J Heart Lung Transplant. 2021 Feb 5:S1053-2498(21)01999-9. doi: 10.1016/j.healun.2021.01.1965. Online ahead of print.

ABSTRACT

BACKGROUND: Operating room (OR) extubation has been reported after lung transplantation (LT) in small cohorts. This study aimed to evaluate the prognosis of OR-extubated patients. The secondary objectives were to evaluate the safety of this approach and to identify its predictive factors.

METHODS: This retrospective single-center cohort study included patients undergoing double lung transplantation (DLT) from January 2012 to June 2019. Patients undergoing multiorgan transplantation, repeat transplantation, or cardiopulmonary bypass during the study period were excluded. OR-extubated patients were compared with intensive care unit (ICU)-extubated patients.

RESULTS: Among the 450 patients included in the analysis, 161 (35.8%) were extubated in the OR, and 4 were reintubated within 24 hours. Predictive factors for OR extubation were chronic obstructive pulmonary disease (COPD)/emphysema (p = .002) and cystic fibrosis (p = .005), recipient body mass index (p = .048), and the PaO2/FiO2 ratio 10 minutes after second graft implantation (p < .001). OR-extubated patients had a lower prevalence of grade 3 primary graft dysfunction at day 3 (p < .001). Eight (5.0%) patients died within the first year after OR extubation, and 49 (13.5%) patients died after ICU extubation (log-rank test; p = .005). After adjustment for OR extubation predictive factors, the multivariate Cox regression model showed that OR extubation was associated with greater one-year survival (adjusted hazard ratio = 0.40 [0.16-0.91], p = .028).

CONCLUSIONS: OR extubation was associated with a favorable prognosis after DLT, but the association should not be interpreted as causality. This fast-track protocol was made possible by a team committed to developing a comprehensive strategy to enhance recovery.

PMID:33632637 | DOI:10.1016/j.healun.2021.01.1965

Nutr Metab Cardiovasc Dis. 2020 Dec 17:S0939-4753(20)30520-2. doi: 10.1016/j.numecd.2020.12.011. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: During aerobic physical activity (PA), hypoglycemia is common in people with type 1 diabetes (T1D). Few studies have compared the effectiveness of different carbohydrate (CHO) intake strategies to prevent PA-induced hypoglycemia. Our objective was to compare the efficacy of two CHO intake strategies, same total amount but different CHO intake timing, to maintain glucose levels in the target range (4.0-10.0 mmol/L) during PA in people with T1D.

METHODS AND RESULTS: An open-label, randomized, crossover study in 33 participants (21 adults; 12 adolescents). Participants practiced 60 min PA sessions (ergocyle) at 60% VO2peak 3.5 h after lunch comparing an intake of 0.5 g of CHO per kg of body weight applied in a pre-PA single CHO intake (SCI) or in a distributed CHO intake (DCI) before and during PA. The percentage of time spent in glucose level target range during PA was not different between the two strategies (SCI: 75 ± 35%; DCI: 87 ± 26%; P = 0.12). Hypoglycemia (<4.0 mmol/L) occurred in 4 participants (12%) with SCI compared to 6 participants (18%) with DCI (P = 0.42). The SCI strategy led to a higher increase (P = 0.01) and variability of glucose levels (P = 0.04) compared with DCI.

CONCLUSIONS: In people living with T1D, for a 60 min moderate aerobic PA in the post-absorptive condition, a 0.5 g/kg CHO intake helped most participants maintain acceptable glycemic control with both strategies. No clinically significant difference was observed between the SCI and DCI strategies. ClinicalTrials.gov Identifier: NCT03214107 (July 11, 2017).

PMID:33632598 | DOI:10.1016/j.numecd.2020.12.011

J Breath Res. 2021 Feb 25;15(2):026012. doi: 10.1088/1752-7163/abda55.

ABSTRACT

In patients with cystic fibrosis (CF), pulmonary exacerbations (PEx) have an important influence on well-being, quality of life, and lung function decline. Early detection combined with early treatment may prevent severe PEx. To determine whether early detection of PEx is possible by non-invasive markers (volatile organic compounds) in exhaled breath. In a 1 year prospective observational pilot study, 49 children with CF were studied. At clinical visits with an interval of 2 months, lung function, volatile organic compounds (VOCs) in exhaled breath by means of gas chromatography-time-of-flight-mass spectrometry, and medication use were assessed. PEx were recorded. Random forest (RF) classification modelling was used to select discriminatory VOCs, followed by building of receiver operating characteristic curves. An inverse relation between the predictive power of a set of VOCs and time between exhaled breath sampling and the onset of PEx was found. When this time period was within 7 d, the RF model with the nine most discriminatory VOCs was able to correctly predict 79% of the children with an upcoming PEx or remaining stable (sensitivity 79% and specificity 78%). This result was validated by means of bootstrapping within the RF classification model. PEx in children with CF can be detected at an early stage by means of exhaled VOCs. The highest predictive value was reached if time between sampling and the onset of an exacerbation was no longer than 7 d.

PMID:33630756 | DOI:10.1088/1752-7163/abda55

Cell Rep. 2021 Feb 23;34(8):108782. doi: 10.1016/j.celrep.2021.108782.

ABSTRACT

In cystic fibrosis (CF) airways, Pseudomonas aeruginosa forms cellular aggregates called biofilms that are thought to contribute to chronic infection. To form aggregates, P. aeruginosa can use different mechanisms, each with its own pathogenic implications. However, how they form in vivo is controversial and unclear. One mechanism involves a bacterially produced extracellular matrix that holds the aggregates together. Pel and Psl exopolysaccharides are structural and protective components of this matrix. We develop an immunohistochemical method to visualize Pel and Psl in CF sputum. We demonstrate that both exopolysaccharides are expressed in the CF airways and that the morphology of aggregates is consistent with an exopolysaccharide-dependent aggregation mechanism. We reason that the cationic exopolysaccharide Pel may interact with some of the abundant anionic host polymers in sputum. We show that Pel binds extracellular DNA (eDNA) and that this interaction likely impacts current therapies by increasing antimicrobial tolerance and protecting eDNA from digestion.

PMID:33626358 | DOI:10.1016/j.celrep.2021.108782

Med Ultrason. 2021 Feb 1. doi: 10.11152/mu-3058. Online ahead of print.

ABSTRACT

Ultrasound (US) is an ideal diagnostic tool for paediatric patients owning to its high spatial and temporal resolution, real-time imaging, and lack of ionizing radiation and bedside availability. The lack of superficial adipose tissue and favorable acoustic windows in children makes US the first line of investigation for the evaluation of pleural and chest wall abnormali-ties. Lung parenchyma was previously thought to be inaccessible to ultrasound due to the presence of the air and bony thorax. The change in attitude and growing awareness of the diagnostic possibilities has led to lung ultrasound (LUS) being accepted as a valuable point of care method. In addition, the application of LUS has widened with improvements in technology such as higher resolution transducers, harmonic imaging and contrast-enhanced ultrasound. In the current World Federation of Societies for Ultrasound in Medicine and Biology (WFUMB) paper series the topic will be introduced, the technical requirements explained and the use of ultrasound in the lung and pleura in pediatric patients are discussed.

PMID:33626123 | DOI:10.11152/mu-3058

Pharmgenomics Pers Med. 2020 Dec 1;13:679-686. doi: 10.2147/PGPM.S278806. eCollection 2020.

ABSTRACT

PURPOSE: Cystic fibrosis (CF) is one of the most common monogenic diseases with an autosomal recessive inheritance. Carrier screening leads to a reduction in the number of children born with CF disease. The aim of this study was to develop the custom panel for the diagnosis of heterozygous carriage of polymorphic variants in the CFTR gene and to establish their allelic frequencies (AF) in one of the Russian regions where ethnic Russians predominate.

PATIENTS AND METHODS: The diagnostic panel was designed on the basis of data from the register of CF patients in Russia for 2017 and validated on 22 blood samples of patients with previously genetically established CF. The study participants (n=642) for CF variants estimation were randomly selected from the population-based cohort study ESSE-Vologda. Genotypes were determined by real-time PCR on the QuantStudio 12K Flex Real-Time PCR System. Data processing was performed using the TaqMan Genotyper Software.

RESULTS: The proposed diagnostic panel allowed simultaneous analysis of 60 variants of the CFTR gene. A total of 23 carriers of the following variants were identified among 642 participants: F508del (rs113993960) with a frequency of 2.02%, L138ins (rs397508686) and 394delTT (rs121908769) - 0.47%, CFTRdele2.3 (c.54-5940_273+10250del21080; p.S18Rfs*16) - 0.31%, R117H (rs78655421), and G542X (rs113993959) - 0.16%. The frequency of heterozygotes in the Russian population was 3.58% or 1:28 (CI95%: 2.28-5.33% by Clopper-Pearson exact method).

CONCLUSION: High frequency of heterozygous CFTR variants carriers and availability of highly productive diagnostic panel for detection of CFTR variants suggest the prospect of carrier screening for some common CF variants among Russian population.

PMID:33623413 | PMC:PMC7894124 | DOI:10.2147/PGPM.S278806

BMJ Open Respir Res. 2021 Feb;8(1):e000861. doi: 10.1136/bmjresp-2020-000861.

ABSTRACT

INTRODUCTION: The incubation of airway epithelia cells at low temperatures is a common in vitro experimental approach used in the field of cystic fibrosis (CF) research to thermo-stabilise F508del-CFTR and increase its functional expression. Given that the airway epithelium includes numerous ion transporters other than CFTR, we hypothesised that there was an impact of low temperature incubation on CFTR-independent ionoregulatory mechanisms in airway epithelia derived from individuals with and without CF.

METHODS: After differentiation at the air-liquid interface, nasal epithelia were incubated at either 37°C or 29°C (low temperature) for 48 hours prior to analysis in an Ussing chamber.

RESULTS: While F508del-CFTR activity was increased after low temperature incubation, activity of CFTR in non-CF epithelia was unchanged. Importantly, cultures incubated at 29°C demonstrated decreased transepithelial potential difference (TEPD) and short-circuit currents (Isc) at baseline. The predominant factor contributing to the reduced baseline TEPD and Isc in 29°C cultures was the reduced activity of the epithelial sodium channel (ENaC), evidenced by a reduced responsiveness to amiloride. This effect was observed in cells derived from both non-CF and CF donors.

DISCUSSION: Significant transcriptional downregulation of ENaC subunits β and γ were observed, which may partially explain the decreased ENaC activity. We speculate that low temperature incubation may be a useful experimental paradigm to reduce ENaC activity in in vitro epithelial cultures.

PMID:33622672 | DOI:10.1136/bmjresp-2020-000861

Predictors of starting antimicrobial treatment in patients with nontuberculous mycobacterial lung disease in the Italian scenario: A SITA GIOVANI-IRENE promoted web-survey.

Respir Med. 2021 Feb 15;179:106341

Authors: Lombardi A, Colaneri M, Sambo M, Di Matteo A, Sacchi P, Fabbiani M, Codecasa L, Aliberti S, Blasi F, Bandera A, Bruno R, Gori A

Abstract
The disease burden due to nontuberculous mycobacteria is growing worldwide, consequently to improved diagnostic abilities and an increase in the individuals at risk. Uncertainties exist about the right moment on which start treatment. We investigated the clinical features associated with starting an antimicrobial treatment in patients with nontuberculous mycobacterial lung disease among Italian physicians involved in the field. We found that in real life predictors of starting antimicrobial treatment are quite adherent to international guidelines, with some uncertainties regarding the implication of immunosuppressive drugs.

PMID: 33618080 [PubMed - as supplied by publisher]

Interval versus constant-load exercise training in adults with Cystic Fibrosis.

Respir Physiol Neurobiol. 2021 Feb 19;:103643

Authors: Kaltsakas G, Chynkiamis N, Anastasopoulos N, Zeliou P, Karapatoucha V, Kotsifas K, Diamantea F, Inglezos I, Koulouris NG, Vogiatzis I

Abstract
BACKGROUND: The efficacy of interval exercise (IE) compared to constant-load exercise (CLE) training remains unsettled in adults with Cystic Fibrosis (CF).
METHODS: Twenty-four adults with CF were randomised to 30-min IE (100% peak work capacity (WRpeak) for 30-s alternated with 40% WRpeak for 30-s; n = 12) or 30-min CLE (70% WRpeak; n = 12) training, 3 times weekly, for 12 weeks. Isometric quadriceps muscle strength was assessed using a strain gauge Myometer.
RESULTS: The magnitude of improvement in quadriceps muscle strength was greater (p = 0.037) in the IE (by 32 ± 13 Nm) compared to the CLE (by 23 ± 12 Nm) groups. Maximum inspiratory and expiratory mouth pressures were significantly improved only in the IE group (by 30 ± 10 cmH2O; p = 0.009 and 13 ± 4 cmH2O; p = 0.007, respectively). Arterial oxygen saturation during training was higher (p = 0.002) for IE (94 ± 1%) compared to CLE (91 ± 1%), whereas dyspnoea scores were lower (p = 0.001) for IE (3.8 ± 0.7) compared to CLE (5.9 ± 0.8) CONCLUSIONS: IE is superior to CLE in improving peripheral and respiratory muscle strength and preferable to CLE because it is associated with lower exercise-induced arterial oxygen desaturation and breathlessness.

PMID: 33618051 [PubMed - as supplied by publisher]

Clinical characteristics associated with lung function decline in individuals with adult-diagnosed cystic fibrosis: Contemporary analysis of the Canadian CF Registry.

Chest. 2021 Feb 19;:

Authors: Desai S, Stanojevic S, Lam GY, Stephenson AL, Quon BS

Abstract
BACKGROUND: Individuals diagnosed with cystic fibrosis (CF) as adults represent a rare but growing subset of the CF population; there are limited studies describing their lung function trajectories.
RESEARCH QUESTION: What is the overall trajectory of lung function and clinical characteristics associated with lung function decline in people diagnosed with CF as adults?
STUDY DESIGN: and Methods: The Canadian CF Patient Registry was used to identify patients with CF who were ≥18 years of age at diagnosis and received a diagnosis between 2000 and 2017. Linear mixed effects models were used to quantify the change in lung function over age and to examine clinical characteristics associated with lung function decline.
RESULTS: Lung function was stable in early adulthood, with a decline in middle adulthood (age 30 to 50), and a greater decline after the age of 50. Individuals diagnosed at older ages (>50 years: slope of -0.71%/year, 41 to 50: -0.68%/year, 31 to 40: -0.29%/year, 18 to 30: -0.28%/year) and those presenting with pulmonary symptoms (slope of -0.41%/year) compared with no pulmonary symptoms at baseline were associated with faster rate of lung function decline.
INTERPRETATION: The lung function of adult-diagnosed CF individuals in the Canadian CF registry declines slowly compared to estimates from the overall adult CF population. Adult-diagnosed individuals who are older and present with pulmonary symptoms at diagnosis experience a faster rate of lung function decline and should be monitored more closely.

PMID: 33617807 [PubMed - as supplied by publisher]

Functional relationship between CFTR and RAC3 expression for maintaining cancer cell stemness in human colorectal cancer.

Cell Oncol (Dordr). 2021 Feb 22;:

Authors: Palma AG, Soares Machado M, Lira MC, Rosa F, Rubio MF, Marino G, Kotsias BA, Costas MA

Abstract
PURPOSE: CFTR mutations not only cause cystic fibrosis, but also increase the risk of colorectal cancer. A putative role of CFTR in colorectal cancer patients without cystic fibrosis has so far, however, not been investigated. RAC3 is a nuclear receptor coactivator that has been found to be overexpressed in several human tumors, and to be required for maintaining cancer stemness. Here, we investigated the functional relationship between CFTR and RAC3 for maintaining cancer stemness in human colorectal cancer.
METHODS: Cancer stemness was investigated by analysing the expression of stem cell markers, clonogenic growth and selective retention of fluorochrome, using stable transfection of shCFTR or shRAC3 in HCT116 colorectal cancer cells. In addition, we performed pathway enrichment and network analyses in both primary human colorectal cancer samples (TCGA, Xena platform) and Caco-2 colorectal cancer cells including (1) CD133+ or CD133- side populations and (2) CFTRwt or CFTRmut cells (ConsensusPathDB, STRING, Cytoscape, GeneMANIA).
RESULTS: We found that the CD133+ side population expresses higher levels of RAC3 and CFTR than the CD133- side population. RAC3 overexpression increased CFTR expression, whereas CFTR downregulation inhibited the cancer stem phenotype. CFTR mRNA levels were found to be increased in colorectal cancer samples from patients without cystic fibrosis compared to those with CFTR mutations, and this correlated with an increased expression of RAC3. The expression pattern of a gene set involved in inflammatory response and nuclear receptor modulation in CD133+ Caco-2 cells was found to be shared with that in CFTRwt Caco-2 cells. These genes may contribute to colorectal cancer development.
CONCLUSIONS: CFTR may play a non-tumor suppressor role in colorectal cancer development and maintenance involving enhancement of the expression of a set of genes related to cancer stemness and development in patients without CFTR mutations.

PMID: 33616840 [PubMed - as supplied by publisher]

Novel Correctors and Potentiators Enhance Functional Rescue of CFTR Nonsense Mutation Translational Readthrough.

Am J Respir Cell Mol Biol. 2021 Feb 22;:

Authors: Mutyam V, Sharma J, Li Y, Peng N, Chen J, Tang LP, Falk Libby E, Singh AK, Conrath K, Rowe SM

Abstract
Premature termination codons (PTCs) in cystic fibrosis transmembrane conductance regulator (CFTR) result in nonfunctional CFTR protein and are the proximate cause of ~11% of CF-causing alleles for which no treatments exist. CFTR corrector, lumacaftor and the potentiator ivacaftor improve CFTR function with terminal PTC mutations, and enhance the effect of readthrough agents. Novel correctors GLPG2222 (C1), GLPG3221 (C2), and potentiator GLPG1837 compare favorably to lumacaftor and ivacaftor in vitro. Here, we evaluated the effect of correctors C1a and C2a (derivatives of C1 and C2) and GLPG1837 alone or in combination with the readthrough compound G418, on CFTR function using heterologous FRT, genetically engineered 16HBE14o-, and primary human cells with PTC mutations. In FRT lines pretreated with G418, GLPG1837 elicited dose-dependent increases in CFTR activity that exceeded ivacaftor in FRT-W1282X and FRT-R1162X. A three-mechanism strategy consisting of G418, GLPG1837, and two correctors (C1a+C2a) yielded the greatest functional improvements in FRT and 16HBE14o- PTC variants, noting correction and potentiation without readthrough was sufficient to stimulate CFTR activity for W1282X. GLPG1837+C1a+C2a restored substantial function in G542X/F508del human bronchial epithelial cells and even more for W1282X/F508del, largely due to the corrector/potentiator effect with no additional benefit from G418. In G542X/R553X or R1162X/R1162X organoids, enhanced forskolin induced swelling (FIS) was observed with G418+GLPG1837+C1a+C2a although GLPG1837+C1a+C2a alone was sufficient to improve FIS in W1282X/W1282X organoids. Combination of CFTR correctors, potentiators and readthrough compounds augments the functional repair of CFTR nonsense mutations, indicating the potential for novel correctors and potentiators to restore function to truncated W1282X CFTR.

PMID: 33616476 [PubMed - as supplied by publisher]

Change in circulating proteins during treatment of pulmonary exacerbation in patients with cystic fibrosis.

Health Sci Rep. 2021 Mar;4(1):e246

Authors: Wagner BD, Berkalieva A, Borges M, Fleming G, Graham N, Peterson E, Jin X, Zemanick ET

PMID: 33614983 [PubMed]

What is important for people with nontuberculous mycobacterial disease? An EMBARC-ELF patient survey.

ERJ Open Res. 2021 Jan;7(1):

Authors: Shteinberg M, Boyd J, Aliberti S, Polverino E, Harris B, Berg T, Posthumus A, Ruddy T, Goeminne P, Lloyd E, Alan T, Altenburg J, Crossley B, Blasi F, Chalmers J

Abstract
Patients' experiences of NTM pulmonary disease highlight important and unmet needs for better pharmacological treatment and education of medical staff https://bit.ly/3mjrlwh.

PMID: 33614773 [PubMed]

Williams-Campbell syndrome: an unusual presentation in an adult patient.

BJR Case Rep. 2021 Feb 01;7(1):20200052

Authors: Rohilla M, Previgliano C, Geimadi A, Sangster G

Abstract
Objective: Williams-Campbell syndrome (WCS) is a rare congenital disorder, which leads to bronchiectasis affecting fourth to sixth order of bronchial divisions. Symptoms include cough, sputum, wheeze and recurrent pulmonary infections, classically seen in the paediatric age group with selective bronchiectasis of the mid-order bronchioles. The literature describing diagnosis of Williams-Campbell syndrome in adult population is very sparse.
Methods: This report presents a 62-year-old female with cough, fever, dyspnea and generalized body ache. She has had multiple admissions to the hospital since her childhood due to recurrent lower respiratory tract infections. Imaging findings demonstrated multiple cystic thin walled airways, compatible with bronchiectatic changes in the upper, middle and lower lobes bilaterally, bronchial wall thickening with air-fluid levels prominent in the fifth and sixth generation bronchial divisions, with normal calibre trachea and central bronchi. These radiological findings are consistent with diagnosis of Williams-Campbell syndrome, which was diagnosed after ruling out the other common causes of bronchiectasis.
Conclusion: Williams-Campbell syndrome is a rare congenital cystic lung disease, the diagnosis of which is made by exclusion of common causes of bronchiectasis such as cystic fibrosis, allergic bronchopulmonary aspergillosis, tuberculosis, dyskinetic cilia syndrome and alpha-1 antitrypsin deficiency. Whenever the clinical picture is consistent with bronchiectasis, especially involving the mid-order bronchioles and recurrent pulmonary infections, it is wise to include WCS in the list of differential diagnoses, even in the adult population.

PMID: 33614112 [PubMed]

Next-Generation Sequencing for Molecular Diagnosis of Cystic Fibrosis in a Brazilian Cohort.

Dis Markers. 2021;2021:9812074

Authors: Cambraia A, Junior MC, Zembrzuski VM, Junqueira RM, Cabello PH, de Cabello GMK

Abstract
Cystic fibrosis (CF), an autosomal recessive genetic disease, is recognized as one of the most prevalent diseases in Caucasian populations. Epidemiological data show that the incidence of CF varies between countries and ethnic groups in the same region. CF occurs due to pathogenic variants in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR), located on chromosome 7q31.2. To date, more than 2,000 variants have been registered in the CFTR database. The study of these variants leads to the diagnosis and the possibility of a specific treatment for each patient through precision medicine. In this study, complete screening of CFTR was performed through next-generation sequencing (NGS) to gain insight into the variants circulating in the population of Rio de Janeiro and to provide patient access to treatment through genotype-specific therapies. Samples from 93 patients with an inconclusive molecular diagnosis were subjected to full-length screening of CFTR using an Illumina NGS HiSeq platform. Among these patients, 46 had two pathogenic variants, whereas 12 had only one CFTR variant. Twenty-four variants were not part of our routine screening. Of these 24 variants, V938Gfs∗37 had not been described in the CF databases previously. This research achieved a molecular diagnosis of the patients with CF and identification of possible molecular candidates for genotype-specific treatments.

PMID: 33613790 [PubMed - in process]

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells.

Front Physiol. 2021;12:619442

Authors: Veltman M, De Sanctis JB, Stolarczyk M, Klymiuk N, Bähr A, Brouwer RW, Oole E, Shah J, Ozdian T, Liao J, Martini C, Radzioch D, Hanrahan JW, Scholte BJ

Abstract
A deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) function in CF leads to chronic lung disease. CF is associated with abnormalities in fatty acids, ceramides, and cholesterol, their relationship with CF lung pathology is not completely understood. Therefore, we examined the impact of CFTR deficiency on lipid metabolism and pro-inflammatory signaling in airway epithelium using mass spectrometric, protein array. We observed a striking imbalance in fatty acid and ceramide metabolism, associated with chronic oxidative stress under basal conditions in CF mouse lung and well-differentiated bronchial epithelial cell cultures of CFTR knock out pig and CF patients. Cell-autonomous features of all three CF models included high ratios of ω-6- to ω-3-polyunsaturated fatty acids and of long- to very long-chain ceramide species (LCC/VLCC), reduced levels of total ceramides and ceramide precursors. In addition to the retinoic acid analog fenretinide, the anti-oxidants glutathione (GSH) and deferoxamine partially corrected the lipid profile indicating that oxidative stress may promote the lipid abnormalities. CFTR-targeted modulators reduced the lipid imbalance and oxidative stress, confirming the CFTR dependence of lipid ratios. However, despite functional correction of CF cells up to 60% of non-CF in Ussing chamber experiments, a 72-h triple compound treatment (elexacaftor/tezacaftor/ivacaftor surrogate) did not completely normalize lipid imbalance or oxidative stress. Protein array analysis revealed differential expression and shedding of cytokines and growth factors from CF epithelial cells compared to non-CF cells, consistent with sterile inflammation and tissue remodeling under basal conditions, including enhanced secretion of the neutrophil activator CXCL5, and the T-cell activator CCL17. However, treatment with antioxidants or CFTR modulators that mimic the approved combination therapies, ivacaftor/lumacaftor and ivacaftor/tezacaftor/elexacaftor, did not effectively suppress the inflammatory phenotype. We propose that CFTR deficiency causes oxidative stress in CF airway epithelium, affecting multiple bioactive lipid metabolic pathways, which likely play a role in CF lung disease progression. A combination of anti-oxidant, anti-inflammatory and CFTR targeted therapeutics may be required for full correction of the CF phenotype.

PMID: 33613309 [PubMed]

Outcomes of cystic fibrosis pulmonary exacerbations treated with antibiotics with activity against anaerobic bacteria.

J Cyst Fibros. 2021 Feb 18;:

Authors: Castner LM, Zimbric M, Cahalan S, Powell C, Caverly LJ

Abstract
BACKGROUND: Obligate and facultative anaerobic bacteria are prevalent in cystic fibrosis (CF) airways. Increases in anaerobe relative abundance have been associated with CF pulmonary exacerbations (PEx); however, the impact of antibiotic treatment of anaerobes during PEx is unknown. We hypothesized that PEx treated with antibiotics with activity against anaerobes would improve outcomes compared to antibiotics without anaerobic activity.
METHODS: This was a single-center, retrospective study of people with CF, ages 6 years and older, treated with intravenous (IV) antibiotics for PEx. IV antibiotics were classified as either broad or minimal anaerobic activity. PEx treated with broad anaerobe coverage were propensity-score matched to PEx treated with minimal anaerobic coverage. The primary outcome, % of baseline % predicted forced expiratory volume in one second (ppFEV1) recovered, was compared between antibiotic categories with a linear mixed model. The secondary outcome, time to next PEx, was assessed using a Prentice Williams Petersen model.
RESULTS: 514 PEx from 182 patients were included. Broad anaerobe coverage was used in 27% of PEx, and was used more often for older patients (p < 0.001) with worse baseline ppFEV1 (p < 0.001), and with Achromobacter (p < 0.001) or Burkholderia infections (p = 0.002). In the matched PEx, broad anaerobe coverage was not a significant predictor of % of baseline ppFEV1 recovered (∆ppFEV1 = -2.4, p = 0.09). Broad anaerobe coverage was also not a significant predictor of time to next PEx (HR 0.89, 95% CI 0.7-1.13, p = 0.35).
CONCLUSIONS: In this single center, retrospective study, antibiotics with broad activity against anaerobes were not associated with improved outcomes of CF PEx.

PMID: 33612403 [PubMed - as supplied by publisher]

Pediatr Pulmonol. 2021 Feb 23. doi: 10.1002/ppul.25251. Online ahead of print.

ABSTRACT

BACKGROUND: Prior studies have estimated healthcare costs for cystic fibrosis (CF) of $8000-$131,000, but do not account for impacts of CF modulator therapy. This study aims to assess utilization patterns and cost of CF care in a center in the United States.

METHODS: Care utilization patterns and costs at a large pediatric-adult CF center were examined from November 2017 to November 2018. Subjects were stratified by age and cost (excluding pharmacy costs) were calculated based on hospital-derived utilization charges.

RESULTS: A total of 166 patients were reviewed with mean clinical charges of $28,755. Lower lung function ($23,032 normal lung function, $62,293 moderate reduction, $186,786 severe reduction; p = .05), hospitalizations ($85,452 yes, $6362 no; p = .0001), Pseudomonas positive culture ($48,660 positive, $22,013 negative, p = .0001), and CF-related diabetes ($161,892 CFRD, $22,153 no CFRD; p = .001) were associated with increased charges. Patients utilizing Ivacaftor had lower charges compared to lumacaftor-ivacaftor ($6633 vs. $33,039; p = .05) and tezacaftor-ivacaftor ($6633 vs. $64,434; p = .002).

CONCLUSION: Our study characterized utilization and care charges among a CF cohort. Lower lung function, hospitalizations, and CFRD were associated with increased charges.

PMID:33621440 | DOI:10.1002/ppul.25251

Aging (Albany NY). 2021 Feb 17;13. doi: 10.18632/aging.202537. Online ahead of print.

ABSTRACT

Renal tubules are vulnerable targets of various factors causing kidney injury in diabetic kidney disease (DKD), and the degree of tubular lesions is closely related to renal function. Abnormal renal tubular epithelial cells (RTECs) differentiation and depletion of cell junction proteins are important in DKD pathogenesis. Caudal-type homeobox transcription factor 2 (CDX2), represents a key nuclear transcription factor that maintains normal proliferation and differentiation of the intestinal epithelium. The present study aimed to evaluate the effects of CDX2 on RTECs differentiation and cell junction proteins in DKD. The results demonstrated that CDX2 was mainly localized in renal tubules, and downregulated in various DKD models. CDX2 upregulated E-cadherin and suppressed partial epithelial-mesenchymal transition (EMT), which can alleviate hyperglycemia-associated RTECs injury. Cystic fibrosis transmembrane conductance regulator (CFTR) was regulated by CDX2 in NRK-52E cells, and CFTR interfered with β-catenin activation by binding to Dvl2, which is an essential component of Wnt/β-catenin signaling. CFTR knockdown abolished the suppressive effects of CDX2 on Wnt/β-catenin signaling, thereby upregulating cell junction proteins and inhibiting partial EMT in RTECs. In summary, CDX2 can improve renal tubular lesions during DKD by increasing CFTR amounts to suppress the Wnt/β-catenin signaling pathway.

PMID:33621200 | DOI:10.18632/aging.202537