A Pilot Study of Mindfulness-Based Cognitive Therapy to Improve Well-Being for Health Professionals Providing Chronic Disease Care.

J Pediatr. 2020 May 13;:

Authors: Hente E, Sears R, Cotton S, Pallerla H, Siracusa C, Filigno SS, Boat T

Abstract
OBJECTIVE: To assess the efficacy of mindfulness-based cognitive therapy delivered onsite during work hours in reducing stress and improving well-being in an interdisciplinary chronic care health care team.
STUDY DESIGN: A longitudinal, mixed methods, observational pilot study using a survey created from validated assessment tools to measure effectiveness of training. Surveys were completed before training, and 1 and 15 months after training. Twenty-four professionals in the cystic fibrosis Centers at Cincinnati Children's Hospital and the University of Cincinnati participated in 6 mindfulness-based cognitive therapy training sessions. Sessions incorporated mindfulness, cognitive therapy, and experiential exercises for processing feelings related to stress and burnout.
RESULTS: The presurvey and 1-month postsurvey responses revealed statistically significant improvements for empathy, perceived stress, depersonalization, anxiety, perspective taking, resilience, and negative affect. Sustained effects were seen at 15 months for empathy, perspective taking, and depressive symptoms. The 1-month post-training surveys reported a quarter of respondents (25%) practiced skills at least 5 times in between sessions; at 15 months, 35% reported practicing at the same frequency. Participants reported using mindfulness skills for personal stressful events (74%), work-related general stress (65%), patient-related stress (30%), sleep or general relaxation (22%), and wellness (13%).
CONCLUSIONS: Group mindfulness-based cognitive therapy training was feasible and effective in decreasing stress for interdisciplinary cystic fibrosis care team members who elected to participate. Further investigation is needed to determine optimal dose of training, durability of perceived benefits, and generalizability to health care professionals working with other chronic disorders.

PMID: 32417086 [PubMed - as supplied by publisher]

Theranostic Nanoparticles for Pancreatic Cancer Treatment.

Endocr Metab Immune Disord Drug Targets. 2020 May 16;:

Authors: Jaidev LR, Chede LS, Kandikattu HK

Abstract
Pancreatic cancer is one of the low vascular permeable tumors with a high mortality rate. The five-year survival period is ~5%. The field of drug delivery is at its pace in developing unique drug delivery carriers to treat high mortality rate cancers such as pancreatic cancer. Theranostic nanoparticles are the new novel delivery carriers where the carrier is loaded with both diagnostic and therapeutic agents. The present review discusses various therapeutic and theranostic nanocarriers for pancreatic cancer.

PMID: 32416712 [PubMed - as supplied by publisher]

Nocardia Infections: Ten Years Experience from a Tertiary Health Care Center in North India (2007-2016).

Infect Disord Drug Targets. 2020 May 16;:

Authors: Bansal Y, Singla N, Butta H, Aggarwal D, Gulati N, Chander J

Abstract
BACKGROUND: Nocardia species are important cause of infections in humans but are underreported due to missed diagnosis as well as misdiagnosis. Majority of the literature on these infections consists of case reports or series with few articles describing high number of cases.
OBJECTIVE: To study the epidemiology of Nocardia infections in a tertiary care center.
MATERIALS AND METHODS: This retrospective observational study was done in a tertiary care centre of North India over a period of 10 years (2007-2016). The detection of Nocardia spp. from clinical specimens was done by conventional methods viz. direct microscopy (Gram's stain, modified Ziehl-Neelsen stain [1%], KOH examination) and culture.
RESULTS: A total of 25 cases of nocardiosis were diagnosed during the study period. The mean age of the patients was 50.9 years (range 30-72 years) with a male:female ratio of 3:2. The site of disease in these patients included pulmonary (n=18), cutaneous (n=4), perinephric abscess (n=1), ocular (n=1) and bone (n=1). Risk factors associated were underlying lung disease (n=11), smoking (n=7), diabetes (n=5) and steroid therapy (n=4) in pulmonary nocardiosis, iatrogenic (n=1) and leprosy (n=1) in cutaneous nocardiosis, diabetes in perinephric abscess and cataract surgery in ocular nocardiosis. Culture was positive in 12/25 (48%) patients for Nocardia spp. Direct microscopy was positive in 22 patients. We wish to highlight that meticulous observation of KOH wet mount examination helped in clinching the diagnosis of Nocardiosis in 3 cases which were earlier missed by other methods.
CONCLUSIONS: Good communication with the clinician alongside a meticulous effort in the laboratory is essential for appropriate diagnosis and management of these cases.

PMID: 32416708 [PubMed - as supplied by publisher]

A broad-spectrum antibacterial natural product from the cystic fibrosis isolate, Pantoea agglomerans Tx10.

Microbiol Res. 2020 Apr 24;237:126479

Authors: Robinson LJ, Verrett JN, Sorout N, Stavrinides J

Abstract
The prevalence of antibiotic-resistant Gram-positive and Gram-negative pathogens has prompted considerable efforts to identify new antibacterials. Here we show that Pantoea agglomerans Tx10-an isolate from the sputum sample of a cystic fibrosis patient-is a strong competitor that inhibits the growth of a wide range of Gram-positive and Gram-negative bacteria through the production of a secreted compound. A genetic screen to identify the genes involved in the production of this compound resulted in the delineation of a 6-gene biosynthetic cluster. We called this compound Pantoea Natural Product 2 (PNP-2). Assays with mutants deficient in PNP-2 production revealed they were still able to inhibit Erwinia amylovora, suggesting the production of a second antibiotic, which we identified as Pantocin A. We generated Pantocin A knockouts, and a PNP-2/Pantocin A double knockout and used these to evaluate the spectrum of activity of both natural products. We show that strains of Enterobacter, E. coli, Klebsiella, Kosakonia, Pseudocitrobacter, Salmonella, Staphylococcus, and Streptococcus as well as the majority of Pantoea strains assayed are susceptible to PNP-2, indicating a broad spectrum of activity, and potential for therapeutic development.

PMID: 32416447 [PubMed - as supplied by publisher]

Delivery of genome-editing biomacromolecules for treatment of lung genetic disorders.

Adv Drug Deliv Rev. 2020 May 13;:

Authors: Wan T, Ping Y

Abstract
Genome-editing systems based on clustered, regularly interspaced, short palindromic repeat (CRISPR)/associated protein (CRISPR/Cas), are emerging as a revolutionary technology for the treatment of various genetic diseases. To date, the delivery of genome-editing biomacromolecules by viral or non-viral have been proposed as new therapeutic options for lung genetic disorders, such as cystic fibrosis (CF) and α-1 antitrypsin deficiency (AATD), and it has been accepted that these delivery vectors can introduce CRISPR/Cas9 machineries into target cells or tissues in vitro, ex vivo and in vivo. However, the efficient local or systemic delivery of CRISPR/Cas9 elements to the lung, enabled by either viral or by non-viral carriers, still remains elusive. Herein, we first introduce lung genetic disorders and their current treatment options, and then summarize CRISPR/Cas9-based strategies for the therapeutic genome editing of these disorders. We further summarize the pros and cons of different routes of administration for lung genetic disorders. In particular, the potentials of aerosol delivery for therapeutic CRISPR/Cas9 biomacromolecules for lung genome editing are discussed highlighted. Finally, current challenges and future outlooks in this emerging area are briefly discussed.

PMID: 32416111 [PubMed - as supplied by publisher]

Volumetric quantification of lung MR signal intensities using ultrashort TE as an automated score in cystic fibrosis.

Eur Radiol. 2020 May 15;:

Authors: Benlala I, Point S, Leung C, Berger P, Woods JC, Raherison C, Laurent F, Macey J, Dournes G

Abstract
OBJECTIVES: The study aimed to validate automated quantification of high and low signal intensity volumes using ultrashort echo-time MRI, with CT and pulmonary function test (PFT) as references, to assess the severity of structural alterations in cystic fibrosis (CF).
METHODS: This prospective study was performed in a single center between May 2015 and September 2017. Participants with CF completed clinical examination, CT, MRI, and PFT the same day during routine clinical follow-up (M0), and then 1 year after (M12) except for CT. Using MRI, percentage high (%MR-HSV), low (%MR-LSV), and total abnormal (%MR-TSV) signal intensity volumes were recorded, as well as their corresponding attenuation values using CT (%CT-HAV, %CT-LAV, %CT-TAV, respectively). Automated quantifications and visual Bhalla score were evaluated independently by two observers. Correlations were assessed using the Spearman test, comparisons using the Mann-Whitney test, and reproducibility using the intraclass correlation coefficient (ICC).
RESULTS: A total of 30 participants were enrolled (median age 27 years, 18 men). At M0, there was a good correlation between %MR-HSV and %CT-HAV (ρ = 0.70; p < 0.001) and %MR-LSV and %CT-LAV (ρ = 0.60; p < 0.001). Automated MR metrics correlated to PFTs and Bhalla score (p < 0.05) while %MR-TSV was significantly different between CF with and without respiratory exacerbation (p = 0.01) at both M0 and M12. The variation of %MR-HSV correlated to the variation of FEV1% at PFT (ρ = - 0.49; p = 0.008). Reproducibility was almost perfect (ICCs > 0.95).
CONCLUSIONS: Automated quantification of abnormal signal intensity volumes relates to CF severity and allows reproducible cross-sectional and longitudinal assessment.
TRIAL REGISTRATION: Clinical trial identifier: NCT02449785 KEY POINTS: • Cross-sectionally, the automated quantifications of high and low signal intensity volumes at UTE correlated to the quantification of high and low attenuation using CT as reference. • Longitudinally, the variation of high signal intensity volume at UTE correlated to the variation of pulmonary function test and was significantly reduced in CF with an improvement in exacerbation status. • Automated quantification of abnormal signal intensity volumes are objective and reproducible tools to assess structural alterations in CF and follow-up longitudinally, for both research and clinical purposes.

PMID: 32415586 [PubMed - as supplied by publisher]

Structural and biochemical characterization of the exopolysaccharide deacetylase Agd3 required for Aspergillus fumigatus biofilm formation.

Nat Commun. 2020 May 15;11(1):2450

Authors: Bamford NC, Le Mauff F, Van Loon JC, Ostapska H, Snarr BD, Zhang Y, Kitova EN, Klassen JS, Codée JDC, Sheppard DC, Howell PL

Abstract
The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Deletion of a gene encoding a putative deacetylase, Agd3, leads to defects in GAG deacetylation, biofilm formation, and virulence. Here, we show that Agd3 deacetylates GAG in a metal-dependent manner, and is the founding member of carbohydrate esterase family CE18. The active site is formed by four catalytic motifs that are essential for activity. The structure of Agd3 includes an elongated substrate-binding cleft formed by a carbohydrate binding module (CBM) that is the founding member of CBM family 87. Agd3 homologues are encoded in previously unidentified putative bacterial exopolysaccharide biosynthetic operons and in other fungal genomes.

PMID: 32415073 [PubMed - as supplied by publisher]

The CFTR Mutation c.3453G > C (D1152H) Confers an Anion Selectivity Defect in Primary Airway Tissue that Can Be Rescued by Ivacaftor.

J Pers Med. 2020 May 13;10(2):

Authors: Laselva O, Moraes TJ, He G, Bartlett C, Szàrics I, Ouyang H, Gunawardena TNA, Strug L, Bear CE, Gonska T

Abstract
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene variant, c.3453G > C (D1152H), is associated with mild Cystic Fibrosis (CF) disease, though there is considerable clinical variability ranging from no detectable symptoms to lung disease with early acquisition of Pseudomonas aeruginosa. The approval extension of ivacaftor, the first CFTR modulator drug approved, to include D1152H was based on a positive drug response of defective CFTR-D1152H chloride channel function when expressed in FRT cells. Functional analyses of primary human nasal epithelial cells (HNE) from an individual homozygous for D1152H now revealed that while CFTR-D1152H demonstrated normal, wild-type level chloride conductance, its bicarbonate-selective conductance was impaired. Treatment with ivacaftor increased this bicarbonate-selective conductance. Extensive genetic, protein and functional analysis of the nasal cells of this D1152H/D1152H patient revealed a 90% reduction of CFTR transcripts due to the homozygous presence of the 5T polymorphism in the poly-T tract forming a complex allele with D1152H. Thus, we confirm previous observation in patient-derived tissue that 10% normal CFTR transcripts confer normal, wild-type level chloride channel activity. Together, this study highlights the benefit of patient-derived tissues to study the functional expression and pharmacological modulation of CF-causing mutations, in order to understand pathogenesis and therapeutic responses.

PMID: 32414100 [PubMed - as supplied by publisher]

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease.

Genes (Basel). 2020 May 13;11(5):

Authors: Strub MD, McCray PB

Abstract
Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The diversity of mutations and the multiple ways by which the protein is affected present challenges for therapeutic development. The observation that the Phe508del-CFTR mutant protein is temperature sensitive provided proof of principle that mutant CFTR could escape proteosomal degradation and retain partial function. Several specific protein interactors and quality control checkpoints encountered by CFTR during its proteostasis have been investigated for therapeutic purposes, but remain incompletely understood. Furthermore, pharmacological manipulation of many CFTR interactors has not been thoroughly investigated for the rescue of Phe508del-CFTR. However, high-throughput screening technologies helped identify several small molecule modulators that rescue CFTR from proteosomal degradation and restore partial function to the protein. Here, we discuss the current state of CFTR transcriptomic and biogenesis research and small molecule therapy development. We also review recent progress in CFTR proteostasis modulators and discuss how such treatments could complement current FDA-approved small molecules.

PMID: 32414011 [PubMed - as supplied by publisher]

Horses for courses: Learning from functional tests of pulmonary health?

Pediatr Pulmonol. 2020 May 15;:

Authors: Short C, Saunders C, Davies JC

PMID: 32413194 [PubMed - as supplied by publisher]

Flexible link functions in a joint hierarchical Gaussian process model.

Biometrics. 2020 May 15;:

Authors: Su W, Wang X, Szczesniak RD

Abstract
Many longitudinal studies often require jointly modeling a biomarker and an event outcome, in order to provide more accurate inference and dynamic prediction of disease progression. Cystic fibrosis (CF) studies have illustrated the benefits of these models, primarily examining the joint evolution of lung-function decline and survival. We propose a novel joint model within the shared parameter framework that accommodates nonlinear lung-function trajectories, in order to provide more accurate inference on lung-function decline over time and to examine the association between evolution of lung function and risk of a pulmonary exacerbation event recurrence. Specifically, a two-level Gaussian process is used to estimate the nonlinear longitudinal trajectories and a flexible link function is introduced for a more accurate depiction of the binary process on the event outcome. Bayesian model assessment is used to evaluate each component of the joint model in simulation studies and an application to longitudinal data on patients receiving care from a CF center. A nonlinear structure is suggested by both the longitudinal continuous and binary evaluations. Including a flexible link function improves model fit to these data. The proposed hierarchical Gaussian process model with a flexible power link function where Laplace distribution is the baseline (spep) has the best fit of all joint models considered, characterizing how accelerated lung-function decline corresponds to increased odds of experiencing another pulmonary exacerbation. This article is protected by copyright. All rights reserved.

PMID: 32413169 [PubMed - as supplied by publisher]

Combination antimicrobial susceptibility testing for acute exacerbations in chronic infection of Pseudomonas aeruginosa in cystic fibrosis.

Cochrane Database Syst Rev. 2020 May 15;5:CD006961

Authors: Smith S, Ratjen F, Remmington T, Waters V

Abstract
BACKGROUND: Antibiotic therapy for acute pulmonary exacerbations in people with cystic fibrosis is usually chosen based on the results of antimicrobial susceptibility testing of individual drugs. Combination antimicrobial susceptibility testing assesses the efficacy of drug combinations including two or three antibiotics in vitro and can often demonstrate antimicrobial efficacy against bacterial isolates even when individual antibiotics have little or no effect. Therefore, choosing antibiotics based on combination antimicrobial susceptibility testing could potentially improve response to treatment in people with cystic fibrosis with acute exacerbations. This is an updated version of a previously published review.
OBJECTIVES: To compare antibiotic therapy based on conventional antimicrobial susceptibility testing to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis and chronic infection with Pseudomonas aeruginosa.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Cystic Fibrosis Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 19 March 2020. We also searched ongoing trials registries. Date of latest search: 07 April 2020.
SELECTION CRITERIA: Randomised and quasi-randomised controlled studies of antibiotic therapy based on conventional antimicrobial susceptibility testing compared to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in cystic fibrosis due to chronic infection with Pseudomonas aeruginosa.
DATA COLLECTION AND ANALYSIS: Both authors independently selected studies, assessed their quality and extracted data from eligible studies. Additionally, the authors contacted the study investigators to obtain further information.
MAIN RESULTS: The search identified one multicentre study eligible for inclusion in the review. This study prospectively assessed whether the use of multiple combination bactericidal antibiotic testing improved clinical outcomes in participants with acute pulmonary exacerbations of cystic fibrosis who were infected with multiresistant bacteria. A total of 132 participants were randomised in the study. The study investigators provided data specific to the 82 participants who were only infected with Pseudomonas aeruginosa for their primary outcome of time until next pulmonary exacerbation. For participants specifically infected with only Pseudomonas aeruginosa, the hazard ratio of a subsequent exacerbation was 0.82, favouring the control group (95% confidence interval 0.44 to 1.51) (P = 0.52). No further data for any of this review's outcomes specific to participants infected with Pseudomonas aeruginosa were available. The risk of bias for the included study was deemed to be low. The quality of the evidence was moderate for the only outcome providing data solely for individuals with infection due to Pseudomonas aeruginosa. For other outcomes, we were unable to judge the quality of the evidence as no data were available for the relevant subset of participants.
AUTHORS' CONCLUSIONS: The current evidence, limited to one study, shows that there is insufficient evidence to determine effect of choosing antibiotics based on combination antimicrobial susceptibility testing compared to choosing antibiotics based on conventional antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis with chronic Pseudomonas aeruginosa infection. A large international and multicentre study is needed to further investigate this issue. The only study included in the review was published in 2005, and we have not identified any further relevant studies up to March 2017. We therefore do not plan to update this review until new studies are published.

PMID: 32412092 [PubMed - in process]

Longitudinal Associations of the Cystic Fibrosis Airway Microbiome and Volatile Metabolites: A Case Study.

Front Cell Infect Microbiol. 2020;10:174

Authors: Hahn A, Whiteson K, Davis TJ, Phan J, Sami I, Koumbourlis AC, Freishtat RJ, Crandall KA, Bean HD

Abstract
The identification of 16S rDNA biomarkers from respiratory samples to describe the continuum of clinical disease states within persons having cystic fibrosis (CF) has remained elusive. We sought to combine 16S, metagenomics, and metabolomics data to describe multiple transitions between clinical disease states in 14 samples collected over a 12-month period in a single person with CF. We hypothesized that each clinical disease state would have a unique combination of bacterial genera and volatile metabolites as a potential signature that could be utilized as a biomarker of clinical disease state. Taxonomy identified by 16S sequencing corroborated clinical culture results, with the majority of the 109 PCR amplicons belonging to the bacteria grown in clinical cultures (Escherichia coli and Staphylococcus aureus). While alpha diversity measures fluctuated across disease states, no significant trends were present. Principle coordinates analysis showed that treatment samples trended toward a different community composition than baseline and exacerbation samples. This was driven by the phylum Bacteroidetes (less abundant in treatment, log2 fold difference -3.29, p = 0.015) and the genus Stenotrophomonas (more abundant in treatment, log2 fold difference 6.26, p = 0.003). Across all sputum samples, 466 distinct volatile metabolites were identified with total intensity varying across clinical disease state. Baseline and exacerbation samples were rather uniform in chemical composition and similar to one another, while treatment samples were highly variable and differed from the other two disease states. When utilizing a combination of the microbiome and metabolome data, we observed associations between samples dominated Staphylococcus and Escherichia and higher relative abundances of alcohols, while samples dominated by Achromobacter correlated with a metabolomics shift toward more oxidized volatiles. However, the microbiome and metabolome data were not tightly correlated; examining both the metagenomics and metabolomics allows for more context to examine changes across clinical disease states. In our study, combining the sputum microbiome and metabolome data revealed stability in the sputum composition through the first exacerbation and treatment episode, and into the second exacerbation. However, the second treatment ushered in a prolonged period of instability, which after three additional exacerbations and treatments culminated in a new lung microbiome and metabolome.

PMID: 32411616 [PubMed - in process]

Calprotectin as a New Sensitive Marker of Neutrophilic Inflammation in Patients with Bronchiolitis Obliterans.

Mediators Inflamm. 2020;2020:4641585

Authors: Jerkic SP, Michel F, Donath H, Herrmann E, Schubert R, Rosewich M, Zielen S

Abstract
Introduction: Bronchiolitis obliterans (BO) is a chronic disease in which persistent inflammation leads to obstruction and obliteration of the small airways. The aim of this study was to evaluate the value of calprotectin as an inflammatory marker in induced sputum.
Methods: Twenty-eight patients suffering from BO and 18 healthy controls were examined. Lung function was measured by spirometry, body plethysmography, and lung clearance index (LCI). The induced sputum was obtained, cell counts were performed, and cytokines were measured using cytometric bead array (CBA). Calprotectin was quantified in the sputum and serum samples using commercially available sandwich ELISA.
Results: Spirometry parameters including forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and maximum expiratory flow rate at 25% vital capacity (MEF25) were significantly lower in BO patients than in healthy controls, whereas the reserve volume (RV), RV to total lung capacity ratio (RV/TLC), and LCI were significantly increased. In sputum, calprotectin levels, neutrophils, and IL-8 were significantly elevated. Calprotectin levels correlated strongly with IL-8 and other biomarkers, neutrophils FEV1 and MEF25. In serum, calprotectin was significantly diminished in BO patients compared to controls.
Conclusion: Lung function is severely impaired in BO patients. Calprotectin is significantly elevated in the sputum of BO patients and reflects ongoing neutrophilic inflammation.

PMID: 32410855 [PubMed - in process]

Tablet and web-based audiometry to screen for hearing loss in adults with cystic fibrosis.

Thorax. 2020 May 14;:

Authors: Vijayasingam A, Frost E, Wilkins J, Gillen L, Premachandra P, Mclaren K, Gilmartin D, Picinali L, Vidal-Diez A, Borsci S, Ni MZ, Tang WY, Morris-Rosendahl D, Harcourt J, Elston C, Simmonds NJ, Shah A

Abstract
INTRODUCTION: Individuals with chronic lung disease (eg, cystic fibrosis (CF)) often receive antimicrobial therapy including aminoglycosides resulting in ototoxicity. Extended high-frequency audiometry has increased sensitivity for ototoxicity detection, but diagnostic audiometry in a sound-booth is costly, time-consuming and requires a trained audiologist. This cross-sectional study analysed tablet-based audiometry (Shoebox MD) performed by non-audiologists in an outpatient setting, alongside home web-based audiometry (3D Tune-In) to screen for hearing loss in adults with CF.
METHODS: Hearing was analysed in 126 CF adults using validated questionnaires, a web self-hearing test (0.5 to 4 kHz), tablet (0.25 to 12 kHz) and sound-booth audiometry (0.25 to 12 kHz). A threshold of ≥25 dB hearing loss at ≥1 audiometric frequency was considered abnormal. Demographics and mitochondrial DNA sequencing were used to analyse risk factors, and accuracy and usability of hearing tests determined.
RESULTS: Prevalence of hearing loss within any frequency band tested was 48%. Multivariate analysis showed age (OR 1.127; (95% CI: 1.07 to 1.18; p value<0.0001) per year older) and total intravenous antibiotic days over 10 years (OR 1.006; (95% CI: 1.002 to 1.010; p value=0.004) per further intravenous day) were significantly associated with increased risk of hearing loss. Tablet audiometry had good usability, was 93% sensitive, 88% specific with 94% negative predictive value to screen for hearing loss compared with web self-test audiometry and questionnaires which had poor sensitivity (17% and 13%, respectively). Intraclass correlation (ICC) of tablet versus sound-booth audiometry showed high correlation (ICC >0.9) at all frequencies ≥4 kHz.
CONCLUSIONS: Adults with CF have a high prevalence of drug-related hearing loss and tablet-based audiometry can be a practical, accurate screening tool within integrated ototoxicity monitoring programmes for early detection.

PMID: 32409613 [PubMed - as supplied by publisher]

The O2-independent pathway of ubiquinone biosynthesis is essential for denitrification in Pseudomonas aeruginosa.

J Biol Chem. 2020 May 14;:

Authors: Vo CD, Michaud J, Elsen S, Faivre B, Bouveret E, Barras F, Fontecave M, Pierrel F, Lombard M, Pelosi L

Abstract
Many proteobacteria, such as Escherichia coli, contain two main types of quinones, benzoquinones represented by ubiquinone (UQ) and naphthoquinones such as menaquinone (MK) and dimethyl-menaquinone (DMK). MK and DMK function predominantly in anaerobic respiratory chains, whereas UQ is the major electron carrier in the reduction of dioxygen. However, this division of labor is probably not very strict. Indeed, a pathway that produces UQ under anaerobic conditions in an UbiU-, UbiV-, and UbiT-dependent manner has been recently discovered in E. coli However, its physiological relevance is not yet understood because MK and DMK are also present in E. coli Here, we established that UQ9 is the major quinone of Pseudomonas aeruginosa and is required for growth under anaerobic respiration (i.e. denitrification). We demonstrate that the ORFs PA3911, PA3912, and PA3913, which are homologs of the E. coli ubiT, ubiV and ubiU genes, respectively, are essential for UQ9 biosynthesis and thus for denitrification in P. aeruginosa These three genes hereafter are called ubiTPa , ubiVPa , and ubiUPa We show that UbiVPa accommodates an iron-sulfur [4Fe-4S] cluster. Moreover, we report that UbiUPa and UbiTPa can bind UQ and that the isoprenoid tail of UQ is the structural determinant required for recognition by these two Ubi proteins. Since the denitrification metabolism of P. aeruginosa is believed to be important for pathogenicity of this bacterium in individuals with cystic fibrosis, our results highlight that the O2-independent UQ biosynthetic pathway may represent a possible target for antibiotics development to manage P. aeruginosa infections.

PMID: 32409583 [PubMed - as supplied by publisher]

Breaking the diagnosis of cystic fibrosis to parents: A process not a one-off event.

Paediatr Respir Rev. 2020 Apr 17;:

Authors: Bryon M

Abstract
Breaking the news to parents that their child has cystic fibrosis [CF] is most frequently given in the first few weeks of the baby's life as a result of newborn screening. This is optimal to reduce morbidity but can have a significant impact on the parents' mental wellbeing and the parent-child relationship. Parent feedback indicates that assimilating the diagnosis is not a one-off event but a process that takes time. CF professionals therefore need to be aware not only of how they communicate the diagnosis initially but also the ways in which families make sense of this throughout at least the following year. The parent-patient-team relationship is essential to good health outcomes. Key objectives of this paper are to enable: (1) understanding parental responses to the diagnosis which can indicate how well they are managing CF for their child, (2) improving the way in which the diagnosis is communicated and, (3) changing team management of CF in the early years to include parental collaboration to support better mental and physical outcomes.

PMID: 32409170 [PubMed - as supplied by publisher]

An Innovative Lipidomic Workflow to Investigate the Lipid Profile in a Cystic Fibrosis Cell Line.

Cells. 2020 May 12;9(5):

Authors: Dei Cas M, Zulueta A, Mingione A, Caretti A, Ghidoni R, Signorelli P, Paroni R

Abstract
Altered lipid metabolism has been associated to cystic fibrosis disease, which is characterized by chronic lung inflammation and various organs dysfunction. Here, we present the validation of an untargeted lipidomics approach based on high-resolution mass spectrometry aimed at identifying those lipid species that unequivocally sign CF pathophysiology. Of n.13375 mass spectra recorded on cystic fibrosis bronchial epithelial airways epithelial cells IB3, n.7787 presented the MS/MS data, and, after software and manual validation, the final number of annotated lipids was restricted to n.1159. On these lipids, univariate and multivariate statistical approaches were employed in order to select relevant lipids for cellular phenotype discrimination between cystic fibrosis and HBE healthy cells. In cystic fibrosis IB3 cells, a pervasive alteration in the lipid metabolism revealed changes in the classes of ether-linked phospholipids, cholesterol esters, and glycosylated sphingolipids. Through functions association, it was evidenced that lipids variation involves the moiety implicated in membrane composition, endoplasmic reticulum, mitochondria compartments, and chemical and biophysical lipids properties. This study provides a new perspective in understanding the pathogenesis of cystic fibrosis and strengthens the need to use a validated mass spectrometry-based lipidomics approach for the discovery of potential biomarkers and perturbed metabolism.

PMID: 32408521 [PubMed - in process]

The Cystic Fibrosis Impact Questionnaire: qualitative development and cognitive evaluation of a new patient-reported outcome instrument to assess the life impacts of cystic fibrosis.

J Patient Rep Outcomes. 2020 May 13;4(1):36

Authors: McCarrier KP, Hassan M, Hodgkins P, Suthoff E, McGarry LJ, Martin ML

Abstract
BACKGROUND: Patients with cystic fibrosis (CF) experience significant disease burden, including progressive pulmonary decline and reduced survival. This multicenter qualitative study was conducted to develop a new patient-reported outcome (PRO) measure to assess the impact of CF on patients' quality of life: the Cystic Fibrosis Impact Questionnaire (CF-IQ). Semi-structured qualitative concept elicitation (CE) interviews with patients and caregivers documented CF-related symptoms, impacts, and treatment experiences. Coded interview data were considered alongside existing PROs, published literature, and expert opinion to develop an initial scale. Three rounds of cognitive interviews evaluated respondent comprehension and facilitated refinement of the CF-IQ.
RESULTS: Adult (N = 20) and pediatric (N = 22) patients with CF and their parents/caregivers (N = 22) completed CE interviews at 7 US clinics. The sample included patients aged 6-58 years, 57% females, and represented a broad range of disease severity (forced expiratory volume in 1 s range: 22%-127% predicted). Interviews identified 59 unique CF-related impact concepts in domains, including activity limitations (physical, social, leisure), functional limitations (school, work), vulnerability/lack of control, emotional impact, treatment burden, and future outlook. Concept saturation was achieved, and a draft questionnaire was developed. Findings from the cognitive interviews (n = 18) confirmed that instructions, items, and response scales were relevant and clear, and interpreted as intended by patients.
CONCLUSION: The CF-IQ is a 40-item novel PRO scale assessing a comprehensive set of patient-relevant concepts to characterize the multifaceted nature of CF. Qualitative interview data support the content validity of the CF-IQ, which is currently undergoing additional psychometric evaluation in patients with CF.

PMID: 32405878 [PubMed]

Direct Amoxicillin Challenge without Preliminary Skin Testing for Pediatric Patients with Penicillin Allergy Labels.

Ann Allergy Asthma Immunol. 2020 May 11;:

Authors: Wang LA, Patel K, Kuruvilla ME, Shih J

PMID: 32407949 [PubMed - as supplied by publisher]