Similarity Measure Development for Case-Based Reasoning- A Data-driven Approach

In this paper, we demonstrate a data-driven methodology for modelling the local similarity measures of various attributes in a dataset. We analyse the spread in the numerical attributes and estimate their distribution using polynomial function to showcase an approach for deriving strong initial value ranges of numerical attributes and use a non-overlapping distribution for categorical attributes such that the entire similarity range [0,1] is utilized. We use an open source dataset for demonstrating modelling and development of the similarity measures and will present a case-based reasoning (CBR) system that can be used to search for the most relevant similar cases

Dose-dependent T-cell Dynamics and Cytokine Cascade Following rVSV-ZEBOV Immunization.

BACKGROUND: The recent West African Ebola epidemic led to accelerated efforts to test Ebola vaccine candidates. As part of the World Health Organisation-led VSV Ebola Consortium (VEBCON), we performed a phase I clinical trial investigating rVSV-ZEBOV (a recombinant vesicular stomatitis virus-vectored Ebola vaccine), which has recently demonstrated protection from Ebola virus disease (EVD) in phase III clinical trials and is currently in advanced stages of licensing. So far, correlates of immune protection are incompletely understood and the role of cell-mediated immune responses has not been comprehensively investigated to date. METHODS: We recruited 30 healthy subjects aged 18-55 into an open-label, dose-escalation phase I trial testing three doses of rVSV-ZEBOV (3×105 plaque-forming units (PFU), 3×106 PFU, 2×107 PFU) (ClinicalTrials.gov; NCT02283099). Main study objectives were safety and immunogenicity, while exploratory objectives included lymphocyte dynamics, cell-mediated immunity and cytokine networks, which were assessed using flow cytometry, ELISpot and LUMINEX assay. FINDINGS: Immunization with rVSV-ZEBOV was well tolerated without serious vaccine-related adverse events. Ebola virus-specific neutralizing antibodies were induced in nearly all individuals. Additionally, vaccinees, particularly within the highest dose cohort, generated Ebola glycoprotein (GP)-specific T cells and initiated a cascade of signaling molecules following stimulation of peripheral blood mononuclear cells with Ebola GP peptides. INTERPRETATION: In addition to a benign safety and robust humoral immunogenicity profile, subjects immunized with 2×107 PFU elicited higher cellular immune responses and stronger interlocked cytokine networks compared to lower dose groups. To our knowledge these data represent the first detailed cell-mediated immuneprofile of a clinical trial testing rVSV-ZEBOV, which is of particular interest in light of its potential upcoming licensure as the first Ebola vaccine. VEBCON trial Hamburg, Germany (NCT02283099)

Does self-monitoring reduce blood pressure? Meta-analysis with meta-regression of randomized controlled trials

Introduction. Self-monitoring of blood pressure (BP) is an increasingly common part of hypertension management. The objectives of this systematic review were to evaluate the systolic and diastolic BP reduction, and achievement of target BP, associated with self-monitoring. Methods. MEDLINE, Embase, Cochrane database of systematic reviews, database of abstracts of clinical effectiveness, the health technology assessment database, the NHS economic evaluation database, and the TRIP database were searched for studies where the intervention included self-monitoring of BP and the outcome was change in office/ambulatory BP or proportion with controlled BP. Two reviewers independently extracted data. Meta-analysis using a random effects model was combined with meta-regression to investigate heterogeneity in effect sizes. Results. A total of 25 eligible randomized controlled trials (RCTs) (27 comparisons) were identified. Office systolic BP (20 RCTs, 21 comparisons, 5,898 patients) and diastolic BP (23 RCTs, 25 comparisons, 6,038 patients) were significantly reduced in those who self-monitored compared to usual care (weighted mean difference (WMD) systolic −3.82 mmHg (95% confidence interval −5.61 to −2.03), diastolic −1.45 mmHg (−1.95 to −0.94)). Self-monitoring increased the chance of meeting office BP targets (12 RCTs, 13 comparisons, 2,260 patients, relative risk = 1.09 (1.02 to 1.16)). There was significant heterogeneity between studies for all three comparisons, which could be partially accounted for by the use of additional co-interventions. Conclusion. Self-monitoring reduces blood pressure by a small but significant amount. Meta-regression could only account for part of the observed heterogeneity

Role of complement and antibodies in controlling infection with pathogenic simian immunodeficiency virus (SIV) in macaques vaccinated with replication-deficient viral vectors

<p>Abstract</p> <p>Background</p> <p>We investigated the interplay between complement and antibodies upon priming with single-cycle replicating viral vectors (SCIV) encoding SIV antigens combined with Adeno5-SIV or SCIV pseudotyped with murine leukemia virus envelope boosting strategies. The vaccine was applied via spray-immunization to the tonsils of rhesus macaques and compared with systemic regimens.</p> <p>Results</p> <p>Independent of the application regimen or route, viral loads were significantly reduced after challenge with SIVmac239 (p < 0.03) compared to controls. Considerable amounts of neutralizing antibodies were induced in systemic immunized monkeys. Most of the sera harvested during peak viremia exhibited a trend with an inverse correlation between complement C3-deposition on viral particles and plasma viral load within the different vaccination groups. In contrast, the amount of the observed complement-mediated lysis did not correlate with the reduction of SIV titres.</p> <p>Conclusion</p> <p>The heterologous prime-boost strategy with replication-deficient viral vectors administered exclusively via the tonsils did not induce any neutralizing antibodies before challenge. However, after challenge, comparable SIV-specific humoral immune responses were observed in all vaccinated animals. Immunization with single cycle immunodeficiency viruses mounts humoral immune responses comparable to live-attenuated immunodeficiency virus vaccines.</p

VEGF receptors on PC12 cells mediate transient activation of ERK1/2 and Akt: comparison of nerve growth factor and vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) and endostatin are angiogenic and anti-angiogenic molecules, respectively, that have been implicated in neurogenesis and neuronal survival. Using alkaline phosphatase fusion proteins, we show that the PC12 neuronal cell line contains cell membrane receptors for VEGF but not for endostatin and the collagen XV endostatin homologue. Immunocytochemistry confirmed that proliferating and differentiated PC12 cells express VEGF receptors 1, 2 and neuropilin-1. While no functional effects of VEGF on PC12 cell proliferation and differentiation could be observed, a slight VEGF-induced reduction of caspase-3 activity in differentiated apoptotic PC12 cells was paralleled by transient activation of ERK1/2 and Akt. In direct comparison, nerve growth factor proved to be a strikingly more potent neuroprotective agent than VEGF

Treatment of Branch Retinal Vein Occlusion induced Macular Edema with Bevacizumab

BACKGROUND: Branch retinal vein occlusion is a frequent cause of visual loss with currently insufficient treatment options. We evaluate the effect of Bevacizumab (Avastin) treatment in patients with macular edema induced by branch retinal vein occlusion. METHODS: Retrospective analysis of 32 eyes in 32 patients with fluorescein angiography proven branch retinal vein occlusion, macular edema and Bevacizumab treatment. Outcome measures were best corrected visual acuity in logMAR and central retinal thickness in OCT. RESULTS: Visual acuity was significantly better 4 to 6 weeks after Bevacizumab treatment compared to visual acuity prior to treatment (before 0.7 +/- 0.3 and after 0.5 +/- 0.3; mean +/- standard deviation; p < 0.01, paired t-test). Gain in visual acuity was accompanied by a significant decrease in retinal thickness (454 +/- 117 to 305 +/- 129 microm, p < 0.01, paired t-test). Follow up (170, 27 - 418 days; median, range) shows that improvement for both visual acuity and retinal thickness last for several months after Bevacizumab use. CONCLUSION: We present evidence that intravitreal Bevacizumab is an effective and lasting treatment for macular edema after branch retinal vein occlusion

Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

How do MNC R&amp;D laboratory roles affect employee international assignments?

Research and development (R&#38;D) employees are important human resources for multinational corporations (MNCs) as they are the driving force behind the advancement of innovative ideas and products. International assignments of these employees can be a unique way to upgrade their expertise; allowing them to effectively recombine their unique human resources to progress existing knowledge and advance new ones. This study aims to investigate the effect of the roles of R&#38;D laboratories in which these employees work on the international assignments they undertake. We categorise R&#38;D laboratory roles into those of the support laboratory, the locally integrated laboratory and the internationally interdependent laboratory. Based on the theory of resource recombinations, we hypothesise that R&#38;D employees in support laboratories are not likely to assume international assignments, whereas those in locally integrated and internationally interdependent laboratories are likely to assume international assignments. The empirical evidence, which draws from research conducted on 559 professionals in 66 MNC subsidiaries based in Greece, provides support to our hypotheses. The resource recombinations theory that extends the resource based view can effectively illuminate the international assignment field. Also, research may provide more emphasis on the close work context of R&#38;D scientists rather than analyse their demographic characteristics, the latter being the focus of scholarly practice hitherto