2026

Adnan Bhat, Anchit Chauhan, Maulinkumar Patel, Mariam Shahabi , Umar Iqbal, Mohammed Elzeneini 6 et al.     Cardiovascular disease-associated admissions in patients with Cystic Fibrosis: A 7-Year U.S. National Inpatient Sample Analysis   Heart Lung. 2026 Jan 8:78:102701. doi: 10.1016/j.hrtlng.2025.102701. Online ahead of print.  https://pubmed.ncbi.nlm.nih.gov/41512346/

Background: As survival improves for people with cystic fibrosis (PwCF) in the era of CFTR modulators, cardiovascular (CV) diseases are emerging as clinically important comorbidities. Beyond age-related risks, mechanistic pathways such as systemic inflammation, chronic hypoxia, CF-related diabetes, and CFTR-related endothelial dysfunction may contribute to CV injury. However, national-level data on CV outcomes in PwCF remain limited.
Objectives: We hypothesized that primary cardiac admissions in PwCF are increasing over time and associated with worse in-hospital outcomes compared to non-cardiac admissions.

Methods: We retrospectively analyzed adult (≥18 years) PwCF hospitalizations in the U.S. National Inpatient Sample (2016-2022). Primary cardiac admissions were defined by a principal diagnosis of atrial fibrillation (AF), heart failure (HF), or myocardial infarction (MI) using ICD-10 codes. Outcomes included in-hospital mortality, length of stay (LOS), charges, and discharge disposition. Temporal trends in cardiac admissions were modeled using negative binomial regression with an offset for total CF hospitalizations; Joinpoint regression was performed as a complementary method. Descriptive statistics and multivariable regression models adjusted for age, sex, and race were used. A p-value <0.05 was considered statistically significant.
Results: Among 121,290 PwCF hospitalizations, 520 (0.43%) were for cardiac causes. PwCF with cardiac admissions were older (median 62 vs. 29 years, p < 0.001) and had more traditional CV comorbidities. Cardiac admission rates increased by 16.4% per year from 2016 to 2022 (IRR 1.16 [1.04-1.29], p = 0.009) in negative binomial regression. Joinpoint regression detected no significant inflection points and estimated a non-significant APC of 16.4% per year (95% CI 10.9-57.4, p = 0.214). Unadjusted mortality was higher for cardiac vs. non-cardiac admissions (OR 3.70, 95% CI 1.61-8.53, p = 0.002), but not significant after adjustment (OR 1.36, 95% CI 0.55-3.34, p = 0.468).

Conclusion: Our findings indicated higher in-hospital mortality among PwCF admitted for cardiac causes, and more discharge to nursing facilities among PwCF admitted for cardiac causes. There is a need for greater CV screening, and geriatric care in PwCF.

Adnan Bhat  is Assistant professor in the Department of Hospital Medicine, University of Florida, Gainesville, Florida

Pierre-Regis Burgel. Strategies for the identification of people with cystic fibrosis responsive to CFTR modulator triple combinations. Review J Cyst Fibros. 2026 Jan;25(1):3-8. doi: 10.1016/j.jcf.2025.12.019. Epub 2025 Dec 30.free article.https://pubmed.ncbi.nlm.nih.gov/41469310/

The triple combinations of CFTR modulators, elexacaftor-tezacaftor-ivacaftor and more recently vanzacaftor-tezacaftor-deutivacaftor, have transformed the clinical course of cystic fibrosis (CF). These drug combinations were identified for their ability to restore CFTR function in F508del epithelial cells, and their efficacy has been shown in large randomized clinical trials involving people with CF with at least one F508del variant. Approximately 20 % of pwCF worldwide have no F508del variant however. Recent data show that CFTR modulator triple combinations may be effective in a large subset of pwCF with non-F508del, often rare, CFTR variants. The purpose of this review is to explore the various strategies that may contribute to the identification of all patients with modulator-responsive CFTR variants in order to expand access to these transformative therapies.

Pierre-Regis Burgel is at the Respiratory Medicine and French Cystic Fibrosis National Reference Center, Hôpital Cochin, AP-HP. Centre Université Paris Cité,

H L Chandler, M Germuska, T M Lancaster, C Xanthe, C O’leary, S Stirk, H Lu, K Murphy, C Metzler-Baddeley, R G Wise, J Duckers 4.     J Cyst Fibros
. 2026 Jan;25(1):166-171. doi: 10.1016/j.jcf.2025.08.010. Epub 2025 Aug 30.
Imaging brain vascular function in Cystic Fibrosis: an MRI study of cerebral blood flow and brain oxygenation https://pubmed.ncbi.nlm.nih.gov/40885605/

Background: Cystic fibrosis (CF) is a progressive inherited disorder that primarily affects the lungs. With recent breakthroughs in effective treatments for CF that increase life-expectancy, a higher prevalence of age-related comorbidities has been reported including cardiovascular disease, stroke and cognitive decline. Despite the known relationship between cardiovascular health and cerebrovascular function, very little is known about brain blood flow and oxygen metabolism in people with CF (PwCF).

Methods: In 14 PwCF and 56 healthy age / sex matched controls, we used pseudo-continuous arterial spin labelling (pCASL) to quantify cerebral perfusion in grey-matter and T2-Relaxation-Under-Spin-Tagging (TRUST) to estimate global oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO2).

Results: Compared to healthy controls, PwCF showed elevated CMRO2 (p =0.015). There were no significant between-group differences in grey-matter CBF (p =0.342), or whole brain OEF (p =0.091). However, regional analysis showed certain areas with higher CBF in PwCF (p < .05, FDR).

Conclusions: Our results show increased CMRO2 and regional CBF in PwCF, which could be explained by potential differences in PaO2/PaCO2 and/or endothelial cell function. Our findings highlight the need for further investment in brain research in PwCF to reduce the risk of early cerebrovascular breakdown that leads to premature cognitive decline.

Hannah  L Chandler is research associate at the Cardiff University Brain Research Imaging Centre (CUBRIC), Cardiff University, Cardiff, United Kingdom.

Flora Charbonneau , Magali Dupuy-Grasset , Jeanne Languepin, Marie-Laure Laroche. Recognizing Arthralgia as a Potential Adverse Effect of CFTR Modulators: A Case Report Case Reports Clin Ther. 2026 Jan;48(1):117-120. doi: 10.1016/j.clinthera.2025.11.007. Epub 2025 Dec 5.Free article.  https://pubmed.ncbi.nlm.nih.gov/41353054/

Authors’ conclusions.     Highly effective CFTRm represent a major therapeutic advancement for individuals with CF. Nonetheless, their full safety profile remains to be fully elucidated, particularly regarding potential effects on joint health. This case highlights that CFTRm can induce arthralgia, while also underscoring the complexity of managing this adverse event. Given the substantial clinical benefits of CFTRm, particularly in terms of pulmonary function and overall quality of life, discontinuation of therapy solely for the relief of joint pain is often not a viable option. This presents a therapeutic dilemma for both patients and clinicians. It is therefore essential that healthcare providers remain vigilant for the emergence or worsening of joint symptoms in patients whose disease is otherwise well controlled, as this may be an underrecognized adverse effect of CFTRm therapy. Early recognition and systematic reporting are crucial to improving understanding and guiding future management strategies. Full details in the free full article.

Flora Charbonneau is at the Regional Center of Pharmacovigilance, Department of Pharmacology, Toxiycology and Pharmacovigilance, Limoges’ University Hospital, Limoges, France

Yuxin Chen, Daan Caudri, Eleni-Rosalina Andrinopoulou , Catherine A Byrnes, Joyce Cheney, Peter J Cooper, et al  ; Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) and Follow-up of the ACFBAL (CF-FAB) study groups.  Progression of structural lung disease and lung function in adolescents with cystic fibrosis. J Cyst Fibros 2026 Jan;25(1):78-85. doi: 10.1016/j.jcf.2025.11.009. Epub 2025 Nov 23.https://pubmed.ncbi.nlm.nih.gov/41285645/

Background: Cystic fibrosis (CF) lung disease begins early in life and progresses throughout childhood into adolescence. Children completing the Australasian CF Bronchoalveolar Lavage (ACFBAL) trial were followed longitudinally (CF-FAB study) to determine progression of CF lung disease during adolescence using visual and automatic methods and to correlate CT-derived metrics with spirometry outcomes.

Methods: CTs from start and end visits of CF-FAB (mean 24 [SD 12] months apart) were analysed using visual PRAGMA-CF scoring and automatic bronchus-artery (BA) analysis. PRAGMA-CF assessed %Disease by summing %Bronchiectasis, %Mucus plugging, % Airway wall thickening on inspiratory scans and %Trapped air on expiratory scans. The BA-analysis segments the bronchial tree, identifies segmental bronchi (G0) and distal generations (G1, G2, G3…), measures diameters of bronchial outer wall (Bout), inner wall (Bin), wall thickness (Bwt), and artery (A), and computes BA-ratios (Bout/A, Bin/A, Bwt/A, Bwa/Boa[=bronchial wall area/bronchial outer area]) to evaluate bronchial dilatation and wall thickening.
Results: 120 children (median age 13 years, IQR 11.4-14) contributed 115 start and 105 end scans. Eleven children were treated with CFTR modulators prior to the start of the study and four received the treatment during the study. Progression was found in PRAGMA-CF %Bronchiectasis (p=0.02) and %Mucus plugging (p=0.02), and Bout/A (p=0.01), Bwt/A (p<0.001), and Bwa/Boa (p<0.001). Spirometry outcomes showed no significant decline. BA-metrics correlated more strongly with spirometry outcomes than PRAGMA-CF scores.

Conclusion: Heterogeneous progression of structural lung disease in children with CF during adolescence was detected using visual PRAGMA-CF scores and automatic BA-analysis. Spirometry outcomes showed no significant decline.

Yuxin Chen is at  the Department of Paediatrics, Division of Respiratory Medicine and Allergology, Sophia Children’s Hospital, Erasmus MC, Rotterdam and  The Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.

Carla Colombo , Paola Medino, Marco Cipolli, Francesca Lucca , Giulia Cucchetto , Federico Alghisi, Fabiana Ciciriello,  et al.     COVID-19 in people with Cystic Fibrosis beyond the pre-omicron era: a prospective study with a specific focus on long COVID.  J Cyst Fibros. 2026 Jan;25(1):172-178. doi: 10.1016/j.jcf.2025.08.015. Epub 2025 Sep 3       https://pubmed.ncbi.nlm.nih.gov/40908194/

Background: The long-term clinical consequences of COVID-19 in cystic fibrosis (CF) remain largely unexplored. This study aimed to assess the incidence of long COVID in a large population of people with CF.

Methods: This prospective, multicentre study enrolled individuals with confirmed SARS-CoV-2 infection between July 2021 and October 2022. Data collected included clinical features prior to infection, symptoms during the acute phase, hospitalization and symptom persistence after 1 and 6 months. Long COVID was defined according to CDC criteria as persistence of at least one COVID-related symptom for one or more months after diagnosis. The mean variation of FEV1 recorded 6 months after acute infection was also evaluated.
Results: A total of 1102 people with CF were recruited (median age: 18 years, 520 younger than 18). The infection was symptomatic in 90.1 % of cases. During the acute phase, 8 subjects required oxygen support; 31 were hospitalized, one patient required intensive care. Complications included one thromboembolic event and two episodes of myocarditis, but no patient died. Mean variation of FEV1 after 6 months from the infection was +1.8 % (95 % CI: 1.0-2.7). Long COVID was documented in 64 subjects (5.8 %, 95 % CI: 4.5-7.4) with a variety of symptoms which were still present in 12 cases 6 months after infection (1.1 %, 95 % CI: 0.6-1.9).

Conclusions: In the omicron phase of the pandemic, COVID-19 was relatively mild and did not negatively impact pulmonary function after 6 months. Long COVID was observed at all ages, but extrapulmonary symptoms were more frequent and persistent in adults.

Carla Colombo is at the Cystic Fibrosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy.

Parveen Fathima, Edward Pan, Julie Marsh, Shivanthan Shanthikumar , Sheila Sivam , Adam Jaffe, et al.      Characteristics, treatment and lung function outcomes of pulmonary exacerbations in cystic fibrosis: insights from the BEAT-CF cohort.   Eur Respir J. 2026 Jan 8;67(1):2501349. doi: 10.1183/13993003.01349-2025. Print 2026 Jan..https://pubmed.ncbi.nlm.nih.gov/41067870/

Background: Pulmonary exacerbations pose a significant clinical burden on people with cystic fibrosis (pwCF). Whether management of exacerbations should change in the context of modulator therapy is unclear. We describe the characteristics, treatment and lung function outcomes of pulmonary exacerbations requiring intravenous antibiotic therapy (PERITs) in a contemporary Australian cohort of pwCF, in an era of rapidly broadening access to modulator therapy.
Methods: PwCF receiving care at 11 Australian specialist centres were prospectively enrolled between 14 October 2020 and 9 October 2024. Spirometry data and treatments received during a PERIT were collected systematically.
Results: A total of 982 pwCF were enrolled, with 593 PERITs recorded in 323 individuals. The median (interquartile range) age at PERIT start was 12 (7-17) years and the mean±sd baseline forced expiratory volume in 1 s (FEV1) % predicted across PERITs was 80±21%. Approximately 62% (n=366) of PERITs occurred in people receiving modulator therapy. Intravenous tobramycin (63%) and piperacillin-tazobactam (43%) were the most frequently used antibiotics. Among participants with spirometry at baseline and at Day 7 (n=296) or Day 60 (n=383), 41% (n=120) and 44% (n=169) were below their baseline at Day 7 and Day 60 after commencing treatment, respectively; 8% were >10% below their baseline FEV1 % predicted at both time-points. Recovery patterns were consistent regardless of baseline lung function, Pseudomonas aeruginosa colonisation or modulator use.
Conclusion: The pattern and magnitude of lung function impairment during PERITs is similar among those receiving and not receiving modulator therapy. This underscores the continued need for evidence to help clinicians balance treatment burden against the risk of irreversible loss of lung function.

Parveen Fathima is at the Health and Clinical Analytics, Sydney School of Public Health, The University of Sydney, Sydney

Charlotte Mouliade, Lucia Parlati, Stylianos Tzedakis, Mathis Collier, Samir Bouam , Anais Vallet-Pichard, Valérie D’Halluin-Venier, Reem Kanaan, Stanislas Pol, Philippe Sogni, Pierre-Régis Burgel, Vincent Mallet ; Demosthenes Research Group Cystic fibrosis liver disease progression in the era of elexacaftor-tezacaftor-ivacaftor.   JHEP Rep. 2025 Jul 5;7(10):101512. doi: 10.1016/j.jhepr.2025.101512. eCollection 2025 Oct.https://pubmed.ncbi.nlm.nih.gov/41070102/

Background & aims: The effect of elexacaftor-tezacaftor-ivacaftor (ETI) on cystic fibrosis liver disease (CFLD) outcomes remains unknown. Thus, we investigated the association between the ETI rollout and trends in CFLD progression in a nationwide cohort.

Methods: Using the French National Hospital Discharge Database (2014-2023), we measured the incidence of CFLD progression (decompensated cirrhosis, gastroesophageal variceal bleeding, primary liver cancer, or liver transplantation) before and after ETI became available (December 2019) in patients with cystic fibrosis (pwCF) aged ≥12 years. Death without CFLD progression and lung transplantation were treated as competing events. Incidence rates were compared across ETI calendar eras in both the full cohort and a 1:1 propensity score-matched sample. Analyses used Kaplan-Meier curves, Fine-Gray competing risk models, and adjusted incidence rate ratios (aIRRs).

Results: The cohort included 10,083 pwCF (median age: 19 years [IQR 14-29]; 52.6% male), with 24.6% censored pre-ETI and 75.4% post-ETI. The overall incidence of CFLD progression was 3.7 per 1,000 person-years: 25.4 pre-ETI versus 1.2 post-ETI (p <0.001). The incidence of all CFLD outcomes, including non-bleeding varices, declined post-ETI (p <0.001). In matched analyses, pwCF censored during the ETI era had a lower incidence of CFLD progression (aIRR 0.28, 95% CI: 0.18-0.43; p <0.001). In addition, deaths in pwCF occurred at an older age during the ETI era.

Conclusions: The incidence of CFLD progression declined during the ETI rollout. While these findings suggest an association between ETI availability and improved liver outcomes, unmeasured confounders and concurrent changes in management might have also contributed. Thus, further studies are needed to confirm causality and understand underlying mechanisms.

Impact and implications: In this nationwide French cohort study of over 10,000 people with cystic fibrosis, we observed a significant decline in the incidence of cystic fibrosis liver disease outcomes following the rollout of elexacaftor-tezacaftor-ivacaftor (ETI) in December 2019. The rate dropped from 25.4 to 1.2 per 1,000 person-years post-ETI. Matched analyses confirmed a reduced risk of liver disease progression, with an adjusted incidence rate ratio of 0.28. Although the findings suggest ETI may improve liver outcomes in people with cystic fibrosis, potential confounding factors necessitate further research to establish causality and understand the underlying biological mechanisms.

Charlotte Mouliade is at the AP-HP Centre Université Paris Centre, Groupe Hospitalier Cochin Port Royal, DMU Cancérologie et Spécialités Médico-Chirurgicales, Service des Maladies du foie, Paris, France.

Sara Naimimohasses, Ankit Ray, Eunice Tan, Asher Wiggins , Bima J Hasjim, Shiyi Chen, Mamatha Bhat.  Impact of Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapies on Liver Transplant Outcomes. Gastro Hep Adv 2025 Sep 14;5(2):100810. doi: 10.1016/j.gastha.2025.100810. eCollection 2026.https://pubmed.ncbi.nlm.nih.gov/41362828/

Background and aims: Up to 40% of patients with cystic fibrosis (CF) develop CF-related liver disease (CFrLD), which can progress to the point of requiring liver transplantation (LT). Advances in CF transmembrane conductance regulator (CFTR) modulator therapies, especially triple therapy modulators, have significantly improved pulmonary outcomes, but their impact on LT for CFrLD remains unclear.
Methods: Using data from the Scientific Registry of Transplant Recipients in 2000-2023, we analyzed trends in LT waitlisting for CFrLD pre- and post-U.S. Food and Drug Administration (FDA) approval of CFTR modulators: ivacaftor (January 31, 2012; single therapy), ivacaftor-lumacaftor (July 2, 2015; dual therapy), and ivacaftor-tezacaftor-elexacaftor (October 21, 2019; triple therapy). We compared the waitlist characteristics and post-LT outcomes of pre- and post-FDA approval eras.
Results: Of 258,090 patients waitlisted for LT, 551 (0.2%) had CFrLD. The proportion of CFrLD patients on the LT waitlist decreased after FDA approval of triple CFTR modulators (0.23% to 0.14%; P < .0004). Patients waitlisted after FDA approval of single and dual CFTR modulators were, on average, older (17.4 vs 20.6 years; P < .001 and 18.0 vs 20.8 years; P = .004). Median model for end-stage liver disease-sodium scores were higher among individuals waitlisted following the approval of dual (9 [6-14] vs 10 [8-15], P < .013) and triple (9 [6-14] vs 12.5 [8-17], P < .003) CFTR modulators. There were no significant differences in post-LT survival pre- and post-FDA approval of single, dual, or triple CFTR therapy.

Conclusion: These findings suggest that CFTR modulators may mitigate CFrLD complications and delay the need for waitlisting as physicians await the patient’s response to therapy and reassess the need for LT.

Sara Naimimohasses is at the   Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, Canada.

Pedro Del Palacio-García , Carmen García-Muñoz, María Dolores Canales-Siguero, Maria Carmen Luna-Paredes, Enrique Salcedo-Lobato, Fernando Huecas-Jiménez, Carlota Esperanza Vaquer-Ferrer , José Miguel Ferrari-Piquer.   Multidisciplinary approach to prenatal cystic fibrosis with cystic fibrosis transmembrane regulator modulators: Experience in a clinical case.  Case Reports Farm Hosp. 2026 Jan 28:S1130-6343(25)00213-2. doi: 10.1016/j.farma.2025.09.005. Online ahead of print. Full text available  via free article.  https://pubmed.ncbi.nlm.nih.gov/41611548/

Pedro Del Palacio-Garci is at Servicio de Farmacia Hospitalaria, Hospital Universitario 12 de Octubre, Madrid, Spain.

Pierre-Emmanuel Rautou , Sophie Hillaire, Simone Gambazza,Pierre-Emmanuel Rautou, Sophie Hillaire, Simone Gambazza, Carla Colombo.  Elexacaftor-tezacaftor-ivacaftor and cystic fibrosis liver disease: A turning point that calls for cautious optimism.   Editorial JHEP Rep. 2025 Nov 26;8(2):101688. doi: 10.1016/j.jhepr.2025.101688. eCollection 2026  Free full article  Feb.https://pubmed.ncbi.nlm.nih.gov/41551410/

The authors note the  study by Mouliade et al., published in this issue of JHEP Reports,(and abstracted below) provides the first large-scale, population-based evidence suggesting that elexacaftor–tezacaftor–ivacaftor (ETI) therapy may modify the natural history of CFLD. Using exhaustive French nationwide hospital data over nearly a decade (2014–2023), the authors report a marked reduction in the incidence of CFLD progression and all-cause, in-hospital mortality among French people with cystic fibrosis (pwCF) aged over 12 years during the period following the introduction of ETI (available in France since December 2019).

Ratou et al note  the  findings of Mouliade et al are striking and carry major implications for both hepatology and CF. Yet, as is often the case when an apparently simple message arises from complex, heterogeneous data, they invite both enthusiasm and caution.

Pierre-Emmanuel Rautou is at Université Paris-Cité, Inserm, Centre de recherche sur l’inflammation, UMR 1149, Paris, France. and P-HP, Hôpital Beaujon, Service d’Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France.

Charlotte Roy. Update on paediatric lung transplantation: an overview of a challenging therapeutic. Paediatr Respir Rev. 2026 Jan 11:S1526-0542(26)00002-3. doi: 10.1016/j.prrv.2026.01.002.  https://pubmed.ncbi.nlm.nih.gov/41565508/

Paediatric lung transplantation is a rare but increasingly successful therapeutic option for children with end-stage respiratory failure. Over the past decade, its epidemiology has shifted, with cystic fibrosis becoming an uncommon indication and a growing proportion of candidates presenting with interstitial lung disease or pulmonary arterial hypertension. In parallel, advances in donor allocation, the development of size-reduction surgical techniques and the reconditioning of marginal lungs have expanded the donor pool and reduced waiting-list mortality, including in small children. Peri-operative improvements-including broader use of extracorporeal life support as a bridge to transplantation-have further strengthened early and long-term outcomes. At the same time, progress in infectious disease prophylaxis and antiviral therapy, coupled with a more refined understanding of rejection mechanisms, is reshaping post-transplant care. Together, these developments underscore the importance of early referral to specialised paediatric transplant centres to ensure timely assessment and optimal access to advanced supportive strategies.

Charlotte Roy is a paediatrician at the Department of Paediatric Pulmonology and Allergology, University Hospital Necker-Enfants Malades, AP-HP, Université Paris Cité, France

Rachel G Sinkey, Bryan Garcia, Christopher Miles Fowler, Stefanie Krick, Kevin J Ryan , Edward P Acosta, Jennifer S Guimbellot   Pharmacokinetic assessment of elexacaftor/tezacaftor/ivacaftor and their metabolites in maternal blood, cord blood, the neonate, and breastmilk of a cystic fibrosis carrier mother/affected fetus dyad   Case Reports J Cyst Fibros. 2026 Jan;25(1):28-31. doi: 10.1016/j.jcf.2025.11.013. Epub 2025 Nov 28.https://pubmed.ncbi.nlm.nih.gov/41314865/

There are a paucity of data regarding the pharmacokinetics (PK) of elexacaftor (ELX)/tezacaftor(TEZ)/ivacaftor(IVA)(ETI) in pregnant and/or lactating mothers and their offspring. We conducted a PK assessment of ETI and their metabolites in maternal/neonatal/cord blood and breast milk from a cystic fibrosis (CF) carrier mother/affected fetus dyad, collecting specimens at delivery, 1 and 4 weeks after birth. The infant received on-label direct dosing after 1 month of life; all PK samples were collected prior to initiation of neonatal dosing and analyzed using LC-MS/MS. Measured metabolites were IVA-M1, IVA-M6, ELX-M23 and TEZ-M1. The female infant was born at 37 weeks gestation with successful meconium passage on the first day of life. Sweat chloride at 15 days (16 and 17 mmol/L) and immunoreactive trypsinogen (27.5 ng/mL) were normal. Neonatal genetics confirmed F508del/P67L genotype. Parent drug concentrations were measurable in cord blood and capillary heel sticks, indicating they cross the placenta. After delivery, the infant’s only source of modulators was via breast milk. Breast milk concentrations were measured at 1 and 4 weeks of life. Relative to maternal concentrations, ETI and their metabolites were present at lower concentrations. Heel stick specimens revealed undetectable IVA, but ELX and TEZ were below the assay limit. IVA-M1 and IV-M6 concentrations were lower at 1 and 4 weeks relative to delivery. To our knowledge, this is the first report of ETI metabolite concentrations following in utero administration.

Rachel Sinkey is Assistant Professor at theDepartment of Obstetrics & Gynecology, University of Alabama at Birmingham, 1700 Sixth Avenue S Suite 10270, Birmingham, AL 35233, USA

Alan Shi, Cole Cornwell, Kyunghee Yang, Paul M Beringer.  Quantitative Systems Toxicology Predicts Ivacaftor-Induced Oxidative Stress Contributes to CFTR Modulator Hepatotoxicity. Clin Pharmacol Ther. 2026 Jan;119(1):208-218. doi: 10.1002/cpt.70073. Epub 2025 Sep 23.DOI: 10.1002/cpt.70073 https://pubmed.ncbi.nlm.nih.gov/40985277/

Cystic fibrosis (CF) is a chronic hereditary disease that affects tens of thousands of people worldwide. The introduction of CFTR modulator therapies such as elexacaftor/tezacaftor/ivacaftor (ETI) has significantly improved the quality of life of people with CF. However, ETI has been shown in clinical trials to cause elevations in liver enzymes, and real-world cases of drug-induced liver injury (DILI) have also been reported. The mechanism of ETI-mediated DILI is currently unknown, hindering the development of more effective mitigation strategies for this adverse reaction. Through in vitro assays and quantitative systems toxicology modeling using DILIsym, this study revealed that ivacaftor contributed most significantly to ETI-mediated DILI, primarily via reactive oxygen species production, resulting in mitochondrial dysfunction due to electron transport chain inhibition. DILIsym modeling also predicted liver enzyme elevations following daily dosing of ETI at a comparable frequency (6.0%) to that of clinical data (8.0%). Simulations of the therapeutic effects of DILI mitigation strategies for ETI showed that dose reduction and antioxidant administration may significantly reduce the frequency of liver enzyme elevations due to ETI.

Alan Chi is a PHD student at the Mann school ofPharmacy Souther California

Sacha Spelier , Maud I M van der Wijst, Isabelle Fajac, Damian G Downey. Ageing with cystic fibrosis: Challenges ahead. J Cyst Fibros
. 2026 Jan 7:S1569-1993(25)02546-9. doi: 10.1016/j.jcf.2025.12.015. Online ahead of print. FREE article. https://pubmed.ncbi.nlm.nih.gov/41506936/

As life expectancy for people with cystic fibrosis continues to improve due to advances in care and CFTR modulator therapies, age-related comorbidities are emerging as new clinical challenges. This short review summarizes insights from a symposium focusing on ageing and CF at the 20th ECFS Basic Science Conference in March 2025 in Pisa, Italy. Mechanisms of ageing and their involvement in CF disease are first outlined. We then highlight two age-associated comorbidities in CF, cardiovascular disease and colorectal cancer, and outline future research directions to clarify how CF-specific and general ageing mechanisms intersect. Understanding these processes will be crucial for tailoring long-term care strategies in the ageing CF population.

Sacha Speller is in the  Department of Pediatric Respiratory Medicine, Wilhelmina Children’s Hospital, University Medical Center, Utrecht University, Utrecht,

— Suggest  viewers  read the full article via link for more details  of  the  increasingly important subject of aging in CF

Dogus Vuralli.   From Pathophysiology to Treatment: Contemporary Approaches to CFRD in the Pediatric and Adolescent Population. Review Pediatr Diabetes
. 2026 Jan 16:2026:5539725. doi: 10.1155/pedi/5539725. eCollection 2026.https://pubmed.ncbi.nlm.nih.gov/41552835/

Cystic fibrosis-related diabetes (CFRD) is the most prevalent nonrespiratory complication of cystic fibrosis (CF), with its prominence growing as survival rates improve due to advances in CFTR modulator therapies. Its prevalence increases with age, affecting nearly 50% of patients with CF (PwCF) over 30 years old. CFRD primarily results from progressive pancreatic fibrosis leading to insulin deficiency, further compounded by intermittent insulin resistance during pulmonary exacerbations and systemic inflammation. Key risk factors include pancreatic insufficiency, female sex, severe CFTR genotypes (such as p.F508del homozygosity), CF-related liver disease, and family history of type 2 diabetes. The early stages of CFRD are often asymptomatic, necessitating proactive screening. Annual oral glucose tolerance tests (OGTT) beginning at age 10 are challenging to perform but remain the gold standard for early detection, while continuous glucose monitoring (CGM) is increasingly recognized as a valuable complementary tool. Diagnosis is based on standard OGTT criteria, with indeterminate glycemia (INDET) and impaired glucose tolerance (IGT) recognized as prediabetic stages requiring close monitoring. Even early abnormalities in glucose metabolism may be associated with declines in pulmonary function and nutritional status, underscoring the need for rigorous surveillance and timely therapeutic intervention. Early initiation of insulin treatment can substantially mitigate these complications and improve clinical outcomes. Insulin remains the cornerstone of CFRD management, is recommended as the primary treatment for patients with CFRD (PwCFRD) rather than dietary modification alone. While pilot studies and observational cohorts have suggested potential benefits of early insulin treatment in individuals with early glycemic abnormalities such as INDET or IGT, findings from randomized controlled trials do not provide evidence to justify initiating insulin before CFRD is established. Management strategies should be individualized, with personalized glycemic targets. Insulin dosing aims to achieve the maximum tolerable dose to maintain a low HbA1c, control postprandial hyperglycemia without inducing hypoglycemia, minimize catabolism, and preserve optimal nutrition and pulmonary health without restricting carbohydrate intake. Regular glucose monitoring, quarterly HbA1c measurements, and annual screening for microvascular complications starting 5 years after diagnosis are essential to optimize outcomes. The advent of CFTR modulator therapies has revolutionized CF care, significantly improving outcomes and quality of life for PwCF. These therapies also show promise in improving glucose regulation and may impact the prevalence, onset, and course of CFRD. However, current data remain inconclusive, and the long-term effects are still being elucidated. Future directions in CFRD research include refining screening protocols, exploring adjunctive noninsulin therapies, and developing predictive biomarkers. This review summarizes the current understanding of CFRD pathophysiology, diagnosis, and management strategies, emphasizing the importance of early intervention and personalized care in the context of evolving CF treatment approaches and their potential to improve prognosis for PwCF.

Dogus Vuralli  from  the The Genetics and Genomic Medicine Research and Teaching Department, University College London (UCL) Great Ormond Street Institute of Child Health, 30 Guilford Street, London, and also the Department of Pediatric Endocrinology, Hacettepe University Faculty of Medicine, Ankara, Türkiye