bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Quaternary Structure Epitope on Dengue Virus Serotype 2 Is the Target of Durable Type-Specific Neutralizing Antibodies
Authors: Gallichotte E. N. , Widman D. G. , Yount B. L. , Wahala W. M. , Durbin A. , Whitehead S. , Sariol C. A. , Crowe J. E. , de Silva A. M. , Baric R. S. 
Published: October 2015

ABSTRACT
Dengue virus serotype 2 (DENV2) is widespread and responsible for severe epidemics. While primary DENV2 infections stimulate serotype-specific protective responses, a leading vaccine failed to induce a similar protective response. Using human monoclonal antibodies (hMAbs) isolated from dengue cases and structure-guided design of a chimeric DENV, here we describe the major site on the DENV2 envelope (E) protein targeted by neutralizing antibodies. DENV2-specific neutralizing hMAb 2D22 binds to a quaternary structure epitope. We engineered and recovered a recombinant DENV4 that displayed the 2D22 epitope. DENV2 neutralizing antibodies in people exposed to infection or a live vaccine tracked with the 2D22 epitope on the DENV4/2 chimera. The chimera remained sensitive to DENV4 antibodies, indicating that the major neutralizing epitopes on DENV2 and -4 are at different sites. The ability to transplant a complex epitope between DENV serotypes demonstrates a hitherto underappreciated structural flexibility in flaviviruses, which could be harnessed to develop new vaccines and diagnostics.

IMPORTANCE
Dengue virus causes fever and dengue hemorrhagic fever. Dengue serotype 2 (DENV2) is widespread and frequently responsible for severe epidemics. Natural DENV2 infections stimulate serotype-specific neutralizing antibodies, but a leading DENV vaccine did not induce a similar protective response. While groups have identified epitopes of single monoclonal antibodies (MAbs), the molecular basis of DENV2 neutralization by polyclonal human immune sera is unknown. Using a recombinant DENV displaying serotype 2 epitopes, here we map the main target of DENV2 polyclonal neutralizing antibodies induced by natural infection and a live DENV2 vaccine candidate. Proper display of the epitope required the assembly of viral envelope proteins into higher-order structures present on intact virions. Despite the complexity of the epitope, it was possible to transplant the epitope between DENV serotypes. Our findings have immediate implications for evaluating dengue vaccines in the pipeline as well as designing next-generation vaccines.
Activities to support the implementation of complex interventions as part of routine care: a review of the quality of reporting in cluster randomised controlled trials
Authors: McMahon Naoimh E , Holland Emma-Joy , Miller Colette , Patel Kulsum , Connell Louise A 
Published: October 2015

ObjectiveTo review a sample of cluster randomised controlled trials and explore the quality of reporting of (1) enabling or support activities provided to the staff during the trial, (2) strategies used to monitor fidelity throughout the trial and (3) the extent to which the intervention being tested was delivered as planned.DesignA descriptive review.Data sources and study selectionWe searched MEDLINE for trial reports published between 2008 and 2014 with combinations of the search terms ‘randomised’, ‘cluster’, ‘trial’, ‘study’, ‘intervention’ and ‘implement*’. We included trials in which healthcare professionals (HCPs) implemented the intervention being tested as part of routine practice. We excluded trials (1) conducted in non-health services settings, (2) where the intervention explicitly aimed to change the behaviours of the HCPs and (3) where the trials were ongoing or for which only trial protocols were available.Data collectionWe developed a data extraction form using the Template for Intervention Description and Replication (TIDieR checklist). Review authors independently extracted data from the included trials and assessed quality of reporting for individual items.ResultsWe included 70 publications (45 results publications, 25 related publications). 89% of trials reported using enabling or support activities. How these activities were provided (75.6%, n=34) and how much was provided (73.3%, n=33) were the most frequently reported items. Less than 20% (n=8) of the included trials reported that competency checking occurred prior to implementation and data collection. 64% (n=29) of trials reported collecting measures of implementation. 44% (n=20) of trials reported data from these measures.ConclusionsAlthough enabling and support activities are reported in trials, important gaps exist when assessed using an established checklist. Better reporting of the supports provided in effectiveness trials will allow for informed decisions to be made about financial and resource implications for wide scale implementation of effective interventions.
Patient safety climate strength: a concept that requires more attention
Authors: Ginsburg Liane , Gilin Oore Debra 
Published: October 2015

BackgroundWhen patient safety climate (PSC) surveys are used in healthcare, reporting typically focuses on PSClevel(mean or per cent positive scores). This paper explores how an additional focus on PSCstrengthcan enhance the utility of PSC survey data.Setting and participants442 care providers from 24 emergency departments (EDs) across Canada.MethodsWe use anonymised data from theCan-PSCSPSC instrument collected in 2011 as part of the Qmentum accreditation programme. We examine differences in climate strength across EDs using the Rwg(j) and intraclass correlation coefficients measures of inter-rater agreement.ResultsAcross the six survey dimensions, median Rwg(j) was sufficiently high to support shared climate perceptions (0.64–0.83), but varied widely across the 24 ED units. We provide an illustrative example showing vastly different climatestrength(Rwg(j) range=0.17–0.86) for units with an equivalentlevelof PSC (eg, climate mean score=3).ConclusionsMost PSC survey results focus solely on climate level. To facilitate improvement in PSC, we advocate a simple, holisticsafety climate profileincluding three metrics: climatelevel(using mean or per cent positive climate scores), climatestrength(using the Rwg(j), or SD as a proxy) and theshapeof the distribution (using histograms to see the distribution of scores within units). In PSC research, we advocate paying attention to climate strength as an important variable in its own right. Focusing on PSC level and strength can further understanding of the extent to which PSC is a key variable in the domain of patient safety.
LONG-TERM SAFETY OF ALEMTUZUMAB IN RELAPSING-REMITTING MULTIPLE SCLEROSIS: PREGNANCY AND INFECTION DATA FROM A COHORT OF PATIENTS ON OPEN LABEL STUDIES IN CAMBRIDGE
Authors: McCarthy Claire , Tuohy Orla , Azzopardi Laura , Kousin-Ezewu Onajite , Jones Joanne , Compston Alastair , Coles Alasdair 
Published: October 2015

BackgroundAlemtuzumab is recently licensed for use in active relapsing-remitting multiple sclerosis (RRMS) in Europe and the USA. This observational cohort study investigated the long term safety of alemtuzumab in RRMS.MethodsClinical data was collected from a cohort of 87 patients who participated in open label studies of alemtuzumab in Cambridge, UK from 1999 to 2012. Pregnancy outcomes and the occurrence of moderate to severe infections were recorded.ResultsOver a median 7-year follow-up (range 33–144 months), no serious infections occurred that required hospitalisation. There were 11 cases of varicella zoster virus reactivation and one case of primary varicella zoster virus infection. In this cohort 15 babies were born to 12 women treated with alemtuzumab. The median interval from their most recent alemtuzumab treatment to birth was 26 months (range 13–86 months). All of the babies were healthy and delivered without complications. One woman had experienced a miscarriage at 8 weeks gestation but went on to have two successful pregnancies.ConclusionsDuring prolonged follow-up of this cohort of patients treated with alemtuzumab no serious infections occurred. No increased risk of miscarriage or foetal abnormality was seen in the small number of pregnancies studied.
MANAGEMENT OF FINGOLIMOD FIRST DOSE OBSERVATION (FDO) IN THE UK
Authors: Pamies P , Webber B , Pull E 
Published: October 2015

BackgroundFingolimod (Gilenya) is a sphingosine 1-phosphate receptor (S1PR) modulator approved for use in relapsing-remitting multiple sclerosis. Fingolimod can lead to reduced pacemaker cell excitability, slowing heart rate (HR) and, possibly, atrioventricular block. Cardiac monitoring is required for a minimum of 6 hours on commencing the first dose of fingolimod.Regent's Park Heart Clinics (RPHC) is a cardiology services provider engaged by Novartis Pharmaceuticals UK to provide NHS clinicians with a fingolimod FDO service.ObjectiveTo describe the results of a UK FDO service for fingolimod.MethodsRPHC provides a cardiac physiologist/nurse to visit sites between 0800–1700 hrs with electrocardiography (ECG) equipment. 12-lead ECG is performed at baseline and six hours after initiation with continuous cardiac monitoring throughout. Blood pressure and HR measurement is performed hourly. Where patients have evidence of clinically important cardiac effects, monitoring is extended up to eight hours or overnight as required.ResultsFrom 4/July/2012 to 26/January/2015, RPHC provided FDO for 1013 patients. 975 (96%) were discharged at six hours; 29 (3%) were discharged at eight hours. 9 (1%) required an overnight stay. 1 patient discontinued treatment.Conclusion96% of 1013 fingolimod patients were discharged at 6-hours post-first dose. No patients required pharmacological intervention.
A NEW CLINICAL TOOL (BRIT) TO MONITOR IVIG EFFICACY IN PATIENTS WITH STIFF PERSON SYNDROME
Authors: Weerasinghe Savinda , Sadalage Girija , Jacob Saiju 
Published: October 2015

Stiff person syndrome (SPS) is a chronic, progressive neurological disorder characterized by painful muscle spasms and rigidity with high titres of circulating anti-GAD antibodies.Intravenous immunoglobulin (IVIg) has been proven to be very effective in reducing the symptoms associated with SPS, most notably stiffness. Patients report being able to walk for the first time in months or even years and partake in activities of daily living including showering and household chores. A reduction in falls is also noted in patients receiving IVIg. Most patients report a drastically improved quality of life after receiving IVIg with significant improvement in pain, general mental health, social functioning, vitality and energy.At present, there is no standardised method of monitoring the effectiveness of IVIg treatment in patients with stiff person syndrome. We devised a standardised questionnaire with a combination of modified Rankin scale and Flanagan's QOLS and prospectively studied 12 SPS patients receiving IVIg therapy. We named this the Birmingham Response to IVIg Treatment (BRIT) scale.The BRIT scale can be used to monitor IVIg efficacy in a variety of chronic neurological conditions (especially ones without other monitoring tools, eg: INCAT score for CIDP) and would be a very useful addition to the neurology practice.
GOING BLIND ON DIALYSIS: NYCTALOPIA DUE TO TRANEXAMIC ACID
Authors: Rudd Darren , Jaiser Stephan , Bradshaw Karen , Archibald Neil 
Published: October 2015

Tranexamic acid (TNA) is a fibrinolytic inhibitor used to control haemorrhage. Impairment of vision, particularly of colour perception, is a rare adverse effect.A 79 year-old man with end-stage renal failure (ESRF) was treated with tranexamic acid for bleeding from duodenal angiodysplasia. Over four days his vision deteriorated bilaterally, and he complained of poor acuity unless in a brightly sunlit environment.On examination, visual acuity was poor within the ward but improved markedly when looking out of the window or shining a bright torchlight on objects. Visual fields, pupillary reflexes, fundoscopy and remaining neurological examination were normal.Full-field electroretinogram (ERG) demonstrated severe photoreceptor dysfunction, especially of rods. TNA was discontinued and vision improved subjectively within days. Serial ERG showed continuing recovery of rod function over several months.Patients with ESRF often have duodenal angiodysplasia, and TNA is commonly used to minimise bleeding. Previously reported effects of TNA on colour vision (chromatopsia) presumably arise through impaired cone function. By contrast, our patient exhibited predominant rod dysfunction, and the clinical manifestation of nyctalopia expands the known spectrum of adverse effects of TNA. Rapid discontinuation of TNA is vital to minimise visual sequelae.
ZEBRAFISH AS A MODEL OF GLUCOCEREBROSIDASE 1 (GBA1) DEFICIENCY
Authors: Keatinge Marcus , DaCosta Marc , Menke Aswin , Chen Yu-Chia , Bui Hai Hoang , O'Neill Mike , Bandmann Oliver 
Published: October 2015

ObjectivesTo establish and characterise glucocerebrosidase 1 (GBA1) mutant zebrafish line.BackgroundHomozygous GBA1 mutations (GBA1−/−) cause Gaucher disease (GD), heterozygote GBA1 mutations (GBA+/−) are the most common risk factor for Parkinson's disease (PD). The aim of this project was to develop a zebrafish model of GBA1 deficiency and study PD-relevant mechanisms.MethodsGenome editing, RT PCR, behavioural analysis, Immunohistochemistry, H/E staining, in situ hybridisation, biochemical assays.ResultsHomozygous mutants (GBA1−/−) developed normally and did not experience dopaminergic (DA) cell loss during development but displayed loss of DA neurons at 12 weeks. Video tracking revealed a large decrease in spontaneous movements in GBA1−/− compared to WT and an intermediate motor phenotype in GBA1+/− in juvenile zebrafish. All homozygous mutants had to be culled at 3 months of age due to the severity of the phenotype. Established GD biomarkers such as hexosaminidase or chitotriosidase activity were markedly abnormal (p<0.0001). Furthermore, there was marked impairment of mitochondrial respiratory chain activity in GBA−/−.ConclusionsGBA1−/− zebrafish share key biochemical and morphological features with GBA1 knockout mice or indeed human GD. This new vertebrate model system for GBA1 deficiency will be useful to study the interaction between GBA1 haploinsufficiency, alpha-synuclein and exogenous toxins.
GENE SET ENRICHMENT ANALYSIS IN AMYOTROPHIC LATERAL SCLEROSIS
Authors: Chen Zhongbo , Lin Kuang , Shatunov Aleksey , Jones Ashley , Al-Chalabi Ammar 
Published: October 2015

BackgroundAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. We examined the phylogenetics of ALS-susceptibility genes from our previously-published genome-wide association study (GWAS).MethodsWe examined the association between ALS-susceptibility genes and hybridisation from the Neanderthal genome using a modified gene set enrichment analysis (GSEA). These gene sets comprise thirteen candidate regions for Neanderthal to non-African human gene flow [UCSC Genome Browser]. We ranked the ascending p-values of 442,057 GWAS SNPs and simulated the distribution 100,000 times. The resulting empirical p-value, comparing observed with expected mean rank, identified which gene sets are over-represented at the top of the rank list. Bonferroni corrections for multiple testing were applied.Results6,402 imputed GWAS SNPs fell into the thirteen gene sets. We found that the regions on chromosomes 6 and 9 accrued the lowest observed mean ranks (8,594 and 7,096 respectively) and were not different from expected mean ranks after simulation for those regions – empirical p-values before Bonferroni correction were 0.086 for chromosome 6 and 0.071 for chromosome 9.DiscussionUsing GSEA to evaluate European ALS GWAS data in the context of pre-defined gene sets refutes the theory that ALS-susceptibility loci may have arisen from Neanderthal to non-African modern human gene flow.
A SPASTIC ATAXIC GAIT WITH A BIT MORE BITE
Authors: Chance Leah , Gray Orla 
Published: October 2015

A 39 year old female presented to a District General Hospital with fatigue, light-headedness and shortness of breath. Investigations revealed an iron deficient anaemia, initially presumed due to poor diet. Clinical examination revealed a moderate cerebellar ataxia and spastic paraparesis. Investigations included normal MRI of Whole Spine and Vitamin B12 level. MRI Brain revealed abnormal T2 and FLAIR high signal within the superior aspect of the corticospinal tracks bilaterally.Further investigation revealed low serum copper of 0.6 mcgmol/L (12.6–26.7), low serum caeruloplasmin of 0.05 g/L (0.16–0.45) and low twenty-four hour urinary copper of 0.05 mcgmol/24 hours (0–0.6) confirming copper deficiency. Serum zinc was elevated at 16.3mcgmol/L (8–15) at neurology clinic assessment, confirming the diagnosis of zinc toxicity. The patient's astute pharmacist highlighted the potential source of excess zinc ingestion as overuse of a well known denture adhesive.A literature search and overview of the physiology of copper, zinc and iron metabolism helped to marry all aspects of the case supporting the diagnosis of copper deficiency secondary to zinc toxicity due to overuse of a zinc containing denture adhesive.
THE RELATIONSHIP BETWEEN CLOCK DRAWING AND COGNITION IN PARKINSON'S
Authors: Cosgrove Jeremy , Jamieson Stuart , Smith Stephen , Alty Jane 
Published: October 2015

IntroductionClock drawing (CD) requires executive function, attention and visuospatial ability. Our objective was to investigate CD in Parkinson's subjects with and without cognitive impairment.Methods107 subjects completed the Montreal Cognitive Assessment (MoCA), classifying into normal cognition (PD-NC – MoCA ≥26) and cognitive impairment (PD-CI–MoCA <26). CD was scored using MoCA criteria; a maximum of 3 points, one each for correct contour, clock face and clock hands.ResultsPD-CI (n=57) and PD-NC were matched for all demographics except age (PD-CI were older, P 0.032). 35% of PD-CI scored full marks compared to 90% of PD-NC (sensitivity 0.64, specificity 0.9, age adjusted-odds ratio for predicting PD-CI 15.63, 95% CI 5.18 – 47.62, P<0.001). 88% of PD-CI scored points for contour and 60% scored points for clock face. In contrast, all PD-NC scored points for contour and clock face (P <0.001). 42% of PD-CI and 90% of PD-NC correctly drew clock hands (P<0.001).ConclusionsIn this cohort, inability to score maximum points for CD was associated with PD-CI. Correctly drawing clock hands was the hardest component for both groups. Incorrect contour or clock face was highly specific for PD-CI.
NEXT GENERATION SEQUENCING IN FAMILIAL CEREBRAL SMALL VESSEL DISEASE - AN ONGOING STUDY
Authors: Tan Rhea , Markus Hugh 
Published: October 2015

Cerebral small vessel disease (SVD) is the most common form of stroke and vascular dementia. CADASIL (notch3 mutations) is most frequent but other monogenic causes more recently identified include CARASIL (HTRA1 gene), RVCL (TREX1 gene) and COL4A1 and 2. Diagnostic tests for these are often inaccessible and expensive and there are families with clinical monogenic SVD in whom no known variants are detected.Next generation sequencing offers the potential to screen for these diseases, which present with similar phenotypes, more cost-effectively and rapidly in a single test. It could also identify novel genes underlying SVD. As part of the NHS GEL and NIHR BRIDGE projects, whole genome sequencing is being applied to SVD. Individuals with younger onset SVD and a family history, with negative notch3 screening, are being recruited from centres throughout England.Data (blood sample and phenotypic information) can be collected by phone and blood sent through the post, or participants seen at a research clinic in one of the seven recruitment sites. Testing is provided free of charge. Any SVD causative mutations are fed back to the patient via the referring clinician. We are interested in receiving potential recruits who can be referred to Rhea Tan yyrt2@medschl.cam.ac.uk.
STIFF PERSON SYNDROME PRESENTING AS ‘STIFF EYES’
Authors: Vinjam Maruthi Ravi , Shanmugarajan Priya , Ford Helen 
Published: October 2015

A 47-year previously fit and well lady presented with 6 weeks history of generalised lethargy, weight loss and neck pain. Her examination revealed left supra-clavicular lymph nodes. Subsequent investigations revealed left grade 2 invasive ductal carcinoma of her left breast. This was treated with local excision.She presented to hospital four weeks following her surgery with progressive double vision and unsteadiness. Her cranial nerve examination showed severly restricted pursuit and saccadic horizontal eye movements with intact vertical eye movements. She had normal strength with intact deep tendon reflexes with plantar flexor response. Her MRI head and spine with contrast and CSF examination, including cytology was normal.Two weeks into her admission she progressively developed generalised stiffness and severe axial and peripheral rigidity which was made worse with touch or emotions. These symptoms responded to benzodiazepines and baclofen. Her anti-amphiphysin antibodies were positive confirming the diagnosis of stiff person syndrome.Her breast cancer was treated aggressively with chemotherapy. Her stiffness and rigidity improved briefly following her chemotherapy. Eye movement's problems were described in anti-GAD related stiff person syndrome, which is due to GABA depletion. This is first ever-reported case where eye movement problem (Stiff eyes) is the initial presentation of a anti-amphiphysin antibody related stiff person syndrome.
A Pooled Analysis of Reproductive Factors, Exogenous Hormone Use, and Risk of Multiple Myeloma among Women in the International Multiple Myeloma Consortium
Authors: Costas Laura , Lambert Brice H. , Birmann Brenda M. , Moysich Kirsten B. , De Roos Anneclaire J. , Hofmann Jonathan N. , Baris Dalsu , Wang Sophia S. , Camp Nicola J. , Tricot Guido , Atanackovic Djordje , Brennan Paul , Cocco Pierluigi , Nieters Alexandra , Becker Nikolaus , Maynadié Marc , Foretová Lenka , Boffetta Paolo , Staines Anthony , Brown Elisabeth E. , de Sanjosé Silvia 
Published: October 2015

Abstract
Background: Female sex hormones are known to have immunomodulatory effects. Therefore, reproductive factors and exogenous hormone use could influence the risk of multiple myeloma in women. However, the role of hormonal factors in multiple myeloma etiology remains unclear because previous investigations were underpowered to detect modest associations.
Methods: We conducted a pooled analysis of seven case–control studies included in the International Multiple Myeloma Consortium, with individual data on reproductive factors and exogenous hormone use from 1,072 female cases and 3,541 female controls. Study-specific odds ratios and corresponding 95% confidence intervals (CI) were estimated using logistic regression and pooled analyses were conducted using random effects meta-analyses.
Results: Multiple myeloma was not associated with reproductive factors, including ever parous [OR = 0.92; 95% confidence interval (CI), 0.68–1.25], or with hormonal contraception use (OR = 1.04; 95% CI, 0.80–1.36). Postmenopausal hormone therapy users had nonsignificantly reduced risks of multiple myeloma compared with never users, but this association differed across centers (OR = 0.65; 95% CI, 0.37–1.15, I2 = 76.0%, Pheterogeneity = 0.01).
Conclusions: These data do not support a role for reproductive factors or exogenous hormones in myelomagenesis.
Impact: Incidence rates of multiple myeloma are higher in men than in women, and sex hormones could influence this pattern. Associations with reproductive factors and exogenous hormone use were inconclusive despite our large sample size, suggesting that female sex hormones may not play a significant role in multiple myeloma etiology. Cancer Epidemiol Biomarkers Prev; 25(1); 217–21. ©2015 AACR.