validated outcome measures for gastrointestinal symptoms in CF.

PATIENTS AND METHODS: CF Tummy Tracker was developed through a 5-stage approach in accordance with regulatory guidance. This included development and refinement of a conceptual framework; item generation; refinement; reduction; selection; and initial PROM testing. A mixed-methods approach, consisting of expert panel discussions, a focus group, interviews, and an online survey, was used. In initial testing, participants completed the PROM daily for 14 days via a smartphone application. This study was performed from March 14, 2022, December 12, 2023.

RESULTS: The CF community were involved throughout the development via a focus group (n=7 pwCF), interviews (n=11 pwCF), and an online survey (n=180 pwCF). A formative model was confirmed for the PROM. The final PROM, CF Tummy Tracker, consists of 10 items capturing gastrointestinal symptom burden, tested in 151 pwCF. The PROM reported no floor or ceiling effects, high test-retest reliability (intra-class correlation coefficient=0.94), and strong correlation with the anchor question.

CONCLUSION: CF Tummy Tracker aims to address the gap in validated CF-specific PROMs for daily completion. Further testing of the psychometric properties of the PROM are planned in a new patient cohort to validate its use in clinical trials and support its use in both electronic and paper formats to increase accessibility.

PMID:40568613 | PMC:PMC12191005 | DOI:10.1016/j.mcpdig.2025.100203

bioRxiv [Preprint]. 2025 May 2:2025.05.02.651457. doi: 10.1101/2025.05.02.651457.

ABSTRACT

Microorganisms commonly exist in polymicrobial communities, where they can respond to interspecies secreted molecules by altering behaviors and physiology, however, the underlying mechanisms remain underexplored. Here we investigated interactions between Stenotrophomonas maltophilia and Pseudomonas aeruginosa , co-infecting opportunistic pathogens found in pneumonia and chronic lung infections, including in cystic fibrosis. We found that S. maltophilia forms robust protective multicellular aggregates upon exposure to P. aeruginosa secreted factors. Experimental evolution for lack of aggregation selected for fimbrial mutations and we found that fimbriae are required on both interacting S. maltophilia cells for aggregation. Untargeted metabolomics and targeted validations revealed that the quorum sensing molecule Pseudomonas quinolone signal (PQS) directly induced S. maltophilia aggregation, and co-localized with the aggregates. Further, in co-culture with P. aeruginosa , wild-type S. maltophilia formed aggregates, resulting in up to 75-fold increased survival from P. aeruginosa competition compared to fimbrial mutants. Finally, multiple other bacterial species similarly aggregated upon exposure to P. aeruginosa exoproducts, indicating a more general response. Collectively, our work identifies a novel multispecies interaction where a quorum sensing molecule from a co-infecting pathogen is sensed as a 'danger' signal, thereby inducing a protective multicellular response.

PMID:40568125 | PMC:PMC12190822 | DOI:10.1101/2025.05.02.651457

bioRxiv [Preprint]. 2025 Mar 31:2025.03.31.646159. doi: 10.1101/2025.03.31.646159.

ABSTRACT

Prokaryotes carry clusters of phage defense systems in "defense islands" that have been extensively exploited bioinformatically and experimentally for discovery of immune functions. However, little effort has been dedicated to determining which specific system(s) within defense islands limit lytic phage reproduction in clinical bacterial strains. Here, we employed the CRISPR-based Cascade-Cas3 system to delete defense islands in a Pseudomonas aeruginosa clinical isolate to identify mechanisms of lytic phage antagonism. Deletion of one island in a cystic fibrosis-derived clinical isolate sensitized the strain to phages from the Pbunavirus family, which are commonly used as therapeutics. The causal defense system is a Type IIS restriction endonuclease-like protein (END PaCF1 ), common in Pseudomonads, however it lacks an associated methyltransferase typical Type IIS R-M systems. END PaCF1 protects bacteria against phages with hypermodified DNA and is surprisingly agnostic to the specific structure of the modification, which is unlike typical type IV restriction endonucleases. In END PaCF1 , the endonuclease domain is fused to a catalytically inactive Endonuclease III (iEndoIII), a domain that recognizes non-canonical bases to repair DNA in prokaryotes and eukaryotes. We therefore propose that nucleases containing an i En doIII d omain ( END nucleases) can sense diverse DNA hypermodifications. Our findings reveal modularity of the sensing and cleavage domains, as expected of a modification-dependent endonucleases. We further show that some hypermodified phages, including Pbunavirus family members and Wrowclawvirus family (Pa5oct-like) of jumbo phages, encode END nuclease inhibitors that directly bind to the nuclease, likely via the iEndoIII domain. These inhibitors are necessary for Pbunavirus to plaque on clinical isolates and sufficient to enable other hypermodified phages to plaque in the presence of this defense system.

PMID:40568115 | PMC:PMC12191111 | DOI:10.1101/2025.03.31.646159

J Funct Morphol Kinesiol. 2025 Jun 4;10(2):212. doi: 10.3390/jfmk10020212.

ABSTRACT

Background: Physical exercise intervention in cystic fibrosis (CF) is of recent interest; however, no specific method to detect improvements in body composition and cardiovascular performance after transplantation has been investigated. This study aims to verify the feasibility of an exercise prescription program in CF lung-transplanted patients compared to other solid organ transplanted recipients (OLT) in terms of cardio-respiratory and body composition performance. Methods: The two groups, trained with a moderate intensity program, were evaluated by body composition analysis and a cardiopulmonary test (CPET) and compared to healthy subjects (HS). Results: A total of 10 CF, 10 OLT, and 10 HS were included. BMI was significantly lower in the CF group with lower total and appendicular free fat mass (p = 0.01). The CF group also showed significantly lower functional and cardiovascular parameters in the CPET test (peak VO2, VOR/HR) compared to the OLT and HS groups, but similar ventilatory response (VE/VCO2 slope) to OLT. In the CF group, free fat mass and functional parameters (peak VO2 and VO2/HR) were negatively correlated (r = -0.51 and -0.52, respectively). Conclusions: CF patients would benefit from an individualized exercise prescription program to improve all cardiovascular parameters, overall body composition, and, consequently, related respiratory parameters. Peak VO2 and body composition should be largely used to plan exercise prescription program among transplanted CF.

PMID:40566462 | DOI:10.3390/jfmk10020212

J Clin Med. 2025 Jun 18;14(12):4335. doi: 10.3390/jcm14124335.

ABSTRACT

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) treatment is showing remarkable beneficial effects in people with Cystic Fibrosis (pwCF) harboring the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Although this therapy is generally well tolerated in pwCF, some adverse events (AEs) have been recently described both in controlled studies and in post-marketing observations. Methods: We followed 414 pwCF carrying F508del CFTR that initiated ETI treatment, recording AEs for a period of 5 years. Results: A total of 142 AEs were reported. The most frequent AEs in the whole cohort were liver marker elevation, skin rush, epigastric pain, headache, and depression. Considering pediatric subjects, psychiatric and gastrointestinal disorders were the most frequent AEs. Only one patient reported a severe AE, leading to treatment discontinuation. In case of AEs, different decisions on ETI treatment were made, including temporary interruption and temporary or permanent dosage modification. Conclusions: Throughout the long-term observational period, almost 21% of pwCF experienced at least one AE. Psychiatric disorders, in particular attention deficit, were the most prevalent issue in our pediatric cohort, whereas adult patients mainly reported depression, anxiety and sleep disorders. This study therefore strengthen the recommendation of screening for changes in mental health during ETI treatment. AEs led to the permanent reduction of ETI dosage in 32% of cases, raising the issue of safety in relation to dosage reduction, efficacy, and minimum ETI levels. Eventually, this study highlights the need for a longitudinal monitoring of ETI safety since a significant number of AEs occurred after one year of treatment.

PMID:40566080 | DOI:10.3390/jcm14124335

J Clin Med. 2025 Jun 18;14(12):4331. doi: 10.3390/jcm14124331.

ABSTRACT

Background: Elevated immunoglobulin G (IgG) levels are associated with worse lung function and disease severity in people with cystic fibrosis (PwCF). This study evaluated whether elevated IgG levels-defined as values above the 97.5th percentile (Z-score ≥ 1.96 standard deviations above the mean)-can predict progression to severe lung disease. Methods: A retrospective cohort study of children and adults with CF at a single-center clinic was performed. Patients with elevated baseline IgG Z-scores were compared to those with normal or low IgG levels. Progression to severe lung disease was defined as % predicted FEV1 < 40%, referral for lung transplantation, or death. Kaplan-Meier survival curves and Cox models were used to analyze clinical outcomes. A sensitivity analysis was conducted for patients aged 18 years or older. Results: Of 97 patients, 31 (31.9%) had elevated IgG levels. Progression to severe lung disease occurred in 14 (14.4%) patients, 12 (85.7%) of whom had elevated IgG. These patients were significantly older and had a higher prevalence of Pseudomonas aeruginosa colonization. Among adults, those with elevated IgG had lower baseline % predicted FEV1 and greater annual lung function decline. Elevated IgG was independently associated with progression to severe lung disease (adjusted hazard ratio [aHR]: 9.8; 95% CI: 1.9-48.6), even after adjusting for Pseudomonas colonization and annual % predicted FEV1 decline. Conclusions: Elevated IgG was associated with progression to severe lung disease in PwCF and correlated with older age, Pseudomonas colonization, and-in adults-lower baseline lung function and faster decline. These findings highlight elevated serum IgG as a meaningful prognostic biomarker for identifying high-risk PwCF who may benefit from closer monitoring and earlier intervention.

PMID:40566076 | DOI:10.3390/jcm14124331

Genes (Basel). 2025 May 30;16(6):671. doi: 10.3390/genes16060671.

ABSTRACT

Background/Objectives: The clinical utility of reproductive carrier screening varies based on the genes tested, variant reporting policies, and the screened patient population. This study aims to evaluate the outcomes of carrier screening among reproductive couples undergoing testing in a routine clinical setting. Methods: A total of 1595 couples, primarily referred by reproductive endocrinology and infertility specialists, underwent couple-based carrier screening across 390 genes. Carrier states were assessed on a couple basis and reported only if a couple were at risk of having affected offspring. At-risk conditions were classified by severity, as well as their likelihood of clinical impact based on the specific variants detected in each at-risk couple. Secondary findings with potential personal utility were also evaluated. Results: Among the screened couples, 4.2% were at risk of having a child with a genetic condition. When limited to high-clinical-impact results, the at-risk couple rate decreased to 1.0%, with 44% of these cases involving CFTR, SMN1, or FMR1. Secondary findings were identified in 1.7% of individuals. Conclusions: Carrier screening for only CFTR, SMN1, and FMR1 will miss more than half of at-risk couples, underscoring the importance of broader carrier screening. Specific variants and their combinations can influence the predicted clinical impact of at-risk conditions, marking a key advantage of couple-based reporting. Secondary findings were common, highlighting the importance of discussing these potential findings during pre-test counselling.

PMID:40565563 | DOI:10.3390/genes16060671

Int J Mol Sci. 2025 Jun 11;26(12):5597. doi: 10.3390/ijms26125597.

ABSTRACT

People with diabetes are at increased risk of developing lung infections and have more severe complications. However, the link between these risks and outcomes is unknown. These trends are also seen in people with chronic lung diseases, including cystic fibrosis (CF); however, less is known about the underlying mechanism of disease in these cases. Traditional CF bacterial pathogens are often associated with worse disease outcomes in non-CF individuals with diabetes or hyperglycemia who have other acute or chronic airway disease, yet how diabetes and hyperglycemia further compound chronic CF infections is less clear. In this review, we focus on what has been observed clinically regarding bacterial respiratory infections and diabetes, and we discuss model systems used to study these relationships. We also review what is known about the role of diabetes in chronic CF lung disease and how information gleaned from the general population can inform future research directions in the new era of highly effective modulator therapies for CF.

PMID:40565059 | DOI:10.3390/ijms26125597

Children (Basel). 2025 Jun 14;12(6):778. doi: 10.3390/children12060778.

ABSTRACT

Background: One of the most common genetic variants among individuals with cystic fibrosis screen-positive inconclusive diagnosis (CFSPID) is 5T;12TG. Classified as having "varying clinical consequences" (VVCC), it may produce a wide spectrum of CF phenotypes when combined in trans with a pathogenic variant on the other CFTR allele, ranging from asymptomatic cases to CFTR-related disorders (CFTR-RD) or classical cystic fibrosis (CF). The 5T;12TG variant is currently eligible for modulator treatment in the United States. Methods: We conducted a retrospective analysis of CFSPID children born between July 2009 and June 2023 in the Community of Madrid (Spain) who carried at least one 5T;12TG variant in trans with another CFTR variant. Data collected included trends in sweat chloride (SC) values, respiratory and digestive symptoms, lung function by spirometry, microbiological findings in nasopharyngeal aspirates, anthropometric data, and fecal elastase levels. Results: Twenty-one children (52.3% females; median age: 4.66 years [IQR 3.6-6.9]) were included. Eighteen had 5T;12TG in trans with a CF-causing variant (CFc), two had another VVCC variant, and one had a variant of unknown significance (VUS). After a median follow-up of 3.45 years [IQR 1.4-4.3], all the children remained asymptomatic. However, SC values rose to intermediate levels in nine (42.8%) of the children. No isolates of Pseudomonas aeruginosa were identified. Lung function and pancreatic markers remained normal. Conclusions: This is the first Spanish cohort of children with CFSPID and the 5T;12TG allele. Although clinical symptoms did not manifest during childhood, the SC value increased to intermediate values in 42.8% of the cohort, so these may require long-term follow-up to observe conversions to CFTR-RD or CF. The potential initiation of modulator therapy based solely on SC levels or emerging symptoms warrants careful consideration.

PMID:40564735 | DOI:10.3390/children12060778

Biomolecules. 2025 Jun 6;15(6):828. doi: 10.3390/biom15060828.

ABSTRACT

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene, leading to defective ion transport and impaired function of various organs. Chronic inflammation, oxidative stress, and microbial dysbiosis are key pathological features of CF patients, contributing to disease progression, lung damage, and an increased susceptibility to infections. Emerging evidence suggests that in CF patients these factors can promote cancer development, especially lung cancer. Chronic inflammation in CF, driven by immune cell dysfunction, results in the release of pro-inflammatory cytokines and reactive oxygen species (ROSs), fostering an environment conducive to cancer initiation. Oxidative stress can amplify cellular damage and hinder airway remodeling. ROSs not only damage cellular components such as lipids, proteins, and DNA but also disrupt lung homeostasis, creating a favorable environment for cancer development. Furthermore, the lung microbiome in CF patients is often dysbiotic, with a reduced diversity and the predominance of pathogenic bacteria such as Pseudomonas aeruginosa, which exacerbate inflammation and may contribute to carcinogenesis. This review explores the mechanisms linking CF to lung cancer, examining the potential clinical implications of these mechanisms for early detection, monitoring, and targeted therapies for lung cancer prevention in CF patients.

PMID:40563468 | DOI:10.3390/biom15060828

Mol Cell Biochem. 2025 Jun 25. doi: 10.1007/s11010-025-05331-x. Online ahead of print.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies have revolutionized the treatment of cystic fibrosis (CF) by targeting the underlying protein defect. Investigating how elexacaftor/tezacaftor/ivacaftor (ETI) therapy affects interferon (IFN) signalling and inflammatory cytokine production in CF airway epithelial cells may clarify its role in alleviating the dysregulated innate immune response. Clinical efficacy was evaluated in 26 modulator-naive CF patients with at least one F508del mutation before and after 3 and 6 months of ETI treatment. Type I/III IFNs, IFNLR1, IFN-stimulated genes (ISG15, ISG56), interleukin 8 (IL-8) and IL-1β mRNA levels were analysed by RT real-time PCR in CF airway samples (n = 74). Patients showed significant improvements in pulmonary function (ppFEV1, 3 months: 12.5%, 6 months: 17.6%), BMI (3 months: 0.9 kg/m2, 6 months: 1.4 kg/m2), and sweat chloride (3 months: - 32.1 mEq/L, 6 months: - 44.4 mEq/L) compared to baseline (all p ≤ 0.001). The total number of exacerbations was also reduced (p = 0.002). Increased levels of IFNβ (p < 0.001) were found after 6 months of ETI therapy, whilst ISG15 and ISG56 decreased significantly (p = 0.022, p = 0.004). After 3 months, CF patients produced reduced levels of IL-8 and IL-1β (p = 0.001, p = 0.011) and even significantly lower levels after 6 months (p < 0.001, p < 0.001). ETI treatment appears to restore IFNβ expression and reduce levels of inflammatory genes (ISGs, IL-8 and IL-1β) in the airways, highlighting the potential of ETI to improve the dysregulated inflammatory status in CF.

PMID:40560491 | DOI:10.1007/s11010-025-05331-x

Int J Neonatal Screen. 2025 Jun 4;11(2):43. doi: 10.3390/ijns11020043.

ABSTRACT

Cystic fibrosis (CF) is a chronic, autosomal-recessive disorder caused by mutations in the CFTR gene, leading to thickened secretions that affect multiple organ systems. This study examines the effectiveness of Georgia's national CF screening program, which was initiated in 2012 and includes the measurement of immunoreactive trypsinogen (IRT) levels at birth. An analysis of data from 2022 and 2023 revealed a decrease in follow-up attendance for sweat chloride testing among newborns with elevated IRT levels, from 59.9% to 51.2%. The birth prevalence of cystic fibrosis in Georgia varied, suggesting a need to improve both the accessibility of free testing and the quality of follow-up care. Identified barriers include limited access to screening results for pediatricians and the cost of follow-up tests. Recommendations include incorporating free sweat chloride and genetic testing into the national program, as well as improving community education and coordination with social agencies. The identification of 29 CFTR mutations in patients underscores the importance of continued genetic counseling. Overall, while the screening program shows promise, addressing these barriers is essential to improve outcomes and ensure the timely diagnosis and management of cystic fibrosis in Georgia.

PMID:40559180 | DOI:10.3390/ijns11020043

Antibiotics (Basel). 2025 May 29;14(6):554. doi: 10.3390/antibiotics14060554.

ABSTRACT

BACKGROUND: Inhalational antibiotics have been used effectively to treat chronic diseases such as Pseudomonas aeruginosa infections associated with cystic fibrosis. This approach may enhance treatment options for difficult-to-treat, acute pneumonic diseases. Liposomal encapsulated ciprofloxacin (Lipoquin and/or Apulmiq) has provided protection in murine models of plague, anthrax, Q fever and tularemia. Development of the ability to deliver these drugs to nonhuman primates (NHPs) would enable further extrapolation of the data observed in small animal models of infection to humans.

METHODS: In this study, the methodology was established to deliver Apulmiq to common marmosets (Callithrix jacchus). Marmosets were anaesthetised with a novel, reversible anaesthetic comprising fentanyl, medetomidine and midazolam (FMM). They were placed into plethysmography tubes with their heads in an exposure chamber. The LC Sprint jet nebuliser or Pari eFlow Rapid nebuliser were used to aerosolise Apulmiq into the exposure chamber. Animals were euthanised after dosing and the concentration of ciprofloxacin was assessed in the plasma and lungs of the animals.

RESULTS: Non-compartmental pharmacokinetic analysis determined that a 30 min exposure of drug was required to reach a human-equivalent target dose of 0.8 mg/kg body weight in the lungs.

CONCLUSIONS: This approach can now be used to assess the efficacy of inhalational liposomal ciprofloxacin in NHP infection models.

PMID:40558143 | DOI:10.3390/antibiotics14060554

Adv Respir Med. 2025 Jun 17;93(3):20. doi: 10.3390/arm93030020.

ABSTRACT

Poor sleep quality and excessive daytime sleepiness are commonly reported by individuals with cystic fibrosis. The potential impact of comorbid sleep-disordered breathing (SDB), particularly obstructive sleep apnea (OSA), has not been extensively studied in the CF population. At present, there are no specific recommendations available to help clinicians identify patients with CF who are at increased risk of sleep disorders. Home sleep apnea testing using a validated peripheral arterial tonometry (PAT) device may offer an accurate diagnosis of OSA in a more convenient and low-cost method than in-lab polysomnography. In this single-center study of 19 adults with CF, we found an increased prevalence of OSA among individuals with CF compared to general population estimates. Although associations with an FEV < 70% predicted and a modified Mallampati score ≥ 3 were observed, these odds ratios did not reach statistical significance, likely reflecting limited power in this small pilot sample. There was no association found between the self-reported presence of nocturnal cough or snoring and OSA. We also found no association between OSA and abnormal scores on commonly used, validated sleep questionnaires, suggesting that CF-specific scales may be needed for effective screening in the CF clinic.

PMID:40558119 | DOI:10.3390/arm93030020

Front Cell Infect Microbiol. 2025 Jun 10;15:1582339. doi: 10.3389/fcimb.2025.1582339. eCollection 2025.

ABSTRACT

Pseudomonas aeruginosa is a major opportunistic pathogen that causes chronic infections, particularly in patients with cystic fibrosis and chronic obstructive pulmonary disease (COPD). The type VI secretion system (T6SS) is a primary virulence factor of P. aeruginosa in chronic infections. The objective of this study was to elucidate the regulatory mechanisms and pathogenic effects of the T6SS during P. aeruginosa infection, utilizing transcriptome sequencing and functional assays. We found that T6SS expression is elevated in P. aeruginosa isolated from chronically infected patients. Deletion of the retS gene activates P. aeruginosa PAO1 T6SS while repressing T3SS in vitro. Bacterial and cellular transcriptome sequencing analyses showed that T6SS genes were upregulated, while T3SS genes were downregulated in the ΔretS mutant. Additionally, the expression levels of the fimbriae gene cupC, the histidine phosphotransfer protein hptC (PA0033), and the transcription factor PA0034 were significantly increased. Subsequent experiments revealed that adhesion mediated by cupC enhances the contact-killing activity of the T6SS. Deletion of the hptC-PA0034 operon results in the down-regulation of cupC expression. The ΔretSΔcupC and ΔretSΔhptC-PA0034 mutants exhibited reduced cytotoxicity compared to the ΔretS mutant, similar to the ΔretSΔclpV1ΔclpV2 mutant. The ΔretS infection increased cell death, inflammatory factors (IL-1β, IL-6, TNF-α), and reactive oxygen species compared to a T6SS-inactive strain. Importantly, our study demonstrates that the T6SS activates the PDE4C pathway in epithelial cells, leading to significant cellular alterations. The application of PDE inhibitors effectively mitigates cell damage and inflammatory responses. These findings highlight the critical role of T6SS in modulating host cell signaling and suggest potential therapeutic strategies for conditions associated with T6SS-mediated inflammation.

PMID:40557319 | PMC:PMC12185982 | DOI:10.3389/fcimb.2025.1582339