mSystems. 2025 Mar 19:e0135424. doi: 10.1128/msystems.01354-24. Online ahead of print.

ABSTRACT

Burkholderia cenocepacia is an opportunistic pathogen that has been associated with nosocomial outbreaks in hospitals and can cause severe respiratory infections among immunocompromised patients and individuals suffering from cystic fibrosis. The transmissibility and intrinsic antibiotic resistance of B. cenocepacia pose a significant challenge in healthcare settings. In this study, with the aim to identify novel drug targets to fight B. cenocepacia infections, we employed a genome-wide transposon sequencing (Tn-seq) approach to unravel fitness determinants required for survival in Galleria mellonella (in vivo infection model) and pig lung tissue (ex vivo organ model). A total of 698 and 117 fitness genes were identified for each of the models, respectively, and 62 genes were found to be important for both. To confirm our results, we constructed individual mutants in selected genes and validated their fitness in the two models. Among the various determinants identified was a rare genomic island (I35_RS03700-I35_RS03770) involved in O-antigen and lipopolysaccharide synthesis. We demonstrate that this gene cluster is required for virulence in the G. mellonella infection model but, by contrast, counteracts efficient colonization of pig lung tissue. Our results highlight the power of the Tn-seq approach to unravel fitness determinants that could be used as therapeutic targets in the future and show that the choice of the infection model for mutant selection is paramount.

IMPORTANCE: The opportunistic pathogen Burkholderia cenocepacia has been associated with nosocomial infections in healthcare facilities, where it can cause outbreaks involving infections of the bloodstream, respiratory tract, and urinary tract as well as severe complications in immunocompromised patients. With the aim to identify novel targets to fight B. cenocepacia infections, we have used a genome-wide approach to unravel fitness genes required for host colonization in a clinical strain, B. cenocepacia H111. Among the various determinants that we identified is a rare genomic island that modifies the bacterial lipopolysaccharide. Our results highlight the power of the transposon sequencing approach to identify new targets for infection treatment and show the importance of using different infection models.

PMID:40105327 | DOI:10.1128/msystems.01354-24

Infect Med (Beijing). 2025 Feb 5;4(1):100168. doi: 10.1016/j.imj.2025.100168. eCollection 2025 Mar.

ABSTRACT

Phages, including the viruses that lyse bacterial pathogens, offer unique therapeutic advantages, including their capacity to lyse antibiotic-resistant bacteria and disrupt biofilms without harming the host microbiota. The lack of new effective antibiotics and the growing limitations of existing antibiotics have refocused attention on phage therapy as an option in complex clinical cases such as burn wounds, cystic fibrosis, and pneumonia. This review describes clinical cases and preclinical studies in which phage therapy has been effective in both human and veterinary medicine, and in an agricultural context. In addition, critical challenges, such as the narrow host range of bacteriophages, the possibility of bacterial resistance, and regulatory constraints on the widespread use of phage therapy, are addressed. Future directions include optimizing phage therapy through strategies ranging from phage cocktails to broadening phage host range through genetic modification, and using phages as vaccines or biocontrol agents. In the future, if phage can be efficiently delivered, maintained in a stable state, and phage-antibiotic synergy can be achieved, phage therapy will offer much needed treatment options. However, the successful implementation of phage therapy within the current standards of practice will also require the considerable development of regulatory infrastructure and greater public acceptance. In closing, this review highlights the promise of phage therapy as a critical backup or substitute for antibiotics. It proposes a new role as a significant adjunct to, or even replacement for, antibiotics in treating multidrug-resistant bacterial infections.

PMID:40104270 | PMC:PMC11919290 | DOI:10.1016/j.imj.2025.100168

iScience. 2025 Feb 12;28(3):111999. doi: 10.1016/j.isci.2025.111999. eCollection 2025 Mar 21.

ABSTRACT

Pre-existing respiratory diseases may influence coronavirus disease (COVID-19) susceptibility and severity. However, the molecular mechanisms underlying the airway epithelial response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection severity in patients with chronic respiratory diseases remain unelucidated. Using an in vitro model of differentiated primary bronchial epithelial cells, we aimed to investigate the molecular mechanisms of SARS-CoV-2 infection in pre-existing cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Our study revealed reduced susceptibility of CF and COPD airway epithelia to SARS-CoV-2, relative to that in healthy controls. Mechanistically, reduced transmembrane serine protease 2 (TMPRSS2) activity potentially contributed to this resistance of CF epithelium. Upregulated complement and inflammatory pathways in CF and COPD epithelia potentially primed the antiviral state prior to infection. Analysis of a COVID-19 patient cohort validated our findings, correlating specific inflammatory markers (IP-10, SERPINA1, and CFB) with COVID-19 severity. This study elucidates SARS-CoV-2 pathogenesis and identifies potential biomarkers for clinical monitoring.

PMID:40104058 | PMC:PMC11914195 | DOI:10.1016/j.isci.2025.111999

Sci Rep. 2025 Mar 18;15(1):9264. doi: 10.1038/s41598-025-94184-x.

ABSTRACT

Measuring the quality of life in patients with cystic fibrosis is an important element of the patient care process. Many tools have been created for this measurement among adults. One of them is the Cystic Fibrosis Questionnaire-Revised 14+ (CFQ-R 14+). Its measurement properties have not been comprehensively assessed in the population of Polish adults. The aim of the study is to verify the construct validity, including structural and criterion validity, as well as internal consistency, of the Polish version of the CFQ-R 14+ in the population of adults with cystic fibrosis. We conducted a cross-sectional survey among adults with cystic fibrosis. After preparing the database, we performed a confirmatory factor analysis (CFA) followed by exploratory factor analysis (EFA) using the parallel analysis method principal axis factoring with Oblimin rotation. Intercorrelations of questionnaire factors and the occurrence of relationships among items for the general scale results was checked. We also presented basic descriptive statistics (mean, median, standard deviation, skewness, kurtosis, minimum and maximum values). The analyses included responses from 220 adult patients. CFA results did not show adequate goodness of fit (χ2(1025) = 2112.35, p < 0.001; CFI = 0.831; TLI = 0.814; RMSEA = 0.069; SRMR = 0.074). After EFA, 6 factors were extracted, considering 40 out of 50 questions of the CFQ-R 14+. CFQ-R 14+ may be useful in assessing the quality of life of Polish adult patients with cystic fibrosis. Our analysis demonstrates that the optimal factor structure of the tool in this population includes 6 scales.

PMID:40102545 | DOI:10.1038/s41598-025-94184-x

Lung. 2025 Mar 18;203(1):49. doi: 10.1007/s00408-025-00802-w.

ABSTRACT

PURPOSE: The objective was to study comparative efficacies of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, vanzacaftor-tezacaftor-deutivacaftor (VTD), elexacaftor-tezacaftor-ivacaftor (ETI), tezacaftor-ivacaftor (Tez-Iva), and lumacaftor-ivacaftor (Lum-Iva) in people with cystic fibrosis (pwCF), aged ≥ 12 years, carrying at least one F508del-CFTR-allele.

METHODS: Data from randomized controlled or randomized active comparator trials were included in this network meta-analysis which used frequentist approach for comparing the efficacy of drugs and ranking based on P-scores. Outcomes of interest were mean differences in percentage-predicted forced expiratory volume in one second (ppFEV1), CF questionnaire-revised respiratory domain (CFQ-R) scores, sweat chloride (SwCl) levels, and odds ratios (OR) for serious adverse events (SAE).

RESULTS: Data from 13 studies were analyzed. Compared to placebo, the effects of VTD and ETI on ppFEV1 were almost quadruple of Tez-Iva and Lum-Iva (VTD: 12.78 [95% confidence intervals: 6.41; 19.15] and ETI: 11.95 [7.40; 16.50]) and almost seven times of Tez-Iva and Lum-Iva for CFQ-R (VTD: 21.23 [- 28.72; 71.18] and ETI: 19.27 [10.56; 27.98]). A statistically significant difference was noted between VTD and ETI in SwCl reduction (mean difference: - 8.59 [- 15.53; - 1.65]). There were no statistically significant ORs for SAEs for any CFTR modulators but VTD, ETI, and Tez-Iva were least associated with SAEs (ORs were 0.15 [0.01; 1.79], 0.49 [0.31; 0.78], and 0.74 [0.50; 1.09], respectively, as compared to placebo). Overall, P-score ranking ranked VTD as first and ETI as second, followed by others.

CONCLUSION: VTD and ETI were more efficacious than Tez-Iva and Lum-Iva in pwCF with at least one F508del-CFTR-allele.

PMID:40102290 | DOI:10.1007/s00408-025-00802-w

Br J Sports Med. 2025 Mar 18:bjsports-2024-109184. doi: 10.1136/bjsports-2024-109184. Online ahead of print.

ABSTRACT

OBJECTIVE: To synthesise data on the associations between cardiorespiratory fitness (CRF) and health in children and adolescents, evaluate the certainty of evidence and identify knowledge gaps.

DESIGN: An overview of systematic reviews with meta-analyses. Results were pooled using forest plots and certainty of evidence evaluated with GRADE.

DATA SOURCES: Medline, Embase, Scopus, CINAHL and SPORTDiscus were searched from January 2002 to March 2024.

ELIGIBILITY CRITERIA FOR SELECTED STUDIES: Systematic reviews with meta-analyses exploring CRF and health in children and adolescents aged <18 years.

RESULTS: From the 9062 records identified, 14 reviews were included. Meta-analysed data from 125 164 observations covering 33 health outcomes were compiled, showing favourable (n=26) or null (n=7) associations with CRF. Among general populations, the associations were weak-to-moderate, with favourable links between CRF and indicators of anthropometry and adiposity, cardiometabolic and vascular health, and mental health and well-being. Among clinical populations, CRF was lower in participants with a condition compared with healthy controls, with the largest difference for newly diagnosed cancer (mean difference=-19.6 mL/kg/min; 95%CI: -21.4,-17.8). Patients with cystic fibrosis had a greater risk for all-cause mortality when comparing low CRF vs. high (relative risk=4.9; 95%CI: 1.1, 22.1). The certainty of evidence ranged from very low to moderate.

CONCLUSION: CRF shows promising links to numerous health outcomes in paediatric populations, though the low certainty of evidence calls for further research. High-quality longitudinal evidence is warranted to confirm the findings and investigate a predictive role of childhood CRF for future health.

PMID:40101938 | DOI:10.1136/bjsports-2024-109184

ACS Infect Dis. 2025 Mar 18. doi: 10.1021/acsinfecdis.4c01045. Online ahead of print.

ABSTRACT

Antimicrobial resistance (AMR) poses a major threat to human health globally. Approximately 5 million deaths were attributed to AMR in 2019, and this figure is predicted to worsen, reaching 10 million deaths by 2050. In the search for new compounds that can tackle AMR, FtsZ inhibitors represent a valuable option. In the present study, a structure-based virtual screening is reported, which led to the identification of derivative C11 endowed with an excellent minimum inhibitory concentration value of 2 μg/mL against Staphylococcus aureus. Biochemical assays clarified that compound C11 targets FtsZ by inhibiting its polymerization process. C11 also showed notable antimicrobial activity against S. aureus cystic fibrosis isolates and methicillin-resistant S. aureus strains. Derivative C11 did not show cytotoxicity, while it had a synergistic effect with methicillin. C11 also showed increased survival in the Galleria mellonella infection model. Lastly, structure-activity relationship and binding mode analyses were reported.

PMID:40100965 | DOI:10.1021/acsinfecdis.4c01045

Cell Mol Life Sci. 2025 Mar 18;82(1):121. doi: 10.1007/s00018-025-05633-9.

ABSTRACT

Cystic fibrosis (CF) is a rare disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a chloride channel with an important role in the airways. Despite the clinical efficacy of present modulators in restoring the activity of defective CFTR, there are patients who show persistent pulmonary infections, mainly due to Pseudomonas aeruginosa. Recently, we reported an unprecedented property of antimicrobial peptides i.e. Esc peptides, which consists in their ability to act as potentiators of CFTR carrying the most common mutation (the loss of phenylalanine 508) affecting protein folding, trafficking and gating. In this work, by electrophysiology experiments and computational studies, the capability of these peptides and de-novo designed analogs was demonstrated to recover the function of other mutated forms of CFTR which severely affect the channel gating (G551D and G1349D). This is presumably due to direct interaction of the peptides with the nucleotide binding domains (NBDs) of CFTR, followed by a novel local phenomenon consisting in distancing residues located at the cytosolic side of the NBDs interface, thus stabilizing the open conformation of the pore at its cytosolic end. The most promising peptides for the dual antimicrobial and CFTR potentiator activities were also shown to display antipseudomonal activity in conditions mimicking the CF pulmonary ion transport and mucus obstruction, with a higher efficacy than the clinically used colistin. These studies should assist in development of novel drugs for lung pathology in CF, with dual CFTR potentiator and large spectrum antibiotic activities.

PMID:40100363 | DOI:10.1007/s00018-025-05633-9

ACS Appl Mater Interfaces. 2025 Mar 18. doi: 10.1021/acsami.4c20874. Online ahead of print.

ABSTRACT

Bacterial biofilms present significant therapeutic challenges due to their resistance to conventional antimicrobial treatment. Mucins typically serve as a protective barrier against pathogens, yet certain bacteria, such as Pseudomonas aeruginosa (P. aeruginosa), can exploit these glycoproteins as attachment sites for biofilm formation. This study introduces boronic acid-functionalized polyethyleneimine (PEI-BA) as a promising antibiofilm agent that effectively blocks bacterial adhesion to mucin-rich surfaces. Through the multivalent presentation of boronic acid groups, PEI-BA reversibly forms boronate ester bonds with mucin glycans, creating a protective barrier. Our findings show that PEI-BA prevents bacterial attachment through a nonbactericidal mechanism, potentially reducing the risk of resistance development. Notably, PEI-BA synergizes with a conventional antibiotic, tobramycin, significantly enhancing biofilm inhibition compared to either treatment alone. Systematic evaluation of PEI-BA formulations identified optimal functionalization levels, balancing glycan-binding capability with solubility. From a biomaterials design perspective, we demonstrate how rational polymer modification can transform a potent but cytotoxic antimicrobial agent (i.e., PEI) into a safe and effective antibiofilm material, opening further possibilities for managing biofilm-associated infections in clinical settings. This work establishes boronic acid-based nanomaterials as promising candidates for biofilm prevention and antibiotic enhancement, particularly in conditions like cystic fibrosis, where mucin-bacterial interactions contribute to disease progression.

PMID:40099915 | DOI:10.1021/acsami.4c20874

Nat Biotechnol. 2025 Mar 17. doi: 10.1038/s41587-025-02616-w. Online ahead of print.

NO ABSTRACT

PMID:40097678 | DOI:10.1038/s41587-025-02616-w

Nat Nanotechnol. 2025 Mar 17. doi: 10.1038/s41565-025-01877-5. Online ahead of print.

ABSTRACT

The active transport and retention principle is an alternative mechanism to the enhanced permeability and retention effect for explaining nanoparticle tumour delivery. It postulates that nanoparticles actively transport across tumour endothelial cells instead of passively moving through gaps between these cells. How nanoparticles transport across tumour endothelial cells remains unknown. Here we show that nanoparticles cross tumour endothelial cells predominantly using the non-receptor-based macropinocytosis pathway. We discovered that tumour endothelial cell membrane ruffles capture circulating nanoparticles, internalize them in intracellular vesicles and release them into the tumour interstitium. Tumour endothelial cells have a higher membrane ruffle density than healthy endothelium, which may partially explain the elevated nanoparticle tumour accumulation. Receptor-based endocytosis pathways such as clathrin-mediated endocytosis contribute to nanoparticle transport to a lesser extent. Nanoparticle size determines the degree of contribution for each pathway. Elucidating the nanoparticle transport mechanism is crucial for developing strategies to control nanoparticle tumour delivery.

PMID:40097646 | DOI:10.1038/s41565-025-01877-5

JAMA Netw Open. 2025 Mar 3;8(3):e250908. doi: 10.1001/jamanetworkopen.2025.0908.

ABSTRACT

IMPORTANCE: Black pregnant patients are significantly more likely than their White counterparts to undergo peripartum urine drug screening (UDS) and subsequent reporting to child protective services (CPS).

OBJECTIVE: To evaluate the association of removing isolated cannabis use and limited prenatal care as order indications, combined with clinician-facing clinical decision support, with racial parity in peripartum UDS and CPS reporting.

DESIGN, SETTING, AND PARTICIPANTS: This quality improvement study assessed 9396 pregnant patients at a single tertiary care center in a Midwestern US urban metropolitan region who delivered before (June 1, 2021, to September 31, 2022) and after (October 1, 2022, to January 31, 2024) the intervention.

EXPOSURE: Updated UDS indications combined with clinical decision support.

MAIN OUTCOMES AND MEASURES: Primary outcomes included UDS and CPS report rate by race before vs after the intervention. The secondary outcome was the rate of nonprescribed, noncannabis substance-positive UDS. Neonatal outcomes were included as balancing measures.

RESULTS: Of 9396 female patients (median [IQR] age, 29 [24-33] years; 4305 [45.8%] Black, 4277 [45.5%] White, and 814 [8.7%] other race) included in the analysis, 4639 and 4757 delivered in the preintervention and postintervention periods, respectively. There was a small but statistically significant decrease in the number of Black patients before vs after the intervention (2210 [47.6%] vs 2095 [44.0%], P = .005); there were no significant differences in other race groups, median age, or multiparity. Before the intervention, 513 (23.2%) and 228 (11.1%) Black and White patients, respectively, had UDS (P < .001) compared with 95 (4.5%) and 79 (3.6%) Black and White patients, respectively, after the intervention (P = .40). Before the intervention, an association between Black race and CPS report was observed (249 [11.3%] Black and 119 [5.8%] White patients, P < .001); there was no association between race and CPS report after the intervention (87 [4.2%] Black and 78 [3.5%] White patients, P = .67). There was no association between the intervention and the percentage of UDS results that were positive for nonprescribed, noncannabis substances (107 [2.5%] preintervention vs 88 [2.0%] postintervention; P = .14). There was no significant association between the intervention and any measured neonatal outcomes.

CONCLUSIONS AND RELEVANCE: In this quality improvement study, removal of isolated cannabis use and limited prenatal care as UDS indications, coupled with clinical decision support, was associated with improved racial equity in UDS testing and CPS reporting. The intervention was not associated with a significant change in UDS positivity for nonprescribed, noncannabis substances. These findings suggest that this intervention improved equity in UDS practices without decreasing identification of clinically relevant substance use.

PMID:40094663 | PMC:PMC11915058 | DOI:10.1001/jamanetworkopen.2025.0908

Pancreatology. 2025 Feb 28:S1424-3903(25)00043-2. doi: 10.1016/j.pan.2025.02.015. Online ahead of print.

ABSTRACT

BACKGROUND: Pancreatic exocrine insufficiency (PEI) is defined as a reduction in pancreatic exocrine secretion below a level that allows normal digestion of nutrients. Pancreatic disease and pancreatic surgery are the main causes of PEI, but other conditions can affect the digestive function of the pancreas.

METHODS: In collaboration with European Digestive Surgery (EDS), European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), European Society for Clinical Nutrition and Metabolism (ESPEN), European Society of Digestive Oncology (ESDO), and European Society of Primary Care Gastroenterology (ESPCG) the working group developed European guidelines for the diagnosis and therapy of PEI. United European Gastroenterology (UEG) provided both endorsement and financial support for the development of the guidelines.

RESULTS: Recommendations covered topics related to the clinical management of PEI: concept, pathogenesis, clinical relevance, general diagnostic approach, general therapeutic approach, PEI secondary to chronic pancreatitis, PEI after acute pancreatitis, PEI associated with pancreatic cancer, PEI secondary to cystic fibrosis, PEI after pancreatic surgery, PEI after esophageal, gastric, and bariatric surgery, PEI in patients with type 1 and type 2 diabetes, and PEI in other conditions.

CONCLUSIONS: The European guidelines for the diagnosis and therapy of PEI provide evidence-based recommendations concerning key aspects of the etiology, diagnosis, therapy, and follow-up, based on current available evidence. These recommendations should serve as a reference standard for existing management of PEI and as a guide for future clinical research. This article summarizes the recommendations and statements.

PMID:40097316 | DOI:10.1016/j.pan.2025.02.015

Am J Physiol Lung Cell Mol Physiol. 2025 Mar 17. doi: 10.1152/ajplung.00258.2024. Online ahead of print.

ABSTRACT

Cigarette smoke (CS) is a leading cause of chronic obstructive pulmonary disease (COPD). Here, we investigated whether the ion channel amplifier nesolicaftor rescues CS-induced mucociliary and ion channel dysfunction. Since CS increases expression of transforming growth factor-beta1 (TGF-β1), human bronchial epithelial cells (HBEC) from healthy donors were used for TGF-β1 and COPD donors (COPD-HBEC) for CS exposure experiments. CS and TGF-β1 induce mucociliary dysfunction by increasing MUC5AC and decreasing ion channel conductance important for mucus hydration. These include cystic fibrosis transmembrane conductance regulator (CFTR) and apical large-conductance, Ca2+-activated K+ (BK) channels. Nesolicaftor rescued CFTR and BK channel dysfunction, restored ciliary beat frequency (CBF), and decreased mucus viscosity and MUC5AC expression in CS-exposed COPD-HBEC. Nesolicaftor further reversed reductions in ASL volumes, CBF, and CFTR and BK conductance, and blocked the increase in extracellular signal-regulated kinase (ERK) signaling in TGF-β1-exposed normal HBEC. Mechanistically, nesolicaftor increased, as expected, binding of PCBP1 to CFTR mRNA, but surprisingly also to LRRC26 mRNA, which encodes the gamma subunit required for BK function. Similar to nesolicaftor, the angiotensin receptor blocker (ARB) losartan rescued TGF-β1-mediated decreases in PCBP1 binding to LRRC26 mRNA. In addition, the ARB telmisartan restored PCBP1 binding to CFTR and LRRC26 mRNAs to rescue CFTR and BK function in CS-exposed COPD-HBEC. Thus, nesolicaftor and ARBs act on the same target and were therefore neither additive nor synergistic in their actions. These data demonstrate that nesolicaftor and ARBs may provide benefits in COPD by improving ion channel function important for mucus hydration.

PMID:40095970 | DOI:10.1152/ajplung.00258.2024

Pediatr Nephrol. 2025 Mar 17. doi: 10.1007/s00467-025-06715-3. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a life-shortening multisystem disease resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, causing the most devastating phenotypes in the airway and pancreas. Significant advances in treatment for CF lung disease, including the expanded use of high-efficiency modulator therapies (HEMT) such as Trikafta, have dramatically increased both quality of life and life expectancy for people with CF (PwCF). With these advances, long-term extrapulmonary manifestations are more frequently recognized. Pseudo-Barter syndrome, acute kidney injury (AKI) induced by medications or dehydration, amyloidosis, nephrolithiasis, and IgA and diabetic nephropathies have been previously reported in PwCF. Newer data suggest that chronic kidney disease (CKD) is a new morbidity in the aging CF population, affecting 19% of people over age 55. CKD carries a high risk of premature death from cardiovascular complications. Studies suggest that CFTR dysfunction increases kidneys' vulnerability to injury caused by the downstream effects of CF. Improving the mutant CFTR function by HEMT may help to tease apart the kidney responses resulting from extrinsic factors and those intrinsically related to the CFTR gene mutations. Additionally, given the novelty of HEMT approaches, the potential off-target effects of their long-term use are currently unknown. We review the evolving kidney complications in PwCF and propose the term CF-related kidney disease. We hope this review will increase awareness about the changing phenotype of kidney dysfunction in PwCF and help prevent morbidity related to this condition.

PMID:40095037 | DOI:10.1007/s00467-025-06715-3

mBio. 2025 Mar 17:e0036325. doi: 10.1128/mbio.00363-25. Online ahead of print.

ABSTRACT

The human pathogenic fungus Aspergillus fumigatus establishes dual biofilm interactions in the lungs with the pathogenic bacterium Pseudomonas aeruginosa. Screening of 21 A. fumigatus null mutants revealed seven mutants (two G protein-coupled receptors, three mitogen-activated protein kinase receptors, a Gα protein, and one histidine kinase receptor) with reduced biofilm formation, specifically in the presence of P. aeruginosa. Transcriptional profiling and metabolomics analysis of secondary metabolites produced by one of these mutants, ΔgpaB (gpaB encodes a Gα protein), showed GpaB controls the production of several important metabolites for the dual biofilm interaction, including pyripyropene A, a potent inhibitor of mammalian acyl-CoA cholesterol acyltransferase. Deletion of pyr2, encoding a non-reducing polyketide synthase essential for pyripyropene biosynthesis, showed reduced A. fumigatus Δpyr2-P. aeruginosa biofilm growth, altered macrophage responses, and attenuated mouse virulence in a chemotherapeutic murine model. We identified pyripyropene as a novel player in the ecology and pathogenic interactions of this important human fungal pathogen.IMPORTANCEAspergillus fumigatus and Pseudomonas aeruginosa are two important human pathogens. Both organisms establish biofilm interactions in patients affected with chronic lung pulmonary infections, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease. Colonization with A. fumigatus is associated with an increased risk of P. aeruginosa colonization in CF patients, and disease prognosis is poor when both pathogens are present. Here, we identified A. fumigatus genetic determinants important for the establishment of in vitro dual A. fumigatus-P. aeruginosa biofilm interactions. Among them, an A. fumigatus Gα protein GpaB is important for this interaction controlling the production of the secondary metabolite pyripyropene. We demonstrate that the lack of pyripyropene production decreases the dual biofilm interaction between the two species as well as the virulence of A. fumigatus in a chemotherapeutic murine model of aspergillosis. These results reveal a complete novel role for this secondary metabolite in the ecology and pathogenic interactions of this important human fungal pathogen.

PMID:40094363 | DOI:10.1128/mbio.00363-25

medRxiv [Preprint]. 2025 Mar 6:2025.03.05.25323327. doi: 10.1101/2025.03.05.25323327.

ABSTRACT

Sweat parameters such as volume and chloride concentration may offer invaluable clinical insights for people with CF (PwCF). Pilocarpine-induced sweat collection for chloridometry measurement is the gold-standard for sweat chloride, but this technique is cumbersome and not suitable for remote settings. We have previously reported the utility of a skin-interfaced microfluidic device (CF Patch) in conjunction with a smartphone image processing platform that enables real-time measurement of sweating rates and sodium chloride loss in laboratory and remote settings. Here we conducted clinical studies characterizing the accuracy of the CF Patch compared to pilocarpine-induced sweat measurements using chloridometry and tested the feasibility of exercise-induced sweat chloride measurements in PwCF. The CF Patch demonstrated strong correlations compared to sweat chloride measured by chloridometry across clinic and remote settings and detected greater day-to-day sweat chloride variability in PwCF on CFTR modulators than healthy volunteers. These findings demonstrate that the CF Patch is suitable as a remote management device capable of measuring chloride concentrations and offers the potential of monitoring the efficacy of CF medication regimens.

PMID:40093258 | PMC:PMC11908303 | DOI:10.1101/2025.03.05.25323327

Turk Arch Pediatr. 2025 Mar 3;60(2):147-152. doi: 10.5152/TurkArchPediatr.2025.24199.

ABSTRACT

Objective: Patient-reported quality of life (QoL) measurement is crucial in making clinical decisions in unison with the patients. The current gold standard for cystic fibrosis (CF) is the Cystic Fibrosis Questionnaire-Revised (CFQ-R), which has different applications for different age groups and requires a computer program to be evaluated. There is a need for a straightforward way to evaluate QoL in both pediatric and adult patients with CF. The study aims to establish the validity and reliability of the Turkish version of the Alfred Wellness Score (AWESCORE) test that has been developed to evaluate QoL in patients with CF. Materials and Methods: This study is a methodological study. The AWESCORE form was translated into Turkish and was applied to patients above 10 years of age. It includes 10 questions. Each question was scored using a numerical rating scale of 0-10. Total scores ranged from 0 to 100. Test-retest reliability was assessed over 24 hours. To determine validity, comparisons were sought between stable subjects and those in pulmonary exacerbation, and between AWESCORE and CFQ-R. Results: A total of 99 patients were included, 29 of whom were during their acute exacerbation period (29%). All questions showed intraclass correlation coefficient (ICC) values above 0.9, indicating excellent reliability. Scores were higher during clinical stability compared to pulmonary exacerbation (mean ± SD): 79.35 ± 6.51 versus 41.93 ± 8.58 (P < .001). All questions were significantly worse in the acute exacerbation period, showing excellent validity with P values below .001 for each question. Conclusion: The Turkish version of the AWESCORE is valid and reliable in its ability to evaluate QoL in patients with CF.

PMID:40091631 | DOI:10.5152/TurkArchPediatr.2025.24199

Turk Arch Pediatr. 2025 Mar 3;60(2):117-125. doi: 10.5152/TurkArchPediatr.2025.24257.

ABSTRACT

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder that primarily affects the respiratory and gastrointestinal systems. It results from variants in the CFTR gene, leading to dysfunctional chloride channels, thickened mucus secretion, and subsequent multisystem complications. Significant advances have been made in CF treatment, particularly with the development of CFTR modulators, which are unique to genotypes and have improved clinical outcomes in many people with CF. However, the benefits of these therapies are not universal, with a considerable portion of the CF population-especially those with rare mutations-still without access to effective treatment options. This review provides a comprehensive overview of the pathophysiology and genetic basis of CF, explores current and emerging treatments, and discusses the ongoing challenges in the field.

PMID:40091461 | DOI:10.5152/TurkArchPediatr.2025.24257

Respir Med. 2025 Mar 14:108042. doi: 10.1016/j.rmed.2025.108042. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic pulmonary infection with pathogens such as Pseudomonas aeruginosa is associated with lung function decline and increased mortality in people with cystic fibrosis (CF). The relationship between sputum bacterial load and the severity of pulmonary exacerbations remains unclear. This study aimed to explore the relationship between sputum bacterial load and clinical response to antibiotic treatment of pulmonary exacerbations in children with CF.

METHODS: Multicentre prospective longitudinal study of children with CF receiving IV tobramycin for a pulmonary exacerbation and who had prior isolation of Gram-negative bacteria and able to expectorate sputum. Lung function (FEV1) and sputum bacterial load were assessed. Bacterial load was performed using quantitative PCR on either intact (live) bacterial cells or all bacterial DNA (live+dead) and targeted either P. aeruginosa only or all bacteria.

RESULTS: Twelve children (14 admissions) were enrolled and each provided ≥2 sputum samples; 11 children (13 admissions) also had ≥2 FEV1 measurements. In 10 admissions where FEV1 improved, five showed a reduction in all live bacteria, with a median reduction by 8.65×106 copies/g (73% reduction). Live P. aeruginosa was detected in 8/10 children and in seven, a median reduction of 2.99×107 copies/g (90% reduction) was observed. Improved FEV1 correlated with greater reductions in live+dead P. aeruginosa (ρ = -0.63, p = 0.04).

CONCLUSION: A greater reduction in total sputum P. aeruginosa bacterial load (live+dead) was associated with improved lung function (FEV1) in children with CF receiving tobramycin.

PMID:40090524 | DOI:10.1016/j.rmed.2025.108042