Cystic fibrosis transmembrane conductance regulator modulators: precision medicine in cystic fibrosis.

Curr Opin Pediatr. 2018 Mar 13;:

Authors: Burgener EB, Moss RB

Abstract
PURPOSE OF REVIEW: The aim of this study was to describe the newest development in cystic fibrosis (CF) care, CF transmembrane conductance regulator (CFTR) modulator therapies.
RECENT FINDINGS: Phase II results showing CFTR modulator triple therapies are more effective than current CFTR modulators.
SUMMARY: CFTR modulator therapy targets the protein defective in CF and boosts its function, but the drug must match mutation pathobiology. Ivacaftor, a CFTR potentiator, was the first modulator approved in 2012, with impressive improvement in lung function and other measures of disease in patients with gating and other residual function mutations (∼10% of CF patients). In 2015, the combination of lumacaftor, a CFTR corrector, and ivacaftor was approved for patients homozygous for the F508del mutation (∼40-50% of the CF population) with positive but less impressive clinical response and 10-20% incidence of intolerance. A next-generation CFTR corrector, tezacaftor, with ivacaftor equally effective and better tolerated than lumacaftor, has also received US Food and Drug Administration approval. Novel CFTR correctors, entering Phase 3 trials in triple modulator combination with tezacaftor-ivacaftor, appear substantially more effective for patients who are homozygous for the F508del mutation and can provide benefit for patients with a single F508del mutation. This offers promise of effective CFTR modulator therapy for nearly 90% of CF patients.

PMID: 29538046 [PubMed - as supplied by publisher]

Occurrence of Pseudomonas aeruginosa in waters: Implications for patients with cystic fibrosis (CF).

Lett Appl Microbiol. 2018 Mar 14;:

Authors: Caskey S, Stirling J, Moore JE, Rendall JC

Abstract
Chronic P. aeruginosa infection is associated with increased morbidity and mortality in patients with cystic fibrosis (CF). Current understanding of risk factors for acquisition is limited and so the aim of this study was to examine a large sample of environmental waters from diverse sources. Environmental water samples [n= 7904] from jacuzzis, hydrants, swimming pools, hot tubs, plunge pools, bottled natural mineral water (NMW), taps, springs, ice machines, water coolers, bores and showers were examined for the presence of P. aeruginosa. P. aeruginosa was detected in 524/7904 (6.6%) waters examined. Hot tubs [51/243; 20.9%], tap water [3/40; 8%] and jacuzzis [432/5811; 7.4%] were the most likely environments where P. aeruginosa was isolated. P. aeruginosa was isolated from bottled water [2/67; 3%]. Our study highlights the ubiquitous nature of P. aeruginosa in the environment. Given CF patients are frequently counselled to make lifestyle changes to minimize P. aeruginosa exposure, these results have important implications. In particular, the occurrence of P. aeruginosa in tap water highlights the need to disinfect the CF patients' nebuliser after each use. This article is protected by copyright. All rights reserved.

PMID: 29537700 [PubMed - as supplied by publisher]

Response to the authors of the article "Multifocal fixed drug eruption to ceftazidime in a child with cystic fibrosis.

Pediatr Allergy Immunol. 2018 Mar 14;:

Authors: Pipet A, Rochefort-Morel C, Drouet M, Nicolie B, Bernier C, Hoarau C, Marty C, Magnan A

Abstract
We react to your very well-described and documented case of fixed-drug eruption (FDE) to ceftazidime. You assess that "this is the first case of FDE to ceftazidime in a child with cystic fibrosis". This is not completely right. This article is protected by copyright. All rights reserved.

PMID: 29537668 [PubMed - as supplied by publisher]

Preconception risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease.

Cochrane Database Syst Rev. 2018 Mar 14;3:CD010849

Authors: Hussein N, Weng SF, Kai J, Kleijnen J, Qureshi N

Abstract
BACKGROUND: Globally, about five per cent of children are born with congenital or genetic disorders. The most common autosomal recessive conditions are thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease, with higher carrier rates in specific patient populations. Identifying and counselling couples at genetic risk of the conditions before pregnancy enables them to make fully informed reproductive decisions, with some of these choices not being available if genetic counselling is only offered in an antenatal setting. This is an update of a previously published review.
OBJECTIVES: To assess the effectiveness of systematic preconception genetic risk assessment to improve reproductive outcomes in women and their partners who are identified as carriers of thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease in healthcare settings when compared to usual care.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Registers. In addition, we searched for all relevant trials from 1970 (or the date at which the database was first available if after 1970) to date using electronic databases (MEDLINE, Embase, CINAHL, PsycINFO), clinical trial databases (National Institutes of Health, Clinical Trials Search portal of the World Health Organization, metaRegister of controlled clinical trials), and hand searching of key journals and conference abstract books from 1998 to date (European Journal of Human Genetics, Genetics in Medicine, Journal of Community Genetics). We also searched the reference lists of relevant articles, reviews and guidelines and also contacted subject experts in the field to request any unpublished or other published trials.Date of latest search of the registers: 20 June 2017.Date of latest search of all other sources: 16 November 2017.
SELECTION CRITERIA: Any randomised or quasi-randomised controlled trials (published or unpublished) comparing reproductive outcomes of systematic preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease when compared to usual care.
DATA COLLECTION AND ANALYSIS: We identified 25 papers, describing 16 unique trials which were potentially eligible for inclusion in the review. However, after assessment, no randomised controlled trials of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease were found.
MAIN RESULTS: No randomised controlled trials of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease were included. One ongoing trial has been identified which may potentially eligible for inclusion once completed.
AUTHORS' CONCLUSIONS: As no randomised controlled trials of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis, or Tay-Sachs disease were found for inclusion in this review, the research evidence for current policy recommendations is limited to non-randomised studies.Information from well-designed, adequately powered, randomised trials is desirable in order to make more robust recommendations for practice. However, such trials must also consider the legal, ethical, and cultural barriers to implementation of preconception genetic risk assessment.

PMID: 29537064 [PubMed - as supplied by publisher]

Most bicarbonate secretion by Calu-3 cells is mediated by CFTR and independent of pendrin.

Physiol Rep. 2018 Mar;6(5):

Authors: Huang J, Kim D, Shan J, Abu-Arish A, Luo Y, Hanrahan JW

Abstract
Bicarbonate plays an important role in airway host defense, however, its transport mechanisms remain uncertain. Here we examined the relative contributions of the anion channel CFTR (cystic fibrosis transmembrane conductance regulator, ABCC7) and the anion exchanger pendrin (SLC26A4) to HCO3- secretion by the human airway cell line Calu-3. Pendrin and CFTR were both detected in parental Calu-3 cells, although mRNA and protein expression appeared higher for CFTR than for pendrin. Targeting pendrin transcripts with lentiviral shRNA reduced pendrin detection by immunofluorescence staining but did not alter the rates of HCO3- or fluid secretion, HCO3- transport under pH-stat conditions, or net HCO3- flux across basolaterally permeabilized monolayers. Intracellular pH varied with step changes in apical Cl- and HCO3- concentrations in control and pendrin knockdown Calu-3 cells, but not in CFTR deficient cells. Exposure to the proinflammatory cytokine IL-4, which strongly upregulates pendrin expression in airway surface epithelia, had little effect on Calu-3 pendrin expression and did not alter fluid or HCO3- secretion. Similar results were obtained using air-liquid interface and submerged cultures, although CFTR and pendrin mRNA expression were both lower when cells were cultured under submerged conditions. While the conclusions cannot be extrapolated to other airway epithelia, the present results demonstrate that most HCO3- secretion by Calu-3 cells is mediated by CFTR.

PMID: 29536650 [PubMed - in process]

Lung Transplantation in Cystic Fibrosis and the Impact of Extracorporeal Circulation.

Arch Bronconeumol. 2018 Mar 10;:

Authors: Jauregui A, Deu M, Romero L, Roman A, Moreno A, Armengol M, Solé J

Abstract
INTRODUCTION: Lung disease is the major cause of death among cystic fibrosis (CF) patients, affecting 80% of the population. The impact of extracorporeal circulation (ECC) during transplantation has not been fully clarified. This study aimed to evaluate the outcomes of lung transplantation for CF in a single center, and to assess the impact of ECC on survival.
METHODS: We performed a retrospective observational study of all trasplanted CF patients in a single center between 1992 and 2011. During this period, 64 lung transplantations for CF were performed.
RESULTS: Five- and 10-year survival of trasplanted patients was 56.7% and 41.3%, respectively. Pre-transplantation supplemental oxygen requirements and non-invasive mechanical ventilation (NIMV) do not seem to affect survival (P=.44 and P=.63, respectively). Five- and 10-year survival among patients who did not undergo ECC during transplantation was 75.69% and 49.06%, respectively, while in those did undergo ECC during the procedure, 5- and 10-year survival was 34.14% and 29.87%, respectively (P=.001). PaCO2 is an independent risk factor for the need for ECC.
CONCLUSIONS: The survival rates of CF patients undergoing lung transplantation in our hospital are similar to those described in international registries. Survival is lower among patients receiving ECC during the procedure. PaCO2 is a risk factor for the need for ECC during lung transplantation.

PMID: 29534846 [PubMed - as supplied by publisher]

Peptide Nucleic Acids as a Tool for Site-Specific Gene Editing.

Molecules. 2018 Mar 11;23(3):

Authors: Ricciardi AS, Quijano E, Putman R, Saltzman WM, Glazer PM

Abstract
Peptide nucleic acids (PNAs) can bind duplex DNA in a sequence-targeted manner, forming a triplex structure capable of inducing DNA repair and producing specific genome modifications. Since the first description of PNA-mediated gene editing in cell free extracts, PNAs have been used to successfully correct human disease-causing mutations in cell culture and in vivo in preclinical mouse models. Gene correction via PNAs has resulted in clinically-relevant functional protein restoration and disease improvement, with low off-target genome effects, indicating a strong therapeutic potential for PNAs in the treatment or cure of genetic disorders. This review discusses the progress that has been made in developing PNAs as an effective, targeted agent for gene editing, with an emphasis on recent in vivo, nanoparticle-based strategies.

PMID: 29534473 [PubMed - in process]

Related Articles

Health care-associated infections studies project: An American Journal of Infection Control and National Healthcare Safety Network data quality collaboration.

Am J Infect Control. 2017 Dec 01;45(12):1394-1395

Authors: Allen-Bridson K, Gross C, Anttila A, Brooks JE, Hebden JN, Leaptrot D, Ryan G, Scalise E, Smith H, Wright MO

Abstract
This case study is part of a series centered on the Centers for Disease Control and Prevention/National Healthcare Safety Network (NHSN) health care-associated infection (HAI) surveillance definitions. This specific case study focuses on the definitions and protocols used to make HAI infection determinations, such as the infection window period and secondary bloodstream infection attribution period. The case reflects the real-life and complex patient scenarios that infection preventionists (IPs) face when identifying and reporting HAIs to NHSN. The intent of the case study series is to foster standardized application of the NHSN HAI surveillance definitions among IPs and encourage accurate determination of HAI events. An online survey link is provided where participants may confidentially answer questions related to the case study and receive immediate feedback in the form of correct answers and explanations and rationales. Details of the case study, answers, and explanations have been reviewed and approved by NHSN staff. We hope that participants take advantage of this educational offering and thereby gain a greater understanding of NHSN HAI surveillance definitions.

PMID: 29195584 [PubMed - indexed for MEDLINE]

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Whole Exome Sequencing in a Rare Disease: A Patient with Anomalous Left Coronary Artery from the Pulmonary Artery (Bland-White-Garland Syndrome).

OMICS. 2016 05;20(5):325-7

Authors: Hekim N, Batyraliev T, Trujillano D, Wang W, Dandara C, Karben Z, Saygılı Eİ, Çetin Z, Mıhcıoğlu D, Türkmen S, İkidağ MA, Cüce MA, Rolfs A

PMID: 27195969 [PubMed - indexed for MEDLINE]

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Notice NOT-AI-18-021 from the NIH Guide for Grants and Contracts

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Funding Opportunity RFA-FD-18-008 from the NIH Guide for Grants and Contracts. FDA is announcing its intention to receive and consider a single source application for the award of a cooperative agreement in fiscal year 2018 to the University of California-Davis (UC Davis) to support the Western Center for Food Safety (WCFS). The purposes of this continued support are to: 1. Carry out multidisciplinary applied research that addresses "real world" issues related to food safety and food defense, agricultural practices, and the impact of agricultural practices on subsequent food processing associated with FDA-regulated products; 2. Develop and implement outreach and communication programs with stakeholders to identify research needs and to facilitate the utilization of the knowledge produced by the research program; 3. Provide opportunities to leverage additional resources among U.S. government agencies, non-governmental organizations, universities, industry, and consumers to achieve real-world solutions that address food safety and food defense issues. 4. Support the implementation of the Food Safety Modernization Act (FSMA) through research, education, and outreach with particular emphasis on the science behind the standards associated with the produce safety and preventive controls regulation.

Funding Opportunity RFA-AI-18-004 from the NIH Guide for Grants and Contracts. The purpose of this initiative is to support Genomic Centers for Infectious Diseases (GCID) to promote broad use and expand the application of genomics technologies and computational analysis to understand infectious diseases, with an emphasis on pathogens, their interaction with the host and microbiome, and to aid in the development of novel genomics-based tools to diagnose, prevent and treat infectious diseases. The GCID will support innovative technology development in all aspects of genomics, including the use of synthetic and genome editing technologies as well as functional genomics to address basic, translational, and clinically relevant questions in host-pathogen interactions. The knowledge generated, including research data, analytical software tools, computational models, experimental protocols, and reagents, is expected to be widely disseminated to the scientific community through publicly accessible databases and reagent repositories.

Funding Opportunity PA-18-708 from the NIH Guide for Grants and Contracts. The purpose of this funding opportunity is to encourage small businesses to develop technologies and approaches (i.e., novel ways to use new or existing technologies) that will enable researchers to better understand and manipulate the dynamic structure and/or function of brain localized G-protein coupled receptors (GPCRs) and/or potentially identify novel selective and specific agonists, antagonists, or allosteric modulators for these receptor subtypes, with a focus on mental health function or dysfunction. Technologies and approaches aimed at either well characterized receptor subtypes or understudied/orphan receptors would be of potential interest to NIMH.

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