J Cyst Fibros. 2021 Dec 10:S1569-1993(21)02142-1. doi: 10.1016/j.jcf.2021.11.008. Online ahead of print.

NO ABSTRACT

PMID:34903495 | DOI:10.1016/j.jcf.2021.11.008

Biol Res. 2021 Dec 13;54(1):38. doi: 10.1186/s40659-021-00361-3.

ABSTRACT

BACKGROUND: Defective chloride transport in airway epithelial cells (AECs) and the associated lung disease are the main causes of morbidity and early mortality in cystic fibrosis (CF). Abnormal airway iron homeostasis and the presence of lipid peroxidation products, indicative of oxidative stress, are features of CF lung disease.

RESULTS: Here, we report that CF AECs (IB3-1) are susceptible to ferroptosis, a type of cell death associated with iron accumulation and lipid peroxidation. Compared to isogenic CFTR corrected cells (C38), the IB3-1 cells showed increased susceptibility to cell death upon exposure to iron in the form of ferric ammonium citrate (FAC) and the ferroptosis inducer, erastin. This phenotype was accompanied by accumulation of intracellular ferrous iron and lipid peroxides and the extracellular release of malondialdehyde, all indicative of redox stress, and increased levels of lactate dehydrogenase in the culture supernatant, indicating enhanced cell injury. The ferric iron chelator deferoxamine (DFO) and the lipophilic antioxidant ferrostatin-1 inhibited FAC and erastin induced ferroptosis in IB3-1 cells. Glutathione peroxidase 4 (GPX4) expression was decreased in IB3-1 cells treated with FAC and erastin, but was unchanged in C38 AECs. Necroptosis appeared to be involved in the enhanced susceptibility of IB3-1 AECs to ferroptosis, as evidenced by partial cell death rescue with necroptosis inhibitors and enhanced mixed lineage kinase domain-like (MLKL) localisation to the plasma membrane.

CONCLUSION: These studies suggest that the increased susceptibility of CF AECs to ferroptosis is linked to abnormal intracellular ferrous iron accumulation and reduced antioxidant defences. In addition, the process of ferroptotic cell death in CF AECs does not appear to be a single entity and for the first time we describe necroptosis as a potential contributory factor. Iron chelation and antioxidant treatments may be promising therapeutic interventions in cystic fibrosis.

PMID:34903297 | DOI:10.1186/s40659-021-00361-3

mBio. 2021 Dec 14:e0314821. doi: 10.1128/mbio.03148-21. Online ahead of print.

ABSTRACT

Drugs called CFTR modulators improve the physiologic defect underlying cystic fibrosis (CF) and alleviate many disease manifestations. However, studies to date indicate that chronic lung infections that are responsible for most disease-related mortality generally persist. Here, we investigated whether combining the CFTR modulator ivacaftor with an intensive 3.5-month antibiotic course could clear chronic Pseudomonas aeruginosa or Staphylococcus aureus lung infections in subjects with R117H-CFTR, who are highly ivacaftor-responsive. Ivacaftor alone improved CFTR activity, and lung function and inflammation within 48 h, and reduced P. aeruginosa and S. aureus pathogen density by ∼10-fold within a week. Antibiotics produced an additional ∼10-fold reduction in pathogen density, but this reduction was transient in subjects who remained infected. Only 1/5 P. aeruginosa-infected and 1/7 S. aureus-infected subjects became persistently culture-negative after the combined treatment. Subjects appearing to clear infection did not have particularly favorable baseline lung function or inflammation, pathogen density or antibiotic susceptibility, or bronchiectasis scores on CT scans, but they did have remarkably low sweat chloride values before and after ivacaftor. All persistently P. aeruginosa-positive subjects remained infected by their pretreatment strain, whereas subjects persistently S. aureus-positive frequently lost and gained strains. This work suggests chronic CF infections may resist eradication despite marked and rapid modulator-induced improvements in lung infection and inflammation parameters and aggressive antibiotic treatment. IMPORTANCE Recent work shows that people with CF and chronic lung infections generally remain persistently infected after treatment with drugs that target the CF physiological defect (called CFTR modulators). However, changes produced by modulators could increase antibiotic efficacy. We tested the approach of combining modulators and intensive antibiotics in rapid succession and found that while few subjects cleared their infections, combined treatment appeared most effective in subjects with the highest CFTR activity. These findings highlight challenges that remain to improve the health of people with CF.

PMID:34903059 | DOI:10.1128/mbio.03148-21

Diagn Microbiol Infect Dis. 2021 Nov 18;102(3):115596. doi: 10.1016/j.diagmicrobio.2021.115596. Online ahead of print.

ABSTRACT

The dissemination of multiple-drug resistant high virulent strains of P. aeruginosa in patients with cystic fibrosis is of concern worldwide. Herein, we describe genomic characteristics of ST235 isolates recovered from cystic fibrosis patients in Russia. Successful core-genome background and acquired resistance determinants provide spreading of high-risk clones in cystic fibrosis populations.

PMID:34902620 | DOI:10.1016/j.diagmicrobio.2021.115596

Biomed Res Int. 2021 Dec 2;2021:5262000. doi: 10.1155/2021/5262000. eCollection 2021.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disorder, caused by diverse genetic variants for the CF transmembrane conductance regulator (CFTR) protein. Among these, p.Phe508del is the most prevalent variant. The effects of this variant on the physiology of each tissue remains unknown. This study is aimed at predicting cell signaling pathways present in different tissues of fibrocystic patients, homozygous for p.Phe508del. The study involved analysis of two microarray datasets, E-GEOD-15568 and E-MTAB-360 corresponding to the rectal and bronchial epithelium, respectively, obtained from the ArrayExpress repository. Particularly, differentially expressed genes (DEGs) were predicted, protein-protein interaction (PPI) networks were designed, and centrality and functional interaction networks were analyzed. The study reported that p.Phe508del-mutated CFTR-allele in homozygous state influenced the whole gene expression in each tissue differently. Interestingly, gene ontology (GO) term enrichment analysis revealed that only "neutrophil activation" was shared between both tissues; however, nonshared DEGs were grouped into the same GO term. For further verification, functional interaction networks were generated, wherein no shared nodes were reported between these tissues. These results suggested that the p.Phe508del-mutated CFTR-allele in homozygous state promoted tissue-specific pathways in fibrocystic patients. The generated data might further assist in prediction diagnosis to define biomarkers or devising therapeutic strategies.

PMID:34901273 | PMC:PMC8660202 | DOI:10.1155/2021/5262000

Front Pediatr. 2021 Nov 24;9:784692. doi: 10.3389/fped.2021.784692. eCollection 2021.

ABSTRACT

In response to the novel coronavirus (COVID-19) pandemic, all in-person cystic fibrosis (CF) appointments were converted to telemedicine visits at UCSF Benioff Children's Hospital. The purpose of our study was to learn about the experiences that patients, families, and providers had with telemedicine visits and to assess their interest in using telemedicine in the future. Our hypothesis was that most patients, families, and providers want to continue telemedicine visits in the future. An anonymous 11-question survey was distributed to patients, families, and providers in November and December 2020. The survey was completed by 46 of 72 families (64% response rate) and 24 of 25 providers (96% response rate). Thirty-seven families (80%) and 21 providers (88%) were satisfied with their telemedicine experience. Thirty-three families (72%) want to have telemedicine visits in the future. Thirty-five families (76%) and 22 providers (92%) were satisfied with their experience using Zoom. Forty families (87%) and 19 providers (90%) want 2 or more visits each year to be via telemedicine. Our study showed that most families and providers were satisfied with telemedicine, would like to continue using telemedicine, and prefer to have at least 2 of the 4 recommended annual CF visits via telemedicine. Our survey identified the following benefits to telemedicine: decreased travel time, decreased cost, and avoiding exposure to COVID. However, we need to ensure that we do not exacerbate existing health disparities for families that do not speak English and/or do not have the internet capabilities to support telemedicine technology.

PMID:34900879 | PMC:PMC8653948 | DOI:10.3389/fped.2021.784692

Front Cell Infect Microbiol. 2021 Nov 26;11:759944. doi: 10.3389/fcimb.2021.759944. eCollection 2021.

ABSTRACT

BACKGROUND: Cystic fibrosis is an inherited disease that predisposes to progressive lung damage. Cystic fibrosis patients are particularly prone to developing pulmonary infections. Fungal species are commonly isolated in lower airway samples from patients with cystic fibrosis. Fungal spores are prevalent in the air.

METHODS: We performed environmental air sampling surveillance at the Manchester Adult Cystic Fibrosis Centre, UK (MACFC) over a 14-month period to assess fungal growth inside and outside the CF center.

RESULTS: Airborne counts of fungal spores peaked from May to October, both in outdoor and indoor samples. Collection of meteorological data allowed us to correlate fungal presence in the air with elevated temperatures and low wind speeds. Additionally, we demonstrated patient rooms containing windows had elevated fungal counts compared to rooms not directly connected to the outdoors.

CONCLUSIONS: This study suggests that airborne Aspergillus fumigatus spores were more abundant during the summer months of the survey period, which appeared to be driven by increased temperatures and lower wind speeds. Indoor counts directly correlated to outdoor A. fumigatus levels and were elevated in patient rooms that were directly connected to the outdoor environment via an openable window designed for ventilation purposes. Further studies are required to determine the clinical implications of these findings for cystic fibrosis patients who are predisposed to Aspergillus related diseases, and in particular whether there is seasonal influence on incidence of Aspergillus related conditions and if screening for such complications such be increased during summer months and precautions intensified for those with a known history of Aspergillus related disease.

PMID:34900752 | PMC:PMC8662344 | DOI:10.3389/fcimb.2021.759944

Stat Med. 2021 Dec 12. doi: 10.1002/sim.9279. Online ahead of print.

ABSTRACT

In omics experiments, estimation and variable selection can involve thousands of proteins/genes observed from a relatively small number of subjects. Many regression regularization procedures have been developed for estimation and variable selection in such high-dimensional problems. However, approaches have predominantly focused on linear regression models that ignore correlation arising from long sequences of repeated measurements on the outcome. Our work is motivated by the need to identify proteomic biomarkers that improve the prediction of rapid lung-function decline for individuals with cystic fibrosis (CF) lung disease. We extend four Bayesian penalized regression approaches for a Gaussian linear mixed effects model with nonstationary covariance structure to account for the complicated structure of longitudinal lung function data while simultaneously estimating unknown parameters and selecting important protein isoforms to improve predictive performance. Different types of shrinkage priors are evaluated to induce variable selection in a fully Bayesian framework. The approaches are studied with simulations. We apply the proposed method to real proteomics and lung-function outcome data from our motivating CF study, identifying a set of relevant clinical/demographic predictors and a proteomic biomarker for rapid decline of lung function. We also illustrate the methods on CD4 yeast cell-cycle genomic data, confirming that the proposed method identifies transcription factors that have been highlighted in the literature for their importance as cell cycle transcription factors.

PMID:34897771 | DOI:10.1002/sim.9279

Eur J Cell Biol. 2021 Dec 2;101(1):151189. doi: 10.1016/j.ejcb.2021.151189. Online ahead of print.

ABSTRACT

Primary cultures of the human airway epithelium (AE) cells are an indispensable tool in studies of pathophysiology of genetic and environmental pulmonary diseases, including cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and chronic obstructive pulmonary disease (COPD). Air-liquid interface (ALI) culture is the best method to follow the differentiation of ciliated cells, whose dysfunction forms the basis of PCD. Here, we used custom-designed Taqman Low Density Array (TLDA), qRT-PCR-based assay, to analyze expression of 14 AE genes in cells from healthy donors, cultured in ALI settings using Pneumacult medium, with the focus on genes involved in cilia differentiation and in PCD pathogenesis. The results of TLDA assay were compared with the bulk RNAseq analysis, and placed in the cellular context using immunofluorescent staining (IF) of ALI cultured cells. Expression analysis revealed culture time-related upregulation of the majority of cilia-related genes, followed by the appearance of respective protein signals visualized by IF. Strong correlation of TLDA with RNAseq results indicated that TLDA assay is a reliable and scalable approach to analyze expression of selected genes specific for different AE cell types. Characterization of temporal and inter-donor changes in the expression of these genes, performed in healthy donors and in well-defined ALI/Pnemacult culture conditions, provides a useful reference relevant for a broad spectrum of functional studies where the in vitro AE differentiation is in focus.

PMID:34896770 | DOI:10.1016/j.ejcb.2021.151189

Chest. 2021 Dec 9:S0012-3692(21)04444-5. doi: 10.1016/j.chest.2021.11.035. Online ahead of print.

ABSTRACT

BACKGROUND: During the COVID-19 pandemic, the University of Virginia adult cystic fibrosis (CF) center transitioned from in-person clinical encounters to a model that included interdisciplinary telemedicine. The pandemic presented an unprecedented opportunity to assess the impact of the interdisciplinary telemedicine model on clinical CF outcomes.

RESEARCH QUESTION: What are the clinical outcomes of a care model that includes interdisciplinary telemedicine (IDC-TM) compared to in-person clinical care for persons with cystic fibrosis during the COVID-19 pandemic?

STUDY DESIGN AND METHODS: Adults with CF were included. Pre-pandemic year (PPY) was defined as March 17, 2019 through March 16, 2020 and pandemic year (PY) as March 17, 2020 through March 16, 2021. Subjects were enrolled starting in PY. Pre-pandemic data were gathered retrospectively. Telemedicine visits were defined as clinical encounters via secured video communication. Hybrid visits were in-person evaluations by physician, with in-clinic video communication by other team members. In-person visits were encounters with in-person providers only. All encounters included pre-visit screening. Outcomes were lung function, BMI, exacerbations, and antibiotic use. %FEV1, exacerbations, and antibiotic use were adjusted for the effect of elexacaftor/ tezacaftor/ ivacaftor (ETI).

RESULTS: 124 subjects participated. 110 subjects were analyzed (mean age 35, range 18-69). 95% had access to telemedicine (n=105). Telemedicine visits accounted for 64% of encounters (n=260), hybrid visits with telemedicine support 28% (n=114), and in-person visits 7% (n=30). There was no difference in lung function or exacerbation rate during PY. BMI increased from 25 to 26 (t100 = -4.72, P < 0.001). Antibiotic use decreased from 316 episodes to 124 (z = 8.81, P < 0.0001).

INTERPRETATION: This CF care model which includes IDC-TM successfully monitored lung function and BMI, identified exacerbations, and followed guidelines-based care during the pandemic. A significant decrease in antibiotic use suggests social mitigation strategies were protective.

PMID:34896356 | DOI:10.1016/j.chest.2021.11.035

J Cyst Fibros. 2021 Dec 8:S1569-1993(21)02155-X. doi: 10.1016/j.jcf.2021.11.014. Online ahead of print.

ABSTRACT

BACKGROUND: Most people with cystic fibrosis (pwCF) suffer from gastrointestinal symptoms and are at risk of gut complications. Gut microbiota dysbiosis is apparent within the CF population across all age groups, with evidence linking dysbiosis to intestinal inflammation and other markers of health. This pilot study aimed to investigate the potential relationships between the gut microbiota and gastrointestinal physiology, transit, and health.

STUDY DESIGN: Faecal samples from 10 pwCF and matched controls were subject to 16S rRNA sequencing. Results were combined with clinical metadata and MRI metrics of gut function to investigate relationships.

RESULTS: pwCF had significantly reduced microbiota diversity compared to controls. Microbiota compositions were significantly different, suggesting remodelling of core and rarer satellite taxa in CF. Dissimilarity between groups was driven by a variety of taxa, including Escherichia coli, Bacteroides spp., Clostridium spp., and Faecalibacterium prausnitzii. The core taxa were explained primarily by CF disease, whilst the satellite taxa were associated with pulmonary antibiotic usage, CF disease, and gut function metrics. Species-specific ordination biplots revealed relationships between taxa and the clinical or MRI-based variables observed.

CONCLUSIONS: Alterations in gut function and transit resultant of CF disease are associated with the gut microbiota composition, notably the satellite taxa. Delayed transit in the small intestine might allow for the expansion of satellite taxa resulting in potential downstream consequences for core community function in the colon.

PMID:34895838 | DOI:10.1016/j.jcf.2021.11.014

Infect Dis Ther. 2021 Dec 10. doi: 10.1007/s40121-021-00564-x. Online ahead of print.

NO ABSTRACT

PMID:34893960 | DOI:10.1007/s40121-021-00564-x

Cochrane Database Syst Rev. 2021 Dec 10;12:CD013079. doi: 10.1002/14651858.CD013079.pub3.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) a life-limiting inherited disease affecting a number of organs, but classically associated with chronic lung infection and progressive loss of lung function. Chronic infection by Burkholderia cepacia complex (BCC) is associated with increased morbidity and mortality and therefore represents a significant challenge to clinicians treating people with CF. This review examines the current evidence for long-term antibiotic therapy in people with CF and chronic BCC infection.

OBJECTIVES: The objective of this review is to assess the effects of long-term oral and inhaled antibiotic therapy targeted against chronic BCC lung infections in people with CF. The primary objective is to assess the efficacy of treatments in terms of improvements in lung function and reductions in exacerbation rate. Secondary objectives include quantifying adverse events, mortality and changes in quality of life associated with treatment.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched online trial registries and the reference lists of relevant articles and reviews. Date of last search: 12 April 2021.

SELECTION CRITERIA: Randomised controlled trials (RCTs) of long-term antibiotic therapy in people with CF and chronic BCC infection.

DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and assessed the quality of the evidence using GRADE.

MAIN RESULTS: We included one RCT (100 participants) which lasted 52 weeks comparing continuous inhaled aztreonam lysine (AZLI) and placebo in a double-blind RCT for 24 weeks, followed by a 24-week open-label extension and a four-week follow-up period. The average participant age was 26.3 years, 61% were male and average lung function was 56.5% predicted. Treatment with AZLI for 24 weeks was not associated with improvement in forced expiratory volume in one second (FEV1), mean difference 0.91% (95% confidence interval (CI) -3.15 to 4.97) (moderate-quality evidence). The median time to the next exacerbation was 75 days in the AZLI group compared to 51 days in the placebo group, but the difference was not significant (P = 0.27) (moderate-quality evidence). Similarly, the number of participants hospitalised for respiratory exacerbations showed no difference between groups, risk ratio (RR) 0.88 (95% CI 0.53 to 1.45) (moderate-quality evidence). Overall adverse events were similar between groups, RR 1.08 (95% CI 0.98 to 1.19) (moderate-quality evidence). There were no significant differences between treatment groups in relation to mortality (moderate-quality evidence), quality of life or sputum density. In relation to methodological quality, the overall risk of bias in the study was assessed to be unclear to low risk.

AUTHORS' CONCLUSIONS: We found insufficient evidence from the literature to determine an effective strategy for antibiotic therapy for treating chronic BCC infection.

PMID:34889457 | DOI:10.1002/14651858.CD013079.pub3

Ann Hum Genet. 2021 Dec 9. doi: 10.1111/ahg.12450. Online ahead of print.

ABSTRACT

Cystic fibrosis is the most common life-limiting autosomal recessive disease in western countries with an incidence of 1:2500 in United States and 1:1000 in some European countries. Similar incidences were noted for the Middle East with variations from 1 in 2560 to 1 in 15,876 according to the degree of consanguinity. This is a preliminary systematic study that aims to assess the incidence and carrier rate of cystic fibrosis in the Middle Eastern Lebanese population; known for a high frequency of consanguinity. One hundred thirteen DNA samples were collected from neonatal blood cards obtained from newborns to healthy unrelated families with no previous history of Cystic fibrosis. Screening for Cystic Fibrosis-causing pathogenic variants was performed using next generation sequencing, and 17 different single nucleotide variants were detected, including six pathogenic and likely pathogenic. 5.5%-7% newborns were found to be carriers of a variant strongly suggestive of pathogenicity and comparable to published literature worldwide. This pilot analysis highlights the challenging interpretation of CFTR variants in a country underrepresented by large ethnic population analyses, and stresses the importance of premarital screening programs for Cystic fibrosis.

PMID:34888852 | DOI:10.1111/ahg.12450

World J Crit Care Med. 2021 Nov 9;10(6):334-344. doi: 10.5492/wjccm.v10.i6.334. eCollection 2021 Nov 9.

ABSTRACT

Flexible bronchoscopy (FB) has become a standard of care for the triad of inspection, sampling, and treatment in critical care patients. It is an invaluable tool for diagnostic and therapeutic purposes in critically ill patients in intensive care unit (ICU). Less is known about its role outside the ICU, particularly in the intermediate care unit (IMCU), a specialized environment, where an intermediate grade of intensive care and monitoring between standard care unit and ICU is provided. In the IMCU, the leading indications for a diagnostic work-up are: To visualize airway system/obstructions, perform investigations to detect respiratory infections, and identify potential sources of hemoptysis. The main procedures for therapeutic purposes are secretion aspiration, mucus plug removal to solve atelectasis (total or lobar), and blood aspiration during hemoptysis. The decision to perform FB might depend on the balance between potential benefits and risks due to frailty of critically ill patients. Serious adverse events related to FB are relatively uncommon, but they may be due to lack of expertise or appropriate precautions. Finally, nowadays, during dramatic recent coronavirus disease 2019 (COVID-19) pandemic, the exact role of FB in COVID-19 patients admitted to IMCU has yet to be clearly defined. Hence, we provide a concise review on the role of FB in an IMCU setting, focusing on its indications, technical aspects and complications.

PMID:34888159 | PMC:PMC8613715 | DOI:10.5492/wjccm.v10.i6.334

Front Immunol. 2021 Nov 23;12:754702. doi: 10.3389/fimmu.2021.754702. eCollection 2021.

ABSTRACT

The IL-36 family of cytokines were identified in the early 2000's as a new subfamily of the IL-1 cytokine family, and since then, the role of IL-36 cytokines during various inflammatory processes has been characterized. While most of the research has focused on the role of these cytokines in autoimmune skin diseases such as psoriasis and dermatitis, recent studies have also shown the importance of IL-36 cytokines in the lung inflammatory response during infectious and non-infectious diseases. In this review, we discuss the biology of IL-36 cytokines in terms of how they are produced and activated, as well as their effects on myeloid and lymphoid cells during inflammation. We also discuss the role of these cytokines during lung infectious diseases caused by bacteria and influenza virus, as well as other inflammatory conditions in the lungs such as allergic asthma, lung fibrosis, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Finally, we discuss the current therapeutic advances that target the IL-36 pathway and the possibility to extend these tools to treat lung inflammatory diseases.

PMID:34887860 | PMC:PMC8651476 | DOI:10.3389/fimmu.2021.754702

Eur Respir J. 2021 Dec 9:2100208. doi: 10.1183/13993003.00208-2021. Online ahead of print.

ABSTRACT

BACKGROUND: Digital biomarkers are a promising novel method to capture clinical data in a home-setting. However, clinical validation prior to implementation is of vital importance. The aim of this study was to clinically validate physical activity, heart rate, sleep and FEV1 as digital biomarkers measured by a smartwatch and portable spirometer in children with asthma and cystic fibrosis (CF).

METHODS: This was a prospective cohort study including 60 children with asthma and 30 children with CF (age 6-16). Participants wore a smartwatch, performed daily spirometry at home and completed a daily symptom questionnaire for 28-days. Physical activity, heart rate, sleep and FEV1 were considered candidate digital endpoints. Data from 128 healthy children was used for comparison. Reported outcomes were compliance, difference between patients and controls, correlation with disease-activity and potential to detect clinical events. Analysis was performed with linear mixed effect models.

RESULTS: Median compliance was 88%. On average, patients exhibited lower physical activity and FEV1 compared to healthy children, whereas the heart rate of children with asthma was higher compared to healthy children. Days with a higher symptom score were associated with lower physical activity for children with uncontrolled asthma and CF. Furthermore, FEV1 was lower and (nocturnal) heart rate was higher for both patient groups on days with more symptoms. Candidate biomarkers and showed a distinct pattern before- and after a pulmonary exacerbation.

CONCLUSION: Portable spirometer- and smartwatch-derived digital biomarkers show promise as candidate endpoints for use in clinical trials or clinical care in pediatric lung disease.

PMID:34887326 | DOI:10.1183/13993003.00208-2021

Int J Mol Sci. 2021 Dec 2;22(23):13064. doi: 10.3390/ijms222313064.

ABSTRACT

SLC26A9, a constitutively active Cl- transporter, has gained interest over the past years as a relevant disease modifier in several respiratory disorders including Cystic Fibrosis (CF), asthma, and non-CF bronchiectasis. SLC26A9 contributes to epithelial Cl- secretion, thus preventing mucus obstruction under inflammatory conditions. Additionally, SLC26A9 was identified as a CF gene modifier, and its polymorphisms were shown to correlate with the response to drugs modulating CFTR, the defective protein in CF. Here, we aimed to investigate the relationship between SLC26A9 and CFTR, and its role in CF pathogenesis. Our data show that SLC26A9 expression contributes to enhanced CFTR expression and function. While knocking-down SLC26A9 in human bronchial cells leads to lower wt- and F508del-CFTR expression, function, and response to CFTR correctors, the opposite occurs upon its overexpression, highlighting SLC26A9 relevance for CF. Accordingly, F508del-CFTR rescue by the most efficient correctors available is further enhanced by increasing SLC26A9 expression. Interestingly, SLC26A9 overexpression does not increase the PM expression of non-F508del CFTR traffic mutants, namely those unresponsive to corrector drugs. Altogether, our data indicate that SLC26A9 stabilizes CFTR at the ER level and that the efficacy of CFTR modulator drugs may be further enhanced by increasing its expression.

PMID:34884866 | DOI:10.3390/ijms222313064

PLoS One. 2021 Dec 9;16(12):e0259964. doi: 10.1371/journal.pone.0259964. eCollection 2021.

ABSTRACT

Nontuberculous mycobacteria (NTM) are opportunistic human pathogens that are commonly found in soil and water, and exposure to these organisms may cause pulmonary nontuberculous mycobacterial disease. Persons with cystic fibrosis (CF) are at high risk for developing pulmonary NTM infections, and studies have shown that prolonged exposure to certain environments can increase the risk of pulmonary NTM. It is therefore important to determine the risk associated with different geographic areas. Using annualized registry data obtained from the Cystic Fibrosis Foundation Patient Registry for 2010 through 2017, we conducted a geospatial analysis of NTM infections among persons with CF in Florida. A Bernoulli model in SaTScan was used to identify clustering of ZIP codes with higher than expected numbers of NTM culture positive individuals. Generalized linear mixed models with a binomial distribution were used to test the association of environmental variables and NTM culture positivity. We identified a significant cluster of M. abscessus and predictors of NTM sputum positivity, including annual precipitation and soil mineral levels.

PMID:34882686 | DOI:10.1371/journal.pone.0259964

Eur J Drug Metab Pharmacokinet. 2021 Dec 9. doi: 10.1007/s13318-021-00734-9. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: The number of adults living with cystic fibrosis (CF) has increased and will continue to do so with the approval of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Because systemic aminoglycosides are commonly administered for CF pulmonary exacerbations, we sought to define optimized dosing regimens using a population pharmacokinetic modeling and simulation approach.

METHODS: Adult CF patients admitted for pulmonary exacerbation, receiving at least 72 h of systemic gentamicin, tobramycin, or amikacin, with measured concentrations were included. Covariates [e.g., age, weight, creatinine clearance (CRCL)] were screened. Population modeling was completed using Monolix, and simulations were conducted in R. Simulated exposures were calculated using noncompartmental analysis. Once-daily fixed (10 mg/kg) and exposure-matched dosing (i.e., 15, 10, 7.5, 6 mg/kg for ages 20, 30, 40, and 50 years, respectively) strategies were compared. First-24 h exposures were evaluated for each strategy according to the probability of target attainment (PTA) (ratio of peak plasma concentrations relative to the minimum inhibitory concentration [Cmax/MIC] or ratio of the area under the concentration-time curve to MIC [AUC/MIC]) and the probability of toxic exposure (PTE) (trough concentration, Ctrough > 2 mg/l).

RESULTS: Forty-eight adult patients (55% female) were included. A one-compartment model best fit the data. Estimates for volume of distribution (V) and clearance (CL) were 22 l and 5.57 l/h, respectively. Weight significantly modified CL and V. Age significantly modified CL and was more influential than CRCL. PTA was > 90% at MICs ≤ 1 mg/l for fixed doses of 10 mg/kg and for exposure-matched doses at MIC ≤ 1 mg/l. Exposure-matched dosing reduced PTE roughly 50% in patients aged 40 and 50 years vs. fixed dosing.

CONCLUSIONS: Exposure-matching maintained PTA at MICs ≤ 1 mg/l while reducing toxicity risk in older patients compared to fixed dosing. Confirmatory studies are needed.

PMID:34882292 | DOI:10.1007/s13318-021-00734-9