Health technology assessment (HTA) coverage recommendations differ across countries for the same drugs. Unlike previous studies, this study adopts a mixed methods research design to investigate, in a systematic manner, these differences.N = 35) were compared using a validated methodological framework that breaks down these complex decision processes into stages facilitating their understanding, analysis and comparison, namely: (1) the clinical/cost-effectiveness evidence, (2) its interpretation (e.g. part of the deliberative process) and (3) influence on the final decision. This allowed qualitative and quantitative identification of the criteria driving recommendations and highlighted cross-country differences.HTA recommendations for ten orphan drugs appraised in England (NICE), Scotland (SMC), Sweden (TLV) and France (HAS)  and other decision modulators  also rendered uncertainty and cost-effectiveness estimates more acceptable. The different HTA approaches  and ways identified of dealing with orphan drug particularities also had implications on the final decisions.This research contributes to better understanding the drivers of these complex decisions and why countries make different decisions. It also contributed to identifying those factors beyond the standard clinical and cost-effectiveness tools used in HTA, and their role in shaping these decisions. Providing equal access to affordable medicines across countries is high on the political agenda in many OECD countries including those in the European Union . In realThis problem, together with its implications, has been identified and possible explanations examined. Eight studies compared HTA drug coverage recommendations across countries and highlighted the extent of these differences , 17–22. Through the application of a validated mixed methods framework , the objFour of the most well-established European HTA bodies were included in the study based on purposive sampling , which uAll drug-indication pairs with an orphan designation from the European Medicines Agency (EMA)  and apprMixed methods were used to systematically examine the HTA decision processes for individual drugs and countries on the basis of a validated methodological framework. The approach used was an exploratory sequential mixed methods design, where the qualitative strand took priority and preceded the quantitative strand. The framework consisted in a coding manual and case study template . This alThis multi-level research design allowed for an in-depth analysis of the criteria driving these decision-making processes and of their role in shaping these decision processes in each country, and whether they explained cross-national differences. This research did not aim to generalise findings, but was interested in exploring and elucidating the reasons behind the HTA decisions, which are mainly qualitative in nature . The quaData sources comprised publicly available HTA reports, other official documents (e.g. memos in Sweden) and comments from competent authorities. Although the aims of the HTA reports differ (e.g. advice versus decision), they were assumed to be transparent and reflect the key determinants driving the recommendations . The maiQualitative analysis was conducted in the first stage of the research. On the basis of the framework, all the relevant information at each step of the decision process was identified. This information was compiled into existing case study forms to ensure its completeness and comparability across countries. Thematic analysis was undertaken to code this information in the HTA reports using the NVivo 10 software . Coding The qualitative data collected were transformed into quantitative categorical nominal variables by exporting the data into Stata 13 . Thematiκ = 0) to perfect agreement (κ = 1), and where negative values of κ correspond to cases when agreement was less than that expected by chance . For example, uncertainty was addressed for lenalidomide by imposing a third line restriction , or a future re-assessment once more evidence is collected (TLV). Another modulating factor was the ability to implement a lower discount rate on costs and effects captured in the model, as was seen for mifamurtide by NICE and SMC, whereas the high ICER was acceptable for TLV given the severity of the condition, but was rejected by HAS for the reasons discussed in the next paragraph.A final contrast was seen when assessing cost-effectiveness versus clinical benefit, also resulting in opposite conclusions. A number of compounds rejected by NICE and SMC received an important SMR rating with a 65–100 % coverage rate , and a high ASMR rating associated with a more favourable pricing scheme . The negative recommendations issued by NICE and SMC were due to the high ICER and main parameter of interest included. There were also drugs positively appraised by NICE and SMC, which received very low SMR ratings [e.g. moderate (30 %) and weak (15 %) coverage] and an ASMR V or a rejection by HAS . This was because of the lack of comparative data as a result of the early marketing authorisation granted (ofatumumab) and early scientific advice received (mannitol dry), or the highly uncertain evidence presented (mifamurtide). Mannitol dry and mifamurtide also had in common that they were the only two drugs that were not part of the temporary authorisation scheme (ATU) in France.This study adopted a mixed methods research design based on an existing methodological framework to investigate HTA decision processes for ten drug and indication pairs across four countries, and showed important variations and contradictory trends across countries. Differences at each stage of the HTA process were identified, partly explaining the reasons for differing HTA recommendations across countries, while illustrating the complexity of these processes. First, heterogeneity was seen in the evidence accounted for, in the interpretation of the same evidence, and in the different ways of dealing with the same uncertainty Table . These wResults from this in-depth analysis of ten orphan drugs suggest that HTA is not a simple analysis of clinical and/or cost-effectiveness, but remains a flexible process subject to the decision maker’s interpretation about uncertainty and social values as part of the deliberative process of HTA. This study contributes to shedding light on some of the factors being accounted for, which may not necessarily be explicitly defined as part of the decision process. Policymakers should be aware of the more comprehensive set of factors accounted for in these decisions, and the different ways of applying HTA, including how countries dealt with the issues specific to—but not limited to—orphan drugs. The implications of these findings are discussed here, together with the study limitations.A first contrast was seen between the HTA recommendations driven by cost-effectiveness and those by clinical benefit. Some drugs with a recognised positive clinical benefit in France were rejected in some, but not all, of the other countries partly due to their high ICER . This finding is in line with one study that compared NICE coverage and HAS ASMR decisions for a sample of anticancer drugs, showing a significant association between the QALY gain and ASMR ratings, but none when accounting for costs (ICER) . This alFurther contrasts were also seen within those countries assessing cost-effectiveness. The acceptability of the ICER, based on similar economic models and comparators, differed due to the agency-specific or process-specific modulators identified: (a) disease severity for TLV, (b) SMC modifiers, (c) patient access schemes, (d) NICE end-of-life criteria, (e) imposing restrictions, or (f) continuous data generation and future re-assessment. The first four reflect adjusted willingness-to-pay thresholds and special considerations for orphan drugs, while the latter two cases relate to the ability to modulate the ICER by identifying circumstances or subgroups for which the treatment is cost-effective, or accepting greater uncertainty for a limited period of time until more evidence is generated. Findings for Sweden are in line with a recent study that demonstrated the positive impact of disease severity on reimbursement decisions, despite severity not being explicitly defined . The abiResults illustrate the type of issues encountered when dealing with orphan drugs in terms of the nature of the evidence presented  and the types of issues highlighted by the HTA bodies , corresponding to what characterises orphan drugs , 50. DifResults also suggest possible misalignments between the incentives implemented for marketing authorisation and their effect at HTA level. For three drugs, the evidence presented was very uncertain due to its low quality and lack of comparative data . This was a consequence of the early marketing authorisation granted or early scientific advice received, which negatively influenced the HTA decisions made: low ASMR ratings (V) in France and rejected in the other countries. Two exceptions, however, were identified (NICE’s recommendations for mannitol dry and trabectedin), where uncertainty was deemed acceptable thanks to the different mechanisms modulating the ICER or to the consideration of other forms of evidence . These examples may constitute ways forward in dealing with such scenarios in the future. Additionally in France, all study drugs were made available as part of their temporary authorisation scheme (ATU), with the exception of mannitol dry and mifamurtide. The former received an ASMR V rating and the latter was rejected, which occurs very rarely in France. This may imply that continuous data collection is an additional factor that contributes to accepting greater uncertainty in France.RCT weaknesses are well known and include limitations around safety and generalizability to heterogeneous populations or clinical practice, as well as the cost to conduct them . SimilarThis study identified differences across countries in the type of evidence that is considered appropriate and in interpreting the same evidence, contributing to explaining different HTA recommendations. A more formalised and consistent recognition of the acceptability criteria for evidence and uncertainty is needed, which could be achieved by generating criteria based on past decisions such as the specific circumstances (e.g. early marketing authorisation) or quality standards  required. The agency-specific risk and value preferences identified in this study could also be a good starting point for shedding light on the more common circumstances already arising in the different countries.This research is in line with the recognised need to better understand pricing and reimbursement systems through cross-country learning and sharing of experiences . It may Results and the systematic approach used may also feed into other forms of research around priority setting. The retrospective identification of the criteria driving previous decisions, applied in this study, is also recognised as one approach to criteria elicitation for multiple criteria decision analysis (MCDA) when used for priority setting . When coA more recent study developed a value proposition based on 19 social value arguments about orphan drug reimbursement decisions, summarised into four value-bearing factors  . Most ofThis research is not without its limitations. First, the data was mainly collected from secondary sources. It would have been preferable to have full information about the submissions (e.g. manufacturer submission), but this was not possible in the current scheme. The information obtained by applying the methodological framework was unavoidably limited by the level of detail provided in the HTA reports and whether the framework captures all aspects of the decision-making process . The infThis research contributes to better understanding, in a systematic manner, what is driving these complex decision processes in practice, and why countries make different decisions. It also contributes to identifying those factors beyond the standard clinical and cost-effectiveness tools used in HTA, how they influenced the decision and how they were provided. The implications of this research are all the more important given the shift towards niche markets and personalised medicine, where an increasing number of the treatments undergoing regulatory and coverage processes are characterised by some of the important issues discussed in this paper.


Preventive chemotherapy to control soil-transmitted helminth infections in at-risk population groups [Thank you for sharing the review by Savioli and colleagues  on Preven groups  and for Several Member States, partners, and other units in WHO requested that the Departments of Control of Neglected Tropical Diseases and Nutrition for Health and Development assess all the evidence supporting the recommendations issued by the Organization on deworming.A guideline review —the formA Guideline Development Group (GDG) on soil-transmitted helminth infections (STHs) was established and included 16 experts, external to WHO, with different areas of expertise, perspectives, and geographical origin .The GDG reviewed all available evidence, including the recent Cochrane and Campbell reviews –6 and otSeveral of the five critical areas in which this WHO guideline ‘does not provide the necessary leadership’, according to Savioli and colleagues , includeWe agree that programme managers need to continue to use existing practical manuals since WHO recommendations on deworming remain unchanged. These manuals include those on controlling STHs, achieving universal access to safe water and adequate sanitation and hygiene interventions, and addressing all forms of malnutrition.The ‘critical contemporary topics’ mentioned by Savioli and colleagues  are in pWe thank the authors of the review for their attention to the work of WHO and for their broad agreement with the conclusions of this guideline. While we recognise that they have concerns with the widely accepted methods used by WHO to develop evidence-informed guidelines, we nonetheless look forward to working with all of our partners to decrease the global burden of STHs and other neglected tropical diseases.In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products, or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article’s original URL.


Patient decision aids (DAs) are support tools designed to provide patients with relevant information to help them make informed decisions about their healthcare. While DAs can be effective in improving patient knowledge and decision quality, it is unknown what types of information and evidence are used to populate such decision tools.Systematic methods were used to identify and appraise the relevant literature and patient DAs published between 2006 and 2015. Six databases  and reference list searching were used. Articles evaluating the effectiveness of the DAs were appraised using the Cochrane Risk of Bias tool. The content, quality and sources of evidence in the decision aids were evaluated using the IPDASi-SF and a novel classification system. Findings were synthesised and a narrative analysis was performed on the results.Thirteen studies representing ten DAs met the inclusion criteria. The IPDASI-SF score ranged from 9 to 16 indicating many of the studies met the majority of quality criteria. Sources of evidence were described but reports were sometimes generic or missing important information. The majority of DAs incorporated high quality research evidence including systematic reviews and meta-analyses. Patient and practice evidence was less commonly employed, with only a third of included DAs using these to populate decision aid content. The quality of practice and patient evidence ranged from high to low. Contextual factors were addressed across all DAs to varying degrees and covered a range of factors.This is an initial study examining the information and evidence used to populate DAs. While research evidence and contextual factors are well represented in included DAs, consideration should be given to incorporating high quality information representing all four pillars of evidence based practice when developing DAs. Further, patient and expert practice evidence should be acquired rigorously and DAs should report the means by which such evidence is obtained with citations clearly provided.The online version of this article (doi:10.1186/s12911-017-0415-7) contains supplementary material, which is available to authorized users. The  status’ . Effecti status’ , 5, 6. F status’ . Despite status’ , 10.n = 20), identifying that while half used high quality evidence , others used less robust evidence  [A recent examination by Montori et al.  of 257 Dopinion)  demonstrWhile research evidence is essential to guide decision making, it can be argued that it does not reflect the totality of evidence and is by itself not sufficient to facilitate patient-centred decision making . EBP is It is suggested that use of evidence from the four components of EBP and the synthesis of such information in DAs is required in order to effectively contribute to fully informed patients and evidence based shared decision making. To the authors’ knowledge no published study has evaluated DAs using a comprehensive EBP framework. Thus, the aim of this review is to examine the evidence being used in DAs so as to fully understand what information patients receive to inform their treatment decisions when using DAs. For this purpose, the components of evidence based practice (EBP) including research evidence, practice evidence, patient evidence and contextual factors will be used to guide the evaluation. In addition, the quality and source of this information will also be established using a novel grading classification framework.This systematic review was conducted according to the PRISMA 2009 checklist  was used to assess the quality of the DAs , 20. TheAs no tool existed to complete this task, a novel classification tool  of DAs integrated patient evidence as a source of information Table . Two DAsContextual factors were generally addressed to some degree by all DAs Table . The majThe DAs examined in this study reflect a highly specified rather than generic group i.e. they were treatment DAs (they did not for example represent those used for assessment), representing Anglo-Saxon countries, evaluated using RCTs which had supporting documentation available in the form of published papers and technical documents. Thus, the review focused on a small number of DAs which met these criteria and the study findings should be interpreted with this in mind.The purpose of the IPDASi-SF is to present an overall impression of quality based on whether DAs contain suggested components and complete a rigorous development and evaluation process. According to the IPDASi-SF, the DAs reviewed in this study were of generally good quality, with many aids scoring maximally on rigour of development. This may be partially explained given that the evaluation of research content according to this tool refers predominately to the provision of research citations and not for example, the appropriate use of research to inform DA content. Thus, the IPDASi-SF differs from the novel classification tool developed for this review which assessed all evidence types and determined the quality of evidence according to evidence type and transparency. This demonstrated that a high score on the IPDASi-SF did not necessarily correlate with a high classification grade on using the novel classification tool used in this review. This suggests that while the quality of DAs as assessed using the IPDASi-SF may be sound, the variety of evidence used and the rigour of evidence sources other than research evidence are not guaranteed.all sources of information used to inform content. For example, in one DA citations were only provided for one of three treatment options included [The majority of DAs provided citations for research evidence used to populate content either in the DA itself or in the supporting documentation representing variety in reporting methods. Two DAs developed by the same organisation, provided references within the DA , 34. Forincluded  the resuincluded , 10. It This novel review found that the information used to inform the content of the ten DAs examined is primarily founded on research evidence and contextual factors. Research evidence was well represented across the DAs evaluated, the majority using high quality research evidence categorised according to the A descriptor. This compares to the findings of a systematic review by Montori et al. , which fAs with research evidence, contextual evidence was reported in all aids with a wide range of factors being addressed and each DA containing at least one such factor. The inclusion of contextual information, particularly those representing treatment burden such as out-of-pocket costs and treatment intensity, can be seen as highly patient-centric given that such factors have the potential to dominate patient decision making . DAs whiPractice and patient evidence were conversely not well represented in DA content with only a small subset of DAs incorporating this type of evidence. Further, the quality of such evidence varied and the sourcing of this information was not always transparent suggesting less rigorous rules for obtaining and using such evidence. Practice evidence was least commonly used to populate DAs with the majority (70%) not incorporating any clinical or expert evidence. This absence exists despite findings which demonstrate that patients value the opinion of health professionals when making decisions  and ofteThe use of patient evidence in DAs is a contentious area with lack of consensus regarding its optimal use , 43. ThiThe reduced practice and patient content in DAs may further reflect under researching (and thus lack of availability) of these forms of evidence. Thus, there is a requirement for both forms of evidence to be acquired using established research methods. Such methodologically rigorous research would help improve the reliability and validity of such evidence in addition to strengthening the relevant content used in DAs. It would also be useful when evaluating DAs which have been developed with the totality of evidence in mind, that studies be undertaken to examine how patients’ decisions are influenced by such individual forms of evidence. Further, as Violette et al.  point ouThese recommendations reflect a global move toward patient inclusion in their health care in a variety of ways specifically regarding fully informed shared decision making. As for other decision support tools, the development of DAs is a positive step in this regard and their importance is highlighted in policy and legal developments such as The Patient Protection and Affordable Care Act (2010) in the United States of which Section 3506 calls for the creation of a certification and quality process for patient decision aids and for best practices which include the sharing of developed tools . Such quAs noted, DAs examined in this study reflect a targeted rather than generic group and inclusion for review was limited to those which were evaluated using RCTs which were published in the literature. Thus, the nature of the study meant a lot of DAs were not included in this review and the finding cannot be readily generalised to all DAs.Due to the lack of available tools and need to assess the rigour of patient, practice and contextual evidence, a novel grading system was developed. While unvalidated, this tool went through five iterations before application and was both comprehensive and reflective of the issues being addressed. Further, assessment was completed blindly by two independent reviewers and results were cross-checked by a third reviewer in order to ensure rigor and robustness of methodology employed and results obtained.This study primarily focused on representativeness of information content. Thus information accuracy such as appropriate use of citations was not included in the analysis at this stage.The results of the current review demonstrate that the content of treatment DAs is informed mainly by the results of high quality research evidence and some contextual factors with patient and practice evidence being rarely incorporated. The transparency of reporting evidence sources can also be problematic especially where multiple documents exist regarding the development of the aid. Where patient or practice evidence is used, there are seldom rigorous, research-based methods used for obtaining this information. The same rigour used to retrieve and select research evidence for DAs is required for other forms of evidence to reduce information bias, improve the quality of DAs and enhance informed decision making.


As a well-known theory in studying the effective factors on behaviour, the theory of planned behaviour (TPB) is frequently used in evaluating the health behaviour of people and healthcare providers, but rarely applied in studying the behaviour of health policymakers. The aim of the present study is to design and validate a TPB-based measurement tool for evidence utilisation in health policymaking (the EUPMT) through a mixed approach using confirmatory factor analysis.The study population consisted of all the specialised units and their employees in the five deputies of Iran’s Ministry of Health and Medical Education in 2013. All those eligible were invited to participate in the study, which comprised 373 persons. The reliability of the EUPMT was determined through test-retest and internal consistency. Additionally, its validity was determined by face, content, convergent, discriminant and construct validities. SPSS-20 and LISREL-8.8 were employed to analyse the data. To assess the fitness of the measurement models, three groups of indices were used, i.e. absolute, relative and parsimonious.The content and face validities of the tool were 83% and 67%, respectively. Cronbach’s alpha of different constructs ranged from 0.7 to 0.9. In the test-retest method, the intra-class correlations were between 0.75 and 0.87. Confirmatory factor analysis showed that the penta-factorial structure of the experimental data had acceptable fitness with the TPB .TPB is able to explain the behaviour of evidence utilisation in health policymaking. The finalised TPB-based tool has relatively good reliability and validity to assess evidence utilisation in health policymaking. The EUPMT can be applied to determine the status quo of evidence utilisation in health policymaking, whilst designing interventions for its improvement and assessing their outcomes. TPB is able to explain the behaviour of evidence utilisation in health policymaking.The finalised TPB-based tool has relatively good reliability and validity to assess evidence utilisation in health policymaking.The EUMPT can be applied to determine the status quo of evidence utilisation in health policymaking, whilst designing interventions for its improvement and assessing their outcomes.Health systems often fail to meet the optimal utilisation of research evidence, which itself may lead to inefficacy, reduced quality of life, the life expectancy of citizens and, as a result, reduced productivity . At an iTo study behaviour-related factors, several theories have been presented, including Implementation Intention, Common Sense Self-regulation Model, Operant Learning Theory, Stage Model, and Theory of Planned Behaviour (TPB). TPB has been the dominant theoretical approach to study health-related behaviours over the past three decades . This thTPB has been extensively applied in psychology and healthcare disciplines, and its efficacy in predicting individual health-related behaviour has been shown in a couple of systematic reviews . Based oThe application of TPB on any behaviour requires the identification of affecting factors on the intended behaviour and the development of a specific tool to measure their effects on the behaviour. Like any other measurement tool, an evaluation of the psychometric properties of this tool, such as validity and reliability, is required . There aMakkar et al. , in a syBrennan et al.  developeThe reliability of the SEER tool was examined by test-retest and internal consistency and its validity was tested by confirmatory factor analysis and criterion validity. The bivariate correlations of individual capacity subscales and corresponding constructs of the tool proposed by Brennan et al.  present The present study was conducted to design a tool to assess evidence utilisation in health policymaking through the indirect approach to design predicting constructs of TPB and to assess its validity, reliability and factorial structure. Our aim was to design a tool that may be employed to determine the status quo (current beliefs and intentions about using research to inform policy), as well as to design interventions and assess their outcomes. The ultimate aim was to help promote the utilisation of evidence in health policies and its transformation into an organisational culture in health policymaking organisations.A cross-sectional study of factor analysis type was conducted to design and determine the validity, reliability and factorial structure of the tool evaluating evidence utilisation in health policymaking.The study population consisted of specialised units and their employees in the Central Department of Iran’s Ministry of Health and Medical Education (MOHME), including the office director, officer-in-charge, Head of the National Health Plan and expert officers Table . The CenThe inclusion criteria of the study were a minimum of 2 years’ professional experience in the Central Department of MOHME and participation in the development of policy briefs. Although some guidelines about sample size for confirmatory factor analysis (CFA) have been published so far, there is no consensus regarding this . Many reThere are two approaches to designing the questions of predicting constructs of TPB , namely the direct and indirect approaches . In the In the indirect approach, a qualitative study is first designed and implemented based on TPB constructs. To measure the construct of the ATB, some open questions arise, e.g. ‘in your opinion, what are the advantages of using evidence in developing the policy briefs?’ If one of the stated advantages is, for example, ‘to avoid wasting the resources’, to measure this attitude, two questions are designed as follows: 1. Developing the evidence-based policy briefs prevents wasting the resources ; 2. Preventing wasting the resources is … for me . As it might be noted, the first question measures the likelihood of studied behavioural outcomes while the second measures its utility in respondent opinion. The indirect approach is superior to the direct approach such that, in the indirect approach, specific factors related to the behaviour are identified and measured; therefore, using a tool that has been designed based on this approach can be more helpful in accurately designing the interventions for improving the considered behaviour.The required qualitative study has already been carried out and published to identify the effective variables on the use of evidence in health policymaking based on TPB . In thisBefore conducting the study, the necessary permissions were acquired from the Ethics Board of Iran University of Medical Sciences (IUMS: 93.105.352). To ensure the confidentiality of data, the completed questionnaires were received in sealed envelopes and opened on a certain day. Completion of the questionnaire was followed up three times. If lost, another questionnaire would be handed over to the participant. The researcher tried to gain the informed participation consent of the eligible individuals by introducing himself and explaining the aim and process of the study. In the case of expressing informed consent by participants, the questionnaires were given to them and a specific date was assigned for its delivery.The validity of the tool was tested through face, content and construct validities, and subsequently improved. Content validity refers to the capability of selected questions in reflecting features of measured constructs. Face validity assessed to what extent the questions of a scale are similar to the issue that they are designed to measure. Both validities can be calculated for any of the questions of a scale and to the whole scale –27. QuanConstruct validity shows the extent to which observed scores on the tool are predicted by the theory upon which the tool was based. Accumulation of evidence about the face, convergent and discriminant validities of a tool is used to provide evidence of construct validity . It is dTo evaluate the reliability of the direct questions, internal consistency was tested by calculating Cronbach’s alpha coefficient. Test-retest reliability of the indirect questions was tested by calculating the intraclass correlation coefficient (ICC) . The tim2 to ‘degree of freedom’ ratio (acceptable < 3), the goodness-of-fit index (GFI) and the adjusted GFI (AGFI) (acceptable < 0.9) were used. The Bentler-Bonett normed fit index and the non-normed fit index were used from the relative fit indices, and the root mean squared error of approximation was employed as a parsimonious fit index. To ensure the accuracy of data entry, 10% of the data were imported to Excel software by another individual and the correspondence of data was evaluated with Epi-info software [To assess the goodness-of-fit of the measurement models, three groups of indices  were used. Among the absolute fit indices, the χsoftware . The disUpon testing the reliability of the indirect questions, the ICC of seven questions was lower than 0.6 and thus they were omitted along with their corresponding questions . After removing these variables, the ICC of the behaviour, ATB, SN and PBC constructs, and that of the entire tool, were estimated to be 0.75, 0.83, 0.87 and 0.89, respectively. Cronbach’s alpha for the behaviour construct was smaller than 0.7, which improved after removing question 4. Cronbach’s alpha coefficients for the behaviour and intention constructs were 0.75 and 0.88, respectively.The response rate of the construct validity test was 92.76%. Despite following the participants up to three times and extending the dates of completion for the questionnaires, 27 individuals did not return their questionnaire. Non-response bias was not tested, as the response rate was high. Table 2 value calculated in Bartlett’s sphericity test was significant at P < 0.001, at a degree of freedom of 253, which is justified for the CFA test.The Kaiser-Meyer-Olkin value was 0.89, indicating the adequacy of sample size for the CFA. The χThe TPB-based measurement model of EUPMT for the standard estimate state is illustrated in Fig. The results of the EFA revealed that most of the observed variables had a correlation higher than 0.5 with only one of the constructs, and their correlation with the other factors was lower than 0.5; hence, these results provided evidence of their discriminant validity. However, correlations predicted by the theoretical model for seven variables were not observed. The rotated factorial matrix output Varimax revealed six constructs instead of three. Upon comparing the factorial weight and the variables’ constructional associations, evidence of the discriminant validity of 17 variables was provided. One variable had no acceptable factorial weight in either of the constructs (questions 55 and 56). However, the remaining six variables may have represented the construct(s) that the theory was unable to explain. Thus, the status of these six variables was examined to see whether they could represent a new construct(s) or not. The remaining six variables were equally distributed among the three constructs supplementary to the theory. The variables ‘workload’ (Questions 60 and 61) and ‘crowded and noisy workplace’ (Questions 62 and 63) were placed in one construct. ‘The colleagues’ norm’ (Questions 32 and 33) and ‘selection of MOHME experts on the basis of their competencies’ were put in another construct. ‘Time-consuming nature of the process’ (Questions 8 and 9) and ‘selection of the managers of MOHME among the faculty members’ (Questions 47 and 48) were placed in the third construct.The two variables ‘workload’ and ‘crowded and noisy workplace’ were evidently among the participants’ control beliefs and logically should have acquired suitable factorial weight in the PBC construct. Therefore, these variables were not able to build a new differentiated construct from the TPB constructs. ‘The colleagues’ norm’ and ‘selection of MOHME’ experts on the basis of their competencies’ did not have a mutual semantic association that could build a new distinctive construct from TPB constructs. Moreover, the former variable is evidently part of the SN construct, and the latter variable is part of the PBC construct. Therefore, logically, they should have gained good factorial weight in their corresponding constructs. The variables ‘time-consuming nature of the process’ and ‘selection of the managers of MOHME among the faculty members’ did not have a mutual semantic association such that they could form a new independent construct from TPB constructs. Furthermore, the participants considered ‘time-consuming nature of the process’ as a disadvantage of the evidence utilisation to develop a policy brief, which was a negative attitude toward the behaviour. Logically, it is expected that a good factorial weight will be found in its relevant construct, i.e. ATB. Most participants recognised ‘selection of the managers of MOHME among the faculty members’ as an environmental/organisational facilitator for developing evidence-based policy briefs, which is a positive control belief and should have acquired acceptable factorial weight in its relevant construct, i.e. PBC. Therefore, the surplus constructs of TPB derived from the EFA could not build new constructs to a better explanation for developing evidence-based policy briefs and thus they were removed along with their corresponding questions .2) of their variables with the other constructs; thus, these results provided evidence of their discriminant validity. Overall, evidence about the convergent and discriminant validity of 23 variables (40 questions) was provided.The factorial weight of the observed variables and the mean variance extracted for the other constructs was greater than 0.5; hence, these results provided evidence of their convergent validity. The mean extracted variance for each of the constructs was greater than the squared correlation coefficient  and the fact that a signed invitation with the name of the participants was sent out; the measures to protect the confidentiality of responses ; the interesting subject matter in the participants’ opinion; the timing delivery of completed questionnaires by participants within a 2-week period; three follow up reminders to receive the completed questionnaire and redelivering of the questionnaire in case of loss; collection of the data by the researcher instead of hiring interviewers; and suggesting the importance of the study considering the researcher’s degree (PhD), which was effective in motivating the participants. The researcher could draw the informed participation of the participants followed by introducing himself and explaining the objectives and steps of the study. Explaining the steps of the study was effective in increasing motivation. Finally, the fact that the questionnaires were not provided through translation or reviewing of previous texts, but rather were prepared through in-depth interviews of the participants’ co-workers, was also viewed positively.EUPMT has been designed based on one of the most famous and prestigious behaviour theories (TPB). Moreover, SEER used the framework of SPIRIT , which was developed based on a literature review and interviews with policymakers . While tThe reliability of the tool proposed by Boyko et al.  (assessiAmong the limitations of the study is the use of self-reported data. To prevent social desirability bias, the questionnaires were received anonymously and in sealed envelopes. However, the bias may still be affecting the data. Another limitation of the study is the lack of testing of the criterion validity, which could provide further evidence of the validity of the EUPMT. Although the use of objective tools such as SAGE provides a more detailed profile of using the evidence in health policymaking, its use is difficult in practice. Other limitations of SAGE may be neglecting the mechanisms, structures and systems that can help improve the capacity of policymakers to use evidence, as well as focusing on barriers in using the evidence and ignoring the facilitators .The results showed that real data on utilisation of evidence in health policymaking support the TPB; in other words, the TPB is also capable of explaining the use of evidence in health policymaking. EUPMT has relatively good reliability and validity to assess evidence utilisation in health policymaking. This tool may be employed to determine the status quo of evidence utilisation in health policymaking, to design interventions for its improvement and to assess the outcomes of conducted interventions. The EUPMT can effectively help health policymakers promote the utilisation of evidence in the development of policy briefs and transform it into an organisational culture.


In the present study, the social ranking perception in competition was explored. Brain response , as well as self-perception of social ranking, cognitive performance, and personality trait  were considered during a competitive joint-action. Subjects were required to develop a strategy to obtain a better outcome than a competitor (C) . A pre-feedback (without a specific feedback on the performance) and a post-feedback condition (which reinforced the improved performance) were provided. It was found that higher-BAS participants responded in greater measure to perceived higher cognitive performance (post-feedback condition), with increased left prefrontal activity, higher ranking perception, and a better real performance (reduced RTs). These results were explained in term of increased sense of self-efficacy and social position, probably based on higher-BAS sensitivity to reinforcing conditions. In addition, the hemispheric effect in favor of the left side characterized the competitive behavior, showing an imbalance for high-BAS in comparison to low-BAS in the case of a rewarding (post-feedback) context. Therefore, the present results confirmed the significance of BAS in modulating brain responsiveness, self-perceived social position, and real performance during an interpersonal competitive action which is considered highly relevant for social status. The effect of a competitive task in the brain was recently explored by different perspectives . There iConversely, previous research also suggested an important role for social interactions and self-perception in achieving accurate self-knowledge and self-improvement, particularly in response to performance-related social comparisons. It was shown, in fact, that social status perception reciprocally affects performance on tasks that involve comparing our own performance with that of others : in otheTherefore, competition is a social-evaluative phenomenon and such competitive situations can increase the level of cognitive demand on the performer beyond what is required to simply execute the task. The increase in such demand may explain, in part, how competition influences the quality of performance (with a better or worse effect) and brain responsiveness due to the attendant alterations of the performer’s mental state and the underlying neural processes .It was also shown that an extended neural circuit linking limbic, prefrontal, and striatal structures may reflect the emotional, cognitive, and behavioral components of rank-related social interactions . Recent More specifically, the perception of competition influences the internal evaluation and may manifest as an increase in cerebral cortical activation in some prefrontal areas, and affect the performance outcomes. However, it remains to be answered whether and how an increase in cerebral cortical activity is specifically promoted by competition-induced social evaluation when the cognitive performance is artificially manipulated. Indeed no previous research, to date, has manipulated the social environment via direct competition to assess this possibility. Thus, taking into account previous research, two relevant aspects were underestimated and, in our opinion, should be deeply considered to evaluate the competition effect on social self-perception and cognitive outcomes: firstly, the presence of an inter-subjective real interaction where the co-partner is present and actively implicated in the competitive exchange ; secondlAbout the first aspect, in the present research the subject’s performance on a cognitive task and his/her related social ranking were artificially manipulated in a dyadic vis-à-vis competition which stressed the necessity to win and to obtain a better score than the partner, therefore in interaction with a competitor (C). Indeed, in contrast to previous studies , we inclAbout the second aspect, we supposed that the way individuals judge their social ranking positions partially depends on some personality factors, such as the degree to which their own behavior is balanced between “approaching” in response to rewards (to be more responsive to winning) and non-punishments, or “withdrawing” from non-reward and punishments (being more sensitive to losing). These emotional and motivational components appear to be highly relevant with respect to self-perception in social contexts and social ranking. Indeed recent research found that motivations and emotions are able to manipulate the perception of social hierarchies by inducing more positive versus negative predispositions in social relationships . SpecifiAbout BIS/BAS cortical correlates, they appear to be lateralized and they are viewed as mutually inhibitory: respectively, the left PFC was shown to support the approach-related motivations and emotions, whereas the right PFC was found to be involved in withdrawal-related motivations and emotions . TherefoIndeed, firstly the modulation of EEG brain oscillations was considered as a valid measure of brain activation, and it has often been applied to describe distinct responsiveness by the two hemispheres to different emotional and social conditions . In factTherefore, the aim of the present study was to investigate the neurophysiological bases of social ranking perception underlying the execution of a competitive joint-action by using both EEG and fNIRS acquisition. Based on our hypotheses, the observed performance and the external feedback from one hand, and the personality components (BIS/BAS) from the other hand, may affect the self-perception of social position and hierarchy, and they effectively may modulate our cognitive performance in social contexts. That is, the perceived effectiveness of our behavior in term of performance during a competitive task and specific BAS components positively guide self-perception of our position within the social ranking and consequently these mechanisms may impact on the real cognitive outcomes (improved performance). Concerning the cognitive performance, consistent better performance should be found for higher-BAS trait when perceiving an improved ranking, as an effect of more reinforcing and rewarding outcomes. That is, the “improving performance effect” should be more significant in high-BAS as a concomitant result of perceived dominance and rewarding situations, which high-BAS judge as positive in greater measure.The cortical correlates of these cognitive and social mechanisms are supposed to be related to the prefrontal areas, with a specific contribution of the left and right hemisphere. Therefore it is crucial to consider the implication of the PFC and a possible lateralization effect in response to social ranking perception, in combination with personality components , 2015. WFinally, the three levels of social ranking perception, personality components, and cognitive performance should be consonant, since we expected a correlated increased self-perception of social position and a better performance in relation to higher-BAS, with a concomitant higher activation of left prefrontal areas.M = 21.06, SD = 3.24). The participants were all right-handed and presented normal or corrected-to-normal visual acuity. Exclusion criteria were history of psychopathology . Halfway, in fact, participants received a general evaluation of their performance. Actually, both trial-feedbacks and the general-feedback were artificially managed. The feedback order (two sessions) was counterbalanced across subjects. For what concerns the general feedback, participants were told that they had an outcome “well above” their competitor’s one and were encouraged to maintain their performance level, during the second part of the experiment . Across the task, after an initial mean performance, subjects were constantly reinforced about their good performance by presenting the up-arrows in 70% of cases, while the dash or the down-arrows appeared only in 30% of cases (mainly at the beginning of the task) to make the task more credible and plausible. In addition, after each block of 25 trials, subjects were required to evaluate their performance and efficacy in term of their ranking on a 7-point Likert scale . Finally a post-session questionnaire explored the following aspects: degree of their engagement in the task; trust in the received feedback; relevance of task for their social status perception; perceived improving of ranking position. The data showed that participants were strongly engaged in the task (94% were strongly engaged); trusted in external feedback (95%); considered the task as relevant for social status (94%); improved their ranking position during the task (96%).The cognitive task consisted in a sustained selective attention task. Participants were required to select a target stimulus between non-targets, based on four different options of shape/color: the stimuli might interchangeably be a triangle or a circle, colored red or green. They were required to distinguish between target/non-target by focusing attention on each stimulus. The target was displayed on the video (indicated as the target for selection) and the successive stimuli were presented one after another. The target stimulus features changed every 25 trials. The subjects were instructed to make a two-alternative forced-choice response by pressing a left/right button. Each stimulus was presented for 500 ms, with a 300 ms inter-stimulus interval (ISI). After each trial, composed by three stimuli, subjects received a feedback, after 5000 ms, signaled by two up-arrows (high score); a dash (mean performance); or two down-arrows (low score). This feedback remained for 5000 ms. After the feedback, an inter-trial interval (ITI) occurred for other 5000 ms. The task was composed by two sessions: the first which did not include a specific general feedback to performance , and a second one which included a specific positive feedback to performance ; Reward: M = 23.76 (SD = 2.88); Drive: M = 12.98 (SD = 3.15); Fun Seeking: M = 13.09 (SD = 2.11). Cronbach’s alpha was calculated for BAS (0.96) and for each BAS subscale . Based on these ratings we created two sub-groups: high-BAS and low-BAS subjects. The first group included subjects with high-BAS scoring ; the second group included subjects with low BAS scoring . Since BIS and BAS were orthogonally distributed and systematically participants higher in BAS were lower in BIS, BIS was not used in this phase of research. Only one subject was removed from the final analysis since he showed a mixed-profile (both high-BAS and high-BIS score).Behavioral Activation System scores were calculated by using the Italian version  of CarveAbout gender distribution, for both high-BAS and low-BAS groups there was an equal distribution  of genders.Electroencephalographic recordings were performed with two 16-channel portable EEG-System . An ElectroCap with Ag/AgCl electrodes was used to record EEG from active scalp sites referred to the earlobes . To obtain a signal proportion to the power of the EEG frequency band, the filtered signal samples (epoch 1000 ms) were squared . An averFigure 2).The following channels were acquired. For the statistical analysis left and right frontal  alpha power activity was considered . Emitter-detector distance was 30 mm for contiguous optodes and near-infrared light of two wavelengths (760 and 850 nm) were used. NIRS optodes were attached to the subject’s head using a NIRS-EEG compatible cup, with respect to the international 10/5 system.fNIRS measurements were conducted with the NIRScout System  using a 8-channel array of optodes (four light sources/emitters and four detectors) covering the prefrontal area. Emitters were placed on positions FC3–FC4 and F1–F2, while detectors were placed on FC1–FC2 and F3–F4  and deoxygenated hemoglobin (HHb) were recorded from a 120 s starting baseline. Signals obtained from the eight NIRS channels were measured with a sampling rate of 6.25 Hz, and analyzed and transformed according to their wavelength and location, resulting in values of the changes in the concentration of oxygenated and deoxygenated hemoglobin for each channel. Hemoglobin quantity is scaled in mmold = (m1 - m2)/s. Accordingly, m1 and m2 are the mean concentration values during the baseline and trial, and s means the SD of the baseline. The mean concentration value of 5 s immediately before the trial was used as event-related baseline. Then, the effect sizes obtained from the eight channels were averaged in order to increase the signal-to-noise ratio. Although the raw data of NIRS were originally relative values and could not be averaged directly across subjects or channels, the normalized data such as the effect size could be averaged regardless of the unit  were calculated as the difference of the means of the baseline and trial divided by the standard deviation (SD) of the baseline: the unit . In factthe unit .Post hoc comparisons  were applied to the data. Bonferroni test was applied for multiple comparisons.Four sets of analyses were performed with respect to behavioral  and neurophysiological  measures. Repeated measure ANOVAs were applied to these dependent measures with the independent within subjects factors condition (pre-post feedback) and the between factor BAS (high-BAS vs. low-BAS) applied to ER, RTs and self-perception variables; while within factors condition and hemisphere side , and the between factor BAS were applied to alpha band and O2Hb variable. The RTs were recorded from the stimulus onset, and ER was calculated as the total number of incorrect detections out of the total trial for each category. Higher values represented increased incorrect responses. About self-perception, the increased or decreased self-perceived ranking was considered. Alpha band modulation, O2Hb and HHb were calculated for each block. For all ANOVA tests, the degrees of freedom were corrected using Greenhouse–Geisser epsilon where appropriate. Finally, a series of regression analyses was applied to BAS, cognitive performance , self-perception, O2Hb, and alpha modulation.A preliminary analysis was conducted with gender as independent factor, to exclude any gender effect for both behavioral and neuropsychological measures. No significant effect was found at the statistical analysis.F = 6.43, p ≤ 0.001, η2 = 0.32]. High-BAS showed an increased ER in post-feedback compared to pre-feedback condition , whereas high-BAS did not differ from low-BAS in pre-  or post-feedback  . Also, no significant differences were found for low-BAS between pre- and post-feedback .ANOVA indicated a significant interaction effect BAS × Cond , with decreased RTs during post-feedback condition; for BAS , with decreased RTs for high-BAS; and an interaction effect BAS × Cond . High-BAS showed decreased RTs in post-feedback compared to pre-feedback condition , and reduced RTs compared to low-BAS in post-feedback . No other comparison was statistically significant .ANOVA indicated significant main effects for Cond . Indeed high-BAS showed higher ranking perception than low-BAS in pre-feedback  and post-feedback . In addition, high-BAS revealed higher ranking in post- than pre-feedback  .About the evaluation of their ranking position in term of performance, ANOVA indicated significant interaction effects for BAS × Cond , with decreased left alpha activity (increased brain response) for post-feedback compared to pre-feedback condition; BAS × Lat , with increased left activity  for high-BAS than low-BAS ; BAS × Lat × Cond , with increased left response for high-BAS in post-feedback than pre-feedback condition ; and with increased left response for high-BAS than low-BAS in post-feedback condition  .ANOVA indicated significant interaction effects for Lat × Cond  with increased left activity for post-feedback compared to pre-feedback condition; BAS × Lat , with increased left activity for high-BAS than low-BAS ; BAS × Lat × Cond , with increased left response for high-BAS in post-feedback than pre-feedback condition ; and with increased left response for high-BAS than low-BAS in post-feedback condition  .As shown by ANOVA, Lat × Cond was significant [R2 = 0.26, p = 0.001; Figures 8A–D), since increased BAS was related to RTs reduction. In contrast, no significant result was found for ER . In addition, BAS predicted self-ranking score , with a positive relation between the two measures. Also, left alpha  and left O2Hb  values were predicted by BAS, as shown in Figure 8. Indeed BAS increased values explained alpha reduction (brain activation) within the left PFC; similarly BAS increased values explained O2Hb increasing within the left PFC.Distinct stepwise regression analyses were performed. Predictor variables were BAS scores and the predicted variable were, respectively, self-ranking, performance , alpha and O2Hb. As shown, BAS score predicted RTs  and hemodynamic brain activity (O2Hb) were considered in high- and low-BAS profile subjects, to elucidate how this motivational trait component may affect subjects in formulating self-representation (ranking position) and self-improvement (cognitive performance) in an interpersonal context. Based on our research, some main results were observed. A first result was related to the systematic PFC response  to social ranking perception during competition. This PFC activation was mainly found in response to reinforcing condition (positive post-feedback) induced in the subjects for their competitive joint-action. In relation to this enhanced PFC responsiveness, a specific lateralization effect was found, with increased left activity in comparison to the right one. A second main result was related to the improved performance in terms of RTs, with reduced RTs after a positive reinforce. Also, self-perception of ranking position showed to be increased in relation to post-reinforce condition. A third main result was obtained for BAS variable, with a consistent impact of higher-BAS scorings on brain activity , cognitive performance , and self-perception (with higher ranking for high-BAS).About the first effect, a consistent PFC contribution was detected in response to post-feedback condition which reinforced the good subjective performance compared to C’s performance. Specifically, as shown by EEG and fNIRS data, the PFC was mainly implicated when subject were informed about their better outcomes. This result is in line with previous research which suggested a main role of the VMPFC in responding to status . Indeed,In parallel to variations in brain activity, a general better performance with decreased RTs was found especially when subjects perceived themselves as a better performer than the other competitor. This main result was in line with previous data, which pointed out the role of a competitive contexts to induce improved cognitive outcomes  compared to cooperative ones, mainly when we develop a general sense of dominance and superiority than others. More interestingly, the post-feedback condition revealed concomitant and simultaneous increased PFC responsiveness, better cognitive outcomes, and a significant increased self-perception ranking. Therefore, the external evidence  of a good cognitive performance produced also a consistent impact on social perception, with higher self-attribution in ranking position. In parallel it was able to induce a real higher cognitive performance compared to no-feedback condition.We may suppose that this consistent effect was related to the impact of the perceived performance on the cognitive real performance, when this rating was compared to that of the C. Secondly, this intrinsic relation between brain, cognitive behavior, and social representation might highlight the possibility of considering the reciprocal influence of the PFC and self-perception, and of the PFC and the cognitive task, as they may be represented as two sides of the same coin. That is, a sort of “circular effect” may be adduced: from one hand, the social significance of the performance for the social hierarchy appears to be highly relevant in modulating the subjects’ performance across the task , that is modulated by the prefrontal areas which could support the social perception process. From the other hand, the suggested increasing in cognitive outcomes may affect the self-perception of ranking position, with evident gains for the subjective representation of social status. Also, in this second case the PFC may support the reciprocal relationship between cognitive performance and social representation, reinforcing the “social value” of the prefrontal areas .At this regard the theory of social comparison processes  suggesteIn concomitance, a clear hemispheric lateralization effect was observed. As elucidated by the present data, a left lateralized cortical network within the PFC was found in concomitance to positive feedback. More generally, in this study, the left hemispheric effect was demonstrated to be prominent to explain our results, taking into account both O2Hb and EEG modulations. The fact that this cortical “unbalance” in favor of the left hemisphere in response to positive reinforcing conditions was also accompanied by a better performance and an increased social efficacy during post-feedback condition in terms of ranking attribution, may suggest an underlying link between the left cortical activity, the external social ranking representation, and the effective behavior. The specific cortical localization may suggest the consistent over-activation of the left cortical system and a concomitant predominance of this brain area in managing subjects’ cognitive behavior when they perceived to be higher in ranking. To support this interpretation, previous research demonstrated that high social power perception is indeed associated with greater left frontal brain activity compared to low social power .However, to deeply comprehend the present data we need to refer to a crucial and ampler construct, that is the role of a personality component defined as “approach attitude.”In fact, it has been previously suggested that the frontal cortical asymmetry in favor of the left hemisphere is associated to approach motivations and with general dominance and, therefore, to BAS, together with the ability to regulate positive emotions . SpecifiMore generally, as shown by the regression analysis, in the present research it was observed that personality approach attitude (high-BAS) was able to modulate brain activity , social ranking perception, and cognitive performance. Indeed the perception of ranking was improved in post-feedback for high-BAS, with self-representation as higher in social status compared to the C. Moreover, we may describe high-BAS performance as better than low-BAS one, mainly in term of RTs, although they generally have “paid” for their RT reduction with higher ER in post-feedback. In the case of competition high-BAS had significant higher PFC responsiveness, but limited to a specific module localized within the left hemisphere, as shown by both EEG  and O2Hb . Therefore the lateralization effect was also confirmed in the case of high-BAS with higher left PFC after post-feedback reinforce.per se both the self-perception of efficacy and competition and, consequently, the subjects’ real performance. Indeed we may state that a more consistent approach attitude and positive motivation may support a concomitant left side hyperactivation which supports the self-representation of an increased social ranking in cooperative contexts, with an improved real cognitive performance. Nevertheless, the role of BAS was not able in absolute to explain the present results, since we had a significant generalized higher left hemispheric activity also independently from BAS contribution. In other terms, the “basic” left lateralized BAS effect due to approach attitude might not exhaustively explain the increased effect found in post-feedback condition, with higher left DLPFC activity as a consequence of positive reinforcing. We may suggest that the left PFC contribution in competition may be also intended as a specific cortical module associated to positive experiences, positive feelings, and emotional valence.These results are in line with some previous studies which demonstrated that high cortical left unbalance is related to approach-related conditions, with higher prevalence of high-frequency oscillations in the left than the right PFC . It is pIn general the relevance of BAS construct may also be related to these three levels of explanation, also integrated each other: the sense of self-efficacy; the sensitivity to the reinforcing conditions and rewarding aspects; the dominance trait. From the first perspective, this raises the possibility that our personality and our subjective comprehension of social hierarchies may interact to impact our social success and sense of well-being. At this regard, it is possible that high-BAS implicitly assessed their own  social hierarchical status more than what low-BAS did in relation to the task they performed, with particular respect to increased social efficacy perception. It is also possible that the improved self-perception of ranking  may have introduced a reinforcing cue able to significantly modify the behavioral performance .Secondly, higher-BAS subjects may be more attentive to conditions that produce a significant positive reinforce, and that reinforce the behaviors which are active in nature, ingenerating positive emotions and positive self-perception of approaching attitude , as showThirdly, more generally we have to consider the extent to which higher-BAS individuals are more proactive and dominant in achieving their outcomes when an interpersonal goal has to be obtained . By virtTo summarize, what about the causal relations between these multiple constructs? Indeed whereas we know that BAS and external feedback are effective in modulating the cognitive performance and the brain responsiveness, regression analyses told us that BAS construct was able to affect simultaneously the neurophysiological level (EEG and O2Hb), the ranking perception and the cognitive performance. Therefore we may suppose that personality components  can modulate the self-perception, with significant impact on the cognitive performance. At the same time, it is able to affect the cortical activity. It is probably due to the original responsiveness to the approach condition that an increased PFC responsiveness was entailed with a specific left lateralization effect. In other term, the increased perception of self-efficacy, induced by the positive external feedback, was enhanced in the case of high-BAS and it may support both the higher PFC implication and the concomitant effective improved cognitive outcomes. Therefore we may suggest a sort of “ripple reinforcing effect,” where the personality trait manage the virtuous social (ranking perception), cognitive (effective performance), and brain  responses. In addition, we found that the left side system – more related to BAS polarity – accounts for the increased performance and improved self-perception: BAS subjects showed a more intense response within the left hemisphere in the case of high reinforced competitive outcomes.Future research should more exhaustively consider a direct comparison between cooperative and competitive tasks, to elucidate the main impact of personality components (BAS) in these two different social contexts. In addition, the distinct role of EEG and hemodynamic measures should be better tested in order to furnish a clear overview about the specificity of each of them in explaining the joint-actions. Finally, future research should provide a complete analysis of the joint-strategies used by competitors by applying specific hyperscanning method in order to consider the joint brain activities of the two actors.MB: Planned the experiment; supervised data acquisition and data analysis; discussed the results; wrote the paper. MV: Acquired and analyzed the data; discussed the results; wrote the paper.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.


Clostridium difficile is the leading cause of healthcare–associated infections. Given the high incidence of C.difficile infection (CDI) and the lack of primary preventionthrough immunization, health care professionals should be aware of the mostcurrent guidance, as well as strengths and limitations of the evidence baseunderpinning this guidance.We identified publicly available national or organizational guidelinesrelated to CDI infection and prevention control (IPC) published between 2000and 2015 and for any health care setting through an internet search usingthe Google search engine. We reviewed CDI–targeted IPC recommendationsand describe the assessment of evidence in available guidelines.We identified documents from 28 countries/territories, mainly from acute carehospitals in North America, the Western Pacific, and Europe (18 countries).We identified only a few specific recommendations for long–term carefacilities (LTCFs) and from countries in South America (Uruguay and Chile),South East Asia (Thailand), and none for Africa or Eastern Mediterranean. Of10 IPC areas, antimicrobial stewardship was universally recognized asessential and supported by high quality evidence. Five other widely reported“strong” recommendations were: effective environment cleaning, case isolation, use of personal protectiveequipment, surveillance, and education. Several unresolved and emergingissues were documented and currently available evidence was classifiedmainly as of mixed quality.Our review underlines the need for targeted CDI IPC guidelines in severalcountries and for LTCFs. International harmonisation on the assessment ofthe evidence for best practices is needed as well as more robust evidence tosupport targeted recommendations. C. difficile is the leading cause of health care–associatedinfections (HAI) worldwide affecting especially the elderly and hospitalised patients[patients–5. The bpatients,7.Mountpatients,9 and Lapatients,11 contrpatients,12,13. GThere are wide variations in the availability or levels of implementation of effectiveInfection Prevention and Control (IPC) measures for CDI. A national survey in Canadaidentified an extensive lack of antimicrobial stewardship programmes, less than 25% ofthe 33 participating hospitals  in 2005.In this review, we describe the availability of documents that outline recommendationsand actions for the prevention and control of CDI. We present a structured assessment ofkey elements of CDI–IPC strategies together with their strengths of recommendationand levels of evidence across 10 IPC areas followed by a discussion of current issues. Asummary of unresolved issues to inform future research is also provided.difficile” “clostridiumdifficile”, “policy”,“strategies”, “control”, “prevention”,“recommendation”, “guideline”, and“protocol.” Guidelines were defined as documents with systematicallydeveloped statements to assist practitioners and patients to make decisionsabout appropriate health care for specific clinical circumstances [Two reviewers  conducted an internet search (with the Google searchengine) in July 2015 of publicly available national or organizationalguidelines, related to CDI control . Keywords used included“mstances ,21,22.For each area, we first present a brief description of the guidance identified,followed by a summary of the quality of evidence assessment and strength ofrecommendations identified in the guidelines (see below). We then present adiscussion of current literature supporting recommendations or an overview ofrelevant issues.strong recommendation ; recommended,consideration, and legal requirement.Strategies were also classified as Basic, Special , orUnresolved Issue/Area ofResearch/Inconclusive in one guideline [Online SupplementaryDocument(OnlineSupplementary Document)).Seven documents graded the quality of evidence –29 (fouruideline . (See ApOnline Supplementary Document(Online SupplementaryDocument).Globally, 42 documents with targeted IPC recommendations for CDI were identified.patients , frequenpatients ); the plpatients ; and thepatients ,35. The patients , especiapatients ,31.Approaches to reduce transmission and to minimise host susceptibility by prudentantibiotic use were widely reported, but differences in other areas existed, asshown in Antibiotics: The strong risk posedby antibiotics for CDI was mentioned in the majority of documents  [studies) , judiciostudies) . Asignistudies) .ASP require adequate resourcing , thus they need to be welldesigned, integrated, audited, and monitored as parts of larger HAI IPCstrategies . FurtherProbiotics: Several guidelines recognized the suggested use ofprobiotics for the prevention of CDI. Nine documents labeled it as anarea of research or declared no recommendation canbe made. Others mentioned probiotics within descriptions related toCDI treatment and their potential role in preventing recurrences of CDI, butoffered no formal recommendation  for CDI[ for CDI. Althoug for CDI–72 and s for CDI. In lighGastric acid suppressants: Guidance indicates that proton pumpinhibitors (PPI) and histamine receptor antagonists (H2RA) should beconsidered as important risk factors for CDI but conclude that the issue remainsunresolved with no official recommendation for CDI  was generally recommended.However, extended contact precautions until the discharge of the CDI case [Isolation of CDI cases, confirmed and suspected, was widely recommended togetherwith the use of en–suite bathrooms or individual bedpans. Guidelines alsorecommended cohorting CDI patients  as they are non–sporicidal and do notremove C. difficile spores from contaminated hands. Guidance onbest practices varied and included the preferential use of soap and water whencaring for patients with CDI, especially during outbreaks, raising awareness andwarning health care providers about the limitations of ABHRs [The importance and challenges associated with effective hand hygiene in thecontext of of ABHRs ,48,49, oof ABHRs .Evidence assessment: The reported quality of the evidence on theprotective effect of isolation/cohorting and on the optimum duration of contactprecautions for CDI ranged from low to high. Evidence was graded of high qualityfor outbreak situations, in one guideline [uideline .The use of gloves and gowns was strongly recommended, but the quality ofavailable evidence was deemed mixed.area ofcontroversy [C. difficile spores. However, while the use of ABHRalone is not effective, its use does not appear to be detrimental in terms ofimpacting directly on CDI rates [The evidence on the effect of different hand hygiene practices was reported to beof moderate quality and the efficacy and usefulness of disinfection overhand–washing for hand hygiene purposes was reported as an troversy . ThesedDI rates .Discussion: It is noteworthy that there is a reliance onevidence from studies of multidrug–resistant organisms to prevent CDIthrough patient–care strategies [rategies  and a parategies ,22. AddiC. difficileacquisition rate in a facility with single–rooms in its ICU wards comparedto multi–bed rooms [C. difficilespores and evidence of contamination after resolution of diarrhea has been found[Challenges to elucidate the effect of isolation procedures as a means to preventtransmission of CDI will be influenced by each facility’s ability todetect CDI cases promptly, availability of isolation rooms, and duration ofmeasures. Nonetheless, recent attempts have been made to provide an estimate ofthe effect of isolating CDI cases. For instance, a retrospective cohort studyreported a 43% (95% CI 7–65%) drop in ed rooms . Anincred rooms . Althougen found,77, the C. difficile spores andhand washing is preferred (a message conveyed in most guidelines), concernsexist about compliance and detrimental effects of mixed instructions for handhygiene [C. difficile transmission [Hand hygiene and adequate use of PPE is vital for HAI prevention. Although theuse of ABHRs is inadequate to eliminate hygiene . Recentlhygiene . Clearlyhygiene , but a ssmission .C. difficile transmission. Chlorine–based andsporicidal agents were the most commonly recommended solutions. The use of othertechnologies, including UV light or hydrogen peroxide vapor, was discussed andhighlighted as an unresolved issue [All documents addressed the importance of environmental cleaning to prevented issue ,81. The Evidence assessment: Despite the high level of agreement acrossguidelines on the use of sporicidal chlorine–based solutions, the optimumtype of solution used for environmental cleaning of C.difficile was considered to remain as an area ofcontroversy [troversy . ThestrDiscussion: Published data on the effect of environmentaldecontamination with solutions currently recommended to prevent CDI transmission“have not been consistent” and the effect ofbleach has only been demonstrated in outbreak situations [C. difficile colonisedpatients, but more research is needed [tuations  and in ctuations . Beyonds needed .Education was defined as instructions, information, training, educationalcampaigns or workshops for health care facility workers, patients, or visitorson any aspect of CDI–IPC. Over half of the guidelines recommended aneducation component for education of staff , patients and/or visitors  oEvidence assessment: The quality of evidence to not conduct atest of cure after CDI’s symptoms resolution was awarded the highest scorein Europe, but moderate and low scores in recent guidelines by US–basedorganizations [C. difficileamong asymptomatic patients, with published studies being of moderate and lowquality. The strength of recommendation for CDI–targeted surveillancesystems ranged from strong to conditional, and of legal character. Mandatory orlegal components regarding reporting of cases were described for the UK,Ireland, and Hungary, compared to recommended laboratory–based sentineland facility–based voluntary systems in other countries.izations ,26. GuidDiscussion: Prompt case detection is vital for theimplementation of IPC strategies for CDI. Concerted efforts to better understandand address the burden of CDI, such as for the development of case definitionsfor surveillance [eillance  and impreillance  and diagThe use and implications of differential CDI case detection methods have beendescribed in recent studies ,15,90,91Over half of documents included a labeled and separate section forrecommendations during outbreaks or periods of increased incidence ,60,62,63Definitions based on exceeding triggers based on local CDI epidemiology ,34,35 wiDefined thresholds and criteria  As resources and logistics allow, setting up dedicated administrativesystems to manage admissions and staff to CDI–affected wards.Documents lacking a clear section for IPC of outbreaks, drew attention tospecific strategies by differentiating best practices during outbreaks ascompared to endemic periods . Our review underlines previous findings of a lack of uniformity in theassessment of evidence in guidelines [In light of previous widespread of idelines and suggC.difficile’s epidemiology continues to evolve and review ofguidelines by qualified local professional bodies is necessary to recommend bestpractices, based on the strongest quality of research. Such exercises have thepotential to support the development of context–appropriate tools fordifferent stakeholders, such as checklists, cleaning regimes, or educationpackages for health care workers , cleaniC. difficile is a common pathogencausing diarrhea [The paucity of guidelines pertinent to different types of health care settings isconcerning due to the increased incidence of CDI in the last 20 years. It isalso of concern that the overall effect of interventions in high risk settingssuch as LTCFs is under–recognized, where suboptimal compliance torecommendations has previously been identified , where Cdiarrhea , and whediarrhea . It is idiarrhea ,97. We rC. difficile–associated deaths, and detailedmethods to strengthen coordination of IPC teams.Beyond single and targeted strategies, organizational accountability, mentionedin few of the guidelines, demands particular attention as it is essential fordevelopment of country–specific implementation of strategies.Stakeholders’ roles and responsibilities, including that of governmentsand senior management staff, need to be clear and informed by evidence relevantto national structures. For instance, in the UK, investigations on significantrecent outbreaks have resulted in reports with recommendations which inform theroles of responsibilities of care and management staff ,99. RecoAvailable evidence indicates that multi–faceted programmes of CDIprevention have the potential to be substantially effective andcost–saving. In the UK, CDI–IPC strategies include legislativesupport , hand and environmental hygienecampaigns, and optimised testing/diagnosis techniques . In addiBox 1Area of controversy• Ability of diluted sodium hypochlorite or other sporicidal agents usedfor environmental decontamination .• Reliance on alcohol–based hand hygiene products .C. difficile without CDI history [• Management, including detection or isolation, of patients colonized(asymptomatic) with  history ,45.Unresolved issues (UI) or other (O) strategies identified inguidelinesCase detection, including roles of different health care workers inCDI–IPCNotification systems or laboratory–based alert systemsO: Role of community pharmacists ,medicalUI: Alert for changes in the rate, complications, or severity of CDI that mayindicate the introduction of new strains  or for cUI: Role of nurses (standing orders or nurse–driven protocols) .Transmission controlO: Use of bleach or cleaning wipes for disinfection or Fluorescent markers oradenosine triphosphate to measure organic material ,34–36.O: Development of protocols for disinfection of equipment and environment andmonitoring ,35.O: Visitor and staff management: visitors/staff with diarrhea should notvisit patients in the hospital .O: Facility design  ,35.UI: Use of gown and gloves by visitors .UI: Use of soap that contains antiseptic substances .UI: No–touch disinfection technologies as component of IPC strategies .Pharmacological agentsUI: Use of Vaccines and immunotherapies .UI: Role of probiotics as primary prophylaxis .UI: Restriction of gastric acid suppressants ,26.EducationUI: On–going assessment of CDI knowledge and intensified CDI educationamong health care and cleaning personnel .LTCF Research questions and relevant issuesNotification of CDI among LTCF residents to relevant staff in the acute caresetting if transfer is necessary ,58.Attention to CDI cases’ activities and placement (shared rooms) .Monitoring compliance with infection prevention and control guidance andadequate implementation of strategies  .The following research questions uestions C.difficile or CDI? If so, what determinants are responsible?• Are older patients truly at increased risk of acquiring • Are therapeutic strategies equally effective in older population andin younger adults?• Are differences between risks for CDI outbreaks explained byvariations in antibiotic exposure or are there other factors?C.difficile between residents in long–term caresettings?; What is the role of environment, and patient carepractices?• What are the variables that influence transmission of • What level of environmental cleaning, hand hygiene, or glove use isoptimal to limit transmission of the organism?• Are infection control recommendations different for patients withdiarrhoea compared with those without?Notably, there is a need for higher quality and comparable evidence on theattributable effects of existing CDI prevention measures, especially duringendemic periods ,18,22. AUnderstanding the prophylactic effects of pharmacological methods is an area ofgreat interest for CDI–IPC. Passive immunization to toxins TcdA and TcdBhas been tested for the prevention of recurrences. Given its high cost andtransient protection, active immunization is currently viewed as a potentiallymore cost–effective strategy. Both toxoid–based and peptide vaccinesare currently under development ,102. AnoThe present review has limitations. We relied on electronic search methods ofpublicly available documents. We also relied on translation to examine the fulltext of several guidelines and one document could not be translated . HoweverC.difficile has not been extensively examined . However, we did not retrieve IPC guidelines for CDI from severalcountries in South America, South East Asia, and Europe and none from Africa andEastern Mediterranean. We reviewed documents for Bulgaria, Hungary, Macedonia,Poland, and Romania, which were not included in a previous assessment of Europeanguidelines. Our review also found only a few clear and specific recommendations forLTCFs and nursing homes, mainly from North America, Europe and Western Pacific. Thisrepresents a large gap in an important global infection control area. Thus, thisreview adds to the existing collection of IPC guidance availability for C.difficile [Our review findings indicate a widespread awareness of the importance ofCDI–IPC guidelines but there are significant gaps which still exist. Thereview identified published guidelines from regions which have experienced anincrease in the incidence of CDI in recent years  and also countries where epidemiology of ifficile ,104 and This review of guidelines also highlights the need for greater internationalharmonisation in the assessment of the evidence underpinning IPC recommendations forCDI and for more research. Key strategies strongly and consistently recommended inpublished guidelines included: ASP, environmental and medical devices cleaning, useof protective equipment (gloves and gowns), and prompt isolation of CDI cases.Surveillance and education were also strongly recommended. High quality research,other than for high–risk antibiotics, is still needed. Our review shows thatmuch of the evidence underpinning the guidance was graded of medium to low level, bythe use of 4 different ranking schemes (assessed only in guidelines from the USA andEurope) and different primary studies were considered in different guidelines. Therecommended establishment of surveillance and standardised monitoring systems willhelp develop comparable studies and better evaluate the effect of interventions onCDI incidence in the future.C. difficile. Strategies on the use of probiotics, gastricacid suppressants, and on the potential roles of IPC stakeholders could benefit fromclear recommendations statements. Studies that provide more robust estimates ofinterventions’ effects in high–risk settings such as LTCF and ofemerging IPC technologies, such as vaccines, have the potential to informcoordinated efforts and advise priority setting exercises.Our review of unresolved issues and inconsistently identified strategies indicatesthat implementation of CDI–IPC measures variations between world regionsexist, mainly for hand hygiene and case detection approaches (including laboratorytesting policies). Country–specific organizational accountability rolesrequire key attention for successful IPC efforts and control outbreaks associatedwith