Pharmaceutics. 2025 Feb 6;17(2):200. doi: 10.3390/pharmaceutics17020200.

ABSTRACT

Background: The combination of ivacaftor, tezacaftor and elexacaftor (ETI) is approved for patients with cystic fibrosis (CF) aged two years and older and at least one F508del mutation in the CFTR gene. Variability in ETI treatment response has been repeatedly reported, and its reasons are unclear and understudied. Objectives: We present a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the rapid and simultaneous quantification of ETI in plasma, dried plasma spots (DPS), and whole blood volumetric absorptive microsampling (VAMS). Methods: The method utilizes a rapid extraction protocol with 200 μL methanol after the addition of deuterated internal standards. Chromatographic separation was achieved using a reversed-phase Hypersil Gold aQ column (Thermo Fisher Scientific). The method was validated according to ICH (International Council on Harmonisation) guidelines M10 for bioanalytical method validation, demonstrating linearity in the concentration range 0.020-12.000 µg/mL. It was also proved accurate and reproducible with no matrix effect. This method was applied to anonymized samples from patients undergoing ETI treatment: eight plasma and DPS and five VAMS samples were analyzed. Results: ETI concentrations measured in plasma and DPS were interchangeable, whereas ETI concentrations in VAMS were lower than in plasma, as expected for molecules with high plasma protein binding (99%). A correction factor based on the hematocrit value was used to calculate the equivalent plasma concentration from VAMS concentrations. Conclusions: This method is suitable for pharmacokinetic (PK) studies and could facilitate the centralization of samples to specialized laboratories, supporting multicenter studies.

PMID:40006567 | DOI:10.3390/pharmaceutics17020200

Pharmaceuticals (Basel). 2025 Feb 7;18(2):225. doi: 10.3390/ph18020225.

ABSTRACT

Background/Objectives: Mycobacterium abscessus (MAB) is a highly resilient pathogen that causes difficult-to-treat pulmonary infections, particularly in individuals with cystic fibrosis (CF) and other underlying conditions. Its ability to form robust biofilms within the CF lung environment is a major factor contributing to its resistance to antibiotics and evasion of the host immune response, making conventional treatments largely ineffective. These biofilms, encased in an extracellular matrix, enhance drug tolerance and facilitate metabolic adaptations in hypoxic conditions, driving the bacteria into a persistent, non-replicative state that further exacerbates antimicrobial resistance. Treatment options remain limited, with multidrug regimens showing low success rates, highlighting the urgent need for more effective therapeutic strategies. Methods: In this study, we employed artificial sputum media to simulate the CF lung environment and conducted high-throughput screening of 24,000 compounds from diverse chemical libraries to identify inhibitors of MAB biofilm formation, using the Crystal Violet (CV) assay. Results: The screen established 17 hits with ≥30% biofilm inhibitory activity in mycobacteria. Six of these compounds inhibited MAB biofilm formation by over 60%, disrupted established biofilms by ≥40%, and significantly impaired bacterial viability within the biofilms, as confirmed by reduced CFU counts. In conformational assays, select compounds showed potent inhibitory activity in biofilms formed by clinical isolates of both MAB and Mycobacterium avium subsp. hominissuis (MAH). Key compounds, including ethacridine, phenothiazine, and fluorene derivatives, demonstrated potent activity against pre- and post-biofilm conditions, enhanced antibiotic efficacy, and reduced intracellular bacterial loads in macrophages. Conclusions: This study results underscore the potential of these compounds to target biofilm-associated resistance mechanisms, making them valuable candidates for use as adjuncts to existing therapies. These findings also emphasize the need for further investigations, including the initiation of a medicinal chemistry campaign to leverage structure-activity relationship studies and optimize the biological activity of these underexplored class of compounds against nontuberculous mycobacterial (NTM) strains.

PMID:40006039 | DOI:10.3390/ph18020225

Pharmaceuticals (Basel). 2025 Jan 27;18(2):175. doi: 10.3390/ph18020175.

ABSTRACT

This manuscript provides a comprehensive review of advancements in dry powder inhaler (DPI) technology for pulmonary and systemic drug delivery, focusing on proteins, peptides, nucleic acids, and small molecules. Innovations in spray-drying (SD), spray freeze-drying (SFD), and nanocarrier engineering have led to enhanced stability, bioactivity, and aerosol performance. Studies reveal the critical role of excipients, particle morphology, and device design in optimizing deposition and therapeutic efficacy. Applications include asthma, cystic fibrosis, tuberculosis (TB), and lung cancer, with emerging platforms such as ternary formulations and siRNA-loaded systems demonstrating significant clinical potential. Challenges such as stability, scalability, and patient adherence are addressed through novel strategies, including Quality by Design (QbD) approaches and advanced imaging tools. This work outlines pathways for future innovation in pulmonary drug delivery.

PMID:40005989 | DOI:10.3390/ph18020175

J Clin Med. 2025 Feb 18;14(4):1362. doi: 10.3390/jcm14041362.

ABSTRACT

The Hungarian Pancreatic Study Group (HPSG) was established with the aim of advancing pancreatology. Our summary outlines the methodologies, key results, and future directions of the HPSG. Methodological elements included, the formation of strategic national and international collaborations, the establishment of patient registries and biobanks, and a strong focus on education and guideline development. Key results encompassed, pioneering research on pancreatic ductal function and the role of cystic fibrosis transmembrane conductance regulator (CFTR) in inflammation, significant advancements in understanding acute and chronic pancreatitis, and the execution of numerous clinical trials to explore new therapeutic approaches. Despite challenges, such as securing funding and translating research into clinical practice, the HPSG's commitment to patient care and scientific innovation has been unwavering. The group aims to deepen research into pancreatic cancer and chronic pancreatitis, conduct more randomized controlled trials (RCTs), and expand its efforts internationally by involving global staff and patients. The authors hope that this summary inspires others to undertake similar initiatives and contribute to the global advancement of medical research and patient care in pancreatology.

PMID:40004893 | DOI:10.3390/jcm14041362

Children (Basel). 2025 Jan 28;12(2):157. doi: 10.3390/children12020157.

ABSTRACT

BACKGROUND/OBJECTIVES: Cystic fibrosis (CF) is a life-limiting genetic disorder affecting multiple organ systems. This study compared clinical outcomes, hospitalization rates, and survival between children and adolescents with CF who received CFTR modulator therapies (ivacaftor, lumacaftor, tezacaftor, and elexacaftor).

METHODS: A retrospective cohort study was conducted using data from the TriNetX global collaborative network. Patients with CF aged 2-12 years (children) and 13-18 years (adolescents) who received CFTR modulator therapies were included. The propensity score matching balanced baseline characteristics between the two age groups.

RESULTS: After propensity score matching, 946 patients per group were analyzed. The incidence of respiratory failure (3.81% vs. 1.06%, p < 0.001) and respiratory infections (62.7% vs. 57.5%, p = 0.021) were significantly higher in adolescents compared to children. Adolescents had a higher risk of respiratory failure (HR = 3.6, 95% CI = 1.79-7.21, p < 0.001) and respiratory infections (HR = 1.09, 95% CI = 1.01-1.17, p < 0.001). Adolescents also had a higher hospitalization rate (29.6% vs. 20.3%, p < 0.001), with a 47% higher risk (HR = 1.47, 95% CI = 1.22-1.77, p = 0.001), more hospital visits per person (8.8 vs. 3.7, p = 0.004), and longer hospital stays (32.7 vs. 20.4 days, p = 0.006). Mortality rates were similar between the groups (1.58% vs. 1.26%, p = 0.56).

CONCLUSIONS: CF patients who initiated CFTR modulator therapies during adolescence had a higher incidence of respiratory failure, respiratory infections, hospitalization rates, and healthcare resource utilization compared to those who started therapy in childhood, despite similar mortality rates. These findings highlight the importance of the early initiation of CFTR modulator therapies.

PMID:40003259 | DOI:10.3390/children12020157

Diagnostics (Basel). 2025 Feb 16;15(4):474. doi: 10.3390/diagnostics15040474.

ABSTRACT

Hyperpolarized xenon-129 MRI (129XeMRI) has emerged as a powerful tool in the identification, evaluation, and assessment of disease endotyping and in response to interventions for a myriad of pulmonary diseases. Growing investigative efforts ranging from basic science to application in translational research have employed 129XeMRI in the evaluation of pulmonary conditions such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, and cystic fibrosis (CF). The novel feature of 129XeMRI is its ability to generate anatomic and physiologic readouts of the lung with resolution from the whole lung down to the lobar level. Additional advantages include being non-invasive and non-radioactive, and utilizing an inexpensive and ubiquitous noble gas as an inhalation contrast agent: xenon-129. In this review, we outline the clinical advances provided by 129XeMRI among common pulmonary diseases with high healthcare burdens in recent decades.

PMID:40002625 | DOI:10.3390/diagnostics15040474

Antibiotics (Basel). 2025 Feb 11;14(2):177. doi: 10.3390/antibiotics14020177.

ABSTRACT

Background/Objectives: The pulmonary administration of antibiotics can be advantageous in treating pulmonary infections by promoting high intrapulmonary drug concentrations with reduced systemic exposure. However, limited benefits have been observed for pulmonary administration versus other administration routes due to its rapid clearance from the lung. Here, the effects of structural modifications on the epithelial permeability and antibacterial potency of a third-generation cephalosporin were investigated to improve the understanding of drug properties that promote intrapulmonary retention and how they may impact efficacy. Methods: Ceftazidime was modified by attaching 18 hydrophobic, hydrophilic, and mucus-binding motifs to the carboxylic acid distant from the beta-lactam by amidation. Epithelial permeability was investigated by drug transport assays using human bronchial epithelial air-liquid interface cultures. Antibacterial potency was determined by microtiter MIC assays with B. pseudomallei, P. aeruginosa, E. coli, and S. aureus. Results: A 40-50% reduction in the transepithelial transport rate was exhibited by two PEGylated ceftazidime analogs (mPEG8- and PEG5-pyrimidin-2-amine-ceftazidime) and n-butyl-ceftazidime. An increase in the transport rate was exhibited by four analogs bearing small and hydrophobic or negatively charged motifs (n-heptane-, phenyl ethyl-, glutamic acid-, and 4-propylthiophenyl boronic acid-ceftazidime). The antibacterial potency was reduced by ≥10-fold for most ceftazidime analogs against B. pseudomallei, P. aeruginosa, and E. coli but was retained by seven ceftazidime analogs primarily bearing hydrophobic motifs against S. aureus. Conclusions: The covalent conjugation of PEGs with MW > 300 Da reduced the epithelial permeability of ceftazidime, but these modifications severely reduced antibacterial activity. To improve the pulmonary retention of antibiotics with low membrane permeability, this work suggests future molecular engineering studies to explore high-molecular-weight prodrug strategies.

PMID:40001420 | DOI:10.3390/antibiotics14020177

Antibiotics (Basel). 2025 Feb 8;14(2):169. doi: 10.3390/antibiotics14020169.

ABSTRACT

Background/Objectives: Pulmonary delivered tobramycin (TOB) is a standard treatment for Pseudomonas aeruginosa lung infections, that, along with Staphylococcus aureus, is one of the most common bacteria causing recurring infections in CF patients. However, the only available formulation on the market containing tobramycin, TOBI®, is sold at a price that makes the access to the treatment difficult. Therefore, this work focuses on the development and characterization of an ionic complex between a polyelectrolyte, hyaluronic acid (HA) and its salt, sodium hyaluronate (NaHA), and TOB to be formulated as an inhalable dry powder. Methods: The solid state complex obtained by spray drying technique was physicochemically characterized by infrared spectroscopy, thermal analysis and X-ray diffraction, confirming an ionic interaction for both complexes. Results: The powder density, geometric size, and morphology along with the aerodynamic performance showed suitable properties for the powder formulations to reach the deep lung. Moisture uptake was found to be low, with the complex HA-TOB remaining physicochemically unchanged, while the NaHA-TOB required significant protection against humidity. The biopharmaceutical in vitro experiments showed a rapid dissolution which can have a positively impact in reducing side effects, while the drug release study demonstrated a reversible polyelectrolyte-drug interaction. Microbiological experiments against P. aeruginosa and S. aureus showed improved bacterial growth inhibition and bactericidal efficacy, as well as better inhibition and eradication of biofilms when compared with to TOB. Conclusions: A simple polyelectrolyte-drug complex technique represents a promising strategy for the development of antimicrobial dry powder formulations for pulmonary delivery in the treatment of cystic fibrosis (CF) lung infections.

PMID:40001413 | DOI:10.3390/antibiotics14020169

Antibiotics (Basel). 2025 Feb 7;14(2):165. doi: 10.3390/antibiotics14020165.

ABSTRACT

The lack of available treatments in pediatric non-cystic fibrosis (non-CF) bronchiectasis is a major concern, especially in the context of the increasing disease burden due to better detection rates with advanced imaging techniques. Recurrent infections in these patients are the main cause of deterioration, leading to impaired lung function and increasing the risk of morbidity and mortality. Since pediatric non-CF bronchiectasis with early recognition and appropriate treatment can be reversible, optimal management is an issue of growing significance. The use of inhaled antibiotics as a treatment option, although a standard of care for CF patients, has been poorly studied in patients with non-CF bronchiectasis, especially in children. In this review, we present the current data on the potential use of inhaled antibiotics in the treatment of non-CF bronchiectasis and assess their safety and efficacy profile, focusing mainly on children. We conclude that inhaled antibiotics as an adjuvant maintenance treatment option could be tried in a subgroup of patients with frequent exacerbations and recent or chronic Pseudomonas aeruginosa infection as they appear to have beneficial effects on exacerbation rate and bacterial load with minimal safety concerns. However, the level of evidence in children is extremely low; therefore, further research is needed on the validity of this recommendation.

PMID:40001409 | DOI:10.3390/antibiotics14020165

Antimicrob Resist Infect Control. 2025 Feb 25;14(1):17. doi: 10.1186/s13756-025-01527-4.

ABSTRACT

BACKGROUND/INTRODUCTION: Antipseudomonal antibiotics are frequently used in patients admitted to hospitals. Many of these substances are classified as a reserve or watch status by the WHO. Inappropriate risk assessment of invasive detection of P. aeruginosa (PAE) can be a reason for overuse of antipseudomonal antibiotics. Therefore it is important to define relevant and specific risk factors for invasive PAE detection.

OBJECTIVE: The objective of this study was to identify risk factors for invasive detection of PAE in patients upon hospital admission.

METHODS: All patients 18 years of age and older with a detection of PAE and/or Enterobacterales in clinical samples taken within 48 h of admission to one of the hospitals of Charité Universitätsmedizin Berlin between 2015 and 2020 were included into this retrospective cohort study.

RESULTS: Overall, we included a total of 27,710 patients. In 3,764 (13.6%) patients PAE was detected in clinical samples taken within 48 h after admission. The most frequently detected Enterobacterales was E. coli in 14.142 (51%) patients followed by Klebsiella spp. in 4.432 (16%) patients. Multivariable regression analysis identified that prior colonisation with a multi drug resistant PAE or detection of a PAE in clinical samples during a previous hospitalisation increased the risk for invasive detection of PAE (OR 39.41; 95% CI 28.54-54.39) and OR 7.87 (95% CI 6.60-9.38) respectively. Admission to a specialised ward for patients with cystic fibrosis was associated with an increased risk (OR 26.99; 95% CI 20.48-35.54). Presence of chronic pulmonary disease (OR 2.05; 95% CI 1.85-2.26), hemiplegia (OR 2.16; 95% CI 1.90-2.45) and male gender (OR 1.60; 95% CI 1.46-1.75) were associated with a modest increase in risk for presence of PAE.

CONCLUSION: Patients with a prior detection of P. aeruginosa or admission to a cystic fibrosis ward had the highest risk for invasive detection of P. aeruginosa. Adherence to specific risk scores based on local risk factors could help to optimize prescription of anti-pseudomonal antibiotics that categorized as reserve and watch.

PMID:40001254 | DOI:10.1186/s13756-025-01527-4

Nutrition. 2025 Jan 27;133:112694. doi: 10.1016/j.nut.2025.112694. Online ahead of print.

ABSTRACT

OBJECTIVES: Having an optimal nutritional status and getting adequate energy and nutrients are important factors that affect the success of the treatment of cystic fibrosis (CF) and increase survival. The objective of this study was to determine the nutritional status, nutritional intake, and dietary quality among children aged 2 to 14 with CF. We aimed to assess the impact of a nutrition education intervention provided to mothers on these parameters and compare the results with a control group.

METHODS: Participants (n = 46) were divided into two groups, one group received nutrition education, the other group did not receive any intervention, and all participants were followed up in the 1st and 3rd months of the study. Each participant completed a questionnaire form prepared by the researcher including general information about the patient, anthropometric data, 3-day dietary intake, and Mediterranean Diet Quality Index.

RESULTS: While the children's Mediterranean Diet Quality Index scores did not change significantly during the study period, the proportion of children in the education group who had adequate nutrition according to body mass index percentile for age increased from 42.0% to 48.0%. In addition, energy (kcal), fat (g), and monounsaturated fatty acids (g) intake, vitamin D, E, K, B6, biotin, and iron intakes of the education group increased significantly during the study (P < 0.05).

CONCLUSIONS: This study contributes to the literature by showing that nutrition education given to mothers for CF children, improves the nutritional status of children and increases their energy and nutrient intakes.

PMID:39999653 | DOI:10.1016/j.nut.2025.112694

Pediatr Pulmonol. 2025 Feb;60(2):e71018. doi: 10.1002/ppul.71018.

ABSTRACT

BACKGROUND: Patients with primary ciliary dyskinesia (PCD) are commonly treated for pulmonary exacerbations with intravenous tobramycin, but data on tobramycin pharmacokinetics in PCD is lacking. The objective of this study was to compare tobramycin pharmacokinetics in pediatric patients with PCD to those with cystic fibrosis (CF).

METHODS: This retrospective study included pediatric patients hospitalized for a pulmonary exacerbation between January 2018 and June 2023. Included patients were treated with systemic tobramycin and had two concentrations usable to calculate patient-specific pharmacokinetics. Each patient with PCD was matched 1:2 to patients with CF based on age. The primary outcome was tobramycin elimination rate constant.

RESULTS: Seven patients with PCD were matched to 14 patients with CF. Baseline characteristics were similar between groups. The final tobramycin dose was not significantly different between groups (9.3 vs. 11.8 mg/kg, p = 0.192). All doses were infused over 30 min every 24 h. Tobramycin elimination rate constant (0.510 vs. 0.493 h-1, p = 0.433) and volume of distribution (0.31 vs. 0.23 L/kg, p = 0.640) were not different between groups. No patient experienced acute kidney injury. Additionally, both groups experienced similar duration of tobramycin therapy (12.3 vs. 9.6 days, p = 0.184) and length of stay (12.0 vs. 12.6 days, p = 0.801).

CONCLUSIONS: No difference in tobramycin elimination rate constant was found between patients with PCD and those with CF. Clinical outcomes were not significantly different between groups. Although not statistically significant, a lower tobramycin dose was observed in patients with PCD.

PMID:39998853 | DOI:10.1002/ppul.71018

Radiology. 2025 Feb;314(2):e241793. doi: 10.1148/radiol.241793.

ABSTRACT

Background Although pericardial calcification has been observed on chest CT scans in patients with cystic fibrosis (CF), its prevalence and characteristics have not been elucidated. Purpose To determine the prevalence and characteristics of pericardial calcification, and identify clinical variables associated with it, in adult patients with CF and to compare this prevalence with that in individuals without CF. Materials and Methods This was a retrospective, single-center case-control study including consecutive patients with CF who underwent chest CT between January 2021 and December 2022. Control group 1 included individuals without CF matched for age and sex. Control group 2 included individuals with previous Mycobacterium tuberculosis infection and no concomitant diagnosis of CF matched for sex. Control group 3 included patients with primary ciliary dyskinesia. Qualitative and quantitative evaluations of pericardial calcification were performed. The χ2 test and Fisher exact test were used for comparisons of categorical variables; the Kruskal-Wallis test and Mann-Whitney U test were used for comparisons of continuous variables. Results Of the 348 adult patients with CF (mean age, 35 years ± 13 [SD]; 193 [55%] male patients), 62 (18%) had pericardial calcification at CT. The prevalence of pericardial calcification was 1% (four of 348) in control group 1, 2% (two of 100) in control group 2, and 4% (one of 24) in control group 3 (P < .001). Pericardial calcification developed de novo in 66% (41 of 62) and progressed in 21% (13 of 62) of patients with CF. The distribution of pericardial calcification in patients with CF was most frequently multifocal (58%; 36 of 62). The median calcium score of pericardial calcification was 65 (IQR, 28-375). In patients with CF, older age, lower forced expiratory volume in 1 second, higher vitamin D level, and a higher prevalence of Burkholderia cenocepacia ET12 infection were associated with pericardial calcification. Conclusion Pericardial calcification was more prevalent in adult patients with CF than in individuals without CF and progressed over time in some patients. © RSNA, 2025 Supplemental material is available for this article.

PMID:39998371 | DOI:10.1148/radiol.241793

Respirology. 2025 Feb 25. doi: 10.1111/resp.70009. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: β-ENaC-Tg mice serve as a relevant model of muco-obstructive lung disease and diffuse-type emphysema, with impaired mucociliary clearance, mucus obstruction, chronic airway inflammation, structural lung damage, and altered lung function. The aim of this study was to undertake a comprehensive analysis of lung function and mechanics of the adult β-ENaC-Tg model.

METHODS: Adult β-ENaC-Tg and wild-type littermates underwent X-ray velocimetry (XV) scans using a Permetium XV scanner (4DMedical, Melbourne, Australia). For comparative lung mechanics, lung function assessments were conducted with a flexiVent system (SCIREQ, Montreal, Canada).

RESULTS: XV imaging demonstrated elevated ventilation defect percentage, mean specific ventilation, and ventilation heterogeneity in β-ENaC-Tg mice. Spatial analysis of ventilation maps indicated increased ventilation variability in the peripheral lung regions, as well as an increased proportion of under-ventilated areas. The flexiVent analysis indicated that compared to wild types, β-ENaC-Tg mice have a significantly more compliant lungs with increased inspiratory capacity, reduced tissue elastance, and increased hysteresivity (heterogeneity), suggesting loss of parenchymal integrity.

CONCLUSION: This research highlights the utility of XV imaging in evaluating ventilation defects in the β-ENaC-Tg model and provides a comprehensive lung function analysis.

PMID:39998270 | DOI:10.1111/resp.70009

mBio. 2025 Feb 25:e0354824. doi: 10.1128/mbio.03548-24. Online ahead of print.

ABSTRACT

Cystic fibrosis is a genetic disorder that affects mucus clearance, particularly of the lungs. As a result, cystic fibrosis patients often experience infections from bacteria, which contribute to the disease progression. Pseudomonas aeruginosa is one of the most common opportunistic pathogens associated with cystic fibrosis. The presence of P. aeruginosa complicates the treatment due to its high antibiotic resistance. Thus, research is ongoing to treat these infections with bacterial viruses instead, known as bacteriophages. Notably, P. aeruginosa clinical strains possess a variety of phage defense mechanisms that may limit the effectiveness of phage therapy. In this study, we compared the defense system repertoire of P. aeruginosa strains isolated from cystic fibrosis patients with those from non-cystic fibrosis patients. Our findings reveal that P. aeruginosa strains isolated from cystic fibrosis patients have fewer phage defense mechanisms per strain than from non-cystic fibrosis patients, suggesting altered phage selection pressures in strains colonizing CF patient lungs.IMPORTANCECystic fibrosis patients often experience chronic Pseudomonas aeruginosa lung infections, which are challenging to treat with antibiotics and contribute to disease progression and eventual respiratory failure. Phage therapy is being explored as an alternative treatment strategy for these infections. However, assessing strain susceptibility to phage treatment is essential for ensuring efficacy. To address this, we investigated whether CF-associated clinical P. aeruginosa strains have a distinct phage defense repertoire compared with those isolated from other lung patients. We observed that CF-associated P. aeruginosa strains have significantly fewer phage defenses, possibly affecting the susceptibility of these strains to phage infection.

PMID:39998178 | DOI:10.1128/mbio.03548-24

J Fungi (Basel). 2025 Feb 4;11(2):116. doi: 10.3390/jof11020116.

ABSTRACT

Allergic bronchopulmonary aspergillosis (ABPA) is a well-known complication in children and young people with cystic fibrosis (CF) and without treatment causes structural lung damage. We performed a longitudinal observational study to identify clinical risk factors for ABPA in a cohort of children and young people with CF aged 8 to 17 years at baseline. Anonymised annual review UK CF Registry data from 2009 to 2019 for patients aged 8-17 years in 2009 were collected, with lung transplant recipients excluded. Baseline characteristics are presented for the whole group and cross-sectional comparisons made according to the presence of ABPA or not in 2009. Longitudinal analysis from 2009 to 2019 was completed on the group without ABPA in 2009 to identify predictors for the subsequent development of ABPA using a complementary log-log regression model. In 2009, there were 1612 patients, of which 1420 were ABPA-negative and 192 ABPA-positive. Aspergillus colonisation (p = 0.01) and IV antibiotic use (p < 0.0001) were associated with having ABPA in 2009. Longitudinal analysis of the group without ABPA in 2009 identified male gender, younger age, lower lung function, Pseudomonas aeruginosa infection, and Aspergillus colonisation to be significantly associated with the development of ABPA (p < 0.0001). Ivacaftor was significantly associated with reduced ABPA (OR 0.46, p = 0.01) but not lumacaftor/ivacaftor (OR 0.64, p = 0.28). Chronic oral macrolide use was significantly associated with increased risk of development of ABPA (OR 1.30, p < 0.0001). This study shows that lower lung function, Aspergillus colonisation, and Pseudomonas aeruginosa infection in children with CF were associated with the development of ABPA, highlighting the need for enhanced surveillance in these patients. This is the first study to show a protective association of ivacaftor and ABPA.

PMID:39997410 | DOI:10.3390/jof11020116

Curr Issues Mol Biol. 2025 Feb 11;47(2):119. doi: 10.3390/cimb47020119.

ABSTRACT

Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride and bicarbonate channel localized on the plasma membrane of epithelial cells. Over the last three decades, high-throughput screening assays have been extensively employed in identifying drugs that target specific defects arising from CFTR mutations. The two main categories of such compounds are potentiators, which enhance CFTR gating by increasing the channel's open probability, and correctors, which improve CFTR protein folding and trafficking to the plasma membrane. In addition to these, other investigational molecules include amplifiers and stabilizers, which enhance the levels and the stability of CFTR on the cell surface, and read-through agents that promote the insertion of correct amino acids at premature termination codons. Currently, four CFTR modulators are clinically approved: the potentiator ivacaftor (VX-770), either as monotherapy or in combination with the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Among these, the triple combination VX-445/VX-661/VX-770 (marketed as Trikafta® in the US and Kaftrio® in Europe) has emerged as the most effective CFTR modulator therapy to date, demonstrating significant clinical benefits in phase III trials for patients with at least one F508del CFTR allele. Despite these advancements, the mechanisms of action and binding sites of these modulators on CFTR have only recently begun to be elucidated. A deeper understanding of these mechanisms could provide essential insights for developing more potent and effective modulators, particularly in combination therapies. This narrative review delves into the mechanism of action, binding sites, and combinatorial effects of approved and investigational CFTR modulators, highlighting ongoing efforts to broaden therapeutic options for individuals with CF.

PMID:39996840 | DOI:10.3390/cimb47020119

Sci Rep. 2025 Feb 24;15(1):6551. doi: 10.1038/s41598-025-91073-1.

ABSTRACT

A novel lytic bacteriophage, PSA-KC1, was isolated from wastewater. In this study, the whole genome of the bacteriophage PSA-KC1 was analyzed, and its lytic properties were assessed. PSA-KC1 has a linear double-stranded DNA genome with a total length of 43,237 base pairs and a GC content of 53.6%. In total, 65 genes were predicted, 46 of which were assigned functions as structural proteins involved in genome replication, packaging or phage lysis. PSA-KC1 belongs to the genus Septimatrevirus under the Caudoviricetes class. The aim of this study was to investigate the efficacy of the lytic bacteriophage PSA-KC1 and compare it with that of the Pyophage phage cocktail on 25 multi drug resistant (MDR) Pseudomonas aeruginosa strains isolated from sputum samples of cystic fibrosis patients. Seventeen of these strains were susceptible (68%) to the PSA-KC1 lytic phage we isolated, whereas eight clinical strains were resistant. However, 22 (88%) of the P. aeruginosa strains were susceptible to the Pyophage cocktail, and three (12%) were resistant to the Phage cocktail. At the end of our study, a new lytic phage active against multidrug-resistant P. aeruginosa strains from CF patients was isolated, and its genome was characterized. Since the PSA-KC1 phage does not contain virulence factors, toxins or integrase genes, it can be expected to be a therapeutic candidate with the potential to be used safely in phage therapy.

PMID:39994360 | DOI:10.1038/s41598-025-91073-1

PLoS One. 2025 Feb 24;20(2):e0318249. doi: 10.1371/journal.pone.0318249. eCollection 2025.

ABSTRACT

OBJECTIVE: The autosomal recessive disease congenital chloride diarrhea (CLD), caused by loss-of-function mutations in the solute carrier family 26 member 3 (SLC26A3) gene, shows association with inflammatory bowel disease (IBD). However, it is unclear whether IBD risk is associated with genetic or immune signatures. SLC26A3 interacts with several ion transporters linked to intestinal inflammation, such as cystic fibrosis transmembrane conductance regulator (CFTR) and solute carrier family 9 member 3 (SLC9A3) causing congenital sodium diarrhea. We hypothesized that other epithelial channels affecting intestinal salt balance might modulate CLD phenotype or IBD risk.

MATERIALS AND METHODS: We analyzed 495 gene variants within 33 ion transporters among 28 patients with CLD and 44,443 population controls.

RESULTS: We found three intronic variants at or near the CFTR locus (rs17132543, rs2283054 and rs76622533) showing statistically significant (P < 1.42x10-5) associations with CLD.

CONCLUSIONS: These data demonstrate enrichment of rare variants at the CFTR locus in chromosomes harboring the Finnish founder mutation for CLD.

PMID:39992989 | DOI:10.1371/journal.pone.0318249

Med J Armed Forces India. 2024 Nov-Dec;80(6):731-734. doi: 10.1016/j.mjafi.2022.11.006. Epub 2023 Jan 4.

ABSTRACT

Infantile refractory diarrhea presents after first few days of life leading to intestinal insufficiency. It is a diagnostic challenge due to varied etiologies like food senstive enteropathy, anatomical defects and dysmotility disorders, transport and enzymatic defects, pancreatic malabsorption - cystic fibrosis (CF), primary epithelial causes like microvillus inclusion disease (MVID), tufting enteropathy and heparan sulfate deficiency, immunodeficiencies, metabolic diseases and autoimmune enteropathy. It is refractory to treatment making the patient dependent on total parenteral nutrition. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), is one of the rarest causes of intractable diarrhea. It occurs due to mutations in the FOXP3 gene, leading to dysfunction of T-regulatory cells and is characterised by diarrhoea, diabetes, and dermatitis. We aim to evaluate various causes of infantile refractory chronic diarrhea, and to present one such case of IPEX syndrome from this part of the world due to mutation not been reported in literature so far.

PMID:39990538 | PMC:PMC11842919 | DOI:10.1016/j.mjafi.2022.11.006