bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Autophagosomal SNARE Protein Syntaxin 17 Is an Essential Factor for the Hepatitis C Virus Life Cycle
Authors: Ren Huimei , Elgner Fabian , Jiang Bingfu , Himmelsbach Kiyoshi , Medvedev Regina , Ploen Daniela , Hildt Eberhard 
Published: April 2016

ABSTRACT

Syntaxin 17 is an autophagosomal SNARE (soluble
N
-ethylmaleimide-sensitive factor attachment protein receptor) protein required for the fusion of autophagosomes with lysosomes to form autolysosomes and thereby to deliver the enclosed contents for degradation. Hepatitis C virus (HCV) induces autophagy. In light of the observation that the number of viral particles formed by HCV-infected cells is much greater than the number of infectious viral particles finally released by HCV-infected cells, the regulation of fusion between autophagosomes and lysosomes might fulfill a key function controlling the number of released virions. HCV-replicating cells possess a decreased amount of syntaxin 17 due to impaired expression and increased turnover of syntaxin 17. Overexpression of syntaxin 17 in HCV-replicating cells diminishes the number of released infectious viral particles and decreases the amount of intracellular retained viral particles by favoring the formation of autolysosomes, in which HCV particles are degraded. Inhibition of lysosomal acidification by bafilomycin rescues the decreased release of virions from syntaxin 17-overexpressing cells, while induction of autophagy by rapamycin enforces the impairment of release under these conditions. Vice versa, inhibition of syntaxin 17 expression by specific small interfering RNAs results in an elevated amount of intracellular retained viral particles and facilitates the release of HCV virions by impairment of autophagosome-lysosome fusion. HCV genome replication, however, is not affected by modulation of syntaxin 17 expression. These data identify syntaxin 17 to be a novel factor controlling the release of HCV. This is achieved by regulation of autophagosome-lysosome fusion, which affects the equilibrium between the release of infectious viral particles and lysosomal degradation of intracellular retained viral particles.

IMPORTANCE
Hepatitis C virus (HCV) induces autophagy. Syntaxin 17 is an autophagosomal SNARE protein required for the fusion of autophagosomes with lysosomes. In HCV-infected cells, a major fraction of the
de novo
-synthesized viral particles is not released but is intracellularly degraded. In this context, the effect of HCV on the amount and distribution of syntaxin 17 and the relevance of syntaxin 17 for the viral life cycle were investigated. This study demonstrates that the amount of syntaxin 17 decreased in HCV-replicating cells. In addition, syntaxin 17 is identified to be a novel factor controlling the release of HCV, and the relevance of autophagosome-lysosome fusion as a regulator of the amount of released viral particles is revealed. Taken together, these findings indicate that syntaxin 17 is involved in the regulation of autophagosome-lysosome fusion and thereby affects the equilibrium between the release of infectious viral particles and the lysosomal degradation of intracellularly retained viral particles.
NOD1 Participates in the Innate Immune Response Triggered by Hepatitis C Virus Polymerase
Authors: Vegna Serena , Gregoire Damien , Moreau Marie , Lassus Patrice , Durantel David , Assenat Eric , Hibner Urszula , Simonin Yannick 
Published: April 2016

ABSTRACT

Hepatitis C virus (HCV) triggers innate immunity signaling in the infected cell. Replication of the viral genome is dispensable for this phenotype, and we along with others have recently shown that NS5B, the viral RNA-dependent RNA polymerase, synthesizes double-stranded RNA (dsRNA) from cellular templates, thus eliciting an inflammatory response, notably via activation of type I interferon and lymphotoxin β. Here, we investigated intracellular signal transduction pathways involved in this process. Using HepaRG cells, a model that largely recapitulates the
in vivo
complexities of the innate immunity receptor signaling, we have confirmed that NS5B triggered increased expression of the canonical pattern recognition receptors (PRRs) specific for dsRNA, namely, RIG-I, MDA5, and Toll-like receptor 3 (TLR3). Unexpectedly, intracellular dsRNA also led to accumulation of NOD1, a receptor classically involved in recognition of bacterial peptidoglycans. NOD1 activation, confirmed by analysis of its downstream targets, was likely due to its interaction with dsRNA and was independent of RIG-I and mitochondrial antiviral signaling protein (MAVS/IPS-1/Cardif/VISA) signaling. It is likely to have a functional significance in the cellular response in the context of HCV infection since interference with the NOD1 pathway severely reduced the inflammatory response elicited by NS5B.

IMPORTANCE
In this study, we show that NOD1, a PRR that normally senses bacterial peptidoglycans, is activated by HCV viral polymerase, probably through an interaction with dsRNA, suggesting that NOD1 acts as an RNA ligand recognition receptor. In consequence, interference with NOD1-mediated signaling significantly weakens the inflammatory response to dsRNA. These results add a new level of complexity to the understanding of the cross talk between different classes of pattern recognition receptors and may be related to certain complications of chronic hepatitis C virus infection.
Multifactorial intervention to prevent cardiovascular disease in patients with early rheumatoid arthritis: protocol for a multicentre randomised controlled trial
Authors: Svensson Annemarie Lyng , Christensen Robin , Persson Frederik , Løgstrup Brian Bridal , Giraldi Annamaria , Graugaard Christian , Fredberg Ulrich , Blegvad Jesper , Thygesen Tina , Hansen Inger Marie Jensen , Colic Ada , Bagdat Döne , Ahlquist Palle , Jensen Hanne Slott , Hørslev-Petersen Kim , Sheetal Ekta , Christensen Torben Grube , Svendsen Lone , Emmertsen Henrik , Ellingsen Torkell 
Published: April 2016

IntroductionCardiovascular morbidity is a major burden in patients with rheumatoid arthritis (RA). In this study, we compare the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment of modifiable risk factors for cardiovascular disease (CVD) in patients with early RA fulfilling the 2010 American College of Rheumatology European League Against Rheumatism (ACR/EULAR) criteria.Methods and analysisThe study is a prospective, randomised, open label trial with blinded end point assessment and balanced randomisation (1:1) conducted in 10 outpatient clinics in Denmark. The primary end point after 5 years of follow-up is a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke and cardiac revascularisation. Secondary outcomes are: the proportion of patients achieving low-density lipoprotein cholesterol <2.5 mmol/L, glycated haemoglobin <48 mmol/mol, blood pressure <140/90 mm  Hg for patients without diabetes and <130/80 mm Hg for patients with diabetes and normoalbuminuria (urinary albumin creatinine ratio <30 mg/g) after 1 year of follow-up and the proportion of patients in each treatment group achieving low RA disease activity after 1 year, defined as a disease activity score C-reactive protein (DAS28-CRP) <3.2 and a DAS28-CRP score <2.6 after 12, 24 and 60 months. Furthermore, all hospitalisations for acute and elective reasons will be adjudicated by the event committee after 12, 24 and 60 months. Three hundred treatment-naive patients with early RA will be randomly assigned (1:1) to receive either conventional treatment administered and monitored by their general practitioner according to national guidelines (control group) or a stepwise implementation administered and monitored in a quarterly rheumatological nurse-administered set-up of behaviour modification and pharmacological therapy targeting (1) hyperlipidaemia, (2) hypertension, (3) hyperglycaemia and (4) microalbuminuria (intervention group).Ethics and disseminationThis protocol is approved by the local ethics committee (DK-S-2014007) and The Danish Health and Medicines Authority. Dissemination will occur through presentations at National and International conferences and publications in international peer-reviewed journals.Trial registration numberNCT02246257
Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol
Authors: Dickstein Yaakov , Leibovici Leonard , Yahav Dafna , Eliakim-Raz Noa , Daikos George L , Skiada Anna , Antoniadou Anastasia , Carmeli Yehuda , Nutman Amir , Levi Inbar , Adler Amos , Durante-Mangoni Emanuele , Andini Roberto , Cavezza Giusi , Mouton Johan W , Wijma Rixt A , Theuretzbacher Ursula , Friberg Lena E , Kristoffersson Anders N , Zusman Oren , Koppel Fidi , Dishon Benattar Yael , Altunin Sergey , Paul Mical 
Published: April 2016

IntroductionThe emergence of antibiotic-resistant bacteria has driven renewed interest in older antibacterials, including colistin. Previous studies have shown that colistin is less effective and more toxic than modern antibiotics. In vitro synergy studies and clinical observational studies suggest a benefit of combining colistin with a carbapenem. A randomised controlled study is necessary for clarification.Methods and analysisThis is a multicentre, investigator-initiated, open-label, randomised controlled superiority 1:1 study comparing colistin monotherapy with colistin–meropenem combination therapy for infections caused by carbapenem-resistant Gram-negative bacteria. The study is being conducted in 6 centres in 3 countries (Italy, Greece and Israel). We include patients with hospital-associated and ventilator-associated pneumonia, bloodstream infections and urosepsis. The primary outcome is treatment success at day 14, defined as survival, haemodynamic stability, stable or improved respiratory status for patients with pneumonia, microbiological cure for patients with bacteraemia and stability or improvement of the Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes include 14-day and 28-day mortality as well as other clinical end points and safety outcomes. A sample size of 360 patients was calculated on the basis of an absolute improvement in clinical success of 15% with combination therapy. Outcomes will be assessed by intention to treat. Serum colistin samples are obtained from all patients to obtain population pharmacokinetic models. Microbiological sampling includes weekly surveillance samples with analysis of resistance mechanisms and synergy. An observational trial is evaluating patients who met eligibility requirements but were not randomised in order to assess generalisability of findings.Ethics and disseminationThe study was approved by ethics committees at each centre and informed consent will be obtained for all patients. The trial is being performed under the auspices of an independent data and safety monitoring committee and is included in a broad dissemination strategy regarding revival of old antibiotics.Trial registration numberNCT01732250 and 2012-004819-31; Pre-results.
Varicella zoster virus-associated morbidity and mortality in Africa: a systematic review protocol
Authors: Hussey Hannah S , Abdullahi Leila H , Collins Jamie E , Muloiwa Rudzani , Hussey Gregory D , Kagina Benjamin M 
Published: April 2016

IntroductionVaricella zoster virus (VZV) causes varicella (chicken pox) and herpes zoster (shingles). Worldwide, these diseases are associated with significant morbidity. Most of the epidemiological data on VZV come from high income countries. There are few data on VZV in Africa, where tropical climates and high HIV/AIDS prevalence rates are expected to impact the epidemiology of VZV. Safe and effective vaccinations for both varicella and herpes zoster exist, but are not routinely used in Africa. There are very few data available on VZV disease burden in Africa to guide the introduction of these vaccines on the continent. Our aim is to conduct a systematic review of the VZV-associated morbidity and mortality in Africa, which will provide critical information that could be used to develop vaccination policies against these diseases in Africa.Methods and analysisElectronic databases will be searched and all studies published after 1974 that meet predefined criteria will be assessed. The primary outcomes for the study are VZV incidence/prevalence, hospitalisation rates and total death rates. The secondary outcome for this study is the proportion of VZV hospitalisations and/or deaths associated with HIV/AIDS. Two reviewers will screen the titles and abstracts, and then independently review the full texts, to determine if studies are eligible for inclusion. A risk of bias and quality assessment tool will be used to score all included studies. Following standardised data extraction, a trend analysis using R-programming software will be conducted to investigate the trend of VZV. Depending on the characteristics of included studies, subgroup analyses will be performed. This review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.Ethics and disseminationAs this is a protocol for a systematic review, which will use already published data, no ethics approval is required. Findings will be disseminated in peer-reviewed journals.Trial registration numberCRD42015026144.
Factors influencing women's attitudes towards antenatal vaccines, group BStreptococcusand clinical trial participation in pregnancy: an online survey
Authors: McQuaid Fiona , Jones Christine , Stevens Zoe , Plumb Jane , Hughes Rhona , Bedford Helen , Voysey Merryn , Heath Paul T , Snape Matthew D 
Published: April 2016

ObjectivesTo explore factors influencing the likelihood of antenatal vaccine acceptance of both routine UK antenatal vaccines (influenza and pertussis) and a hypothetical group BStreptococcus(GBS) vaccine in order to improve understanding of how to optimise antenatal immunisation acceptance, both in routine use and clinical trials.SettingAn online survey distributed to women of childbearing age in the UK.Participants1013 women aged 18–44 years in England, Scotland and Wales.MethodsData from an online survey conducted to gauge the attitudes of 1013 women of childbearing age in England, Scotland and Wales to antenatal vaccination against GBS were further analysed to determine the influence of socioeconomic status, parity and age on attitudes to GBS immunisation, using attitudes to influenza and pertussis vaccines as reference immunisations. Factors influencing likelihood of participation in a hypothetical GBS vaccine trial were also assessed.ResultsWomen with children were more likely to know about each of the 3 conditions surveyed (GBS: 45% vs 26%, pertussis: 79% vs 63%, influenza: 66% vs 54%), to accept vaccination (GBS: 77% vs 65%, pertussis: 79% vs 70%, influenza: 78% vs 68%) and to consider taking part in vaccine trials (37% vs 27% for a hypothetical GBS vaccine tested in 500 pregnant women). For GBS, giving information about the condition significantly increased the number of respondents who reported that they would be likely to receive the vaccine. Health professionals were the most important reported source of information.ConclusionsIncreasing awareness about GBS, along with other key strategies, would be required to optimise the uptake of a routine vaccine, with a specific focus on informing women without previous children. More research specifically focusing on acceptability in pregnant women is required and, given the value attached to input from healthcare professionals, this group should be included in future studies.
Portrait of trauma care in Quebec's rural emergency departments and identification of priority intervention needs to improve the quality of care: a study protocol
Authors: Fleet Richard , Tounkara Fatoumata Korika , Ouimet Mathieu , Dupuis Gilles , Poitras Julien , Tanguay Alain , Fortin Jean Paul , Trottier Jean-Guy , Ouellet Jean , Lortie Gilles , Plant Jeff , Morris Judy , Chauny Jean Marc , Lauzier François , Légaré France 
Published: April 2016

IntroductionTrauma remains the primary cause of death in individuals under 40 years of age in Canada. In Quebec, the Trauma Care Continuum (TCC) has been demonstrated to be effective in decreasing the mortality rate among trauma victims. Although rural citizens are at greater risk for trauma and trauma death, no empirical data concerning the effectiveness of the TCC for the rural population in Quebec are available. The emergency departments (EDs) are important safety nets for rural citizens. However, our data indicate that access to diagnostic support services, such as intensive care units and CT is limited in rural areas. The objectives are to (1) draw a portrait of trauma services in rural EDs; (2) explore geographical variations in trauma care in Quebec; (3) identify adaptable factors that could reduce variation; and (4) establish consensus solutions for improving the quality of care.Methods and analysisThe study will take place from November 2015 to November 2018. A mixed methodology (qualitative and quantitative) will be used. We will include data (2009–2013) from all trauma victims treated in the 26 rural EDs and tertiary/secondary care centres in Quebec. To meet objectives 1 and 2, data will be gathered from the Ministry's Database of the Quebec Trauma Registry Information System. For objectives 3 and 4, the project will use the Delphi method to develop consensus solutions for improving the quality of trauma care in rural areas. Data will be analysed using a Poisson regression to compare mortality rate during hospital stay or death on ED arrival (objectives 1 and 2). Average scores and 95% CI will be calculated for the Delphi questionnaire (objectives 3 and 4).Ethics and disseminationThis protocol has been approved by CSSS Alphonse-Desjardins research ethics committee (Project MP-HDL-2016-003). The results will be published in peer-reviewed journals.
Royal College of General Practitioners Research and Surveillance Centre (RCGP RSC) sentinel network: a cohort profile
Authors: Correa Ana , Hinton William , McGovern Andrew , van Vlymen Jeremy , Yonova Ivelina , Jones Simon , de Lusignan Simon 
Published: April 2016

PurposeThe Royal College of General Practitioners Research and Surveillance Centre (RCGP RSC) is one of the longest established primary care sentinel networks. In 2015, it established a new data and analysis hub at the University of Surrey. This paper evaluates the representativeness of the RCGP RSC network against the English population.Participants and methodThe cohort includes 1 042 063 patients registered in 107 participating general practitioner (GP) practices. We compared the RCGP RSC data with English national data in the following areas: demographics; geographical distribution; chronic disease prevalence, management and completeness of data recording; and prescribing and vaccine uptake. We also assessed practices within the network participating in a national swabbing programme.Findings to dateWe found a small over-representation of people in the 25–44 age band, under-representation of white ethnicity, and of less deprived people. Geographical focus is in London, with less practices in the southwest and east of England. We found differences in the prevalence of diabetes (national: 6.4%, RCPG RSC: 5.8%), learning disabilities (national: 0.44%, RCPG RSC: 0.40%), obesity (national: 9.2%, RCPG RSC: 8.0%), pulmonary disease (national: 1.8%, RCPG RSC: 1.6%), and cardiovascular diseases (national: 1.1%, RCPG RSC: 1.2%). Data completeness in risk factors for diabetic population is high (77–99%). We found differences in prescribing rates and costs for infections (national: 5.58%, RCPG RSC: 7.12%), and for nutrition and blood conditions (national: 6.26%, RCPG RSC: 4.50%). Differences in vaccine uptake were seen in patients aged 2 years (national: 38.5%, RCPG RSC: 32.8%). Owing to large numbers, most differences were significant (p<0.00015).Future plansThe RCGP RSC is a representative network, having only small differences with the national population, which have now been quantified and can be assessed for clinical relevance for specific studies. This network is a rich source for research into routine practice.
Prescribing patterns of combined hormonal products containing cyproterone acetate, levonorgestrel and drospirenone in the UK
Authors: Cea-Soriano Lucía , Wallander Mari-Ann , García Rodríguez Luis Alberto 
Published: April 2016

BackgroundThere are limited data to show the levels of prescribing of combined oral contraceptives (COCs) and other hormonal products containing estrogen/progestogen combinations that may be outside the product licence.AimsTo determine the diagnosis/indication recorded at the time of prescription of cyproterone acetate/ethinylestradiol (CPA/EE) and two COCs, levonorgestrel/EE (LNG/EE) and drospirenone/EE (DRSP/EE).Design and settingRetrospective study using a primary care database, The Health Improvement Network (THIN).MethodsWomen in THIN aged 12–49 years prescribed CPA/EE, LNG/EE or DRSP/EE in 2002–2010 were identified. Overall use of each product and proportion of new users each year were determined. Among new users, database codes were analysed to infer the reason for prescription.ResultsThe proportion of new users of each product in 2002 and 2010, respectively, were: LNG/EE, 2.03% and 2.40%; CPA/EE, 0.45% and 0.27%; and DRSP/EE, 0.27% and 0.56%. Most new users prescribed CPA/EE had a record of acne (51.0% and 79.2% in 2002 and 2010, respectively) or hirsutism (3.0% and 5.0% in 2002 and 2010, respectively); the proportion of new users with a record only for contraception decreased from 32.9% in 2002 to 8.6% in 2010. Among new users prescribed DRSP/EE or LNG/EE in 2010, 43.2% and 30.8% of women, respectively, did not have a record indicating use for contraception.ConclusionsAdherence to prescribing guidelines for CPA/EE has improved over time. A substantial proportion of women using DRSP/EE or LNG/EE had records for hormone-responsive conditions only, suggesting that many women were prescribed these therapies for non-contraceptive use.