All health systems struggle to meet health needs within constrained resources. This is especially true for low-income countries. It is critical that they can learn from wider contexts in order to improve their performance. This article examines policy transfer and evidence use linked to it in low- and middle-income settings. The objective was to inform international investments in improved learning across health systems.The article uses a comparative case study design, drawing on case studies conducted in Bangladesh, Burkina Faso, Cambodia, Ethiopia, Georgia, Nepal, Rwanda and Solomon Islands. One or two recent health system reforms were selected in each case and 148 key informants were interviewed in total, using a semi-structured tool focused on different stages of the policy cycle. Interviewees were selected for their engagement in the policy process and represented political, technical, development partner, non-governmental, academic and civil society constituencies. Data analysis used a framework approach, allowing for new themes to be developed inductively, focusing initially on each case and then on patterns across cases.The selected policies demonstrated a range of influences of externally imposed, co-produced and home-grown solutions on the development of initial policy ideas. Eventual uptake of policy was strongly driven in most settings by local political economic considerations. Policy development post-adoption demonstrated some strong internal review, monitoring and sharing processes but there is a more contested view of the role of evaluation. In many cases, learning was facilitated by direct personal relationships with local development partner staff. While barriers and facilitators to evidence use included supply and demand factors, the most influential facilitators were incentives and capacity to use evidence.These findings emphasise the agency of local actors and the importance of developing national and sub-national institutions for gathering, filtering and sharing evidence. Developing demand for and capacity to use evidence appears more important than augmenting supply of evidence, although specific gaps in supply were identified. The findings also highlight the importance of the local political economy in setting parameters within which evidence is considered and the need for a conceptual framework for health system learning. All health systems face challenges managing complex and changing health needs, with these challenges being the greatest in low-income countries due to the larger health needs, faster population growth  and leasknowledge about policies, administrative arrangements, institutions etc. in one time and/or place is used in the development of policies, administrative arrangements and institutions in another time and/or place” [Globalisation and the activity of international organisations involved in the design, implementation and analysis of regional and domestic policies have facilitated dialogue and sharing of ideas and experiences across actors in different settings. The process of using the ideas, content and lessons from implementing policy from other countries, or what this study terms ‘learning across systems’, falls under the broader literature on policy transfer. Transfer is defined as the intentional process through which “r place” . Unintenr place” .A small but growing set of literature seeks to understand policy transfer processes in the health sector of low-income countries. Mechanisms of policy transfer that are identified include learning, coercion, socialisation and competition . FinanciStudies of evidence-based policy-making link to the policy transfer literature by highlighting the types of evidence that currently  inform policy, including systematic or scientific research, practical experience and political judgement . Many alDrawing from eight country case studies, this article seeks to supplement existing literature by drawing on the insights and experience of policy-makers in low-income countries and assessing their demand for evidence, how it is met (or not) and what barriers they perceive to exist. It aims to understand how learning has occurred in these case studies of health policy reform and what could be done to strengthen it. It was undertaken by Oxford Policy Management to inform the Bill and Melinda Gates Foundation on priorities for investment in supporting cross-country learning on effective health system policies.The wider study within which the case studies were nested started in early 2017 with three scoping literature reviews focussed on (1) the content of learning across health systems, in terms of which topics comparative health systems literature has addressed since 2000 and using which methods ; (2) a rHow do national and sub-national decision-makers access and use ideas and evidence about how to make their health systems work better and where does international evidence fit in that picture?What gaps do national and sub-national decision-makers perceive in their access to appropriate health system evidence in general, and evidence about other countries’ experiences in particular?The country case studies aimed to answer two research questions, as follows:Case studies were selected from countries that were categorised as low income in 2000 and performed well in meeting Millennium Development Goal targets by 2015  . From thMutuelles de Santé) in Burkina Faso, and CBHI and performance-based financing in Rwanda.One to two policies or programmes (policy is used as shorthand for both in this article) were chosen per country. The policy selection criteria were simply that the reforms were undertaken within the past decade , and involved significant change to at least one health system block. The studied reforms (described further in Box 1) cover a wide range of reforms, including the Health Extension Programme (HEP) in Ethiopia, the Sector Wide Approach and community clinics in Bangladesh, Health Equity Funds and Special Operating Agencies in Cambodia, hospital privatisation and health sector financing reforms in Georgia, the Integrated Management of Maternal, Neonatal and Childhood Illness programme in Nepal, the Role Delineation Policy in Solomon Islands, health financing reforms, including community-based health insurance  conceptualisation; (2) uptake or implementation; and (3) further policy development, once a policy has been implemented. We then examine what respondents told us about the mechanisms of learning, which operate at international, regional and national levels. This follows the themes that emerged inductively from the interviews conducted and reflects not just findings on the specific tracer policies but also respondent’s wider comments on learning and evidence use. Finally, we present cross-cutting themes in relation to facilitators and barriers to learning, which are grouped into factors focussed on the demand for and supply of evidence.In the case of the initial phase of the Integrated Management of Child Illness programme in Nepal, the country was adopting a specific international package, which was more or less standard practice across most countries.In three cases , the broad idea behind the policies was initially promoted by major international agencies, but was more actively adopted in the sense of being seen to meet a local need and fit with local contexts.In three cases , the policies emerged from a partnership of development partners and government, with ideas being introduced from other contexts but being incubated and developed in substantive ways in-country. Later iterations of Nepal’s Integrated Management of Child Illness followed this path too, through the shift to community-based delivery and the introduction of the package of newborn care.In one case (Role Delineation Policy in Solomon Islands), the idea was developed locally as a means of achieving more equitable, but affordable, health services after a period of ethnic tension. The approach drew on some regional inspiration and technical support from bilateral and multilateral partners.Finally, in the Ethiopian HEP, there was no significant external input, though the policy was influenced in cross-sectoral learning internally from agricultural extension workers in Ethiopia within one state, and later scaled up.All of the reforms either started from or were accompanied by a local recognition of a problem. In relation to the origin of the policies, looking across the eight contexts, five broad models emerged, ranging from least to most home-grown, as follows:These points illustrate how countries adopted international ideas, but the case studies that were undertaken uncovered many situations in which evidence was not sought, or was altogether ignored. Non-adoption of international ideas and the rejection of advice from other countries had varying consequences. In Ethiopia, the international consensus was antagonistic to community health workers in the late 1990s, when the HEP programme was being developed in Tigray. The government continued to support it, however, as it seemed one of the few feasible ways to reach a dispersed rural population in a context of limited resources and infrastructure. The decision is widely seen to have paid off. Similarly, Cambodia has resisted adopting a clear purchaser-provider split for Special Operating Agencies, despite some international encouragement to do so. Nepal has resisted a number of WHO-recommended adjustments to clinical guidelines, on the basis that they are not in line with wider health system strategy or capacity. Georgia pursued hospital privatisation in the face of cautionary international advice and the legacy of that has been much more mixed.It is clear from the case studies that the drivers of uptake, or moving ahead with implementation of a policy, are rooted firmly in the local political economy. In the case of Ethiopia, for example, the drivers were historical as well as ideological (the government having recently been engaged in grassroots mobilisation during civil war), combined with political imperatives  and pragmatism (other options were not feasible with the resources available). Ideological influences, industry lobbying and the powerful role of international agencies  are also documented in Georgia, for instance.Published, peer-reviewed evidence was rarely mentioned as the impetus or main source of information for policy development in the case studies. It was most likely to be consulted for review of clinical protocols, as this is an area in which local contextualisation is regarded as less critical. The influence of published studies is also seen to occur through their dissemination from international agencies such as in the influence of international researchers on healthcare in Burkina Faso and the research on sector-wide approaches that was incorporated by proposals from donor partners in Bangladesh. That said, local evidence being published in an international peer-reviewed journal was said to give it credibility and feed a sense of pride, with both increasing the likelihood of it being acted on.Robust evidence may be lacking for a policy , but if the concept fits well into the socio-political context and enjoys political patronage, then reforms will still be undertaken. The cases of Cambodia and Georgia, where senior politicians made executive policy decisions that were not exactly aligned with the evidence presented, also highlight how governments can set the parameters for when they will or will not over-ride evidence, and how the choice and application of evidence is often ‘purpose-driven’ and predefined by political agendas. In Cambodia, early evidence suggested that contracting services out (to non-government organisations) achieved positive results. The government has been concerned about the sustainability of this option, and adopted a contracting in approach instead. This is an example of some policy options being beyond consideration, even if the evidence may have appeared to be in their favour. This is in contrast to some evidence-informed modifications that have been made by the same government to the operationalisation of Health Equity Funds .The case studies suggest that internal learning is the key to successful policy development over time. Further, capacities, skills and culture that support good examples in this respect are likely to be linked to the ability to filter experiences from other contexts intelligently.The case studies illustrated the effective use of annual reviews to assess and improve policy performance , adjustment of policies based on local evidence , using national and international routine data sources for monitoring , use of evidence from operational research (in Cambodia), and technical assistance to identify the existing – and possible future – cost structures and affordability of interventions (Solomon Islands). Countries like Rwanda, Nepal, Cambodia and Ethiopia were also effective at sharing lessons across sites internally.By contrast, the role of policy evaluation was much more contested. In some settings, like Bangladesh and Ethiopia, there was resistance to formally evaluating high-priority national programmes, while in others, like Nepal, there were reported tussles over the ownership of the evaluation process. While some countries (e.g. Cambodia) used evaluations actively as a means of lesson-learning and mid-course corrections, many of the apparently successful policies were never formally evaluated, reflecting the higher stakes and more politicised nature of evaluative processes, compared to continuous learning through observation of a policy’s outcomes over time.A wide range of mechanisms that had supported learning processes within and across countries were mentioned by key informants. These are outlined in rough order of frequency, starting with the international ones.International study tours were the most commonly mentioned mechanism for international learning, used across all eight sites, typically early on in the policy development process and including a variety of constituencies . These are typically facilitated by development partners and were seen as important, although suggestions for improving their effectiveness (such as better follow-up) were also made.Country decision-makers and technical staff also use direct relationships with development partner staff to gain advice on topics of interest at all policy stages. Development partners facilitate access to and share ideas and evidence in all settings. Some organisations are widely influential, for example, WHO. Others are seen as offering specific expertise , though bilateral and multilateral funding agencies are also seen as having their own agendas. Personal relationships with development partner staff are highly important, especially when their presence in-country is long-term, or the country has a small population.Attending international meetings on specific topics of relevance was also highlighted as influential in five settings , particularly regional meetings that focused on a specific, shared problem.Technical assistance programmes were perceived to be of particular importance in learning about reforms in other countries and in supporting implementation in Bangladesh, Cambodia, Georgia, Solomon Islands, Rwanda and Burkina Faso.Many countries shared ideas and evidence internally and with external stakeholders such as development partners through routine health system governance structures, such as coordination and technical working groups . In some instances, countries systematically established groups to review international published evidence to refine specific health packages .Capacity-building through formal training or on the job experience also played a role, with countries tending to initially train abroad but gradually develop local capacity and institutions , also in order to better retain trained staff.Regional networks also played a role, though these were less frequently mentioned. In the Solomon Islands, regional professional networks may have facilitated idea transfer, including through contractors working across countries, and regional training networks were highlighted as significant. In (former-)francophone African countries (Rwanda and Burkina Faso), influential individual consultants working across countries and community of practice networks were cited as having contributed to the spread of ideas, including through their reports. Burkina Faso was the only context where civil society – in the form of advocacy groups, working with international partners – was cited as having influenced policy uptake.Within countries, pilot projects supported by international non-governmental organisations played an important role in developing some of the policies . Some countries also used domestic study tours and meetings to exchange learning across regions within their country (e.g. Ethiopia).It was also encouraging that some countries have started to focus on how to share lessons from their own experiences and becoming ‘centres of excellence’ in particular areas, such as Rwanda, which has set up institutions to share lessons on performance-based financing (amongst others), and Ethiopia, which has established an international institute for training and research on rural primary healthcare.Facilitators of learning were grouped into those which predominantly affect the demand for evidence, those which are more linked to evidence supply, and finally some which are related to the evidence topic and its presentation.In relation to demand, having a performance-oriented organisational culture within government was mentioned as a key factor in three settings . Linked to this is proactive identification of evidence needs by the country . Growing government financing, confidence and leadership in setting parameters within which evidence is used was highlighted in Cambodia, where a process of growing government leadership was accompanied by a transition in the demand for evidence originating within international organisations to originating within government. This demand can often be focused on internal learning, however, more than seeking evidence from other contexts.Factors tending to increase confidence in suppliers of evidence included that the latter have in-country staff with embedded knowledge of the health system (highlighted in Bangladesh and Ethiopia). In some cases, authority derives from international agency authority (e.g. for the WHO package), as well as from donor funding and endorsement .In terms of credible evidence supply, this can be facilitated by the development of networks of international and local researchers, producing strong evidence on local policies and building capacity for local analysis (Cambodia). Similarly, consulting groups which maintain deep local roots in the local context while also connecting to international evidence can be effective evidence suppliers (Georgia).Regional factors were again less prominent but, within West Africa, shared regional identities may play a role, facilitating learning across countries (Burkina Faso), while Nepal has consistently looked to India and Bangladesh for their experiences of community-based care. Shared languages also play a role, for example, francophone African policy, teaching and consulting networks were cited as influential in Rwanda.The content of the reforms also matters. If reforms are technical and do not imply large structural changes, they will be easier to adopt . In terms of the topic and its presentation, evidence is considered by decision-makers when it is politically relevant, accessible and locally applicable (Georgia). It needs to be adapted to the local cultural and geographic context. It is also important that it is presented at the right time in the budget or policy cycle and is communicated in the most acceptable way .In relation to demand for or use of evidence, cited barriers are grouped into those relating to incentives and those relating to capacity, while on the evidence supply side, capacity and resource factors dominated. Some specific gap areas were also mentioned.Despite good leadership at the top, lack of accountability for results and weaknesses in supervision at middle management level and below were both barriers to acquiring and implementing learning from others (Solomon Islands). Politicised priorities and institutional constraints to be able to put evidence into effective use were highlighted as barriers in Bangladesh, while fragmentation in the sector and unclear roles was another constraint for operationalisation of policies . Civil society was not reported to have played a strong role in the policy cycle in most places (only in Burkina Faso was its influence noted). The lack of an evaluation culture was mentioned in Bangladesh and Solomon Islands, and the issue of decisions being made outside the sector was also raised in the latter. The role of vested interests was highlighted in the Georgia case study, while in others, donor funding was noted to skew priorities. All of these undermine the role and utility of evidence.Sharing and accessing information can also face barriers. A controlling approach to evidence release was highlighted in Rwanda and Ethiopia and, in some contexts, access to information was even more limited at local  levels (e.g. Burkina Faso). Others highlighted the per diem-orientation in relation to participation in meetings, where lesson-learning is further weakened if there is a lack of dialogue and feedback from meetings (Solomon Islands). Sharing of information and evidence is largely personal and unstructured in some settings, rather than being institutional (Burkina Faso). In some places, simple factors like lack of connectivity and ICT skills remain a barrier .Lack of capacity to use evidence well was also mentioned (in Burkina Faso), leading to lack of adaptation of policies from the surrounding region, while in other places (Solomon Islands) participants did not perceive the relevance of evidence from other countries, even evidence from close neighbours (Fiji and Papua New Guinea), which share some similarities but have differences in governance and financing.On the supply side, a number of countries noted weak in-country capacity to generate evidence , including the lack of a national institute to perform close-to-policy work; indeed, the Solomon Islands had just one person specifically responsible for research in the Health Ministry, which is not atypical in low-income settings (some have nobody with this role). Having a smaller territory and being geographically isolated may be factors here. Researchers are often unable to be independent because of funding constraints (e.g. Burkina Faso), leading to ad hoc and poor-quality research. Limited national resources to support evidence generation locally were highlighted, especially for health systems research . In some cases, the withdrawal of international support aggravated these challenges (Georgia).In relation to international agency advice, it is also worth highlighting that pressures and ideas coming from international actors are not always supported by international consensus; indeed, in many cases, international players provide conflicting advice (Georgia), even over technical decisions like on best procedures for Integrated Management of Maternal, Neonatal and Childhood Illness in Nepal. Advice can also be biased by donors’ ‘pet projects’ (Burkina Faso). This is manageable if governments have clear priorities; however, capacity to set clear priorities is itself commonly a barrier in these settings.Some noted that, while there is relatively good access to policy documents and general guidance online, it is harder to find operational information on how to implement specific reforms . Furthermore, it was noted by several respondents that the substantial amount of online information may be useful, yet it is difficult to access and time-consuming to sift through. There is therefore a demand for a brokerage function that would identify high quality, implementable information from other studies and reports. Some also felt that there was a lack of access to practical information, such as regional drug prices or trends in non-communicable diseases (Solomon Islands), while language barriers and limited access to journals remain challenges in some areas such as in Burkina Faso.Many of the case study findings are consistent with the broader literature on health policy transfer in low- and middle-income countries , 37. BotBy starting from actual policy decisions , we find that many of our studied policies were home-grown or at least heavily home-incubated . We can speculate that this may link with their subsequent good performance, either due to higher ownership and/or a correlation between the capacity to innovate and the capacity to manage implementation well. Social factors determining the effectiveness of policies, such as cultural norms changing how maternal health policies in Nepal and community clinics in Bangladesh are implemented, were understood by policy-makers. As a result, formative and technical recommendations from international agencies that conflict with these norms are generally rejected or adjusted by policy-makers.The commitment of ‘national elites’ to policy transfer is commonly cited throughout both literature and the case studies as crucial for the success of policy implementation , 40. EliInternational agencies are often cited as important since they mobilise interest and resources around issues that affect when and how a policy is conceptualised . BennettThe case studies overwhelmingly suggest that local political and economic factors determine when and what international evidence is used and whether that use is instrumental or conceptual (symbolic use was not raised in these case studies) –16. PoliIt is also striking that conflict or crisis had propelled reforms in the majority of our case studies , presumably creating the need and motivation to innovate, as well as a momentum to reduce inertia, challenge path dependencies and willingness to risk policy errors . ResourcThe existence of policy networks is another mechanism that is widely identified as important in conceptualisation by both published studies and the case studies. Policy networks consisting of formal or informal relationships between governments and other policy stakeholders  are undeOther studies on health policy transfer suggest that evaluation is needed to improve dissemination of progress in health policy reform and implementation , follow-Our findings highlight the importance of continuous learning and many positive examples of institutions which are doing this in different contexts. This is an important supplement to current literature, which does not provide much insight into how continuous learning affects uptake of evidence in health policy transfer. Most of the findings highlight the importance of developing the domestic incentives and demand for evidence – areas of gap in supply of evidence were reportedly more minor by comparison, as seen from the national level, though this is not to deny on-going access barriers. Smith et al. , for exaThe case studies illustrate how evidence that is used to inform policy is not ‘systematic’ in nature, in that evidence is often not systematically collected, examined or applied. This supports the views of most practitioners and many academics  that theThere are some important limitations to note, which include that the countries were selected as relatively strong performers which had undertaken some form of significant health system reform in recent years. The selection allowed for the study of how evidence had, or not, informed policies. However, the findings may not be representative of a wider set of countries that may be less active in policy innovation. It should also be noted that each case study was conducted in a limited time, and thus not all perspectives are reflected and included. We can therefore regard the findings as a rich snapshot, rather than as a complete account. We also highlight our inductive approach to analysis, which meant that a structured comparison of learning across systems within a pre-determined theoretical framework was not undertaken.However, the article can inform the future development of a conceptual framework for learning health systems, which should include not just internal factors  but also openness to and mechanisms for filtering international experiences and evidence  by different actors and for different purposes . Existing frameworks do not adequately reflect the agency we found for local decision-makers, as much of the focus is on ‘push’ models, such as policy transfer (which emphasises the transfer of specific ideas) and evidence-based policy-making (which emphasises getting research into practice), both neglecting a more active role of demanding, shaping and co-creating knowledge in the local arena.This article reviews the experiences of eight low- and low–middle-income countries which have adopted health system reforms in the past two decades. Using key informant interviews with those directly engaged in the reforms at different periods of time, it probes whether and how international policy transfer occurred, how evidence informed the different stages of the policy cycle, what mechanisms were effective for learning and what barriers and facilitators were perceived by the participants. Extra focus was placed on unpacking the role of learning from other countries throughout the reform process. The findings emphasise the agency of national and sub-national players and the importance of developing local institutions for gathering, filtering and sharing evidence, locally as well as south–south. Developing demand for and capacity to use evidence appears more significant (in terms of current barriers) than augmenting the supply internationally, although specific gap areas were identified by respondents, especially in relation to more operational and practical questions. The case studies also highlighted that, beyond an initial sharing of information, a lot of work is needed to adequately contextualise and internalise ideas in a new setting. The overall learning process  is a long-term and complex endeavour, in some cases taking 15 to 20 years before a lesson can be said to be ‘in action’ at a national level. The findings also highlight the importance of the local political economy in setting the parameters within which evidence is considered and the importance of trusting relationships between national and international individuals and organisations. Finally, we highlight the need for a theoretical framework within which to further analyse learning across health systems.Box 1: Background on case study countries and policiesRecent health sector reforms in Bangladesh commenced with the Health and Population Sector Strategy developed by government and donor partners in 1997, resulting in the pooling of donor funds through a Sector-Wide Approach. The introduction of one-stop services through Community Health Clinics to replace domiciliary services provided by Family Planning Services field staff were also established in 1998 to herald a major shift in family planning services, from door-to-door to clinic based .Mutuelles de Santé), as a health financing policy intervention, has had a long history in Burkina Faso, from the first experiments in the late 1980s to the 288 schemes identified in 2013. Moreover, the community-based health insurance ‘movement’ is said to have given rise to significant policy initiatives such as the planned universal health insurance  [Community-based health insurance (erselle) .Cambodia’s health sector has been innovative. Among many initiatives that have accompanied the longer-term process of health reform that began in the mid-1990s, two in particular have attracted significant international attention. The Health Equity Fund (which was initiated in 2000) is now a nationwide social health protection scheme, delivering publicly provided health services to the poorest one-fifth of the population. On the supply side, the development of a unique form of contracting in the delivery of public health services (launched in different forms in the mid-1990s) has begun to produce observable results in the management of health service delivery .One of the policies credited with making a substantial contribution to progress towards achieving the health-related Millennium Development Goals 4, 5 and 6 in Ethiopia is the government’s flagship Health Extension Program. Launched in 2003 and gradually scaled up nationwide, the Health Extension Program helped develop a new cadre of paid female community health workers, supported by volunteers at community level and contributed to universal access to primary health services in rural areas .Georgia has introduced extensive health sector reforms and made significant progress against the Millennium Development Goals by 2010. However, while some of the reforms were driven by international best practice, closely resembling developments in the region , others were home-grown and sometimes quite radical  .Despite the constraints, Nepal made substantial progress in reaching the Millennium Development Goals, especially in reducing child mortality. Community- and facility-based health interventions focused on child health such as Integrated Management of Childhood Illness , vitamin A supplementation, immunisation, and deworming programmes contributed to achieving the reduction. This was facilitated by a network of 50,000 female community health volunteers that played an important role in promoting health and reducing the gap between the community and the health facility .Rwanda achieved substantial population health improvements and is particularly known for what is widely considered to be a successful introduction of community-based health insurance and performance-based financing, alongside wider health reforms including more effective aid coordination . IntroduThe Role Delineation Policy in the Solomon Islands was developed to better define the range and level of services – or packages of care – to be delivered to populations across the country. It is designed to be a strategic and system-wide reform, delivering needed services, particularly to rural areas, in a way that is financially and institutionally sustainable. Over the 15 years through which it has been developed, the Role Delineation Policy has become a central part of policy for improved health services .


A recent article ” (Lund and Iyer's emphasis). Despite this opinion of these authors, it was shown many years ago by I.J.Good in two brief notes in the Journal of Statistical Computation and Simulation . There is uncertainty about E, so it should be analyzed probabilistically. Use of the argument of conditional probability leads to ff, rather than forms such as f or variants of it. The expression f does not involve the evidence, which reduces considerations further to f. Propositions Hp and Hd are mutually exclusive so if E is to be a function of both Hp and Hd then f is a combination of two functions, one that involves Hp and not Hd and one that involves Hd and not Hp. Value may thus be expressed as a function of the probabilities of E given Hp (and I) and of E given Hd (and I). Again, this makes implicit assumptions, namely that there is a probability that can be associated with evidence and that is dependent on a proposition and background information. For ease of notation explicit mention of I will be omitted from notation in what follows.In order to show that the likelihood ratio is the only way to evaluate evidence, it is necessary to introduce some mathematical notation. This is a device to ease the presentation of the argument. The argument could be made verbally but would be lengthy and more difficult to follow. Consider evidence x = Pr(E ∣ Hp) and y = Pr(E ∣ Hd). The assumption that V is a function only of these probabilities can be represented mathematically asLet f.for some function T which is irrelevant to E, to Hp and to Hd. Irrelevance is taken in the probabilistic context to be equivalent to independence so that T may be taken to be independent of E, of Hp and of Hd. It is then permissible for Pr(T) to be given notation which does not refer to any of E, Hp or Hd. Thus, let Pr(T) be denoted by θ. ThenNow, consider another piece of evidence Similarly,E, T) is f by the definition of f. However, evidence T is irrelevant and has no effect on the value of evidence E. Thus, the value of the combined evidence , f, is equal to the value V of E, f, andThe value of (T).for all θ in the interval  of possible values of Pr for which this can be said to be the case is the class which are functions of x/y orThe only class of functions of  can be rewritten asE ∣ Hp)) is added to the prior log probability for Hp in one scale and log(Pr(E ∣ Hd)) is added to the prior log probability for Hd in the other scale. The difference in the sums of the two pairs of log probabilities is a more intuitive characteristic of the evidence to which the term weight may be applied than the ratio of the probabilities of the evidence given the respective propositions.Expressions to the left of the negative sign in the last line are associated with one pan in the scales, expressions to the right with the other pan. Thus log(Pr(CA drafted this commentary which results from equal and direct intellectual contributions of all listed authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Malawi has one of the highest maternal mortality rates in the world, with unsafe abortion as a major contributor. Curettage is most frequently used as the surgical method for treating incomplete abortions, even though it is costly for an impoverished health system and the less expensive and safe manual vacuum aspiration (MVA) method is recommended.The aim of this 2016–17 study is to explore health worker’s perception of doing MVA 1 year after an educational intervention. Focus group discussions were recorded, transcribed verbatim, and analyzed using content analysis for interpreting the findings. A knowledge, attitude and practice survey was administered to health professionals to obtain background information before the MVA training program was introduced.Prior to the training sessions, the participants demonstrated knowledge on abortion practices and had positive attitudes about participating in the service, but preferred curettage over MVA. The training was well received, and participants felt more confident in doing MVA after the intervention. However, focus group discussions revealed obstacles to perform MVA such as broken equipment and lack of support. Additionally, the training could have been more comprehensive. Still, the participants appreciated task-sharing and team work.Training sessions are considered useful in increasing the use of MVA. This study provides important insight on how to proceed in improving post-abortion care in a country where complications of unsafe abortion are common and the health system is low on resources. The aim of this study was to explore health worker’s perception of using manual vacuum aspiration (MVA) 1 year after an educational intervention. The health personnel in Malawi who treat women with incomplete abortions are medical interns, clinical officers and nurses/midwives. The training was designed as a refresher course as health personnel usually are trained how to do MVA during their studies. Altogether, 53 health personnel received the training and filled out questionnaires on knowledge, attitude and practice before the training had started. After 1 year, focus group discussions were arranged with 33 of the previously trained health personnel. There was an almost equal number of nurses, clinical officers and medical interns in the survey and in the focus groups, which included fairly equal numbers of male and female participants and a good age spread among the participants. Even though the participants demonstrated knowledge on the benefits of using MVA prior to the training, most of the health personnel used curettage because of a lack of confidence, broken equipment and high gestational age of the expectant mothers. The training sessions were considered useful, but could have been extended to several days and have included actual patients. Our findings provide important insight on how to proceed in improving post-abortion care in a country where complications of unsafe abortion are common and the health system is low on resources.”, and worldwide around 25 million unsafe abortions are performed every year . .Motivation seems to be an important factor for doing MVA. Since the health care providers were working in busy hospitals with a big patient load, they were not motivated to perform a procedure that is more time consuming than others. On the other hand, participants knew that MVA is safer and should be done according to the guidelines. MVA can also be done as an outpatient procedure, which means patients do not have to wait so long before the procedure nor stay overnight.“It’s much better to do MVA. Normally when we do evacuations there is more risk of complications. When you do MVA you don’t have the same risk of complications.” The nurses were motivated and content about having this extra task which could improve the situation for the patients and help the clinical officers.“I feel MVAs will help improve the situation because these MVA can be done without clinicians. It helps many patients and a clinician doesn’t have to be around. We really have a very experienced team here to take care of the patients. We are ready to take care of them.” “MVA is safer and nurses can also do it which saves your time.” Our study shows that conducting a refresher training among health personnel was well received by the participants. The health workers are well aware of the high prevalence of abortions and the possible complications. They also have knowledge of MVA as the recommended and preferred treatment, but the majority use curettage due to obstacles at different levels. The participants felt more confident after the training, and were content that they now had more treatment options. An additional benefit was more teamwork and task-sharing at the district hospitals, where the nurses can care for many of the patients with incomplete abortions. The extensive shortage of healthcare workers made the WHO develop global recommendations and guidelines on task-sharing as a tool for countries to implement safe task-sharing processes . TraininThe individual health worker’s experience and previous education, practice, support, access to supervision and acceptance of MVA influences the confidence of using the suggested tool, irrespective of their appreciation of the training given. The KAP survey revealed that health personnel think that treating patients with incomplete abortions is an important part of their job. They did not oppose to treating these patients because of personal moral beliefs in contrast to a study from Zimbabwe where the health personnel referred to the women in negative terms . The heaMoreover, the clinical officers in the district hospitals were pleased that the nurses could share their workload. An anticipation is that if senior doctors and clinical officers encourage the nurses their confidence in performing MVAs will evolve. Lack of encouragement from colleagues and the leadership was seen as an obstacle and should be addressed. It is clear that the motivation is there and small measures could be taken to try increase their confidence. Encouraging health workers to follow guidelines would be instrumental to increase use of MVA. Our study demonstrates that the health workers were knowledgeable about the guidelines and recommendation to use MVA. However, this was not built on by the leadership nor was MVA use implemented. In our assessment, this constitutes a missed opportunity to improve PAC.A previous Malawian study has shown that training and task-shifting efforts seem to have had a positive effect on maternal mortality . FurtherMost specialists work at the larger hospitals, and have the opportunity to engage and ensure that their patients are being treated according to the existing guidelines. Concurrently, specialists have an overarching responsibility to the rural District Hospitals in supervising clinical activities there. However, the lack of consultants in gynecology makes it very hard to adequately supervise all such facilities. Nevertheless, it is essential for all countries to insert a continuum of care, and this is especially so in low-income regions with high maternal mortality.The guidelines by the WHO, International Federation of Gynecology and Obstetrics (FIGO) and the Malawi Ministry of Health clearly state that vacuum aspiration is the preferred surgical method for treatment of incomplete abortions in the first trimester and that the use of curettage should be decreased to the minimum , 23, 42.The collaboration between Norwegian and Malawian researchers, obstetricians, gynecologists and midwives with experiences of treating patients with incomplete abortions was important for gaining an in-depth understanding of the data and to ensure credibility. The different personal and professional backgrounds of the authors were also helpful in the indicated classification/illustration/interpretation exercises. The first author lived in Malawi for several years and was onsite during the entire data collection process to ensure consistency, dependability and thereby building trust. During the whole process, she kept in mind how her role as a medical doctor, and a white expatriate woman, could have affected the data collection. To enhance the transferability of the project full details on the setting, the participants, data collection and qualitative analyses procedures are provided.A strength of our study is that the follow-up FGDs were employed to explore the views on MVA and PAC of local health personnel. It supplemented the KAP survey data and gave us insight not only about the participants’ knowledge on the Malawian abortion law, symptoms and complications after abortions, but also their attitudes about abortions and the methods and practices in use at a community/hospital level. Training sessions are common in Malawi and other developing countries, but there is little data on follow ups. A possible limitation is whether the participants were sharing their actual perceptions rather than what they thought the researchers wanted to hear, or what was expected of them. However, the participants were speaking in a freely and uninhibited manner, and were encouraged by the moderator to be honest and give critical feedback.Our study shows that the organized MVA-training provided was well received the health personnel and had a role in increasing the use of MVA in the treatment of incomplete abortions. A lack of properly working equipment, insufficient staff and time, and an absence of leadership support were major obstacles to employing MVA. Furthermore, our study suggests that attitudes and change in practices to use another and recommended uterine evacuation method is complex as it challenges various concerns, such as the individual health provider’s perspective, team work, leadership and policy issues. Change in behavior therefore needs to be addressed at several levels, and a health systems approach is recommended.


Given the recognized importance of preventing poor dietary behaviors during adolescence, we need a better understanding of college students’ dietary behaviors. Studies have found that individual factors and electronic health  literacy may affect one’s dietary behaviors. However, few studies have fully investigated the effect of the three levels of eHealth literacy  and the interactive effect of individual factors  and the three levels of eHealth literacy on the four aspects of dietary behaviors .This study aimed to investigate whether individual differences and higher eHealth literacy are associated with more positive dietary behaviors and less unhealthy dietary intake.The eHealth Literacy Scale is a 12-item instrument designed to measure college students’ functional, interactive, and critical eHealth literacy. The Dietary Behaviors Scale is a 14-item instrument developed to measure four aspects of dietary behaviors of college students. A questionnaire was administered to collect background information about participants’ gender, monthly expenses, and frequency of cooking. A national sample of college students was surveyed, and 813 responses were obtained. We conducted a multiple regression analysis to examine the association among individual factors, eHealth literacy, and dietary behaviors.P=.01), and interactive eHealth literacy was positively related to balanced diet  and consumer health . Moreover, critical eHealth literacy was positively related to consumer health  and regular eating habits . Finally, the interactive effect between gender and interactive eHealth literacy was negatively related to balanced diet . The interactive effect between monthly expenses and functional eHealth literacy was positively related to balanced diet , although the interactive effect between monthly expenses and critical eHealth literacy was negatively related to balanced diet .This study found that functional eHealth literacy was negatively related to unhealthy food intake (beta=−.11; This study showed that Taiwanese college students with higher functional eHealth literacy were more likely to engage in fewer unhealthy food consumption practices. Those who had higher interactive and critical eHealth literacy were more likely to engage in positive dietary behaviors than those with functional eHealth literacy. Surprisingly, females with high interactive eHealth literacy were more likely to have a poor balanced diet. In contrast, students with higher monthly expenses and higher functional eHealth literacy were more likely to have a balanced diet. However, students with higher monthly expenses and higher critical eHealth literacy were less likely to maintain a balanced diet. The importance of preventing poor dietary behaviors during adolescence has been recognized because of its impact on long-term health issues such as the development of obesity and other noncommunicable diseases . StudentDietary behaviors, including consumer health, balanced diet, regular eating habits, and unhealthy food intake, can be viewed as positive or negative actions in relation to maintaining or enhancing health . ConsumeHealth literacy refers to an individual’s ability to access, understand, and use information to promote and maintain good health . StudiesNorman and Skinner  have defThe integrative model of eHealth use (IMeHU) indicates that people with high eHealth literacy are not only more inclined to use the internet to find answers to health-related questions but are also able to understand the information that they find, verify its veracity, and use it to promote health behaviors . StudiesThe IMeHU suggests that individual factors may affect one’s health behaviors . StudiesSimilarly, little attention has been paid to the interactive effect of individual factors and the three levels of eHealth literacy on the four aspects of dietary behaviors. It is necessary to clarify the effects of individual factors and the three levels of eHealth literacy, as well as how the interactive effect of these 2 elements affects the four aspects of dietary behaviors, to develop an effective health education program to promote healthy dietary behaviors among college students. Therefore, the objective of this study was to investigate the associations among individual factors, eHealth literacy, and dietary behaviors in Taiwanese college students with the goal of determining whether high eHealth literacy is associated with more positive dietary behaviors and less unhealthy dietary intake and to investigate the interactive effects of individual factors and eHealth literacy on the four aspects of dietary behaviors. In accordance with the IMeHU  and the This study was conducted nationwide in Taiwan. The list of colleges came from Taiwan’s Ministry of Education. Sampling units were drawn from within each region. We contacted teachers at selected colleges to request their assistance in the pen-and-paper survey distribution. Ultimately, 1100 college students from 10 schools were recruited to participate in the survey. Of the 895 surveys received, we excluded 25 blank surveys, 34 surveys with incomplete respondents’ individual factors, and 23 surveys with fixed mode answers. However, 21 surveys with fewer than 3 items incomplete were retained. We applied expectation-maximization method of multiple imputation to the missing data. In other words, 813 surveys were statistically analyzed in this study . We gathered the respondents’ individual factors, including information about age, gender , monthly expenses , and frequency of cooking . The frequency of cooking was measured by asking how often the students cooked by themselves and was rated based on the responses on a scale from 1 (never) to 5 .Participants’ eHealth literacy was evaluated using the eHealth Literacy Scale (eHLS) , which cThe items were answered using a 5-point Likert scale, with scores ranging from 1  to 5 . High scores on the respective levels indicated higher functional, interactive, and critical eHealth literacy. Cronbach alpha is a statistic commonly quoted by authors to demonstrate that tests and scales that have been constructed or adopted for research projects are fit for the research purpose. The alpha values of .45 to .98 for this instrument have been described as acceptable . Within The participants’ dietary behaviors were evaluated using the Dietary Behaviors Scale (DBS) . Using iThe items were answered using a 5-point Likert scale, with scores ranging from 1 (never) to 5 . High scores in the individual aspects indicated positive attitudes and decisions about product purchases, more balanced and regular eating habits, and more consumption of unhealthy food. Within the sample used in this study, the Cronbach alpha values of consumer health, balanced diet, regular eating habits, and unhealthy food intake were .82, .72, .59, and .68, respectively, indicating that the DBS had acceptable internal reliability .Analyses were conducted using SPSS 17.0 (IBM Corp). We performed 4 multiple regression analyses to examine the explanatory power of the four aspects of dietary behaviors. In the model, individual factors, the 3 levels of eHealth literacy, and the interaction of these 2 elements were entered. Gender was viewed as a dummy variable where males were coded as 0, and monthly expenses and frequency of cooking were viewed as continuous variables.The study adopted an anonymous questionnaire in line with the government’s institutional review board rules for exempt review. The questionnaire instructions informed the participants of the research purpose and confidentiality and indicated that they had the right to refuse to participate at any time. The participants received the questionnaire and gifts at the same time; even if a participant decided to drop out of the investigation, he or she still received the gifts (a pen and an L-folder). This approach was intended to be fair to each participant, to avoid the impact of gift incentives on the participants, and to provide compensation for the participants.Among all participants, the mean scores of functional eHealth literacy, interactive eHealth literacy, and critical eHealth literacy were 3.56 (SD 0.77), 3.57 (SD 0.71), and 3.59 (SD 0.72), respectively, indicating that college students had medium or higher levels of eHealth literacy.On the DBS, the mean scores of the regular eating habits, balanced diet, unhealthy food intake, and consumer health were 3.15 (SD 0.73), 2.92 (SD 0.70), 3.02 (SD 0.72), and 3.12 (SD 0.76), respectively. This result indicated that college students had positive consumer health and regular eating habits although they did not maintain a balanced diet. Moreover, they sometimes ate unhealthy food.In the multiple regression analysis, first, the tolerance and variance inflation factor (VIF), as 2 collinearity diagnostic factors, were examined to assess multicollinearity in this study. The collinearity diagnostics results showed that tolerance ranged from 0.28 to 0.99, and VIF ranged from 1.01 to 3.78. These results indicate that explanatory variables in this multiple regression model were weakly linearly related .P=.01), and interactive eHealth literacy was positively related to balanced diet  and consumer health . Moreover, critical eHealth literacy was positively related to consumer health  and regular eating habits . Thus, hypothesis 1 was partially supported.The results of the multiple regression analysis are displayed in P<.001). The interactive effect between monthly expenses and functional eHealth literacy was positively related to balanced diet , although the interactive effect between monthly expenses and critical eHealth literacy was negatively related to balanced diet . Therefore, hypothesis 2 was partially supported.The study found that the interactive effect between gender and interactive eHealth literacy was negatively related to balanced diet  rather than an average of kilocalories and consumption per day. Thus, our measure of unhealthy food intake may not accurately indicate the effect of interactive and critical eHealth literacy on unhealthy food intake. Third, the study sample was educated and age restricted in Taiwan. Thus, the findings should not be overgeneralized and should be interpreted in light of the sample’s homogeneity. Finally, because the study presented some interesting and paradoxical findings, along with the associations among these factors, eHealth literacy, and dietary behaviors among college students, further studies should examine a broad range of intrapersonal , interpersonal , cultural , and environmental factors (food availability and food cost) as well as social norms and beliefs that might be influential in determining college students’ eating behavior and dietary intake.This study, to our knowledge, was the first to establish an association among individual factors, the 3 levels of eHealth literacy, and the four aspects of dietary behaviors among college students. This study found that Taiwanese college students with interactive and critical eHealth literacy were more likely to engage in positive dietary behaviors than those with functional eHealth literacy. For the group of students with high monthly expenses, the role of functional eHealth literacy was greater than that of critical eHealth literacy in balanced diet. Moreover, Taiwanese college students with functional eHealth literacy were less likely to engage in unhealthy food intake. These findings have important implications for health educators, who should provide college students with information to help them understand the risks of high-calorie, high-fat, high-salt, or high-sugar diets and thereby reduce their consumption of unhealthy food. As an interactive effect between gender and interactive eHealth literacy on balanced diet was identified, further research is needed to help female college students critically evaluate the credibility and risks of Web-based health information about losing weight and thereby participate in healthy eating practices.


Witnessed resuscitation canrepresent an opportunity to understand and cope with the rational andirrational in the situation in a shared manner, as well as mitigate ordignify the mourning. Research on the family’s presence during resuscitation maneuversAs a general standard, at countless inpatient and out-of-hospital services, theprofessionals try to distance the relatives from the victims of a cardiorespiratoryarrest, with a view to avoiding that they hinder the professionals during theapplication of cardiopulmonary resuscitation techniques. Excluding the relatives isjustified under the premise that the invasive procedures and the aggression duringthe cardiopulmonary resuscitation can provoke stress in the family members and thattheir presence could compromise the performance of the medical teamThe literature review, however, presents contradictory results concerning the meaningof the concept of family presence during the resuscitation maneuvers and the nursingprofessionals’ attitudes, adding positive and negative opinions and provoking acontinuous debate.-The objective in this study is to review the most relevant evidence on the nurses’attitudes towards the presence of relatives during cardiopulmonary resuscitationmaneuvers inpatient and out-of-hospital services. The idea to have a family memberpresent during the cardiopulmonary resuscitation is supportedThe lack of protocols on the witnessed resuscitation concept arouses controversiesabout ethical-care issues deriving from health practice.CardiopulmonaryResuscitation, Heart Arrest, Attitude ofHealth Personnel, Emergency Nursing, Familypresence/Witness; in Spanish, English and Portuguese;the following inclusion criteria were used: presence of relatives during thecardiopulmonary resuscitation maneuvers; application of invasive techniques thatmight be necessary in the procedure and inpatient and out-of-hospital emergencyservices for adults. Both the qualitative and quantitative method were included inthe review.An integrative literature review was undertaken, covering the period from 2008 to2015. As for the databases related to the health sciences, Pubmed-Medline, Lilacsand Scielo were used. The bibliographic search in the databases was based on thefollowing descriptors and/or key words: Therefore, articles related to the pediatric context and articles referring tocritical and intensive care services were excluded.To facilitate the research process, the following guiding question was formulated:Which are the attitudes of emergency nurses to the concept of witnessedresuscitation?In view of the lack of methodological uniformity for the integrative reviews, inorder to analyze the documents, the methodological structure of the systematicreviewAmong the 20 final articles that could be included in the review, ten were analyzedin accordance with the criteria of relevance and pertinence, including this total inBesides the impact factor of the journal from which the article was taken, thefollowing criteria were adopted: surprising results; theoretical and practicalimportance; new and interesting ideas; new framework; internal validity: use ofappropriate design and method; external validity; the presented results and/ortheory are generalizable; sufficient description of the method and procedure forother researchers to replicate them; theoretical or practical results with a highdegree of implementation; theoretical or practical results useful to society; andclear specification of the type of study. In addition, the intention was to create asynthetic document, for which those articles were selected that truly offer adetermining contribution.Concerning the limitations of the study, it is highlighting that, given the novelnature of the theme, after applying the filters established, the number of recordswas limited. This justifies the need to expand the research in this field.The ten articles included in the review produced two subcategories related to theattitudes and emotions of the nursing professionals about the concept witnessedresuscitation. It should be highlighted that most of the articles analyzed come fromEnglish-language literature, 92 % being located in the database Web of Science, 7 %in Lilacs and 1 % in Scielo.American Heart Association and the EuropeanResuscitation CouncilThe main result this integrative review contributes relates to the controversiesamong the resuscitation team members regarding the concept of witnessedresuscitation; that is so although the most recent CPR guides, such as the guides ofthe The concept generates an ongoing debate among the nurses, with great variation in theperceived risks or benefits of the family members’ presenceQualitative research on witnessed resuscitation could reveal more concrete aspectsthan quantitative studies and reveal specific benefits of the family’s presenceduring the resuscitation event. Recent qualitative studiesThe literature review shows us results on the existing relation between the nature ofthe background experience in witnessed resuscitation situations and theirattitudesLess articles were found in Spanish. Among these, a qualitative studyIn short, the nurses’ attitudes in executing witnessed resuscitation maneuvers beforerelatives are dynamically concentrated in these main themes during the maneuversthrough different emotions, conducts and behaviors, distributed between signifying anegative experience that affects the professional wellbeing or a positive experienceleading to the resilience of nursing. A team member needs to support the relativesduring the resuscitation maneuvers.In the end, the literature review shows us important benefits of witnessedresuscitation. In addition, most of the nurses consider that, when accomplishing theresuscitation maneuvers in the presence of relatives, their stress, lack of controland emotional tension neither provoke interference nor hamper the nurse’s work;thus, the family’s presence is valued, considering it as beneficial, stress reducingand facilitating the mourning process, which is a right of the patient and thefamily.The literature review shows multiple studies on the emergency nurses’ attitudes, inwhich we can distinguish two categories that contain the different attitudes thewitnessed resuscitation event produces; these can be summarized as follows: - Positive attitudes: tranquility, empathy, safety, pride and facilitating themourning process. The witnessed resuscitation can be an opportunity to understandand confront the rational and irrational in the situation in a shared manner and tomitigate or dignify the mourning.- Negative attitudes: stress, fear, impotence and mainly the feeling that the familymembers can make the accomplishment of the resuscitation maneuvers moredifficult.The evidence shows the multiple benefits of witnessed resuscitation, as being presentduring the resuscitation provokes tranquility and satisfaction in the relatives, aswell as the need to actively prepare the nurses to enhance their confidence in viewof the management of the concept, which justifies the need to establish protocolsfor this situation. The establishment of agreed protocols would be recommended,which identify when, how and to whom the witnessed resuscitation should beoffered.In the light of the review, it was verified that witnessed resuscitation is acontroversial and current team in intra and out-of-hospital emergency care, leavingmany unanswered questions nowadays. In that sense, the health professionals areimmersed in a great emotional debate in their daily work, when they need to performviolent, invasive techniques or maneuvers in the presence of family members, underthe emotional burden this action provokes. Therefore, discrepancies emerge among thenurses from different contexts and geographical zones with regard to the concept ofwitnessed resuscitation.It should be kept in mind that the extra-hospital environment is hostile, in which wecan often feel unprotected, for example, when a patient is resuscitated at his ownhome, in the presence of the family, listening to what the team comments; thismoment requires great physical and mental effort towards the victim of the cardiacarrest. Nevertheless, it should never be forgotten that the family will need oursupport; hence, a holistic and comprehensive focus needs to be established in viewof the family’s needs.Concerning the implications of the findings for professional practice, the knowledgeand study of the witnessed resuscitation concept and the attitudes observed in thenurses could consolidate its promotion and use, due to the different benefits ofthis technique the studies evidenced, although some controversies were evidenced; wefound a higher value of the nursing professionals’ attitudes. In fact, two branchesof the implications were visible: an immediate implication that reflects the safetyin practice and the defense of the patient’s values (principle of autonomy), andanother indirect implication, which is related to the consequences for the relativesin terms of an easier mourning process.Finally, the need to investigate new and different approaches to witnessedresuscitation should be emphasized in the different areas in which nursingestablishes its resuscitation work, from the perspective of the people who areexperiencing this. Therefore, the use of the qualitative method should be boosted asa complement to the quantitative method, in order to understanding how the family’spresence during the resuscitation maneuvers is perceived.


Understanding the factors involved in the development of broadly neutralizing antibody (bNAb) responses in natural infection can guide vaccine design aimed at eliciting protective bNAb responses. Most of the studies to identify and study the development of bNAb responses have been performed in individuals who had become infected via homo- or heterosexual HIV-1 transmission; however, the prevalence and characteristics of bNAb responses in injecting drug users (IDUs) have been underrepresented. We retrospectively studied the prevalence of bNAb responses in HIV-1 infected individuals in the Amsterdam Cohort, including 50 male and 35 female participants who reported injecting drug use as the only risk factor. Our study revealed a significantly lower prevalence of bNAb responses in females compared to males. Gender, transmission route and CD4+ count at set point, but not viral load, were independently associated with the development of bNAb responses in IDUs. To further explore the influences of gender in the setting of IDU, we also looked into the Swiss 4.5k Screen. There we observed lower bNAb responses in female IDUs as well. These results reveal that the emergence of bNAbs may be dependent on multiple factors, including gender. Therefore, the effect of gender on the development of bNAb responses is a factor that should be taken into account when designing vaccine efficacy trials. An effective HIV-1 vaccine should be capable of eliciting broadly neutralizing antibodies (bNAbs), defined as the ability to neutralize various heterologous viruses from different subtypes, in order to provide protection against HIV-1 acquisition ,3. DurinThe most predictable clinical markers for the development of bNAbs are duration of infection, high viral load, and in some cohorts low CD4+ T cell count ,17,30,31Most of the studies to identify bNAb responses were performed in individuals who were infected via homo-  or heterosexual HIV-1 transmission. The determinants of bNAb induction in injecting drug users (IDUs) remains underrepresented, while the immunomodulatory effect of drug use ,41,42,43The Amsterdam Cohort Studies on HIV-1 infection and AIDS (Amsterdam Cohort) are being conducted in accordance with the ethical principles set out in the declaration of Helsinki, and all participants provided written informed consent. The study was approved by the institutional Medical Ethics Committee of the Academic Medical Center, University of Amsterdam.Data from the Swiss 4.5 Screen integrated as a comparison group in the current study comprised solely the re-analysis of previously generated data ,38. EthiWe screened serum samples from participants of the Amsterdam Cohort for the presence of bNAb responses. The study population consisted of a total of 299 HIV-1 infected MSM ,44 and 8n = 15) [Sera were tested for bNAb responses in a pseudovirus assay involving six tier-2 viruses  in a single round of viral infection developed by Monogram Biosciences. This six-virus panel covered 93% of the variation in neutralization of a larger pseudovirus panel n = 15) . For eacn = 15) ,39, and  . For ean = 15) .Differences between groups were analyzed with a Mann–Whitney test. Mann–Whitney tests and Spearman correlation tests were performed in GraphPad prism 7 . A univariate and multivariate regression analysis on both the IDU and MSM cohort was performed using SPSS with the logarithmic transformed GMT as dependent factor and mode of transmission, gender, viral load at setpoint, and CD4+ T cell count at setpoint as potential predictors. Mode of transmission and gender were grouped as MSM male, IDU male and IDU female. As the MSM cohort did not include females, gender and mode of transport could not be separated as independent variables. The effect of bNAb responses on disease progression was analyzed in a Kaplan–Meier and Cox proportional hazard analysis using clinical AIDS (1993 CDC definition) as an endpoint. Individuals were divided into 3 groups: those who neutralized ≤ 1; 2 or 3; or ≥ 4 viruses at an ID50 titer ≥ 100. Left truncation of follow-up time was performed for the time between the imputed SC date and first seropositive visit using S-Plus 8 . P-values < 0.05 were considered significant.In order to determine the effect of IDU-transmission route on bNAb activity amongst participants in the Swiss 4.5 k Screen, we used uni- and multivariable Tobit regression models with the neutralization score determined previously  as an ouenv) was PCR amplified from DNA isolated from PBMCs that were infected in vitro with a single clonal HIV-variant and subsequently sequenced as described previously [env sequences from within the first year post-SC from these individuals were available. To assess if multiple virus transmission (MVT) has occurred in the IDU and MSM, we analyzed the earliest available env sequences, within 3 months of SC (MSM = 8 and IDU = 5), as previously described [The HIV-1 envelope gp160 gene  and compared with the MSM participants of the Amsterdam Cohort . Of the 384 HIV-1 infected individuals (IDU and MSM combined), 25% developed bNAb responses, defined by their ability to neutralize ≥ 4 viruses of the six-virus panel, at ID50 titers > 100. The prevalence of bNAbs in the IDUs was lower compared to the prevalence in the MSM    ( 0.0009) A. The IDct test) .n = 35), which allowed a comparison of exclusively men of both the IDUs (n = 50) and MSM (n = 299) (p = 0.1126). This suggested that the female gender contributed to the differences between the IDU and MSM in the Amsterdam Cohort. Therefore, we compared the GMT values between all the men (n = 349) and women (n = 35), irrespective of the route of HIV-1 transmission. HIV-1 infected men had higher GMT values than HIV-1 infected women (p = 0.0005). A similar trend was observed within the IDU cohort (p = 0.0593); however, this was not statistically significant, most likely due to the low number of participants per group. Furthermore, male IDUs were more frequently classified as elite neutralizers than female IDUs  B. After U cohort B (p = 0.p < 0.001), and a positive correlation between the viral load at setpoint, and the development of bNAbs . These correlations were stronger when only the MSM were analyzed . Conversely, in the IDUs, a similar trend was observed between the CD4+ T cell count at setpoint and bNAb responses , while no correlation with viral load at setpoint was observed, which could be due to the low number of participants. To determine whether these parameters were independently associated with the development of bNAb responses, we performed a multivariate model analysis on the combined IDU and MSM cohorts using all parameters as covariates .Duration of infection was shown to be a very important predictor for bNAb development. In our study, we included patients and samples based on similar time points post-SC (~3 years post-SC), and therefore we did not observe a correlation between duration of infection and GMT. In addition to duration of infection, high viral load and low CD4+ T cell count were the strongest predictors for the development of bNAb responses in previous studies ,17,31,33variates . As the n = 16) had a similar time to AIDS compared to IDU with intermediate NAb breadth  or those with no bNAb responses . The results indicate that bNAbs in IDUs also had no beneficial effect on the clinical course of infection, similar to bNAbs in individuals who were infected via (MSM) or heterosexual transmission [bNAb responses generally have no effect on disease progression ,52. Conssmission ,36.env diversity in these individuals. However, we found that the sequence diversity of viruses isolated within the first three months post-SC may be higher in the IDUs compared to the MSM. Although the numbers of individuals eligible for inclusion in these analyses was small and the trend did not reach statistical significance (P = 0.0932), it may point at possible MVT in (some of) the IDUs (env diversity (>0.01) and demonstrated phylogenetic evidence of MVT (p = 0.022). Nevertheless, we could not find significant evidence for an association between viral diversity and bNAb development. However, we note that the number of individuals for which early env sequences were available and the number of sequences per timepoint were too small to study this reliably.Viral diversity has been shown to correlate with the development of bNAb responses ,36. Therthe IDUs C. InterePrevious studies on clinical variables associated with the development of bNAb responses did not show a strong association with the gender of the infected individual ,54,55,56We found that individuals in the Amsterdam Cohort infected with HIV-1 via contaminated needles generally had lower bNAb titers compared to HIV-1 infected MSM. This finding was not related to the calendar period in which the participants were infected or the subtype with which they were infected, because the MSM and IDU participants of the Amsterdam Cohort are similar in both respects (infection between 1982 and 1997 and exclusive infection with subtype B for both MSM and IDUs). Moreover, no significant differences in age, disease course, ethnicity and viral loads were observed between the IDU and MSM participants, which could explain the difference in bNAb development between these two groups. Interestingly, this difference appears to be independently associated with female gender in the IDU group, with females having lower bNAb responses compared to male IDUs. Previous studies have not observed such a difference when male versus female heterosexual HIV-1 transmission was studied ,16,17,31The most predictable clinical markers for the development of bNAbs observed in previous studies are a high viral load and a reduced CD4+ T cell count ,16,17,31In the Swiss 4.5K Screen, female IDUs had significantly lower neutralization scores than male IDUs, who displayed higher neutralization activity than MSM, suggesting a positive influence of the IDU status in men but not women on bNAb development. A higher neutralization activity amongst male IDUs was not observed in the Amsterdam Cohort. The differences in bNAb responses between MSM and male IDU within the two cohorts, strengthen the observation that female gender was the strongest association for lower bNAb responses. Notably, in contrast to the Amsterdam Cohort, no strong effect of CD4+ T cell counts on bNAb activity were seen in the Swiss 4.5K Screen, as the negative association of CD4 cell counts with bNAb responses was lost in multivariable testing. Some of these individual differences may be in part due to differential cohort size and design. For instance, as the Swiss 4.5K screen recruited individuals at different stages of the infection, whereas the Amsterdam IDU cohort was selected from a narrower range, the predictive capacity of CD4 and viral load may differ. Despite the individual differences, the two cohorts strengthen the key observation that female IDUs have lower bNAb responses compared to male IDUs, indicating that there is a fundamental difference in bNAb development between male and female IDU. Interestingly, in most previous studies, this gender bias was not observed in women with heterosexual transmission ,54,55,56Recreational drugs can have various immune-modulating properties depending on the frequency of use and type of drug used ,42. For Viral diversity within the first year of infection, another proposed marker for bNAb development, did not correlate with bNAb development. Interestingly, despite the lower overall prevalence of bNAb responses in the IDU group, more elite neutralizers were found in this group, with 6% of male IDUs qualifying as elite neutralizers compared to only 0.3% of MSM and 0% of female IDUs. When we analyzed the viral diversity of samples obtained in the first three months post-SC, we did find that all but one IDU demonstrated evidence consistent with a pattern associated with MVT. These findings are in concordance with other studies in which MVT has been observed in up to 60% of the IDU individuals . InteresIn conclusion, we found that women infected with HIV-1 using contaminated needles developed bNAb responses less efficiently than men that attracted HIV-1 via the same transmission route. This difference is most likely multifactorial, where early viral diversity caused by multivariant transmission, CD4+ T cell count, viral load and drug use may all play a role. Therefore, the effect of gender on the development of bNAb responses is a factor that should be considered when designing vaccine efficacy trials.


Economic evaluation can inform whether strategies designed to improve the quality of health care delivery and the uptake of evidence-based practices represent a cost-effective use of limited resources. We report a systematic review and critical appraisal of the application of health economic methods in improvement/implementation research.A systematic literature search identified 1668 papers across the Agris, Embase, Global Health, HMIC, PsycINFO, Social Policy and Practice, MEDLINE and EconLit databases between 2004 and 2016. Abstracts were screened in Rayyan database, and key data extracted into Microsoft Excel. Evidence was critically appraised using the Quality of Health Economic Studies (QHES) framework.N = 16) and implementation (N = 14) studies. The most common intervention evaluated (43%) was staffing reconfiguration, specifically changing from physician-led to nurse-led care delivery. Most studies (N = 19) were ex-post economic evaluations carried out empirically—of those, 17 were cost effectiveness analyses. We found four cost utility analyses that used economic modelling rather than empirical methods. Two cost-consequence analyses were also found. Specific implementation costs considered included costs associated with staff training in new care delivery pathways, the impacts of new processes on patient and carer costs and the costs of developing new care processes/pathways. Over half (55%) of the included studies were rated ‘good’ on QHES. Study quality was boosted through inclusion of appropriate comparators and reporting of incremental analysis (where relevant); and diminished through use of post-hoc subgroup analysis, limited reporting of the handling of uncertainty and justification for choice of discount rates.Thirty studies were included—all health economic studies that included implementation or improvement as a part of the evaluation. Studies were conducted mostly in Europe (62%) or North America (23%) and were largely hospital-based (70%). The field was split between improvement (The quantity of published economic evaluations applied to the field of improvement and implementation research remains modest; however, quality is overall good. Implementation and improvement scientists should work closely with health economists to consider costs associated with improvement interventions and their associated implementation strategies. We offer a set of concrete recommendations to facilitate this endeavour. Implementation Science [improvement science as the scientific approach to achieving better patient experience and outcomes through changing provider behaviour and organisation, using systematic change methods and strategies [implementation science as the scientific study of methods to promote the uptake of research findings into routine health care practice or policy [Both improving health care and implementation of evidence-based practices are receiving increasing attention within the wider applied health research field. A recent editorial in  Science  discusserategies . We defir policy .This paper presents a review of the application of economic evaluation to evaluative studies of service improvement initiatives and interventions focused on facilitating the implementation of evidence into practice. The aim of economic evaluation is to present evidence on the costs and consequences (in terms of patient outcomes) of quality improvement strategies and methods for increasing the uptake of evidence-based practices compared to the ‘status quo’. In doing so, it informs whether specific initiatives are (or have been) a worthwhile (or ‘cost-effective’) use of the limited resources of health systems.Depending on the service and population context, the methods used in economic evaluations can vary depending on the perspective taken. This can range from a narrow assessment of patient outcomes alongside immediate health care provider cost impacts through to the quantification of costs and consequences affecting other  sectors, organisations and wider society. In health programme evaluation, economic evaluations are most frequently carried out ‘ex-post’ or ‘after the fact’, using empirical methods applied to cost and outcome data extracted from trials or other research designs used to evaluate initiatives being tested in specific populations and settings. Economic evaluations can also be applied ‘ex-ante’—to inform option appraisal and pre-implementation decision making using available evidence and modelling to simulate the costs and outcomes of alternatives, e.g. in relation to population scale up or geographical spread of strategies and methods for improvement and evidence uptake.While economic evaluation has become an integral part of health technology assessment, its application within improvement and implementation evaluative research remains relatively limited . In two The aim of this study was to examine what advances have been made in the use of economic analysis within implementation and improvement science research, specifically in relation to the quantity and quality of published economic evidence in this field; and to what extent economic evaluations have considered implementation and improvement as part of a holistic approach to evaluating interventions or programmes within the applied health arena.A systematic review methodology was undertaken. A search strategy was developed to capture evidence published after 2003 (the date of most recent evidence review) and the last searches were performed on 16th March 2016. The searches were performed on the following databases: Agris, Embase, Global Health, HMIC, PsycINFO, Social Policy and Practice, MEDLINE and EconLit. These databases were chosen to attempt to capture the widest range of health improvement, social scientific and health economic studies.The search strategy Table  was desiWe searched across a wide range of clinical settings, including primary, secondary and tertiary care and public health.The completed search results were downloaded into Endnote X6 for citation management and deduplication. Screening was done in Rayyan, a web-based literature screening program [Were published in the English languageStudy protocols, methodological papers or conference abstracts were excluded .Reported on a completed studyWere published after 2003 and before 16th March 2016Were conducted in public health, primary, secondary or tertiary careStudies were included if they:ImplementationQuality/service improvementHealth or clinical service deliveryStaff behaviour changePatient behaviour changeFurther, studies were included if they covered aspects of:Had patient focused outcomes or outcomes as overall service improvement that would improve patient outcomes or care, expressed as quantifiable outcomesHad economic elements, expressed as quantifiable outcomesCost effectiveness analysisCost-utility analysisCost-benefit analysisCost-consequence analysisBurden of diseaseReported one of the following health economic methodologies:And they also:Randomised controlled trialsHybrid effectiveness-implementation trialsComparative controlled trials without random assignmentBefore and after studiesSystematic reviewsTime series study designThe following study designs were included:Studies or papers that did not fall within the above criteria were excluded. No geographical exclusions were applied. Cost-only studies were not included as the aim of this review was to establish the extent that both costs and benefits were being considered as part of a holistic approach to evaluation of implementation and improvement interventions.To mitigate for potential selection bias after screening, keyword searching was done in Rayyan for the main keywords within the excluded categories . These were then re-screened by the first author. Studies that included only minimal discussion of costs or costing with no evidence of application of appropriate, standard costing methods (as per the criteria above) were excluded.Screened studies were downloaded from Rayyan and transferred into a template developed in Microsoft Excel 2016 for detailed data extraction. During screening, each included study was tagged in Rayyan with the reasons for inclusion, type of economic evaluation  standardised framework . The QHEFigure In total, the initial search strategy identified 1668 articles, of which 1566 were excluded, 1525 during the initial screen and 41 following full text screening. Reasons for exclusion were as follows: the study did not include implementation or quality improvement research aspects (575); it did not include economic aspects (447); was not within a health care/public health setting (437); it was in a language other than English (22); it was incomplete (19); or it was not a full refereed publication  (37).Thirty studies were included in the final evidence review and synthesis.Table Sixteen of the included studies were identified as ‘improvement’ studies  was used in all but one study, and in 81% of studies the data sources for the analysis were from randomised controlled trials, the highest scoring type of evidence in the QHES instrument  with those identified in this review (2004 to 2016) shows evidence of a general improvement in quality over the past two decades, with the caveat that the two reviews used different quality appraisal frameworks. For example, only 42% of studies reviewed by Hoomans et al. included evaluation of costs and outcomes against ‘standard practice/status quo’ comparators, compared to 95% of studies in our review. Likewise, costing methodology was only deemed adequate in 11% of cases included in the Hoomans et al. review, compared to 76% of the studies in this review. Justification for the outcome measures used was not reported in any of the studies included in Hoomans et al. but reported in 68% of studies included here. This is a welcome improvement of applied economics within health care implementation and improvement research. We attribute it at least partly to improvements in reporting economic analyses over time, which would appear to have made an impact on the studies we captured. Additionally, the expanding application of health economic evaluations within the improvement and implementation sphere where high-quality study reporting has been a major recent focus has also plausibly contributed to improved reporting. Future evidence reviews will confirm whether this pattern is sustained over time.This review offers an updated synthesis of an emerging field of economics evaluations of health care intervention evaluations covering both implementation and improvement science studies. The strict inclusion criteria mean that the reviewed evidence is cohesive. The systematic appraisal we carried out also allows us a longitudinal critique of the quality of economic studies in this field. Despite not being able to directly compare the quality assessment from the previous reviews, we would argue that the QHES used here is based on Drummond’s guidelines (used in prior reviews) and is designed to cover the same topics, but offers a simpler, quantifiable format that is easier to apply. This review has some limitations. First, while our search strategy was quite broad, our inclusion criteria were strict, which may have limited the number of studies that we identified and synthesised. We aimed to clearly demarcate the economic analyses carried out within healthcare implementation and improvement interventions research—and to explicitly include papers that included both costs and benefits, and so did not include cost-only studies. We also only considered papers reported in English. Taken together, these criteria are stricter than those applied to prior reviews, which were more inclusive of qualitative outcomes and costing studies.Utilise published guidance on conducting economic evaluation in implementation research and quality improvement projects. Existing implementation frameworks  make refInclude detailed consideration of the measurement of the resource implications and ‘hidden’ costs relating to wider support activities required to initiate service improvement or to implement evidence into practice .Ensure that economic methods become fully integrated into the application of more recent methodological advancements in the evaluative design of improvement and implementation strategies, including ‘hybrid’ designs that seek to jointly test impact on implementation and patient outcomes. This would also provide an opportunity to explore the inter-linkages and relationships between implementation outcomes and economic measures of impact and the cost-effectiveness of improvement and implementation strategies.While most of the economic studies included in this review were both ex-post and empirical, we would also highlight the value of ex-ante economic evaluation in policy-making contexts. This could be informative either at the early phase of an improvement or implementation project, to guide choices over which options are most likely to yield a cost-effective use of resources (and to rule out those that are likely to be excessively costly compared to expected benefits), or for quantifying the benefits and costs of spread of best practice and delivery at scale.Finally, we would strongly recommend use of published guidelines and quality assurance frameworks to guide both the design and reporting of economic evaluations. Examples include the QHES framework (used here), the Consolidated Health Economic Reporting Standards (CHEERS) guidance  or the DOur review demonstrates an increasing number of health economic evaluations nested within implementation and improvement research studies, which further appear to be improving in methodological quality in recent years. Based on our review, we offer the following recommendations and areas for improvement in the continued application of health economic methods to improvement and implementation science evaluative research:Economic evaluation can inform choices over whether and how resources should be allocated to improve services and for implementing evidence into health care practice. Our systematic review of the recent literature has shown that the quality of economic evidence in the field of improvement and implementation science has improved over time, though there remains scope for continued improvement in key areas and for increased collaboration between health economics and implementation science.


The use of non-cholesterol sterols as biomarkers for cholesterol metabolism is well established in health-related topics. However, their roles in various metabolic conditions need to be investigated, especially since dietary interventions and pharmacological treatments can affect cholesterol metabolism due to their underlying mechanisms. This rationale highlights the importance of the systematic review entitled “Non-Cholesterol Sterol Concentrations as Biomarkers for Cholesterol Absorption and Synthesis in Different Metabolic Disorders: A Systematic Review” by Mashnafi et al. published in a recent edition of Nutrients . NeverthMashnafi et al. retrieved the articles from three important databases; however, their search was limited to only English language and cross-sectional study designs. These limitations narrow the search literature and risk missing many relevant studies. Various other languages and study designs could have improved the comprehensiveness of the findings . In addiMoreover, there is no evidence to demonstrate that the authors registered their protocol or proof to show that they used any structured guidelines in the analysis such as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, which could ensure adequate reporting of results. Following these guidelines could minimize bias, improve the quality of the review, and enable future updates ,5. WhileWell-designed reviews must incorporate relevant articles and use transparent, reproducible, and objective methodological approaches in order to be useful for informing clinical decisions and guiding policymaking. However, the presence of methodological flaws affects the quality of the evidence and the accuracy of conclusions. Therefore, to obtain a high-quality systematic review, authors should follow guidelines such as those recommended by the Cochrane Collaborations or the International Committee of Medical Journal Editors.