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New oral anticoagulants (NOACs) are likely to have a major impact in the next few years, changing clinical practice of anticoagulation therapy. Evidence on its efficacy and superiority to vitamin K antagonists (VKAs) in treating non-cancer patients have been reported in a few clinical trials. However, patients with cancer are complicated by the prothrombotic nature of the disease, need for potentially invasive surgery and interventions, and altered drug handling. This chapter examines the available evidence and guidelines on the use of NOAC in patients with cancer.

The past few years have seen a rapid growth in the development and exploitation of X-ray diffraction on ultrafast time-scales. One area of physics which has benefited particularly from these advances is the the field of shock-waves. Whilst it has been known for many years that crystalline matter, subjected to uniaxial shock compression, can undergo plastic deformation and, for certain materials, polymorphic phase transformations, it has hitherto not been possible to observe the rearrangement of the atoms on the pertinent timescales. We have used laser-plasma generated X-rays to study how single crystals of metals (copper and iron) react to uniaxial shock compression, and observed rapid plastic flow (in the case of copper), and directly observed the famous alpha-epsilon transition in Iron. These studies have been complemented by large-scale multi-million atom molecular dynamics simulations, yielding significant information on the underlying physics.© (2006) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Major policy initiatives such as the Quality and Outcomes Framework (QOF) in the national contract for UK general practitioners might variably be informed by evidence at their inception, implementation and subsequent evolution. But what evidence gets admitted into these policy debates-and what is left out? Using QOF as an example, this article demonstrates what an analysis of the relationship between policy and the associated research can tell us about the underlying policy assumptions and about the role of evidence in policy debates. © 2013 Copyright CIPFA.

Detection of microbial antigens in clinical samples can lead to rapid diagnosis of an infection and administration of appropriate therapeutics. A major barrier in diagnostics development is determining which of the potentially hundreds or thousands of antigens produced by a microbe are actually present in patient samples in detectable amounts against a background of innumerable host proteins. In this report, we describe a strategy, termed in vivo microbial antigen discovery (InMAD), that we used to identify circulating bacterial antigens. This technique starts with “InMAD serum,” which is filtered serum that has been harvested from BALB/c mice infected with a bacterial pathogen. The InMAD serum, which is free of whole bacterial cells, is used to immunize syngeneic BALB/c mice. The resulting “InMAD immune serum” contains antibodies specific for the soluble microbial antigens present in sera from the infected mice. The InMAD immune serum is then used to probe blots of bacterial lysates or bacterial proteome arrays. Bacterial antigens that are reactive with the InMAD immune serum are precisely the antigens to target in an antigen immunoassay. By employing InMAD, we identified multiple circulating antigens that are secreted or shed during infection using Burkholderia pseudomallei and Francisella tularensis as model organisms. Potential diagnostic targets identified by the InMAD approach included bacterial proteins, capsular polysaccharide, and lipopolysaccharide. The InMAD technique makes no assumptions other than immunogenicity and has the potential to be a broad discovery platform to identify diagnostic targets from microbial pathogens., IMPORTANCE Effective treatment of microbial infection is critically dependent on early diagnosis and identification of the etiological agent. One means for rapid diagnosis is immunoassay for antigens that are shed into body fluids during infection. Immunoassays can be inexpensive, rapid, and adaptable to a point-of-care format. A major impediment to immunoassay for diagnosis of infectious disease is identification of appropriate antigen targets. This report describes a strategy that can be used for identification of microbial antigens that are shed into serum during infection by the biothreats Burkholderia pseudomallei and Francisella tularensis. Termed InMAD (in vivo microbial antigen discovery), the strategy has the potential for application to a broad spectrum of microbial pathogens.

In situ picosecond X-ray diffraction has proved to be a useful tool in furthering our understanding of the response of shocked crystals at the lattice level. To date the vast majority of this work has used single crystals as the shocked samples, owing to their diffraction efficiency, although the study of the response of polycrystalline samples is clearly of interest for many applications. We present here the results of experiments to develop sub-nanosecond powder/polycrystalline diffraction using a cylindrical pinhole camera. By allowing the incident X-ray beam to impinge on the sample at non-normal angles, the response of grains making a variety of angles to the shock propagation direction can potentially be interrogated. © 2007 American Institute of Physics.

Seventy six senior academics from 11 countries invite The BMJ ’s editors to reconsider their policy of rejecting qualitative research on the grounds of low priority. They challenge the journal to develop a proactive, scholarly, and pluralist approach to research that aligns with its stated mission

Background Despite largely successful control efforts, malaria remains a significant public health problem in Thailand. Based on microscopy, the northwestern province of Tak, once Thailand’s highest burden area, is now considered a low-transmission region. However, microscopy is insensitive to detect low-level parasitaemia, causing gross underestimation of parasite prevalence in areas where most infections are subpatent. The objective of this study was to assess the current epidemiology of malaria prevalence using molecular and serological detection methods, and to profile the antibody responses against Plasmodium as it relates to age, seasonal changes and clinical manifestations during infection. Three comprehensive cross-sectional surveys were performed in a sentinel village and from febrile hospital patients, and whole blood samples were collected from infants to elderly adults. Genomic DNA isolated from cellular fraction was screened by quantitative-PCR for the presence of Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi. Plasma samples were probed on protein microarray to obtain antibody response profiles from the same individuals. Results Within the studied community, 90.2 % of Plasmodium infections were submicroscopic and asymptomatic, including a large number of mixed-species infections. Amongst febrile patients, mixed-species infections comprised 68 % of positive cases, all of which went misdiagnosed and undertreated. All samples tested showed serological reactivity to Plasmodium antigens. There were significant differences in the rates of antibody acquisition against P. falciparum and P. vivax, and age-related differences in species-specific immunodominance of response. Antibodies against Plasmodium increased along the ten-month study period. Febrile patients had stronger antibody responses than asymptomatic carriers. Conclusions Despite a great decline in malaria prevalence, transmission is still ongoing at levels undetectable by traditional methods. As current surveillance methods focus on case management, malaria transmission in Thailand will not be interrupted if asymptomatic submicroscopic infections are not detected and treated. Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1393-4) contains supplementary material, which is available to authorized users.

This chapter uses “knowledge mobilization” as an umbrella term to cover activities aimed at collating and communicating research-based knowledge within the health care system and within health care organizations. It explores the nature, use and flow of knowledge, focusing in particular on the role of research-based knowledge and its interactions with other forms of knowing, and on the organizational and management arrangements for health care delivery rather than on evidence-based practice per se. The chapter is underpinned by the premise that knowledge flow in health care is often slow, intermittent and uncertain. Specific, active, knowledge mobilization strategies that take account of context, politics and the individuals and groups involved are therefore needed to help ensure that research-based knowledge informs policy and practice.

Modern health care policy frequently invokes notions of cultural change as a key means of achieving performance improvement and good quality health care. This chapter aims to sharpen thinking around the theory and feasibility of culture change in health care contexts by setting out some of the key conceptual and practical challenges that need to be addressed by policy makers, health care managers, researchers, and by others seeking to understand, assess and change cultures in health care organizations. It begins by introducing some of the sources of ideas, conceptual underpinnings and key concerns with using organizational culture, before considering the evidence on the linkages between culture and health care performance and the wide range of models that have been used to understand culture change and the management of cultural diversity in health care organizations. The chapter closes by arguing that the diverse and contested nature of understanding about culture will necessarily mean that there will be diverse and contested ways of seeking to harness the power of culture to deliver the desired improvements in health care quality and performance. What is clear is attempting to enact culture change to improve health care performance is a difficult, uncertain and risky enterprise and may not always generate the anticipated outcomes. As in many other areas of management we are in need of a more secure evidence base that is underpinned by a more sophisticated understanding of these complex and dynamic organizational phenomena.

Many outstanding problems in solid-Earth science relate to the geodynamical explanation of geochemical observations. Currently, extensive geochemical databases of surface observations exist, but satisfying explanations of underlying mantle processes are lacking. One way to address these problems is through numerical modelling of mantle convection while tracking chemical information throughout the convective mantle. We have implemented a new way to track both bulk compositions and concentrations of trace elements in a finite-element mantle convection code. Our approach is to track bulk compositions and trace element abundances via particles. One value on each particle represents bulk composition and can be interpreted as the basalt component. In our model, chemical fractionation of bulk composition and trace elements happens at self-consistent, evolving melting zones. Melting is defined via a composition-dependent solidus, such that the amount of melt generated depends on pressure, temperature and bulk composition of each particle. A novel aspect is that we do not move particles that undergo melting; instead we transfer the chemical information carried by the particle to other particles. Molten material is instantaneously transported to the surface layer, thereby increasing the basalt component carried by the particles close to the surface and decreasing the basalt component in the residue. The model is set to explore a number of radiogenic isotopic systems, but as an example here the trace elements we choose to follow are the Pb isotopes and their radioactive parents. For these calculations we will show (1) the evolution of the distribution of bulk compositions over time, showing the buildup of oceanic crust (via melting-induced chemical separation in bulk composition), i.e. a basalt-rich layer at the surface, and the transportation of these chemical heterogeneities through the deep mantle; (2) the amount of melt generated over time; (3) the evolution of the concentrations and abundances of different isotopes of the trace elements (U, Th, K and Pb) throughout the mantle; and (4) a comparison to a semi-analytical theory relating observed arrays of correlated Pb isotope compositions to melting age distributions (Rudge, 2006).

Organic fluorescent dyes are widely used for the visualization of bound antibody in a variety of immunofluorescence assays. However, the detection equipment is often expensive, fragile, and hard to deploy widely. Quantum dots (Qdot) are nanocrystals made of semiconductor materials that emit light at different wavelengths according to the size of the crystal, with increased brightness and stability. Here, we have evaluated a small benchtop "personal" optical imager (ArrayCAM) developed for quantification of protein arrays probed by Qdot-based indirect immunofluorescence. The aim was to determine if the Qdot imager system provides equivalent data to the conventional organic dye-labeled antibody/laser scanner system. To do this, duplicate proteome microarrays of Vaccinia virus, Brucella melitensis and Plasmodium falciparum were probed with identical samples of immune sera, and IgG, IgA, and IgM profiles visualized using biotinylated secondary antibodies followed by a tertiary reagent of streptavidin coupled to either P3 (an organic cyanine dye typically used for microarrays) or Q800 (Qdot). The data show excellent correlation for all samples tested (R > 0.8) with no significant change of antibody reactivity profiles. We conclude that Qdot detection provides data equivalent to that obtained using conventional organic dye detection. The portable imager offers an economical, more robust, and deployable alternative to conventional laser array scanners.

Consumer and regulatory tests for improvement in pedestrian protection are now firmly established. A change in the vehicle frontal stiffness profiles as a result of these tests is less well established. The purpose of this paper is to contribute to the knowledge base on the vehicle frontal stiffness in pedestrian impacts. Using data recorded as part of the European New Car Assessment Programme, a series of 139 impact tests using headform and legform impactors were used to calculate the vehicle frontal stiffness profile of eight cars manufactured between 2006 and 2010. To account for one of the limitations of the legform as a device for measuring the stiffness of a surface, a methodology for determining a correction factor using the multi-body modelling software MADYMO is presented. Comparison with previous published work showed that the stiffness of the windscreen was unchanged, but that the stiffnesses of the bonnet and front bumper were reduced.

Aims Biochemical marker testing has improved the evaluation and management of patients with cardiovascular diseases over the past decade. Natriuretic peptides (NPs), used in clinical practice to assess cardiac dysfunction, exhibit many limitations, however. We used an unbiased proteomics approach for the discovery of novel diagnostic plasma biomarkers of heart failure (HF). Methods and results A proteomics pipeline adapted for very low-abundant plasma proteins was applied to clinical samples from patients admitted with acute decompensated HF (ADHF). Quiescin Q6 (QSOX1), a protein involved in the formation of disulfide bridges, emerged as the best performing marker for ADHF (with an area under the receiver operator characteristic curve of 0.86, 95% confidence interval: 0.79–0.92), and novel isoforms of NPs were also identified. Diagnostic performance of QSOX1 for ADHF was confirmed in 267 prospectively collected subjects of whom 76 had ADHF. Combining QSOX1 to B-type NP (BNP) significantly improved diagnostic accuracy for ADHF by particularly improving specificity. Using thoracic aortic constriction in rats, QSOX1 was specifically induced within both left atria and ventricles at the time of HF onset. Conclusion The novel biomarker QSOX1 accurately identifies ADHF, particularly when combined with BNP. Through both clinical and experimental studies we provide lines of evidence for a link between ADHF and cardiovascular production of QSOX1.

Many of the practices around the sharing of social research are stuck in ‘information-telling’ mode and fail to draw on approaches from other fields that are concerned with influencing deeper beliefs, values, assumptions or mental models. This paper seeks to scope out some of these other areas of ‘influencing’ to consider their relevance for the communication of social research. We conclude that, despite some attendant risks, there is scope for using a wider repertoire of approaches to communicating social research findings.

Despite the importance of Salmonella infections in human and animal health, the target antigens of Salmonella -specific immunity remain poorly defined. We have previously shown evidence for antibody-mediating protection against invasive Salmonellosis in mice and African children. To generate an overview of antibody targeting in systemic Salmonellosis, a Salmonella proteomic array containing over 2,700 proteins was constructed and probed with immune sera from Salmonella -infected mice and humans. Analysis of multiple inbred mouse strains identified 117 antigens recognized by systemic antibody responses in murine Salmonellosis. Importantly, many of these antigens were independently identified as target antigens using sera from Malawian children with Salmonella bacteremia, validating the study of the murine model. Furthermore, vaccination with SseB, the most prominent antigenic target in Malawian children, provided mice with significant protection against Salmonella infection. Together, these data uncover an overlapping immune signature of disseminated Salmonellosis in mice and humans and provide a foundation for the generation of a protective subunit vaccine.

Background: market reforms in England have been identified as making a clear distinction between English health policy and health policy in the devolved systems in Northern Ireland, Scotland and Wales. Patient choice is a high profile policy in the English National Health Service that constitutes significant changes to the demand side of health care. It is not clear what national differences this has led to regarding implementation of policy. This article presents the findings from a large UK-wide study on the development and implementation of policies related to patient choice of provider. The findings reported here relate specifically to the policy development and organizational implementation of choice in order to examine the impact of devolution on health care policy. Aim: this study examines patient choice of provider across all four countries of the UK to understand the effect of differences in national policies on the organization and service how choice of provider presented to patients. Methods: at the macro-level, we interviewed policymakers and examined policy and guidance documents to analyze the provenance and determinants of national policy in each UK nation. At the Primary Care Trust or Health Board level, we interviewed a range of public and private health service providers to identify the range of referral pathways and where and when choices might be made. Finally, we interviewed ear, nose and throat, and orthopaedics patients to understand how such choices were experienced. Findings: while we found that distinct rhetorical differences were identifiable at a national policy level, these were less visible at the level of service organization and the way choices were provided to patients. Conclusion: historical similarities in both the structure and operation of health care, coupled with common operational objectives around efficient resource use and waiting times, mediate how strategic policy is implemented and experienced in the devolved nations of the UK.

Successful vaccination against smallpox with conventional vaccinia virus is usually determined by the development of a vesicular skin lesion at the site of vaccinia inoculation, called a “take.” Although previous vaccination is known to be associated with attenuation of the take, the immunology that underlies a no-take in vaccinia-naïve individuals is not well understood. We hypothesized that antibody profiling of individuals before and after receiving vaccinia virus would reveal differences between takes and no-takes that may help better explain the phenomenon. Using vaccinia virus proteome microarrays and recombinant protein enzyme-linked immunosorbent assays (ELISAs), we first examined the antibody response in vaccinia-naïve individuals that failed to take after receiving different doses of the replication-competent DryVax and Aventis Pasteur (APSV) smallpox vaccines. Most that received diluted vaccine failed to respond, although four no-takes receiving diluted vaccine and four receiving undiluted vaccine mounted an antibody response. Interestingly, their antibody profiles were not significantly different from those of controls that did show a take. However, we did find elevated antibody titers in no-takes prior to receiving DryVax that were significantly different from those of takes. Although the sample size studied was small, we conclude the failure to take in responders correlates with preexisting immunity of unknown etiology that may attenuate the skin reaction in a way similar to previous smallpox vaccination.

Cardiff University students have used the freedom of the Formula Student rules to create an innovative chassis that combines a high performance with an efficient manufacturing process. All aluminium sandwich panels were pre-cut using computer numerical control routing, which is a rapid low-cost operation that produced highly accurate results. Assembling the monocoque consisted of folding and bonding panels along pre-routed lines and reinforcing the relevant joints. This required no specialist tools or equipment and was a rapid non-labour-intensive operation. The key design features, the manufacturing techniques, and the results of experimental and computational performance testing are presented here. This chassis construction technique is the result of research and development for seven years over six generations of Formula Student race cars.

This paper presents a parametric study of the injury risk in collisions of race cars designed for the European Formula Student competition. The study is motivated by the fact that only a limited assessment of driver safety is required for this competition. The approach was to model a Formula Student car in a mathematical dynamic model environment. A parametric study was then carried out to investigate the sensitivity of injury to various system variables. These were the crash pulse, the occupant stature, and the occupant posture. These system variables, under close examination, can be changed to alter the occupant kinematics or, in other words, they change the injury risk. The results of the analysis showed that the risk of injury in a frontal impact was dependent on the system variables. The risk of an abbreviated injury scale (AIS)2+ injury was 22.3 per cent in the baseline constant- g test, increasing to 35.2 per cent in the worst case. For AIS3+ the values were 5.1 per cent and 11 per cent, respectively. The study also showed that the occupant restraint conditions in a Formula Student car had a significant influence on the distribution of the injury risk between the body regions. The variation in the injury risk highlighted by this study, both in absolute terms and in the distribution between the body regions, showed that there are limitations to the use of vehicle kinematics in their current guise as a predictive tool for the injury risk. The results of this study represent a significant step in the understanding of the injury risk in a Formula Student frontal impact.

Correctly packaged, foam-filled fluids are a material technology that will lead to enhanced pedestrian safety. It is the combination of energy absorption mechanisms and how this combination can be altered by changes to the properties of the constituent components that provides significant opportunity for tailoring the response of the energy absorber to meet the different demands placed upon it. To date, the research stream has tended to focus on one-factor-at-a-time (OFAT) characterisation in order to develop an understanding of the individual energy absorption mechanisms present in the system. It is unlikely that the full implications of setting the design variables could be understood for such a complex system using an OFAT approach. An experimental design approach to the problem of characterising the response of foam-filled fluids is proposed. To demonstrate the applicability of this approach, the work presented here investigated four process parameters over a limited number of levels. Out of the four parameters, velocity and length were shown to be the significant process parameters determining peak load; velocity and capsule size were shown to be the significant process parameters determining deflection; and viscosity was shown to be the significant process parameter determining absorber efficiency. On the basis of the work presented, a methodology for simultaneous optimisation is proposed that will support the vehicle designer in the development of a foam-filled bumper system. The work is considered timely because of changes in regulations and will support the automotive industry and the requirement to design future vehicles that afford additional protection for pedestrians.

Background: Internationally, nurses face ongoing difficulties in making a reality of evidence-based practice. Existing studies suggest that nurse managers (NMs) should play a key role in leading and facilitating evidence-based practice, but the nature of this role has not yet been fully explored or articulated. This is one of the first studies to investigate the roles of NMs in evidence-based practice implementation. Methodology and Methods: Using a case study approach the study explores five propositions in relation to the NMs’ potential evidence-based practice role and the extent to which their attitudes, knowledge, and skills support such a role. In doing so, it draws on interviews (n= 51), documentary analysis and observational data. Findings: Data analysis reveals that the role of NMs in facilitating evidence-based practice is under-articulated, largely passive and currently limited by competing demands. Progress in implementing evidence-based practice in the case study sites is largely explained by factors other than the role played by NMs. As such, the findings expose significant discrepancies between NMs’ actual roles and those espoused in the literature as being necessary. Contextual factors are important and it is clear that the role of the contemporary NM places considerable emphasis on management and administration to the detriment of clinical practice concerns. Conclusions: The study reveals that NMs are only involved in evidence-based practice implementation in a passive role, not the full engagement described in the literature as being necessary. This study adds previously lacking detail of the roles of NMs. It elucidates why exhortations to NMs to become more involved in evidence-based practice implementation are ineffective without action to address the problems identified.

Background There is an increasing literature on learning organisations as a way of fostering communication, teamwork, collaboration and collective learning, thereby promoting quality improvement and enhancing patient safety. An increasing number of instruments are being developed in an attempt to measure learning organisation characteristics. However, the majority of these tools are created for a business setting, have not been scientifically tested and have not been applied in healthcare. Objective To evaluate elements of the validity and reliability of an instrument (ie, learning practice inventory (LPI)) for diagnosing learning practice characteristics in primary healthcare. Method Content validity was evaluated using a modified nominal group technique and a content validity rating scale. Construct validity and reliability evaluation was undertaken with 10 staff members from 10 general practices in the west of Scotland. Staff completed the inventory twice, 4–6 weeks apart. Applying generalisability theory, a variance component analysis was performed. Results The main findings present evidence that the inventory has acceptable reliability and content validity. The results also demonstrate that the inventory can reflect the consistent and uniquely different perspectives of particular designations of staff within a practice. It is possible to compare practices' overall learning environments and to identify specific areas of practice strength as well as areas for development. Conclusion This study demonstrates the psychometric properties of a learning practice diagnostic inventory. It highlights the consistently different perspectives that individual staff groups have on the function of their practice, suggesting that the success of quality improvement initiatives may be compromised without the involvement and true engagement of each staff group.

Rationale and objectives The growing interest in patient-focused health care in the National Health System (NHS), especially in the wake of high-profile failures in clinical practice, has underlined the need to involve patients in the design and evaluation of organizational change management programmes at the local level. This includes an evaluation of the relevance of culture and how culture might be assessed and managed in the delivery of high-quality and safe care. The purpose of this study is to compare and contrast the perspectives of health care professionals and patient representatives on purposeful attempts to manage culture change in the English NHS. Methods We used the mixed approach, but with more quantitative than qualitative data. A postal questionnaire survey of clinical governance leads and patient representatives from 276 NHS trusts was followed up with a focus group discussion of eight of the survey participants and semi-structured interviews with 18, including health care professionals and patient representatives from various organizations. We used spss to analyse the survey data and Atlas.ti to analyse the qualitative data. Results and conclusions Both clinical governance leads and patient representatives considered culture management and change to be integral to quality and safety improvement efforts. However, clinical governance leads were more positive than patient representatives about anticipated results from ongoing efforts to manage culture change at the local level. Further, in spite of general agreement on various attributes for culture assessment efforts, there was a striking difference in the level of importance respondents attached to blame free (more important to clinical governance managers) and customization (more important to patient representatives).

This, the first John Barron Memorial Lecture, sketches his activity in the 1980s for the UGC in reshaping institutional provision in Classics and in Archaeology, in order to explore its best routes of healthy survival. It reviews developments in Britain within the study of antiquity in the last twenty years, but also reviews current and likely future transformations of the wider environment, both fiscal-financial and technological – all of which threaten marginalization, if not extinction. It then notes that the erosion of the Humboldtian vision of the discipline makes it appear derivative, inward-looking, and lacking an externally recognised raison d'être. That view is best controverted by identifying the most promising future markets in terms of age, world geography, delivery systems, and basic curiosity and interest, and above all by identifying the attitudes which the study of pre-Islamic antiquity can and should instil.

The commissioning and production of social sciences research is largely governed and shaped by the norms and values of the academic community, in which research influence and impact on practice are often not prioritised, or are somewhat taken for granted. This paper explores how the research commissioning process might be reconfigured to make research influence and impact issues of central importance. Using examples from a UK government funded health services research programme in which the authors have both been closely involved, it discusses the mission or purpose of research; the nature of research needs and the way that research priorities are set; the products of research and the way such outputs are used; and the nature of healthcare organisations and decision makers who are the intended users of research. It concludes that reinventing the research commissioning process to give primacy to influence and impact opens up exciting possibilities: a world where researchers have detailed and nuanced understandings about local organisational contexts, and are active participants in interpreting the research discourse for managers; and a world where managers are actively engaged with the ideas, theories, insights and critiques that come from research, are participants in local data collection and analysis, and are on a constant quest for reflexive application of these insights in their local contexts.

Wellington's first independent command has been seen as a short, but intense, ‘baptism of fire’ in which the young Lieutenant-Colonel Arthur Wellesley commanded a small force against the insurgent, or ‘freebooter’, Dhoondiah Vagh. New evidence presented here, however, demonstrates that the three-month military campaign was preceded by several months of political negotiation and intelligence gathering designed to isolate Dhoondiah and starve him of sanctuary, support and sustenance. As a result, the campaign was much more complex than previously thought, and demonstrates important lessons about British imperial expansion in the region at the beginning of the nineteenth century, on the nature of British authority in India, and on the opening stages of the military career of the future Duke of Wellington.

A major component of the adaptive immune response to infection is the generation of protective and long-lasting humoral immunity. Traditional approaches to understanding the host’s humoral immune response are unable to provide an integrated understanding of the antibody repertoire generated in response to infection. By studying multiple antigenic responses in parallel, we can learn more about the breadth and dynamics of the antibody response to infection. Measurement of antibody production following vaccination is also a gauge for efficacy, as generation of antibodies can protect from future infections and limit disease. Protein microarrays are well suited to identify, quantify and compare individual antigenic responses following exposure to infectious agents. This technology can be applied to the development of improved serodiagnostic tests, discovery of subunit vaccine antigen candidates, epidemiologic research and vaccine development, as well as providing novel insights into infectious disease and the immune system. In this review, we will discuss the use of protein microarrays as a powerful tool to define the humoral immune response to bacteria and viruses.

An investigation of the power law relationship between Nusselt number (Nu) and Rayleigh number (Ra) for Earth’s convecting mantle is presented. The Nu(Ra) relationship was calculated from the results of a model with three dimensional spherical geometry and free slip boundary conditions. Both basally and internally heated convection has been examined. For Nu(Ra)=aRaβ, β was found to be 0.294±0.004 for basally heated systems, which is lower than the value of 1/3 suggested by conventional boundary layer theory. The exponent β=0.337±0.009 for internally heated systems, when the internally heated Ra is converted to a basally heated equivalent for comparison. The influence of the method used to calculate β was also considered, with particular attention paid to high Ra. As an example of the significance of β=0.29 rather than 1/3, a Ra of 109 results in a surface heat flux which is ≈32% lower. Within the range of Ra used in this study, there is no evidence that β changes at high Ra. Therefore, that mechanism cannot be used to moderate mantle temperature when projecting back to early Earth conditions. The differing planform of basally and internally heated models was shown to result in different scaling relationships between root mean square surface velocity and Ra for the two modes of heating, in particular, a much lower surface velocity for internally heated cases relative to equivalent Ra basally heated cases.

Summary Objectives To assess changes in senior management culture in English NHS hospitals between 2001 and 2008. Design Longitudinal study comprising cross-sectional surveys of board levels managers at three time-points using a validated culture measurement instrument – the Competing Values Framework. Setting English NHS hospital trusts. Main outcomes There has been a decline in ‘Clan’ and an increase in more competitive ‘Rational’ cultures among senior management teams in NHS hospital trusts during the period 2001–2008. Conclusions Government policy for the NHS has espoused the desirability of competition, particularly since 2002. Our data suggest that corresponding changes in the cultures of senior management teams in NHS hospital trusts is beginning to occur, with the expectation that these organizations will pursue more competitive strategies.

BackgroundIn reattribution, general practitioners (GPs) request psychosocial information directly and explain medically unexplained symptoms (MUS) using psychosocial information in the consultation. We explored whether reattribution training (RT) increased the communication of psychosocial information and decreased communication about somatic intervention between GPs and their MUS patients.MethodA cluster randomized controlled trial (RCT) of RT versus usual treatment in GPs from 16 practices and 141 patients with MUS on audio-recorded and transcribed doctor–patient communication in an index consultation. In a secondary data analysis, the Liverpool Clinical Interaction Analysis Scheme (LCIAS) was applied by an experienced rater to each turn of speech in the transcript from the index consultation blind to treatment allocation.ResultsAfter RT, patients were more likely to disclose and discuss psychosocial problems, and propose psychosocial explanations for symptoms; around 25% of patients discussed psychosocial information extensively. In the RT group, GPs did not seek new psychosocial disclosure but they reduced advocacy for somatic intervention. After RT, GPs suggested, on average, two utterances of psychosocial explanation and six utterances of somatic intervention.ConclusionsAfter RT, some patients discussed psychosocial issues extensively but GPs did not probe underlying psychosocial issues. They gave mixed psychosocial and somatic messages about MUS, which may have increased patients' concerns about their health. GPs should actively seek the disclosure of underlying psychosocial problems and give clear, unambiguous messages to MUS patients when they are willing to discuss psychosocial issues.

Developed in industry in the 1980s, and applied in a limited way in health care from the 1990s, Six Sigma uses a range of statistical and other tools to reduce variations in processes. Although Six Sigma is a particularly challenging quality improvement approach to use in healthcare settings, some process improvements have been reported and there is growing interest in using a combination of lean thinking and Six Sigma approaches in the NHS.

Background Previous national survey research has shown significant deficits in routine postoperative pain management in the UK. This study used an organizational change perspective to explore in detail the organizational challenges faced by three acute pain services in improving postoperative pain management. Methods Case studies were conducted comprising documentary review and semi-structured interviews (71) with anaesthetists, surgeons, nurses, other health professionals, and managers working in and around three broadly typical acute pain services. Results Although the precise details differed to some degree, the three acute pain services all faced the same broad range of inter-related challenges identified in the organizational change literature (i.e. structural, political, cultural, educational, emotional, and physical/technological challenges). The services were largely isolated from wider organizational objectives and activities and struggled to engage other health professionals in improving postoperative pain management against a background of limited resources, turbulent organizational change, and inter- and intra-professional politics. Despite considerable efforts they struggled to address these challenges effectively. Conclusions The literature on organizational change and quality improvement in health care suggests that it is only by addressing the multiple challenges in a comprehensive way across all levels of the organization and health-care system that sustained improvements in patient care can be secured. This helps to explain why the hard work and commitment of acute pain services over the years have not always resulted in significant improvements in routine postoperative pain management for all surgical patients. Using this literature and adopting a whole-organization quality improvement approach tailored to local circumstances may produce a step-change in the quality of routine postoperative pain management.

Lean thinking was developed by Toyota in the 1950s. It emphasises streamlining processes to provide what the customer wants with minimal wasted time, effort or cost. The approach uses a range of tools, such as ‘value stream mapping’ (identifying and removing any unnecessary steps in a process) and 5S (a series of five steps to enable workforce teams to look at the environment they work in and to start to identify the blocks in current processes). Lean thinking approaches have been applied in healthcare settings with some success in reducing waste. The approaches appear to be particularly useful in streamlining processes in support departments, rather than mainstream clinical services. Successful wholesale application has not yet been demonstrated in healthcare settings.

This article draws on both a cross-sector literature review of mechanisms to promote evidence-based practice and a specific review of ways of improving research use in social care. At the heart of the article is a discussion of three models of evidence-based practice: the research-based practitioner model, the embedded research model, and the organizational excellence model. The article concludes that the ideas contained within each of these models are likely to be appropriate at different times and for different service settings. There is a need to build on such models to develop a coherent framework for strategies to promote research use.

Background: There is growing international interest in managing organisational culture as a lever for healthcare improvement. This has prompted a practical need to understand what instruments and tools exist for assessing cultures in healthcare contexts. The present study was undertaken to determine the culture assessment tools being used in the English NHS and assess their fitness for purpose. Methods: Postal questionnaire survey of clinical governance leads in 275 English NHS organisations, with a response rate of 77%. Results: A third of the organisations were currently using a culture assessment instrument to support their clinical governance activity. Although we found a high degree of satisfaction with existing instruments, in terms of ease of use and relevance, there is an immediate practical need to develop new and better bespoke culture assessment tools to bridge the gap between the cultural domains covered by extant instruments and the broader range of concerns of clinical governance managers. Conclusion: There is growing interest in understanding and shaping local cultures in healthcare, which is not yet matched by widespread use of available instruments. Even though extant tools cover many of the most important cultural attributes identified by clinical governance managers, the over-riding focus of tools in use is on safety rather than a holistic assessment of the dimensions of healthcare quality and performance.

Developed in Japan in the 1950s, Total Quality Management/Continuous Quality Improvement (TQM/CQI) approaches have been taken up in a variety of forms by many healthcare organisations since the early 1990s. Although TQM/CQI has several strengths, including a strong customer focus and the use of data to analyse variations in quality, its use in health care has encountered a range of practical and cultural obstacles. In the first of five articles looking at major approaches to quality improvement that have been used in healthcare organisations in the past two decades, the authors review the potential of TQM/CQI and the challenges of using this approach to improve patient care.

Hot-spots are anomalous regions of magmatism that cannot be directly associated with plate tectonic processes. They are widely-regarded as the surface expression of upwelling mantle plumes. Hot-spots exhibit variable life-spans, magmatic productivity and fixity. This suggests that a wide-range of upwelling structures coexist within Earth's mantle, a view supported by geochemical and seismic evidence, but, thus far, not fully-reproduced by numerical models. Here, results from a new, global, 3-D spherical, mantle convection model are presented, which better reconcile hot-spot observations, the key modification from previous models being increased convective vigor. Model upwellings show broad-ranging dynamics; some drift slowly, while others are more mobile, displaying variable life-spans, intensities and migration velocities. Such behavior is consistent with hot-spot observations, indicating that the mantle must be simulated at the correct vigor and in the appropriate geometry to reproduce Earth-like dynamics. Thermally-driven mantle plumes can explain the principal features of hot-spot volcanism on Earth.

A complete description of the serological response following exposure of humans to complex pathogens is lacking and approaches suitable for accomplishing this are limited. Here we report, using malaria as a model, a method which elucidates the profile of antibodies that develop after natural or experimental infection or after vaccination with attenuated organisms, and which identifies immunoreactive antigens of interest for vaccine development or other applications. Expression vectors encoding 250 Plasmodium falciparum (Pf) proteins were generated by PCR/recombination cloning; the proteins were individually expressed with >90% efficiency in Escherichia coli cell-free in vitro transcription and translation reactions, and printed directly without purification onto microarray slides. The protein microarrays were probed with human sera from one of four groups which differed in immune status: sterile immunity or no immunity against experimental challenge following vaccination with radiation-attenuated Pf sporozoites, partial immunity acquired by natural exposure, and no previous exposure to Pf. Overall, 72 highly reactive Pf antigens were identified. Proteomic features associated with immunoreactivity were identified. Importantly, antibody profiles were distinct for each donor group. Information obtained from such analyses will facilitate identifying antigens for vaccine development, dissecting the molecular basis of immunity, monitoring the outcome of whole-organism vaccine trials, and identifying immune correlates of protection.

PurposeThe purpose of this paper is to present an adaptive finite element procedure that improves the quality of convection dominated mid‐ocean ridge (MOR) and subduction zone (SZ) simulations in geodynamics.Design/methodology/approachThe method adapts the mesh automatically around regions of high‐solution gradient, yielding enhanced resolution of the associated flow features. The approach utilizes an automatic, unstructured mesh generator and a finite element flow solver. Mesh adaptation is accomplished through mesh regeneration, employing information provided by an interpolation‐based local error indicator, obtained from the computed solution on an existing mesh.FindingsThe proposed methodology works remarkably well at improving solution accuracy for both MOR and SZ simulations. Furthermore, the method is computationally highly efficient.Originality/valueTo date, successful goal‐orientated/error‐guided grid adaptation techniques have, to the knowledge, not been utilized within the field of geodynamics. This paper presents the first true geodynamical application of such methods.

Purpose – The purpose of this paper, based on a nation‐wide survey, is to explore how clinical governance managers in the English NHS are seeking to engage with the culture(s) of their organisation to support quality improvement.Design/methodology/approach – All English NHS primary and acute trusts, a total of 325, were contacted for R&D approval between March and September 2006. Clinical governance leads of organisations which gave their approval, 276 (or 85 per cent), were targeted in a nation‐wide postal survey between October 2006 and February 2007. A response rate of 77 per cent was obtained. The questionnaire contained mostly closed questions about the role and importance of culture in clinical governance and the use of tools for culture assessment. The questionnaire was piloted with eight respondents, seven in clinical governance from both primary care and acute trusts, and one from the National Patient Safety Agency. Useful feedback was received from five of the respondents, which was used to revi...

Humans and other animals with Lyme borreliosis produce antibodies to a number of components of the agentBorrelia burgdorferi, but a full accounting of the immunogens during natural infections has not been achieved. Employing a protein array produced in vitro from 1,292 DNA fragments representing ∼80% of the genome, we compared the antibody reactivities of sera from patients with early or later Lyme borreliosis to the antibody reactivities of sera from controls. Overall, ∼15% of the open reading frame (ORF) products (Orfs) ofB. burgdorferiin the array detectably elicited an antibody response in humans with natural infections. Among the immunogens, 103 stood out on the basis of statistical criteria. The majority of these Orfs were also immunogenic with sera obtained from naturally infectedPeromyscus leucopusmice, a major reservoir. The high-ranking set included severalB. burgdorferiproteins hitherto unrecognized as immunogens, as well as several proteins that have been established as antigens. The high-ranking immunogens were more likely than nonreactive Orfs to have the following characteristics: (i) plasmid-encoded rather than chromosome-encoded proteins, (ii) a predicted lipoprotein, and (iii) a member of a paralogous family of proteins, notably the Bdr and Erp proteins. The newly discovered antigens included Orfs encoded by several ORFs of the lp36 linear plasmid, such as BBK07 and BBK19, and proteins of the flagellar apparatus, such as FliL. These results indicate that the majority of deduced proteins ofB. burgdorferido not elicit antibody responses during infection and that the limited sets of immunogens are similar for two different host species.

The limited relaxation of shapes of impact craters and high correlation between topography and gravity are some of the reasons that support the widely accepted view that the interior of Venus is dry compared to Earth. The fact that the atmospheric abundance of 40Ar is only ~ 25% of the radiogenic gas produced inside Venus argues that Venus is not thoroughly degassed and its interior has not been dried over time. Therefore Venus must have lost its water very early in its history, before any significant 40Ar was produced. Current ideas suggest that Venus did not suffer a major impact. Therefore one would not expect it to have been substantially molten. As a result degassing all its water would be difficult and losing all the water without leaving oxygen in the atmosphere would also be very difficult.\ud \ud To overcome the above difficulties in explaining a dry Venus interior, a new hypothesis is proposed that Venus formed by a near head-on collision of two large planetary embryos, as might be expected from favoured oligarchic planetary accretion. Such a collision would be sufficiently large to melt totally and briefly vapourise a significant proportion of both bodies. This would allow much of the released water to react rapidly with iron. Depending upon the reaction hydrogen is either expected to escape to space or enter the core. Oxygen would form FeO, most of which would enter the core, together with other iron reaction products. Most everything else not caught in the hydrodynamic escape driven by any hydrogen stream would be gravitationally retained by the final body. The model can therefore reconcile the 40Ar data, a virtually oxygen free atmosphere and a dry interior. An appropriate large collision also provides an easy explanation for the retrograde rotation of Venus. The possible implications for inner core and magnetic field formation; and atmosphere evolution including effects on D/H, C, N and inert gases are also discussed. A simple test of this hypothesis is that, in contrast to the current Venus paradigm, little or no hydrated minerals should be found on the surface.

The smallpox vaccine is widely considered the gold standard for human vaccines, yet the key antibody targets in humans remain unclear. We endeavored to identify a stereotypic, dominant, mature virion (MV) neutralizing antibody target in humans which could be used as a diagnostic serological marker of protective humoral immunity induced by the smallpox vaccine (vaccinia virus [VACV]). We have instead found that diversity is a defining characteristic of the human antibody response to the smallpox vaccine. We show that H3 is the most immunodominant VACV neutralizing antibody target, as determined by correlation analysis of immunoglobulin G (IgG) specificities to MV neutralizing antibody titers. It was determined that purified human anti-H3 IgG is sufficient for neutralization of VACV; however, depletion or blockade of anti-H3 antibodies revealed no significant reduction in neutralization activity, showing anti-H3 IgG is not required in vaccinated humans (or mice) for neutralization of MV. Comparable results were obtained for human (and mouse) anti-L1 IgG and even for anti-H3 and anti-L1 IgG in combination. In addition to H3 and L1, human antibody responses to D8, A27, D13, and A14 exhibited statistically significant correlations with virus neutralization. Altogether, these data indicate the smallpox vaccine succeeds in generating strong neutralizing antibody responses not by eliciting a stereotypic response to a single key antigen but instead by driving development of neutralizing antibodies to multiple viral proteins, resulting in a “safety net” of highly redundant neutralizing antibody responses, the specificities of which can vary from individual to individual. We propose that this is a fundamental attribute of the smallpox vaccine.

Modified vaccinia virus Ankara (MVA) is a highly attenuated vaccinia virus that is under consideration as an alternative to the conventional smallpox vaccine Dryvax. MVA was attenuated by extensive passage of vaccinia virus Ankara in chicken embryo fibroblasts. Several immunomodulatory genes and genes that influence host range are deleted or mutated, and replication is aborted in the late stage of infection in most nonavian cells. The effect of these mutations on immunogenicity is not well understood. Since the structural genes appear to be intact in MVA, it is hypothesized that critical targets for antibody neutralization have been retained. To test this, we probed microarrays of the Western Reserve (WR) proteome with sera from humans and macaques after MVA and Dryvax vaccination. As most protein sequences of MVA are 97 to 99% identical to those of other vaccinia virus strains, extensive binding cross-reactivity is expected, except for those deleted or truncated. Despite different hosts and immunization regimens, the MVA and Dryvax antibody profiles were broadly similar, with antibodies against membrane and core proteins being the best conserved. The responses to nonstructural proteins were less well conserved, although these are not expected to influence virus neutralization. The broadest antibody response was obtained for hyperimmune rabbits with WR, which is pathogenic in rabbits. These data indicate that, despite the mutations and deletions in MVA, its overall immunogenicity is broadly comparable to that of Dryvax, particularly at the level of antibodies to membrane proteins. The work supports other information suggesting that MVA may be a useful alternative to Dryvax.

Background Acquisition of malaria immunity in low transmission areas usually occurs after relatively few exposures to the parasite. A recent Plasmodium vivax experimental challenge trial in malaria naïve and semi-immune volunteers from Colombia showed that all naïve individuals developed malaria symptoms, whereas semi-immune subjects were asymptomatic or displayed attenuated symptoms. Sera from these individuals were analyzed by protein microarray to identify antibodies associated with clinical protection. Methodology/Principal Findings Serum samples from naïve (n = 7) and semi-immune (n = 9) volunteers exposed to P. vivax sporozoite-infected mosquito bites were probed against a custom protein microarray displaying 515 P. vivax antigens. The array revealed higher serological responses in semi-immune individuals before the challenge, although malaria naïve individuals also had pre-existing antibodies, which were higher in Colombians than US adults (control group). In both experimental groups the response to the P. vivax challenge peaked at day 45 and returned to near baseline at day 145. Additional analysis indicated that semi-immune volunteers without fever displayed a lower response to the challenge, but recognized new antigens afterwards. Conclusion Clinical protection against experimental challenge in volunteers with previous P. vivax exposure was associated with elevated pre-existing antibodies, an attenuated serological response to the challenge and reactivity to new antigens., Author Summary Malaria remains an important public health problem worldwide, with 13.8 million cases caused by Plasmodium vivax, a parasite species that predominates in South-East Asia and the American continent. Despite the epidemiological importance of this species, studies of the immune response and their potential for vaccine development are limited. Here we use a high-throughput technique (protein microarray) to identify antibodies in serum from malaria naïve and semi-immune Colombian volunteers experimentally infected with P. vivax. We show a higher response in semi-immune individuals before the challenge. Meanwhile, at day 45 after infection, both groups had the highest antibody response to several P. vivax proteins. Additional analysis indicated that semi-immune volunteers without fever recognized new antigens, which may represent promising targets for vaccine development. Taken together, these findings represent a significant step forward in the understanding of the humoral immune response to P. vivax malaria infection, particularly the extent of immune priming upon a first parasite encounter.