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The Naxos dome, in the middle of the Aegean domain, exposes the former root of the Alpine orogenic belt and represents a key natural example to investigate the development of gravitational instabilities during orogenic evolution and their impact on crustal differentiation. The Naxos dome is cored by migmatites with structures depicting second order domes with a diameter of 1–2 km nested in the first order deca-kilometer scale dome that formed at the onset of orogenic collapse. Zircon grains from the migmatites record a succession of crystallization-dissolution cycles with a period of 1–2 Myr. These features have been attributed to the development of convective and diapiric gravitational instabilities, related to thermally induced and compositional buoyancy. In this paper, we test the pertinence of this model with a thermal-mechanical numerical experiment performed with a volume of fluid method (VOF) known to preserve material phase interfaces during large deformation of viscous layers. Partial melting of the crust is modeled by strain-rate and temperature dependent viscosity and temperature dependent density. Moreover, horizontal layers with density, viscosity and heat production variations mimic more felsic or more mafic lithologies in a crust of intermediate composition. With basal heating, gravitational instabilities initiate with local segregation of the buoyant versus heavier layers, followed by diapiric upwelling of buoyant pockets of aggregated less dense material. Convection starts after 5 Myr, approximately when half of the crust has a viscosity lower than 1019 Pa s. The size of the convection cells increases as the temperature rises in the crust and reaches ∼25 km in diameter after ca. 20 Myr, which defines the size of first order domes. Some of the heterogeneous material is entrained in the convection cells with a revolution period of 1 to 3 Myr. However, most of the denser material accumulates in the lower crust, while the buoyant material segregates at the top of the convection cells and forms diapirs that correspond to second order domes, of several kilometers in diameter and nested within the first order domes. This model, which reproduces the first order characteristic dimensions of the Naxos nested domes and the periodicity of their zircon geochronological record, demonstrates the efficiency of gravitational instabilities in the formation of migmatite domes and, more generally, in the multi-scale dynamics of crustal differentiation leading to a felsic upper crust, an intermediate middle crust and a mafic lower crust.

Abstract Background There is guidance in the United Kingdom about what long-term care stroke survivors should receive, but a lack of guidance about who should deliver it and where this care should take place. This is a key issue given the evidence that current needs are not well addressed. The purpose of this study was to explore when a referral from generalist to specialist services is appropriate in the long-term management of stroke survivors. Methods A modified RAND-Appropriateness method was used to gain consensus from a range of stroke specialist and generalist clinicians. Ten panelists rated fictional patient scenarios based on long-term post-stroke needs. Round 1 was an online survey in which panelists rated the scenarios for a) need for referral to specialist care and b) if referral was deemed necessary, need for this to be specifically to a stroke specialist. Round 2 was a face-to-face meeting in which panelists were presented with aggregate scores from round 1, and invited to discuss and then re-rate the scenarios. Results Seventeen scenarios comprising 69 referral decisions were discussed. Consensus on whether the patient needed to be referred to a specialist was achieved for 59 (86%) decisions. Of the 44 deemed needing referral to specialists, 18 were judged to need referral to a stroke-specialist and 14 to a different specialist. However, for 12 decisions there was no consensus about which specialist the patient should be referred to. For some scenarios (spasticity; incontinence; physical disability; communication; cognition), referral was deemed to be indicated regardless of severity, whereas indications for referral for topics such as risk factor management and pain depended on complexity and/or severity. Conclusions There was broad agreement about when a stroke survivor requires referral to specialist care, but less agreement about destination of referral. Nevertheless, there was agreement that some of the longer-term issues facing stroke survivors are best addressed by stroke specialists, some by other specialists, and some by primary care. This has implications for models of longer-term stroke care, which need to reflect that optimal care requires access to, and better co-ordination between, both generalist and specialist healthcare.

Abstract Background Primary care may be an avenue to increase coverage of HIV testing but it is unclear what challenges primary healthcare professionals in low- and middle-income countries face. We describe the HIV testing practices in community health centres (CHCs) and explore the staff’s attitude towards further development of HIV testing services at the primary care level in China. Methods We conducted a national, cross-sectional survey using a stratified random sample of CHCs in 20 cities in 2015. Questionnaires were completed by primary care doctors and nurses in CHCs, and included questions regarding their demographics, clinical experience and their views on the facilitators and barriers to offering HIV testing in their CHC. Multivariate logistic regression was conducted to examine the association between staff who would offer HIV testing and their sociodemographic characteristics. Results A total of 3580 staff from 158 CHCs participated. Despite the majority (81%) agreeing that HIV testing was an important part of healthcare, only 25% would provide HIV testing when requested by a patient. The majority (71%) were concerned about reimbursement, and half (47%) cited lack of training as a major barrier. Almost half (44%) believed that treating people belonging to high-risk populations would scare other patients away, and 6% openly expressed their dislike of people belonging to high-risk populations. Staff who would offer HIV testing were younger (adjusted odds ratio (aOR) 0.97 per year increase in age, 95% confidence interval (CI):0.97–0.98); trained as a doctor compared to a nurse (aOR 1.79, 95%CI:1.46–2.15); held a bachelor degree or above (aOR 1.34, 95%CI:1.11–1.62); and had previous HIV training (aOR 1.55, 95%CI:1.27–1.89). Conclusions Improving HIV training of CHC staff, including addressing stigmatizing attitudes, and improving financial reimbursement may help increase HIV testing coverage in China.

Introduction: For more than a decade the English NHS has pursued integrated care through three national pilot programmes. The independent evaluators of these programmes here identify several common themes that inform the development of integrated care. Description: The three pilot programmes shared the aim of better coordination between hospital and community-based health services and between health and social care. Each programme recruited local pilot sites that designed specific interventions to support inter-professional and inter-organisational collaboration. The pilots were highly heterogenous and results varied both within and between the three programmes. While staff were generally positive about their achievements, pilots had mixed success especially in reducing unplanned hospital admissions. Common facilitators to achieving pilots’ objectives included effective senior leadership and shared values, simple interventions and additional funding. Barriers included short timescales, poor professional engagement, information and data sharing problems, and conflicts with changing national policy. Discussion: There was little stable or shared understanding of what ‘integrated care’ meant resulting in different practices and priorities. An increasing focus on reducing unplanned hospital use among national sponsors created a mismatch in expectations between local and national actors. Conclusion: Pilots in all three national programmes made some headway against their objectives but were limited in their impact on unplanned hospital admissions.

Primary care (PC) is an essential building block for any high quality healthcare system, and has a particularly positive impact on vulnerable patients. It contributes to the overall performance of health systems, and countries that reorient their health system towards PC are better prepared to achieve universal health coverage. Monitoring the actual performance of PC in health systems is essential health policy to support PC. However, current indicators are often too narrowly defined to account for quality of care in the complex populations with which PC deals. This article reviews a number of conceptual frameworks developed to capture PC values in robust measures and indicators that can inform policy and practice performance. Each have benefits and limitations. Further work is needed to develop meaningful primary health care (PHC) and PC measures to inform strategic action by policymakers and governments for improved overall performance of health systems.

Autor przedstawia dzieje Austriackiej Biblioteki Narodowej (ABN; Österreichische Nationalbibliothek), której zasoby sięgają XIV w. Następnie omawia genezę, metodologię i zawartość serii założonej przez Franza Wickhoffa, wydawanej od 1905 r. pt. Beschreibendes Verzeichnis der illuminierten Handschriften in Österreich, stanowiącej opisowy wykaz rękopisów iluminowanych w Austrii. W przypadku katalogowania rękopisów dawnej biblioteki dworskiej (Hofbibliothek), a od 1920 r. ABN, przełomem stało się zainicjowanie przez Juliusa Schlossera i Hermanna Juliusa Hermanna podserii: Die Illuminierten Handschriften und Inkunabeln der Nationalbibliothek in Wien. W latach 1923-1938 wydano 15 tomów tej podserii z opisami ponad 1500 manuskryptów. Po II wojnie światowej prace te kontynuował Franz Unterkircher publikując w 1957 i 1959 r. dwa tomy inwentarza obejmującego wszystkie (ponad 5000 jednostek) rękopisy iluminowane ABN oraz Otton Pächt, który zainicjował nową serię wydawniczą pt. Die Illuminierten Handschriften und Inkunabeln der Österreichischen Nationalbibliothek, wydawaną od 1974 r. Jego następca Gerhard Schmidt zainicjował projekt pt. „Szkoły środkowoeuropejskie” – Mitteleuropäische Schulen (MeSch). Jego celem jest skatalogowanie środkowoeuropejskich rękopisów iluminowanych.

This contribution reviews the challenges of imaging collisional orogens, focusing on the example of the Pyrenean domain. Indeed, important progresses have been accomplished regarding our understanding of the architecture of this mountain range over the last decades, thanks to the development of innovative passive imaging techniques, relying on a more thorough exploitation of the information in seismic signals, as well as new seismic acquisitions. New tomographic images provide evidence for continental subduction of Iberian crust beneath the western and central Pyrénées, but not beneath the eastern Pyrénées. Relics of a Cretaceous hyper-extended and segmented rift are found within the North Pyrenean Zone, where the imaged crust is thinner (10–25 km). This zone of thinned crust coincides with a band of positive Bouguer anomalies that is absent in the Eastern Pyrénées. Overall, the new tomographic images provide further support to the idea that the Pyrénées result from the inversion of hyperextended segmented rift systems.

Increased investment in primary care is associated with lower healthcare costs and improved population health. The allocation of scarce resources should be driven by robust models that adequately describe primary care activities and spending within a health system, and allow comparisons within and across health systems. However, disparate definitions result in wide variations in estimates of spending on primary care. We propose a new model that allows for a dynamic assessment of primary care spending (PC Spend) within the context of a system’s total healthcare budget. The model articulates varied definitions of primary care through a tiered structure which includes overall spending on primary care services, spending on services delivered by primary care professionals and spending delivered by providers that can be characterised by the ‘4Cs’ (first contact, continuous, comprehensive and coordinated care). This unifying framework allows a more refined description of services to be included in any estimate of primary care spend and also supports measurement of primary care spending across nations of varying economic development, accommodating data limitations and international health system differences. It provides a goal for best accounting while also offering guidance, comparability and assessments of how primary care expenditures are associated with outcomes. Such a framework facilitates comparison through the creation of standard definitions and terms, and it also has the potential to foster new areas of research that facilitate robust policy analysis at the national and international levels.

Background: The increasing difficulty experienced by general practices in meeting patient demand is leading to new approaches being tried, including greater use of telephone consulting. Objectives: To evaluate a ‘telephone first’ approach, in which all patients requesting a general practitioner (GP) appointment are asked to speak to a GP on the telephone first. Methods: The study used a controlled before-and-after (time-series) approach using national reference data sets; it also incorporated economic and qualitative elements. There was a comparison between 146 practices using the ‘telephone first’ approach and control practices in England with regard to GP Patient Survey scores and secondary care utilisation (Hospital Episode Statistics). A practice manager survey was used in the ‘telephone first’ practices. There was an analysis of practice data and the patient surveys conducted in 20 practices using the ‘telephone first’ approach. Interviews were conducted with 43 patients and 49 primary care staff. The study also included an analysis of costs. Results: Following the introduction of the ‘telephone first’ approach, the average number of face-to-face consultations in practices decreased by 38% [95% confidence interval (CI) 29% to 45%; p

Background: There has been an increased focus towards improving quality of care within the NHS in the last 15 years; as part of this, there has been an emphasis on the importance of patient feedback within policy, through National Service Frameworks and the Quality and Outcomes Framework. The development and administration of large-scale national patient surveys to gather representative data on patient experience, such as the national GP Patient Survey in primary care, has been one such initiative. However, it remains unclear how the survey is used by patients and what impact the data may have on practice. Objectives: Our research aimed to gain insight into how different patients use surveys to record experiences of general practice; how primary care staff respond to feedback; and how to engage primary care staff in responding to feedback. Methods: We used methods including quantitative survey analyses, focus groups, interviews, an exploratory trial and an experimental vignette study. Results: (1) Understanding patient experience data. Patients readily criticised their care when reviewing consultations on video, although they were reluctant to be critical when completing questionnaires. When trained raters judged communication during a consultation to be poor, a substantial proportion of patients rated the doctor as ‘good’ or ‘very good’. Absolute scores on questionnaire surveys should be treated with caution; they may present an overoptimistic view of general practitioner (GP) care. However, relative rankings to identify GPs who are better or poorer at communicating may be acceptable, as long as statistically reliable figures are obtained. Most patients have a particular GP whom they prefer to see; however, up to 40% of people who have such a preference are unable regularly to see the doctor of their choice. Users of out-of-hours care reported worse experiences when the service was run by a commercial provider than when it was run by a not-for profit or NHS provider. (2) Understanding patient experience in minority ethnic groups. Asian respondents to the GP Patient Survey tend to be registered with practices with generally low scores, explaining about half of the difference in the poorer reported experiences of South Asian patients than white British patients. We found no evidence that South Asian patients used response scales differently. When viewing the same consultation in an experimental vignette study, South Asian respondents gave higher scores than white British respondents. This suggests that the low scores given by South Asian respondents in patient experience surveys reflect care that is genuinely worse than that experienced by their white British counterparts. We also found that service users of mixed or Asian ethnicity reported lower scores than white respondents when rating out-of-hours services. (3) Using patient experience data. We found that measuring GP–patient communication at practice level masks variation between how good individual doctors are within a practice. In general practices and in out-of-hours centres, staff were sceptical about the value of patient surveys and their ability to support service reconfiguration and quality improvement. In both settings, surveys were deemed necessary but not sufficient. Staff expressed a preference for free-text comments, as these provided more tangible, actionable data. An exploratory trial of real-time feedback (RTF) found that only 2.5% of consulting patients left feedback using touch screens in the waiting room, although more did so when reminded by staff. The representativeness of responding patients remains to be evaluated. Staff were broadly positive about using RTF, and practices valued the ability to include their own questions. Staff benefited from having a facilitated session and protected time to discuss patient feedback. Conclusions: Our findings demonstrate the importance of patient experience feedback as a means of informing NHS care, and confirm that surveys are a valuable resource for monitoring national trends in quality of care. However, surveys may be insufficient in themselves to fully capture patient feedback, and in practice GPs rarely used the results of surveys for quality improvement. The impact of patient surveys appears to be limited and effort should be invested in making the results of surveys more meaningful to practice staff. There were several limitations of this programme of research. Practice recruitment for our in-hours studies took place in two broad geographical areas, which may not be fully representative of practices nationally. Our focus was on patient experience in primary care; secondary care settings may face different challenges in implementing quality improvement initiatives driven by patient feedback. Recommendations for future research include consideration of alternative feedback methods to better support patients to identify poor care; investigation into the factors driving poorer experiences of communication in South Asian patient groups; further investigation of how best to deliver patient feedback to clinicians to engage them and to foster quality improvement; and further research to support the development and implementation of interventions aiming to improve care when deficiencies in patient experience of care are identified. Funding: The National Institute for Health Research Programme Grants for Applied Research programme.

Aim: This study updates a previous scoping review published by the National Institute for Health Research (NIHR) in 2006 (Roland M, McDonald R, Sibbald B. Outpatient Services and Primary Care: A Scoping Review of Research Into Strategies For Improving Outpatient Effectiveness and Efficiency. Southampton: NIHR Trials and Studies Coordinating Centre; 2006) and focuses on strategies to improve the effectiveness and efficiency of outpatient services. Findings from the scoping review: Evidence from the scoping review suggests that, with appropriate safeguards, training and support, substantial parts of care given in outpatient clinics can be transferred to primary care. This includes additional evidence since our 2006 review which supports general practitioner (GP) follow-up as an alternative to outpatient follow-up appointments, primary medical care of chronic conditions and minor surgery in primary care. Relocating specialists to primary care settings is popular with patients, and increased joint working between specialists and GPs, as suggested in the NHS Five Year Forward View, can be of substantial educational value. However, for these approaches there is very limited information on cost-effectiveness; we do not know whether they increase or reduce overall demand and whether the new models cost more or less than traditional approaches. One promising development is the increasing use of e-mail between GPs and specialists, with some studies suggesting that better communication (including the transmission of results and images) could substantially reduce the need for some referrals. Findings from the substudies: Because of the limited literature on some areas, we conducted a number of substudies in England. The first was of referral management centres, which have been established to triage and, potentially, divert referrals away from hospitals. These centres encounter practical and administrative challenges and have difficulty getting buy-in from local clinicians. Their effectiveness is uncertain, as is the effect of schemes which provide systematic review of referrals within GP practices. However, the latter appear to have more positive educational value, as shown in our second substudy. We also studied consultants who held contracts with community-based organisations rather than with hospital trusts. Although these posts offer opportunities in terms of breaking down artificial and unhelpful primary–secondary care barriers, they may be constrained by their idiosyncratic nature, a lack of clarity around roles, challenges to professional identity and a lack of opportunities for professional development. Finally, we examined the work done by other countries to reform activity at the primary–secondary care interface. Common approaches included the use of financial mechanisms and incentives, the transfer of work to primary care, the relocation of specialists and the use of guidelines and protocols. With the possible exception of financial incentives, the lack of robust evidence on the effect of these approaches and the contexts in which they were introduced limits the lessons that can be drawn for the English NHS. Conclusions: For many conditions, high-quality care in the community can be provided and is popular with patients. There is little conclusive evidence on the cost-effectiveness of the provision of more care in the community. In developing new models of care for the NHS, it should not be assumed that community-based care will be cheaper than conventional hospital-based care. Possible reasons care in the community may be more expensive include supply-induced demand and addressing unmet need through new forms of care and through loss of efficiency gained from concentrating services in hospitals. Evidence from this study suggests that further shifts of care into the community can be justified only if (a) high value is given to patient convenience in relation to NHS costs or (b) community care can be provided in a way that reduces overall health-care costs. However, reconfigurations of services are often introduced without adequate evaluation and it is important that new NHS initiatives should collect data to show whether or not they have added value, and improved quality and patient and staff experience. Funding: The NIHR Health Services and Delivery Research programme.

Background: Advancing Quality (AQ) is a voluntary programme providing financial incentives for improvement in the quality of care provided to NHS patients in the north-west of England. Objectives: (1) To identify the impact of AQ on key stakeholders and clinical practice; (2) to assess its cost-effectiveness; (3) to identify key factors that assist or impede its successful implementation; and (4) to provide lessons for the wider implementation of pay-for-performance schemes across the NHS. Design: We tested whether or not the financial incentives of AQ had an impact on mortality using two methods: a between-region difference-in-differences analysis comparing the North West region and the rest of England for the incentivised and non-incentivised conditions and a triple-difference analysis comparing performance on the incentivised conditions, as well as the non-incentivised conditions, in the North West region and the rest of England. A cost-effectiveness analysis of AQ based on the first 18 months of the programme was also undertaken. We used interviews and observation to explore how and why changes occurred. Results: Risk-adjusted mortality rates for all three of the conditions we studied (pneumonia, heart failure and myocardial infarction) decreased in both the North West region and the rest of England during the first 18 months of the scheme. The reduction in mortality for incentivised conditions was greater in the North West region than in the rest of England. Compared with non-incentivised conditions within the North West region, there was a significant reduction in overall mortality for incentivised conditions, comprising a statistically significant reduction in pneumonia and non-significant reductions in the other two conditions. Comparing mortality for the incentivised conditions with mortality for these conditions in other regions, there was a significant reduction in overall mortality in the North West region, again made up of individually significant reductions in pneumonia and non-significant reductions in the other two conditions. The reduction in mortality over the 18-month period studied for non-incentivised conditions was not significantly different between the North West region and the rest of England. The between-region difference-in-differences analysis after 42 months showed that risk-adjusted mortality for the incentivised conditions fell in the rest of England and the North West region. This reduction in the rest of England was significantly larger than in the North West region and was concentrated in pneumonia. However, the reductions in mortality were larger for the non-incentivised conditions in the North West region than in the rest of England between these periods. For incentivised conditions, the triple-difference analysis shows a larger reduction in mortality for the rest of England than in the North West region between the short- and long-term periods. Conclusions: Based on the first 18 months, the AQ programme was a relatively effective and cost-effective intervention. However, findings at 42 months are open to interpretation. One interpretation is that the short-term improvements were not sustained and that the observed improvements in mortality in the non-incentivised conditions within hospitals participating in AQ were unrelated to the programme. An alternative interpretation is that these improvements are related to the positive spillover effect of AQ. Further research should be undertaken to determine the explanation for the findings. Funding: The National Institute for Health Research Health Services and Delivery Research programme.

Background: Available evidence on effective interventions to reduce length of stay in hospital is wide-ranging and complex, with underlying factors including those acting at the health system, organisational and patient levels, and the interface between these. There is a need to better understand the diverse literature on reducing the length of hospital stay. Objectives: This study sought to (i) describe the nature of interventions that have been used to reduce length of stay in acute care hospitals; (ii) identify the factors that are known to influence length of stay; and (iii) assess the impact of interventions on patient outcomes, service outcomes and costs. Data sources: We searched MEDLINE (Ovid), EMBASE, the Health Management Information Consortium and System for Information on Grey Literature in Europe for the period January 1995 to January 2013 with no limitation of publication type. Methods: We conducted a rapid evidence synthesis of the peer-reviewed literature on organisational interventions set in or initiated from acute hospitals. We considered evidence published between 2003 and 2013. Data were analysed drawing on the principles of narrative synthesis. We also carried out interviews with eight NHS managers and clinical leads in four sites in England. Results: A total of 53 studies met our inclusion criteria, including 19 systematic reviews and 34 primary studies. Although the overall evidence base was varied and frequently lacked a robust study design, we identified a range of interventions that showed potential to reduce length of stay. These were multidisciplinary team working, for example some forms of organised stroke care; improved discharge planning; early supported discharge programmes; and care pathways. Nursing-led inpatient units were associated with improved outcomes but, if anything, increased length of stay. Factors influencing the impact of interventions on length of stay included contextual factors and the population targeted. The evidence was mixed with regard to the extent to which interventions seeking to reduce length of stay were associated with cost savings. Limitations: We only considered assessments of interventions which provided a quantitative estimate of the impact of the given organisational intervention on length of hospital stay. There was a general lack of robust evidence and poor reporting, weakening the conclusions that can be drawn from the review. Conclusions: The design and implementation of an intervention seeking to reduce (directly or indirectly) the length of stay in hospital should be informed by local context and needs. This involves understanding how the intervention is seeking to change processes and behaviours that are anticipated, based on the available evidence, to achieve desired outcomes (‘theory of change’). It will also involve assessing the organisational structures and processes that will need to be put in place to ensure that staff who are expected to deliver the intervention are appropriately prepared and supported. With regard to future research, greater attention should be given to the theoretical underpinning of the design, implementation and evaluation of interventions or programmes. There is a need for further research using appropriate methodology to assess the effectiveness of different types of interventions in different settings. Different evaluation approaches may be useful, and closer relationships between researchers and NHS organisations would enable more formative evaluation. Full economic costing should be undertaken where possible, including considering the cost implications for the wider local health economy. Funding: The National Institute for Health Research Health Services and Delivery Research programme.

Care is better coordinated when doctors have personal responsibility for their patients. Continuity and a sense of personal responsibility are becoming more difficult to provide in hospitals, in part because of the European Working Time Directive. However, in many countries general practitioners are self-employed and able to organise their practices as they wish. In the UK, they increasingly do so in ways that make it difficult for patients to get continuity of care. This is despite most patients being clear that they want to see a regular doctor, and professional bodies in primary care consistently promoting continuity as a core value. General practitioners need to decide whether continuity of care matters. If it does, then they need to take a lead in ensuring that care is organised so that patients who want to see a regular doctor are able to do so. Suggestions are included for how contemporary practice can be organised to promote this traditional but still highly relevant value.

Introduction: In 2009, the English Department of Health appointed 16 integrated care pilots which aimed to provide better integrated care. We report the quantitative results from a multi-method evaluation of six of the demonstration projects which used risk profiling tools to identify older people at risk of emergency hospital admission, combined with intensive case management for people identified as at risk. The interventions focused mainly on delivery system redesign and improved clinical information systems, two key elements of Wagner's Chronic Care Model. Methods: Questionnaires to staff and patients. Difference-in-differences analysis of secondary care utilisation using data on 3,646 patients and 17,311 matched controls, and changes in overall secondary care utilisation. Results: Most staff thought that care for their patients had improved. More patients reported having a care plan but they found it significantly harder to see a doctor or nurse of their choice and felt less involved in decisions about their care. Case management interventions were associated with a 9% increase in emergency admissions. We found some evidence of imbalance between cases and controls which could have biased this estimate, but simulations of the possible effect of unobserved confounders showed that it was very unlikely that the sites achieved their goal of reducing emergency admissions. However, we found significant reductions of 21% and 22% in elective admissions and outpatient attendance in the six months following an intervention, and overall inpatient and outpatient costs were significantly reduced by 9% during this period. Area level analyses of whole practice populations suggested that overall outpatient attendances were significantly reduced by 5% two years after the start of the case management schemes. Conclusion: Case management may result in improvements in some aspects of care and has the potential to reduce secondary care costs. However, to improve patient experience, case management approaches need to be introduced in a way which respects patients' wishes, for example the ability to see a familiar doctor or nurse.

Background. In 2008, the English Department of Health appointed 16 'Integrated Care Pilots' which used a range of approaches to provide better integrated care. We report qualitative analyses from a three year multi-method evaluation to identify barriers and facilitators to successful integration of care. Theory and methods. Data were analysed from transcripts of 213 in-depth staff interviews, and from semi-structured questionnaires (the 'Living Document') completed by staff in pilot sites at six points over a two-year period. Emerging findings were therefore built from 'bottom up' and grounded in the data. However, we were then interested in how these findings compared and contrasted with more generic analyses. Therefore after our analyses were complete we then systematically compared and contrasted the findings with the analysis of barriers and facilitators to quality improvement identified in a systematic review by Kaplan et al (2010) and the analysis of more micro-level shapers of behaviour found in Normalisation Process Theory (May et al 2007). Neither of these approaches claims to be full blown theories but both claim to provide mid-range theoretical arguments which may be used to structure existing data and which can be undercut or reinforced by new data.Results and discussion. Many barriers and facilitators to integrating care are those of any large scale organisational change. These include issues relating to leadership, organisational culture, information technology, physician involvement, and availability of resources. However, activities which appear particularly important for delivering integrated care include personal relationships between leaders in different organisations, the scale of planned activities, governance and finance arrangements, support for staff in new roles, and organisational and staff stability. We illustrate our analyses with a 'routemap' which identifies questions that providers may wish to consider when planning interventions to improve the integration of care.

Background: In response to concerns that the needs of the aging population for well-integrated care were increasing, the English National Health Service (NHS) appointed 16 Integrated Care Pilots following a national competition. The pilots have a range of aims including development of new organisational structures to support integration, changes in staff roles, reducing unscheduled emergency hospital admissions, reduced length of hospital stay, increasing patient satisfaction, and reducing cost. This paper describes the evaluation of the initiative which has been commissioned. Study design and data collection methods: A mixed methods approach has been adopted including interviews with staff and patients, non-participant observation of meetings, structured written feedback from sites, questionnaires to patients and staff, and analysis of routinely collected hospital utilisation data for patients/service users. The qualitative analysis aims to identify the approaches taken to integration by the sites, the benefits which result, the context in which benefits have resulted, and the mechanisms by which they occur. Methods of analysis: The quantitative analysis adopts a 'difference in differences' approach comparing health care utilisation before and after the intervention with risk-matched controls. The qualitative data analysis adopts a 'theory of change' approach in which we triangulate data from the quantitative analysis with qualitative data in order to describe causal effects (what happens when an independent variable changes) and causal mechanisms (what connects causes to their effects). An economic analysis will identify what incremental resources are required to make integration succeed and how they can be combined efficiently to produce better outcomes for patients. Conclusion: This evaluation will produce a portfolio of evidence aimed at strengthening the evidence base for integrated care, and in particular identifying the context in which interventions are likely to be effective. These data will support a series of evaluation judgements aimed at reducing uncertainties about the role of integrated care in improving the efficient and effective delivery of healthcare.

Abstract Background Nogo-66 receptor NgR1 and its structural homologue NgR2 are binding proteins for a number of myelin-associated inhibitory factors. After neuronal injury, these inhibitory factors are responsible for preventing axonal outgrowth via their interactions with NgR1 and NgR2 expressed on neurons. In vitro, cells expressing NgR1/2 are inhibited from adhering to and spreading on a myelin substrate. Neuronal injury also results in the presence of dendritic cells (DCs) in the central nervous system, where they can come into contact with myelin debris. The exact mechanisms of interaction of immune cells with CNS myelin are, however, poorly understood. Methods Human DCs were differentiated from peripheral blood monocytes and mouse DCs were differentiated from wild type and NgR1/NgR2 double knockout bone marrow precursors. NgR1 and NgR2 expression were determined with quantitative real time PCR and immunoblot, and adhesion of cells to myelin was quantified. Results We demonstrate that human immature myeloid DCs express NgR1 and NgR2, which are then down-regulated upon maturation. Human mature DCs also adhere to a much higher extent to a myelin substrate than immature DCs. We observe the same effect when the cells are plated on Nogo-66-His (binding peptide for NgR1), but not on control proteins. Mature DCs taken from Ngr1/2 knockout mice adhere to a much higher extent to myelin compared to wild type mouse DCs. In addition, Ngr1/2 knockout had no effect on in vitro DC differentiation or phenotype. Conclusions These results indicate that a lack of NgR1/2 expression promotes the adhesion of DCs to myelin. This interaction could be important in neuroinflammatory disorders such as multiple sclerosis in which peripheral immune cells come into contact with myelin debris.

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.

Multiple sclerosis (MS) is a prototypical autoimmune disease of the central nervous system (CNS). In addition to CD4+ T cells, memory B cells are now recognized as a critical cell type in the disease. This is underlined by the fact that the best-characterized environmental risk factor for MS is the Epstein-Barr virus (EBV), which can infect and persist in memory B cells throughout life. Several studies have identified changes in anti-EBV immunity in patients with MS. Examples include elevated titers of anti-EBV nuclear antigen 1 (EBNA1) antibodies, interactions of these with the MS-associated HLA-DR15 haplotype, and molecular mimicry with MS autoantigens like myelin basic protein (MBP), anoctamin-2 (ANO2), glial cell adhesion molecule (GlialCAM), and alpha-crystallin B (CRYAB). In this study, we employ a simple in vitro assay to examine the memory B cell antibody repertoire in MS patients and healthy controls. We replicate previous serological data from MS patients demonstrating an increased secretion of anti-EBNA1380-641 IgG in cell culture supernatants, as well as a positive correlation of these levels with autoantibodies against GlialCAM262-416 and ANO21-275. For EBNA1380-641 and ANO21-275, we provide additional evidence suggesting antibody cross-reactivity between the two targets. Further, we show that two efficacious MS treatments - natalizumab (NAT) and autologous hematopoietic stem cell transplantation (aHSCT) - are associated with distinct changes in the EBNA1- directed B cell response and that these alterations can be attributed to the unique mechanisms of action of these therapies. Using an in vitro system, our study confirms MS-associated changes in the anti-EBNA1 memory B cell response, EBNA1380-641 antibody cross-reactivity with ANO21-275, and reveals treatment-associated changes in the immunoglobulin repertoire in MS. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) and spectrum disorder (NMO/SD) represent a vexing process and its clinical variants appear to have at their pathogenic core the loss of immune tolerance to the aquaporin-4 water channel protein. This process results in a characteristic pattern of astrocyte dysfunction, loss, and demyelination that predominantly affects the spinal cord and optic nerves. Although several empirical therapies are currently used in the treatment of NMO/SD, none has been proven effective in prospective, adequately powered, randomized trials. Furthermore, most of the current therapies subject patients to long-term immunologic suppression that can cause serious infections and development of cancers. The following is the first of a 2-part description of several key immune mechanisms in NMO/SD that might be amenable to therapeutic restoration of immune tolerance. It is intended to provide a roadmap for how potential immune tolerance restorative techniques might be applied to patients with NMO/SD. This initial installment provides a background rationale underlying attempts at immune tolerization. It provides specific examples of innovative approaches that have emerged recently as a consequence of technical advances. In several autoimmune diseases, these strategies have been reduced to practice. Therefore, in theory, the identification of aquaporin-4 as the dominant autoantigen makes NMO/SD an ideal candidate for the development of tolerizing therapies or cures for this increasingly recognized disease.

Neuromyelitis optica spectrum disorder (NMO/SD) and its clinical variants have at their core the loss of immune tolerance to aquaporin-4 and perhaps other autoantigens. The characteristic phenotype is disruption of astrocyte function and demyelination of spinal cord, optic nerves, and particular brain regions. In this second of a 2-part article, we present further perspectives regarding the pathogenesis of NMO/SD and how this disease might be amenable to emerging technologies aimed at restoring immune tolerance to disease-implicated self-antigens. NMO/SD appears to be particularly well-suited for these strategies since aquaporin-4 has already been identified as the dominant autoantigen. The recent technical advances in reintroducing immune tolerance in experimental models of disease as well as in humans should encourage quantum leaps in this area that may prove productive for novel therapy. In this part of the article series, the potential for regulatory T and B cells is brought into focus, as are new approaches to oral tolerization. Finally, a roadmap is provided to help identify potential issues in clinical development and guide applications in tolerization therapy to solving NMO/SD through the use of emerging technologies. Each of these perspectives is intended to shine new light on potential cures for NMO/SD and other autoimmune diseases, while sparing normal host defense mechanisms.

We present a major release of the Tomofast-x open-source gravity and magnetic inversion code that incorporates several functionalities enhancing its performance and applicability for both industrial and academic studies. The code has been re-designed with a focus on real-world mineral exploration scenarios, while offering flexibility for applications at regional scale or for crustal studies. This new version includes several major improvements: magnetisation vector inversion, inversion of multi-component magnetic data, wavelet compression, improved handling of topography with support for non-uniform grids, a new and efficient parallelisation scheme, a flexible parameter file, and optimised input–output operations. Extensive testing has been conducted on a large synthetic dataset and field data from a prospective area of the Eastern Goldfields (Western Australia) to explore new functionalities with a focus on inversion for magnetisation vectors and magnetic susceptibility, respectively. Results demonstrate the effectiveness of Tomofast-x 2.0 in real-world studies in terms of both the recovery of subsurface features and performances on shared and distributed memory machines. Overall, with its updated features, improved capabilities, and performances, the new version of Tomofast-x provides a free open-source, validated advanced and versatile tool for constrained gravity and magnetic inversion. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.