The immediate effects of a single autogenic drainage session on ventilatory mechanics in adult subjects with cystic fibrosis.

PLoS One. 2018;13(3):e0195154

Authors: Wallaert E, Perez T, Prevotat A, Reychler G, Wallaert B, Le Rouzic O

Abstract
INTRODUCTION: The aim of this study was to gain insight into the physiological changes occurring in subjects with cystic fibrosis (CF) after autogenic drainage (AD). Changes in respiratory system resistance (Rrs), reactance (Xrs), and spirometry were analyzed in adult CF subjects after a single AD physiotherapy session.
METHODS: This prospective observational study was conducted during the annual check-up of adult CF subjects in stable condition. Spirometry and Rrs and Xrs measurements using the forced oscillations technique at 5, 11, and 19 hertz (Hz) were performed before and 30 min after a 20-min AD session. Control CF subjects were tested at baseline and 50 min without AD. Results are expressed as mean ± standard deviation or median [interquartile range].
RESULTS: Thirty subjects were included in the physiotherapy group (age 29 [25-34] years, forced expiratory volume in 1 s (FEV1) 40.3 [30.1-57.9]% predicted) and 11 in the control group (age 31 [28.5-36.5] years, FEV1 43.6 [31.1-51.9] % predicted). No significant changes in any parameter were observed in the control group. AD modestly but significantly increased the forced vital capacity (FVC) and FEV1 (p<0.001). Inspiratory resistance was also significantly improved by AD: Rrs5 from 5.74±2.39 to 5.24±2.17 cmH2O/L/s, p<0.05; Rrs11 from 4.83±1.98 to 4.32±1.7 cmH2O/L/s, p = 0.003; and Rrs19 from 4.18 [3.46-5.07] to 3.86 [2.76-4.98] cmH2O/L/s, p<0.001. In contrast, AD had no significant effects on frequency dependence of resistance (Rrs5-Rrs19) or expiratory resistance. Inspiratory Xrs5, but not ΔXrs5 (expiratory-inspiratory Xrs), was improved by AD (p<0.05). Moderate correlations were detected between the improvement in FEV1 and FVC and inspiratory resistance (r = 0.53, p = 0.005 and r = 0.44, p = 0.02, respectively).
CONCLUSION: A single session of AD improved inspiratory airway resistance, except in the distal airways. The forced oscillations technique provides a new tool for understanding the pathophysiological effects of airway clearance physiotherapy in CF.

PMID: 29596479 [PubMed - in process]

Chapter 6.3. Studies on Hepatic Metabolic Disorders Driven by ESPGHAN Members: The Case of Alpha1-Antitrypsin Deficiency, Cystic Fibrosis, and Urea Cycle Defects.

J Pediatr Gastroenterol Nutr. 2018 Apr;66 Suppl 1:S129-S133

Authors: Paolella G, Alfano G, Vajro P

PMID: 29596184 [PubMed - in process]

Implementing carrier screening for cystic fibrosis outside the clinic: ethical analysis in the light of the personalist view.

Clin Ter. 2018 Mar-Apr;169(2):e71-e76

Authors: Di Pietro ML, Teleman AA, Gonzalez-Melado FJ, Zace D, Di Raimo FR, Lucidi V, Refolo P

Abstract
BACKGROUND: Cystic Fibrosis (CF) is an autosomal recessive genetic disease. Two models for screening CF are normally used: newborn screening and population-based CF carrier screening. In turn, there are three main models of population-based CF carrier screening: prenatal carrier screening, preconception carrier screening, and carrier screening outside clinical settings.
AIM: To evaluate, in the light of the personalist view, the use of carrier screenings for CF outside the clinic, i.e. in non-clinical settings, such as school and workplaces.
METHODS: Analysis has been carried out according to the "Personalist approach" (also called "Triangular model"), an ethical method for performing ethical analysis within HTA process. It includes factual, anthropological and ethical data in a ''triangular'' normative reflection process.
FINDINGS: Implementing carrier screening for cystic fibrosis outside the clinical settings allows acquisition of knowledge for informing reproductive choices, that can be considered as valuable; benefit-risk ratio seems to be not much favorable; autonomous and responsible decisions can be taken only under certain conditions; economic advantage is difficult to determine; therefore, from a personalist view, implementing carrier screenings outside the clinic seems not to be ethically justified.
CONCLUSIONS: In accordance with the personalist perspective, public health programs providing carrier screenings outside the clinic should not be implemented.

PMID: 29595869 [PubMed - in process]

Cytochrome P450 3A4 induction: lumacaftor versus ivacaftor potentially resulting in significantly reduced plasma concentration of ivacaftor.

Drug Metab Lett. 2018 Mar 27;:

Authors: Schneider EK

Abstract
BACKGROUND & OBJECTIVE: Since release of ivacaftor-lumacaftor several red-flags have been raised that highlight the clinical efficacy of this combination strategy may be be limited due to antagonistic drug-drug interactions. </p><p> Method: The effect of ivacaftor, its major metabolites M1 and M6, lumacaftor and the novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator tezacaftor at 10 µg/mL on the enzymatic activity of the major xenobiotic metabolizing enzymes CYP1A2 and CYP3A4 as well as the minor enzymes CYP2B6 and CYP2C9 was assayed. </p><p> Results: Lumacaftor (3.74 x 105 ± 3.11 x 104 RLU), and ivacaftor-M6 (3.43 x 105 ± 7.61 x 103 RLU) markedly induced the activity of CYP3A4. Ivacaftor (2.22 x 105 ± 3.94 x 104 RLU) showed a lower relative ratio of luminescence units compared to chloramphenicol (3.17 x 105 ± 1.55 x 104 RLU). Interestingly, ivacaftor-M1 (6.74 x 104 ± 3.09 x 104 RLU) and the novel CFTR modulator tezacaftor (2.40 x 104 ± 8.14 x 104 RLU) did not show CYP3A4 induction. In the CYP1A2 and CYP2C9 assay, all metabolites showed a decrease in the ratio of luminescence units compared to the controls. Ivacaftor, its major metabolites, lumacaftor and tezacaftor all showed slight increase in the ratio of luminescence units compared to the control rifampin with CYP2B6. </p><p> Conclusion: All in all, present findings would suggest that, lumacaftor and ivacaftor-M6 are strong inducers of CYP3A4, potentially reducing ivacaftor concentrations; ivacaftor itself induces CYP3A4 to some extent.

PMID: 29595119 [PubMed - as supplied by publisher]

Related Articles

A Simple and Rapid Gene Disruption Strategy in Mycobacterium abscessus: On the Design and Application of Glycopeptidolipid Mutants.

Front Cell Infect Microbiol. 2018;8:69

Authors: Viljoen A, Gutiérrez AV, Dupont C, Ghigo E, Kremer L

Abstract
Little is known about the disease-causing genetic determinants that are used by Mycobacterium abscessus, increasingly acknowledged as an important emerging pathogen, notably in cystic fibrosis. The presence or absence of surface exposed glycopeptidolipids (GPL) conditions the smooth (S) or rough (R) M. abscessus subsp. abscessus (M. abscessus) variants, respectively, which are characterized by distinct infective programs. However, only a handful of successful gene knock-out and conditional mutants have been reported in M. abscessus, testifying that genetic manipulation of this mycobacterium is difficult. To facilitate gene disruption and generation of conditional mutants in M. abscessus, we have designed a one-step single cross-over system that allows the rapid and simple generation of such mutants. Cloning of as small as 300 bp of the target gene allows for efficient homologous recombination to occur without additional exogenous recombination-promoting factors. The presence of tdTomato on the plasmids allows easily sifting out the large background of mutants spontaneously resistant to antibiotics. Using this strategy in the S genetic background and the target gene mmpL4a, necessary for GPL synthesis and transport, nearly 100% of red fluorescent clones exhibited a rough morphotype and lost GPL on the surface, suggesting that most red fluorescent colonies obtained after transformation incorporated the plasmid through homologous recombination into the chromosome. This system was further exploited to generate another strain with reduced GPL levels to explore how the presence of these cell wall-associated glycolipids influences M. abscessus hydrophobicity as well as virulence in the zebrafish model of infection. This mutant exhibited a more pronounced killing phenotype in zebrafish embryos compared to its S progenitor and this effect correlated with the production of abscesses in the central nervous system. Overall, these results suggest that the near-complete absence of GPL on the bacterial surface is a necessary condition for optimal pathogenesis of this mycobacterium. They also suggest that GPL content affects hydrophobicity of M. abscessus, potentially altering the aerosol transmission, which is of particular importance from an epidemiological and clinical perspective.

PMID: 29594066 [PubMed - in process]

Related Articles

C3 glomerulopathy in cystic fibrosis: a case report.

BMC Nephrol. 2018 Mar 28;19(1):73

Authors: Santoro D, Siligato R, Vadalà C, Lucanto M, Cristadoro S, Conti G, Buemi M, Costa S, Sabadini E, Magazzù G

Abstract
BACKGROUND: C3 glomerulonephritis is a rare glomerulopathy characterized at renal biopsy by C3 deposition, alone or with scanty immunoglobulins, as well as by an electron-dense material in mesangium, subendothelial and subepithelial space. An abnormal systemic activation of the alternative pathway of the complement cascade is responsible for the development of the disease if triggered by several possible environmental conditions. We report the first case in literature of a patient affected by cystic fibrosis and C3GN.
CASE PRESENTATION: Our case involves a young woman with cystic fibrosis, who had persistent microscopic hematuria, proteinuria and hypocomplementemia C3 for over three months. Renal biopsy confirmed the diagnosis of C3 glomerulopathy. Complement system dysregulation was tested and resulted in a strong terminal pathway activation proved by high levels of sC5b-9 complex, amounting to 1588 ng/ml (normal value < 400 ng/ml). Next generation sequencing (NGS) showed polymorphism in CFH (p.V62I in SCR1) and THBD (p.A473V), already known as pathogenic for C3GN, as well as a mutation in C3 (p.R102G) associated only with age-related macular degeneration (AMD) so far. Treatment was based on ACE inhibitors and kidney function is currently stable (GFR 50 ml/min, serum creatinine 1.7).
CONCLUSIONS: The co-existence of C3 glomerulopathy in a patient with CF, which is characterized by chronic infection/inflammation, makes this case an interesting model of chronic altered systemic activation of the alternative pathway of the complement cascade.

PMID: 29592796 [PubMed - in process]

Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders.

Genet Med. 2018 Mar 29;:

Authors: Ewans LJ, Schofield D, Shrestha R, Zhu Y, Gayevskiy V, Ying K, Walsh C, Lee E, Kirk EP, Colley A, Ellaway C, Turner A, Mowat D, Worgan L, Freckmann ML, Lipke M, Sachdev R, Miller D, Field M, Dinger ME, Buckley MF, Cowley MJ, Roscioli T

Abstract
PurposeWhole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed individuals and only preliminary data on the cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway.MethodsWES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID).ResultsReanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis.ConclusionEarly application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed individual at a 12-month time point increases total diagnoses by 11%.GENETICS in MEDICINE advance online publication, 29 March 2018; doi:10.1038/gim.2018.39.

PMID: 29595814 [PubMed - as supplied by publisher]

AUDIOME: a tiered exome sequencing-based comprehensive gene panel for the diagnosis of heterogeneous nonsyndromic sensorineural hearing loss.

Genet Med. 2018 Mar 29;:

Authors: Guan Q, Balciuniene J, Cao K, Fan Z, Biswas S, Wilkens A, Gallo DJ, Bedoukian E, Tarpinian J, Jayaraman P, Sarmady M, Dulik M, Santani A, Spinner N, Abou Tayoun AN, Krantz ID, Conlin LK, Luo M

Abstract
PurposeHereditary hearing loss is highly heterogeneous. To keep up with rapidly emerging disease-causing genes, we developed the AUDIOME test for nonsyndromic hearing loss (NSHL) using an exome sequencing (ES) platform and targeted analysis for the curated genes.MethodsA tiered strategy was implemented for this test. Tier 1 includes combined Sanger and targeted deletion analyses of the two most common NSHL genes and two mitochondrial genes. Nondiagnostic tier 1 cases are subjected to ES and array followed by targeted analysis of the remaining AUDIOME genes.ResultsES resulted in good coverage of the selected genes with 98.24% of targeted bases at >15 ×. A fill-in strategy was developed for the poorly covered regions, which generally fell within GC-rich or highly homologous regions. Prospective testing of 33 patients with NSHL revealed a diagnosis in 11 (33%) and a possible diagnosis in 8 cases (24.2%). Among those, 10 individuals had variants in tier 1 genes. The ES data in the remaining nondiagnostic cases are readily available for further analysis.ConclusionThe tiered and ES-based test provides an efficient and cost-effective diagnostic strategy for NSHL, with the potential to reflex to full exome to identify causal changes outside of the AUDIOME test.Genetics in Medicine advance online publication, 29 March 2018; doi:10.1038/gim.2018.48.

PMID: 29595809 [PubMed - as supplied by publisher]

Related Articles

Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort.

Genes Immun. 2018 Mar 28;:

Authors: Shaw KA, Cutler DJ, Okou D, Dodd A, Aronow BJ, Haberman Y, Stevens C, Walters TD, Griffiths A, Baldassano RN, Noe JD, Hyams JS, Crandall WV, Kirschner BS, Heyman MB, Snapper S, Guthery S, Dubinsky MC, Shapiro JM, Otley AR, Daly M, Denson LA, Kugathasan S, Zwick ME

Abstract
In the United States, approximately 5% of individuals with inflammatory bowel disease (IBD) are younger than 20 years old. Studies of pediatric cohorts can provide unique insights into genetic architecture of IBD, which includes Crohn's disease (CD) and ulcerative colitis (UC). Large genome-wide association studies have found more than 200 IBD-associated loci but explain a minority of disease variance for CD and UC. We sought to characterize the contribution of rare variants to disease development, comparing exome sequencing of 368 pediatric IBD patients to publicly available exome sequencing (dbGaP) and aggregate frequency data (ExAC). Using dbGaP data, we performed logistic regression for common variants and optimal unified association tests (SKAT-O) for rare, likely-deleterious variants. We further compared rare variants to ExAC counts with Fisher's exact tests. We did pathway enrichment analysis on the most significant genes from each comparison. Many variants overlapped with known IBD-associated genes (e.g. NOD2). Rare variants were enriched in CD-associated loci (p = 0.009) and showed suggestive enrichment in neutrophil function genes (p = 0.05). Pathway enrichment implicated immune-related pathways, especially cell killing and apoptosis. Variants in extracellular matrix genes also emerged as an important theme in our analysis.

PMID: 29593342 [PubMed - as supplied by publisher]

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Funding Opportunity RFA-HL-19-015 from the NIH Guide for Grants and Contracts. The Physician-Scientist Research Award for Early Stage Investigators is intended to support the independence of physician-scientist faculty committed to academic careers in heart, lung, and blood diseases, and sleep disorders and related implementation research.

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Funding Opportunity PAR-18-734 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity announcement (FOA) is to promote initial establishment of basic science-clinical collaborations by providing small grants to teams of basic scientists, physician scientists, and/or clinicians. These interdisciplinary teams may include but are not limited to the following: developmental biologists, cell biologists, geneticists, genomicists, physician scientists including individuals with DVM/VMD degrees, clinicians, epidemiologists, biostatisticians, and/or bioinformaticists.

Funding Opportunity PAR-18-733 from the NIH Guide for Grants and Contracts. The NIH Common Fund has established the Gabriella Miller Kids First Pediatric Research Program (Kids First) to develop a pediatric research data resource populated by genome sequence and phenotype data that will be of high value for the communities of investigators who study the genetics of childhood cancers and/or structural birth defects. The overall goal of the Gabriella Miller Kids First Pediatric Data Resource is to help researchers understand the underlying mechanisms of these conditions, leading to more refined diagnostic capabilities and ultimately more targeted therapies, as well as to develop an integrated pediatric research data resource by obtaining and aggregating genome sequence and phenotype data for as many relevant structural birth defects and pediatric cancer cohorts as possible and to advance research in this area through the broad sharing of these data with the research community. This FOA is intended to promote meritorious small research projects focused on the development and analyses of childhood cancer and/or structural birth defects datasets that are part of the Kids First Data Resource or could be included in the Kids First Data Resource. Development of statistical methodology appropriate for analyzing genome-wide data relevant to childhood cancer and/or structural birth defects may also be proposed.

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