J Antimicrob Chemother. 2021 Jul 20:dkab222. doi: 10.1093/jac/dkab222. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine the activity of murepavadin in comparison with tobramycin, colistin and aztreonam, against cystic fibrosis (CF) Pseudomonas aeruginosa isolates growing in biofilms. The biofilm-epidemiological cut-off (ECOFF) values that include intrinsic resistance mechanisms present in biofilms were estimated.

METHODS: Fifty-three CF P. aeruginosa isolates from respiratory samples were tested using the Calgary (closed system) device, while 4 [2 clinical (one smooth, one mucoid) and 2 reference strains] were tested using the BioFlux, a microfluidic open model of biofilm testing. Biofilm was stained with SYTO9® and propidium iodide. The minimal biofilm inhibitory concentration (MBIC) and the minimal biofilm eradication concentration (MBEC) were determined. The MBIC-ECOFF and the MBEC-ECOFF were calculated.

RESULTS: Colistin, tobramycin and murepavadin presented similar MBIC50/MBIC90 values (4/32, 8/64 and 2/32, respectively). Murepavadin exhibited the lowest MBEC90 (64 mg/L). Aztreonam MBIC and MBEC values were higher than those of the other antibiotics tested. Tobramycin and murepavadin had the lowest MBEC-ECOFF (64 and 128 mg/L, respectively), while those of aztreonam and colistin exceeded 512 mg/L. Using the BioFlux, for the PAO1, PAO mutS and the smooth clinical strain, a significant difference (P < 0.0125) was observed when comparing the fluorescence of treated and untreated biofilms. For the mucoid strain, only the biofilm treated with aztreonam (MBIC and MBEC) and tobramycin (MBEC) showed differences with respect to the untreated biofilm.

CONCLUSIONS: Murepavadin demonstrated good activity against P. aeruginosa biofilms both in open and closed systems. The MBIC-ECOFF and the MBEC-ECOFF are proposed as new parameters to estimate the activity of antibiotics on biofilms.

PMID:34283223 | DOI:10.1093/jac/dkab222

Nanomedicine (Lond). 2021 Jul 20. doi: 10.2217/nnm-2021-0179. Online ahead of print.

ABSTRACT

The aim of this study was to investigate the distribution, tolerance, and anticancer and antiviral activity of Zn-based physiometacomposites (PMCs). Manganese, iron, nickel and cobalt-doped ZnO, ZnS or ZnSe were synthesized. Cell uptake, distribution into 3D culture and mice, and biochemical and chemotherapeutic activity were studied by fluorescence/bioluminescence, confocal microscopy, flow cytometry, viability, antitumor and virus titer assays. Luminescence and inductively coupled plasma mass spectrometry analysis showed that nanoparticle distribution was liver >spleen >kidney >lung >brain, without tissue or blood pathology. Photophysical characterization as ex vivo tissue probes and LL37 peptide, antisense oligomer or aptamer delivery targeting RAS/Ras binding domain (RBD) was investigated. Treatment at 25 μg/ml for 48 h showed ≥98-99% cell viability, 3D organoid uptake, 3-log inhibition of β-Galactosidase and porcine reproductive respiratory virus infection. Data support the preclinical development of PMCs for imaging and delivery targeting cancer and infectious disease.

PMID:34282923 | DOI:10.2217/nnm-2021-0179

BMJ Open Respir Res. 2021 Jul;8(1):e000927. doi: 10.1136/bmjresp-2021-000927.

ABSTRACT

INTRODUCTION: Improvements in the treatment of cystic fibrosis (CF) have resulted in longer survival and an increased focus on optimising daily functioning with the condition. Patient-reported outcome measures (PROMs) are valuable tools in evaluating the health-related quality of life of persons with chronic diseases. PROMs may be incorporated into clinical registries to assess and provide feedback regarding the health-related quality of life of the affected population. This study uses qualitative methodology to describe the views of patients with CF, caregivers and clinicians on the usefulness and practicality of incorporating a PROM in the Australian Cystic Fibrosis Data Registry (ACFDR).

METHODS: We conducted semistructured interviews with a convenience sample of patients with CF (n=5), caregivers (n=7) and clinicians (n=13) on their opinions on incorporating the Cystic Fibrosis Questionnaire-Revised or the Cystic Fibrosis Quality of Life Questionnaire into the ACFDR. We analysed data into topics and subtopics using conventional content analysis.

RESULTS: Participants believed that PROMs could generate useful aggregate health-related quality of life data to support better understanding of the experiences of the modern CF population. Participants emphasised that implementation must be supported by processes to feedback data to patients and clinicians. Most participants preferred electronic PROMs administration for easy integration into existing systems and the potential to support feedback.

CONCLUSION: Patients, caregivers and clinicians in this study generally supported the usefulness and practicality of PROM implementation in the ACFDR.

PMID:34281916 | DOI:10.1136/bmjresp-2021-000927

Int J Mol Sci. 2021 Jul 1;22(13):7100. doi: 10.3390/ijms22137100.

ABSTRACT

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality; thus, therapeutic targets continue to be developed. Anoctamin1 (ANO1), a novel drug target considered for the treatment of NSCLC, is a Ca2+-activated chloride channel (CaCC) overexpressed in various carcinomas. It plays an important role in the development of cancer; however, the role of ANO1 in NSCLC is unclear. In this study, diethylstilbestrol (DES) was identified as a selective ANO1 inhibitor using high-throughput screening. We found that DES inhibited yellow fluorescent protein (YFP) fluorescence reduction caused by ANO1 activation but did not inhibit cystic fibrosis transmembrane conductance regulator channel activity or P2Y activation-related cytosolic Ca2+ levels. Additionally, electrophysiological analyses showed that DES significantly reduced ANO1 channel activity, but it more potently reduced ANO1 protein levels. DES also inhibited the viability and migration of PC9 cells via the reduction in ANO1, phospho-ERK1/2, and phospho-EGFR levels. Moreover, DES induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage in PC9 cells, but it did not affect the viability of hepatocytes. These results suggest that ANO1 is a crucial target in the treatment of NSCLC, and DES may be developed as a potential anti-NSCLC therapeutic agent.

PMID:34281152 | DOI:10.3390/ijms22137100

Antimicrob Agents Chemother. 2021 Jul 19:AAC0073721. doi: 10.1128/AAC.00737-21. Online ahead of print.

ABSTRACT

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC24/MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC24/MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

PMID:34280011 | DOI:10.1128/AAC.00737-21

Intern Med J. 2021 Jul;51(7):1168-1172. doi: 10.1111/imj.15408.

ABSTRACT

Time to symptom limitation (Tlim ) achieved during constant work rate tests is considerably more responsive to change than measures commonly recorded during ramp-based tests, such as peak rate of oxygen uptake and maximal work rate (Wmax ). There is limited literature on the use of, and physiological and symptom responses to, constant work rate cycle ergometry tests in people with cystic fibrosis (CF). The results of this study provide evidence that the constant work rate cycle ergometry test, when conducted at 80% of the Wmax , elicits peak physiological and symptom responses and appears to be safe in adults with CF. For clinicians prescribing exercise at an intensity approaching or equivalent to 80% of the Wmax in a non-laboratory-based setting, consideration needs to be given to the level of supervision and patient monitoring required.

PMID:34278700 | DOI:10.1111/imj.15408

J Clin Pharm Ther. 2021 Jul 18. doi: 10.1111/jcpt.13494. Online ahead of print.

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: The off-label use of vedolizumab (VDZ) for inflammatory bowel disease in children is increasing. We report on possibly the first case of VDZ-associated pulmonary manifestations in paediatrics.

CASE SUMMARY: This report details the case of a 13-year-old child with ulcerative colitis who was initiated on VDZ due to persistent active disease. After the first three doses, he developed a persistent and productive cough. Microbiological work-up was normal. VDZ discontinuation led to the resolution of symptoms.

WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first case report of VDZ-associated pulmonary manifestations in paediatrics. A direct, pro-inflammatory effect of VDZ has been hypothesized, but further studies are warranted.

PMID:34278581 | DOI:10.1111/jcpt.13494

Patterns (N Y). 2021 Jul 14:100325. doi: 10.1016/j.patter.2021.100325. Online ahead of print.

ABSTRACT

An effective monotherapy to target the complex and multifactorial pathology of SARS-CoV-2 infection poses a challenge to drug repositioning, which can be improved by combination therapy. We developed an online network pharmacology-based drug repositioning platform, COVID-CDR (http://vafaeelab.com/COVID19repositioning.html), that enables a visual and quantitative investigation of the interplay between the drug primary targets and the SARS-CoV-2-host interactome in the human protein-protein interaction network. COVID-CDR prioritizes drug combinations with potential to act synergistically through different, yet potentially complementary pathways. It provides the options for understanding multi-evidence drug-pair similarity scores along with several other relevant information on individual drugs or drug pairs. Overall, COVID-CDR is the first-of-its-kind online platform that provides a systematic approach for pre-clinical in silico investigation of combination therapies for treating COVID-19 at the fingertips of the clinicians and researchers.

PMID:34278363 | PMC:PMC8277549 | DOI:10.1016/j.patter.2021.100325

Cureus. 2021 Jun 11;13(6):e15601. doi: 10.7759/cureus.15601. eCollection 2021 Jun.

ABSTRACT

Objectives To explore the independent association between cannabis abuse and subsequent hospitalizations for acute pancreatitis (AP) and delineate the demographic differences among AP in patients with and without persistent cannabis abuse. Methods We conducted a retrospective cross-sectional study using the nationwide inpatient sample and included 50,444,133 patients (age 18-50 years) with a primary discharge diagnosis for medical illnesses and further grouped by presence of AP (N = 666,248). We used the logistic regression model to measure the odds ratio (OR) of the association between cannabis abuse and hospitalization for AP and adjusted it for demographic confounders and comorbid risk factors. Results Cannabis abuse significantly increases the odds for AP-related hospitalization (OR 2.12, P <0.001). When the regression model was controlled for potential risk factors (gall stones, cystic fibrosis, hypertriglyceridemia, hypercalcemia, hyperparathyroidism, abdominal surgeries, tobacco abuse, and alcohol abuse), cannabis abuse did not increase the odds for AP-related hospitalization (OR 0.72, P <0.001) due to the significant effect caused by gallstones (OR 30.98, P <0.001) and alcohol abuse (OR 12.69, P <0.001). AP inpatients with cannabis abuse were younger compared to non-cannabis abusers (mean age, 35.7 vs. 37.9 years), and majorly male (70.9% vs. 53.8%). AP was considerably more prevalent in whites (60.6%), followed by blacks (18.3%) and Hispanics (15.2%). Conclusion Cannabis abuse increased the unadjusted odds for AP-related hospitalization by two times, but after controlling for potential risk factors the adjusted odds of association significantly reduced. Cannabis-induced AP can be treated if a problematic recreational cannabis use pattern is discontinued at an earlier stage. Therefore, awareness campaigns and early supportive therapy among cannabis abusers might help diagnose and treat the comorbidity and improve the quality of life.

PMID:34277222 | PMC:PMC8272951 | DOI:10.7759/cureus.15601

Front Genet. 2021 Jul 2;12:631221. doi: 10.3389/fgene.2021.631221. eCollection 2021.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disease caused by genetic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is a common hereditary disease in Caucasians while rare in the Chinese. Until now, only 87 Chinese patients have been reported with molecular confirmations. The variant spectrum and clinical features of Chinese CF patients are obviously different from those of Caucasians.

MATERIALS AND METHODS: Whole-exome sequencing was applied to analyze the exome of three individuals who have only the typical CF phenotype in the respiratory system from two consanguineous families. The protein domain and structure analysis were applied to predict the impact of the variants. Sanger sequencing was applied to validate the candidate variants.

RESULTS: A previously reported homozygous variant in CFTR (NM_000492.4: c.1000C > T, p.R334W) was identified in proband I. A novel homozygous variant in a polymorphic position (NM_000492.4: c.1409T > A, p.V470E) was identified in two individuals in the family II. The novel CFTR variant predicted to be disease-causing is the first, to the best of our knowledge, to be reported in CFTR. However, in vitro validation is still needed.

CONCLUSION: Our finding expands the variant spectrum of CFTR, reveals clearer clinical phenotype distinction and variant spectrum distinction between Chinese and Caucasian CF patients, and contributes to a more rapid genetic diagnosis and future genetic counseling.

PMID:34276759 | PMC:PMC8283821 | DOI:10.3389/fgene.2021.631221

Front Physiol. 2021 Jun 30;12:687381. doi: 10.3389/fphys.2021.687381. eCollection 2021.

ABSTRACT

Airway epithelium forms a physical barrier that protects the lung from the entrance of inhaled allergens, irritants, or microorganisms. This epithelial structure is maintained by tight junctions, adherens junctions and desmosomes that prevent the diffusion of soluble mediators or proteins between apical and basolateral cell surfaces. This apical junctional complex also participates in several signaling pathways involved in gene expression, cell proliferation and cell differentiation. In addition, the airway epithelium can produce chemokines and cytokines that trigger the activation of the immune response. Disruption of this complex by some inflammatory, profibrotic, and carcinogens agents can provoke epithelial barrier dysfunction that not only contributes to an increase of viral and bacterial infection, but also alters the normal function of epithelial cells provoking several lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or lung cancer, among others. While nitric oxide (NO) molecular pathway has been linked with endothelial function, less is known about the role of the NO system on the bronchial epithelium and airway epithelial cells function in physiological and different pathologic scenarios. Several data indicate that the fraction of exhaled nitric oxide (FENO) is altered in lung diseases such as asthma, COPD, lung fibrosis, and cancer among others, and that reactive oxygen species mediate uncoupling NO to promote the increase of peroxynitrite levels, thus inducing bronchial epithelial barrier dysfunction. Furthermore, iNOS and the intracellular pathway sGC-cGMP-PKG are dysregulated in bronchial epithelial cells from patients with lung inflammation, fibrosis, and malignancies which represents an attractive drug molecular target. In this review we describe in detail current knowledge of the effect of NOS-NO-GC-cGMP-PKG pathway activation and disruption in bronchial epithelial cells barrier integrity and its contribution in different lung diseases, focusing on bronchial epithelial cell permeability, inflammation, transformation, migration, apoptosis/necrosis, and proliferation, as well as the specific NO molecular pathways involved.

PMID:34276407 | PMC:PMC8279772 | DOI:10.3389/fphys.2021.687381

J Cyst Fibros. 2021 Jul 16:S1569-1993(21)01297-2. doi: 10.1016/j.jcf.2021.07.001. Online ahead of print.

NO ABSTRACT

PMID:34275759 | DOI:10.1016/j.jcf.2021.07.001

J Cyst Fibros. 2021 Jul 15:S1569-1993(21)01292-3. doi: 10.1016/j.jcf.2021.06.008. Online ahead of print.

NO ABSTRACT

PMID:34275758 | DOI:10.1016/j.jcf.2021.06.008

J Cyst Fibros. 2021 Jul 15:S1569-1993(21)01298-4. doi: 10.1016/j.jcf.2021.06.013. Online ahead of print.

ABSTRACT

BACKGROUND: Adding a slow vital capacity (SVC) to multiple breath washout (MBW) allows quantification of otherwise overlooked signal from under/un-ventilated lung units (UVLU) and may provide a more comprehensive assessment of airway disease than conventional lung clearance index (LCI2.5).

METHODS: We conducted a pilot study on people undergoing MBW tests: 10 healthy controls (HC) and 43 cystic fibrosis (CF) subjects performed an SVC after the standard end of test. We term the new outcome LCI with Short extension (LCIShX). We assessed (i) CF/ HC differences, (ii) variability (iii) effect of pulmonary exacerbation (PEx)/treatment and (iv) relationship with CF computed tomography (CFCT) scores.

RESULTS: HC/ CF group differences were larger with LCIShX than LCI2.5 (P<0.001). Within the CF group UVLU was highly variable and when abnormal it did not correlate with corresponding LCI2.5. Signal showed little variability during clinical stability (n = 11 CF; 2 visits; median inter-test variability 2.6% LCIShX, 2.5% LCI2.5). PEx signal was significantly greater for LCIShX both for onset and resolution. Both MBW parameters correlated significantly with total lung CT scores and hyperinflation but only LCIShX correlated with mucus plugging.

CONCLUSIONS: UVLU captured within the LCIShX varies between individuals; the lack of relationship with LCI2.5 demonstrates that new, additional information is being captured. LCIShX repeatability during clinical stability combined with its larger signal around episodes of PEx may lend it superior sensitivity as an outcome measure. Further studies will build on this pilot data to fully establish its utility in monitoring disease status.

PMID:34275757 | DOI:10.1016/j.jcf.2021.06.013

Pediatr Transplant. 2021 Jul 18:e14086. doi: 10.1111/petr.14086. Online ahead of print.

ABSTRACT

BACKGROUND: New drugs may further decrease the need for lung transplant (LTx) in pediatric patients with cystic fibrosis (CF), but few studies highlight pediatric non-CF LTx characteristics and outcomes.

METHODS: The ISHLT registry was used to report morbidity, graft failure, and survival for primary pediatric (<18 years) LTx performed 1990-2017. Recipient/donor characteristics and long-term outcomes were analyzed for CF and non-CF recipients. Survival was assessed using Kaplan-Meier curves.

RESULTS: Of 2232 primary LTx, (43% in males), 918 (41%) were performed for non-CF indications; most commonly pulmonary hypertension (43%). Non-CF patients were younger (median age 11 vs. 15, p < .001), and more frequently on inotropes and/or extracorporeal membrane oxygenation (15% vs. 2.4%, p < .001) at transplant, compared to CF recipients. In-hospital major complications more commonly affected CF LTx recipients (57% vs. 48%, p = .003), but 30-day mortality was higher in the non-CF group (9% non-CF vs. 5% CF, p < .001). One-, five-, and ten-year mortality was 18%, 50%, and 65% for CF recipients, respectively, and 21%, 45%, and 58% for non-CF recipients (p = .01 at 10 years). Five-year survival was significantly better for non-CF females versus CF females (56% vs. 48%, p = .013), but was similar between groups for males (55% vs. 54%, p = .305). While age was a late outcomes risk factor, pulmonary hypertension and later transplants eras were protective.

CONCLUSIONS: Early mortality is higher and late mortality is lower in non-CF LTx. Current non-CF LTx outcomes leave room for improvement. Further study is needed to evaluate the effects of center volume and pediatric-specific experience on outcomes.

PMID:34275181 | DOI:10.1111/petr.14086

Photochem Photobiol Sci. 2021 Jul 17. doi: 10.1007/s43630-021-00066-2. Online ahead of print.

ABSTRACT

Chronic lung infections are among the most diffused human infections, being often associated with multidrug-resistant bacteria. In this framework, the European project "Light4Lungs" aims at synthesizing and testing an inhalable light source to control lung infections by antimicrobial photoinactivation (aPDI), addressing endogenous photosensitizers only (porphyrins) in the representative case of S. aureus and P. aeruginosa. In the search for the best emission characteristics for the aerosolized light source, this work defines and calculates the photo-killing action spectrum for lung aPDI in the exemplary case of cystic fibrosis. This was obtained by applying a semi-theoretical modelling with Monte Carlo simulations, according to previously published methodology related to stomach infections and applied to the infected trachea, bronchi, bronchioles and alveoli. In each of these regions, the two low and high oxygen concentration cases were considered to account for the variability of in vivo conditions, together with the presence of endogenous porphyrins and other relevant absorbers/diffusers inside the illuminated biofilm/mucous layer. Furthermore, an a priori method to obtain the "best illumination wavelengths" was defined, starting from maximizing porphyrin and light absorption at any depth. The obtained action spectrum is peaked at 394 nm and mostly follows porphyrin extinction coefficient behavior. This is confirmed by the results from the best illumination wavelengths, which reinforces the robustness of our approach. These results can offer important indications for the synthesis of the aerosolized light source and definition of its most effective emission spectrum, suggesting a flexible platform to be considered in further applications.

PMID:34275118 | DOI:10.1007/s43630-021-00066-2

Hum Mol Genet. 2021 Jul 19:ddab206. doi: 10.1093/hmg/ddab206. Online ahead of print.

ABSTRACT

Many hereditary cancer syndromes are associated with an increased risk of small and large intestinal adenocarcinomas. However, conditions bearing a high risk to both adenocarcinomas and neuroendocrine tumors are yet to be described. We studied a family with 16 individuals in four generations affected by a wide spectrum of intestinal tumors, including hyperplastic polyps, adenomas, small intestinal neuroendocrine tumors, and colorectal and small intestinal adenocarcinomas. To assess the genetic susceptibility and understand the novel phenotype we utilized multiple molecular methods, including whole genome sequencing, RNA sequencing, single cell sequencing, RNA in situ hybridization, and organoid culture. We detected a heterozygous deletion at the cystic fibrosis locus (7q31.2) perfectly segregating with the intestinal tumor predisposition in the family. The deletion removes a topologically associating domain (TAD) border between CFTR and WNT2, aberrantly activating WNT2 in the intestinal epithelium. These consequences suggest that the deletion predisposes to small intestinal neuroendocrine tumors and small and large intestinal adenocarcinomas, and reveals the broad tumorigenic effects of aberrant WNT activation in the human intestine.

PMID:34274970 | DOI:10.1093/hmg/ddab206

Cytokine. 2021 Jul 15;146:155635. doi: 10.1016/j.cyto.2021.155635. Online ahead of print.

ABSTRACT

BACKGROUND: Elevated circulating levels of YKL-40 correlate with disease severity in Cystic Fibrosis (CF), but the role of YKL-40 in the inflammatory response in CF is still under investigation. Our main goal was to evaluate if YKL-40 can modulate the expression of major cytokines (IL-6, IL-10, IL-13) implicated in the inflammatory response in CF. A secondary goal was to explore the interactions between YKL-40 and other circulating proteins to determine the impacts on cytokine modulation.

METHOD: Peripheral blood mononuclear cells (PBMCs) were isolated from the blood of 83 adult CF patients in stable clinical condition. PBMCs were treated with human YKL-40 followed by the measure of IL-6, IL-10 and IL-13 gene expression. Protein arrays were used to explore the interactions between YKL-40 and circulating proteins. Interaction with Galectin-3 (GAL3) was identified, and confirmed by binding assay. Cytokine gene expressions were again monitored by RT-qPCR after PBMC treatment with GAL3, with or without YKL-40 co-stimulation.

RESULTS: Following YKL-40 stimulation, PBMC gene expression of IL-6, IL-10 and IL-13 varies across patients. IL-6 and IL-13 are coexpressed, but this response was different in male and female patients. GAL3 protein was detected in the blood of CF patients, and a molecular interaction with YKL-40 was identified. GAL3 did not interfere with the YKL-40 stimulation of IL-6, IL-10 and IL-13 but may modulate the coexpression.

CONCLUSION: We observed that YKL-40 stimulation had a variable impact on IL-6, IL-10, and IL-13 gene expression in CF PBMCs and uncovered an interaction between GAL3 and YKL-40 in the serum of CF patients. Our findings suggest that YKL-40 is not only a biomarker of disease severity in CF, but it might play an active role in the inflammatory pathophysiology of the disease.

PMID:34274729 | DOI:10.1016/j.cyto.2021.155635

Pediatr Pulmonol. 2021 Jul 17. doi: 10.1002/ppul.25586. Online ahead of print.

ABSTRACT

BACKGROUND: Despite the availability of cystic fibrosis (CF) screening countrywide, diagnostic delay is still a crucial issue. The objectives of this study were to explore the stages of the NBS process, determine the risk factors associated with diagnostic delay and evaluate parent anxiety and experience throughout the process.

METHODS: This is a multicenter cross-sectional study. A questionnaire was completed by parents of newborns diagnosed with CF via NBS in 17 centers. Socio-demographic characteristics, parent knowledge and experiences related to NBS, sweat test availability in the region of residence and time to the definitive CF diagnosis were assessed through this questionnaire. Parents' anxiety levels were evaluated through the State-Trait Anxiety Inventory scales one and two. Delayed diagnosis (DD) was defined as definite CF diagnosis beyond the 8th week of life. Predictors of delayed CF diagnosis were evaluated by univariate and multivariate analysis.

RESULTS: A total of 220 CF patients diagnosed via NBS were enrolled; 82 (37.3%) babies had DD. Multivariable analysis indicated that residence in the Southeast Anatolia region of Turkey (OR=10.79, 95%CI=2.37-49.2) was associated with higher incidence of DD compared with other regions in Turkey. Of the total, 216 (98.1%) of the caregivers regarded the NBS program as useful and 180 (82%) reported high anxiety levels.

CONCLUSION: Organization of newborn screening should take into account regional and socio-cultural characteristics in order to improve early diagnosis of CF and also reduce the anxiety level of parents. This article is protected by copyright. All rights reserved.

PMID:34273142 | DOI:10.1002/ppul.25586

Nat Commun. 2021 Jul 16;12(1):4358. doi: 10.1038/s41467-021-24575-x.

ABSTRACT

Premature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores protein function by selectively suppressing translation termination at PTCs. Poor efficacy of current readthrough agents prompted us to search for better compounds. An NMD-sensitive NanoLuc readthrough reporter was used to screen 771,345 compounds. Among the 180 compounds identified with readthrough activity, SRI-37240 and its more potent derivative SRI-41315, induce a prolonged pause at stop codons and suppress PTCs associated with cystic fibrosis in immortalized and primary human bronchial epithelial cells, restoring CFTR expression and function. SRI-41315 suppresses PTCs by reducing the abundance of the termination factor eRF1. SRI-41315 also potentiates aminoglycoside-mediated readthrough, leading to synergistic increases in CFTR activity. Combining readthrough agents that target distinct components of the translation machinery is a promising treatment strategy for diseases caused by PTCs.

PMID:34272367 | DOI:10.1038/s41467-021-24575-x