This paper aims to describe the contextual factors that gave rise to evidence-based medicine (EBM), as well as its controversies and limitations in the current health context. Our analysis utilizes two frameworks: (1) a complex adaptive view of health that sees both health and healthcare as non-linear phenomena emerging from their different components; and (2) the unified approach to the philosophy of science that provides a new background for understanding the differences between the phases of discovery, corroboration, and implementation in science.The need for standardization, the development of clinical epidemiology, concerns about the economic sustainability of health systems and increasing numbers of clinical trials, together with the increase in the computer’s ability to handle large amounts of data, have paved the way for the development of the EBM movement. It was quickly adopted on the basis of authoritative knowledge rather than evidence of its own capacity to improve the efficiency and equity of health systems. The main problem with the EBM approach is the restricted and simplistic approach to scientific knowledge, which prioritizes internal validity as the major quality of the studies to be included in clinical guidelines. As a corollary, the preferred method for generating evidence is the explanatory randomized controlled trial. This method can be useful in the phase of discovery but is inadequate in the field of implementation, which needs to incorporate additional information including expert knowledge, patients’ values and the context.EBM needs to move forward and perceive health and healthcare as a complex interaction, i.e. an interconnected, non-linear phenomenon that may be better analysed using a variety of complexity science techniques. Over the past 20 years or more, the concept of evidence-based medicine (EBM) has increasingly been accepted as the gold standard for decision making in medical/health practice and policy.…the conscientious, explicit and judicious use of best evidence in making decisions about the care of individual [sic] patients. The practice of evidence-based medicine means integrating individual clinical experience with the best available external clinical evidence from systematic research”  of a particular disease for the better” , and that the pursuit of cure at all costs may restrict the supply of care, but the bias has at least been declared” [The historical and philosophical basis for EBM started with a broad health system’s perspective. In the 1930s, the then medical student, Cochrane, demanded on a protest placard that “be free” , p. 1. T better” , p. 2. C system” , p. 2. Ieclared” , p. 7.The beginnings of the EBM approach were clearly focused on understanding the complexities of the ‘workings of the healthcare system’ and its relationship to making the ‘best possible decision’s for the care of patients’. However, these complexities have rapidly been reduced to a narrow focus on standardised and typically single disease management guidelines.One of the main objectives of EBM is to make large amounts of scientific knowledge more accessible, and developing clinical guidelines with recommendations to support clinical decisions seemed the obvious way to proceed.Although clinical guidelines are useful they are also limiting if, for instance, they only draw on one source of information (i.e. the explanatory RCT). These guidelines will also restrain the freedom of professionals to use other sources of knowledge in their clinical decision making, like knowing patients’ preferences and clinical experiences . EvidencThe preoccupation with the quality of the studies used to develop clinical guidelines most likely explains the transformation of the broader EBM framework into its narrower RCT-driven form. The difficulties in translating the recommendations contained in EBM guidelines into practice and policy and the consecutive process of revision of the reductionist EBM approach to guidelines has been reviewed by others , 57, 58.The initial problems with translating evidence-based guidelines into practice were attributed to the difficulties in properly rating the supporting body of research. Hence, a detailed analysis of the grading of RCTs was suggested . The Grahigh quality evidence doesn’t necessarily imply strong recommendations, and strong recommendations can arise from low quality evidence” [Recognition of the need to separate assessment of quality of evidence from the strength of recommendations was a major step forward – “vidence” . HoweverIn recognition of the need for systematic and explicit approaches in the development and grading of recommendations, guideline development standards now require a summary of findings , 64 or eThe EBM community is starting to respond to criticism of limiting evidence and is attempting to incorporate and value other sources of knowledge, such as observational studies and the findings of qualitative research. Nevertheless, the fundamental flaws inherent in the grading systems remain such as the assumption that: study designs and quality can be arranged in a systematic but simplistic linear structure, when, in reality, the use of different and highly relevant information such as patient preferences, and applicability to local or practice contexts would lead to completely different grading systems ; and thaimplies that the scientist separates her scientific knowledge from fundamental value assumptions which she assumes in means-end inferences”. Means-end inferences and abduction are used in EBM guideline development without an adequate formalization of their contribution to the construction of the guideline recommendations [It is important to consider that scientific knowledge is divided in three major areas: discovery, corroboration and implementation, and that the information of one domain cannot be directly applied to the others , 28. TheIn the fields of discovery and corroboration the important criterion is internal validity . In the field of implementation, the important criterion is the degree of external validity of the results applicability to the local context and acceptability of the intervention/s to the patient. External validity is important as it means that the results can be generalized to different persons, settings and times. There is an inverse relationship between internal and external validity. If the final purpose of EBM was to improve the health of real people in real settings, external validity should be emphasized and strengthened. It is not only crucial to know if a treatment is effective in controlled situations , but also that it is going to be effective in the real world . While the grading systems for developing clinical guidelines used by EBM are systematic and reliable, they often prioritize internal validity and therefore are not ‘fit for purpose’. The emphasis on internal validity has contributed to the failure of EBM, as recommendations – being based on experimental designs where variables and confounders are controlled (RCTs) – often fail to be translatable into practice because the research context does not reflect real world clinical practice/reality , 68.The EBM and guideline communities have also recognized the limited implementation of guidelines jeopardized by their current static and unfriendly structure , 54, 69.The Lancet in 2005 [The new paradigm is population-based risk and disease assessment, systems of disease prevention and health promotion, community-based intervention and provider contacts within a framework of automated information, evidence-based medicine, and defined protocols of care, with explicit collection of outcomes information” [The leap from discovery/corroboration to implementation was partly reflected in the criticism made in  in 2005  and in t in 2005 . Even thrmation” . Epsteinrmation” , 73.A more fundamental question would be, can real world outcomes be achieved/evaluated with randomized controlled trials? In short, the answer is no, if we only use explanatory randomized trials as preferred by its proponents. However, pragmatic controlled trials that, by definition, are conducted under usual conditions offering practitioners considerable freedom in deciding how to apply the intervention to be tested, are not obtrusive , and use administrative databases for the detection of outcomes, can offer a valid alternative. While explanatory RCTs will be linked to discovery and corroboration and will aspire to removing variability, pragmatic controlled trials (even including randomization) fit in the area of implementation and embrace variability as the norm , 75. TheMost likely, EBM grew too fast to effectively incorporate its original propositions: evidence, expert knowledge, and patients’ preferences . The relAs an a priori, evidence is context sensitive, and therefore to some extent tacit , and botThere is an imperative to explore and then learn from other disciplines on how to use research evidence and incorporate it with local context and expert knowledge to achieve best possible patient outcomes. For example, in other areas of science, e.g. conservation science and artificial intelligence, expert knowledge is routinely incorporated in the analysis. Expert-Based Collaborative Analysis is a systematic procedure to incorporate expert knowledge into data analysis; such an approach has been proven to be useful when dealing with complex issues and can be seen as a powerful tool in the current health context characterized by an increase in the number of patients with multiple conditions, resulting from heterogeneous genomic/pathophysiological pathways and diverse personal needs .In future, the inclusion of ‘expert knowledge’ in the analysis of research data might produce more usable evidence for clinical decision-making. In this sense, EBM needs to go beyond the sole use of the RCT and acknowledge that scientific knowledge is multidimensional and cannot be arranged in only one hierarchical system. Knowledge coming from studies using different methodological approaches is complementary . Hence, The most important challenge facing the EBM-movement is the provision of a detailed description of its methods for scientific reasoning. This requires an analysis of its taxonomic principles, including formal definitions of ‘scientific knowledge’, ‘evidence’, and ‘decision making’ in health, as well as the different types of logic inferences used in the scientific reasoning process . As otheIt should also be highlighted that health systems research involves different disciplines  with different perspectives, epistemologies, and ways of conceptualizing and conducting research. Health systems research, as intimated by Cochrane, is broader than identifying ‘clinical effectiveness’ – ‘efficiency’ and ‘equality’ are equally important considerations for achieving successful implementation of health system improvement; therefore, all stakeholders’ fundamental value assumptions should be explicit.Ethics approval was not required as this manuscript is a narrative review of published papers.aThey signed as a group but in a footnote they included their names.bIt refers to the fact that even though the majority of papers have little impact on the scientific community (the hath not), a small number of them attracts the attention of the community and receive a lot of citations (the hath abundance).cAs an aside, Cochrane’s observations working as a doctor in a prisoners of war camp provided him with the empirical evidence of the great benefits of care, its scientific basis has been untangled by the study of psychoneuroimmunology.


Integrated Community Case Management of Childhood Illness (iCCM) is a policy for providing treatment for malaria, diarrhoea and pneumonia for children below 5 years at the community level, which is generating increasing evidence and support at the global level. As countries move to adopt iCCM, it becomes important to understand how this growing evidence base is viewed and used by national stakeholders. This article explores whether, how and why evidence influenced policy formulation for iCCM in Niger, Kenya and Mozambique, and uses Carol Weiss’ models of research utilization to further explain the use of evidence in these contexts. A documentary review and in-depth stakeholder interviews were conducted as part of retrospective case studies in each study country. Findings indicate that all three countries used national monitoring data to identify the issue of children dying in the community prior to reaching health facilities, whereas international research evidence was used to identify policy options. Nevertheless, policymakers greatly valued local evidence and pilot projects proved critical in advancing iCCM. World Health Organization and United Nations Children's Fund (UNICEF) functioned as knowledge brokers, bringing research evidence and experiences from other countries to the attention of local policymakers as well as sponsoring site visits and meetings. In terms of country-specific findings, Niger demonstrated both Interactive and Political models of research utilization by using iCCM to capitalize on the existing health infrastructure. Both Mozambique and Kenya exhibit Problem-Solving research utilization with different outcomes. Furthermore, the persistent quest for additional evidence suggests a Tactical use of research in Kenya. Results presented here indicate that while evidence from research studies and other contexts can be critical to policy development, local evidence is often needed to answer key policymaker questions. In the end, evidence may not be enough to overcome resistance if the policy is viewed as incompatible with national goals. Key MessagesLocal data, such as national surveys and health monitoring data, served to define the policy problem of children dying at home but overall policy formulation was influenced by a broader variety of evidence, including research, experiences in other countries, and both local and international pilot projects.Local evidence was highly valued by local decision makers and the lack of it inhibited policy progress.Development partners brought evidence to policy discussions, especially peer-reviewed publications and guidelines.Evidence of interactive, political, problem-solving and tactical models of research utilization was seen in the three study countries.Integrated Community Case Management of Childhood Illness (iCCM) is a policy that encompasses the treatment of malaria with artemisinin combination therapy (ACT) and other antimalarials, treatment of diarrhoea with low-osmolarity oral rehydration salts (ORS) and zinc and treatment of pneumonia with antibiotics, all provided for children below 5 years by community health workers (CHWs) at the household and/or community level. This policy has evolved in recent years in response to limited success of earlier child survival strategies.After the Alma Ata conference in 1978 (1978), the ‘child survival revolution’ in global public health advocated for several key interventions that shifted attention towards vertical, disease-specific programmes to combat childhood illness, such as the control of diarrhoeal disease and immunization . The IMCThe evidence base for the delivery of curative services at the community level for the individual pathologies of diarrhoea, malaria and pneumonia is substantial , while tThis article is part of a larger cross-country case study aiming to analyse iCCM policy development using Walt and Gilson’s policy triangle framework . AlthougOne early approach from the public administration literature to understanding how evidence influenced policies proposed three mechanisms: instrumentally, resulting in direct change; conceptually, enlightening users in unspecific ways or symbolically, to support existing positions , althougKatherine Smith draws from Weiss’ work to study UK policies and has advocated for exploring complexity in policymaking and the different potential mechanisms for evidence writ large to influence policy, including recognizing the variety of actors in this process and the central role of politics as more than a barrier to evidence-informed policy . There aVarious researchers have explored how context affects evidence use and how policymakers faced the same issue and evidence interpret and use evidence differently  the current stage of iCCM policy and programme development, (2) the level of role expansion required for CHWs to take on iCCM and (3) whether CHWs are paid or are volunteers. Countries were identified based on researcher-developed profiles drawing on discussions with United Nations Children's Fund (UNICEF) and country officials, other researchers work on iCCM and results from an earlier iCCM policy survey .The methodological approach included a documentary review and in-depth interviews with key stakeholders in the country, which were triangulated to support analysis and corroborate findings . PotentiAn analysis plan was developed collaboratively between the team at JHSPH and in-country research teams through in-person workshops following a descriptive content analysis approach . A commoFor this article, we focus on three countries where iCCM policy development progressed at varying speeds to explore the use of evidence in highly variable contexts: Niger, an early adopter with full implementation of iCCM; Mozambique, where policy development moved more slowly but was adopted; and Kenya, which had yet to adopt a comprehensive iCCM policy. The study was implemented in each country by a local research team, with the exception of Niger where a JHSPH doctoral student took the lead on the research with support from local researchers. Data were collected between January and September 2012. Ethical approval was obtained from JHSPH, Great Lakes University-Kisumu in Kenya and the National Bioethics Committees in Mozambique and Niger.The results from the three study countries presented here represent 204 documents and a total of 72 interviews , with coAlthough over 80% of the Nigerien population has always been rural, health services in Niger have historically been concentrated in cities; the problem of limited access to health care was thus well-known to policymakers in the 1990s and early 2000s . OngoingIn 1997, Niger became one of the first Francophone countries to adopt IMCI, and between 2001 and 2010 over 2000 health huts were built in rural areas . The huts were staffed by a new cadre of CHWs based at health posts. These CHWs have a middle school education and receive 6 months of training with 1 week targeted for iCCM. They are paid a salary ($100/month) through HIPC funds, and therefore are not entirely integrated into the health system infrastructure . Later, in 2006, a policy promulgated by President Tandja guaranteed free health care to children below 5 years, and significantly increased health centre attendance , pressure increased to make progress on child survival rates and indeed MDG 4 is mentioned in almost all iCCM documents, and progress towards all the MDGs was regularly reported on by the National Institute of Statistics in Niger ; 2010.The CHW cadre that was already in place paired with the network of health huts that had been established during President Tandja’s tenure allowed for iCCM to be viewed as a viable solution that built on the existing health infrastructure in place and extend the reach of the health system.“They went to Senegal, they saw the Senegalese experience, they came back here and we worked in the Madarounfa district [and] trained some people for the screening and diagnosis of ARIs.” (Niger—Development Partner 024)“We took the scientific evidence, for instance ARIs in Senegal. This is really the foundation. Also surveys from Pakistan, and India and WHO and USAID were targeting Benin and some other countries … There was scientific evidence indicating the basis for the management of respiratory conditions, and therefore combined with the other conditions, this is iCCM …” (Niger—Development Partner 003)International partners played a key role in raising awareness and interest in iCCM as a policy option, largely by sharing evidence of potential interventions with Nigerien policymakers. One primary way they did so was by organizing regional meetings and supporting Nigerien stakeholders’ attendance. A regional meeting in Dakar in 2005 sponsored by United States Agency for International Development (USAID) was especially influential as Senegalese participants shared their experiences with community management of acute respiratory infections.“The role of evidence is that there is no point reinventing the wheel. These are things that are immediately applicable because they have proven their worth. They do not need to be tested anymore and this makes you move faster to achieve a reduction in child mortality and morbidity.” (Niger—Clinician 007)“WHO enjoys great trust. They have a lot of confidence in WHO directives. We present the directives and later they adapt [them] …” (Niger—Development Partner 006)International partners also shared evidence on iCCM from scientific journals, specifically the 2003 ‘Lancet’ series on child survival Although the totality of the evidence was seen as influential in its own right, there was still a need to conduct a local pilot project to demonstrate feasibility. The pilot was viewed as a necessary precursor to large-scale implementation to adapt iCCM to the local context; it was conducted in Madarounfa in 2005 with community volunteers—not CHWs—emulating the project in Senegal.The pilot was refocused to work with CHWs in 2006 once it was realized that community volunteers could not legally handle antibiotics. A mid-term evaluation of the Madarounfa pilot was released in 2007 indicating positive results and the decision was rapidly made to scale up iCCM nationwide. iCCM policy was adopted in 2008 .Kenya’s health system is better resourced than many other countries in sub-Saharan Africa with 0.93 health workers per 1000 population, including 0.05 physicians and 0.41 nurses and midwives per 1000, respectively , and IntKenya has had policies and programmes on home management of malaria including treatment, and the use of ORS for diarrhoea ; 2010. T“Looking at the countries’ data, you find that almost 50% of the children do not access the facilities. So that means that quite a number of children are missing health interventions at the community level. We don’t want them to miss out in this treatment intervention; we want to take interventions near to them so that we can reduce the deaths due to severe diseases and eventually have an impact on reducing mortality rates.” (Kenya—NGO 014)As in Niger, policymakers were aware of challenges to access health-care services at the community level as identified in various policy documents, a DHS survey  and an I“I would say it has been consultative enough, the government was not initially ready for it despite the overwhelming evidence that iCCM works. But through advocacy and push from international organizations the government is now supporting it. We see the big role of non-state actors in influencing the process, particularly WHO and UNICEF. Left to government alone it would have taken much longer.” (Kenya—NGO 019)International partners were a main source of evidence in this case as well. The 2003 Lancet series on child survival was shared at stakeholder meetings, and UNICEF sponsored a study tour for Ministry of Health officials in 2009 to Malawi, Ethiopia and India to see iCCM policies in action. WHO also organized a meeting in Nairobi in 2011 on ‘coordinated approaches to pneumonia and diarrhea prevention and control’ , which w“Yes … there were some citations that were made from I think Cuba where similar iCCM activities had happened, they cited also Malawi which I disputed because I know how Malawi looks like, the iCCM is not by CHWs, they mistake the people they normally call health surveillance assistants … the picture for Kenya is very different … because they [others] are community members but not volunteers. They are all in government pay roll.” Kenyan Ministry of Health decision makers questioned the applicability of the evidence from other settings that was being shared with them. In particular, they questioned whether iCCM was an appropriate policy for their country given the structure of their health system, the composition of their CHW cadre and the greater availability of nurses who could be delivering these services.There have been a number of efforts in Kenya over the years to pilot community-level delivery of treatment but with limited success. An early trial started by CARE in the Siaya district in the late 1990s trained CHWs to use a simplified IMCI algorithm for treating diarrhoea, malaria and pneumonia. However, the results indicated that CHWs were not treating children correctly “For pneumonia (pauses) I think there is a long way to go, there are discussions that are ongoing at the moment to look at possibilities of whether we can actually introduce treatment of pneumonia at community level and what the government has, at that level, to give us evidence or how it would work for that matter so for me- pneumonia has longer way to go than any of the other two.” Given these unconvincing experiences with local pilots for pneumonia care, treatment with antibiotics is still being debated by policymakers as they deem existing evidence to be insufficient. Kenyan stakeholders felt that new pneumonia-specific pilots were needed before making a decision on the policy. Two pilots focused on antibiotic treatment for pneumonia at the community level were commissioned by WHO and its partners and carried out by Kenya Medical Research Institute (KEMRI) and AMREF and were ongoing at the time of this study.et al. this issue). Commitment to the overall policy is unclear and there was a general feeling across respondent groups that iCCM was being pushed by external partners. Kenya has reached consensus on some aspects of iCCM but these are only present in training guidelines for CHWs which had been drafted in 2011 and were finalized in 2013 (electronic versions are not available yet)  , not in et al. this issue). The revitalization of CHWs, known as ‘Agentes Polivalentes Elementares’ or APEs, was seen as a critical way through which to institutionalize the government’s commitment to community involvement in addressing health issues. As such, CHWs are seen as part of the Ministry of Health and their activities are integrated into the health system Like in the other study countries, large-scale surveys identified access as a significant cause of child mortality and the commitment to meet the MDGs put pressure on Mozambican policymakers to advance policies and programmes that would address this issue . This waThere had been a long history of CHWs treating malaria and diarrhoea at the community level, and of using evidence to update the recommendations for CHW-delivered treatment before the advent of iCCM as a self-contained policy. The policy regarding medications to treat malaria was updated in 2011 based on evidence from international studies as well as local studies . In respThe National Policy of Infant and Neonatal Health in 2006  proposed“… but it was more due to advocacy to change to dispersible amoxicillin, because it was recommended by WHO … it was more local advocacy from Save the Children, Malaria Consortium and UNICEF …” “… [these] were studies that were done using community workers—this figure in the community—trained to use antibiotics in case of pneumonia or zinc, ORS in the case of diarrhea that could get good results. Then there starts to be a lot of disseminating results in Africa, in Kenya, in Uganda, then countries that do not adhere to policies recommended by WHO and UNICEF would be countries who would be at the margin of others who want to achieve the millennium goals. Often therapeutic policies go against policies, in other words the external pressure is very strong to the point of changing the own national treatment policy … we suddenly see that things are being changed but it is due to external pressure.” (Mozambique—NGO 018)UNICEF, WHO and international NGOs shared evidence from guidelines, research and experiences of other countries, including Zambia, Malawi, Uganda and from Latin America, supporting the delivery of antibiotics by CHWs in order to advocate for the introduction of antibiotics for pneumonia which was facing resistance. The advocacy went so far as to push for amoxicillin instead of cotrimoxazole.“… there is a study in Mozambique on zinc conducted by Dr. Mbofana in Beira, which we used to influence the pharmacy staff in order to change the content of Kit C within the new APE criteria …” International partners helped generate local evidence to support different iCCM components. Likewise, in 2009 a local study supported by WHO and USAID and carried out by the National Institute of Health evaluated the potential for including zinc in the community strategy for treating childhood diarrhoea . The fin“… do you know who sent the Lancet series to translate? … Ivo Garrido received [it], liked … the Lancet opened his eyes to … neonatal … and … zinc for diarrhea cases at the primary level … all this reduces a good percentage of infant mortality …” In 2007, Paulo Ivo Garrido—Minister of Health at the time—found the 2003 Lancet series on child survival so convincing that he had the articles translated into Portuguese and disseminated for discussion during a key meeting on community involvement demonstrating high-level political commitment to iCCM-related strategies. His support helped finalize the inclusion of iCCM activities in the CHW policy.The case studies of Niger, Kenya and Mozambique present three varying experiences with evidence. As we map these case studies to Weiss’ models of utilization, we see different dynamics at work. The interplay between different forces in Niger suggests an Interactive model of research utilization. However, the opportunity for policymakers to use iCCM to capitalize on existing investments in health huts and CHWs also indicates a Political model. The use of evidence in Mozambique was fairly straightforward and aimed at answering specific policy-relevant questions, such as a project piloting zinc for diarrhoea treatment. This kind of use is most aligned with the Problem-Solving model and also reflects the historical use of evidence to inform child survival policies in Mozambique. In Kenya, there seem to be two models at work. First, the resistance to community-level pneumonia treatment by CHWs was not overcome by existing evidence, including local pilot projects that showed limited success, suggesting that policymakers used a Problem-Solving approach by ‘not’ adopting community pneumonia treatment. Furthermore, the broader resistance to CHWs providing clinical care and the lack of financial commitment calls into question the overall support that Kenyan policymakers have for an overarching iCCM policy. Thus, their demands for more and more evidence may actually be a stalling technique to postpone a final decision suggesting a Tactical use of research.Linking Weiss’ models with the policy triangle framework, we see that although all three countries identified child mortality as a key issue, the role of evidence in defining a policy solution was murkier (process) depending on the commitment to iCCM as a potential policy (issue), the local health system infrastructure (context) and the interplay between national and international stakeholders in sharing and pushing evidence (actors). Unsurprisingly, the value of evidence varied by context but there are several lessons that can be drawn from this study regarding how policymakers used evidence.First, different types of evidence had specific usefulness in the policymaking process. National monitoring data, such as surveys, programme evaluations and service utilization data, were essential in recognizing the policy issue at hand, and highlighting issues around access to health services and that children were ‘dying at home’ before reaching facilities; on this point there was consensus across stakeholders in each country. Research evidence was more crucial to identifying policy options, specifically community-level interventions, but was also more likely to be debated, with local pilot projects playing a critical role in all study countries in different ways. The Lancet series on child survival was widely recognized across settings to have played a major role as a source of evidence. This series was being used and referenced several years after its publication though interestingly, it appears that respondents ascribed to the series a message that it did not directly make: that child survival interventions should be delivered at the community level. This misconception could have resulted for a number of reasons. It is possible that readers simply misconstrued and/or extrapolated the findings. Alternatively, because the series was shared with national policymakers through international partners, it is also possible that the message was mediated and modified either to justify a more community-oriented approach or because in the intervening years the field had moved beyond the series’ original message. Unfortunately, our study could not determine the main reason underlying this shift in interpretation of the series’ message.et al. this issue). These actors functioned largely as knowledge brokers by sharing research studies regarding iCCM interventions, sharing other countries’ experiences with iCCM, and sponsoring and supporting site visits to other countries and regional meetings. UNICEF and WHO’s role as trusted actors in the policy arena provided them and their technical assistance with good standing among local actors. By virtue of their position and mandate, these agencies have access to evidence from a variety of sources that they can then ‘digest’ and streamline to bring to bear during policy discussions. et al. this issue) and promoted at the national level through advocacy, joint statements and guidelines and study trips.Second, it is critical to acknowledge the role of development partners in introducing evidence in iCCM policy discussions, especially UNICEF and WHO  were the same, does it all fall to the specific context and the process of policy development? Further research is needed to explore these distinctions more deeply.There are several limitations to this study. First, this cross-country analysis drew primarily from the individual country reports and the synthesis report with limited examination of primary data sources. Although we are confident that the individual country reports were thorough, it is possible that some details were missed given the need to synthesize data sources to present a cohesive picture, but we mitigated this by going back to country case study authors and original data. Second, the data collection for these case studies took place between 2 and 4 years after formal policy adoption and even more distantly from policy formulation, which likely affected the recall of our respondents. We addressed this by interviewing a variety of stakeholders involved in policy development but also triangulating our findings with the documentary review.As global-level initiatives are translated into national settings, it is important to recognize that international evidence may be insufficiently convincing; more importantly, national policymakers may make an evidence-informed decision by determining that a specific policy should not be implemented in their country. It is clear that public health policies require multiple sources of evidence, especially local data, highlighting the need for targeted funding aimed at answering key questions posed by local policymakers regarding implementability and sustainability. Efforts of this nature have begun (


Clinical practice guidelines are widely distributed by medical associations and relied upon by physicians for the best available clinical evidence. International findings report that financial conflicts of interest (FCOI) with drug companies may influence drug recommendations and are common among guideline authors. There is no comparable study on exclusively Canadian guidelines; therefore, we provide a case study of authors’ FCOI declarations in guidelines from the Canadian Medical Association (CMA) Infobase. We also assess the financial relationships between guideline-affiliated organizations and drug companies.Using a population approach, we extracted first-line drug recommendations and authors’ FCOI disclosures in guidelines from the CMA Infobase. We contacted the corresponding authors on guidelines when FCOI disclosures were missing for some or all authors. We also extracted guideline-affiliated organizations and searched each of their websites to determine if they had financial relationships with drug companies.We analyzed 350 authors from 28 guidelines. Authors were named on one, two, or three guidelines, yielding 400 FCOI statements. In 75.0 % of guidelines at least one author, and in 21.4 % of guidelines all authors, disclosed FCOI with drug companies. In 54.0 % of guidelines at least one author, and in 28.6 % of guidelines over half of the authors, disclosed FCOI with manufacturers of drugs that they recommended. Twenty of 48 authors on multiple guidelines reported different FCOI in their disclosures. Eight guidelines identified affiliated organizations with financial relationships with manufacturers of drugs recommended in those guidelines.This is the first study to systematically describe FCOI disclosures by authors of Canadian guidelines and financial relationships between guideline-affiliated organizations and pharmaceutical companies. These financial relationships are common. Because authoritative value is assigned to guidelines distributed by medical associations, we encourage them to develop formal policies to limit the potential influence of FCOI on guideline recommendations.The online version of this article (doi:10.1186/s12913-016-1646-5) contains supplementary material, which is available to authorized users. Clinicians rely on clinical practice guidelines (CPGs) for guidance when making treatment decisions for patients. Although CPGs should be based on critical analysis of the best available scientific evidence, authors’ recommendations in some guidelines have been based on lower levels of evidence or expert opinion . Therefohttps://www.cma.ca/En/Pages/clinical-practice-guidelines.aspx) lists guidelines that meet the following criteria: include information to help patients and physicians make decisions about appropriate health care for specific clinical circumstances; be produced by an authoritative Canadian organization or if produced outside of Canada be officially endorsed by such an organization; have been developed or reviewed in the last 5 years; and have evidence that a literature search was performed during guideline development [CPGs are widely distributed by professional medical associations, such as the Canadian Medical Association (CMA). The CMA Infobase  assessed and documented whether guidelines recommended specific drugs based on recommendation tables or, in their absence, within the text. We considered a “recommendation” to have been made when authors stated that one or more specific medications were appropriate first-line treatments for a particular patient population. We excluded guidelines that either recommended only drug classes as opposed to specific medications, or mentioned or acknowledged specific drugs without making clear first-line recommendations Fig. .Fig. 1GuSpecific drugs for first-line treatment were recommended in 102 guidelines. Guidelines that provided only titles of organizations, committees, or associations in lieu of individually named authors or committee members were excluded, leaving 77 guidelines. Forty additional guidelines that provided neither disclosures, nor corresponding authors’ contact information were excluded .a priori to extract FCOI disclosure information for a maximum of 25 authors per guideline, including chairs, co-chairs, principle authors, co-authors, and committee members. We assumed that all committee members who were named within the guideline had voted on its recommendations, even if they were not explicitly listed as authors. We also assumed that anyone who was not identified as an author or named committee member  did not vote on the final recommendations in the guidelines and we excluded them. When more than 25 authors and/or committee members, which will hereafter be referred to collectively as authors, were named on a guideline, we assigned each a random value using Microsoft Excel [Because of resource limitations, we decided ft Excel . OrganizWe recorded whether the medications recommended in the guidelines were on-patent or if there were off-patent versions available in Canada by consulting the Compendium of Pharmaceuticals and Specialties (CPS) and Health Canada’s Drug Products Database –24 for tFinally, we identified the guideline-affiliated organizations. We visited each of the organizations’ websites to identify the pharmaceutical companies with which they disclosed having financial relationships. We did not examine whether conferences held by these organizations had pharmaceutical company sponsors.This study has received ethics approval from the Ethics Review Board at York University and conforms to the standards of the Tri-Council Research Ethics guidelines (Certificate #: 2014-186). Written informed consent for participation in this study was obtained from participants.We obtained FCOI disclosures for authors on 28 guidelines. Twelve were most recently reviewed or published in 2013 and 16 in 2012.Out of 400 FCOI disclosure statements for 350 unique authors, 188 (47.0 %) declared FCOI with pharmaceutical companies. Individual authors declared FCOI with up to 19 drug companies . Out of these 188 FCOI declarations, 97 were relevant, 65 were non-relevant, and 26 were vague. Two-hundred and twelve (53.0 %) of the 400 declarations stated that the authors were either free of FCOI with drug companies or had conflicts with only non-commercial organizations (Table Three-hundred and two unique authors (86.3 %) were each on one guideline, while 46 (13.1 %) were each on two guidelines and two (0.6 %) were each on three guidelines.Of the authors on one guideline, 119 (34.0 %) disclosed FCOI with drug companies, while 162 (46.3 %) disclosed that they had either conflicts with non-commercial organizations or were free of FCOI with drug companies. Twenty-one (6.0 %) disclosed vague FCOI with drug companies  at least one author disclosed FCOI with drug companies, while in six guidelines (21.4 %) all authors disclosed FCOI with drug companies  (Table In 15 guidelines (54.0 %) at least one author disclosed relevant FCOI , while in one guideline (3.6 %) all authors disclosed relevant FCOI. In eight guidelines (28.6 %), over half of the authors declared relevant FCOI . In total, 39 organizations were found. Nineteen of the 39 organizations (49.0 %) identified financial relationships with pharmaceutical companies on their respective websites. In eight guidelines (26.0 %), at least one drug recommended for first-line treatment was manufactured by a pharmaceutical company listed on the affiliated organizations’ website . Relevant financial ties are also common amongst guideline authors, as authors in 15 guidelines (54.0 %) reported FCOI with manufacturers of drugs that they recommend as first-line treatments. Twenty authors on two or three guidelines disclosed different FCOI in their statements. Eight guidelines identified affiliated organizations that had financial relationships with drug companies that manufactured drugs recommended for first-line treatment.To our knowledge, our study is the first to systematically describe FCOI disclosures by authors on Canadian guidelines, as well as the financial relationships between the guideline-affiliated organizations and pharmaceutical companies. We used a population approach to guideline inclusion and did not exclude guidelines based on medical specialty or disease category.This study contributes to existing international studies on FCOI disclosures across medical specialties, which have produced results similar to our findings. Cosgrove and colleagues found that in three psychiatry guidelines, 18 of 20 (90 %) authors held FCOI with pharmaceutical companies and none of these ties were disclosed in the guideline. On two of the three guidelines assessed, 100 % of the working group members possessed FCOI . Neuman In a study analyzing 17 cardiovascular guidelines, Mendelson and colleagues found that 277 out of 498 (56.0 %) authors reported FCOI . A 2013 We believe that our results provide a conservative estimate of the prevalence of FCOI disclosed by guideline authors as we did not conduct external web or publication searches to determine the completeness of the FCOI disclosures in the guidelines. Our exclusion of 40 guidelines based on their lack of both FCOI disclosure sections and corresponding author contact information reflects findings that guidelines commonly contain no information about potential FCOI .Finally, consistent with related research , 27, 20 We excluded guidelines if either authors or committee members were not explicitly named, limiting the scope of our analysis. Additionally, our analyses accounted for neither drugs that were recommended for second- or third-line treatment, nor the strength of evidence used to make first-line drug recommendations. We did not differentiate among the types of FCOI that the authors disclosed. Finally, we did not consider the funding source(s) of the guidelines. Our results are preliminary since our sample size of guidelines is limited.Our findings support the need for future research to measure not only the prevalence, but also underreporting of FCOI in guidelines. Our results also suggest a need for accurate and consistent disclosures. Future research is also necessary to determine whether guideline authors’ reported FCOI are associated with their drug treatment guideline recommendations.After the Association of Scientific Medical Societies in Germany  instituted new disclosure rules in 2010, the prevalence of guidelines with disclosures increased from 8 to 95 % in 2011. This reform requires guideline-creating groups to ensure that both their members’ declarations and the procedures used to declare, document, and the disclosures themselves are made public .Physicians tend to have confidence in, and attribute value to, guidelines issued or distributed by official professional associations . Therefo


In a Perspective linked to the study by Michael Valenzuela and colleagues, Druin Burch considers the context, content, and limitations of what we know about computerized cognitive enhancement.Please see later in the article for the Editors' Summary PLOS Medicine:This Perspective discusses the following new study published in 10.1371/journal.pmed.1001756 Lampit A, Hallock H, Valenzuela M (2014) Computerized Cognitive Training in Cognitively Healthy Older Adults: A Systematic Review and Meta-Analysis of Effect Modifiers. PLoS Med 11(11): e1001756. doi:Michael Valenzuela and colleagues systematically review and meta-analyze the evidence that computerized cognitive training improves cognitive skills in older adults with normal cognition.PLOS MedicineComputerized cognitive training (CCT) “is modestly effective at improving cognitive performance in healthy older adults”, find Michael Valenzuela and colleagues, who systematically review the evidence in this week's CCT has a market approaching a billion dollars a year Adherents to evidence-based medicine seek reliable proof that interventions make a helping difference, and they attempt to make sure that evidence supports branding. Outside of medicine, consumers are treated as capable of making up their own minds about purchases with less help from regulatory oversight. The participants in the studies reviewed here were not enrolled as patients, and most users of CCT programmes have not been prescribed them by physicians. Being asked to pay money for “standardized computerized tasks with clear cognitive rationale” People driven by fear of cognitive decline might reasonably seek guidance about CCT programmes from their physicians. It is otherwise unclear whether providing advice about CCT to those without related symptoms is the business of doctors, except perhaps in the context of the WHO's famously all-embracing definition of health as a “state of complete physical, mental, and social well-being” Practising Sudoku may have benefits Valenzuela and colleagues show effects that are statistically significant but uncertain in their impact on human capacity and performance. Their review, they note, “provides no indication about the durability of the observed gains, nor their transfer into real-life outcomes such as independence, quality of life, daily functioning, or risk of long-term cognitive morbidity”. Such a careful summary is worthwhile, as much for clarifying what is not yet known as for what is. It suggests that clinical trial methodology remains necessary to examine the proposed benefits of CCT. As bloodletting for infection was accepted as beneficial less than a century ago The review's message regarding the limitations of CCT may fail to reach many who are lured by the promises prominent on training websites. Consumers may not make informed decisions, and those experiencing symptoms of dementia or the fear of such symptoms may mistake CCT products for proven medical interventions. That care needs to be taken over the potential for such misunderstanding is plain. Even clinical situations that involve informed consent may not result in realistic expectations: in a study of patients undergoing coronary angioplasty for stable angina between 2009 and 2011, when the evidence showed it did not prevent death, 90% who consented agreed to the procedure in the belief that it did If cardiologists and patients together cannot interpret clear, high-quality evidence, it is reasonable to worry how a limited evidence base will collide with a public wishing to believe in it and a billion-dollar industry based on encouraging them. The benefits and limitations of CCT need to be clearly demonstrated and communicated if the public are not to invest money and time with unrealistic expectations of what they will gain. For CCT to promise more than it delivers and for it to encourage people to oversimplify such a serious matter as the care of their own minds would be a grave pity. Those doctors who once used animal testicles to refresh human vitality and sexual potency, and to augment intelligence and reverse its age-related decline, made a great deal of money from their work. They also performed it sincerely, showed it to be supported by clear rationale, and demonstrated that it made encouraging changes to short-term outcomes CCT programmes may or may not be medicine, but to be properly assessed their powers certainly require the tools of evidence-based medicine. Does a billion-dollar gap exist between our knowledge about “standardized computerized tasks with clear cognitive rationale” and the industry selling them? Valenzuela and colleagues' overview of the evidence for CCT in cognitively intact older adults suggests it does. It makes clear what remains to be discovered and suggests promising lines of inquiry. Their paper is of use to those planning thoughtful research in the field. It will not be the fault of the authors if the small effects shown, specific to particular subgroups and short-term outcomes, lead to the marketing departments of profitable companies declaring, with added confidence and effect, that their products are “scientifically proven” and doing so without being legally responsible for consumers or patients mistaking what that means.


There are many critical steps for the clinical efficacy of antigen-specific T cell-based immunotherapies among which traffic to and access to tumor beds of effector T cells, are the most limiting . PreclinWe set up an orthotopic preclinical model in which renal carcinoma cells (RenCa) expressing the human mucin 1 tumor-associated xeno-antigen are injected into the sub-capsular space of kidney in BALB/c mice. We then evaluated the impact of the route of injection on the therapeutic efficacy of a Modified Vaccinia virus Ankara expressing the human mucin 1 xeno-antigen (MVA-MUC1).+ lymphocytes is associated with therapeutic protection. We observe that infiltration of CD8+ lymphocytes is not limited to tumor-bearing kidneys and is also detected in naive kidneys, liver and lungs. Kidney infiltrating lymphocytes are characterized by an effector memory phenotype and express PD-1 and Tim3 immune checkpoints molecules. Biodistribution experiments indicate that MVA encoded antigens quickly reach deep organs and in particular APC from the spleen upon i.v. injection of MVA in comparison to s.c. injection, resulting in a faster generation of MUC1 specific CD8+ T cells. Unexpectedly, addition of ODN1826 to MVA-MUC1 immunization does not result in an increase in the frequency of MUC1 specific T cells detected in the spleen. Instead, ODN1826 was associated with a more pronounced modification of the tumor microenvironment towards a TH1 type inflammatory response and a recruitment of activated lymphocytes.We show that intravenous administration of MVA-MUC1 is therapeutically superior to subcutaneous injection. Therapeutic efficacy of MVA-MUC1 can be further enhanced by intravenous administration of a TLR9 ligand (ODN1826). Substantial and necessary infiltration of tumor-bearing kidneys by CD8+ T cells in an orthotopic model of renal carcinoma. This therapeutic efficacy can be further increased through the use of ODN1826. This study supports the clinical evaluation of MVA-based immunotherapies via the intravenous route.Intravenous injection of MVA-MUC1 is associated with therapeutic efficacy and deep organ infiltration by MUC1-specific CD8


Liver tumours are fortunately rare in children. Benign tumours such as haemangiomas and cystic mesenchymal hamartomas are typically seen in infancy, often before 6 months of age. After that age, malignant hepatic tumours increase in frequency. The differentiation of a malignant from benign lesion on imaging can often negate the need for biopsy. Ultrasound is currently the main screening tool for suspected liver pathology, and is ideally suited for evaluation of hepatic lesions in children due to their generally small size. With increasing research, public awareness and parental anxiety regarding radiation dosage from CT imaging, MRI is now unquestionably the modality of choice for further characterisation of hepatic mass lesions.Nevertheless the cost, length of imaging time and perceived complexity of a paediatric liver MR study can be intimidating to the general radiologist and referring clinician. This article outlines standard MR sequences utilised, reasons for their utilisation, types of mixed hepatocyte specific/extracellular contrast agents employed and imaging features that aid the interpretation of paediatric liver lesions. The two commonest paediatric liver malignancies, namely hepatoblastoma and hepatocellular carcinoma are described. Differentiation of primary hepatic malignancies with metastatic disease and mimickers of malignancy such as focal nodular hyperplasia (FNH) and hepatic adenomas are also featured in this review..Imaging should aim to clarify the presence of a lesion, the likelihood of malignancy and potential for complete surgical resection. Reviewing and reporting the studies should address these issues in a systematic fashion whilst also commenting upon background liver parenchymal appearances. Clinical information and adequate patient preparation prior to MR imaging studies help enhance the diagnostic yield. Primary hepatic tumours account for only 1–2 % of all childhood cancers . MetastaThe aims of imaging are therefore directed at answering three main issues – confirming the presence of a liver lesion(s), defining it’s precise extent and whether it can be confidently characterised. The latter two findings will govern the need for biopsy or the approach for potential surgical management. Accurate radiological assessment is crucial at this stage, as it may negate the need for biopsy with benign processes , or alteThis article will describe the method by which to address the aforementioned factors whilst providing a general overview of the imaging findings in the two commonest malignant paediatric hepatic tumours and pitfalls in their diagnosis and follow-up imaging.Ultrasound examination is the principal screening modality for identification of a suspected intra-abdominal mass in a child. Despite its ability to characterise the presence, size, solid component and vascularity of a liver mass - the mere presence of a lesion without an already established diagnosis should form the basis for further imaging with MRI. In some European centres, contrast enhanced ultrasound (CEUS) techniques may be adopted at this stage to help characterise likelihood of malignancy  and may The advantages in utilising MRI for liver lesions include the lack of ionising radiation, good multi-planar spatial resolution  and excellent soft tissue characterisation. Nevertheless not all medical institutions possess the resources required to perform MRI studies in paediatric patients. This may be due to a variety of factors including cost, longer scanning times, the need for sedation in young patients, lack of local radiological expertise and machine availability. Where these limitations cannot be overcome or where urgent treatment and diagnosis are required, CT imaging may be performed, although the increased radiation burden and reduced soft tissue contrast makes it much less ideal . If CT wWhen performing MR studies in children, adequate patient preparation can make a significant difference to the quality of the resultant images. Ideally patients should have nothing by mouth for 4 h prior to the study. Sedation or general anaesthesia may be needed  if the child is unable to hold his or her breath for longer than 20 s or if he or she cannot remain still for the approximately 45 min scan . OccasioDespite the paucity of studies comparing diagnostic yield in liver lesion detection when utilising a 1.5 T versus 3 T magnet, our experience and those of other institutions are that a higher magnet strength produces better spatial resolution and is preferable in younger children when a choice exists , 13.The length of the study can be variable and will be in part determined by patient co-operation (if un-sedated) and type of intravenous contrast agent used. Contrast agents for paediatric liver imaging fall predominantly into two subclasses, namely the typical extracellular agents (ECAs) used in most abdominal imaging, and mixed hepatocyte specific/extracellular agents. Both contrast agent subclasses include gadolinium-based media, containing a central gadolinium ion bound to a specific ligand, which determines the properties and anatomical distribution of the agent.Mixed hepatocyte specific/extracellular agents are actively transported into hepatocytes and partially excreted through the biliary system. These therefore permit a more delayed ‘hepatobiliary phase’ imaging post administration allowing visualisation of the central biliary anatomy, thereby prolonging the length of the examination. Although routinely utilised with an excellent safety profile , they arExamples of the two commonly used agents in this subclass include gadoxetate disodium  and gadobenate dimeglumine . Approximately 50 % of gadoxetate and 3–5 % of gadobenate is excreted through the biliary system, with the remainder excreted via the kidneys. Hepatobiliary phase imaging can be performed 20 min after injection of gadoxetate and 40 min after injection of gadobenate . Both ag2) and dynamic post contrast 3D or 4D GRE sequences , arterial (at 20–30s after injection), portovenous (40–60s) and equilibrium (5 min)) and a delayed hepatobiliary phase [Standard liver imaging protocols usually consist of axial T1, axial  T2 weighted fast/turbo spin echo sequences, axial 3D gradient recalled echo (GRE) sequences (out/in phase) or T1 DIXON GRE (to provide out/in phase with fat suppressed and water supressed images), axial  balanced steady state free precession (SSFP), axial diffusion weighted images  level in particular is key, as this is elevated in the majority of patients with hepatoblastomas and HCCs , 22. It Patients with certain background medical histories ) are prone to develop hepatoblastomas, whereas those with underlying glycogen storage diseases, biliary atresia, alpha-1 anti-trypsin deficiency and tyrosinaemia are prone to developing HCC. Children with a history of a treated solid tumour with chemotherapy and/or radiation therapy have also been shown to have a predisposition towards the development of FNHs .Finally, it is also important to consider whether the patient is suffering from background liver disease, such as decompensated liver cirrhosis, which will reduce the level of hepatocyte uptake and biliary excretion of mixed hepatocyte specific/extracellular contrast agents  and hindLesion presence, number, anatomical location and imaging characteristics,Background liver parenchymal appearances,Evidence of metastatic spread, vascular or biliary complications,Other non- hepatobiliary findings .After reviewing the clinical information, a systematic approach should be adopted during image review and reporting, ensuring that the following issues are addressed:2), with lesions being more apparent on this sequence than on the usual T2 weighted sequences [In identification of liver lesions, many authors have purported the usefulness of the low b-value diffusion weighted images  are staged prior to commencement of therapy according to the PRETreatment EXTent of tumour (PRETEXT) system, designed by the International Childhood Liver Tumor Strategy Group (SIOPEL) . The staThe latest version of this staging system, established in 2005, requires the radiologist to delineate the number of anatomical sections that are involved and those that are free of tumour. There are 4 anatomical sections described in the staging system which are divided based on groupings of the Couinaud’s segmentation of the liver. The PRETEXT score represents the number of contiguous sections that must be resected to completely excise the tumour.Additional imaging information for PRETEXT staging including hepatic, portal venous and IVC involvement Fig. , lymph nHCC is the most common primary hepatic malignancy in adolescence and the second most common primary paediatric malignancy of the liver. Paediatric HCC differs from adult-type HCC in several important ways. First, pre-existing liver disease is only present in 30–50 % of paediatric patients , 43. WhiUnfortunately, the prognosis for HCCs occurring in children tends to be poorer than those observed in adults , with adThe fibrolamellar variant of HCC is more commonly seen in young adults Fig. . It is hFibrolamellar HCC is often included in a differential diagnosis list with focal nodular hyperplasia due to the presence of a central stellate scar. However, it can be differentiated from FNH based on the appearance of the central scar and the appearance of the tumour on the hepatobiliary phase. Fibrolamellar HCC has a hypointense scar on T2-weighted images while FNH has a hyperintense scar on the same sequence. On the hepatobiliary phase of enhancement fibrolamellar HCC is hypointense to the background liver while FNH is isointense to hyperintense to the background liver.Metastases from non-hepatic primary malignancies are commoner than those from primary hepatic tumours in general (such as those from Wilms’ tumours and neuroblastomas ). Liver Neuroblastoma metastases tend to demonstrate peripheral enhancement on arterial phase imaging with central progression of enhancement and peripheral washout on portal venous phase sequences. In some cases, they may also remain isointense . A potenAs previously mentioned, mixed hepatocyte specific/extracellular agents are useful in helping to differentiate FNHs from other hepatic lesions. The presence of normal functioning hepatocytes within the FNH allow uptake of this contrast. There is enhancement of the FNH in the arterial phase due to contrast material leaking from the vascular space into the interstitial space, however during the hepatobiliary phase of imaging there is active hepatocellular uptake (depending on presence of transporter proetein OATP1B1/3 ) and theA pitfall in interpretation may occur when trying to differentiate FNHs from regenerative nodules, as both can be hyperintense in the hepatobiliary phase. Whilst pre-contrast features can sometimes be helpful in making the differentiation, it may be difficult in scenarios where there is haemorrhage or fatty deposition within the FNH, or in the presence of background liver disease. Lesions that do not conform to those of a typical FNH therefore warrant biopsy .Hepatocellular adenomas also contain hepatocytes (like FNH), although not malformed biliary ducts. Fat content may be present within them, but is non-specific for the diagnosis . CurrentMR imaging for characterising paediatric liver tumours provides excellent soft tissue contrast. The usage of mixed hepatocyte specific/extracellular contrast agents allows for better lesion characterisation and location, particularly with respect to the biliary system and for differentiating FNH from other liver lesions.Imaging should aim to clarify the presence of a lesion, the likelihood of malignancy and potential for complete surgical resection. Reviewing and reporting the studies should address these issues in a systematic fashion whilst also commenting upon background liver parenchymal appearances. Clinical information and adequate patient preparation prior to MR imaging studies help enhance the diagnostic yield.


By combining the advantages of argument map and Bayesian network, a case description model based on evidence (CDMBE), which is suitable to continental law system, is proposed to describe the criminal cases. The logic of the model adopts the credibility logical reason and gets evidence-based reasoning quantitatively based on evidences. In order to consist with practical inference rules, five types of relationship and a set of rules are defined to calculate the credibility of assumptions based on the credibility and supportability of the related evidences. Experiments show that the model can get users' ideas into a figure and the results calculated from CDMBE are in line with those from Bayesian model. So far, there are many classical models in legal argument domain, such as argument graph models of informal logic, argument map, and Bayesian network. Argument map has two stages, assumption recognition and assumption proof. User recognizes the assumptions according to the case and evaluates the possibility of the assumptions by evidences . WigmoreThe above studies are suitable for common law system. However, Chinese law system belongs to continental law system; that is, a judgment must be based on some legal provisions. Mighui Xiong, a professor of Sun Yat-sen University of China, a member of the International Association for the Artificial Intelligence and Law (IAAIL), thinks that traditional logic cannot provide logical defense for legal argumentation, but the informal argument can, which introduces coherence, adequacy, and acceptability to nonmonotonic logic to make legal arguments more reasonable –8. In paThe literatures about argument map can be traced to  1931 in . ToulminStatistics method in information technology is usually used in legal reasoning. However, it has incurred the “argumentation about probability”  in the lCDMBE combines the intuition of Wigmore chart with the calculability of Bayesian network, by which the final assumption's credibility can be figured out by 5 kinds of syntagmatic relationships between evidences and intermediate assumptions based on credibility and supportability. CDMBE has a good description capability that it can describe any legal case. And it has a strict calculability that the reasoning results are reasonable when the credibility and supportabilities are correctly set by a user. CDMBE can be used as a tool of case analysis and knowledge storage so that the knowledge can be used as a data source of legal data mining.Evidence means any fact that can prove an assumption is reasonable. It comes from a series of legal procedures, for example, collecting, examining, and verifying materials. Chinese procedural law specifies 7 kinds of evidences: physical evidence, witness testimony, statement of victim, expert conclusion, investigation records, audiovisual material, and other evidences. In order to represent accurately knowledge of legal cases, we introduce 7 kinds of evidences into CDMBE and define two characters, credibility and supportability.Physical evidence is an object or a trace, which can prove the truth of a case by its external features, attributes, and existing form. Physical evidence is indirect and dependent, which must be used with the other evidence to confirm one another. For example, fingerprints left at the scene must be the same as the defendant's fingerprints to prove the defendant was once in the scene. In CDMBE, the rectangle is used to represent physical evidence.Witness testimony refers to the witness's statement about what he perceived in the case. The effectiveness of the witness testimony can be estimated by the qualification of the witness, authenticity, and objectivity. In CDMBE, punched tape is used to represent witness testimony.Statement of victim refers to the statement made by a victim. The effectiveness of the statement of victim can be estimated by the following aspects: source, rationality, relationship between the victim and the defendant, ability and character of proof, conflicts with other evidences, and so forth. In CDMBE, parallelogram is used to represent the statement of victim.Expert conclusion is a conclusive report made by commissioned appraiser after checking, analyzing, and judging a professional problem with specialized knowledge and modern technology. The following aspects need be considered: whether the appraiser is qualified, whether the proof ability of the identified material is sufficient, whether the identification method is scientific, whether the appraiser is affected by other events, and whether the conclusion conflicts with other evidences. In CDMBE, stored data is used to represent expert conclusion.Investigation records refer to the investigation records about the crime scene, objects, and bodies made by professional investigators according to their privileges and legal procedures. In general, investigation records are objective and strong proofs. The effectiveness of the investigation records can be estimated by the following aspects: whether they are made according to legal procedures, whether the content is objective, complete, and accurate, and whether the facts in the recording can be confirmed with other evidences. In CDMBE, internal storage is used to represent investigation records.Audiovisual material means multimedia information stored in tape, CD, computer, and so forth. In CDMBE, card is used to represent this kind of material.Evidence that does not belong to the above types can be classified into other evidences. In CDMBE, document is used to represent other evidences.Assumption is one of the human thinking methods. It is a speculative statement on an unknown fact, which begins with facts and reasoning by scientific methods.The assumptions in CDMBE include amount of intermediate assumptions and a final assumption, the conclusion. Like evidences, assumptions also have credibility and supportability. But its credibility is calculated from the lower level evidences and assumptions.The testimonial power comes from Law of Evidence. Since it is not defined in Chinese law, its concept is not unified –27. In tIn Law of Evidence, the testimonial power has three characters: objectivity, relevance, and legality . The objThe credibility is a character of evidence and assumption. And it is a quantitative description about the objectivity and legality of evidence or assumption. The supportability is a quantitative description about the relationship between assumption and its lower level evidences or assumptions. It is represented as a line with an arrow in CDMBE. The credibility is a decimal between 0 and 1; the supportability is a decimal between −1 and 1. When positive, the evidence has confirmed effect on the conclusion. When negative, the evidence has falsified effect on the conclusion.If the probability of Tom holding the murderous weapon at the crime scene is 0.9 , a direct way to calculate the testimonial power is to multiply credibility and supportability. But when credibility and supportability are both small , the testimonial power descends too fast. In order to mitigate the trend, the formula is defined as follows.i is an evidence or an assumption, its credibility is Ci, and its supportability for the high level assumption is Si; then its testimonial power Pi can be defined asSuppose The credibility of an assumption can be calculated by the testimonial powers of evidences or assumptions in lower level. However, the relationships among evidences and assumptions are complicated, which are classified as conjunction, recombination, aggregation, reinforcement, and coupling in Law of Evidence . In thisConjunction means that all the constitutive requirements of an assumption must be proved in order to prove the assumption. For example, to prove an assumption that Tom was convicted of killing someone, the four constitutive requirements must be proved; that is, the subject of crime, Tom, is a person with full criminal responsibilities, the subjectivity is on purpose, the object of crime is a person's life, and the objectivity is the fact that Tom took the person's life. Only when the four constitutive requirements are proved correct, the assumption is true.h is an assumption, P1, P2,…, Pn are the testimonial powers of evidences and assumptions in lower level, and their relationship is conjunction; then h's credibility Ch can be defined asSuppose Recombination means that an assumption can only be proved true when all required evidences exist at the same time. For example, it needs to be proved that Tom has a chance to kill Jerry at Jerry's home. Evidence 1 is that Jerry died at his home. Evidence 2 is that Tom was at Jerry's home when Jerry died. Recombination is similar to conjunction, and in CDMBE they have the same formula (formula (When two independent evidences support one assumption and make it stricter, the two evidences have aggregation relationship. For example, evidence 1 shows Tom arrived at Jerry's home at 8:20 am, evidence 2 shows that Tom left Jerry's home at 8:35 am, and then it can be firmly proved that Tom is at Jerry's home at 8:30 am.By analyzing some cases, we think that the aggregation result should be stronger than the strongest testimonial power when the evidences' testimonial powers are all strong, while the aggregation result should be weaker than the weakest one when the evidences' testimonial powers are all weak, and the aggregation result should be between the weakest and the strongest one when some testimonial powers are strong and others are weak.h is an assumption, P1, P2,…, Pn are the descending order of the testimonial powers of evidences and assumptions in lower level, and their relationship is aggregation; then h's credibility Ch can be defined asSuppose The concept of reinforcement is from common law system. It is defined as a relationship between supplemental evidences and the chief evidence, which can strengthen the chief evidence's testimonial power.h is an assumption, MP is the testimonial power of the chief evidence, P1, P2,…, Pn are the descending order of the testimonial powers of supplemental evidences, and their relationship is reinforcement; then h's credibility Ch can be defined asSuppose Coupling means a chain of reasoning. That is, when an assumption is proved by another assumption, their relationship is coupling. The coupling's credibility can be calculated by formula  because The case in Agatha Christie's novel “Witness for the Prosecution” is selected as the experimental data. In the section, authors describe the facts, analyze the case, simulate the court trial process, reason the judgment by CDMBE, and compare the analysis results with the Bayesian Network model built by Norman Fenton.When drawing a CDMBE graph, a top-down process must be followed, which means that a top-level graph must be drawn firstly and then unfolded. The top-level graph is composed of a final assumption and several constitutive requirements.A case generally has 4 common requirements: the subject refers to the person who implements the criminal act, the object refers to a social relationship, like political or economic relationship, which is protected by law and violated by the criminal act, the subjectivity refers to the subjective attitude of defendant when he or she commits a crime, and the objectivity refers to the criminal act .From the description of the case in the novel “Witness for the Prosecution,” we identified 47 key items from the case, as In Using the CDMBE graph, the court trial process can be deduced by adding evidences and assumptions step by step, which can be used to analyze the changes caused by evidences. Firstly, a top-level graph is initialized by analyzing the constitutive requirements, including items 1 to 11. Then, the plaintiff adduces evidence groups 1 to 3. Finally, the defendant adduces evidence groups 4 to 7. The changes of the credibility of the final assumption are shown in In order to make the case description model more intuitive and more accurate to reason, we proposed the CDMBE, which defines assumption and evidence as basic elements, uses credibility and supportability to calculate the testimonial power, and uses syntagmatic relationships to reason the credibility of the final assumption. Experiments show that the CDMBE model is easy to be understood, by which users can clarify their thoughts. At the same time, the model has a strict calculability and can reason legal argument quantitatively. And its analysis results are similar to that of Fenton's object-oriented Bayesian model and are accordant with reality.


Juvenile Systemic Sclerosis (JSS) is characterized by Raynaud's phenomenon (RP) and digital ulcers (DU). Conventional therapy includes calcium channel blockers (CCB) A growing number of vasodilators is available for treatment of refractory patients but there is no clear evidence of the best option. To aid clinical decision-making, a consensus of expert was undertaken.nd line vasodilators for RP and DU.To identify the best therapeutic options and define the sequence of 2nd line vasodilators c) identification of outcome measures to define RP and DU improvement, d) systematic literature review; e) summary report of the latest scientific evidence f) expert consensus meeting; g) rating of the strength of evidence. RAND/UCLA appropriateness method was used for rating the medical decision: items were rated on a 9-point scale on each drug option. There were two scoring rounds: first: anonymous and independent rating of the appropriateness of vasodilators based on scientific evidence and best clinical judgment. Differences in scoring were discussed at a face-to-face meeting, followed by a second rating round. Consensus was reached on appropriate/inappropriateness.Steps in the process of consensus were: a) Identification of expert panel (EP) members, b) Identification of 2st appropriate indication Iloprost; 2nd bosentan, 3rd sildenafil; 4th trepostinil.The EP included 10 physicians from a tertiary center who are involved in the care of patients with JSS: 3 pediatric rheumatologists, 2 dermatologists, 1 pediatrician, 1 gastroenterologist, 1 nephrologist, 1 nutricionist, 1 pharmacologist, and a moderator. The EP identified 4 drugs for analysis: bosentan, iloprost, sildenafil, and trepostinil. Outcome measures were selected according to the literature references and EP judgment. RP improvement definition: ≥ 30% improvement according to the physician  and ≥ 30% improvement in at least 2 patient-related domains (pain or function). Patient domains were: a) number of episodes, b) pain in a VAS, c) function , d) RP episodes average duration (in minutes). DU improvement definition: a favorable change in all physician- and patient-related domains: patient's domains: a) pain (VAS) b) function (VAS); physician's domains: a) ulcer activity (VAS) b) horizontal and transverse DU diameter (in mm). Systematic literature review was performed independently by 5 EP members and guided by the moderator. All articles in English were eligible. Data bases included pubmed and Cochrane. The search strategy included all relevant terms: bosentan, iloprost, sildenafil, trepostinil, RP, DU, combined in different sets of keywords. The summary report of the scientific evidence included 25 articles. Ranking of papers according to the strength of evidence showed: 1a (1 paper), 1b (7), 2b (2), 3b (2), 4(8), 5(5). After second scoring round: 1The EP reached a consensus on vasodilator drugs, providing direction for common dilemmas in the pharmacologic treatment of RP and DU in refractory patients.None declared.


This study aims to develop consensus evidence-based clinical guidelines for caries prevention and management by caries risk assessment for pre-school children in Hong Kong.Hong Kong Society of Paediatric Dentistry using a two-round web-based Delphi process. The reviewers were invited to contribute any comments on the draft-adapted guidelines and rated their agreement with each recommendation using a 9-point Likert scale. During the second round, 36 participants received anonymous feedback from the first round and assessed a narrowed list of 28 recommendations. Recommendations were retained and classified according to the median score and rating percentages by the reviewers.Employing the ADAPTE process, guidelines for caries prevention and management by caries risk assessment for pre-school children with a preliminary list of 91 recommendations was complied. External review of the guidelines was conducted by a panel of 41 reviewers from the A total of 70 out of 91 recommendations were retained , and 21 recommendations were discarded. Recommendations and guidelines were outlined.Caries prevention and management guidelines for pre-school children were developed for use in Hong Kong using the ADAPTE process and Delphi consensus to develop evidence-based recommendations. This can facilitate the translation of guidelines into dental practice. Dental caries in pre-school children remains a problem in Hong Kong. In a recent population-based oral health survey, the caries experience of pre-school children was over 50% in Hong Kong, with an extensive proportion of untreated carious teeth (over 90%) . One in The high degree of untreated dental caries indicates that there is inadequate access to quality oral healthcare for pre-school children in Hong Kong. Management of pre-school children’s oral health requires commitment from professionals, patients and their families. Dentists’ attitudes can contribute to the problem, resulting in a barrier to provide adequate and quality dental care . DentistClinical practice guidelines are systematically developed statements that can assist practitioners and patients in making decisions about appropriate healthcare for specific clinical circumstances , 7. It ihttp://www.g-i-n.net/gin [Expectations and requirements have been proposed internationally for the development of quality clinical guidelines , 9. The .net/gin . The ADAThe Delphi technique is a formal iterative structured process that aims to gather consensus of opinion, judgement or choice among a panel of experts –15. The There are several quality guidelines for managing dental caries for pre-school children worldwide. Nevertheless, guidelines ascribed to other countries or areas can encounter barriers to their practical application in a context with a different culture and healthcare system . LocalisHong Kong Society of Paediatric Dentistry (HKSPD), was identified and invited to be the collaborator on developing the guidelines. An introduction to guideline development and the ADAPTE process was presented to the members of the Society.The project was led by a team of researchers based at the Faculty of Dentistry, the University of Hong Kong. The team comprised of specialists in the field of Dental Public Health and Paediatric Dentistry. Members of the team reported no conflict of interests. The scope and key questions for the guidelines were established. The key stakeholder, the A search for relevant guidelines, protocols or policy statements in guideline repository websites, websites of various key guideline development organisations, and dental professional organisations, plus MEDLINE (Ovid), PubMed, Google and several other databases was conducted. The subject heading ‘dental caries’ was used for the search in combination with several other keyword terms: ‘tooth decay’ or ‘diagnosis’ or ‘management’ or ‘prevention’ or ‘approach’ or ‘caries risk’ or ‘caries risk assessment’ or ‘caries assessment’ or ‘caries prediction’ or ‘children’. An appropriate search strategy for each database was employed.Twenty non-duplicate guidelines, protocols or policy statements were identified in the search. No language restrictions were applied at this point. The retrieved guidelines were screened according to list of a priori inclusion/exclusion criteria: (1) dental caries, regarding its diagnosis, prevention, management or risk assessment was the main topic of the guidelines; (2) the target population of the guidelines was pre-school children with primary dentition; (3) the guidelines were for local or national use; (4) publication date should be from 2000 onwards to date of the search (December 2011); (5) indication that a literature search, ideally using a systematic method, had been conducted; (6) references were included; and (7) explicit link between the recommendations and the supporting evidence was indicated.Eleven guidelines/protocols were retained for further assessment after initial screening based on the inclusion/exclusion criteria. A panel group with four clinical teaching staff from the Department of Paediatric Dentistry of the University of Hong Kong was set up. The panel members were briefed about the guideline development and evaluation process for the retrieved guidelines by the guideline development group. They were invited to review the 11 retrieved guidelines and appraise their quality using the AGREE II  instrument individually . The AGRThree ‘Source’ guidelines for adaptation in the ADAPTE process were selected –20. The The recommendations from the three source guidelines were compiled in a recommendation matrix and compared. The grading and levels of evidence associated with each of the recommendations provided by the source guidelines were placed within each cell and was critically appraised using the SIGN methodology checklist .The consistency between the evidence presented in the source guidelines, their interpretation of the evidence, and the resulting recommendations were evaluated. The original evidence supporting the interpretations and recommendations in the source guidelines were reviewed. The currency of the source guidelines for the adaptation process was also assessed to ascertain whether the most current evidence had been included.A literature search of databases and websites for systematic reviews and randomised clinical trials, quasi-randomised trials or longitudinal cohort studies since the source guidelines published was conducted. The relevant publications were critically appraised and graded. The publications searched were between 2004 and June 2012. Year 2004 was the end date of search in the oldest source guideline by SIGN . This liDraft-adapted/adopted recommendations and summaries of the evidence were assessed by the guideline development group for (1) consistency between the evidence presented, (2) its interpretation and the resulting adapted/adopted recommendations, and (3) the effect of any new evidence on the recommendations. For each of the draft-adapted/adopted recommendations, their acceptability and applicability in the local Hong Kong context, taking culture, organisation and expertise of dental services and population characteristic, beliefs and values into account, were discussed and considered in the meetings among the guideline development group. Using informal consensus, the recommendations were either adapted, updated or rejected based on the latest evidence identified. A preliminary list of 91 draft recommendations was developed.A consultation draft of the adapted guidelines was produced with the preliminary list of 91 draft recommendations. The draft was circulated among the guideline development group members for comment and was revised where necessary.All 68 ordinary and associate members (excluding guideline development group members and panel members) of the HKSPD (key stakeholder) were invited to be external reviewers by email. Ordinary HKSPD members were either registered paediatric dentists or practitioners who had completed structured training in the specialty and were experts in Paediatric Dentistry in Hong Kong. Associate members of HKSPD were general medical or dental practitioners who were interested in the practice of Paediatric Dentistry. All of them would be the potential users of the developing guidelines.Electronic copies of the consultation draft of the adapted guidelines were circulated to the external reviewers. The external reviewers were invited to contribute any comments on the consultation draft of the developing guidelines. An Internet-based structured questionnaire on a 5-point Likert scale was used to ask the external reviewers about their view on the strengths and weaknesses of the consultation draft, any need for modification, whether they would approve the draft guidelines and use them in their practice, and how it would impact or change their current practice. The 22 items about the external reviewers’ general view on the guidelines were added up to create a general view score ranging from 0 to 110, with a higher score indicating a more positive attitude towards the guidelines. The external reviewers consented to participate in the guideline external review process and for the data to be published.A two-round Internet-based password-protected Delphi consensus process was conducted among the external reviewers. The Delphi process was carried out to collect opinions or comments from external reviewers so as to establish consensus recommendations for the guidelines. Before each round, external reviewers were reminded of the upcoming surveys by at least four emails. The draft recommendations were presented to the external reviewers. They rated their agreement with each of the 91 preliminary adapted/adopted recommendations using a 9-point Likert scale  and to contribute any comments on the recommendations. They were given the option of not commenting on a recommendation when the topic was outside their respective areas of expertise. This process was repeated during the second round, in which reviewers’ ratings, dissenting opinions or uncertainty, or absence of evidence were combined and provided anonymously to all of them. They were allowed to revise their first round responses in view of further responses in the second round. After the first round, the guideline development group met to modify some recommendations for clarity and presentation for the second round.For the first round of Delphi, recommendations rated by < 20% of the external reviewers were discarded. Recommendations rated by 80% of the external reviewers were discarded if the overall median score fell within the bottom tertile  and deferred until the second round if the overall median score was 4–6 . Recommendations with overall median scores within the top tertile (7–9) were classified as follows: those rated by < 80% of the external reviewers were deferred until the second round, and those rated by ≥ 80% of the external reviewers were classified as ‘high agreement’ if they had an overall median score of 9 or as ‘agreement’ they had an overall median score of 7 or 8.Similarly, in the second round of Delphi, recommendations rated by < 20% of the external reviewers were discarded. Recommendations rated by 80% of the external reviewers were discarded if the overall median score fell between 1 and 6. Recommendations with an overall median score within the top tertile (7–9) were classified as follows: those rated by < 80% of the external reviewers were discarded, and those rated by ≥ 80% of the external reviewers were classified as for the first round. The classification of recommendations according to the overall median score and percentage of ratings by external reviewers in the two-round Delphi process is illustrated in Fig. Data were analysed using IBM® SPSS Statistics 19 . Recommendation-specific medians were estimated for each round. The inter-rater agreement between participants in each round was evaluated using intraclass correlation coefficient with 95% confidence intervals (CI). Microsoft Excel for Mac 2011 was used for preparing tabular and graphic presentation.All the feedback from the external reviewers were documented and presented in the guideline development group meeting for discussion. The guidelines and recommendations were further revised to incorporate feedback from the external reviewers where necessary.The flow chart in Fig. N = 70) that had gained consensus from the external reviewers in the Delphi process were included in the final list of recommendations of the guidelines.All the participated external reviewers rated all the items. Of the original 91 recommendations, 70 were retained and classified as follows: five items reached consensus (‘high agreement’), 65 items reached near consensus (‘agreement’), 21 items were discarded. Results of the recommendations in the two-round Internet-based Delphi consensus surveys are listed in Table The ratings of the external reviewers about their general views on the strengths and weaknesses of the guidelines are listed in Table Clinical practice guidelines are the major means to summarise and translate rapidly changing research evidence into practice and assist clinical decision making , 26. CliDeveloping clinical practice guidelines using the ADAPTE process and Delphi consensus has not been reported in the literature. This approach allows developing guidelines with consensus evidence-based recommendations. The literature suggests that guidelines developed without active participation and involvement of the intended users and which were partially without credible scientific basis were not fully supported by the profession and were poorly accepted by the practitioners , 28. ADAHong Kong Society of Paediatric Dentistry, who were either specialists of paediatric dentistry or dental/medical practitioners with active participation in the field. This heterogeneous sample ensured that a wide spectrum of opinions of the guideline could be collected. The group consisted of 41 members in round 1 and 36 members in round 2, thus reducing the potential of selection bias of ‘experts’ for the Delphi process [A consensus approach using the Delphi technique was employed during the external review process of the guidelines. Delphi strengthened the external review process of this guideline development. In addition to external reviewers’ comments and views on the draft-adapted guidelines, their consensus on the guidelines’ recommendations was achieved. External reviewers were members of the  process , 14, 30. process . InvolveThe response rate in the second round of Delphi  dropped when compared to the first round . Recruitment of dental practitioners in a research study is a challenge and it is also difficult to retain a high response rate in each round of Delphi , 14. InsThe consensus level of the Delphi technique in the literature ranges from 51% to 80%; a bench mark of 70% is used in many cases . We usedThe online implementation of the Delphi technique for external review was well received. External reviewers completed the two-round web-based Delphi external review of the guideline over a period of 5 months. They contributed extensive and supportive comments on the guidelines and the recommendations.Not all evidence-based recommendations were accepted by the external reviewers. Although the recommendation, ‘All children should be encouraged to brush their teeth under adult supervision with fluoride toothpaste containing at least 1000 ppm F’ was based on strong evidence , it was Using the ADAPTE process and Delphi consensus, evidence-based clinical guidelines for caries prevention and management by caries risk assessment for pre-school children in Hong Kong were developed. These guidelines can facilitate the translation of evidence into practice. The framework for developing the guidelines could be employed elsewhere.AGREE II, Appraisal of Guidelines for Research and Evaluation II instrument; HKSPD, Hong Kong Society of Paediatric Dentistry; SIGN, Scottish Intercollegiate Guideline Network (SIGN)