Cystic Fibrosis Patients Research Articles

Elucidating the augmented resistance profile of Scedosporium/Lomentospora species to azoles in a cystic fibrosis mimic environment.

Scedosporium/Lomentospora species are ranked as the second most frequently isolated filamentous fungi from cystic fibrosis (CF) patients. Previously, we demonstrated that the minimum inhibitory concentration (MIC) for voriconazole and posaconazole increased when performed on a mucin-containing synthetic CF sputum medium (SCFM) compared to the standard medium, RPMI-1640. In this study, we have expanded the MIC comparison to four additional azoles and investigated characteristics linked to azole resistance in Scedosporium apiospermum, Scedosporium minutisporum, Scedosporium aurantiacum and Lomentospora prolificans. MIC was assayed by CLSI protocol, efflux pump activity was assessed by rhodamine 6G and sterols were analysed by gas chromatography-mass spectrometry (GC-MS). Overall, MICs for fluconazole, itraconazole, voriconazole, posaconazole, miconazole and ketoconazole increased by least 2-fold when susceptibility tests were performed using SCFM compared to RPMI. The activity of efflux pumps was similar in both media; however, in RPMI, but not in SCFM, the activity was induced by voriconazole and fluconazole. Additionally, MICs for those antifungals decreased more noticeably in SCFM than in RPMI in the presence of the efflux pump inhibitor PaβN. The SCFM-grown cells presented fewer sterols in their composition, and consequently higher membrane fluidity, than RPMI-grown cells. GC-MS analysis demonstrated a remodulation in the sterol profile in SCFM- compared to RPMI-grown cells. Accordingly, when the MIC assay was performed in the presence of the membrane stressor NaCl (3%), the susceptibility to voriconazole and fluconazole increased more in SCFM- than RPMI-grown cells. Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.

Automated lung segmentation on chest MRI in children with cystic fibrosis

IntroductionSegmentation of lung structures in medical imaging is crucial for the application of automated post-processing steps on lung diseases like cystic fibrosis (CF). Recently, machine learning methods, particularly neural networks, have demonstrated remarkable improvements, often outperforming conventional segmentation methods. Nonetheless, challenges still remain when attempting to segment various imaging modalities and diseases, especially when the visual characteristics of pathologic findings significantly deviate from healthy tissue.MethodsOur study focuses on imaging of pediatric CF patients [mean age, standard deviation (7.50 ± 4.6)], utilizing deep learning-based methods for automated lung segmentation from chest magnetic resonance imaging (MRI). A total of 165 standardized annual surveillance MRI scans from 84 patients with CF were segmented using the nnU-Net framework. Patient cases represented a range of disease severities and ages. The nnU-Net was trained and evaluated on three MRI sequences (BLADE, VIBE, and HASTE), which are highly relevant for the evaluation of CF induced lung changes. We utilized 40 cases for training per sequence, and tested with 15 cases per sequence, using the Sørensen-Dice-Score, Pearson’s correlation coefficient (r), a segmentation questionnaire, and slice-based analysis.ResultsThe results demonstrated a high level of segmentation performance across all sequences, with only minor differences observed in the mean Dice coefficient: BLADE (0.96 ± 0.05), VIBE (0.96 ± 0.04), and HASTE (0.95 ± 0.05). Additionally, the segmentation quality was consistent across different disease severities, patient ages, and sizes. Manual evaluation identified specific challenges, such as incomplete segmentations near the diaphragm and dorsal regions. Validation on a separate, external dataset of nine toddlers (2–24 months) demonstrated generalizability of the trained model achieving a Dice coefficient of 0.85 ± 0.03.Discussion and conclusionOverall, our study demonstrates the feasibility and effectiveness of using nnU-Net for automated segmentation of lung halves in pediatric CF patients, showing promising directions for advanced image analysis techniques to assist in clinical decision-making and monitoring of CF lung disease progression. Despite these achievements, further improvements are needed to address specific segmentation challenges and enhance generalizability.

Exploring the Role of Tertiary Lymphoid Structures Using a Mouse Model of Bacteria-Infected Lungs.

Animal models can be helpful tools for deciphering the generation, maintenance, and role of tertiary lymphoid structures (TLS) during infections or tumor development. We describe here the establishment of a persistent lung infection in immune-competent mice by intratracheal instillation of agarose beads containing Pseudomonas aeruginosa or Staphylococcus aureus bacteria. After instillation, animals develop a chronic pulmonary infection, marked by the presence of TLS. This experimental setting allows the study of the function of TLS induced by bacteria encountered in patients with cystic fibrosis (CF) as P. aeruginosa and S. aureus are the two main bacterial strains that infect the bronchi of adult CF patients. Additionally, we describe also how to manipulate the immune response in these infected animals by targeting immune cells involved in TLS function. Overall, this approach makes it possible to explore the role of chronic inflammation in the induction and maintenance of TLS in infected tissues.

Polymorphisms of the Vitamin D Binding Protein (VDBP) and Free Vitamin D in Patients with Cystic Fibrosis

Objectives/Background: Vitamin D-binding protein (VDBP) and free vitamin D are new markers that are being studied as a possible markers of vitamin D status. The main aim of our study was to analyze the VDBP genotype and quantify the levels of free vitamin D in a sample of cystic fibrosis (CF) patients. Methods: We conducted a multicenter, cross-sectional, and prospective study including patients with CF and exocrine pancreatic insufficiency who were clinically stable. We investigated vitamin D levels (total and free) and the different VDBP haplotypes. Free vitamin D levels were measured using an electro-chemiluminescence assay. Results: A sample of 48 patients was obtained (52% male; median age 13.8 years). The most common allele of VDBP was Gc1s (72%) > Gc2 (52%) > Gc1f (27%). The median calcidiol was 21.2 ng/mL (IR 15.3–26.9), and 81% had levels in the insufficiency range: 23 patients (48%) below 20 ng/mL, and 16 (33%) between 20 and 30 ng/mL. The median free vitamin D level was 4.2 pg/mL (IR 3.9–5.6). A positive correlation was observed between calcidiol and free vitamin D levels (r = 0.871; p < 0.0001). After adjustment for season, vitamin D supplementation, sex, and CF-related diabetes, patients with Gc1f polymorphism had a lower risk of vitamin D deficiency, OR 0.22 (95% CI 0.05–0.99), and p = 0.027. A negative linear trend was observed between the polymorphisms grouped into three categories (Gc1/Gc1, Gc1/Gc2, and Gc2/Gc2, in that order) and vitamin D and free vitamin D levels (p = 0.025 and p = 0.033, respectively). Conclusion: In CF, as in the general population, the most common VDBP haplotype in the Caucasian race is Gc1s. VDBP polymorphisms influence serum vitamin D and free vitamin D levels in CF patients. There is a good correlation between free vitamin D and calcidiol levels, suggesting that measuring the latter in CF does not seem to provide any additional benefit.

Imaging of cystic fibrosis manifestations in the abdomen.

Cystic fibrosis is a common inherited autosomal recessive disease affecting 35,000 persons in the United States. It is caused by mutations of the cystic fibrosis transmembrane regulator (CFTR) gene, located on the long arm of chromosome 7.This protein carries chlorine in the membranes of epithelial cells of exocrine glands. Mutations in the CFTR gene results in production of abnormally viscous mucus. Although it primarily affects the lungs, cystic fibrosis is a multisystem disease with involvement of extra thoracic organs including the liver, pancreas, kidneys and digestive tract.With advances in the management of cystic fibrosis resulting in improved life expectancy, cystic fibrosis patients are surviving into adulthood and extrapulmonary disease has become more commonplace. It is essential that radiologists are aware of the spectrum of potential manifestations of cystic fibrosis to allow accurate diagnosis.The purpose of this manuscript is to provide an overview of the pathophysiology and imaging findings of abdominal entities unique to patients with cystic fibrosis. We will present a wide spectrum of renal, pancreatic, gastrointestinal, hepatobiliary and post-transplant cases describing the typical findings that will assist radiologists in providing a timely diagnosis for patients with cystic fibrosis.

Respiratory Outcomes of Interrupted Modulator Therapies in Children With Cystic Fibrosis.

Cystic fibrosis (CF) is a multisystemic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in defective synthesis or function of the CFTR protein. Historically, CF treatment focused on managing symptoms and complications. Fortunately, modulator drugs are now available to directly target the defective CFTR protein. However, in some countries, such as Turkey, these drugs are not covered by social insurance. Consequently, many CF patients face barriers to accessing modulatory therapies or must interrupt their treatment. This study demonstrates the impact of interrupting modulator therapy on pulmonary function, emphasizing the need for uninterrupted continuous treatment. In this study, 39 CF patients receiving elexacaftor-tezacaftor-ivacaftor (ETI) at our clinic were retrospectively analyzed. Among the patients, 18 experienced one or more interruptions, ranging from 15 to 210 days during ETI treatment. We analyzed pulmonary function test results from 27 interruption periods. At the beginning of the interruption, the mean percent predicted FEV1 (ppFEV1) was 69.59% ± 25.87%, which decreased to 64.96% ± 24.52% by the end of the interruption. There was a significant decrease with a mean change of 4.62 ± 8.49 (p = 0.008). However, no significant correlation was found between the interruption duration and FEV1 change. Our results demonstrate that pulmonary functions are adversely affected by interruption periods, regardless of their duration. Even short interruptions have a significant impact on pulmonary functions. This underscores the need for uninterrupted continuation of modulatory treatment and for improved policies to ensure equitable access to treatment.

Uncovering bacterial-mammalian cell interactions via single-cell tracking

BackgroundThe interactions between bacterial pathogens and host cells are characterized by a multitude of complexities, leading to a wide range of heterogeneous outcomes. Despite extensive research, we still have a limited understanding of how bacterial motility in complex environments impacts their ability to tolerate antibiotics and adhere to mammalian cell surfaces. The challenge lies in unraveling the complexity of these interactions and developing quantitative microscopy approaches to predict the behavior of bacterial populations.ResultsTo address this challenge, we directed our efforts towards Pseudomonas aeruginosa, a pathogenic bacterium known for producing thick films in the lungs of cystic fibrosis patients, and Escherichia coli, used as a proof of concept to develop and demonstrate our single-cell tracking approaches. Our results revealed that P. aeruginosa exhibits diverse and complex interactions on mammalian cell surfaces, such as adhesion, rotational motion, and swimming, unlike the less interactive behavior of Escherichia coli. Our analysis indicated that P. aeruginosa demonstrated lower mean-squared displacement (MSD) values and greater adherence to mammalian cells compared to E. coli, which showed higher MSD slopes and less frequent adherence. Genetic mutations in membrane proteins of P. aeruginosa resulted in altered displacement patterns and reduced adhesion, with the ΔfliD mutant displaying a more Gaussian displacement distribution and significantly less adherence to mammalian cells. Adhesion and tolerance mechanisms are diverse and complex, potentially involving distinct pathways; however, our findings highlight the therapeutic potential of targeting the fliD gene (encoding a critical flagellum protein), as its deletion not only reduced adherence but also antibiotic tolerance.ConclusionsOverall, our findings underscore the importance of single cell tracking in accurately assessing bacterial behavior over short time periods and highlight its significant potential in guiding effective intervention strategies.

Sinus mucocele leads to unilateral proptosis in an infant patient with cystic fibrosis; a literature review and a case report study

Introduction and Importance: Cystic fibrosis (CF) is a widespread life-shortening recessive genetic disease and can present with sinus mucocele. Sinus mucocele is a rare condition, with limited prevalence data on unilateral proptosis. Case presentation: We present a case of a 19-month-old boy with CF who experienced worsening proptosis and exotropia in his right eye. A brain and orbit MRI revealed diffuse polypoid mucosal thickening, possible dense fungal deposit, deformity of the mid face, especially on the right side, with more prominent bulging of medical and inferior walls of the right lobe, a right ethmoidal mucocele causing ocular globe displacement, medial rectus compression, and optic nerve. An examination of the eye fundus showed disc edema and vascular congestion. Endoscopic sinus surgery successfully drained the mucocele, and treatment with antibiotics and corticosteroids led to symptom improvement and resolution of proptosis within three weeks. Clinical Discussion: Mucoceles represent an uncommon complication associated with CF in pediatric patients. Consequently, any child presenting with this issue should undergo evaluation for CF. Investigating this infrequent condition’s underlying mechanisms and consequences may improve treatment approaches and outcomes for those impacted. Conclusion: Sinus mucocele with unilateral proptosis in CF patients is uncommon, and endoscopic sinus surgery appears to be an effective cure for this complication, even in the pediatric population at high risk, like CF patients.

Structural determinants of protein kinase A essential for CFTR channel activation

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the anion channel mutated in cystic fibrosis (CF) patients, is activated by the catalytic subunit of protein kinase A (PKA-C). PKA-C activates CFTR both noncatalytically, through binding, and catalytically, through phosphorylation of multiple serines in CFTR's regulatory (R) domain. Here, we identify key molecular determinants of the CFTR/PKA-C interaction essential for these processes. By comparing CFTR current activation in the presence of ATP or an ATP analog unsuitable for phosphotransfer, as well as pseudosubstrate peptides of various lengths, we identify two distinct specific regions of the PKA-C surface which interact with CFTR to cause noncatalytic and catalytic CFTR stimulation, respectively. Whereas the "substrate site" mediates CFTR phosphorylation, a distinct hydrophobic patch (the "docking site") is responsible for noncatalytic CFTR activation, achieved by stabilizing the R domain in a "released" conformation permissive to channel gating. Furthermore, by comparing PKA-C variants with different posttranslational modification patterns, we find that direct membrane tethering of the kinase through its N-terminal myristoyl group is an unappreciated fundamental requirement for CFTR activation: PKA-C demyristoylation abolishes noncatalytic, and profoundly slows catalytic, CFTR stimulation. For the F508del CFTR mutant, present in ~90% of CF patients, maximal activation by demyristoylated PKA-C is reduced by ~10-fold compared to that by myristoylated PKA-C. Finally, in bacterial genera that contain common CF pathogens, we identify virulence factors that demyristoylate PKA-C in vitro, raising the possibility that during recurrent bacterial infections in CF patients, PKA-C demyristoylation may contribute to the exacerbation of lung disease.

Interspecies interactions alter the antibiotic sensitivity of Pseudomonas aeruginosa.

Polymicrobial infections are infections that are caused by multiple pathogens and are common in patients with cystic fibrosis (CF). Although polymicrobial infections are associated with poor treatment responses in CF, the effects of the ecological interactions between co-infecting pathogens on antibiotic sensitivity and treatment outcome are poorly characterized. To this end, we systematically quantified the impact of these effects on the antibiotic sensitivity of Pseudomonas aeruginosa for nine antibiotics in medium conditioned by 13 secondary cystic fibrosis-associated bacterial and fungal pathogens through time-kill assays. We fitted pharmacodynamic models to these kill curves for each antibiotic-species combination and found that interspecies interactions changing the antibiotic sensitivity of P. aeruginosa are abundant. Interactions that lower antibiotic sensitivity are more common than those that increase it, with generally more substantial reductions than increases in sensitivity. For a selection of co-infecting species, we performed pharmacokinetic-pharmacodynamic modeling of P. aeruginosa treatment. We predicted that interspecies interactions can either improve or reduce treatment response to the extent that treatment is rendered ineffective from a previously effective antibiotic dosing schedule and vice versa. In summary, we show that quantifying the ecological interaction effects as pharmacodynamic parameters is necessary to determine the abundance and the extent to which these interactions affect antibiotic sensitivity in polymicrobial infections.IMPORTANCEIn cystic fibrosis (CF) patients, chronic respiratory tract infections are often polymicrobial, involving multiple pathogens simultaneously. Polymicrobial infections are difficult to treat as they often respond unexpectedly to antibiotic treatment, which might possibly be explained because co-infecting pathogens can influence each other's antibiotic sensitivity, but it is unknown to what extent such effects occur. To investigate this, we systematically quantified the impact of co-infecting species on antibiotic sensitivity, focusing on P. aeruginosa, a common CF pathogen. We studied for a large set co-infecting species and antibiotics whether changes in antibiotic response occur. Based on these experiments, we used mathematical modeling to simulate P. aeruginosa's response to colistin and tobramycin treatment in the presence of multiple pathogens. This study offers comprehensive data on altered antibiotic sensitivity of P. aeruginosa in polymicrobial infections, serves as a foundation for optimizing treatment of such infections, and consolidates the importance of considering co-infecting pathogens.

A phase I study assessing the safety and tolerability of SPL84, an inhaled antisense oligonucleotide for treatment of cystic fibrosis patients with the 3849 +10kb C->T

BackgroundAntisense Oligonucleotides (ASOs) are small synthetic nucleic acid molecules able to bind specific sequences within target Ribonucleic Acid (RNA) molecules. SPL84 is an ASO drug developed for treatment of cystic fibrosis (CF) patients carrying the 3849 + 10 kb C->T Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) splicing mutation. The 3849 + 10 kb C->T variant leads to inclusion of cryptic exon harboring stop codon leading to the production of truncated non-functional CFTR proteins. in vitro, SPL84 treatment results in splicing modulation, which leads to an increase of correctly spliced CFTR RNA and higher levels of functional CFTR proteins. MethodsSPL84 was tested in a blinded, placebo-controlled phase 1 study in thirty two (32) healthy volunteers (HVs), each received a single dose of either SPL84 or placebo by inhalation. A total of 8 participants were randomized to each of the 4 escalating cohorts in a 3:1 ratio (active: placebo). Safety and tolerability were evaluated by monitoring adverse events (AEs), vital signs, physical exam findings, spirometry, electrocardiograms (ECG), and analyses of safety laboratories. Blood samples were obtained periodically over 24 h for measurement of systemic exposure. ResultsThere were no significant changes from baseline in vital signs, clinical laboratory values, ECG, physical examination, or pulmonary function. There were no Serious Adverse Events (SAEs) in the study, and there were no significant adverse events. The systemic exposure to SPL84 was low and tended to be dose dependent. The exposure, expressed in terms of area under the curve to infinity (AUCinf), at the no observed adverse effect level (NOAEL) in 9-week toxicological mice study was 7.51 µg/ml*hrs, which is ∼20 times higher than the exposure at the 160 mg dose (444 ng/ml*hrs). ConclusionsSPL84 was safe and well-tolerated when administered as a single inhaled dose to HVs at doses up to 160 mg, with minimal systemic exposure. There were no safety issues observed, no SAEs, no significant related AEs, and, importantly, no significant effect on pulmonary function. The successful completion of the study enabled the initiation of multi-dosing of CF patients in a phase 2 clinical study.

Optimization of a novel series of ENaC inhibitors, leading to the selection of the long-acting inhaled clinical candidate ETD001, a potential new treatment for cystic fibrosis.

Cystic Fibrosis (CF) results from the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel of key importance in the airway epithelia. CFTR helps control optimal hydration of the airways, a crucial requirement for healthy lungs. CFTR modulators have recently been approved as an effective treatment option for many genetic variants of CF. The epithelial sodium channel (ENaC), unlike CFTR which is secretory, is an absorptive pathway, and therefore its inhibition is an alternative and potentially complementary approach to aid hydration of the airways. Due to the adverse effect of ENaC inhibition in the kidney we, as have several others, focused on the design and synthesis of novel ENaC inhibitors for direct delivery to the airways via inhalation. A new series of ENaC inhibitors is described, wherein the well-established pyrazine core of first-generation inhibitors was replaced with a pyrrolopyrazine. Aiming for high retention at the surface of the lung following inhalation, optimization of this template focused on significantly increasing polarity to minimize passive cellular permeability. The resulting optimized clinical candidate ETD001 demonstrates potent inhibition of ENaC (59 nM) prolonged retention in the airways of rats (13% of the delivered dose retained after 6h) following intratracheal administration and potent and long-acting effect in a sheep model of mucociliary clearance following inhalation (ED100 (4-6h) = 9 μg/kg). ETD001 entered a phase II study in CF patients in July 2024.

Exogenous insulin does not reduce protein catabolism in pre-diabetic cystic fibrosis patients: A randomized clinical trial

BackgroundCystic Fibrosis (CF) patients historically suffered from undernutrition, infection and inflammation. Insulin insufficiency-related protein catabolism further compromised health. We aimed to determine whether insulin improves protein catabolism in CF youth with abnormal glucose tolerance (AGT). MethodsThis double-masked, placebo-controlled trial in CF youth age 10–25 with AGT who were in their usual state of health used triple-tracer stable-isotope methodology to measure protein turnover during a baseline test meal and after four weeks of insulin/placebo treatment. Healthy controls were assessed once. CF patients were randomized 1:1:1 to once-daily long-acting insulin (0.25 U/kg/d), three-times daily rapid-acting insulin (0.5 U/15gr carbohydrate), or injectable placebo. ResultsThirty CF patients completed the study. There were no differences in any measure of protein turnover between insulin- and placebo-treated subjects, including endogenous protein breakdown (primary study endpoint). In contrast to earlier studies, protein turnover in the 37 CF patients who completed the baseline meal was normal compared to 20 healthy controls. Meal isotope appeared in plasma earlier in CF than controls, suggesting more rapid gut emptying. The study was interrupted by the pandemic; futility analysis led to study discontinuation before the planned remaining 15 CF patients were studied. ConclusionsRecent advances in CF have led to remarkable clinical improvements. In this study, CF youth with AGT had normal protein catabolism at baseline. Pre-meal or daily basal insulin therapy, while safe and well tolerated, did not significantly enhance protein turnover and does not appear to be necessary in clinically stable patients prior to development of CFRD.

The Future of Cystic Fibrosis Care: Exploring AI's Impact on Detection and Therapy

: Cystic Fibrosis (CF) is a fatal hereditary condition marked by thicker mucus production, which can cause problems with the digestive and respiratory systems. The quality of life and survival rates of CF patients can be improved by early identification and individualized therapy measures. With an emphasis on its applications in diagnosis and therapy, this paper investigates how Artificial Intelligence (AI) is transforming the management of Cystic Fibrosis (CF). AI-powered algorithms are revolutionizing CF diagnosis by utilizing huge genetic, clinical, and imaging data databases. In order to identify CF mutations quickly and precisely, machine learning methods evaluate genomic profiles. Furthermore, AI-driven imaging analysis helps to identify lung and gastrointestinal issues linked to cystic fibrosis early and allows for prompt treatment. Additionally, AI aids in individualized CF therapy by anticipating how patients will react to already available medications and enabling customized treatment regimens. Drug repurposing algorithms find prospective candidates from already-approved drugs, advancing treatment choices. Additionally, AI supports the optimization of pharmacological combinations, enhancing therapeutic results while minimizing side effects. AI also helps with patient stratification by connecting people with CF mutations to therapies that are best for their genetic profiles. Improved treatment effectiveness is promised by this tailored strategy. The transformational potential of artificial intelligence (AI) in the field of cystic fibrosis is highlighted in this review, from early identification to individualized medication, bringing hope for better patient outcomes, and eventually prolonging the lives of people with this difficult ailment.

Trehalose polyphleates participate in Mycobacterium abscessus fitness and pathogenesis.

Mycobacteria produce a large repertoire of surface-exposed lipids with major biological functions. Among these lipids, trehalose polyphleates (TPPs) are instrumental in the infection of Mycobacterium abscessus by the therapeutic phage BPs. However, while the biosynthesis and transport of TPPs across the membrane by MmpL10 have been reported, the role of TPPs in host infection remains enigmatic. Here, we addressed whether the loss of TPPs influences interactions with macrophages and the virulence of M. abscessus. As anticipated, the deletion of mmpL10 in smooth (S) and rough (R) variants of M. abscessus abrogated TPP production, which was rescued upon gene complementation. Importantly, infection of human THP-1 cells with the mmpL10 mutants was associated with decreased intramacrophage survival and a reduced proportion of infected cells. The rough mmpL10 mutant showed an impaired capacity to block phagosomal acidification and was unable to co-localize with Galectin-3, a marker of phagosomal membrane damage. This suggests that TPPs participate, directly or indirectly, in phagolysosomal fusion and in phagosomal membrane damage to establish cytosolic communication. The TPP defect that affects the fitness and virulence of M. abscessus was further demonstrated in zebrafish embryos using a rough clinical strain resistant to phage BPs and harboring a frameshift mutation in mmpL10. Infection with this strain was correlated with a slight decrease in embryo survival and a reduced bacterial burden as compared to the corresponding parental and complemented derivatives. Together, these results indicate that TPPs are important surface lipids contributing to the pathogenicity of M. abscessus.IMPORTANCETrehalose polyphleates (TPPs) are complex lipids associated with the mycobacterial cell surface and were identified 50 years ago. While the TPP biosynthetic pathway has been described recently, the role of these lipids in the biology of mycobacteria remains yet to be established. The wide distribution of TPPs across mycobacterial species suggests that they may exhibit important functions in these actinobacteria. Here, we demonstrate that Mycobacterium abscessus, an emerging multidrug-resistant pathogen that causes severe lung diseases in cystic fibrosis patients, requires TPPs for survival in macrophages and virulence in a zebrafish model of infection. These findings support the importance of this underexplored family of lipids in mycobacterial pathogenesis.

Therapeutic Interventions for Pseudomonas Infections in Cystic Fibrosis Patients: A Review of Phase IV Trials.

Pseudomonas aeruginosa (Pa) poses a significant threat to individuals with cystic fibrosis (CF), as this bacterium is highly adaptable and resistant to antibiotics. While early-stage Pa infections can often be eradicated with aggressive antibiotic therapy, chronic infections are nearly impossible to eliminate and require treatments that focus on long-term bacterial suppression. Without such suppression, these persistent infections can severely damage the lungs, leading to serious complications and a reduced life expectancy for CF patients. Evidence for a specific treatment regimen for managing Pa infections in CF patients remains limited. This narrative review provides a detailed analysis of antimicrobial therapies assessed in completed phase IV trials, focusing on their safety and efficacy, especially with prolonged use. Key antibiotics, including tobramycin, colistin, meropenem, aztreonam, ceftolozane/tazobactam, ciprofloxacin, and azithromycin, are discussed, emphasizing their use, side effects, and delivery methods. Inhaled antibiotics are preferred for their targeted action and minimal side effects, while systemic antibiotics offer potency but carry risks like nephrotoxicity. The review also explores emerging treatments, such as phage therapy and antibiofilm agents, which show promise in managing chronic infections. Nonetheless, further research is necessary to enhance the safety and effectiveness of existing therapies while investigating new approaches for better long-term outcomes.

Анализ эффективности и безопасности применения CFTR-модулятора лумакафтор/ивакафтор у пациентов с муковисцидозом в разных возрастных группах

Russia’s first registered CFTR-modulator lumacaftor/ivacaftor was developed for patients with cystic fibrosis (CF) with the F508del/F508del genotype. The purpose of this research was to study the efficacy and safety of lumacaftor/ivacaftor therapy in different age groups. Materials and methods used: the data of homozygotes for F508del aged 2 to 18 y/o in the Russian CF Patient Registry who had been treated with lumacaftor/ivacaftor were analyzed. The effectiveness of therapy was evaluated in 3 age groups based on examination data, nutritional status, spirometry, sweat test at the start of therapy and after 12 months. In order to assess the safety, examination data, assessment of adverse events (AE), blood biochemical parameters, blood pressure and lens condition were taken into account in 334 pediatric patients in the first month of therapy and in 180 after 12 months. Results: decrease in sweat conductivity was noted in three age groups (p<0.001), only in the 2 to 6 y/o age group were negative values obtained in 6.8%. An increase in BMI was observed in the 6 to 12 y/o and 12 to 18 y/o age groups (р<0.001) whilst an improvement in FVC was observed only in the 12 to 18 y/o age group (p=0.015). Changes in biochemical parameters were statistically significant, both downward and upward, only in the age groups of 6 to 12 y/o and 12 to 18 y/o, changing not significantly. Withdrawal of the drug was required in only a single patient with a persistent increase in transaminase level. Fluctuations in blood pressure occurred within the normal age limits. Frequency of AE was comparable with the results of other studies, it was noted at the start in all groups and after 12 months more often in the age group of 12 to 18 y/o. The best tolerance was noted in the age group of 2 to 6 y/o. Conclusion: for the first time, the efficacy and tolerability of lumacaftor/ivacaftor in patients with CF in Russia was studied against the age aspect according to the 2022-2024 Registry. In the 2 to 6 y/o age group, the achievement of normal sweat test values and the lowest number of adverse reactions were noted, while in the 12 to 18 y/o age group, the positive dynamics were noted for a greater number of indicators, incl. an increase in FVC.

Impact of CFTR modulatory therapies on liver function and fibrosis indices in cystic fibrosis patients: a retrospective analysis from two Romanian medical centers

Background. Patients with cystic fibrosis (CF) frequently require modulatory therapies such as Lumacaftor/Ivacaftor (LI) and Elexacaftor/Tezacaftor/Ivacaftor (ETI) to manage their condition. Given the potential hepatic complications associated with CF, it is critical to understand the impact of these therapies on liver function and fibrosis indices. This study aimed to evaluate the changes in liver function markers and fibrosis indices in CF patients undergoing LI and ETI therapies, with a specific focus on the influence of underlying hepatic disease. Methods. In this retrospective analysis, liver function markers and fibrosis indices were assessed in CF patients receiving ETI (n=24), LI (n=4), or a combination of both (LI/ETI, n=8). Key liver function markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, platelet count, and fibrosis indices (APRI and FIB-4), were measured at baseline and at various time points up to 12 months. Results. In patients receiving LI therapy, ALT and AST levels demonstrated a slight but non-significant decrease over six months, accompanied by significant fluctuations in total bilirubin levels. Among those receiving ETI therapy, ALT and AST levels initially increased but stabilized over time, while total bilirubin levels significantly increased from baseline to 12 months. No significant differences were observed in liver function markers between patients with and without hepatic disease under ETI therapy. Trends in fibrosis indices (APRI and FIB-4) were modest and largely non-significant across both therapies. Conclusions. ETI therapy appears to be safe for CF patients, including those with pre-existing hepatic disease, with no significant deterioration in liver function over a 12-month period. However, the observed fluctuations in bilirubin levels underscore the necessity for ongoing monitoring. Further research is warranted to investigate the long-term hepatic effects of LI and ETI therapies.

CFTrack: Advanced Diagnostic, Monitoring, and Tracking Device for Cystic Fibrosis Care.

Cystic fibrosis (CF) is a genetic disorder that primarily affects the respiratory, digestive, and reproductive systems. In the United States, approximately 32,000 individuals, spanning both children and adults, suffer from CF, and roughly 1,000 new cases are diagnosed annually. The current gold standard for CF diagnosis is the sweat test, yet this method is plagued by issues such as being time-consuming, expensive, challenging to replicate, and lacking treatment monitoring capabilities. In contrast, the emerging field of wearable sweat biosensors has gained significant attention due to their potential for noninvasive health monitoring. Despite this, there remains a conspicuous absence of a wearable sweat biosensor tailored specifically for CF diagnosis and monitoring. Here, this study introduces a flexible wearable sweat biosensor, named CFTrack, designed to address the unique challenges associated with CF. This proposed CFTrack biosensor not only facilitates CF diagnosis but also enables the monitoring of medication treatment effectiveness and tracks therapy activities. In addition, it operates in a self-powered and customized manner, ensuring seamless integration into the daily lives of individuals with CF. Given that sweat tests and fitness routines are the predominant methods for diagnosing and treating cystic fibrosis patients, respectively, the proposed CFTrack biosensor leverages ion concentration in sweat for diagnostic purposes. Additionally, it incorporates a motion-tracking function to monitor physical activity, providing a comprehensive approach to CF management. To evaluate the feasibility of the proposed CFTrack biosensor, a comprehensive evaluation has been performed including numerical simulations, theoretical analyses, and experimental tests. The results demonstrate the efficacy of the proposed CFTrack biosensor in diagnosing and monitoring CF conditions while also showcasing its ability to effectively track the progress of patients undergoing physical therapy. The proposed CFTrack biosensor resolves key issues associated with existing sweat sensors including high energy consumption, intricate fabrication procedures, and the absence of continuous monitoring capabilities. By addressing these challenges, the proposed sweat biosensor aims to revolutionize CF diagnosis and monitoring, offering a more efficient and user-friendly alternative to current methods.

Genetic and clinical factors influencing CF-associated liver disease: the impact of SERPINA1 variants and CFTR genotypes in Romanian pediatric cystic fibrosis patients.

Hepatic disease represents a significant complication in children with cystic fibrosis (CF), yet its relationship with specific genetic factors, including CFTR (Cystic fibrosis transmembrane conductance regulator) mutations and SERPINA1 alleles, is not well understood. This study aims to clarify these associations within a Romanian pediatric CF population. In this cross-sectional, prospective study, we examined 71 children with CF, comparing those with hepatic disease (n=25) to those without (n=46). We collected comprehensive clinical, biochemical, and genetic data, focusing on CFTR genotypes and SERPINA1 alleles. Key outcomes included the prevalence of hepatic disease in relation to specific genotypes, fibrosis markers, and liver function tests. The DF508/DF508 genotype was the most prevalent, occurring in 49% of the cohort. No significant associations were found between hepatic disease and specific CFTR genotypes or SERPINA1 alleles. However, children with hepatic disease exhibited significantly higher fibrosis scores (APRI and FIB-4), suggesting more advanced liver involvement. Additionally, a slight delay in CF diagnosis was observed in those with hepatic disease, though this difference did not reach statistical significance. This pioneering study in Romania underscores the complexity of hepatic disease in CF. While specific CFTR genotypes and SERPINA1 alleles were not significantly associated with hepatic complications, the findings emphasize the importance of early diagnosis and monitoring using fibrosis markers to identify children at risk for liver involvement.