Nucleic Acids Res. 2025 Mar 20;53(6):gkaf216. doi: 10.1093/nar/gkaf216.

ABSTRACT

Premature termination codon (PTC) diseases account for ∼12% of all human disease mutations. Although there are no FDA approved treatments for increasing PTC readthrough, one readthrough inducing drug, ataluren, has conditional approval for treatment of Duchenne muscular dystrophy elsewhere. Ataluren displays low toxicity in clinical trials for treatment of PTC diseases, but its therapeutic effects are inconsistent. The messenger RNA (mRNA) sequence context of a PTC is a major determinant of PTC readthrough efficiency. We have shown that ataluren stimulates readthrough exclusively by competitively inhibiting release factor complex (RFC) catalysis of translation termination. Here, using an in vitro reconstituted system, we demonstrate that PTC identity and the immediately adjacent mRNA sequence contexts modulate RFC activity in terminating peptide elongation. Such modulation largely determines the effectiveness of ataluren in stimulating readthrough, whether added alone or in combination with either the aminoglycoside G418 or an anticodon edited aa-tRNA, which stimulate readthrough by mechanisms orthogonal to that of ataluren. Our results suggest a potential rationale for the variability of ataluren effectiveness in stimulating readthrough. We hypothesize that patients harboring a PTC mutation within a sequence context promoting strong interaction with RFC will be resistant to ataluren, but that ataluren treatment will be more effective for patient sequences conferring weaker interaction with RFC.

PMID:40156864 | DOI:10.1093/nar/gkaf216

Laryngoscope. 2025 Mar 29. doi: 10.1002/lary.32155. Online ahead of print.

ABSTRACT

OBJECTIVES: Olfactory dysfunction (OD) is common among people with cystic fibrosis (PwCF) and chronic rhinosinusitis (CRS). OD is associated with impaired quality of life (QOL) and dietary alterations in certain non-CF populations. This study explored relationships between OD, QOL, and modulator use in PwCF.

METHODS: This is a cross-sectional analysis of an ongoing multicenter, prospective study (2019-2023) investigating PwCF with comorbid CRS. Participants completed the 40-Question Smell Identification Test (SIT-40), 22-question SinoNasal Outcome Test-(SNOT-22), Questionnaire of Olfactory Disorders (QOD-NS), and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Clinical and sinus CT data were collected. After stratification by SIT-40 score, data was analyzed by chi-square, Kruskal-Wallis, Spearman correlation, and logistic regression to identify factors associated with OD.

RESULTS: Of 59 participants, those with anosmia (n = 12) had worse eating-related QOL (CFQ-R eating) compared to individuals with normosmia (n = 16) and hyposmia (n = 31). Participants with anosmia had worse sinus CT scores than those with hyposmia. Although PwCF treated with highly effective modulator therapy (HEMT; n = 30) had better CT scores vs. non-HEMT individuals (n = 23), rates of OD in both groups were comparable. Higher SNOT-22 total scores were associated with increased odds of hyposmia or anosmia. In an eating-related QOD-NS subscore, those with worse CFQ-R eating had 2.38 times higher odds of having OD. Each point decrease in CFQ-R eating domain score was associated with 10% increased odds of OD.

CONCLUSION: In PwCF, OD was associated with increased CRS severity, impaired olfactory QOL, and decreased CFQ-R eating. There were no differences in SIT-40 or QOD-NS scores based on HEMT status.

TRIAL REGISTRATION: NCT04469439.

PMID:40156369 | DOI:10.1002/lary.32155

Int J Tuberc Lung Dis. 2025 Mar 31;29(4):153-158. doi: 10.5588/ijtld.24.0544.

ABSTRACT

<sec><title>BACKGROUND</title>Post-infectious bronchiolitis obliterans (PIBO) is a complication of severe childhood respiratory infection resulting in small airway injury, bronchiectasis, and prolonged respiratory consequences. Risk factors for PIBO and PIBO-associated bronchiectasis are unclear.</sec><sec><title>METHODS</title>This retrospective study identified all children with PIBO at a South African tertiary hospital between 1 January 2016 and 31 December 2022. The clinical characteristics, chest CT findings, and details of prior hospitalisation for respiratory infection were collected, and the characteristics of those with and without bronchiectasis were compared.</sec><sec><title>RESULTS</title>A total of 59 children were included (median age at primary lung insult: 10 months, IQR 6-17; median age at PIBO diagnosis: 16 months, IQR 11-28). Twenty-three had comorbidities, most frequently premature birth (30.5%) and HIV infection (6.8%). The most common pathogen was adenovirus (n = 41; 69.5%). At initial lung insult, 19 (32.2%) required mechanical ventilation. Mosaic attenuation on the chest CT was present in all. Thirty-three (55.9%) had bronchiectasis. The clinical characteristics, ventilation, causative pathogen, and comorbidity were similar in those with and without bronchiectasis.</sec><sec><title>CONCLUSION</title>Bronchiectasis occurs frequently in paediatric PIBO and is present within months of initial respiratory insult with no identified risk factors. Premature birth is common and may contribute to PIBO development.</sec>.

PMID:40155792 | DOI:10.5588/ijtld.24.0544

Biomedicines. 2025 Mar 13;13(3):707. doi: 10.3390/biomedicines13030707.

ABSTRACT

Backgroung/objectives: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of malignant lymphoma and is a heterogeneous disease with various gene and chromosomal abnormalities. The development of novel therapeutic treatments has improved DLBCL prognosis, but patients with early relapse or refractory disease have a poor outcome (with a mortality of around 40%). Metabolic reprogramming is a hallmark of cancer cells. Fatty acid (FA) metabolism is frequently altered in cancer cells and recently emerged as a critical survival path for cancer cell survival. Methods: We first performed the metabolic characterization of an extended panel of DLBCL cell lines, including lipid droplet content. Then, we investigated the effect of drugs targeting FA metabolism on DLBCL cell survival. Further, we studied how the combination of drugs targeting FA and either mitochondrial metabolism or mTOR pathway impacts on DLBCL cell death. Results: Here, we reveal, using a large panel of DLBCL cell lines characterized by their metabolic status, that targeting of FA metabolism induces massive DLBCL cell death regardless of their OxPhos or BCR/glycolytic subtype. Further, FA drives resistance of DLBCL cell death induced by mitochondrial stress upon treatment with either metformin or L-asparaginase, two FDA-approved antimetabolic drugs. Interestingly, combining inhibition of FA metabolism with that of the mTOR oncogenic pathway strongly potentiates DLBCL cell death. Conclusion: Altogether, our data highlight the central role played by FA metabolism in DLBCL cell survival, independently of their metabolic subtype, and provide the framework for the use of drugs targeting this metabolic vulnerability to overcome resistance in DLBCL patients.

PMID:40149683 | PMC:PMC11940118 | DOI:10.3390/biomedicines13030707

J Biol Chem. 2025 Mar 26:108460. doi: 10.1016/j.jbc.2025.108460. Online ahead of print.

ABSTRACT

Activation of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl‒ channel requires PKA phosphorylation at the regulatory (R) domain to relieve inhibition of ATP-dependent channel activity. This study aimed to identify the primary inhibitory site that prevents channel activation. CFTR mutants with deletion of residues 760-783 (ΔR760-783) elicited constitutive macroscopic and single-channel Cl‒ currents in the presence of ATP before PKA phosphorylation, suggesting that protein segment R760-783 in the R domain blocks CFTR activation. With the background of ΔR760-835, further deletion of R708-759 led to fully active channels in the presence of ATP, but absence of PKA, suggesting that R708-759 prevents the activation of ΔR760-835-CFTR. R760-783 peptides were unstructured in buffered solutions in circular dichroism spectroscopy and the N771P mutation that interrupts the α-helix formation induced no apparent constitutive current before PKA phosphorylation. These data suggest that interpeptide interactions by α-helices likely contribute trivially to the blocking effect of R760-783. CFTR mutants with small deletions or alanine replacements containing any one of residues R766 and S768 in a PKA consensus sequence and M773 and T774 generated PKA-independent CFTR Cl‒ currents. Similarly, introducing the mutations Q767C or T774C into a control CFTR construct produced constitutive CFTR Cl‒ currents by positively charged MTSET modification of target cysteines. Moreover, PKA-independent single-channel activity was evidently observed in R766K-, S768K- and T774K-CFTR mutants. Therefore, the four residues R766, S768, M773 and T774 may form an inhibitory module that precludes CFTR activation through side-chain interactions. This inhibitory mechanism might be emulated by other PKA-dependent proteins.

PMID:40154618 | DOI:10.1016/j.jbc.2025.108460

Am J Respir Crit Care Med. 2025 Mar 28. doi: 10.1164/rccm.202409-1792OC. Online ahead of print.

ABSTRACT

RATIONALE: Mycobacteroides abscessus infections affect immunocompromised patients and those with underlying pulmonary disease. Conventional imaging cannot distinguish M. abscessus infections from underlying pulmonary disease or sterile inflammation, requiring invasive procedures for definitive diagnosis.

OBJECTIVE: We evaluated 11C-para-aminobenzoic acid (11C-PABA), a chemically identical radioanalog of PABA, to detect and localize infections due to M. abscessus.

METHODS: In vitro uptake assays were performed to test the metabolism and accumulation of PABA into M. abscessus reference and clinical isolates. Dynamic 11C-PABA positron emission tomography (PET) was performed in a mouse model of M. abscessus pulmonary infection and in a patient with microbiologically-confirmed M. abscessus pulmonary infection (NCT05611905).

MAIN RESULTS: 11C-PABA was intracellularly metabolized by M. abscessus to 11C-7,8-dihydropteroate. Additionally, and the reference and all thirteen randomly chosen clinical isolates, including three resistant to trimethoprim-sulfamethoxazole, rapidly accumulated PABA. No PABA accumulation was noted by heat-inactivated bacteria or mammalian cells. Dynamic 11C-PABA PET in a mouse model of M. abscessus pulmonary infection rapidly distinguished infection from sterile inflammation and also accurately monitored response to antibiotic treatment. Finally, dynamic 11C-PABA PET in a 33-year-old female with cystic fibrosis and microbiologically confirmed M. abscessus pulmonary infection was safe and demonstrated significantly higher and sustained PET uptake in the affected lesions.

CONCLUSIONS: 11C-PABA PET is an innovative, clinically-translatable, noninvasive, bacteria-specific diagnostic to differentiate M. abscessus infections from underlying pulmonary disease in patients. This tool could also help in monitoring treatment responses and enable precision medicine approaches for patients with complicated infections. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:40153540 | DOI:10.1164/rccm.202409-1792OC

J Proteome Res. 2025 Mar 28. doi: 10.1021/acs.jproteome.4c00827. Online ahead of print.

ABSTRACT

Intercellular communication is important for host immunity in response to bacterial infections. Nontuberculous mycobacterium (NTM), such as Mycobacterium abscessus (M. ab), is a group of environmental bacteria that can cause severe lung infections in individuals with pre-existing lung conditions, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). There is limited knowledge understanding the interaction between airway epithelial cells and immune cells during NTM infections. In this study, we characterized microvesicles (MVs) released from uninfected and M. ab-infected human bronchial epithelial cells and investigated the effect of these MVs on the activation and polarization of THP-1-derived macrophages in cell culture. Our results indicate that MVs released by M. ab-infected human bronchial epithelial cells stimulated the activation of M2-polarized macrophages in cell culture when compared to MVs released by uninfected cells. Additionally, the proteomic analysis for isolated MVs showed that the proteins involved in the cell adhesion pathway were enriched in MVs from M. ab-infected human bronchial epithelial cells compared to MVs from uninfected cells. Among those, the cell surface protein, intercellular adhesion molecule 1 (ICAM-1), regulated the uptake of MVs released by M. ab-infected human bronchial epithelial cells by recipient macrophages in cell culture. In conclusion, our data suggest that in response to M. ab infection, human airway epithelial cells release MVs to modulate the activation of macrophages, which are key cells for mycobacterial intracellular survival in the host.

PMID:40153482 | DOI:10.1021/acs.jproteome.4c00827

Lung. 2025 Mar 28;203(1):55. doi: 10.1007/s00408-025-00806-6.

ABSTRACT

PURPOSE: Cystic fibrosis (CF) is a genetic disease caused by mutations in the CFTR gene, leading to multisystemic complications, particularly in the lungs. CFTR dysfunction results in altered ion transport, chronic inflammation, and progressive lung damage. The triple therapy elexacaftor/tezacaftor/ivacaftor (ETI) has demonstrated significant improvements in pulmonary function and quality of life. This study aimed to evaluate the anti-inflammatory effects of ETI by analysing systemic cytokine profiles over 12 months.

METHODS: A prospective study included 32 CF patients ≥ 18 years with at least one delF508 mutation, undergoing ETI therapy. Clinical stability was ensured prior to therapy initiation. Demographic data, BMI (Body Mass Index), FEV1% (Forced expiratory Volume in the first second), VR/TLC (residual volume/total lung capacity) and sweat chloride concentrations were recorded at baseline, 6 months and 12 months. Inflammatory markers, including fibrinogen, C-reactive protein (CRP), and a panel of 8 cytokines, were measured using multiplex bead-based immunoassays and electrochemiluminescence. Longitudinal changes were analysed using mixed-effects models and statistical tests, with significance set at p < 0.05.

RESULTS: During a 12-month follow-up, the neutrophils number and proinflammatory biomarkers analyzed, fibrinogen, CRP, GM-CSF, IFN- γ, IL-1 α, IL-1 β, IL-8 (CXCL8), IL-12p70, IL-17A (CTLA-8), and TNF-α, significantly decreased, while eosinophils remained stable. Mixed-effects models confirmed the significant association of inflammatory biomarkers with FEV1, BMI, sweat chloride levels, and VR/TLC highlighting the role of inflammation in the progression of CF.

CONCLUSIONS: ETI demonstrated marked anti-inflammatory effects in CF patients, reducing systemic inflammation and improving clinical parameters.

PMID:40153049 | DOI:10.1007/s00408-025-00806-6

Med Lett Drugs Ther. 2025 Mar 31;67(1725):e56. doi: 10.58347/tml.2025.1725d.

NO ABSTRACT

PMID:40152724 | DOI:10.58347/tml.2025.1725d

Cochrane Database Syst Rev. 2025 Mar 28;3:CD015313. doi: 10.1002/14651858.CD015313.pub2.

ABSTRACT

BACKGROUND: Chronic suppurative lung disease (CSLD) is an umbrella term to define the spectrum of endobronchial suppurative lung disease, including bronchiectasis and protracted bacterial bronchitis (PBB), associated with chronic wet or productive cough. Research that explores new therapeutic options in children with CSLD has been identified by clinicians and patients as one of the top research priorities. Mucolytic agents work to improve mucociliary clearance and interrupt the vicious vortex of airway infection and inflammation, hence they have potential as a therapeutic option.

OBJECTIVES: To assess the effects of mucolytics for reducing exacerbations, improving quality of life and other clinical outcomes in children with CSLD (including PBB and bronchiectasis), and to assess the risk of harm due to adverse events.

SEARCH METHODS: An Information Specialist searched the Cochrane Airways Trials Register to June 2022, and a review author searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases to 27 September 2024. Other review authors handsearched respiratory journals.

SELECTION CRITERIA: We included randomised controlled trials (RCTs), of both cross-over and parallel design, that compared a mucolytic with a placebo or 'no intervention' control group and included children (aged 18 years and under) with any type of CSLD (including PBB and bronchiectasis). We excluded studies with adult participants and studies in children with cystic fibrosis, empyema, pulmonary abscess or bronchopulmonary fistula.

DATA COLLECTION AND ANALYSIS: Two authors independently reviewed titles and abstracts to assess eligibility for inclusion. The authors then assessed study quality and extracted data. They assessed the quality of the study using the Cochrane risk of bias tool (RoB 2), and used GRADE to assess the certainty of evidence. Outcomes of interest to be analysed included: i) for maintenance or stable state: rate of exacerbations, ii) for exacerbation state: time to resolution of respiratory exacerbation, iii) lung function - forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), iv) quality of life and v) adverse events. Only one study met the inclusion criteria, so we could not perform a meta-analysis. Data were continuous, so we reported outcomes as mean differences.

MAIN RESULTS: The sole included RCT was a cross-over study of 63 children in the total cohort, with reported data and analysis of only 52 children (26 per arm) with non-cystic fibrosis bronchiectasis. The study compared 3% hypertonic saline nebulised before chest physiotherapy with a control arm (physiotherapy alone), with each phase lasting eight weeks. Children in the hypertonic saline arm had a mean age of 9.80 (SD 2.97) years and 42.3% were male; those in the control arm had a mean age of 9.10 (SD 2.40) years and 38.4% were male. Only results of the first arm of the cross-over study were included in this review. The RCT reported a clinically important difference between the groups for our review's primary outcome: rate of respiratory exacerbations. The mean number of exacerbations per child-year was 2.50 (SD 0.64) in the intervention group and 7.80 (SD 1.05) in the control group (mean difference (MD) -5.30, 95% CI -5.77 to -4.83; 1 study, 52 participants; very low-certainty evidence). The RCT also reported that the percentage point improvement in mean % predicted FEV1 and FVC from baseline to week eight was better with hypertonic saline compared to control. Mean FEV1 improvement was 14.15% (SD 5.50) in the intervention group versus 5.04% (SD 5.55) in the control group (MD 9.11%, 95% CI 6.11 to 12.11; 1 study, 52 participants; very low-certainty evidence). While for FVC, the mean improvement was 13.77% (SD 5.73) compared with 7.54% (SD 4.90), respectively (MD 6.23%, 95% CI 3.33 to 9.13; 1 study, 52 participants; very low-certainty evidence). Quality of life measures were not used. We judged the study to have a high risk of bias due to unblinding, missing data, deviation from the intended intervention and reporting bias with measurement and selection of outcome measures. The authors reported that there were no dropouts due to adverse events. No data were available regarding quality of life. The included study assessed mucolytic use during a stable state, and we found no studies of mucolytic use during an exacerbation. We also found no studies assessing oral mucolytics, other inhaled mucolytics, use in PBB, or in settings other than hospital outpatients. We also found two ongoing studies, one using hypertonic saline and one using an oral mucolytic agent erdosteine, which will potentially be included in future updates of this review.

AUTHORS' CONCLUSIONS: This systematic review is limited to a single small study, which we judged to be at high risk of bias. It remains uncertain whether regular nebulised hypertonic saline during a stable state reduces exacerbations or improves lung function. Further multi-centre, well-designed RCTs of longer duration that investigate various mucolytics are required to answer this important clinical question.

PMID:40152354 | DOI:10.1002/14651858.CD015313.pub2

Pediatr Pulmonol. 2025 Apr;60(4):e71067. doi: 10.1002/ppul.71067.

NO ABSTRACT

PMID:40152078 | DOI:10.1002/ppul.71067

Bioengineering (Basel). 2025 Mar 3;12(3):254. doi: 10.3390/bioengineering12030254.

ABSTRACT

Pancreatitis is a prominent and severe type of inflammatory disorder that has grabbed a lot of scientific and clinical interest to prevent its onset. It should be detected early to avoid the development of serious complications, which occur due to long-term damage to the pancreas. The accurate measurement of biomarkers that are released from the pancreas during inflammation is essential for the detection and early treatment of patients with severe acute and chronic pancreatitis, but this is sub-optimally performed in clinically relevant practices, mainly due to the complexity of the procedure and the cost of the treatment. Clinically available tests for the early detection of pancreatitis are often time-consuming. The early detection of pancreatitis also relates to disorders of the exocrine pancreas, such as cystic fibrosis in the hereditary form and cystic fibrosis-like syndrome in the acquired form of pancreatitis, which are genetic disorders with symptoms that can be correlated with the overexpression of specific markers such as creatinine in biological fluids like urine. In this review, we studied how to develop a minimally invasive system using hydrogel-based biosensors, which are highly absorbent and biocompatible polymers that can respond to specific stimuli such as enzymes, pH, temperature, or the presence of biomarkers. These biosensors are helpful for real-time health monitoring and medical diagnostics since they translate biological reactions into quantifiable data. This paper also sheds light on the possible use of Ayurvedic formulations along with hydrogels as a treatment strategy. These analytical devices can be used to enhance the early detection of severe pancreatitis in real time.

PMID:40150718 | DOI:10.3390/bioengineering12030254

Children (Basel). 2025 Feb 25;12(3):277. doi: 10.3390/children12030277.

ABSTRACT

Background/Objectives: Home spirometry allows people with cystic fibrosis (CF) to monitor their lung function from home. However, there are concerns about its feasibility and validity compared to traditional clinic spirometry. The aim of this study was to evaluate the feasibility and validity of telehealth spirometry for patients with CF living in a regional setting. Methods: This retrospective study included forty-eight people with cystic fibrosis (pwCF) aged 6-33 years. Participants performed home spirometry using a portable flow sensor spirometer over a one-year period, without supervision. Spirometry readings from portable spirometers were compared with the nearest in-clinic spirometry using the intra-correlation coefficient (ICC) and Bland-Altman plots. Data were collected over a period of one year, with regular intervals of measurements. Results: In 427 of the 877 (48.6%) attempted sessions, successful spirometry at home was recorded. Although we showed good reliability between at-home and in-clinic measurements using the Bland-Altman plots and intraclass correlation co-efficient (ICC) (values ranged from 0.76 to 0.88), analysis of the 117 pairs of at-home and in-clinic spirometries showed that mean differences of forced expiratory volume in the 1st sec (FEV1) and forced vital capacity (FVC) obtained at home (both in liter and z-score) had, on average, lower values than the corresponding values at the clinic. Conclusions: Home-based telehealth spirometry is feasible among pwCF and provides advantages, especially for those from remote or secluded areas. However, lower values in FVC and FEV1 obtained through home spirometry should not be used interchangeably with clinic values.

PMID:40150559 | DOI:10.3390/children12030277

Biomedicines. 2025 Feb 22;13(3):558. doi: 10.3390/biomedicines13030558.

ABSTRACT

Background/Objectives: Patients suffering from rare diseases are particularly vulnerable to vitamin D deficiency. The role of vitamin D status in rare disease management remains insufficiently investigated and employed in routine clinical practice. Methods: This review analyses current data on vitamin D status in selected rare diseases of organs involved in vitamin D metabolism: skin (epidermolysis bullosa, morphea), liver (autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis), kidney (Alport syndrome, Fabry disease), and cystic fibrosis as a model of a systemic rare disease. Additionally, this review critically examines potential drug-vitamin D interactions in the context of rare disease patient polypharmacy. Results: Evidence suggests that vitamin D deficiency is prevalent in rare disease patient populations, often at once exacerbating and being simultaneously exacerbated by the underlying condition. Vitamin D deficiency correlates with worse clinical outcomes and lower quality of life across the examined diseases. Immunoregulatory properties of vitamin D appear relevant for rare diseases with autoimmune components. Conclusions: An urgent need for developing disease-specific clinical practice guidelines, implementing routine vitamin D monitoring in rare disease patient care, and introducing tailored supplementation under the principles of precision medicine is emphasized.

PMID:40149535 | DOI:10.3390/biomedicines13030558

Antibiotics (Basel). 2025 Mar 18;14(3):317. doi: 10.3390/antibiotics14030317.

ABSTRACT

Background:Nocardia species are an emergent pathogen in people with CF (pwCF) or bronchiectasis. Their clinical role and management remain unclear, and their isolation is a challenge. In this paper, we describe four cases of Nocardia detection, in two pwCF and two patients with non-CF bronchiectasis or primary ciliary dyskinesia (PCD). Methods: We conducted a multicenter retrospective study, involving pwCF and non-CF people with bronchiectasis who presented with a Nocardia detection and were followed at three CF Italian centers (Florence, Verona, and Cerignola). Results:Nocardia detection was associated with clinical and radiological respiratory exacerbation and decline in lung function. In one CF patient, Nocardia was not detected in sputum cultures after starting Elexacaftor-Tezacaftor-Ivacaftor therapy. Conclusions: Managing Nocardia detection in patients with underlying lung diseases such as CF, PCD, or bronchiectasis presents significant challenges for clinicians.

PMID:40149127 | DOI:10.3390/antibiotics14030317

Antibiotics (Basel). 2025 Mar 14;14(3):302. doi: 10.3390/antibiotics14030302.

ABSTRACT

Pseudomonas aeruginosa is one of the leading causes of nosocomial respiratory tract infections, significantly affecting morbidity and mortality. It can persist in the lungs of patients with cystic fibrosis (CF) for extended periods because of its adaptive capacity. The main aim of this study was to determine the phenotypic and genotypic resistance to antibiotics of clinical isolates of P. aeruginosa that persist in patients with CF receiving long-term antimicrobial therapy. The study included nine strains of P. aeruginosa isolated from the sputum of patients with CF admitted to the hospital. Susceptibility to antibiotics was determined using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. Whole-genome sequencing was performed for phylogeny, sequence typing, and to identify antibiotic-resistant genes. The study showed that during long-term persistence in the lungs of patients receiving antibacterial therapy, the restoration of susceptibility to antibiotics occurred in some cases. Multilocus sequence typing and phylogeny revealed six sequence types. Functional annotation identified 72 genes responsible for resistance to antibacterial and chemical substances, with either chromosomal or plasmid localisation.

PMID:40149112 | DOI:10.3390/antibiotics14030302

J Cyst Fibros. 2025 Mar 26:S1569-1993(25)00079-7. doi: 10.1016/j.jcf.2025.03.011. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a disease triggered by more than 2,100 variants in a single gene encoding for the CF Transmembrane Conductance Regulator (CFTR) protein, which is expressed in epithelial cells, where it functions an anion channel. A new era of high-throughput technologies ('omics') enabled the production and exploration of large CF-related datasets with unprecedented detail. However, this knowledge is scattered among different resources thus requiring a significant amount of time and training to collect and exploit. The objective of this work is to build a resource (CyFidb) that concentrates CF-related information in a single repository.

METHODS: This tool results from the intense manual curation of 407 scientific articles, including studies with CFTR variants in distinct conditions, drug treatments and cells/tissues.

RESULTS: CyFidb is divided into three levels of information: protein-protein interactions, gene expression and functional studies, from which it is possible to search and extract information.

CONCLUSIONS: CyFidb is an open-access resource (https://cyfidb.di.fc.ul.pt) designed to provide continuously updated, curated information on CFTR variants and their associated biological data.

PMID:40148144 | DOI:10.1016/j.jcf.2025.03.011

Respir Med. 2025 Mar 25:108056. doi: 10.1016/j.rmed.2025.108056. Online ahead of print.

ABSTRACT

BACKGROUND: People with cystic fibrosis-related diabetes (CFRD) are known to have reduced exercise capacity (EC), which in turn is related to increased morbidity and mortality. The aim of this study was to examine whether dysglycaemia may independently influence exercise capacity in people with CF (pwCF).

METHODS: Results from clinically conducted cardiopulmonary exercise tests were analysed retrospectively in 139 pwCF alongside routine clinical data. Subjects were grouped according to glycaemic status; normal glucose tolerance (NGT; n=43) and dysglycaemia; impaired glucose tolerance (IGT; n=17) and CFRD (n=79). Anthropometric data was assessed using chi-squared tests. Regression models were developed using analysis of co-variance (ANCOVA) to evaluate predictors of exercise capacity and correlations between variable were assessed using the Pearson method.

RESULTS: Maximal oxygen uptake (VO2max) was reduced in the CFRD group compared to NGT and IGT (p<0.01), however this was dependent on higher FEV1% in the NGT and IGT groups (p<0.001) and significant differences were no longer present when FEV1 was accounted for. A higher proportion of those with dysglycaemia were ventilatory limited (NGT;42%, IGT; 72% & CFRD; 65%, p<0.05). Age, gender, BMI, intravenous antibiotic days and FEV1% were significant predictors of VO2max across all patients (adjusted R2=0.528, p<0.001). HbA1c is a small but significant predictor of VO2max in patients with dysglycaemia (p<0.05).

CONCLUSIONS: Adults with CFRD have reduced VO2max compared to NGT or IGT which is mediated by poorer lung function and higher overall disease burden. In individuals with CFRD, better glycaemic control is associated with a greater EC.

PMID:40147571 | DOI:10.1016/j.rmed.2025.108056

R I Med J (2013). 2025 Apr 1;108(4):26-31.

ABSTRACT

BACKGROUND: Novel therapies have increased life expectancy for people with cystic fibrosis (pwCF), shifting care to adult providers with limited CF experience. Hospitalizations expose trainees to CF care, but educational tools for managing CF exacerbations are scarce.

METHODS: A six-year longitudinal study assessed internal medicine resident physician trainees' (RPTs) experience managing hospitalized pwCF. A mixed-method survey of RPTs informed the creation of educational and workflow tools, including a video didactic and order set. A targeted knowledge assessment measured the effectiveness of these tools. Multidisciplinary team meetings also tracked challenges and outcomes.

RESULTS: Among 48 RPTs surveyed, 83% cared for pwCF during training. Most reported less comfort managing pwCF compared to diseases like chronic obstructive pulmonary disease (COPD). Immediately after implementing targeted educational tools, knowledge scores improved, particularly in CF-related diabetes management (38.4% correct pre vs 61.5% correct post, p=0.04).

CONCLUSION: Rare disease education requires focused assessments of learners' needs, sustained reinforcement, and adaptable tools to maintain effectiveness.

PMID:40146222

Tuberk Toraks. 2025 Mar;73(1):11-19. doi: 10.5578/tt.202501999.

ABSTRACT

INTRODUCTION: Early diagnosis with newborn screening programs and prolonged life expectancy with new treatment strategies have made cardiovascular disease (CVD) one of the important issues in cystic fibrosis (CF). In the early stages of CVD, it is difficult to recognize and follow-up increased arterial stiffness with conventional methods. Different measurement methods are needed. Therefore, in this study, we aimed to use arterial stiffness measurements in the follow-up of children with CF.

MATERIALS AND METHODS: This is a follow-up study examining the changes in arterial stiffness in children with CF by repeating hemodynamic measurements [augmentation index (AIx) and pulse wave velocity (PWV)]. We repeated hemodynamic measurements and CF-related CVD risk factors (Atherosclerosis risk factors: Fasting blood sugar, lipid profiles, and HbA1c) and systemic inflammation markers [C-reactive protein (CRP) and immunoglobulin G and pulmonary function tests] in children undergoing routine annual complication evaluation and examined changes during follow-up.

RESULT: Hemodynamic measurements could be repeated in 37 of 52 patients due to inclusion criteria. Mean age of the study group was 12 ± 4.5 years and 48.6% were female. There was a statistically significant increase in high density lipoprotein, HbA1c, and CRP and a decrease in low density lipoprotein and FEV1 at the follow-up. Heart rate, central blood pressure, augmented pressure, and PWV were similar. AIx, peripheral systolic blood pressure (SBP), and mean arterial pressure were increased significantly (p< 0.05). The increase in AIx was greater than expected for age and greater in female patients and in those with low body mass index, moderate-severe disease, and high CRP levels. Also, the change in AIx was positively correlated with changes in peripheral SBP and CRP.

CONCLUSIONS: This is the first study to evaluate the use of PWV and AIx in the follow-up of children with CF and showed that arterial stiffness measured with AIx increased at follow-up. The use of markers of arterial stiffness in CF from childhood onwards may enable early detection and monitoring of CVD risk and future prevention.

PMID:40145819 | DOI:10.5578/tt.202501999