Education Bill: provisions relating to Wales

This is a background briefing on the Education Bill. "The Education Bill was presented to the UK Parliament by the Rt. Hon Michael Gove MP, the Secretary of State for Education, on 26 January 2011. Although most of the Bill relates to England only, it contains numerous provisions which relate to Wales. These include framework powers which would extend the legislative powers of the National Assembly in relation to the professional standards of teachers and the funding of pre-16 education and training. The Bill also provides Welsh Ministers with powers in relation to aspects of education in Wales, including powers over student finance. This paper provides a guide to all of the Welsh provisions contained in the Bill." - Cover

Structured innovation approach for application to the wave energy sector

As part of sector-wide rethink on the development process of wave energy converters (WECs), public-sector development programmes are implementing funding stage-gates that are based on performance validation. The aim of such programmes is to produce a commercially ready technology. However, a key limitation is the assumption that participating concepts cover enough of the parameter space and that a potential ‘winner’ is amongst them. Structured innovation approaches are used in other industrial sectors to analyse many alternatives concepts and as an initial step to avoid narrowing the design focus too early. This research investigated the development of such an approach for application to wave energy. A ‘concept generation and evaluation tool’ was developed which can be used to scan the parameter space and identify concepts that have the potential to achieve a target return on investment for a given location and available resource. An initial review of structured innovation tools and metrics led to the conclusion that a technoeconomic value based approach was the best way to identify promising concepts. The development of the tool was then broken down into three objectives. The first objective was to develop a flexible method for providing resource and site characteristics. This was required to easily compare concepts in a number of different deployment scenarios and to provide results which were not location specific. Two ‘Resource Estimating Relationships’ (RER) were found through least squares fitting to reference data. These can be used to generate key resource characteristics from a small subset of high-level parameters. The first RER estimates a probability distribution of sea states based on site power level and geographic region. The second RER then estimates vessel delay durations to represent the average time spent waiting for a weather window in summer and winter. To demonstrate this method, results were provided for an analysis of two WEC types, one operating in heave and one operating in surge, and for high and low energy sites in six regions. The results showed significant regional differences in the evolution of wave climate with increasing power level and consequently, differences in the amount of energy captured by each WEC. This suggests that a deployment scenario may be profitable for one WEC type but not for another. In addition, there were significant variations in other key cost drivers, including the extreme sea state and vessel delay durations. The second objective was to develop a techno-economic model that can be used at the concept creation phase of technology development. Few attempts have been made at early stage techno-economic assessment and existing methods had to be tailored for this application. This included finding parametric expressions to model cost and the development of a simple stochastic model to estimate reliability. To demonstrate the functionality of the model, results were provided for an analysis of the relationship between site power level and WEC scale. Levelised cost of energy (LCoE) values of 0.69 £/kWh and 0.20 £/kWh were found for the heave and surge WECs respectively and were achieved by optimising power level and the principal WEC dimension. However, these values are higher than is currently considered to be competitive and the results suggested that further technological improvement is required. The results also suggested that an optimal site power level, in the range of 30 kW/m to 60 kW/m, exists in each of the six regions analysed. The third, and final, objective was to develop a scoring method for indicating likelihood of development success. A ‘commercial attractiveness’ score is based on the value of LCoE as provided by the techno-economic model. In addition, a ‘technical achievability’ metric was developed to indicate whether technological improvements are realisable within a specified development period. The final set of results show how thresholds for each score can be used to identify promising concepts and deployment scenario combinations, this being the main aim of the research. The results highlight that certain structural material and PTO technologies are more likely to provide a cost-competitive WEC and that careful consideration is needed for selecting deployment locations and WEC scales depending on the WEC type. Overall, the work presented in this thesis shows how a tool can be developed for facilitating structured innovation in the wave energy sector

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

ABSTRACT Treatment of HIV-infected patients coinfected with Mycobacterium tuberculosis is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB) drugs. The aim of this study was to quantify the effect of cobicistat (COBI) or ritonavir (RTV) in modulating DDIs between darunavir (DRV) and rifampin (RIF) in a human hepatocyte-based in vitro model. Human primary hepatocyte cultures were incubated with RIF alone or in combination with either COBI or RTV for 3 days, followed by coincubation with DRV for 1 h. The resultant DRV concentrations were quantified by high-performance liquid chromatography with UV detection, and the apparent intrinsic clearance (CL int.app. ) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CL int.app. in a concentration-dependent manner. Linear regression analysis showed that log 10 RTV and log 10 COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CL int.app. , where β was equal to −234 (95% confidence interval [CI] = −275 to −193; P &lt; 0.0001) and −73 (95% CI = −89 to −57; P &lt; 0.0001), respectively. RTV was more effective in lowering 10 μM RIF-induced elevations in DRV CL int.app. (half-maximal [50%] inhibitory concentration [IC 50 ] = 0.025 μM) than COBI (IC 50 = 0.223 μM). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CL int.app. , with RTV being more potent than COBI. These data provide the first in vitro experimental insight into DDIs between RIF and COBI-boosted or RTV-boosted DRV and will be useful to inform physiologically based pharmacokinetic (PBPK) models to aid in optimizing dosing regimens for the treatment of patients coinfected with HIV and M. tuberculosis . </jats:p

Signalling 2013: from Structure to Function 89 cAMP signalling in the vasculature: the role of Epac (exchange protein directly activated by cAMP)

Abstract The second messenger cAMP plays a central role in mediating vascular smooth muscle relaxation in response to vasoactive transmitters and in strengthening endothelial cell-cell junctions that regulate the movement of solutes, cells and macromolecules between the blood and the surrounding tissue. The vasculature expresses three cAMP effector proteins: PKA (protein kinase A), CNG (cyclic-nucleotide-gated) ion channels, and the most recently discovered Epacs (exchange proteins directly activated by cAMP). Epacs are a family of GEFs (guanine-nucleotide-exchange factors) for the small Ras-related GTPases Rap1 and Rap2, and are being increasingly implicated as important mediators of cAMP signalling, both in their own right and in parallel with the prototypical cAMP target PKA. In the present paper, we review what is currently known about the role of Epac within blood vessels, particularly with regard to the regulation of vascular tone, endothelial barrier function and inflammation

Acute kidney injury: electronic alerts in primary care - findings from a large population cohort

Background: Electronic reporting of AKI has been used to aid early AKI recognition although its relevance to CA-AKI and primary care has not been described. Aims: We described the characteristics and clinical outcomes of patients with CA-AKI, and AKI identified in primary care (PC-AKI) through AKI e-Alerts. Design: A prospective national cohort study was undertaken to collect data on all e-alerts representing adult CA-AKI. Method: The study utilised the biochemistry based AKI electronic (e)-alert system that is established across the Welsh National Health Service. Results: 28.8% of the 22,723 CA-AKI e-alerts were classified as PC-AKI. Ninety-day mortality was 24.0% and lower for PC-AKI vs. non-primary care (non-PC) CA-AKI. Hospitalisation was 22.3% for PC-AKI and associated with greater disease severity, higher mortality, but better renal outcomes (non-recovery: 18.1% vs. 21.6%; progression of pre-existing CKD: 40.5% vs. 58.3%). 49.1% of PC-AKI had a repeat test within seven days, 42.5% between seven and ninety days, and 8.4% was not repeated within ninety days. There was significantly more non-recovery (24.0% vs. 17.9%) and progression of pre-existing CKD (63.3% vs. 47.0%) in patients with late repeated measurement of renal function compared to those with early repeated measurement of renal function. Conclusion: The data demonstrate the clinical utility of AKI e-alerts in primary care. We recommend that a clinical review, or referral together with a repeat measurement of renal function within seven days should be considered an appropriate response to AKI e-alerts in primary care

Multi-omics studies demonstrate Toxoplasma gondii-induced metabolic reprogramming of murine dendritic cells

Toxoplasma gondii is capable of actively invading almost any mammalian cell type including phagocytes. Early events in phagocytic cells such as dendritic cells are not only key to establishing parasite infection, but conversely play a pivotal role in initiating host immunity. It is now recognized that in addition to changes in canonical immune markers and mediators, alteration in metabolism occurs upon activation of phagocytic cells. These metabolic changes are important for supporting the developing immune response, but can affect the availability of nutrients for intracellular pathogens including T. gondii. However, the interaction of T. gondii with these cells and particularly how infection changes their metabolism has not been extensively investigated. Herein, we use a multi-omics approach comprising transcriptomics and metabolomics validated with functional assays to better understand early events in these cells following infection. Analysis of the transcriptome of T. gondii infected bone marrow derived dendritic cells (BMDCs) revealed significant alterations in transcripts associated with cellular metabolism, activation of T cells, inflammation mediated chemokine and cytokine signaling pathways. Multivariant analysis of metabolomic data sets acquired through non-targeted liquid chromatography mass spectroscopy (LCMS) identified metabolites associated with glycolysis, the TCA cycle, oxidative phosphorylation and arginine metabolism as major discriminants between control uninfected and T. gondii infected cells. Consistent with these observations, glucose uptake and lactate dehydrogenase activity were upregulated in T. gondii infected BMDC cultures compared with control BMDCs. Conversely, BMDC mitochondrial membrane potential was reduced in T. gondii-infected cells relative to mitochondria of control BMDCs. These changes to energy metabolism, similar to what has been described following LPS stimulation of BMDCs and macrophages are often termed the Warburg effect. This metabolic reprogramming of cells has been suggested to be an important adaption that provides energy and precursors to facilitate phagocytosis, antigen processing and cytokine production. Other changes to BMDC metabolism are evident following T. gondii infection and include upregulation of arginine degradation concomitant with increased arginase-1 activity and ornithine and proline production. As T. gondii is an arginine auxotroph the resultant reduced cellular arginine levels are likely to curtail parasite multiplication. These results highlight the complex interplay of BMDCs and parasite metabolism within the developing immune response and the consequences for adaptive immunity and pathogen clearance

Deriving Current Cost Requirements from Future Targets:Case Studies for Emerging Offshore Renewable Energy Technologies

This work investigates potential cost reduction trajectories of three emerging offshore renewable energy technologies (floating offshore wind, tidal stream, and wave) with respect to meeting ambitious cost targets set out in the Strategic Energy Technology Implementation Plans (SET-Plans) for Offshore Wind and Ocean Energy. A methodology is presented which calculates target costs for current early-stage devices, starting from the 2030 SET-Plan levelised cost targets. Component-based experience curves have been applied as part of the methodology, characterised through the comparative maturity level of each technology-specific cost centre. The resultant early-stage target costs are then compared with actual costs for current devices to highlight where further cost reduction is still required. It has been found that innovation and development requirements to reach these targets vary greatly between different technologies, based on their current level of technological maturity. Future funding calls and programmes should be designed with these variables in mind to support innovative developments in offshore renewables. The method presented in this paper has been applied to publicly available cost data for emerging renewable technologies and is fully adaptable to calculate the innovation requirements for specific early-stage renewable energy devices

Bringing Structure to the Wave Energy Innovation Process with the Development of a Techno-Economic Tool

Current wave energy development initiatives assume that available designs have the potential for success through continuous learning and innovation-based cost reduction. However, this may not be the case, and potential winning technologies may have been overlooked. The scenario creation tool presented in this paper provides a structured method for the earliest stages of design in technology development. The core function of the scenario creation tool is to generate and rank scenarios of potential Wave Energy Converter (WEC) attributes and inform the user on the areas of the parameter space that are most likely to yield commercial success. This techno-economic tool uses a structured innovation approach to identify commercially attractive and technically achievable scenarios, with a scoring system based on their power performance and costs. This is done by leveraging performance and cost data from state-of-the-art wave energy converters and identifying theoretical limits to define thresholds. As a result, a list of scored solutions is obtained depending on resource level, wave energy converter hull shape, size, material, degree of freedom for power extraction, and efficiency. This scenario creation tool can be used to support private and public investors to inform strategy for future funding calls, and technology developers and researchers in identifying new avenues of innovation