Cell Mol Life Sci. 2025 Apr 7;82(1):144. doi: 10.1007/s00018-025-05587-y.

ABSTRACT

The cystic fibrosis (CF) causing variant G542X harbours a premature translation stop signal in the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA. This results in nonsense-mediated decay and loss of functional CFTR protein which leads to defective anion transport and the development of CF disease pathology. Currently available CF modulator therapies cannot be used to treat this variant. We used an adenine base editor (ABE8e Cas9) and guide RNA (sgRNA)/enhanced green fluorescent protein (EGFP) plasmids encapsulated in receptor targeted nanoparticles (RTN), delivered to Bmi-1 transduced basal human CF nasal epithelial cells harbouring the homozygous CFTR G542X variant, to convert the stop codon to G542R, a variant which is amenable to modulator therapy. ABE resulted in 17% of alleles edited to G542R and further selection of GFP fluorescent cells by FACS liberated a population with 52% G542R edited alleles with no editing of neighbouring adenines (A) and few off target edits using a gRNA homology-based approach. In cells differentiated at air-liquid-interface (ALI), 17% and 52% editing of CFTR G542X increased mRNA abundance. 52% editing alone or 17% and 52% editing of CFTR G542X plus treatment with CFTR modulators (VX-445/VX-661/VX-770; ETI/Trikafta/Kaftrio) increased epithelial CFTR protein expression, CFTR protein band C abundance, CFTR172 inhibitable anion transport, and changes in airway surface liquid height and pH in response to vasoactive intestinal peptide (VIP) stimulation. Epithelial scratch repair speed and directionality was also improved. These data provide proof-of-concept that ABE of G542X to G542R in human CF airway epithelial cells could provide a feasible therapy for this variant.

PMID:40192756 | DOI:10.1007/s00018-025-05587-y

Respir Med. 2025 Apr 4:108076. doi: 10.1016/j.rmed.2025.108076. Online ahead of print.

ABSTRACT

The European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) herein proposes guidance for the use of chest CT-scans for the regular monitoring of lung disease in CF. Statements were completed in a 3-step process: the questions were identified via an anonymous online survey, followed by a comprehensive literature search, and a final Delphi process. The guidance recommends the use of ultra-low dose CT scans (effective radiation dose, 0.08 mSv; equivalent to 2 to 4 chest X-rays), tracking of patients' cumulative radiation and effective communication strategies using "de-medicalised" information for shared decision making. Chest CT scans (with lung volume monitoring) are not recommended systematically in both children and adults. Ultimate responsibility for justifying a chest CT scan lies with the individual professionals directly involved, the final decision being influenced by indications, costs, expertise, available material, resources and/or the patient's values, as well as possible impact on treatment modalities.

PMID:40189162 | DOI:10.1016/j.rmed.2025.108076

Respir Med. 2025 Apr 4:108087. doi: 10.1016/j.rmed.2025.108087. Online ahead of print.

ABSTRACT

BACKGROUND: Diagnostic tests for cystic fibrosis (CF) are not readily available in resource-limited settings, which leads to delay in diagnosis and treatment of children with CF.

METHODS: In a multicentric prospective study, children with recurrent/ persistent pneumonia, failure to thrive, or steatorrhea with suspicion of CF were enrolled. Sweat chloride concentration was measured to confirm the diagnosis of CF. Diagnostic accuracy of various clinical features, ancillary laboratory investigations (serum electrolytes, blood gas, stool fat globules), and aquagenic wrinkling for CF diagnosis was estimated. CF clinical diagnostic score (CF-CDS) was developed by combining significant parameters in stepwise logistic regression.

RESULTS: Of 860 children enrolled, 313 (36.7%) were diagnosed with CF. History of a sibling with CF, clubbing, hyponatremia, metabolic alkalosis, stool fat globule positivity, sputum Pseudomonas isolation, and aquagenic wrinkling within 3 minutes were found to be independently associated with a diagnosis of CF. CF-CDS score developed by combining these parameters demonstrated excellent diagnostic accuracy for diagnosis of CF [AUROC of 0.923 (95%CI: 0.899, 0.946)]. At a cut-off of ≥ 2.5, CF-CDS had sensitivity and specificity of 87.64% and 81.02%, respectively.

CONCLUSION: CF-CDS has excellent diagnostic accuracy for diagnosis of CF in children and can be used to decide on starting treatment of CF pending confirmatory tests when confirmatory tests are not readily available.

PMID:40189161 | DOI:10.1016/j.rmed.2025.108087

ISME J. 2025 Apr 6:wraf065. doi: 10.1093/ismejo/wraf065. Online ahead of print.

ABSTRACT

Virulent bacteriophages (or phages) are viruses that specifically infect and lyse a bacterial host. When multiple phages co-infect a bacterial host, the extent of lysis, dynamics of bacteria-phage and phage-phage interactions are expected to vary. The objective of this study is to identify the factors influencing the interaction of two virulent phages with different Pseudomonas aeruginosa growth states (planktonic, an infected epithelial cell line, and biofilm) by measuring the bacterial time-kill and individual phage replication kinetics. A single administration of phages effectively reduced P. aeruginosa viability in planktonic conditions and infected human lung cell cultures, but phage-resistant variants subsequently emerged. In static biofilms, the phage combination displayed initial inhibition of biofilm dispersal, but sustained control was achieved only by combining phages and meropenem antibiotic. In contrast, adherent biofilms showed tolerance to phage and/or meropenem, suggesting a spatio-temporal variation in the phage-bacterial interaction. The kinetics of adsorption of each phage to P. aeruginosa during single- or co-administration were comparable. However, the phage with the shorter lysis time depleted bacterial resources early and selected a specific nucleotide polymorphism that conferred a competitive disadvantage and cross-resistance to the second phage. The extent and strength of this phage-phage competition and genetic loci conferring phage resistance, are, however, P. aeruginosa genotype dependent. Nevertheless, adding phages sequentially resulted in their unimpeded replication with no significant increase in bacterial host lysis. These results highlight the interrelatedness of phage-phage competition, phage resistance and specific bacterial growth state (planktonic/biofilm) in shaping the interplay among P. aeruginosa and virulent phages.

PMID:40188480 | DOI:10.1093/ismejo/wraf065

Arch Bronconeumol. 2025 Mar 18:S0300-2896(25)00082-1. doi: 10.1016/j.arbres.2025.03.003. Online ahead of print.

ABSTRACT

BACKGROUND: In patients with non-cystic fibrosis bronchiectasis (BE) Pseudomonas aeruginosa (PA) has been recently associated with low rather than high number of exacerbations without distinguishing chronic versus intermittent infection. The aim of our study was to determine whether the intermittent or chronic stage of P. aeruginosa (PA) infection is associated with the rate of exacerbations, quality of life and respiratory microbiome biodiversity after a one-year follow-up.

METHODS: We conducted a longitudinal study, with 1-year follow-up, in patients with BE intermittently or chronically infected by PA involving sequential (3-monthly) measurements of microbiological (cultures, PA load, phenotype and biofilms presence) immunological (Serum IgGs against P. aeruginosa were measured by ELISA immunoassay) and clinical variables (Quality-of-Life and the number exacerbations). Additionaly, 16S sequencing was performed on a MiSeq Platform and compared between chronically infected patients with the mucoid PA versus intermittently infected patients with the non-mucoid PA.

RESULTS: We collected 235 sputa and 262 serum samples from 80 BE patients, 61 with chronic and 19 with intermittent PA infection. Chronically compared to intermittently. Presented reduced quality of life but less hospitalized exacerbations after 1-year follow-up. Chronically infected patients presented reduced sputum biodiversity and higher systemic IgGs against P. aeruginosa levels that were associated to decreased number of hospitalized exacerbations.

CONCLUSIONS: The assessment of Chronic versus intermittent P. aeruginosa infection has clinical implications such as quality of life, rate of hospitalized exacerbations and lung microbiome biodiversity. The distinction of these two phenotypes is easy to perform in clinical practice.

TRIAL REGISTRATION: NCT04803695.

PMID:40187923 | DOI:10.1016/j.arbres.2025.03.003

Pediatr Allergy Immunol Pulmonol. 2025 Apr 4. doi: 10.1089/ped.2024.0142. Online ahead of print.

ABSTRACT

Background: Although the forced oscillation technique has been used for many years in children, there is still inconclusive results about its efficiency in cystic fibrosis (CF). Moreover, no studies have been conducted on impulse oscillometry (IOS) in children with primary ciliary dyskinesia (PCD). Methods: Age, sex, weight, height, body mass index, and oscillometric parameters were compared in 3-6-year-old children with CF and PCD and healthy children. Results: This prospective study included 27 children with CF, 21 with PCD, and 27 healthy children, with mean ages of 4.11 ± 1.08, 4.33 ± 1.23, and 4.41 ± 0.79 years, respectively. No significant differences were revealed in the comparison of the z-scores of the parameters of the CF group with those of the healthy group. However, in the PCD group, z-scores of R5 and Z5 were significantly higher than those in the healthy group (P = 0.018 and P = 0.008, respectively). In addition, z-scores of X10, X15, and X20 were significantly lower in children with PCD compared with the healthy group (P = 0.013, P = 0.033, and P = 0.029, respectively). Conclusions: This first study simultaneously reporting IOS results in preschool children with CF or PCD showed a significant difference of resistance and reactance of airways between PCD and healthy children. This study is also very significant in showing that IOS can be performed in young children who are unable to cooperate with spirometry. In contrast, no such differences were noted between CF and healthy controls, possibly due to thick mucus affecting sound wave transmission through the airways in CF. In addition, IOS may be less effective in detecting early pulmonary disease, as in some studies it failed to identify abnormalities in young children with CF even when spirometry is abnormal.

PMID:40184233 | DOI:10.1089/ped.2024.0142

Pediatr Pulmonol. 2025 Apr;60(4):e71057. doi: 10.1002/ppul.71057.

ABSTRACT

INTRODUCTION: Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by abnormalities in the motile cilia. Diagnosis could be hard to make, but genetic analysis could be important for the diagnosis and for defining prognosis.

AIM OF THE STUDY: To evaluate the clinical, ultrastructural, and molecular characteristics of a cohort of PCD subjects.

MATERIALS AND METHODS: The study cohort included PCD patients enrolled in two Italian centers. Clinical data were retrospectively collected consulting medical records. All patients underwent nasal brushing and peripheral blood sampling for ultrastructural analysis of motile cilia and genetic testing, respectively.

RESULTS: A total of 39 patients with PCD were enrolled (median age 25.5 years, range 2.5-54.3 years). All patients showed common clinical features, which included SIT in 22/39 (56.4%), chronic rhinitis in 31/39 (79.5%), chronic sinusitis in 26/37 (66.7%), chronic cough in 32/39 (82.1%), and neonatal respiratory distress in 46.2% (18/39). The genetic defect was identified in 27/39 patients (69.2%), while a diagnostic ultrastructure was found in 27/35 (77.1%). Assessing genotype-phenotype correlations, subjects with biallelic pathogenic variants in CCDC39 and CCDC40 genes had a significantly lower forced expiratory volume in the first second of exhalation value (p = 0.017) than subjects with pathogenic variants in DNAH5 or in other PCD-related genes.

CONCLUSIONS: Our study further highlights the high heterogeneity of ultrastructural defects and genetics characterizing patients with PCD, as well as providing additional evidence that patients with biallelic pathogenic variants in CCDC39 or CCDC40 display a worse clinical phenotype than patients with pathogenic variants in other PCD genes.

PMID:40183288 | DOI:10.1002/ppul.71057

Ther Adv Endocrinol Metab. 2025 Apr 2;16:20420188251328210. doi: 10.1177/20420188251328210. eCollection 2025.

ABSTRACT

Cystic fibrosis-related bone disease (CFBD) is a common endocrinopathy in people living with cystic fibrosis (CF) that is complex and multifactorial in origin. People with CF experience high rates of progressive bone density loss and increased fracture risk. Focus on prevention and treatment of CFBD is of increasing importance in a now aging CF population. This review will discuss current practices in CFBD, gaps in knowledge, and potential future studies with the goal of advancing the clinical care of patients with CFBD.

PMID:40183033 | PMC:PMC11967205 | DOI:10.1177/20420188251328210

Front Genet. 2025 Mar 20;16:1543623. doi: 10.3389/fgene.2025.1543623. eCollection 2025.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a common monogenic multisystem disease caused primarily by variants in the CFTR gene. Emerging evidence suggests that some variants, which are described as missense, synonymous or nonsense variants in the literature or databases, may be deleterious by affecting the pre-mRNA splicing process.

METHODS: We analyzed 27 exonic variants in the CFTR gene utilizing bioinformatics tools and identified candidate variants that could lead to splicing changes through minigene assays. Ultimately, we selected eight candidate variants to assess their effects on pre-mRNA splicing. The numbering of DNA variants is based on the complementary DNA (cDNA)sequence of CFTR (Ref Seq NM_000492.4).

RESULTS: This study assessed the impact of CFTR variants on exon splicing by combining predictive bioinformatics tools with minigene assays. Among the eight candidate single nucleotide alterations, five variants (c.488A>T,c.1117G>T, c.1209G>T, c.3239A>G and c.3367G>C) were identified as causing exon skipping.

CONCLUSION: Our study employed a minigene system, which offers great flexibility for assessing aberrant splicing patterns when patient mRNA samples are not accessible, to investigate the effects of exonic variants on pre-mRNA splicing. Our experimental outcomes highlight the importance of analyzing exonic variations at the mRNA level.

PMID:40182926 | PMC:PMC11965618 | DOI:10.3389/fgene.2025.1543623

Eur Respir J. 2025 Apr 3;65(4):2500089. doi: 10.1183/13993003.00089-2025. Print 2025 Apr.

NO ABSTRACT

PMID:40180359 | DOI:10.1183/13993003.00089-2025

Respir Med. 2025 Apr 1:108080. doi: 10.1016/j.rmed.2025.108080. Online ahead of print.

ABSTRACT

BACKGROUND: Despite recent improvements in treatment modalities for cystic fibrosis (CF), there is currently limited evidence and a lack of consensus regarding optimal treatment strategies for the different aspects of CF, including pulmonary exacerbations (PEx). We aimed to establish a prospective cohort of people with CF (pwCF) to evaluate alternative approaches to managing CF in the era of modulator therapies.

METHODS: We prospectively enrolled children and adults with CF receiving care at specialist CF centres across Australia. Participant data were systematically collected on demography, clinical signs and symptoms, comorbidities, spirometry, participant reported outcomes, microbiology and treatments received. Here we describe the demographic, microbiological and clinical characteristics of the participants at enrolment, to understand the representativeness of the cohort for planning future nested studies.

RESULTS: Between 14 October 2020 and 31 December 2023, 927 pwCF were enrolled across eleven Australian CF centres. Of these, 51% (n=472) were male, 77% (n=709) were <18 years old, 88% (n=811) had a highest ppFEV1 (percent predicted forced expiratory volume exhaled in the first second) of ≥70% in the preceding year, and 35% (n=322) reported detection of Pseudomonas aeruginosa in their airway specimens.

CONCLUSIONS: We have established a contemporary cohort of pwCF with granular clinical and treatment data for PEx. This cohort will enable future nested studies focused on PEx management and other aspects of CF care. Understanding the baseline characteristics of these participants, as presented here, is critical for interpreting subsequent outcomes and for identifying factors that may influence disease progression and response to therapies.

PMID:40180198 | DOI:10.1016/j.rmed.2025.108080

J Psychosom Res. 2025 Mar 28;192:112118. doi: 10.1016/j.jpsychores.2025.112118. Online ahead of print.

NO ABSTRACT

PMID:40179605 | DOI:10.1016/j.jpsychores.2025.112118

Angew Chem Int Ed Engl. 2025 Apr 3:e202505714. doi: 10.1002/anie.202505714. Online ahead of print.

ABSTRACT

Antibiotic-resistant bacteria of the genus Pandoraea, frequently acquired from the environment, are an emerging cause of opportunistic respiratory infections, especially in cystic fibrosis (CF) patients. However, their specialized metabolites, including niche and virulence factors, remained unknown. Through genome mining of environmental and clinical isolates of diverse Pandoraea species, we identified a highly conserved biosynthesis gene cluster (pan) that codes for a non-ribosomal peptide synthetase (NRPS) assembling a new siderophore. Using bioinformatics-guided metabolic profiling of wild type and a targeted null mutant, we discovered the corresponding metabolites, pandorabactin A and B. Their structures and chelate (gallium) complexes were elucidated by a combination of chemical degradation, derivatization, NMR, and MS analysis. Metagenomics and bioinformatics of sputum samples of CF patients indicated that the presence of the pan gene locus correlates with the prevalence of specific bacteria in the lung microbiome. Bioassays and mass spectrometry imaging showed that pandorabactins have antibacterial activities against various lung pathogens (Pseudomonas, Mycobacterium, and Stenotrophomonas) through depleting iron in the competitors. Taken together, these findings offer first insight into niche factors of Pandoraea and indicate that pandorabactins shape the diseased lung microbiota through the competition for iron.

PMID:40178319 | DOI:10.1002/anie.202505714

J Antimicrob Chemother. 2025 Apr 3:dkaf101. doi: 10.1093/jac/dkaf101. Online ahead of print.

ABSTRACT

OBJECTIVES: Mycobacterium abscessus is the most frequent of the rapidly growing mycobacteria responsible for lung infections in patients suffering from cystic fibrosis and COPD. Imipenem is currently recommended in the treatment of these infections in spite of β-lactamase production. Since the targets of β-lactams include transpeptidases of both the l,d and d,d specificities, we tested, in vitro, intracellularly and in vivo, a combination of two β-lactams active on these enzymes, amoxicillin and imipenem, alone or in combination with the β-lactamase inhibitor relebactam.

METHODS: Drug combinations were evaluated against M. abscessus CIP 104536T and clinical isolates (n = 35) by determining MICs, FIC indices and time-killing. Drug combinations were also evaluated in macrophages and in mice.

RESULTS: In the presence of relebactam, synergy between amoxicillin and imipenem was observed against both M. abscessus CIP 104536T and the clinical isolates. Against M. abscessus CIP 104536T, the addition of 1 mg/L imipenem and 4 mg/L relebactam led to a decrease in the MIC of amoxicillin from 64 to 1 mg/L. The triple combination was active in vitro and intracellularly (a 4.30 decrease in the log10 cfu/mL and 82% killing, respectively). The triple combination was effective in reducing log10 cfu in mouse organs and mouse spleen weights, and in preventing losses in mouse weights.

CONCLUSIONS: The amoxicillin/imipenem/relebactam combination was synergistic in vitro and effective in vivo against M. abscessus. Since these drugs are clinically available, the triple combination should be considered by clinicians and further evaluated based on the reporting of the patient outcomes.

PMID:40177837 | DOI:10.1093/jac/dkaf101

JAC Antimicrob Resist. 2025 Apr 2;7(2):dlaf047. doi: 10.1093/jacamr/dlaf047. eCollection 2025 Apr.

ABSTRACT

Mycobacterium abscessus (MAB) is a rapidly growing, non-tuberculous mycobacterium that has emerged as a significant pathogen in both pulmonary and extrapulmonary infections. It is rising in prevalence, especially among individuals with underlying lung conditions such as cystic fibrosis and chronic obstructive pulmonary disease, highlighting its growing clinical importance. The treatment of MAB infections is notoriously challenging due to intrinsic resistance to many antibiotics and low cure rates, typically <50%. Macrolides are a cornerstone in the treatment of MAB infections because regimens that include effective macrolide therapy are associated with higher cure rates. However, MAB possesses intrinsic and acquired drug resistance mechanisms against macrolides, complicating drug susceptibility testing and selection of highly effective treatment regimens. This review aims to provide a summary of the current understanding of macrolide resistance mechanisms in MAB. We explored the epidemiology of resistance in different countries and the molecular mechanisms involved. We have highlighted the variability in sensitivity of existing markers to predict phenotypic macrolide drug resistance across different countries, suggesting the involvement of unknown resistance mechanisms. By synthesizing current knowledge and identifying gaps in the literature, this review seeks to inform clinical practice and guide future research efforts in the fight against MAB drug resistance.

PMID:40177306 | PMC:PMC11961302 | DOI:10.1093/jacamr/dlaf047

Pharmacol Res Perspect. 2025 Apr;13(2):e70083. doi: 10.1002/prp2.70083.

ABSTRACT

The combination of Elexacaftor/Tezacaftor/Ivacaftor (ETI) has resulted in a significant improvement in lung function and global clinical parameters, which have not been previously achieved with other CFTR modulators. However, there is a paucity of evidence in the literature on the long-term use of ETI in adolescents and patients with severe pulmonary impairment. Furthermore, the response to ETI may differ between homozygotes and heterozygotes, as well as between naïve patients and those previously treated with other CFTR modulators. A retrospective study was conducted to examine changes in percent predicted forced expiratory volume in 1 s (ppFEV1), body-mass index (BMI), and sweat chloride concentration (SwCl) at baseline and at 6, 12 and 24 months after the initiation of ETI. Secondary outcomes included the number of pulmonary exacerbations, Cystic Fibrosis Questionnaire-Revised (CFQ-R) score, adverse events, mortality and transplantation rates. 139 subjects were included and followed up for up to 2 years after starting ETI. The results demonstrated a significant improvement in ppFEV1 and BMI after 12 months of therapy (respectively, 16%, p < 0.001; +1.5 kg/m2, p = 0.005), with a slight decline in the values after 24 months. This effect was independent of genotype and showed a different degree of response in naïve subjects compared to patients previously treated with other CFTR modulators. SwCl decreased from 84 to 37 mmol/L over 24 months (p < 0.001). 58.3% reduction of PEx rate was observed compared to the number of exacerbations prior to ETI. Overall, lung function, SwCl, PEx rate, CFQ-R scores and BMI improved after 24 months of ETI treatment. ETI was well tolerated, and none of the patients interrupted the treatment due to toxicity.

PMID:40176392 | DOI:10.1002/prp2.70083

Int J Biol Macromol. 2025 Mar 31:142627. doi: 10.1016/j.ijbiomac.2025.142627. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa (P. aeruginosa) is a multidrug-resistant opportunistic pathogen responsible for chronic obstructive pulmonary disease (COPD), cystic fibrosis, and ventilator-associated pneumonia (VAP), leading to cancer. Developing an efficacious vaccine remains the most promising strategy for combating P. aeruginosa infections. In this study, we employed an advanced in silico strategy to design a highly efficient and stable mRNA vaccine using immunoinformatics tools. Whole proteome data were utilized to identify highly immunogenic vaccine candidates using subtractive proteomics. Three extracellular proteins were prioritized for T- and linear B-cell epitope prediction. Beta-definsin protein sequence was incorporated as an adjuvant at the N-terminus of the construct. A total of 3 CTL, 3 HTL, and 3 linear B cell highly immunogenic epitopes were combined using specific linkers to design this multi-peptide construct. The 5' and 3' UTR sequences, Kozak sequence with a stop codon, and signal peptides followed by a poly-A tail were incorporated into the above vaccine construct to create our final mRNA vaccine. The vaccines exhibited antigenicity scores >0.88, ensuring high antigenicity with no allergenic or toxic. Physiochemical properties analysis revealed high solubility and thermostability. Three-dimensional structural analysis determined high-quality structures. Vaccine-receptor docking and molecular dynamic simulations demonstrated strong molecular interactions, stable binding affinities, dynamic nature, and structural stability of this vaccine, with significant immunogenic responses of the immune system against the vaccine. The immunological simulation indicates successful cellular and humoral immune responses to defend against P. aeruginosa infection. Validation of the study outcomes necessitates both experimental and clinical testing.

PMID:40174835 | DOI:10.1016/j.ijbiomac.2025.142627

EBioMedicine. 2025 Apr 1;114:105670. doi: 10.1016/j.ebiom.2025.105670. Online ahead of print.

ABSTRACT

BACKGROUND: Small airways (<2 mm diameter) are major sites of airflow obstruction in chronic obstructive pulmonary disease (COPD). This study aimed to quantify the impact of small airway disease, characterized by narrowing, occlusion, and obliteration, on airflow parameters in smokers and end-stage patients with COPDs.

METHODS: We performed computational fluid dynamics (CFD) simulations of inspiratory airflow in three lung groups: control non-used donor lungs (no smoking/emphysema history), non-used donor lungs with a smoking history and emphysema, and explanted end-stage COPD lungs. Each group included four lungs, with two tissue cylinders. Micro-CT-scanned small airways were segmented into 3D models for CFD simulations to quantify pressure, resistance, and shear stress. CFD results were benchmarked against simplified linear and Weibel models.

FINDINGS: CFD simulations showed higher pressures in COPD vs. controls (p = 0.0091) and smokers (p = 0.015), along with increased resistance (p = 0.0057 vs. controls; p = 0.0083 vs. smokers) and up to a tenfold rise in shear stress (p = 0.010 vs. controls). Narrowing and occlusion were shown to independently increase pressure, resistance, and shear stress, which were validated through segmentation corrections. Pressures and resistance assessed with simplified models were up to seven-fold higher for smokers and even 72 higher for COPD compared with CFD values.

INTERPRETATION: These findings show that increased airflow parameters can explain the association between small airway disease and airflow limitation in COPD, underscoring small airway vulnerability. Additionally, they highlight the limitations of theoretical models in accurately capturing small airway disease.

FUNDING: Supported by the KU Leuven (C16/19/005).

PMID:40174553 | DOI:10.1016/j.ebiom.2025.105670

PLoS Pathog. 2025 Apr 2;21(4):e1013021. doi: 10.1371/journal.ppat.1013021. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen responsible for airway infections in immunocompromised individuals, including those with cystic fibrosis (CF). P. aeruginosa has a type III secretion system (T3SS) that translocates effectors into host cells. ExoS is a T3SS effector with ADP ribosyltransferase (ADPRT) activity. ExoS ADPRT activity promotes P. aeruginosa virulence by inhibiting phagocytosis and limiting oxidative burst in neutrophils. The P. aeruginosa T3SS also translocates flagellin, which can activate the NLRC4 inflammasome, resulting in: 1) gasdermin-D pores, release of IL-1β and pyroptosis; and 2) histone 3 citrullination (CitH3), nuclear DNA decondensation and expansion into the neutrophil cytosol with incomplete NET extrusion. However, studies with P. aeruginosa PAO1 indicate that ExoS ADPRT activity inhibits the NLRC4 inflammasome in neutrophils. Here, we identified an ExoS+ CF clinical isolate of P. aeruginosa with a hyperactive T3SS. Variants of the hyperactive T3SS mutant or PAO1 were used to infect neutrophils from C57BL/6 mice that were wildtype or engineered to have a CF genotype or defects in inflammasome assembly. Responses to NLRC4 inflammasome assembly or ExoS ADPRT activity were assayed and found to be similar for C57BL/6 or CF neutrophils. ExoS ADPRT activity in the hyperactive T3SS mutant regulated inflammasome, nuclear DNA decondensation and incomplete NET extrusion responses, like PAO1, but promoted enhanced CitH3 and plasma membrane rupture (PMR). Glycine supplementation inhibited PMR by the hyperactive T3SS mutant, suggesting ninjurin-1 is required for this process. These results identify enhanced neutrophil PMR as a pathogenic activity of ExoS ADPRT in hypervirulent P. aeruginosa.

PMID:40173191 | DOI:10.1371/journal.ppat.1013021

Am J Health Syst Pharm. 2025 Apr 2:zxaf071. doi: 10.1093/ajhp/zxaf071. Online ahead of print.

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PURPOSE: A customized Epic scoring tool for monitoring medications requiring renal dose adjustment utilizing Epic Bugsy and a custom renal function trend scoring column was developed and implemented in June 2023 at UT Southwestern Medical Center (UTSW) to replace the manual review and intervention (i-Vent) documentation process.

METHODS: This retrospective, observational cohort study evaluated pharmacist interventions and antimicrobial dosing before and after implementation of the UTSW renal clinical pharmacist responsibility (CPR) dose adjustment tool. Adult patients (aged 18 years or older) requiring renal dose adjustment were included. The preintervention group included patients admitted between July 1 and August 31, 2022, whereas the postintervention group included patients admitted from July 1 through August 31, 2023. Patients exempt from the institutional automatic adult renal dosing guideline (ie, those with cystic fibrosis, solid organ transplantation, or bone marrow transplantation) or actively receiving renal replacement therapy during the index encounter were excluded.

RESULTS: In a comparable 2-month timespan, implementation of the renal CPR dose adjustment tool resulted in a 68.2% increase in the number of renal dosing interventions completed (P < 0.0001), a 47.2% reduction in the number of unique alerts requiring pharmacist review (P < 0.0001), and an increase in the proportion of actionable interventions per alert requiring review from 11.1% before implementation to 39.4% after implementation (P < 0.0001). Pharmacist satisfaction with the renal monitoring workflow also improved with implementation.

CONCLUSION: In a comparable 2-month timespan, implementation of the renal CPR dose adjustment tool at UTSW resulted iin improvements in interventions completed, a reduction in alerts requiring review, an increased total duration that selected antimicrobials were dosed appropriately, and improved pharmacist satisfaction.

PMID:40172577 | DOI:10.1093/ajhp/zxaf071