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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.)

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.)

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: An adequate nutritional status in patients with cystic fibrosis correlates with higher survival and better pulmonary function. Body mass index (BMI) is an anthropometric indicator with independent association with pulmonary function, and it can hide alterations of nutritional status in cystic fibrosis., Objective: To determine the relationship of lung function with BMI and body composition parameters in children with cystic fibrosis in a Hight Complexity institution between 2015 and 2018., Materials and Methods: It was an observational study with analytical, cross-sectional, and retrospective scope, including 33 patients between 5 and 17 years old. Spearman's test was applied to evaluate correlation of FEV1 (forced expiratory volume in first second) with BMI and five body composition parameters by bioelectrical impedance using InbodyS10 equipment. Statistical significance was considered with p < 0.05., Results: Positive correlation was obtained between FEV1 and appendicular skeletal muscle mass between lung function and percentage of fat-free mass (p = 0.006) and phase angle (p = 0.001). Percent fat mass had a negative correlation with FEV1 (p = 0.007). BMI and fat free mass index did not correlate with lung function (p = 0.085)., Conclusions: Appendicular skeletal muscle mass correlated better than BMI with lung function in children with cystic fibrosis. It is recommended to perform anthropometric follow-up by BMI complemented with body composition study in children with cystic fibrosis. Analyses with larger populations are required to standardize its use., Competing Interests: Declaration of competing interest The authors have no conflicts of interest related to this article., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

The introduction of CFTR modulator drugs like elexacaftor-tezacaftor-ivacaftor (ETI) has transformed the management of cystic fibrosis (CF), significantly improving symptoms, lung function, and quality of life, while reducing reliance on intravenous antibiotics. However, respiratory exacerbations in the CFTR modulators era remain poorly understood from both pathophysiological and clinical perspectives. We present the case of a 20-year-old Caucasian woman with CF (F508del/L1077P) who, after three years of ETI treatment, experienced a severe episode of hemoptysis, despite being almost asymptomatic in the weeks leading up to admission, requiring bronchial artery embolization. Following ETI treatment, auscultatory findings and FEV 1 changes may be less significant, making the detection of respiratory exacerbation more challenging. This highlights the need for heightened vigilance in managing such cases and underscores the challenge of diagnosing and managing exacerbations in the era of modulators. Long term real-world studies are essential to comprehend the evolving course of the disease during ETI treatment., Competing Interests: Declarations 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.)

Background: Non-invasive and sensitive clinical endpoints are needed to monitor onset and progression of early lung disease in children with cystic fibrosis (CF). We compared lung clearance index (LCI), FEV 1 , functional and structural lung magnetic resonance imaging (MRI) outcomes in Swiss children with CF diagnosed following newborn screening., Methods: Lung function (LCI, FEV 1 ) and unsedated functional and structural lung MRI was performed in 79 clinically stable children with CF (3 - 8 years) and 75 age-matched healthy controls. Clinical information was collected throughout childhood., Results: LCI, ventilation and perfusion defects, and structural MRI scores were significantly higher in children with CF compared with controls, but FEV 1 was not different between groups. Lung MRI outcomes correlated significantly with LCI (morphology score (r = 0.56, p < 0.001); ventilation defects (r = 0.43, p = 0.001); perfusion defects (r = 0.64, p < 0.001), but not with FEV 1 . Lung MRI outcomes were more sensitive to detect impairments in children with CF (abnormal ventilation and perfusion outcomes in 47 %, morphology score in 30 %) compared with lung function (abnormal LCI in 21 % and FEV 1 in 4.8 %). Pulmonary exacerbations, respiratory hospitalizations, and increase in patient-reported cough was associated with higher LCI and higher structural and functional MRI outcomes., Conclusions: The LCI and lung MRI outcomes non-invasively detect even mild early lung disease in young children with CF diagnosed following newborn screening. Pulmonary exacerbations and early respiratory symptoms were risk factors for structural and functional impairment in childhood., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. P. Latzin reports the followind COIs: - Grants from Vertex and OM Pharma paid to the institution - Participation on data safety monitoring boards or advisory boards of Polyphor, Santhera DMC, Vertex, OM Pharma, Vifor, Sanofi Aventis - Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Vertex, Vifor, OM Pharma Jakob Usemann reports: Grants from - Swiss lung foundation - Palatin Foundation, Basel, Switzerland Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: - Vertex - Zurich Lung foundation Support for attending meetings and/or travel from Vertex Kathryn Ramsey reports: Support for the present manuscript form: -Swiss National Science Foundation Ambizione Research Grant (168173), paid to the institution Leadership or fiduciary role in other board, society, committee or advocacy group, unpaid Global Lung Initiative MBW Task Force Elisabeth Kieninger reports: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Sanofi-Aventis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: COMBAT-CF showed that children aged 0-3 years treated with azithromycin did clinically better than placebo but there was no effect on CT-scores. We reanalysed CTs using an automatic bronchus-artery (BA) analysis., Method: Inspiratory and expiratory CTs at 12 and 36 months were analysed. BA-analysis measures BA-diameters: bronchial outer wall (B out ), bronchial inner wall (B in ), artery (A), and bronchial wall thickness (B wt ) and computes BA-ratios: B out /A and B in /A for bronchial widening, B wt /A and B wa /B oa (bronchial wall area/bronchial outer area) for bronchial wall thickening. Low attenuation regions (LAR) were analysed using an automatic method. Mixed-effect model was used to compare BA-outcomes at 36 months between treatment groups., Results: 228 CTs (59 placebo; 66 azithromycin) were analysed. The azithromycin group had lower B wa /B oa (p = 0.0034) and higher B in /A (p = 0.001) relative to placebo. B out /A (p = 0.0088) was higher because of a reduction in artery diameters which correlated to a reduction in LAR., Conclusion: Azithromycin-treated infants with CF show a reduction in bronchial wall thickness and possibly a positive effect on lung perfusion., Competing Interests: Declaration of competing interest HAWMT reports grants from the Cystic Fibrosis Foundation, has a part time position as chief medical officer for Thirona, and Erasmus MC is expected to receive future license royalties for PRAGMA-CF. JPC is employee and shareholder at Thirona. SMS reports grants from the Cystic Fibrosis Foundation and National Health and Medical Research Foundation, and Telethon Kids Institute is expected to receive future license royalties for PRAGMA-CF. All other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Insulin remains the only recommended medical treatment for cystic fibrosis related diabetes (CFRD) Whilst there is an established role for orally bioavailable incretin mimetic agents such as the dipeptidyl peptidase-4 inhibitors (DPP4-I) in Type 2 diabetes mellitus, there exists little data on their utility in CFRD., Aim: To examine the use of DPP4-I therapy in patients with CFRD at a single large adult cystic fibrosis center., Method: People with CFRD prescribed a DPP4-I were identified from our specialist CFRD clinic and records were retrospectively examined for indication for therapy, tolerability and effectiveness. Analysis of continuous glucose monitoring data Libre 2 was done for these patients (CGM) pre and at least 3 months post therapy was performed., Results: 23 people with CF (PwCF) with a mean (SD) age of 35.0 ± 2.4 years were included in this analysis . In 21 patients DPP4-I was prescribed as a monotherapy and it was given in combination with insulin in 2 others. Indications for therapy included reactive hypoglycaemia (n = 10) post prandial hyperglycaemia (8), insulin avoidance (3), metformin intolerance (1) and unclear (1). Therapy was well tolerated with no discontinuations due to adverse effects. Significant improvements were noted in Time in Range- Pre vs Post: 78.0 [67.5 - 84.0] vs 89.0 [79.8 - 96.0]%, p = 0.005, Time above Range -Pre vs Post: 19.5 [12.5 - 30.8] vs 6.0 [2.5 - 16.5]%, p = 0.006 and glucose variability Pre versus Post: 28.3 [25.4 - 31.1] vs 26.9 [23.1 - 31.3], p = 0.021, Of the 10 subjects who initiated therapy for hypoglycaemia, 7 reported an improvement in symptoms. No significant difference was found in weight pre and post: 61.5 ± 15.0 kg vs 62.5 ± 15.3 kg, p = 0.326 or Hba1c pre vs post: 41.0 [36.0 - 53.3] mmol/mol versus 40.5 [36.8 - 47.3], p = 0.727., Conclusion: DPP4-I is well tolerated in CFRD and can lead to an improved glycaemic control in these patients with significant improvement in validated CGM metrics., Competing Interests: Declaration of competing interest All authors hereby declare we have no conflict of interest to disclose with regards to this manuscript, (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Factors associated with severe COVID-19 infection have been identified; however, the impact of infection on longer-term outcomes is unclear. The objective of this study was to examine the impact of COVID-19 infection on the trajectory of lung function and nutritional status in people with cystic fibrosis (pwCF)., Methods: This is a retrospective global cohort study of pwCF who had confirmed COVID-19 infection diagnosed between January 1, 2020 and December 31, 2021. Forced expiratory volume in one second percent predicted (ppFEV 1 ) and body mass index (BMI) twelve months prior to and following a diagnosis of COVID-19 were recorded. Change in mean ppFEV 1 and BMI were compared using a t-test. A linear mixed-effects model was used to estimate change over time and to compare the rate of change before and after infection., Results: A total of 6,500 cases of COVID-19 in pwCF from 33 countries were included for analysis. The mean difference in ppFEV 1 pre- and post-infection was 1.4 %, (95 % CI 1.1, 1.7). In those not on modulators, the difference in rate of change pre- and post-infection was 1.34 %, (95 % CI -0.88, 3.56) per year (p = 0.24) and -0.74 % (-1.89, 0.41) per year (p = 0.21) for those on elexacaftor/tezacaftor/ivacaftor. No clinically significant change was noted in BMI or BMI percentile before and after COVID-19 infection., Conclusions: No clinically meaningful impact on lung function and BMI trajectory in the year following infection with COVID-19 was identified. This work highlights the ability of the global CF community to unify and address critical issues facing pwCF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors of this manuscript receive funding in the form of consulting fees or honoraria from Vertex Pharmaceuticals, Chiesi Pharmaceuticals, Enterprise Therapeutics, Gilead Sciences, GSK, Astra-Zeneca, Insmed, MSD, Sanofi, Viartis, Zambon, Limbic, Effrx Pharmaceuticals and Omron. Additionally, there is an author who serves on the Novartis Data and Safety Monitoring Board. There are several authors who are employed by the Cystic Fibrosis Foundation (CFF). The CFF, to advance drug development and search for a cure, have contracts with several companies to help fund the development of potential treatments and/or cures for cystic fibrosis. Pursuant to these contracts, CFF may receive milestone-based payments, equity interests, royalties on the net sales of therapies, and/or other forms of consideration. Resulting revenue received by CFF is used in support of our mission. See “How Drugs Get on the Pipeline” on the CFF website for more information. Additionally, CFF may license CFF Patient Registry data to some companies to monitor drug safety as part of the U.S. Food and Drug Administration's required Phase 4 clinical trials process and to encourage research aimed at improving the care of people with CF, while maintaining our obligation and commitment to protect the privacy of Registry participants. In connection with these licenses, and upon request, CFF may also assist company researchers in interpreting CFF Patient Registry data to aid in designing, analyzing, and interpreting real world studies in CF., (Copyright © 2024. Published by Elsevier B.V.)

A scoping review methodological framework formed the basis of this review. A search of two electronic databases captured relevant literature published from 2013. 1184 articles were screened, 200 of which met inclusion criteria. Included studies were categorised as tests for either respiratory infections OR pulmonary exacerbations. Data were extracted to ascertain test type, sample type, and indication of use for each test type. For infection, culture is the most common testing method, particularly for bacterial infections, whereas PCR is utilised more for the diagnosis of viral infections. Spirometry tests, indicating lung function, facilitate respiratory infection diagnoses. There is no clear definition of what an exacerbation is in persons with CF. A clinical checklist with risk criteria can determine if a patient is experiencing an exacerbation event, however the diagnosis is clinician-led and will vary between individuals. Fuchs criteria are one of the most frequently used tests to assess signs and symptoms of exacerbation in persons with CF. This scoping review highlights the development of home monitoring tests to facilitate earlier and easier diagnoses, and the identification of novel biomarkers for indication of infections/exacerbations as areas of current research and development. Research is particularly prevalent regarding exhaled breath condensate and volatile organic compounds as an alternative sampling/biomarker respectively for infection diagnosis. Whilst there are a wide range of tests available for diagnosing respiratory infections and/or exacerbations, these are typically used clinically in combination to ensure a rapid, accurate diagnosis which will ultimately benefit both the patient and clinician., Competing Interests: Declaration of competing interest Raasti Naseem, Nicola Howe, Cameron Williams, Sara Pretorius and Kile Green received funding for this work as part of a wider study from LifeArc (http://www.lifearc.org) and collaborating organisations through the CFAMR Syndicate (https://cfamr.org.uk/) and declare no conflicts of interest. The NIHR had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2024 [The Author]. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of competing interest All authors declare no conflict of interest.

Background: Minimal clinically important difference (MCID) is important to establish as a meaningful outcome in research when using patient reported outcome measures (PROMs). We determined the MCID using the distribution-based approach for three measurements used as part of the GALAXY study, which is an observational prospective study on gastrointestinal (GI) symptoms in cystic fibrosis (CF)., Methods: Four hundred and two persons with cystic fibrosis (PwCF) participated in the GALAXY study, all with baseline values available for all questionnaires. Mean age was 20.9 years (2.1- 61.1) with 75 females and 94 males under the age of 18 (42.04 %) and 118 females and 115 males aged 18 or older (57.99 %). MCID was measured for Patient Assessment of Constipation Symptoms (PAC-SYM), Patient Assessment of Upper Gastrointestinal Symptoms (PAGI-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL) and their subscales. Two distribution-based approaches, defined as multiplications of the standard deviation (SD) or standard error of the mean (SEM), were used to approximate the MCID., Results: The two distribution-based approaches for determining the MCID estimates produced comparable results in trends in MCIDs across the subscales and total scores. In general, MCID estimates of subscales for all three measurements were higher than their total score MCIDs. The one-half SD- and SEM-based MCID estimates for total scores of each questionnaire are as follows: PAC-SYM: 0.26 and 0.14; PAGI-SYM: 0.32 and 0.15; PAC-QOL: 0.27 and 0.18, respectively., Conclusion: This paper establishes initial MCIDs estimated by the distribution-based approach for the PAC-SYM, PAGI-SYM and PAC-QOL that can now be used to evaluate interventional studies that may impact gastrointestinal symptoms in PwCF., Competing Interests: Declaration of competing interest Dr. Meghana Sathe has received research support from Anagram Therapeutics, Inc and the Cystic Fibrosis Foundation. Dr. Sarah Jane Schwarzenberg consults with Abbvie, Renexxion, and UpToDate. Dr. Baha Moshiree has the following COI to report: She is a consultant for Salix Pharmaceuticals, Ardelyx, and Ironwood. She is on advisory boards for AbbVie, Takeda and Salix and has grant support from Restalsis, ATMO, CF Foundation and Medtronic. She has served as speaker for Ardelyx, Ironwood, Nestle Foundation and QOL Medical. She also has two patents through University of Miami and Wake Forest Medical University pertaining to small bowel capsule (Gut capsule) and blue muffin stool transit test. Dr. A Jay Freeman serves as a consultant for AbbVie and Takeda. He has received research support from the CFF, NIH, Allergan and Travere Therapeutics., (Copyright © 2024. Published by Elsevier B.V.)

Rationale: Cystic Fibrosis (CF) progresses through recurrent infection and inflammation, causing permanent lung function loss and airway remodeling. CT scans reveal abnormally low-density lung parenchyma in CF, but its microstructural nature remains insufficiently explored due to clinical CT limitations. To this end, diffusion-weighted 129 Xe MRI is a non-invasive and validated measure of lung microstructure. In this work, we investigate microstructural changes in people with CF (pwCF) relative to age-matched, healthy subjects using comprehensive imaging and analysis involving pulmonary-function tests (PFTs), and 129 Xe MRI., Methods: 38 healthy subjects (age 6-40; 17.2 ± 9.5 years) and 39 pwCF (age 6-40; 15.6 ± 8.0 years) underwent 129 Xe-diffusion MRI and PFTs. The distribution of diffusion measurements (i.e., apparent diffusion coefficients (ADC) and morphometric parameters) was assessed via linear binning (LB). The resulting volume percentages of bins were compared between controls and pwCF. Mean ADC and morphometric parameters were also correlated with PFTs., Results: Mean whole-lung ADC correlated significantly with age (P < 0.001) for both controls and CF, and with PFTs (P < 0.05) specifically for pwCF. Although there was no significant difference in mean ADC between controls and pwCF (P = 0.334), age-adjusted LB indicated significant voxel-level diffusion (i.e., ADC and morphometric parameters) differences in pwCF compared to controls (P < 0.05)., Conclusions: 129 Xe diffusion MRI revealed microstructural abnormalities in CF lung disease. Smaller microstructural size may reflect compression from overall higher lung density due to interstitial inflammation, fibrosis, or other pathological changes. While elevated microstructural size may indicate emphysema-like remodeling due to chronic inflammation and infection., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matthew M. Willmering, Jason C. Woods, and Laura L. Walkup are consultants to Polarean., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Effective detection of early lung disease in cystic fibrosis (CF) is critical to understanding early pathogenesis and evaluating early intervention strategies. We aimed to compare ability of several proposed sensitive functional tools to detect early CF lung disease as defined by CT structural disease in school aged children., Methods: 50 CF subjects (mean±SD 11.2 ± 3.5y, range 5-18y) with early lung disease (FEV 1 ≥70 % predicted: 95.7 ± 11.8 %) performed spirometry, Multiple breath washout (MBW, including trapped gas assessment), oscillometry, cardiopulmonary exercise testing (CPET) and simultaneous spirometer-directed low-dose CT imaging. CT data were analysed using well-evaluated fully quantitative software for bronchiectasis and air trapping (AT)., Results: CT bronchiectasis and AT occurred in 24 % and 58 % of patients, respectively. Of the functional tools, MBW detected the highest rates of abnormality: S cond 82 %, MBW TG RV 78 %, LCI 74 %, MBW TG IC 68 % and S acin 51 %. CPET VO 2 peak detected slightly higher rates of abnormality (9 %) than spirometry-based FEV 1 (2 %). For oscillometry AX (14 %) performed better than Rrs (2 %) whereas Xrs and R5-19 failed to detect any abnormality. LCI and S cond correlated with bronchiectasis (r = 0.55-0.64, p < 0.001) and AT (r = 0.73-0.74, p < 0.001). MBW-assessed trapped gas was detectable in 92 % of subjects and concordant with CT-assessed AT in 74 %., Conclusions: Significant structural and functional deficits occur in early CF lung disease, as detected by CT and MBW. For MBW, additional utility, beyond that offered by LCI, was suggested for S cond and MBW-assessed gas trapping. Our study reinforces the complementary nature of these tools and the limited utility of conventional oscillometry and CPET in this setting., Competing Interests: Declaration of competing interest The authors have no conflict of interests to declare, (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: Cystic fibrosis-related liver disease (CFLD) is a chronic cholangiopathy that increases morbidity and mortality in patients with CF. Current treatments are unsatisfactory, and incomplete understanding of CFLD pathogenesis hampers therapeutic development. We have previously shown that mouse CF cholangiocytes respond to lipopolysaccharide with excessive inflammation. Thus, we investigated the role of the gut-liver axis in the pathogenesis of CFLD., Methods: Wild-type (WT), whole-body Cftr knockout (CFTR-KO) and gut-corrected (CFTR-KO-GC) mice were studied. Liver changes were assessed by immunohistochemistry and single-cell transcriptomics (single-cell RNA sequencing), inflammatory mediators were analysed by proteome array, faecal microbiota by 16S ribosomal RNA sequencing and gut permeability by FITC-dextran assay., Results: The livers of CFTR-KO mice showed ductular proliferation and periportal inflammation, whereas livers of CFTR-KO-GC mice had no evident pathology. Single-cell RNA sequencing analysis of periportal cells showed increased presence of neutrophils, macrophages and T cells, and activation of pro-inflammatory and pathogen-mediated immune pathways in CFTR-KO livers, consistent with a response to gut-derived stimuli. CFTR-KO mice exhibited gut dysbiosis with enrichment of Enterobacteriaceae and Enterococcus spp., which was associated with increased intestinal permeability and mucosal inflammation, whereas gut dysbiosis and inflammation were absent in CFTR-KO-GC mice. Treatment with nonabsorbable antibiotics ameliorated intestinal permeability and liver inflammation in CFTR-KO mice. Faecal microbiota transfer from CFTR-KO to germ-free WT mice did not result in dysbiosis nor liver pathology, indicating that defective intestinal CFTR is required to maintain dysbiosis., Conclusion: Defective CFTR in the gut sustains a pathogenic microbiota, creates an inflammatory milieu, and alters intestinal permeability. These changes are necessary for the development of cholangiopathy. Restoring CFTR in the intestine or modulating the microbiota could be a promising strategy to prevent or attenuate liver disease., Impact and Implications: Severe cystic fibrosis-related liver disease (CFLD) affects 10% of patients with cystic fibrosis (CF) and contributes to increased morbidity and mortality. Treatment options remain limited due to a lack of understanding of disease pathophysiology. The cystic fibrosis transmembrane conductance regulator (CFTR) mediates Cl - and HCO 3 - secretion in the biliary epithelium and its defective function is thought to cause cholestasis and excessive inflammatory responses in CF. However, our study in Cftr-knockout mice demonstrates that microbial dysbiosis, combined with increased intestinal permeability caused by defective CFTR in the intestinal mucosa, acts as a necessary co-factor for the development of CFLD-like liver pathology in mice. These findings uncover a major role for the gut microbiota in CFLD pathogenesis and call for further investigation and clinical validation to develop targeted therapeutic strategies acting on the gut-liver axis in CF., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Elexacaftor/tezacaftor/ivacaftor (ETI) is a CFTR modulator therapy that has dramatically improved the health outcomes for many people with cystic fibrosis (pwCF). There is increasing interest in the role of CFTR modulators in the prevention and treatment of respiratory infections in pwCF. A male patient with F508del homozygous cystic fibrosis developed cavitary Mycobacteroides abscessus subspecies bolletii & massiliense respiratory infection. Antimycobacterial treatment was not given as, in discussion with the patient's family, it was deemed unlikely that the intensive regimen would be tolerated by the patient on account of his autism spectrum disorder. Following initiation of ETI, there was a rapid clinical and radiological improvement in this patient's cavitary lung disease. This case adds to the evidence base that suggests CFTR modulators, particularly ETI, may restore innate immune function leading to improved outcomes for pulmonary infection in pwCF., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

This systematic review summarizes the impact of cystic fibrosis (CF) on sexual and reproductive health (SRH) in males and females, covering pubertal development, hormonal function, family planning, and fertility. Included articles featured historical CF diagnostic criteria, preclinical or clinical data (retrospective cohorts or open label trials), while excluded articles lacked full text availability, explicit methodology, or comparisons between CF and non-CF patients. Genotype differences in CFTR mutations influenced symptom severity. Males with CF experienced delayed puberty, hypogonadism, infertility from obstructive azoospermia, and semen parameter issues. Female CF patients showed decreased fertility, possibly linked to disrupted ionic balance and ovarian cystic disease. Assistive reproductive technologies addressed fertility issues, but success varied based on disease severity and genotype. CFTR modulators aided pulmonary function and sexual health but require further assessment for fertility benefits., 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 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Pulmonary exacerbations in people with cystic fibrosis are associated with significant morbidity and reduced quality of life. Pulmonary exacerbation treatment guidelines, published by an expert panel assembled by the Cystic Fibrosis Foundation nearly 15 years ago, were primarily consensus-based as there were several gaps in the evidence base. In particular, limited evidence existed regarding optimal pulmonary exacerbation treatment strategies, including duration of antibiotic therapy, treatment location, antibiotic selection, and the role of systemic corticosteroids. Over the last decade, results from observational studies and large multi-center randomized controlled trials have begun to answer important questions related to pulmonary exacerbation treatment. This review focuses on the diagnosis, etiology, and changing epidemiology of pulmonary exacerbations, and also summarizes the most recent and up-to-date studies describing pulmonary exacerbation treatment. Finally, this review provides consideration for future pulmonary exacerbation research priorities, particularly in the current highly effective modulator therapy era., Competing Interests: Declaration of competing interest Jonathan D Cogen is a co-principal investigator for the STOP360-AG and STOP-PEDS studies of pulmonary exacerbation both funded by the Cystic Fibrosis Foundation. Bradley S Quon is principal investigator of two studies to phenotype pulmonary exacerbations funded by the Cystic Fibrosis Foundation and Gilead Sciences., (Copyright © 2024. Published by Elsevier B.V.)

Background: Azithromycin is used for children with cystic fibrosis (CF) for its immunomodulatory and anti-inflammatory action. This study investigated the short-term alterations in QTc interval associated with azithromycin prophylaxis in pediatric patients with CF., Methods: This study included 121 patients with mild CF, of whom 76 received azithromycin (patient group) and 45 did not receive azithromycin (control group). The patient and control groups were categorized according to age as under 12 years of age and over 12 years of age. The first presentation measured all the patient and control groups at basic QTc time intervals. The QTc intervals of all patients were then remeasured systemically at 1, 3, and 6 months. Age categories and QTc intervals that were calculated at each month in the patient and control groups were compared statistically., Results: A statistically significant difference was detected in the patient group between the initial QTc interval time and the electrocardiogram (ECG) findings in the first and third months after prophylaxis treatment (p < 0.001; p = 0.01). However, no statistically significant difference was detected in the sixth month (p > 0.05) in all groups. Almost all of the children's QTc intervals were within normal range and within the safety zone (under 0.44 s). No statistically significant difference was detected in the control group between the initial ECG and the QTc intervals measured at 1, 3, and 6 months., Conclusion: Short-term use of azithromycin prophylaxis in pediatric patients with mild CF slightly increased the QTc interval in the first and third months of follow-up. Nevertheless, all QTc interval changes fell within the safety zone. Notably, 1 month of follow-up treatment should be performed to check for any alteration in the QTc interval. If increased QTc interval duration is not detected in the first month, azithromycin prophylaxis can be safely prescribed., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Copyright © 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Background: Impaired glycemic control and the subsequent development of Cystic fibrosis Related Diabetes (CFRD) are prevalent complications, affecting up to 50 % of adults with cystic fibrosis (CF). CFTR modulator (CFTRm) therapies improve pulmonary functions, reduce exacerbation rates, increase survival in people with CF (pwCF) and appear to have a positive effect on extrapulmonary manifestations, such as nutritional state, improvements in upper respiratory symptoms, and quality of life. Initial findings indicate that CFTRm may have a positive impact on short-term glycemic control; however, long-term effects remain uncertain at present., Methods: In this retrospective study, data were collected and analyzed on 15 pwCF, ages 13-37 years, started on CFTRm therapy. Oral Glucose Tolerance Test (OGTT) results were compared pre- and post-CFTRm therapy., Results: The 120-min OGTT value decreased from 159.7 mg/dL to 130.4 mg/dL post-CFTRm (p = 0.047). The average time elapsed between the two OGTTs was 49.87 months (ranging 9-157 months, median 38 months). Glycemic status improved in six pwCF (two CFRD to normal (NGT)/indeterminate (INDET) glucose tolerance; two impaired glucose tolerance (IGT) to INDET; two INDET to NGT) and worsened in one (IGT to CFRD). Six pwCF and NGT remained stable with no changes in glycemic status throughout the follow-up period., Conclusions: CFTRm therapy may decelerate the glycemic control deterioration in pwCF over an extended period. These findings indicate the need for periodic OGTTs following the initiation of CFTRm therapy to appropriately adjust insulin requirements and prevent hypoglycemia. Further larger cohorts are required to authenticate and substantiate these findings., 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 Ltd. All rights reserved.)

Background: Sexual dysfunction (erectile dysfunction in males, sexual dissatisfaction, sexual interest/arousal disorders, and dyspareunia in females) has not been the subject of indepth research in people with cystic fibrosis (CF). This study aimed to determine the prevalence of sexual dysfunction in adults with CF, factors associated with sexual dysfunction, and the impact of sexual dysfunction on quality of life., Method: We conducted a multicentre study in adults with cystic fibrosis followed in specialist centres in Western France. We assessed erectile dysfunction and its severity using the IIEF5 self-questionnaire (International Index of Erectile Function); the FSFI (Female Sexual Function Index) was used to assess sexual function in females, and we evaluated quality of life in both sexes using the CFQ-R14+ questionnaire., Results: In total, 77 males and 74 females completed the sexual function questionnaire (mean age 32+/- 10 and 25+/- 8,5 years respectively). Among them, 21 % of males and 30 % of females reported sexual dysfunction. CFQ-R14+ score was significantly lower in males with erectile dysfunction than those without (p < 0.001). Faecal incontinence was associated with more frequent sexual dysfunction in females and higher severity of erectile dysfunction in males., Conclusion: The prevalence of sexual disorders is relatively high in males and females with cystic fibrosis. Therefore, it seems important to train specialist teams to address the issue of sexuality without embarrassment, and to encourage them to seek out and treat faecal incontinence, which is associated with greater severity or frequency of these symptoms., Competing Interests: Declaration of competing interest None., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Despite translational evidences suggesting that cystic fibrosis-related abnormal glucose tolerance (CF-related AGT) may begin early in life and is known to be associated with increased morbidity and mortality, current guidelines recommend screening for AGT only from 10 years of age, thus missing the opportunity for early detection and intervention., Methods: A systematic review and meta-analysis (PROSPERO number: CRD42021282516) was conducted on studies that reported data on the prevalence of AGT or its subtypes in CF populations. Pooled proportions, risk, and odds ratios with 95 % confidence intervals (CI) were calculated. One-stage dose-response random-effect meta-analysis was used to assess the effect of age on CF-related diabetes (CFRD)., Results: The quantitative analysis included 457 studies and data from 520,544 patients. Every third child with CF (chwCF) (0.31 [95 % CI 0.25-0.37]) and every second adult with CF (awCF) (0.51 [95 % CI 0.45-0.57]) were affected by AGT. Even in the 5-10 years of age subgroup, the proportion of AGT was 0.42 [95 % CI 0.34-0.51]. The prevalence of prediabetes remained unchanged (impaired glucose tolerance in chwCF:0.14 [95 % CI 0.10-0.18]) vs. awCF:0.19 [95 % CI 0.14-0.25]), whereas the proportion of CFRD increased with age (0-5: 0.005 [95 % CI 0.0001-0.15]; 5-10: 0.05 [95 % CI 0.01-0.27]; 10-18: 0.11 [95 % CI 0.08-0.14]; >18 years of age: 0.27 [95 % CI 0.24-0.30])., Conclusion: CF-related AGT is common under 10 years of age. Our study suggests considering earlier AGT screening, starting from 5 years of age. This highlights the imperative for additional research for guideline adjustments and provides the opportunity for early intervention., 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. Published by Elsevier B.V.)

Background: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown., Methods: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy., Results: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV 1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications., Conclusions: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies., Competing Interests: Declaration of competing interest MCC received honoraria for lectures from Vertex. EP received a grant from Grifols; consulting fees from Moderna, Pfizer, Insmed and Chiesi; honoraria for lectures from Moderna, Pfizer, Vertex, GSK, TEVA, Chiesi and Insmed; payment for expert testimony from Chiesi; and support for attending meetings from Moderna, Pfizer, Vertex, GSK and Insmed. AG received consuting fees (personal) from Vertex, Menarini and Zambon; honoraria for lectures (personal) from Insmed and Vertex; support for attending meetings from Neupharma and Zambon; and payment (personal) for participation on a Data Safety Monitoring (DSM) Board or Advisory Board from Vertex. She is also an Associate Editor for Respiratory Research, Managment board member at IRENE NTM network and ERS chair Adult CF group-assembly 10. DP received consulting fees from Vertex. MMZ received support from the ECFS to attend the European CF meeting 2023. MS received grants from GSK and Trudell pharma; consulting fees (personal) from AstraZeneca, Boehringer Ingelheim, Dexel, Kamada, Synchrony medical, Trumed and Zambon; honoraria for lectures (personal) from AstraZeneca, Boehringer Ingelheim, Kamada and Sanofi; support for attending meetings from Boehringer Ingelheim, AstraZeneca and Kamada; payment (personal) for participating on DSM Board or Advisory Board from Bonus Biotherapeutics, Boehringer Ingelheim and AstraZeneca; and received oPEP devices for clinical trial from Trudell Medical International. She is also an Associate Editor at AJRCCM; Management board member at the Israeli Pulmonology society, Israeli society for Tuberculosis and mycobacterial diseases; and Editorial board member: Chest ERJ taskforce-bronchiectasis guidelines. DGD received grants from Chiesi; consulting fees from Vertex, Proteostasis and Insmed; honoraria for lectures from Chiesi and Gilead. He is also the current Director of the European CF Society Clinical Trials Network. PML received grant (institution) and payment for testimony (personal) from Vertex; consulting fees and honoraria for lectures (personal) from Vertex and Chiesi; support for attending meetings (personal) from Chiesi, Pari and AstraZeneca; and participation on a DSM Board or Advisory Board for Vertex and AstraZeneca. PJ received consulting fees from Centrum hydraulického výzkumu spol. s.r.o.; honoraria for lectures from MSD and Vertex; support for attending meetings, and participation on a DSM Board or Advisory Board from Chiesi: and leadership or fiduciary role in Vertex. TMK received a grant from the Cystic Fibrosis Foundation and the National Institutes of Health; consulting fees from the Cystic Fibrosis Foundation; and honoraria for lectures from the Johns Hopkins Institute. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Antibiotic-resistant bacteria associated with LRTIs are frequently associated with inefficient treatment outcomes. Antibiotic-resistant Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus, infections are strongly associated with pulmonary exacerbations and require frequent hospital admissions, usually following failed management in the community. These bacteria are difficult to treat as they demonstrate multiple adaptational mechanisms including biofilm formation to resist antibiotic threats. Currently, many patients with the genetic disease cystic fibrosis (CF), non-CF bronchiectasis (NCFB) and chronic obstructive pulmonary disease (COPD) experience exacerbations of their lung disease and require high doses of systemically administered antibiotics to achieve meaningful clinical effects, but even with high systemic doses penetration of antibiotic into the site of infection within the lung is suboptimal. Pulmonary drug delivery technology that reliably deliver antibacterials directly into the infected cells of the lungs and penetrate bacterial biofilms to provide therapeutic doses with a greatly reduced risk of systemic adverse effects. Inhaled liposomal-packaged antibiotic with biofilm-dissolving drugs offer the opportunity for targeted, and highly effective antibacterial therapeutics in the lungs. Although the challenges with development of some inhaled antibiotics and their clinicals trials have been studied; however, only few inhaled products are available on market. This review addresses the current treatment challenges of antibiotic-resistant bacteria in the lung with some clinical outcomes and provides future directions with innovative ideas on new inhaled formulations and delivery technology that promise enhanced killing of antibiotic-resistant biofilm-dwelling bacteria., 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.)

Chronic lung infections caused by Pseudomonas aeruginosa play a significant role in the mortality and morbidity of cystic fibrosis (CF) patients. The widespread bacterial resistance to conventional antimicrobials demands identifying new strategies to complement or replace current antibiotic therapies. In this study, we evaluated the antibacterial, antibiofilm, and antivirulence properties of cell-free supernatants (CFS) from several Lactobacillus probiotic strains against P. aeruginosa isolated from the sputum of CF patients. A strong and fast antibacterial activity of CFS from different strains of lactobacilli was observed at acidic pH towards P. aeruginosa, both in planktonic and biofilm mode of growth, in conditions mimicking CF lung. Interestingly, although when adjusted at pH 6.0, CFS lost most of their antibacterial potential, they retained some antivirulence activity towards P. aeruginosa, largely dependent on the dose, exposure time, and the Lactobacillus-P. aeruginosa strain combination. In vivo testing in the invertebrate Galleria mellonella model disclosed the lack of toxicity of acidic CFS and their ability to prevent P. aeruginosa infection. For the first time, the results revealed lactobacilli postbiotic activities in the context of the pulmonary environment, pointing to innovative postbiotics' uses in anti-infective therapy., Competing Interests: Declaration of competing interest The authors of this article declare that they do not have any conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Competing Interests: Conflict of interest The author declares that he has no conflicts of interest with the contents of this article.

Introduction: Inflammation appears early in cystic fibrosis (CF) pathogenesis, with specific elevated inflammatory markers in bronchoalveolar lavage fluid (BALF) correlating with structural lung disease. Our aim was to identify markers of airway inflammation able to predict bronchiectasis progression over two years with high sensitivity and specificity., Methods: Children with CF with two chest computed tomography (CT) scans and bronchoscopies at a two-year interval were included (n= 10 at 1 and 3 years and n= 27 at 3 and 5 years). Chest CTs were scored for increase in bronchiectasis (Δ%Bx), using the PRAGMA-CF score. BALF collected with the first CT scan were analyzed for neutrophil% (n= 36), myeloperoxidase (MPO) (n= 25), neutrophil elastase (NE) (n= 26), and with a protein array for inflammatory and fibrotic markers (n= 26)., Results: MPO, neutrophil%, and inducible T-cell costimulator ligand (ICOSLG), but not clinical characteristics, correlated significantly with Δ%Bx. Evaluation of neutrophil%, NE, MPO, interleukin-8 (IL-8), ICOSLG, and hepatocyte growth factor (HGF), for predicting an increase of > 0.5% of Δ%Bx in two years, showed that IL-8 had the best sensitivity (82%) and specificity (73%). Neutrophil%, ICOSLG and HGF had sensitivities of 85, 82, and 82% and specificities of 59, 67 and 60%, respectively. The odds ratio for risk of >0.5% Δ%Bx was higher for IL-8 (12.4) than for neutrophil%, ICOSLG, and HGF (5.9, 5.3, and 6.7, respectively). Sensitivity and specificity were lower for NE and MPO)., Conclusions: High levels of IL-8, neutrophil%, ICOSGL and HGF in BALF may be good predictors for progression of bronchiectasis in young children with CF., Competing Interests: Declaration of competing interest There is no conflict of interest associated with this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: In cystic fibrosis (CF), coughing is associated with a risk of pelvic floor dysfunction. However, data on the prevalence of symptoms (stress urinary incontinence, bladder overactivity, dysuria, and faecal incontinence) are lacking in males and females with CF. The impact of incontinence on adherence to respiratory care has not been studied., Methods: We conducted a multicentre study in adults with CF followed in the North-West French CF network. Urinary disorders and their severity were assessed using the Urinary Symptom Profile (USP) self-report questionnaire; the impact of urinary disorders on general quality of life was measured using the SF-Qualiveen questionnaire; faecal incontinence was assessed using the Wexner self-report questionnaire; and the CFQ-R14+ questionnaire was used to assess quality of life. A self-administered questionnaire developed for the study assessed the impact of symptoms on respiratory care., Results: Of the 178 people with CF included, 34 % reported stress urinary incontinence, with a large female predominance (63.5 % of females vs. 7.5 % of males), 65 % bladder overactivity (including 16 % urge incontinence) and 50 % faecal incontinence, also with a female predominance. Neither urinary nor faecal incontinence were related to the severity of the respiratory impairment (FEV1). Quality of life was particularly affected in women. Stress urinary Incontinence symptoms affected respiratory care in both sexes., Conclusion: The prevalence of functional urinary and faecal disorders was high in adults with CF and impacted on quality of life and respiratory care. Therefore, multidisciplinary teams must have knowledge of symptoms, the diagnostic tools and management strategies to provide specific treatment., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objectives: Cystic Fibrosis is an autosomal recessive condition. It is a multisystem disease treated with a broad range of pharmacological therapies, diet and nutrition, and physiotherapy. Previous studies suggest that people with cystic fibrosis have a higher prevalence of developmental defects of enamel which may place this population at a greater risk of developing oral diseases such as caries. The aim of this study was to assess a cohort of people with cystic fibrosis (PwCF) for the presence of developmental defects of enamel and compare the results with a control group of people without cystic fibrosis., Methods: A cross sectional study involving 92 participants with cystic fibrosis and 92 controls was conducted in Cork University Dental School & Hospital. All participants completed a detailed questionnaire prior to undergoing a full clinical examination. The Developmental Defect of Enamel Index was used as a measurement index. All data was statistically analysed with the help of statisticians from Cystic Fibrosis Registry of Ireland., Results: 64 % (n = 59) of PwCF had enamel defects compared to just 30 % (n = 28) of people without cystic fibrosis. The median number of teeth affected by enamel defects in the study group was 1.5, compared to 0 in the control group., Conclusion: In this study the cohort of PwCF had more enamel defects than people without CF. Further research is required to investigate the aetiology of these findings., Clinical Significance: Clinicians should be vigilant after teeth have erupted in PwCF as they may have an increased susceptibility to developmental defects of enamel., 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. Published by Elsevier Ltd.)

Background: Gut dysbiosis is implicated in colorectal cancer (CRC) pathogenesis. Cystic fibrosis (CF) is associated with both gut dysbiosis and increased CRC risk. We therefore compared the faecal microbiota from individuals with CF to CRC and screening samples. We also assessed changes in CRC-associated taxa before and after triple CF transmembrane conductance regulator (CFTR) modulator therapy., Methods: Bacterial DNA amplification comprising V4 16S rRNA analysis was conducted on 84 baseline and 53 matched follow-up stool samples from adults with CF. These data were compared to an existing cohort of 430 CRC and 491 control gFOBT samples from the NHS Bowel Cancer Screening Programme. Data were also compared to 26 previously identified CRC-associated taxa from a published meta-analysis., Results: Faecal CF samples had a lower alpha diversity and clustered distinctly from both CRC and control samples, with no clear clinical variables explaining the variation. Compared to controls, CF samples had an increased relative abundance in 6 of the 20 enriched CRC-associated taxa and depletion of 2 of the 6 taxa which have been reported as reduced in CRC. Commencing triple modulator therapy had subtle influence on the relative abundance of CRC-associated microbiota (n = 23 paired CF samples)., Conclusions: CF stool samples were clearly dysbiotic, clustering distinctly from both CRC and control samples. Several bacterial shifts in CF samples resembled those observed in CRC. Studies assessing the impact of dietary or other interventions and the longer-term use of CFTR modulators on reducing this potentially pro-oncogenic milieu are needed., Competing Interests: Declaration of Competing Interest D.G.P speaker/board honoraria from Vertex. H.W: Received previous funding from Gilead, which was not directly related to this research project and from Health Education England for simulated placement delivery funding. L.R.C, H.M.W, D.B, A.F.B, L.W., J.D., C.Y., S.B., M.B., P.Q and declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Aspergillus infection is known to be associated with worse respiratory outcomes in people with CF (pwCF) and is a well-recognised complication of severe SARS-CoV-2 infection. The aim of this observational cross-sectional study was to examine the association of pre-existing Aspergillus infection and/or allergic bronchopulmonary aspergillosis (ABPA) in pwCF and severity of COVID-19., Methods: Data on SARS-CoV-2 infections in pwCF from January 2020 to June 2021 were collected by the European Cystic Fibrosis Society Patient Registry. The primary outcome was COVID-19 severity measured by hospitalisation comparing those with Aspergillus infection and/or ABPA in the 12 months preceding COVID-19 and those without., Results: In total, 1095 pwCF were diagnosed with SARS-CoV-2 and information on pre-existing Aspergillus/ABPA status was available from 807. PwCF and SARS-CoV-2 in the Aspergillus/ABPA group (n = 153), in comparison to the non-Aspergillus/ABPA group (n = 654), were more likely to be hospitalised (adjusted OR 1.79 (1.19 to 2.85); p = 0.005) and their disease course was more likely to be complicated by sepsis (adjusted OR 7.78 (1.78 to 49.43); p = 0.008). The association with hospital admission was no longer significant after excluding patients with ABPA. Secondary analysis comparing pwCF who received antifungal treatment (n = 18), versus those who did not (n = 474) during COVID-19, showed a higher rate of hospitalisation (p < 0.001); intensive care unit admission (p < 0.001), and requirement for invasive ventilation (p < 0.001) in the antifungal treated group., Conclusion: We show that pre-existing Aspergillus/ABPA is associated with increased rates of hospitalisation and sepsis during COVID-19 in pwCF., 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 © 2023. Published by Elsevier B.V.)

Background: High frequency chest wall oscillation (HFCWO) is a form of airway clearance therapy that has been available since the mid-1990s and is routinely used by patients suffering from retained pulmonary secretions. Patients with cystic fibrosis (CF), neuromuscular disease (NMD), and other disorders, including bronchiectasis (BE) and COPD (without BE), are commonly prescribed this therapy. Limited evidence exists describing HFCWO use in the BE population, its impact on long-term management of disease, and the specific patient populations most likely to benefit from this therapy. This study sought to characterize the clinical characteristics of patients with BE who have documented use of HFCWO at baseline and 1-year follow-up., Methods: An analysis from a large national database registry of patients with BE was performed. Demographic and clinical characteristics of all patients receiving HFCWO therapy at baseline are reported. Patients were stratified into two groups based on continued or discontinued use of HFCWO therapy at 1-year follow-up., Results: Over half (54.8 %) of patients who reported using HFCWO therapy had a Modified Bronchiectasis Severity Index (m-BSI) classified as severe, and the majority (81.4 %) experienced an exacerbation in the prior two years. Of patients with 1-year follow-up data, 73 % reported continued use of HFCWO. Compared to patients who discontinued therapy, these patients were more severe at baseline and at follow-up suggesting that patients with more severe disease are more likely to continue HFCWO therapy., Conclusions: Patients who have more severe disease and continue to experience exacerbations and hospitalizations are more likely to continue HFCWO therapy., Clinical Trial Registration: NA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ashwin Basavaraj reports writing assistance was provided by LeeAnn Phipps. AB - Consultant and Advisory Board for Baxter, Insmed, Physio-Assist, Dymedso, Zambon. Medical education consulting for Tactile Medical. Principal investigator on clinical trial sponsored by Baxter with funding to institution. Educational grant funding received from Insmed to institution. RC - No disclosures to report. BB – Employee relationship with Baxter. MM - Grant funding from Insmed and COPD foundation. Consulting fees from Insmed, Boehringer-Ingelheim, and Tactile Medical. Payment/honoraria for presentations/lectures from Insmed. Participation on data safety monitoring/advisory board for AN2, Renovion. TA - Support as medical director of the Bronchiectasis and NTM research registry. Has participated in clinical trials sponsored by Bayer, Aradigm, Zambon., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Cystic fibrosis (CF) is characterized by highly viscous mucus obstructing the lower and upper airways, chronic neutrophil inflammation and infection resulting not only in lung destruction but also in paranasal sinus involvement. The pathogenesis of CF-associated chronic rhinosinusitis (CRS) is still not well understood, and it remains unclear how the microbiome in the upper airways (UAW) influences paranasal sinus inflammation., Methods: In a cross-sectional study in pediatric patients with CF under stable disease conditions, we examined the microbiome in relation to inflammation by comparing nasal swabs (NS) and nasal lavage (NL) as two UAW sampling methods. The microbiota structure of both NS and NL was determined by 16S rRNA gene amplicon sequencing. In addition, pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and proteases (SLPI, TIMP-1, NE/A1-AT complex) as well as neutrophil elastase activity were measured in NL., Results: Simultaneous NS and NL samples were collected from 36 patients with CF (age range: 7 - 19 years). The microbiome of NS samples was shown to be significantly lower in α-diversity and evenness compared to NL samples. NS samples were particularly found to be colonized with Staphylococcus species. NL microbiome was shown to correlate much better with the sinonasal inflammation status than NS microbiome. Especially the detection of Moraxella in NL was associated with increased inflammatory response., Conclusion: Our results show that the NL microbiome reflects sinonasal inflammation better than NS and support NL as a promising tool for simultaneous assessment of the UAW microbiome and inflammation in children with CF., Competing Interests: Declaration of competing interest M.A.M. reports grants from Vertex Pharmaceuticals; fees for advisory board participation or consulting from Abbvie, Antabio, Arrowhead Pharmaceuticals, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Pari, Prieris, Recode, Santhera, Splisense, Vertex Pharmaceuticals; lecture honoraria from Vertex Pharmaceuticals; travel support from Boehringer Ingelheim and Vertex Pharmaceuticals outside the submitted work. The other authors have nothing to declare., (Copyright © 2023. Published by Elsevier B.V.)

Background: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults., Methods: Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I., Results: The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17-25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01)., Conclusions: Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD., Competing Interests: Declaration of Competing Interest DT, JS, RBT, KPH and AJ have no conflicts of interest to disclose. PB has accepted speaking fees and honoraria from Vertex pharmaceuticals and advisory board fees from INSMED. VA has accepted speaking fees and honoraria from Vertex pharmaceuticals and Roche diagnostics., (Copyright © 2023. Published by Elsevier B.V.)

Background: No evidence exists to guide the frequency of obtaining bacterial respiratory cultures during inpatient treatment of pediatric cystic fibrosis (CF) pulmonary exacerbations (PEx). At our institution, admission and weekly respiratory cultures are routinely collected to guide antimicrobial selection. This study evaluates the extent that this practice informs clinical management and the healthcare-related costs associated with routinely repeating cultures., Methods: All children with CF with at least one hospital admission for IV antibiotics from January 2015 to December 2019 were included. Data collected included patient demographics, culture results, and antibiotic history. Respiratory cultures were numbered from the last clinic culture (`Culture 1'), culture on admission (`Culture 2'), and so on (`Cultures 3-6'). Outcomes assessed were microbiological results, frequency and timing of antibiotic change, and total microbiological laboratory costs., Results: Seventy-eight children with 224 admissions and 695 bacterial cultures were analyzed. Repeated microbiology sampling revealed 118 new bacterial species in 82 admissions.  Culture 2 was most likely to identify a new bacterial species (91/115, 79.1 %) and most likely to be followed by a change in antibiotic (33/37; 89.2 %). The total cost of all cultures was $18,264.79. Eliminating Cultures 3-6 from routine practice could represent a 51 % cost-savings ($9,362.89), without significant impact on identification of new clinically relevant isolates., Conclusion: Ongoing bacterial surveillance during a CF PEx beyond admission culture provides minimal information, rarely impacts clinical management, and can increase healthcare costs. An optimized approach would be to routinely obtain admission cultures and to obtain further cultures only if clinically indicated., Competing Interests: Declaration of Competing Interest JHR reports unrestricted research funding and travel support from Vertex Pharmaceuticals and medical advisory board fees from Sanofi. The other authors have no financial disclosures to report., (Copyright © 2023. Published by Elsevier B.V.)

Previous studies indicate that hospital rather than home treatment of pulmonary exacerbations (PEx) in people with cystic fibrosis (CF) can improve outcomes. We evaluated characteristics of adult participants from the Standardized Treatment of Pulmonary Exacerbations (STOP2) trial with two separate comparisons: (1) those who were treated initially in hospital (N = 768) to those treated initially at home (N = 214) and (2) those treated only in hospital (N = 328) to those who were treated only at home or both at home and in hospital (N = 654). Participants who had Medicaid insurance, were treated for shorter duration, and traveled longer to reach treatment centers were more likely to have been treated initially in the hospital. Having Medicaid insurance, being treated for a shorter duration, and being male were associated with being treated only in the hospital. This analysis suggests decisions about the location of treatment are based on pragmatic factors rather than on clinical characteristics., Competing Interests: Declaration of Competing Interest Grants from the Cystic Fibrosis Foundation in part supported the salaries of LSG, RNH, SLH, PAF, CHG, NEW, DBS, and LK. Grants from the NIH in part supported the salaries of SLH, PAF, and CHG. DBS received payments for committee work from the Cystic Fibrosis foundation. DBS's institution also grant support payments from Gilead Sciences and the CHEST Foundation. DBS received personal payment for participation on an advisory board for Vertex Pharmaceuticals., (Copyright © 2023. Published by Elsevier B.V.)

Chronic rhinosinusitis is a common manifestation of CF that is associated with impaired quality of life and can be difficult to treat. CFTR modulator therapy has resulted in significant improvements in lower respiratory and nutritional outcomes for people with CF however their impact on chronic rhinosinusitis has received less attention. We review the literature in relation to chronic rhinosinusitis in CF and examine the impact of CFTR modulator therapy on symptoms, imaging, endoscopic appearances, and olfactory outcomes in the treatment of chronic rhinosinusitis. While an overall improvement in symptoms, imaging and endoscopic appearances is seen in response to treatment, limited impact is documented on olfaction. Outcome measures employed were heterogenous, limiting comparison of findings. There is a need for well powered prospective real-world studies with standardised outcome measures., 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 © 2023. Published by Elsevier B.V.)

Objectives: The impressive improvements of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) function by elexacaftor/tezacaftor/ivacaftor (ETI) result in changes in the detection frequencies of Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA). We assessed determinants of the response to ETI with regards to SA and PA detection frequencies as documented in the German CF registry for people with CF (pwCF) ≥12 years., Methods: We evaluated changes in the detection frequencies of SA and PA for 21 months before and after initiation of ETI and used different statistical tests to identify determinants of detection changes., Results: We included data from 1092 pwCF with results from culture-dependent diagnostics for SA and PA detection from 7944 microbiological samples before and 6.845 microbiological samples after initiation of ETI. Detections of SA decreased from 54.3% to 44.3% and 40.2% and those of PA from 39.9% to 31.9% and 22.6% 3 and 21 months after initiation of therapy, respectively (all P <0.001). Reduction of SA and PA were observed in throat swabs and sputa, associated significantly with age, previous lung function, and were dependent on pre-ETI colonization status., Conclusions: The different patterns of reductions of SA and PA suggest that pathogen-specific biological processes govern the responsiveness of microbiological colonization towards ETI in pwCF., Competing Interests: Declarations of competing interest AMD reports receiving money paid to her institution for the performance of clinical studies and personal remuneration by Vertex Pharmaceuticals Inc. for medical education writing and participation in an advisory board. She received grants from the German Ministry for Health and Education and the German Science Foundation. She is an unpaid member of the executive board, the scientific advisory board and the registry working group of the German patients’ advocacy group Muko e.V. SS reports no conflict of interest. LN reports receiving money paid to his institution by Vertex Pharmaceuticals Inc. for the performance of clinical studies and personal remuneration from Articulate Science for medical writing. He is an unpaid member of the Trial Steering Committee for CF STORM, medical lead of the German CF registry, and the pharmacovigilance study manager of the European Cystic Fibrosis Society Patient Registry (ECFSPR). MB and SH report publication support by Chiesi Inc. (see below) paid to the Mukoviszidose Institute gGmbH (MI). BT reports receiving grant support by the German Ministry for Education and the German Science Foundation and personal remuneration from Vertex Pharmaceutical Inc. for educational events and lectures and the Helmholtz Institut für Infektionsforschung., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Bronchial artery embolisation (BAE) is a treatment used to manage haemoptysis. We performed a 7-year review of BAE procedures for haemoptysis at our CF centre aiming to evaluate the incidence and outcomes of patients with neurovascular complications post-BAE. Our review suggests that whilst BAE is an effective method for controlling life-threatening haemoptysis, patients are at risk of developing neurovascular complications with long term residual symptoms, and therefore careful consideration should be given in offering BAE, especially to otherwise well patients with chronic small volume haemoptysis and managing teams should have a low threshold to image symptomatic patients., 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 © 2023. Published by Elsevier B.V.)

Competing Interests: Declaration of Competing Interest LJM is a consultant for Egetis Therapeutics and Harmony Biosciences. JEG reports no conflicts of interest.

Background: Restless legs syndrome (RLS) is a sensorimotor disorder that is prevalent in chronic inflammatory conditions. RLS prevalence, risk factors, and impact on sleep in CF have not been extensively characterized to date., Methods: An initial cohort was examined, including 75 persons with CF (PwCF) and 75 control subjects, to look at the prevalence and severity of RLS. A second validation cohort of 191 PwCF was then enrolled from two CF centers to examine risk factors for RLS. A diagnosis of RLS was made according to the International RLS Study Group (IRLSSG) criteria. Sleep quality was identified using the Pittsburgh sleep quality index (PSQI). Epworth sleepiness scale (ESS) was used to measure daytime sleepiness. We then analyzed laboratory and clinical risk factors and sleep symptoms for potential risk factors for RLS., Results: In the initial cohort, 36 % of PwCF had RLS, and 9 % of these had significant RLS. In contrast, only 15 % of controls had RLS, and none had significant RLS. In the second larger validation cohort with 191 subjects, a comparable prevalence of RLS was identified. Higher hemoglobin A1c, use of SSRI/SNRI medications, worse PSQI and ESS sleep quality scores, lower lung function, and higher antibiotic usage were significantly associated with a diagnosis of RLS. By multivariate multinominal logistic regression analysis, higher HbA1c and worse PSQI global sleep quality scores were independent predictors of significant RLS., Conclusions: RLS is highly prevalent in CF. Higher HbA1c and poor sleep quality, signified by higher PSQI, were each independent predictors of RLS., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Opportunistic bacterial infection is a hallmark of cystic fibrosis (CF) lung disease and early mortality. Poorly characterized prevalence changes have accompanied two decades of health improvements, with CFTR modulators likely to further affect infection epidemiology., Methods: Bacterial prevalence change trends across birth cohorts were assessed with linear regression using 2001-2019 US CF Foundation Patient Registry data. Informative missingness was assessed, as was age-to-age infection status., Results: Bacterial prevalence constantly changed from 2001 to 2019, with changes differing across birth cohorts. Informative censoring affected prevalence change for some organisms. Age-to-age infection status changes were greater than net changes in bacterial prevalence and varied by age., Conclusions: CF infection epidemiology changed over two decades and will continue to do so. Understanding how modulators affect infection epidemiology will require creative designs for longitudinal prevalence change studies emphasizing prevalence changes independent of effects on lung biology., Competing Interests: Declaration of Competing Interest The authors have no competing interests relative to this content to report. MWK received salary support to his institution from the Cystic Fibrosis Foundation and the National Institutes of Health (UL1TR002548). JJL received salary support from the Cystic Fibrosis Foundation (CAVERL22AB0)., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Burkholderia cepacia complex (BCC) infection in cystic fibrosis (CF) is associated with increased morbidity and mortality. Current UK guidance recommends segregation of people with CF according to infection status. To date there is no universally agreed consensus on the number of negative samples or time interval since last isolation of BCC for eradication to be deemed successful., Methods: All cases of new BCC isolation at Manchester Adult Cystic Fibrosis Centre were followed-up between May 2002-May 2022. The number of subsequent positive and negative sputum samples for BCC were recorded, as well as eradication treatment received. Eradication was deemed successful if there were ≥3 negative sputum samples and no further positive sputum samples for the same species and strain ≥12 months until the end of follow-up., Results: Of 46 new BCC isolation, 25 were successfully eradicated and 21 resulted in chronic infection. 5 (16.7%) cases with exclusively negative sputum samples 6-12 months after initial isolation had subsequent samples that were culture-positive for BCC and 3 (10.7%) cases with exclusively negative sputum samples after 12-24 months had subsequent culture-positive samples. Cases where BCC was eradicated had a greater median number of days of eradication treatment (42, IQR 21-63) compared to those in whom BCC isolation resulted in chronic infection (28, IQR 14-42), p = 0.04., Conclusions: A cautious approach to segregation should be maintained after new isolation of BCC in CF, as some individuals with ≥3 negative samples 12-24 months after initial isolation had subsequent sputum samples culture-positive for BCC., Competing Interests: Declaration of Competing Interest DT, LP, HG, DK and AJ have no conflicts of interest to declare. AH has received personal and speaking fees from Vertex Pharmaceuticals, Boehringer Ingelheim and Roche Genentech., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)