J Dent. 2024 Feb 17:104893. doi: 10.1016/j.jdent.2024.104893. Online ahead of print.

ABSTRACT

OBJECTIVES: Cystic Fibrosis is an autosomal recessive condition. It is a multisystem disease treated with a broad range of pharmacological therapies, diet and nutrition, and physiotherapy. Previous studies suggest that people with cystic fibrosis have a higher prevalence of developmental defects of enamel which may place this population at a greater risk of developing oral diseases such as caries. The aim of this study was to assess a cohort of people with cystic fibrosis (PwCF) for the presence of developmental defects of enamel and compare the results with a control group of people without cystic fibrosis.

METHODS: A cross sectional study involving 92 participants with cystic fibrosis and 92 controls was conducted in XXXXXXXXXXXXXXX. All participants completed a detailed questionnaire prior to undergoing a full clinical examination. The Developmental Defect of Enamel Index was used as a measurement index. All data was statistically analysed with the help of statisticians from Cystic Fibrosis Registry XXXXX.

RESULTS: 64% (n=59) of PwCF had enamel defects compared to just 30% (n=28) of people without cystic fibrosis. The median number of teeth affected by enamel defects in the study group was 1.5, compared to 0 in the control group.

CONCLUSION: In this study the cohort of PwCF had more enamel defects than people without CF. Further research is required to investigate the aetiology of these findings.

CLINICAL SIGNIFICANCE: Clinicians should be vigilant after teeth have erupted in PwCF as they may have an increased susceptibility to developmental defects of enamel.

PMID:38373520 | DOI:10.1016/j.jdent.2024.104893

J Cell Mol Med. 2024 Feb;28(4):e18142. doi: 10.1111/jcmm.18142.

ABSTRACT

We identified and characterized multiple cell-type selective enhancers of the CFTR gene promoter in previous work and demonstrated active looping of these elements to the promoter. Here we address the impact of genomic spacing on these enhancer:promoter interactions and on CFTR gene expression. Using CRISPR/Cas9, we generated clonal cell lines with deletions between the -35 kb airway enhancer and the CFTR promoter in the 16HBE14o- airway cell line, or between the intron 1 (185 + 10 kb) intestinal enhancer and the promoter in the Caco2 intestinal cell line. The effect of these deletions on CFTR transcript abundance, as well as the 3D looping structure of the locus was investigated in triplicate clones of each modification. Our results indicate that both small and larger deletions upstream of the promoter can perturb CFTR expression and -35 kb enhancer:promoter interactions in the airway cells, though the larger deletions are more impactful. In contrast, the small intronic deletions have no effect on CFTR expression and intron 1 enhancer:promoter interactions in the intestinal cells, whereas larger deletions do. Clonal variation following a specific CFTR modification is a confounding factor particularly in 16HBE14o- cells.

PMID:38372567 | DOI:10.1111/jcmm.18142

Pediatr Pulmonol. 2024 Feb 19. doi: 10.1002/ppul.26906. Online ahead of print.

ABSTRACT

INTRODUCTION: Children's rare lung diseases are a heterogeneous group of rare lung diseases with significant morbidity and mortality. There is very limited information on the incidence and prevalence of children's rare lung diseases in Asia. We investigated the nationwide incidence, prevalence, and pattern of medical service utilization of children's rare lung diseases in Korea.

METHODS: We studied patients who were diagnosed with rare lung diseases coded per International Statistical Classification of Diseases and Related Health Problems, 10th Edition and registered in the national rare diseases database of confirmed patients. Data was extracted from the Korean National Health Insurance Service Claims database over 2019-2021.

RESULTS: Average incidence rate was 12.9 new cases per million children per year, and average prevalence rate was 60.2 cases per million children during the study period of 2019-2021. We found that more than 65% of new cases were diagnosed before 2 years of age. ChILD, primary ciliary dyskinesia, and cystic fibrosis were usually diagnosed after 6 years of age. Congenital airway and lung anomalies were often diagnosed before 2 years of age. Busan and Gyeongsangnam-do residents tended to visit hospitals near their place of residence, while residents of other areas tended to visit hospitals in Seoul regardless of their area of residence.

CONCLUSIONS: We examined the epidemiology of rare lung diseases in children in South Korea. Our estimation of the incidence and prevalence could be used for sustainable health care and equitable distribution of health care resources.

PMID:38372471 | DOI:10.1002/ppul.26906

Front Microbiol. 2024 Feb 2;15:1340585. doi: 10.3389/fmicb.2024.1340585. eCollection 2024.

ABSTRACT

Bacterial infections represent a key public health issue due to the occurrence of multidrug-resistant bacteria. Recently, the amount of data supporting the dynamic control of epigenetic pathways by environmental cues has triggered research efforts toward the clarification of their role in microbial infections. Among protein post-translational modifications, reversible acetylation is the most implicated in the feedback to environmental stimuli and in cellular homeostasis. Accordingly, the latest studies identified the histone deacetylase 6 (HDAC6) enzyme as a crucial player in the complex molecular machinery underlying bacterial clearance or killing. A very important milestone for the elucidation of the consequence of HDAC6 activity in bacterial infections is herein described, unveiling for the first time the role of a potent HDAC6 inhibitor in interfering with biofilm formation and modulating virulence factors of P. aeruginosa. We demonstrated that compound F2F-2020202 affected the production of some important virulence factors in P. aeruginosa, namely pyocyanin and rhamnolipids, clearly impairing its ability to form biofilm. Furthermore, evidence of possible QS involvement is supported by differential regulation of specific genes, namely RhlI, phAz1, and qsrO. The data herein obtained also complement and in part explain our previous results with selective HDAC6 inhibitors able to reduce inflammation and bacterial load in chronic infection models recapitulating the cystic fibrosis (CF) phenotype. This study fosters future in-depth investigation to allow the complete elucidation of the molecular mechanisms underlying HDAC6's role in bacterial infections.

PMID:38371939 | PMC:PMC10869609 | DOI:10.3389/fmicb.2024.1340585

Front Cell Infect Microbiol. 2024 Feb 2;14:1296295. doi: 10.3389/fcimb.2024.1296295. eCollection 2024.

ABSTRACT

Lung cancer has the highest mortality rate among all cancers worldwide. The 5-year overall survival rate for non-small cell lung cancer (NSCLC) is estimated at around 26%, whereas for small cell lung cancer (SCLC), the survival rate is only approximately 7%. This disease places a significant financial and psychological burden on individuals worldwide. The symbiotic microbiota in the human body has been significantly associated with the occurrence, progression, and prognosis of various diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. Studies have demonstrated that respiratory symbiotic microorganisms and their metabolites play a crucial role in modulating immune function and contributing to the pathophysiology of lung cancer through their interactions with the host. In this review, we provide a comprehensive overview of the microbial characteristics associated with lung cancer, with a focus on the respiratory tract microbiota from different locations, including saliva, sputum, bronchoalveolar lavage fluid (BALF), bronchial brush samples, and tissue. We describe the respiratory tract microbiota's biodiversity characteristics by anatomical region, elucidating distinct pathological features, staging, metastasis, host chromosomal mutations, immune therapies, and the differentiated symbiotic microbiota under the influence of environmental factors. Our exploration investigates the intrinsic mechanisms linking the microbiota and its host. Furthermore, we have also provided a comprehensive review of the immune mechanisms by which microbiota are implicated in the development of lung cancer. Dysbiosis of the respiratory microbiota can promote or inhibit tumor progression through various mechanisms, including DNA damage and genomic instability, activation and regulation of the innate and adaptive immune systems, and stimulation of epithelial cells leading to the upregulation of carcinogenesis-related pathways.

PMID:38371298 | PMC:PMC10873922 | DOI:10.3389/fcimb.2024.1296295

bioRxiv. 2024 Feb 6:2024.02.06.579193. doi: 10.1101/2024.02.06.579193. Preprint.

ABSTRACT

Bacteria evolving within human hosts encounter selective tradeoffs that render mutations adaptive in one context and deleterious in another. Here, we report that the cystic fibrosis-associated pathogen Burkholderia dolosa overcomes in-human selective tradeoffs by acquiring successive point mutations that alternate phenotypes. We sequenced the whole genomes of 931 respiratory isolates from two recently infected patients and an epidemiologically-linked, chronically-infected patient. These isolates are contextualized using 112 historical genomes from the same outbreak strain. Within both newly infected patients, diverse parallel mutations that disrupt O-antigen expression quickly arose, comprising 29% and 63% of their B. dolosa communities by 3 years. The selection for loss of O-antigen starkly contrasts with our previous observation of parallel O-antigen-restoring mutations after many years of chronic infection in the historical outbreak. Experimental characterization revealed that O-antigen loss increases uptake in immune cells while decreasing competitiveness in the mouse lung. We propose that the balance of these pressures, and thus whether O-antigen expression is advantageous, depends on tissue localization and infection duration. These results suggest that mutation-driven alternation during infection may be more frequent than appreciated and is underestimated without dense temporal sampling.

PMID:38370793 | PMC:PMC10871308 | DOI:10.1101/2024.02.06.579193

Mol Biol Evol. 2024 Feb 14:msae022. doi: 10.1093/molbev/msae022. Online ahead of print.

ABSTRACT

Selective forces in the environment drive bacterial adaptation to novel niches, choosing the fitter variants in the population. However, in dynamic and changing environments, the evolutionary processes controlling bacterial adaptation are difficult to monitor. Here, we follow 9 people with cystic fibrosis chronically infected with Pseudomonas aeruginosa, as a proxy for bacterial adaptation. We identify and describe the bacterial changes and evolution occurring between 15 and 35 years of within host evolution. We combine whole genome sequencing, RNAseq and metabolomics, and compare the evolutionary trajectories directed by the adaptation of four different P. aeruginosa lineages to the lung. Our data suggest divergent evolution at the genomic level for most of the genes, with signs of convergent evolution with respect to acquisition of mutations in regulatory genes, which drive the transcriptional and metabolomic program at late time of evolution. Metabolomics further confirmed convergent adaptive phenotypic evolution as documented by reduction of the quorum sensing molecules acyl-homoserine lactone, phenazines and rhamnolipids (except for quinolones). The modulation of the quorum sensing repertoire suggests that similar selective forces characterize at late times of evolution independent of the patient. Collectively, our data suggest that similar environments and similar P. aeruginosa populations in the patients at prolonged time of infection are associated with an overall reduction of virulence-associated features and phenotypic convergence.

PMID:38366124 | DOI:10.1093/molbev/msae022

BMJ Open Qual. 2024 Feb 16;13(1):e002387. doi: 10.1136/bmjoq-2023-002387.

ABSTRACT

OBJECTIVE: Surveys are a commonly used tool in quality improvement (QI) projects, but little is known about the standards to which they are designed and applied. We aimed to investigate the quality of surveys used within a QI collaborative, and to characterise the common errors made in survey design.

METHODS: Five reviewers (two research methodology and QI, three clinical and QI experts) independently assessed 20 surveys, comprising 250 survey items, that were developed in a North American cystic fibrosis lung transplant transition collaborative. Content Validity Index (CVI) scores were calculated for each survey. Reviewer consensus discussions decided an overall quality assessment for each survey and survey item (analysed using descriptive statistics) and explored the rationale for scoring (using qualitative thematic analysis).

RESULTS: 3/20 surveys scored as high quality (CVI >80%). 19% (n=47) of survey items were recommended by the reviewers, with 35% (n=87) requiring improvements, and 46% (n=116) not recommended. Quality assessment criteria were agreed upon. Types of common errors identified included the ethics and appropriateness of questions and survey format; usefulness of survey items to inform learning or lead to action, and methodological issues with survey questions, survey response options; and overall survey design.

CONCLUSION: Survey development is a task that requires careful consideration, time and expertise. QI teams should consider whether a survey is the most appropriate form for capturing information during the improvement process. There is a need to educate and support QI teams to adhere to good practice and avoid common errors, thereby increasing the value of surveys for evaluation and QI. The methodology, quality assessment criteria and common errors described in this paper can provide a useful resource for this purpose.

PMID:38365431 | DOI:10.1136/bmjoq-2023-002387

Proc Natl Acad Sci U S A. 2024 Feb 20;121(8):e2315190121. doi: 10.1073/pnas.2315190121. Epub 2024 Feb 16.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion transporter required for epithelial homeostasis in the lung and other organs, with CFTR mutations leading to the autosomal recessive genetic disease CF. Apart from excessive mucus accumulation and dysregulated inflammation in the airways, people with CF (pwCF) exhibit defective innate immune responses and are susceptible to bacterial respiratory pathogens such as Pseudomonas aeruginosa. Here, we investigated the role of CFTR in macrophage antimicrobial responses, including the zinc toxicity response that is used by these innate immune cells against intracellular bacteria. Using both pharmacological approaches, as well as cells derived from pwCF, we show that CFTR is required for uptake and clearance of pathogenic Escherichia coli by CSF-1-derived primary human macrophages. CFTR was also required for E. coli-induced zinc accumulation and zinc vesicle formation in these cells, and E. coli residing in macrophages exhibited reduced zinc stress in the absence of CFTR function. Accordingly, CFTR was essential for reducing the intramacrophage survival of a zinc-sensitive E. coli mutant compared to wild-type E. coli. Ectopic expression of the zinc transporter SLC30A1 or treatment with exogenous zinc was sufficient to restore antimicrobial responses against E. coli in human macrophages. Zinc supplementation also restored bacterial killing in GM-CSF-derived primary human macrophages responding to P. aeruginosa, used as an in vitro macrophage model relevant to CF. Thus, restoration of the zinc toxicity response could be pursued as a therapeutic strategy to restore innate immune function and effective host defense in pwCF.

PMID:38363865 | DOI:10.1073/pnas.2315190121

HNO. 2024 Feb 16. doi: 10.1007/s00106-024-01428-9. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a complex systemic disease involving numerous organ systems. With improved treatment options and increasing life expectancy of persons with CF (PwCF), extrapulmonary manifestations are coming increasingly into the focus. From birth, almost all PwCF have radiologically detectable pathologies in the upper airways attributable to CF-associated chronic rhinosinusitis (CF-CRS).

OBJECTIVE: The aim of this work is to provide an up-to-date overview of CF-CRS from the otorhinolaryngology perspective and to provide the reader with background knowledge and current developments.

PATHOPHYSIOLOGY: The cystic fibrosis transmembrane conductance regulator (CFTR) gene defect leads to increased viscosity of sinonasal secretions and reduced mucociliary clearance, causing chronic infection and inflammation in the upper airway segment and, consequently, to CF-CRS.

CLINICAL PICTURE AND DIAGNOSTICS: The clinical picture of CF-CRS comprises a wide spectrum from asymptomatic to symptomatic courses. CF-CRS is diagnosed clinically and radiologically.

THERAPY: Sinonasal saline irrigation is recommended as a conservative treatment measure. Topical corticosteroids are also commonly used. Surgical therapy is reserved for highly symptomatic treatment-refractory patients without a sufficient response to conservative treatment including CFTR modulator (CFTRm) therapies. Depending on the CFTR mutation, CFTRm therapies are the treatment of choice. They not only improve the pulmonary and gastrointestinal manifestations in PwCF, but also have positive effects on CF-CRS.

CONCLUSION: The ENT specialist is part of the interdisciplinary team caring for PwCF. Depending on symptom burden and treatment responsiveness, CF-CRS should be treated conservatively and/or surgically. Modern CFTRm have a positive effect on the clinical course of CF-CRS.

PMID:38363326 | DOI:10.1007/s00106-024-01428-9

J Med Microbiol. 2024 Feb;73(2). doi: 10.1099/jmm.0.001791.

ABSTRACT

Pseudomonas aeruginosa is one of the most versatile bacteria with renowned pathogenicity and extensive drug resistance. The diverse habitats of this bacterium include fresh, saline and drainage waters, soil, moist surfaces, taps, showerheads, pipelines, medical implants, nematodes, insects, plants, animals, birds and humans. The arsenal of virulence factors produced by P. aeruginosa includes pyocyanin, rhamnolipids, siderophores, lytic enzymes, toxins and polysaccharides. All these virulent elements coupled with intrinsic, adaptive and acquired antibiotic resistance facilitate persistent colonization and lethal infections in different hosts. To date, treating pulmonary diseases remains complicated due to the chronic secondary infections triggered by hospital-acquired P. aeruginosa. On the contrary, this bacterium can improve plant growth by suppressing phytopathogens and insects. Notably, P. aeruginosa is one of the very few bacteria capable of trans-kingdom transmission and infection. Transfer of P. aeruginosa strains from plant materials to hospital wards, animals to humans, and humans to their pets occurs relatively often. Recently, we have identified that plant-associated P. aeruginosa strains could be pathologically similar to clinical isolates. In this review, we have highlighted the genomic and metabolic factors that facilitate the dominance of P. aeruginosa across different biological kingdoms and the varying roles of this bacterium in plant and human health.

PMID:38362900 | DOI:10.1099/jmm.0.001791

Pediatr Pulmonol. 2024 Feb 16. doi: 10.1002/ppul.26915. Online ahead of print.

ABSTRACT

BACKGROUND: Can physiotherapy with a positive expiratory pressure (PEP) mask improve peripheral ventilation inhomogeneity, a typical feature of children with cystic fibrosis (cwCF)? To answer this question, we used the nitrogen multiple-breath washout (N2 MBW) test to measure diffusion-convection-dependent inhomogeneity arising within the intracinar compartment (Sacin *VT).

METHODS: For this randomized, sham-controlled crossover trial, two N2 MBW tests were performed near the hospital discharge date: one before and the other after PEP mask therapy (1 min of breathing through a flow-dependent PEP device attached to a face mask, followed by three huffs and one cough repeated 10 times) by either a standard (10-15 cmH2 0) or a sham (<5 cmH2 0) procedure on two consecutive mornings. Deception entailed misinforming the subjects about the nature of the study; also the N2 MBW operators were blinded to treatment allocation. Study outcomes were assessed with mixed-effect models.

RESULTS: The study sample was 19 cwCF (ten girls), aged 11.4 (2.7) years. The adjusted Sacin *VT mean difference between the standard and the sham procedure was -0.015 (90% confidence interval [CI]: -∞ to 0.025) L-1 . There was no statistically significant difference in Scond *VT and lung clearance index between the two procedures: -0.005 (95% CI: -0.019 to 0.01) L-1 and 0.49 (95% CI: -0.05 to 1.03) turnovers, respectively.

CONCLUSION: Our findings do not support evidence for an immediate effect of PEP mask physiotherapy on Sacin *VT with pressure range 10-15 cmH2 0. Measurement with the N2 MBW and the crossover design were found to be time-consuming and unsuitable for a short-term study of airway clearance techniques.

PMID:38362833 | DOI:10.1002/ppul.26915

Pharmacotherapy. 2024 Feb;44(2):207. doi: 10.1002/phar.2906.

NO ABSTRACT

PMID:38362633 | DOI:10.1002/phar.2906

Pharmacotherapy. 2024 Feb;44(2):208-209. doi: 10.1002/phar.2907.

NO ABSTRACT

PMID:38362632 | DOI:10.1002/phar.2907

Front Cardiovasc Med. 2024 Feb 1;11:1285223. doi: 10.3389/fcvm.2024.1285223. eCollection 2024.

ABSTRACT

INTRODUCTION: We conducted a study to determine the prevalence of structural heart disease in patients with CF, the characteristics of a cardiomyopathy not previously described in this population, and its possible relationship with nutritional deficiencies in CF.

METHODS: We studied 3 CMP CF patients referred for heart-lung transplantation and a prospective series of 120 adult CF patients. All patients underwent a clinical examination, blood tests including levels of vitamins and trace elements, and echocardiography with evaluation of myocardial strain. Cardiac magnetic resonance imaging (CMR) was performed in patients with CMP and in a control group. Histopathological study was performed on hearts obtained in transplant or necropsy.

RESULTS: We found a prevalence of 10% (CI 4.6%-15.4%) of left ventricular (LV) dysfunction in the prospective cohort. Myocardial strain parameters were already altered in CF patients with otherwise normal hearts. Histopathological examination of 4 hearts from CF CMP patients showed a unique histological pattern of multifocal myocardial fibrosis similar to Keshan disease. Four of the five CF CMP patients undergoing CMR showed late gadolinium uptake, with a characteristic patchy pattern in 3 cases (p < 0.001 vs. CF controls). Selenium deficiency (Se < 60 µg/L) was associated with more severe LV dysfunction, higher prevalence of CF CMP, higher NTproBNP levels, and more severe pulmonary and digestive involvement.

CONCLUSION: 10% of adults with CF showed significant cardiac involvement, with histological and imaging features resembling Keshan disease. Selenium deficiency was associated with the presence and severity of LV dysfunction in these patients.

PMID:38361580 | PMC:PMC10867141 | DOI:10.3389/fcvm.2024.1285223

BMC Complement Med Ther. 2024 Feb 15;24(1):89. doi: 10.1186/s12906-024-04378-5.

ABSTRACT

BACKGROUND: Evening primrose oil (EPO), extracted from the seeds of Oenothera biennis, has gained attention for its therapeutic effects in various inflammatory conditions.

METHOD: We performed a systematic search in multiple databases and defined the inclusion criteria based on the following PICOs: P: Patients with a form of inflammatory condition, I: EPO, C: Placebo or other therapeutic interventions, O: changes in inflammatory markers or patients' symptoms; S: randomized controlled trials. The quality of the RCTs was evaluated using Cochrane's RoB tool.

RESULTS: Several conditions were investigated in the literature. In rheumatoid arthritis, mixed results were observed, with some studies reporting significant improvements in symptoms while others found no significant impact. EPO showed some results in diabetes mellitus, atopic eczema, menopausal hot flashes, and mastalgia. However, it did not demonstrate effectiveness in chronic hand dermatitis, tardive dyskinesia, psoriatic arthritis, cystic fibrosis, hepatitis B, premenstrual syndrome, contact lens-associated dry eyes, acne vulgaris, breast cyst, pre-eclampsia, psoriasis, or primary Sjogren's syndrome. Some results were reported from multiple sclerosis after EPO consumption. Studies in healthy volunteers indicated no significant effect of EPO on epidermal atrophy, nevertheless, positive effects on the skin regarding hydration and barrier function were achieved.

CONCLUSION: Some evidence regarding the potential benefits of EPO in inflammatory disorders were reported however caution is due to the limitations of the current survey. Overall, contemporary literature is highly heterogeneous and fails to provide strong recommendations regarding the efficacy of EPO on inflammatory disorders. Further high-quality studies are necessitated to draw more definite conclusions and establish O. biennis oil effectiveness as an assuring treatment option in alleviating inflammatory conditions.

PMID:38360611 | DOI:10.1186/s12906-024-04378-5

J Cyst Fibros. 2024 Feb 14:S1569-1993(24)00015-8. doi: 10.1016/j.jcf.2024.02.001. Online ahead of print.

ABSTRACT

BACKGROUND: Sweat chloride (SC) concentrations in people with cystic fibrosis (PwCF) reflect relative CF transmembrane conductance regulator (CFTR) protein function, the primary CF defect. Populations with greater SC concentrations tend to have lesser CFTR function and more severe disease courses. CFTR modulator treatment can improve CFTR function within specific CF genotypes and is commonly associated with reduced SC concentration. However, SC concentrations do not necessarily fall to concentrations seen in the unaffected population, suggesting potential for better CFTR treatment outcomes. We characterized post-modulator SC concentration variability among CHEC-SC study participants by genotype and modulator.

METHODS: PwCF receiving commercially approved modulators for ≥90 days were enrolled for a single SC measurement. Clinical data were obtained from chart review and the CF Foundation Patient Registry (CFFPR). Variability of post-modulator SC concentrations was assessed by cumulative SC concentration frequencies.

RESULTS: Post-modulator SC concentrations (n = 3787) were collected from 3131 PwCF; most (n = 1769, 47 %) were collected after elexacaftor/tezacaftor/ivacaftor (ETI) treatment. Modulator use was associated with lower SC distributions, with post-ETI concentrations the lowest on average. Most post-ETI SC concentrations were <60 mmol/L (79 %); 26 % were <30 mmol/L. Post-ETI distributions varied by genotype. All genotypes containing at least one F508del allele had individuals with post-ETI SC ≥60 mmol/L, with the largest proportion being F508del/minimal function (31 %).

CONCLUSIONS: Post-modulator SC concentration heterogeneity was observed among all genotypes and modulators, including ETI. The presence of PwCF with post-modulator SC concentrations within the CF diagnostic range suggests room for additional treatment-associated CFTR restoration in this population.

PMID:38360461 | DOI:10.1016/j.jcf.2024.02.001

J Cyst Fibros. 2024 Feb 14:S1569-1993(23)01683-1. doi: 10.1016/j.jcf.2023.11.012. Online ahead of print.

ABSTRACT

BACKGROUND: Prescribers have an increasing range of inhaled antimicrobial formulations to choose from when prescribing both eradication and chronic suppression regimens in cystic fibrosis (CF). This study aimed to investigate the decision-making process behind prescribing of inhaled antimicrobials for Pseudomonas aeruginosa infections.

METHODS: A questionnaire was developed using Microsoft Forms and then forwarded to 57 Principal Investigators (PIs), at each of the CF centres within the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN). Data collection occurred between November 2021 and February 2022.

RESULTS: The response rate was 90 % (n = 51/57 PIs), with at least 50 % of CF centers in each of the 17 countries represented in the ECFS-CTN. Physicians used a median of eight factors in their decision-making process with delivery formulations (92.2 %), adherence history (84.3 %), and antibiotic side-effect profile (76.5 %) often selected. Nebulised tobramycin or colistin were frequently selected as the inhaled antimicrobial in first-line eradication (n = 45, 88.2 %) and chronic suppression regimens (n = 42, 82.4 %). Combination regimens were more often chosen in eradication (first-line: n = 35, 68.6 %, second-line: n = 34, 66.7 %) and later chronic suppression regimens (third-line: n = 27, 52.9 %) than monotherapy. For pwCF also prescribed CFTR modulator therapies, most PIs did not alter inhaled antimicrobial regimens (n = 40, 78.4 %), with few pwCF (n = 18, 35.3 %) or PIs (n = 10, 19.6 %) deciding to stop inhaled antimicrobials.

CONCLUSIONS: The inhaled antimicrobial prescribing decision-making process is multifactorial. Nebulised tobramycin or colistin are often used in initial eradication and chronic suppression regimens. To date, CFTR modulator therapy has had a limited impact on the prescribing of inhaled antimicrobial regimens.

PMID:38360460 | DOI:10.1016/j.jcf.2023.11.012

JCI Insight. 2024 Feb 15:e165826. doi: 10.1172/jci.insight.165826. Online ahead of print.

ABSTRACT

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene lead to cystic fibrosis (CF), a life-threating autosomal recessive genetic disease. While recently approved Trikafta dramatically ameliorates CF lung diseases, there is still a lack of effective medicine to treat CF-associated liver disease (CFLD). To address this medical need, we used a recently established CF rabbit model to test if Sotagliflozin, a Sodium-Glucose cotransporter 1 and 2 (SGLT1/2) inhibitor drug that is approved to treat diabetes, can be repurposed to treat CFLD. Sotagliflozin treatment led to systemic benefits to CF rabbits, evidenced by increased appetite and weight gain as well as prolonged lifespan. For CF liver related phenotypes, the animals benefited from normalized blood chemistry and bile acid parameters. Further, Sotagliflozin alleviated non-alcoholic steatohepatitis (NASH)-like phenotypes including liver fibrosis. Intriguingly, Sotagliflozin treatment markedly reduced the otherwise elevated endoplasmic reticulum (ER) stress responses in the liver and other affected organs of CF rabbits. In summary, our work demonstrates that Sotagliflozin attenuates liver disorders in CF rabbits, and merits Sotagliflozin as a potential drug to treat CFLD.

PMID:38358827 | DOI:10.1172/jci.insight.165826

Am J Respir Crit Care Med. 2024 Feb 15. doi: 10.1164/rccm.202401-0181ED. Online ahead of print.

NO ABSTRACT

PMID:38358817 | DOI:10.1164/rccm.202401-0181ED