bluuebunny/crossref_metadata_2025_split huggingface dataset:
Equine Viperin Restricts Equine Infectious Anemia Virus Replication by Inhibiting the Production and/or Release of Viral Gag, Env, and Receptor via Distortion of the Endoplasmic Reticulum
Authors: Tang Yan-Dong , Na Lei , Zhu Chun-Hui , Shen Nan , Yang Fei , Fu Xian-Qiu , Wang Yu-Hong , Fu Li-Hua , Wang Jia-Yi , Lin Yue-Zhi , Wang Xue-Feng , Wang Xiaojun , Zhou Jian-Hua , Li Cheng-Yao 
Published: August 2014

ABSTRACT
Viperin is an endoplasmic reticulum (ER)-associated multifunctional protein that regulates virus replication and possesses broad antiviral activity. In many cases, viperin interferes with the trafficking and budding of viral structural proteins by distorting the membrane transportation system. The lentivirus equine infectious anemia virus (EIAV) has been studied extensively. In this study, we examined the restrictive effect of equine viperin (eViperin) on EIAV replication and investigated the possible molecular basis of this restriction to obtain insights into the effect of this cellular factor on retroviruses. We demonstrated that EIAV infection of primary equine monocyte-derived macrophages (eMDMs) upregulated the expression of eViperin. The overexpression of eViperin significantly inhibited the replication of EIAV in eMDMs, and knockdown of eViperin transcription enhanced the replication of EIAV in eMDMs by approximately 45.8%. Further experiments indicated that eViperin restricts EIAV at multiple steps of viral replication. The overexpression of eViperin inhibited EIAV Gag release. Both the α-helix domain and radical S-adenosylmethionine (SAM) domain were required for this activity. However, the essential motifs in SAM were different from those reported for the inhibition of HIV-1 Gag by human viperin. Furthermore, eViperin disrupted the synthesis of both EIAV Env and receptor, which consequently inhibited viral production and entry, respectively, and this disruption was dependent on the eViperin α-helix domain. Using immunofluorescence assays and electron microscopy, we demonstrated that the α-helix domain is responsible for the distortion of the endoplasmic reticulum (ER). Finally, EIAV did not exhibit counteracting eViperin at the protein level.

IMPORTANCE
In previous studies, viperin was indicated as restricting virus replications primarily by the inhibition of virus budding. Here, we show that viperin may have multiple antiviral mechanisms, including the reduction of EIAV Gag budding and Env expression, and these activities are dependent on different viperin domains. We especially demonstrate that the overexpression of viperin inhibits EIAV entry by decreasing the level of virus receptor. Therefore, viperin restriction of viruses is determined largely by the dependence of virus on the cellular membrane transportation system.
The N Terminus of the Influenza B Virus Nucleoprotein Is Essential for Virus Viability, Nuclear Localization, and Optimal Transcription and Replication of the Viral Genome
Authors: Sherry Lee , Smith Matt , Davidson Sophie , Jackson David 
Published: August 2014

ABSTRACT

The nucleoprotein (NP) of influenza viruses is a multifunctional protein with essential roles throughout viral replication. Despite influenza A and B viruses belonging to separate genera of the
Orthomyxoviridae
family, their NP proteins share a relatively high level of sequence conservation. However, NP of influenza B viruses (BNP) contains an evolutionarily conserved N-terminal 50-amino-acid extension that is absent from NP of influenza A viruses. There is conflicting evidence as to the functions of the BNP N-terminal extension; however, this has never been assessed in the context of viral infection. We have used reverse genetics to assess the significance of this region on the functions of BNP and virus viability. The truncation of more than three amino acids prevented virus recovery, suggesting that the N-terminal extension is essential for virus viability. Mutational analysis indicated that multiple regions of the protein are involved in the nuclear localization of BNP, with the entire N-terminal extension required for this to function efficiently. Viruses containing mutations in the first 10 residues of BNP demonstrated few differences in nuclear localization; however, the viruses exhibited significant reductions in viral mRNA transcription and genome replication, resulting in significantly attenuated phenotypes. Mutations introduced to ablate a previously reported nuclear localization signal also resulted in a significant decrease in mRNA production during early stages of viral replication. Overall, our results demonstrate that the N-terminal extension of BNP is essential to virus viability not only for directing nuclear localization of BNP but also for regulating viral mRNA transcription and genome replication.

IMPORTANCE
The multifunctional NP of influenza viruses has roles throughout the viral replication cycle; therefore, it is essential for virus viability. Despite high levels of homology between the NP of influenza A and B viruses, the NP of influenza B virus contains an evolutionarily conserved 50-amino-acid N-terminal extension that is absent from the NP of influenza A viruses. In this study, we show that this N-terminal extension is essential for virus viability, and we confirm and expand upon recent findings that this region of BNP is required for nuclear localization of the protein. Furthermore, we demonstrate for the first time that the N terminus of BNP is involved in regulating viral mRNA transcription and replication of the viral genome. As the NP of influenza A virus lacks this N-terminal extension, these viruses may have evolved separate mechanisms to regulate these processes.
Camden active spaces: Does the construction of active school playgrounds influence children's physical activity levels? A longitudinal quasi-experiment protocol
Authors: Smith Lee , Kipps Courtney , Aggio Daniel , Fox Paul , Robinson Nigel , Trend Verena , Munnery Suzie , Kelly Barry , Hamer Mark 
Published: August 2014

IntroductionPhysical activity is essential for every facet of children's health. However, physical activity levels in British children are low. The school environment is a promising setting to increase children's physical activity but limited empirical evidence exists on how a change in the outdoor physical school environment influences physical activity behaviour. The London Borough of Camden is redesigning seven existing school playgrounds to engage children to become more physically active. The primary aim of this project is to evaluate the impact of the redesigned playgrounds on children's physical activity, well-being and physical function/fitness.Method and analysisThis project will use a longitudinal quasi-experimental design. Seven experimental schools and one control school will take part. One baseline data collection session and two follow-ups will be carried out. Between baseline and follow-up, the experimental school playgrounds will be redesigned. At baseline, a series of fitness tests, anthropometric and questionnaire measurements, and 7-day objective physical activity monitoring (Actigraph accelerometer) will be carried out on children (aged 5–16 years). This will be repeated at follow-up. Changes in overall physical activity levels and levels during different times of the day (eg, school breaks) will be examined. Multilevel regression modelling will be used to analyse the data.Ethics and disseminationThe results of this study will be disseminated through peer-review publications and scientific presentations. Ethical approval was obtained through the University College London Research Ethics Committee (Reference number: 4400/002).
A novel approach to Junior Doctor Induction: A near-peer based curriculum developed and delivered by outgoing Foundation year doctors
Authors: Sukcharoen Kittiya , Everson Matthew , van Hamel Clare 
Published: August 2014

AbstractThere is a 4-12% increase in mortality in the month following the start of Foundation Year 1 doctors (FY1s) in the UK. In 2012 the National Health Service announced a compulsory shadowing period for FY1s, aiming to increase familiarity with the environment in which the FY1 would be commencing work. There is no national curriculum of the content for this shadowing period and evidence suggests variable content of induction programmes across the UK.Our project aimed to provide a near-peer induction, based on needs previously identified by a national survey and outgoing FY1s’ experiences. The day consisted of expert-led lectures, interactive practical sessions delivered by outgoing FY1s, and simulated tasks within the clinical environment where they were about to commence work. The day was evaluated by questionnaires distributed to participants before and after the induction to measure whether there was a change in the perceived confidence of the FY1s in different aspects of their role.There was a 61% improvement in familiarity of equipment and knowing how to request investigations. Confidence levels increased by 45% and 28% in prescribing insulin and intravenous fluids, respectively. There was a 9% improvement in feeling adequately prepared to recognise the critically ill patient. Confidence was high in prescribing intravenous fluids (72% pre-induction and 100% post-induction) and simple analgesics (94% pre-induction and 96% post-induction).The induction day improved self-perceived confidence in all measured areas. The largest increase was in the area given most focus during the day - knowledge of the environment. Combining factual content with orientation of the environment increases confidence for new FY1s. Teaching by outgoing FY1s provides insight into what the job entails. We recommend this style of induction to maximise preparedness within a limited time frame.
Does a single dose of intravenous dexamethasone reduce Symptoms in Emergency department patients with low Back pain and RAdiculopathy (SEBRA)? A double-blind randomised controlled trial
Authors: Balakrishnamoorthy Ravichandra , Horgan Isabelle , Perez Siegfried , Steele Michael Craig , Keijzers Gerben B 
Published: August 2014

ObjectiveTo assess the effect of a single dose of intravenous dexamethasone in addition to routine treatment on visual analogue scale (VAS) pain scores at 24 h in emergency department (ED) patients with low back pain with radiculopathy (LBPR).MethodsDouble-blind randomised controlled trial of 58 adult ED patients with LBPR, conducted in one tertiary and one urban ED. The intervention was 8 mg of intravenous dexamethasone (or placebo) in addition to current routine care. The primary outcome was the change in VAS pain scores between presentation and 24 h. Secondary outcomes included VAS pain scores at 6 weeks, ED length of stay (EDLOS), straight leg raise (SLR) angles and Oswestry functional scores.ResultsPatients treated with dexamethasone had a 1.86 point (95% CI 0.31 to 3.42, p=0.019) greater reduction in VAS pain scores at 24 h than placebo (dexamethasone: −2.63 (95% CI −3.63 to −1.63) versus placebo: −0.77 (95% CI −2.04 to 0.51)). At 6 weeks, both groups had similar significant and sustained decrease in VAS scores compared with baseline. Patients receiving dexamethasone had a significantly shorter EDLOS (median: 3.5 h vs 18.8 h, p=0.049) and improved SLR angle at discharge (14.7°, p=0.040). There was no difference in functional scores.ConclusionsIn patients with LBPR, a single dose of intravenous dexamethasone in addition to routine management improved VAS pain scores at 24 h, but this effect was not statistically significant at 6 weeks. Dexamethasone may reduce EDLOS and can be considered as a safe adjunct to standard treatment.Trial registration numberACTRN12611001020976.
ONE YEAR MORTALITY ASSOCIATED WITH THE SIMPLIFIED MISSED SCORE
Authors: Sivayoham Narani , Holmes Paul , Mitchinson Sophie , Cecconi Maurizio , Rhodes Andrew 
Published: August 2014

Objectives & BackgroundEarly recognition and treatment of sepsis in the emergency department (ED) has been shown to reduce mortality. At present, we are able to identify patients who satisfy the septic shock criteria. However, many patients admitted to the intensive care unit (ICU) do not satisfy the shock criteria whilst in the ED yet have a mortality rate of approximately 30% (unpublished internal data). The Mortality In Severe Sepsis in the Emergency Department (MISSED) score was derived and validated in ED patients admitted to the ICU. This score enables identification of patients at high risk of death. The score has now been simplified. The simplified MISSED score is made up of three independent variables which predict mortality in sepsis. They are, age >65 years, a serum albumin <27 g/l and an INR of >1.3. The score ranges from 0 to 3 depending on the number of variables present at presentation in the ED. The simplified MISSED score has been internally validated in 674 ED patients admitted in 2012. The aim of this study is to identify the mortality rate associated with the simplified MISSED score at one year from the index admission.MethodsOf the 674 patients studied in the internal ED validation study, those with active malignancy and those whose final diagnosis was not one of infection were identified from the hospital IT system and excluded. The date a patients was last known to be alive before loss to follow up and dates of death were obtained from the hospital IT system. The in-hospital mortality rates and the one year mortality rates from the date of admission, were calculated for each of the simplified MISSED scores.ResultsOf the 674 patients 100 had active malignancy and a further 44 did not have a final diagnosis of an infection. Thus 144 patients were excluded. The study population consisted of 530 patients. Of the 102 deaths which occurred within a year of the index admission 42 occurred on the index admission. The mortality rates associated with the simplified MISSED scores of 0, 1, 2 and 3 on the index admission were 0.5%, 7.5%, 26.8% and 25% and at one-year were 2.1%, 22.2%, 43.7% and 66.7%, respectively. The hazard ratio for mortality at 1 year for a score of 2 or 3 compared to a score of 0 or 1 was 3.9 [95% confidence interval 2.2–6.9], p<0.0001.ConclusionIn patients admitted with an infection, increasing simplified MISSED scores in the ED were associated with significantly increased mortality rates at one year.Kaplan Meier plot illustrating the one-year survival associated with the simplified MISSED score
THE LONG AND WINDING ROAD: DO PATIENTS DETERIORATE DURING LONG AMBULANCE JOURNEYS TO HOSPITAL
Authors: Thorp Victoria , Kang Sujin , Dykes Linda 
Published: August 2014

Objectives & BackgroundPrevious investigators have demonstrated increased mortality with longer distance from hospital in respiratory patients but it is unclear if these findings are applicable to all patients/conditions. However, it is widely assumed that patients may deteriorate during long journeys, which contributes to fear of service reconfiguration by public and professionals alike. We wished to ascertain whether clinical deterioration occurs during long ambulance journeys (up to 70 miles) to hospital from our rural catchment area.MethodsRetrospective chart review of adult medical/surgical patients arriving at our ED by land ambulance from home. Trauma and psychiatric cases were excluded.Power calculation, based upon a previous pilot study, required a sample of 635 to achieve a power of 0.8 at alpha 0.05, assuming the true partial correlation to be at least 0.15. Spearman's correlation coefficient was used.A convenience sample of 991 patients was used between September 2013–April 2014.The NHS Early Warning Score (NEWS) was used to estimate illness severity on ambulance arrival at scene (“pick-up”) and to ED (“arrival”) and relationship with distance from hospital analysed.We subtracted “arrival” from “pick-up” NEWS as a measure of clinical deterioration, and correlated with distance from hospital.ResultsThere was no statistically significant relationship between clinical deterioration and distance from hospital. When sub-categorised into clinical groups (e.g. respiratory, cardiology etc.) there continued to be no correlation between deterioration en-route and distanceConclusionOur findings suggest that adult patients living further from hospital arenotmore unwell on pick-up, they arenotdeteriorating en-route, and longer journeys to hospital donotnecessarily lead to patients coming to harm.However, we did not explore any relationship to later mortality/morbidity.We appeal to colleagues in those areas of the UK with electronic ambulance records linked to hospital records to repeat this work with a much larger sample and wider range of end-points, in order to provide a definitive answer to this important question.
A Modern Cohort of Duodenal Obstruction Patients: Predictors of Delayed Transition to Full Enteral Nutrition
Authors: Bairdain Sigrid , Yu David C. , Lien Chueh , Khan Faraz Ali , Pathak Bhavana , Grabowski Matthew J. , Zurakowski David , Linden Bradley C. 
Published: August 2014

Background. A common site for neonatal intestinal obstruction is the duodenum. Delayed establishment of enteral nutritional autonomy continues to challenge surgeons and, since early institution of nutritional support is critical in postoperative newborns, identification of patients likely to require alternative nutritional support may improve their outcomes. Therefore, we aimed to investigate risk factors leading to delayed establishment of full enteral nutrition in these patients.Methods. 87 patients who were surgically treated for intrinsic duodenal obstructions from 1998 to 2012 were reviewed. Variables were tested as potential risk factors. Median time to full enteral nutrition was estimated using the Kaplan-Meier method. Independent risk factors of delayed transition were identified using the multivariate Cox proportional hazards regression model.Results. Median time to transition to full enteral nutrition was 12 days (interquartile range: 9–17 days). Multivariate Cox analysis identified three significant risk factors for delayed enteral nutrition: gestational age (GA) ≤ 35 weeks (P < .001), congenital heart disease (CHD) (P=.02), and malrotation (P = .03).Conclusions. CHD and Prematurity are most commonly associated with delayed transition to full enteral nutrition. Thus, in these patients, supportive nutrition should strongly be considered pending enteral nutritional autonomy.
Abstract ES2-2: Triple Negative Breast Cancer: Subtypes, Molecular Targets, and Therapeutic Approaches
Authors: Pietenpol JA 
Published: August 2014

Abstract
The term “triple negative breast cancer” (TNBC) is used to classify 10%–20% of all breast cancers that lack estrogen receptor (ER) and progesterone receptor expression as well as amplification of the human epidermal growth factor receptor 2 (HER2)1. Disease heterogeneity and the absence of well-defined molecular targets have made treatment of TNBC challenging. To make significant clinical advances for TNBC patients, integrative and comprehensive genomic and molecular analyses of TNBC are required to understand the complexity of the disease as well as to allow identification of homogeneous subsets and ‘driver pathways’ that can then be therapeutically targeted. In response to this need, we compiled an extensive number of TNBC gene expression (GE) profiles and initiated molecular subtyping of the disease2. We identified two basal-like TNBC subtypes with cell cycle and DDR GE signatures (BL1 and BL2); two mesenchymal subtypes with high expression of genes involved in differentiation and growth factor pathways (M and MSL); an immunomodulatory (IM) type; and a luminal subtype driven by androgen signaling (LAR). Differential GE was used to designate 25 TNBC cell line models representative of these subtypes. Predicted ‘driver’ signaling pathways were pharmacologically targeted in these preclinical models as proof of concept that analysis of distinct GE signatures can inform therapy selection. Representative BL1 and BL2 subtype cell lines preferentially respond to cisplatin. Mesenchymal, basal, and luminal subtype lines with aberrations in PI3K signaling have the greatest sensitivity, in general, to phosphatidylinositol 3-kinase (PI3K) inhibitors. The LAR subtype cell lines express AR and are uniquely sensitive to bicalutamide (AR antagonist). We have also developed “TNBCtype,” a web-based subtyping tool for candidate TNBC tumor samples using our GE metadata and classification methods3. The approaches used and data generated have value for biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.
1. Dent, R., Trudeau, M., Pritchard, K.I., Hanna, W.M., Kahn, H.K., Sawka, C.A., Lickley, L.A., Rawlinson, E., Sun, P., and Narod, S.A. (2007). Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13, 4429–4434. 2. Lehmann, B.D., Bauer, J.A., Chen, X., Sanders, M.E., Chakravarthy, A.B., Shyr, Y., and Pietenpol, J.A. (2011). Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 121: 2750–67. 3. Chen, X., Li, J., Gray, W.H., Lehmann, B.D., Bauer, J.A., Shyr, Y., and Pietenpol, J.A. (2012). TNBCtype: A Subtyping Tool for Triple-Negative Breast Cancer. Cancer informatics 11, 147–156.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES2-2.
Abstract ES2-3: The Clonal and Mutational Composition of Triple Negative Breast Cancers
Authors: Aparicio S 
Published: August 2014

Abstract
The notion that cancers are mosaics, composed of clones of cells has been fundamental to cancer biology for several decades. Clonal evolution may underpin clinical features of cancer, such as emergence of treatment resistance, the heterogeneous responses of metastatic disease within individual patients and divergence between primary and metastatic disease. Spatial and temporal variation in clonal composition poses significant challenges for diagnostic sampling and disease monitoring. We have recently developed next generation sequencing approaches to these questions and applied them to the understanding of mutational and clonal composition of primary triple negative breast cancers (TNBC). The notion that triple negative breast cancers form a distinct disease entity is already strongly challenged by expression analysis and small scale mutational analysis. Our results show that both the mutational composition and clonal structure of primary triple negative breast cancers is in fact a complete spectrum, exploding the notion of TNBC (currently defined), as a distinct disease. Clonal analysis suggests a means by which the genetic complexity might be reduced by following patient evolution over time and space. I will discuss the specific implications of the mutational and transcriptome landscapes of TNBC in relation to possible disease biologies.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr ES2-3.