Virtual Research Integration Collaboration: Procedural report

The aim of the project is to build a framework for the integration of basic science and clinical research to manage research lifecycles and allow for integration of scientific approaches throughout these lifecycles into the everyday work practice of the consortia that manage translational clinical research. The project will take the CORE VRE and embed it into a National centre for surgical excellence, the Royal National Orthopaedic Hospital (RNOH). The VRE will integrate both with the institutional systems and research life cycle, and with the national systems such as the National Health Service (NHS). It is our aim to integrate the CORE VRE with myExperiment to provide a set of services at RNOH to cover the four main areas of the research cycle, namely: the monitoring and governance of trials (experiment research administration); the trial protocols (experiment workflows); the publishing, dissemination and discussion on the results of trials in a repository; and the discovery of information from the repository and other resources. For this community, there are three tightly coupled areas of focus: research, clinical practice, and education (in the form of continuing professional development and training of the next generation of surgeons). In this project, our user community will be heavily involved in co-designing and codeployment of the tool set, and in particular the front end of the workbench will be user focused. The tools will need to be available to staff anywhere with the organisation, as clinicians need to be able to enter the data during clinics and directors of research need to be able to monitor the trials. This will bring with it a number of inter-operability issues, as we move data between the VRE, the hospital systems (NHS) and the institutional systems. To aid the understanding of the how the system will be used, we outline a typical ‘research cycle’ that includes the practice of a clinical specialist in orthopaedics (who may also be a Higher surgical trainee) and a basic scientist. The purpose of this is to identify time essential information provision and interaction with pervasive technologies. For new researchers one of the most difficult tasks is to learn good practice or find related experiments to learn how to instantiate the protocols; in many organisations it is often easier to repeat an experiment than to find the results of a similar previous experiment. In this abstracted model of the research lifecycle, we have split up the cycle into four main research activities. In each of these activities the different issues and stakeholders are addressed. The wider community nationally is represented by the Musculoskeletal network of Greater London, NHS, e-science, Surgical and VRE communities. It is through the Musculoskeletal network of Greater London that we will be able to co-ordinate knowledge and demonstrations to advise the community and for continuity. This project will impact on the wider academic community in the UK, initially through dissemination via organisations such as BriteNet (Tissue Engineering), The British Orthopaedic Association, British Orthopaedic Research Society, and the British Elbow and Shoulder Society as the groups tied into the consortia development

Hypoxic conditions promote a proliferative, poorly differentiated phenotype in COPD lung tissue progenitor cells in vitro

Acknowledgements The authors would like to acknowledge the support of the UHNM theatre staff, Dr. Sana Iftikhar and Dr. Daniel Gey van Pittius for their assistance in acquiring participant lung tissue. Funding Information: This work was supported by funding from the North Staffordshire Medical Institute 50th Anniversary Award and The Royal Society-Newton Mobility Grant. The authors would like to acknowledge the support of the UHNM theatre staff, Dr. Sana Iftikhar and Dr. Daniel Gey van Pittius for their assistance in acquiring participant lung tissue.Peer reviewedPublisher PD

Catch before a fall – an iPad application for Osteoporosis Risk Assessment

The Virtual Research Integration Collaboration (VRIC) project provides a framework for the integration of basic science and clinical research. It enables the management of research lifecycles by integrating scientific approaches with everyday work practice in a virtual research environment (VRE). “Catch Before a Fall” (CBaF) is a clinical research project using VRIC. CBaF is aimed at calculating patients’ risk factor of developing osteoporosis and of having an osteoporosis related fracture within the next 10 years. Patients’ data are collected through CBaF and stored in data structures that match the VRIC architecture for automatic importing via a script written for that purpose. Data analysis is conducted in VRIC and the conclusion of the research process is followed up within that tool. In this paper, we describe how CBaF was designed to follow the VRIC framework, and discuss the technical development work of the application

Climate scenarios for California

Possible future climate changes in California are investigated from a varied set of climate change model simulations. These simulations, conducted by three state-of-the-art global climate models, provide trajectories from three greenhouse gas (GHG) emission scenarios. These scenarios and the resulting climate simulations are not “predictions,” but rather are a limited sample from among the many plausible pathways that may affect California’s climate. Future GHG concentrations are uncertain because they depend on future social, political, and technological pathways, and thus the IPCC has produced four “families” of emission scenarios. To explore some of these uncertainties, emissions scenarios A2 (a medium-high emissions) and B1 (low emissions) were selected from the current IPCC Fourth climate assessment, which provides several recent model simulations driven by A2 and B1 emissions. The global climate model simulations addressed here were from PCM1, the Parallel Climate Model from the National Center for Atmospheric Research (NCAR) and U.S. Department of Energy (DOE) group, and CM2.1 from the National Oceanic and Atmospheric Administration (NOAA) Geophysical Fluids Dynamics Laboratory (GFDL). As part of the scenarios assessment, a statistical technique using properties of historical weather data was employed to correct model biases and “downscale” the global-model simulation of future climates to a finer level of detail, onto a grid of approximately 7 miles (12 kilometers), which is more suitable for impact studies at the scales needed by California decision makers. In current climate-change simulations, temperatures over California warm significantly during the twenty-first century, with temperature increases from approximately +3ºF (1.5ºC) in the lower emissions scenario (B1) within the less responsive model (PCM1) to +8ºF (4.5ºC) in the higher emissions scenario (A2) within the more responsive model (CM2.1). Three of the simulations (all except the low-emission scenario run of the low-response model) exhibit more warming in summer than in winter. In all of the simulations, most precipitation continues to occur in winter, with virtually all derived from North Pacific winter storms. Relatively little change in overall precipitation is projected. Climate warming has a profound influence in diminishing snow accumulations, because there is more rain and less snow, and earlier snowmelt. These snow losses increase as the warming increases, so that they are most severe under climate changes projected by the more sensitive model with the higher GHG emissions

Evaluation of improved coloured targets to control riverine tsetse in East Africa: A Bayesian approach

Background Riverine tsetse (Glossina spp.) transmit Trypanosoma brucei gambiense which causes Gambian Human African Trypanosomiasis. Tiny Targets were developed for cost-effective riverine tsetse control, and comprise panels of insecticide-treated blue polyester fabric and black net that attract and kill tsetse. Versus typical blue polyesters, two putatively more attractive fabrics have been developed: Vestergaard ZeroFly blue, and violet. Violet was most attractive to savannah tsetse using large targets, but neither fabric has been tested for riverine tsetse using Tiny Targets. Methods We measured numbers of G. f. fuscipes attracted to electrified Tiny Targets in Kenya and Uganda. We compared violets, Vestergaard blues, and a typical blue polyester, using three replicated Latin squares experiments. We then employed Bayesian statistical analyses to generate expected catches for future target deployments incorporating uncertainty in model parameters, and prior knowledge from previous experiments. Results Expected catches for average future replicates of violet and Vestergaard blue targets were highly likely to exceed those for typical blue. Accounting for catch variability between replicates, it remained moderately probable (70–86% and 59–84%, respectively) that a given replicate of these targets would have a higher expected catch than typical blue on the same day at the same site. Meanwhile, expected catches for average violet replicates were, in general, moderately likely to exceed those for Vestergaard blue. However, the difference in medians was small, and accounting for catch variability, the probability that the expected catch for a violet replicate would exceed a Vestergaard blue equivalent was marginal (46– 71%)

Supplementary material from "Why are biting flies attracted to blue objects?"

Diurnal biting flies are strongly attracted to blue objects. This behaviour is widely exploited for fly control, but its functional significance is debated. It is hypothesized that blue objects resemble animal hosts; blue surfaces resemble shaded resting places and blue attraction is a by-product of attraction to polarized light. We computed the fly photoreceptor signals elicited by a large sample of leaf and animal integument reflectance spectra, viewed under open/cloudy illumination and under woodland shade. We then trained artificial neural networks (ANNs) to distinguish animals from leaf backgrounds, and shaded from unshaded surfaces, in order to find the optimal means of doing so based upon the sensory information available to a fly. After training, we challenged ANNs to classify blue objects used in fly control. Trained ANNs could make both discriminations with high accuracy. They discriminated animals from leaves based upon blue-green photoreceptor opponency and commonly misclassified blue objects as animals. Meanwhile, they discriminated shaded from unshaded stimuli using achromatic cues and never misclassified blue objects as shaded. We conclude that blue-green opponency is the most effective means of discriminating animals from leaf backgrounds using a fly's sensory information, and that blue objects resemble animal hosts through such mechanisms

Effect of Immunosuppression on T-Helper 2 and B-Cell Responses to Influenza Vaccination

Background. Influenza vaccine immunogenicity is suboptimal in immunocompromised patients. However, there are limited data on the interplay of T- and B- cell responses to vaccination with simultaneous immunosuppression. Methods. We collected peripheral blood mononuclear cells from transplant recipients before and 1 month after seasonal influenza vaccination. Before and after vaccination, H1N1-specific T- and B-cell activation were quantified with flow cytometry. We also developed a mathematical model using T- and B-cell markers and mycophenolate mofetil (MMF) dosage. Results. In the 47 patients analyzed, seroconversion to H1N1 antigen was demonstrated in 34%. H1N1-specific interleukin 4 (IL-4)-producing CD4+ T-cell frequencies increased significantly after vaccination in 53% of patients. Prevaccine expression of H1N1-induced HLA-DR and CD86 on B cells was high in patients who seroconverted. Seroconversion against H1N1 was strongly associated with HLA-DR expression on B cells, which was dependent on the increase between prevaccine and postvaccine H1N1-specific IL-4+CD4+ T cells (R2 = 0.35). High doses of MMF (≥2 g/d) led to lower seroconversion rates, smaller increase in H1N1-specific IL-4+CD4+ T cells, and reduced HLA-DR expression on B cells. The mathematical model incorporating a MMF-inhibited positive feedback loop between H1N1-specific IL-4+CD4+ T cells and HLA-DR expression on B cells captured seroconversion with high specificity. Conclusions. Seroconversion is associated with influenza-specific T-helper 2 and B-cell activation and seems to be modulated by MM

Immunomodulatory Function of Interleukin 28B During Primary Infection With Cytomegalovirus

Background. Feedback mechanisms between interferons α and λ (IFNs) may be affected by single nucleotide polymorphisms (SNP) in interleukin 28B (IL-28B; IFN-λ3) promoter region and may influence cytomegalovirus (CMV) replication. Methods. We associated IL-28B SNPs with the risk of CMV replication after transplantation. Next, we examined the effect of IL-28B genotypes on IL-28B, and IFN-stimulated gene (ISG) expression, and CMV replication in human foreskin fibroblast (HFF) and peripheral blood mononuclear cells (PBMCs). Results. Transplant recipients with an IL-28B SNP (rs8099917) had significantly less CMV replication (P = .036). Both HFF-cells and PBMCs with a SNP showed lower IL-28B expression during infection with CMV, but higher "antiviral” ISG expression (eg, OAS1). Fibroblasts with a SNP had a 3-log reduction of CMV replication at day 4 (P = .004). IL-28B pretreatment induced ISG expression in noninfected fibroblasts, but a relative decrease of ISG expression could be observed in CMV-infected fibroblasts. The inhibitory effects of IL-28B could be abolished by siRNA or antagonistic peptides against the IL-28 receptor. In fibroblasts, inhibition of IL-28 signaling resulted in an increase of ISG expression and 3-log reduction of CMV-replication (P = .01). Conclusions. We postulate that IL-28B may act as a key regulator of ISG expression during primary CMV infection. IL-28B SNPs may be associated with higher antiviral ISG expression, which results in better replication contro

Eliciting and prioritising determinants of improved care in multimorbidity: A modified online Delphi study

BACKGROUND: Multimorbidity is a major challenge to health and social care systems around the world. There is limited research exploring the wider contextual determinants that are important to improving care for this cohort. In this study, we aimed to elicit and prioritise determinants of improved care in people with multiple conditions. METHODS: A three-round online Delphi study was conducted in England with health and social care professionals, data scientists, researchers, people living with multimorbidity and their carers. RESULTS: Our findings suggest a care system which is still predominantly single condition focused. 'Person-centred and holistic care' and 'coordinated and joined up care', were highly rated determinants in relation to improved care for multimorbidity. We further identified a range of non-medical determinants that are important to providing holistic care for this cohort. CONCLUSIONS: Further progress towards a holistic and patient-centred model is needed to ensure that care more effectively addresses the complex range of medical and non-medical needs of people living with multimorbidity. This requires a move from a single condition focused biomedical model to a person-based biopsychosocial approach, which has yet to be achieved

No Evidence for XMRV Nucleic Acids, Infectious Virus or Anti-XMRV Antibodies in Canadian Patients with Chronic Fatigue Syndrome

The gammaretroviruses xenotropic murine leukemia virus (MLV)-related virus (XMRV) and MLV have been reported to be more prevalent in plasma and peripheral blood mononuclear cells of chronic fatigue syndrome (CFS) patients than in healthy controls. Here, we report the complex analysis of whole blood and plasma samples from 58 CFS patients and 57 controls from Canada for the presence of XMRV/MLV nucleic acids, infectious virus, and XMRV/MLV-specific antibodies. Multiple techniques were employed, including nested and qRT-PCR, cell culture, and immunoblotting. We found no evidence of XMRV or MLV in humans and conclude that CFS is not associated with these gammaretroviruses