Respir Med. 2025 Apr 8:108091. doi: 10.1016/j.rmed.2025.108091. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a complex genetic disorder necessitating extensive treatment regimens leading to significant medication burden. The recent use of modulator therapies have questioned the necessity of traditional CF treatments, prompting re-evaluation of strategies to reduce treatment burden. This study aimed to identify the barriers and enablers to deprescribing from the perspectives of doctors, nurses, and pharmacists caring for people with CF (PwCF).

METHODS: A qualitative study design employing semi-structured interviews was utilised. Healthcare practitioners (HCPs) across Australia were recruited and interviewed. Interviews were transcribed and analysed using NVivo 1.3 software, guided by an existing framework focusing on self-efficacy, feasibility, inertia, and awareness.

RESULTS: Eleven HCP participated (doctors, n=3, nurses, n=4, pharmacists, n=4). Low self-efficacy was the most prominent barrier to deprescribing, founded on a perceived lack of evidence. Feasibility was an enabler when patient factors were present, particularly PwCF's experiences of reducing medications independently. Likewise, the presence of pharmacists in CF clinics and multidisciplinary team meetings were identified as facilitators. Inertia to continue entrenched prescribing habits and fear of adverse outcomes deterred deprescribing. Similarly, HCPs reported having little awareness of the need for deprescribing in daily practice, as their primary focus was on addressing acute problems.

CONCLUSIONS: Enhancing self-efficacy through evidence-based guidelines and increasing feasibility by fostering collaborative approaches among HCPs and PwCF may improve deprescribing practices in CF care. As evidence on the benefits and safety of deprescribing grows, it should be integrated into clinical guidelines to alleviate medication burden and improve quality of life for PwCF.

PMID:40210134 | DOI:10.1016/j.rmed.2025.108091

J Heart Lung Transplant. 2025 Apr 8:S1053-2498(25)01899-6. doi: 10.1016/j.healun.2025.04.001. Online ahead of print.

ABSTRACT

BACKGROUND: Childhood interstitial lung disease (chILD) is heterogeneous, associated with significant morbidity and can cause organ failure. In these cases, lung transplantation (LuTx) is a treatment option. Data on indications and outcome after LuTx for chILD is limited. We compared characteristics of LuTx for chILD to the indications cystic fibrosis (CF) and pulmonary hypertension (PH).

METHODS: chILD-patients <18 years who underwent LuTx at our center between Jan 1st, 2011 and Sep 30th, 2023, were retrospectively analysed and divided into two groups depending on their age at disease manifestation: Children in the chILD A group predominantly became ill during the first two years of life, chILD B patients thereafter. Outcomes were compared to patients with CF and PH.

RESULTS: 101 children were included (chILD A 12; chILD B 19; CF 49; PH 21). Patients in the chILD A group were younger (mean age 1.5 vs., 12.9, 15.2, 10.9 years) and frequently required mechanical ventilation before LuTx (41.7%, vs. 10.5%, 2%, 9.5%, respectively). Their median ICU stay (23 vs. 4, 2, 13 days) and median hospital stay (48 vs. 27, 30, 42 days) after LuTx was longer. Patients with chILD B had the lowest pre-transplant ICU requirement (21.1% vs. 66.7% for chILD A, 30.6% for CF and 47.6% for PH) and short median hospital stay. Five year survival was comparable in all groups (80.2%, 86.5%, 80.4%, and 81.2%).

CONCLUSION: LuTx for patients with chILD shows favourable outcome, although younger chILD A patients had a higher pre-transplant morbidity and longer ICU and hospital stay surrounding the transplantation.

PMID:40209866 | DOI:10.1016/j.healun.2025.04.001

Am J Respir Crit Care Med. 2025 Apr 10. doi: 10.1164/rccm.202411-2231OC. Online ahead of print.

ABSTRACT

RATIONALE: Clinical and real-world studies show elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is efficacious and safe in people with cystic fibrosis (CF) ≥12 years of age with at least one F508del allele.

OBJECTIVES: Given the potential for life-long ELX/TEZ/IVA use, long-term safety and efficacy of ELX/TEZ/IVA was assessed.

METHODS: In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function genotypes (from 24-week parent study 445-102 [n = 399]) or with the F508del-F508del genotype (from 4-week parent study 445-103 [n = 107]) received ELX/TEZ/IVA (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours) over 192 weeks.

MEASUREMENTS AND MAIN RESULTS: Primary endpoint was safety and tolerability. Mean exposure to ELX/TEZ/IVA was 172.6 weeks. Most participants had adverse events classified as mild (12.8%) or moderate (60.7%) in severity. Eighteen participants (3.6%) had adverse events that led to treatment discontinuation. After starting ELX/TEZ/IVA, participants had consistent increases in percent predicted FEV1 (ppFEV1), Cystic Fibrosis Questionnaire-Revised respiratory domain score, and body mass index, with decreases in sweat chloride concentration and pulmonary exacerbations rates; these improvements were maintained through 192 weeks. The mean annualized rate of change in ppFEV1 was 0.02 percentage points (95% CI, -0.14 to 0.19) after initiation of ELX/TEZ/IVA.

CONCLUSIONS: During this 192-week open label extension study, the longest clinical study of a CFTR modulator to date, ELX/TEZ/IVA remained generally safe and well-tolerated. Participants had sustained improvements in lung function, respiratory symptoms, CFTR function, pulmonary exacerbation rates, and nutritional status. The estimated annualized rate of change in ppFEV1 suggests no evidence of pulmonary function loss across the study population over the 4-year treatment period. These results confirm the favorable long-term safety profile and durable disease-modifying clinical benefits of ELX/TEZ/IVA in adolescents and adults with CF. Clinical trial registration available at www.

CLINICALTRIALS: gov, ID: NCT03525574.

PMID:40209082 | DOI:10.1164/rccm.202411-2231OC

MethodsX. 2025 Mar 22;14:103267. doi: 10.1016/j.mex.2025.103267. eCollection 2025 Jun.

ABSTRACT

In this study, we present a detailed workflow for the isolation, quantitation, and evaluation of mucin proteins. These methods are applicable to a variety of biological, mucin-containing samples from the airways and other mucosal organ systems. While this report focuses on the salivary MUC5B protein from the respiratory system, the presented methodologies can be applied to other mucins, contributing to a broader application of these techniques. We used a simplified isopycnic centrifugation to purify and enrich MUC5B from human saliva. Isolated MUC5B was then subjected to a Bradford protein assay using a bovine submaxillary mucin (BSM) standard, which more accurately reflects the mucin concentration in our samples compared to a bovine serum albumin (BSA) standard. Additionally, we compare the mucin levels following quantitation using agarose polyacrylamide gel electrophoresis. Our findings show a near 2-fold increase in quantitation from the more representative, BSM standard, suggesting its importance for mucin studies. These methods support a wide range of experimental applications looking to assess mucins, thereby contributing to the broader field of mucin studies and advancing our understanding of the implications of mucins in health and disease.•A streamlined, one-step isopycnic ultracentrifugation to isolate MUC5B from human saliva•A Mucin Bradford assay that is modified from existing Bradford assay techniques to better quantitate mucin for mucin studies•An agarose-polyacrylamide gel electrophoresis method used to visualize and confirm the isolation and quantitation of mucin.

PMID:40207064 | PMC:PMC11981757 | DOI:10.1016/j.mex.2025.103267

Pharmazie. 2025 Mar 31;80(1):10-16. doi: 10.1691/ph.2025.4544.

ABSTRACT

Transmembrane 16A (TMEM16A) is highly expressed in interstitial cells of Cajal (ICC) and participates in ICC-mediated rhythmic contractile activity of intestinal smooth muscle. TMEM16A is also expressed in epithelium of intestine with a minor contributor to transepithelial fluid secretion, while other unidentified Ca2+ -activated Cl - channels (unCaCCs) are mainly responsible for this physiological process. TMEM16A/CaCCs dysfunction can lead to disorders of intestinal motility and transepithelial fluid secretion. TMEM16A/CaCCs regulators are important tools to identify unCaCCs and study the physiopathological functions related to TMEM16A/CaCCs. In the present study, coumarins were identified as TMEM16A inhibitors in a concentration- and time-dependent manner in TMEM16A-expressed Fischer rat thyroid (FRT) epithelial cells. Coumarins attenuated intestinal motility by inhibiting TMEM16A in vivo and ex vivo. Coumarins inhibited CaCCs-mediated Cl- currents induced by ATP in T84 and HT-29 cells or by carbachol (CCh) in mouse colonic mucosa with reduction of ATP-induced increase of cytoplasmic Ca2+ concentration in HT-29 cells. Coumarins inhibited basolateral Ca2+ -activated K+ channels without affecting Na + /K + -ATPase activity in mouse colonic mucosa. Coumarins did not show inhibition of cystic fibrosis transmembrane conductance regulator (CFTR), but mild activation of CFTR-mediated Cl - currents under the low concentration forskolin (FSK) in CFTR-expressed FRT cells, while coumarins did not activate CFTR-mediated Cl- currents in mouse colonic mucosa. This study was the first to demonstrate that coumarins attenuate intestinal motility by inhibiting TMEM16A, which may provide a strategy for clinical drug intervention aimed at reducing secretory diarrhea.

PMID:40205671 | DOI:10.1691/ph.2025.4544

BMC Microbiol. 2025 Apr 9;25(1):203. doi: 10.1186/s12866-025-03920-w.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa is a major pathogen in cystic fibrosis (CF), where chronic and intermittent infections significantly affect patient outcomes. This study aimed to investigate the molecular epidemiology of P. aeruginosa in CF patients from the Brazilian Amazon, focusing on genotypic diversity, resistance profiles, and virulence factors.

METHODS: A cross-sectional study included 72 P. aeruginosa isolates from 44 CF patients treated at a regional reference center between 2018 and 2019. Antimicrobial susceptibility patterns were determined using VITEK-2 system and Kirby-Bauer disk diffusion. Virulotypes were defined by molecular detection of exoS, exoU, exoT, exoY, algU, and algD genes. Genetic diversity was assessed using multilocus sequence typing (MLST). Demographic data, clinical severity, and spirometry results were also collected.

RESULTS: Among the patients, 54.55% experienced intermittent infections, while 45.45% had chronic infections. Chronic infections were associated with older age, lower FEV1, and reduced Shwachman-Kulczycki scores. Multidrug resistance was observed in 15.3% of isolates, particularly against ciprofloxacin and piperacillin/tazobactam. The exoU gene was present in 55.56% of isolates, an uncommon finding in CF populations. High genetic diversity was evident, with 37 sequence types (STs), including 14 novel STs. High-risk clones (HRCs) constituted 25% of isolates, with ST274 being the most prevalent (12.5%). Longitudinal analysis revealed transient colonization in intermittent infections, while chronic infections were dominated by stable clones.

CONCLUSION: This study highlights the molecular and clinical dynamics of P. aeruginosa in CF patients from the Brazilian Amazon. Chronic infections were linked to severe lung impairment , while intermittent infections were dominated by HRCs. These findings underscore the need for robust genotypic surveillance to mitigate the burden of P. aeruginosa in CF populations.

PMID:40205346 | DOI:10.1186/s12866-025-03920-w

Respir Med. 2025 Apr 7:108086. doi: 10.1016/j.rmed.2025.108086. Online ahead of print.

ABSTRACT

This study evaluates the clinical impact of transitioning from the GLI 2012 to the race-neutral GLI 2022 spirometry equations in people with cystic fibrosis (pwCF). Spirometry data from a large adult CF centre showed an increase in average ppFEV1 (71.1% to 75%, p<0.01), with White patients showing the greatest change (4.56%). Fewer patients met lung transplantation thresholds, and 1.7% became newly eligible for clinical trials, while 7% became ineligible. These findings suggest the need for further research on the long-term implications of GLI 2022 across respiratory conditions.

PMID:40204244 | DOI:10.1016/j.rmed.2025.108086

Microbiology (Reading). 2025 Apr;171(4). doi: 10.1099/mic.0.001553.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has significantly changed the course of the disease in people with cystic fibrosis (CF) (pwCF). The approved triple therapy of elexacaftor, tezacaftor and ivacaftor (ETI), commercially known as Trikafta, increases CFTR channel function, leading to improvements in sweat chloride concentration, exercise capacity, body mass index, lung function and chronic respiratory symptoms. Because of this, the majority of pwCF are living longer and having fewer CF exacerbations. However, colonization with the common CF respiratory pathogens persists and remains a major cause of morbidity and mortality. Here, we review the current literature on the effect of ETI on the respiratory microbiota and discuss the challenges in addressing CF lung infections in the era of these new life-extending therapies.

PMID:40202901 | DOI:10.1099/mic.0.001553

Expert Opin Drug Discov. 2025 Apr 9. doi: 10.1080/17460441.2025.2490250. Online ahead of print.

ABSTRACT

INTRODUCTION: The advent of variant-specific disease-modifying drugs into clinical practice has provided remarkable benefits for people with cystic fibrosis (PwCF), a multi-organ life-limiting inherited disease. However, further efforts are needed to maximize therapeutic benefits as well as to increase the number of PwCF taking CFTR modulators.

AREA COVERED: The authors discuss some of the key limitations of the currently available CFTR modulator therapies (e.g. adverse reactions) and strategies in development to increase the number of available therapeutics for CF. These include novel methods to accelerate theratyping and identification of novel small molecules and cellular targets representing alternative or complementary therapies for CF.

EXPERT OPINION: While the CF therapy development pipeline continues to grow, there is a critical need to optimize strategies that will accelerate testing and approval of effective therapies for (ultra)rare CFTR variants as traditional assays and trials are not suitable to address such issues. Another major barrier that needs to be solved is the restricted access to currently available modulator therapies, which remains a significant burden for PwCF who are from racial and ethnic minorities or living in underprivileged regions.

PMID:40202089 | DOI:10.1080/17460441.2025.2490250

JAC Antimicrob Resist. 2025 Apr 8;7(2):dlaf053. doi: 10.1093/jacamr/dlaf053. eCollection 2025 Apr.

ABSTRACT

OBJECTIVES: Pseudomonas aeruginosa is one of the major drivers of morbidity and mortality in patients with chronic underlying diseases. Whereas cystic fibrosis (CF) P. aeruginosa strains have been well studied, non-CF bronchiectasis isolates have received less scientific attention.

METHODS: We determined the antibiotic susceptibility profiles of a collection of 100 P. aeruginosa isolates recovered from a total of 100 non-CF bronchiectasis patients attending a Catalonian hospital. All carbapenemase-producing isolates were characterized by WGS.

RESULTS: Twelve isolates were classified as MDR (12%) and six were found to be carbapenemase (VIM-2) producers (6%). Of note, two of the VIM-2-producing isolates were carbapenem susceptible due to the presence of inactivating mutations in MexAB-OprM efflux pump components. These isolates exhibited properties of chronic P. aeruginosa isolates, such as mutator or mucoid phenotypes that are associated with persistent infections despite intensive antibiotic therapies. The phylogenetic analysis evidenced that all VIM-2 isolates belonged to the high-risk clone ST235. Core-genome MLST analysis revealed 7-260 allelic differences, arguing against recent transmission but a common source of infection or an ancient interpatient transmission event could not be ruled out.

CONCLUSIONS: Altogether, these findings suggest that P. aeruginosa chronic respiratory infections can be an important and silent reservoir of transferable resistance determinants and P. aeruginosa high-risk clones, thus contributing to their increased resistance and worldwide dissemination.

PMID:40201539 | PMC:PMC11976719 | DOI:10.1093/jacamr/dlaf053

Physiotherapy. 2025 Feb 13:101772. doi: 10.1016/j.physio.2025.101772. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess the impact of combining positive expiratory pressure (PEP) and nebulisation on lung delivery by measuring the urinary concentration of amikacin, used as a biomarker in people with cystic fibrosis.

DESIGN: Randomised crossover study.

PARTICIPANTS: Nine people with cystic fibrosis.

INTERVENTION: A solution of amikacin was nebulised using a nebuliser alone or a nebuliser in combination with a PEP device.

OUTCOME MEASURES: After nebulisation, urine samples were collected over 24 hours. The total amount of amikacin excreted in urine was calculated, reflecting the lung dose. The elimination rate constant was also calculated, and represents total drug elimination by excretion and metabolism.

RESULTS: No differences in lung dose, half-life or elimination rate constant were observed between the two methods of nebulisation. Lung dose divided by respiratory rate was significantly greater for nebulisation in combination with PEP.

CONCLUSION: The use of nebulisation in combination with PEP does not result in clinically significant improvements in drug delivery in people with mild-to-moderate cystic fibrosis. However, this combination can be used safely to reduce the duration of physiotherapy sessions without compromising drug delivery.

TRIAL REGISTRATION: NCT02535130. CONTRIBUTION OF THE PAPER.

PMID:40199650 | DOI:10.1016/j.physio.2025.101772

Pulm Ther. 2025 Apr 8. doi: 10.1007/s41030-025-00293-3. Online ahead of print.

ABSTRACT

INTRODUCTION: ARISE was a global clinical trial designed to generate evidence demonstrating the utility of the patient-reported outcome instruments Quality of Life-Bronchiectasis (QOL-B) [Respiratory Domain (RD) only] and Patient-Reported Outcomes Measurement Information System Short Form v1.0-Fatigue 7a (PROMIS F SF-7a) in patients with newly diagnosed or recurrent Mycobacterium avium complex lung disease (MACLD). Here, we describe trial conduct, patient characteristics, and patient-reported symptoms at baseline among patients enrolled in ARISE.

METHODS: Adult patients with newly diagnosed or recurrent non-cavitary MACLD who had not initiated antibiotic treatment for their current MAC infection were enrolled; data including comorbidities and prior MACLD history were collected during screening. Symptom burden was assessed using QOL-B, PROMIS F SF-7a, and Functional Assessment of Chronic Illness Therapy (FACIT) questionnaires.

RESULTS: Of 99 patients from 12 countries enrolled in ARISE, the median age was 69.0 years; most were white (80.8%) and female (77.8%). This was the first diagnosis of MACLD for 72.7% of patients. Patients frequently reported having a comorbid respiratory disorder: bronchiectasis (49.5%), asthma (21.2%), and chronic obstructive pulmonary disease (16.2%). At baseline, mean (± SD) and median QOL-B RD scores were 65.0 (± 15.3) and 66.7; PROMIS F SF-7a T-scores were 53.8 (± 8.2) and 55.1; and FACIT-Fatigue scores were 35.0 (± 9.6) and 37.0.

CONCLUSIONS: Patients in ARISE were representative of a real-world patient population with MACLD. Comorbid chronic respiratory diseases were common in patients with new or recurrent MACLD, and substantial disease burden at the time physicians initiated MACLD treatment was evidenced by impairment across measures of fatigue and QOL-B domains.

GOV IDENTIFIER: NCT04677543.

PMID:40198465 | DOI:10.1007/s41030-025-00293-3

Curr Microbiol. 2025 Apr 8;82(6):236. doi: 10.1007/s00284-025-04167-4.

ABSTRACT

Cystic fibrosis (CF) is a polymicrobial infection characterized by interactions among various bacterial species that affect one another's cohabitation. The investigation of interspecies interactions in dual infections is essential to understand their reaction in the environment better and assist in the development of treatment regimens and innovative disease control approaches. Our hypothesis posits that co-infection interactions promote the adaptation of Staphylococcus aureus and Pseudomonas aeruginosa, potentially leading to synergistic action. To explore this, we examined dual-species interactions in co-isolated pairs of these organisms from Egyptian CF patients using laboratory media and artificial sputum media (ASM). Based on demographic data, 82 collected bacterial isolates from single, dual, and triple cultures were identified from 50 enrolled patients. In the interaction of the pairs in mimic media, P. aeruginosa exo-products significantly enhanced the biofilm formation and growth of S. aureus. Conversely, S. aureus did not inhibit P. aeruginosa biofilm formation. Furthermore, the biofilm mode of dual-organism growth provides protection in the CF context, as bacterial biofilms can withstand much higher antimicrobial levels compared to planktonically grown bacteria. Additionally, key biofilm genes regulated by quorum sensing were differentially expressed in both species in an isolate-dependent manner, highlighting their significant role in coexistence dual-species biofilm coexistence. In conclusion, our study illuminates the competitive and cooperative interactions between these two pathogens, which impact their coexistence and encourage biofilm production. This, in turn, accelerates disease progression and compromises patient health.

PMID:40198369 | DOI:10.1007/s00284-025-04167-4

mBio. 2025 Apr 8:e0064625. doi: 10.1128/mbio.00646-25. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that poses a significant public health threat, particularly in healthcare settings. A key determinant of P. aeruginosa virulence is the regulated synthesis and release of extracellular products, which is controlled by a cell density-dependent signaling system known as quorum sensing (QS). P. aeruginosa uses a complex QS network, including two systems that rely on diffusible N-acylhomoserine lactone (AHL) signal molecules. The LuxR-type receptor RhlR is unique in that it requires not only its cognate AHL but also the accessory protein PqsE to maximally bind to promoter DNA and initiate transcription. Our group previously demonstrated that PqsE physically interacts with RhlR, enhancing its affinity for target promoters across the P. aeruginosa genome. Although LuxR-type receptors are widespread in Gram-negative bacteria and important for pathogenesis, PqsE orthologs are restricted to Pseudomonas and Burkholderia species. This study explored the conservation of PqsE and examined PqsE ortholog structure-function across different species. Our results show that PqsE in Pseudomonas retains their functional interactions with RhlR homologs, unlike PqsE orthologs in Burkholderia spp., which do not interact with their respective LuxR-type receptors. Additionally, we assessed the AHL preferences of different receptors and hypothesized that the PqsE-RhlR interaction evolved to stabilize the inherently unstable RhlR, preventing its degradation. Indeed, we observe higher levels of RhlR protein turnover in a strain lacking pqsE compared to a wild-type strain of PA14, which can be partially rescued in a strain of P. aeruginosa lacking the Lon protease.

IMPORTANCE: Pseudomonas aeruginosa, a major pathogen for patients with cystic fibrosis and a primary constituent of healthcare-associated infections, relies on a complex quorum-sensing (QS) network to coordinate virulence factor production. Central to this system is the interaction between two proteins, PqsE and RhlR, which drive gene expression essential for pathogenesis. Our study investigates the conservation of the PqsE-RhlR interaction across related bacterial species, revealing that PqsE in Pseudomonas can enhance RhlR activity, while orthologs in Burkholderia lack this capacity. These findings offer new insights into the specificity and evolution of QS mechanisms, highlighting the PqsE-RhlR interaction as a potentially selective target for treating P. aeruginosa infections.

PMID:40197035 | DOI:10.1128/mbio.00646-25

bioRxiv [Preprint]. 2025 Mar 24:2025.03.21.644589. doi: 10.1101/2025.03.21.644589.

ABSTRACT

Pseudomonas aeruginosa (PA) causes severe respiratory infections utilizing multiple virulence functions. Our previous findings on PA quorum sensing (QS)-regulated small molecule, 2'-aminoacetophenone (2-AA), secreted by the bacteria in infected tissues, revealed its effect on immune and metabolic functions favouring a long-term presence of PA in the host. However, studies on 2-AA's specific effects on bronchial-airway epithelium and pulmonary endothelium remain elusive. To evaluate 2AA's spatiotemporal changes in the human airway, considering endothelial cells as the first point of contact when the route of lung infection is hematogenic, we utilized the microfluidic airway-on-chip lined by polarized human bronchial-airway epithelium and pulmonary endothelium. Using this platform, we performed RNA-sequencing to analyse responses of 2-AA-treated primary human pulmonary microvascular endothelium (HPMEC) and adjacent primary normal human bronchial epithelial (NHBE) cells from healthy female donors and potential cross-talk between these cells. Analyses unveiled specific signaling and biosynthesis pathways to be differentially regulated by 2-AA in epithelial cells, including HIF-1 and pyrimidine signaling, glycosaminoglycan, and glycosphingolipid biosynthesis, while in endothelial cells were fatty acid metabolism, phosphatidylinositol and estrogen receptor signaling, and proinflammatory signaling pathways. Significant overlap in both cell types in response to 2-AA was found in genes implicated in immune response and cellular functions. In contrast, we found that genes related to barrier permeability, cholesterol metabolism, and oxidative phosphorylation were differentially regulated upon exposure to 2-AA in the cell types studied. Murine in-vivo and additional in vitro cell culture studies confirmed cholesterol accumulation in epithelial cells. Results also revealed specific biomarkers associated with cystic fibrosis and idiopathic pulmonary fibrosis to be modulated by 2-AA in both cell types, with the cystic fibrosis transmembrane regulator expression to be affected only in endothelial cells. The 2-AA-mediated effects on healthy epithelial and endothelial primary cells within a microphysiological dynamic environment mimicking the human lung airway enhance our understanding of this QS signaling molecule. This study provides novel insights into their functions and potential interactions, paving the way for innovative, cell-specific therapeutic strategies to combat PA lung infections.

PMID:40196568 | PMC:PMC11974707 | DOI:10.1101/2025.03.21.644589

BMJ Public Health. 2025 Apr 2;3(1):e001584. doi: 10.1136/bmjph-2024-001584. eCollection 2025 Jan.

ABSTRACT

OBJECTIVES: In countries at the forefront of gender equality policy, mothers still play a more pronounced role than fathers in the provision of parental care for their children. This study aimed to explore gender equality in attendance at doctor's appointments among caregivers of children with chronic diseases before and after the introduction of video conference visits.

METHODS: Children aged 0-17 years diagnosed with cystic fibrosis, inflammatory bowel disease, diabetes or a chronic neurological disease at Gothenburg's and Lund's paediatric hospitals were included. Data on caregiver attendance from 2019 to 2022 were retrospectively collected from medical records. Doctors' appointments were categorised as in-person, telephone or video conference visits. Using mixed-effects models, we evaluated trends in parental attendance and assessed the associations between different types of appointments and gender equality in healthcare.

RESULTS: A total of 347 participants were included between 2019 and 2022, resulting in 6134 appointments. Overall attendance rates were 74% for mothers and 44% for fathers, corresponding to a difference of 30%-points (95% CI 27% to 32%-points, p<0.001). Mothers had consistently higher attendance rates across all types of appointments (all p<0.05). The attendance gap between mothers and fathers remained similar over time, except for video conference visits where an increase in maternal attendance was observed (p<0.001) while paternal attendance remained constant (p=0.90). Video conference visits had higher joint attendance rates than in-person and telephone appointments (both p<0.001).

CONCLUSION: Mothers attended paediatric outpatient visits more frequently than fathers across all appointment types. The gender gap in attendance remained unchanged after the introduction of video conference visits, while the joint attendance increased. Future interventions should explore structural strategies to enhance gender equality in caregiver attendance.

PMID:40196439 | PMC:PMC11973768 | DOI:10.1136/bmjph-2024-001584

Front Immunol. 2025 Mar 24;16:1550724. doi: 10.3389/fimmu.2025.1550724. eCollection 2025.

ABSTRACT

Pseudomonas aeruginosa is a prevalent opportunistic Gram-negative bacterial pathogen. One of its key virulence factors is pyocyanin, a redox-active phenazine secondary metabolite that plays a crucial role in the establishment and persistence of chronic infections. This review provides a synopsis of the mechanisms through which pyocyanin exacerbates pulmonary infections. Pyocyanin induces oxidative stress by generating reactive oxygen and nitrogen species which disrupt essential defense mechanisms in respiratory epithelium. Pyocyanin increases airway barrier permeability and facilitates bacterial invasion. Pyocyanin also impairs mucociliary clearance by damaging ciliary function, resulting in mucus accumulation and airway obstruction. Furthermore, it modulates immune responses by promoting the production of pro-inflammatory cytokines, accelerating neutrophil apoptosis, and inducing excessive neutrophil extracellular trap formation, which exacerbates lung tissue damage. Additionally, pyocyanin disrupts macrophage phagocytic function, hindering the clearance of apoptotic cells and perpetuating inflammation. It also triggers mucus hypersecretion by inactivating the transcription factor FOXA2 and enhancing the IL-4/IL-13-STAT6 and EGFR-AKT/ERK1/2 signaling pathways, leading to goblet cell metaplasia and increased mucin production. Insights into the role of pyocyanin in P. aeruginosa infections may reveal potential therapeutic strategies to alleviate the severity of infections in chronic respiratory diseases including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).

PMID:40196115 | PMC:PMC11973339 | DOI:10.3389/fimmu.2025.1550724

J Law Med Ethics. 2025 Apr 8:1-9. doi: 10.1017/jme.2025.48. Online ahead of print.

ABSTRACT

Genome editing, prominently led by the revolutionary CRISPR-Cas9 technology, is a powerful tool with significant applications in diverse fields, particularly in medicine and agriculture. It empowers scientists with the ability to effect precise genetic modifications, thereby potentially paving the way for advanced treatments for genetic disorders such as Huntington's disease, hemophilia, and cystic fibrosis. Yet, the significant capabilities of this technology also brings to the fore a myriad of intricate bioethical, legal, and regulatory dilemmas. In light of these complexities, this article endeavors to conduct a comprehensive scoping review of the existing literature on the most significant ethical implications emanating from genome editing. In conducting this review, we utilized the power of software tools like EndNote and Rayyan to aid in the systematic and thorough review of the literature. EndNote, a reference management software, was instrumental in organizing and managing the references and bibliographies, while Rayyan, a web application designed for managing and screening records for systematic and scoping reviews, proved crucial in the import and management of text records for the review.The review identified as main aspects of ethical, bioethical and medico-legal interest the exacerbation of social inequalities, safety concerns such as off-target mutations and immunological risks, ecological and evolutionary implications, and challenges to human dignity. It highlights the necessity for equitable access, rigorous regulation, and public engagement to address these issues responsibly.The ultimate objective of this article is to underscore the importance of an informed and inclusive dialogue regarding genome editing. Such dialogue is pivotal for fostering responsible innovation in this rapidly advancing field, ensuring that scientific progress aligns with ethical considerations. By presenting a comprehensive examination of the ethical implications of genome editing, we aim to contribute to this ongoing dialogue and promote a balanced and nuanced understanding of this impactful technology.

PMID:40195291 | DOI:10.1017/jme.2025.48

Pharmacogenomics. 2025 Apr 7:1-8. doi: 10.1080/14622416.2025.2490465. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) is an evolving field that integrates genetic information into clinical decision-making to optimize drug therapy and minimize adverse drug reactions (ADRs). Its application in rare disease (RD) drug development is promising, given the genetic basis of many RDs and the need for precision medicine approaches. Despite significant advancements, challenges persist in developing effective therapies for RDs due to small patient populations, genetic heterogeneity, and limited surrogate biomarkers. The Orphan Drug Act in the U.S. has incentivized RD drug development. However, the traditional drug approval process is constrained by logistical and economic challenges, necessitating innovative PGx-driven strategies. Identifying genetic biomarkers in the early drug development stages can optimize dose selection, enhance therapeutic efficacy, and reduce ADRs. Case studies such as eliglustat for Gaucher disease and ivacaftor for cystic fibrosis demonstrate the efficacy of PGx-guided treatment strategies. Integrating PGx into global drug development requires the harmonization of regulatory policies and increased diversity in genetic research. Artificial intelligence (AI) tools further enhance genetic analysis, disease prediction, and clinical decision-making. Modernizing drug labeling with PGx information is critical to ensuring safe and effective druguse. Collectively, PGx offers transformative potential in RD therapeutics by facilitating personalized medicine approaches and addressing unmet medical needs.

PMID:40194983 | DOI:10.1080/14622416.2025.2490465

Neurology. 2025 Apr 8;104(7_Supplement_1):3302. doi: 10.1212/WNL.0000000000210927. Epub 2025 Apr 7.

ABSTRACT

OBJECTIVE: To use concept mapping to ascertain preferences of people with epilepsy of child-bearing potential (PWECP) ages 14-26 years and caregivers for reproductive health counseling by neurologists.

BACKGROUND: The American Academy of Neurology (AAN) recommends that neurologists counsel PWECP ages 12-44 years old annually about at least two of three topics: folic acid, interactions between antiseizure medications (ASMs) and contraceptives, and ASM effects on pregnancy and/or fetal/child development. However, guideline development did not include the perspectives of younger PWECP or caregivers.

DESIGN/METHODS: We recruited PWECP ages 14-26 years and caregivers from one institution's child neurology clinics, a research registry, and epilepsy-related listservs. Participants: 1) generated topics about epilepsy and reproductive health important for neurologist counseling of PWECP ages 14-26 years, 2) sorted topics into conceptually-related categories, and 3) rated topics' importance on 5-point Likert scales for PWECP ages 14-17 and 18-26 years.

RESULTS: Thirty-four PWECP and 20 caregivers generated 37 topics, which were sorted/rated by 35 PWECP and 23 caregivers. Consensus categories included "Contraception," "Hormonal changes" (including hormonal influences on seizures, catamenial epilepsy), "Sex and Epilepsy" (including sexual function, relationships), "Parenthood with Epilepsy" (including heritability/genetics, post-partum concerns), "Pregnancy with Epilepsy" (including effects of seizures/ASMs during pregnancy), and "Preparing for Pregnancy" (including planning, folic acid, fertility). There was a negligible positive correlation (r=0.05) between importance for ages 14-17 and 18-26. For ages 14-17 years, categories rated at least 4/5 for importance included "Contraception" (4.50/5), "Sex and Epilepsy" (4.32/5), "Hormonal Changes" (4.3/5)," and "Preparing for Pregnancy" (4.12/5). For ages 18-26 years, all categories were rated at least 4/5: "Pregnancy with Epilepsy" (4.64/5), "Preparing for Pregnancy" (4.56/5), "Contraceptives" (4.51/5), "Parenthood with Epilepsy" (4.48/5), "Sex and Epilepsy" (4.47/5), and "Hormonal Changes" (4.21/5).

CONCLUSIONS: PWECP ages 14-26 want counseling about reproductive health and epilepsy from neurologists that is more comprehensive than current AAN recommendations and tailored by age. Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff. Disclosure: The institution of Dr. Kirkpatrick has received research support from American Epilepsy Society. The institution of Dr. Kirkpatrick has received research support from Child Neurologist Career Development Program. The institution of Dr. Kirkpatrick has received research support from Child Neurology Foundation. Dr. Kirkpatrick has received personal compensation in the range of $500-$4,999 for serving as a Meeting Attendee with One8 Foundation. Dr. Kirkpatrick has received personal compensation in the range of $500-$4,999 for serving as a Meeting Attendee with Brigham and Women's Hospital. Dr. Kirkpatrick has received personal compensation in the range of $0-$499 for serving as a Meeting Attendee with Pediatric Epilepsy Research Consortium. Dr. Kirkpatrick has a non-compensated relationship as a Board of Directors member with My Epilepsy Story that is relevant to AAN interests or activities. Miss Friel has nothing to disclose. Ms. Rivero-Guerra has nothing to disclose. Ms. Tao has nothing to disclose. Dr. Kassiri has nothing to disclose. Dr. Clements has nothing to disclose. The institution of Dr. Briscoe Abath has received research support from Harvard Medical School. Dr. Briscoe Abath has a non-compensated relationship as a Board of Trustees Member with Brother's Brother Foundation that is relevant to AAN interests or activities. Dr. Briscoe Abath has a non-compensated relationship as a Professional Advisory Board with Epilepsy Foundation that is relevant to AAN interests or activities. The institution of Dr. Pennell has received research support from NIH. Dr. Pennell has received publishing royalties from a publication relating to health care. Dr. Burke has nothing to disclose. Dr. Baumann has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant with Projet Jeune Leader (NGO). Dr. Baumann has received personal compensation in the range of $500-$4,999 for serving as a Consultant with Asian Disaster Preparedness Center. The institution of Traci Kazmerski has received research support from Cystic Fibrosis Foundation. The institution of Traci Kazmerski has received research support from NIH.

PMID:40193723 | DOI:10.1212/WNL.0000000000210927