AIMS:Postprandial administration of ultra-fast-acting insulin (PP-UFI) may offer greater flexibility for individuals with cystic fibrosis-related diabetes (CFRD). This study evaluated whether PP-UFI provides glycaemic control comparable to standard mealtime fast-acting insulin (MT-FI). METHODS:Adults with CFRD were enrolled in an open-label, multicentre, randomized phase IV crossover trial with a two-sequence, four-period design. Participants received MT-FI or PP-UFI using connected insulin pens for 3-month periods. The primary endpoint was time in range (TIR: 70-180 mg/dL). Mixed-effects models accounted for repeated measures and treatment sequence. RESULTS:Thirty-eight participants were enrolled (mean age: 33 ± 11 years; 56% receiving CFTR modulators), and 34 were included in the intention-to-treat analysis. Baseline TIR was 74% [68-83], time below range (<70 mg/dL) was 4.1% [1.9-6.7], and ppFEV1 was 71 ± 25%. The estimated difference between MT-FI and PP-UFI was + 1.1 percentage points (95% CI: -1.1 to + 3.3; p = 0.316), with no statistically significant difference observed. Formal equivalence was not demonstrated. Other CGM metrics, HbA1c, and insulin doses were comparable between treatments. CONCLUSION:These findings support the potential of postprandial ultra-fast-acting insulin as a flexible treatment option for adults with CFRD.

BACKGROUND:Several studies have shown improvements in glucose control after initiating elexacaftor/tezacaftor/ivacaftor (ETI) in cystic fibrosis-related diabetes (CFRD) patients. However, ETI's impact on insulin treatment remains unclear. This observational multicenter study aimed to analyze insulin treatment characteristics in adults with preexisting CFRD after ETI treatment initiation. METHODS:Data on diabetes treatment and continuous glucose monitoring (CGM) were retrospectively collected for 1 year before and up to 2 years after ETI treatment initiation in adults with CFRD from 13 French CF centers. We analyzed the type of insulin treatment, insulin doses, daily distribution, and CGM parameters after 1 year of ETI therapy. RESULTS:From April to December 2024, 107 individuals were included. The mean age was 33.2 ± 9.3 years, 49% were female, and diabetes treatment was diet for 14%, multiple daily injections for 65%, and pump for 21% of patients. After 1 year of ETI, total and bolus insulin doses decreased significantly from 0.37 IU/kg/day (0.19-0.60) to 0.30 IU/kg/day (0.17-0.49) (P = 0.02) and from 0.27 IU/kg/day (0.14-0.50) to 0.17 IU/kg/day (0.10-0.30), P = 0.0003) respectively. Among patients on a diet, 33.3% started insulin treatment, while 6.5% of patients on insulin treatment discontinued insulin. CGM parameters showed significant decreases in time below the range <70 mg/dL (from 3% [1-8.5] to 2% [0-4], P = 0.001) and coefficient of variation (from 35% [28.7-41.7] to 33.1% [26.8-39.2], P = 0.001). CONCLUSIONS:These findings indicate a reduction in insulin doses, particularly prandial insulin, as well as decreased glucose variability and hypoglycemia following ETI therapy in CFRD patients. Further long-term studies are needed to confirm these results.

Achromobacter xylosoxidans is an opportunistic pathogen in both cystic fibrosis (CF) and non-CF patients, in whom biofilm formation contributes to bacterial persistence and antibiotic tolerance. This study aimed to characterize early and mature biofilm formation in 57 clinical A. xylosoxidans isolates using complementary and physiologically relevant approaches and to compare biofilm phenotypes according to isolate origin (CF/non-CF). Early adhesion was assessed using the Biofilm Ring Test®, mature biofilm viable biomass was quantified under static conditions by colony-forming units counts, and biofilm dynamics were analyzed in a continuous-flow microfluidic system. The effects of five clinically relevant antibiotics (trimethoprim-sulfamethoxazole, piperacillin-tazobactam, meropenem, imipenem, and cefiderocol) were evaluated under dynamic conditions at sub-inhibitory concentrations (0.5 × Minimum Inhibitory Concentration (MIC)) and on preformed biofilm at inhibitory concentrations (10 × MIC). Non-CF isolates displayed faster early adhesion than CF isolates, whereas mature biofilm biomass was comparable between groups. If early adhesion did not predict mature biofilm biomass, dynamic biofilm coverage under flow conditions correlated with static mature biofilm levels. Sub-inhibitory antibiotic concentrations failed to prevent initial adhesion and elicited three distinct responses: biofilm formation enhancement (piperacillin-tazobactam, meropenem, imipenem), no effect (trimethoprim-sulfamethoxazole), or biofilm reduction (cefiderocol). Exposing mature biofilm to 10 × MIC identified trimethoprim-sulfamethoxazole and cefiderocol as the most effective agents in biofilm biomass reduction, whereas carbapenems and piperacillin-tazobactam were less effective. These findings provide new insights into A. xylosoxidans biofilm biology and may help guide therapeutic strategies for infections caused by this emerging, increasingly drug-resistant pathogen.

The colonization and persistence of Pseudomonas aeruginosa in chronically diseased lungs are driven by various virulence factors. However, pulmonary infections in cystic fibrosis (CF) patients are predominantly polymicrobial. While Achromobacter xylosoxidans is an opportunistic pathogen in these patients, its impact on P. aeruginosa virulence during co-infection remains largely unknown. This study investigated P. aeruginosa interaction with two clonally related A. xylosoxidans strains, Ax 198 and Ax 200, co-isolated from CF sputum. We found that the interaction was strain-dependent, with Ax 200 significantly reducing P. aeruginosa virulence in a zebrafish model, providing the first in vivo evidence of this interaction. Proteomic analysis revealed that P. aeruginosa proteome was differently impacted by the two A. xylosoxidans strains, with Ax 200 altering proteins involved in biofilm formation, swimming motility, iron acquisition, and secretion systems. These findings were validated by phenotypic assays, confirming that A. xylosoxidans affected major P. aeruginosa virulence phenotypes, including biofilm formation, swimming motility, and siderophore production. Genetic analysis confirmed that distinct regulatory mechanisms, including iron cycle pathways, may account for the strain-dependent effects. These findings reveal a novel multi-target competitive mechanism through which A. xylosoxidans significantly disrupts P. aeruginosa virulence.

BACKGROUND:Among people with cystic fibrosis, sweat chloride and lung function response to elexacaftor-tezacaftor-ivacaftor (ETI) is variable. We hypothesised that the presence of two versus one ETI-responsive CFTR variant could predict response variability. METHODS:In this analysis of two real-world observational studies, data from a French national cohort of adults (aged ≥18 years) with cystic fibrosis and at least one F508del variant treated with ETI and the French compassionate programme for ETI in people (aged ≥6 years) with cystic fibrosis without F508del were used to examine sweat chloride concentrations (SCCs) after ETI initiation, and the absolute change in SCC and percentage of predicted forced expiratory volume in 1 s (ppFEV1) following ETI initiation. The ETI responsiveness of CFTR variants was determined following the French compassionate programme's classification. FINDINGS:Among 1266 participants, 834 had two ETI-responsive variants and 432 had only one. Median SCC after ETI initiation was 36 mmol/L (IQR 24-50) in participants with two ETI-responsive variants and 53 mmol/L (26-72) in those with only one (p<0·0001). The proportion of participants with SCC of less than 30 mmol/L was 298 (36%) of 834 among those with two ETI-responsive variants and 65 (15%) of 432 in those with one ETI-responsive variant (χ2 p<0·00001). Multivariable analyses showed that the number of ETI-responsive variants was a determinant of SCC after ETI initiation (p<0·0001) but not of the absolute change in ppFEV1 (p=0·80). INTERPRETATION:People with cystic fibrosis with two responsive CFTR variants had a better correction of CFTR function in sweat glands after ETI initiation than those with only one responsive variant, but the response in terms of ppFEV1 was similar. These findings suggest that maximal improvement in lung function could be reached with current CFTR modulators and that no further increase in lung function would be expected from more potent restoration of CFTR function. Reaching normal lung function in people with cystic fibrosis and established lung disease might be limited by irreversible lung damage, suggesting that new therapeutic strategies aimed at improving lung function should be developed. FUNDING:Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR.

ABSTRACT Elexacaftor/tezacaftor/ivacaftor (ETI) significantly improves treatment outcomes for people with cystic fibrosis (pwCF) with at least one F508del allele. In 2023, the Food and Drug Administration approved ETI for children with CF aged 2–5 years. However, real‐world pharmacokinetic‐pharmacodynamic data for ETI in pediatric and adult populations are still limited. This study aimed to characterize the population PK of ETI in children with CF (chCF) and evaluate current dosing recommendations. Population PK modeling was conducted using Monolix software on 150 ETI concentrations obtained from therapeutic drug (TDM) monitoring in 96 children with CF aged 2–18 years, as part of the MODUL‐CF study. Area under the curve was derived from individual Bayesian pharmacokinetic estimates. A one‐compartment model with a lag time, first‐order absorption, and elimination best described the PK of elexacaftor/ivacaftor, while the PK of tezacaftor followed a one‐compartment model with first‐order absorption and elimination. A large between‐subject variability was observed. The effect of body weight was significant on apparent clearance and volume of distribution parameters using allometric scaling. Children weighing 30–40 kg who received the adult‐recommended dose showed higher drug exposure compared to adults with cystic fibrosis. This is the first study to describe the population pharmacokinetics of ETI in chCF aged 2–18 years, revealing high between‐subject variability for all three drugs. In this context, TDM is likely essential for managing ETI exposure levels and guiding dosing adjustments. The appropriateness of current dosing recommendations for children under 12 years old weighing 30–40 kg remains to be clarified.

BACKGROUND:Lenabasum is a cannabinoid receptor 2 (CB2) agonist under development for cystic fibrosis (CF), targeting inflammation. We evaluated the efficacy and safety of lenabasum in people with CF (pwCF). METHODS:We conducted a global, 28-week, randomized, double-blind, placebo-controlled Phase 2b trial. PwCF were ≥12 years old with 2-3 pulmonary exacerbations (PEx) treated with intravenous (IV) antibiotics (or 1 PEx treated with IV and ≥1 PEx treated with oral antibiotics) in the past year. Subjects were randomized 2:1:2 to lenabasum 20 mg BID, lenabasum 5 mg BID, or placebo BID. Primary endpoint was rate of PEx, comparing lenabasum 20 mg BID to placebo. RESULTS:Among 447 subjects from 21 countries, mean age was 26.9 (10.3 SD) years, 53.6% were female, 45.2% homozygous for F508del, and 24.9% received CFTR modulators. Highest ppFEV1 in the previous year was 69.2% with the majority having 1-2 PEx treated with IV antibiotics (2-7 PEx treated with either IV or oral antibiotics). PEx incidence over 28 weeks was 0.84 for placebo, 0.75 for lenabasum 5 mg BID, and 0.91 for lenabasum 20 mg BID; rates were not lower relative to placebo in the 5 mg (incidence rate ratio (IRR)=0.89, 95% CI 0.66 to 1.19, p = 0.44) or the 20 mg group (IRR 1.08, 95% CI 0.86 to 1.37, p = 0.51). PEx occurred less frequently in participants from Eastern Europe, but there was no evidence of regional variation in treatment efficacy. Lenabasum was well tolerated, without safety signals. CONCLUSION:Lenabasum did not improve key clinical outcomes in this Phase 2b study in pwCF.

Lung disease is variable among patients with cystic fibrosis (CF) and depends on genetic and environmental factors. To better understand the molecular determinants of lung disease variability, we carried out an epigenome-wide association study (EWAS) in sputum samples from patients with CF. We profiled 64 sputum samples using Human Methylation EPIC BeadChips and assessed the correlation between DNA methylation levels and four clinical traits: lung function (FEV1pp), lung function variation (FEV1pp slope), presence and number of pulmonary exacerbations. Sputum samples were collected at four time points over an 18-month follow-up period. Selected CpG sites were reassessed in independent sputum samples from the same cohort by pyrosequencing. In the EWAS, we identified two differentially methylated CpG sites (cg11047325/SOCS3, p = 4 × 10–6; cg18608055/SBNO2, p = 6 × 10–7) that correlated with lung function. They were validated in independent sputum samples from the same cohort using pyrosequencing. Additionally, three CpG sites (cg23107754, cg03209812 and cg09600088) split patients with declining lung function from those whose lung function either improved or remained stable (accuracy = 0.80). Of interest for CF-related diabetes, one of these CpG sites (cg09600088) maps to the BRSK2 gene, which plays a role in pancreatic beta cell function. Finally, a DNA methylation signature of 23 CpG sites predicted patients with pulmonary exacerbation (accuracy = 0.84). We provide the first longitudinal assessment of genome-wide DNA methylation in a cohort of patient with CF and identify CpG sites that predict clinical traits of key importance for lung disease. The associated genes play a critical role in inflammation or pancreatic endocrine activity. Overall, our results underscore the emerging role of DNA methylation as a key modulator of disease severity in CF.

BACKGROUND:It is unclear whether sensitization patterns differentiate children with severe recurrent wheeze (SRW)/severe asthma (SA) from those with non-severe recurrent wheeze (NSRW)/non-severe asthma (NSA). Our objective was to determine whether sensitization patterns can discriminate between children from the French COBRAPed cohort with NSRW/NSA and those with SRW/SA. METHODS:IgE to 112 components (c-sIgE) (ImmunoCAP® ISAC) were analyzed in 125 preschools (3-6 years) and 170 school-age children (7-12 years). Supervised analyses and clustering methods were applied to identify patterns of sensitization among children with positive c-sIgE. RESULTS:We observed c-sIgE sensitization in 51% of preschool and 75% of school-age children. Sensitization to house dust mite (HDM) components was more frequent among NSRW than SRW (53% vs. 24%, p < .01). Sensitization to non-specific lipid transfer protein (nsLTP) components was more frequent among SA than NSA (16% vs. 4%, p < .01) and associated with an FEV1/FVC < -1.64 z-score. Among sensitized children, seven clusters with varying patterns were identified. The two broader clusters identified in each age group were characterized by "few sensitizations, mainly to HDM." One cluster (n = 4) with "multiple sensitizations, mainly to grass pollen, HDM, PR-10, and nsLTP" was associated with SA in school-age children. CONCLUSIONS:Although children with wheeze/asthma display frequent occurrences and high levels of sensitization, sensitization patterns did not provide strong signals to discriminate children with severe disease from those with milder disease. These results suggest that the severity of wheeze/asthma may depend on both IgE- and non-IgE-mediated mechanisms.

Introduction : Les aidants sont généralement peu impliqués dans les programmes d’ETP que leur proche malade peut suivre. Cependant, la transmission des connaissances et des compétences par des patients éduqués atteints d’une maladie chronique vers leur aidant a déjà été mise en évidence. Ce phénomène s’appelle « effet de Halo ». Dans le cadre de la mucoviscidose, nous formulons l’hypothèse que cet effet de halo existe également, chez des patients adultes et adolescents. Méthode : L’étude a été menée au Centre de Ressource et de Compétence de la Mucoviscidose (CRCM) de Montpellier auprès de 61 patients (31 adultes, 30 mineurs) et de leur aidant proche. Des questionnaires en miroir pour patient et aidant ont été utilisés pour mesurer la fréquence et la qualité de la transmission vers l’aidant des connaissances et des compétences acquises par les patients grâce à l’ETP, ainsi que l’impact de cette transmission sur la gestion quotidienne de la mucoviscidose. Résultats : L’étude révèle que 83,6 % des patients (P) ont transmis des connaissances à leurs aidants (A), bien que cette perception soit légèrement plus faible du côté des aidants (67,8 %). L’effet de Halo a eu un impact significatif sur la gestion quotidienne de la maladie (P = 91,7 %, A = 93,4 %), avec une capacité notable des aidants à gérer les urgences (P = 85 %, A = 90 %) et à soutenir psychologiquement les patients (P = 80,4 %, A = 80,3 %). L’aide fournie par l’aidant vers son proche a été considérée efficace (P = 80,3 %, A = 81,9 %), elle a contribué à améliorer la relation entre eux (P = 61,7 %, A = 80,3 %) ainsi qu’avec les professionnels de santé (P = 64 %, A = 74,6 %). Les comparaisons entre adultes et adolescents ne montrent pas de différences significatives. La participation partielle de l’aidant au programme d’ETP parait aider significativement le patient dans plusieurs aspects de sa prise en charge de la maladie comme la gestion de l’alimentation, du sommeil et les relations avec les professionnels de santé. Discussion : Les résultats confirment l’existence de l’effet de Halo, avec une transmission des compétences du patient vers son aidant, ce qui renforce le soutien apporté dans la gestion de la maladie. L’étude souligne l’importance d’inclure plus systématiquement les aidants dans le processus d’ETP, car leur participation améliore encore certains aspects. L’effet de Halo semble avoir un impact similaire, que le patient soit adulte ou mineur. Ces données confirment les résultats déjà publiés chez des patients atteints de diverses pathologies chroniques ou dans le cadre de la périnatalité entre des femmes éduquées et leur conjoint. Conclusion : Cette étude démontre l’existence et l’importance de l’effet Halo dans l’ETP des patients atteints de mucoviscidose, avec des répercussions positives sur la gestion de la maladie et la qualité de vie des patients et de leurs aidants. Des études futures, prospectives et incluant des analyses qualitatives, permettront d’approfondir la compréhension de ce phénomène.

Rationale: Limited data exist on the safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease. Objectives: To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease. Methods: A prospective observational study, including all adults aged 18 years and older with percentage predicted forced expiratory volume in 1 second (ppFEV1) ⩽ 40 who initiated ETI from December 2019 to June 2021 in France, was conducted. PwCF were followed until August 8, 2022. Results: ETI was initiated in 434 pwCF with a median ppFEV1 of 30 (interquartile range, 25-35), including 27 with severe cystic fibrosis liver disease and 183 with diabetes. PwCF were followed for a median of 587 (interquartile range, 396-728) days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was due mostly to lung transplantation (n = 5) or death (n = 4). Absolute increase in ppFEV1 by a mean of +14.2% (95% confidence interval, 13.1-15.4%) occurred at 1 month and persisted throughout the study. Increase in ppFEV1 in the youngest age quartile was almost twice that of the oldest quartile (P < 0.001); body mass index < 18.5 kg/m2 was found in 38.6% at initiation versus 11.3% at 12 months (P = 0.0001). Increases in serum concentrations of vitamins A and E, but not 25-hydroxy vitamin D3, were observed. Significant reductions in the percentages of pwCF using oxygen therapy, noninvasive ventilation, nutritional support, and inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of patients with diabetes. Conclusions: ETI is safe in pwCF and advanced lung disease, with multisystem pulmonary and extrapulmonary benefits.

Cefiderocol is a siderophore-conjugated cephalosporin increasingly used in the management of Achromobacter infections. Testing for cefiderocol susceptibility is challenging with distinct recommendations depending on the pathogens. We evaluated the performance of commercial tests for testing cefiderocol susceptibility in the Achromobacter genus and reviewed the literature. Diffusion (disks, MIC gradient test strips [MTS], Liofilchem) and broth microdilution (BMD) methods (ComASP™, Liofilchem; UMIC®, Bruker) were compared with the BMD reference method according to the EUCAST guidelines on 143 Achromobacter strains from 14 species with MIC50/90 of ≤ 0.015/0.5 mg/L. A literature search was conducted regardless of method or species. None of the methods tested fulfilled an acceptable essential agreement (EA). MTS displayed the lowest EA (30.8

Abstract Background Achromobacter spp. are opportunistic pathogens, mostly infecting immunocompromised patients and patients with cystic fibrosis (CF) and considered as difficult-to-treat pathogens due to both intrinsic resistance and the possibility of acquired antimicrobial resistance. Species identification remains challenging leading to imprecise descriptions of resistance in each taxon. Cefiderocol is a broad-spectrum siderophore cephalosporin increasingly used in the management of Achromobacter infections for which susceptibility data remain scarce. We aimed to describe the susceptibility to cefiderocol of a collection of Achromobacter strains encompassing different species and isolation sources from CF or non-CF (NCF) patients. Methods We studied 230 Achromobacter strains (67 from CF, 163 from NCF patients) identified by nrdA gene-based analysis, with available susceptibility data for piperacillin–tazobactam, meropenem and trimethoprim–sulfamethoxazole. Minimal inhibitory concentrations (MICs) of cefiderocol were determined using the broth microdilution reference method according to EUCAST guidelines. Results Strains belonged to 15 species. A. xylosoxidans represented the main species (71.3%). MICs ranged from ≤ 0.015 to 16 mg/L with MIC50/90 of ≤ 0.015/0.5 mg/L overall and 0.125/2 mg/L against 27 (11.7%) meropenem-non-susceptible strains. Cefiderocol MICs were not related to CF/NCF origin or species although A. xylosoxidans MICs were statistically lower than those of other species considered as a whole. Considering the EUCAST non-species related breakpoint (2 mg/L), 228 strains (99.1%) were susceptible to cefiderocol. The two cefiderocol-resistant strains (A. xylosoxidans from CF patients) represented 3.7% of meropenem-non-susceptible strains and 12.5% of MDR strains. Conclusions Cefiderocol exhibited excellent in vitro activity against a large collection of accurately identified Achromobacter strains, irrespective of species and origin.

Elexacaftor-tezacaftor-ivacaftor (ETI) was approved in 2019 by the United States Food and Drug Administration (FDA) and in 2020 by the European Medicines Agency (EMA) for people with cystic fibrosis (pwCF). It is a combination of small molecules that bind to the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein, thus allowing the rescue of CFTR structure and function [1]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Pierre-Régis Burgel reports support for the present manuscript from Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, Filière Maladie Rare Muco CFTR. In addition, Pierre-Régis Burgel reports grants from Vertex Pharmaceuticals, GSK; consulting fees from Astra Zeneca, Chiesi, GSK, Insmed, Vertex, Viatris, Zambon; travel support Astra Zeneca, Chiesi; outside the submitted work. Conflict of interest: Isabelle Sermet-Gaudelus reports support for the present manuscript from Vertex Therapeutics, Tavanta. In addition, Isabelle Sermet-Gaudelus reports grants from Vertex Therapeutics, Tavanta; outside the submitted work. Conflict of interest: Isabelle Durieu and Jeanne Languepin report travel support from Mylan, outside the submitted work. Conflict of interest: Anne Guillaumot reports travel support from Asten, Boehringer Ingelheim, GSK, LFB, CSL Behring, Roche, Menarini; outside the submitted work. Conflict of interest: Camille Audousset reports travel support from Zambon, Viatris; advisory board participation from Vertex Pharmaceuticals; outside the submitted work. Conflict of interest: Raphaël Chiron reports travel support from ECFC; advisory board participation with Zambon, Vertex; outside the submitted work. Conflict of interest: Laurence Weiss reports travel support from Viatris; advisory board participation from Vertex; outside the submitted work. Conflict of interest: Isabelle Fajac reports grants from AbbVie, Bayer, Boehringer Ingelheim, Insmed, GSK, Vertex Pharmaceuticals, Zambon; consulting fees from AbbVie, Boehringer Ingelheim, Kither Biotech, Vertex Pharmaceuticals; leadership role with European Cystic Fibrosis Society; outside the submitted work. Conflict of interest: Clémence Martin reports lecture honoraria from Chiesi, AstraZeneca, Boehringer, GSL; travel support from Chiesi, Boehringer; outside the submitted work. Conflict of interest: All other authors have nothing to disclose.

Background The European Medicines Agency has approved the cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) for people with cystic fibrosis (CF) carrying at least one F508del variant. The United States Food and Drug Administration (FDA) also approved ETI for people with CF carrying one of 177 rare variants. Methods An observational study was conducted to evaluate the effectiveness of ETI in people with CF with advanced lung disease who were not eligible for ETI in Europe. All patients with no F508del variant and advanced lung disease (defined as having a percent predicted forced expiratory volume (ppFEV1) <40% and/or being under evaluation for lung transplantation) and enrolled in the French compassionate programme initiated ETI at recommended doses. Effectiveness was evaluated by a centralised adjudication committee at 4-6 weeks in terms of clinical manifestations, sweat chloride concentration and ppFEV1. Results Among the first 84 people with CF included in the programme, ETI was effective in 45 (54%), and 39 (46%) were considered to be nonresponders. Among the responders, 22 (49%) out of 45 carried a CFTR variant that is not currently approved by the FDA for ETI eligibility. Important clinical benefits, including suspending the indication for lung transplantation, a significant decrease in sweat chloride concentration by a median (interquartile range (IQR)) -30 (-14--43) mmol center dot L-1 (n=42; p<0.0001) and an improvement in ppFEV1 by +10.0 (6.0-20.5) percentage points (n=44; p<0.0001), were observed in those for whom treatment was effective. Conclusion Clinical benefits were observed in a large subset of people with CF with advanced lung disease and CFTR variants not currently approved for ETI.

In cystic fibrosis (CF), Pseudomonas aeruginosa (Pa) is a major pathogen that can persistently colonize patients. Genetic studies showed a high diversity of Pa, the success of widespread or 'international' clones and described epidemic clones in CF and Epidemic High-Risk (ERH) clones. Here, we characterized Pa genetic diversity over time after first colonization in CF patients, with the aim of accurately describing the dynamics of colonization in a context of scarce longitudinal studies including the first isolated Pa strain. Results represent the first genotyping data available for CF Pa in France. Forty-four CF patients with a first Pa colonization were included; 265 strains collected over 7 years in these patients were genotyped by multiplex rep-PCR, multilocus sequence typing, pulsed-field gel electrophoresis and/or whole genome sequencing. Forty-one sequence types were identified: 4 were unknown, 22 never previously reported for CF patients, and 6 corresponded to widespread clones colo-nizing 16 patients (36%). Unrelated strains were identified in 41 patients (93%). Twenty-six patients (59%) presented a recurrence during the study period. No specific clones were associated with transient, recurrent or persistent colonization. Our longitudinal study revealed that 9 of the 26 patients with recurrence (35%) harbored strains of different genotypes. Great genetic diversity was observed among initial Pa isolates excluding any cross -transmission. Persistent colonization may appear more complex than expected, imitating persistence, with successive colonization events by unrelated Pa.

Staphylococcus aureus is a major human pathogen whose characteristics support its success in various clinical settings including Cystic Fibrosis (CF). In CF, S. aureus is indeed the most commonly identified opportunistic pathogen in children and the overall population. S. aureus colonization/infection, either by methicillin-susceptible or methicillin-resistant strains, will become chronic in about one third of CF patients. The persistence of S. aureus in CF patients' lungs, despite various eradication strategies, is favored by several traits in both host and pathogen. Among the latter, living in biofilm is a highly protective way to survive despite deleterious environmental conditions, and is a common characteristic shared by the main pathogens identified in CF. This is why CF has earned the status of a biofilm-associated disease for several years now. Biofilm formation by S. aureus, and the molecular mechanisms governing and regulating it, have been extensively studied but have received less attention in the specific context of CF lungs. Here, we review the current knowledge on S. aureus biofilm in this very context, i.e., the importance, study methods, molecular data published on mono- and multi-species biofilm and anti-biofilm strategies. This focus on studies including clinical isolates from CF patients shows that they are still under-represented in the literature compared with studies based on reference strains, and underlines the need for such studies. Indeed, CF clinical strains display specific characteristics that may not be extrapolated from results obtained on laboratory strains.

Rationale: Limited information is available on the clinical status of people with Cystic Fibrosis (pwCF) carrying 2 nonsense mutations (PTC/PTC). The main objective of this study was to compare disease severity between pwCF PTC/PTC, compound heterozygous for F508del and PTC (F508del/PTC) and homozygous for F508del (F508del + / + ). Methods: Based on the European CF Society Patient Registry clinical data of pwCF living in high and middle income European and neighboring countries, PTC/PTC ( n = 657) were compared with F508del + /+ ( n = 21,317) and F508del/PTC(n = 4254).CFTR mRNA and protein activity levels were assessed in primary human nasal epithelial (HNE) cells sampled from 22 PTC/PTC pwCF. Main results: As compared to F508del + /+ pwCF; both PTC/PTC and F508del/PTC pwCF exhibited a significantly faster rate of decline in Forced Expiratory Volume in 1 s (FEV1) from 7 years (-1.33 for F508del + / + ,-1.59 for F508del/PTC;-1.65 for PTC/PTC, p < 0.001) until respectively 30 years (-1.05 for F508del + / + ,-1.23 for PTC/PTC, p = 0.048) and 27 years (-1.12 for F508del + / + ,-1.26 for F508del/PTC, p = 0.034). This resulted in lower FEV1 values in adulthood. Mortality of pediatric pwCF with one or two PTC alleles was significantly higher than their F508del homozygous pairs. Infection with Pseudomonas aeruginosa was more frequent in PTC/PTC versus F508del + /+ and F508del/PTC pwCF. CFTR activity in PTC/PTC pwCF's HNE cells ranged between 0% to 3% of the wild-type level. Conclusions: Nonsense mutations decrease the survival and accelerate the course of respiratory disease in children and adolescents with Cystic Fibrosis.(c) 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Background: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays antiinflammatory properties and analgesic effects. Methods: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 >= 40%. ROSCO-CF was a multicenter, double-blind, placebo controlled, dose-ranging study (20 0, 40 0, 80 0 mg roscovitine, orally administered daily for 4 days/week/4 weeks). Results: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 20 0/40 0/80 0 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group. Conclusion: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol. (C) 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.