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The most common CFTR mutant in cystic fibrosis (CF), ΔF508 CFTR, is eliminated by ubiquitination even in the presence of CF drugs, reducing their therapeutic efficacy. RFFL is one of the ubiquitin ligases that remove ΔF508 CFTR from the cell surface despite treatment with the triple combination of CFTR modulators (TEZ/ELX/IVA) used clinically. Although RFFL knockdown has been shown to enhance the efficacy of TEZ/ELX/IVA in cell culture models, its impact in mouse models has not been evaluated. Here, we demonstrate that RFFL ablation significantly improves the effect of TEZ/ELX/IVA, resulting in enhanced function of ΔF508 CFTR in mouse organoids. Since RFFL knockout mice showed no significant abnormalities, our findings support RFFL inhibition as a promising strategy to improve CFtreatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Environmental exposures and community characteristics have been linked to accelerated lung function decline in people with cystic fibrosis (CF), but geomarkers, the measurements of these exposures, have not been comprehensively evaluated in a single study. To determine which geomarkers have the greatest predictive potential for lung function decline and pulmonary exacerbation (PEx), a retrospective longitudinal cohort study was performed using novel Bayesian joint covariate selection methods, which were compared with respect to PEx predictive accuracy. Non-stationary Gaussian linear mixed effects models were fitted to data from 151 CF patients aged 6-20 receiving care at a CF Center in the midwestern US (2007-2017). The outcome was forced expiratory volume in 1 s of percent predicted (FEV1pp). Target functions were used to predict PEx from established criteria. Covariates included 11 routinely collected clinical/demographic characteristics and 45 geomarkers comprising 8 categories. Unique covariate selections via four Bayesian penalized regression models (elastic-net, adaptive lasso, ridge, and lasso) were evaluated at both 95 % and 90 % credible intervals (CIs). Resultant models included one to 6 geomarkers (air temperature, percentage of tertiary roads outside urban areas, percentage of impervious nonroad outside urban areas, fine atmospheric particulate matter, fraction achieving high school graduation, and motor vehicle theft) representing weather, impervious descriptor, air pollution, socioeconomic status, and crime categories. Adaptive lasso had the lowest information criteria. For PEx predictive accuracy, covariate selection from the 95 % CI elastic-net had the highest area under the receiver-operating characteristic curve (mean ± standard deviation; 0.780 ± 0.026) along with the 95 % CI ridge and lasso methods (0.780 ± 0.027). The 95 % CI elastic-net had the highest sensitivity (0.773 ± 0.083) while the 95 % CI adaptive lasso had the highest specificity (0.691 ± 0.087), suggesting the need for different geomarker sets depending on monitoring goals. Surveillance of certain geomarkers embedded in prediction algorithms can be used in real-time warning systems for PEx onset., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: None.

Bronchiectasis is an irreversible bronchial dilatation. It is chronically progressive through a vicious circle of secretion retention, infection, inflammation and structural damage. The underlying causes are diverse and the severity of the disease is variable, which makes both the diagnostics and treatment challenging. Computed tomography (CT) is the gold standard in the diagnosis of bronchiectasis and can be helpful in clarifying the etiology. The type of bronchiectasis, the distribution of the bronchiectasis within the lungs and associated findings are particularly relevant. Imaging is also important in monitoring the progression of bronchiectasis. In the usual report of the findings this is carried out visually and descriptively, while semiquantitative scores and computer-aided quantitative analysis of the respiratory tract enable a more precise assessment and are used in particular for clinical studies., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Gastrointestinal (GI) complications are a significant source of morbidity for people with cystic fibrosis (PwCF). Historically, dietary recommendations in CF have focused on calories, typically emphasizing a high fat diet. The changing landscape of CF highlights the need to update this nutritional strategy. There is little research into how the quality of calories consumed by PwCF influences nutritional outcomes, GI symptoms, or likely contributors: intestinal inflammation and GI microbiology. We assessed the feasibility of a whole foods-based diet (WFD) and avoidance of ultra-processed foods, measuring safety/tolerability, adherence, and GI symptoms, as well as fecal measures of inflammation and microbiota among children with CF (CwCF) with GI symptoms., Methods: Single center, 4-week dietary intervention involving CwCF aged 5-14 years who screened positive on GI symptom questionnaire. Assessments included weight, symptom questionnaires and adverse events (AEs). Stool was analyzed for microbiota (16S rRNA) and calprotectin., Results: 108 children were pre-screened, 9 enrolled and 8 initiated and completed the study. There were no significant changes in weight and no AEs. PEDS-QL GI identified overall improvement in symptoms. Certain symptom domains (constipation, diarrhea, gas/bloating, stomach pain and hurt) demonstrated significant improvement on the WFD. Of two participants with abnormal fecal calprotectin at enrollment, both exhibited decreased values on WFD. There was no significant change in microbiota diversity., Conclusion: A WFD diet was feasible and safe in CwCF. There was improvement in GI symptom scores based on both parent and child assessments. Larger studies are needed to further investigate effects on intestinal inflammation and microbiota., Competing Interests: Conflict of interest The authors of this manuscript have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Aim: Renal excretion of excess HCO 3 depends on renal cystic fibrosis transmembrane conductance regulator (CFTR) and is impaired in people with cystic fibrosis (pwCF). Urine HCO - depends on renal cystic fibrosis transmembrane conductance regulator (CFTR) and is impaired in people with cystic fibrosis (pwCF). Urine HCO 3 - excretion following oral NaHCO 3 -loading may be a simple in vivo biomarker of CFTR function. In this study, we investigated changes in urine acid/base parameters following oral NaHCO 3 -loading to comprehensively assess the physiological response to the test and evaluate HCO 3 - as the primary test result., Methods: Urine acid/base parameters (titratable acid (TA), NH 4 + , net acid excretion (NAE) and pH) were measured in bio-banked urine samples from controls (n = 10) and pwCF (n = 50) who completed the challenged urine HCO 3 - test. The association between urine acid/base excretion parameters and clinical CF disease characteristics and CFTR modulator therapy-induced changes were assessed., Results: Before treatment, challenged urine acid/base excretion associated with important CF disease characteristics. TA excretion and NAE were lower in pwCF with residual function mutations, 7.9 and 16.6 mmol/3 h, respectively, and lower TA excretion and NAE associated with pancreatic sufficiency. A lower excretion of TA, NH 4 + , and NAE associated with a higher percentage of predicted FEV 1 (1.3%, 2.5% and 0.8% per mmol/3 h higher, respectively). Modulator treatment decreased TA excretion and NAE (-2.9 and -5.3 mmol/3 h, respectively)., Conclusion: Following acute NaHCO 3 -loading, increased base excretion is mirrored by decreased acid excretion. Urine HCO 3 - excretion sufficiently represents the additional urine acid/base parameters as test result. The observed changes in acid excretion support CFTR modulator-induced increase of CFTR-dependent type B intercalated cell HCO 3 - secretion and the use of the challenged urine HCO 3 - test as a possible CFTR-biomarker., (© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Objectives: To resolve the epidemiology of airway infections with Burkholderia cepacia complex (Bcc) in patients with cystic fibrosis (pwCFs) over 40 years at a single treatment center., Methods: All Bcc and Burkholderia gladioli airway isolates were collected from pwCFs who presented at the cystic fibrosis outpatient and the lung transplantation clinics from 1983 to 2022., Results: The collection of 1205 strains is dominated by B. multivorans (56%), followed by B. cenocepacia (16%), B. stabilis (10%), and B. orbicola (9%). A total of 27 pwCFs experienced a single self-limiting episode of airway infection with Bcc. A total of 13 pwCFs were harboring Bcc for 1.7-13.6 years and 15 pwCFs were persistently infected with Bcc. A total of 16 Bcc-positive pwCFs received a lung transplant. Fatal post-transplant sepsis happened in one patient with B. multivorans, two with B. cenocepacia, and two with B. orbicola., Conclusions: After the first acquisition of Bcc, transient carriage was 2.7 times more frequent than persistent colonization. Infections with B. cenocepacia or B. orbicola confer a higher risk for post-transplant sepsis than an infection with B. multivorans., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Cystic Fibrosis is a multi-system disease, arising from a mutation of the cystic fibrosis transmembrane conductance regulator gene (CFTR). There is a lack of information regarding oral disease levels among people with cystic fibrosis. As part of an ongoing study assessing oral health in adults with cystic fibrosis at Cork University Dental School & Hospital, a systematic review of available literature was conducted to ascertain the caries experience of people with cystic fibrosis. The objective was to systematically present and evaluate the literature comparing caries experience between people with cystic fibrosis and people without cystic fibrosis., Methods: Five online databases were searched; Embase, Scopus, Web of Science Core Collection, Medline Ebsco and Cochrane Library. Studies that reported caries experience in people with cystic fibrosis were included in this review., Results: The initial search identified 1199 publications from online databases. Twenty-one studies were included for qualitative analysis. Fourteen studies reported a lower caries experience in children with CF compared to children without CF, five studies reported a higher caries experience in adults with CF, and two studies found inconclusive evidence regarding the association between caries experience and CF status. All studies had a risk of bias that may influence results., Conclusion: Despite a lack of complete unanimity between all studies, there is a general trend that children with cystic fibrosis have a lower caries experience than their healthy counterparts, whereas adults with cystic fibrosis have a higher caries experience. The review highlights the need for further studies involving adults with cystic fibrosis as the majority of studies primarily consist of paediatric populations., Clinical Significance: Dental practitioners should be aware that adults with cystic fibrosis have higher caries experience. Tailored approaches to dental care specific to cystic fibrosis individuals should be developed., Competing Interests: Declaration of competing interest I Dr Fiona O'Leary the corresponding author confirm on behalf of all authors that there have been no involvements that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated. There was no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Cystic fibrosis (CF) patients frequently experience gut microbiota dysbiosis. Probiotic supplementation is a potential therapeutic approach to modify gut microbiota and improve CF management through the gut-lung axis. The aim of this study was to investigate the effect of Lactobacillus reuteri supplementation on pulmonary function test, respiratory symptoms and growth in CF patients., Methods: A randomized, placebo-controlled clinical trial was carried out on 40 children with CF aged from 6 to 20 years. Participants were designated to receive either L. reuteri or placebo daily for 4 months. Pulmonary function tests, weight, height and body mass index (BMI) z-scores were measured pre and post treatment., Results: The median baseline BMI of the patients was 16.28 kg m -2 . A significant change in the probiotic group's BMI z-score after the study period was observed (P = 0.034) but not for weight and height z-scores (P > 0.05). After treatment, Pseudomonas aeruginosa grew in sputum cultures of seven in the placebo and one patient in the intervention group (P = 0.03) while at baseline it grew in the sputum of four patients in each group. There was no significant difference in forced expiratory volume in the first second, forced expiratory flow at 25-75% or forced vital capacity change between the two groups after the treatment period (P > 0.05). Additionally, no significant differences were found in pulmonary exacerbations, hospitalization frequencies or COVID-19 infection between the two groups during the study (P > 0.05)., Conclusion: The results suggest that L. reuteri supplementation may impact the growth of severely malnourished CF patients. Furthermore, it may be concluded that this strain might reduce P. aeruginosa in the sputum culture of CF patients. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Background: Respiratory infection is a major cause of disease severity in people with cystic fibrosis (PwCF). This project aimed to establish the CF community's opinion regarding cross infection (CI), nebuliser hygiene, antimicrobial resistance, personal impact of microbiological findings and the role of the microbiology laboratory., Methods: A questionnaire was completed anonymously (n = 280; PwCF (n = 128), parents (n = 123); friends/family/carers/charity personnel (n = 29)) from 13 countries. Readability scores (Flesch Reading Ease (FRE), Flesch Kincaid Grade Level (FKGL)) were determined for CI/IP&C information from six national CF charities and 21 scientific abstracts., Results: Respondents (72.5%) indicated knowledge of laboratory aspects of CF microbiology was important, however implications of microbiological findings on personal health/well-being were of higher importance (p < 0.0001). Cross infection/infection prevention & control (CI/IP&C) was of highest importance (95.6% respondents) with 27.3% indicating they were not given adequate information, particularly in older respondents (50 y+) (p = 0.006) versus young adults (16-29 y) and respondents from the Middle East versus N. America (p = 0.022) and Europe (p = 0.045). Responses highlighted how CI/IP&C health literacy could be enhanced. Respondents (77.3%), particularly females (p < 0.0001), indicated they would increase the frequency of nebuliser disinfection following guidance on infection risks/best practice, therefore an educational video was prepared. CI/IP&C readability scores (mean ± sd) from CF charities (FRE 52.5 ± 10.8; FKGL 9.7 ± 2.3) were more readable (p < 0.0001) than scientific abstracts (FRE 13.3 ± 11.1; FKGL 16.9 ± 2.3), however not meeting the targets (FRE≥60 and FKGL≤8)., Conclusion: There is a requirement for further CI/IP&C evidence-based guidance, policies/guidelines, education awareness, best practice in the home environment and multi-modal communication, enabling the CF community to make informed choices on lifestyle behaviours., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Australasian College for Infection Prevention and Control. Published by Elsevier B.V. All rights reserved.)

Background: Patients with cystic fibrosis (CF) experience increased oxidative stress. Tele-exercise can be a new method to improve exercise in CF., Objective: This study aimed to investigate the effect of telehealth-based exercise training using different modalities (combined exercise training group, CombG, core stabilization exercise group, SG), in comparison with control group (CG), on exercise capacity, oxidative stress, and irisin in children with CF., Methods: Thirty-nine children with CF (mean age=11.41±2.18 years, mean FEV 1 (z-score)=-0.66±1.96) were included in the study. The children were randomly allocated to groups. The CombG and SG performed core stabilization exercises (CS) 3 days per week for 8 weeks. The CombG also performed aerobic exercises 3 days per week in addition to CS. Physical activity (PA) recommendations were provided to the CG. Exercise capacity was evaluated using the Modified Shuttle Test (MST). Oxidative stress was assessed using total antioxidant status (TAS), total oxidant status (TOS), Oxidative Stress Index (OSI), malondialdehyde (MDA), and superoxide dismutase (SOD). The irisin level was also measured., Results: Children's baseline sex, age, BMI, and FEV 1 z-scores were similar (p > 0.05). The MST distance (p = 0.047,np 2 =0.157) and%MST distance (p = 0.045, np 2 =0.159) significantly improved in the CombG compared with the SG and CG. Although TAS and SOD decreased over time (p < 0.05), no significant changes were observed for TAS, TOS, OSI, MDA, SOD, and irisin parameters between the groups after training (p > 0.05)., Conclusions: Combining aerobic exercise training with core stabilization applied using telehealth improved exercise capacity more than core stabilitation training only or PA recommendations in children with CF., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Telehealth and home spirometry feasibility for children has been established, but their impact on cystic fibrosis (CF) disease progression remains unassessed. We aimed to evaluate the effects of telehealth and home spirometry on CF disease progression and care., Methods: Children with CF aged 5-17 years from all Swedish CF centers were provided with home spirometers. A minimum of two in-person visits were replaced with telemedicine visits and participants were instructed to conduct home spirometry before visits. Linear mixed-effects models were used to compare annual CF disease trajectories during the intervention period and prepandemic period (1 January 2019 to 28 February 2020). Participants and caregivers completed study questionnaires., Results: A total of 59 individuals completed the study over a mean (SD) period of 6.8 (1.4) months, made 3.1 (1.0) physical visits and 2.2 (0.6) telehealth visits per patient year during the study period. The mean difference (95% CI) between the intervention and prepandemic period progression rate for FEV 1 %, lung clearance index and BMI were -0.4 (-1.3 to 0.5, p = 0.39), 0.11 (-0.07 to 0.28, p = 0.25) and -0.02 (-0.13 to 0.08, p = 0.70), respectively. There were no major shifts in the incidence of airway pathogens, sputum cultures, or antibiotics use between the periods (p > 0.05). The intervention did not increase stress. Almost all participants and caregivers expressed a desire to continue with home spirometry and telemedicine., Conclusion: Combining telehealth and physical visits with access to home spirometry demonstrated comparable effectiveness as exclusively in-person care with enhanced flexibility and personalization of CF care., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Newborn screening (NBS) for cystic fibrosis (CF) is universal in the United States. Protocols vary but include an immunoreactive trypsinogen (IRT) level and CFTR variant panel. California CF NBS has a 3-step screening: IRT level, variant panel, and CFTR sequencing if only one variant identified on panel., Methods: This was a cohort study of infants with CF born in California (2007-2021) to examine racial and ethnic differences in having a false-negative NBS result for CF and at which step the false-negative occurred. We examined how different CFTR variant panels would improve detection of variants by race and ethnicity: original 39-variant panel, current 75-variant panel, and all 402 disease-causing CFTR variants in the CFTR2 database., Results: Of the 912 infants born in California with CF, 84 had a false-negative result: 38 due to low IRT level and 46 with a high IRT value (but incomplete variant detection). Asian (OR 6.3) and Black infants (OR 2.5) were more likely to have a false-negative screening result than non-Hispanic white infants. The majority of false-negative screening (but CF diagnosis) cases among American Indian/Native Alaskan and non-Hispanic White infants were due to low IRT levels. The majority of Asian and Hispanic infants with false-negative screening had no variants detected. Detection of two CFTR variants was improved with the 75-variant panel in Black, Hispanic, and non-Hispanic White infants and with the 402-variant panel in Black, Hispanic, non-Hispanic White, and other race infants., Conclusions: Larger CFTR panels in NBS improved the detection of CF in all races and ethnicities., (© 2024 Wiley Periodicals LLC.)

Background: The decline in pulmonary function is a predictor of disease progression in patients with cystic fibrosis (CF). This study aimed to determine the decline rate of percent predicted forced expiratory volume in 1 s (ppFEV1) based on the data of the CF Registry of Turkey. The secondary aim was to investigate the risk factors related to the decline in ppFEV1., Methods: A retrospective cohort study of CF patients over 6 years old, with pulmonary function data over at least 2 years of follow-up was extracted from the national CF registry for years 2017-2019. Patients were classified according to disease severity and age groups. Multivariate analysis was used to predict the decline in ppFEV1 and to investigate the associated risk factors., Results: A total of 1722 pulmonary function test results were available from 574 patients over the study period. Mean diagnostic age was older and weight for age, height for age, and body mass index z scores were significantly lower in the group of ppFEV1 < 40, while chronic Pseudomonas aeruginosa (p < .001) and mucoid P. aeruginosa colonization (p < .001) were significantly higher in this group (p < .001). Overall mean annual ppFEV1 decline was -0.97% (95% confidence interval [CI] = -0.02 to -1.92%). The mean change of ppFEV1 was significantly higher in the group with ppFEV1 ≥ 70 compared with the other (ppFEV1 < 40 and ppFEV1: 40-69) two groups (p = .004). Chronic P. aeruginosa colonization (odds ratio [OR] = 1.79 95% CI = 1.26-2.54; p = .01) and initial ppFEV1 ≥ 70 (OR = 2.98 95% CI = 1.06-8.36), p = .038) were associated with significant ppFEV1 decline in the whole cohort., Conclusions: This data analysis recommends close follow-up of patients with normal initial ppFEV1 levels at baseline; advocates for early interventions for P. aeruginosa; and underlines the importance of nutritional interventions to slow down lung disease progression., (© 2024 Wiley Periodicals LLC.)

Background: Elexacaftor-tezacaftor-ivacaftor (ETI) is a highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulating therapy for people with CF and at least one F508del variant. However, there is limited data about the safety and efficacy of this therapy in pediatric populations and in real-world settings. This study aimed at evaluating the effectiveness, tolerability, and safety of ETI in children with CF., Methods: This was a prospective observational study including all children aged 6-11 years who initiated ETI therapy between October 2022 and March 2023 at the Pediatric CF Center of Milan (Italy). Study outcomes included changes in sweat chloride concentration, FEV 1 , LCI 2.5 , body mass index (BMI), tolerance, and safety. Mean changes in study outcomes from baseline through 24 weeks were estimated using mixed-effects regression models., Results: The study included 34 children with CF (median age: 8.3 years). At Week 12, we observed an average decrease in LCI 2.5 of 2.3 units (95% confidence interval [CI]: -3.1; -1.5). At Week 24, sweat chloride concentration decreased by 63 mEq/L (95% CI: -69; -58), FEV 1 increased by 8.8 percentage point (95% CI: 3.7; 13.9) and BMI increased by 0.15 standard deviation scores (95% CI: 0.04; 0.25). Skin rashes appeared in 6 patients which spontaneously resolved within a few days. One month after treatment initiation, one patient experienced an elevation in liver function test results, which subsequently decreased during follow-up visits without necessitating discontinuation of therapy., Conclusions: Our data indicate that ETI therapy is well tolerated by children with CF and is effective in improving signs of lung function abnormalities from early childhood., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Pseudomonas aeruginosa is an opportunistic pathogen that is responsible for infections in people living with chronic respiratory conditions, such as cystic fibrosis (CF) and non-CF bronchiectasis (NCFB). Traditionally, in people with chronic respiratory disorders, P. aeruginosa infection has been managed with a combination of inhaled and intravenous antibiotic therapies. However, due in part to the prolonged use of antibiotics in these people, the emergence of multi-drug resistant P. aeruginosa strains is a growing concern. The development of anti-virulence therapeutics may provide a new means of treating P. aeruginosa lung infections whilst also combatting the AMR crisis, as these agents are presumed to exert reduced pressure for the emergence of drug resistance as compared to antibiotics. However, the pipeline for developing anti-virulence therapeutics is poorly defined, and it is currently unclear as to whether in vivo and in vitro models effectively replicate the complex pulmonary environment sufficiently to enable development and testing of such therapies for future clinical use. Here, we discuss potential targets for P. aeruginosa anti-virulence therapeutics and the effectiveness of the current models used to study them. Focus is given to the difficulty of replicating the virulence gene expression patterns of P. aeruginosa in the CF and NCFB lung under laboratory conditions and to the challenges this poses for anti-virulence therapeutic development.

Objective: People living with cystic fibrosis (PwCF) are at increased risk of mental health conditions. There is little evidence addressing psychotropic medication use in PwCF. This study aimed to estimate the dispensing prevalence of antidepressant, anxiolytic, antipsychotic, psychostimulant, and hypnotic/sedative medication in PwCF in Australia between 2013 and 2022., Method: A 10% random sample of Australian Pharmaceutical Benefits Scheme data was used to identify PwCF and their medications between 2013 and 2022. Annual prevalence of psychotropic medication dispensing was estimated using a 3-year rolling average, stratified by sex, age, and medication class., Results: Psychotropic medications were dispensed to 206/478 (41.3%) PwCF. Antidepressant and anxiolytic dispensing prevalence was highest in adult females, increasing from 201 5 by 50% to their peak in 2021 (antidepressants 36.8%; anxiolytics 12.3%). Psychostimulant prevalence was highest in adolescent males and increased over three-fold during the study period from 3.6% to 13.2%. The prevalence of antipsychotic medication was lower than other classes with adult females having the highest prevalence (3.1% and 5.8% in 201 5 and 2022 respectively). Hypnotic/sedative medications remained consistently low or decreased in all groups except male children, where it increased from 0.6% to 2.8% from 201 5 to 2022., Conclusion: Psychotropic medication use is higher among Australian PwCF compared to the general population, with varying prevalence across age and sex groups. This is of interest due to complexities with CF comorbidities and potential medication influences and interactions. Future studies should investigate the reasons for psychotropic use disparities within PwCF with the aim to establish targeted guidelines and optimize outcomes., Competing Interests: Declaration of competing interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

In cystic fibrosis, bacteria-bacteriophage interaction in the lower airways is poorly understood. We present the near-complete genome of the uncultured Siphovirus-like bacteriophage, Staphylococcus aureus phage COMBAT-CF&#95;PAR1, isolated from the lower airways. The genome spans 41,510 bp with 33.45% guanine-cytosine content and contains 65 open reading frames.

Background: Currently, patients with cystic fibrosis do not routinely monitor their respiratory function at home., Objective: This study aims to assess the clinical validity of using different connected health devices at home to measure 5 physiological parameters to help prevent exacerbations on a personalized basis from the perspective of patient empowerment., Methods: A multicenter interventional pilot study including 36 patients was conducted. Statistical process control-the cumulative sum control chart (CUSUM)-was used with connected health device measures with the objective of sending patients alerts at a relevant time in order to identify their individual risk of exacerbations. Associated patient education was delivered. Quantitative and qualitative data were collected., Results: One-half (18/36) of the patients completed the protocol through the end of the study. During the 12-month intervention, 6162 measures were collected with connected health devices, 387 alerts were sent, and 33 exacerbations were reported. The precision of alerts to detect exacerbations was weak for all parameters, which may be partly related to the low compliance of patients with the measurements. However, a decrease in the median number of exacerbations from 12 months before the study to after the 12-month intervention was observed for patients., Conclusions: The use of connected health devices associated with statistical process control showed that it was not acceptable for all patients, especially because of the burden related to measurements. However, the results suggest that it may be promising, after adaptations, for early identification and better management of exacerbations., Trial Registration: ClinicalTrials.gov NCT03304028; https://clinicaltrials.gov/study/NCT03304028., (©Enora Le Roux, Moreno Ursino, Ivana Milovanovic, Paul Picq, Jeremie Haignere, Gilles Rault, Dominique Pougheon Bertrand, Corinne Alberti. Originally published in JMIR Formative Research (https://formative.jmir.org), 28.10.2024.)

Insulin secretion is impaired in individuals with cystic fibrosis (CF), contributing to high rates of CF-related diabetes (CFRD) and substantially increasing disease burden. To develop improved therapies for CFRD, better knowledge of pancreatic pathology in CF is needed. Glucagon like peptide-1 (GLP-1) from islet α cells potentiates insulin secretion by binding GLP-1 receptors (GLP-1Rs) on β cells. We determined whether expression of GLP-1 and/or its signaling components are reduced in CFRD, thereby contributing to impaired insulin secretion. Immunohistochemistry of pancreas from humans with CFRD versus no-CF/no-diabetes revealed no difference in GLP-1 immunoreactivity per islet area, whereas GLP-1R immunoreactivity per islet area or per insulin-positive islet area was reduced in CFRD. Using spatial transcriptomics, we observed several differentially expressed α- and/or β-cell genes between CFRD and control pancreas. In CFRD, we found upregulation of α-cell PCSK1 which encodes the enzyme (PC1/3) that generates GLP-1, and downregulation of α-cell PCSK1N which inhibits PC1/3. Gene set enrichment analysis also revealed α and β cell-specific pathway dysregulation in CFRD. Together, our data suggest intra-islet GLP-1 is not limiting in CFRD, but its action may be restricted due to reduced GLP-1R protein levels. Thus, restoring β-cell GLP-1R protein expression may improve β-cell function in CFRD., (© 2024. The Author(s).)

Cystic fibrosis (CF) is a genetic disorder that primarily affects the respiratory, digestive, and reproductive systems. In the United States, approximately 32,000 individuals, spanning both children and adults, suffer from CF, and roughly 1,000 new cases are diagnosed annually. The current gold standard for CF diagnosis is the sweat test, yet this method is plagued by issues such as being time-consuming, expensive, challenging to replicate, and lacking treatment monitoring capabilities. In contrast, the emerging field of wearable sweat biosensors has gained significant attention due to their potential for noninvasive health monitoring. Despite this, there remains a conspicuous absence of a wearable sweat biosensor tailored specifically for CF diagnosis and monitoring. Here, this study introduces a flexible wearable sweat biosensor, named CFTrack, designed to address the unique challenges associated with CF. This proposed CFTrack biosensor not only facilitates CF diagnosis but also enables the monitoring of medication treatment effectiveness and tracks therapy activities. In addition, it operates in a self-powered and customized manner, ensuring seamless integration into the daily lives of individuals with CF. Given that sweat tests and fitness routines are the predominant methods for diagnosing and treating cystic fibrosis patients, respectively, the proposed CFTrack biosensor leverages ion concentration in sweat for diagnostic purposes. Additionally, it incorporates a motion-tracking function to monitor physical activity, providing a comprehensive approach to CF management. To evaluate the feasibility of the proposed CFTrack biosensor, a comprehensive evaluation has been performed including numerical simulations, theoretical analyses, and experimental tests. The results demonstrate the efficacy of the proposed CFTrack biosensor in diagnosing and monitoring CF conditions while also showcasing its ability to effectively track the progress of patients undergoing physical therapy. The proposed CFTrack biosensor resolves key issues associated with existing sweat sensors including high energy consumption, intricate fabrication procedures, and the absence of continuous monitoring capabilities. By addressing these challenges, the proposed sweat biosensor aims to revolutionize CF diagnosis and monitoring, offering a more efficient and user-friendly alternative to current methods.

Background: The cystic fibrosis (CF) Responsibility. Independence. Self-care. Education. (R.I.S.E.) program was developed to provide assessment and education, supporting transition readiness for people with cystic fibrosis (pwCF). Lack of integration within electronic health records (EHR) was a barrier to implementation of CF R.I.S.E. University of Michigan was able to integrate CF R.I.S.E. into EHR., Aim: To improve implementation and EHR documentation of CF R.I.S.E. module completion by pwCF across two (CF) programs from baseline (10.5%) to 75% per month in 6 months (January through June 2023)., Methods: Two CF programs utilized quality improvement (QI) methods and tools and ad hoc support by a CF Learning Network (QI) specialist. Eligibility included pwCF ≥16 years old seen in CF clinics who accepted CF R.I.S.E., Participation: Beginning January 2, 2023, programs met in biweekly, virtual meetings to discuss implementation. Deidentified data were collected monthly tracking modules completed by pwCF and number of team members engaging with CF R.I.S.E. and documenting in EHR. Data timelines were baseline (November-December 2022), project period (January-June 2023), and post-project (July-December 2023)., Results: Completion rates increased from baseline (10.5%) to 48% (range 33% to 81%) through December 2023. During the project, an average 7.7 team members completed an average 19.2 modules per month. Post-project, an average 8 team members completed an average 16.5 modules per month., Conclusions: This collaboration demonstrated how utilization of EHR allowed for successful CF R.I.S.E. improvement at both programs. Shared software utilization and QI initiatives may be a way to facilitate timely dissemination of best practices through learning health systems., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Thirty-nine clinical isolates of Pseudomonas aeruginosa collected from 11 cystic fibrosis (CF) patients at two CF attention centers over 10 years were subjected to whole genome sequencing (WGS). Phenotypic tests (i.e., elastase, motility, biofilm, growth rate, and antibiotic susceptibility) were performed to correlate results. A single strain of P. aeruginosa was found to persist over time in longitudinal isolates. No transmission between patients or centers was observed. A tendency to lack genes related to pyoverdine, flagellum, pili, and O-antigen was observed, whereas those related to biofilm, phenazine, and pyochelin were conserved among isolates. In a patient with a 10-year follow-up, a single strain of P. aeruginosa persisted and showed a gradual decrease in elastase activity and growth rate, demonstrating an adaptive phenotype. IMPORTANCE This study investigates the genomic and phenotypic characteristics of Pseudomonas aeruginosa isolates from Mexican cystic fibrosis (CF) patients, an underrepresented group in CF research. To our knowledge, it is the first to use whole genome sequencing (WGS) to study longitudinally collected P. aeruginosa isolates from this population, evaluating both genomic features and clonal relationships. Remarkably, the study includes samples from one patient over 10 years, offering an extended observation time compared to existing literature. Unlike similar studies, which often lack phenotypic testing, this research incorporates various virulence-related phenotypic assays, enhancing our understanding of gene-to-phenotype correlations. Two potential mechanisms for the loss of elastolytic activity were identified. Furthermore, we conduct an in-depth mobilome analysis, an area that remains largely unexplored in CF contexts. Whole genome sequencing data are publicly available through the NCBI SRA database, facilitating further re-analysis for studies on P. aeruginosa in CF, as well as epidemiological and population structure research.

The combination of elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta) reverses the primary defect in Cystic Fibrosis (CF) by improving CFTR mediated Cl - and HCO 3 - secretion by airway epithelial cells (AEC), leading to improved lung function and less frequent exacerbations and hospitalizations. However, studies have shown that CFTR modulators like ivacaftor, a component of ETI, has numerous effects on CF cells beyond improved CFTR channel function. Because little is known about the effect of ETI on CF AEC gene expression we exposed primary human AEC to ETI for 48 hours and interrogated the transcriptome by RNA-seq and qPCR. ETI increased CFTR Cl - secretion, and defensin gene expression ( DEFB1 ) an observation consistent with reports of decreased bacterial burden in the lungs of people with CF (pwCF). ETI decreased MMP10 and MMP12 gene expression, suggesting that ETI may reduce proteolytic induced lung destruction in CF. ETI also reduced the expression of the stress response gene heme oxygenase ( HMOX1 ). qPCR analysis confirmed DEFB1 , HMOX1 , MMP10 and MMP12 gene expression results observed by RNA-seq. Gene pathway analysis revealed that ETI decreased inflammatory signaling, cellular proliferation and MHC Class II antigen presentation. Collectively, these findings suggest that the clinical observation that ETI reduces lung infections in pwCF is related in part to drug induced increases in DEFB1 , and that ETI may reduce lung damage by reducing MMP10 and MMP12 gene expression. Moreover, pathway analysis also identified several other genes responsible for the ETI induced reduction in inflammation observed in pwCF.

Background: Cystic fibrosis (CF) in children requires complex and time-consuming daily care, presenting significant challenges for families and caregivers. Family caregivers caring for children with CF report diverse and complex needs., Objective: This review aimed to identify the supportive care needs of family caregivers of children with CF., Review Methods: This scoping review was conducted to identify the supportive care needs of family caregivers for children with CF using the methodology proposed by Arksey and O'Malley. The Preferred Reporting Items for Systematic review and Meta-Analysis extension for Scoping Reviews checklist was used as a guide. The inclusion criteria included full-text quantitative and qualitative English articles from January 2000 to Apr 2024., Data Sources: Structured searches were conducted using Magiran, MEDLINE (PubMed), Scopus, ScienceDirect, SID (Science Information Database), Web of Science and Google Scholar search engines., Findings: A search across six databases, including Magiran (96), PubMed (680), Scopus (828), ScienceDirect (972), SID (Science Information Database) (47) and Web of Science (409), identified 3032 records. An additional 1185 related articles were found through a manual search of the reference lists and the Google Scholar search engine bringing the total to 4217. Out of 4217 initial articles, 21 eligible articles were reviewed. The findings from this study indicated that family caregivers of children with CF face multidimensional needs requiring comprehensive attention and support including educational/informational, psychological/emotional, spiritual, social, family-related, health and child development and growth needs., Conclusion: Addressing the needs of family caregivers of children with CF requires a multidimensional approach including multidisciplinary team support across various domains., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Mucociliary clearance (MCC) impairment can be due to mucus abnormalities or to a ciliary dysfunction, which can be innate, or secondary to infection and/or inflammation. In cystic fibrosis (CF), it is well documented that MCC is impaired due to mucus abnormalities, but little is known concerning ciliary beating. This study aimed to confirm that ciliary dyskinesia is present in CF, and if this might be innate or secondary to the chronic infection and/or inflammation., Methods: Ciliated epithelial samples were obtained by nasal brushing from 51 CF patients, and from 30 healthy subjects. Ciliary beating was evaluated using digital high-speed videomicroscopy at 37 °C, allowing to evaluate ciliary beat frequency (CBF) and the percentage of abnormal beat pattern (CBP); this was repeated after air-liquid interface (ALI) cell culture., Results: Ciliary dyskinesia was higher in CF patients than in healthy subjects, with a lower CBF and a higher percentage of abnormal CBP. Ciliary dyskinesia, already present in childhood, normalized after ALI cell culture. A chronic airway colonization did not worsen ciliary dyskinesia., Conclusions: We showed that, in CF, a ciliary dyskinesia, present from childhood, might contribute to the impaired MCC. Our results also found that the abnormal ciliary beating was not associated with a chronic infection, and resolved after ALI cell culture, suggesting that ciliary dyskinesia in CF is not innate, and might be secondary to chronic inflammation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anne-Lise Poirrier reports a relationship with GSK that includes: consulting or advisory and speaking and lecture fees. Anne-Lise Poirrier reports a relationship with Sanofi that includes: consulting or advisory and speaking and lecture fees. Renaud Louis reports a relationship with GSK that includes: consulting or advisory, funding grants, and speaking and lecture fees. Renaud Louis reports a relationship with AstraZeneca that includes: consulting or advisory, funding grants, and speaking and lecture fees. Renaud Louis reports a relationship with Chiesi that includes: funding grants and speaking and lecture fees. Florence Schleich reports a relationship with GSK that includes: consulting or advisory, funding grants. Florence Schleich reports a relationship with AstraZeneca that includes: consulting or advisory, funding grants. Florence Schleich reports a relationship with ALK that includes: consulting or advisory. Florence Schleich reports a relationship with Novartis that includes: consulting or advisory. Celine Kempeneers reports a relationship with Sanofi that includes: consulting or advisory., (Copyright © 2024. Published by Elsevier B.V.)

Background: Cystic fibrosis (CF) is a multisystem disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We describe the distribution of CFTR mutation profiles in sub-tropical Queensland, Australia, and characterise the phenotypes associated with 'rare' CFTR mutation combinations. Methods: We conducted a retrospective observational study to analyse the CFTR mutation profiles of 322 people with CF (pwCF) under the care of a large adult CF centre in Queensland, Australia. Molecular pathology results were available for all identifiable CFTR mutations. The CFTR2 database was utilised to characterise the less common CFTR mutations to define mutation classes and explore associated phenotypic sequelae. Results: In total, eighty-seven different genotypes were identified within our CF cohort, with the most abundant mutation being the F508del mutation, 298/322 (92.5%). Thirty-six pwCF with CFTR mutations are considered to have 'rare' CFTR mutations, and eleven with previously undefined phenotypes. For these eleven pwCF, late diagnosis in adulthood was confirmed in 5/11 pwCF (45.5%) with CFTR modulator therapy only initiated in 5/11 (45.5%). Conclusions: The profile of more common CFTR genotypes within our cohort of adult pwCF living in Queensland, Australia, generally reflects the global predominance of F508del, G542X, G551D, N1303K, and R117H. The phenotypic heterogeneity of disease seen within the eleven pwCF in our cohort with previously undefined CFTR genotypes highlights that rare mutations can also be associated with severe disease and continue to be at risk of delayed diagnosis. Access to CFTR modulator therapies for this group of pwCF remains limited and should remain a research priority.

Background/objectives: Cystic fibrosis (CF) is one of the most common autosomal-recessive disorders worldwide. The incidence of CF depends on the prevalence of cystic fibrosis transmembrane conductance regulator gene ( CFTR ) mutations in the population, which is determined by genetic diversity and ethnicity., Methods: The search for the causes of mutations in the transmembrane conductance regulator gene (CFTR) was carried out using targeted next-generation sequencing (NGS) on the Illumina platform in patients with cystic fibrosis from the Republic of Bashkortostan (Russia), taking into account the ethnic structure of the sample., Results: A total of 35 distinct causal variants were found in 139 cases from 129 families. Five (F508del, E92K, 3849+10kbC>T, CFTRdele2.3, L138ins) explain 78.7% of identified CF causal alleles. Variants N13103K and 394delTT were found in four families each. Variants 2143delT, S1196X, W1282X, Y84X, G194R, and 1525-1G>A, as well as the two previously described complex alleles-c. [S466X; R1070Q] and str.[G509D;E217G]-were found in two or three families each. Twenty additional variants occurred only once. Variant c.3883&#95;3888dup has not been described previously. Thus, regional and ethnic features were identified in the spectrum of frequencies of pathogenic variants of the CFTR gene in the three major sub-groups of patients-Russians, Tatars, and Bashkirs., Conclusions: Taking into account these results, highlighting the genetic specificity of the region, a more efficient search for CFTR mutations in patients can be performed. In particular it is possible to choose certain test kits for quick and effective genetic screening before use of NGS sequencing.

Background/objectives: Elexacaftor, tezacaftor, and ivacaftor (ETI) have significantly improved lung function in people with cystic fibrosis (pwCF). Despite exceptional improvements in most cases, treatment-related inter-subject variability and drug-drug interactions that complicate modulator therapy have been reported., Methods: This retrospective analysis presents data on the serum concentration of ETI in our pwCF with full or reduced dosage from August 2021 to December 2023 via routine therapeutic drug monitoring (TDM). The data were compared with the maximum drug concentrations (Cmax) from the pharmaceutical company's summary of product characteristics., Results: A total of 786 blood samples from 155 pwCF (41% female, 59% male) were analyzed. The examinations were divided into four groups: full dose within the given tmax (38.5% of all measurements), full dose outside the tmax (29%), reduced dose within the tmax (19.2%), and reduced dose outside the tmax (13.2%). In pwCF receiving the full dose and blood taken within the tmax, 45.3% of serum concentrations of elexacaftor, 51.1% of serum concentrations of ivacaftor, and 8.9% of serum concentrations of tezacaftor were found to be above the Cmax, respectively. For those on reduced doses within the tmax, 24.5% had a serum concentration of elexacaftor, 23.2% had a serum concentration of ivacaftor, and 2.5% had a serum concentration of tezacaftor above the Cmax, respectively., Conclusions: Many pwCF under ETI therapy have Cmax values for elexacaftor and ivacaftor above the recommended range, even on reduced doses or before the tmax was reached. This highlights the value of a TDM program. Further pharmacokinetic studies are necessary.

Gallstones, microlithiasis, gallbladder sludge, and micro-gallbladder are frequently reported in cystic fibrosis patients, and modulators could modify gallbladder disease, probably reducing biliary secretions viscosity., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

The severity of lung disease as well as other disease manifestations have dramatically improved in those patients with cystic fibrosis (CF) that both have mutations responsive to small molecule- based therapies with CF transmembrane regulator (CFTR) modulators and do have access to these drugs. Unfortunately, these medications are not available to many patients with CF across the globe with access largely limited to high income countries. For those eligible to CFTR modulators new questions have arisen regarding the ongoing need for other medications addressing CF lung disease as well current care models with tight monitoring. This article aims to summarize how CF care may change in the future making a plea to expand the availability of highly effective medications to every child with CF that could benefit from treatment., (© 2024 Wiley Periodicals LLC.)

Cystic Fibrosis (CF) is the most common inherited disorder and is characterized by an inflammatory phenotype. Here, we found that in bronchial epithelium reconstituted form lung tissue biopsies from patients with CF, the RNA-binding protein tristetraprolin (TTP), a key regulator of inflammation, is dysregulated in cells that strongly express cytokines and interleukins. TTP activity is regulated by extensive post-translational modifications, particularly phosphorylation. We found that in addition to mRNA downregulation, phosphorylated TTP (which cannot bind to mRNA) accumulated in CF cultures, suggesting that the imbalance in TTP phosphorylation status could contribute to the inflammatory phenotype in CF. We confirmed TTP destabilizing role on IL8 mRNA through its 3'UTR sequence in CF cells. We next demonstrated that TTP phosphorylation is mainly regulated by MK2 through activation of ERK, which also was hyperphosphorylated. TTP is considered a mRNA decay factor with some exception, and we present a new positive role of TTP in CF cultures. We determined that TTP binds to specific ARE motifs on the 3'UTR of mRNA sequences and also, for the first time, to the 3'UTR of Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) where TTP binding stabilizes the mRNA level. This study identified new partners that can be targeted in CF and proposes a new way to control CFTR gene expression.

Introduction: The impact of ETI therapy on pulmonary function and nutritional status has been widely studied; the literature on the possible outcomes on glycemic control and insulin requirement in patients affected by CFRD is controversial., Aim: The main objective of our study was to evaluate HbA1c levels in patients with cystic fibrosis-related diabetes (CFRD) after one year of therapy with elexacaftor/tezacaftor/ivacaftor (ETI). The secondary objective was to study the changes in the total daily insulin dose (TDD), pulmonary function and metabolism in this population., Materials and Methods: A retrospective single-center observational study was conducted at the Regional Cystic Fibrosis Centre and Diabetology Centre of IRCCS Istituto Giannina Gaslini. The observation period was divided into four different time points: initiation (T0), 3 months (T 3mo ), 6 months (T 6mo ) and 12 months (T 12mo ) of ETI therapy. Demographic and clinical data were collected. The results were then stratified by genotype (homozygous or heterozygous F508del)., Results: Twenty-eight patients with CFRD undergoing insulin therapy were included. TDD (IU) significantly decreased at T 3mo and T 6mo , but not at T 12mo , whereas HbA1c decreased significantly at all three times. The number of hospitalizations and pulmonary exacerbations decreased significantly., Conclusion: We demonstrated both improvement in glycemic control (by means of HbA1c) and insulin requirement in insulin-dependent CFRD patients after one year of ETI treatment.

Background: The constellation of hypertension, truncal obesity, impaired fasting glucose, low high-density lipoprotein, and hypertriglyceridemia is known as metabolic syndrome (MetSyn) and is associated with cardiovascular and other diseases. Elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) is associated with weight gain but effects on cardiovascular risk are unknown. This study sought to investigate ETI exposure and risk for development of MetSyn in pwCF., Methods: A prospective cohort study including pwCF ≥ 18 years old exposed to ETI was performed. All data for calculating MetSyn was collected from the electronic medical record at initiation and 1 year ± 3 months after starting ETI. A total of 152 pwCF exposed to ETI and 34 pwCF never exposed to CF transmembrane conductance regulator modulators were included in the analysis. Changes to hypertension classification was also examined over this period., Results: After 1 year of ETI there was an increase in MetSyn from 13 to 30 pwCF, p < 0.0001. No new cases of MetSyn were seen in the group not exposed to ETI. After 1 year of ETI, more people met criteria for class 1 (BP 130-139/90-99 mm Hg) or class 2 hypertension (BP ≥140/≥90 mm Hg) regardless of prior modulator exposure, p < 0.0001., Conclusions: Exposure to ETI for 1 year resulted in an increased number of cases of MetSyn. There was an increased incidence of hypertension associated with ETI exposure. Additional studies are needed to further examine this trend and to determine if these changes will translate to cardiovascular complications over time., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Raksha Jain has financial interests in the form of grants from the Cystic Fibrosis Foundation, NIH, Vertex Pharmaceuticals, and Sound Pharma though these are unrelated to the content of this manuscript. She has consulting fees to Boehringer Ingelheim Pharmaceuticals and Recode though these are unrelated to the content of this manuscript. David Finklea has financial interests in the form of a grant from the Cystic Fibrosis Foundation though it is unrelated to the content of this manuscript., (Copyright © 2024. Published by Elsevier B.V.)

Limiting the availability of transition metals at infection sites serves as a critical defense mechanism employed by the innate immune system to combat microbial infections. Pseudomonas aeruginosa exhibits a remarkable ability to thrive in zinc-deficient environments, facilitated by intricate cellular responses governed by numerous genes regulated by the zinc-responsive transcription factor Zur. Many of these genes have unknown functions, including those within the predicted PA2911-PA2914 and PA4063-PA4066 operons. A structural bioinformatics investigation revealed that PA2911-PA2914 comprises a TonB-dependent outer membrane receptor and inner membrane ABC-permeases responsible for importing metal-chelating molecules, whereas PA4063-PA4066 contains genes encoding a MacB transporter, likely involved in the export of large molecules. Molecular genetics and biochemical experiments, feeding assays, and intracellular metal content measurements support the hypothesis that PA2911-PA2914 and PA4063-PA4066 are engaged in the import and export of the pyochelin-cobalt complex, respectively. Notably, cobalt can reduce zinc demand and promote the growth of P. aeruginosa strains unable to import zinc, highlighting pyochelin-mediated cobalt import as a novel bacterial strategy to counteract zinc deficiency. These results unveil an unexpected role for pyochelin in zinc homeostasis and challenge the traditional view of this metallophore exclusively as an iron transporter., Importance: The mechanisms underlying the remarkable ability of Pseudomonas aeruginosa to resist the zinc sequestration mechanisms implemented by the vertebrate innate immune system to control bacterial infections are still far from being fully understood. This study reveals that the Zur-regulated gene clusters PA2911-2914 and PA4063-PA4066 encode systems for the import and export of cobalt-bound pyochelin, respectively. This proves to be a useful strategy to counteract conditions of severe zinc deficiency since cobalt can replace zinc in many proteins. The discovery that pyochelin may contribute to cellular responses to zinc deficiency leads to a reevaluation of the paradigm that pyochelin is a siderophore involved exclusively in iron acquisition and suggests that this molecule has a broader role in modulating the homeostasis of multiple metals., Competing Interests: The authors declare no conflict of interest.

The measurement of cytokines in induced sputum and nasal lavage (NL) samples has been performed for years in people with cystic fibrosis (CF). The aim of this study was to directly compare sputum and NL samples and interpret results based on disease severity in patients who were categorized as having mild or severe lung disease. The categorization was based primarily on structural abnormalities detected on lung computed tomography and secondarily on lung function. The serum inflammatory markers neutrophil elastase (NE), IL-1β, 2, 6, 8, 10 and 17a were measured in each sputum and NL sample. Thirty-two sample pairs from 29 patients were included in this study (13 mild, 19 severe). In the patients classified as severe, many systemic inflammatory markers as well as sputum cytokines were significantly higher compared to those in the mild patients. However, all the markers measured in the NL were higher in the mild patients ( p =< 0.05 for NE, IL-6 and IL-8). In addition, many cytokines in the NL correlated negatively with those in the sputum samples. Major differences in the cytokine levels were shown although the samples were obtained at the same time in the same patient. Advanced structural lung disease was closely related to systemic and lower airway inflammation, whereas preserved lung function was associated with higher levels in the NL. We hypothesize that the main part of the immune response takes place in the nasal mucosa in patients with minor pulmonary changes. Our results suggest that inflammation must be interpreted individually depending on the compartment in which it is measured. Further research is needed to accurately understand inflammatory markers measured in NL.

Purpose: Staphylococcus aureus is one of the most prevalent pathogens in cystic fibrosis (CF), being of special relevance those methicillin-resistant (MRSA). The livestock-associated (LA)-MRSA lineage CC398 is an emerging problem, specially related to pig-farming (PF) environments. The objective was to characterize the S. aureus isolates recovered from CF-patients in a Spanish hospital located in a region with high-PF activity., Methods: Forty-two isolates were obtained (January-October/2022) and characterised (one/patient). The antimicrobial resistance phenotype/genotype was evaluated by Microscan/PCR. The presence of virulence and Immune Evasion Cluster (IEC) genes as well as the agr type was determined by PCR. MLST and spa-typing were studied by PCR-sequencing., Results: Nine of the 42 isolates were MRSA (21.4 %), and 8 of them multidrug resistant (MDR). Among MRSA, 6 spa-types were detected, assigned to CC1, CC5, CC8, CC30, and CC398. Four MRSA isolates belonged to the lineage CC398-t011-IEC negative (animal adapted-clade, LA-MRSA). The remaining 33 isolates were methicillin-susceptible (MSSA), of 26 spa-types and associated with 11 CCs (predominant: CC5, CC30, and CC398). Seven MSSA isolates were of the lineage CC398 (spa-types t034, t108, t571, t20352); four of them were IEC-positive and erm(T)-positive (t571, and t20352, human-adapted CC398 clade), being IEC-negative the remaining three. The tst and eta/etb genes were identified in 12 and 2 isolates, respectively (none CC398). Small-colony-variants were demonstrated in 9 isolates (two CC398, both MDR)., Conclusion: The lineage CC398 was very frequent among CF-patients (26.2 %), both among MSSA and MRSA. The emergence of LA-MRSA-CC398 in CF-patients requires monitorization, especially in hospitals of high-PF-regions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Central venous catheters including totally implantable venous access devices (TIVADs) have revolutionised the management of pulmonary infections and exacerbations in patients with cystic fibrosis (CF). While being better tolerated by the patient, these have allowed aggressive intravenous antibiotic therapies during recurrent hospitalisations. Given improvement in procedural strategies and operator experience, many patients with CF undergo lung transplants in the course of their disease nowadays. TIVADs can be associated with thrombosis leading to superior vena cava (SVC) obstruction and SVC syndrome which can pose a challenge, especially during the transplant surgery. We describe a case of successful management of SVC syndrome in a patient with CF undergoing a lung transplant, highlighting the strategies used to minimise risks associated with such a procedure., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in incidence globally and challenging to manage. The 2020 multisociety treatment guideline and the 2022 consensus recommendations provide comprehensive evidence-based guides to manage pulmonary diseases caused by the most common NTM. However, with >190 different NTM species that may require different multidrug regimens for treatment, the breadth and complexity of NTM-PD remain daunting for both patients and clinicians. In this narrative review, we aim to distill this broad, complex field into principles applicable to most NTM species and highlight important nuances, specifically elaborating on the presentation, diagnosis, principles of patient-centered care, principles of pathogen-directed therapy, and prospects of NTM-PD., Competing Interests: Potential conflicts of interest . S. H. K. reports consulting with AN2 Therapeutics, Insmed, and Paratek Pharmaceuticals; investigator work with Insmed; and speaker work with AN2 Therapeutics, Insmed, and Paratek Pharmaceuticals. J. D. M. reports consulting with Intuitive Surgical. D. E. G. reports advisory board work with Insmed and consulting with AN2 Therapeutics, Insmed, and Paratek Pharmaceuticals. C. L. D. reports grant support from AN2 Therapeutics, Bugworks, Insmed, Juvabis, and Paratek Pharmaceuticals; advisory board work with AN2 Therapeutics, AstraZeneca, Cepheid, Hyfe, Insmed, MannKind, Matinas Biopharma, NobHill, Spero Therapeutics, and Zambon; consulting with Genentech and Pfizer; and data monitoring committee work with Otsuka Pharmaceutical and the Gates Foundation. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)