bluuebunny/crossref_metadata_2025_split huggingface dataset:
Homology-Based Identification of a Mutation in the Coronavirus RNA-Dependent RNA Polymerase That Confers Resistance to Multiple Mutagens
Authors: Sexton Nicole R. , Smith Everett Clinton , Blanc Hervé , Vignuzzi Marco , Peersen Olve B. , Denison Mark R. 
Published: June 2016

ABSTRACT
Positive-sense RNA viruses encode RNA-dependent RNA polymerases (RdRps) essential for genomic replication. With the exception of the large nidoviruses, such as coronaviruses (CoVs), RNA viruses lack proofreading and thus are dependent on RdRps to control nucleotide selectivity and fidelity. CoVs encode a proofreading exonuclease in nonstructural protein 14 (nsp14-ExoN), which confers a greater-than-10-fold increase in fidelity compared to other RNA viruses. It is unknown to what extent the CoV polymerase (nsp12-RdRp) participates in replication fidelity. We sought to determine whether homology modeling could identify putative determinants of nucleotide selectivity and fidelity in CoV RdRps. We modeled the CoV murine hepatitis virus (MHV) nsp12-RdRp structure and superimposed it on solved picornaviral RdRp structures. Fidelity-altering mutations previously identified in coxsackie virus B3 (CVB3) were mapped onto the nsp12-RdRp model structure and then engineered into the MHV genome with [nsp14-ExoN(+)] or without [nsp14-ExoN(−)] ExoN activity. Using this method, we identified two mutations conferring resistance to the mutagen 5-fluorouracil (5-FU): nsp12-M611F and nsp12-V553I. For nsp12-V553I, we also demonstrate resistance to the mutagen 5-azacytidine (5-AZC) and decreased accumulation of mutations. Resistance to 5-FU, and a decreased number of genomic mutations, was effectively masked by nsp14-ExoN proofreading activity. These results indicate that nsp12-RdRp likely functions in fidelity regulation and that, despite low sequence conservation, some determinants of RdRp nucleotide selectivity are conserved across RNA viruses. The results also indicate that, with regard to nucleotide selectivity, nsp14-ExoN is epistatic to nsp12-RdRp, consistent with its proposed role in a multiprotein replicase-proofreading complex.

IMPORTANCE
RNA viruses have evolutionarily fine-tuned replication fidelity to balance requirements for genetic stability and diversity. Responsibility for replication fidelity in RNA viruses has been attributed to the RNA-dependent RNA polymerases, with mutations in RdRps for multiple RNA viruses shown to alter fidelity and attenuate virus replication and virulence. Coronaviruses (CoVs) are the only known RNA viruses to encode a proofreading exonuclease (nsp14-ExoN), as well as other replicase proteins involved in regulation of fidelity. This report shows that the CoV RdRp (nsp12) likely functions in replication fidelity; that residue determinants of CoV RdRp nucleotide selectivity map to similar structural regions of other, unrelated RNA viral polymerases; and that for CoVs, the proofreading activity of the nsp14-ExoN is epistatic to the function of the RdRp in fidelity.
Arabidopsis RNA Polymerases IV and V Are Required To Establish H3K9 Methylation, but Not Cytosine Methylation, on Geminivirus Chromatin
Authors: Jackel Jamie N. , Storer Jessica M. , Coursey Tami , Bisaro David M. 
Published: June 2016

ABSTRACT

In plants, RNA-directed DNA methylation (RdDM) employs small RNAs to target enzymes that methylate cytosine residues. Cytosine methylation and dimethylation of histone 3 lysine 9 (H3K9me2) are often linked. Together they condition an epigenetic defense that results in chromatin compaction and transcriptional silencing of transposons and viral chromatin. Canonical RdDM (Pol IV-RdDM), involving RNA polymerases IV and V (Pol IV and Pol V), was believed to be necessary to establish cytosine methylation, which in turn could recruit H3K9 methyltransferases. However, recent studies have revealed that a pathway involving Pol II and RNA-dependent RNA polymerase 6 (RDR6) (RDR6-RdDM) is likely responsible for establishing cytosine methylation at naive loci, while Pol IV-RdDM acts to reinforce and maintain it. We used the geminivirus
Beet curly top virus
(BCTV) as a model to examine the roles of Pol IV and Pol V in establishing repressive viral chromatin methylation. As geminivirus chromatin is formed
de novo
in infected cells, these viruses are unique models for processes involved in the establishment of epigenetic marks. We confirm that Pol IV and Pol V are not needed to establish viral DNA methylation but are essential for its amplification. Remarkably, however, both Pol IV and Pol V are required for deposition of H3K9me2 on viral chromatin. Our findings suggest that cytosine methylation alone is not sufficient to trigger
de novo
deposition of H3K9me2 and further that Pol IV-RdDM is responsible for recruiting H3K9 methyltransferases to viral chromatin.

IMPORTANCE
In plants, RNA-directed DNA methylation (RdDM) uses small RNAs to target cytosine methylation, which is often linked to H3K9me2. These epigenetic marks silence transposable elements and DNA virus genomes, but how they are established is not well understood. Canonical RdDM, involving Pol IV and Pol V, was thought to establish cytosine methylation that in turn could recruit H3K9 methyltransferases, but recent studies compel a reevaluation of this view. We used BCTV to investigate the roles of Pol IV and Pol V in chromatin methylation. We found that both are needed to amplify, but not to establish, DNA methylation. However, both are required for deposition of H3K9me2. Our findings suggest that cytosine methylation is not sufficient to recruit H3K9 methyltransferases to naive viral chromatin and further that Pol IV-RdDM is responsible.
Retrospective study of imported falciparum malaria in French paediatric intensive care units
Authors: Lanneaux Justine , Dauger Stéphane , Pham Luu-Ly , Naudin Jérôme , Faye Albert , Gillet Yves , Bosdure Emmanuelle , Carbajal Ricardo , Dubos François , Vialet Renaud , Chéron Gérard , Angoulvant François 
Published: June 2016

ObjectiveThe World Health Organization (WHO) severity criteria for paediatric Plasmodium falciparum (Pf) malaria are based on studies in countries of endemic malaria. The relevance of these criteria for other countries remains unclear. We assessed the relevance of these criteria in an industrialised country.DesignRetrospective case-control study.SettingEight French university hospitals, from 2006 to 2012.PatientsChildren with Pf malaria admitted to paediatric intensive care units (cases: n=55) or paediatric emergency departments (controls: n=110).Main outcome measuresDescriptive analysis of WHO severity criteria and major interventions (mechanical ventilation, blood transfusion, fluid challenge, treatment of cerebral oedema, renal replacement therapy). Thresholds were set by receiver operating characteristics curve analysis.ResultsAltered consciousness (71% vs 5%), shock (24% vs 1%), renal failure (20% vs 1%), anaemia <50 g/L (7% vs 2%), acidosis (38% vs 0%), bilirubin level >50 µmol/L (25% vs 8%) and parasitaemia >10% (30% vs 8%) were more frequent in cases (p<0.01). All these criteria were associated with major interventions (p<0.001). Respiratory distress (six cases), and hypoglycaemia (two cases) were infrequent. Thrombocytopenia <50 000/mm3 (46% vs 7%) and anaemia (haemoglobin concentration <70 g/L (41% vs 13%)) were more frequent in cases (p<0.0001).ConclusionsThe WHO severity criteria for paediatric Pf malaria are relevant for countries without endemic malaria. The infrequent but severe complications also provide a timely reminder of the morbidity and mortality associated with this condition worldwide. In non-endemic countries haemoglobin <70 g/L and platelet count <50 000/mm3 could be used as additional criteria to identify children needing high level of care.
Identifying acne treatment uncertainties via a James Lind Alliance Priority Setting Partnership
Authors: Layton Alison , Eady E Anne , Peat Maggie , Whitehouse Heather , Levell Nick , Ridd Matthew , Cowdell Fiona , Patel Mahenda , Andrews Stephen , Oxnard Christine , Fenton Mark , Firkins Lester 
Published: June 2016

ObjectivesThe Acne Priority Setting Partnership (PSP) was set up to identify and rank treatment uncertainties by bringing together people with acne, and professionals providing care within and beyond the National Health Service (NHS).SettingThe UK with international participation.ParticipantsTeenagers and adults with acne, parents, partners, nurses, clinicians, pharmacists, private practitioners.MethodsTreatment uncertainties were collected via separate online harvesting surveys, embedded within the PSP website, for patients and professionals. A wide variety of approaches were used to promote the surveys to stakeholder groups with a particular emphasis on teenagers and young adults. Survey submissions were collated using keywords and verified as uncertainties by appraising existing evidence. The 30 most popular themes were ranked via weighted scores from an online vote. At a priority setting workshop, patients and professionals discussed the 18 highest-scoring questions from the vote, and reached consensus on the top 10.ResultsIn the harvesting survey, 2310 people, including 652 professionals and 1456 patients (58% aged 24 y or younger), made submissions containing at least one research question. After checking for relevance and rephrasing, a total of 6255 questions were collated into themes. Valid votes ranking the 30 most common themes were obtained from 2807 participants. The top 10 uncertainties prioritised at the workshop were largely focused on management strategies, optimum use of common prescription medications and the role of non-drug based interventions. More female than male patients took part in the harvesting surveys and vote. A wider range of uncertainties were provided by patients compared to professionals.ConclusionsEngaging teenagers and young adults in priority setting is achievable using a variety of promotional methods. The top 10 uncertainties reveal an extensive knowledge gap about widely used interventions and the relative merits of drug versus non-drug based treatments in acne management.
Older, vulnerable patient view: a pilot and feasibility study of the patient measure of safety (PMOS) with patients in Australia
Authors: Taylor Natalie , Hogden Emily , Clay-Williams Robyn , Li Zhicheng , Lawton Rebecca , Braithwaite Jeffrey 
Published: June 2016

ObjectivesThe UK-developed patient measure of safety (PMOS) is a validated tool which captures patient perceptions of safety in hospitals. We aimed (1) to investigate the extent to which the PMOS is appropriate for use with stroke, acute myocardial infarction (AMI) and hip fracture patients in Australian hospitals and (2) to pilot the PMOS for use in a large-scale, national study ‘Deepening our Understanding of Quality in Australia’ (DUQuA).ParticipantsStroke, AMI and hip fracture patients (n=34) receiving care in 3 wards in 1 large hospital.Methods2 phases were conducted. First, a ‘think aloud’ study was used to determine the validity of PMOS with this population in an international setting, and to make amendments based on patient feedback. The second phase tested the revised measure to establish the internal consistency reliability of the revised subscales, and piloted the recruitment and administration processes to ensure feasibility of the PMOS for use in DUQuA.ResultsOf the 43 questions in the PMOS, 13 (30%) were amended based on issues patients highlighted for improvement in phase 1. In phase 2, a total of 34 patients were approached and 29 included, with a mean age of 71.3 years (SD=16.39). Internal consistency reliability was established using interitem correlation and Cronbach's α for all but 1 subscale. The most and least favourably rated aspects of safety differed between the 3 wards. A study log was categorised into 10 key feasibility factors, including liaising with wards to understand operational procedures and identify patterns of patient discharge.ConclusionsCapturing patient perceptions of care is crucial in improving patient safety. The revised PMOS is appropriate for use with vulnerable older adult groups. The findings from this study have informed key decisions made for the deployment of this measure as part of the DUQuA study.
Antithrombotic drugs and non-variceal bleeding outcomes and risk scoring systems: comparison of Glasgow Blatchford, Rockall and Charlson scores
Authors: Taha Ali S , McCloskey Caroline , Craigen Theresa , Angerson Wilson J 
Published: June 2016

ObjectivesAntithrombotic drugs (ATDs) cause non-variceal upper gastrointestinal bleeding (NVUGIB). Risk scoring systems have not been validated in ATD users. We compared Blatchford, Rockall and Charlson scores in predicting outcomes of NVUGIB in ATD users and controls.MethodsA total of 2071 patients with NVUGIB were grouped into ATD users (n=851) and controls (n=1220) in a single-centre retrospective analysis. Outcomes included duration of hospital admission, the need for blood transfusion, rebleeding requiring surgery and 30-day mortality.ResultsDuration of admission correlated with all scores in controls, but correlations were significantly weaker in ATD users. Rank correlation coefficients in control versus ATD: 0.45 vs 0.20 for Blatchford; 0.48 vs 0.32 for Rockall and 0.42 vs 0.26 for Charlson (all p<0.001). The need for transfusion was best predicted by Blatchford (p<0.001 vs Rockall and Charlson in both ATD users and controls), but all scores performed less well in ATD users. Area under the receiver operation characteristic curve (AUC) in control versus ATD: 0.90 vs 0.85 for Blatchford; 0.77 vs 0.61 for Rockall and 0.69 vs 0.56 for Charlson (all p<0.005). In predicting surgery, Rockall performed best; while mortality was best predicted by Charlson with lower AUCs in ATD patients than controls (p<0.05). Stratification showed the scores' performance to be age-dependent.ConclusionsBlatchford score was the strongest predictor of transfusion, Rockall's had the strongest correlation with duration of admission and with rebleeding requiring surgery and Charlson was best in predicting 30-day mortality. Modifications of these systems should be explored to improve their efficiency in ATD users.
Dural carotid cavernous fistulas: endovascular treatment and assessment of the correlation between clinical symptoms and the Cognard classification system
Authors: Griauzde Julius , Gemmete Joseph J , Pandey Aditya S , Chaudhary Neeraj 
Published: June 2016

ObjectiveTo present our experience with endovascular treatment of dural carotid cavernous fistulas (DCCFs) and determine if there is a correlation between clinical symptoms and the Cognard classification system.MethodsWe searched our institutional neurovascular database to identify patients treated for DCCFs from January 1995 to May 2015. DCCFs were defined as a vascular shunt between meningeal branches of the internal carotid artery (ICA), external carotid artery (ECA), or both, draining into the cavernous sinus. Clinical symptoms were recorded based on clinical examination. Lesions were classified on angiography using the Cognard and Barrow classification systems. Treatment goal was defined as symptomatic cure based on clinical examination, cure of ophthalmic venous drainage, and cortical venous reflux on angiography.ResultsThe search revealed 37 patients with DCCFs; 32 DCCFs underwent endovascular treatment. The primary treatment goal was met in 30/32 (94%) lesions, with one neurologic complication (1/34; 3%). We identified 31 Cognard IIa fistulas, 4 Cognard IIa+b, 2 Cognard IIb, 7 Barrow B, 7 Barrow C, and 23 Barrow D fistulas. Eye redness, proptosis, and ocular pain were significantly lower in the Cognard IIb group than in the Cognard IIa and IIa+b groups (p=0.0015). Intracranial hemorrhage was more likely in the Cognard IIb group than in the Cognard IIa and IIa+b groups, with marginal significance (p=0.054). No correlation was seen between symptomatology and the Barrow classification.ConclusionsEndovascular treatment of DCCFs has a high degree of clinical success and a low complication rate. The Cognard system is suitable for grading DCCFs as it correlates with presenting symptomatology and venous drainage patterns. The Barrow classification adds no value in grading DCCFs.
A pilot study of neurointerventional research level of evidence and collaboration
Authors: Fargen Kyle M , Mocco J , Spiotta Alejandro M , Rai Ansaar , Hirsch Joshua A 
Published: June 2016

IntroductionNo studies have sought to provide a quantitative or qualitative critique of research in the field of neurointerventional surgery.ObjectiveTo analyze recent publications from theJournal of Neurointerventional Surgery(JNIS) to test a new method for assessing research and collaboration.MethodsWe reviewed allJNISOnline First publications from 25 February 2015 to 24 February 2016. All publications—human or non-human research, systematic reviews, meta-analyses, or literature reviews—were included; editorials and commentaries were excluded. For each publication, study design, number of patients, authors, contributing centers, and study subject were recorded. Level of evidence was defined using a new scale.ResultsA total of 206 articles met inclusion criteria. Only 4% were prospective studies. Twenty-eight per cent of scientific research featured patient series of nine or less. The majority of publications were categorized as low-level evidence (91%). Forty-seven per cent involved individuals from a single center, with 87% having collaboration from three or fewer centers. International collaboration was present in 19%. While 256 institutions from 31 countries were represented, 66% were represented in only one publication.ConclusionsWe queriedJNISOnline First articles from a 1-year period in a pilot study to test a new method of analyzing research quality and collaboration. The methodology appears to adequately quantify the studies into evidence tiers that emulate previously published, widely accepted scales. This may be useful for future comparison of peer-reviewed journals or for studying the quality of research being performed in different disease processes or medical specialties.
Use of medical abbreviations and acronyms: knowledge among medical students and postgraduates
Authors: Awan Safia , Abid Shahab , Tariq Muhammad , Zubairi Ali Bin Sarwar , Kamal Ayeesha , Arshad Sadia , Masood Qamar , Kashif Waqar , Hamid Saeed 
Published: June 2016

Abstract

Introduction
Inappropriate use of abbreviations and acronyms in healthcare has become an international patient safety issue. The aim of this study was to assess the knowledge of medical abbreviations and acronyms among residents of the department of medicine at a tertiary-care hospital.

Methods
Internal medicine residents (IMRs), subspecialty residents (SRs) and students were asked to complete a self-administered questionnaire which comprised standard abbreviations used in medicine and its various subspecialties. Scores obtained by the residents were classified into three categories: &gt;70% correct answers; 50–69% correct answers; &lt;50% correct answers.

Results
A total of 77 IMRs, SRs and medical students participated. Overall, good responses were achieved by 53 (68.8%), 16 (20.8%) attained satisfactory responses, and eight (10.4%) had unsatisfactory scores. The majority of SRs achieved good responses (19/22 (86%)), followed by IMRs (30/40 (75%)) and students (4/15 (26.7%)). Evaluation of their knowledge taken from the list of ‘do not use’ abbreviations showed that 89.6% reported using ‘Q.D.’ instead of ‘once a day’, and 93% used ‘IU’ instead of the entire phrase ‘international unit’. The top five ‘not to use’ abbreviations were ZnSO4, µg, MgSO4, IU and SC, with the frequency 100%, 96%, 94.8%, 93% and 90%, respectively.

Conclusions
This study showed that there is a knowledge gap among trainees in medicine regarding the meaning and usage of common medical abbreviations. We therefore recommend proper education of trainees in medicine to ensure they understand the meaning of abbreviations and are aware of the list of ‘do not use’ abbreviations.
Nucleolin Promotes Heat Shock–Associated Translation of VEGF-D to Promote Tumor Lymphangiogenesis
Authors: Morfoisse Florent , Tatin Florence , Hantelys Fransky , Adoue Aurelien , Helfer Anne-Catherine , Cassant-Sourdy Stephanie , Pujol Françoise , Gomez-Brouchet Anne , Ligat Laetitia , Lopez Frederic , Pyronnet Stephane , Courty Jose , Guillermet-Guibert Julie , Marzi Stefano , Schneider Robert J. , Prats Anne-Catherine , Garmy-Susini Barbara H. 
Published: June 2016

Abstract
The vascular endothelial growth factor VEGF-D promotes metastasis by inducing lymphangiogenesis and dilatation of the lymphatic vasculature, facilitating tumor cell extravasion. Here we report a novel level of control for VEGF-D expression at the level of protein translation. In human tumor cells, VEGF-D colocalized with eIF4GI and 4E-BP1, which can program increased initiation at IRES motifs on mRNA by the translational initiation complex. In murine tumors, the steady-state level of VEGF-D protein was increased despite the overexpression and dephosphorylation of 4E-BP1, which downregulates protein synthesis, suggesting the presence of an internal ribosome entry site (IRES) in the 5′ UTR of VEGF-D mRNA. We found that nucleolin, a nucleolar protein involved in ribosomal maturation, bound directly to the 5′UTR of VEGF-D mRNA, thereby improving its translation following heat shock stress via IRES activation. Nucleolin blockade by RNAi-mediated silencing or pharmacologic inhibition reduced VEGF-D translation along with a subsequent constriction of lymphatic vessels in tumors. Our results identify nucleolin as a key regulator of VEGF-D expression, deepening understanding of lymphangiogenesis control during tumor formation. Cancer Res; 76(15); 4394–405. ©2016 AACR.
Inflammatory Markers of CRP, IL6, TNFα, and Soluble TNFR2 and the Risk of Ovarian Cancer: A Meta-analysis of Prospective Studies
Authors: Zeng Fangfang , Wei Huishan , Yeoh Engkiong , Zhang Zheqing , Ren Ze-Fang , Colditz Graham A. , Tworoger Shelley S. , Su Xuefen 
Published: June 2016

Abstract
Background: There has been growing evidence showing that inflammatory markers play an important role in the development of ovarian cancer. We conducted a meta-analysis on the associations between circulating levels of C-reactive protein (CRP), interleukin 6 (IL6), tumor necrosis factor α (TNFα), and soluble TNFα receptor 2 (TNFR2), and the risk of ovarian cancer.
Methods: A systematic search of PubMed and EMBASE up until January 19, 2016 was conducted to retrieve prospective studies. The summary risk estimates were pooled using random-effects models. The dose–response relationship was assessed using generalized least-squares trend estimation.
Results: Seven nested case–control studies and one prospective cohort study were included in the review. For circulating CRP, women in the highest category had a significantly increased risk of ovarian cancer than women in the lowest category, with no significant between-study heterogeneity [pooled relative risk (RR) = 1.91; 95% confidence intervals (CI) 1.51–2.40; P &lt; 0.001; I2 = 0.0%]. Influence analyses further supported this positive association. A positive dose–response relationship was also observed (pooled RR = 1.15; 95% CI, 1.03–1.30 per 5 mg/L of CRP). Publication bias was found. However, the association persisted after correction using the trim-and-fill method. No significant association was observed for circulating IL6, TNFα, and soluble TNFR2.
Conclusion: This meta-analysis provides evidence that elevated levels of CRP, but not circulating IL6, TNFα, or soluble TNFR2, are significantly associated with an increased risk of ovarian cancer.
Impact: These results suggest that circulating CRP may play a role in the etiology of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 25(8); 1231–9. ©2016 AACR.