Erratum: Profile Of Tezacaftor/Ivacaftor Combination And Its Potential In The Treatment Of Cystic Fibrosis [Erratum].

Ther Clin Risk Manag. 2019;15:1207

Authors:

Abstract
[This corrects the article DOI: 10.2147/TCRM.S165027.].

PMID: 31696867 [PubMed - in process]

Aquagenic wrinkling of the palms.

G Ital Dermatol Venereol. 2019 Jun;154(3):364-366

Authors: Donnarumma M, Megna M, Napolitano M, Patruno C

PMID: 29368852 [PubMed - indexed for MEDLINE]

32 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2019/11/07

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52 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2019/11/05

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

54 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2019/11/04

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Immune and Cytokine Dysfunction in Cystic Fibrosis.

Am J Respir Cell Mol Biol. 2019 Nov;61(5):656-658

Authors: Leung ST, Khoury O, Barrios C, Ortega VE, Atala A, Murphy SV

PMID: 31674827 [PubMed - in process]

The CYSMA web server: an example of integrative tool for in silico analysis of missense variants identified in Mendelian disorders.

Hum Mutat. 2019 Nov 01;:

Authors: Sasorith S, Baux D, Bergougnoux A, Paulet D, Lahure A, Bareil C, Taulan-Cadars M, Roux AF, Koenig M, Claustres M, Raynal C

Abstract
Exome sequencing used for molecular diagnosis of Mendelian disorders considerably increases the number of missense variants of unclear significance, whose pathogenicity can be assessed by a variety of prediction tools. As performance of algorithms may vary according to the datasets, complementary specific resources are needed to improve variants interpretation. As a model, we were interested in the Cystic Fibrosis Transmembrane conductance Regulator gene (CFTR) causing cystic fibrosis, in which at least 40% of missense variants are reported. CYSMA (CYStic fibrosis Missense Analysis) is a new web server designed for online estimation of pathological relevance of CFTR missense variants. CYSMA generates a set of computationally derived data, ranging from evolutionary conservation to functional observations from three-dimensional structures, provides all available allelic frequencies, clinical observations and references for functional studies. Compared to software classically used in analysis pipelines on a dataset of 141 well-characterized missense variants, CYSMA was the most efficient tool to discriminate benign missense variants, with a specificity of 85%, and a very good sensitivity of 89%. These results suggest that such integrative tools could be adapted to numbers of genes involved in Mendelian disorders to improve the interpretation of missense variants identified in the context of diagnosis. This article is protected by copyright. All rights reserved.

PMID: 31674704 [PubMed - as supplied by publisher]

Excess mucus viscosity and airway dehydration impact COPD airway clearance.

Eur Respir J. 2019 Oct 31;:

Authors: Lin VY, Kaza N, Birket SE, Kim H, Edwards LJ, LaFontaine J, Liu L, Mazur M, Byzek SA, Hanes J, Tearney GJ, Raju SV, Rowe SM

Abstract
The mechanisms by which cigarette smoking impairs airway mucus clearance are not well understood. We recently established a ferret model of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) exhibiting chronic bronchitis. We investigated the effects of cigarette smoke on mucociliary transport (MCT).Adult ferrets were exposed to cigarette smoke for 6 months, with in vivo mucociliary clearance (MCC) measured by Tc-labeled DTPA (Tc-DTPA) retention. Excised tracheae were imaged with micro-optical coherence tomography. Mucus changes in primary human airway epithelial cells and ex vivo ferret airways were assessed by histology and particle tracking microrheology. Linear mixed models for repeated measures identified key determinants of MCT.Compared to air controls, cigarette smoke-exposed ferrets exhibited mucus hypersecretion, delayed MCC (-89.0%, p<0.01), and impaired tracheal MCT (-29.4%, p<0.05). Cholinergic stimulus augmented airway surface liquid (ASL) depth (5.8±0.3 to 7.3±0.6 µm, p<0.0001) and restored MCT (6.8±0.8 to 12.9±1.2 mm·min-1, p<0.0001). Mixed model analysis controlling for covariates indicated smoking exposure, mucus hydration (ASL) and CBF were important predictors of MCT. Ferret mucus was hyperviscous following smoke exposure in vivo or in vitro and contributed to diminished MCT. Primary cells from smokers with and without COPD recapitulated these findings, which persisted despite the absence of continued smoke exposure.Cigarette smoke impairs MCT by inducing airway dehydration and increased mucus viscosity, and can be partially abrogated by cholinergic secretion of fluid secretion. These data elucidate the detrimental effects of cigarette smoke exposure on mucus clearance and suggest additional avenues for therapeutic intervention.

PMID: 31672759 [PubMed - as supplied by publisher]

Differences in clinical outcomes of paediatric cystic fibrosis patients with and without meconium ileus.

J Cyst Fibros. 2019 Oct 28;:

Authors: Tan SMJ, Coffey MJ, Ooi CY

Abstract
BACKGROUND: Meconium ileus (MI) affects up to 20% of newborns with cystic fibrosis (CF). We compared clinical outcomes between Australian paediatric CF patients with and without meconium ileus (non-MI).
METHODS: This was a retrospective case-control study of MI and non-MI patients in New South Wales, Australia, from 1988 to 2010. MI patients were matched 1:1 with pancreatic insufficient non-MI patients for age, sex and CF clinic. Clinical measurements, nutrition and gastrointestinal outcomes over this period were compared between groups using linear mixed models for continuous variables to account for age.
RESULTS: There were 162 matched pairs (N=324, 52% female) with mean (SD) age of 15.3 (8.2) and 14.9 (7.9) years for MI and non-MI patients respectively (P=0.6). MI patients aged 5-23 had poorer FEV1% compared to non-MI patients (estimate -0.070 SE [0.02], P=0.003). There were no significant differences in P. aeruginosa isolation rates; however S. aureus isolation rates were lower in MI patients (72%) compared to non-MI (82%) (OR 0.6 [0.3-1.0], P=0.03). Chronic colonisation rates for P. aeruginosa and S. aureus were not significantly different between groups. MI patients aged 2-20 had significantly lower BMI Z-scores over time (estimate -0.25 SE [0.1], P=0.02). MI patients were more likely to receive oral feed supplements (OR 2.8 [1.4-6.1], P=0.003) and gastrostomy formation (OR 4.4 [1.1-24.6], P=0.02).
CONCLUSIONS: CF patients with MI may have worse lung function, growth and nutrition than non-MI patients over time. Meconium ileus may be an early poor prognostic factor for CF.

PMID: 31672555 [PubMed - as supplied by publisher]

Risk factors for progression of structural lung disease in school-age children with cystic fibrosis.

J Cyst Fibros. 2019 Oct 28;:

Authors: Svedberg M, Gustafsson P, Tiddens H, Imberg H, Pivodic A, Lindblad A

Abstract
BACKGROUND: Computed tomography (CT) is used to monitor progression of structural lung disease (SLD) in children with cystic fibrosis (CF). Our goals were to identify the risk factors for the annual progression of SLD and the impacts of airway pathogens on SLD.
METHOD: Seventy-five school-aged children diagnosed with CF underwent 200 CT scans at Gothenburg CF Centre in the period 2003-2015. SLD was evaluated with a quantitative scoring system. Mixed models were used to calculate the yearly progression rates of SLD and FEV1 and to analyse the effects of common airway pathogens in CF.
RESULTS: The yearly mean progression (95% CI) rates for total disease (%Dis), bronchiectasis (%Be), and FEV1 were 0.62 (0.38-0.86), 0.43 (0.28-0.58) and -0.16 (-0.18-0.13), respectively. Adjusting for airway pathogens, the yearly mean progression rates for %Dis, %Be and FEV1 were 0.23 (-0.04-0.51), 0.12 (0.00-0.25), and -0.12 (-0.16-0.08), respectively. A single infection with P aeruginosa was associated with significant increase in lung damage, assessed as %Dis (p = 0.044) and%Be (p = 0.0047), but not in FEV1 (p = 0.96). At age of 7 years, there was a good correlation between the extent of SLD and subsequent progression of %Dis (r = 0.63, p = 0.0042) and %Be (r = 0.74, p = 0.0057) while there was no significant correlation between the FEV1 and the rate of decline of FEV1 (r = -0.22, p = 0.12).
CONCLUSION: Intermittent respiratory infections with P aeruginosa were associated with significant SLD but no change in FEV1. More SLD at the age of 7 years signals a higher progression rate of SLD subsequently.

PMID: 31672554 [PubMed - as supplied by publisher]

Non-cystic fibrosis bronchiectasis in children and adolescents: Neglected and emerging issues.

Pediatr Neonatol. 2019 Oct 11;:

Authors: Poeta M, Maglione M, Borrelli M, Santamaria F

Abstract
Pediatric non-cystic fibrosis (CF) bronchiectasis is characterized by endobronchial suppuration, airway neutrophilic inflammation and poor mucus clearance and is associated with persistent productive cough due to recurrent airway infections. Most recommendations are based on expert opinion or extrapolated from CF practice. The present narrative review aims to address some issues on the management of children or adolescents with non CF-bronchiectasis that still require attention, and analyze what available literature offers to reply to open questions. We focused on the potential offered by technological advances on lung disease assessment through novel chest imaging techniques and new or old pulmonary function tests. We also summarized the main novelties in the disease prevention and treatment. Finally, a novel diagnostic algorithm is proposed, that might help physicians in the daily clinical decision-making process. Future directions for research on pediatric non-CF bronchiectasis should include larger study populations and longer prospective clinical trials, as well as new clinical and laboratory endpoints to determine the underlying mechanisms of lung disease progression and support the role of new and existing treatments.

PMID: 31672477 [PubMed - as supplied by publisher]

Improved detection of CFTR variants by targeted next-generation sequencing in male infertility: a case series.

Reprod Biomed Online. 2019 Aug 22;:

Authors: Smits R, Oud M, Vissers L, Lugtenberg D, Braat D, Fleischer K, Ramos L, D'Hauwers K

Abstract
RESEARCH QUESTION: Congenital bilateral absence of vas deferens (CBAVD) is characterized by 'obstructive azoospermia' in male patients with primary infertility. In the routine clinical workup of infertile men, patients with an absence of vas deferens are screened for CFTR variants. However, current genetic testing panels do not cover all variants, missing some CBAVD cases. Here, CFTR testing was explored by targeted next-generation sequencing (NGS) to improve variant detection.
DESIGN: Five individuals with heterozygous pathogenic CFTR variants were identified using targeted NGS in a cohort of 1112 idiopathic infertile men with azoospermia or severe oligozoospermia. Pre-screening exclusion criteria were CBAVD by clinical examination with positive CFTR sequence analysis as part of routine fertility workup.
RESULTS: Cases 1, 2 and 3 presented with CBAVD after which CFTR screening by mutation panel analysis was negative. Case 4 presented with congenital unilateral absence of vas deferens, after which CFTR panel analysis identified a heterozygous p.(Phe508del) variant. Case 5 presented with a palpable vas deferens so CFTR panel analysis was not offered. In all five men, targeted NGS revealed additional pathogenic variants: p.(Arg117Cys) and p.(Arg1158*) (case 1); p.(Asp110His) and p.(Ser945Leu) (case 2); p.(Arg248Thr) and p.(Phe508Cys) (case 3); p.(Gly463Ser) (case 4); p.(Phe508del) (case 4 and 5); and p.(Arg117His) (case 5).
CONCLUSIONS: Targeted NGS led to the detection of five infertile men with CFTR variants who would otherwise have remained undiagnosed after routine genetic screening during the fertility workup for azoospermia or severe oligozoospermia. Given the wide availability of affordable targeted NGS, the data suggest that full gene analysis, and not mutation panels, should be considered to screen CFTR in azoospermic men.

PMID: 31672438 [PubMed - as supplied by publisher]

Isolation, Characterization, Differentiation and Immunomodulatory Capacity of Mesenchymal Stromal/Stem Cells from Human Perirenal Adipose Tissue.

Cells. 2019 Oct 29;8(11):

Authors: Baer PC, Koch B, Hickmann E, Schubert R, Cinatl J, Hauser IA, Geiger H

Abstract
Mesenchymal stromal/stem cells (MSCs) are immature multipotent cells, which represent a rare population in the perivascular niche within nearly all tissues. The most abundant source to isolate MSCs is adipose tissue. Currently, perirenal adipose tissue is rarely described as the source of MSCs. MSCs were isolated from perirenal adipose tissue (prASCs) from patients undergoing tumor nephrectomies, cultured and characterized by flow cytometry and their differentiation potential into adipocytes, chondrocytes, osteoblasts and epithelial cells. Furthermore, prASCs were stimulated with lipopolysaccharide (LPS), lipoteichoic acid (LTA) or a mixture of cytokines (cytomix). In addition, prASC susceptibility to human cytomegalovirus (HCMV) was investigated. The expression of inflammatory readouts was estimated by qPCR and immunoassay. HCMV infection was analyzed by qPCR and immunostaining. Characterization of cultured prASCs shows the cells meet the criteria of MSCs and prASCs can undergo trilineage differentiation. Cultured prASCs can be induced to differentiate into epithelial cells, shown by cytokeratin 18 expression. Stimulation of prASCs with LPS or cytomix suggests the cells are capable of initiating an inflammation-like response upon stimulation with LPS or cytokines, whereas, LTA did not induce a significant effect on the readouts (ICAM-1, IL-6, TNFα, MCP-1 mRNA and IL-6 protein). HCMV broadly infects prASCs, showing a viral load dependent cytopathological effect (CPE). Our current study summarizes the isolation and culture of prASCs, clearly characterizes the cells, and demonstrates their immunomodulatory potential and high permissiveness for HCMV.

PMID: 31671899 [PubMed - in process]

Clinical significance of Pseudomonas aeruginosa 2-alkyl-4-quinolone quorum-sensing signal molecules for long-term outcomes in adults with cystic fibrosis.

J Med Microbiol. 2019 Oct 31;:

Authors: Webb K, Fogarty A, Barrett DA, Nash EF, Whitehouse JL, Smyth AR, Stewart I, Knox A, Williams P, Halliday N, Cámara M, Barr HL

Abstract
Introduction. Pseudomonas aeruginosa is an important respiratory pathogen in cystic fibrosis (CF), which is associated with an accelerated decline in lung function, frequent pulmonary exacerbations and increased mortality. P. aeruginosa produces intercellular signalling molecules including 2-alkyl-4-quinolones (AQs), which regulate virulence-factor production and biofilm formation in the CF airways. Studies have shown that AQs are detectable in the sputum and plasma of adults with CF and chronic pulmonary P. aeruginosa.Aim. We tested the hypothesis that the presence of six AQs in plasma or sputum obtained from adults with CF was associated with long-term adverse clinical outcomes.Methodology. We analysed clinical data over an 8 year follow period for 90 people with CF who had previously provided samples for AQ analysis at clinical stability. The primary outcome was all cause mortality or lung transplantation. Secondary outcomes were the rate of lung-function decline and the number of intravenous (IV) antibiotic days for pulmonary exacerbations.Results. There was no statistical association between the presence of any of the six measured AQs and the primary outcomes or the secondary outcome of decline in lung function. One of the six AQs was associated with IV antibiotic usage. The presence of 2-nonyl-3-hydroxy-4(1 h)-quinolone (C9-PQS) in sputum was associated with an increase in the number of IV antibiotic days in the follow-up period (Mann-Whitney; P=0.011).Conclusion. Further investigation to confirm the hypothesis that C9-PQS may be associated with increased antibiotic usage for pulmonary exacerbations is warranted as AQ-dependent signalling is a potential future target for anti-virulence therapies.

PMID: 31671047 [PubMed - as supplied by publisher]

Realizing the Dream of Molecularly Targeted Therapies for Cystic Fibrosis.

N Engl J Med. 2019 Oct 31;:

Authors: Collins FS

PMID: 31670919 [PubMed - as supplied by publisher]

PEGylated mucus-penetrating nanocrystals for lung delivery of a new FtsZ inhibitor against Burkholderia cenocepacia infection.

Nanomedicine. 2019 Oct 25;:102113

Authors: Costabile G, Provenzano R, Azzalin A, Scoffone VC, Chiarelli LR, Rondelli V, Grillo I, Zinn T, Lepioshkin A, Savina S, Miro A, Quaglia F, Makarov V, Coenye T, Brocca P, Riccardi G, Buroni S, Ungaro F

Abstract
C109 is a potent but poorly soluble FtsZ inhibitor displaying promising activity against Burkholderia cenocepacia, a high-risk pathogen for cystic fibrosis (CF) sufferers. To harness C109 for inhalation, we developed nanocrystal-embedded dry powders for inhalation suspension consisting in C109 nanocrystals stabilized with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) embedded in hydroxypropyl-β-cyclodextrin (CD). The powders could be safely re-dispersed in water for in vitro aerosolization. Owing to the presence of a PEG shell, the rod shape and the peculiar aspect ratio, C109 nanocrystals were able to diffuse through artificial CF mucus. The promising technological features were completed by encouraging in vitro/in vivo effects. The formulations displayed no toxicity towards human bronchial epithelial cells and were active against planktonic and sessile B. cenocepacia strains. The efficacy of C109 nanosuspensions in combination with piperacillin was confirmed in a Galleria mellonella infection model, strengthening their potential for combined therapy of B. cenocepacia lung infections.

PMID: 31669084 [PubMed - as supplied by publisher]

Is meconium ileus associated with worse outcomes in cystic fibrosis?

J Cyst Fibros. 2019 Oct 25;:

Authors: Sathe M, Houwen R

PMID: 31668933 [PubMed - as supplied by publisher]

Complete nontuberculous mycobacteria whole genomes using an optimized DNA extraction protocol for long-read sequencing.

BMC Genomics. 2019 Oct 30;20(1):793

Authors: Bouso JM, Planet PJ

Abstract
BACKGROUND: Nontuberculous mycobacteria (NTM) are a major cause of pulmonary and systemic disease in at-risk populations. Gaps in knowledge about transmission patterns, evolution, and pathogenicity during infection have prompted a recent surge in genomic NTM research. Increased availability and affordability of whole genome sequencing (WGS) techniques provide new opportunities to sequence and construct complete bacterial genomes faster and at a lower cost. However, extracting large quantities of pure genomic DNA is particularly challenging with NTM due to its slow growth and recalcitrant cell wall. Here we report a DNA extraction protocol that is optimized for long-read WGS of NTM, yielding large quantities of highly pure DNA with no additional clean-up steps.
RESULTS: Our DNA extraction method was compared to 6 other methods with variations in timing of mechanical disruption and enzymatic digestion of the cell wall, quantity of matrix material, and reagents used in extraction and precipitation. We tested our optimized method on 38 clinical isolates from the M. avium and M. abscessus complexes, which yielded optimal quality and quantity measurements for Oxford Nanopore Technologies sequencing. We also present the efficient completion of circularized M. avium subspecies hominissuis genomes using our extraction technique and the long-read sequencing MinION platform, including the identification of a novel plasmid.
CONCLUSIONS: Our optimized extraction protocol and assembly pipeline was both sufficient and efficient for genome closure. We expect that our finely-tuned extraction method will prove to be a valuable tool in long-read sequencing and completion of mycobacterial genomes going forward. Utilization of comprehensive, long-read based approaches will advance the understanding evolution and pathogenicity of NTM infections.

PMID: 31666009 [PubMed - in process]

Identification of CFTR variants in Latino patients with cystic fibrosis from the Dominican Republic and Puerto Rico.

Pediatr Pulmonol. 2019 Oct 30;:

Authors: Zeiger AM, McGarry ME, Mak ACY, Medina V, Salazar S, Eng C, Liu AK, Oh SS, Nuckton TJ, Jain D, Blackwell TW, Kang HM, Abecasis G, Oñate LC, Seibold MA, Burchard EG, Rodriguez-Santana J

Abstract
BACKGROUND: In cystic fibrosis (CF), the spectrum and frequency of CFTR variants differ by geography and race/ethnicity. CFTR variants in White patients are well-described compared with Latino patients. No studies of CFTR variants have been done in patients with CF in the Dominican Republic or Puerto Rico.
METHODS: CFTR was sequenced in 61 Dominican Republican patients and 21 Puerto Rican patients with CF and greater than ​​​​60 mmol/L sweat chloride. The spectrum of CFTR variants was identified and the proportion of patients with 0, 1, or 2 CFTR variants identified was determined. The functional effects of identified CFTR variants were investigated using clinical annotation databases and computational prediction tools.
RESULTS: Our study found 10% of Dominican patients had two CFTR variants identified compared with 81% of Puerto Rican patients. No CFTR variants were identified in 69% of Dominican patients and 10% of Puerto Rican patients. In Dominican patients, there were 19 identified CFTR variants, accounting for 25 out of 122 disease alleles (20%). In Puerto Rican patients, there were 16 identified CFTR variants, accounting for 36 out of 42 disease alleles (86%) in Puerto Rican patients. Thirty CFTR variants were identified overall. The most frequent variants for Dominican patients were p.Phe508del and p.Ala559Thr and for Puerto Rican patients were p.Phe508del, p.Arg1066Cys, p.Arg334Trp, and p.I507del.
CONCLUSIONS: In this first description of the CFTR variants in patients with CF from the Dominican Republic and Puerto Rico, there was a low detection rate of two CFTR variants after full sequencing with the majority of patients from the Dominican Republic without identified variants.

PMID: 31665830 [PubMed - as supplied by publisher]

Risk factors for development of aminoglycoside resistance among gram-negative rods.

Am J Health Syst Pharm. 2019 Oct 30;76(22):1838-1847

Authors: Richter SE, Miller L, Needleman J, Uslan DZ, Bell D, Watson K, Humphries R, McKinnell JA

Abstract
PURPOSE: Development of scoring systems to predict the risk of aminoglycoside resistance and to guide therapy is described.
METHODS: Infections due to aminoglycoside-resistant gram-negative rods (AR-GNRs) are increasingly common and associated with adverse outcomes; selection of effective initial antibiotic therapy is necessary to reduce adverse consequences and shorten length of stay. To determine risk factors for AR-GNR recovery from culture, cases of GNR infection among patients admitted to 2 institutions in a major academic hospital system during the period 2011-2016 were retrospectively analyzed. Gentamicin and tobramycin resistance (GTR-GNR) and amikacin resistance (AmR-GNR) patterns were analyzed separately. A total of 26,154 GNR isolates from 12,516 patients were analyzed, 6,699 of which were GTR, and 2,467 of which were AmR.
RESULTS: In multivariate analysis, risk factors for GTR-GNR were presence of weight loss, admission from another medical or long-term care facility, a hemoglobin level of <11 g/dL, receipt of any carbapenem in the prior 30 days, and receipt of any fluoroquinolone in the prior 30 days (C statistic, 0.63). Risk factors for AmR-GNR were diagnosis of cystic fibrosis, male gender, admission from another medical or long-term care facility, ventilation at any point prior to culture during the index hospitalization, receipt of any carbapenem in the prior 30 days, and receipt of any anti-MRSA agent in the prior 30 days (C statistic, 0.74). Multinomial and ordinal models demonstrated that the risk factors for the 2 resistance patterns differed significantly.
CONCLUSION: A scoring system derived from the developed risk prediction models can be applied by providers to guide empirical antimicrobial therapy for treatment of GNR infections.

PMID: 31665763 [PubMed - in process]