Journal of Cystic Fibrosis最新文献

{"title":"WS11.06Resistance to the combination of β-lactams and β-lactamase inhibitors in Mycobacterium abscessus","authors":"M. Bitar ,&nbsp;M. Arthur ,&nbsp;J.-L. Mainardi","doi":"10.1016/j.jcf.2025.03.557","DOIUrl":"10.1016/j.jcf.2025.03.557","url":null,"abstract":"<div><h3>Objectives</h3><div><em>Mycobacterium abscessus</em> is an opportunistic pathogen responsible for chronic lung infections in cystic fibrosis patients. The treatment of these infections is complex and relies on a combination of different antibiotics, including a carbapenem (imipenem (IMI)). We have previously shown that second-generation β-lactamase inhibitors belonging to the diazabicyclooctanes (DBOs) family, avibactam (AVI) and relebactam, improve β-lactams activity. Recently, we identified a synergistic effect <em>in vitro, in vivo</em>, and intracellularly between two β-lactams, IMI and amoxicillin (AMOX), in the presence of DBOs against <em>M. abscessus</em>. The current objective is to identify the targets of the triple antibiotics combination.</div></div><div><h3>Methods</h3><div>The targets of the triple combination IMI/AMOX/AVI were determined by selecting resistant mutants from the <em>M. abscessus</em> CIP104536 strain on increasing concentrations of IMI and AMOX, in the presence of a fixed concentration of AVI (4 mg/l). Antibiotic susceptibility was assessed using the disk diffusion method, and the genomes of mutants were sequenced by the Illumina® platform.</div></div><div><h3>Results</h3><div>In total, 23 mutants were obtained from nine independent experiments in one to four steps. Two of the 23 mutants grew on the highest tested concentrations of AMOX (4096 mg/l) and IMI (32 mg/l). Analysis of the 23 sequenced genomes revealed no mutations in β-lactam targets. Different mutations affecting efflux pumps, permeability, regulation, and metabolism were identified. The disk diffusion method revealed acquired resistance to antibiotics belonging to different families.</div></div><div><h3>Conclusion</h3><div><em>In vitro</em> resistance to the triple combination is not associated with mutations in β-lactam targets but appears to be due to mutations in efflux pumps or mutations affecting the mycomembrane permeability. The next objective will be to evaluate the risk of the emergence of resistance associated with the administration of the triple combination in a murine model of infection.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S23"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS12.03Changes in faecal pancreatic elastase in children with cystic fibrosis after 6 months of elexacaftor/tezacaftor/ivacaftor: results from the BEGIN study","authors":"A. Dutta ,&nbsp;C.E. Pope ,&nbsp;C. O'Rourke ,&nbsp;R. Buckingham ,&nbsp;R. Russell ,&nbsp;S.L. Heltshe ,&nbsp;D.H. Leung ,&nbsp;J. Sullivan ,&nbsp;K. Larson Ode ,&nbsp;E.T. Zemanick ,&nbsp;L. Hoffman","doi":"10.1016/j.jcf.2025.03.560","DOIUrl":"10.1016/j.jcf.2025.03.560","url":null,"abstract":"<div><h3>Objectives</h3><div>Many children with CF (CwCF) have Exocrine Pancreatic Insufficiency (EPI) at birth, causing malnutrition and impaired growth. While EPI is often considered irreversible, studies of CwCF treated with ivacaftor demonstrated significantly increased faecal elastase (FE), indicating improvement in EPI. In contrast, FE did not change in adults with the severe F508del mutation treated with elexacaftor/tezacaftor/ivacaftor (ETI) in the PROMISE study. It remains unknown if those differences were due to the milder mutations or younger age of participants in ivacaftor versus ETI studies. We measured FE during BEGIN, a multi-center, prospective observational study of CwCF and ETI.</div></div><div><h3>Methods</h3><div>Paired faecal samples (n=150) were collected before and 6mo after initiating ETI from CwCF 2-5y (n=75) participating in BEGIN (28 F508del heteroz., 47 homoz.; mean age 4.1y at baseline). FE was measured with a FE-1 ELISA approved for clinical use, categorizing participants by manufacturer's recommendations (severe PI, FE&lt;100 µg/g; mild-moderate PI, 100-200; normal, &gt;200). Paired t-tests compared mean FE pre- and post-ETI; p-values less than 5% were considered significant.</div></div><div><h3>Results</h3><div>Mean FE increased significantly from baseline to 6 months (from 95 to 125 µg/mL, p=0.002). 8 CwCF (11%) had increases in FE sufficient to change clinical category, including 2 who improved from “severe insufficiency” to “mild to moderate”, 2 from “severe” to “normal”, and 4 from “mild to moderate” to “normal”. By comparison, 3 CwCF (4%) had decreased FE to a worsening clinical category. There was no impact of baseline age on FE change (p=0.27); in contrast, CwCF homozygous for F508del had smaller mean improvements (1.7-fold increase in FE) compared to heterozygotes (4.4-fold increase) (p=0.03).</div></div><div><h3>Conclusions</h3><div>FE significantly improved for 11% CwCF after 6 mo of ETI therapy, and clinical EPI status normalized for 8% of CwCF. Our findings suggest PI may be partially reversible for some young CwCF with ETI.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S24"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS14.02In silico, in vitro and ex vivo characterization of CFTR pathogenic variants localized in the Fourth Intracellular Loop and their rescue by modulators","authors":"E. Pesce ,&nbsp;V. Tomati ,&nbsp;V. Capurro ,&nbsp;M. Lena ,&nbsp;C. Pastorino ,&nbsp;M. Astore ,&nbsp;S. Kuyyucak ,&nbsp;B. Chevalier ,&nbsp;E. Sondo ,&nbsp;F. Cresta ,&nbsp;V. Terlizzi ,&nbsp;S. Costa ,&nbsp;M.C. Lucanto ,&nbsp;V. Daccò ,&nbsp;L. Claut ,&nbsp;F. Ficili ,&nbsp;R. Bocciardi ,&nbsp;F. Zara ,&nbsp;C. Castellani ,&nbsp;L.J. Galietta ,&nbsp;N. Pedemonte","doi":"10.1016/j.jcf.2025.03.571","DOIUrl":"10.1016/j.jcf.2025.03.571","url":null,"abstract":"<div><div>The most effective treatment for people with CF (pwCF) carrying the F508del mutation is the triple combination of Elexacaftor-Tezacaftor-Ivacaftor (ETI). Although initially developed for F508del, CFTR modulators can correct the underlying defect(s) in other CFTR mutants. Previous studies have investigated the impact of several missense variants within the Intracellular Loop 4 (ICL4) on CFTR protein maturation and channel activity. We performed a detailed analysis of selected variants in the ICL4 using computational, functional and biochemical methodologies, to understand their impact on CFTR structure and function.</div><div>Mutations affecting L1065P, R1066C, and L1077P result in disruptions of hydrophobic interactions, salt bridges, and helical integrity, respectively, leading to compromised structural stability of CFTR. Analyses of single variants expressed heterologously in immortalized bronchial cells showed that, upon ETI, rescued activity for both L1065P and R1066C was close to 50% of the wild-type CFTR activity. Biochemical studies of ICL4 variants expression pattern in CFBE41o- cells, following treatment for 24 h, demonstrate the appearance of the band C, corresponding to mature, fully glycosylated protein, with no changes in the immature band. Cell surface measurements of CFTR performed using the HiBiT complementation assay in transiently transfected HEK293 cells confirmed partial restoration of CFTR surface expression, in the same range as observed with F508del. Finally, our study provides evidence in primary nasal cells from a cohort of pwCF that L1065P and R1066C, can be effectively rescued by ETI. Upon treatment with modulators, the CFTR-mediated current averaged around 25%-45% of the activity measured in non-CF epithelia.</div><div>Supported by Fondazione Ricerca Fibrosi Cistica grants FFC #9/2019 and FFC #10/2021, Italian Ministry of Health grants GR-2018–12367126 and PNRR-MR1-2023-12378412 and Cystic Fibrosis Foundation grant PEDEMO20G0.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S27-S28"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS04.03Stool and symptom testing in colorectal evaluation for neoplasia in cystic fibrosis (SCREEN-CF)","authors":"N. Taylor ,&nbsp;S. Sivam ,&nbsp;J. van Dorst ,&nbsp;M.J. Coffey ,&nbsp;S. Visser ,&nbsp;P. Haber ,&nbsp;A. Volovets ,&nbsp;C.Y. Ooi","doi":"10.1016/j.jcf.2025.03.512","DOIUrl":"10.1016/j.jcf.2025.03.512","url":null,"abstract":"<div><h3>Objectives</h3><div>This study evaluated the utility of faecal calprotectin (FC), tumour pyruvate kinase isoenzyme type M2 (TuM2-PK), and immunochemical faecal occult blood test (iFOBT) for detecting colorectal cancer (CRC) and adenomatous polyps (AP) in people with cystic fibrosis (pwCF), who face elevated CRC and ileocolonic malignancy (ICM) risks. Colonoscopy, the gold standard, carries procedural risks in pwCF, highlighting the need for non-invasive stool biomarkers.</div></div><div><h3>Methods</h3><div>A prospective study of pwCF meeting CRC screening criteria and undergoing colonoscopy at a single Australian centre (2019–2023). Faecal samples for FC, TuM2-PK, and iFOBT were collected within three months of colonoscopy. Colonoscopy findings of AP and/or ICM were recorded. Biomarker cut-offs were determined using receiver operating characteristic (ROC) analysis and Youden's J statistic.</div></div><div><h3>Results</h3><div>Among 49 participants [mean (SD) age 47.8 (8.2) years; 47% male], 24.5% (12/49) had AP and 4.0% (2/49) had ICM. The youngest patient with AP or ICM was 43. Performance of biomarkers in detecting ICM and AP is presented in Tables 1 and 2.</div></div><div><h3>Conclusion</h3><div>This study highlights the prevalence of AP and ICM in pwCF, emphasizing CRC screening importance. All biomarkers performed well for ICM, but FC was the only effective tool for AP detection, offering high sensitivity. FC thresholds may guide colonoscopy decisions in pwCF. Validation in larger cohorts is warranted.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S8"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS09.04Beyond chloride: a multi-omic integration analysis to identify the effects of elexacaftor/tezacaftor/ivacaftor in F508del primary airway epithelial cultures","authors":"M. Kelly-Aubert ,&nbsp;V. Laigle ,&nbsp;E. Bardin ,&nbsp;A. Hatton ,&nbsp;C. Guerrera ,&nbsp;C. Bole ,&nbsp;S. Grassin Delyle ,&nbsp;V. Stoven ,&nbsp;I. Sermet-Gaudelus","doi":"10.1016/j.jcf.2025.03.543","DOIUrl":"10.1016/j.jcf.2025.03.543","url":null,"abstract":"<div><div>Elexacaftor/Tezacaftor/Ivacaftor (ETI) has changed the prognosis and quality of life of CF patients, and functional studies have ascertained their role in restoring CFTR-dependent chloride secretion; however, other pathways could be improved by ETI. We undertook a multi-omic approach to decipher which pathways, other than chloride secretion, could be involved in ETI's mechanisms of action.</div><div><strong>Methods:</strong> We generated air-liquid differentiated primary epithelial cultures from nasal brushings from eight F508del homozygous patients and seven healthy age- and sex-paired controls. After a 48-hour treatment with ETI or DMSO, samples were collected for transcriptomic, proteomic and untargeted metabolomic analysis.</div><div><strong>Results:</strong> In F508del cultures, ETI induced a significant differential expression of 208 genes, 37 proteins, 16 polar and 168 apolar metabolites. Gene set enrichment analysis on the transcriptomic and proteomic data and a similar metabolite-based pathway enrichment analysis on the untargeted metabolomic data revealed that several pathways were significantly up- or down-regulated by ETI in F508del cultures whereas none were significantly modified in WT cultures. This included TNFa/NFKB signaling and the epithelial mesenchymal transition pathway, both down regulated by ETI; and the interferon-dependent immune response pathways, upregulated by ETI. The pathway most affected by ETI, both at a transcriptomic and proteomic level was oxidative phosphorylation. Multi-omics integration and network analysis allowed to build a network comprising the differentially expressed genes, proteins, and metabolites and highlighted key mitochondria-related pathways: oxidative phosphorylation, Krebs cycle and fatty acid metabolism.</div><div><strong>Conclusion:</strong> The convergence of our transcriptomic, proteomic and metabolomic data and integrated network underlines the robustness of multi-omic approaches and pinpoints an unexpected effect of ETI on mitochondrial metabolism in F508del cells.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S18-S19"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS08.01Reshaping but not restoring: The impact of elexacaftor/tezacaftor/ivacaftor on the lung microbiome and interactome in people with cystic fibrosis and advanced lung disease","authors":"C. Premuda ,&nbsp;A. Gramegna ,&nbsp;J.K. Narayana ,&nbsp;F.X. Ivan ,&nbsp;T.K. Jaggi ,&nbsp;S. Aliberti ,&nbsp;S. Chotirmall ,&nbsp;F. Blasi","doi":"10.1016/j.jcf.2025.03.534","DOIUrl":"10.1016/j.jcf.2025.03.534","url":null,"abstract":"<div><div>Lung disease, driven by bacterial chronic infection, is the leading cause of morbidity and mortality in adults with cystic fibrosis (awCF). The recent introduction of elexacaftor/tezacaftor/ivacaftor (ETI) has led to significant improvements in overall health, prompting investigation into its effects on chronic lung infections. However, traditional microbiology has limited sensitivity in capturing microbiological changes post-ETI. We aimed to assess microbiome and microbial interaction changes before and after ETI in awCF and advanced lung disease by the use of culture-independent technologies.</div><div>AwCF were prospectively recruited at the Adult CF Center, Policlinico Hospital, Milan, Italy. Participants were categorized into two groups: an ETI-treated group of 12 individuals with advanced lung disease and a control group of 20 individuals not eligible for early ETI access. Baseline and follow-up sputum samples were collected to examine lung microbiome and interactome changes.</div><div>We demonstrated an increase in microbiome alpha-diversity and a shift towards commensal species one month following ETI, though this effect diminished after one year. A progressive shift in bacterial community composition was observed over time, resembling that of bronchiectasis patients from the same geographic region. Interactome analysis revealed significant rewiring, with new potential CF pathogens emerging within the year.</div><div>These findings highlight the possible role of culture-independent approaches for personalized medicine in CF, indicating that while ETI induces microbiome shifts, a fully normalized microbiome may not be achieved. Therefore, maintaining chronic therapies, including inhaled antibiotics, in this population could be crucial for effectively managing persistent microbiome alterations.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S15-S16"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS08.03Remodelling of cystic fibrosis respiratory microbiota in response to extended elexacaftor/tezacaftor/ivacaftor therapy","authors":"H. Gavillet ,&nbsp;L. Hatfield ,&nbsp;M. Hardman ,&nbsp;G.G. Einarsson ,&nbsp;C.S. Thornton ,&nbsp;M.D. Parkins ,&nbsp;J. Duckers ,&nbsp;J.M. Bomberger ,&nbsp;Y. Hilliam ,&nbsp;S.E. Lee ,&nbsp;R.W. Lord ,&nbsp;A. Jones ,&nbsp;A. Horsley ,&nbsp;T.W.V. Daniels ,&nbsp;C.C. Teneback ,&nbsp;M.J. Wargo ,&nbsp;K. Schutz ,&nbsp;D.W. Rivett ,&nbsp;C. van der Gast","doi":"10.1016/j.jcf.2025.03.536","DOIUrl":"10.1016/j.jcf.2025.03.536","url":null,"abstract":"<div><h3>Objectives</h3><div>The introduction of the highly effective CFTR modulator Elexacaftor/Tezacaftor/Ivacaftor (ETI) has revolutionised clinical outcomes for adults with CF (awCF) eligible for treatment. Despite this little is understood about the long-term impact of ETI on the respiratory microbiota in awCF. In this multi-centre study, we investigated changes to the respiratory microbiota of awCF from before onset of ETI therapy to on-ETI therapy of up to 3 years.</div></div><div><h3>Methods</h3><div>Respiratory samples were collected from 303 awCF from 6 centres in the UK (Cardiff, Manchester, &amp; Southampton), Canada (Calgary), and USA (Dartmouth &amp; Vermont). This consisted of pre-ETI samples stratified to severe, moderate, and mild disease groups based on %FEV1, and on-ETI samples taken at approximately 6 months, 1, 2, &amp; 3 years. Samples from 11 non-CF healthy participants were included as a comparator group. Microbiota sequencing was performed on all samples.</div></div><div><h3>Results</h3><div>Microbiota diversity increased with therapy duration. With diversity at years 2 and 3 being comparable (P&gt;0.05) to that observed in the mild disease pre-ETI and healthy groups. Microbiota composition became increasingly similar to mild CF/healthy groups with increasing therapy duration but was still significantly different (P&lt;0.05) at 3 years. Dominance of CF pathogens reduced with therapy duration, with a shift to microbiota characterised by strict anaerobes associated with better clinical outcomes. Despite the reduction in abundance many CF pathogens still persisted.</div></div><div><h3>Conclusions</h3><div>Long-term ETI therapy resulted in positive changes in the respiratory microbiota, typically associated with better clinical outcomes and microbiota more closely resembling mild CF/healthy microbiota. Despite a positive trajectory towards a healthy-like microbiota, we posit that progression in awCF is impeded by the cumulative effects of progressive airway and lung parenchymal damage, along with the impacts of long-term and continued antibiotic therapy.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S16"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS15.01Post-lung transplant survival for people with cystic fibrosis before and during the elexacaftor/tezacaftor/ivacaftor era","authors":"K.J. Ramos ,&nbsp;A. Anand ,&nbsp;M.C. Bradford ,&nbsp;D. Young ,&nbsp;T. Milinic ,&nbsp;O.J. McElvaney ,&nbsp;C.H. Goss ,&nbsp;S.G. Kapnadak","doi":"10.1016/j.jcf.2025.03.576","DOIUrl":"10.1016/j.jcf.2025.03.576","url":null,"abstract":"<div><h3>Objective</h3><div>Evaluate survival outcomes after lung-transplant (LTx) for people with cystic fibrosis (CF) in the United States (US) before and after the introduction of elexacaftor/tezacaftor/ivacaftor (ETI). Published US CF Foundation Patient Registry (CFFPR) data showed that almost half of LTx recipients were prescribed ETI prior to LTx in 2020-2022. At the 2024 North American CF Conference, the Toronto Program presented reduced survival for LTx recipients with CF in the ETI era.</div></div><div><h3>Methods</h3><div>LTx recipients with CF between Oct 1, 2016 and Dec 31, 2022 were identified using the Scientific Registry of Transplant Recipients dataset (the US national transplant registry), with follow-up through Jan 2024. Prior to the European CF Society annual scientific meeting, data will be linked with the CFFPR to allow for determination of ETI status for recipients at the time of LTx. Pre-ETI era was defined as Oct 1, 2016 to Sept 30, 2019 (ETI FDA-approved in the US in Oct 2019). We summarized demographics in both eras using descriptive statistics and calculated Kaplan-Meier estimates of one-year survival after LTx by transplant year, starting in Jan 2017.</div></div><div><h3>Results</h3><div>There were 803 LTx recipients with CF, 637 in the pre-ETI era and 166 in the ETI era. Recipients were 47% male, 95% White, 4% Black, and 7% Hispanic compared to 54%, 92%, 7%, and 14% in the pre-ETI vs ETI era, respectively. The proportion with Medicaid insurance increased from 20% to 27% between eras. The median (IQR) age was 31 years (25-38) pre-ETI and 31 years (25-40) in the ETI era. Qualitative assessment of 1-year survival estimates showed a decline in survival in the ETI era, which was most pronounced in 2021 (Table).</div></div><div><h3>Conclusions</h3><div>Post-transplant survival for people with CF may have worsened in the ETI era. There are shifts in some patient characteristics but not significantly older age. Understanding whether survival estimates differ for people on ETI vs. not prescribed ETI at the time of LTx is a critical next step.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S29-S30"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS16.01Elucidating the pathogenesis of cystic fibrosis-related diabetes with induced pluripotent stem cells","authors":"I. Khondaker,&nbsp;D. Prasca-Chamorro,&nbsp;S.H. Park,&nbsp;M. Cao,&nbsp;J. Rapalo-Guarrero,&nbsp;D. Betancourth,&nbsp;G. Bao","doi":"10.1016/j.jcf.2025.03.582","DOIUrl":"10.1016/j.jcf.2025.03.582","url":null,"abstract":"<div><h3>Objectives</h3><div>Diabetes is the most common comorbidity of Cystic Fibrosis (CF), affecting nearly 50% of adult CF patients and severely worsening CF related disease mortality. While the root cause of CF-related diabetes (CFRD) is a mutation in the <em>CFTR</em> gene, the molecular mechanisms leading to CFRD are unclear, largely due to a lack of models that faithfully recapitulate human disease. The overall objectives of this study are to establish induced pluripotent stem cell (iPSC) derived islets (SC-islets) as a novel model for CFRD disease study and determine the consequence of the <em>CFTR</em> mutation in islet endocrine cell types.</div></div><div><h3>Methods</h3><div>iPSCs with <em>G542X/G542X</em> or <em>F508del/F508del CFTR</em> mutations (CF-iPSCs) were differentiated to SC-islets alongside wild-type (WT) H1 stem cells. SC-islet differentiation efficiency and hormone secretion were quantified with intracellular flow cytometry and enzyme linked immunosorbent assays (ELISAs).</div></div><div><h3>Results</h3><div><em>G542X</em>-, <em>F508del</em>-, and H1-SCs differentiate to NKX6.1+/INS+ beta cells with 39±3%, 39±3%, and 42±2% efficiency, and GCG+/INS- alpha cells with 19±2%, 19±1%, and 35±4% efficiency respectively. <em>G542X</em>-, <em>F508del</em>-, and H1-beta cells are glucose responsive <em>in vitro</em> and secrete insulin at 1.8±0.4, 1.6±0.3, and 1.8±0.4 mIU/ml/10³ cells in high (20 mM) glucose conditions. <em>G542X</em>-, <em>F508del</em>-, and H1-alpha cells secrete 0.060±0.003, 0.84±0.24, and 0.70±0.12 pmol/L/10³ cells at low (2 mM) glucose conditions.</div></div><div><h3>Conclusion</h3><div>Our results demonstrate that CF-iPSCs differentiate to alpha and beta cells, and that there is no significant difference in insulin secretion for CF SC-islets and H1 SC-islets <em>in vitro</em>. Notably, our results show that <em>G542X</em>-islets secrete significantly lower glucagon at low glucose conditions compared to <em>F508del</em>- and H1-islets. Overall, these studies suggest a role for CFTR in alpha cell function and establish SC-islets as a novel and valuable model for studying CFRD.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S31"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS07.02Investigating imaging biomarkers in cystic fibrosis preschoolers using manual and Artificial intelligence-based algorithms","authors":"P. Raut ,&nbsp;M. Bonte ,&nbsp;B. Manai ,&nbsp;P. Makani ,&nbsp;D. Caudri ,&nbsp;H.M. Janssens","doi":"10.1016/j.jcf.2025.03.529","DOIUrl":"10.1016/j.jcf.2025.03.529","url":null,"abstract":"<div><h3>Introduction</h3><div>Monitoring structural lung changes in preschoolers with cystic fibrosis (PrewCF) is challenging, but CT could be used to quantify structural lung changes. This study evaluates and compares manual vs automated image analysis tools as possible sensitive biomarkers in PrewCF.</div></div><div><h3>Methods</h3><div>76 Erasmus MC-Sophia PrewCF (1-5 yrs) were included, with 177 CT's. Manual PRAGMA-CF score include %Bronchiectasis (%BE), %Mucus plugging (%MP), %Airway wall thickening (%AWT), and overall %Disease (%DIS). With the AI-based LungQ^TM platform (Thirona) automated PRAGMA-AI was used to calculate %BE, %AWT and %DIS. Bronchial dimensions were assessed with the Bronchus-Artery (BA) method, and number of mucus plugs with the Mucus plugging (MP) algorithm. Manual and automated outcomes were compared using correlation, ICC and multivariable regression. Finally, progression over time was evaluated in 41 PrewCF with &gt;1 CT scans using both methods.</div></div><div><h3>Results</h3><div>All 177 CT's were scored manually, 126 (71%) also processed successfully with LungQ (free-breathing: 64%; inspiratory: 98%). AWT was the most prevalent abnormality. Correlations between manual and automatic PRAGMA analysis were strong for %DIS (0.67, CI:0.56-0.75, p&lt;0.001), moderate for %BE (0.53, CI:0.39-0.65, p&lt;0.001) and %AWT (0.59, CI:0.46-0.69, p&lt;0.001). ICC's showed good agreement for %DIS (0.77, CI:0.69-0.83), moderate for %AWT (0.58, CI:0.42-0.70) and weak for %BE (0.35, CI:0.18-0.50). In a backward stepwise multivariable model automated outer bronchial diameter (Bout/A ratio; β=2.54, p=0.01) and mucus plugs (β=0.18, p&lt;0.001) remained independent significant predictors of manual %DIS. Significant progression over time was detected using the manual %DIS and %AWT, as well as automated %DIS and bronchial wall thickness (Bwt/A ratio).</div></div><div><h3>Conclusion</h3><div>Both manual and automated CT analysis are feasible in PrewCF and methods show reasonable agreement. Both methods were able to detect significant disease progression over a 2-4 year period</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S14"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}