Cholesterol and coronary heart disease: screening and treatment

Coronary heart disease (CHD) is a major cause of morbidity and mortality in the United Kingdom, accounting for just under one quarter of all deaths in 1995: 27% among men and 21% among women.1 Although many CHD deaths occur among elderly people, CHD accounts for 31% of male and 13% of female deaths within the 45–64 age group

Arc welding of high strength aluminium alloys for armour systems applications

The ternary Al-Cu-Mg system 2xxx series aluminium alloys were examined as construction materials for armour system applications based upon comparable ballistic properties to the currently employed Al-7xxx series alloys. Utilising MIG welding solidification cracking was evident when welding constrained Al-2024 candidate base material using Al-2319 filler, the only available consumable wire for this series. A previously developed thermodynamic model suggested that an incompatible weld chemistry resulted when welding with this filler which would result in hot cracking due to a wide weld pool freezing range and a low volume fraction of eutectic liquid. As this filler wire was the only commercially available Al-2xxx filler this was seen as the principal limiting factor for exploiting this alloy series. The solution was to vary and control weld chemistry. Two approaches were taken. Firstly advanced arc welding was used to control weld dilution with the base material. A clad layer exhibiting a less crack susceptible composition was deposited using the Cold Metal Transfer process and the binary Al-2319 filler wire. Onto this layer the same filler could then be deposited to provide a structural joint. Although not fully validated, by limiting weld dilution with the base material this technique showed potential as an alternative method for suppressing solidification cracking. The second approach, which forms the core of this work, adapted the conventional tandem MIG welding process to mix different series consumable fillers in a single weld pool to control weld composition. A range of ternary weld mixtures were produced which resulted in the development of a robust thermodynamic model. Validation using this system resulted in weld cracking being eradicated. The concept was then further developed to weld using three filler wires; this expanded the mixing range and allowed further model validation. A range of crack free compositions were produced with differing mechanical properties. An optimum weld composition was determined that was then used for characterisation of the weldment. By varying heat input, base material HAZ softening was controlled with joint failure confined to the weld / base material interface. This was attributed to grain boundary liquation due to the welding temperatures involved resulting in solute rich grain boundaries. These areas did not deform easily under tensile loading initiating fracture of the joint. Acceptable joint strengths were realised however ductility was reduced due to the identified failure mode. Although not tested to military specifications, acceptable mechanical test values were recorded which were closely compliant with the minimum requirements for armour system specifications. As a consequence a filler wire composition was recommended for future prototype development.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Conformance relations for distributed testing based on CSP

Copyright @ 2011 Springer Berlin HeidelbergCSP is a well established process algebra that provides comprehensive theoretical and practical support for refinement-based design and verification of systems. Recently, a testing theory for CSP has also been presented. In this paper, we explore the problem of testing from a CSP specification when observations are made by a set of distributed testers. We build on previous work on input-output transition systems, but the use of CSP leads to significant differences, since some of its conformance (refinement) relations consider failures as well as traces. In addition, we allow events to be observed by more than one tester. We show how the CSP notions of refinement can be adapted to distributed testing. We consider two contexts: when the testers are entirely independent and when they can cooperate. Finally, we give some preliminary results on test-case generation and the use of coordination messages. © 2011 IFIP International Federation for Information Processing

The switch between acute and persistent paramyxovirus infection caused by single amino acid substitutions in the RNA polymerase P subunit

Paramyxoviruses can establish persistent infections both in vitro and in vivo, some of which lead to chronic disease. However, little is known about the molecular events that contribute to the establishment of persistent infections by RNA viruses. Using parainfluenza virus type 5 (PIV5) as a model we show that phosphorylation of the P protein, which is a key component of the viral RNA polymerase complex, determines whether or not viral transcription and replication becomes repressed at late times after infection. If the virus becomes repressed, persistence is established, but if not, the infected cells die. We found that single amino acid changes at various positions within the P protein switched the infection phenotype from lytic to persistent. Lytic variants replicated to higher titres in mice than persistent variants and caused greater infiltration of immune cells into infected lungs but were cleared more rapidly. We propose that during the acute phases of viral infection in vivo, lytic variants of PIV5 will be selected but, as the adaptive immune response develops, variants in which viral replication can be repressed will be selected, leading to the establishment of prolonged, persistent infections. We suggest that similar selection processes may operate for other RNA viruses

The multiple sclerosis risk sharing scheme monitoring study - early results and lessons for the future

Background: Risk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS. Methods: This case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis ( MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments. Results: Centres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies. Conclusion: Successful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed

Identifying evidence for past mining and metallurgy from a record of metal contamination preserved in an ombrotrophic mire near Leadhills, SW Scotland, UK

This study presents a new 3600-year record of past metal contamination from a bog located close to the Leadhills and Wanlockhead orefield of southwest Scotland. A peat core, collected from Toddle Moss, was radiocarbon (14C) dated and analysed for trace metal concentrations (by EMMA) and lead isotopes (by ICP-MS) to reconstruct the atmospheric deposition history of trace metal contamination, in particular, lead. The results show good agreement with documented historical and archaeological records of mining and metallurgy in the region: the peak in metal mining during the 18th century, the decline of lead mining during the Anglo-Scottish war and lead smelting during the early medieval period. There may also have been earlier workings during the Late Bronze and Iron Ages indicated by slight increases in lead concentrations, the Pb/Ti ratio and a shift in 206Pb/207Pb ratios, which compare favourably to the signatures of a galena ore from Leadhills and Wanlockhead. In contrast to other records across Europe, no sizeable lead enrichment was recorded during the Roman Iron Age, suggesting that the orefield was not a significant part of the Roman lead extraction industry in Britain. These findings add to the various strands of archaeological evidence that hint at an early lead extraction and metallurgical industry based in southern Scotland. The results also provide further evidence for specific regional variations in the evolution of mining and metallurgy and an associated contamination signal during prehistoric and Roman times across Europe

RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBP alpha- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction

Acute myeloid leukemia (AML) is associated with mutations in transcriptional and epigenetic regulator genes impairing myeloid differentiation. The t(8;21) (q22;q22) translocation generates the RUNX1-ETO fusion protein, which interferes with the hematopoietic master regulator RUNX1. We previously showed that the maintenance of t(8;21) AML is dependent on RUNX1-ETO expression. Its depletion causes extensive changes in transcription factor binding, as well as gene expression, and initiates myeloid differentiation. However, how these processes are connected within a gene regulatory network is unclear. To address this question, we performed Promoter-Capture Hi-C assays, with or without RUNX1-ETO depletion and assigned interacting cis-regulatory elements to their respective genes. To construct a RUNX1- ETO-dependent gene regulatory network maintaining AML, we integrated cis-regulatory element interactions with gene expression and transcription factor binding data. This analysis shows that RUNX1-ETO participates in cis-regulatory element interactions. However, differential interactions following RUNX1- ETO depletion are driven by alterations in the binding of RUNX1-ETO-regulated transcription factors

Market access agreements for pharmaceuticals in Europe: diversity of approaches and underlying concepts

<p>Abstract</p> <p>Background</p> <p>Market Access Agreements (MAA) between pharmaceutical industry and health care payers have been proliferating in Europe in the last years. MAA can be simple discounts from the list price or very sophisticated schemes with inarguably high administrative burden.</p> <p>Discussion</p> <p>We distinguished and defined from the health care payer perspective three kinds of MAA: Commercial Agreements (CA), Payment for Performance Agreements (P4P) and Coverage with Evidence Development (CED). Apart from CA, the agreements assumed collection and analysis of real-life health outcomes data, either from a cohort of patients (CED) or on per patient basis (P4P). We argue that while P4P aim at reducing drug cost to payers without a systematic approach to addressing uncertainty about drugs' value, CED were implemented provisionally to reduce payer's uncertainty about value of a medicine within a defined time period.</p> <p>Summary</p> <p>We are of opinion that while CA and P4P have a potential to reduce payers' expenditure on costly drugs while maintaining a high list price, CED address initial uncertainty related to assessing the real-life value of new drugs and enable a final HTA recommendation or reimbursement and pricing decisions. Further, we suggest that real cost to health care payers of drugs in CA and P4P should be made publicly available in a systematic manner, to avoid a perverse impact of these MAA types on the international reference pricing system.</p