bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Herpes Simplex Virus VP11/12 Tyrosine-Based Motifs in Binding and Activation of the Src Family Kinase Lck and Recruitment of p85, Grb2, and Shc
Authors: Strunk Ulrike , Saffran Holly A. , Wu Frederick W. , Smiley James R. 
Published: August 2013

ABSTRACT
Previous studies have shown that the abundant herpes simplex virus 1 (HSV-1) tegument protein VP11/12, encoded by gene UL46, stimulates phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling: it binds the Src family kinase (SFK) Lck, is tyrosine phosphorylated, recruits the p85 subunit of PI3-kinase, and is essential for the activation of Akt during HSV-1 infection. The C-terminal region of VP11/12 contains tyrosine-based motifs predicted to bind the SH2 domains of SFKs (YETV and YEEI), p85 (YTHM), and Grb2 (YENV) and the phosphotyrosine-binding (PTB) domain of Shc (NPLY). We inactivated each of these motifs in the context of the intact viral genome and examined effects on binding and activation of Lck and recruitment of p85, Grb2, and Shc. Inactivating the p85, Grb2, or Shc motif reduced (p85) or eliminated (Grb2 and Shc) the interaction with the cognate signaling molecule without greatly affecting the other interactions or activation of Lck. Inactivating either SFK motif had only a minor effect on Lck binding and little or no effect on recruitment of p85, Grb2, or Shc. In contrast, inactivation of both SFK motifs severely reduced Lck binding and activation and tyrosine phosphorylation of VP11/12 and reduced (p85) or eliminated (Grb2 and Shc) binding of other signaling proteins. Overall, these data demonstrate the key redundant roles of the VP11/12 SFK-binding motifs in the recruitment and activation of SFKs and indicate that activated SFKs then lead (directly or indirectly) to phosphorylation of the additional motifs involved in recruiting p85, Grb2, and Shc. Thus, VP11/12 appears to mimic an activated growth factor receptor.
A Strain-Specific Epitope of Enterovirus 71 Identified by Cryo-Electron Microscopy of the Complex with Fab from Neutralizing Antibody
Authors: Lee Hyunwook , Cifuente Javier O. , Ashley Robert E. , Conway James F. , Makhov Alexander M. , Tano Yoshio , Shimizu Hiroyuki , Nishimura Yorihiro , Hafenstein Susan 
Published: August 2013

ABSTRACT
Enterovirus 71 (EV71) is a picornavirus that causes outbreaks of hand, foot, and mouth disease (HFMD), primarily in the Asia-Pacific area. Unlike coxsackievirus A16, which also causes HFMD, EV71 induces severe neuropathology leading to high fatalities, especially among children under the age of 6 years. Currently, no established vaccines or treatments are available against EV71 infection. The monoclonal antibody MA28-7 neutralizes only specific strains of EV71 that have a conserved glycine at amino acid VP1-145, a surface-exposed residue that maps to the 5-fold vertex and that has been implicated in receptor binding. The cryo-electron microscopy structure of a complex between EV71 and the Fab fragment of MA28-7 shows that only one Fab fragment occupies each 5-fold vertex. A positively charged patch, which has also been implicated in receptor binding, lies within the Fab footprint. We identify the strain-specific epitope of EV71 and discuss the possible neutralization mechanisms of the antibody.
Cerebral blood flow velocity changes during upright positioning in bed after acute stroke: an observational study
Authors: Aries Marcel J , Elting Jan Willem , Stewart Roy , De Keyser Jacques , Kremer Berry , Vroomen Patrick 
Published: August 2013

ObjectivesNational guidelines recommend mobilisation in bed as early as possible after acute stroke. Little is known about the influence of upright positioning on real-time cerebral flow variables in patients with stroke. We aimed to assess whether cerebral blood flow velocity (CBFV) changes significantly after upright positioning in bed in the acute stroke phase.DesignObservational study.Participants47 patients with acute ischaemic stroke measured in the subacute phase after symptom onset and 20 healthy controls.Primary and secondary outcome measuresWe recorded postural changes in bilateral transcranial Doppler (primary outcome) and simultaneously recorded near-infrared spectroscopy, end-tidal CO2, non-invasive blood pressure data and changes in neurological status (secondary outcomes).MethodsPostures included the supine, half sitting (45°), sitting (70°) and Trendelenburg (−15°) positions. Using multilevel analyses, we compared postural changes between hemispheres, outcome groups (using modified Rankin Scale) as well as between patients and healthy controls.ResultsThe mean patient age was 62±15 years and median National Institute of Health Stroke Scale score on admission was 7 (IQR 5–14). Mean proportional CBFV changes on sitting were not significantly different between healthy controls and affected hemispheres in patients with stroke. No significant differences were found between affected and unaffected stroke hemispheres and between patients with unfavourable and favourable outcomes. During upright positioning, no neurological worsening or improvement was observed in any of the patients.ConclusionsNo indications were found that upright positioning in bed in mild to moderately affected patients with stroke compromises flow and (frontal)oxygenation significantly during the subacute phase of stroke. Supine or Trendelenburg positioning does not seem to augment real-time flow variables.
071 Improving CPGs Implementation by Integrative Programs: Example of the Elective Caesarean Section
Authors: Musset S , Martinowsky M , Danscoine A , Bataillon R , Laurence M 
Published: August 2013

BackgroundIn France, one in five women gives birth by caesarean section and in almost half of cases, caesarean section is planned. Elective caesarean is a subject of controversy (some indications, maternal request) and its practice is marked by highly disparities in the country.ObjectiveTo improve the relevant practice of elective caesarean.MethodsIn a short time, an integrative process was developed with systematic reviews, working group of multidisciplinary health professionals and patients, focus group, implementation network.ResultsFor serving the identified needs, we updated guidelines, developed information for/with the patients, and produced implementation tools adapted to the different medical indications. Clinical situations which may lead to a planned caesarean section are varied and complex. For each of them, we redefined the indications of caesarean section or vaginal delivery. For elective caesarean, women should be informed as soon as possible, with provided developed tools, to enable an informed discussion with the caregiver and to improve the maternal experience. The decision elements to report in the medical record were defined and a set of tools with the approach ‘patient journey’ developed: clinical pathways, evaluation criteria of relevance or grids, examples of improvement actions and indicators. In February 2013, more than 183 establishment of health were engaged in the programme.ConclusionsWe provided a set of implementation tools to improve the relevance of planned caesarean section. The continuous feedback by the different actors will allow enriching electronic version tools and sharing knowledge in the field, thus enabling a continuous improvement process.
080 Implantable Miniature Telescope – Implementing Guidelines When Evidence Is Uncertain
Authors: Gupta A , Garg P , Patel D 
Published: August 2013

BackgroundAge-related macular degeneration (AMD) is the third leading cause of blindness in industrialised countries. The heavy burden of the disease, the expected increase in the number of cases, and a lack of effective treatment options highlight the need to examine new therapies. The implantable miniature telescope (IMT) is a potential new treatment for AMD. However, few high-quality studies are currently available to assess its effectiveness. Despite limited evidence, the US Food and Drug Administration (FDA) and Medicare granted regulatory approval, potentially increasing patient demand.ContextIn the context of limited available evidence, but potential patient demand driven by lack of alternatives, a large, US-based integrated healthcare system rapidly developed evidence-based guidance and implementation strategies for IMT.Description of Best PracticeA systematic review was conducted to assess IMT effectiveness. A centralised, collaborative panel of experts was convened based upon clinical expertise, interest in providing IMT surgery, and potential operational volume. Evidence-based recommendations informed rapid development of an implementation strategy over six months. The strategy involved 1) centralised patient review and selection; 2) consent forms that describe benefit vs. harms; and 3) surgical training standards. Rapid development and distribution of the implementation strategy ensured that IMT would be provided in a timely and appropriate clinical context. The centralised process facilitated development of a patient database to track outcomes and inform future research.Lessons for Guideline Developers, Adaptors, Implementers, and/or UsersRapid, collaborative, and evidence-based development of clinical guidance and implementation strategies is an effective model for spreading best practices in an environment of uncertain or low-quality evidence.
082 Effect of Wording and Presentation of Electronic Alerts on Behavior of Providers Caring for Out-of-Control Diabetics
Authors: Stone E , Hsu H 
Published: August 2013

BackgroundGuideline implementation through electronic point-of-care alerting has been shown to be effective. The best displays of these alerts have not been well studied.ObjectivesTo assess the effect of wording and presentation of electronic alerts on insulin ordering by providers caring for out-of-control diabetics on 2 or more oral hypoglycemic agents.MethodsAn electronic message to the provider caring for an out-of-control diabetic was displayed. Prior to randomisation, a generic message was presented to all providers. Health centres were then randomised to 1 of 4 specific messages recommending insulin. Messages differed by wording (active/passive voice) and presentation (black text/red and black text). A 2-arm RCT was then performed where health centres were randomised to a complete absence of any alert or to one of the specific messages.ResultsThe generic alert triggered 56,878 times. Providers prescribed insulin 5.11 % of the time. During the 4-arm RCT, the alerts triggered 11,744, 11,826, 11,742, and 11,554 times and insulin was prescribed 5.17%, 5.01%, 5.11% and 5.20% respectively. There were no statistically significant differences amongst the 4 rates (p = 0.67) nor was there a statistically significant difference between insulin ordering with the generic message compared to insulin ordering with the more specific messages (p = 0.62). For the 2-arm RCT, insulin ordering remained at 5% for the specific messages and was 0% where there was no alert (P<0.05)Lessons for Guideline Developers, Adaptors, Implementers, and/or UsersExtra effort to craft wording and develop eye-catching electronic alerts may not be worthwhile. Guideline adherence was improved by an electronic alert.
P012 The EHR
Authors: Chan Wiley 
Published: August 2013

Guidelines must adhere to a rigorous, transparent, evidence-based methodology and contain explicit, actionable recommendations to ensure acceptance and facilitate implementation by clinicians and health care delivery systems. In addition to these core requirements, guidelines must be implemented in clinical practice to deliver better health outcomes for our patients. Use of Electronic Health Records (EHRs) is an effective way to embed guidance at the point of care and impact clinical care. Most EHR tools are aimed at clinicians and health care delivery system staff. However, interactive EHR tools aimed at patients that enhance patient engagement in their health care have great potential. Examples of the various types of EHR tools used in Kaiser Permanente will be presented. The characteristics of the various EHR tools available that are associated with their rate of use and their impact will be explored. The concept of EHR content implementation lifecycle will be presented. Each stage in this lifecycle is important: Requirements Definition, Design, Develop/Build, Deploy/Champion; Measure/Evaluate; Maintain/Revise. As an example of Requirements Definition, careful planning and management are necessary to ensure that EHR tools are focused on key points in the clinical pathways to address root causes of performance gaps, and support clinical workflows.The EHR is a powerful tool to embed guidance and affect clinical care. But effective use of EHR tools also requires strong support from organisational leadership, centralised coordinated governance, and collaboration with end-users. EHR tools must be integrated into the larger health care delivery system’s infrastructure, to be effective in supporting and impacting clinical care.
090 N of One Guidelines - A New Method to Manage Multimorbidity?
Authors: Scherer M , Muche-Borowski C , Schäfer I , Hansen H , Wagner H , Dubben H , Blozik E , Lühmann D , Szecsenyi J 
Published: August 2013

BackgroundAdherence to current monomorbidity-focused, mono-disciplinary guidelines may result in undesirable effects for persons with several comorbidities, in adverse interactions between drugs and diseases, conflicting management strategies, and polypharmacy. As yet no satisfactory approaches exist to address multimorbidity (MM) in clinical guidelines since this patient group is too heterogeneous as to be met by guideline recommendations.Objectivesto develop a set of case-based (N = 1) guidelines for common disease combinations identified through epidemiological research and expert (GP) consultations.MethodsWe followed a new 5-step, mixed methods approach comprising: (1) review of epidemiological data on MM patterns; (2) interdisciplinary focus groups developed case vignettes according to both internal evidence and the results of step 1; (3) development of case-based recommendations according to case vignettes (N of one guidelines); (4) informal consensus of recommendations; (5) formal consensus.ResultsStep one revealed three different approaches for the selection criteria of case vignettes: first, cases addressing MM disease patterns from epidemiological studies (MM clusters); second, cases addressing triads of the 6 most prevalent chronic conditions; third, cases according to a problem-oriented prioritisation of focus group participants. All in all 10 N-of-one guidelines according to 10 cases could be developed according to the new 5-step-process.DiscussionWe present a new approach in order to capture the complex and heterogeneous problems of MM through evidence-based and case-based recommendations. This set of N-of-one-guidelines may serve as a framework of evidence-based recommendations for MM patients as the base for the development of meta-tools for both guideline developers and clinicians.
P043 Five major areas of research of GRADE system
Authors: Chen Y , Yao L , Wang Q , Wu Q , Wang X , Yang K 
Published: August 2013

BackgroundOver the past 10 years, more and more guideline developers and systematic review authors adopt the GRADE method. Also, many researchers and groups become interested in discussing, studying and developing it.MethodsWe searched and analysed all GRADE papers published in academic journals from 2004 to 2012, abstracts in Cochrane colloquium from 2000 to 2012 and G-I-N Conferences from 2003 to 2012, attended GRADE workshops and meeting in GIN and Cochrane colloquium.ResultsWe found the following five major areas of research of GRADE system: 1. Comparison and Trend Analysis between GRADE and other different rating systems 2. Reasons analysis for downgrading and upgrading the quality of evidence and agreement test for different raters in systematic reviews 3. How to from evidence to recommendations in guidelines 4. Exploration of the application of GRADE in clinical stage (e.g. whether the guideline covers prevention, screening, assessment, treatment, rehabilitation or monitoring); Exploration of the application of GRADE in different areas such as public health, health policy and system. 5. The establishment and development of GRADE centre such as the Chinese GRADE centre and Spanish GRADE centre and how to promote the implementation of GRADE.ConclusionAs a new paradigm, the GRADE approach provides a comprehensive, explicit, and transparent methodology for grading the quality of evidence and strength of recommendations about the management of patients, however, GRADE is not a perfect system and still need to develop itself and been disseminated widely.
P070 Toolbox for the Complete Process of Guideline Development, Revision, Implementation and Evaluation
Authors: Hilbink M , Ouwens M , Kool T 
Published: August 2013

BackgroundProblems in the process of guideline development, revision, implementation and evaluation are commonly perceived.ObjectivesTo support and improve the process of guideline development, revision, implementation and evaluation.MethodsAfter reaching consensus about topics for which there was a huge need for support, we composed thirteen working groups consisting of 4–5 representatives of various Dutch institutions involved in guideline development and implementation. Each group developed a support tool on a specific topic. 150 experts commented the draft version of the tools. Subsequently, the tools were used in more than 40 guideline projects to evaluate their practical value. The final versions of the tools have been disseminated by internet and will be adopted by the National Dutch Quality Insitute.ResultsA toolbox containing 13 tools on the following topics: 1. Analysis of clinical care gaps 2. Cost-effectiveness 3. Organization and cooperation 4. Dealing with conflicts 5. International cooperation 6. Project management 7. Formulating specific recommendations 8. Attention for sex differences 9. Guidelines and shared decision making 10. Knowledge gaps 11. Implementation 12. Monitoring 13. Electronic disclosure A both Dutch and English-language version website on guideline development and implementation in the broader context, with incorporation of the tools.DiscussionThis project yielded a toolbox with tools on topics and activities that offered scope for further international development.Implications for Guideline Developers/UsersUsing these tools might improve the quality of guidelines, which in turn results in higher guideline adherence. Better guideline adherence might eventually lead to improved quality of care.
P093 Determining Pharmacist Awareness And Implementation Of The Nice Medicines Adherence Guideline
Authors: Thornton J , Tait S , Steinke D , Ashcroft D , Elliot N 
Published: August 2013

BackgroundUp to 50% of medicines are not taken as recommended with potential for reduced benefits or treatment failure and financial implications of the unused medicines. The NICE clinical guideline on Medicines Adherence is relevant to all healthcare workers but there has been no formal assessment of its uptake among pharmacists.ObjectivesTo determine awareness and application of the Medicines Adherence guideline among UK hospital pharmacistsMethodA postal self-completion questionnaire was sent to hospital pharmacies across northwest England. Descriptive statistics were used to analyse the responses and key themes identified from free-text comments.ResultsThere were 45 responses. Pharmacists were aware of the guideline via communication from NICE (26%), pharmaceutical/medical press (20%) and local communication (14%). 20% of respondents reported that their hospital/department had guidance in place before publication of the guideline and 23% that their hospital issued guidance after publication. 39% already used the principles of the guideline in their practice and further independent action was not needed whereas 22% changed their practice. Although most pharmacists considered they had adequate experience and training, insufficient time and technical support were major barriers to addressing adherence issues in practice.DiscussionImproved communication about the guideline is needed. Many pharmacists want to apply the principles of the guideline but need support to overcome barriers to effective implementation.Implications for Guideline Developers/UsersGuideline developers could help implementation by disseminating relevant guideline information more specifically at pharmacists. Cross-referral to the Medicines Adherence guideline could be included in all other relevant NICE guidelines.
P098 The Canadian Task Force On Preventive Health Care: Process For Critical Appraisal Of Externally-Produced Guidelines
Authors: Shane A , Tonelli M , Birtwhistle R , Pottie K , Bell N , Singh H , Gorber S , L Dunfield 
Published: August 2013

BackgroundThe Canadian Task Force on Preventive Health Care (CTFPHC) was re-established in 2010, with a mandate to produce clinical practice guidelines (CPGs) for primary preventive care, based on systematic analysis of scientific evidence.ContextIn order to increase the range of topics for which the CTFPHC provides guidance, while operating with defined resources, it was necessary to explore alternative dissemination methods. In addition to developing new guidelines and updating existing guidelines, the CTFPHC has developed a process for identifying high quality guidelines produced by other organisations on topics relevant to the CTFPHC’s mandate.Description of Best PracticeThe process is comprised of 12 steps. When a CPG is identified for appraisal, a literature scan for recently produced guidelines on the same topic by other organisations is conducted. The resultant CPGs are qualitatively assessed based on 5 criteria. The CPG most appropriate for appraisal undergoes AGREEII assessment, followed by development of a summary report that includes a commentary which discusses the strengths, limitations, link between evidence review and CPG and content of the CPG.Lessons for Guideline Developers, Adaptors, Implementers and/or UsersThrough several iterations, a robust process has been developed, with 3 appraisals completed. Two essential steps were identified: systematic selection of guidelines for appraisal, and engagement of KT experts in selecting product format. Because an appraisal identifies CPGs developed using a standard and rigorous methodology, and does not imply the CTFPHC’s agreement with the recommendations, it is essential that the summary report contain information required by practitioners to ensure a benefit is gained from its dissemination.