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

BMC Health Serv Res. 2025 Mar 15;25(1):383. doi: 10.1186/s12913-025-12491-5.

ABSTRACT

General practice-based care for Australian children is facing low levels of clinical guideline adherence particularly in three key areas: asthma, type 1 diabetes and antibiotic use. We offer an implementation science-informed position paper, providing a broad overview of how we aim to address this issue. This is the co-designed National Paediatric Applied Research Translation Initiative (N-PARTI), a bespoke, three-phased research solution by deploying mixed methods, simulation and scale-up of evidence into practice.

PMID:40089760 | DOI:10.1186/s12913-025-12491-5

J Cyst Fibros. 2025 Mar 14:S1569-1993(25)00075-X. doi: 10.1016/j.jcf.2025.03.007. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has been highly effective for improving pulmonary disease and nutritional outcomes. However, the effect of this therapy on glycemic control in people with cystic fibrosis related diabetes (CFRD) is unclear. This study aimed to examine real-world effects of ETI on glycemia as captured by hemoglobin A1c (HbA1c) in people with pre-existing CFRD.

METHODS: Retrospective chart review was performed at 4 US CF centers. Individuals with CFRD included in the study started ETI before December 2020, and had an HbA1c within 1 year before and up to 2 years after ETI initiation. A sub-analysis comparing CGM data and insulin dosing within the year before and after ETI was performed. Summary statistics were calculated and within-subject results compared.

RESULTS: A total 175 individuals with CFRD had HbA1c data before and after ETI. Mean (±SD) age was 32.4 (±12.4) years, 49.1 % female. HbA1c were compared a median (IQR) of -40 (-93, 0) days before and 290 (107, 441) days after ETI initiation. Median (IQR) HbA1c decreased from 6.4 % (5.8, 7.2) to 6.0 % (5.5, 6.8), p<0.001. A subgroup of 13 individuals had CGM and basal insulin data for comparison. No changes were observed in CGM metrics, however, basal insulin dose in these patients decreased (p=0.03).

CONCLUSION: Findings suggest clinical improvements in glycemia following ETI initiation in people with CFRD. Further studies are required to better understand the mechanisms by which ETI may modulate insulin and glucose dynamics in individuals with existing CFRD.

PMID:40089409 | DOI:10.1016/j.jcf.2025.03.007

J Cyst Fibros. 2025 Mar 14:S1569-1993(25)00076-1. doi: 10.1016/j.jcf.2025.03.008. Online ahead of print.

ABSTRACT

BACKGROUND: The clinical efficacy of elexacaftor-tezacaftor-ivacaftor (ETI) in children with cystic fibrosis (cwCF) is variable; some respond, while others do not or have side effects. The pharmacokinetics (PK) of ETI are poorly described in published research, particularly when it comes to children. Knowledge of the PK in this population may provide more insight into the exposure-response relationship of the drugs and its corresponding inter-patient variability (IIV). The aim of this study was to evaluate the PK of ETI in cwCF in a real-world setting.

METHODS: A prospective, observational PK study was conducted in cwCF starting with ETI. PK samples were collected at home using dried blood spots (DBS), and during regular outpatient hospital visits. Clinical efficacy and safety data were gathered and evaluated. Population PK (popPK) models were developed using nonlinear mixed-effects modelling.

RESULTS: A total of 29 children were included in this study. Novel popPK models were developed for ETI and its main metabolites. There was significant variability in AUC of ETI within and between age groups, aligning with the references in the product information. All children had concentrations within or above the range needed for a clinical response. An exploratory exposure-response analysis found no direct linear relationship between AUC and sweat chloride, or ppFEV1.

CONCLUSIONS: This study is the first analysis of ETI popPK in cwCF. The developed popPK models may be used to further study the exposure-response relationship and its variability within cwCF, as a basis for more personalized dosing.

PMID:40089408 | DOI:10.1016/j.jcf.2025.03.008

United European Gastroenterol J. 2025 Mar 15. doi: 10.1002/ueg2.70011. Online ahead of print.

ABSTRACT

Malabsorption is a complex and multifaceted condition characterised by the defective passage of nutrients into the blood and lymphatic streams. Several congenital or acquired disorders may cause either selective or global malabsorption in both children and adults, such as cystic fibrosis, exocrine pancreatic insufficiency (EPI), coeliac disease (CD) and other enteropathies, lactase deficiency, small intestinal bacterial overgrowth (SIBO), autoimmune atrophic gastritis, Crohn's disease, and gastric or small bowel resections. Early recognition of malabsorption is key for tailoring a proper diagnostic work-up for identifying the cause of malabsorption. Patient's medical and pharmacological history are essential for identifying risk factors. Several examinations like endoscopy with small intestinal biopsies, non-invasive functional tests, and radiologic imaging are useful in diagnosing malabsorption. Due to its high prevalence, CD should always be looked for in case of malabsorption with no other obvious explanations and in high-risk individuals. Nutritional support is key in management of patients with malabsorption; different options are available, including oral supplements, enteral or parenteral nutrition. In patients with short bowel syndrome, teduglutide proved effective in reducing the need for parenteral nutrition, thus improving the quality of life of these patients. Primary care physicians have a central role in early detection of malabsorption and should be involved into multidisciplinary teams for improving the overall management of these patients. In this European consensus, involving 10 scientific societies and several experts, we have dissected all the issues around malabsorption, including the definitions and diagnostic testing (Part 1), high-risk categories and special populations, nutritional assessment and management, and primary care perspective (Part 2).

PMID:40088199 | DOI:10.1002/ueg2.70011

J Assoc Physicians India. 2025 Mar;73(3):86-89. doi: 10.59556/japi.73.0858.

ABSTRACT

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is an immune-mediated hypersensitivity reaction to Aspergillus, a common environmental fungus. It is typically seen in asthmatic patients and those with cystic fibrosis. Lack of clinical suspicion and misdiagnosis often make the management of this condition difficult.

CASE DESCRIPTION: We are reporting a case of ABPA that was diagnosed and managed at Divisional Railway Hospital, Kharagpur, South Eastern Railway. The patient was a 66-year-old female who presented with fever, cough, and shortness of breath. She had been asthmatic since childhood and was on treatment for the same. On initial evaluation, her clinical and radiological features were suggestive of community-acquired pneumonia and were treated with antibiotics. However, the patient did not show improvement, and asthma also remained poorly controlled despite treatment. This raised the possibility of ABPA in this patient. The International Society for Human and Animal Mycology-ABPA (ISHAM-ABPA) working group criterion was used for making the diagnosis. She was successfully managed with low-dose steroids and itraconazole.

CONCLUSION: A high index of clinical suspicion is needed for timely detection of ABPA. Features of nonresolving pneumonia in the background of poorly controlled asthma raised the possibility of ABPA in this patient. Misdiagnosis and delay in initiating proper treatment can lead to permanent lung damage, such as bronchiectasis and lung fibrosis, which can even lead to life-threatening complications like cor pulmonale and respiratory failure.

PMID:40087942 | DOI:10.59556/japi.73.0858

Respir Med. 2025 Mar 13:108016. doi: 10.1016/j.rmed.2025.108016. Online ahead of print.

ABSTRACT

Cystic Fibrosis (CF) is a life-limiting, inherited condition in which a novel class of oral medicine, CFTR modulators, has revolutionised symptoms and health indicators, providing an opportunity to evaluate traditional treatment regimens with the hope of reducing burden. Additionally, there is cautious optimism that life expectancy for people with CF born today could ultimately compare to that of the general population. Given this potential, there is a need and requirement to optimise treatment to balance burden with the best clinical outcomes for each person with CF in an individualised manner. Personalised data-Linkage to Understand Treatment Optimisation (PLUTO) is a clinical framework, developed within the 14-Centre UK CFHealthHub Learning Health System collaborative, designed for use at an individual level for people with CF taking CFTR modulators. The PLUTO framework encourages use of two routinely collected clinical outcome measure (FEV1 and BMI) to determine health status. Where FEV1 or BMI trends suggest that optimal health outcomes are not being achieved for a person with CF, PLUTO supports consideration of adherence to both CFTR modulators and inhaled therapy to help guide the next steps. PLUTO is designed to support people with CF and their clinical teams to individualise care and optimise outcomes for those taking CFTR modulators, using data available in routine clinical encounters.

PMID:40087032 | DOI:10.1016/j.rmed.2025.108016

Eur J Clin Microbiol Infect Dis. 2025 Mar 14. doi: 10.1007/s10096-025-05092-x. Online ahead of print.

NO ABSTRACT

PMID:40085382 | DOI:10.1007/s10096-025-05092-x

Turk J Pediatr. 2025 Feb 20;67(1):22-30. doi: 10.24953/turkjpediatr.2025.4680.

ABSTRACT

BACKGROUND: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) variants are essential for determining eligibility for CFTR modulator drugs (CFTRms). In contrast to Europe and the USA, the treatment eligibility profile of cystic fibrosis (CF) patients in Türkiye is not known. In this study we aimed to determine the eligibility of CF patients in Türkiye for the CFTRms.

METHODS: The Cystic Fibrosis Registry of Türkiye (CFrT) data was used to determine the age of patients in the year 2021 and the genetic variants they were carrying. Age- and CFTR-variant appropriate modulator therapies were determined using the Vertex® algorithm.

RESULTS: Among a total of 1930 registered patients, CTFR gene analysis was performed on a total of 1841 (95.4%) patients. Mutations were detected in one allele in 10.7% (198 patients), and in both alleles in 79% (1455 patients) of patients. A total of 855 patients (51.7% for whom at least 1 mutation was detected) were eligible for the drugs. The most appropriate drug among genotyped patients was found to be elexacaftor/tezacaftor/ivacaftor for 486 patients (26.4%), followed by ivacaftor for 327 patients (17.7%) and lumacaftor/ivacaftor for 42 patients (2%).

CONCLUSIONS: Only half of patients registered in CFrT were eligible for CFTRms, which is a significant difference from the CFTR variant profile seen in USA and Europe. However, access to treatment is hampered for some patients whose genes are not analysed. Further studies in CF populations, where rare mutations are relatively more common, will contribute to the field of CFTR modulator treatments for such rare mutations.

PMID:40084730 | DOI:10.24953/turkjpediatr.2025.4680

Exp Ther Med. 2025 Feb 25;29(4):85. doi: 10.3892/etm.2025.12835. eCollection 2025 Apr.

ABSTRACT

The coronavirus disease-19 (COVID-19) pandemic has been a very significant health issue in the period between 2020 and 2023, forcing research to characterize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequences and to develop novel therapeutic approaches. Interleukin-6 (IL-6) and IL-8 are considered significant therapeutic targets for COVID-19 and emerging evidence has suggested that microRNAs (miRNAs/miRs) serve a key role in regulating these genes. MiRNAs are short, 19-25 nucleotides in length, non-coding RNAs that regulate gene expression at the post-transcriptional level through the sequence-selective recognition of the 3'-untranslated region (3'-UTR) of the regulated mRNAs, eventually repressing translation, commonly, via mRNA degradation. For example, among several miRNAs involved in the regulation of the COVID-19 'cytokine storm', miR-93-5p can inhibit IL-8 gene expression by directly targeting the 3'-UTR of IL-8 mRNA. In addition, miR-93-5p can regulate Toll-like receptor-4 (TLR4) and interleukin-1 receptor-associated kinase 4 (IRAK4) expression, thus affecting the nuclear factor-κB (NF-κB) pathway and the expression of NF-κB-regulated genes, such as IL-6, IL-1β and other hyper-expressed genes during the COVID-19 'cytokine storm'. In the present study, the results provided preliminary evidence suggesting that the miR-93-5p-based miRNA therapeutics could be combined with the anti-inflammatory aged garlic extract (AGE) to more effectively inhibit IL-8 gene expression. The human bronchial epithelial IB3-1 cell line was employed as experimental model system. IB3-1 cells were stimulated with the BNT162b2 COVID-19 vaccine and transfected with pre-miR-93-5p in the absence or in the presence of AGE, to verify the inhibitory effects on the BNT162b2-induced expression of the IL-8 gene. The accumulation of IL-8 mRNA was assessed by RT-qPCR; the release of IL-8 protein was determined by Bio-Plex assay. In addition, the possible applications of TLR4/NF-κB inhibitory agents (such as miR-93-5p and AGE) for treating human pathologies at a hyperinflammatory state, such as COVID-19, cystic fibrosis and other respiratory diseases, were summarized.

PMID:40084194 | PMC:PMC11904878 | DOI:10.3892/etm.2025.12835

BMC Infect Dis. 2025 Mar 13;25(1):358. doi: 10.1186/s12879-025-10736-6.

ABSTRACT

This systematic review evaluates the efficacy and safety of COVID-19 vaccines in individuals with cystic fibrosis (CF). A systematic search of major databases conducted between December 2019 and January 2024 identified eight cohort studies comprising 1,361 CF patients. Studies without subgroup analyses specific to CF patients were excluded, which may have limited the generalizability of findings, particularly for CF lung transplant recipients. COVID-19 vaccines generally induced robust serological responses following the second and third doses, although reduced antibody levels were observed in lung transplant recipients. Factors influencing humoral response included prior SARS-CoV-2 infection, age, inhaled corticosteroid use, and immunosuppressive therapy. Vaccination-related adverse events were predominantly mild. Although breakthrough infections were reported, severe COVID-19 outcomes were infrequent among vaccinated CF patients. The evidence supports the immunogenicity and safety of COVID-19 vaccines in the CF patients. However, individualized vaccination strategies may be necessary for CF lung transplant recipients and those on immunosuppressive therapies. Further research is essential to optimize vaccination strategies and to identify risk factors associated with breakthrough infections in this high-risk population.

PMID:40082759 | DOI:10.1186/s12879-025-10736-6

Cell Death Differ. 2025 Mar 13. doi: 10.1038/s41418-025-01474-y. Online ahead of print.

ABSTRACT

The plasma concentrations of acyl CoA binding protein (ACBP) encoded by the gene diazepam binding inhibitor (DBI) are increased in patients with severe osteoarthritis (OA). Here, we show that knee OA induces a surge in plasma ACBP/DBI in mice subjected to surgical destabilization of one hind limb. Knockout of the Dbi gene or intraperitoneal (i.p.) injection of a monoclonal antibody (mAb) neutralizing ACBP/DBI attenuates OA progression in this model, supporting a pathogenic role for ACBP/DBI in OA. Furthermore, anti-ACBP/DBI mAb was also effective against OA after its intraarticular (i.a.) injection, as monitored by sonography, revealing the capacity of ACBP/DBI to locally reduce knee inflammation over time. In addition, i.a. anti-ACBP/DBI mAb improved functional outcomes, as indicated by the reduced weight imbalance caused by OA. At the anatomopathological level, i.a. anti-ACBP/DBI mAb mitigated histological signs of joint destruction and synovial inflammation. Of note, i.a. anti-ACBP/DBI mAb blunted the OA-induced surge of plasma ACBP/DBI, as well as that of other inflammatory factors including interleukin-1α, interleukin-33, and tumor necrosis factor. These findings are potentially translatable to OA patients because joints from OA patients express both ACBP/DBI and its receptor GABAARγ2. Moreover, a novel mAb against ACBP/DBI recognizing an epitope conserved between human and mouse ACBP/DBI demonstrated similar efficacy in mitigating OA as an anti-mouse ACBP/DBI-only mAb. In conclusion, ACBP/DBI might constitute a promising therapeutic target for the treatment of OA.

PMID:40082721 | DOI:10.1038/s41418-025-01474-y

JAMA Netw Open. 2025 Mar 3;8(3):e250572. doi: 10.1001/jamanetworkopen.2025.0572.

ABSTRACT

IMPORTANCE: Inequitable access to transplant in the US is well recognized, yet the nature and extent of upstream disparities in care prior to transplant are unknown.

OBJECTIVE: To understand patterns of referral for lung transplant by race, ethnicity, and neighborhood-level socioeconomic status.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included adults aged 18 to 80 years with obstructive and restrictive lung disease from a single large-volume transplant center in Cleveland, Ohio, who were diagnosed between January 1, 2006, and May 11, 2023.

EXPOSURES: Neighborhood resources.

MAIN OUTCOMES AND MEASURES: The main outcome was the transition to the next stage of the transplant care continuum, death, or a lapse in care. Cause-specific Cox proportional hazards regression models were used to account for death as a competing risk, adjusting for age at index encounter (respective to each cohort), diagnosis, and sex as covariates.

RESULTS: This study included 30 050 patients with obstructive and restrictive lung disease with primary care encounters (mean [SD] age, 65 [13] years; 56.1% female), 73 817 with a pulmonary medicine encounter, 4198 undergoing lung transplant evaluation, and 1378 on the lung transplant waiting list. In a multivariable model including age, diagnosis, sex, area deprivation index, and race and ethnicity (including 3.3% Hispanic, 15.2% non-Hispanic Black, and 81.5% non-Hispanic White individuals), patients residing in the least-resourced neighborhoods were 97% more likely to die without transitioning to pulmonary medicine (hazard ratio [HR], 1.97 [95% CI, 1.78-2.17]), 90% more likely to die prior to lung transplant evaluation (HR, 1.90 [95% CI, 1.77-2.04]), 40% more likely to die prior to placement on the waiting list (HR, 1.40 [95% CI, 1.11-1.76]), and 97% more likely to die prior to transplant (HR, 1.97 [95% CI, 1.18-3.29]) compared with patients residing in the most-resourced neighborhoods. These patients were also 13% less likely to transition to pulmonary medicine (HR, 0.87 [95% CI, 0.82-0.92]) and 45% less likely to be placed on the waiting list (HR, 0.55 [95% CI, 0.44-0.68]) despite a 69% increased likelihood of transplant evaluation (HR, 1.69 [95% CI, 1.36-2.09]). While non-Hispanic Black patients had lower risks of death across all stages of care, they experienced a 39% lower likelihood of proceeding to lung transplant evaluation (HR, 0.61 [95% CI, 0.51-0.74]). Racial differences in the cumulative incidence of waiting list placement were found, but differences were not consistent across levels of neighborhood resources.

CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of patients diagnosed with restrictive and obstructive pulmonary disease, increased mortality risks and decreased likelihood of care escalations for patients who were socioeconomically disadvantaged and for racial and ethnic minority patients were found. These results suggest potential interventions for advancing equitable access to lung transplant.

PMID:40080022 | PMC:PMC11907320 | DOI:10.1001/jamanetworkopen.2025.0572

Microb Pathog. 2025 Mar 11:107473. doi: 10.1016/j.micpath.2025.107473. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a prominent bacterial pathogen that causes several nosocomial infections and is notorious for its environmental resilience and rapid development of resistance to frontline antibiotics. A major cause of mortality and morbidity among cystic fibrosis patients, multidrug-resistant P. aeruginosa is often targeted with the antibiotic colistin as a last option. However, increasing reports of colistin resistance among P. aeruginosa is a significant concern. Though the molecular mechanisms responsible for the development of colistin resistance are well known, the evolutionary trajectory to colistin resistance is an important area of investigation. In this work, using the adaptive laboratory evolution (ALE) approach we have evolved a colistin-sensitive P. aeruginosa ancestral strain to a resistant one. During the process of laboratory evolution in 106 generations, colistin MIC was increased 32-fold. The evolved strain had lower fitness than the ancestral strain, as evidenced by a lower growth rate. Moreover, the evolved strain produced more biofilm and less pyocyanin pigment. Interestingly, the evolved strain showed collateral sensitivity to several antibiotics, including ampicillin, tetracycline, streptomycin, gentamycin, nalidixic acid, trimethoprim, rifampicin, and chloramphenicol. On analysing various TCS modules involved in the development of colistin resistance, a novel missense mutation (V136G) was detected in the PmrB sensor kinase. In silico analysis indicated that the V136G substitution would destabilize the PmrB kinase structure, making the mutation deleterious. However, the functionality of the PmrB mutant remains to be validated experimentally.

PMID:40081679 | DOI:10.1016/j.micpath.2025.107473