PLoS One. 2023 Feb 16;18(2):e0281769. doi: 10.1371/journal.pone.0281769. eCollection 2023.

ABSTRACT

Mycobacterium abscessus infections are relatively common in patients with cystic fibrosis and are clinically challenging, with frequent intrinsic resistance to antibiotics. Therapeutic treatment with bacteriophages offers some promise but faces many challenges including substantial variation in phage susceptibilities among clinical isolates, and the need to personalize therapies for individual patients. Many strains are not susceptible to any phages or are not efficiently killed by lytic phages, including all smooth colony morphotype strains tested to-date. Here, we analyze a set of new M. abscessus isolates for the genomic relationships, prophage content, spontaneous phage release, and phage susceptibilities. We find that prophages are common in these M. abscessus genomes, but some have unusual arrangements, including tandemly integrated prophages, internal duplications, and they participate in active exchange of polymorphic toxin-immunity cassettes secreted by ESX systems. Relatively few strains are efficiently infected by any mycobacteriophages, and the infection patterns do not reflect the overall phylogenetic relationships of the strains. Characterization of these strains and their phage susceptibility profiles will help to advance the broader application of phage therapies for NTM infections.

PMID:36795728 | DOI:10.1371/journal.pone.0281769

EMBO J. 2023 Feb 16:e112165. doi: 10.15252/embj.2022112165. Online ahead of print.

ABSTRACT

The opportunistic pathogen Pseudomonas aeruginosa adapts to solid surfaces to enhance virulence and infect its host. Type IV pili (T4P), long and thin filaments that power surface-specific twitching motility, allow single cells to sense surfaces and control their direction of movement. T4P distribution is polarized to the sensing pole by the chemotaxis-like Chp system via a local positive feedback loop. However, how the initial spatially resolved mechanical signal is translated into T4P polarity is incompletely understood. Here, we demonstrate that the two Chp response regulators PilG and PilH enable dynamic cell polarization by antagonistically regulating T4P extension. By precisely quantifying the localization of fluorescent protein fusions, we show that phosphorylation of PilG by the histidine kinase ChpA controls PilG polarization. Although PilH is not strictly required for twitching reversals, it becomes activated upon phosphorylation and breaks the local positive feedback mechanism established by PilG, allowing forward-twitching cells to reverse. Chp thus uses a main output response regulator, PilG, to resolve mechanical signals in space and employs a second regulator, PilH, to break and respond when the signal changes. By identifying the molecular functions of two response regulators that dynamically control cell polarization, our work provides a rationale for the diversity of architectures often found in non-canonical chemotaxis systems.

PMID:36795017 | DOI:10.15252/embj.2022112165

Infect Microbes Dis. 2022 Sep;4(3):103-110. doi: 10.1097/im9.0000000000000101. Epub 2022 Aug 16.

ABSTRACT

The primary defect in cystic fibrosis (CF) is abnormal chloride and bicarbonate transport in the cystic fibrosis transmembrane conductance regulator (CFTR) epithelial ion channel. The apical surface of the respiratory tract is lined by an airway surface liquid layer (ASL) composed of mucin comprising mainly MUC5A and MUC5B glycoproteins. ASL homeostasis depends on sodium bicarbonate secretion into the airways and secretion deficits alter mucus properties leading to airway obstruction, inflammation, and infections. Downstream effects of abnormal ion transport in the lungs include altered intrinsic immune defenses. We observed that neutrophils killed Pseudomonas aeruginosa more efficiently when it had been exposed to sodium bicarbonate, and formation of neutrophil extracellular traps (NETs) by neutrophils was augmented in the presence of increasing bicarbonate concentrations. Physiological levels of bicarbonate sensitized P. aeruginosa to the antimicrobial peptide cathelicidin LL-37, which is present in both lung ASL and in NETs. Sodium bicarbonate has various uses in clinical medicine and in the care of CF patients, and could be further explored as a therapeutic adjunct against Pseudomonas infections.

PMID:36793929 | PMC:PMC9928163 | DOI:10.1097/im9.0000000000000101

Genet Med. 2023 Feb 12:100813. doi: 10.1016/j.gim.2023.100813. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the cost-effectiveness of population-based expanded reproductive carrier screening (RCS) for a 300 recessive genes panel from health service and societal perspectives.

METHODS: A microsimulation model (PreConMod) was developed using 2016 Australian Census data as the base population. Epidemiological, health and indirect cost data were based on literature review. The study assessed the incremental-cost-effectiveness-ratio (ICER) of expanded RCS compared with (i) no population screening (ii) three-condition screening for cystic fibrosis, spinal muscular atrophy, and fragile X syndrome in a single birth cohort. Averted affected births and health service savings with expanded RCS were projected to year 2061. Both one-way and probability sensitivity analyses were conducted to assess the uncertainty of the parameter inputs.

RESULTS: Expanded RCS was cost-saving compared with no population screening and cost-effective compared to the three-condition screening (ICER of $6,287 per QALY gained) at an uptake rate of 50% for RCS, 59% for IVF and preimplantation genetic testing, 90% for prenatal diagnosis testing and 50% for elective termination of affected pregnancies and a cost of A$595 per couple screened. Our model predicts that expanded RCS would avert one-third of affected births in a single birth cohort and reduce lifetime health service spending by A$632.0 million. Expanded RCS was estimated to be cost saving from the societal perspective.

CONCLUSION: Expanded RCS is cost-effective from the health service and societal perspectives. Expanded RCS is projected to avert significantly more affected births and result in health service saving beyond those expected from three-condition screening or no population screening.

PMID:36789890 | DOI:10.1016/j.gim.2023.100813

Crit Care. 2023 Feb 14;27(1):60. doi: 10.1186/s13054-023-04331-x.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa pneumonia is commonly treated with systemic antibiotics to ensure adequate treatment of multidrug resistant (MDR) bacteria. However, intravenous (IV) antibiotics often achieve suboptimal pulmonary concentrations. We therefore aimed to evaluate the effect of inhaled amikacin (AMK) plus IV meropenem (MEM) on bactericidal efficacy in a swine model of monolateral MDR P. aeruginosa pneumonia.

METHODS: We ventilated 18 pigs with monolateral MDR P. aeruginosa pneumonia for up to 102 h. At 24 h after the bacterial challenge, the animals were randomized to receive 72 h of treatment with either inhaled saline (control), IV MEM only, or IV-MEM plus inhaled AMK (MEM + AMK). We dosed IV MEM at 25 mg/kg every 8 h and inhaled AMK at 400 mg every 12 h. The primary outcomes were the P. aeruginosa burden and histopathological injury in lung tissue. Secondary outcomes included the P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage fluid, the development of antibiotic resistance, the antibiotic distribution, and the levels of inflammatory markers.

RESULTS: The median (25-75th percentile) P. aeruginosa lung burden for animals in the control, MEM only, and MEM + AMK groups was 2.91 (1.75-5.69), 0.72 (0.12-3.35), and 0.90 (0-4.55) log10 CFU/g (p = 0.009). Inhaled therapy had no effect on preventing dissemination compared to systemic monotherapy, but it did have significantly higher bactericidal efficacy in tracheal secretions only. Remarkably, the minimum inhibitory concentration of MEM increased to > 32 mg/L after 72-h exposure to monotherapy in 83% of animals, while the addition of AMK prevented this increase (p = 0.037). Adjunctive therapy also slightly affected interleukin-1β downregulation. Despite finding high AMK concentrations in pulmonary samples, we found no paired differences in the epithelial lining fluid concentration between infected and non-infected lungs. Finally, a non-significant trend was observed for higher amikacin penetration in low-affected lung areas.

CONCLUSIONS: In a swine model of monolateral MDR P. aeruginosa pneumonia, resistant to the inhaled AMK and susceptible to the IV antibiotic, the use of AMK as an adjuvant treatment offered no benefits for either the colonization of pulmonary tissue or the prevention of pathogen dissemination. However, inhaled AMK improved bacterial eradication in the proximal airways and hindered antibiotic resistance.

PMID:36788582 | DOI:10.1186/s13054-023-04331-x

Biophys J. 2023 Feb 10;122(3S1):458a. doi: 10.1016/j.bpj.2022.11.2464.

NO ABSTRACT

PMID:36784349 | DOI:10.1016/j.bpj.2022.11.2464

Biophys J. 2023 Feb 10;122(3S1):112a. doi: 10.1016/j.bpj.2022.11.786.

NO ABSTRACT

PMID:36782493 | DOI:10.1016/j.bpj.2022.11.786

J Magn Reson Imaging. 2023 Feb 14. doi: 10.1002/jmri.28638. Online ahead of print.

ABSTRACT

BACKGROUND: Multiple-breath washout (MBW) 129 Xe MRI (MBW Xe-MRI) is a promising technique for following pediatric cystic fibrosis (CF) lung disease progression. However, its repeatability in stable CF needs to be established to use it as an outcome measure for novel therapies.

PURPOSE: To assess intravisit and intervisit repeatability of MBW Xe-MRI in healthy and CF children.

STUDY TYPE: Prospective, longitudinal cohort study.

SUBJECTS: A total of 18 pediatric subjects (7 healthy, 11 CF).

FIELD STRENGTH/SEQUENCE: A 3 T/2D coronal hyperpolarized (HP) 129 Xe images using GRE sequence.

ASSESSMENT: All subjects completed MBW Xe-MRI, pulmonary function tests (PFTs) (spirometry, nitrogen [N2 ] MBW for lung clearance index [LCI]) and ventilation defect percent (VDP) at baseline (visit 1) and 1-month after. Fractional ventilation (FV), coefficient of variation (CoVFV ) maps were calculated from MBW Xe-MRI data acquired between intervening air washout breaths performed after an initial xenon breath-hold. Skewness of FV and CoVFV map distributions was also assessed.

STATISTICAL TESTS: Repeatability: intraclass correlation coefficients (ICC), within-subject coefficient of variation (CV%), repeatability coefficient (CR). Agreement: Bland-Altman. For correlations between MBW Xe-MRI, VDP and PFTs: Spearman's correlation. Significance threshold: P < 0.05.

RESULTS: For FV, intravisit median [IQR] ICC was high in both healthy (0.94 [0.48, 0.99]) and CF (0.83 [0.04, 0.97]) subjects. CoVFV also had good intravisit ICC in healthy (0.92 [0.42, 0.99]) and CF (0.79 [0.02, 0.96]) subjects. Similarly, for FV, intervisit ICC was high in health (0.94 [0.68, 0.99]) and CF (0.89 [0.61, 0.97]). CoVFV also had good intervisit ICC in health (0.92 [0.42, 0.99]) and CF (0.78 [0.26, 0.94]). FV had better intervisit repeatability than VDP. CoVFV correlated significantly with LCI (R = 0.56). Skewness of FV distributions significantly distinguished between cohorts at baseline.

DATA CONCLUSION: MBW Xe-MRI had high intravisit and intervisit repeatability in healthy and stable CF subjects. CoVFV correlated with LCI, suggesting the importance of ventilation heterogeneity to early CF.

EVIDENCE LEVEL: 1.

TECHNICAL EFFICACY: Stage 2.

PMID:36786650 | DOI:10.1002/jmri.28638

Biophys J. 2023 Feb 10;122(3S1):173a-174a. doi: 10.1016/j.bpj.2022.11.1084.

NO ABSTRACT

PMID:36782818 | DOI:10.1016/j.bpj.2022.11.1084

Am J Respir Cell Mol Biol. 2023 Feb 13. doi: 10.1165/rcmb.2022-0264OC. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a pathological condition of unknown etiology which results from injury to the lung and an ensuing fibrotic response that leads to thickening of the alveolar walls and obliteration of the alveolar space. The pathogenesis is not clear and there are currently no effective therapies for IPF. Small airway disease and mucus accumulation are prominent features in IPF lungs, similar to Cystic Fibrosis (CF) lung disease. The ATP12A gene encodes the alpha-subunit of the non-gastric H+, K+-ATPase, which functions to acidify the airway surface fluid and impairs mucociliary transport function in cystic fibrosis patients. We hypothesize that the ATP12A protein may play a role in the pathogenesis of IPF. Our studies demonstrate that ATP12A protein is overexpressed in distal small airways from IPF patient lungs compared to normal human lungs. In addition, overexpression of the ATP12A protein in mouse lungs worsened the bleomycin (BLEO)-induced experimental pulmonary fibrosis. This was prevented by a potassium-competitive proton pump blocker, vonoprazan (VON). This data supports the concept that the ATP12A protein plays an important role in the pathogenesis of lung fibrosis. Inhibition of the ATP12A protein has the potential as a novel therapeutic strategy in IPF.

PMID:36780662 | DOI:10.1165/rcmb.2022-0264OC

Microbiol Spectr. 2023 Feb 13:e0309922. doi: 10.1128/spectrum.03099-22. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen of considerable medical importance, owing to its pronounced antibiotic tolerance and association with cystic fibrosis and other life-threatening diseases. The aim of this study was to highlight the genes responsible for P. aeruginosa biofilm tolerance to antibiotics and thereby identify potential new targets for the development of drugs against biofilm-related infections. By developing a novel screening approach and utilizing a public P. aeruginosa transposon insertion library, several biofilm-relevant genes were identified. The Pf phage gene (PA0720) and flagellin gene (fliC) conferred biofilm-specific tolerance to gentamicin. Compared with the reference biofilms, the biofilms formed by PA0720 and fliC mutants were completely eliminated with a 4-fold-lower gentamicin concentration. Furthermore, the mreC, pprB, coxC, and PA3785 genes were demonstrated to play major roles in enhancing biofilm tolerance to gentamicin. The analysis of biofilm-relevant genes performed in this study provides important novel insights into the understanding of P. aeruginosa antibiotic tolerance, which will facilitate the detection of antibiotic resistance and the development of antibiofilm strategies against P. aeruginosa. IMPORTANCE Pseudomonas aeruginosa is an opportunistic pathogen of high medical importance and is one of the main pathogens responsible for the mortality of patients with cystic fibrosis. In addition to inherited antibiotic resistance, P. aeruginosa can form biofilms, defined as communities of microorganisms embedded in a self-produced matrix of extracellular polymeric substances adhering to each other and/or to a surface. Biofilms protect bacteria from antibiotic treatments and represent a major reason for antibiotic failure in the treatment of chronic infections caused by cystic fibrosis. Therefore, it is crucial to develop new therapeutic strategies aimed at specifically eradicating biofilms. The aim of this study was to generalize a novel screening method for biofilm research and to identify the possible genes involved in P. aeruginosa biofilm tolerance to antibiotics, both of which could improve the understanding of biofilm-related infections and allow for the identification of relevant therapeutic targets for drug development.

PMID:36779712 | DOI:10.1128/spectrum.03099-22

Case Reports Immunol. 2023 Feb 2;2023:1006376. doi: 10.1155/2023/1006376. eCollection 2023.

ABSTRACT

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESSs) syndrome is an idiosyncratic drug-induced reaction that rarely occurs in children but can lead to serious complications. It manifests most commonly with fever, extensive skin eruptions, and eosinophilia. Symptoms typically develop two to six weeks after the initiation of the inciting drug. Visceral organ involvement especially the liver can also occur and if not recognized early and the inciting drug is not stopped immediately, it can lead to liver failure. Therefore, early diagnosis is important but can be very challenging because of disease rarity, lack of a diagnostic test, and its overlap with other common pediatric allergic and infectious conditions. Case Presentation. A 2.5-year-old boy with known diagnosis of cystic fibrosis, bilateral bronchiectasis, pancreatic insufficiency, and chronic airway colonization with Pseudomonas aeruginosa was admitted to our hospital with acute pulmonary exacerbation of CF lung disease. He was treated with intravenous piperacillin-tazobactam and intravenous amikacin in addition to airway clearance. On day 18 of treatment, the patient developed high grade fever followed by diffuse erythematous and pruritic maculopapular rash. Blood tests showed high eosinophilia, high C-reactive protein (CRP), and high liver enzymes levels. The clinical features and the laboratory findings were consistent with the DRESS syndrome. Therefore, all antibiotics were discontinued. Progressive resolution of the symptoms was observed within two days. Laboratory abnormalities were also normalized in the follow-up clinic visit 4 months later.

CONCLUSION: Our case demonstrates the importance of early recognition of the DRESS syndrome in children who develop fever and skin rashes with eosinophilia while undergoing long-term antibiotic treatment. Prompt discontinuation of the offending drug is the cornerstone therapy and results in the resolution of symptoms and prevention of serious complications.

PMID:36778654 | PMC:PMC9911254 | DOI:10.1155/2023/1006376

bioRxiv. 2023 Feb 4:2023.02.04.527134. doi: 10.1101/2023.02.04.527134. Preprint.

ABSTRACT

Cystic fibrosis (CF) is one of the most prevalent lethal genetic diseases with over 2000 identified mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pharmacological chaperones such as Lumacaftor (VX-809), Tezacaftor (VX-661) and Elexacaftor (VX-445) treat mutation-induced defects by stabilizing CFTR and are called correctors. These correctors improve proper folding and thus facilitate processing and trafficking to increase the amount of functional CFTR on the cell surface. Yet, CFTR variants display differential responses to each corrector. Here, we report variants P67L and L206W respond similarly to VX-809 but divergently to VX-445 with P67L exhibiting little rescue when treated with VX-445. We investigate the underlying cellular mechanisms of how CFTR biogenesis is altered by correctors in these variants. Affinity purification-mass spectrometry (AP-MS) multiplexed with isobaric Tandem Mass Tags (TMT) was used to quantify CFTR protein-protein interaction changes between variants P67L and L206W. VX-445 facilitates unique proteostasis factor interactions especially in translation, folding, and degradation pathways in a CFTR variant-dependent manner. A number of these interacting proteins knocked down by siRNA, such as ribosomal subunit proteins, moderately rescued fully glycosylated P67L. Importantly, these knock-downs sensitize P67L to VX-445 and further enhance the correction of this variant. Our results provide a better understanding of VX-445 biological mechanism of action and reveal cellular targets that may sensitize unresponsive CFTR variants to known and available correctors.

PMID:36778339 | PMC:PMC9915750 | DOI:10.1101/2023.02.04.527134

Front Pharmacol. 2023 Jan 27;14:1114584. doi: 10.3389/fphar.2023.1114584. eCollection 2023.

ABSTRACT

Background: Defects in expression, maturation or function of the epithelial membrane glycoprotein CFTR are causative for the progressive disease cystic fibrosis. Recently, molecular therapeutics that improve CFTR maturation and functional defects have been approved. We aimed to verify whether we could detect an improvement of CFTR protein expression and maturation by triple therapy with elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA). Methods: Rectal suction biopsies of 21 p.Phe508del homozygous or compound heterozygous CF patients obtained pre- and during treatment with ELX/TEZ/IVA were analyzed by CFTR Western blot that was optimized to distinguish CFTR glycoisoforms. Findings: CFTR western immunoblot analysis revealed that-compared to baseline-the levels of CFTR protein increased by at least twofold in eight out of 12 patients upon treatment with ELX/TEZ/IVA compared to baseline (p < 0.02). However, polydispersity of the mutant CFTR protein was lower than that of the fully glycosylated wild type CFTR Golgi isoform, indicating an incompletely glycosylated p.Phe508el CFTR protein isoform C* in patients with CF which persists after ELX/TEZ/IVA treatment. Interpretation: Treatment with ELX/TEZ/IVA increased protein expression by facilitating the posttranslational processing of mutant CFTR but apparently did not succeed in generating the polydisperse spectrum of N-linked oligosaccharides that is characteristic for the wild type CFTR band C glycoisoform. Our results caution that the lower amounts or immature glycosylation of the C* glycoisoform observed in patients' biomaterial might not translate to fully restored function of mutant CFTR necessary for long-term provision of clinical benefit.

PMID:36778025 | PMC:PMC9911415 | DOI:10.3389/fphar.2023.1114584

J Pediatr Pharmacol Ther. 2023;28(1):63-70. doi: 10.5863/1551-6776-28.1.63. Epub 2023 Feb 3.

ABSTRACT

OBJECTIVE: An institution's tobramycin pharmacokinetics (PK) database was reviewed to evaluate the efficacy and safety of empiric tobramycin dosing and monitoring strategies used in pediatric patients with cystic fibrosis (CF). The relationship between patient age and tobramycin dosing needed to achieve the area under the curve (AUC) goal was investigated.

METHODS: Retrospective chart review was performed for patients who received tobramycin during a CF exacerbation from 2009 to 2019 who received PK monitoring by pediatric pharmacists. Tobramycin dosing needed to achieve an AUC of 100 mg·hr/L was calculated for each patient. Serum creatinine and concomitant nephrotoxin use were collected as surrogate nephrotoxicity endpoints to evaluate safety.

RESULTS: Goal AUC (100 ± 15 mg·hr/L) was achieved based on initial or repeat PK calculations in 43.5% (95% CI, 37.7-49.3) of 85 unique patients across 326 encounters. Patients with calculated recommended doses of 9.5 to 11.9 mg/kg every 24 hours empirically achieved goal AUC in 77% (78/101) of encounters. The odds of achieving goal AUC were 56% higher for children aged 10 vs 5 years (OR = 1.56; 95% CI, 1.04-2.34; p = 0.033) and 32% higher for children aged 15 vs 10 years (OR = 1.32; 95% CI, 1.07-1.61; p = 0.008). Overall rates of acute kidney injury and concomitant nephrotoxin use were 10.8% (95% CI, 6.2-15.5) and 80.7% (95% CI, 74.3-87.1), respectively.

CONCLUSIONS: Desired AUC was achieved by 43.5% of pediatric patients with CF using tobramycin 10 mg/kg every 24 hours. Older patient age was associated with higher initial AUC attainment and fewer dose modifications. Younger children may require higher weight-based dosing to meet AUC goals.

PMID:36777977 | PMC:PMC9901314 | DOI:10.5863/1551-6776-28.1.63

Oncoimmunology. 2023 Feb 6;12(1):2174723. doi: 10.1080/2162402X.2023.2174723. eCollection 2023.

NO ABSTRACT

PMID:36776523 | PMC:PMC9908291 | DOI:10.1080/2162402X.2023.2174723

Oncoimmunology. 2023 Feb 7;12(1):2175506. doi: 10.1080/2162402X.2023.2175506. eCollection 2023.

NO ABSTRACT

PMID:36776522 | PMC:PMC9908292 | DOI:10.1080/2162402X.2023.2175506

Pediatr Pulmonol. 2023 Feb 12. doi: 10.1002/ppul.26352. Online ahead of print.

ABSTRACT

BACKGROUND: The extent to which environmental exposures and community characteristics of the built environment collectively predict rapid lung-function decline, during adolescence and early adulthood in CF, has not been examined.

OBJECTIVE: To identify built environment characteristics predictive of rapid CF lung function decline.

METHODS: We performed a retrospective, single-center, longitudinal cohort study (n = 173 individuals with CF aged 6-20 years, 2012-2017). We used a stochastic model to predict lung function, measured as forced expiratory volume in 1 second (FEV1 ) of % predicted. Traditional demographic/clinical characteristics were evaluated as predictors. Built environmental predictors included exposure to elemental carbon attributable to traffic sources (ECAT), neighborhood material deprivation (poverty, education, housing, and healthcare access), greenspace near the home, and residential drivetime to the CF center.

MEASUREMENTS AND MAIN RESULTS: The final model, which included ECAT, material deprivation index, and greenspace, alongside traditional demographic/clinical predictors, significantly improved fit and prediction, compared to only demographic/clinical predictors (Likelihood Ratio Test statistic: 26.78, p<0.0001; difference in Akaike Information Criterion: 15). An increase of 0.1 ug/m3 of ECAT was associated with 0.104% predicted/yr (95% CI: 0.024, 0.183) more rapid decline. Although not statistically significant, material deprivation was similarly associated (0.1-unit increase corresponded to additional decline of 0.103% predicted/year [-0.113, 0.319]). High-risk regional areas of rapid decline and age-related heterogeneity were identified from prediction mapping.

CONCLUSION: Traffic-related air pollution exposure is an important predictor of rapid pulmonary decline that, coupled with community-level material deprivation and routinely collected demographic/clinical characteristics, enhance CF prognostication and enable personalized environmental health interventions. This article is protected by copyright. All rights reserved.

PMID:36775890 | DOI:10.1002/ppul.26352

Rev Mal Respir. 2023 Feb 10:S0761-8425(23)00037-2. doi: 10.1016/j.rmr.2023.01.014. Online ahead of print.

ABSTRACT

Cystic fibrosis is a disease caused by a mutation on the CFTR gene coding for a chloride channel. The dominant mutation F508del eliminates the CFTR protein at the surface of epithelial cells, causing an accumulation of viscous mucus in the airways. In advanced stages of the disease, respiratory failure is associated with cellular hypoxia. Our project aims not only to describe the impact of hypoxia on ion channels and to highlight the underlying signaling pathways involved, but also to test the effectiveness of current CF treatments under the above-mentioned conditions.

PMID:36775781 | DOI:10.1016/j.rmr.2023.01.014

Clin Chest Med. 2023 Mar;44(1):15-33. doi: 10.1016/j.ccm.2022.10.001.

ABSTRACT

Lung transplantation can be lifesaving for patients with advanced lung disease. Demographics are evolving with recipients now sicker but determining candidacy remains predicated on one's underlying lung disease prognosis, along with the likelihood of posttransplant success. Determining optimal timing can be challenging, and most programs favor initiating the process early and proactively to allow time for patient education, informed decision-making, and preparation. A comprehensive, multidisciplinary evaluation is used to elucidate disease progrnosis and identify risk factors for poor posttransplant outcomes. Candidacy criteria vary significantly by center, and close communication between referring and transplant providers is necessary to improve access to transplant and outcomes.

PMID:36774161 | DOI:10.1016/j.ccm.2022.10.001