J Cyst Fibros. 2022 Jan 12:S1569-1993(21)02150-0. doi: 10.1016/j.jcf.2021.11.010. Online ahead of print.

ABSTRACT

BACKGROUND: Treatment for pulmonary exacerbations of cystic fibrosis (CF) can produce a range of positive and negative outcomes. Understanding which of these outcomes are achievable and desirable to people affected by disease is critical to agreeing to goals of therapy and determining endpoints for trials. The relative importance of outcomes resulting from treatment of these episodes are not reported. We aimed to (i) quantify the relative importance of outcomes resulting from treatment for pulmonary exacerbations and (ii) develop patient and proxy carer-reported weighted outcome measures for use in adults and children, respectively.

METHODS: A discrete choice experiment (DCE) survey was conducted. Participants were asked to make a series of hypothetical decisions about treatment for pulmonary exacerbations to assess how they make trade-offs between different attributes of health. Data were analysed using a conditional logistic regression model. The correlation coefficients from these data were rescaled to enable generation of a composite health outcome score between 0 and 100 (worst to best health state).

RESULTS: 362 individuals participated (167 people with CF and 195 carers); of these, 206 completed the survey (56.9%). Most participants were female and resided in Australia. Difficult/painful breathing had the greatest impact on the preferred health state amongst people with CF and carers alike. Avoidance of gastrointestinal problems also heavily influenced decision-making.

CONCLUSIONS: These data should be considered when making treatment decisions and determining endpoints for trials. Further research is recommended to quantify the preferences of children and to determine whether these align with those of their carer(s).

PMID:35033463 | DOI:10.1016/j.jcf.2021.11.010

Respir Med. 2022 Jan 6;192:106736. doi: 10.1016/j.rmed.2022.106736. Online ahead of print.

ABSTRACT

BACKGROUND: A1006E is a Cystic Fibrosis (CF) mutation that is still not widely known. We report phenotypic features and geographic distribution of the largest cohort of people with CF (pwCF) carrying A1006E to date.

METHODS: Study of European pwCF carrying A1006E mutation, included in the European CF Society Patient Registry (ECFSPR). Genotype, ancestries and all variables recorded were compared to a cohort of F508del/F508del patients. Rate of decline in percentage-of-predicted FEV1 (ppFEV1) was also analyzed using the 2010-2017 ECFSPR.

RESULTS: 44 pwCF carrying A1006E were reported (59% males), median age 33 years old (3-58), 54.5% Spanish and 40.9% Italian, most with ancestry in Murcia (Spain) and Lazio (Italy) regions. Compared to F508del homozygous, A1006E-pwCF were significantly older (75% vs. 52.5% ≥ 18 years old) and diagnosed at later median age (6.98 vs. 0.29 years); showed lower rates of meconium ileus (2.33% vs. 17.7%), pancreatic insufficiency (27.91% vs. 99.26%), diabetes (2.33% vs. 21.98%), liver disease (6.98% vs. 36.72%) and Pseudomonas aeruginosa chronic colonization (30.95% vs. 42.51%); and presented better nutrition (BMI z-score 0.44 vs. -0.43) and ppFEV1 (90.8% vs. 78.6%), with 18.9% (most >40 years old) having a ppFEV1<70%. Additional ppFEV1 decline (0.96% per year) was attributed to F508del/F508del genotype (p = 0.0007). None died or needed organ transplantation during the study period.

CONCLUSIONS: A1006E-pwCF are mainly of Western Mediterranean Spanish and Italian descent. When compared with F508del/F508del-pwCF, they usually have a milder form of the disease, associated with pancreatic sufficiency and slower FEV1 decline. However, some will develop progressive respiratory impairment during adulthood.

PMID:35032736 | DOI:10.1016/j.rmed.2022.106736

Clin Transplant. 2022 Jan 15:e14593. doi: 10.1111/ctr.14593. Online ahead of print.

ABSTRACT

BACKGROUND: Advanced age is considered a risk factor for lung transplantation (LTX). We sought to evaluate the long-term outcomes of LTX in the septuagenarian.

METHODS: LTX recipients in the UNOS transplant registry (May 1, 2005 to June 12, 2020) were stratified into 18-59, 60-69, and > = 70 years of age. Recipient and transplant characteristics were evaluated for survival, cause of death (COD), length of stay (LOS), and complications. A Kaplan-Meier analysis examined long-term survival for all patients stratified by age, specifically looking at cause of death.

RESULTS: A total of 27632 recipients were identified. As recipients aged, we found a decrease in proportion of cystic fibrosis and an increase in restrictive disease while obstructive disease peaked in the 60-69yo cohort (p<0.001). Septuagenarians had higher rates of single LTX, male gender and white race (p<0.001). Older recipients had significantly longer donor recovery distances traveled with paradoxical shorter ischemic times, shorter hospital LOS and were transplanted at higher volume centers. There was no difference with in-hospital mortality among groups (p = 0.5). Acute rejection during initial hospitalization, rejection within 1 year, and post-transplant dialysis incidence decreased with age. Graft failure was a common COD in younger patients while malignancy and cardio/cerebrovascular diseases were common COD in > = 70yo.

CONCLUSION: Select septuagenarian LTX candidates may be safely transplanted with relatively few complications. Immunosenescence and conditions of the aged are likely contributing factors to the decreased rejection and graft failure observations. Septuagenarians should not be excluded from LTX consideration based solely on age. Transplantation in septuagenarians should only be done in very selected patients (screened for malignancies and atherosclerotic disease) and these recipients should be carefully followed after transplantation because of these risk factors. This article is protected by copyright. All rights reserved.

PMID:35032351 | DOI:10.1111/ctr.14593

Eur J Clin Pharmacol. 2022 Jan 15. doi: 10.1007/s00228-021-03272-0. Online ahead of print.

NO ABSTRACT

PMID:35032180 | DOI:10.1007/s00228-021-03272-0

Environ Sci Pollut Res Int. 2022 Jan 15. doi: 10.1007/s11356-022-18534-2. Online ahead of print.

ABSTRACT

Diabetes mellitus (DM) is a worldwide ailment which leads to chronic complications like cardiac disorders, renal perturbations, limb amputation and blindness. Type one diabetes (T1DM), Type two diabetes (T2DM), Another types of diabetes, such as genetic errors in function of β-cell and action of insulin, cystic fibrosis, chemical-instigated diabetes or following tissue transplantation), and pregnancy DM (GDM). In response to nutritional ingestion, the gut may release a pancreatic stimulant that affects carbohydrate metabolism. The duodenum produces a 'chemical excitant' that stimulates pancreatic output, and researchers have sought to cure diabetes using gut extract injections, coining the word 'incretin' to describe the phenomena. Incretins include GIP and GLP-1. The 'enteroinsular axis' is the link between pancreas and intestine. Nutrient, neuronal and hormonal impulses from intestine to cells secreting insulin were thought to be part of this axis. In addition, the hormonal component, incretin, must meet two requirements: (1) it secreted by foods, mainly carbohydrates, and (2) it must induce an insulinotropic effect which is glucose-dependent. In this review, we clarify the ability of using incretin-dependent treatments for treating DM.

PMID:35031999 | DOI:10.1007/s11356-022-18534-2

J Immunol. 2022 Jan 14:ji1901171. doi: 10.4049/jimmunol.1901171. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is an inherited life-threatening disease accompanied by repeated lung infections and multiorgan inflammation that affects tens of thousands of people worldwide. The causative gene, cystic fibrosis transmembrane conductance regulator (CFTR), is mutated in CF patients. CFTR functions in epithelial cells have traditionally been thought to cause the disease symptoms. Recent work has shown an additional defect: monocytes from CF patients show a deficiency in integrin activation and adhesion. Because monocytes play critical roles in controlling infections, defective monocyte function may contribute to CF progression. In this study, we demonstrate that monocytes from CFTRΔF508 mice (CF mice) show defective adhesion under flow. Transplanting CF mice with wild-type (WT) bone marrow after sublethal irradiation replaced most (60-80%) CF monocytes with WT monocytes, significantly improved survival, and reduced inflammation. WT/CF mixed bone marrow chimeras directly demonstrated defective CF monocyte recruitment to the bronchoalveolar lavage and the intestinal lamina propria in vivo. WT mice reconstituted with CF bone marrow also show lethality, suggesting that the CF defect in monocytes is not only necessary but also sufficient to cause disease. We also show that monocyte-specific knockout of CFTR retards weight gains and exacerbates dextran sulfate sodium-induced colitis. Our findings show that providing WT monocytes by bone marrow transfer rescues mortality in CF mice, suggesting that similar approaches may mitigate disease in CF patients.

PMID:35031577 | DOI:10.4049/jimmunol.1901171

Dis Colon Rectum. 2022 Jan 12. doi: 10.1097/DCR.0000000000002162. Online ahead of print.

ABSTRACT

BACKGROUND: With advances in medical care, patients with cystic fibrosis are more commonly living into adulthood yet there are limited data describing the need for gastrointestinal surgery and its outcomes in adult cystic fibrosis patients.

OBJECTIVE: We aim to use a national administrative database to evaluate trends in abdominal gastrointestinal surgery and associated postoperative outcomes among adult cystic fibrosis patients.

DESIGN: This was a national retrospective cohort study.

SETTING: A national all payor administrative database from 2000-2014 was used.

PATIENTS: Patients included all adult (age ≥18) patients with cystic fibrosis undergoing abdominal gastrointestinal surgery.

MAIN OUTCOME MEASURES: The primary outcome was trend over time in number of surgical admissions. Secondary outcomes included morbidity and mortality by procedure type.

RESULTS: We identified 3,075 admissions for abdominal surgery of which 28% were elective. Major GI surgical procedures increased over the study period (p<0.01) while appendectomy and cholecystectomy did not demonstrate a clear trend (p=0.90). The most common procedure performed was cholecystectomy (n=1,280; 42%). The most common major surgery was segmental colectomy (n=535; 18%). Obstruction was the most common surgical indication (n=780; 26%). For major surgery, in-hospital mortality was 6%, morbidity 37% and mean length of stay 15.9 days (SE 1.2).

LIMITATIONS: The study is limited by a lack of granular physiologic and clinical data within the administrative data source.

CONCLUSIONS: Major surgical admissions for adult patients with cystic fibrosis are increasing with the majority being non-elective. Major surgery is associated with significant morbidity, mortality and prolonged length of hospital stay. These findings may inform perioperative risk for adult patients with cystic fibrosis in need of gastrointestinal surgery. See Video Abstract at http://links.lww.com/DCR/B850.

PMID:35030557 | DOI:10.1097/DCR.0000000000002162

J Antimicrob Chemother. 2022 Jan 13:dkab479. doi: 10.1093/jac/dkab479. Online ahead of print.

ABSTRACT

BACKGROUND: Acquired antimicrobial resistance among Achromobacter isolates from cystic fibrosis (CF) patients is frequent. Data concerning the mechanisms involved are scarce. The role of the AxyXY-OprZ and AxyEF-OprN Resistance Nodulation Division (RND) efflux systems has been demonstrated, but not that of AxyABM.

OBJECTIVES: To explore the role of efflux systems in the acquired multiresistance observed in a one-step mutant selected after ofloxacin exposure.

METHODS: The in vitro resistant mutant NCF-39-Bo2 and its parental strain NCF-39 (MICs of meropenem of 8 and 0.19 mg/L, of ceftazidime of 12 and 3 mg/L, of cefiderocol of 0.094 and 0.032 mg/L and of ciprofloxacin of 8 and 1.5 mg/L, respectively) were investigated by RNA-seq and WGS. Gene inactivation and reverse transcription quantitative PCR (RT-qPCR) were used to explore the role of the efflux systems of interest.

RESULTS: RNA-seq showed that the AxyABM efflux system was overproduced (about 40-fold) in the in vitro mutant NCF-39-Bo2 versus its parental strain NCF-39. A substitution in AxyR, the putative regulator of AxyABM, was detected in NCF-39-Bo2. Gene inactivation of axyB (encoding the transporter component) in NCF-39-Bo2 led to a decrease in MICs of ciprofloxacin (5-fold), meropenem (64-fold), ceftazidime (12-fold) and cefiderocol (24-fold). Inactivation of axyB in the clinical isolate AXX-H2 harbouring a phenotype of resistance close to that of NCF-39-Bo2 enhanced the activity of the same molecules, especially meropenem.

CONCLUSIONS: AxyABM overproduction is involved in acquired resistance of Achromobacter to ciprofloxacin, meropenem and ceftazidime, antibiotics widely used in CF patients, and increases the MIC of the new promising antibiotic cefiderocol.

PMID:35029278 | DOI:10.1093/jac/dkab479

J Investig Allergol Clin Immunol. 2022 Jan 12:0. doi: 10.18176/jiaci.0780. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess the consensus level among a multidisciplinary expert panel on the transition of adolescents with severe asthma from pediatric to adult care.

METHODS: A 61-item survey was developed based on guidelines for other chronic pathologies, covering transition planning, preparation, effective transfer, and follow-up. A two-round Delphi process assessed the consensus level among 98 experts (49 pediatricians, 24 allergists and 25 pulmonologists). Consensus was established with ≥70% agreement.

RESULTS: Forty-two items (70%) reached consensus. No age range to initiate the transition was agreed upon by the panelists. The main goal to achieve during the transition identified by the experts is that adolescents gain autonomy to manage their severe asthma and prescribed treatments. The panelists agreed on the importance of developing an individualized plan, promoting patient's autonomy, and identifying home environment factors. They agreed that the adult healthcare team should have expertise in severe asthma, biologics and management of adolescent patients. Pediatric and adult healthcare teams should share clinical information, agree on the criteria to maintain the biological therapy, and have an on-site joint visit with the patient before the effective transfer. Adult healthcare professionals should closely follow the patient after the effective transfer to ensure correct inhaler technique, treatment adherence and attendance to healthcare appointments.

CONCLUSION: This consensus document provides the first roadmap for Spanish pediatric and adult teams to ensure that key aspects of the transition process in severe asthma are covered. The implementation of these recommendations will improve the quality of care offered to the patient.

PMID:35029151 | DOI:10.18176/jiaci.0780

Pediatr Pulmonol. 2022 Jan 13. doi: 10.1002/ppul.25830. Online ahead of print.

ABSTRACT

INTRODUCTION: Multiple breath washout (MBW) is used for early detection of cystic fibrosis (CF) lung disease, with SF6 MBW commonly viewed as the reference method. The use of N2 MBW in infants and toddlers has been questioned for technical and physiological reasons, but a newly correction of the N2 -signal has minimized the technical part. The present study aimed to assess the remaining differences and the contributing mechanisms for the differences between SF6 and N2 MBW,corrected - such as tidal volume reduction during N2 washout with pure O2 .

METHOD: This was a longitudinal multicenter cohort study. SF6 MBW and N2 MBW were performed prospectively at three CF centres in the same visits in 154 test occasions across 62 children with CF (mean age 22.7 months). Offline analysis using identical algorithms to the commercial available program provided outcomes of N2,original and N2,corrected for comparison with SF6 MBW.

RESULTS: Mean FRCN2,corrected was 14.3% lower than FRCN2,original , and 1.0% different from FRCSF6 . LCIN2,corrected was 25.2% lower than LCIN2,original , and 7.3% higher than LCISF6 . Mean (SD) tidal volume decreased significantly during N2 MBW,corrected compared to SF6 MBW (-13.1mL [-30.7; 4.6], p<0.0001, equal to -12.0% [-25.7; 1.73]), but this tidal volume reduction did not correlate to the differences between LCIN2,corrected and LCISF6 . The absolute differences in LCI increased significantly with higher LCISF6 (0.63/LCISF6 ) and (0.23/LCISF6 ) respectively for N2,original and N2,corrected , but the relative differences was stable across disease severity for N2,corrected , but not for N2,original .

CONCLUSION: Only minor residual differences between FRCN2,corrected and FRCSF6 remained showing that the two methods measure gas volumes very similar in this age range. Small differences in LCI were found. Tidal volume reduction during N2 MBW did not affect differences. The corrected N2 MBW can now be used with confidence in young children with CF, although not interchangeably with SF6 . This article is protected by copyright. All rights reserved.

PMID:35029068 | DOI:10.1002/ppul.25830

J Pharm Anal. 2021 Dec;11(6):732-738. doi: 10.1016/j.jpha.2021.02.004. Epub 2021 Feb 28.

ABSTRACT

Inhaled antibiotics such as colistin and ciprofloxacin are increasingly used to treat bacterial lung infections in cystic fibrosis patients. In this study, we established and validated a new HPLC-MS/MS method that could simultaneously detect drug concentrations of ciprofloxacin, colistin and ivacaftor in rat plasma, human epithelial cell lysate, cell culture medium, and drug transport media. An aliquot of 200 μL drug-containing rat plasma or cell culture medium was treated with 600 μL of extraction solution (acetonitrile containing 0.1% formic acid and 0.2% trifluoroacetic acid (TFA)). The addition of 0.2% TFA helped to break the drug-protein bonds. Moreover, the addition of 0.1% formic acid to the transport medium and cell lysate samples could significantly improve the response and reproducibility. After vortexing and centrifuging, the sample components were analyzed by HPLC-MS/MS. The multiple reaction monitoring mode was used to detect the following transitions: 585.5-101.1 (colistin A), 578.5-101.1 (colistin B), 393.2-337.2 (ivacaftor), 332.2-314.2 (ciprofloxacin), 602.3-101.1 (polymyxin B1 as internal standard (IS)) and 595.4-101.1 (polymyxin B2 as IS). The running time of a single sample was only 6 min, making this a time-efficient method. Linear correlations were found for colistin A at 0.029-5.82 μg/mL, colistin B at 0.016-3.14 μg/mL, ivacaftor at 0.05-10.0 μg/mL, and ciprofloxacin at 0.043-8.58 μg/mL. Accuracy, precision, and stability of the method were within the acceptable range. This method would be highly useful for research on cytotoxicity, animal pharmacokinetics, and in vitro drug delivery.

PMID:35028178 | PMC:PMC8740159 | DOI:10.1016/j.jpha.2021.02.004

BMJ Case Rep. 2022 Jan 13;15(1):e245238. doi: 10.1136/bcr-2021-245238.

ABSTRACT

Pseudomonas aeruginosa choroidal abscess is a rare condition which tends to affect patients with cystic fibrosis (CF) who have undergone double lung transplantation. Various surgical treatment strategies have been described but almost universally have had a dismal prognosis. We present a case of pseudomonas choroidal abscess in a CF patient with previous double lung transplantation who was managed with medical treatment, with intravitreal and systemic antibiotics, without surgical intervention, which led to successful resolution of the choroidal abscess, preservation of the eye and retention of vision.

PMID:35027377 | DOI:10.1136/bcr-2021-245238

Talanta. 2022 Jan 7;240:123210. doi: 10.1016/j.talanta.2022.123210. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa (P. aeruginosa), a ubiquitous opportunistic pathogen, can frequently cause chronic obstructive pulmonary disease, cystic fibrosis and chronic wounds, and potentially lead to severe morbidity and mortality. Timely and adequate treatment of nosocomial infection in clinic depends on rapid detection and accurate identification of P. aeruginosa and its early-stage antibiotic susceptibility test. Traditional methods like plating culture, polymerase chain reaction, and enzyme-linked immune sorbent assays are time-consuming and require expensive equipment, limiting the rapid diagnostic application. Advanced sensing strategy capable of fast, sensitive and simple detection with low cost has therefore become highly desired in point of care testing (POCT) of nosocomial pathogens. Within this review, advanced detection and sensing strategies for P. aeruginosa cells along with associated quorum sensing (QS) molecules over the last ten years are discussed and summarized. Firstly, the principles of four commonly used sensing strategies including localized surface plasmon resonance (LSPR), surface-enhanced Raman spectroscopy (SERS), electrochemistry, and fluorescence are briefly overviewed. Then, the advancement of the above sensing techniques for P. aeruginosa cells and its QS biomarkers detection are introduced, respectively. In addition, the integration with novel compatible platforms towards clinical application is highlighted in each section. Finally, the current achievements are summarized along with proposed challenges and prospects.

PMID:35026633 | DOI:10.1016/j.talanta.2022.123210

Int J Pharm. 2022 Jan 10:121457. doi: 10.1016/j.ijpharm.2022.121457. Online ahead of print.

ABSTRACT

Dry powder inhalation therapy has been shown to be an effective method for treating respiratory diseases like asthma, Chronic Obstructive Pulmonary Diseases and Cystic Fibrosis. It has also been widely accepted and used in clinical practices. Such success has led to great interest in inhaled therapy on treating systemic diseases in the past two decades. The current coronavirus (COVID-19) pandemic also has increased such interest and is triggering more potential applications of dry powder inhalation therapy in vaccines and antivirus drugs. Would the inhaled dry powder therapy on systemic disorders be as encouraging as expected? This paper reviews the marketed and in-development dry powder inhaler (DPI) products on the treatment of systemic diseases, their status in clinical trials, as well as the potential for COVID-19 treatment. The advancements and unmet problems on DPI systems are also summarized. With countless attempts behind and more challenges ahead, it is believed that the dry powder inhaled therapy for the treatment of systemic disorders still holds great potential and promise.

PMID:35026316 | DOI:10.1016/j.ijpharm.2022.121457

Curr Protoc. 2022 Jan;2(1):e341. doi: 10.1002/cpz1.341.

ABSTRACT

Human embryonic stem cells (ES) and induced pluripotent stem cells (iPSC) are powerful tools that have the potential to generate in vitro human lung epithelial cells. However, challenges in efficiency and reproducibility remain in utilizing the cells for therapy discovery platforms. Here, we optimize our previously published protocols to efficiently generate three developmental stages of the lung model (fetal lung epithelial progenitors, fLEP; immature airway epithelial spheroid, AES; air-liquid interface culture, ALI), and demonstrate its potential for cystic fibrosis (CF) drug discovery platforms. The stepwise approach directs differentiation from hPSC to definitive endoderm, anterior ventral foregut endoderm, and fetal lung progenitor cells. The article also describes the generation of immature airway epithelial spheroids in Matrigel with epithelial cells sorted by a magnetic-activated cell sorting system, and the generation of adult-like airway epithelia through air-liquid interface conditions. We demonstrate that this optimized procedure generates remarkably higher cystic fibrosis transmembrane conductance regulator (CFTR) expression and function than our previous method, and thus is uniquely suitable for CF research applications. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: hESC/hiPSC differentiation to fetal lung progenitors Basic Protocol 2: Formation of airway epithelial spheroids Alternate Protocol 1: Cryopreservation of airway epithelial spheroids Basic Protocol 3: Differentiation and maturation in air-liquid interface culture Alternate Protocol 2: Differentiation and maturation of epithelial progenitors from airway epithelial spheroids in ALI culture.

PMID:35025140 | DOI:10.1002/cpz1.341

Access Microbiol. 2021 Dec 7;3(12):000286. doi: 10.1099/acmi.0.000286. eCollection 2021.

ABSTRACT

Five hundred and thirty-four unrelated Pseudomonas aeruginosa isolates from inanimate habitats, patients with cystic fibrosis (CF) and other human infections were sequenced in 19 genes that had been identified previously as the hot spots of genomic within-host evolution in serial isolates from 12 CF lungs. Amplicon sequencing confirmed a significantly higher sequence diversity of the 19 loci in P. aeruginosa isolates from CF patients compared to those from other habitats, but this overrepresentation was mainly due to the larger share of synonymous substitutions. Correspondingly, non-synonymous substitutions were either rare (gltT, lepA, ptsP) or benign (nuoL, fleR, pelF) in some loci. Other loci, however, showed an accumulation of non-neutral coding variants. Strains from the CF habitat were often mutated at evolutionarily conserved positions in the elements of stringent response (RelA, SpoT), LPS (PagL), polyamine transport (SpuE, SpuF) and alginate biosynthesis (AlgG, AlgU). The strongest skew towards the CF lung habitat was seen for amino acid sequence variants in AlgG that clustered in the carbohydrate-binding/sugar hydrolysis domain. The master regulators of quorum sensing lasR and rhlR were frequent targets for coding variants in isolates from chronic and acute human infections. Unique variants in lasR showed strong evidence of positive selection indicated by d N/d S values of ~4. The pelA gene that encodes a multidomain enzyme involved in both the formation and dispersion of Pel biofilms carried the highest number of single-nucleotide variants among the 19 genes and was the only gene with a higher frequency of missense mutations in P. aeruginosa strains from non-CF habitats than in isolates from CF airways. PelA protein variants are widely distributed in the P. aeruginosa population. In conclusion, coding variants in a subset of the examined loci are indeed characteristic for the adaptation of P. aeruginosa to the CF airways, but for other loci the elevated mutation rate is more indicative of infections in human habitats (lasR, rhlR) or global diversifying selection (pelA).

PMID:35024551 | PMC:PMC8749138 | DOI:10.1099/acmi.0.000286

Front Cell Infect Microbiol. 2021 Dec 27;11:761596. doi: 10.3389/fcimb.2021.761596. eCollection 2021.

ABSTRACT

Scedosporium spp. are the second most prevalent filamentous fungi after Aspergillus spp. recovered from cystic fibrosis (CF) patients in various regions of the world. Although invasive infection is uncommon prior to lung transplantation, fungal colonization may be a risk factor for invasive disease with attendant high mortality post-transplantation. Abundant in the environment, Scedosporium aurantiacum has emerged as an important fungal pathogen in a range of clinical settings. To investigate the population genetic structure of S. aurantiacum, a MultiLocus Sequence Typing (MLST) scheme was developed, screening 24 genetic loci for polymorphisms on a tester strain set. The six most polymorphic loci were selected to form the S. aurantiacum MLST scheme: actin (ACT), calmodulin (CAL), elongation factor-1α (EF1α), RNA polymerase subunit II (RPB2), manganese superoxide dismutase (SOD2), and β-tubulin (TUB). Among 188 global clinical, veterinary, and environmental strains, 5 to 18 variable sites per locus were revealed, resulting in 8 to 23 alleles per locus. MLST analysis observed a markedly high genetic diversity, reflected by 159 unique sequence types. Network analysis revealed a separation between Australian and non-Australian strains. Phylogenetic analysis showed two major clusters, indicating correlation with geographic origin. Linkage disequilibrium analysis revealed evidence of recombination. There was no clustering according to the source of the strains: clinical, veterinary, or environmental. The high diversity, especially amongst the Australian strains, suggests that S. aurantiacum may have originated within the Australian continent and was subsequently dispersed to other regions, as shown by the close phylogenetic relationships between some of the Australian sequence types and those found in other parts of the world. The MLST data are accessible at http://mlst.mycologylab.org. This is a joined publication of the ISHAM/ECMM working groups on "Scedosporium/Pseudallescheria Infections" and "Fungal Respiratory Infections in Cystic Fibrosis".

PMID:35024355 | PMC:PMC8744116 | DOI:10.3389/fcimb.2021.761596

J Clin Transl Endocrinol. 2021 Dec 13;27:100283. doi: 10.1016/j.jcte.2021.100283. eCollection 2022 Mar.

ABSTRACT

Cystic fibrosis-liver disease (CFLD) is one of the most common non-pulmonary complications in the CF population, is associated with significant morbidity and represents the third leading cause of mortality in those with CF. CFLD encompasses a broad spectrum of hepatobiliary manifestations ranging from mild transaminitis, biliary disease, hepatic steatosis, focal biliary cirrhosis and multilobular biliary cirrhosis. The diagnosis of CFLD and prediction of disease progression remains a clinical challenge. The identification of novel CFLD biomarkers as well as the role of newer imaging techniques such as elastography to allow for early detection and intervention are active areas of research focus. Biliary cirrhosis with portal hypertension represents the most severe spectrum of CFLD, almost exclusively develops in the pediatric population, and is associated with a decline in pulmonary function, poor nutritional status, and greater risk of hospitalization. Furthermore, those with CFLD are at increased risk for vitamin deficiencies and endocrinopathies including CF-related diabetes, CF-related bone disease and hypogonadism, which can have further implications on disease outcomes and management. Effective treatment for CFLD remains limited and current interventions focus on optimization of nutritional status, identification and treatment of comorbid conditions, as well as early detection and management of CFLD specific sequelae such as portal hypertension or variceal bleeding. The extent to which highly effective modulator therapies may prevent the development or modify the progression of CFLD remains an active area of research. In this review, we discuss the challenges with defining and evaluating CFLD and the endocrine considerations and current management of CFLD.

PMID:35024343 | PMC:PMC8724940 | DOI:10.1016/j.jcte.2021.100283

Comput Struct Biotechnol J. 2021 Dec 15;20:175-186. doi: 10.1016/j.csbj.2021.12.008. eCollection 2022.

ABSTRACT

The default removal of low-abundance (rare) taxa from microbial community analyses may lead to an incomplete picture of the taxonomic and functional microbial potential within the human habitat. Publicly available shotgun metagenomics data of healthy children and children with cystic fibrosis (CF) were reanalysed to study the development of the rare species biosphere, which was here defined by either the 15th, 25th or 35th species abundance percentile. We found that healthy children contained an age-independent network of abundant (core) and rare species with both entities being essential in maintaining the network structure. The protein sequence usage for more than 100 bacterial metabolic pathways differed between the core and rare species biosphere. In CF children, the background structure was underdeveloped and random forest bootstrapping based on all constituents of the early airway metagenome and host-associated factors indicated that rare taxa were the most important variables in deciding whether a child was healthy or suffered from the life-limiting CF disease. Attempts failed to make the age-independent CF network as robust as the healthy structure when an increasing number of bacterial taxa from the healthy network was incorporated into the CF structure by computer-based model simulations. However, the transfer of a key combination of taxa from the healthy to the CF network structure with high species diversity and low species dominance, correlated with a more robust CF network and a topological approximation of CF and healthy graph structures. Rothia mucilaginosa, Streptococci and rare species were essential in improving the underdeveloped CF network.

PMID:35024091 | PMC:PMC8713036 | DOI:10.1016/j.csbj.2021.12.008

Am J Respir Crit Care Med. 2022 Jan 12. doi: 10.1164/rccm.202106-1426OC. Online ahead of print.

ABSTRACT

RATIONALE: Cystic Fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene and is characterized by sustained inflammation. Adenosine-5'-Triphosphate (ATP) triggers interleukin (IL)-1β secretion via the P2X7 receptor (P2X7R) and activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome.

OBJECTIVES: To explore the effect of the CFTR modulator Trikafta (Elexacaftor/Tezacaftor/Ivacaftor) on CFTR expression and the ATP/P2X7R signaling axis in monocytes and on circulating pro-inflammatory markers.

METHODS: Inflammatory mediators were detected in blood from 42 patients with CF (PWCF) before and after 3 months of Trikafta therapy. Markers of inflammasome activation and IL-1β secretion were measured in monocytes, and following stimulation with ATP and lipopolysaccharides (LPS) in the presence or absence of the P2X7R inhibitor, A438079.

MEASUREMENTS AND MAIN RESULTS: P2X7R is overexpressed in CF monocytes and receptor inhibition decreased NLRP3 expression, caspase-1 activation, and IL-1β secretion. In vitro and in vivo, P2X7R expression is regulated by CFTR function and intracellular chloride (Cl-) levels. Trikafta therapy restored CFTR expression yet decreased P2X7R in CF monocytes, resulting in normalized Cl- and potassium efflux, and reduced intracellular calcium levels. CFTR modulator therapy decreased circulating levels of ATP and LPS and reduced inflammasome activation and IL-1β secretion.

CONCLUSIONS: P2X7R expression is regulated by intracellular Cl- levels, and in CF monocytes promotes inflammasome activation. Trikafta therapy significantly increased CFTR protein expression and reduced ATP/P2X7R -induced inflammasome activation. P2X7R may therefore be a promising target to reduce inflammation in PWCF non-eligible for Trikafta or other CFTR modulator therapy.

PMID:35021019 | DOI:10.1164/rccm.202106-1426OC