IUBMB Life. 2025 May;77(5):e70027. doi: 10.1002/iub.70027.

ABSTRACT

Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care.

PMID:40420818 | DOI:10.1002/iub.70027

Health Technol Assess. 2025 May;29(19):1-111. doi: 10.3310/CPLD8546.

ABSTRACT

BACKGROUND: Cystic fibrosis is a life-limiting genetic condition that affects over 9000 people in England. Cystic fibrosis is usually diagnosed through newborn screening and causes symptoms throughout the body, including the lungs and digestive system. Around 90% of individuals with cystic fibrosis have at least one copy of the F508del mutation on the cystic fibrosis transmembrane conductance regulator gene.

OBJECTIVES: To appraise the clinical effectiveness and cost-effectiveness of elexacaftor-tezacaftor-ivacaftor, tezacaftor-ivacaftor and lumacaftor-ivacaftor within their expected marketing authorisations for treating people with cystic fibrosis and at least one F508del mutation, compared with each other and with established clinical management before these treatments.

METHODS: A de novo systematic literature review (search date February 2023) was conducted searching electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), bibliographies of relevant systematic literature reviews, clinical trial registers, recent conferences and evidence provided by Vertex Pharmaceuticals (Boston, MA, USA). Data on the following outcomes were summarised: acute change in per cent predicted forced expiratory volume in 1 second (change in weight-for-age z-score; and change in pulmonary exacerbation frequency requiring intravenous antibiotics. Network meta-analyses were conducted where head-to-head data were not available. Data from clinical trials and real-world evidence were examined to assess long-term effectiveness. A patient-level simulation model was developed to assess the cost-effectiveness of the three modulator treatments. The model employed a lifetime horizon and was developed from the perspective of the National Health Service.

RESULTS: Data from 19 primary studies and 7 open-label extension studies were prioritised in the systematic literature review. Elexacaftor/tezacaftor/ivacaftor was associated with a statistically significant increase in predicted forced expiratory volume in 1 second and weight-for-age z-score and a reduction in pulmonary exacerbations compared with established clinical management, lumacaftor/ivacaftor and tezacaftor/ivacaftor, and also led to a reduction in the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management, although the magnitude of this decrease was uncertain. Lumacaftor/ivacaftor and tezacaftor/ivacaftor were also associated with a statistically significant increase in predicted forced expiratory volume in 1 second and reduction in pulmonary exacerbations relative to established clinical management, but with a smaller effect size than elexacaftor/tezacaftor/ivacaftor. There was some evidence that tezacaftor/ivacaftor reduced the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management, but little evidence that lumacaftor/ivacaftor reduced the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management. The incremental cost-effectiveness ratios from the economic analysis were confidential. However, for all genotypes studied the incremental cost-effectiveness ratios were above what would be considered cost-effective based on the National Institute for Health and Care Excellence threshold of £20,000-30,000 per quality-adjusted life-year gained.

CONCLUSIONS: Despite the improved clinical benefits observed, none of the cystic fibrosis transmembrane conductance regulator gene modulators assessed would be considered cost-effective based on the National Institute for Health and Care Excellence threshold of £20,000-30,000 per quality-adjusted life-year gained. This is largely driven by the high acquisition costs of cystic fibrosis transmembrane conductance regulator gene modulator treatments.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42023399583.

FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135829) and is published in full in Health Technology Assessment; Vol. 29, No. 19. See the NIHR Funding and Awards website for further award information.

PMID:40418577 | DOI:10.3310/CPLD8546

Front Cell Infect Microbiol. 2025 May 9;15:1569331. doi: 10.3389/fcimb.2025.1569331. eCollection 2025.

ABSTRACT

INTRODUCTION: Chronic bacterial infections are responsible for significant morbidity and mortality in cystic fibrosis (CF) patients. Pseudomonas aeruginosa (Pa), the dominant CF pathogen, and Mycobacterium abscessus (Mab) can individually cause persistent, difficult to treat pulmonary infections. Co-infection by both pathogens leads to severe disease and poor clinical outcomes. Although interactions between Pa and other co-infecting pathogens in CF patients have been the focus of numerous studies, the dynamics of Pa-Mab interactions remain poorly understood.

METHODS: To address this knowledge gap, the study examined how Mab and Pa influenced each other through culture-based growth assays and molecular-based dual RNAseq analysis. Growth was measured by CFU determination and luminescence reporter -based readouts.

RESULTS: In initial studies, we noted that the growth of Pa continued unimpeded in a planktonic co-culture model, whereas Pa appeared to exert a bacteriostatic effect on Mab. Strikingly, exposure of Mab to cell-free spent supernatant of Pa resulted in a dramatic, dose-dependent bactericidal effect. Initial characterization indicated that this potent Pa-derived anti-Mab cidal activity was mediated by a heat-sensitive, protease-insensitive soluble factor of >3kDa size. Further analysis demonstrated that expression of this mycobactericidal factor requires LasR, a central regulator of Pa quorum sensing (QS). In contrast, ΔLasR Pa was still able to exert a bacteriostatic effect on Mab during co-culture, pointing to additional LasR-independent factors able to antagonize Mab growth. However, the ability of Mab to adapt during co-culture to counter the cidal effects of a LasR regulated factor suggested complex interspecies dynamics. Dual RNAseq analysis of Mab-Pa co-cultures revealed significant transcriptional remodeling of Mab, with differential expression of 68% of Mab genes compared to minimal transcriptional changes in Pa. Transcriptome analysis reflected slowed Mab growth and metabolic changes akin to a non-replicating persister phase. A tailored Mab response to Pa was evident by enhanced transcript levels of genes predicted to counteract alkylquinolone QS signals, respiratory toxins, and hydrogen cyanide.

DISCUSSION: The study showed Mab is capable of coexisting with Pa despite Pa's antagonistic effects, eliciting an adaptive molecular response in Mab. This study provides the first transcriptome-level insight into genetic interactions between the two CF pathogens offering potential strategies for disrupting their communities in a CF lung to improve patient clinical performance. Moreover, identification of a novel antimicrobial natural product with potent cidal activity against Mab could lead to new drug targets and therapies for Mab infections.

PMID:40415956 | PMC:PMC12098619 | DOI:10.3389/fcimb.2025.1569331

J Cardiothorac Vasc Anesth. 2025 May 8:S1053-0770(25)00351-9. doi: 10.1053/j.jvca.2025.04.033. Online ahead of print.

ABSTRACT

OBJECTIVES: To predict severe primary graft dysfunction (PGD3) after double-lung transplantation in cystic fibrosis (CF) patients using intraoperative data.

DESIGN: A retrospective single-center cohort study.

SETTING: University Hospital, France.

PARTICIPANTS: CF patients who underwent double-lung transplantation between 2012 and 2019. Patients younger than age 18 and those with multiorgan transplants, retransplantation, or intraoperative cardiopulmonary bypass were excluded.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: Sixty-nine variables were recorded in real-time across the nine time-points. PGD3 occurred in 24 patients (15.5%). PGD3 WAS ASSESSED ON POSTOPERATIVE DAY 3: A logistic regression model to predict PGD3 was developed using data collected at nine predefined time-points during surgery, from start (recipient and donor variables) to finish. The model's area under the curve improved progressively during surgery, rising from 0.764 to 0.892. The optimal model incorporated five variables: three associated with reduced PGD3 risk (preoperative pulmonary hypertension, donor body mass index, and PaO₂/FiO₂ ratio at surgery's end) and two were linked to increased risk (lactate level at second pulmonary artery clamping and extracorporeal membrane oxygenation [ECMO] use at surgery's end). The risk of PGD3 increased by a factor of 11.48 (95% CI 4.48-29.39; p < 0.001) when ECMO was required at the end of surgery and by 1.29 (95% CI: 1.02-1.63; p = 0.035) for each 1 mEq/L rise in lactate concentration at time-point 7 (second pulmonary artery clamping).

CONCLUSIONS: This predictive model underscores the adverse impact of sustained ECMO placed at the end of surgery and elevated intraoperative lactate levels on PGD3 risk.

PMID:40414788 | DOI:10.1053/j.jvca.2025.04.033

Respir Med. 2025 May 23:108178. doi: 10.1016/j.rmed.2025.108178. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has led to substantial improvements in the clinical outcome of people with cystic fibrosis (pwCF). However, its effects on exercise capacity remain uncertain.

METHODS: This retrospective cohort study included 71 pwCF who started ETI between March 2020 and September 2022. The best performance on the 6-minute walk test (6MWT), defined as the peak walking distance achieved, was compared between the 12 months preceding ETI initiation and the first 14 months of treatment. Pulmonary function tests (PFT) and Cystic Fibrosis Questionnaire-Revised (CFQ-R) were analyzed at treatment initiation and after 12 months.

RESULTS: After starting ETI, the 6MWT was performed at a median interval of 356 [296-380] days. The mean 6-minute walk distance (6MWD) was 641 m ±85.5 at baseline. After treatment, the 6MWD showed a significant absolute increase of 15.8 m (P=0.007). Improvement was greater in pwCF with a percent predicted FEV1 (ppFEV1) ≤40, showing a mean increase of 37.8 m (P=0.009), and in those without prior CFTR modulator therapy with an increase of 21.6 m (P=0.016). After 12 months, the absolute increase in ppFEV1 was 15.8 (P<0.001). The absolute changes from baseline in CFQ-R physical and respiratory scores were 17.9 (P<0.001) and 27 points (P<0.001), respectively. No correlation was found between changes in 6MWT and changes in PFT results.

CONCLUSIONS: ETI improved exercise capacity in pwCF, as evidenced by a significant increase in the 6MWD. ETI was also associated with improvements in physical-related quality of life. Changes in PFT results cannot predict changes in 6MWT results after ETI therapy.

PMID:40414317 | DOI:10.1016/j.rmed.2025.108178

Respir Med. 2025 May 23:108177. doi: 10.1016/j.rmed.2025.108177. Online ahead of print.

ABSTRACT

BACKGROUND: The role of Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in non-cystic fibrosis lung diseases, including COPD, is not well understood. The objective of this study was to assess the prevalence of intermediate sweat chloride levels, 30-59 mmol/L, in healthy young adults and the relationship between sweat chloride and pulmonary function.

METHODS: Healthy volunteers > 18 years of age were enrolled in this single center, prospective, cross-sectional pilot study. Sweat chloride testing was performed by pilocarpine iontophoresis. Study participants completed the ATS-DLD LHS-III modified general respiratory symptom questionnaire, spirometry pre- and post- inhaled bronchodilator, and Lung Clearance Index.

RESULTS: 93 subjects were enrolled. 1 subject withdrew and 2 had insufficient sweat volumes collected. Median (IQR) age was 27 years (25, 33) and 40% were male. Median (IQR) sweat chloride was 21 mmol/L (12, 29). 25/90 subjects (28%) had intermediate sweat chloride values, median 37 (33, 40) mmol/L. 60% of individuals with intermediate sweat chloride values were male as compared to 34% of individuals with normal sweat chloride values, p<0.001. Median FEV1 (% predicted) was 100 (90, 109), FEV1/FVC 0.83 (0.81, 0.86), and LCI was 6.01 (5.38, 6.98). There were no differences in pulmonary function between those with normal and intermediate sweat chloride values.

CONCLUSIONS: A significant number of healthy young adults have intermediate sweat chloride levels, but no differences in spirometry and LCI were found. Larger studies, including genetic analyses, are needed to determine if mild CFTR dysfunction impacts respiratory health, especially in older individuals with respiratory co-morbidities.

PMID:40414315 | DOI:10.1016/j.rmed.2025.108177

Fetal Diagn Ther. 2025 May 23:1-12. doi: 10.1159/000546547. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is a severe genetic disorder with a carrier frequency of 1 in 30. In Denmark, prenatal testing is offered when there is a family history of CF or ultrasound anomalies suggest an increased risk of the disease. This study evaluates indications for prenatal CF testing and their outcomes.

METHODS: Clinical indications and genetic results were analyzed for pregnancies undergoing CF testing in the Central Denmark Region between August 2012 to 2023. The data were categorized according to clinical indication.

RESULTS: Among 302 prenatal CF tests, echogenic bowel was the most frequent (44.7%, N = 135), leading to identification of one CF-affected fetus (0.7%). The second most common indication was EB together with non-CF-associated ultrasound findings (29.5%, N = 89), with no CF-affected fetuses. Known CF predisposition due to family history (15.6%, N = 47) identified five affected fetuses (10.6%) and 25 carriers (53.2%). No CF cases were detected in other included groups (N = 31).

CONCLUSION: This data shows that echogenic bowel has a low positive predictive value for cystic fibrosis in the fetus (1:230) in a country with combined first trimester screening but no systematic pre-conception or prenatal screening program for cystic fibrosis. Although the relative risk is increased compared to the general population (1:2,500), echogenic bowel appears to be a marker of limited clinical utility. In settings without dedicated CF screening strategies, this underscores the importance of considering the most effective allocation of diagnostic resources.

PMID:40414202 | DOI:10.1159/000546547

Contraception. 2025 May 22:110969. doi: 10.1016/j.contraception.2025.110969. Online ahead of print.

ABSTRACT

Abysmal sexual and reproductive health (SRH) outcomes in the United States persist due to multiple factors, including diminishing SRH care access and inequities in care for socially or economically marginalized populations. Digital innovations have the potential to address gaps in SRH care as scalable, low-cost, patient-centered solutions that supplement the formal healthcare system. Our multidisciplinary team has developed a suite of patient-facing digital tools to help address suboptimal SRH care delivery for marginalized individuals capable of pregnancy, including those with chronic medical conditions. These tools-MyPath for reproductive preferences, prepregnancy health, and contraception; MyVoice for SRH needs of people with rheumatic/autoimmune disease or cystic fibrosis; MyDecision for tubal sterilization; and MyHealthyPregnancy for tailored pregnancy support-are guided by principles of community engagement, person-centeredness, and health equity. In the wake of the Dobbs v. Jackson Women's Health Organization 2022 Supreme Court decision overturning federal abortion protections, as well as the rapidly shifting policy landscape under the current administration, there are new considerations for use and implementation of digital SRH tools. In this commentary, we draw directly from lessons learned in our work to discuss emerging concerns related to data privacy and pregnancy criminalization, trust in healthcare providers and systems, and research. We then propose recommendations for researchers seeking to create, implement, and evaluate these tools with the goal of safeguarding reproductive autonomy and achieving health equity in this new policy context.

PMID:40412590 | DOI:10.1016/j.contraception.2025.110969

Respir Med. 2025 May 21:108171. doi: 10.1016/j.rmed.2025.108171. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease that often leads to progressive lung disease and lung transplantation. CF transmembrane conductance regulator modulators (CFTRm) improve lung function in people with CF. The US Scientific Registry of Transplant Recipients (SRTR) data were used to assess rates of lung transplant waitlisting, waitlist removal, pre-transplant mortality, and lung transplantation in people with CF (CF cohort) compared to those with other respiratory conditions (non-CF cohort) across three time periods: (i) prior to approval of any CFTRm (Pre-CFTRm era); (ii) from approval of ivacaftor to pre-approval of elexacaftor/tezacaftor/ivacaftor (Pre-ETI CFTRm era); and (iii) after approval of ETI (ETI era). Among the CF cohort, new waitlistings decreased by 78% in ETI era compared to Pre-ETI CFTRm era while rates increased in the non-CF cohort. Among the CF cohort, waitlist removal for improving condition increased 18-fold in ETI era compared to Pre-ETI CFTRm era; rates remained stable among the non-CF cohort. Lung transplants decreased by 72% in ETI era compared to pre-ETI CFTRm era; rates increased among the non-CF cohort. These results suggest the availability of ETI is associated with reductions in demand for lung transplants for people with CF, increasing availability of donor lungs for non-CF candidates.

PMID:40409741 | DOI:10.1016/j.rmed.2025.108171

Med Anthropol. 2025 May 23:1-16. doi: 10.1080/01459740.2025.2507972. Online ahead of print.

ABSTRACT

Cystic fibrosis is a rare genetic disease that significantly reduces life expectancy. Therapy can delay the progression of the disease, but it is onerous, time-consuming and makes the disease more visible, creating a sense of not belonging to the healthy peer group that young people desperately want. Recent, very expensive advances in therapeutic interventions have dramatically reduced both the therapeutic load and the visibility of the condition. Drawing on a long-term ethnographic study in Germany, I explore how this changes the ways people with cystic fibrosis negotiate belonging, which is experienced as a metaphorical immigration into the world of the healthy.

PMID:40407871 | DOI:10.1080/01459740.2025.2507972

Rhinology. 2025 May 23. doi: 10.4193/Rhin25.132. Online ahead of print.

ABSTRACT

Chronic rhinosinusitis (CRS) with nasal polyps occurs in 6-57% of individuals with cystic fibrosis (CF) (1). According to the EPOS 2020 guidelines, CF-related CRS is classified as secondary diffuse, non-type-2 CRS (2). In contrast, most nasal polyposis in the general population is associated with primary, type-2 CRS. This educationally-oriented classification system facilitates the categorization of CRS in distinct groups. However, it may suggest that each type of CRS is caused by a single underlying mechanism, potentially leading clinicians to overlook that, in reality, multiple factors can drive CRS development. The incidence of CRS stemming from multiple etiologies remains currently underexplored. We report an illustrative case of a CF patient with concomitant NSAID-Exacerbated Respiratory Disease (NERD), necessitating two distinct targeted therapies to achieve effective symptomatic relief.

PMID:40407713 | DOI:10.4193/Rhin25.132

Int J Neonatal Screen. 2025 May 20;11(2):39. doi: 10.3390/ijns11020039.

ABSTRACT

The publication of Cystic Fibrosis Newborn Screening: A Systematic Review-Driven Consensus Guideline from the United States Cystic Fibrosis Foundation (CFF) presents the challenge of implementation. CFF is prepared to partner with stakeholders to enhance newborn screening (NBS) practices. Through funding provided to the Center for Public Health Innovation (CPHI), the CFF has helped establish two genetic testing resource centers to help states implement CFTR sequencing within the NBS algorithm. CPHI, with CFF funding, is facilitating quality improvement collaboratives that unite CF clinicians and NBS staff nationwide to share best practices in laboratory methods, communication, and education. CFF continues to fund the Screening Improvement Program Award for Optimizing the Diagnosis of Infants and has developed a toolkit to help CF care teams collaborate with NBS programs on guideline implementation. Together, these initiatives aim to support states and CF providers in adapting their algorithms and processes. By identifying current best practices to improve timeliness, sensitivity, and equity in CF NBS, CFF seeks to promote better outcomes for all individuals with CF. Recognizing the competing demands on state public health departments, CFF is committed to partnering with stakeholders to ensure meaningful improvements in CF NBS.

PMID:40407522 | DOI:10.3390/ijns11020039

Respirology. 2025 May 23. doi: 10.1111/resp.70047. Online ahead of print.

ABSTRACT

Treatment targets in severe asthma have evolved towards a remission-focused paradigm guided by precision medicine. This novel concept requires a shift from evaluating the efficacy of therapies based on a single outcome at a single time point to an outcome that captures the complexity of asthma remission involving several domains assessed over a sustained period. Since the concept is still emerging, multiple definitions have been proposed, ranging from symptom control and exacerbation-free to resolution of underlying pathobiology, with varying rigour in each parameter. Understanding the strengths and weaknesses of the current construct is needed to progress further. We conducted a roundtable discussion with 27 asthma experts to address this issue, and discussions were narratively synthesised and summarised. The participants observed that between one in three and one in five people treated with targeted biological therapies or macrolides experience low disease activity over a sustained period. They unanimously agreed that labelling the attained clinical state as clinical remission is useful as a clinical (e.g., facilitating a treat-to-target approach), policy (e.g., widening eligibility criteria for biologics), and scientific (e.g., a path to understanding cure) tool. Current remission rates vary significantly due to definition variability. When assessing remission, it is essential to consider confounding factors (e.g., steroid use for adrenal insufficiency). More research is required to reach an acceptable definition, and including the patient's voice in such research is essential. In conclusion, the concept of treatment-induced clinical remission is possible and valuable in asthma. However, further refinement of the definition is required.

PMID:40407301 | DOI:10.1111/resp.70047

Front Immunol. 2025 May 8;16:1493950. doi: 10.3389/fimmu.2025.1493950. eCollection 2025.

ABSTRACT

Mucoinflammatory lung disease in cystic fibrosis (CF) is characterized by airway surface liquid (ASL) layer dehydration and mucins hyperconcentration, which leads to airway obstruction, inflammation, bronchiectasis, and increased susceptibility to recurrent bacterial infections. Epidermal growth factor receptor (EGFR) is known to regulate airway mucous cell metaplasia (MCM) and mucins expression, but the role of EGFR pathway in the pathogenesis of CF-like lung disease remains unclear. Therefore, we hypothesized that airway epithelial cell-specific deficiency of EGFR mitigates mucoinflammatory responses in Scnn1b-transgenic (Tg+) mice that phenocopy human CF-like lung disease. To test this hypothesis, we examined the effect of airway epithelial cell-specific EGFR deficiency on the manifestation of mucoinflammatory outcomes in Tg+ mice. The airway epithelial cell-specific EGFR-deficient wild-type (WT) mice did not exhibit any obvious structural and functional defects in the lungs. The deletion of EGFR in airway epithelial cells in Tg+ mice, however, resulted in increased recruitment of neutrophils and macrophages into the lung airspaces, which was accompanied by significantly increased bronchoalveolar lavage fluid (BALF) levels of inflammatory mediators, including KC, G-CSF, MIP-2, MIP-1α, TNF-α, and MIP-1β. Additionally, as compared with the EGFR-sufficient Tg+ mice, the airway epithelial cell-specific EGFR-deficient Tg+ mice exhibited significantly increased postnatal mortality and compromised bacterial clearance. The deletion of EGFR in the airway epithelial cells of Tg+ mice resulted in an increased degree of mucus obstruction, which was associated with an increase in MCM and MUC5B production. Some of the molecular markers of type 2 inflammation, including Il13, Slc26a4, and Retnla, were significantly increased in airway epithelial cell-specific EGFR-deficient Tg+ mice versus EGFR-sufficient Tg+ mice. Taken together, our data show that EGFR deletion in the airway epithelial cells compromises postnatal survival, delays bacterial clearance, and modulates inflammatory and mucus obstruction-relevant endpoints, i.e., MCM, MUC5B production, and mucus obstruction, in Tg+ mice.

PMID:40406132 | PMC:PMC12094982 | DOI:10.3389/fimmu.2025.1493950

Clin Pharmacokinet. 2025 May 22. doi: 10.1007/s40262-025-01516-1. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Elexacaftor-tezacaftor-ivacaftor (ETI), a combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, has become the therapeutic standard of care for most people with cystic fibrosis (pwCF). People with cystic fibrosis exhibit differences in CFTR genotypes and have important differences in phenotypic characteristics including age, body weight, pancreatic status, disease severity, and comorbidities. While these differences predict large interindividual variability (IIV) in ETI exposure, there is a unique dose regimen recommended for adults. This raises questions around the "one-dose fits all" strategy.

OBJECTIVES: The aims of this study were to describe real-world population pharmacokinetics (Pop-PK) of ETI in adults with CF and identify factors associated with IIV.

METHOD: As part of the ongoing French national observational cohort study the Pop-PK analysis included 552 plasma concentrations drawn routinely from 325 adults with CF.

RESULTS: A one-compartment model with first order absorption and elimination best represented all three compounds, and an additional lag-time for elexacaftor PK data. Large IIV was observed in ETI, with an area under the curve (AUC0-24h for elexacaftor and tezacaftor, and AUC0-12h for ivacaftor) ranging respectively, from 58.7-422.9 mg⋅h/L; 38.0-207.7 mg⋅h/L and 4.9-64.9 mg⋅h/L. The main sources of IIV identified in the final ETI Pop-PK models were body weight, age, exocrine pancreatic insufficiency and CFTR genotype.

CONCLUSION: This study established the first ETI Pop-PK analysis in adults with CF and identified several covariates that explain IIV. Therapeutic drug monitoring may be beneficial for patients with a small body weight, older ages, carrying one ETI-responsive CFTR variant or those with no exocrine pancreatic insufficiency and especially for patients who combine these characteristics. Therapeutic drug monitoring may also prove to be useful in individuals experiencing adverse events, in those with reduced effectiveness, or to help manage non-adherence issues.

PMID:40405059 | DOI:10.1007/s40262-025-01516-1

BMJ Open Qual. 2025 May 22;14(2):e003230. doi: 10.1136/bmjoq-2024-003230.

ABSTRACT

BACKGROUND: Surveys are widely used in healthcare to gather knowledge and information about services provided. There is a recognised gap between survey findings and their impact on practice, particularly for standardised surveys conducted at the national or organisational level. Findings are more likely to be acted on where there is a culture and infrastructure supportive of quality improvement (QI), but little is known about the experiences of local QI teams designing and using surveys in practice.

OBJECTIVE: To understand the experiences of QI teams designing and using surveys within a national QI collaborative, including perceived value and challenges.

METHODS: Using an interactive research approach, 14 semistructured interviews were conducted with members of the Cystic Fibrosis Lung Transplant Transition Learning and Leadership Collaborative. Data were analysed through multiple rounds of coding and inductive thematic analysis.

RESULTS: Collaborative participants viewed surveys positively as an improvement tool. The design and use of surveys was a team-based effort, embedded within the structure of the collaborative. Surveys illuminated local, microsystem and mesosystem data and provided patient and staff insights. As one step in the QI journey, surveys helped shape the direction of local QI work, resulting in positive changes in areas such as working relationships, patient interactions, staff education and work processes.Challenges experienced included: response rates and survey design, inability to act on findings, issues of sensitivity and anonymity, expertise to design surveys, time requirements, and survey fatigue.

CONCLUSIONS: Surveys played a crucial role in driving QI efforts, leading to impactful changes in practice. Used within a supportive collaborative context, surveys became an essential tool for ongoing learning and improvement, highlighting the distinct needs of surveys used in QI compared with research.

PMID:40404211 | DOI:10.1136/bmjoq-2024-003230

Sante Publique. 2025;37(1):209-223. doi: 10.3917/spub.251.0209.

ABSTRACT

INTRODUCTION: The care paths and lives of cystic fibrosis patients were profoundly altered during the health crisis in France. Patient experiences can be used to provide lessons on how to adapt to a crisis.

PURPOSE OF THE STUDY: The ExPaParM collaborative study analyzed the experiences of a varied sample of patients and identified changes in practices in Cystic Fibrosis Centers (CFC), with the aim of characterizing adaptations made and destabilizing events experienced during this crisis, using a systemic approach.

RESULTS: Adaptation practices aiming to minimize the impact of the crisis or maintain the recommended quality of care, as far as possible, have been identified. These adaptations concern the individual level (patient and family), local care, care management at CFCs, and hospital organization. When the crisis has negatively affected patients, resilience factors based on individual and family skills, a relationship of trust with professionals, and informal solidarity networks have enabled complex situations to be overcome.

CONCLUSION: Strong points prior to the crisis proved decisive: the structuring of CFC teams, digital resources, therapeutic patient education, and a circuit for disseminating information related to cystic fibrosis. Reducing vulnerability to a future crisis also means securing essential medicines for the disease, organizing protected hospital circuits, and developing patient preparedness plans.

PMID:40402727 | DOI:10.3917/spub.251.0209

Acta Microbiol Immunol Hung. 2025 May 22. doi: 10.1556/030.2025.02578. Online ahead of print.

ABSTRACT

Stenotrophomonas maltophilia has emerged as an opportunistic pathogen originating from the environments, causing nosocomial infections, particularly in immunocompromised individuals and patients with cystic fibrosis. Although this microorganism exhibits low virulence, its infections are associated with high morbidity and mortality rates. S. maltophilia is intrinsically resistant to many antimicrobial agents used in clinical practices, therefore, posing significant treatment challenges. The multidrug resistance in S. maltophilia results from a combination of intrinsic, adaptive, and acquired mechanisms. S. maltophilia genome carries an array of genes encoding multidrug efflux pumps, which are key contributors to its broad-spectrum antibiotic resistance by expelling a wide range of drugs and reducing their intracellular concentrations to nontoxic levels. The majority of these efflux pumps belong to the resistance-nodulation-cell division (RND) family, while a lesser fraction is classified under the major facilitator superfamily (MFS) and the adenosine triphosphate binding cassette (ABC) family. In terms of function, substrate specificity, and complex gene regulation, these multidrug efflux pumps contribute not only to the survival of S. maltophilia under antibiotic stress but also to its resilience against other chemical challenges, including oxidative stress-generating substances and biocides. The roles of certain efflux pump systems in acquired and adaptive antibiotic resistance, as well as their potential applications as drug targets to enhance the efficacy of routinely used antibiotics through the use of small molecules capable of functioning as efflux pump inhibitors, are also discussed. A deeper understanding of these mechanisms can contribute to the more effective management against antibiotic-resistant S. maltophilia.

PMID:40402604 | DOI:10.1556/030.2025.02578

Crit Care Med. 2025 May 22. doi: 10.1097/CCM.0000000000006716. Online ahead of print.

ABSTRACT

OBJECTIVES: Soluble ST2 (sST2), a decoy receptor for the alarmin interleukin-33 (IL-33), has been implicated in adverse clinical outcomes in acute respiratory failure (ARF). We evaluated sST2 distribution across diverse cohorts of patients with different etiologies of ARF, compared plasma and lower respiratory tract (LRT) concentrations, and examined associations with individual organ dysfunction, biological subphenotypes, and outcomes.

DESIGN: Observational study.

SETTING: Multicenter cohorts of ARF patients.

PATIENTS: A total of 1432 ARF patients, including 863 non-COVID and 569 COVID-19 cases, from five cohorts.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: sST2 levels were measured in plasma and LRT specimens (when available) and analyzed for associations with ARF etiology, severity, organ dysfunction, systemic host response, subphenotypes, and 30-day mortality. Plasma sST2 levels were higher in non-COVID ARF patients compared with COVID-19 patients (p < 0.05) and were markedly elevated compared with LRT levels (> 19-fold), with weak intercompartmental correlation. Elevated plasma sST2 levels were associated with extrapulmonary organ dysfunction and a hyperinflammatory ARF subphenotype but not with respiratory indices, including hypoxemia. Plasma sST2 independently predicted 30-day mortality in pooled cohort data, adjusted for age, sex, and illness severity. In longitudinal measurements, nonsurvivors had persistently elevated plasma sST2 levels in the first 2 weeks of critical illness compared with survivors.

CONCLUSIONS: Plasma sST2 levels independently predict outcomes in ARF and are strongly associated with extrapulmonary organ dysfunction. The weak correlation between plasma and LRT sST2 levels suggests a predominantly systemic source. These findings highlight the potential of the IL-33/ST2 axis as a therapeutic target and warrant further investigation into its role in multiple organ dysfunction in ARF.

PMID:40402026 | DOI:10.1097/CCM.0000000000006716

J Biomol Struct Dyn. 2025 May 22:1-12. doi: 10.1080/07391102.2025.2499949. Online ahead of print.

ABSTRACT

One of the most important public health concerns is the rise of the multi-drug resistance bacteria in the recent years. Pseudomonas aeruginosa is a frequent Gram-negative bacterium prominent in the hospital-acquired illness and is considered as an opportunistic human pathogen responsible for causing nosocomial infections. Numerous burn victims, cystic fibrosis patients, and those with neutropenic malignancy die as a result of it. The current approach involves molecular docking for the predominant recognition of the drug binding site for the designing of the potent inhibitors for inhibiting the membrane protein of Pseudomonas aeruginosa. The present study has targeted 11 outer membrane proteins of Pseudomonas aeruginosa with 12 different FDA approved drugs. Protein modeling has been applied to create the target proteins. As per the results revealed out from the docking perspective, Piperacillin which has been categorized under the broad-spectrum antibiotics has emerged out as one of the forerunners as compared to the other group of antibiotics as it exhibited highest binding energy, i.e. -10.4 kcal/mol. Hence, the compound has been validated using in-silico tools such as ADME and PROTOX-II server which indicates its nontoxic nature. Molecular dynamics simulations were conducted for EGCG-OprP, Piperacillin-OprB, OprP (Apoprotein), and OprB (Apoprotein) complexes to assess their binding efficacy. Statistical parameters such as RMSD, RMSF, h-bond interactions, and % occupancies indicated stability in ligand binding. Protein RMSD values plateaued at approximately 0.5 nm, while ligand RMSD values remained below 0.2 nm, affirming stability in binding OprP and OprB. H-bond analysis revealed stable contacts for EGCG and Piperacillin, and % occupancies indicated specific interactions. Energetics analysis yielded deltaG values of -30.45 for EGCG and -56.66 for Piperacillin, suggesting efficient binding with OprP and OprB. This positioned Piperacillin as a promising candidate for future pharmacological studies, considering its classification as a broad-spectrum antibiotic against P. aeruginosa. The study served as a crucial roadmap for designing drugs to inhibit this formidable pathogen amid rising antibiotic resistance, emphasizing its significance in the ongoing battle against infectious diseases.

PMID:40401805 | DOI:10.1080/07391102.2025.2499949