Eur Respir Rev. 2024 Jul 24;33(173):240085. doi: 10.1183/16000617.0085-2024. Print 2024 Jul.

ABSTRACT

Bronchiectasis presents a significant challenge due to its rising prevalence, associated economic burden and clinical heterogeneity. This review synthesises contemporary understanding and literature of bronchiectasis exacerbations, addressing the transition from stable state to exacerbations, underlining the importance of early and precise recognition, rigorous severity assessment, prompt treatment, and prevention measures, as well as emphasising the need for strategies to assess and improve early and long-term patient outcomes. The review highlights the interplay between stable state phases and exacerbations in bronchiectasis, introducing the concept of "exogenous and endogenous changes in airways homeostasis" and the "adapted island model" with a particular focus on "frequent exacerbators", a group of patients associated with specific clinical characteristics and worse outcomes. The pathophysiology of exacerbations is explored through the lens of microbial and nonmicrobial triggers and the presence and the activity of comorbidities, elaborating on the impact of both exogenous insults, such as infections and pollution, and endogenous factors such as inflammatory endotypes. Finally, the review proposes a multidisciplinary approach to care, integrating advancements in precision medicine and biomarker research, paving the way for tailored treatments that challenge the traditional antibiotic paradigm.

PMID:39048130 | DOI:10.1183/16000617.0085-2024

Biochem Biophys Res Commun. 2024 Jul 20;733:150433. doi: 10.1016/j.bbrc.2024.150433. Online ahead of print.

ABSTRACT

The most common CFTR mutant in cystic fibrosis (CF), ΔF508 CFTR, is eliminated by ubiquitination even in the presence of CF drugs, reducing their therapeutic efficacy. RFFL is one of the ubiquitin ligases that remove ΔF508 CFTR from the cell surface despite treatment with the triple combination of CFTR modulators (TEZ/ELX/IVA) used clinically. Although RFFL knockdown has been shown to enhance the efficacy of TEZ/ELX/IVA in cell culture models, its impact in mouse models has not been evaluated. Here, we demonstrate that RFFL ablation significantly improves the effect of TEZ/ELX/IVA, resulting in enhanced function of ΔF508 CFTR in mouse organoids. Since RFFL knockout mice showed no significant abnormalities, our findings support RFFL inhibition as a promising strategy to improve CFtreatment.

PMID:39047427 | DOI:10.1016/j.bbrc.2024.150433

AMB Express. 2024 Jul 23;14(1):84. doi: 10.1186/s13568-024-01742-z.

ABSTRACT

Cystic Fibrosis Transmembrane Regulator (CFTR) is a significant protein that is responsible for the movement of ions across cell membranes. The cystic fibrosis (CF) occur due to the mutations in the CFTR gene as it produces the dysfunctional CFTR protein. The sequence of CFTR protein as a target structure was retrieved from UniProt and PDB database. The ligands selection was performed through virtual screening and top 3 ligands choose out of 65 ligands silibinins, curcumin, demethoxycurcumin were selected with a reference drug Trikafta (R*). According to docking, ADMET analyses, the natural ligands (Silibinins and Curcumin) displayed best binding energy, pharmacokinetic and free toxicity than other natural compounds and reference drug (R*). An MD simulation for 200 ns was also established to ensure that natural ligands (Silibinins and Curcumin) attached to the target protein favorably and dynamically, and that protein-ligand complex stability was maintained. It is concluded that silibinins and curcumins have a better capacity to decrease the effect of mutant CFTR protein through improved trafficking and the restoration of original function. In conclusion, in silico studies demonstrate the potential of silibinins and curcumin as therapeutic agents for cystic fibrosis, particularly for the D614G mutated protein. Their ability to increase CFTR function while reducing cellular stress and inflammation, together with their favorable safety profile and accessibility could make them valuable additions to cystic fibrosis treatment options. Further experimental and clinical validation will be required to fully realize their potential and include them into effective therapy regimens.

PMID:39043981 | DOI:10.1186/s13568-024-01742-z

Sci Rep. 2024 Jul 23;14(1):16895. doi: 10.1038/s41598-024-66473-4.

ABSTRACT

SARS-CoV-2-contributes to sickness and death in COVID-19 patients partly by inducing a hyper-proinflammatory immune response in the host airway. This hyper-proinflammatory state involves activation of signaling by NFκB, and unexpectedly, ENaC, the epithelial sodium channel. Post-infection inflammation may also contribute to "Long COVID"/PASC. Enhanced signaling by NFκB and ENaC also marks the airway of patients suffering from cystic fibrosis, a life-limiting proinflammatory genetic disease due to inactivating mutations in the CFTR gene. We therefore hypothesized that inflammation in the COVID-19 airway might similarly be due to inhibition of CFTR signaling by SARS-CoV-2 spike protein, and therefore activation of both NFκB and ENaC signaling. We used western blot and electrophysiological techniques, and an organoid model of normal airway epithelia, differentiated on an air-liquid-interface (ALI). We found that CFTR protein expression and CFTR cAMP-activated chloride channel activity were lost when the model epithelium was exposed to SARS-CoV-2 spike proteins. As hypothesized, the absence of CFTR led to activation of both TNFα/NFκB signaling and α and γ ENaC. We had previously shown that the cardiac glycoside drugs digoxin, digitoxin and ouabain blocked interaction of spike protein and ACE2. Consistently, addition of 30 nM concentrations of the cardiac glycoside drugs, prevented loss of both CFTR protein and CFTR channel activity. ACE2 and CFTR were found to co-immunoprecipitate in both basal cells and differentiated epithelia. Thus spike-dependent CFTR loss might involve ACE2 as a bridge between Spike and CFTR. In addition, spike exposure to the epithelia resulted in failure of endosomal recycling to return CFTR to the plasma membrane. Thus, failure of CFTR recovery from endosomal recycling might be a mechanism for spike-dependent loss of CFTR. Finally, we found that authentic SARS-CoV-2 virus infection induced loss of CFTR protein, which was rescued by the cardiac glycoside drugs digitoxin and ouabain. Based on experiments with this organoid model of small airway epithelia, and comparisons with 16HBE14o- and other cell types expressing normal CFTR, we predict that inflammation in the COVID-19 airway may be mediated by inhibition of CFTR signaling by the SARS-CoV-2 spike protein, thus inducing a cystic fibrosis-like clinical phenotype. To our knowledge this is the first time COVID-19 airway inflammation has been experimentally traced in normal subjects to a contribution from SARS-CoV-2 spike-dependent inhibition of CFTR signaling.

PMID:39043712 | DOI:10.1038/s41598-024-66473-4

Pediatr Pulmonol. 2024 Jul 23. doi: 10.1002/ppul.27179. Online ahead of print.

ABSTRACT

BACKGROUND: One-third of people with cystic fibrosis (pwCF) are food insecure, with profound negative implications for their health. This qualitative study explored lived experiences with food insecurity among pwCF or their caregivers and summarized their perspectives on food insecurity screening in the cystic fibrosis (CF) programs where they receive care.

METHODS: Semi-structured qualitative interviews were conducted with two groups: (1) adults with CF and (2) parents or caregivers of children with CF. PwCF or their caregivers with previously documented food insecurity were referred for participation by pediatric and adult CF programs across the United States. Interviews were recorded and transcribed, and data were coded and analyzed by two independent coders using a content-analysis approach with a constant comparative method to generate themes.

RESULTS: A total of 26 participants from 22 CF programs were interviewed. The sample included 17 adults with CF and nine parents of children with CF. Participants were predominantly White (88%) and female (92%). Five overarching themes emerged: (1) food insecurity among CF patients and their families is onerous, (2) financial constraints imposed by the CF disease contribute to food insecurity, (3) federal and state programs provide limited food assistance, and other support is minimal, (4) shame and stigma engulf conversations around food insecurity with CF care teams, and (5) food insecurity screening in clinical settings is critical.

CONCLUSIONS: Food insecurity among pwCF is invisible, but its consequences are dire. Assistance is limited, screening is inconsistent, and stigma is widespread. There is an urgent need to normalize food insecurity screening, standardize the screening process, and expand food assistance programs for pwCF.

PMID:39041893 | DOI:10.1002/ppul.27179

Ann Am Thorac Soc. 2024 Jul 23. doi: 10.1513/AnnalsATS.202404-366OC. Online ahead of print.

ABSTRACT

Rationale Evaluating approaches to reduce treatment burden is a research priority among people with CF (pwCF) on highly effective modulators including elexacaftor/tezacaftor/ivacaftor (ETI). Objective To evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods SIMPLIFY participants ≥12 years old on ETI and comprising a subgroup using both HS and DA at study entry were randomized to the HS or DA trial, and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY versus a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth and percent predicted forced expiratory volume in one second (ppFEV1) at study entry. Results There were 43 participants who discontinued both therapies by the end of SIMPLIFY and 63 who remained on both, with overall average ppFEV1 at study entry 96.7% and average duration of follow up from beginning of the first trial to completion of the second trial 3.9 months, including time between trials. No clinically meaningful difference in the change in ppFEV1 from baseline to completion of the second trial was observed between those who discontinued versus remained on both therapies (difference: 0.22% Off-On, 95% CI: -1.60,2.03). Changes in LCI2.5, patient reported, and safety outcomes were also comparable. Patient reported treatment burden, as measured by a CFQ-R subscale, significantly decreased in those discontinuing both therapies. Conclusions SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared to those who remained on both therapies. These data continue to inform a new era of post-modulator care of pwCF.

PMID:39041864 | DOI:10.1513/AnnalsATS.202404-366OC

Am J Physiol Gastrointest Liver Physiol. 2024 Jul 23. doi: 10.1152/ajpgi.00145.2024. Online ahead of print.

ABSTRACT

Mucocele formation in dogs is a unique and enigmatic muco-obstructive disease of the gallbladder caused by amassment of abnormal mucus that bears striking pathological similarity to cystic fibrosis. We investigated the role of CFTR in the pathogenesis of this disease. The location and frequency of disease-associated variants in the coding region of CFTR was compared using whole genome sequence data from 2,642 dogs representing breeds at low-risk, high-risk, or with confirmed disease. Expression, localization, and ion transport activity of CFTR was quantified in control and mucocele gallbladders by NanoString, Western blotting, immunofluorescence imaging, and studies in Ussing chambers. Our results establish significant loss of CFTR-dependent anion secretion by mucocele gallbladder mucosa. A significantly lower quantity of CFTR protein was demonstrated relative to E-cadherin in mucocele compared to control gallbladder mucosa. Immunofluorescence identified CFTR along the apical membrane of epithelial cells in control gallbladders but not in mucocele gallbladder epithelium. Decreases in mRNA copy number for CFTR was accompanied by decreases in mRNA for the Cl-/HCO3- exchanger SLC26A3, K+ channels (KCNQ1, KCNN4), and vasoactive intestinal polypeptide receptor (VIPR1) which suggest a driving force for change in secretory function of gallbladder epithelial cells in the pathogenesis of mucocele formation. There were no significant differences in CFTR gene variant frequency, type, or predicted impact comparing low risk, high risk, and definitively diagnosed groups of dogs. This study describes a unique, naturally occurring muco-obstructive disease of the canine gallbladder, with uncanny similarity to cystic fibrosis, and driven by underlying failure of CFTR function.

PMID:39041675 | DOI:10.1152/ajpgi.00145.2024

Front Pediatr. 2024 Jul 8;12:1347983. doi: 10.3389/fped.2024.1347983. eCollection 2024.

ABSTRACT

OBJECTIVE: This study is an addition to the already published prospective randomized double-blinded trial by Tschiedel et al. that compared two different sedation regimes in fiberoptic flexible bronchoscopy in pediatric subjects. The objective of the presented study is to analyze the correlation between the neutrophil percentage of the bronchoalveolar lavage fluid (BALF) and coughing episodes during bronchoscopy.

METHODS: Fifty subjects, aged 1-17 years, received flexible fiberoptic bronchoscopy under deep sedation. The BALF of 39 subjects was analyzed with reference to cytology and microbiology.

RESULTS: The percentage of neutrophils from the total cell count ranged from 0% to 95.3% (median 2.7). Nineteen patients (49%) had a percentage of ≥3.0%. Pearson's correlation showed a high correlation (r = 0.529, p = 0.001) between the coughing episodes per minute and the neutrophil percentage in the BALF. Analysis of variance showed a significant difference in neutrophil percentage between the indication groups (p = 0.013). The t-test (p = 0.019) showed a significant difference between the neutrophil percentage for patients with a probable airway infection under immunosuppression (median 2.9) and patients with cystic fibrosis (median 49.6). The linear regression analysis showed a significantly stronger impact of the neutrophil percentage on coughing frequency than the sedation regime (βneutrophils = 0.526 with p = 0.001 vs. βsedation = 0.165 with p = 0.251).

CONCLUSION: When bronchoscopy is to be performed on a pediatric patient with suspected bacterial or viral infection, and therefore neutrophilic airway inflammation, coughing is to be expected.

PMID:39040668 | PMC:PMC11260698 | DOI:10.3389/fped.2024.1347983

ERJ Open Res. 2024 Jul 22;10(4):00151-2024. doi: 10.1183/23120541.00151-2024. eCollection 2024 Jul.

ABSTRACT

INTRODUCTION: Brensocatib is an investigational, oral, reversible inhibitor of dipeptidyl peptidase-1 shown to prolong time to first exacerbation in adults with bronchiectasis. Outlined here are the clinical trial design, and baseline characteristics and treatment patterns of adult patients enrolled in the phase 3 ASPEN trial (NCT04594369).

METHODS: The ASPEN trial is a global study enrolling patients with a clinical history consistent with bronchiectasis (cough, chronic sputum production and/or recurrent respiratory infections), diagnosis confirmed radiologically and ≥2 exacerbations in the prior 12 months. It was designed to evaluate the impact of two brensocatib doses (10 mg and 25 mg) on exacerbation rate over a 52-week treatment period versus placebo. Comprehensive clinical data, including demographics, disease severity, lung function, Pseudomonas aeruginosa status and quality of life, were collected at baseline.

RESULTS: 1682 adults from 35 countries were randomised from December 2020 to March 2023. Mean age was 61.3 years and 64.7% were female. ∼70% had moderate-to-severe Bronchiectasis Severity Index (BSI) scores, 29.3% had ≥3 exacerbations in the prior 12 months and 35.7% were positive for P. aeruginosa. Mean BSI scores were highest in Australia/New Zealand (8.3) and lowest in Latin America (5.9). Overall, the most common aetiology was idiopathic (58.4%). In P. aeruginosa-positive versus P. aeruginosa-negative patients, lung function was lower, with greater long-term macrolide (21.5% versus 14.0%) and inhaled corticosteroid use (63.5% versus 53.9%). There was wide regional variation in long-term antibiotic use in patients with bronchiectasis and P. aeruginosa.

DISCUSSION: ASPEN baseline characteristics and treatment profiles were representative of a global bronchiectasis population.

PMID:39040578 | PMC:PMC11261371 | DOI:10.1183/23120541.00151-2024

Heliyon. 2024 Jun 22;10(13):e33439. doi: 10.1016/j.heliyon.2024.e33439. eCollection 2024 Jul 15.

ABSTRACT

BACKGROUND: Knowledge of prevalence and epidemiology of cystic fibrosis (CF) and healthcare resource use among Finnish people with CF is incomplete.

METHODS: We conducted a population-based matched cohort study using retrospective real-world data from linked Finnish national registries. Electronic healthcare data and drug purchases of 102 people with CF were analyzed between January 2015 and December 2019 (follow-up). A 5-fold control population was matched by sex, age, and place of residence. Comorbidities and medication use that occurred at any time during follow-up were assessed; annual rates of hospital service use were adjusted for follow-up.

RESULTS: The prevalence of CF in Finland was 1.85 per 100,000. Median age at diagnosis was 1 year, with 60 % diagnosed at age <2 years and 80 % at age <10 years. Median age at death in people with CF was 31.4 years (n < 5); no controls died. The most common comorbidities included chronic sinusitis (39.2 %), pneumonia (38.2 %), diabetes (20.6 %), and nasal polyps (18.6 %). The most purchased medications were antibiotics (99.0 %) and pancreatic enzymes (84.3 %). The annualized rate of hospital visits was higher in people with CF vs controls (outpatient: mean [SD], 17.4 [14.5] vs 0.9 [3.3]; median, 13.6 vs 0.4, respectively; inpatient: mean [SD], 1.0 [1.66] vs 0.03 [0.14]; median, 0.34 vs 0, respectively).

CONCLUSIONS: The prevalence of CF in Finland is remarkably low, likely reflecting unique population characteristics and, in part, delayed diagnosis. Antibiotic use is frequent among Finnish people with CF. Inpatient hospital visits are >30 times higher in people with CF than matched controls.

PMID:39040318 | PMC:PMC11261030 | DOI:10.1016/j.heliyon.2024.e33439

Front Cell Dev Biol. 2024 Jul 8;12:1361084. doi: 10.3389/fcell.2024.1361084. eCollection 2024.

ABSTRACT

Idiopathic cholangiopathies are diseases that affect cholangiocytes, and they have unknown etiologies. Currently, orthotopic liver transplantation is the only treatment available for end-stage liver disease. Limited access to the bile duct makes it difficult to model cholangiocyte diseases. In this study, by mimicking the embryonic development of cholangiocytes and using a robust, feeder- and serum-free protocol, we first demonstrate the generation of unique functional 3D organoids consisting of small and large cholangiocytes derived from human pluripotent stem cells (PSCs), as opposed to traditional 2D culture systems. At day 28 of differentiation, the human PSC-derived cholangiocytes expressed markers of mature cholangiocytes, such as CK7, CK19, and cystic fibrosis transmembrane conductance regulator (CFTR). Compared with the 2D culture system-generated cholangiocytes, the 3D cholangiocyte organoids (COs) showed higher expression of the region-specific markers of intrahepatic cholangiocytes YAP1 and JAG1 and extrahepatic cholangiocytes AQP1 and MUC1. Furthermore, the COs had small-large tube-like structures and functional assays revealed that they exhibited characteristics of mature cholangiocytes, such as multidrug resistance protein 1 transporter function and CFTR channel activity. In addition to the extracellular matrix supports, the epidermal growth factor receptor (EGFR)-mediated signaling regulation might be involved in this cholangiocyte maturation and differentiation. These results indicated the successful generation of intrahepatic and extrahepatic cholangiocytes by using our 3D organoid protocol. The results highlight the advantages of our 3D culture system over the 2D culture system in promoting the functional differentiation and maturation of cholangiocytes. In summary, in advance of the previous works, our study provides a possible concept of small-large cholangiocyte transdifferentiation of human PSCs under cost-effective 3D culture conditions. The study findings have implications for the development of effective cell-based therapy using COs for patients with cholangiopathies.

PMID:39040044 | PMC:PMC11260683 | DOI:10.3389/fcell.2024.1361084

Pediatr Radiol. 2024 Jul 22. doi: 10.1007/s00247-024-05979-5. Online ahead of print.

ABSTRACT

Analysis of the liver using imaging for persons with cystic fibrosis (CF) continues to evolve as new medical therapies are developed improving and extending life. In the 2010s, therapies targeted at modulating protein folding became available to those with CF. Therapeutic options have continued to expand, now providing both correction of protein folding and stabilization for most gene mutations that code for the CF transmembrane receptor protein (CFTR). Today, approximately 80% of persons with CF are eligible for highly effective modulator therapy. With these advancements, the impact of CF on the liver has become more complex, adding metabolism of CFTR modulators to intrinsic CF hepatobiliary involvement (CFHBI) and adding not previously appreciated vascular changes within the liver due to increased longevity in persons with CF. A combination of serum biomarkers and imaging is needed to add clarity to the diagnosis and monitoring of the severity of liver disease. A substantial portion of persons with CF will develop at least CFHBI and a subset will develop advanced cystic fibrosis-associated liver disease (aCFLD); therefore, diagnosis and monitoring need to begin in childhood. In this review, we cover the use of and need for imaging, including elastography, ultrasound, and magnetic resonance imaging (MRI), in diagnosing and monitoring CFHBI and its associated complications.

PMID:39039200 | DOI:10.1007/s00247-024-05979-5

J Nonnewton Fluid Mech. 2024 Aug;330:105281. doi: 10.1016/j.jnnfm.2024.105281. Epub 2024 Jun 24.

ABSTRACT

The formation of a liquid plug inside a human airway, known as airway closure, is computationally studied by considering the elastoviscoplastic (EVP) properties of the pulmonary mucus covering the airway walls for a range of liquid film thicknesses and Laplace numbers. The airway is modeled as a rigid tube lined with a single layer of an EVP liquid. The Saramito-Herschel-Bulkley (Saramito-HB) model is coupled with an Isotropic Kinematic Hardening model (Saramito-HB-IKH) to allow energy dissipation at low strain rates. The rheological model is fitted to the experimental data under healthy and cystic fibrosis (CF) conditions. Yielded/unyielded regions and stresses on the airway wall are examined throughout the closure process. Yielding is found to begin near the closure in the Saramito-HB model, whereas it occurs noticeably earlier in the Saramito-HB-IKH model. The kinematic hardening is seen to have a notable effect on the closure time, especially for the CF case, with the effect being more pronounced at low Laplace numbers and initial film thicknesses. Finally, standalone effects of rheological properties on wall stresses are examined considering their physiological values as baseline.

PMID:39036645 | PMC:PMC11258864 | DOI:10.1016/j.jnnfm.2024.105281

Learn Health Syst. 2024 Apr 15;8(3):e10417. doi: 10.1002/lrh2.10417. eCollection 2024 Jul.

ABSTRACT

INTRODUCTION: The rapid development of artificial intelligence (AI) in healthcare has exposed the unmet need for growing a multidisciplinary workforce that can collaborate effectively in the learning health systems. Maximizing the synergy among multiple teams is critical for Collaborative AI in Healthcare.

METHODS: We have developed a series of data, tools, and educational resources for cultivating the next generation of multidisciplinary workforce for Collaborative AI in Healthcare. We built bulk-natural language processing pipelines to extract structured information from clinical notes and stored them in common data models. We developed multimodal AI/machine learning (ML) tools and tutorials to enrich the toolbox of the multidisciplinary workforce to analyze multimodal healthcare data. We have created a fertile ground to cross-pollinate clinicians and AI scientists and train the next generation of AI health workforce to collaborate effectively.

RESULTS: Our work has democratized access to unstructured health information, AI/ML tools and resources for healthcare, and collaborative education resources. From 2017 to 2022, this has enabled studies in multiple clinical specialties resulting in 68 peer-reviewed publications. In 2022, our cross-discipline efforts converged and institutionalized into the Center for Collaborative AI in Healthcare.

CONCLUSIONS: Our Collaborative AI in Healthcare initiatives has created valuable educational and practical resources. They have enabled more clinicians, scientists, and hospital administrators to successfully apply AI methods in their daily research and practice, develop closer collaborations, and advanced the institution-level learning health system.

PMID:39036530 | PMC:PMC11257059 | DOI:10.1002/lrh2.10417

Cureus. 2024 Jun 21;16(6):e62821. doi: 10.7759/cureus.62821. eCollection 2024 Jun.

ABSTRACT

Background Cystic fibrosis (CF) is a genetic disorder of the cystic fibrosis transmembrane conductance regulator chloride channel that leads to impaired mucus clearance in the airways, which leads to deteriorations in lung function and chronic respiratory infection. These effects of CF contribute to the hypothesis that patients with CF may be at increased risk of complications when they catch coronavirus disease 2019 (COVID-19), which swept the world in a global pandemic starting in 2019. Overall, however, the role of CF in COVID-19 has not been well studied, particularly in pediatric patients. Methods In this retrospective review, pediatric patients with CF who contracted COVID-19 (3/1/2020-3/1/2023) (N=69) were compared to two equally sized control cohorts of patients with only CF or COVID-19 matched based on demographics and clinical baselines. Occurrences of adverse outcomes (emergency room visits, hospitalizations, CF pulmonary exacerbations, etc.) were assessed for each subject. The mean percentage of predicted forced expiratory volume in 1 second (FEV1%pred) was also assessed for CF patients. Fisher's exact test assessed differences between the proportions of subjects who experienced each outcome. Independent two-variable t-testing assessed mean FEV1%pred differences. Analysis was conducted using IBM SPSS Statistics for Windows, Version 29 (Released 2023; IBM Corp., Armonk, New York, United States) with a significance α=0.05. Ad hoc power analysis was conducted using G*Power v3.1. Results Overall, CF/COVID subjects fared similarly to control groups without either CF or COVID-19 history, including among subgroups stratified based on baseline respiratory function, P. aeruginosa colonization status, and COVID-19 vaccination status. One notable finding was that CF/COVID subjects experienced significantly fewer pulmonary exacerbations compared to CF-only subjects (p=0.004). Conclusion In conclusion, pediatric CF patients performed similarly to their peers without CF with regard to COVID-19 and generally did not demonstrate significant deteriorations in pulmonary function following infection. Lower incidence of pulmonary exacerbations in CF/COVID subjects could be explained by stringent monitoring by parents, quarantine, or close pulmonology follow-up. These findings will provide guidance on management and care for pediatric CF patients with COVID-19.

PMID:39036102 | PMC:PMC11260353 | DOI:10.7759/cureus.62821

J Cyst Fibros. 2024 Jul 20:S1569-1993(24)00793-8. doi: 10.1016/j.jcf.2024.07.008. Online ahead of print.

ABSTRACT

The mental health effects of elexacaftor/tezacaftor/ivacaftor (ETI) on adults with CF are still uncertain with mixed findings from published studies. To systematically investigate the impact of ETI on symptoms of anxiety and depression in adults with CF, Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire (PHQ-9) scores were evaluated at baseline, 6 months, and 12 months post-ETI. Overall, GAD-7 and PHQ-9 scores improved at 6 months post-ETI, with a greater proportion of individuals experiencing a clinically significant improvement (vs. worsening) of their symptoms, which was sustained at 12 months. Factors influencing mental health outcomes included pre-existing psychiatric diagnoses and psychiatric medication use. In conclusion, although there was overall improvement in anxiety and depression symptoms post-ETI, approximately 10 % of individuals experienced clinically significant worsening.

PMID:39034264 | DOI:10.1016/j.jcf.2024.07.008

Pancreatology. 2024 Jul 17:S1424-3903(24)00689-6. doi: 10.1016/j.pan.2024.07.009. Online ahead of print.

NO ABSTRACT

PMID:39034207 | DOI:10.1016/j.pan.2024.07.009

J Cyst Fibros. 2024 Jul 19:S1569-1993(24)00794-X. doi: 10.1016/j.jcf.2024.07.010. Online ahead of print.

ABSTRACT

BACKGROUND: Acrolein, an aldehyde in smoke from tobacco products, inhibits CFTR function in vitro. Ivacaftor is an FDA-approved potentiator that improves mutant CFTR function. This human clinical study investigated the relationship between two urinary markers of tobacco smoke exposure - the acrolein metabolite 3-HPMA and the nicotine metabolite NNAL - and sweat chloride response to ivacaftor in the G551D Observational Trial (GOAL).

METHODS: 3-HPMA (low: <50th centile; moderate: 50-75th centile; high: >75th centile) and NNAL (detectable/undetectable) in GOAL samples was quantified with LC-MS/MS. Self-report of tobacco smoke exposure (Y/N) served as a subjective measure. Change in sweat chloride from pre- to 6 months post-ivacaftor treatment (ΔSC) was the primary CFTR-dependent readout.

RESULTS: The sample included 151 individuals, mean age 20.7 (SD 11.4) years, range 6-59 years. Smoke exposure prevalence was 15 % per self-reports but 27 % based on detectable NNAL. 3-HPMA was increased in those reporting tobacco smoke exposure (607 vs 354 ng/ml, p = 0.008), with a higher proportion of smoke-exposed in the high- vs low-acrolein group (31 % vs 9 %, p=0.040). Compared to low-acrolein counterparts, high-acrolein participants experienced less decrease in sweat chloride (-35.2 vs -48.2 mmol/L; p = 0.020) and had higher sweat chloride values (50.6 vs 37.6 mmol/L; p = 0.020) 6 months post-ivacaftor. The odds of ivacaftor-mediated potentiation to near normative CFTR function (defined as SC6mo <40 mmol/L) was more than twice as high in the low-acrolein cohort (OR: 2.51, p = 0.026).

CONCLUSIONS: Increased urinary 3-HPMA, an acrolein metabolite of tobacco smoke, is associated with a diminished sweat chloride response to ivacaftor potentiation of CFTR function.

PMID:39033068 | DOI:10.1016/j.jcf.2024.07.010

J Biol Chem. 2024 Jul 18:107594. doi: 10.1016/j.jbc.2024.107594. Online ahead of print.

ABSTRACT

Drug metabolism is one of the main processes governing the pharmacokinetics and toxicity of drugs via their chemical biotransformation and elimination. In humans, the liver, enriched with cytochrome P450 (CYP) enzymes, plays a major metabolic and detoxification role. The gut microbiome and its complex community of microorganisms can also contribute to some extent to drug metabolism. However, during an infection when pathogenic microorganisms invade the host, our knowledge of the impact on drug metabolism by this pathobiome remains limited. The intrinsic resistance mechanisms and rapid metabolic adaptation to new environments often allow the human bacterial pathogens to persist, despite the many antibiotic therapies available. Here, we demonstrate that a bacterial CYP enzyme, CYP107S1, from Pseudomonas aeruginosa, a predominant bacterial pathogen in cystic fibrosis (CF) patients, can metabolize multiple drugs from different classes. CYP107S1 demonstrated high substrate promiscuity and allosteric properties much like human hepatic CYP3A4. Our findings demonstrated binding and metabolism by the recombinant CYP107S1 of fluoroquinolone antibiotics (ciprofloxacin and fleroxacin), a CF transmembrane conductance regulator potentiator (ivacaftor), and a SERM antimicrobial adjuvant (raloxifene). Our in vitro metabolism data were further corroborated by molecular docking of each drug to the heme active site using a CYP107S1 homology model. Our findings raise the potential for microbial pathogens modulating drug concentrations locally at the site of infection, if not systemically, via CYP-mediated biotransformation reactions. To our knowledge, this is the first report of a CYP enzyme from a known bacterial pathogen that is capable of metabolizing clinically utilized drugs.

PMID:39032655 | DOI:10.1016/j.jbc.2024.107594

Eur J Obstet Gynecol Reprod Biol. 2024 Jul 1;300:219-223. doi: 10.1016/j.ejogrb.2024.06.045. Online ahead of print.

ABSTRACT

OBJECTIVE: The pregnancy, delivery, and neonatal outcomes of pregnancies complicated by cystic fibrosis (CF) have yet to be evaluated in a prolonged, population-based study. We sought to evaluate the obstetric and neonatal outcomes in pregnant patients with CF using a national population database.

STUDY DESIGN: Retrospective population-based cohort study utilizing the Healthcare Cost and Utilization Project, Nationwide Inpatient Sample (HCUP-NIS). All women who delivered or had a maternal death in the US (2004-2014) were included in the study. Pregnancy, delivery, and neonatal outcomes were compared between women with an ICD-9 diagnosis of cystic fibrosis to those without.

RESULTS: Overall, 9 096 159 women met the inclusion criteria. Of these, 629 women (6.9/100000) had CF. Women with CF were more likely to be younger and have pregestational diabetes mellitus compared to those without. CF in pregnancy was associated with an increased risk of developing gestational diabetes mellitus [aOR 3.20 (95 %CI 2.48-4.15), p = 0.0001], placenta previa [aOR 2.74 (95 %CI 1.30-5.79), p = 0.008], preterm delivery [aOR 2.17 (95 %CI 1.71-2.77), p = 0.0001], operative vaginal delivery [aOR 1.59 (95 %CI 1.17-2.16), p = 0.003], and death [aOR 86.41 (95 %CI 30.91-241.58), p = 0.0001], and a decreased likelihood of having a spontaneous vaginal delivery [aOR 0.80 (95 %CI 0.66-0.97), p = 0.02]. Patients with CF were more likely to experience deep venous thrombosis [aOR 7.64 (95 %CI 1.90-30.72), p = 0.004] and disseminated intravascular coagulation [aOR 3.68 (95 %CI 1.37-9.87), p = 0.01] compared to those without. The risk of delivering a fetus with congenital anomalies was similar between groups.

CONCLUSION: Pregnant patients with CF have an increased risk of developing adverse maternal and delivery outcomes. As such, these patients should receive vigilant surveillance during pregnancy.

PMID:39032310 | DOI:10.1016/j.ejogrb.2024.06.045