'It depends': what 86 systematic reviews tell us about what strategies to use to support the use of research in clinical practice.

BACKGROUND: The gap between research findings and clinical practice is well documented and a range of strategies have been developed to support the implementation of research into clinical practice. The objective of this study was to update and extend two previous reviews of systematic reviews of strategies designed to implement research evidence into clinical practice. METHODS: We developed a comprehensive systematic literature search strategy based on the terms used in the previous reviews to identify studies that looked explicitly at interventions designed to turn research evidence into practice. The search was performed in June 2022 in four electronic databases: Medline, Embase, Cochrane and Epistemonikos. We searched from January 2010 up to June 2022 and applied no language restrictions. Two independent reviewers appraised the quality of included studies using a quality assessment checklist. To reduce the risk of bias, papers were excluded following discussion between all members of the team. Data were synthesised using descriptive and narrative techniques to identify themes and patterns linked to intervention strategies, targeted behaviours, study settings and study outcomes. RESULTS: We identified 32 reviews conducted between 2010 and 2022. The reviews are mainly of multi-faceted interventions (n = 20) although there are reviews focusing on single strategies (ICT, educational, reminders, local opinion leaders, audit and feedback, social media and toolkits). The majority of reviews report strategies achieving small impacts (normally on processes of care). There is much less evidence that these strategies have shifted patient outcomes. Furthermore, a lot of nuance lies behind these headline findings, and this is increasingly commented upon in the reviews themselves. DISCUSSION: Combined with the two previous reviews, 86 systematic reviews of strategies to increase the implementation of research into clinical practice have been identified. We need to shift the emphasis away from isolating individual and multi-faceted interventions to better understanding and building more situated, relational and organisational capability to support the use of research in clinical practice. This will involve drawing on a wider range of research perspectives (including social science) in primary studies and diversifying the types of synthesis undertaken to include approaches such as realist synthesis which facilitate exploration of the context in which strategies are employed.

Do you see the problem? Visualising a generalised 'complex local system' of antibiotic prescribing across the United Kingdom using qualitative interview data.

Antimicrobial resistance (AMR) is often referred to as a complex problem embedded in a complex system. Despite this insight, interventions in AMR, and in particular in antibiotic prescribing, tend to be narrowly focused on the behaviour of individual prescribers using the tools of performance monitoring and management rather than attempting to bring about more systemic change. In this paper, we aim to elucidate the nature of the local antibiotic prescribing 'system' based on 71 semi-structured interviews undertaken in six local areas across the United Kingdom (UK). We applied complex systems theory and systems mapping methods to our qualitative data to deepen our understanding of the interactions among antibiotic prescribing interventions and the wider health system. We found that a complex and interacting set of proximal and distal factors can have unpredictable effects in different local systems in the UK. Ultimately, enacting performance management-based interventions in the absence of in-depth contextual understandings about other pressures prescribers face is a recipe for temporary solutions, waning intervention effectiveness, and unintended consequences. We hope our insights will enable policy makers and academics to devise and evaluate interventions in future in a manner that better reflects and responds to the dynamics of complex local prescribing systems.

"Attending to Collaboration" in Major System Change in Healthcare in England: A Response Comment on "'Attending to History' in Major System Change in Healthcare in England: Specialist Cancer Surgery Service Reconfiguration".

In this short article we comment upon the recent article by Perry et al "Attending to History" in Major System Change in Healthcare in England: Specialist Cancer Surgery Service Reconfiguration. We welcome the engagement with power, history and heuristics in the Perry et al paper. Our article discusses the importance of researcher positionality in Major System Change research, alongside managerial power and the centrality of politics to remaking health and care services. Additionally, we highlight the work of Ansell and Gash focused on 'collaborative governance' and its potential to offer insight in relation to Major System Change.

Structural basis of template strand deoxyuridine promoter recognition by a viral RNA polymerase.

Recognition of promoters in bacterial RNA polymerases (RNAPs) is controlled by sigma subunits. The key sequence motif recognized by the sigma, the -10 promoter element, is located in the non-template strand of the double-stranded DNA molecule ~10 nucleotides upstream of the transcription start site. Here, we explain the mechanism by which the phage AR9 non-virion RNAP (nvRNAP), a bacterial RNAP homolog, recognizes the -10 element of its deoxyuridine-containing promoter in the template strand. The AR9 sigma-like subunit, the nvRNAP enzyme core, and the template strand together form two nucleotide base-accepting pockets whose shapes dictate the requirement for the conserved deoxyuridines. A single amino acid substitution in the AR9 sigma-like subunit allows one of these pockets to accept a thymine thus expanding the promoter consensus. Our work demonstrates the extent to which viruses can evolve host-derived multisubunit enzymes to make transcription of their own genes independent of the host.

Computational models in the service of X-ray and cryo-electron microscopy structure determination.

Critical assessment of structure prediction (CASP) conducts community experiments to determine the state of the art in computing protein structure from amino acid sequence. The process relies on the experimental community providing information about not yet public or about to be solved structures, for use as targets. For some targets, the experimental structure is not solved in time for use in CASP. Calculated structure accuracy improved dramatically in this round, implying that models should now be much more useful for resolving many sorts of experimental difficulties. To test this, selected models for seven unsolved targets were provided to the experimental groups. These models were from the AlphaFold2 group, who overall submitted the most accurate predictions in CASP14. Four targets were solved with the aid of the models, and, additionally, the structure of an already solved target was improved. An a posteriori analysis showed that, in some cases, models from other groups would also be effective. This paper provides accounts of the successful application of models to structure determination, including molecular replacement for X-ray crystallography, backbone tracing and sequence positioning in a cryo-electron microscopy structure, and correction of local features. The results suggest that, in future, there will be greatly increased synergy between computational and experimental approaches to structure determination.

Quantitative description of a contractile macromolecular machine.

Contractile injection systems (CISs) [type VI secretion system (T6SS), phage tails, and tailocins] use a contractile sheath-rigid tube machinery to breach cell walls and lipid membranes. The structures of the pre- and postcontraction states of several CISs are known, but the mechanism of contraction remains poorly understood. Combining structural information of the end states of the 12-megadalton R-type pyocin sheath-tube complex with thermodynamic and force spectroscopy analyses and an original modeling procedure, we describe the mechanism of pyocin contraction. We show that this nanomachine has an activation energy of 160 kilocalories/mole (kcal/mol), and it releases 2160 kcal/mol of heat and develops a force greater than 500 piconewtons. Our combined approach provides a quantitative and experimental description of the membrane penetration process by a CIS.

Structure and Function of the T4 Spackle Protein Gp61.3.

The bacteriophage T4 genome contains two genes that code for proteins with lysozyme activity-e and 5. Gene e encodes the well-known T4 lysozyme (commonly called T4L) that functions to break the peptidoglycan layer late in the infection cycle, which is required for liberating newly assembled phage progeny. Gene product 5 (gp5) is the tail-associated lysozyme, a component of the phage particle. It forms a spike at the tip of the tail tube and functions to pierce the outer membrane of the Escherichia coli host cell after the phage has attached to the cell surface. Gp5 contains a T4L-like lysozyme domain that locally digests the peptidoglycan layer upon infection. The T4 Spackle protein (encoded by gene 61.3) has been thought to play a role in the inhibition of gp5 lysozyme activity and, as a consequence, in making cells infected by bacteriophage T4 resistant to later infection by T4 and closely related phages. Here we show that (1) gp61.3 is secreted into the periplasm where its N-terminal periplasm-targeting peptide is cleaved off; (2) gp61.3 forms a 1:1 complex with the lysozyme domain of gp5 (gp5Lys); (3) gp61.3 selectively inhibits the activity of gp5, but not that of T4L; (4) overexpression of gp5 causes cell lysis. We also report a crystal structure of the gp61.3-gp5Lys complex that demonstrates that unlike other known lysozyme inhibitors, gp61.3 does not interact with the active site cleft. Instead, it forms a "wall" that blocks access of an extended polysaccharide substrate to the cleft and, possibly, locks the enzyme in an "open-jaw"-like conformation making catalysis impossible.

Exploring the neglected and hidden dimensions of large-scale healthcare change.

Forms of large-scale change, such as the regiona l re-distribution of clinical services, are an enduring reform orthodoxy in health systems of high-income countries. The topic is of relevance and importance to medical sociology because of the way that large-scale change significantly disrupts and transforms therapeutic landscapes, relationships and practices. In this paper we review the literature on large-scale change. We find that the literature is dominated by competing forms of knowledge, such as health services research, and show how sociology can contribute new and critical perspectives and insights on what is for many people a troubling issue.

Biopolitics, space and hospital reconfiguration.

Major service change in healthcare - whereby the distribution of services is reconfigured at a local or regional level - is often a contested, political and poorly understood set of processes. This paper contributes to the theoretical understanding of major service change by demonstrating the utility of interpreting health service reconfiguration as a biopolitical intervention. Such an approach orients the analytical focus towards an exploration of the spatial and the population - crucial factors in major service change. Drawing on a qualitative study from 2011-12 of major service change in the English NHS combining documentary analyses of historically relevant policy papers and contemporary policy documentation (n = 125) with semi-structured interviews (n = 20) we highlight how a particular 'geography of stroke' in London was created building upon multiple types of knowledge: medical, epidemiological, economic, demographic, managerial and organisational. These informed particular spatial practices of government providing legitimation for the significant political upheaval that accompanies NHS service reconfiguration by problematizing existing variation in outcomes and making these visible. We suggest that major service change may be analysed as a 'practice of security' - a way of redefining a case, conceiving of risks and dangers, and averting potential crises in the interests of the population.

Improving research and policy interactions requires a better understanding of what works in different contexts.

There is keen interest in many jurisdictions in finding ways to improve the way that research evidence informs policy. One possible mechanism for this is to embed academics within government agencies either as advisers or full staff members. Our commentary argues that, in addition to considering the role of academics in government as proposed by Glied and colleagues, we need to understand better how research and policy interactions function across policy sectors. We believe more comparative research is needed to understand if and why academics from certain disciplines are more likely to be recruited to work in some policy sectors rather than others. We caution against treating government as monolithic by advocating the same model for collaborative interaction between academics and government. Lastly, we contend that contextualized research is needed to illuminate important drivers of research and policy interactions before we can recommend what is likely to be more and less effective in different policy sectors.

'Holding the line': a qualitative study of the role of evidence in early phase decision-making in the reconfiguration of stroke services in London.

BACKGROUND: Health service reconfigurations are of international interest but remain poorly understood. This article focuses on the use of evidence by senior managerial decision-makers involved in the reconfiguration of stroke services in London 2008-2012. Recent work comparing stroke service reconfiguration in London and Manchester emphasises the ability of senior managerial decision-makers in London to 'hold the line' in the crucial early phases of the stroke reconfiguration programme. In this article, we explore in detail how these decision-makers 'held the line' and ask what the broader power implications of doing so are for the interaction between evidence, health policy and system redesign. METHODS: The research combined semi-structured interviews (n = 20) and documentary analysis of historically relevant policy papers and contemporary stroke reconfiguration documentation published by NHS London and other interested parties (n = 125). We applied a critical interpretive and reflexive approach to the analysis of the data. RESULTS: We identified two forms of power which senior managerial decision-makers drew upon in order to 'hold the line'. Firstly, discursive power, which through an emphasis on evidence, better patient outcomes, professional support and clinical credibility alongside a tightly managed consultation process, helped to set an agenda that was broadly receptive to the overall decision to change stroke services in the capital in a radical way. Secondly, once the essential parameters of the decision to change services had been agreed, senior managerial decision-makers 'held the line' through hierarchical New Public Management style power to minimise the traditional pressures to de-radicalise the reconfiguration through 'top down' decision-making. CONCLUSIONS: We problematise the concept of 'holding the line' and explore the power implications of such managerial approaches in the early phases of health service reconfiguration. We highlight the importance of evidence for senior managerial decision-makers in agenda setting and the limitations of clinical research findings in guiding politically sensitive policy decisions which impact upon regional healthcare systems.

Does the 'diffusion of innovations' model enrich understanding of research use? Case studies of the implementation of thrombolysis services for stroke.

OBJECTIVE: To test whether the model of 'diffusion of innovations' enriches understanding of the implementation of evidence-based thrombolysis services for stroke patients. METHODS: Four case studies of the implementation of evidence on thrombolysis in stroke services in England and Sweden. Semistructured interviews with 95 staff including doctors, nurses and managers working in stroke units, emergency medicine, radiology, the ambulance service, community rehabilitation services and commissioners. RESULTS: The implementation of thrombolysis in acute stroke management benefited from a critical mass of the factors featured in the model including: the support of national and local opinion leaders; a strong evidence base and financial incentives. However, while the model provided a starting point as an organizational framework for mapping the critical factors influencing implementation, to understand properly the process of implementation and the importance of the different factors identified, more detailed analyses of context and, in particular, of the human and social dimensions of change was needed. CONCLUSIONS: While recognising the usefulness of the model of diffusion of innovations in mapping the processes by which diffusion occurs, the use of methods that lend themselves to in-depth analysis, such as ethnography and the application of relevant bodies of social theory, are needed.

The roles of specialisation and evidence-based practice in inter-professional jurisdictions: A qualitative study of stroke services in England, Sweden and Poland.

This paper investigates how the concepts of clinical specialisation and evidence influence the jurisdictional power of doctors, nurses and therapists involved in stroke care in Sweden, England and Poland. How stroke care has become a distinct specialism across Europe and the role that evidence has played in this development are critically analysed. Five qualitative case studies were undertaken across the three countries, consisting of 119 semi-structured interviews with a range of healthcare workers. The informants were purposively selected and their perspectives of evidence-based practice (EBP) within stroke care were explored. The data were analysed through thematic content analysis. The two key themes that emerged from the data were the health professionals' degrees of EBP and specialisation. The results illustrate how the two concepts of clinical specialisation and evidence are interrelated and work together to influence the different professions' degree of professional jurisdiction. It is concluded that doctors' professional dominance gives them full jurisdiction in stroke care and that nurses' and therapists' degrees of jurisdiction is dependent on their ability to specialise.

Methods of Implementation of Evidence-Based Stroke Care in Europe: European Implementation Score Collaboration.

BACKGROUND AND PURPOSE: Differences in stroke care and outcomes reported in Europe may reflect different degrees of implementation of evidence-based interventions. We evaluated strategies for implementing research evidence into stroke care in 10 European countries. METHODS: A questionnaire was developed and administered through face-to-face interviews with key informants. Implementation strategies were investigated considering 3 levels (macro, meso, and micro, eg, policy, organization, patients/professionals) identified by the framing analysis, and different settings (primary, hospital, and specialist) of stroke care. Similarities and differences among countries were evaluated using the categorical principal components analysis. RESULTS: Implementation methods reported by ≥7 countries included nonmandatory policies, public financial incentives, continuing professional education, distribution of educational material, educational meetings and campaigns, guidelines, opinion leaders', and stroke patients associations' activities. Audits were present in 6 countries at national level; national and regional regulations in 4 countries. Private financial incentives, reminders, and educational outreach visits were reported only in 2 countries. At national level, the first principal component of categorical principal components analysis separated England, France, Scotland, and Sweden, all with positive object scores, from the other countries. Belgium and Lithuania obtained the lowest scores. At regional level, England, France, Germany, Italy, and Sweden had positive scores in the first principal component, whereas Belgium, Lithuania, Poland, and Scotland showed negative scores. Spain was in an intermediate position. CONCLUSIONS: We developed a novel method to assess different domains of implementation in stroke care. Clear variations were observed among European countries. The new tool may be used elsewhere for future contributions.

Temporal Changes in the Quality of Acute Stroke Care in Five National Audits across Europe.

Background. Data on potential variations in delivery of appropriate stroke care over time are scarce. We investigated temporal changes in the quality of acute hospital stroke care across five national audits in Europe over a period of six years. Methods. Data were derived from national stroke audits in Germany, Poland, Scotland, Sweden, and England/Wales/Northern Ireland participating within the European Implementation Score (EIS) collaboration. Temporal changes in predefined quality indicators with comparable information between the audits were investigated. Multivariable logistic regression analyses were performed to estimate adherence to quality indicators over time. Results. Between 2004 and 2009, individual data from 542,112 patients treated in 538 centers participating continuously over the study period were included. In most audits, the proportions of patients who were treated on a SU, were screened for dysphagia, and received thrombolytic treatment increased over time and ranged from 2-fold to almost 4-fold increase in patients receiving thrombolytic therapy in 2009 compared to 2004. Conclusions. A general trend towards a better quality of stroke care defined by standardized quality indicators was observed over time. The association between introducing a specific measure and higher adherence over time might indicate that monitoring of stroke care performance contributes to improving quality of care.

Evidence-based practice: reflections from five European case studies.

Background Evidence-based practice (EBP) is now the accepted orthodoxy in clinical practice and developed from evidence-based medicine. EBP is based on a specific type of evidence that is derived from studies based on randomised controlled trials (RCT). This type of evidence is suited to acute medical care and is more problematic for other clinicians such as nurses and therapists, particularly when they are situated within community or primary care settings. Setting Five stroke care services in England (2), Sweden (2) and Poland (1). Aims To reflect on the evidence gained from these case studies to shed light on various aspects of EBP. This paper focuses on three key issues: (1) the importance of context for evidence, (2) the nature of knowledge, and (3) professional hierarchies. Methods Five qualitative case studies into stroke care were carried out in England, Sweden and Poland. One hundred and twenty semi-structured interviews were carried out with a range of healthcare staff who provided specialised and non-specialised stroke care in acute, community and primary care between October 2010 and September 2011. Medical doctors, nurses and different therapists were included in the samples in all five case studies. For this paper, we reflect on some aspects of this work to illuminate the different interprofessional perspectives relating to EBP in stroke care. Results The lack of RCT-based evidence in the community and primary care sectors can lead to the clinicians working in these sectors being perceived as having a lower status. Clinicians use both tacit and encoded knowledge to guide their practice and there existed both intraand interprofessional tensions in these two types of knowledge. The professional hierarchy of stroke teams varies with national context and the role of the non-specialists is less valued in stroke care.

The importance of normative integration in stroke services: case study evidence from Sweden and England.

OBJECTIVES: A number of evidence-based interventions are now available for stroke patients. Good-quality stroke care involves a range of health professionals located across ambulance, hospital, community and primary care services. This study examined the perspectives of health-care workers involved in stroke care in Sweden and England on the integration challenges stroke care presents. METHODS: Four qualitative case studies were carried out in Sweden and England, including 95 semistructured interviews with clinicians and managers associated with four different hospitals providing specialized stroke services. FINDINGS: High levels of organizational, functional, service and clinical integration among clinicians that deliver emergency and acute stroke care were identified. This is frequently lacking among professionals delivering postacute care. These findings are linked to the prevalence or lack of normative and systemic integration in each respective stage of care. CONCLUSIONS: Emphasis on the need to treat stroke as an emergency condition in both countries has created a context in which normative and systemic integration often occurs among clinicians that deliver emergency and acute stroke care, aiding the development of organizational, functional, service and clinical integration across the case study sites. In contrast, integration between hospital and community (rehabilitation and general practice) care is frequently less successful.