Several countries in Sub Saharan Africa have abolished user fees for health care but the extent to which such a policy decision is guided by evidence needs further exploration. We explored the barriers and facilitating factors to uptake of evidence in the process of user fee abolition in Uganda and how the context and stakeholders involved shaped the uptake of evidence. This study builds on previous work in Uganda that led to the development of a middle range theory (MRT) outlining the main facilitating factors for knowledge translation (KT). Application of the MRT to the case of abolition of user fees contributes to its refining.Employing a theory-driven inquiry and case study approach given the need for in-depth investigation, we reviewed documents and conducted interviews with 32 purposefully selected key informants. We assessed whether evidence was available, had or had not been considered in policy development and the reasons why and; assessed how the actors and the context shaped the uptake of evidence.Symbolic, conceptual and instrumental uses of evidence were manifest. Different actors were influenced by different types of evidence. While technocrats in the ministry of health (MoH) relied on formal research, politicians relied on community complaints. The capacity of the MoH to lead the KT process was weak and the partnerships for KT were informal. The political window and alignment of the evidence with overall government discourse enhanced uptake of evidence. Stakeholders were divided, seemed to be polarized for various reasons and had varying levels of support and influence impacting the uptake of evidence.Evidence will be taken up in policy development in instances where the MoH leads the KT process, there are partnerships for KT in place, and the overall government policy and the political situation can be expected to play a role. Different actors will be influenced by different types of evidence and their level of support and influence will impact the uptake of evidence. In addition, the extent to which a policy issue is contested and, whether stakeholders share similar opinions and preferences will impact the uptake of evidence.The online version of this article (doi:10.1186/s12913-014-0639-5) contains supplementary material, which is available to authorized users. User fees for health care have been debated for well over a decade. Though some researchers have argued that they improve the quality of care, and subsequently utilization ,2, otherThe policy-making process is influenced by several factors evidence being just one of them. Political processes, economic considerations, institutions, cultural issues and societal values all impact on health policy development ,19. FurtIn the past, the uptake of evidence has been restricted to instances in which the evidence led directly to development of a policy, a strategy or a guideline, but scholars have shown different ways in which evidence can be used. Evidence may be used to support a position that is already taken (symbolic use), to inform discussions and debate about a topical issue , or used to actually create guidelines or change practice directly  ,24. In tHigh-quality and contextualized evidence will be taken up in policies so as to lead to evidence-informed policies in instances where the MoH leads the KT process and there are partnerships for KT in place.“Evidence must be of high quality, contextualised, provide economically feasible recommendations, and produced in a timely manner by credible researchers. Use of local researchers is helpful but there is a need to separate the roles of researchers and policy makers.strengthened MoH institutional capacity to lead the KT process. Institutionalized platforms for engagement between researchers and policymakers including civil society need to be in place, and mechanisms to coordinate evidence generation and synthesis need to be mainstreamed within the MoH. Policy makers need to be better at knowledge management and the policy-making process needs to be minimally bureaucratic.KT requires Partnerships for KT need to be in place where all stakeholders are involved throughout the process right from evidence generation to application in order to improve trust and build interest. Communities need involvement in evidence generation and KT as well.These contribute to more ownership, adoption and better application of evidence” of the WB, who showed that when you abolish user fees, increases in access would not be significant”.The objectivity of some evidence was a concern as several of the available studies had been undertaken by donors, and these were judged as misleading. According to a MoH respondent, e did have some complaints from the community that people were staying away because of user fees but that evidence was not enough to guide us on the way forward. Although these were also echoed in the UPPA study, we should have done a thorough study to assess how the removal of the user fees would help because some of these problems have persisted even when the services are free. Community complaints should have been a starting point for a study and not a basis for decision making.” In addition, a MoH respondent remarked that “although some evidence was available, it was not enough and also not credible”.The comprehensiveness of the local evidence was also in question, as a journalist stated, “WWe were reading these reports, synthesizing them and bringing evidence as digestible bits to politicians. They would take it or leave it depending on what positions they wanted to take.” Some of the recommendations made by technocrats were actually tabled in cabinet, as reported by a MoH respondent: “we wrote a policy brief for cabinet showing them how much the government had to invest in order to reach the level made by user fees. We made recommendations to the Minister of Health and these were taken into consideration”.Technocrats made an effort to disseminate evidence to politicians, as pointed out by a MoH respondent, “big players like the WB were just pushing their agenda, bringing in all sorts of evidence, some of which was good and some was bad, they used whatever evidence they liked. It is not that people were sitting down and deliberating.” However, respondents reported that, in one of the local studies, a team headed by a researcher from a public university was put in place, with the MoH serving as the secretariat, to collect data on the various aspects of user fees.Weaknesses in the capacity of the MoH to lead in evidence generation, synthesis, and application were reported. The generation and dissemination of evidence was mainly donor driven, with the MoH playing a recipient role, as pointed out by a MoH respondent: “A review of documents confirmed that the inter-ministerial task force on user fees was headed by a researcher and the MoH was the secretariat. Later, a health financing task force, involving MoH official, donors and CSO representatives was put in place to develop policy options on improving health sector financing and was chaired by the MoH.Strong leadership at the MoF was a key issue - the leadership was listening to evidence.” In the MoH, the leadership went through times of strong and weak leadership over the policy timeline for user fees; a MoH respondent stated that “at one point we had a strong leader and at another time we had a consortium of leaders with other interests, so they were not looking out to see what needs strengthening.” In times of strong leadership, leaders in the MoH were reported to be visionary: “there was a culture of questioning whether we were doing things right all the time, we would look at evidence from research studies, surveys and routine monitoring.” (MoH respondent)Although leadership at the MoF was strong, the MoH suffered a high turnover at the senior officer level, which weakened its leadership capacity. The leadership in the MoF was reportedly able to synthesize the evidence, as a MoH respondent stated, “there was a lot of work to be done to produce guidelines on exemptions for those who could not pay and we requested support from UNICEF.” Community involvement on the other hand was limited to being respondents in surveys.KT partnerships are key to improving the uptake of evidence, and these were reported to be in place although several weaknesses were reported regarding their membership, duration, and scope of work. A one-off task force was put in place to coordinate the generation, synthesis, and dissemination of evidence to decision makers, including the cabinet, although it mainly consisted of senior MoH staff, MoF staff, researchers, and the WHO. Donor involvement was only reported in the development of guidelines; the MoH respondent stated that “In addition, a review of documents revealed that throughout the evidence generation and policy discussions, only two task forces were put in place. These task forces were short-lived and only performed specific tasks. The inter-ministerial task force on user fees was tasked with reviewing and synthesizing available data and providing policy options. The working group for health financing convened after the abolition of user fees to provide policy options on improving health sector financing.there was no consultative process in the decision to abolish user fees”.Decision making was reported as non-consultative; one MoH respondent stated that ““Abolition of user fees was in the election manifesto of the ruling party and this showed that they were responding to population concerns.” Second, the community presented the ills of user fees for health care to the president while on a campaign trail, as noted by a CSO respondent: “complaints about user fees were raised to the president during campaigns where he had to offer an incentive to have more votes.” A private not-for-profit service provider further added that “there were community cries about the ills of user fees and indeed the scrapping of user fees was announced at a political rally”.The year in which user fees were abolished, 2001, was marked by presidential elections, and the different candidates were moving around the country canvassing for votes. The issue of improving service delivery and access to health services, specifically the abolition of user fees for health care in public facilities, was in the manifesto of both the ruling party and the leading opposition party. The ills of user fees had been highlighted in the UPPA study whose findings were disseminated widely by the media and CSOs and, even discussed in political circles. A majority of respondents reported that this political window could have provided an opportunity to abolish user fees. According to a MoH respondent, the “I suspect the pronouncement to abolish user fees was through political pressure and competition because the main opposition party was saying ‘we will abolish user fees for health services immediately’ so the captain could not say ‘I will wait for the plan’, they could lose votes”.The opposition candidate was promising to scrap user fees for health care once elected to office and the pronouncement by the president could have been a tactic to pre-empt the opposition manifesto. A MoH respondent stated, “evidence by itself would not have constituted sufficient force to enable the government to make the decision, but because they were under political pressure, evidence gave them reason to make the decision to abolish user fees”.Another MoH respondent argued that evidence was taken seriously because of the political context: Political experience overtook this process and the decision to abolish user fees was not a health sector decision; it was a pronouncement from the head of state. We had not gone to him and given him evidence directly, but communities had complained to him.” A parliamentarian added that the “Abolition of user fees was a political decision, it was not based on systematic evidence but there was some fury from the public that user fees had become politically unsustainable”.The political process impacted the KT process in that it did not allow enough time for the diffusion of evidence, as stated by a MoH respondent, ““The Uganda poverty participatory assessment (UPPA) showed that user fees were a hindrance to accessing care and also to poverty alleviation efforts. This was at a time when the government was keen to reduce poverty and we were writing poverty reduction support credit papers”.There was a move at the global and national level to eradicate poverty and the country wanted to address all issues that would hinder realization of the objectives of the PEAP. A MoH respondent stated, one of the barriers was the limited fiscal space for giving free public goods in all sectors.” In addition, although services were free, there were gaps in service delivery, as a MoH respondent stated, “We saw a tapering off of patient utilization when the community realized that a number of health facilities did not have sufficient supplies of essential medicines so it was useless going for free things when they are actually not there.” Poor planning for the policy change was reported by a donor respondent: “We didn’t put in place proper system structures that when user fees are abolished, something replaces them to ensure continuity of services”.Inadequate funding to implement evidence was cited as a barrier by a MoF respondent: “The ministry’s role was advocacy, defending the position of the MoH, and persuading other people to join us”.Stakeholders played different roles in the uptake of evidence Table . The MoH“The WB had all sorts of publications on user fees and was making the argument that user fees need to be included in social service delivery areas like health and education.” Respondents reported that the debate on user fees started after a WB publication showing that the introduction of user fees would not affect the utilization of health services. User fees were introduced as a demonstration project of the WB. A MoH respondent stated, “We had started decentralization and in each of the thirteen districts we were going to introduce user fees for health care as a pilot and demonstration project of the WB”.The roles of donors were reported as providing funding and generating evidence. Some respondents reported that influential donors dominated the process of evidence generation and decision making about user fees. The CSO respondent stated, CSOs generated evidence which showed that, when user fees are charged for health care, the rural and urban poor are disadvantaged.” Respondents also highlighted the role of CSOs in disseminating evidence; a parliamentarian respondent stated that “CSOs produce policy briefs and distribute them. They find people with influence or who are close to policy makers and put them on their list and every time they find new ideas, new findings, new research, they just disseminate it through their network, and I usually pick a lot of those.” The advocacy role played by CSOs was highlighted by a researcher who stated, “I think their advocacy role helped create sufficient pressure for the government to abolish user fees”.CSOs played a role in generating evidence; a CSO respondent stated that “we used to have newspaper articles highlighting the barriers to access due to user fees.” However, a donor respondent decried the under-utilized role of the media stating, “I don’t think we use the media well enough. Sometimes journalists sit outside the offices of some decision makers and fail to see them and that’s why they end up writing whatever stories they have. Once a journalist mentioned to me that he went and sat outside [X’s] office and was not given an opportunity, and yet with the politicians, they do it very well; they will always want to send their issues across.” A MoH respondent cautioned about the possible negative role of the media, stating that “if the media do not base their publications on evidence, they can be a very detrimental ally”.The role of the media in disseminating evidence was highlighted by a CSO respondent: “donors were strong but their positions were mixed. The [X] from pro poor systems were opposed to user fees while the [X] from a capitalist background were supportive of user fees. WHO and UNICEF had invested a lot in the Bamako initiative so were opposed to user fee abolition. Actually, in the health policy advisory committee, there was no consensus”. (MoH respondent)The level of support and influence by the different stakeholders on the decision to abolish user fees in light of available evidence varied as shown in Figure “The MoH was working on a cabinet memo to reorganize user fees but after 2 months, when presidential campaigns were ongoing, I heard a speech from the president saying ‘I have never supported user fees,’ he even said he will not support user fees, so the minister who had championed the whole user fee issue had to write memos to stop it”.The MoH was also divided in that some officers were strong and supportive of abolishing user fees but others were strong and opposed. Although the officers who were strong and opposed were equally concerned with the evidence which showed a high out of pocket expenditure on health , their ccommunities put the issue of the ills of user fees for health care on the agenda, they were strong in that they are the electorate and the president wanted votes. They kept complaining. They were supportive of the abolition of user fees and they were strong.” A researcher added, “If the voters were that important then, yes, they had influence,” and a service provider remarked that “the community was in full support of user fee abolition because it was to their advantage.”Communities were strong supporters of the abolition of user fees, and influential given the political window as reported by a MoH respondent: “people who had the willingness and ability to pay were feeling that ‘if you take away user fees, that means that I may not get the same quality, yet am willing to pay, I have money’.” (CSO respondent)However, a civil society respondent highlighted a contrary view that the rich in the society were not supportive of abolishing fees for health, stating that “The CSOs supported the abolition of user fees. We had [X] on some of those working groups and they were really pushing for the abolition of user fees for health care, saying that evidence showed that poverty was biting.” This was in reference to the evidence from the UPPA and CSO’s own research. Some CSOs were supportive because they believed there was enough money to fund health services without communities paying, as one donor respondent stated, “The CSOs were against the user fees because they believed that there is a lot of money invested in the health sector and there was no reason for people to pay in order to access health services.”CSOs strongly supported the abolition of user fees, although the reasons behind their support varied. Some had concern for the poor, as a MoH respondent stated, “politicians had a divided opinion, some supported user fee abolition for the purpose of popularity, especially votes. Some were for user fees because they believed that user fees could improve service delivery by offering a small allowance to health workers, which boosted their morale”. The improved availability of drugs and incentives for health workers was also shown in some pilots supported by WHO [Respondents reported that politicians at the national level had divided positions, stating that some supported the abolition of user fees because of potential political gains, whereas others opposed it because they were concerned about service delivery given the evidence of increased availability of medicines as a result of charging a small fee for services ,62. A dod by WHO .es, they were opposing the abolition of user fees just as they are still opposing the abolition of graduated tax, yet they are getting almost 10 times the money they used to collect from graduated tax! They want something they can independently manage”.Politicians at the local government/district level were also divided; some were strong and opposed to the abolition of user fees due to the potential loss in revenue and the preference to generate local revenue that could be managed at the district level rather than receiving grant from the central government s. A CSO respondent noted that “YManagers of health services at the district level and service providers in public health facilities were reported as strongly opposing the abolition of user fees and were influential because the implementation of the policy heavily depended on them; they were opposed because of the potential loss in revenue.researchers were divided, some were for abolishing user fees, some were not, and there was evidence on both sides.”Although researchers were reported as being less influential, they were also divided, with some supporting and some opposing the abolition of user fees. The division was partly reported to be due to the kind of evidence they were generating. A researcher stated that “Various types of evidence were cited in strategic documents and discussion papers as shown in Table Respondents ranked the degree of consistency between policy decisions and available evidence as weak at all stages of policy development Table . Better The present study highlights the ongoing debate on what constitutes evidence and gives good examples of how evidence may be considered, used, or even misused in the policy development process. Our findings show that evidence informed decision making in different ways. The MoH institutional capacity to lead the KT process, the partnerships for KT, the political context and the overall government discourse impacted the uptake of evidence in the abolition of user fees for health care in public health facilities in Uganda.The process of abolishing user fees was informed by evidence generated from formal research but also from community complaints. Though peer-reviewed research has been considered the most appropriate evidence in the past , it is nIn our study, evidence informed policy and decision making in different ways. Some respondents stated that evidence was used to support a decision that was already made, implying ‘symbolic use’, whereas others reported that available evidence was presented in cabinet to guide discussions, implying ‘conceptual use’. Yet others reported that the analysis from losses in revenue if user fees were abolished directly guided budget allocations to the health sector, implying ‘instrumental use’.The characteristics of the available evidence may have impacted how evidence was used in several ways. Concerns were raised regarding the quality of the available evidence, the contradictory conclusions from the research studies, and the limited dissemination of evidence, which are known barriers to the uptake of evidence ,65. The The MoH’s institutional leadership of the KT processes was weak; the process of evidence generation and dissemination was mainly donor driven with the MoH playing primarily a recipient role. We noted a lack of coordinated efforts to synthesize and disseminate evidence, which could have served to resolve the seeming contradictions in the available evidence. This finding may explain the different course of action between the technical (MoH) and political (cabinet) players in addressing the high out of pocket expenditures on health; the technocrats at the central level MoH preferred a re-organization of user fees, and politicians preferred the provision of free health services. In addition, the high turnover of senior positions in the MoH further resulted in weaknesses in leadership due to lost institutional memory and having leaders at certain times who had minimal interest in the use of evidence. The high turnover of senior officers has been highlighted as one of the limitations of the enlightenment model, which infers a notion of gradual sedimentation of ideas over time and the subsequent uptake of evidence in policy ,66. PoliThe consistency between available evidence and policy decisions was highest at the agenda setting stage, decreasing thereafter, implying that the political process may not have allowed enough time for the diffusion of evidence. The lack of a consultative process in decision making was found in this study. Although a challenge that cannot be overlooked is how consultative platforms within which dialogue may occur can work alongside time-bound political processes. Moat & Abelson in their analysis of the influence of institutions in the decision to abolish user fees in Uganda, highlighted the weaknesses of government structures to impact on the decision making process to abolish user fees concluding that “Big man” presidentialism and clientelism thwarted the role of formal institutions. This maThere were some KT partnerships in place, though these were short lived with time-bound assignments. Effective partnerships for KT require mutual trust ,72, but Although funding was made available as part of debt relief, it was inadequate and hampered the uptake of evidence. A tapering off of service utilization due to a lack of essential medicines has been reported in other studies as well . Other rThe different actors played different roles and had varying levels of support and influence. For example, the MoH played an advocacy role previously reported by CSOs and politicians in an earlier study on the roles of actors in KT in Uganda . This chRegarding stakeholders’ level of support and influence, almost all stakeholders were divided, but for varying reasons. Divided views were found among actors on whom funding decisions and the successful implementation of evidence heavily depended. Consensus is however important for the successful implementation of evidence; for example, prioritized resource allocation to implement evidence can only be realized with an agreed upon course of action . In our “…if there was no pressure of any kind, evidence by itself would not have constituted sufficient force to enable the government to make the decision.” The political window is a documented facilitating factor to the uptake of evidence [The political context within which the abolition of user fees occurred also played a role in the uptake of evidence. The timing of presidential elections provided an opportunity. This case is a clear example of Kingdon’s problem of political and policy streams meeting up to form a policy window . In the evidence ,74. In aThere were similarities as well as differences regarding the factors that impacted uptake of evidence looking at our initial MRT and the factors identified in this study. Regarding the characteristics of the available evidence, although the availability of evidence was crucial, its timeliness, scientific rigor, credibility of researchers and separation of roles between researchers and policy makers, as identified in our initial MRT, did not feature prominently in this case study. Regarding the MoH institutional capacity to lead the KT process, although platforms for engagement were in place, they were short lived, weak and of limited involvement. Mainstreamed mechanisms (within the MoH) to coordinate evidence generation, synthesis and dissemination were absent. Regarding partnerships for KT, although these were in place, they were informal, limited in scope and membership. These weaknesses with standing, we note that there multiple uses of evidence in the decision making process.The multiple uses of evidence and lack of emphasis on the scientific rigor of the available evidence can be explained by the nature of the case under study. Even when evidence is available, the success of efforts to effectively disseminate, legitimize and consider evidence objectively in policy development will be impacted on by the characteristics of the issue under consideration . This co; the government was keen to address hindrances to realization of PEAP objectives user fees for health care being one of them. CSOs were in support of abolition of user fees to improve access to health services for the poor, managers and service providers at decentralized levels were opposed because they stood to lose a source of revenue and politicians at the central and decentralized level stood to lose votes. Contandriopouls et al. further state that if an issue is highly salient in that it will attract a lot of attention and; whether actors are familiar with the issue thus it gains prominence on the agenda [we used to have newspaper articles highlighting the barriers to access due to user fees”. These may explain the multiple uses of evidence, lack of consensus on the available evidence and preferred course of action and; the lack of emphasis the scientific rigor of the evidence.In the case of abolition of user fees for health care, the high issue polarisation was noted. The WB was in support of user fees based on their concern to ensure loan sustainabilitye agenda ,74 will e agenda  and stooWe refined the initial MRT as follows.“Evidence will be taken up in policies so as to lead to evidence informed policies in instances where the MoH leads the KT process, there are partnerships for KT in place and, the nature of the policy issue under consideration, the overall government agenda and; the political situation can be expected to play a role”.Evidence must be available and disseminated to stakeholders and;KT requires strengthened MoH institutional capacity to lead the KT processes and platforms for engagement between researchers and policy makers including civil society need to be in place.Partnerships for KT need to be in place. There is need to devise mechanisms for stakeholder engagement and resolving conflict of interest. Communities need involvement in evidence generation and KT as well.A favorable political context in which a political window provides an opportunity for KT and;Evidence aligning with the overall government policy discourse, enhance uptake.These contribute to more ownership, adoption and better application of evidence.The strength of our study is the diversity of respondents, which provides a rich set of information to study the case. In addition, we have used multiple sources of data (interviews and document review) and mixed methods which have increased the validity and reliability of our findings. The multidisciplinary nature of our study team also strengthens the study given the ability to analyze and interpret data from multiple perspectives.Among the weaknesses of our study is recall bias, as the KT processes being studied occurred took place some time ago. However, we think that this is not so much of a limitation given the consistency in responses. The direct impact of the abolition of user fees on peoples’ welfare, which makes it politically attractive, may have affected the nature of responses in cases where some respondents may have had political inclinations, but this was not assessed in our study. We have used scales developed by Hanney et al. in rating the degree of consistence between the available evidence and policy decisions taken. Although this work was been published , the ratThe objective use of evidence in donor-dependent countries remains a challenge, and part of the solution lies in having strong MoH structures to coordinate prioritized research agendas and KT processes. Although the generation of comprehensive evidence takes time, it remains the best option in order to assess all aspects of policy implications and the feasibility of implementation. Such efforts will need to be planned prior to embarking on the policymaking process. In addition, reaching a consensus on available evidence and the possible course of action is crucial, so as to harnessed to all available resources to facilitate implementation.This study has also highlighted other factors which would require more exploration to assess whether outcomes would be different if they were in place, in reference to policies categorized as high issue polarization. These included effective and well-coordinated dissemination of evidence, stakeholders reaching a consensus on the available evidence, the MoH having the negotiating power to take a preferred course of action in line with evidence and, reducing the turnover of senior officers to ensure continuity. In addition, testing our MRT on additional case study will lead to more refinement and perhaps improve the extent to which the MRT can be generalized.“evidence will be taken up in policies so as to lead to evidence informed policies in instances where the MoH leads the KT process, there are partnerships for KT in place and, the nature of the policy issue under consideration, the overall government agenda and; the political situation can be expected to play a role” We acknowledge that context is very important in KT and our refined MRT may not hold true in all contexts. Thus, applying the MRT calls for understanding the context within which KT processes occur; the stakeholders involved and; the nature of the policy that is to be influenced by the evidence. However, we believe that our theory can serve as a starting point for other countries planning to abolish user fees for health care and seeking to maximize the use of evidence.Evidence was used in several ways in the case of the abolition of user fees. We noted symbolic use of evidence in the form of community complaints by the president to abolish user fees; instrumental use of evidence in the form of routine monitoring data by technocrats in the MoH to negotiate for an increase in the health sector allocation and, conceptual use of evidence in the form of survey data by the cabinet to debate the ills of user fees for health care. What is taken as evidence may vary from case to case due to the stakeholders involved and how much interest and influence they wield. We found divergences and convergence with facilitatory factors identified in our earlier MRT on KT in Uganda. Additional factors and themes emerged as well. Respondents perceived the availability of evidence including its dissemination; the MoH institutional capacity to lead KT processes; the existence of partnerships for KT; a favorable political context; and how evidence aligns with the overall government policy discourse as the factors that impacted the uptake of evidence. We refined our initial MRT as “


Pseudomyogenic hemangioendothelioma (PHE) is an unusual vascular tumor of intermediate malignancy that rarely metastasizes and tends to arise in the lower limbs of young adults and children. Histologically, PHE shows fascicular proliferation of eosinophilic spindle cells and/or epithelioid cells showing “pseudomyogenic” morphology. Immunohistochemically, PHE is usually positive for vimentin, cytokeratin, CD31 and ERG.We examined FOSB immunohistochemistry (IHC) in 27 cases consisting of 4 PHE and its histologic mimics including 6 epithelioid hemangioendotheliomas (EHE), 8 angiosarcomas (AS), 4 Kaposi sarcomas (KS) and 5 epithelioid sarcomas (ES). In addition, we performed IHC of CAMTA1 which has recently been established as a useful marker of EHE. We elucidated the diagnostic utility of FOSB IHC in the differential diagnosis of PHE and its histological mimics and also examined the usefulness of FOSB and CAMTA1 IHC combination in the differential diagnosis of the tumors.IHC revealed diffuse and strong FOSB expression in all PHE cases, while the other tumor types demonstrated limited, weak or no FOSB expression. All EHE cases exhibited diffuse and moderate to strong expression of CAMTA1. All tumor types except for EHE showed limited, weak or no CAMTA1 reactivity.Diffuse and strong FOSB expression was specific for PHE in the current series and FOSB IHC is an effective tool for differentiating between PHE and its histological mimics. Moreover, the combination of FOSB and CAMTA1 IHC is useful for distinguishing PHE from EHE. Pseudomyogenic hemangioendothelioma (PHE) is an unusual soft tissue tumor, defined as a vascular tumor of intermediate malignancy that rarely metastasizes in the current World Health Organization (WHO) classification of soft tissue and bone tumors . PHE maiEven though PHE has some characteristic histological features, we may have difficulty in distinguishing PHE from histologically similar vascular and epithelioid tumors of soft tissue including epithelioid hemangioendothelioma (EHE), angiosarcoma (AS), Kaposi sarcoma (KS) and ES, especially with small biopsy specimens. The precise diagnosis of PHE and distinguishing it from similar tumors is very important because the clinical behavior and malignant potential of these tumors are very different. We often use an IHC panel containing several vascular and epithelial markers for making the differential diagnosis of these tumors, although some tumors may show an overlapping immunoreactivity for these markers which sometimes makes it challenging to diagnose PHE. EHE is the most important tumor in the differential diagnosis of PHE, because its histological findings and clinical presentation are similar to those of PHE. Both of them usually show a fascicular proliferation of relatively bland spindle and/or epithelioid cells with eosinophilic cytoplasm. In addition, PHE tends to emerge with multiple musculoskeletal lesions, often involving skeletal bones  and EHE WWTR1-CAMTA1 or YAP1-TFE3 in EHE [WWTR1-CAMTA1 fusion derived from translocation of t and was often observed in most EHE cases. Moreover, recent studies revealed that the specific nuclear expression of CAMTA1 on IHC was a useful tool for the diagnosis of EHE [SERPINE1-FOSB fusion derived from t and significantly higher FOSB mRNA expression in PHE tumor cells [Some studies have clarified specific fusions of 3 in EHE , 5. The  tp3;q25 and s of EHE . Alternaor cells , 9. ThusIn the present study, we elucidated the diagnostic utility of FOSB IHC in the differential diagnosis of PHE and its histological mimics including EHE, AS, KS and ES. We also performed CAMTA1 IHC, an excellent diagnostic marker for EHE , 7, and For IHC, we chose 27 cases consisting of 4 PHEs, 6 EHEs, 8 ASs, 4 KSs, and 5 ESs from the pathology files of the Department of Surgical Pathology, Sapporo Medical University Hospital, Sapporo, Japan. We used biopsy or resected specimens in various sites for the study. We reviewed all hematoxylin and eosin sections and checked previously performed IHC findings. After we confirmed that each case fulfilled the histological criteria and the results of IHC were consistent with each tumor type described above, we selected representative sections suitable for IHC.In brief, PHE consisted of fascicular proliferation of bland, spindle-shaped cells that have oval nuclei and obvious eosinophilic cytoplasm showing myogenic differentiation Fig. . On IHC,IHC was performed using primary rabbit monoclonal FOSB antibody  and rabbit polyclonal CAMTA1 antibody . All slides were loaded into a PT Link module  and subjected to an antigen retrieval/dewaxing protocol with EnVision FLEX Target Retrieval Solution (Dako) with pH 6.0 citrate buffer (FOSB) or pH 9.0 EDTA buffer (CAMTA1) before being transferred to an Autostainer Link 48 instrument (Dako). We then assessed the immunoreactivity of FOSB and CAMTA1 only if the tumor cells showed nuclear immunoreactivity. We semiquantitatively estimated the immunoreactivity according to the percentage of positive tumor cells approximately within a range of 10 %, and staining intensity was graded as weak, moderate or strong. Immunoreactivity was estimated by two observers (S.S. and T.H.).Clinical information is summarized in Table On IHC Table , diffuseSERPINE1-FOSB derived from translocation of t and established PHE as a genetically distinct entity [SERPINE1-FOSB fusion provided a promoter that allowed the strong expression of FOSB [SERPINE1-FOSB fusion detected by RT-PCR [Some studies revealed that PHE has a novel fusion gene of t entity , 9. Walty RT-PCR , and demFOSB expression was often observed in various background cells which often intermingled with tumor cells; therefore, such positivity in background cells may have misled us into placing a higher valuation of FOSB expression. FOSB is one of the transcription factors of the FOS family proteins that regulate cell proliferation and differentiation. The FOSB protein can form dimers with proteins of the JUN family and they consist of major components of activating protein 1 complex that regulates various kinds of gene expression. Several reports have described FOSB expression in normal tissues on IHC. FOSB expression was detected in normal epithelial cells of mammary lobules and terminal duct, and stromal fibroblasts in mammary gland tissue . FOSB isDiffuse and strong FOSB expression was specific for PHE in the current series and FOSB IHC is an effective tool in the differential diagnosis of PHE. Moreover, the combination of FOSB and CAMTA1 IHC is a useful panel for distinguishing PHE from EHE.PHE, pseudomyogenic hemangioendothelioma; EHE, epithelioid hemangioendothelioma; AS, angiosarcoma; KS, Kaposi sarcoma; ES, epithelioid sarcoma; IHC, immunohistochemistry


Trauma is now the leading cause of non-obstetric death in pregnancy. Emergency department (ED) management of trauma in pregnancy may be complicated by physiological compensation for concealed haemorrhage, reduced accuracy of diagnostic examination, a need to coordinate multiple teams, worries about imaging radiation and difficult decisions regarding emergent fetal delivery. Time constraints and emotive circumstances contribute to the challenge. We aimed to develop an evidence-based guideline for early management of trauma or significant haemorrhage concern in pregnant patients presenting to the ED.We conducted a non-systematic literature review of publications pertaining to key components of management of trauma in pregnancy. Based on this, as well as experience from within a major trauma centre in London, an algorithm was developed. A multidisciplinary team involving emergency, obstetric, anaesthetic, radiology and neonatal departments contributed. Existing local guidelines were reviewed for incorporation, as well as nationally published recommendations taught within the MOET (Managing Obstetric Emergencies and Trauma) course.The MOTHER algorithm was created to include pregnant females of ≥20 weeks gestation. It was reproduced in a clear visual format, identifying key resuscitation principles and adopting a stepwise systematic approach. Subsections provided guidance on peri-mortem caesarean as well as management of patients with minimal trauma. Specialty-specific appendices provided individualised team guidance. A decision making tool was developed to aid surgical decisions in abdominal trauma.MOTHER is a simple evidence-based algorithm that aids decisions in the ED, enhances understanding of important physiological principles, incorporates existing resuscitation recommendations and promotes collaboration between teams. As a result MOTHER may reduce adverse events and improve both maternal and fetal outcome. We believe the evidence reviewed is sufficient to recommend adoption of MOTHER at a national level.


Sensor data fusion plays an important role in fault diagnosis. Dempster–Shafer (D-R) evidence theory is widely used in fault diagnosis, since it is efficient to combine evidence from different sensors. However, under the situation where the evidence highly conflicts, it may obtain a counterintuitive result. To address the issue, a new method is proposed in this paper. Not only the statistic sensor reliability, but also the dynamic sensor reliability are taken into consideration. The evidence distance function and the belief entropy are combined to obtain the dynamic reliability of each sensor report. A weighted averaging method is adopted to modify the conflict evidence by assigning different weights to evidence according to sensor reliability. The proposed method has better performance in conflict management and fault diagnosis due to the fact that the information volume of each sensor report is taken into consideration. An application in fault diagnosis based on sensor fusion is illustrated to show the efficiency of the proposed method. The results show that the proposed method improves the accuracy of fault diagnosis from 81.19% to 89.48% compared to the existing methods. With the development of sensor data fusion technology, it is playing a more and more important role in fault diagnosis. On account of the complexity of the target and the background, the data detected by a single sensor are insufficient and unreliable to make a decision. In addition, due to the impact of the surroundings, the information derived from the sensors may contain errors, which leads to an incorrect result in the fault diagnosis system. A multi-sensor system can partially overcome the above limitations and shortages by combining a group of sensors to detect information and make a decision by considering all of the information obtained from the detection system ,2, whichIn practical applications, the information collected from the sensors is imprecise and uncertain. How to deal with the uncertain information effectively to make a reasonable decision or optimization has had great attention paid ,6. To ada fusion . It shoua fusion ,28,29.However, there may exist conflict among the data collected from different sensors. In addition, the error contained in the data can also lead to conflict . It may g method , which ig method ,41. Zhanhe issue .Fan and Zuo introduced a fuzzy membership function and an importance index to improve D-S evidence theory . Three fIt is obvious that the sensor reliability plays a significant role in decision making and fault diagnosis . Sensor networks ,46,47. Rnetworks  in infornetworks . Based oThe proposed method has the following advantages. First, it is a generalized version of our previous work . CompareThe paper is organized as follow. In this section, some preliminaries are briefly introduced below.Dempster–Shafer evidence theory (D-S evidence theory) is also called belief function theory ,16.n mutually-exclusive and collectively-exhaustive events, which is called the frame of discernment. The elements in Θ represent all of the possible faults in the fault domain of the object. Θ, also known as the sample space, is defined as Let Θ be a set of Satisfying:A. Note that A of Θ that satisfying The value en world , the criDempster’s combination rule, also called the orthogonal sum, is defined as follows:K is called the conflict factor between When there are more than two pieces of evidence, these can be combined in the following form:K is adopted to measure the dissimilarity degree between BBAs. However, it does not respect the metric axioms under the conditions of identityand triangle inequality [In Dempster’s combination rule , K is adequality . Here isExample 1: Assume there are two pieces of evidence, Use Equation  directlyIt is obvious that the two pieces of evidence are completely the same. However, the conflict factor is not equal to zero, which is not reasonable. In order to address the issue, Liu proposed a novel approach to measure the degree of conflict, which combines the conflict factor and betting comments . Though evidence . The eviWhen there are multiple pieces of evidence, the distances of every two pieces of evidence can be expressed in the form of a distance matrix On account of the distance measuring the dissimilarity of evidence, the greater the distance of two pieces of evidence is, the less the two pieces of evidence support each other, the greater the conflict between these pieces of evidence is. Thus, the similarity measure Additionally, the similarity measure matrix (SMM) is shown as:The support degree of each evidence is given as:i is given below:After normalization, the credibility degree The bigger the There is no denying that D-S evidence theory  is effecExample 4: Assume there are two pieces of evidence Use Equation , and then pieces of evidence; the weighted averaging method is summarized as:The fusion result distributes total belief to the BBAs . Deng etasonable . In the In fault diagnosis, the weights are given according to the efficiency of the evidence. The more reliable and accurate the evidence is, the higher the weight is. On the contrary, the less reliable and accurate the evidence is, the lower the weight distribution. In this paper, the weights are given based on the reliability of the sensors. The higher credibility a sensor has, the greater effect it will have on the final fusion and decision making.Deng entropy is the generalization of Shannon entropy, which was first proposed by Deng . It is am; the cardinality of the set Let When the belief value is only assigned to a single element, Deng entropy can definitely degenerate to Shannon entropy, namely:For more detailed information, please refer to .μ. Besides, not al of the pieces of evidence are of the same importance. Fan and Zuo introduced the evidence weight to represent evidence importance, which denotes v. The modification of BBAs considering both evidence sufficiency and evidence importance is given below:μ and importance index v, which is defined as Fan and Zuo proposed to improve the evidence by evidence sufficiency, evidence importance and the conflict among evidence . In pracAfter modification, if the BBAs are still in conflict with each other, Fan and Zuo proposed to use the non-conflict factor to modify Dempster’s combination rule. For more detailed information, please refer to .Though Fan and Zuo’s method can handle the conflict problem and perform data fusion effectively, it has some limitations. First, it only considers the static reliability of sensors, such as evidence sufficiency and evidence importance, and ignores the dynamic reliability, which is reflected in the real-time detection process; it is not reasonable in practice. Besides, Fan and Zuo introduced a process of judging the conflict degree between pieces of evidence, according to the degree of different combination rules adopted, which makes it much more complex to make a decision.s means “static reliability”. The sensor reliability is of great value in comprehending and quantifying the sensor performance. Whether the fusion result is reasonable is closely associated with the static reliability of sensors, such as accuracy, work efficiency and experts with different knowledge. The sensor static reliability can be affected by technical factors and noise, such as principle, material, manufacturing craft, and so on. It can be evaluated by comparing the sensor outputs with the actual values in long-term practical applications. In this paper, we adopt evidence sufficiency and evidence importance in Fan and Zuo’s method  to measuIf an evidence has a high sufficiency level and a high level of importance, it will be assigned a high weight, so that it can have a great effect on the final data fusion result and the decision making.The sensor reliability is also related to the target and surrounding properties, such as environment noises, the presence of unknown targets and the deception behaviors of observed targets . Due to Evidence distance is an efficient tool to measure the dissimilarity between every two pieces of evidence . AdditioIn this paper, one contribution is that not only evidence distance, but also Deng entropy are introduced to measure the information volume of the evidence . Supposed of The dynamic reliability combining both evidence distance and Deng entropy denoted Equation . Edi is Equation . The proIf evidence has a high dynamic reliability that is equal to one, this means this piece of evidence is completely reliable. Besides, this piece of evidence has not only the highest credibility, but also the maximum information volume. In addition, this evidence will play a significant part in the final result. On the contrary, if evidence has a very low dynamic reliability, which equals zero, this means this evidence highly conflicts with others, and it may distribute the whole BBA to a single element. It is obvious that this type of evidence will not participate in decision making. The dynamic reliability considering both Deng entropy  and evidBased on all of the above, this paper proposes a new comprehensive method to model the sensor reliability. The new model combining the static reliability and dynamic reliability is more reasonable. It is defined below:Equation  and wd iEquation . Accordin pieces of evidence, the final weights on the basis of Equation ws and thquations  are giveThe final weights after normalization are shown as follows:Use the weights to modify the BBAs, and the results are given below:After the combination by Equation , the finAccording to the proposed method, the fault In D-S evidence theory, the BBA of fault In Fan and Zuo’s method, the belief degree of The new method improves the accuracy of fault diagnosis from 81.19% to 89.48%, which illustrates the efficiency of the new method in conflict management and fault diagnosis.How to efficiently model sensor reliability greatly affects the performance of the sensor fusion system. To address this issue, a new sensor reliability model combining both dynamic reliability and static reliability is presented in this paper. The dynamic property of the sensor reliability is determined by the distance function of the sensor report and the information volume of each sensor report. A new discounting coefficient is proposed to improve the classical Dempster combination rule. An application in fault diagnosis is illustrated to show the efficiency of our proposed method. It seems that our proposed method is more efficient for handling highly conflicting evidence. In addition, from the result obtained in this paper, the new method can identify the fault correctly and improve the accuracy of fault diagnosis from 81.19% to 89.48%.The proposed method has two aspects of merit. From the aspect of the math model of sensor data fusion, the proposed work takes into consideration not only evidence distance, but also the information volume of the sensor itself, which contributes to the dynamic property of sensor reliability more reasonably. From the aspect of a real application in fault diagnosis, the proposed method can effectually handle conflict management. The application results show that the accuracy in fault diagnosis is improved from 81.19% to 89.48%. Besides, it can be easily extended to other multi-sensor systems, which makes it useful to practical engineering.


Clinical practice guidelines need to be regularly updated with current literature in order to remain relevant. This paper reports on the approach taken by the Philippine Academy of Rehabilitation Medicine (PARM). This dovetails with its writing guide, which underpinned its foundational work in contextualizing guidelines for stroke and low back pain (LBP) in 2011.Working groups of Filipino rehabilitation physicians and allied health practitioners met to reconsider and modify, where indicated, the ‘typical’ Filipino patient care pathways established in the foundation guidelines. New clinical guidelines on stroke and low back pain which had been published internationally in the last 3 years were identified using a search of electronic databases. The methodological quality of each guideline was assessed using the iCAHE Guideline Quality Checklist, and only those guidelines which provided full text references, evidence hierarchy and quality appraisal of the included literature, were included in the PARM update. Each of the PARM-endorsed recommendations was then reviewed, in light of new literature presented in the included clinical guidelines. A novel standard updating approach was developed based on the criteria reported by Johnston et al. :646–655, Ten new guidelines on stroke and eleven for low back pain were identified. Guideline quality scores were moderate to good, however not all guidelines comprehensively linked the evidence body underpinning recommendations with the literature. Consequently only five stroke and four low back pain guidelines were included. The modified PARM updating guide was applied by all working groups to ensure standardization of the wording of updated recommendations and the underpinning evidence bases.The updating tool provides a simple, standard and novel approach that incorporates evidence hierarchy and quality, and wordings of recommendations. It could be used efficiently by other guideline updaters particularly in developing countries, where resources for guideline development and updates are limited. When many people are involved in guideline writing, there is always the possibility of ‘slippage’ in use of wording and interpretation of evidence. The PARM updating tool provides a mechanism for maintaining a standard process for guideline updating processes that can be followed by clinicians with basic training in evidence-based practice principles.The online version of this article (doi:10.1186/s13104-015-1588-8) contains supplementary material, which is available to authorized users. The PARM group first published two Filipino-contextualized clinical practice guidelines (CPGs) on stroke rehabilitation, and low back pain, in 2012. They are freely available on the PARM website –5. The PIn line with international recommendations regarding the importance of the currency of evidence in clinical guidelines , 7, the ’ (new) evidence based clinical practice guidelines [However, there are only a few publications that reported methods and approaches for updating guidelines –13. Thisidelines . Internaidelines , 7, 14.Thus, as with guideline contextualization, the PARM group found itself without international guidance, and faced with this question: how do we update clinical practice guidelines using contextually-relevant principles? These principles need to provide a transparent, standard and comprehensive platform which all team members could use, when updating the current stroke and low back pain guidelines, and which could be used ongoing to update other contextualized guidelines as necessary.This paper reports on the approach taken by PARM to develop a standard tool to assist clinicians involved in updating clinical guidelines in developing countries. This tool dovetails with the PARM writing guide , which uEthical approval was obtained from the ethics review board of the Philippine Academy of Rehabilitation Medicine. Informed consent was obtained from each member of the working group involved in this study.As occurred for the original PARM guidelines, all updating work was voluntarily undertaken by a working party of approximately 35 physiatrists (rehabilitation doctors) who were members of the PARM. Participants were invited for their research background and willingness to contribute. The group ranged in age and clinical experience, and approximately 75 % had not been involved in the foundational contextualization process 3 years before. The group met for an intensive weekend of training, discussion and debate about updating processes, and to develop the updating tool. Then smaller working groups undertook to update specific sections of the stroke and low back pain guidelines. Each group applied the updating tool to one or more recommendations before the weekend workshop finished, so that any concerns regarding the updating process could be identified and clarified.uniform thought was coined by the PARM group to identify similar intent, from differently worded recommendations from different guidelines. This was found to be a critical step in the contextualizing process, because guidelines formed the source of recommendations and the evidence base, rather than individual literature. This meant that the working parties often needed to resolve the issue of different wording in recommendations, despite the same intent of the recommendation and the same underpinning references. The evidence body was thus described in six different categories by the PARM contextualization process [To assist in standardizing the guideline contextualization process used in the development of the original guidelines, a PARM writing guide was established . This gu process  , Scottish Intercollegiate Guidelines Network (SIGN), National Health and Medical Research Center (NHMRC), New Zealand Guidelines Group (NZGG), National Guidelines Clearinghouse (NGC), using key words of clinical practice guidelines and stroke rehabilitation (or low back pain). Criteria for inclusion in the updating process were: that the guideline included rehabilitation recommendations; the guideline was available in full text; it was published in English language; published since 2010 ; and not included in the original contextualized PARM guidelines. Moreover, only de novo guidelines, or comprehensive updates of guidelines (which included new literature) were included. Guidelines that re-stated, or adopted the findings of other guidelines, without adding to the body of literature, were excluded.The 14-item guideline appraisal tool by the International Centre for Allied Health Evidence (iCAHE) was applied to each guideline . ParticuThe basis for PARM updating used the four levels proposed by Johnston and his colleagues . The speA flow diagram of process in updating contextualized guidelines is shown as Fig. Additional file Seven potentially relevant CPGs for low back pain were critically appraised and three CPGs scored less than 71 % –26. Thers and mapping the steps in them to CPG Recommendations were a critical part of the contextualization process. Thus they were revisited in the 2014 PARM workshop with the focus on assessing generalizability and applicability of the existing guideline recommendations for the two conditions of interest using NHMRC FORM [As described in Gonzalez-Suarez et al. , designiMRC FORM  and PARMAfter much debate, the working group agreed that the PARM updating tool should be presented in two different ways . Examples of updated recommendation statements are provided in Table As far as we are aware, the PARM updating tool is the first of its kind, developed to reinforce the updating process of contextualized clinical guidelines in a developing country. The use of the Johnston et al.  tool wasnew if fresh evidence was identified, refined if supplementary evidence was identified, and unchanged if now evidence was identified. Parmelli et al. [strong positive, weak positive, weak negative and strong negative as voted on by the multidisciplinary panel in a series of meetings. A fifth recommendation, ‘no recommendation,’ was eliminated from the categories of strength of evidence. This forced the panelists to take a position on a recommendation even in the absence of strong evidence. Johnston [Vernooij et al.  systemati et al.  updated Johnston  revised The PARM updating tool provides a simple, novel and standard approach that considers new evidence’s hierarchy and quality, and revisions of recommendation wordings. It could be used efficiently by other guideline updaters particularly in developing countries, where resources for guideline development and updates are limited. When many people are involved in guideline writing, there is always the possibility of ‘slippage’ in use of wording and interpretation of evidence. The PARM updating tool provides a mechanism for maintaining a standard process for guideline updating processes that can be followed by clinicians with basic training in evidence-based practice principles. The provision of including only high quality reference guidelines in both developing guidelines through contextualization, and updating contextualized guidelines, is one of the strengths of our methodology. A survey by Alonso-Coello  showed tOne of the limitations of our approach is that the researchers did not focus on evaluating the currency of the evidence bases of the included CPGs. Shekelle et al.  have shoPARM has developed a novel framework to assist the process of revising contextualized clinical practice guidelines, dovetailing this with its initial processes to construct a contextualized CPG. Efficiencies of the PARM updating approach included revisiting the patient journey to validate the critical points which required specific recommendations, and a specific writing guide to revise a recommendation when new evidence was available. With this approach, it is envisioned that updating contextualized CPGs processes in the future will be guided by a simple standardized process, and will be effective and efficient in terms of time, finances and manpower.


Wietse Tol and colleagues discuss some of the key challenges for implementation of new WHO guidelines for stress-related mental health disorders in low- and middle-income countries.Please see later in the article for the Editors' Summary The implementation of new WHO mental health guidelines for conditions and disorders specifically related to stress is likely to face obstacles, particularly in low- and middle-income countries.Formulation of evidence-based guidelines is complicated by limited knowledge regarding (a) the effectiveness of commonly implemented interventions, (b) the effectiveness of established evidence-based interventions when used in situations of ongoing adversity, and (c) the effectiveness of widely used cultural practices in LMICs. The application of the guidelines requires improved knowledge on how to reduce potentially harmful practices that are widely applied.The implementation of recommendations regarding psychotherapeutic interventions will require an approach that balances (a) strengthening the availability and capacity of specialists to train and supervise and (b) shifting to the delivery of psychotherapy by non-specialists.The strengthening of evidence for managing these conditions will require collaborative efforts by researchers and practitioners in a manner that is mindful of local sociocultural and health system realities.In 2009, the World Health Organization (WHO) launched the Mental Health Gap Action Programme (mhGAP), which has since been used in more than 50 countries worldwide. The mhGAP is aimed at improving access to evidence-based mental health interventions, by ensuring their integration within non-specialized (primary care) settings, the emphasis being on low- and middle-income countries (LMICs). The evidence-based guidelines formed the basis for the development of the mhGAP Intervention Guide Since then, WHO has been asked repeatedly to provide similar guidelines as a basis for an additional Intervention Guide Module, for conditions specifically associated with major stressors such as potentially traumatic events  and major losses . Exposure to such major stressors is common in many LMICs The approach adopted by WHO was to ensure a comprehensive focus in developing guidelines for adults, children, and adolescents, comprising recommendations on pharmacological and psychological interventions. The guidelines include but extend beyond posttraumatic stress disorder (PTSD) to a range of conditions that are relevant to non-specialized health settings, including symptoms in the first month after exposure ; PTSD; and bereavement in the absence of frank mental disorder. The development Although these guidelines and companion intervention guide are an important first step, their success will rest on their actual implementation in settings with high needs for mental health care. In this paper, we discuss challenges encountered in the formulation of guidelines, as well as potential obstacles that may constrain effective implementation of these guidelines in low-resource settings. We also offer suggestions for how these obstacles may be overcome. The authors represent the Guideline Development Group , WHO secretariat (MvO), and four consultants to the guideline development process .First, the Guideline Development Group (GDG) (see author contributions) discovered that there is a dearth of scientifically rigorous research supporting many of the most commonly used interventions for managing conditions specifically associated with stress. To establish the evidence, the GDG identified recent systematic reviews, or they commissioned reviews in cases for which none were available. The evidence is particularly poor for children and adolescents: for three out of 11 questions asked, no specific recommendations could be made based on existing evidence. In relation to the absence of evidence in general, a notable example in adults concerns symptoms manifesting in the first month after exposure to major stressors. At the outset, the GDG commissioned evidence searches for a broader set of psychological interventions to manage acute traumatic stress symptoms in adults, including problem-solving counseling, relaxation, and psycho-education. However, it was deemed that there was insufficient evidence to recommend either in favor or against the use of these interventions. In humanitarian settings in LMICs specifically, earlier systematic reviews have shown that there is a wide gap between interventions that are commonly implemented and evidence for interventions in such settings Second, a key challenge is the limited availability of mental health resources in LMICs in general, creating a major obstacle to implementation of new mental health recommendations. Lack of resources takes a number of forms, including limits in basic mental health infrastructure, budget, and personnel, particularly in humanitarian settings Third, some practitioners may be reluctant to adhere to recommendations that caution against practices that are widely applied. These include, for example, recommendations not to offer benzodiazepines for acute traumatic stress symptoms, nor to offer structured psychological interventions for bereavement reactions in the absence of frank mental disorder. Studies have revealed the over-prescription of benzodiazepines in some LMIC health care settings Fourth, mhGAP recommendations are based on evidence gathered mainly in well-resourced health settings in industrialized countries. There is uncertainty as to what extent the findings can be generalized across diverse sociocultural settings. Furthermore, there is a paucity of evidence concerning the effectiveness of (a) interventions for specific cultural idioms or concepts of distress Fifth, a number of peer reviewers and the GDG raised questions about the specific challenges of providing effective treatments in contexts where stressors are ongoing. Situations of ongoing adversity, such as in the context of armed conflict, chronic poverty, or intimate partner violence, raise two important questions: (1) whether to prioritize social interventions over psychotherapeutic interventions in this population First, concerted action is needed to strengthen the evidence base for interventions. This will require testing the efficacy of treatments for conditions specifically related to stress that previously have proven efficacious, generally in high-income countries. Also, it will require determining the efficacy of interventions that are currently very popular in practice but have not been rigorously studied. Currently popular interventions include non-specific counseling, psycho-education, structured recreational and sports activities, and provision of child-friendly spaces. In relation to the current knowledge base, there are both consistent and inconsistent findings The evidence base could benefit from action on two fronts: supporting research efforts in LMICs, as well as building the capacity of agencies to measure the outcomes of interventions in the course of program implementation. Research capacity building in LMICs could assist in initiating research projects that are relevant to low-resource settings, e.g., testing culturally congruent approaches for stress management. A recent initiative to set research priorities for mental health and psychosocial support in humanitarian settings, in which there was strong representation from personnel working in LMICs, produced a largely practice-informed research agenda; notably, there was little focus on topics that have dominated debates in the peer-reviewed literature. For example, the agenda focused on a range of disorders and conditions besides PTSD, in spite of the latter diagnosis being the subject of most attention in the literature Second, the limited availability of mental health resources in LMICs will need to be addressed for successful implementation of these guidelines. For example, building the capacity to train and supervise psychotherapeutic interventions in non-specialist settings will be crucial to ensure that such services are sustainable and of sufficient quality Third, if the aim is to ensure that negative recommendations are implemented  it is important to understand (a) the reasons behind practitioners' current use of contra-indicated interventions, (b) barriers to using evidence-based approaches, and (c) strategies that will encourage practitioners to take up evidence-based alternatives. Such research falls within the scope of dissemination and implementation science, a field of research that has not yet received sufficient attention for mental health interventions in LMICs Fourth, lack of knowledge with regard to cultural concepts of distress and the effectiveness of existing cultural practices need to be addressed. This will require a willingness to take seriously local perspectives on mental health across highly diverse sociocultural settings in LMICs. Such efforts would benefit from multidisciplinary collaboration, in which experts in qualitative research  join hands with experts in quantitative research . A recent meta-analysis found a particularly high level of overlap between locally defined cultural concepts of distress and a diagnosis of PTSD. However, one of the major shortcomings of this literature concerned the failure to include cultural concepts of distress in treatment outcome studies Finally, implementation efforts need to be more responsive to the reality that populations affected by humanitarian crises in LMICs commonly are living in settings of ongoing exposure to major stressors. Further research needs to confirm whether evidence-based treatments can be safely and sustainably implemented in low-resource settings with populations exposed to high levels of ongoing adversity and to identify additional promising intervention approaches. Clinical interventions are only part of the picture, given the impact of social and economic factors on mental health in these settings. There is a need to strengthen preventive approaches that address the major social determinants of mental health, including poverty, gender-based violence, and social exclusion In conclusion, although the new WHO recommendations on conditions specifically related to stress present an important step forward, there will be many challenges in implementation. The road ahead is to address these challenges through concerted and multidisciplinary efforts by policy makers, practitioners, and researchers.The authors are responsible for the views expressed in this article and, except for the specifically noted recommendations, they do not necessarily represent the decisions, policies, or views of WHO.


In the brain, 11βHSD1 is a potential therapeutic target implicated in age-associated cognitive dysfunction. We aimed to quantify brain 11βHSD1 activity, both to assess its contribution to systemic cortisol/cortisone turnover and to develop a tool for measuring 11βHSD1 in dementia and following administration of 11βHSD1 inhibitors.2H]2-cortisone and 9,11,12,12 [2H]4-cortisol for 3 h before samples were obtained from the internal jugular vein and an arterialized hand vein. Steroids were quantified by liquid chromatography-tandem mass spectrometry.With ethical approval and informed consent, 8 healthy men aged 38.1 years (sd 16.5) underwent an ECG-gated phase-contrast magnetic resonance scan to quantify internal jugular vein blood flow and were infused with 1,2 [2H]3-cortisol or cortisone into the internal jugular vein.Steady state tracer enrichments were achieved and systemic indices of cortisol/cortisone interconversion were consistent with previous studies in healthy men. However, there was no measurable release or production of cortisol, 9,12,12 [Although cerebral 11βHSD1 reductase activity may be greater in cognitively impaired patients, in healthy men any contribution of 11βHSD1 in the brain to systemic cortisol/cortisone turnover is negligible. The influence of 11βHSD1 in the brain is likely confined to subregions, notably the hippocampus. Alternative approaches are required to quantify pharmacodynamics effects of 11βHSD1 inhibitors in the human brain. The 11β-hydroxysteroid dehydrogenases (11βHSDs) are intracellular enzymes that catalyze interconversion of inactive cortisone and active cortisol; 11βHSD type 1 is a predominant reductase, regenerating cortisol from cortisone, while 11βHSD type 2 is an exclusive dehydrogenase, inactivating cortisol to cortisone. An extensive literature documents the role of 11βHSDs in regulating intracellular glucocorticoid concentrations and hence modulating tissue-specific activation of corticosteroid receptors (reviewed in 2H]2-cortisone (d2-cortisone) by cortisone, and is inhibited by licorice (2H]4-cortisol (d4-cortisol) is infused and production of cortisol is measured by the rate of dilution of d4-cortisol by cortisol  and by 9,12,12-[2H]3-cortisol   glucocorticoid tracers . Productlicorice . A more 11βHSD1) , 6, subc11βHSD1) , and ske11βHSD1) . These s11βHSDs may also play key roles in the brain . 11βHSD2Against this background, quantification of brain 11βHSD1 activity in vivo in humans would be highly desirable. Here, we aimed: (i) to determine whether, as a major organ by mass, brain 11βHSD1 contributes to cortisol/cortisone turnover in vivo; (ii) to establish whether 11βHSD1, as the only 11βHSD isozyme expressed in an adult brain (9/L) or abnormal full blood count or random blood glucose; research participant in the previous 3 months; any contraindication to magnetic resonance (MR) imaging. The study complied with the Declaration of Helsinki; ethical approval was obtained from the local Research Ethics Committee  and all participants gave written informed consent.Participants were recruited through advertisements in the local press and around the University campus. Participants were healthy male volunteers between 18 and 70 years old. Exclusion criteria were glucocorticoid medication (by any route of administration) within the past 3 months; diabetes mellitus, cerebrovascular disease or other significant chronic illness; history of recent heavy alcohol or illegal drug use; current use of any immunosuppressive medication; abnormal screening liver, thyroid, renal or coagulation function  and 9,11,12,12 [2H]4-cortisol (d4-cortisol) were from Cambridge Isotope Laboratories. Solvents were high-performance liquid chromatography (HPLC) grade from Fisher Scientific.Reagents were obtained from Sigma, Steraloids, or VWR. 1,2 3-cortisol (d3-cortisol), cortisone and d2-cortisone) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS). An internal standard solution 8-cortisone , and 0.25 microg 2,2,4,6,6,17A,21,21 [2H]8-corticosterone  with 9 μL methanol] was added to 1.5 mL of plasma, before 15 mL of chloroform was added for extraction of the steroids. The organic phase was then reduced to dryness under oxygen free nitrogen at 60°C before being reconstituted in the mobile phase [acetonitrile: water (35:65) with 0.1% formic acid]. Samples were injected on to a Sunfire C18 column (150 mm × 4.6 mm × 5 μm), with a column temperature of 10°C and a mobile phase flow rate of 1.5 mL/min using an Acquity Ultra Performance Liquid Chromatograph (Waters) coupled to a Qtrap 5500 mass spectrometer (AB Sciex). Ionization was achieved in the positive electrospray mode. The following transitions (precursor→product mass-to-charge ratios) used were as follows: cortisol (363→121), d2-cortisol (365→121), d3-cortisol (366→121), d4-cortisol (367→121), cortisone (361→77), d3-cortisone (364→164), and d2-cortisone (363→165). Steroid concentrations and tracer/tracee ratios were calculated from calibration curves and corrected for background isotopomer enrichments as described previously  of cortisol, d3-cortisol, and cortisone were calculated by dividing the rate of tracer infusion by the relevant tracer/tracee ratio  . In 7 of the 8 subjects, the right internal jugular was found to be dominant or co-dominant on the MR scan and was used for cannulation and measurement of blood flow. In one subject, the left internal jugular vein (IJV) was dominant and was cannulated instead. Mean blood flow in the selected left internal jugular vein for all subjects was 481 mL/min (sd 232).Eight healthy men were recruited with a mean age of 38.1 years (sd 16.5) and mean BMI of 24.9 kg/mEndogenous cortisol and cortisone concentrations in both arterialized and jugular venous samples reduced from baseline to 180 min of infusion, when the first set of arteriovenous samples were obtained, which is consistent with diurnal variation , A and DMean values in arterialized samples in the steady state were used to calculate whole body rates of appearance of cortisol, d3-cortisol, and cortisone , all of We found no detectable interconversion of cortisol and cortisone across the human brain in eight healthy male volunteers, using deuterated glucocorticoid tracers and arteriovenous sampling. Previous studies using this approach have detected interconversion of cortisol plus or minus cortisone within liver, adipose tissue, and skeletal muscle , 5–7. Sy5–In the absence of arteriovenous gradients in cortisol or cortisone concentrations, we did find a net release of d4-cortisol across the brain. It is unclear why there was release of tracer from the brain but it may indicate overpriming and higher circulating d4-cortisol levels earlier in the infusion, with resulting rerelease from the brain during steady state. However, this speculation cannot be tested in the absence of earlier samples.One previous study has evaluated in vivo 11βHSD1 activity in the brain, by measuring peripheral venous plasma and cerebrospinal fluid (CSF) steroid concentrations during d4-cortisol infusion . UnfortuWe took a different approach to measuring steroids in jugular venous blood and calculating arteriovenous differences during steady state tracer infusion. With the measurement of blood flow, this allows absolute quantification of 11βHSD activities for all tissue draining to the cannulated internal jugular vein. 11βHSD1 is known to be expressed in specific neuronal subregions of the human brain: hippocampus (in particular the dentate gyrus and the cornu ammonis), prefrontal cortex, and the area of highest expression, the granule cell layer of the cerebellum . Our subAs there were no previous data on brain release or uptake of cortisol or cortisone, sample size was calculated using data from a previous study on skeletal muscle . With thIf 11βHSD activity in the brain had been detectable with the approach used here, this could have provided a useful pharmacodynamic tool to quantify brain enzyme inhibition by selective 11βHSD1 inhibitors in development for treatment of dementia , 19. As