Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity.

Epistasis refers to the dependence of a mutation on other mutation(s) and the genetic context in general. In the context of human disorders, epistasis complicates the spectrum of disease symptoms and has been proposed as a major contributor to variations in disease outcome. The nonadditive relationship between mutations and the lack of complete understanding of the underlying physiological effects limit our ability to predict phenotypic outcome. Here, we report positive epistasis between intragenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)-the gene responsible for cystic fibrosis (CF) pathology. We identified a synonymous single-nucleotide polymorphism (sSNP) that is invariant for the CFTR amino acid sequence but inverts translation speed at the affected codon. This sSNP in cis exhibits positive epistatic effects on some CF disease-causing missense mutations. Individually, both mutations alter CFTR structure and function, yet when combined, they lead to enhanced protein expression and activity. The most robust effect was observed when the sSNP was present in combination with missense mutations that, along with the primary amino acid change, also alter the speed of translation at the affected codon. Functional studies revealed that synergistic alteration in ribosomal velocity is the underlying mechanism; alteration of translation speed likely increases the time window for establishing crucial domain-domain interactions that are otherwise perturbed by each individual mutation.

Lawmakers' use of scientific evidence can be improved.

Core to the goal of scientific exploration is the opportunity to guide future decision-making. Yet, elected officials often miss opportunities to use science in their policymaking. This work reports on an experiment with the US Congress-evaluating the effects of a randomized, dual-population (i.e., researchers and congressional offices) outreach model for supporting legislative use of research evidence regarding child and family policy issues. In this experiment, we found that congressional offices randomized to the intervention reported greater value of research for understanding issues than the control group following implementation. More research use was also observed in legislation introduced by the intervention group. Further, we found that researchers randomized to the intervention advanced their own policy knowledge and engagement as well as reported benefits for their research following implementation.

The CFTR P67L variant reveals a key role for N-terminal lasso helices in channel folding, maturation, and pharmacologic rescue.

Patients with cystic fibrosis (CF) harboring the P67L variant in the cystic fibrosis transmembrane conductance regulator (CFTR) often exhibit a typical CF phenotype, including severe respiratory compromise. This rare mutation (reported in <300 patients worldwide) responds robustly to CFTR correctors, such as lumacaftor and tezacaftor, with rescue in model systems that far exceed what can be achieved for the archetypical CFTR mutant F508del. However, the specific molecular consequences of the P67L mutation are poorly characterized. In this study, we conducted biochemical measurements following low-temperature growth and/or intragenic suppression, which suggest a mechanism underlying P67L that (1) shares key pathogenic features with F508del, including off-pathway (non-native) folding intermediates, (2) is linked to folding stability of nucleotide-binding domains 1 and 2, and (3) demonstrates pharmacologic rescue that requires domains in the carboxyl half of the protein. We also investigated the "lasso" helices 1 and 2, which occur immediately upstream of P67. Based on limited proteolysis, pulse chase, and molecular dynamics analysis of full-length CFTR and a series of deletion constructs, we argue that P67L and other maturational processing (class 2) defects impair the integrity of the lasso motif and confer misfolding of downstream domains. Thus, amino-terminal missense variants elicit a conformational change throughout CFTR that abrogates maturation while providing a robust substrate for pharmacologic repair.

Perceptions About the Efficacy and Acceptability of Telephone and Video-Delivered Allied Health Care for Adults With Disabilities During the COVID-19 Pandemic: A Cross-sectional National Survey.

OBJECTIVE: To investigate and compare perceptions about the efficacy and acceptability of allied health care delivered via telephone and video call for adults with disabilities during the COVID-19 pandemic. DESIGN: Cross-sectional national survey. SETTING: Participants who accessed occupational therapy, physiotherapy, psychology, or speech pathology care via telephone or via video call from June to September 2020. PARTICIPANTS: Five hundred eighty-one adults with permanent or significant disabilities, or their carers, partners, or family members, who were funded by the Australian National Disability Insurance Scheme. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Experiences (eg, safety, efficacy, ease of use) with telephone and video-delivered care. Data were analyzed by calculating response proportions and chi-square tests to evaluate differences in experiences between allied health professions and between telephone and video modalities. RESULTS: Responses were obtained for 581 adults with disabilities. There was no evidence of differences between experiences with telephone or video-delivered services or across allied health professions. Overall, 47%-56% of respondents found telehealth technology easy to use (vs 17%-26% who found it difficult), 51%-55% felt comfortable communicating (vs 24%-27% who felt uncomfortable), 51%-67% were happy with the privacy and/or security (vs 6%-9% who were unhappy), 74% were happy with the safety (vs 5%-7% who were unhappy), and 56%-64% believed the care they received was effective (vs 17% who believed it was ineffective). Despite this, 48%-51% were unlikely to choose to use telephone or video consultations in the future (vs 32%-36% who were likely). CONCLUSIONS: Adults with disabilities in Australia had generally positive experiences receiving allied health care via telehealth during the COVID-19 pandemic, although some experienced difficulties using and communicating via the technology. Findings indicated no differences between satisfaction with telephone or video modalities, or between physiotherapy, speech pathology, occupational therapy, or psychology services.

What funders are doing to assess the impact of their investments in health and biomedical research.

As pressures to maximize research funding grow, biomedical research funders are increasingly tasked with demonstrating the long-term and real-world impacts of their funded research investments. Over the past three decades, research impact assessments (RIA) have emerged as an important tool for analysing the impacts of research by incorporating logic models, frameworks and indicators to track measures of knowledge production, capacity-building, development of research products, adoption of research into clinical guidelines and policies, and the realization of health, economic and social benefits. While there are currently several models for RIA within the literature, less attention has been paid to how funders can practically select and implement a RIA model to demonstrate the impacts of their own research portfolios. In this paper, a literature review was performed to understand (1) which research funders have performed RIAs of their research portfolios to date; (2) how funders have designed their assessments, including the models and tools they have used; (3) what challenges to and facilitators of success have funders found when adopting the RIA model to their own portfolio; and (4) who participates in the assessments. Forty-four papers from both published and grey literature were found to meet the review criteria and were examined in detail. There is a growing culture of RIA among funders, and included papers spanned a diverse set of funders from 10 countries or regions. Over half of funders (59.1%) used a framework to conduct their assessment, and a variety of methods for collecting impact data were reported. Issues of methodological rigour were observed across studies in the review, and this was related to numerous challenges funders faced in designing timely RIAs with quality impact data. Over a third of articles (36.4%) included input from stakeholders, yet only one article reported surveying patients and members of the public as part of the assessment. To advance RIA among funders, we offer several recommendations for increasing the methodological rigour of RIAs and suggestions for future research, and call for a careful reflection of the voices needed in an impact assessment to ensure that RIAs are having a meaningful impact on patients and the public.

An evaluation of the evidence brief for policy development process in WHO EVIPNet Europe countries.

BACKGROUND: Evidence briefs for policy (EBPs) represent a potentially powerful tool for supporting evidence-informed policy-making. Since 2012, WHO Evidence-Informed Policy Network (EVIPNet) Europe has been supporting Member States in developing EBPs. The aim of this study was to evaluate the process of developing EBPs in Estonia, Hungary and Slovenia. METHODS: We used a rapid appraisal approach, combining semi-structured interviews and document review, guided by the Medical Research Council (MRC) process evaluation framework. Interviews were conducted with a total of 20 individuals familiar with the EBP process in the three study countries. Data were analysed thematically, and emerging themes were related back to the MRC framework components (implementation, mechanisms of impact, and context). We also reflected on the appropriateness of this evaluation approach for EVIPNet teams without evaluation research expertise to conduct themselves. RESULTS: The following themes emerged as important to the EBP development process: how the focus problem is prioritized, who initiates this process, EBP team composition, EBP team leadership, availability of external support in the process, and the culture of policy-making in a country. In particular, the EBP process seemed to be supported by early engagement of the Ministry of Health and other stakeholders as initiators, clear EBP team roles and expectations, including a strong leader, external support to strengthen EBP team capacity and cultural acceptance of the necessity of evidence-informed policy-making. Overall, the evaluation approach was considered feasible by the EBP teams and captured rich qualitative data, but may be limited by the absence of external reviewers and long lag times between the EBP process and the evaluation. CONCLUSIONS: This process occurs in a complex system and must be conceptualized in each country and each EBP project in a way that fits local policy-making culture, priorities, leadership and team styles, roles and available resources. The use of a rapid appraisal approach, combining qualitative interviews and document review, is a feasible method of process evaluation for EVIPNet member countries.

Assessing cell-specific effects of genetic variations using tRNA microarrays.

BACKGROUND: By definition, effect of synonymous single-nucleotide variants (SNVs) on protein folding and function are neutral, as they alter the codon and not the encoded amino acid. Recent examples indicate tissue-specific and transfer RNA (tRNA)-dependent effects of some genetic variations arguing against neutrality of synonymous SNVs for protein biogenesis. RESULTS: We performed systematic analysis of tRNA abunandance across in various models used in cystic fibrosis (CF) research and drug development, including Fischer rat thyroid (FRT) cells, patient-derived primary human bronchial epithelia (HBE) from lung biopsies, primary human nasal epithelia (HNE) from nasal curettage, intestinal organoids, and airway progenitor-directed differentiation of human induced pluripotent stem cells (iPSCs). These were compared to an immortalized CF bronchial cell model (CFBE41o-) and two widely used laboratory cell lines, HeLa and HEK293. We discovered that specific synonymous SNVs exhibited differential effects which correlated with variable concentrations of cognate tRNAs. CONCLUSIONS: Our results highlight ways in which the presence of synonymous SNVs may alter local kinetics of mRNA translation; and thus, impact protein biogenesis and function. This effect is likely to influence results from mechansistic analysis and/or drug screeining efforts, and establishes importance of cereful model system selection based on genetic variation profile.

Ribosomal Stalk Protein Silencing Partially Corrects the ΔF508-CFTR Functional Expression Defect.

The most common cystic fibrosis (CF) causing mutation, deletion of phenylalanine 508 (ΔF508 or Phe508del), results in functional expression defect of the CF transmembrane conductance regulator (CFTR) at the apical plasma membrane (PM) of secretory epithelia, which is attributed to the degradation of the misfolded channel at the endoplasmic reticulum (ER). Deletion of phenylalanine 670 (ΔF670) in the yeast oligomycin resistance 1 gene (YOR1, an ABC transporter) of Saccharomyces cerevisiae phenocopies the ΔF508-CFTR folding and trafficking defects. Genome-wide phenotypic (phenomic) analysis of the Yor1-ΔF670 biogenesis identified several modifier genes of mRNA processing and translation, which conferred oligomycin resistance to yeast. Silencing of orthologues of these candidate genes enhanced the ΔF508-CFTR functional expression at the apical PM in human CF bronchial epithelia. Although knockdown of RPL12, a component of the ribosomal stalk, attenuated the translational elongation rate, it increased the folding efficiency as well as the conformational stability of the ΔF508-CFTR, manifesting in 3-fold augmented PM density and function of the mutant. Combination of RPL12 knockdown with the corrector drug, VX-809 (lumacaftor) restored the mutant function to ~50% of the wild-type channel in primary CFTRΔF508/ΔF508 human bronchial epithelia. These results and the observation that silencing of other ribosomal stalk proteins partially rescue the loss-of-function phenotype of ΔF508-CFTR suggest that the ribosomal stalk modulates the folding efficiency of the mutant and is a potential therapeutic target for correction of the ΔF508-CFTR folding defect.

Understanding the unintended consequences of public health policies: the views of policymakers and evaluators.

BACKGROUND: Public health policies sometimes have unexpected effects. Understanding how policies and interventions lead to outcomes is essential if policymakers and researchers are to intervene effectively and reduce harmful and other unintended consequences (UCs) of their actions. Yet, evaluating complex mechanisms and outcomes is challenging, even before considering how to predict assess and understand outcomes and UCs when interventions are scaled up. We aimed to explore with UK policymakers why some policies have UCs, and how researchers and policymakers should respond. METHODS: We convened a one-day workshop with 14 people involved in developing, implementing or evaluating social and public health policies, and/or evaluating possible unintended effects. This included senior evaluators, policymakers from government and associated agencies, and researchers, covering policy domains from public health, social policy, poverty, and international development. RESULTS: Policymakers suggested UCs happen for a range of reasons: poor policy design, unclear articulation of policy mechanisms or goals, or unclear or inappropriate evidence use, including evaluation techniques. While not always avoidable, it was felt that UCs could be partially mitigated by better use of theory and evidence, better involvement of stakeholders in concurrent design and evaluation of policies, and appropriate evaluation systems. CONCLUSIONS: UCs can be used to explore the mechanisms underpinning social change caused by public health policies. Articulating these mechanisms is essential for truly evidence-informed decision-making, to enable informed debate about policy options, and to develop evaluation techniques. Future work includes trying to develop a holistic stakeholder-led evaluation process.

Effectiveness of assistive technology in improving the safety of people with dementia: a systematic review and meta-analysis.

Objectives: Assistive technology (AT) may enable people with dementia to live safely at home for longer, preventing care home admission. This systematic review assesses the effectiveness of AT in improving the safety of people with dementia living in the domestic setting, by searching for randomised controlled trials, non-randomised controlled trials and controlled before-after studies which compared safety AT with treatment as usual. Measures of safety include care home admission; risky behaviours, accidents and falls at home; and numbers of deaths. The review updates the safety aspect of Fleming and Sum's 2014 systematic review. Method: Seven bibliographic databases, the Social Care Institute for Excellence website and the Alzheimer's Society website were searched for published and unpublished literature between 2011-2016. Search terms related to AT, dementia and older people. Common outcomes were meta-analysed. Results: Three randomised controlled trials were identified, including 245 people with dementia. No significant differences were found between intervention and control groups in care home admission (risk ratio 0.85 95% CI [0.37, 1.97]; Z = 0.37; p = 0.71). The probability of a fall occurring was 50% lower in the intervention group (risk ratio 0.50 95% CI [0.32, 0.78]; Z = 3.03; p = 0.002). One included study found that a home safety package containing AT significantly reduced risky behaviour and accidents (F(45) = 4.504, p < 0.001). Limitations include the few studies found and the inclusion of studies in English only. Conclusion: AT's effectiveness in decreasing care home admission is inconclusive. However, the AT items and packages tested improved safety through reducing falls risk, accidents and other risky behaviour.

The dark side of coproduction: do the costs outweigh the benefits for health research?

BACKGROUND: Coproduction, a collaborative model of research that includes stakeholders in the research process, has been widely advocated as a means of facilitating research use and impact. We summarise the arguments in favour of coproduction, the different approaches to establishing coproductive work and their costs, and offer some advice as to when and how to consider coproduction. DEBATE: Despite the multiplicity of reasons and incentives to coproduce, there is little consensus about what coproduction is, why we do it, what effects we are trying to achieve, or the best coproduction techniques to achieve policy, practice or population health change. Furthermore, coproduction is not free risk or cost. Tensions can arise throughout coproduced research processes between the different interests involved. We identify five types of costs associated with coproduced research affecting the research itself, the research process, professional risks for researchers and stakeholders, personal risks for researchers and stakeholders, and risks to the wider cause of scholarship. Yet, these costs are rarely referred to in the literature, which generally calls for greater inclusion of stakeholders in research processes, focusing exclusively on potential positives. There are few tools to help researchers avoid or alleviate risks to themselves and their stakeholders. CONCLUSIONS: First, we recommend identifying specific motivations for coproduction and clarifying exactly which outcomes are required for whom for any particular piece of research. Second, we suggest selecting strategies specifically designed to enable these outcomes to be achieved, and properly evaluated. Finally, in the absence of strong evidence about the impact and process of coproduction, we advise a cautious approach to coproduction. This would involve conscious and reflective research practice, evaluation of how coproduced research practices change outcomes, and exploration of the costs and benefits of coproduction. We propose some preliminary advice to help decide when coproduction is likely to be more or less useful.

Assessing the policy and practice impact of an international policy initiative: the State of the World's Midwifery 2014.

BACKGROUND: Understanding how policies lead to changes in health systems and in practice helps policymakers and researchers to intervene more successfully. Yet identifying all the possible changes that occur as a result of a new policy is challenging not only methodologically and logistically, as limited resources are available to conduct indefinite evaluations, but also theoretically, as a complete mapping and attribution of post-hoc changes requires a full understanding of the mechanisms underpinning all change. One option is to identify possible changes across a number of policy impact domains. METHODS: Using a Policy Impact Framework, we brought together data from media, documents and interviews to identify changes to midwifery policy, practice and provision, following the launch of a new global policy initiative, the State of the World's Midwifery (SoWMy 2014) report published in 2014. We used these identified impacts to develop a map of the mechanisms underpinning these changes. RESULTS: SoWMy 2014 contributed to a number of changes at national levels, including increased status of midwifery within national governments, improved curricula and training opportunities for midwives, and improved provision of and access to midwifery-led care. These contributions were attributed to SoWMy 2014 via mechanisms such as stakeholder interaction and acquisition of government support, holding national and international dissemination and training events, and a perceived global momentum around supporting midwifery provision. Policy initiatives of this kind can lead to changes in national and international policy dialogue and practice. We identify factors and mechanisms that are likely to increase the scope and scale of these changes, at contextual, national and global levels. CONCLUSIONS: Identifying changes following a policy using a policy impact framework can help researchers and policymakers understand why policies have the effect they do. This is important information for those wishing to increase the effectiveness of future policies and interventions.

Defining 'evidence' in public health: a survey of policymakers' uses and preferences.

Background: Public health (PH) policymakers are encouraged to use evidence in the decision-making process. However, little is known about what types of evidence policymakers working in local settings prefer to use. This study aims to evaluate policymakers' needs and sources of information, at regional and local levels. An electronic survey with telephone follow-up was carried out among PH policymakers and evidence producers ( n = 152) working in a large UK city. Respondents were asked which types of evidence they used regularly, found most useful and what were their main sources of information. Semi-structured interviews ( n = 23) added were analysed quantitatively in addition to the categorical data generated by the survey. Policymakers use a much greater range of evidence and information than is often indicated in the literature on evidence-based policy. Local data were by far the most used ( n = 95%) and most valued ( n = 85%) type of information, followed by practice guidelines. The main sources of information were Government websites (84%), followed by information obtained through personal contacts (71%), including PH professionals, council officers and politicians. Academics were rarely consulted and research evidence was rarely seen as directly relevant. Conclusions: Policymakers use a wider range of evidence types than previously discussed in the literature. Although local data were most valued by policymakers, results suggest that these were accessed through personal contacts, rather than specialized organizations. Systems to provide local high-quality evidence for PH policy should be supported.

Identifying public health policymakers' sources of information: comparing survey and network analyses.

Background: Research suggests that policymakers often use personal contacts to find information and advice. However, the main sources of information for public health policymakers are not known. This study aims to describe policymakers' sources of information. A questionnaire survey of public health policymakers across Greater Manchester (GM) was carried out (response rate 48%). All policy actors above Director level involved in public health policy (finding, analyzing or producing information, producing or implementing policy) in GM were included in the sampling frame. Respondents were provided with a list of sources of information and asked which they used (categorical data) and to name specific individuals who acted as sources of information (network data). Data were analyzed using frequencies and network analysis. The most frequently chosen sources of information from the categorical data were NICE, government websites and Directors of Public Health. However, the network data showed that the main sources of information in the network were actually mid-level managers in the NHS, who had no direct expertise in public health. Academics and researchers did not feature in the network. Both survey and network analyses provide useful insights into how policymakers access information. Network analysis offers practical and theoretical contributions to the evidence-based policy debate. Identifying individuals who act as key users and producers of evidence allows academics to target actors likely to use and disseminate their work.

Evidence-based policymaking is not like evidence-based medicine, so how far should you go to bridge the divide between evidence and policy?

There is extensive health and public health literature on the 'evidence-policy gap', exploring the frustrating experiences of scientists trying to secure a response to the problems and solutions they raise and identifying the need for better evidence to reduce policymaker uncertainty. We offer a new perspective by using policy theory to propose research with greater impact, identifying the need to use persuasion to reduce ambiguity, and to adapt to multi-level policymaking systems.We identify insights from secondary data, namely systematic reviews, critical analysis and policy theories relevant to evidence-based policymaking. The studies are drawn primarily from countries such as the United States, United Kingdom, Canada, Australia and New Zealand. We combine empirical and normative elements to identify the ways in which scientists can, do and could influence policy.We identify two important dilemmas, for scientists and researchers, that arise from our initial advice. First, effective actors combine evidence with manipulative emotional appeals to influence the policy agenda - should scientists do the same, or would the reputational costs outweigh the policy benefits? Second, when adapting to multi-level policymaking, should scientists prioritise 'evidence-based' policymaking above other factors? The latter includes governance principles such the 'co-production' of policy between local public bodies, interest groups and service users. This process may be based primarily on values and involve actors with no commitment to a hierarchy of evidence.We conclude that successful engagement in 'evidence-based policymaking' requires pragmatism, combining scientific evidence with governance principles, and persuasion to translate complex evidence into simple stories. To maximise the use of scientific evidence in health and public health policy, researchers should recognise the tendency of policymakers to base judgements on their beliefs, and shortcuts based on their emotions and familiarity with information; learn 'where the action is', and be prepared to engage in long-term strategies to be able to influence policy; and, in both cases, decide how far you are willing to go to persuade policymakers to act and secure a hierarchy of evidence underpinning policy. These are value-driven and political, not just 'evidence-based', choices.

Improving the identification and management of chronic kidney disease in primary care: lessons from a staged improvement collaborative.

QUALITY PROBLEM: Undiagnosed chronic kidney disease (CKD) contributes to a high cost and care burden in secondary care. Uptake of evidence-based guidelines in primary care is inconsistent, resulting in variation in the detection and management of CKD. INITIAL ASSESSMENT: Routinely collected general practice data in one UK region suggested a CKD prevalence of 4.1%, compared with an estimated national prevalence of 8.5%. Of patients on CKD registers, ∼ 30% were estimated to have suboptimal management according to Public Health Observatory analyses. CHOICE OF SOLUTION: An evidence-based framework for implementation was developed. This informed the design of an improvement collaborative to work with a sample of 30 general practices. IMPLEMENTATION: A two-phase collaborative was implemented between September 2009 and March 2012. Key elements of the intervention included learning events, improvement targets, Plan-Do-Study-Act cycles, benchmarking of audit data, facilitator support and staff time reimbursement. EVALUATION: Outcomes were evaluated against two indicators: number of patients with CKD on practice registers; percentage of patients achieving evidence-based blood pressure (BP) targets, as a marker for CKD care. In Phase 1, recorded prevalence of CKD in collaborative practices increased ∼ 2-fold more than that in comparator local practices; in Phase 2, this increased to 4-fold, indicating improved case identification. Management of BP according to guideline recommendations also improved. LESSONS LEARNED: An improvement collaborative with tailored facilitation support appears to promote the uptake of evidence-based guidance on the identification and management of CKD in primary care. A controlled evaluation study is needed to rigorously evaluate the impact of this promising improvement intervention.

A systematic review of barriers to and facilitators of the use of evidence by policymakers.

BACKGROUND: The gap between research and practice or policy is often described as a problem. To identify new barriers of and facilitators to the use of evidence by policymakers, and assess the state of research in this area, we updated a systematic review. METHODS: Systematic review. We searched online databases including Medline, Embase, SocSci Abstracts, CDS, DARE, Psychlit, Cochrane Library, NHSEED, HTA, PAIS, IBSS (Search dates: July 2000 - September 2012). Studies were included if they were primary research or systematic reviews about factors affecting the use of evidence in policy. Studies were coded to extract data on methods, topic, focus, results and population. RESULTS: 145 new studies were identified, of which over half were published after 2010. Thirteen systematic reviews were included. Compared with the original review, a much wider range of policy topics was found. Although still primarily in the health field, studies were also drawn from criminal justice, traffic policy, drug policy, and partnership working. The most frequently reported barriers to evidence uptake were poor access to good quality relevant research, and lack of timely research output. The most frequently reported facilitators were collaboration between researchers and policymakers, and improved relationships and skills. There is an increasing amount of research into new models of knowledge transfer, and evaluations of interventions such as knowledge brokerage. CONCLUSIONS: Timely access to good quality and relevant research evidence, collaborations with policymakers and relationship- and skills-building with policymakers are reported to be the most important factors in influencing the use of evidence. Although investigations into the use of evidence have spread beyond the health field and into more countries, the main barriers and facilitators remained the same as in the earlier review. Few studies provide clear definitions of policy, evidence or policymaker. Nor are empirical data about policy processes or implementation of policy widely available. It is therefore difficult to describe the role of evidence and other factors influencing policy. Future research and policy priorities should aim to illuminate these concepts and processes, target the factors identified in this review, and consider new methods of overcoming the barriers described.

New directions in evidence-based policy research: a critical analysis of the literature.

Despite 40 years of research into evidence-based policy (EBP) and a continued drive from both policymakers and researchers to increase research uptake in policy, barriers to the use of evidence are persistently identified in the literature. However, it is not clear what explains this persistence - whether they represent real factors, or if they are artefacts of approaches used to study EBP. Based on an updated review, this paper analyses this literature to explain persistent barriers and facilitators. We critically describe the literature in terms of its theoretical underpinnings, definitions of 'evidence', methods, and underlying assumptions of research in the field, and aim to illuminate the EBP discourse by comparison with approaches from other fields. Much of the research in this area is theoretically naive, focusing primarily on the uptake of research evidence as opposed to evidence defined more broadly, and privileging academics' research priorities over those of policymakers. Little empirical data analysing the processes or impact of evidence use in policy is available to inform researchers or decision-makers. EBP research often assumes that policymakers do not use evidence and that more evidence - meaning research evidence - use would benefit policymakers and populations. We argue that these assumptions are unsupported, biasing much of EBP research. The agenda of 'getting evidence into policy' has side-lined the empirical description and analysis of how research and policy actually interact in vivo. Rather than asking how research evidence can be made more influential, academics should aim to understand what influences and constitutes policy, and produce more critically and theoretically informed studies of decision-making. We question the main assumptions made by EBP researchers, explore the implications of doing so, and propose new directions for EBP research, and health policy.

A modified action framework to develop and evaluate academic-policy engagement interventions.

BACKGROUND: There has been a proliferation of frameworks with a common goal of bridging the gap between evidence, policy, and practice, but few aim to specifically guide evaluations of academic-policy engagement. We present the modification of an action framework for the purpose of selecting, developing and evaluating interventions for academic-policy engagement. METHODS: We build on the conceptual work of an existing framework known as SPIRIT (Supporting Policy In Health with Research: an Intervention Trial), developed for the evaluation of strategies intended to increase the use of research in health policy. Our aim was to modify SPIRIT, (i) to be applicable beyond health policy contexts, for example encompassing social, environmental, and economic policy impacts and (ii) to address broader dynamics of academic-policy engagement. We used an iterative approach through literature reviews and consultation with multiple stakeholders from Higher Education Institutions (HEIs) and policy professionals working at different levels of government and across geographical contexts in England, alongside our evaluation activities in the Capabilities in Academic Policy Engagement (CAPE) programme. RESULTS: Our modifications expand upon Redman et al.'s original framework, for example adding a domain of 'Impacts and Sustainability' to capture continued activities required in the achievement of desirable outcomes. The modified framework fulfils the criteria for a useful action framework, having a clear purpose, being informed by existing understandings, being capable of guiding targeted interventions, and providing a structure to build further knowledge. CONCLUSION: The modified SPIRIT framework is designed to be meaningful and accessible for people working across varied contexts in the evidence-policy ecosystem. It has potential applications in how academic-policy engagement interventions might be developed, evaluated, facilitated and improved, to ultimately support the use of evidence in decision-making.