Background: The use of research evidence in health policy-making is a popular line of inquiry for scholars of public health and policy studies, with qualitative methods constituting the dominant strategy in this area. Research on this subject has been criticized for, among other things, disproportionately focusing on high-income countries; overemphasizing ‘barriers and facilitators’ related to evidence use to the neglect of other, less descriptive concerns; relying on descriptive, rather than in-depth explanatory designs; and failing to draw on insights from political/policy studies theories and concepts. We aimed to comprehensively map the global, peer-reviewed qualitative literature on the use of research evidence in health policy-making and to provide a descriptive overview of the geographic, temporal, methodological, and theoretical characteristics of this body of literature.Methods: We conducted a systematic review following PRISMA  guidelines. We searched nine electronic databases, hand-searched 11 health- and policy-related journals, and systematically scanned the reference lists of included studies and previous reviews. No language, date or geographic limitations were imposed.Results: The review identified 319 qualitative studies on a diverse array of topics related to the use of evidence in health policy-making, spanning 72 countries and published over a nearly 40 year period. A majority of these studies were conducted in high-income countries, but a growing proportion of the research output in this area is now coming from low- and middle-income countries, especially from sub-Saharan Africa. While over half of all studies did not use an identifiable theory or framework, and only one fifth of studies used a theory or conceptual framework drawn from policy studies or political science, we found some evidence that theory-driven and explanatory  designs are becoming more common in this literature. Investigations of the barriers and facilitators related to evidence use constitute a large proportion but by no means a majority of the work in this area.Conclusion: This review provides a bird’s eye mapping of the peer reviewed qualitative research on evidence-to-policy processes, and has identified key features of – and gaps within – this body of literature that will hopefully inform, and improve, research in this area moving forward. The relationship between the worlds of scientific research and public policy has long been a preoccupation of social scientists.6 Perhaps most obviously, impact evaluations – including randomized controlled trials, quasi-experiments and other evaluation designs – can provide information on whether and to what extent a given policy or program is likely to be effective, and can therefore aid in the identification of, and adjudication between, competing policy alternatives. Moreover, evidence from both qualitative and quantitative research can help policy-makers to set policy agendas, by identifying, defining and prioritizing policy problems, and understanding and taking into consideration the perceptions of citizens, patients and other stakeholders. Finally, evidence can be drawn upon to identify and systematically account for potential factors affecting the implementation and scaling of policy interventions. Therefore, so it is often argued, research evidence can serve useful functions in various decision-making “stages” within policy processes – most commonly summarized as agenda setting, policy formulation, policy implementation, and policy evaluation8 – the key assumption being that health policy decisions which are informed by evidence are better than they otherwise would be in the absence of evidence.9 Proponents of evidence-informed policy-making in health assert that studies of various kinds can be used to address a range of questions of relevance to health policy-making.10 many – if not most – actual instances of “research utilization” in public sector bodies do not take the form of the direct, instrumental translation of research findings into discrete policy decisions, as models of evidence-based decision-making prescribe. Rather, the influence of research on policy is more often conceptual, following a gradual process through which the ideas that emerge from  science indirectly shape ways of thinking in policy circles, a process that Weiss termed enlightenment.11 Nor is research use necessarily a positive or desirable outcome: evidence can be drawn upon selectively to serve symbolic functions, for instance the legitimation of pre-existing political agendas12 or the justification of political inaction on the grounds that the existing evidence is insufficient.13 In such cases the “consideration” of the evidence by decision-makers might well follow the decision in question, not the other way around. Uses of research evidence can therefore be understood to serve not just instrumental  functions, but also conceptual  and symbolic  functions in policy-making processes.14 However, as was argued in Carol Weiss’s pioneering work 4 decades ago,15 The point here is that the relationship between research evidence and public policy-making – far from the idealized straightforward, linear connection implied in some models – is highly contingent and complex, and can take various forms. It is perhaps no surprise, then, that interpretive qualitative methods are commonly suggested as particularly important to building our understanding of evidence-to-policy processes. Indeed, as argued by Contandriopoulos et al, the phenomenon of knowledge exchange is “ontologically more suited to case studies than to any other method” (p. 453), owing to the complexity of knowledge exchange interventions and to what they call the ‘systemic’ nature of the relevant outcomes, which frustrate attempts at valid quantitative measurement in this field.21 Three of these reviews summarized the literature on the barriers to and facilitators of evidence use, 2 in health policy specifically20 and one, most recently, in public policy more generally.16 A fourth review, originally published in 201117 and subsequently updated in 201821 extended beyond barriers and facilitators to examine a range of facets of decision-making in public health, but limited their included studies to those conducted in countries with universal healthcare systems . Finally, Liverani and colleagues’ systematic review examined political and institutional influences on evidence use in public health policy.18 However, we know of no existing reviews that set out to provide a detailed mapping of these studies in order to paint a broad picture of their characteristics, nor any that were conducted with a specific focus on understanding the qualitative evidence base on the subject of evidence use by health policy-makers. Several systematic reviews focusing on various questions related to the use of research evidence by health policy-makers were published prior to the conduct of the present review.16 The findings from these reviews suggest persistent academic interest in the subject of policy-maker evidence use, and indicate that the speed with which new primary studies on this topic are generated is rapidly growing. For example, roughly half of the 145 studies included in Oliver and colleagues’ review (spanning 2000-2012) were published in 2011 and 2012 alone.16 Researchers have called for more in-depth, qualitative case studies of evidence use processes with attention to the important features of particular policy contexts, and for investigators to make greater use of more direct methods of observing policy-making activities using, for example, techniques commonly associated with ethnography.23 Another common refrain is that this literature is overwhelmingly preoccupied with addressing descriptive questions related to evidence uptake, most notably a disproportionate interest in the identification of barriers to and facilitators of the  use of evidence, to the exclusion of more critical and explanatory concerns.23 Both within and beyond health-related research domains, barriers and facilitators conceptualizations have been criticized for oversimplifying complex social problems and for generating potentially misleading findings about how they might be overcome.26 Furthermore, the evidence-to-policy literature has been criticized for its theoretical naïveté,27 and in particular for its failure to harness theoretical and conceptual insights from political science and policy studies.28 In their 2013 review, Liverani and colleagues determined that only 6 of their 56 included studies “explicitly engaged with political theories or concepts.”18 Such neglect of political science has been identified as a weakness of academic public health more generally.30 In addition to these methodological and conceptual observations, concern has been raised that the research on evidence use is dominated by investigations from industrialized Western countries, and that as a consequence processes of evidence use in Global South are comparatively poorly understood.35 This paper, which reports the findings of an up-to-date systematic review of the qualitative academic literature on the use of research evidence in health policy-making, provides an empirical basis for some of these claims and concerns. While large and growing, the collection of research on the use of evidence by policy-makers – including the subset of this work that uses qualitative approaches – has long been subject to some common concerns and criticisms. From a methodological standpoint, it has been observed that this literature is dominated by the use of interviews and surveys to understand policy-maker perceptions about their use of evidence, with more direct methods of analyzing policy decisions, such as participant observation, sparsely deployed. The objectives of this review were: (1) to systematically map the global, peer-reviewed qualitative literature on the use of research evidence in health policy-making; and (2) to provide a descriptive overview of the studies that make up this literature, with an emphasis on their temporal and geographic distribution, methodological features, and subject matter focus.36 The present review has been reported according to the PRISMA  guidelines.37 We conducted a systematic review of published qualitative research on the role of evidence in health policy-making. In this paper, we provide a descriptive overview of this body of literature. The original protocol for the broader project of which this review is a part was registered with the International Prospective Register of Systematic Reviews  and published elsewhere. In this section we outline the criteria against which studies were assessed for inclusion in the review. Briefly, to be included a study had to:be a qualitative study published in a peer-reviewed journal; policy-makers in policy-making settings; and examine the work of research evidence to inform health policy-making.report data concerning the use of  In the sub-sections that follow, we provide a more detailed explanation of and rationale for these inclusion criteria.40 and was cited as one useful definition in the Cochrane Qualitative and Implementation Methods Group supplementary guidance on qualitative evidence synthesis.41 Methods of qualitative data collection include (but are not limited to) interviews, focus groups, and (participant) observation methods. Methods of qualitative data analysis include, for example, thematic analysis, phenomenological approaches, and grounded theory. This definition excludes studies in which data are collected through interviews or focus groups, but are analyzed exclusively through quantitative methods. To meet these methodological criteria, study authors had to explicitly describe the sources of data on which they drew. We considered studies to have used a qualitative method of data analysis if they used an identifiable term  or citation to refer to the approach, or if it was clear that their procedures corresponded to a recognized method of qualitative analysis. This review includes primary qualitative studies published in peer-reviewed academic journals. We used the following definition of ‘qualitative study’: a study that uses qualitative methods both for data collection and data analysis. This definition is consistent with that used in several recent qualitative syntheses We included mixed methods studies, that is, studies using both qualitative and quantitative methods, provided it was possible to examine the data derived only from the qualitative methods separately from the quantitative data, and where the qualitative component of the study corresponded to our subject matter inclusion criteria. We did not exclude studies according to the epistemological assumptions and/or theoretical traditions on which they were based. That is, we included all work within the broad qualitative paradigm.41 and no such cut-off criteria have found consensus among qualitative reviewers.43 Moreover, since the intention of the present review was to exhaustively catalogue and describe the published qualitative literature in this area , excluding relevant papers on the basis of quality would have been counter to our review objectives. We did not exclude studies on the basis of a hierarchy of qualitative evidence or any other criteria related to study quality. It is not uncommon in reviews of quantitative research to impose a methodological quality “cut-off” based on features related to internal validity. However, the place of quality appraisal in qualitative reviews remains contentious,44 we found that reporting limitations in many interview studies on evidence use often made it difficult to identify the specific professional roles and activities of informants. We therefore excluded studies where it was impossible to determine with confidence that the actors or activities under study were policy-related. This review includes studies involving policy-makers engaged in policy-making activities with an explicit (though not necessarily exclusive) focus on health issues. For the purposes of this review, the population ‘policy-makers’ includes elected officials, appointed civil servants, policy advisors and/or bureaucrats of any rank, working at the local, provincial/state, national, or supranational  levels. Like other researchers in this topic arearesearch evidence by policy-makers working at least in part on health policy. In order to be eligible for inclusion, studies had to explore the use of 45 Recognizing that policy decisions made outside of governmental health authorities, across a variety of policy sectors, can have meaningful impacts on health,46 we included studies in non-health sectors, as long as population health – or the relationship between policy decisions and health outcomes – was a major and explicit focus of the research or of the policy(ies) it examined. For the purposes of this review, health policy decisions are those taken with the explicit goal of promoting population health and/or having to do with the financing and organization of health systems. We took policy-making to refer mainly to governmental planning and strategic decision-making about the organization of health services and public/population health, in contrast to public health management and practice. This excludes decisions related to patient-level, clinical healthcare or clinical governance. This implied distinction between policy actors, on the one hand, and those involved in management  and service delivery , on the other, is in line with previous reviews.research evidence as research produced by academic researchers and/or published in academic journals. This definition is similar to that used in a previous systematic review,47 whose authors found that their original attempt to use a broader definition of research evidence produced results so conceptually heterogeneous that a meaningful synthesis was unfeasible. This definition excludes studies that look exclusively at the use of raw data  by decision-makers. Eligible studies could have examined the use of research evidence in general, a specific methodological category of research  or a particular form of research evidence . The focus on evidence use had to be significant  and explicit . We defined ) on January 20, 2019 using search strategies that were developed in consultation with information retrieval specialists and were subjected to multiple stages of piloting. We improved the sensitivity of each subsequent iteration of our search strategies by assessing detection of a list of key papers that were included in previous reviews on evidence use in policy-making. Strategies were iteratively amended (mainly through the addition of search terms and novel combinations of search terms) until all of these key papers were captured. Where appropriate, we adapted and applied methodological search filters to aid in the identification of qualitative studies.48 Our Medline search strategy is provided in  We electronically searched a broad array of bibliographic databases listed in on Janua Bibliographic databases (no date/language limitation):Applied Social Sciences Index and Abstracts Conference Proceedings Citation Index – Social Science and Humanities Global Health International Bibliography of the Social Sciences International Political Science Abstracts MEDLINE SCOPUS Social Sciences Citation Index Worldwide Political Science Abstracts  Journals (January 2010 to January 2019):BMC Health Services Research BMC Public Health Evidence and Policy Health Policy Health Policy and Planning Health Research Policy and Systems Implementation Science International Journal of Health Policy and Management Journal of Health Politics, Policy and Law Milbank Quarterly Social Science and Medicine Evidence and Policy), (2) our knowledge of their record of having previously published several relevant studies in this topic area , and (3) advice from expert reviewers of early versions of this review’s protocol . We also searched the reference lists of all included studies and of previous reviews whose subject matter focus had similarities with the present review.49 Experts and colleagues were contacted to obtain information about any as yet unidentified studies. Furthermore, we screened an inventory of studies of evidence-to-policy processes of which we were already aware. To offset the inevitable imperfections of electronic database searches, we also sought published studies through other search methods, including journal hand-searching, scanning reference lists, and speaking to experts. We hand-searched all issues of 11 relevant academic journals published from January 2010 to January 2019 (inclusive). Journals were selected for hand-searching on the basis of (1) their central relevance to the topic of the review  conducted many of these tasks in parallel. Such double-screening, and double-extraction is standard practice in systematic reviewing,50 using Covidence systematic review software. BV and AB independently screened all titles and abstracts. Records deemed potentially relevant by both authors were retained for further review. Conflicting judgements were resolved through discussion. Since our aim was to comprehensively locate all studies meeting our inclusion criteria, and because it was often impossible to assess all inclusion criteria with confidence on the basis of titles and abstracts alone, we were deliberately very inclusive at this stage of screening. This was necessary, in large part, because of poor reporting of methodological information in qualitative study abstracts, as well as the ubiquity of relevant terminology  in the titles and abstracts of papers with little relevance to the study of evidence use. As a result we retained a large number of papers for full-text review (see below). Study screening and selection were conducted according to standard systematic review methods Both authors then independently screened the full text versions of all potentially relevant articles for inclusion in the review. All studies deemed to have met the inclusion criteria were included. Again, disagreements were resolved through discussion. Deferral to a third party to resolve disagreements on inclusion decisions was not necessary at either stage. Reasons for the exclusion of studies at the full-text review stage were recorded. A bespoke data extraction sheet was designed in Microsoft Excel to meet the specific objectives of the review. The following descriptive information was recorded for all included studies:Basic study information ; A brief summary of the study’s aim and research questions, and whether the concepts of ‘barriers to’ and/or ‘facilitators of’ the use of evidence were used in the study; Study design, description of data sources and qualitative analysis methods, theories or frameworks used for data collection and/or analysis; Description of the study setting, policy-making context, level of policy-making , and country or countries of focus; Description and number of participants; Description of the policy decision(s) or process(es) and policy sector(s) investigated; Type or form of research evidence investigated, and whether the study investigated instrumental, symbolic, and/or conceptual uses of evidence.  We first independently piloted the data extraction sheet on 30 included studies, which were selected at random. AB and BV compared the extracted data and resolved differences by discussion. During a second phase of piloting we extracted an additional 20 studies in duplicate to further enhance consistency. The remaining studies were divided between BV and AB for independent data extraction. Extractions conducted by AB were double-checked by BV to ensure consistency.52 inspired some of the analyses and the presentation of findings. We used the World Bank’s classification system to divide countries into 4 income groups according to Gross National Income per capita.53 We used colour-coded maps generated using web-based freeware MapChart.net54 to visually represent both the absolute number of studies per country and the density of studies as a proportion of country population. For the latter calculation we drew on data from the United Nations Population Division.55 Data were tabulated and described narratively. Where appropriate, counts, sums, percentages and means were calculated. Previous reviews, including from health policy and systems research,52 Additionally, we coded all studies according to whether or not they sought to identify ‘barriers to’ and/or ‘facilitators of’ evidence uptake, regardless of whether this was the study’s core purpose. In order to characterize the subject matter of the body of included papers, each study was coded with a single ‘core’ primary focus, thrust or purpose, through an iterative, inductive process, following methods described in Erasmus and colleagues’ review of policy implementation research.58 a well-known (if simplistic) conceptual device  which divides the policy process into 4 discrete stages: agenda-setting, policy formulation, policy implementation, and policy evaluation. A popular typology of research use (described above) was used to code studies according to whether they investigated instrumental, symbolic and/or conceptual uses of evidence.14 We drew on a number of common frameworks in order to classify studies. To categorize studies according to the policy activities on which they focus, we used the stages heuristic, The process of identification, screening, selection of studies in this review is summarized in the flow diagram in  Database searches yielded 23 499 records, 13 846 of which remained after manual and software-supported removal of duplicate records. Title and abstract screening of these records identified 345 additional potentially relevant and unique articles, bringing the total number of unique papers for full-text review to 1,070. Following full-text review, a total of 319 papers were found to meet our inclusion criteria  of all included studies  or both health and policy . A smaller number of studies was published in journals related to policy only  or in journals that are not focused specifically on health or policy . Forty-five percent (n = 141) of all studies were published in only 8 different journals, with dies see . Included studies investigated policy processes and decisions in countries from every populated continent, with Europe  and Africa  being the most well-represented and South America  relatively poorly represented. Europe and Africa are not only the most researched continents in absolute terms, but have also seen the greatest increase in research attention in this topic area during recent years see . A small number of included studies focused on country groupings or regions, or settings defined by other characteristics, as opposed to individual countries. These studies investigated decision-making within: the European Union (n = 3), the Eastern Mediterranean Region (n = 2), Caribbean Island States (n = 1), high-income countries (n = 1), low- and middle-income countries (n = 1), industrialized countries (n = 1), and within global multilateral organizations (n = 2). The 319 included studies investigated 72 distinct countries. Whereas 265 (83%) studies focused on a single country, 50 (16%) investigated more than one country, and 4 (1%) did not focus on a specific country or countries. Eight countries alone were studied in more than half (52%) of all included studies: the United Kingdom , the United States , Australia , Canada , Uganda , the Netherlands , India , and Malawi  . The maj A visual depiction of the global distribution of included studies by country of focus is shown in 52 These are summarized thematically in  All studies were assigned to a single category that best summarized their core purpose, focus or general thrust. The single largest category of studies were those whose core focus was to understand the role of research evidence in a specific case of policy change or decision-making . A large number of studies  were centred around a specific category of evidence – most commonly a methodological grouping , or a specific study or studies  – and sought to understand their impact on or use in policy decisions. Also common were studies focused on policy-maker perceptions – related to evidence use generally , or more specifically to their evidence-related needs  and preferred types  and sources  of evidence. Twenty-three studies (7%) were classified as having the identification of factors related to evidence use  as their core objective. However, overall, nearly one-third of studies  investigated barriers and facilitators in some way, usually as one part of a broader set of study objectives. The qualitative study designs and methodological features of included studies are provided in  Forty-eight articles (15%) reported mixed methods studies that used both qualitative and quantitative approaches, whereas the vast majority of studies  relied exclusively on qualitative methods. The overwhelming majority of studies drew on interviews  and/or documents , while focus groups  and methods of observation , were less commonly used. Well over half of all studies  combined multiple sources of qualitative data, with interviews and documents being by far the most common combination. Nearly two-fifths of included papers described using thematic analysis , followed by content analysis , grounded theory approaches , framework analysis , phenomenological approaches ,  discourse analysis , and narrative analysis . We found that the methods of data analysis used in included studies were in many cases not well-described. Almost a fifth of all studies  did not report their analysis at all or were unclear in their reporting of how it was performed, while a minority of studies  described their analysis only in generic or broad terms. Even where reporting of analysis methods bordered on satisfactory, it was still often difficult to categorize. For instance, in the case of studies using what we determined to be a form of thematic analysis almost half  described their procedures without explicitly referring to thematic analysis or a related label, necessitating a degree of judgement on our part. Studies used various theories and frameworks to investigate evidence use in policy, as reported in  The most commonly used theories and conceptual frameworks are reported in the bottom half of  Included studies that involved participant responses  and that reported the number of study participants , investigated a total of 9436 participants. Of these, 8595 (mean = 34) were interview (as opposed to focus group) participants. However, many studies did not report details of the participants and their numbers sufficiently enough to be included in these calculations: in 30 (9%) studies the overall number of participants was not clearly reported; nearly half of studies that drew on participant responses did not provide sufficient information to determine the number of participants who were policy-makers . Among those studies in which it was possible to make such a determination, 60% (2973) of participants were identified as some kind of policy-maker. Where possible, we attempted to distinguish between studies that included political decision-makers  and non-political policy-makers  among their participants. The majority of studies  exclusively included non-political policy-makers, while one quarter  focused on both groups. Only 5% (n = 16) of studies that included participants exclusively targeted politicians. In 54 (17%) of this review’s included studies, authors did not provide sufficient information to determine the types of policy-makers who were interviewed. We categorized included studies according to several policy- and governance-related characteristics. This analysis is summarized in  Well over half of all included studies were concerned, at least in part, with policy-making at the national level . One-hundred thirty-nine studies examined sub-national (41%) policies or policy-making, with 79 (25%) of these studying provincial or state  decision-making, and 75 (24%) studying local-level  policy-making. Seven studies (2%) were concerned with policy-making at the supranational level. These studies examined the use of evidence in decision-making within the European Union, World Health Organization (WHO), and other international policy fora. A considerable number of studies  investigated the perspectives of policy-makers in general without focusing on a particular policy or level of governance. Of the studies that focused on a specific stage or stages of the policy process, we found that most  examined policy formulation, either alone or in addition to other stages. A roughly similar number of studies focused on agenda-setting  and policy implementation , while few focused on policy evaluation . Overall we found that the focus of most studies could not be summarized under the heading of a policy stage . Many of these studies investigated a policy process holistically, or policy-making in general within a particular field, without distinguishing between various policy activities. Unsurprisingly, given the health focus of this review, a great majority of studies looked at policies or policy-making activities within the sectors of public health , healthcare  or both of these. However, a significant number of these studies investigated health-related policies or policy processes that also had relevance in non-health sectors, including criminal justice and law enforcement , transportation , education , environment , and international development . Many studies did not describe in detail  what they understood by the terms “policy” or “policy process.” Many studies termed their focus “policy(making) and practice,” but provided no definitions for, or otherwise distinguished between, these 2 concepts. This was especially the case with studies that examined local levels of policy-making. All studies included in this review focused in some way on the use of academic research evidence. However, whereas some studies focused specifically on research evidence, others considered research alongside other forms of evidence. That is, some studies investigated research use in the context of broader investigations of knowledge or other kinds of evidence. Conversely, many other studies took a more specific focus, studying either a specific methodological category or other type of research evidence , while others still were specifically concerned with what we called evidence “formats,” that is to say, evidence embedded in or communicated via particular vehicles . The research evidence focus of included studies, as described by their authors, is summarized in  Most studies  had a clear, central focus on research evidence or a category (type or format) thereof, as opposed to those that studied ‘knowledge’ or ‘evidence’ more generally , in which the use of other kinds of knowledge  might be studied alongside the use of research evidence. However, it is worth noting that what the study authors subsumed under the terms “evidence,” “research” and “research evidence” differed greatly between the studies. One fifth of all studies  focused on a particular type of research evidence. Of particular interest was the use of economic evaluation , systematic reviews , health technology assessment , evaluation studies , randomized controlled trials , and modelling studies . A small number of studies looked at the use of evidence packaged in different delivery formats, including reports , guidelines or recommendations , and information from evidence ‘services’  and summaries . Regarding the functional categories of evidence use, instrumental use was investigated  by 183 studies (57%), while symbolic and conceptual uses were investigated to a lesser extent, by 64 studies (20%) and 43 studies (13%), respectively. These categories appeared in a number of different combinations in included studies. While a large plurality of studies investigated instrumental uses only , it was also not uncommon for instrumental and symbolic uses , and conceptual, instrumental and symbolic uses  to be studied in combination. Notably, very few studies investigated either symbolic  or conceptual  evidence use without also looking at instrumental uses. Qualitative research on the role of research evidence in health policy-making is a popular area of inquiry, and one that is rapidly expanding. In this systematic review, we sought to comprehensively assemble the qualitative evidence base that has investigated the use of research evidence in health policy-making. This review uncovered 319 published qualitative studies on evidence use in health policy spanning the period from 1982 to 2019. While a large proportion of these studies is still drawn from high-income regions like Western Europe, North America and Australia, a growing proportion of this topic area’s output is now coming from low- and middle-income countries, especially from sub-Saharan Africa.22 and/or ‘barriers and facilitators’23 is one of the most well-travelled lines of inquiry, it does indicate that the cataloguing of such factors is usually not the sole or central focus of qualitative studies of evidence use. We found that a significant number of studies in this topic area – though by no means a majority – sought to catalogue ‘factors’ related to the use of research in policy, and that these studies conceptualized such factors as barriers to and facilitators of evidence uptake. We classified 23 studies as having this as their core objective and, overall, nearly 100 studies – almost one third of included studies – used the barriers and facilitators constructs in some way. While this finding does not contradict the received wisdom in this topic area that the identification of ‘factors affecting’62 the phenomenon of “imposed” evidence use, in which decision-maker attention to research evidence is compelled through external pressure, top-down regulation, and the like,63 and even the performative “production” of the evidence-based policy paradigm itself,64 among a range of other topics. Indeed, as demonstrated in this review, the subject matter of these studies is quite varied. For example, we found that large numbers of studies drew on qualitative methods to study the role of research relative to other competing influences in cases of real-world policy change, to examine how evidence use is influenced by political and governance contexts, and to explore how researchers, research organizations and other external stakeholders influence processes of evidence use. Studies took on issues as diverse as, for instance, strategic uses of research evidence in service of political and corporatist interests,22 We found that many of the studies identified in this review drew on in-depth case studies – often comparative investigations across multiple countries – to examine how and why evidence was used, or not used, in specific instances of policy development or change. This may indicate a gradual shift in research priorities and approaches over time, including a trend toward more such in-depth policy case studies. Still, consistent with previous reviews,18 we identified very few studies that employed designs  and data collection methods  that involve direct, real-time observation of policy-making activities and decisions, and that do not primarily depend on eliciting retrospective perceptions in the context of a research interview or focus group. The literature on evidence-informed policy-making is sometimes said to lack in-depth, rich case studies on policy decisions and processes, and few attempts to study evidence use as it occurs in real-world practice through the use of observational methods.28 For instance, Liverani et al18 observed that studies in this area “do not constitute a clearly defined body of research, developed around shared debates, research questions or theoretical approaches” and that “despite the fundamentally political nature of decision making processes [and] the extensive literature on political institutions…very few works could be identified which explicitly applied policy science perspectives to understand the use of evidence in health policy making” (p. 6). Our review largely confirms this: we noted that while about half of studies used an identifiable theory or conceptual framework, there was a high degree of theoretical variability with no clear dominant approach. While it remains the case that most qualitative studies in this topic area do not explicitly contribute to the development of political science theories and the refinement of policy science concepts, we nevertheless identified a considerable number of studies that employ these theories and conceptual frameworks to guide their data collection and to make sense of their findings. This finding may indicate that calls for greater engagement with policy theories and political concepts are slowly beginning to be heeded by scholars of evidence-to-policy processes in health. Many authors have lamented the theoretical shortcomings of the literature on evidence use in health policy, most notably the lack of engagement with political science and public administration theories and concepts. A key finding of this review is that this literature focuses overwhelmingly on the use of research in the policy activities of technical – as opposed to political – decision-makers. The reasons for this are likely many, but it probably owes in part to the relatively high degree of availability of civil servants for research participation, as compared to political actors, as well as the fact that most engagement with the technical aspects of policy development – that are perhaps more amenable to instrumental and other direct forms of evidence use – is work done by unelected decision-makers working in government bureaucracies. Still, high-level policy decisions relevant to health systems and public health, including large budget allocations, decisions about system restructuring and healthcare reform, and even smaller scale decisions of a politically contentious nature, are taken with the direct participation of politicians. We also found that relatively few studies provided in-depth explorations of symbolic uses of evidence, that is, the marshalling of evidence, often selectively, to serve political or tactical ends . Moving forward, further research on how research evidence features in the decision-making of political actors, including such strategic uses of evidence, would help to provide a more complete picture of the relationship between research and policy processes. In this review, rigorous systematic review methods were used, including careful piloting of procedures in each review phase, strict double-screening and study selection, and quality assurance measures for data extraction. Multiple sources were searched for relevant studies and a highly sensitive bibliographic database search was developed and conducted across 9 databases. This review can therefore be considered a comprehensive collation of the published and peer-reviewed qualitative literature on evidence use in health policy.47 there may exist distinct and idiosyncratic evidential ‘cultures’ in different policy sectors. While the present review probably captures the majority of qualitative studies in the overall topic area of research evidence use in policy-making  these findings are not necessarily generalizable to the evidence-to-policy topic area as a whole. While inclusive and broad in many respects, this review also has a specific focus on health-related policy-making, which may entail some limitations. As suggested by Lorenc and colleagues’ review of evidence use in non-health sector policy decision-making,19 that may provide unique insights about evidence-to-policy processes that are inaccessible to qualitative research. The present review was not designed to capture these studies. Moreover, because of this project’s specific interest in qualitative evidence the review only considered qualitative  studies. Previous reviews demonstrate that a considerable amount of quantitative evidence exists in this topic area65 the descriptive overview reported in this paper does not entail such a synthesis. We did not consider it worthwhile to subject all included studies to quality appraisal with a methodological checklist merely for the purposes of reporting study quality, especially since such instruments are not designed to generate a summary ‘score’ that serves as a standalone indicator of study quality, but instead are meant to function as a tool to facilitate a critical, engaged reading of a study’s methodological strengths and weaknesses.41 We did not conduct any form of quality appraisal or ‘risk of bias’ assessment as part of this review. While we recognize that qualitatively synthesizing studies without consideration of methodological rigor has the potential to bias synthesis findings, Finally, for the purposes of this review, we chose to treat the individual research report  – rather than the study, as is often the case in Cochrane-style reviews – as the unit of analysis. One consequence of this decision is that, in some cases, different reports from the same research project have contributed individually to the descriptive statistics. Thus, these statistics are influenced disproportionately by larger programs of research with comparatively high publication outputs. Given our interest in painting a general picture of the existing qualitative literature in this topic area  we did not consider this to be highly problematic. This systematic review constitutes the most comprehensive mapping of the extant qualitative literature on the use of research evidence in health policy-making conducted to date. It has provided a “bird’s eye view” of this rapidly growing literature, and has identified key features of – and gaps within – this body of research that will hopefully inform future scholarship in this area. The use of research evidence in health policy processes is a burgeoning area of scholarship, and the qualitative literature on this subject is expanding with increasing speed year-on-year. Indeed, well over half of all of the qualitative studies on evidence-to-policy processes in health were published during the past 5 years alone. While high-income countries – especially Australia, Canada, the United Kingdom and the United States – still lead the qualitative research output in this area, the share of research coming from the Global South is growing. Over 100 qualitative studies on evidence use in African health policy have now been published, and the continent is second only to Europe in overall output. Qualitative researchers have investigated a diversity of sub-topics related to evidence use. This review has shown that, while certainly a major preoccupation of evidence-to-policy researchers in this area, barriers to and facilitators of evidence use are not the single dominant focus, at least among qualitative investigations. Attention may be shifting  to less descriptive topics, with several examples of complexity science-informed approaches, explanatory case studies of policy processes, and critical social science investigations of the evidence-based policy paradigm, among many other topics, emerging from this review. While this literature is extensive, this review has identified some notable gaps that future qualitative literature should address. On the methodological front, there remain relatively few studies that draw on qualitative observational methods to investigate the interactions between research and policy in everyday policy activities. Our knowledge of how, why and under what circumstances policy-makers engage with, use, and/or misuse research would benefit from such immersive work by, for example, participant observers. As well, the vast majority of studies explore the role of civil servants and other unelected decision-makers in evidence-to-policy processes, with far less focus on politicians. Further qualitative study of the how political actors engage with evidence – especially, though not exclusively, how they deploy research-based claims for political, tactical and rhetorical purposes – would greatly enrich this literature. Not applicable. Authors declare that they have no competing interests. BV conceived the study and designed and ran the electronic search strategies. AB supported the testing and refinement of the search strategies. Both authors developed the tools and procedures used, screened and selected studies for inclusion, extracted, managed and analyzed the data, and co-drafted the manuscript. Both authors read and approved the final manuscript. There was no dedicated funding for this review. BV received financial support from the Pierre Elliott Trudeau Foundation. AB is financially supported by the Swiss State Secretariat for Education, Research and Innovation SERI (swissuniversities PgB-4) and the Swiss Tropical and Public Health Institute.Supplementary file 1. Sample Search Strategy (MEDLINE).Click here for additional data file.Supplementary file 2. List of Included Studies.Click here for additional data file.


To systematically assess the current related methodological quality of guidelines for the diagnosis and treatment of Clostridioides difficile infection (CDI), revealing the heterogeneity and reasons for guideline recommendations for the diagnosis and treatment of CDI.We searched electronic databases systematically between 2017 and 2021 to find the latest guidelines for the diagnosis and treatment of CDI. The Appraisal of Guidelines for Research and Evaluation (AGREE II) tool was used for quality assessment of the included guidelines. The main recommendations for the diagnosis and treatment of CDI in the guidelines were extracted and evaluated for consistency, and the level of evidence supporting these recommendations was further extracted and analysed.Fourteen guidelines for the diagnosis and treatment of CDI were finally included in this study. There were four guidelines, BSG and HIS, ASCRS, IDSA AND SHEA, and NICE, with an overall score of more than 60%, which is worthy of clinical recommendation. Further analysis of the consistency of the main recommendations for the diagnosis and treatment of CDI in the guidelines showed that the recommendations differed among guidelines. There are no unified classification criteria for the severity of CDI in current studies; some recommendations for the diagnosis and treatment of CDI do not provide evidence to support the recommendations, most recommendations cite low levels of evidence, and there is a lack of high-quality research evidence.The quality of guidelines for the diagnosis and treatment of CDI is uneven. Recommendations on the diagnosis and treatment of CDI have also varied in the guidelines for the past 5 years. Improvements of the aforementioned factors associated with causing heterogeneity would be a rational approach by guideline developers to further update guidelines for the diagnosis and treatment of CDI. Clostridioides difficile (C. difficile) is a gram-positive, spore-forming anaerobic bacillus that is widely distributed in the gut and environment of humans and animals. Over the last decade, the frequency and severity of Clostridioides difficile infections (CDI) have been increasing worldwide and have become one of the most common hospital-acquired infections. Clinical manifestations are diverse, ranging from asymptomatic carrier status to varying degrees of diarrhoea to the most severe life-threatening colitis  .We searched electronic databases, namely, PubMed, Web of Science, Ovid, ScienceDirect, China Knowledge Network, and Wanfang Data. Given that the evidence is more updated and the results vary greatly when the time span is relatively large, we searched the guidelines for the diagnosis and treatment of CDI in the past 5 years to analyse and compare the evidence of the main recommendations. We searched the relevant guidelines for the diagnosis and treatment of CDI published between 2017 and 2021, and to obtain as many guidelines as possible, we also searched the public search tools Google and Baidu. The search strategy included “Clostridium difficile infection”, “diagnosis”, and “therapy”, in combination with the search terms “guideline”, “practice guideline”, “statement”, “recommendations”, and “consensus”. No language restrictions. The references of the included guidelines were also manually searched.Inclusion criteria: (1) The target group included patients with CDI; (2) The guidelines focused on the diagnosis and treatment of CDI; (3) The full text was available online or in print; (4) The guidelines included both English and Chinese versions; (5) If the guidelines had an updated version, we used the latest version. Exclusion criteria: (1) repeated guidelines; (2) evaluation of the guidelines; (3) brief summary of the guidelines; (4) obsolete guideline version; and (5) narrative review. >Two independent reviewers conducted a systematic search of relevant guidelines for the diagnosis and treatment of CDI, screened and identified guidelines that met the inclusion criteria according to the above criteria, and invited a third reviewer to discuss the decision if there was controversy.The quality of the guidelines was assessed using the most recent version of the AGREE II instrument, and the AGREE II instrument is a validated assessment tool designed to provide a framework for the assessment and monitoring of clinical guidelines, which measure and quantify the quality of guidelines . The AGRRelevant guidelines were scored using the agreement measurement scale (MSRA) . RecommeThe normalized scores for each domain were calculated using the method of descriptive statistical analysis and expressed as a percentage; the median and range for each domain are presented. We used two-way ANOVAs to calculate intraclass correlation coefficients (ICCs) to test whether the scores of the four assessors were consistent. ICCs between 0.01 and 0.20 indicate a small agreement; 0.21–0.40, fair; 0.41–0.60, moderate; 0.61–0.80, substantial; and 0.81–1.00, very good. P < 0.05 was considered statistically significant. IBM SPSS version 19.0  was used for statistical analysis.A total of 371 articles were initially retrieved, and after screening by title, abstract and full text, fourteen guidelines on the diagnosis and treatment of CDI were included Figure 1The results of the assessment of the quality of all included guidelines using the AGREE II tool are shown in To further analyse the reasons for the heterogeneity of recommendations for the diagnosis and treatment of CDI among different guidelines, we referred to the key recommendation items for the diagnosis and treatment of CDI in the high-quality guidelines  and refeThe main recommendations and supporting evidence for the diagnosis and treatment of CDI are detailed in In the present study, we assess guidelines related to the diagnosis and treatment of CDI using the AGREE II tool. We discover that the quality of guidelines for the diagnosis and treatment of CDI varies greatly. Most recommendations are highly similar between guidelines, and there are large difference between guidelines in whether colonoscopy is used to diagnose CDI and whether metronidazole is used to treat it. The main reasons for the large difference include the following: there is no uniform definition for CDI, the recommendations for the diagnosis and treatment of CDI involve large differences in items, some indicators (MTR) recommendations are inconsistent, some recommendations do not provide evidence to support the recommendations, some recommendations lack high-quality evidence support, and some guidelines cite long years of evidence. In addition, the quality of guidelines varies significantly from guideline to guideline, or even from domain to domain for the same guideline.In the AGREE II scoring system, the three domains of rigor, participant, and applicability are scored lower.There are very low scores on the rigor domain in the included guidelines. The reasons for this finding include the fact that some guidelines do not involve a search for evidence using a systematic search method ; most guIn the present study, the median total score of the participants domain among the included guidelines is moderate. The reason for this low score may be that the majority of associations that develop guidelines ignore the opinions of patients and the public , and somThe median score of the included guidelines in application is very low. The reasons included the following: some guidelines do not describe facilitating and hindering factors in the application process , some gu(1) The target population of guidelines are different, including paediatric population , critica(2) TC and CCNA diagnosis methods lack sufficient attention. Many guidelines do not have recommendations for TC  and CCNA(3) Some recommendations are contrary: The flexible sigmoidoscopy diagnosis, metronidazole treatment, and bezlotoxumab prevention recommendations are in disagreement between different guidelines; partial guidelines for the recommended use of flexible sigmoidoscopy for the diagnosis of CDI . A prospin vitro activity against C. difficile isolates, but clinical data on its use in the treatment of CDI are severely lacking. Some guidelines mention the use of tigecycline for the treatment of CDI  There is no uniform classification standard for the severity of CDI: For the definition of severe CDI, most guidelines consider it severe if either a leukocyte count of > 15 × 10l is met ; guidelil is met , and forl is met . The guil is met ; a basell is met , and serl is met . Regardi disease . Accordi disease , and unf disease . Differe disease  suggest  disease . For low disease . The gui disease .Our study results provide the following references for the development of relevant guidelines for the diagnosis and treatment of CDI in the future: the update process of the guidelines should be clarified; the opinions of stakeholders, including users and patients, should be considered in the development of the guidelines; the conflicts of interest of guideline developers should be considered, and it should be clearly pointed out whether such conflicts of interest will affect the results of the guidelines; the relevant guidelines should be collected by a systematic method, with strict inclusion and exclusion criteria; the guidelines can be developed by multinational negotiation considering the geographical differences of population; the relevant experts should conduct an external review before publication of the guidelines; the latest evidence should be used to support the recommendations; and it is recommended that international academic groups develop a globally unified classification standard for CDI.There are certain strengths and limitations of our study. The advantages of this study are as follows: (1) we not only collected the English version of the guidelines but also included such guidelines in other languages; (2) we sorted out the important diagnosis and treatment opinions of CDI, compared the evidence sources of each guideline, and analysed the heterogeneity and causes of the main recommendations. The limitations of this study are as follows: (1) to analyse the evidence, considering the update of the evidence, this study only included guidelines from the past 5 years and did not clarify older guidelines; (2) the AGREE II instrument can only focus on the method of developing guidelines, rather than assessing the effect of the recommendations on patients’ clinical outcomes.This study found that the quality of guidelines related to the diagnosis and treatment of CDI varies greatly, mainly because there are no unified classification criteria for the severity of CDI, some guidelines do not provide a source of evidence for their recommendations, and strict inclusion and exclusion criteria are lacking. It is recommended that higher-level studies be conducted to obtain higher-quality evidence and to improve the use of guidelines related to the diagnosis and treatment of CDI by addressing the above issues.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.All the authors contributed in the preparation of this work. TG, WL, and D-LS were drafted and revised the article; TG, WL, H-YH, and D-LS were responsible for the theme, final editing, and preparation of the manuscript for submission; H-YH and D-LS critically revised the manuscript. All authors read and approved the final manuscript.This study was supported by Yunnan young academic and technical leaders reserve talent project (No. 202105AC160049 to D-LS) and Yunnan Province Joint Special Project of Science & Technology Department of Yunnan Province and Kunming Medical University (No. 2019FE001-233 to H-HY).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Infodemic is defined as an information epidemic that can lead to engaging in dangerous behavior. Although the most striking manifestations of the latter occurred on social media, some studies show that dismisinformation is significantly influenced by numerous additional factors, both web-based and offline. These include social context, age, education, personal knowledge and beliefs, mood, psychological defense mechanisms, media resonance, and how news and information are presented to the public. Moreover, various incorrect scientific practices related to disclosure, publication, and training can also fuel such a phenomenon. Therefore, in this opinion article, we seek to provide a comprehensive overview of the issues that need to be addressed to bridge the gap between science and the public and build resilience to the infodemic. In particular, we stress that the infodemic cannot be curbed by simply disproving every single false or misleading information since the belief system and the cultural or educational background are chief factors regarding the success of fake news. For this reason, we believe that the process of forming a critical sense should begin with children in schools . Furthermore, we also believe that themes such as scientific method and evidence should be at the heart of the university education of a future scientist. Indeed, both the public and scientists must be educated on the concepts of evidence and validity of sources, as well as learning how to dialogue appropriately with each other. Finally, we believe that the scientific publishing process could be greatly improved by paying reviewers for their work and by ceasing to pursue academic success at all costs. Infodemiology was defined by Gunther Eysenbach “the science of distribution and determinants of information in an electronic medium, specifically the Internet, or in a population, with the ultimate aim to inform public health and public policy” ,2. The tAlthough infodemics cannot exist without dismisinformation, it is necessary to consider that even correct information  contributes to its spread. Indeed, the juxtaposition of conflicting information only aggravates the negative influence on the lay public . Such a Conspiracy thinking originates from questionings of various kinds, including epistemic, existential, and social . There iBeyond the glaring errors of the press and conspiratorial characters, including scientists, we must ask ourselves the following: has the communication from the scientific community been adequate? On January 14, 2020, the WHO wrote on the official Twitter account “Preliminary investigations conducted by the Chinese authorities have found no clear evidence of human-to-human transmission of the novel #coronavirus (2019-nCoV) […]” . This stOn several occasions during COVID-19, I have had discussions with some scientists who were well-known faces of the web and Italian television. The latter’s nature concerned an aspect that I consider of absolute communicative importance: the scientific validity of public statements. For example, many argued COVID-19–related opinions on their Facebook public profiles based on a single preprint without specifying that those results were not peer reviewed nor confirmed by other literature. One of them even replied that this clarification was unnecessary since he was a peer reviewer, as if a single reviewer could replace the entire peer-review process that includes two or more reviewers—depending on the topic’s relevance—and an editor’s final judgment. What surprises me is the arrogance of people who think they can be above the scientific method and community because they have an academic title or role. All this while we have had direct proof that even Nobel laureates can assert dangerous unscientific nonsense. What lesson is being taught to the public by acting this way? Such an excessive usage of the principle of authority distances us from facts and credible communication and urges the public to give importance to the individual rather than the available evidence.ARReturning to the previous section, we ask ourselves, “what is the reason that prompts scientists to share comments on preprints or other forms of nonpeer-reviewed literature?” During the COVID-19 pandemic, rapid and timely interventions were significant public health challenges . Since CAlongside this, the scientific community has to deal with internal situations. The first we want to discuss is predatory publication. Predatory journals offer rapid publication times at meager costs, making them very attractive to independent researchers who do not have funds available. However, these apparent benefits arise from poor or bogus peer-review processes . Hence, The concepts of degree (or level) of evidence have long been addressed in the literature and differ by health discipline . VariousClass F: regardless of their authority, personal opinions must be ranked with the lowest degree of evidence. This is necessary to ensure consistency in class attribution. In particular, the authority principle must be minimized to prevent unjustified claims  from sowing doubt, fear, and false information. Therefore, all conclusions that have not been moderated or peer reviewed fall into this category.Class E: preprint moderation avoids the circulation of very serious fake news in the scientific world, but it is not comparable to a peer-review process. Indeed, a large number of preprints fueling conspiracy theories and unjustified assumptions have been unearthed . TherefoClass D: this category encompasses academic journals not yet indexed in recognized databases  and not listed among predatory journals . The degree of evidence is sufficient to expose assessments to the public, provided that it is specified that these are premature analyzes. Furthermore, inclusion in this class implies that an extensive literature search has been implemented, ascertaining the absence of known opposite results. If the number of articles reporting contrary findings is comparable, then the scientist is required to express a personal judgment ; in this case, the quality of the evidence is class E. If the number of articles supporting contrary results is significantly greater, then the scientist is required to make a personal judgment and present the quality of the evidence as class F.Class C: the criteria of point D apply, but the probability of disseminating infodemic material further decreases thanks to bibliographic indexing.Class B: the criteria of point C apply, but there must be at least 3 agreeing articles. Evidence proposed by recognized health agencies  can fall into this category.Class A: the criteria in point B apply, but the articles must be systematic meta-analyses or reviews. Evidence proposed by recognized health agencies  can fall into this category.We stress that this scale is indicative and needs to be further elaborated by the scientific community, including all the particular cases that have escaped us, for improving the basic setting. However, we believe it can serve as a general guideline, showing a possible way forward to limit the infodemic drastically. Indeed, the simple fact of specifying the sources and the type of evidence proposed can give the public an idea of the news’ relevance and weight .A colored version of


Background: Hereditary angioedema (HAE) is a rare genetic disease that can lead to potentially life-threatening airway attacks. Although novel therapies for HAE treatment have become available over the past decades, a comparison of all available treatments has not yet been conducted. As such, we will perform a systematic review and network meta-analysis to identify the best evidence-based treatments for the management of acute attacks and prophylaxis of HAE. Methods: This study will include both parallel and crossover randomized controlled trials that have investigated prevention or treatment strategies for HAE attacks. We will search electronic databases, including Medline, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, from inception with no language restrictions. Potential trials will be supplemented through a gray literature search. The process of study screening, selection, data extraction, risk-of-bias assessment, certainty assessment and classification of treatments will be performed independently by a pair of reviewers. Any discrepancy will be addressed through team discussion. A two-step approach of pairwise and network meta-analysis will be performed. The summarized effect estimates of direct and indirect treatment comparisons will be pooled using DerSimonion–Laird random-effects models. The incoherence assumption, in terms of the consistency of direct and indirect effects, will be assessed. An evidence-based synthesis will be performed, based on the magnitudes of effect size, evidence certainty, and ranking of treatment effects, with respect to treatment benefits and harms. Discussion: This systematic review and network meta-analysis will summarize evidence-based conclusions with respect to the ratio of benefits and harms arising from interventions for the treatment of acute attacks and prophylaxis of HAE. Evidence from this network estimate could promote the rational use of interventions among people living with HAE in clinical practice settings. PROSPERO registration number: CRD42021251367. Hereditary angioedema (HAE) is a rare genetic disease that can lead to potentially life-threatening airway attacks . Based oThe combined prevalence rate of HAE types I and II has been estimated to be 1.07 to 1.56 per 100,000, with HAE type I being the most prevalent form . HoweverAlthough effective treatment options have become available for HAE over the past decades, a comparison of interventions in a single framework for patients with HAE has not been conducted. To rank the best evidence-based interventions and inform decision-making for patients, clinicians, and policymakers, we aim to conduct a systematic review and network meta-analysis of published randomized controlled trials (RCTs) to identify the most effective options for HAE management. Moreover, a contextualized clinical and methodological approach will be employed to draw evidence-based conclusions regarding the ratio of the benefits and harms of treatment interventions for people living with HAE.http://crd.york.ac.uk/prospero: accessed on 4 May 2022), registration number, CRD42020196592). The present systematic review and network meta-analysis protocol followed the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement , number of attacks of angioedema before the screening, locations affected by attacks , severity of attacks experienced by the patient , history of laryngeal attacks, history of allergy, history of first-degree relative with HAE, history of psychiatric disorders or other systemic diseases, baseline complement-related variables , laboratory results, and concomitant medications).Specific treatment intervention and comparison group, including individual treatment comparisons, a specific dosage of treatment, indications for use (prophylaxis or treatment), route of administration, concomitant and rescue treatment medications.Predefined outcomes, including specific details of the measurement tools used to assess the outcomes of interest.Two reviewers (S.P. and P.W.) will independently extract the pre-specified information using a standardized approach and predesigned electronic extraction form implemented in Microsoft Excel to gather data as follows:https://automeris.io/WebPlotDigitizer, accessed on 4 May 2022) to extract specific numerical values. Where the mean and standard deviation (SD) of the continuous outcome of interest is not provided, we will calculate the sample mean and its SD based on the sample size, median, range, and/or interquartile range as described elsewhere , where ρ indicates for the correlation coefficient. If ρ is not available, we will use a value of 0.7 for the correlation coefficient between the baseline and end of treatment follow-up, with equal variances among the intervention and comparison groups. For any binary outcome parameters, a correction by 0.5 cells will be applied for trials that reported zero events  versus non-elderly adults [18-65 years] versus older adults [≥65 years]); (ii) sex ; (iii) study size (<50 vs. ≥50 participants); (iv) study design ; (v) HAE type ; and (vi) geographical region of study recruitment . Network meta-regression analyses will be performed by supplementing other covariates, as mentioned in the adjusted network meta-analysis model. Moreover, a set of sensitivity analyses will also be applied for all outcomes in the further analysis to address the robustness of our findings including (i) adding trials that only provide an abstract or unpublished or preprint results; (ii) restricting the analysis to only trials with parallel group design; (iii) excluding trials with high overall risk-of-bias assessment; and (iv) assuming a ρ value of 0.5 in cases with missing correlation coefficients for continuous outcomes.The effect estimates of traditional pairwise meta-analysis and network meta-analysis will be expressed as standardized mean differences (SMDs) and odds ratios (ORs) along with the 95% confidence intervals (95% CIs). If there is limited relevant information of the included trials, we will conduct a systematic review and narrative synthesis with respect to the key participant characteristics and treatment comparisons.p-value < 0.05. All analyses will be performed using STATA software .Statistical significance for all tests will be two-tailed, with Two reviewers (MC and SN) will independently grade the certainty of evidence and rate the evidence for each outcome by applying the modified confidence in network meta-analysis (CINeMA) approach  and GradNext, based on clinical and methodological points of view, we will employ a contextualized approach to establish the treatment network effect estimates with respect to the dimension of efficacy (treatment responses/efficacy for the prevention of attacks) and safety profiles . To draw evidence-based conclusions and classify treatment interventions, key components including evidence certainty, SURCA values, and effect size magnitudes will be incorporated into a single framework assessment. Specifically, the magnitudes of effect size will be estimated to be very small (SMDs < 0.2 or ORs < 1.68), small (SMDs = 0.2–0.4 or ORs = 1.68–3.46), medium (SMDs = 0.5–0.7 or ORs = 3.47–6.71), and large (SMD ≥ 0.8 or ORs > 6.71) ,24. TakeBased on the nature of the systematic review and network meta-analysis study using existing published information, ethical approval is not required. This study involved no individual patient information; thus, informed consent is not required. Our findings will be reported in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 statement guidelines  along wiBefore 2009, there were no US Food and Drug Administration-approved treatment options for acute attacks of angioedema. Treatments available were generally limited to supportive care and efforts to protect the airway ,6,7,8. AGiven diverse study populations, our findings may be underrepresented in some racial or ethnicity parameters, which could limit the generalizability of the study findings. Generally, evidence from clinical trials in several settings almost solely represents the White population. To the best of our knowledge, minority patients living with HAE are underrepresented in clinical trials, and, in particular, those who are at risk for additional disease burden. Evidence suggests that Hispanic patients are underdiagnosed with HAE. Furthermore, disparities in treatment practice and therapeutic interventions have been observed among White and Black HAE patients .This study will summarize all available evidence on both acute attacks and prophylactic treatments for HAE. Our study will be performed based on a comprehensive and rigorous approach with no language restrictions. We will ensure that our findings have a positive effect on the health outcomes of people living with HAE, including their families and caregivers. Moreover, findings from the evidence-based synthesis will also facilitate identifying the best treatment options for HAE care management for healthcare providers, policymakers, researchers, and public society. The study findings will have the potential to influence and inform international guidelines on acute attacks and prophylactic treatment for people living with HAE.This systematic review and network meta-analysis will systematically summarize and compare all available evidence on the safety and efficacy of treatment and prevention options for HAE. Contemporary evidence from this network estimate could promote the rational use of interventions in clinical practice. Our findings will be disseminated in international scientific conferences and a formal peer-reviewed publication.


A review on the mental health needs of adults with intellectual disability (ID) and autism spectrum disorder (ASD) published just over 10 years ago found a limited evidence base for pharmacological intervention in this group. The aim of this paper was therefore to review the evidence in the subsequent 10 years, with a focus on polypharmacy use in adults who have both ID and ASD. A critical literature review of key papers published from 2009 to 2021 was undertaken on adults with both ID and ASD and related to psychopharmacology, polypharmacy, antipsychotics, antidepressants, mood stabilisers and anxiolytics interventions in improving symptoms. After excluding articles for lack of relevance, a review with a focus on the use of polypharmacy was carried out on the retrieved results. Four papers were identified as relevant to adults with both ID and ASD. Three main themes were identified in the review, including the application of pharmacogenetics, the influence of national policy on prescribing practices and safety concerns in a population with multiple health comorbidities. The past decade has produced a small increase in the evidence base on psychopharmacology use in adults with ID and ASD. However, more evidence on the effectiveness and impact of long-term polypharmacy use is required. This is a review focusing on the group of adults with intellectual disability (ID) and autism spectrum disorder. It is an update to a review just over 10 years ago that found a limited evidence base for pharmacological interventions in this group . For aduThe co-occurrence of ID in autism spectrum disorder (ASD) was previously estimated to be between 50% and 70%, although more recent reports suggest the figure to be around 20%, with higher prevalence of ASD in people with more severe ID ,9. A diaA review on the mental health needs of adults with both ID and ASD published over ten years ago found that those who were more vulnerable to psychiatric disorders also had more impaired social skills. Interventions to improve adaptive skills needed further study. A clinic study  found thGood quality evidence for the use of psychotropic medication in adults with ASD is limited. Recommendations are largely based on studies from children , with thwww.england.nhs.uk/stomp) [Accessed on 25 October 2022] was established. STOMP was planned as a three-year programme by the National Health Service in England. A review [Despite this lack of evidence, psychotropic medication prescription rates of 30 to 90% for those with ID and challenging behaviour have been reported . It is iA review  describiIn addition, there is a lack of research to inform clinical practice comparing different medication combinations, specifically the ongoing use of polypharmacy in adults with both ID and ASD who present with problem behaviours. Polypharmacy is recognised in day-to-day practice to occur for adults with ASD as well as those with ID presenting to psychiatric services. A study from Spain of 66 adults with ASD by  found thThe focus of this paper is therefore on adults with ID who also have ASD. This paper neither focuses on autistic adults who do not have significant impairment of intellectual functioning nor on adults with ID who are not autistic. The key aim of this paper is to present the evidence from the past decade on the use of polypharmacy in those who have both ID and ASD. From the limited available evidence, this seems to be the group of patients who are most at risk of being prescribed more than one psychotropic medication. The aim was also to understand the clinical rationale for this practice and whether this practice is monitored, as there is no evidence to support this practice in adults with both ID and ASD. Although only ten years have passed since the last review, this group remains poorly understood. Many patients exhibit behaviours that pose a risk to themselves or others that present significant cost and resource challenges for services and commissioners. Another review from the United States undertaken over a decade ago concluded that the effectiveness of psychotropic medications in managing challenging behaviours in people with ID was minimal and called for controlled studies of higher scientific quality in this area . CurrentThe aim of the review was to examine outcomes of pharmacological interventions in adults with both ASD and ID as relevant to clinical practice with a focus on polypharmacy. The following databases were searched to identify key papers published from 2009 to 2021: Medline, Embase, PsycINFO and Cochrane Library. The search was conducted by the British Medical Association Library in February 2022. The PICO  framework was used to inform the search. PICO is a recognised framework updated in 2022 and used in evidence-based practice to formulate a review question on the effectiveness of an intervention [Adults over the age of 18 years old;Research conducted between 2009 and 2021.The inclusion criteria for the review were:Single case studies;Articles not written in English.The exclusion criteria were:The search was conducted in the British Medical Association (BMA) library. It produced 1060 results. After removing duplicates and following a manual sifting for relevance to the review, 160 papers were identified. The abstracts of all 160 papers were screened by the authors. Of these, 14 papers mentioned polypharmacy in adults with ID and/or ASD in the abstract. Ten of these fourteen papers did not include adults with both ID and ASD; leaving four papers that were eligible to be included in the review. Please see The four papers reviewed see  focused Pharmacogenetics ;Trends in Prescribing ;Multimorbidity and Patient Safety ,25;The research methods employed within the included studies used a mixture of review, observational, clinical examination and existing databases. Though these may not be the most robust methods, they reflect the emergence of this area of research and identify potential issues that relate to interventions and research methods for future studies, which are discussed below.Pharmacogenetics is the study of the influence of genetic factors on the efficacy and tolerability of medication. Though the evidence around the use of antipsychotics has grown in recent years, the application to practice has been limited. A systematic review  examinedA study  was builA multicentre study  from SpaThis review highlights the very limited evidence available for the outcome of polypharmacy practice in adults with both ID and ASD.There were only four papers identified by the current review as relevant to adults with both ID and ASD. Three main themes were identified, including developments in pharmacogenetics, the influence of national policy on prescribing practices and safety concerns in a population with multiple health comorbidities. The studies ranged from examining the potential improvement of treatment outcomes using pharmacogenomics to the analysis of clinical practice data across a number of European countries, including France, Spain and the UK. It appears that although there has been a positive trend toward the prescription of psychotropic medication—for example, as influenced by the national policy in England—further analysis is still required to study the presence of clinical outcome indicators to warrant the use of such medication. A recent study indicates that in many locations across England, antidepressants have become the most widely prescribed psychotropic for adults with ID. However, the clinical indication for this change in practice is unclear . Many inOther papers relevant to the wider debate on the use of psychotropic medication in adults with ASD and ID, that may help to inform future research studies, were also reviewed. These included Sheehan and colleagues , who invA review of the use of psychotropic medication in those with low functioning autism  reportedA systematic review  of the eIn one study, 225 UK psychiatrists working in the field of ID were surveyed using an online questionnaire . Eighty-Indications for the use of polypharmacy is limited by this lack of evidence on the efficacy of the wider group of psychotropic medication in adults with both ID and ASD. The clinician is therefore left with the challenge of identifying which psychotropic medication may work for an individual patient and seeking combinations of medications when there is a limited response to one psychotropic. In addition, as the evidence above shows, patients face challenges withdrawing from any psychotropic medication after initially beginning such medications, and thus require a multi-disciplinary and multi-agency approach. The review identified a need for prospective studies that focus on efficacy and safety given the current concerns. There are two issues, firstly, to ensure prescription practices are safe and appropriately monitored and secondly, to determine if there is evidence for the use of polypharmacy in specific cases. Predictors of psychotropic use include having autism, age and lower functioning. However, predictors can also be behavioural and can include agitation, aggression and self-injury. The development of guidelines, national policy and research are key to improving practice in this area as highlighted in a recent study by . While tThe recently published Lancet Commission on the future care and clinical research in autism proposes a modified step-care approach with a personalised mode of intervention and assessment for individuals with autism and their families . The comGiven the relatively small size of the papers identified for this review, the conclusions will be limited to the effectiveness of polypharmacy in adults with both ASD and ID. The review accessed databases to identify papers. A search engine such as Google Scholar may have identified other papers. The criteria for inclusion were set to be very focused on only adults with both ID and ASD as an attempt to delineate the population under study and to be relevant to the psychiatrists who see this population in their day-to-day clinical practice. However, this brief review has highlighted emerging themes around patient safety and the need for a more personalised approach to treatment. The overall lack of evidence is probably a reflection of developing good quality research within this population. Tyrer et al.  found seTo enhance both future research and practice, there is a need for specific clinical guidelines on the use of polypharmacy to ensure a consistent approach and to develop an awareness of the needs of this group. The benefits of polypharmacy, including the impact of long-term polypharmacy and specific combinations of psychotropic medications, require further evaluation. Over time, it is possible that specialist clinics can develop good practice guidance around complex regimes of polypharmacy to increase the evidence base. It is also possible to implement a shared database that collates current practice in the use of polypharmacy for adults with ID and ASD across Europe.


A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments.The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided.We found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts’ opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives.Monoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term.The online version contains supplementary material available at 10.1186/s10194-022-01431-x. The landscape of migraine prevention has experienced relevant changes since the introduction of the monoclonal antibodies (mAbs) targeting the calcitonin gene-related (CGRP) peptide or the CGRP receptor (together referred to as CGRP-mAbs). These substances form a new class of drugs specifically developed for migraine prevention. In 2019 the European Headache Federation (EHF) issued the first guideline for the use of CGRP-mAbs for migraine prevention in adults . The. The4]. For Expert consensus statements the same wording frame of evidence-based recommendations was followed where possible. No formal rating of the quality of evidence was performed in this case.The guideline document underwent several rounds of revisions among the Panel members until an agreement on all the content was reached. The final version of the document was approved by all contributing authors.This guideline is structured into two parts; the first part reports the evidence-based recommendations, and the second part reports the Expert Consensus Statements.For the evidence-based recommendations, three PICO questions were selected. We considered phase II and phase III RCTs comparing any CGRP-mAb with placebo. Only doses finally available on the market were considered to provide evidence-based recommendations, with the only exception of fremanezumab 225 mg monthly for chronic migraine, which in RCTs had a 675 mg loading dose not used in clinical practice.We selected 23 studies eligible for those PICO questions –29. StudThe summary evidence-based recommendations are reported in Table Population: individuals with episodic migraineIntervention: eptinezumab, erenumab, fremanezumab, galcanezumabComparison: placeboOutcome: reduction in migraine days, responder rate , reduction in the use of acute attack medication, safety Fifteen studies were considered for this question , 28, 29.The quality of evidence for the available compounds and for the different outcomes ranged from moderate to high Table . The eviPopulation: individuals with chronic migraineIntervention: eptinezumab, erenumab, fremanezumab, galcanezumabComparison: placeboOutcome: reduction in migraine days, responder rate , reduction in the use of acute attack medication, safety Ten studies were considered for this question , 27, 29.The quality of evidence for the available compounds and for the different outcomes ranged from moderate to high Table . The eviPopulation: individuals with migraineIntervention: eptinezumab, erenumab, fremanezumab, galcanezumabComparison: antiepileptics , antidepressants (amitriptyline), beta-blockers , calcium-channel blockers (flunarizine), onabotulinumtoxinA, renin-angiotensin system inhibitors Outcome: reduction in migraine days, responder ratio , reduction in the use of acute attack medication, discontinuation, due to adverse events, safety p < 0.001). More individuals with migraine achieved a > 50% reduction in monthly migraine days with erenumab than with topiramate . In the erenumab group, 10.6% discontinued medication due to adverse events compared to 38.9% in the topiramate group . No relevant safety concerns were observed for erenumab. The evidence-based recommendation for question 3 is reported in Table We found only one RCT which compared a CGRP-mAb versus another migraine preventive agent  Table 77. In thiThe summary of statements is reported in Table The previous EHF guideline recommended CGRP-mAbs as a third line treatment for migraine prevention in individuals with migraine and inadequate response, lack of tolerability or lack of compliance to at least two categories of migraine preventatives . Of noteAfter the publication of the previous guideline, CGRP-mAbs became available in Europe and real-world observational studies confirmed the effectiveness of those drugs outside RCTs –34. ToleCGRP-mAbs have an efficacy which is at least comparable to the efficacy of the formerly used preventive drugs. Among the oral prophylactics, high dropout rates were reported especially for amitriptyline, valproate or topiramate . The majWe have scarce information on how to manage other oral preventive treatments in association with CGRP-mAbs in individuals with migraine. Individuals with migraine who are considered for starting a CGRP-mAb may already be taking other preventive drugs. In this case there is the option to stop the ongoing preventative when starting a CGRP-mAb or to continue the oral preventatives and decide later whether to stop. Benefits and risks of the two options should be considered and discussed with individuals with migraine. Polytherapy can also be considered at a later stage in individuals with migraine who still have a relevant residual migraine burden despite having a clinically meaningful relief with a CGRP-mAb. So far, there is no robust evidence either to support or discard the combination of different migraine preventatives. Withdrawal of other preventive drugs can be done early or later in individuals with migraine showing a favorable clinical response after starting the CGRP-mAb. While as general concept monotherapy is preferrable, some individuals with migraine do not have adequate pain relief with a single drug. In those cases, a combination of different drugs might be considered referring to the previous pharmacological history and comorbidities. Combined treatment might be particularly suitable for patients achieving a substantial relative response (e.g. 50% reduction in monthly migraine days) with CGRP-mAbs with a relevant number of residual migraine or headache days . Due to As a rule, treatment can be stopped if it is considered not effective. Available date from RCTs and from observational studies indicated that CGRP-mAbs have a quick onset of action , 40–48 aThe CGRP-mAbs are challenging the conventional temporal paradigm of migraine prevention. With the conventional oral preventative drugs, individuals with migraine were typically treated for 6 to 12 months in order to minimize side effects and to re-evaluate the underlying disease burden given the intrinsic cyclic course of migraine. Treatments were then repeated over time for a variable duration according to clinical needs. Monthly or quarterly administration of CGRP mAbs is more accepted by individuals with migraine than the daily oral regimen. Moreover, the excellent tolerability profile makes the CGRP-mAbs more suitable for prolonged treatments. So far, there are no studies which provide a clear guidance on the optimal duration of migraine preventive treatments. It is highly probable that a broadly generalizable approach does not exist and that also treatment duration needs to be adapted on a case-by-case strategy or considering homogeneous groups of individuals with migraine. One question is still open as to whether a longer duration of treatment may have a disease-modifying effect in individuals with a long history of chronic migraine and be able to provide a stable reduction of migraine or headache days, even after stopping the treatment.All the available RCTs on chronic migraine included individuals with migraine and medication overuse , 22, 23.In addition to evidence from RCTs, there is also evidence from real-world studies suggesting that CGRP-mAbs are highly effective even in the absence of prior detoxification in individuals with medication overuse , 56 and In individuals with migraine and medication overuse there is need of well-designed clinical trials to evaluate the effect of treatment CGRP-mAbs before and after withdrawal of acute medication. Additionally, it should be clarified whether individuals with migraine and medication overuse who do not respond to CGRP-mAbs may benefit from detoxification strategies before initiation of CGRP-mAbs and whether detoxification may change the responder status.All the CGRP-mAbs have an excellent tolerability profile. Nevertheless, tolerability issues may appear and make stopping of one CGRP-mAb necessary. If the reported side effect is specific for a given CGRP-mAb (e.g. constipation related to erenumab) , switchiConsidering the above reported reasons, the panel expressed a consensus statement to recognize the lack of adequate scientific evidence but at the same time we acknowledge that, for some individuals with migraine, a switch may represent the best therapeutic option. RCTs to test a CGRP-mAb switch in individuals with inadequate response to the first CGRP-mAb are needed to provide information on this issue.CGRP-mAbs are unlikely to produce drug interactions which may be particularly relevant in individuals with migraine with comorbidities. Pregnant and nursing women were excluded from RCTs and there is no robust information on the risk for the fetus or the newborn driven by CGRP-mAbs. The limited real-life data available so far have not shown major concerns with the accidental and short-lived exposure to erenumab, galcanezumab, and fremanezumab in pregnancy and lactation . HoweverConcerns regarding vascular safety of these drugs were raised considering that CGRP is among the most potent vasodilators in animals and humans and that CGRP-mediated vasodilation is a rescue mechanism in brain as well as cardiac ischemia –70. AddiConstipation could be related to CGRP-mAb use due to potential inhibition of gastrointestinal motility, which is regulated by CGRP , 80. ConThe available data confirm that monoclonal antibodies targeting the CGRP pathway appear to be effective and safe for migraine prevention even in the long term. Objective biomarkers of treatment response are still lacking; nevertheless, the available RCTs and real-world data can provide insights on treatment individualization, including treatment duration, combination with other treatments, and the management of safety issues.Additional file 1. Conflicts of interest disclosures.