J Vis Exp. 2024 Aug 9;(210). doi: 10.3791/66380.

ABSTRACT

Fourier decomposition is a contrast agent-free 1H MRI method for lung perfusion (Q) and ventilation (V) assessment. After image registration, the time series of each voxel is analyzed with regard to the cardiac and breathing frequency components. Using a standard 2D spoiled gradient-echo sequence with a temporal resolution of ~300 ms, an image-sorting algorithm was developed to produce phase-resolved functional lung imaging (PREFUL) with an increased temporal resolution. Thus, it is feasible to evaluate regional flow volume loops (FVL) during tidal volume breathing and depict the propagation of the pulse wave during the cardiac cycle. This method can be applied at 1.5T or 3T with standard MR hardware without the necessity for sequence programming, as the described protocol can be implemented with the default SPGRE sequence on most systems. PREFUL ventilation MRI has been validated using 129Xe and 19F gas imaging with good regional agreement. Perfusion-weighted PREFUL MRI has been validated using SPECT as well as dynamic contrast enhanced (DCE) MRI. PREFUL has been tested in a dual center dual vendor setting and is currently applied in several ongoing multicenter trials. Furthermore, it is feasible across a range of field strengths (0.55T-3T) and different age groups, including newborns. Quantitative V/Q PREFUL MRI has been used in patients with cystic fibrosis, chronic obstructive pulmonary disease, chronic thromboembolic pulmonary hypertension, and corona virus disease-2019 to quantify disease and monitor treatment change after therapy. Furthermore, PREFUL V/Q imaging has been shown to predict transplant loss due to chronic lung allograft dysfunction in patients after lung transplantation. In summary, PREFUL MRI is a validated technique for quantitative ventilation and pulmonary pulse wave/perfusion imaging for regional pulmonary disease detection, quantification, and treatment monitoring with potential added value to the current clinical routine.

PMID:39185874 | DOI:10.3791/66380

ACS Nano. 2024 Aug 26. doi: 10.1021/acsnano.4c10344. Online ahead of print.

ABSTRACT

Sweat analysis has advanced from diagnosing cystic fibrosis and testing for illicit drugs to noninvasive monitoring of health biomarkers. This article introduces the rapid development of wearable and flexible sweat sensors, highlighting key milestones and various sensing strategies for real-time monitoring of analytes. We discuss challenges such as developing high-performance nanomaterial-based biosensors, ensuring continuous sweat production and sampling, achieving high sweat/blood correlation, and biocompatibility. The potential of machine learning to enhance these sensors for personalized healthcare is presented, enabling real-time tracking and prediction of physiological changes and disease onset. Leveraging advancements in flexible electronics, nanomaterials, biosensing, and data analytics, wearable sweat biosensors promise to revolutionize disease management, prevention, and prediction, promoting healthier lifestyles and transforming medical practices globally.

PMID:39185844 | DOI:10.1021/acsnano.4c10344

An Sist Sanit Navar. 2024 Aug 26;47(2):e1084. doi: 10.23938/ASSN.1084.

ABSTRACT

BACKGROUND: To analyze the knowledge, abilities, and emotional state of cystic fibrosis patients during a specific follow-up period and compare this with the recall they had of the transition (planned and gradual shift from the pediatric unit) / transfer (direct change skipping the steps recommended by the guidelines) to a specialized cystic fibrosis adult unit.

METHODS: Prospective cross-sectional study with cystic fibrosis adult patients under follow-up in a specialist consultation. Group 1 were patients who transitioned and Group 2 were transferred patients. The following information was collected: sociodemographic variables, degree of knowledge, skills, and emotional state using a survey designed for this purpose (as part of the internal consistency validation process). Participants also completed the emotional subscale of Cystic Fibrosis Questionnaire-Revised. Inter-group comparisons were made for the transition/transfer, at the follow-up, and during the evolution.

RESULTS: Thirty-five patients were analyzed; 65.8% male; mean age 31.9 years (SD =10.1). At the transition, Group 1 (n=19; 54.3%) had greater knowledge about their medication and reduced ability to manage appointments and making decisions in comparison to Group 2 at transfer. At follow-up, Group 1 made a better report on their emotional state and significantly improved their ability to manage appointments, communication, and decision-making.

CONCLUSIONS: Patients who were moved to an adult cystic fibrosis unit through transition were more knowledgeable about their medications. However, those who were transferred managed their appointments and decision-making better, but felt sadder.

PMID:39185776 | DOI:10.23938/ASSN.1084

bioRxiv [Preprint]. 2024 Aug 12:2024.08.12.607571. doi: 10.1101/2024.08.12.607571.

ABSTRACT

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene. Although many people with CF (pwCF) are treated using CFTR modulators, some are non-responsive due to their genotype or other uncharacterized reasons. Autologous airway stem cell therapies, in which the CFTR cDNA has been replaced, may enable a durable therapy for all pwCF. Previously, CRISPR-Cas9 with two AAVs was used to sequentially insert two halves of the CFTR cDNA and an enrichment cassette into the CFTR locus. However, the editing efficiency was <10% and required enrichment to restore CFTR function. Further improvement in gene insertion may enhance cell therapy production. To improve CFTR cDNA insertion in human airway basal stem cells (ABCs), we evaluated the use of the small molecules AZD7648 and ART558 which inhibit non-homologous end joining (NHEJ) and micro-homology mediated end joining (MMEJ). Adding AZD7648 alone improved gene insertion by 2-3-fold. Adding both ART558 and AZD7648 improved gene insertion but induced toxicity. ABCs edited in the presence of AZD7648 produced differentiated airway epithelial sheets with restored CFTR function after enrichment. Adding AZD7648 did not increase off-target editing. Further studies are necessary to validate if AZD7648 treatment enriches cells with oncogenic mutations.

PMID:39185207 | PMC:PMC11343149 | DOI:10.1101/2024.08.12.607571

bioRxiv [Preprint]. 2024 Aug 16:2024.08.14.607921. doi: 10.1101/2024.08.14.607921.

ABSTRACT

In our era of rising antibiotic resistance, Stenotrophomonas maltophilia (STM) is an understudied, gram-negative, aerobic bacterium widespread in the environment and increasingly causing opportunistic infections. Treating STM infections remains difficult, leading to an increase in disease severity and higher hospitalization rates in people with Cystic Fibrosis (pwCF), cancer, and other immunocompromised health conditions. The lack of effective antibiotics has led to renewed interest in phage therapy; however, there is a need for well-characterized phages. In response to an oncology patient with a respiratory infection, we collected 18 phages from Southern California wastewater influent that exhibit different plaque morphology against STM host strain B28B, cultivated from a blood sample. Here, we characterize the genomes and life cycle kinetics of our STM phage collection. We hypothesize that genetically distinct phages give rise to unique lytic life cycles that can enhance bacterial killing when combined into a phage cocktail compared to the individual phages alone. We identified three genetically distinct clusters of phages, and a representative from each group was screened for potential therapeutic use and investigated for infection kinetics. The results demonstrated that the three-phage cocktail significantly suppressed bacterial growth compared to individual phages when observed for 48 hours. We also assessed the lytic impacts of our three-phage cocktail against a collection of 46 STM strains to determine if a multi-phage cocktail can expand the host range of individual phages. Our phages remained strain-specific and infect >50% of tested strains. The multi-phage cocktail maintains bacterial growth suppression and prevents the emergence of phage-resistant strains throughout our 40-hour assay. These findings suggest specialized phage cocktails may be an effective avenue of treatment for recalcitrant STM infections resistant to current antibiotics.

IMPORTANCE: Phage therapy could provide a vital strategy in the fight against antimicrobial resistance (AMR) bacterial infections; however, significant knowledge gaps remain. This study investigates phage cocktail development for the opportunistic pathogen Stenotrophomonas maltophilia (STM). Our findings contribute novel phages, their lytic characteristics, and limitations when exposed to an array of clinically relevant STM strains. Eighteen bacteriophages were isolated from wastewater influent from Escondido, California, and subjected to genomic analysis. We investigated genetically distinct phages to establish their infection kinetics and developed them into a phage cocktail. Our findings suggest that a genetically distinct STM phage cocktail provides an effective strategy for bacterial suppression of host strain B28B and five other clinically relevant STM strains. Phage therapy against STM remains poorly understood, as only 39 phages have been previously isolated. Future research into the underlying mechanism of how phage cocktails overwhelm the host bacteria will provide essential information that could aid in optimizing phage applications and impact alternative treatment options.

PMID:39185190 | PMC:PMC11343209 | DOI:10.1101/2024.08.14.607921

F1000Res. 2022 Nov 22;11:379. doi: 10.12688/f1000research.110472.3. eCollection 2022.

ABSTRACT

Background: The main aim of this study was to evaluate whether selected polymorphic variants in genes from the inflammatory pathway can be predictors of pulmonary or digestive manifestation of cystic fibrosis, as well as of severity of lung disease. Materials and methods: Using pyrosequencing and sequencing we have genotyped 12 variants in TNF (rs361525, rs1800629), CXCL8 (rs4073, rs2227306, rs2227307, rs188378669), IL1B (rs16944, rs1143634, rs1142639, rs1143627), IL6 (rs1800795) and IL10 (rs1800896) genes in a cohort of 55 Polish patients with diagnosed cystic fibrosis and controls. In our study group, a pulmonary manifestation of disease revealed 44 of subjects (80%), and digestive symptoms dominated in 11 (20%) of analyzed individuals. Severe lung dysfunction has occurred in 20 (36.4%) of patients. Results: We proved, that two promoter variants of IL1B, rs1143627 (c.-118G > A) and rs16944 (c.-598T > C) are presented significantly more often in patients with severe character of lung disease compared to mild (82.5% vs. 62.8%, p-value 0.030, and 87.5% vs. 64.3%, p-value 0.008, respectively) in cystic fibrosis course. Haplotype AC formed by both changes had also a higher frequency (80%) in patients with severe course compared to the mild character (61.4%) of disease. However, the frequency of promoter variant TNF c.-308C > T (rs1800629) was presented at a significantly lower level in the patient's group compared to healthy controls (2.7% vs. 15%, p-value 0.001). Furthermore, the presence of methicillin-resistant Staphylococcus aureus significantly correlated with the lower FEV1% in patients (p-value 0.01). Conclusions: Genetic variants, rs1143627 and rs16944, of IL1B are promising candidates as predictors of the severe character of lung disease in Polish patients with cystic fibrosis.

PMID:39185143 | PMC:PMC11344199 | DOI:10.12688/f1000research.110472.3

Gene Ther. 2024 Aug 25. doi: 10.1038/s41434-024-00480-y. Online ahead of print.

ABSTRACT

Mutation-agnostic treatments such as airway gene therapy have the potential to treat any individual with cystic fibrosis (CF), irrespective of their CF transmembrane conductance regulator (CFTR) gene variants. The aim of this study was to employ two CF rat models, Phe508del and CFTR knockout (KO), to assess the comparative effectiveness of CFTR modulators and lentiviral (LV) vector-mediated gene therapy. Cells were isolated from the tracheas of rats and used to establish air-liquid interface (ALI) cultures. Phe508del rat ALIs were treated with the modulator combination, elexacaftor-tezacaftor-ivacaftor (ETI), and separate groups of Phe508del and KO tracheal epithelial cells were treated with LV-CFTR followed by differentiation at ALI. Ussing chamber measurements were performed to assess CFTR function. ETI-treated Phe508del ALI cultures demonstrated CFTR function that was 59% of wild-type level, while gene-addition therapy restored Phe508del to 68% and KO to 47% of wild-type level, respectively. Our findings show that rat Phe508del-CFTR protein can be successfully rescued with ETI treatment, and that CFTR gene-addition therapy provides significant CFTR correction in Phe508del and KO ALI cultures to levels that were comparable to ETI. These findings highlight the potential of an LV vector-based gene therapy for the treatment of CF lung disease.

PMID:39183346 | DOI:10.1038/s41434-024-00480-y

J Cyst Fibros. 2024 Aug 24:S1569-1993(24)00828-2. doi: 10.1016/j.jcf.2024.08.002. Online ahead of print.

ABSTRACT

BACKGROUND: The objective of this study was to assess the differential times of submission and approval of CFTR modulators in the United States (US) and the European Union (EU).

METHODS: By collecting publicly available data from the websites of the Food and Drug Administration and the European Medicines Agency, we quantified differential times in submission, review duration, and approvals of initial marketing authorization and variation of indications of CFTR modulators in the US and the EU by December 31, 2023.

RESULTS: Applications regarding marketing of 4 CFTR modulators were submitted 103 (SD ±143) days later in the EU than in the US: 31 (SD ±39) days later for initial approval, and 124 (SD ±155) days for supplemental indications. The regulatory review process was completed in 181 days [IQR, 179 - 182] in the US and 325 days [IQR, 276 - 382] in the EU: 167 days [IQR, 102 - 232] in the US and 346 days [IQR, 302 - 400] in the EU for first approvals, 181 days [IQR, 181 - 182] in the US and 324 days [IQR, 264 - 382] in the EU for supplemental indication approvals. CFTR modulators were approved 267 (SD 143) days later in the EU than in the US: 220 (SD ±76) days for initial approval and 280 (SD ±157) days for supplemental indications.

CONCLUSION: We found significant differences in times of submission and for approval of CFTR modulators between the US and EU, whereby initial approvals and subsequent indication approvals were always first granted in the US.

PMID:39183127 | DOI:10.1016/j.jcf.2024.08.002

J Cyst Fibros. 2024 Aug 24:S1569-1993(24)00829-4. doi: 10.1016/j.jcf.2024.08.003. Online ahead of print.

ABSTRACT

INTRODUCTION: The effects of cystic fibrosis (CF) on females' sexuality have not been described. The aims of the present study were to describe and characterize sexual issues in females with CF.

METHODS: We included adult (≥18 years) females with CF currently or previously in a sexual relationship from 11 adult CF centres in France. We collected quantitative data using a modified version of the self-administered Pelvic Incontinence Sexual Questionnaire IUGA-Revised (PISQ-IR). We performed one-to-one interviews using a semi-directive framework in volunteer females to further characterize the effects of CF on sexual life. We summarized answers to questionnaire as percentages and analysed interviews by theme according to discourse analysis method.

RESULTS: Between November 2019 and July 2021, 212 females completed the PISQR-IR, of whom 15 were interviewed. Of the females who completed the questionnaire, 93.4% were concerned about the discomfort, pain, or unpleasantness they experienced during sexual intercourse. The most frequent cause of sexual difficulties was a lack of vaginal lubrication (78.8%), followed by pain (74.1%) and discomfort. Interviews revealed sexual lives that were uncomfortable or painful, unsatisfying or avoided for most females, with a strong impression of being sexually different, incompetent, and betrayed by their bodies in terms of sexual desire.

CONCLUSION: Sexual difficulties faced by females with CF are highly prevalent. Increasing awareness regarding sex life issues in females with CF appears necessary to improve their management by CF multidisciplinary teams.

PMID:39183126 | DOI:10.1016/j.jcf.2024.08.003

Ann Transplant. 2024 Aug 13;29:e944049. doi: 10.12659/AOT.944049.

ABSTRACT

BACKGROUND End-stage renal disease is a major issue in the management of patients undergoing lung transplantation. Combined kidney-lung transplantation (CKLT) and kidney after lung transplantation (KALT) are the 2 preferred solutions to manage this situation. To evaluate these strategies, we describe kidney and lung graft outcomes and patient survival in patients managed with CKLT and KALT. MATERIAL AND METHODS We conducted a retrospective single-center cohort study. Patients who underwent a CKLT or a KALT were included in this study. Retrospective extraction of data from medical records was performed. RESULTS Seventeen patients underwent CKLT and 9 underwent KALT. Most of the patients had cystic fibrosis and presented renal failure related to anti-calcineurin toxicity. The 30-day and 1-year survival of CKLT recipients were both 75.6%. No patients with KALT died during the follow-up. Kidney graft prognosis was almost exclusively influenced by patient survival in relation to postoperative lung transplant complications. The rate of severe surgical complications was close to 60% for CKLT compared with 30% for KALT. The kidney graft function (estimated kidney graft function) did not differ according to the transplantation strategy. CONCLUSIONS KALT is a safe option, with postoperative morbidity and renal graft function identical to those of kidney transplantation in non-lung-transplanted patients. The results of CKLT depend mainly on the morbidity associated with lung transplantation but remain an attractive option for patients with respiratory failure associated with end-stage renal disease. The choice of transplant strategy must also take into account the most ethical and efficient allocation of kidney grafts.

PMID:39182171 | DOI:10.12659/AOT.944049

Respir Care. 2024 Aug 24;69(9):1218-1219. doi: 10.4187/respcare.12382.

NO ABSTRACT

PMID:39181717 | DOI:10.4187/respcare.12382

J Control Release. 2024 Aug 22:S0168-3659(24)00577-7. doi: 10.1016/j.jconrel.2024.08.029. Online ahead of print.

ABSTRACT

Antimicrobial resistance is considered one of the biggest threats to public health worldwide. Methicillin-resistant S. aureus is the causative agent of a number of infections and lung colonization in people suffering from cystic fibrosis. Moreover, a growing body of evidence links the microbiome to the development of cancer, as well as to the success of the treatment. In this view, the development of novel antibiotics is of critical importance, and SV7, a novel antibiotic active against MRSA at low concentrations, represents a promising candidate. However, the low aqueous solubility of SV7 hampers its therapeutic translation. In this study, SV7 was encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) to improve the solubility profile, to ensure sustained release and eventually support deposition in the airways. Furthermore, PLGA NPs were formulated as dry powder to extend their shelf-life and were shown to efficiently target intracellular infections. After identifying a formulation with suitable physico-chemical characteristics, SV7-loaded NPs were investigated in vitro in terms of inhibitory activity against MRSA, and their safety profile in lung epithelial cells. Subsequently, the activity against MRSA intracellular infections was investigated in a co-culture model of MRSA and macrophages. To test the translatability of our findings, SV7-loaded NPs were tested in vivo in a Galleria mellonella infection model. In conclusion, SV7-loaded NPs showed a safe profile and efficient inhibitory activity against MRSA at low concentrations. Furthermore, their activity against intracellular infections was confirmed, and was retained in vivo, rendering them a promising candidate for treatment of MRSA lung infections.

PMID:39181163 | DOI:10.1016/j.jconrel.2024.08.029

Andrology. 2024 Aug 24. doi: 10.1111/andr.13742. Online ahead of print.

ABSTRACT

BACKGROUND: Current guidelines indicate that patients with extreme oligozoospermia or azoospermia should be tested for chromosomal imbalances, azoospermia factor (AZF) deletions and/or CFTR variants. For other sperm abnormalities, no genetic diagnostics are recommended.

OBJECTIVES: To determine whether exome sequencing (ES) with combined copy number variant (CNV) and single nucleotide variant (SNV) analysis is a reliable first-tier method to replace current methods (validation study), and to evaluate the diagnostic yield after 10 months of implementation (evaluation study).

MATERIALS AND METHODS: In the validation study, ES was performed on DNA of patients already diagnosed with AZF deletions (n = 17), (non-)mosaic sex chromosomal aneuploidies or structural chromosomal anomalies (n = 37), CFTR variants (n = 26), or variants in known infertility genes (n = 4), and 90 controls. The data were analyzed using our standard diagnostic pipeline, with a bioinformatic filter for 130 male infertility genes. In the evaluation study, results of 292 clinical exomes were included.

RESULTS: All previously reported variants in the validation cohort, including clinically relevant Y-chromosomal microdeletions, were correctly identified and reliably detected. In the evaluation study, we identified one or more clinically relevant genetic anomalies in 67 of 292 of all cases (22.9%): these included aberrations that could have been detected with current methods in 30 of 67 patients (10.2% of total), (possible) (mono)genetic causes in the male infertility gene panel in 28 of 67 patients (9.6%), and carriership of cystic fibrosis in nine of 67 patients (3.1%).

CONCLUSION: ES is a reliable first-tier method to detect the most common genetic causes of male infertility and, as additional genetic causes can be detected, in our evaluation cohort the diagnostic yield almost doubled (10.2%-19.8%, excluding CF carriers). A genetic diagnosis provides answers on the cause of infertility and helps the professionals in the counseling for treatment, possible co-morbidities and risk for offspring and/or family members. Karyotyping will still remain necessary for detecting balanced translocations or low-grade chromosomal mosaicism.

PMID:39180390 | DOI:10.1111/andr.13742

J Psychosom Res. 2024 Aug 8;186:111877. doi: 10.1016/j.jpsychores.2024.111877. Online ahead of print.

ABSTRACT

OBJECTIVE: People living with cystic fibrosis (PwCF) are at increased risk of mental health conditions. There is little evidence addressing psychotropic medication use in PwCF. This study aimed to estimate the dispensing prevalence of antidepressant, anxiolytic, antipsychotic, psychostimulant, and hypnotic/sedative medication in PwCF in Australia between 2013 and 2022.

METHOD: A 10% random sample of Australian Pharmaceutical Benefits Scheme data was used to identify PwCF and their medications between 2013 and 2022. Annual prevalence of psychotropic medication dispensing was estimated using a 3-year rolling average, stratified by sex, age, and medication class.

RESULTS: Psychotropic medications were dispensed to 206/478 (41.3%) PwCF. Antidepressant and anxiolytic dispensing prevalence was highest in adult females, increasing from 201 5 by 50% to their peak in 2021 (antidepressants 36.8%; anxiolytics 12.3%). Psychostimulant prevalence was highest in adolescent males and increased over three-fold during the study period from 3.6% to 13.2%. The prevalence of antipsychotic medication was lower than other classes with adult females having the highest prevalence (3.1% and 5.8% in 201 5 and 2022 respectively). Hypnotic/sedative medications remained consistently low or decreased in all groups except male children, where it increased from 0.6% to 2.8% from 201 5 to 2022.

CONCLUSION: Psychotropic medication use is higher among Australian PwCF compared to the general population, with varying prevalence across age and sex groups. This is of interest due to complexities with CF comorbidities and potential medication influences and interactions. Future studies should investigate the reasons for psychotropic use disparities within PwCF with the aim to establish targeted guidelines and optimize outcomes.

PMID:39178579 | DOI:10.1016/j.jpsychores.2024.111877

PLoS Biol. 2024 Aug 23;22(8):e3002781. doi: 10.1371/journal.pbio.3002781. Online ahead of print.

ABSTRACT

Metabolism provides the foundation for all cellular functions. During persistent infections, in adapted pathogenic bacteria metabolism functions radically differently compared with more naïve strains. Whether this is simply a necessary accommodation to the persistence phenotype or if metabolism plays a direct role in achieving persistence in the host is still unclear. Here, we characterize a convergent shift in metabolic function(s) linked with the persistence phenotype during Pseudomonas aeruginosa colonization in the airways of people with cystic fibrosis. We show that clinically relevant mutations in the key metabolic enzyme, pyruvate dehydrogenase, lead to a host-specialized metabolism together with a lower virulence and immune response recruitment. These changes in infection phenotype are mediated by impaired type III secretion system activity and by secretion of the antioxidant metabolite, pyruvate, respectively. Our results show how metabolic adaptations directly impinge on persistence and pathogenicity in this organism.

PMID:39178315 | DOI:10.1371/journal.pbio.3002781

Expert Rev Respir Med. 2024 Aug 23. doi: 10.1080/17476348.2024.2394694. Online ahead of print.

ABSTRACT

INTRODUCTION: The availability of cystic fibrosis transmembrane conductance regulator (CFTR) modulators opens the possibility of discontinuing some chronic pulmonary therapies to decrease cystic fibrosis (CF) treatment burden. However, CFTR modulators may not adequately address neutrophilic inflammation, which contributes to a self-perpetual cycle of viscous CF sputum, airway obstruction, inflammation, and lung function decline.

AREAS COVERED: This review discusses the emerging role of neutrophil extracellular traps in CF and its role in CF sputum viscosity, airway obstruction, and inflammation, based on a literature search of PubMed (1990-present). We summarize clinical trials and real-world studies that support the efficacy of dornase alfa (Pulmozyme) in improving lung function and reducing pulmonary exacerbation in people with CF (PwCF), and we discuss the potential role of dornase alfa in reducing airway inflammation. We also examine the findings of short-term trials evaluating the discontinuation of mucoactive therapy in PwCF receiving CFTR modulators.

EXPERT OPINION: Long-term studies are needed to assess the impact of discontinuing mucoactive therapy in PwCF who are clinically stable while receiving CFTR modulatory therapy. Treatment decisions should take into account the severity of underlying lung disease. People with advanced CF will likely require ongoing mucoactive therapy.

PMID:39176450 | DOI:10.1080/17476348.2024.2394694

World Allergy Organ J. 2024 Jul 29;17(8):100941. doi: 10.1016/j.waojou.2024.100941. eCollection 2024 Aug.

ABSTRACT

BACKGROUND: Aging implies changes in terms of lung function, immune system, and respiratory and extra-respiratory comorbidities. Few studies have specifically addressed the relevance of age on severe asthma burden and control. We aimed to evaluate whether age acts as an independent determinant of asthma severity, in terms of clinical, functional, and inflammatory profile, and to explore potential cofactors that contribute to a more difficult disease control in different age groups.

METHODS: Patients from Severe Asthma Network Italy (SANI) registry were retrospectively divided in subgroups according to their age. Cutoffs for age were established according to quartiles in order to obtain a comparable number of patients for each group, and then rounded for the sake of simplicity.

RESULTS: Overall, 1805 severe asthma patients were analyzed. Lung function represented the most important age-related variable. On the opposite the level of asthma control was not differently distributed among age ranges. In young people the presence of atopy-related comorbidities (allergic rhinitis, atopic dermatitis) predominated, whilst systemic-metabolic and degenerative comorbidities such as diabetes, cardiovascular diseases, anxious-depressive syndrome, and osteoporosis prevailed in elderly. Bronchiectasis and sleep disturbances were significantly associated with age.

CONCLUSIONS: Despite that it cannot be considered a treatable trait, our study suggests that age should be evaluated within a personalized approach to severe asthma patients, in order to provide a better clinical profiling and a more tailored treatment strategy.

PMID:39176287 | PMC:PMC11338937 | DOI:10.1016/j.waojou.2024.100941

Eur Respir J. 2024 Aug 22:2301683. doi: 10.1183/13993003.01683-2023. Online ahead of print.

ABSTRACT

RATIONALE AND OBJECTIVE: Cystic fibrosis (CF) is caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators offer significant improvements, but approximately 10% of patients remain nonresponsive or are intolerant. This study provides an analysis of rSIV.F/HN, a lentiviral vector optimized for lung delivery, including CFTR protein expression, functional correction of CFTR defects and genomic integration site analysis in preparation for a first-in-human clinical trial.

METHODS: Air-liquid interface cultures of primary human bronchial epithelial cells (HBEC) from CF patients (F508del/F508del), as well as a CFTR-deficient immortalized human lung epithelial cell line mimicking Class I (CFTR-null) homozygous mutations, were used to assess transduction efficiency. Quantification methods included a novel proximity ligation assay (PLA) for CFTR protein expression. For assessment of CFTR channel activity, Ussing chamber studies were conducted. The safety profile was assessed using integration site analysis and in vitro insertional mutagenesis studies.

RESULTS: rSIV.F/HN expressed CFTR and restored CFTR-mediated chloride currents to physiological levels in primary F508del/F508del HBECs as well as in a Class I cells. In contrast, the latter could not be achieved by small-molecule CFTR modulators, underscoring the potential of gene therapy for this mutation class. Combination of rSIV.F/HN-CFTR with the potentiator ivacaftor showed a greater than additive effect. The genomic integration pattern showed no site predominance (frequency of occurrence ≤10%), and a low risk of insertional mutagenesis was observed in an in vitro immortalization assay.

CONCLUSIONS: The results underscore rSIV.F/HN as a promising gene therapy vector for CF, providing a mutation-agnostic treatment option.

PMID:39174284 | DOI:10.1183/13993003.01683-2023

Sci Rep. 2024 Aug 22;14(1):19487. doi: 10.1038/s41598-024-70514-3.

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a pneumonia with extremely heterogeneous clinical presentation, ranging from asymptomatic to severely ill patients. Previous studies have reported links between the presence of host genetic variants and the outcome of the COVID-19 infection. In our study, we used whole exome sequencing in a cohort of 444 SARS-CoV-2 patients, admitted to hospital in the period October-2020-April-2022, to search for associations between rare pathogenic/potentially pathogenic variants and COVID-19 progression. We used gene prioritization-based analysis in genes that have been reported by host genetic studies. Although we did not identify correlation between the presence of rare pathogenic variants and COVID-19 outcome, in critically ill patients we detected known mutations in a number of genes associated with severe disease related to cardiovascular disease, primary ciliary dyskinesia, cystic fibrosis, DNA damage repair response, coagulation, primary immune disorder, hemoglobin subunit β, and others. Additionally, we report 93 novel pathogenic variants found in severely infected patients who required intubation or died. A network analysis showed main component, consisting of 13 highly interconnected genes related to epithelial cilium. In conclusion, we have detected rare pathogenic host variants that may have influenced the COVID-19 outcome in Bulgarian patients.

PMID:39174791 | DOI:10.1038/s41598-024-70514-3

Therapie. 2024 Jul 14:S0040-5957(24)00073-8. doi: 10.1016/j.therap.2024.06.005. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis transmembrane regulator (CFTR) channel modulators (ivacaftor, lumacaftor, tezacaftor and elexacaftor) represent a major advance in the management of cystic fibrosis. However, few data are available on the real-life safety profile of these medications, in particular on adverse events that may lead to their discontinuation. The aim of this study is to describe the characteristics and evolution of adverse reactions to the tezacaftor/ivacaftor/elexacaftor combination that led to discontinuation and were reported to the Centre régional de pharmacovigilance (CRPV) in Rennes (France).

MATERIALS AND METHODS: A retrospective study was conducted from December 2021 to May 2023, focusing on cases of discontinuation of the tezacaftor/ivacaftor/elexacaftor combination due to the occurrence of one or more adverse effects, and reported to the CRPV of Rennes, France.

RESULTS: Ten cases of drug discontinuation were reported to the Rennes CRPV (6 women/4 men). Adverse effects mainly involved neuropsychiatric disorders (n=6), followed by liver disorders (n=2), ear, nose and throat disorders (n=1), and digestive disorders (n=1). The average duration of treatment at discontinuation was 339.8 [39-668] days. The drug was reintroduced in 7 patients on average 48.7 [7-123] days after discontinuation, with a dosage adjustments (n=4) consisting of changes in dosing times or a reduction in daily doses, with varying success in alleviating adverse symptoms depending on the case.

CONCLUSION: This small case series suggests that neuropsychiatric adverse effects may occur more frequently than initially described after initiation of tezacaftor/ivacaftor/elexacaftor, and should be carefully screened and monitored. Dosage or administration schedule modifications may be considered for patients experiencing these adverse effects. Further pharmacovigilance studies are needed to better understand the adverse effect profiles of "caftors", their possible risk factors, and the impact of adjusting dosing modalities.

PMID:39174453 | DOI:10.1016/j.therap.2024.06.005