Economic evidence is influential in health technology assessment world-wide. Clinical Practice Guidelines (CPG) can enable economists to include economic information on health care provision. Application of economic evidence in CPGs, and its integration into clinical practice and national decision making is hampered by objections from professions, paucity of economic evidence or lack of policy commitment. The use of state-of-art economic methodologies will improve this. Economic evidence can be graded by ‘checklists’ to establish the best evidence for decision making given methodological rigor. New economic evaluation checklists, Multi-Criteria Decision Analyses (MCDA) and other decision criteria enable health economists to impact on decision making world-wide. We analyse the methodologies for integrating economic evidence into CPG agencies globally, including the Agency of Health Research and Quality (AHRQ) in the USA, National Health and Medical Research Council (NHMRC) and Australian political reforms. The Guidelines and Economists Network International (GENI) Board members from Australia, UK, Canada and Denmark presented the findings at the conference of the International Health Economists Association (IHEA) and we report conclusions and developments since. The Consolidated Guidelines for the Reporting of Economic Evaluations (CHEERS) 24 item check list can be used by AHRQ, NHMRC, other CPG and health organisations, in conjunction with the Drummond ten-point check list and a questionnaire that scores that checklist for grading studies, when assessing economic evidence. Cost-effectiveness Analysis (CEA) thresholds, opportunity cost and willingness-to-pay (WTP) are crucial issues for decision rules in CEA generally, including end-of-life therapies. Limitations of inter-rater reliability in checklists can be addressed by including more than one assessor to reach a consensus, especially when impacting on treatment decisions. We identify priority areas to generate economic evidence for CPGs by NHMRC, AHRQ, and other agencies. The evidence may cover demand for care issues such as involved time, logistics, innovation price, price sensitivity, substitutes and complements, WTP, absenteeism and presentism. Supply issues may include economies of scale, efficiency changes, and return on investment. Involved equity and efficiency measures may include cost-of-illness, disease burden, quality-of-life, budget impact, cost-effective ratios, net benefits and disparities in access and outcomes. Priority setting remains essential and trade-off decisions between policy criteria can be based on MCDA, both in evidence based clinical medicine and in health planning.The online version of this article (doi:10.1186/s12962-017-0063-x) contains supplementary material, which is available to authorized users. Economic evidence is becoming influential in health technology assessment (HTA) world-wide. However, most health care practices and procedures are not subjected to HTAs, thereby limiting the impact of economic evidence. CPGs offer the potential for economists to be centrally involved in increasing the cost-effectiveness of health care provision. However, examples of the use of economic evidence in such guidelines, and the subsequent integration of such evidence into clinical practice and national decision making are limited. This may be because of resistance from the professions, paucity of economic evidence or lack of policy commitment.Important components of the evidence used in the development of CPGs include the use of systematic reviews of the literature, decision rules, WTP, opportunity costs, and end of life/social value judgement along with techniques to grade the economic evidence. Such evidence can be graded by guidelines or ‘checklists’ to establish which evidence should be used to inform decisions based on the rigor of the methodology. New developments in all of these areas are cutting edge techniques that provide a platform for improved contribution by health economists in decision making world-wide and are considered in this paper. The principal purpose of this paper is to address the implications of these methodologies for the integration of economic evidence into CPG agencies world-wide and their implications for Australian reforms by the Parliament, governments and health services. These issues were discussed by Board members of the Guidelines and Economists Network InternationalThe GENI is an international association which enables health economists, epidemiologists, clinicians and medical experts world-wide to work with prominent international bodies, health services and governments. GENI’s agenda is to facilitate the effective integration of CPGs, economic and clinical evidence into national decision making and clinical practice in the health sector. GENI aims to forge linkages with bodies that set the standards for appropriate treatment under different conditions that may link to contracts or regulatory processes such as insurers and national government funding systems. Linkages to Evidence Based Medicine (EBM), service delivery and related government regulatory and funding systems are central. GENI’s has twelve international board members and a large twenty-nine member management team comprising CEO, Medical Advisory Committee, Directors, senior managers and researchers, with over 830 GENI LinkedIn Group affiliates.At the 9th IHEA Congress, five of GENI’s Board members from America, UK, Australia, Canada and Denmark discussed new methodologies and economic guidelines or ‘checklists’ for incorporating economic evidence into CPGs, clinical practice and national decision making. The session considered guidelines recently developed for the conduct and reporting of economic evaluations. These guidelines assess studies for decision-making in technology assessment for reimbursement or developing CPGs. The session also discussed use of CEA evidence in CPG processes in Australia by NHMRC, three Local Hospital Networks (LHNs) in Victoria and implications for related national and state health policy reforms led by the Council of Australian Governments (COAG) and reviewed by the Australian Parliament. An impetus for the international discussion at IHEA was a request from the NHMRC for input from GENI about the Council’s review of its processes to develop and approve guidelines in Australia using the costs and benefits evidence and also socio-economic evidence. The focus on these evidence based medicine (EBM) approaches involving CPGs and CEA evidence has also been an important feature in some reforms by the Australian Parliament, Governments and health services. The methodologies discussed in this paper may further assist this reform agenda, along with the deliberations of the NHMRC and other regulatory bodies that approve CPGs world-wide.inter alia, national implementation of LHN governance structures and hospital Activity Based Funding (ABF) based on the Victorian model. Recommendations were provided to COAG and the Senate based on Victorian evaluations of applications of NHMRC’s CPG methods using CEA in Victorian LHNs and the risk adjustment of ABF, given relevance to legislation for health agreements and related authorities. The Senate also considered reforms for palliative care, rural health and the Aged Care Quality Agency and recommendations were submitted to the Senate about crucial CPG and CEA issues. COAG’s 2016 Heads of Agreements on Public Hospital Funding will reduce ABF for specified adverse events, ineffective or harmful treatments and readmissions. Recommendations to the Senate about risk adjusting ABF and measurements of quality outcomes and disseminating NHMRC’s EBM methods Australia-wide are also discussed. The NHMRC’s CPG development process review is then considered.Firstly, we discuss Australian health policy reforms in Commonwealth-State health agreements involving, That is followed by consideration of the CHEERS Task Force which has consolidated guidelines for assessing health economic evaluation studies and recently published a consensus statement, along with the checklist. Recent developments for MCDA that broaden the objectives of evaluation in health care are considered along with the International Society for Pharmacoeconomics and Outcomes Research’s (ISPOR) MCDA Emerging Good Practices Task Force that has developed a common definition for MCDA in health care and good practice guidelines for conducting MCDA. The Hopkins Review is then discussed which examines if and how economic evidence impacts on health policy, including clinical guidelines, in the USA. It also examines the strengths and weaknesses of existing checklists used to assess best practices in economic evaluations. The review of studies also addresses the use of economic outcomes in policy and decision making. Finally, we conclude with implications of these deliberations world-wide for health services, governments and agencies that develop CPGs such as National Institute of Health and Care Excellence (NICE), US Guidelines clearing house, NHMRC and the USA Centre for Disease Control and Prevention (CDC).In Australia, there are several agreements between Commonwealth and State governments through the Council of Australian Governments (COAG), that specify health policy and reform directions, including the National Healthcare Agreement (NHA), the National Health Reform Agreement (NHRA), National Partnership Agreements and the Intergovernmental Agreement on Federal Financial Relations. Further, the April 2016 Heads of Agreement on Public Hospital Funding forms the basis of negotiations leading towards a time-limited addendum of the NHRA, in the form of an additional schedule, to commence on 1 July 2017.This suite of Agreements is designed to set out the architecture for a nationally unified and locally controlled health system. They also encourage improved quality of care and the cost-effective use of guidelines, clinical pathways and other EBM initiatives .State Centres of EBM Health Services and Workforce Redesign, use of NHMRC and international methods with economic and clinical evidence. an International Centre of EBM and Health Economics and the need for adequate risk adjustment of ABF [Antioch briefed COAG during 2008, 2009 and 2010 about the new health agreements. She also briefed the Australian Senate from 2010 to 2013 on COAG Agreements and related authorities and, in 2016, on new COAG Heads of Agreements. Some briefs included evidence that implementing NHMRC methodologies for CPG implementation with economic and clinical evidence in Victorian LHNs resulted in cost effective service provision in the context of ABF. She recommended the development of t of ABF .Antioch’s  COAG briAntioch’s  COAG briAntioch’s COAG brief, which was also published by the Senate Standing Committee on Finance and Public Administration Inquiry into COAG Reforms relating to Health and Hospitals , stated Antioch’s COAG and Senate submissions indicated that the ‘State Centres’ recommendation arose from national stakeholder engagement during her 2007 presentations in all Australian States and Territories and NZ about the implementation and evaluation of the initiatives she led in the Victorian LHNs and subsequent liaison with the Federal Health Ministers’ Office. The national presentations were sponsored by the Australian Health Care and Hospital Association and the Women’s and Children’s Hospital Australasia in the context of the renegotiation of National Health Agreements. She provided a Cost Benefit Analysis (CBA) of national implementation of the State Centres in her invited submission to the Senate Inquiry concerning the establishment of the National Health Performance Authority and also the Independent Hospital Pricing Authority which calculated net benefits of $269.6 m per annum (2006 prices) , 15. TheParliamentary Inquiries since 2010 made recommendations about policy and legislation to implement elements of the Health Agreements and other health policy. The Senate Report on the Federal Finance  Bill  cited ViThe Senate Inquiries during 2012 into Palliative Care in Australia and Factors Affecting the Supply of Health Services and Medical Professionals in Rural Areas addressed CPGs and the use of health economics to improve efficiency, outcomes and prioritization of health technologies and service delivery. Stakeholders in the Palliative Care Inquiry advocated urgent updated CPGs for palliative care, advanced care directives, dementia diagnosis, pain management and case management to enable improvements in cost effective service provision and continuum of care. Antioch recommended that CPG updates by COAG, Federal Department of Health and NHMRC could use CPGs by NICE and Agency for Healthcare Research Quality (AHRQ) USA CPG Clearinghouse concerning opioids, advanced care directives/planning and radiotherapy. She advocated that CEA evidence for new Australian CPGs in palliative care should be based on NHMRC methodologies . The SenStakeholders in the 2012 Rural Health Senate Inquiry argued for urgent mechanisms for rapid EBM translation of CEA evidence and CPGs into rural practice with the input of economists. They also advocated improved Evidence Based Planning (EBP) to identify rural supply and demand factors and prioritisation. Antioch  recommenAntioch  recommenUnder the April 2016 COAG heads of agreement, which cover public hospital funding from 2017 to 2020, the Commonwealth will provide $2.9 b in additional funding but growth is capped at 6.5% with some funding linked to quality outcomes. The agreements will reduce payments for specified adverse events, ineffective interventions, procedures known to be harmful and readmission rates and the Independent Hospitals Pricing Authority (IHPA) is working with the ACSQHC and COAG to develop implementation details , AntiochIn response to the Senate Select Committee on Health Inquiry on Health Policy, Administration and Expenditure in 2016, Antioch  recommenNHMRC is reviewing its CPG development and implementation methods, including the use of economic evidence and requested advice from GENI on use of the costs and benefits and socio-economic evidence. The advice was provided to the NHMRC in September 2013 and was based on the issues cited herein to 2013. More recent issues covered can further facilitate NHMRC’s review which is still underway. The NHMRC  ‘ProceduEuropean Journal of Health Economics, that scores Drummond et al. [The ISPOR 2013 CHEERS 24 item check list, discussed more fully in the next section, can be used by the NHMRC, in conjunction with Drummond et al’s 10 point check list, when assessing the economic evidence. A questionnaire by Antioch, Jennings, Botti et al. [d et al.  10 pointWe outline below international findings that can also guide NHMRC’s review of CEA thresholds for CPG development and approval. CEA studies should identify the health benefits offered by an intervention; the additional costs imposed on a limited healthcare budget; and the opportunity costs  from commitment of resources to an intervention. An intervention can be considered cost-effective if its benefits outweigh the opportunity costs of health benefits forgone. The opportunity costs in terms of forgone health benefits are reflected in most CEAs by using a cost-effectiveness threshold (CET) .When the maximum acceptable trade-off between costs and effectiveness is known, CEA can inform whether a program providing a trade-off between its costs and its effectiveness should be implemented. By using the maximum WTP per Quality-Adjusted Life Year (QALY), one can establish a decision rule for CEA. This view emanates from welfare economics, which states that welfare is maximized if goods are exchanged when there is a maximum WTP that exceeds the opportunity cost of the good . The NHMCEA used by NICE is an assessment of whether the health expected to be gained from using a new medical technology exceeds the health likely to be forgone as other NHS activities are displaced to accommodate the additional costs of the new technology. The CEA threshold therefore represents an estimate of the health forgone as services are displaced .The challenge for decision makers is to determine and use CETs that reflect supply-side constraints. However, there are few empirically estimated supply-side CETs. One exception is Claxton et al.  study thClaxton et al.  estimateNHMRC  includesOther developments about CEA thresholds in Australia are important to consider. Australia has public insurance coverage for drugs through the Pharmaceutical Benefits Scheme (PBS). Harris et al.  found thShiroiwa, Sung and Fukuda et al.  note thaImportantly, Drummond et al.  note thaWe now consider the CHEERS guidelines, which consolidate previous health economic evaluation guidelines. Requirements of other decision making bodies such as NICE, which uses the NICE Reference Case are also considered and may be instructive for deliberations of other CPG Agencies, including the NHMRC.CHEERS Elaboration and Explanation Report of the ISPOR Health Economic Evaluation Publication Guidelines Good Reporting Practices Task Force’ facilitates the use of the CHEERS statement by providing examples and explanations for each recommendation [The ‘endation .If economic considerations are to be incorporated into clinical guidelines, the guidelines need to reflect the current knowledge on the cost-effectiveness methodology. Therefore, guideline developers need to consult the existing literature on economic evaluation of health care treatments and programmes. The methods for the economic evaluation of health care programmes and treatments have been discussed in the academic literature  and in tCohort simulation tracks a hypothetical cohort of patients simultaneously through the model. Monte Carl simulation randomly selects a patient from the cohort and each patient transits through the model one at a time [Application of these standards for chronic disease interventions involves modelling the natural disease progression and the impact of competing interventions over the patient’s lifetime or similar long-term time horizon. Disease progression stages can involve a Markov process to track a hypothetical cohort of patients through disease stages. Each health state is defined via associated utilities and costs, with results expressed as cost per QALY . The Mart a time . By applt a time .Although various aspects of the methods of economic evaluation are a continuing source of debate, there is much more agreement about the need for reporting standards for studies. That is, although different studies may use different methods, all researchers should have an obligation to report their studies in a transparent fashion. This will help guideline developers and other users of economic evaluations to benefit the most from the existing literature. The most recent attempt to specify reporting guidelines for economic evaluations is the CHEERS initiative .The CHEERS Standards were developed by the Good Research Practices Task Force established by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). The Task Force comprised specialists in the economic evaluation of health care programmes and the editors of journals publishing cost-effectiveness studies of health care interventions. The reporting guidelines were developed through a process consistent with that of the CONSORT initiative for developing guidelines for the reporting of clinical trials .The CHEERS guidelines shown in Additional file and explain why they had adopted a particular approach. A good example of this is the selection of comparators. The CHEERS group felt that, in addition to describing the comparators included in their study, authors should also give their rationale for the selection e.g. One rationale would be to include the current standard of care in the jurisdiction where the study was conducted [One point to note is that, on occasions, the guidelines differ for economic evaluations conducted alongside a single clinical study  and those conducted as part of a decision analytic model, involving the synthesis of data from a number of sources. Several issues arose during the development of the CHEERS guidelines. The main issue related to whether reporting guidelines should merely require the authors of a study to describe their methods, or whether authors should describe onducted . The CHEonducted  to gradeDuring the 1970s and 1980s there was debate in the economics and ethics literature about relevant criteria for making resource allocation decisions in health care. At that time the focus was on clinical and cost-effectiveness. During the subsequent two decades, health technology assessment bodies emerged. There was growing recognition that other criteria are important, relating to equity, acceptability, burden and sustainability. More recently during the 2010s there has been growing interest in decision analytic methods for considering multiple criteria, driven primarily by NICE in the UK and shifts to Value-Based Pricing. MCDA is a methodology designed to help decision-makers when making complex choices—first developed in the 1960s and 1970s . Health Where a group is involved, the priorities of decision makers can conflict, rendering the decision-making process very complex. Reliance on informal processes during decision making can result in suboptimal decisions. A formal process such as MCDA is therefore required to evaluate alternatives and priorities to avoid inconsistency, variability, or a lack of predictability on the importance of specific factors or criterions in the decision. MCDA provides clarity on which criteria are relevant, their relative importance and how the information can be used in a framework for assessing available alternatives. It is an extension of decision theory that covers any decision with multiple objectives  established an MCDA Emerging Good Practices Task Force to establish a common MCDA approach in health care and develop associated good practice guidelines. MCDA is applied in various types of decision making in health care, including benefit risk analysis, health technology assessment, resource allocation, portfolio decision analysis, shared patient clinician decision making and prioritizing patients’ access to services. It allows for the inclusion of preferences and social values .Value measurement models develop and compare numerical scores to determine the extent to which one decision alternative is preferred over another. They often involve additive models—“weighted-sum” models, or “additive multi-attribute value models”. These multiply a numerical score for each alternative on a specific criterion by the relative weight for the criterion and then sum those weighted scores to determine a “total score” for each alternative.Reference-level modelling searches for the alternative that is closest to attaining pre-defined minimum levels of performance on each criterion, using linear programming techniques and aspiration or goal methods.Outranking methods make pair-wise comparisons of alternatives on each criterion which are combined to measure support for each alternative being judged the top-ranked alternative. Outranking algorithms include the Elimination and Choice Expressing Reality (ELECTRE) methods, Preference Ranking Organization Method for Enrichment of Evaluations (PROMETHEE), and geometrical analysis for interactive aid (GAIA)  [ review) .MCDA approaches can be classified into value measurement models, outranking models, and reference-level models .Value mValue measurement approaches are the most widely used approach in health care. However, determining which MCDA model is most appropriate depends on the analysis and decision maker preferences .Decision-makers in the health sector face a global challenge: how do we develop robust, evidence-based, scientific methods for priority setting? This challenge is often most evident in decisions concerning the coverage/reimbursement of new drugs and technologies. Peacock, Mitton and Cromwell et al.  indicateWhen comparing new versus existing drugs/technologies these criteria will often need to be traded-off against one another. For example, a new drug may be more effective, but it may be costlier and targeted towards a smaller sub-population. MCDA can assist decision-makers make trade-offs when resources are constrained. When such trade-offs exist, MCDA offers a structured approach to evaluating and identifying a preferred option by scoring and weighting the various attributes and deriving an aggregate ‘value’. This is in contrast with more traditional committee based approaches, where trade-offs either not discussed or are explored in a more qualitative manner.Some key methodological issues and challenges identified by Peacock et al. . There ai = criteria weights; j represents alternatives; sij = scores for alternatives for different criteria; WBS = Weighted Benefit Score.A simple model is:Priority setting can be conceptualized as a continuous quality-improvement reiterative process involving the following sequential steps: define the aim and scope; form an advisory panel of stakeholders; establish a program budget, develop the decision criteria; identify and rank options; make decisions and specify the rationale; undertake a decision review process and finally, evaluate and improve. The economic evidence and MCDA are applied at the decision criteria development stage through to decision making and rationale specification stage. A review of the literature identified 52 different criteria listed in 14 studies, with the most commonly occurring criteria, in descending order, including accessibility, reducing inequalities, effectiveness, alignment with strategic plan and policies, value for money, affordability and integration with other programs. Peacock et al.  comparedA review of the literature concerning criteria weights in MCDA methods found that four studies did not report weights and seven studies used allocation of points (direct rating). Two studies used a combination of ratio estimation and direct rating. One study used indifference methods (DCEs). Previous studies have also used swing weights (hybrid of indifference method). No studies have used gambles—all choices riskless .With regard to MCDA methods for aggregation rules, Peacock et al.  found thMCDA is useful from several perspectives. The primary aim of MCDA is to develop models of decision-maker objectives and their value trade-offs so that alternatives under consideration can be compared with each other in a consistent and transparent manner. The process is often more important than the numbers. It involves value focussed thinking and values clarification. MCDA practice suggests preferences are constructed as part of the decision-making process, not endowed. It is consistent with deliberative-analytic methods.There are several issues that have arisen involving international consistencies and controversies in the decision criteria used in priority setting, the methods used to elicit criteria weights, and the complexity and transparency of the decision-making process. These fall into four broad methodological challenges. Firstly, how do we decide which stakeholder’s criteria will count—society, governments, private sector, patients, families, health providers, or other decision-makers? Second, which methods should be used to elicit and describe decision-makers preferences, including the relationship between objectives and criteria. Further, the methods used to elicit importance weights for decision-making criteria can be controversial along with the type of aggregation model used to combine criteria scores.Is there any common ground? Economics has often focussed on prescriptive behavioural rules, based on utility maximisation and game theory. On the other hand, psychology has sought to explain actual individual behaviour, and why it can deviate from prescriptive rules. Interestingly, decision analysis, including MCDA, endeavours to combine elements of both approaches through both ‘prescription’ with ‘practicality’. These approaches all share a common heritage from von Neumann and Morgenstern .ISPOR’s 2016s Task Force report provides good-practice guidance on the implementation of MCDA for health care decisions. It incorporates a checklist to support the design, implementation and review of an MCDA; guidance to support checklist implementation; the sequencing of implemented steps and describes the incorporation of budget constraints into an MCDA. It also covers the skills and resources, including software, required to implement MCDA; and canvasses future research directions. ISPOR’s MCDA Good Practice Guidelines checklist is shown in Table Several areas for further research have been identified by Marsh et al.  to addreSystematic reviews are important in improving understanding of comparative effectiveness and relative value of medical interventions in health policy decisions and health guidelines . A studyeconomic evidence impacts on policy including clinical guidelines, used original studies applying quantitative or qualitative methods providing empirical data, in any country. The team excluded opinion or experienced-based articles without newly generated data. They defined ‘best-practice’ checklists as any original listing of recommendations that the authors used in economic evaluation. MEDLINE, EconLit, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase®, and ISI Web of ScienceSM searched 1991 to January 2012. The literature was searched for articles on economic evaluations, outcomes, and guidelines for the decision maker. Paired reviewers independently determined whether articles met eligibility criteria and then extracted data.The review on y or specific decisions, such as reimbursement decisions. Of 37 observational studies on policy impact, 11 (30%) received a favourable rating on more than three of the 8 items on the GRADE quality checklist. Five studies were graded of intermediate quality evidence [Reviewers assessed the quality of each reporting study on policy impact using the standard grading recommendations (GRADE). Of 19,127 titles initially screened, 43 studies on policy impact were included, with all but five published since 2000. The most frequently studied countries were the United Kingdom (15), and Australia, Canada, and the United States (5 each). Most studies (27 studies) considered national-level policy and examined the key health actors involved. Important topics were reimbursement and health package decisions, and priority setting in programming. Thirty studies found evidence that use of economic evidence had a substantial impact on health care policy making, 27 of which emphasized at least one other criterion, such as equity considerations, usually ill-defined (14 studies), clinical effectiveness, budget impact, ethical reasons, and advocacy arguments. The thirty studies confirmed the acceptance of economic evidence as having an impact on either general policevidence .The study concerning best practices for conducting economic evaluations in health care was a systematic review of quality assessment tools . The objThe study involved a review of the criteria for judging that an economic evaluation is of sufficiently high quality to be useful. It also considered the importance of different aspects of the evaluation; and the extent to which high quality on one aspect of an evaluation can compensate for lower quality items. The methods involved a systematic search until January 2012 for articles and guidelines for decision makers. In MEDLINE, EconLit, CINAHL, Embase, and ISI Web of Science. They found that ten peer-reviewed journal articles reported an original checklist. The first in 1992 and last in 2011 (EVEREST and CHEERS in 2013). The number of items ranged from 11 to 57. Perspective was a criterion in all 10. The ten checklists reviewed included those by Adams , Gerard Eleven criteria were in 7–9 lists: including target population, alternatives, study question, design, measurement, valuation, outcome identification, outcome measurement, time adjustment, sensitivity and uncertainties, presentation of results, generalizability, and incremental analysis. Four had evidence of excellent test–retest reliability: none had evidence of excellent inter-rater reliability in two or more studies. Three had evidence of excellent criterion validity, comparing checklists or expert ratings. They concluded that several well-developed checklists exist for investigators, reviewers, and journal editors to use in efforts to ensure more informative and transparent evidence .They also analysed the usefulness of economic evaluation data in systematic reviews of evidence . This adThey found that all stakeholders, including insurers are interested in economic data and the perspectives of patients, providers, and manufacturers. Patients and providers determine the demand for care and manufacturers determine the supply. Decisions are to be based on incremental cost, magnitude of the incremental effect, and the probability that economic evidence will change a decision. There is a high priority for evidence if there is a small effect at a high level of expenditure with a high probability of influencing a decision.Economic data are of interest at many policy levels including approval and monitoring of services, formulary inclusion, insurance coverage, reimbursement rate, preferred practice guideline, technology adoption or non-adoption, or clinical management. They may include information on cost-effectiveness, productivity changes related to disease, price data, responses to price changes. The following areas were of greatest interest: demand for care: time, distance, innovation price, price sensitivity, substitutes and complements, WTP, absenteeism and presentism. Supply of care was of interest including economy of scale, efficiency changes and return on investment. The equity and efficiency measures of particular interest were cost of illness studies; disease burden, Quality of life, budget impact, CEA ratio, net benefits and disparities. Existing economic data may be sufficient. Occasionally, it may be necessary to perform new evaluations in case of inadequate data .There is some evidence that Drummond’s 10-point checklist , when usCOAG, AHMAC, IHPA, ACSQHC and the Australian Department of Health could expedite the Australia-wide dissemination of NHMRC’s methods on using the costs and benefits in CPGs and the subsequent revised methods. This may assist the health industry prepare for implementation of COAG’s 2016 Heads of Agreements on Public Hospital Funding which reduces ABF for specified adverse events, ineffective or harmful treatments and readmissions. IHPA, ACSQHC and COAG can risk adjust ABF and quality outcome measurement, through analysis of complexity markers for state-wide referral services such as transplantation, major trauma and cystic fibrosis to enable equity.


For the prevention and control of chronic diseases, two strategies are frequently highlighted: that public health should be evidence based, and that it should develop a multisectoral approach. At the end of a natural experimental study of the health impacts of new transport infrastructure, we took the opportunity of a knowledge exchange forum to explore how stakeholders assessed, negotiated and intended to apply multisectoral evidence in policy and practice at the intersection of transport and health. We aimed to better understand the challenges they faced in knowledge exchange, as well as their everyday experiences with working in multisectoral remits.In 2015, we conducted participant observation during an interactive event with 41 stakeholders from national and local government, the third sector and academia in Cambridge, UK. Formal and informal interactions between stakeholders were recorded in observational field notes. We also conducted 18 semistructured interviews reflecting on the event and on knowledge exchange in general.We found that stakeholders negotiated a variety of challenges. First, stakeholders had to negotiate relatively new formal and informal multisectoral remits; and how to reconcile the differing expectations of transport specialists, who tended to emphasise the importance of precedence in guiding action, and health specialists’ concern for the rigour and synthesis of research evidence. Second, research in this field involved complex study designs, and often produced evidence with uncertain transferability to other settings. Third, health outcomes of transport schemes had political traction and were used strategically but not easily translated into cost-benefit ratios. Finally, knowledge exchange meant multiple directions of influence. Stakeholders were concerned that researchers did not always have skills to translate their findings into understandable evidence, and some stakeholders would welcome opportunities to influence research agendas.This case study of stakeholders’ experiences indicates that multisectoral research, practice and policymaking requires the ability and capacity to locate, understand and communicate complex evidence from a variety of disciplines, and integrate different types of evidence into clear business cases beyond sectoral boundaries.The online version of this article (doi:10.1186/s12889-016-3940-x) contains supplementary material, which is available to authorized users. WHO Action Plan 2013–2020  And […] the add-ons are always the first things to be cut when budgets are squeezed…” Even shared interests required to be allocated to specific budgets; designated “shared priorities budgets” were considered very limited. Public health policymakers explained that in the absence of shared budgets, a “health benefit” business case was often too readily considered a clear responsibility for the health budget. At the same time, they saw a danger in considering health as a pure “add-on” to other priorities and benefits such as economic growth, because “add-ons” were vulnerable in a time of financial austerity and budget cuts.p value and a good return on investment, and a high impact, […] but transport people would like to hear a good story and know that it’s […] working”. “…this is a bit of a generalisation here, but in general public health people would love to see […] an effectiveness study with a low During the forum, a heated debate focused on the challenge that sharing priorities and budgets also meant co-developing business cases, despite “the use of different language” in health and transport. This was not so much about sector-specific language – all were familiar with the terminology surrounding active travel, for example – but about different expectations of what was considered relevant evidence. Participants described this as a “culture shock” that inexperienced public health trainees, in particular, might experience when entering the world of local policymaking. The consensus was that health colleagues were very used to the notion of evidence synthesis and the status accorded to evidence from randomised controlled trials (RCTs), guided by the notion of an “evidence hierarchy”. In contrast, transport colleagues were more interested in precedence – whether something had been done before and “worked” elsewhere.“[…] there’s a need for key headline quantitative stuff, so like charging for parking we reduced car use by 20% which in turn increased active travel by 60%, […] which is all great […]. But at the same time we need those stories as well because they come to be the ones that people really listen to and can relate to, and certainly in the political environment that we’re working in, the members would much rather hear ‘Barry from Fakenham […] said […] he’s now walking five times a week and he would never have done this unless they started charging for parking’”. While this divergence between evidence synthesis and precedence was largely explained by different disciplinary and training backgrounds, the potential tension between “hard facts” and “good examples” was often reconciled in practice. To make a convincing argument when addressing and lobbying politicians and decision-makers, a third translational effort was described, connecting personalised examples with snappy cost-benefit statistics. While business cases would benefit from convincing statistics demonstrating effectiveness, if a scheme “worked” or “paid off” across sectors, participants felt that elected members liked to see such numbers translated into a relatable illustration.Participants’ descriptions of priorities and preferences, which related to evidence synthesis and precedence, did not, however, map onto neat juxtapositions in their experience with research evidence. Evidence in this field is often derived from evaluating complex population health interventions . In the “…one calculation I want somebody to make is how much of the new development around the city would be able to take place in another city where there isn’t a strong cycling culture […]. So you know much of the development in, as I say, that’s able to take place around Cambridge, in another city possibly wouldn’t be able to because they wouldn’t be viable in transport terms…” Participants were very aware that the evidence produced in this particular study was inherently tied to its setting, Cambridge. In this university city, cycling is relatively common across all ages and backgrounds and compared to the rest of the country , and theClosely related to this challenge of generalisability, participants also understood that evidence was rarely clear-cut when derived from natural experimental studies aiming to evaluate large-scale structural changes, the outcomes of which are difficult to measure, let alone predict. Transport specialists were perhaps more at ease with ambiguous evidence, as they were less experienced with working with clear-cut evidence from RCTs, as described above. However, those working in the health field were not necessarily better equipped to critically appraise the quality and strength of evidence that was not produced through RCTs.“… if you take an RCT about an intervention clearly it’s incredibly important and is very, very clear, but most research is not 100% or anywhere near that to be honest”. “The difficulty is as soon as people have to […] critically appraise things themselves for what’s in it for them you’re going to lose a lot of people because they don’t have the skills or the time or the inclination to do it”. During the forum discussion as much as during the interviews, there were calls for knowledge exchange to include translation of how the evidence was produced, not merely what it meant. Participants said that colleagues often lacked the necessary skills to assess evidence and how it was produced; or to understand how evidence about other interesting and relevant issues, such as the monetary value of particular interventions, might be difficult to produce.potential to influence commuting behaviour through parking charges that warranted further intervention studies to establish a causal relationship – a nuance of research design that seemed less apparent, or less important, to many participants from policy and practice.A case for this was the presentation of evidence from the busway study about the potential effect of charging for car parking on promoting the integration of more active travel into people’s commuting journeys. Understanding of the evidence that was presented was variable, but it was received overwhelmingly positively by the participants as clear-cut evidence showing unambiguous evidence that parking fees could effectively deter people from commuting by car. This sparked much debate about the seductive simplicity, but also the political contentiousness, of seeking to influence behaviour in this way. The heated discussion and subsequent interview responses included references to the need for action if presented with such convincing and  easily-implemented evidence, but also warnings that any such scheme could easily be derailed if it were seen to oppose the political or economic mainstream that worried more about the acceptability of the measures to the electorate. From a research perspective, however, the challenge was different. The researchers who presented the findings on parking charges considered the evidence to be relatively weak. The observational epidemiological research design had indicated only evidence of associations, and therefore of the “…policymakers make decisions on the basis of incomplete evidence because if you waited for complete evidence you’d never make a decision; so there’s this trade-off […]. So it would be good if the debate wasn’t centred on sufficiency of evidence where […] policymakers say ‘does it work or doesn’t it work?’ and the researcher [...] saying ‘well, it’s not as simple as that’ because then it’s a dead debate because it doesn’t take us anywhere”. While the transferability of research findings was a concern, some participants pointed out that decision-making in policy and practice was routinely based on such partial, incomplete evidence.“I’ve started using ‘evidence-informed’ recently. […] you want the scientific evidence but then you’ve also got other sorts of evidence that politicians or policymakers […] will take into account […], and also not all evidence agrees with each other, you do ten studies, they don’t come out with a nice clear answer, […] and actually that doesn’t really matter because what you need then is someone with the judgement to pull those together, use that to inform their decision”. Participants from all sectors discussed this challenge of “not knowing enough” as a common, manageable experience for decision-makers but also as a weakness for lobbying them convincingly. From a research perspective, this was debated in terms of a shift from “evidence-based” to “evidence-informed” practice in public health. This was echoed by suggestions that while practitioners and policymakers might be quite experienced and familiar with the notion of “evidence-informed” practice, researchers might need to be more confident in conveying the “best available” evidence rather than highlighting remaining scientific uncertainties that might delay action.“I always try to say that health […] is a very strong lever to use when we want to talk about active travel. So if I can supply the data that says, if so many more people could cycle or walk, then we’d have so many fewer heart attacks, which means so many fewer admissions, or so many fewer sick leave days, or something. That’s very powerful”. Participants also described their efforts to use evidence strategically. Their comments in both the open forum discussion and individual interviews described a tension when making a case for “health” as a strategic and convincing piece of an argument. Epidemiological evidence for the health benefits of physical activity had political traction, but concrete evidence for the effects of particular interventions – that infrastructure A leads to health outcome B – was hard to come by.“…monetising the costs to the healthcare sector of other policies, so if we make this change to the transport system it will benefits their healthcare system to the tune of X million Pounds is something that some people are really uncomfortable with doing because obviously it’s quite a flawed and simplistic thing to do, but unfortunately if you want to change decision makers’ minds you do need to put it in a way that they understand […]”. On the one hand, a health argument was considered to carry weight when addressing decision-makers, and epidemiological evidence could even be used as proxy cost-benefit evidence because a healthier population or workforce would surely mean lower healthcare costs or more productivity. On the other hand, policymakers and practitioners expressed their frustration that a clear monetary value could often not be attached to a specific infrastructural intervention – in particular, not to the case study at hand – and that this could weaken the argument. Public health was often seen as a “long game”, involving health outcomes that might range from the prevention of chronic disease and early death to more immediate but less quantifiable outcomes such as reduced absenteeism or better mental wellbeing. While they understood that a complex infrastructural change might result in health co-benefits that took a long time to emerge and were difficult to measure or convert to a monetary value, some regretted the lack of an explicit health economics element in the busway study.Finally, participants were all not only receivers of knowledge exchange exercises but – true to the notion of “exchange” – producers of such efforts. Many of our participants not only operated at the intersection of different sectors, and often disciplines, but also had experience in research, practice and/or policymaking, having moved between different professional roles in the course of their careers. Understandings about the direction of influence were echoed by many, but also contested.“So the difficulty is both sides, it’s not just policymakers ignoring evidence or not understanding evidence, it’s researchers translating evidence into usable decision, actionable things”. “I work a lot supervising public health registrars and they have to do a lot of work to simplify their message down to a level where it will actually be engaging and compelling and easy to understand, and I have to do a lot of work with them to keep rewriting the same thing over and over until they get it simple enough that someone [understands] who was in a hurry”. Most participants agreed that it was very important that research spoke effectively and relevantly to issues in policy and practice. However, they recognised that not all researchers might be interested in communicating their research, and that not all policymakers and practitioners had the resources, capability or political will to base their advice and actions on scientific evidence. Knowledge brokers and generalists could help bridge this gap, and some participants attempted to fulfil this role themselves, based on their work across remits.“We’ve got practice going along, we’ve got research saying this is better, but […] they’re just not coming together. […] I mean, research as well […] needs to know what’s coming up, so that they can start working towards it, needs to know what local priorities are. […] But it’s difficult […], I’ve asked for forewarning of potential projects […] and I just get diverted to a website that is publicly available. That’s not helpful. […] People are very scared of sharing and exchanging knowledge, and I think it’s detrimental in the long term”. The other direction of knowledge exchange, heatedly debated both in front of colleagues and anonymously during interviews, was the direction from policy and practice to research. Some suggested that for research to achieve impact, perhaps the policy and practice sectors should have more influence on setting research agendas. Some participants would have liked to see researchers involving policymakers and practitioners from the start of planning new research projects, and that this required effort from both sides and openness to share ideas and plans with each other.“I’m not sure that I think, you know, practitioners should be directing the agenda of academia. That would concern me a bit I think, you know. I think academia should be a very much an independent force…” Others cautioned that evidence produced by research organisations would need to be seen as independent; otherwise it would lose its power, authority and impact.“[…] ideology informing the research that’s done and […] it always has and always will. I think the best that we can do is be open about it and clear about the drivers behind it and understand that this is going to govern the research questions that we ask […]. So I don’t subscribe to the idea that there’s, you know, we’re building an objective body of knowledge and evidence which policymakers should adopt…” This question of the level of involvement in research, and whether there might be a limit to such involvement, seemed to depend on the topic matter and context, and was perhaps most importantly felt in regard to politically charged and highly polarised topics. The importance of assumed “stakes” was raised in relation to contentious schemes such as car parking charges, but some participants felt that any infrastructural “anti- or non-car” scheme would be better supported by independent academic evidence than by third sector advocacy. Others pointed out that evidence was never neutral, and research was certainly not ideology-free.In this ethnographic case study, participants had experienced knowledge exchange in their daily practice as a variety of challenges, tensions and negotiations. Their new roles in the multisectoral field of transport and health varied in formality and priorities which had to be negotiated within and between sectors. Language and expectations of the type of evidence differed and created similar challenges. The most pronounced difference was that between what was described as a preference for precedence by transport specialists, and for systematic evidence synthesis by public health specialists. However, evidence was experienced as contextual, complex, sometimes conflicting and often incomplete. Complex research designs produced partial evidence, but participants suggested that decision-makers were used to making decisions despite such uncertainties. That said, evidence strength could be rated in different ways, sometimes shaped by the ability to “read” evidence correctly, and even seemingly clear-cut evidence could be politically contentious. In addition, the potential health co-benefits of transport schemes were appreciated to have traction in arguments made to decision-makers, but were not necessarily easily investigated by researchers or translated into convincing cost-benefit analyses. Finally, knowledge exchange happened within a context of multiple directions of influence and expectations thereof. Participants discussed that researchers needed the skills to make their evidence understandable, and that some might not be interested or well suited to undertake this task themselves. Instead, knowledge brokers might be better placed to do such translational work. Finally, policymakers and practitioners considered the benefits, but also the potential disbenefits, of influencing research agendas more directly.The findings echo much of the knowledge exchange literature, such as the necessity of translating knowledge into different sectoral and disciplinary languages and having the time and skills to do so , 26, 27,This case study of evidence derived from a natural experimental evaluation represents the challenges of much public health research. Interventions of this kind outside the health sector can create a natural opportunity to produce new learning about how best to produce beneficial outcomes across the health and transport sectors. However, evaluating the impact of complex interplays of social, environmental and political-economic contexts on population health behaviour produces complex evidence that can rarely be distilled into simple, definite answers . Rather Lipsky’s seminal work on “street level bureaucracy” was one of the first that aimed to understand individuals’ efforts to implement organisational decision-making with its inherent uncertainties . He founPart of the uncertainty is that evidence is not always understandable and may be produced through methods that are novel, specialised or complex. Studies from the field of environmental public policy, for example, have described how practitioners and policymakers have to grapple with new research technologies such as modelling, and those skilled to read this evidence are better placed to influence policy outcomes . In our Also, complex population health research does not produce evidence to influence individual clinical decisions, but aims to effect population-level responses in policy and practice and is therefore more exposed to political and public scrutiny . This isWhile much of the knowledge exchange literature has focused on the practice or policy side, it is equally important to note that evidence production – research – is also not free of ideology and politics . Some ofMore research about the uncertain and political nature of evidence is clearly still needed as these play out in different public health contexts in research, policy and practice. While this case study particularly focused on the context of active travel and transport as a target of population health intervention, it indicates that through the lens of a particular context of transport and health, larger barriers to knowledge exchange in multisectoral, evidence-based public health can be identified , 37. MosWe believe the strength of the research design was its case study approach; using a “real life” example of knowledge exchange attached to a particular research project enabled us to understand the contextual factors that shaped, supported and hindered the use of evidence by our stakeholders , 42. ExpOur research design also had limitations. We did not include much of a researcher perspective in this case study, and mostly interviewed stakeholders in policy and practice roles. This was mainly because most of the researchers who attended the forum were attached to the busway study, and were asked to write field notes for this case study. However, some of our participants from policy and practice had experiences as researchers themselves and included reflections from a research perspective. National government representation was also limited at the forum, and therefore in this study. This may have reflected the limited availability of civil servants shortly before a general election in particular, or for knowledge exchange events more generally. This study therefore included a self-selected pool of participants with a particular interest in the multisectoral subject matter and perhaps in evidence-based practice and policy and knowledge exchange more generally. Similarly, this may have limited the responses in the interviews, as those agreeing to be interviewed may have been particularly interested in the topic. While qualitative purposive samples aim for knowledgeable, “information-rich” participants , discussStudies of multisectoral population health interventions, such as those aiming to encourage physical activity by changing the built environment, produce complex evidence and aim to inform practitioners and policymakers across a variety of sectors. Knowledge exchange in multisectoral public health requires people who can locate and interpret evidence from a variety of disciplines, and can find a common language to integrate such evidence clearly into business cases. Practitioners and policymakers would welcome help from researchers to translate complex, challenging and often incomplete evidence into clear recommendations, and clearer mandates from politicians for health as a priority in all remits. These would strengthen their efforts to integrate health benefits in business cases and promote multisectoral cooperation.


Health literacy is an important health promotion concern and recently children and adolescents have been the focus of increased academic attention. To assess the health literacy of this population, researchers have been focussing on developing instruments to measure their health literacy. Compared to the wider availability of instruments for adults, only a few tools are known for younger age groups. The objective of this study is to systematically review the field of generic child and adolescent health literacy measurement instruments that are currently available.A systematic literature search was undertaken in five databases  on articles published between January 1990 and July 2015, addressing children and adolescents ≤18 years old. Eligible articles were analysed, data was extracted, and synthesised according to review objectives.n = 6). Among the instruments, 31 different components related to health literacy were identified. Accordingly, the studies exhibit a variety of implicit or explicit conceptual and operational definitions, and most instruments have been used in schools and other educational contexts. While the youngest age group studied was 7-year-old children within a parent-child study, there is only one instrument specifically designed for primary school children and none for early years.Fifteen generic health literacy measurement instruments for children and adolescents were identified. All, except two, are self-administered instruments. Seven are objective measures (performance-based tests), seven are subjective measures (self-reporting), and one uses a mixed-method measurement. Most instruments applied a broad and multidimensional understanding of health literacy. The instruments were developed in eight different countries, with most tools originating in the United States  contains supplementary material, which is available to authorized users. Health literacy is currently experiencing increased attention in contemporary research, practice, and policy –7. In heCurrent research links limited health literacy to a lack of health knowledge, poor disease management skills, medication treatment errors, inadequate health communication skills, difficulties in navigating the healthcare system, poor access to healthcare services, increased healthcare costs, and poorer health outcomes . In EuroMany scholars argue, in accordance with findings from developmental research, that effective health literacy development begins in early childhood , 20, 21 To identify the needs of children and adolescents and to address specific target areas for action, validated and reliable measurement instruments to assess health literacy are crucial , 26, 27.instrument characteristics;country of origin and setting;target or age group;questionnaire administration mode;participant participation in the development process of the questionnaires;psychometric properties;contextual factors;underlying health literacy models/definitions; andscope of measured components.This present systematic review, therefore, aims to identify, retrieve, analyse, and assess available generic health literacy measurement instruments for children and adolescents ≤18 years old. To specifically and exclusively focus on generic health literacy tools only, measurement tools for domain-specific health literacies, such as mental health literacy, oral health literacy, eHealth literacy, and media health literacy, were excluded from this study. In this review specific attention will be paid to the following:This systematic literature review was conducted as part of the MoMChild project , which is part of the German Health Literacy in Childhood and Adolescence Research Consortium (HLCA).The research team conducted a systematic review of the literature on health literacy measurement instruments for children and adolescents ≤18 years old. To ensure transparency and completeness of the research and to improve the reporting of this review, the 27-item checklist of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA statement) was adopted and included in the supplementary information files of this article. The PRISMA flow diagram  developed the search strategy/method and algorithm. Two researchers  independently searched the databases using identical search algorithms for the respective databases and analysed the data. Three researchers  checked the initial results, and five researchers  critically discussed the search outcomes.The search was performed in five databases: Medline via PubMed, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCOhost, the American Psychological Association (APA) PsycNET search platform, the Educational Resources Information Center (ERIC), and the German Fachinformationssystem Bildung (FIS).The five abovementioned databases were initially searched from May – July 2015 using a composite search term that comprised a combination of three terms for papers published between January 1990 and July 2015. To combine search terms Boolean operators (AND/OR) were used. Wildcard characters were used in order to cover all spelling variations of the search terms. The first search term was “health literacy”, the second addressed the target population , and the third term focused on either one of ten common terms/topics in the context of measurement tools . In the FIS, the search terms “Gesundheitsbildung” and “Gesundheitskompetenz” were used. Additionally, reference lists of included full-text articles were searched manually (OO) for potentially relevant publications. The following algorithm has been used in PubMed, while the search strategy used in PubMed was adapted to the specifications of the other four databases  AND ((child*[Title/Abstract]) OR (adolescen*[Title/Abstract]) OR (youth[Title/Abstract])) AND ((measur*[Title/Abstract]) OR (test*[Title/Abstract]) OR (tool*[Title/Abstract]) OR (instrument*[Title/Abstract]) OR (questionnaire*[Title/Abstract]) OR (assessment*[Title/Abstract]) OR (screen*[Title/Abstract]) OR (survey*[Title/Abstract]) OR (psychometric*[Title/Abstract]) OR (review*[Title/Abstract])))For the purposes of this search, the following inclusion criteria were used  participated in the screening process. Screening took place in two steps: (1) title/abstract screening was performed by two researchers  independently, and (2) full-text analysis of the eligible publications was performed by three researchers . Two researchers  checked the results independently. To find consensus and validate the findings, expert consultations were performed by approaching the other authors . Literature was imported to the reference management software CITAVI 5. The characteristics of the health literacy measurement instruments identified in the relevant publications were analysed and extracted by two researchers independently  based on the objectives of this review. The decision on what data to extract from the articles was based partly on (a) former systematic reviews of health literacy measurement tools , 38 and N = 1132 publications matching the search criteria . The manual search led to the identification of an additional n = 2 articles  were excluded from qualitative synthesis yielding N = 15 articles reporting 15 different questionnaires.This review focused exclusively on generic health literacy measures. The search process identified Among the identified instruments  provided the exact age of the target group, but this was not specified in the other four studies , 44–46. The analysis showed that seven health literacy tools were based on subjective measurement using self-reporting questionnaires , 53, 54.Only two articles reported the involvement of participants in the development of the questionnaire by conducting qualitative research in order to derive meaning about health literacy from the target population , 49. MasNearly all the studies reported the psychometric properties of the instruments (see Table r = 0.09–0.93). However, concurrent validities were often not tested or not reported. REALM-teen [r = 0.83) and SORT-R (r = 0.93). TOFHLAd [r = 0.59) and REALM (r = 0.60). HLS-EU-Q-47 moderately correlated with NVS (r = 0.14), as did the short version, HLS-EU-Q16 (r = 0.09) [r = 0.82). Test-retest reliability was reported for one instrument and was demonstrated to be strong (r = 0.98) for REALM-Teen [Reporting on the convergent validity of most instruments was insufficient. For those provided, these data were positive and moderate (ALM-teen  correlat TOFHLAd  was stro = 0.09) . In termALM-Teen . AlthougALM-Teen .Additionally, Hubbard and Rainey  selectedThis review identified five instruments that measured health literacy related contextual factors , 49, 53.Each instrument used a different, study-specific understanding of health literacy, and two instruments were underpinned with a health literacy definition that was specifically developed for the instrument , 53. In The analysis revealed three different conceptual approaches that underpin the instruments: health literacy was based on (i) a functional literacy model in three studies –52, (ii)To ascertain the scope of the measurement approach, a content analysis of the measured components (sometimes referred to as “dimensions”) was performed that could identify a wide array of skills, competencies, abilities, or certain actions covered by the instruments. To closely relate to the original published study and thereby avoid any false interpretation, we decided to label a specific component as if the authors of the original article had named it explicitly. For example, in Brown et al. , the autThe main objective of this review was to systematically identify, retrieve, analyse, and assess available generic health literacy measurement tools for children and adolescents ≤18 years old. Despite the gap in health literacy research on children and adolescents, our search found 15 available generic measurement tools published between 1990 and 2015. This is the second known systematic review on health literacy measurement tools for children and adolescents. The previous one was conducted by Ormshaw et al.  and consWhile seven health literacy instruments nearly 50%) have been used in North America , 50–52, % have beRegarding the settings in which health literacy was measured, it seems that schools and other educational settings are main loci of interest for measuring the health literacy of children and adolescents. This review found that many health literacy tools are based on school health topics or curricula –46, 48. The findings of this review suggest that the age groups from 11 to 18 years are well reflected by existing health literacy tools  are informed by a multidimensional, multifactorial, or multifaceted and thus broad understanding of health literacy. Still, each understanding is more or less unique, and therefore, comparisons across these health literacy assessment instruments and associated study results are difficult to undertake. Additionally, as the instruments do not cover all their proposed dimensions and components at the operational level, there seem to be some uncertainties regarding how to transform all aspects of the theoretical model into a testable concept within a measurement tool. It is also not clear why a certain model or definition is provided at the conceptual level when at the operational level, something else is indeed being measured. However, when school health education  is the foundation of the health literacy framework, it seems that there is more precise clarification as to why, how, and for what purpose a model was designed and operationalised [Compared to the narrow ‘functional literacy’ approach to health literacy, all other instruments Additional file 2:Search methodology. (PDF 201 kb)


Tylophorine analog DCB-3503 is a potential anticancer and immunosuppressive agent that suppresses the translation of cellular regulatory proteins, including cyclin D1, at the elongation step. However, the molecular mechanism underlying this phenomenon remains unknown. This study demonstrates that DCB-3503 preferentially binds to heat shock cognate protein 70 (HSC70), which is a determinant for cyclin D1 translation by binding to the 3′-untranslated region (3′ UTR) of its mRNA. DCB-3503 allosterically regulates the ATPase and chaperone activities of HSC70 by promoting ATP hydrolysis in the presence of specific RNA binding motifs (AUUUA) of cyclin D1 mRNA. The suppression of cyclin D1 translation by DCB-3503 is not solely caused by perturbation of the homeostasis of microRNAs, although the microRNA processing complex is dissociated with DCB-3503 treatment. This study highlights a novel regulatory mechanism of protein translation with AUUUA motifs in the 3′ UTR of mRNA by HSC70, and its activity can be allosterically modulated by DCB-3503. DCB-3503 may be used to treat malignancies, such as hepatocellular carcinoma or breast cancer with elevated expression of cyclin D1. Tylophorine indica245678910rac-crytopleurine inhibit global protein synthesis at the elongation step of translation1215Tylophorine analogs were first identified and isolated from the herbal medicine Polypeptide/protein synthesis is directed by mRNA translation in the cytoplasm. Ribosome is associated with mRNA during translation, ensuring correct access of activated tRNAs and containing the necessary enzymatic activities to catalyze peptide bond formationThe 70 kDa heat shock proteins (HSP70/HSC70) play fundamental roles in protein homeostasis by chaperoning correct folding, translation, translocation, disaggregation, and degradation18In the current study, we demonstrate that tylophorine analog, DCB-3503, specifically binds to HSC70. DCB-3503 allosterically regulates ATPase and chaperone activity of HSC70, thus inhibiting the translation of cyclin D1 by promoting binding to the AUUUA motif in the 3′–untranslated region (3′ UTR) of mRNA. This mechanism plays a critical role in the regulation of selected sets of mRNA with specific HSC70 binding motifs by tylophorine analogs, such as DCB-3503.We previously demonstrated that treatment with DCB-3503 especially inhibits the translation of a set of cellular regulatory proteins with relatively short half-livesDCB-3503 treatment did not change the expression of HSC70 in HepG2 and Hela cells  and S1C.DCB-3503 treatment inhibits cyclin D1 translation at the elongation stepWe constructed a luciferase reporter bearing the 3′ UTR of cyclin D1 mRNA and transfected it to RKO cells with DOX-inducible HSC70 shRNAs. Renilla plasmid was included in the following transfections to normalize transfection efficiency, extraction conditions, and overall translation status. To distinguish translational output from mRNA turnover, luciferase assays were normalized to the RNA levels of the luciferase-reporter to determine the translation efficiency , miRNA targeting sites, and/or HSC70 binding sites .We transiently transfected luciferase constructs  togetherThe 3′ UTR of mRNA is a potent posttranscriptional regulatory element that interacts with mRNA binding proteins and miRNAsWe then examined the association between HSC70 and key enzymes that repress RNA polymerase II transcript elongation, including negative elongation factor complex member-C/D (TH1L) and -E (NELF-E)Vmax of HSC70 to ATP increased with the addition of 5 μM DCB-3503, or wild-type RNA (wtRNA) containing the HSC70 binding motif (AUUUA) (Vmax of HSC70 under the same conditions (Vmax of HSC70 (Km of HSC70 was unchanged in the presence of DCB-3503 and/or RNA (The ATP or ADP binding state is a determinant for regulating the chaperone activity of HSC70 (AUUUA) . Combininditions . Howeverof HSC70 . The Km d/or RNA .This study revealed a functional role for HSC70 in the translation of mRNAs having a specific motif. Suppression of HSC70 expression does not affect the viability of cultured cells  and S1C;Our results opened an interesting therapeutic perspective for regulating the translation of oncogenes by targeting HSC70. HSP70 family proteins share similar N-terminus ATPase and C-terminus chaperone activities18The regulatory role of DCB-3503 for HSC70 differented from HSC70 inhibitors. Phenylethyynesulfonamide, which binds to the C-terminus of HSP70 but not to that of HSC70 or HSP90, disrupted autophagy but did not induce apoptotic cell death in cancer cells3638Cyclins are a group of regulators of cyclin-dependent kinase (CDK) that coordinate to control shuffle of during mitotic eventsTranslation of cyclin D1 can be controlled by miRNAs. For instance, miRNA-193b suppresses cyclin D1 by binding to its 3′ UTR in melanoma Malme-3M cellset al. reported that tylophorine targets VEGFR2 to exert antiangiogenic and antitumor activitiesMany laboratories including ours, have attempted to identify the molecular targets of tylophorine analogs. Saraswati et al. identified a ribonucleoprotein complex containing caprin-1 as the molecular target of tylophorine to suppress tumor growth1515et al. and our group have demonstrated that the size of the fifth ring on the backbone of tylophorine analogs is a determinant for the mode of action13et al. determined that HSP90 and hnRNP A2/B1 bind to tylophorine analogs using a biotinylated phenanthrene-based tylophorine derivative (PBT-1-6L) through chemical proteomic methods50 under the same conditions. Our results also demonstrated that PBT analogs lost selectivity against key signaling pathways, including NF-κB, CRE, AP-1, and GRE; meanwhile DCB-3503 potently inhibited the NF-κB signaling pathway with nanomolar concentration. In addition, the CH3O- moiety on the R3 and R4 positions are required to maintain the activity of tylophorine analogs in vivo15Qiu ®), a small-molecule inhibitor of tyrosine kinases associated with Raf and vascular endothelial growth factor receptors, remains the only FDA approved drug to treat HCC since 2007http://www.cbioportal.org/index.do, accessed on January 10, 2016). Therefore, the novel allosteric regulation of cyclin D1 translation by DCB-3503 may be used alone or in combination for the treatment of HCC or breast cancer with cyclin D1 amplification.Hepatocellular carcinoma (HCC), a highly chemo-resistant cancer, is the fifth most common cancer worldwide and the second leading cause of cancer-related deathes in ChinaIn summary, DCB-3503 inhibited the translation of cyclin D1 by allosterically regulating the ATPase activity of HSC70. Its effect on translation is distinct based on different motifs in the 3′ UTR of mRNA. The binding mode between DCB-3503 and HSC70 is different from existing HSC70 inhibitors. We propose DCB-3503 as a potential lead compound for developing specific translation inhibitor-based unique mRNA sequences. The underlying mechanisms for regulating the translation of mRNAs without the “AUUUA” motif by DCB-3503 remain unexplored in the current study. The question of whether or not hnRNP U that binds to DCB-3503 serves as the molecular target regulating the translation of other mRNAs should be studied further.Cell culture media, fetal bovine serum (FBS) were purchased from Invitrogen. The DCB series of compounds were synthesized in Dr. David Baker’s laboratory at University of Tennessee. Doxycycline was purchased from Sigma–Aldrich .et al.2, 5 mM 2-mercaptoethanol, complete protease inhibitor). Biotinylated-DCB-3503 was bound overnight at room temperature to a slurry of 50% streptavidin-agarose beads (Invitrogen) in buffer containing 50% DMSO and 50% PBB. Beads were washed to remove unbound compound and then incubated with pre-cleared whole-cell lysates or recombinant protein in 2.5% BSA. Bound proteins were eluted with DCB-3503. Proteins that remained bound to beads were eluted with SDS loading buffer. Samples were separated with SDS-PAGE, and examined by silver staining or Western blot. Specific bands from silver-stained gel were analyzed by LTQ Orbitrap mass spectrophotometry .The affinity purification method was adopted from the reported by Emami t-test (Microsoft Office Excel and Graphpad software). The difference was considered to be statistically significant when p < 0.05.Data were analyzed by two-tailed Student’s How to cite this article: Wang, Y. et al. Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70. Sci. Rep.6, 32832; doi: 10.1038/srep32832 (2016).