PRISMA statement. From 1759 titles identified, 81 full text studies were reviewed and key findings outlined for impetigo, scabies, crusted scabies and tinea. Improvements in primary care and public health management of skin infections will have broad and lasting impacts on overall quality of life including reductions in morbidity and mortality from sepsis, skeletal infections, kidney and heart disease.We conducted a systematic review of the treatment, prevention and public health control of skin infections including impetigo, scabies, crusted scabies and tinea in resource‐limited settings where skin infections are endemic. The aim is to inform strategies, guidelines and research to improve skin health in populations that are inequitably affected by infections of the skin and the downstream consequences of these. The systematic review is reported according to the  Children in developing countries and other resource‐limited settings bear a disproportionate burden of skin infections, owing to poverty, poorer living conditions, normalisation and limited access to primary healthcare Staphylococcus aureus and Streptococcus pyogenes  lead to morbidity, mortality and socioeconomic costs via invasive infection S. aureus has a global incidence estimate of 20–50 cases/100 000 population per year with a case fatality rate of 5–30% Primary infection with impetigo and secondary bacterial infection of scabies, crusted scabies and tinea with the bacteria Systematic reviews of skin infection treatments that have only included randomised clinical trials (RCT) This systematic review is reported according to the Preferred Reporting items for Systematic Reviews and Meta‐Analyses (PRISMA) statement The Cochrane Collaboration's tool for assessing risk of biasTwo reviewers independently scored for methodological quality of clinical trials using The data are presented in a narrative synthesis. Meta‐analysis was not performed due to the heterogeneity of studies. Calculations were performed using STATA13 . For reading ease, results are presented in common theme groups in each area of clinical treatment or public health prevention and control relevant to skin infections in resource‐limited settings. As many population‐based studies incorporate multiple strategies such as health education, treatment and hygiene practices, it is recommended that all evidence is considered by the reader as a whole. We used the GRADE approach to rate evidence across studies for specific clinical outcomes to link evidence‐quality evaluations to recommendations in clinical guidelines  2C)  add benefit in sustaining a reduction in scabies prevalence alone  was followed by randomisation of male boarding school students to a scabies control programme  or control 1A) 2B) 2D) High‐quality evidence supports the use of oral co‐trimoxazole or intramuscular (IM) benzathine penicillin G (BPG) for the treatment of impetigo  High‐quality evidence supports daily hand‐washing with soap for the treatment and prevention of impetigo, with no benefit found for antibacterial soap over regular soap  and standard soap All studies on scabies treatment used clinical cure or symptom relief as end points.2B) 1A) 2C)2C) 2C) 2C) 1D).Seven studies compared topical anti‐parasitic agents for scabies P < 0.05 vs. 30%, P < 0.05) whilst cure at 4 weeks was universal for all three agents High‐quality RCT evidence from an Iranian hospital OPD found that two applications of 5% permethrin achieved a superior clinical cure (85%) compared to 1% lindane (49%), Practice point Box: How is it best to apply topical scabicides?Twenty‐nine studies incorporated a topical scabicide/s, mostly permethrin. Table . One stu1A) Moderate to high‐quality evidence supports the use of oral ivermectin or topical permethrin for the treatment of scabies  1B) 1B) There is moderate quality evidence for MDA to control scabies in resource‐limited communities  Moderate quality evidence that cold cream can be used as an adjunct to topical sulphur for scabies  2C), however, high‐quality studies comparing treatments during outbreaks are required.There is low‐quality evidence for treatment of household contacts for the community control of scabies  1B) 2C) Moderate quality evidence supports oral ivermectin with topical keratolytics and topical antiparasitics for crusted scabies , found 40% achieved complete cure at 4 weeks Moderate‐quality evidence from a retrospective study used a standard treatment protocol in Australian Aboriginal inpatients with crusted scabies achieving 55% without recurrence at 8 years Low‐quality evidence supports topical BB, regular keratolytics, moisturiser and regular screening for new lesions in home‐based case management to prevent crusted scabies 1B) Moderate quality evidence for griseofulvin, terbinafine and fluconazole having similar efficacy for tinea capitis  2C) Low to moderate quality evidence for topical sertaconazole, butenafine, miconazole or clotrimazole over other agents for tinea corporis  1B) 2D) For tinea unguium, moderate to high‐quality evidence recommends oral terbinafine  Daily soap use may be of benefit in the treatment of tinea capitis and tinea corporis. This is recommended in combination with anti‐fungal treatment  2C) An adequate supply of water for washing and cleaning will reduce the burden of impetigo and scabies  Programmes to improve housing may assist in the prevention and control of skin infections in resource‐limited populations  treatments of tinea in a range of resource‐limited populations would be of benefit to make recommendations applicable to real life and uncontrolled settings at the individual and population level. Future integration of treatment of tinea into comprehensive skin disease control programmes that address scabies and impetigo may be a way forward.Despite practical advantages, we found limited evidence for environmental interventions to control skin infections. Although sound attempts to evaluate housing programmes have been made Although 1759 non‐duplicate studies were found for potential inclusion in this systematic review, most were excluded prior to the final appraisal of 81 studies meeting the full inclusion criteria (see Figure A summary of the evidence‐based recommendations for skin infections in high‐burden contexts also highlights the need for further rigorous, experimental studies to fill the evidence gaps. Pragmatic, practical, high‐quality, well‐funded RCTs are essential in the settings where the findings will have external validity if meaningful progress is to be made towards reducing the gap in skin health outcomes between the rich and poor. Acknowledging that RCTs may present ethical issues for some groups Table S1. List of studies included in the systematic review.Table S2. Risk of bias table with overall quality ratings using the GRADE approach for included experimental and controlled studiesTable S3. Risk of bias table with overall quality rating using the GRADE approach for included observational studiesTable S4. Method of application of topical scabicides in 29 included studiesAppendix S1. Definitions for Indigenous peoples and Income groupings usedAppendix S2. Evidence Summary and Recommendations for skin infection‐related research to guide practice in resource‐limited settings.Data S1. PRISMA ChecklistClick here for additional data file.


Severe traumatic brain injury (TBI) continues to represent a global public health issue, and mortality and morbidity in TBI patients remain substantial. There are ongoing international collaborations to provide guidelines for perioperative care and management of severe TBI patients. In addition, new pharmacologic agents are being tested along with cognitive rehabilitation to improve functional independence and outcome in TBI patients. This review will discuss the current updates in the guidelines for the perioperative management of TBI patients and describe potential new therapies to improve functional outcomes.In the most recent guidelines published by The Brain Trauma Foundation, therapeutic options were reviewed based on new and revised evidence or lack of evidence. For example, changes and/or updates were made to the recommendations for the use of sedation and hypothermia in TBI patients, and new evidence was provided for the use of cerebrospinal fluid drainage as a first-line treatment for increased intracranial pressure (ICP). In addition to the guidelines, new ‘multi-potential’ agents that can target several mechanisms are being tested along with cognitive rehabilitation.The major goal of perioperative management of TBI patients is to prevent secondary damage. Therapeutic measures based on established guidelines and recommendations must be instituted promptly throughout the perioperative course to reduce morbidity and mortality. Traumatic brain injury (TBI) is a major cause of death and disability with large direct and indirect costs to society. It affects roughly 3.3–5.3 million people per year in the USA, and the annual direct cost of TBI has been estimated to be $9.2 billion per year ($13.1 billion in 2013) •. AdultsIn 1995, the Brain Trauma Foundation approved guidelines for the initial resuscitation of severely head-injured patients and treatment of intracranial hypertension recognizing the need to standardize care to improve outcomes . The. The6]. The general principles of early management are to maintain adequate oxygenation, stable cerebral perfusion, glycemic control, and maintenance of electrolytes. The clinical management goal in TBI patients is to initiate timely and appropriate therapy to prevent secondary brain injury.http://www.braintrauma.org/coma/guidelines. Recent updates in the guidelines reflect the most current evidence. The primary focuses of the 4th edition were to integrate TBI-specific, evidence-based recommendations with clinical best practices for trauma patients and to provide guidelines or suggestions where evidence is insufficient. Details on the changes within each topic are listed in the latest edition of the guidelines and are reported in the sections for each topic in the guideline document.The current 4th edition of The Brain Trauma Foundation Guidelines for the Management of Severe TBI can be found at Carney et al. .4th edition examined 102 new articles which were used as evidence to update the guidelines [4th edition of the guidelines, https://www.braintrauma.org/coma/guidelines. Basic information about the studies is provided and includes study design, number of patients, and data class. More specific details, including outcomes and results, also are included in the evidence tables and narrative in this document. The authors state that there will be no 5th edition. They are moving to a “Living Guidelines Model” of continuous monitoring of the literature with rapid updates online when warranted [The Brain Trauma Foundation guidelines published in the idelines ••. Thesearranted ••.The updated guidelines for medical management of TBI patients were reviewed with the understanding that there is insufficient evidence for many of our current clinical practices , 8••. HoThere is no doubt that the major goal of perioperative management for TBI patients is to prevent secondary damage. Therapeutic measures based on established guidelines and recommendations must be instituted promptly throughout the perioperative course to reduce morbidity and mortality. The use of new therapeutic agents in combination with intensive rehabilitation efforts shows promise for reducing morbidity in this high-risk population.


A gap between the attitude towards evidence-based medicine (EBM), knowledge and awareness has been reported among physicians from different parts of the world. However, no investigation on Romanian physicians is available in the scientific literature. Our study aimed, firstly, to assess EBM awareness and the knowledge used by Romanian physicians, and, secondly, to compare resident trainees with specialists.Romanian trainee and specialist physicians were invited to participate in this cross-sectional study. The study tool was an online questionnaire designed to explore their awareness, knowledge, usefulness, the attitude in medical documentation, and the use of professional EBM resources. Data were collected by Google Form from January 1st to April 30th, 2017, respecting the responders’ anonymity. Two groups of physicians were investigated as trainees and specialists, respectively. Descriptive statistics  was used to describe the survey-related variables. Statistical significance on qualitative data was calculated with the Chi-square test, Fisher’s exact test, or the Z-test for proportions.Two hundred and 50 physicians participated in this study . In both groups, a significantly high percentage was represented by women as compared to men . The correct definition of EBM was identified by most respondents (75.6%). Affirmatively, both trainees and specialists always looked at levels of evidence when reading scientific literature, but a small percentage  adequately identified the uppermost types of evidence in the hierarchy. Almost a quarter of the respondents shared the name of mobile EBM resources that they used to support the daily practice. Only six out of the 49 listed mobile resources met the EBM criteria.The participants proved to have limited knowledge of EBM and a positive attitude towards the concept. They made use of mobile medical resources without understanding which of these were evidence-based. Evidence-based medicine (EBM) is the medical practice approach designed for optimizing decision-making by emphasizing the use of evidence supported by systematic and valid medical research. Evidence-based medicine starts from the premise that evidence of the highest quality, yielded from meta-analyses, systematic studies, and randomized clinical trials can offer accurate recommendations concerning individual medical decisions . AccordiAguirre-Raya et al. reported in 2016 the perception of EBM among medical students, interns, and specialists and reported a high global index of self-perception 75%), but this proved not to be supported by the global index on knowledge 19%) %, but th, Egypt % %, but , BelgiumMedical applications that run on the smartphone could be an important source of information for EBM. Mobile medical applications emerged in 2008 and are available through dedicated stores  . A studyLittle is known about the clinical use of EBM in Romania. The few available articles are reviews , 18 or aOur study aimed to assess awareness, information and daily use of evidence-based medicine among Romanian physicians.A cross-sectional and descriptive-analytical study was conducted from January 1st to April 1st, 2017.The participants in this study were physicians  working in healthcare institutions in Romania. The graduates become trainees (or resident physicians) whenever they achieve at least 60% of the maximum score in the national examination (200 multiple choice questions answered within 4 hours). The residency period may vary from three to 7 years, depending on the specialty . A specialty exam ends the residency period and the trainees can opt not to do this exam and to start a new residency; these participants were considered in our study as trainees.The questionnaire consisted of three sections. Section A consisted of 13 questions referring to awareness, knowledge of evidence-based medicine, and knowledge of EBM resources. Section B consisted of 11 questions that referred to mobile medical applications . Section C consited of questions referring to the socio-demographic characteristics of the respondents  to avoid multiple participation.The respondents were divided into two groups for analysis, namely: trainees and specialists. The respondents in training were considered trainees, irrespective of whether they were doing the first or second specialty.p-value < 0.05.Qualitative data were presented as numbers and percentages with associated 95% confidence intervals   and wereThe mobile applications used and shared by the respondents were assessed to see whether they respected the evidence-based principles. Any apps that met the following three criteria were considered evidence-based medical applications: references supported the provided information, the degree of recommendation was specified, and the level of evidence was present.Data from 250 participants aged 24 to 63 were analyzed. The majority of respondents were, as expected, trainees. The majority of participants had only one specialty 211/250) and 14 participants were doing the second (13/250) and third specialty (1/250), respectively. The main characteristics of the respondents are presented in Table 1/250 andThe graduation year of the respondents varied from 1978 to 2016; most of the trainees graduated from the Faculty of Medicine 5 years prior to the year when the study was conducted .First year trainee physicians who participated in the study presented the highest percentage (35.8% [28.8 to 43.5]), while the smallest percentage was witnessed by trainees in the 5th (8 participants) or 6th (one participant) year of training.The assessment of EBM self-evaluation and knowledge showed no differences between the respondents when the trainees were compared to the specialists Table .Table 2The majority of respondents declared that they always looked at levels of evidence when reading scientific literature, but fewer than 6% adequately identified the uppermost types of evidence in the hierarchy Table .The financial aspect (39.2% [33.2 to 45.6]) and accessibility  were the main reasons why the use of free sources of professional information was preferred. Sixty-eight of the respondents (27.2% [21.6–33.19]) pointed out that the accuracy of the information in paid scientific sources was higher as compared to free resources, but without providing any arguments. This result strictly reflects the perception of the respondents since the accuracy was not tested.p-value = 0.19). The characteristics of the medical apps used by the groups are summarized in Table p-value = 0.001) used medical applications for disease aetiology (37/170), as compared to the specialists (4/80).As expected, most of the respondents used a smartphone (96.8% [94.0 to 98.8]), with no difference between trainee and specialist respondents , chose to share the medical apps/online resources used in their daily practice or sources of lifelong professional education, resulting in a list of 49 distinct resources. The most frequently listed professional resource was Medscape . Six (most of which are guidelines) out of the 49 listed resources provide access to evidence-based medical literature  as well as in the specialists, without any differences between these two groups. However, the respondents have a positive attitude towards the EBM concept. The mobile medical resources are universally used by all respondents, but a small number of the listed mobile EBM resources is evidence-based.A significantly high percentage of women in the investigated sample reflects the gender distribution of graduates in Romania , 26. A lThe investigated sample had a similar distribution of demographic characteristics of trainees and specialists regarding their workplace and specialty, with most of respondents having a medical specialty . The predominance of medical specialties among respondents of EBM surveys was previously reported .With few exceptions, trainees and specialists showed similar results regarding the EBM self-perception, knowledge, and attitudes towards evidence-based practice. In our sample, a significantly higher percentage of trainees received the information on EBM from their teachers. Similarly, a significantly higher percentage of trainees as compared to specialists were aware of the use of EBM as a source of knowledge and a way to know the structure of a scientific article.Similar results were previously reported regarding the EBM self-assessment as well as the utility of evidence-based practice and the use of the EBM concept in the daily activity , 28. OurIt is widely recognized that accurate and valid scientific evidence is value-laden , but todSimilarities between trainees and specialists were observed regarding the type of medical apps, regarding the situations when these tools were used, and the perception vis-à-vis to their usefulness in healthcare. There were also differences, though. Compared to specialists, trainees had a significantly more frequent use of medical apps out of curiosity and for individual professional study at home. A more frequent use of the disease aetiology apps by trainees, as compared to specialists, which was identified in our study, could be explained by the trainees’ lack of professional experience. Furthermore, a higher percentage of trainees pointed out the absence of scientific references to sustain the evidence and the non-functional application as the main drawbacks of medical apps. Some of the differences may be related to the specialists drawing on higher clinical expertise and clinical pattern recognition, both of which being parts of an evidence-based practice approach. The absence of scientific references and use of non-functional apps by specialists could be explained by the education received by trainees as well as by their eagerness of trying more applications. A minimal number of the medical apps listed by the respondents met the EBM criteria (6/49).Medical apps have brought many benefits to the medical field, namely: chiefly faster decisions, with lower error rates, higher quality medical information, accessibility to it , and supThe main limitation of our study is related to its design. Several issues could be listed, related to the sampling method, data collection, and the content of the survey. Firstly, a non-probabilistic method was used in our study to identify the sample, so the results obtained need to be carefully interpreted. According to the physician medical code, a probabilistic sampling method, such as the simple or stratified by age random method, could be a better solution in order to identify the respondents. Hence, this will closely reflect the population of Romanian physicians, allowing the generalizability of the results. Secondly, the use of Facebook groups as a method to invite the target population to participate in the survey could induce a selection bias, and thus, the investigated sample is not necessarily representative for the Romanian physicians. The largest demographic groups of Facebook users worldwide are represented by 18–27 - year - old women, and 25–34 - year - old men, respectively . In thisConsequently, the reported results have a limited impact on the population of Romanian physicians, thus the behaviour of young physicians outweighing the actions of senior physicians. The use of the random sampling method by considering all Romanian physicians and sending a printed survey by post or an individual e-mail invitation with recall could engender a more realistic picture of the use of EBM in their daily practice by Romanian physicians. Thirdly, the survey that was used evaluated the respondents’ EBM knowledge and the self-perception behaviour in connection with the use of medical evidence, either printed or online. A more in-depth assessment based on problem-based scenarios would allow a reli able assessment of the EBM knowledge and their application in clinical practice. Furthermore, since the “survey approach is a research strategy, not a research method”, it was intended to evaluate “how things are at a specific time” , and thuDespite its limitations, our study has had several characteristics of value. Firstly, our results provided a snapshot regarding EBM self-assessment and knowledge in the group of respondents. Our result supports the need for evidence-based practice training at the level of undergraduate students, trainees as well as specialists. The onsite or online courses, even during scientific meetings and conferences, with the translation of EBM information/knowledge into problem-based learning, could ensure a better understanding of the concepts. The shift from the use of evidence based on the type of the article to the use of medical evidence based on their quality is a must and could be done through more thorough EBM training. Integrating EBM in the daily health care practice could serve as a supplementary resource for knowledge, in addition to guidelines, which are very helpful for clinical decision-making whenever a specific case not covered by the clinical guidelines needs to be managed.Most of the participants in our study were able to identify the correct definition of evidence-based medicine but failed to recognize the levels of evidence correctly. The participants’ attitude towards EBM was positive. Mobile medical apps were used in the daily clinical activity, but the respondents could not differentiate between the apps, which comply and those which do not comply with EBM principles. The changing nature of research evidence supports the move beyond the EBM training to quality assessment regardless of level, grade or evidence.Additional file 1. List of Facebook groups invited to participate in the study.


Related to the Dutch nursing home quality framework implemented in 2017, a staffing guideline was developed, aimed at assisting nursing homes to adequately staff their wards. For the Dutch Ministry of Health, we investigated the evidence base of this guideline. We critically reviewed scientific literature (n=65) and interviewed (inter)national experts (n=8) and potential guideline users (n=5). We found that departing a quality improvement dialogue directly from teams, clients and their families is positive. However, weaknesses were identified as well. Several risks exist for employees to adequately assess resident needs. Furthermore, buy-in is needed from board level to develop a vision on which competencies and amount of staff are needed to fulfill these needs. Examples of guideline improvement recommendations were assisting teams in how to assess resident needs, critically reflect on care provision and considering a role for (top)management. Overall, it was concluded that the value of the guideline was limited.


Local public health service delivery and policy-setting in England was overhauled in 2013, with local government now responsible for the complex tasks involved in protecting and improving population health and addressing health inequalities. Since 2013, public health funding per person has declined, adding to the challenge of public health decision-making. In a climate of austerity, research evidence could help to guide the more effective use of resources, although there are concerns that the reorganisation of public health decision-making structures has disrupted traditional evidence use patterns. This study aimed to explore local public health evidence use and needs in this new decision-making climate.Semi-structured interviews with Public Health Practitioners across three Local Authorities were conducted, with sites purposefully selected to represent urban, suburban and county Local Authorities, and to reflect a range of public health issues that might be encountered. A topic guide was developed that allowed participants to reflect on their experience and involvement in providing evidence for, or making a decision around, commissioning a public health service. Data were transcribed and template analysis was employed to understand the findings, which involved developing a coding template based on an initial transcript and applying this to subsequent transcripts.Increased political involvement in local public health decision-making, while welcomed by some participants as a form of democratising public health, has influenced evidence preferences in a number of ways. Political and individual ideologies of locally elected officials meant that certain forms of evidence could be overlooked in favour of evidence that corresponded to decision-makers’ preferences. Political involvement at the local level has increased the appetite for local knowledge and evidence. Research evidence needs to demonstrate its local salience if it is to contribute to decision-making alongside competing sources, particularly anecdotal information.To better meet decision-making needs of politicians and practitioners, a shift in the scope of public health evidence is required. At a systematic review level, this could involve moving away from producing evidence that reflects broad global generalisations about narrow and simple questions, and instead towards producing forms of evidence that have local applicability and can support complex policy-focussed decisions. The other thing to bring to bear is about ways of working and there is a push here, for instance, to be much more action focused and much more agile…. just get it done.R: Participants spoke freely and sometimes vehemently about how the change in decision-making structures had impacted upon decision-making processes. For a small number of respondents, the transfer of public health commissioning and policy-setting into LA, and the consequent involvement of local politicians in decision-making, brought benefits to public health decision-making, both hypothetical and realised. The politicisation emphasised in earlier studies  was viewOther benefits were also described by participants around the increased scrutiny that local politicians could bring to bear on the evidence underpinning large commissioning decisions. This was expressed in terms of the alternative skills, experience and views that decision-makers with no formal public health training could bring to bear on assembling and interpreting evidence. However, there was greater consistency across the majority of participants that a heightened political climate in public health decision-making had, or potentially could, interrupt the flows of evidence to influence policy and practice in three key ways, namely (1) through imposing an ideology to local public health commissioning and policy-setting that was not always commensurate with need; (2) through necessitating evidence to be ‘packaged’ to meet the needs of local decision-makers; and (3) through changing the type of evidence used in order to provide a persuasive case for action.The political orientation of a LA was described as influential in the types of services that were commissioned. For example, a more libertarian political orientation was implicitly viewed as being associated with a more medicalised model of public health. This discouraged the commissioning of services that could be viewed as ‘mollycoddling’ or ‘lecturing’ people, as explained by one participant who attributed the discontinuation of smoking cessation services in a neighbouring LA as directly linked to it being under Conservative (centre-right) control.I think that in this context in [Local Authority] what we’re trying to achieve as a public health team is fairly strongly in line with the political views of the councillors that we work with…so I haven’t encountered a situation in which it hasn’t been politically convenient to commission something that we have been pushing on based on the evidence.… But it’s really clear that it can and it does happen in other places as well.”“In one site, the impact of political ideology on public health decision-making was generally described as moderate, although it was recognised that local politicisation of public health could be problematic in other areas.reflective kind of space” that public health has traditionally occupied.Yes the councillors of course, they all come from different backgrounds, but they are usually a lot older and they like their libraries and they like the fire service and then you’ve got to talk about sex with them and that’s very difficult. But this is where we rely heavily on our director who has worked fastidiously on getting this message across which is: it [sexual health/ill-health] does exist, and you do need to know about it, and this is the reason why. And actually [what] we can put with that - which always gets the ears open - is the cost associated with the problem…“…the other one we use is if you don’t spend this pound [£] on contraceptive services it’s going to cost you members of the council through housing and education you know….so I know you don’t want to talk about sex but actually involves really simple things and really cheap things and will cost a fortune if we don’t do it.”In a second study site, participants described the way in which the narrow sociodemographic profile of local elected officials could necessitate constructing the case for a service in a different way. For example, as described below, the terms of the argument for providing sexual health services changed from protecting and promoting the psychological and physical wellbeing of the population, to an economic argument around the consequences of ‘unchecked’ sexuality and fertility. In another instance, changing the terms of the debate to a more ‘business focussed’ argument was described as being in conflict with the “In a final study site, two participants described, the negative impacts that electoral accountability had in terms of the focus of public health issues. This was not related to ideology with respect to Labour or Conservative allegiance, but more broadly the ideology of being ‘political’. This extended to claims that public health issues could be deliberately overlooked because of concerns about political reputations and electability.The electoral cycle and political make-up of the council was also described as changing the way in which public health was conceptualised by some participants. Areas with a stable political make-up were those perceived as being able to take more electorally risky commissioning decisions around upstream interventions, and to be able to more fully employ a socioecological  model of public health.I think sometimes it’s the case of getting them [decision-makers] to pay attention to the evidence at all and saying: ‘I know you think that sounds like a good idea but actually if you look at the evidence it won’t work because so and so’. I think sometimes there is that thing in actually convincing them to look at the evidence in the first place or even to think about evidence when something might look like a good idea on face value.”“Several participants described instances where local elected officials relied on tacit knowledge and wisdom in guiding their decision-making. Across sites, participants described the way in which local elected officials would hold the face validity of evidence and ideas in esteem, and described how research-based evidence could sometimes play a secondary role.I: So which types of evidence have you found are more attractive to politicians?“Anecdote! (laughs). ‘Oh I saw this that and the other in my constituency’ that kind of thing.”As is common in previous studies, participants described instances locally elected officials exhibited preferences for anecdotal evidence.However, local politicians’ preferences for anecdotal evidence was also viewed sympathetically by several participants, who viewed utilising knowledge gained directly from engaging with the electorate as important to their roles.I: That’s interesting, so what do you mean by presenting it [research] in an appropriate way?“R: I mean just because most of those members will not have a public health background and that they …their expertise generally lies elsewhere. Some of them come from a health and social care background and so on, and so will have more of an understanding of how things work within a public health system, but others…. So yeah that’s what I was thinking. Producing reports and things that are jargon free on what needs to be done from the research evidence without going into unnecessary detail and so on. So I think that has to be considered.”Most participants discussed ways in which they presented evidence differently for decision-makers who lacked public health training.But we need to develop relationships with the local cabinet member who has responsibilities for various areas that we want to influence, and that’s much more of something that we have had to learn over time. So, what we do is that… we do briefings to our cabinet members on certain topics and to ensure that they are up to date, they know what the state of play is, they know what the evidence is and… are kind of on board with our way of thinking.”“Some participants described that they had become more ‘politically’ aware in their roles than was previously the case, and had changed the way in which they worked to include a greater focus on developing relationships with decision-makers before and during the assembly of evidence in order to better guarantee that the messages did inform commissioning and policy-setting.I think people like those. I think there’s not enough maybe. So, people love those infographics – to spend £x on gives £x – in public health we need more. But in public health I think it’s harder...”“Two instances were described where the increased political involvement did change the type of evidence that was drawn upon. Firstly, most participants discussed the persuasiveness of economic evidence in building up a case for commissioning a service or policy among local decision-makers. Economic evidence, and particularly return on investment evidence, fulfilled other properties also highly regarded by participants, including certainty and interpretability, and was viewed as being suited in communicating complex messages.The cabinet meeting which I attended one of the things that was raised was that we had evidence on the impact of obesity on cost to the NHS and also on health impact and so on but we didn’t have evidence on the impact of obesity on social care and we didn’t have evidence of impact on things that the council directly pays for and that was….well it was still approved…. but it would have made our case stronger if we were able to talk about return on investment and related it to what the council pays for.”“Despite greater demand and usage of economic evidence, and its value in conveying complex messages, participants occasionally described its weaknesses. In some cases, critiques were levelled at the robustness of the underlying assumptions and data when LA sought to generate their own economic evidence. Alternatively, the available economic evidence was critiqued for providing narrow conceptualisations of ‘return’ and ‘investment’ that did not reflect LAs’ broad remit across different services. In addition, economic return on investment evidence was described as showing the value of short-term investments and the resulting long-term savings, which was contrasted with participants’ experience of LAs’ requirement of finding short-term savings on long-term investments.Secondly, qualitative research appeared to occupy an uncertain place and was not uniformly viewed as integral to public health decision-making, perceived by some as an adjunct to enrich or enliven other forms of evidence. One participant suggested that qualitative evidence was deliberately omitted from briefings prepared for locally elected decision-makers because of perceptions that decision-makers would conflate qualitative research with anecdote, the consequences of which could see decision-makers substitute more robust qualitative evidence with their own anecdote, which in turn may be biased or prejudiced. Despite some reservations around how qualitative research should be ‘packaged’ for decision-makers, most participants who discussed qualitative evidence were able to cite examples where this form of evidence had made a valuable contribution in decision-making in uncovering information about hard-to-reach groups or in providing evidence that was otherwise unobtainable about why services had thrived or faltered.We take a project management style approach. We set out a timeline and we give ourselves six months to do evidence and then we write out the spec. [specification].”“Participants described how the use of evidence was inextricably tied to other processes occurring within public health departments that were structured and rigid. Commissioning services was described as a continual and central function of public health departments, and regardless of their actual role, all participants were familiar with the structured processes involved. This meant that gathering evidence to support decision-making, specifically with reference to commissioning, was viewed by some as a contained process, regardless of ambiguities or uncertainties in the evidence.One of the consequences of a structured approach was that evidence tended to be frontloaded, with little flexibility to incorporate additional evidence after the initial service specification. Potential service providers were required to offer evidence of their capacity and experience in providing a service, although there was no expectation that potential providers would make available published research evidence to support a particular course of action or interpretation of a service specification.R1: So, when I think about the sort of style of our HWS [Health and Wellbeing Strategy] - the kind of style of writing - we don’t really cite… there is almost really nothing cited or referenced in that… and part of that is because… the kind of Joe Bloggs is not going to follow up on that sources and references. Actually, what they are interested in is … what the priorities are, what … how that is going to influence the service provision, that kind of thing…“R2: …because if you produce research [it] doesn’t mean that decisions are made based on what you found. I think that, in fairness, we have to use that situation where you know that decision-making is always going to be local, and sometimes use of [people’s] voice tends to trump [research evidence].”Evidence was viewed as a specialism of public health professionals, and of little interest to the public or other stakeholders. For this reason, the provenance of evidence was omitted in public-facing documents. Nevertheless, public involvement in decision-making was viewed as important, although in one description, the involvement of local people in decision-making was directly viewed as competing (and not complementary) with research evidence in influencing decision-making.There is quite a lot of evidence out there so sometimes it’s about how it’s communicated and how you get access to the evidence and you’d look at how it applies. Sometimes it’s about how it fits with your schedule and timing. So we’ve got a timetable for our commissioning and within that I’m looking at the overall commissioning programme for the public health team but within that there are service specialists who are going on training, keeping up to date, and making themselves aware of evidence.”“Time pressures prevented some participants from engaging with research evidence to the degree that they wanted, both in terms of a lack of time and the timeliness of evidence. Rigid commissioning processes placed added emphasis on the timeliness of evidence.I wish we had up to date data there but the ONS [Office for National Statistics] data only comes out every three years….What we’ve done here is we’ve started groups at the [local] level simply because we have such a lag in data, so we actually need to know what is going on at this moment in time, so that’s what we’ve actually done [here].”“A lack of timely evidence also meant that participants would occasionally develop their own solutions to sourcing evidence that better met their timescales.…And to be perfectly honest between ourselves and [lists a total of seven contiguous and non-contiguous authorities] – we’re very different. We have very different populations.”“Participants had a strong affiliation with their LA and maintained a strong organisational identity during interviews. This identity was constructed on the basis of differences from other LAs, even neighbouring areas, and was developed on the basis of differences in the local population demographics, and particularly ethnicity, as well as on the basis of particular facets of organisational culture. In contrast, few participants spoke of public health challenges or a distinctive epidemiological profile as a distinguishing feature of a LA.The big thing about the [named Local Authority’s] way of doing things is that everyone is really driven by actions and seeing impactful things change. I think that kind of evidence locally making an impact is much more powerful than having a NICE [National Institute of Health and Care Excellence] strategy. That’s what will get the attention of the CEO [Chief Executive Officer], the mayor and the lead member.”“Having evidence with local provenance was viewed as a key way of ensuring that evidence influenced decision-making within a LA. This was commensurate with locally elected decision-makers’ preferences, but was also tied to participants’ own conceptualisations of what made their LA unique.Looking at the population and thinking would that work here and how could that work here – those sorts of things. Definitely the demographics – I’d look at the ethnicity but more the economic situation of what was happening with the people – how busy they are. Because a lot of the public health study does rely on the people coming to us. The prevention side in particular is attracting people before an issue gets too large.”“Within both urban sites, participants described factors relating to ethnicity and economic status as determinants of whether evidence was salient.Within the more rural area there was greater emphasis on understanding differences within the LA between larger county towns and cities, and smaller pockets of rural public health challenges.But it’s interesting because a lot of people are going out doing initiatives based on the five ways to mental well-being1. When we did some research in [city] amongst the youngest single mothers they took one look at this at the thing they thought it looked like a bunch of middle-class nonsense. And there’s around in [city] in particular…well it’s a very individual place is [city], there’s very low levels of expectation and very low levels of beliefs in self-efficacy so it’s really important to get into the local population and to understand that mind set to see if this thing that’s been tested on a national level actually would work with the people that we wanted it to work with. And the outcome of having done that research is that we might use it as a framework for commissioning but even using the word well-being doesn’t resonate with the local population.”“Although the high value placed on local evidence may have stemmed from both knowledge of what types of evidence were influential with decision-makers, as well as participants’ own organisational identity, concerns about the generalisability of evidence were also driven by participants’ experience of where national understandings of public health failed to translate to a local level. The example below details one participant’s experience related to a specific policy around wellbeing , and the1Based on a New Economics Foundation Report [n Report .They [systematic reviews] pick up general principles that are self-evident anyway or they are so specific that there is little that is transferable. So a systematic review on dance among women over the age of 75 is quite interesting and potentially quite useful [but] that is not that helpful in helping us think how we spend our limited physical activity budget across a number of different options which might be competing for similar resources.”“Participants reported difficulties in sourcing evidence that reflected the broad remit of the LA and that situated local people and public health issues within broader systems of influence. This included difficulties in obtaining evidence that matched the complex sociodemographic profiles of local people. Participants were also critical of narrow conceptualisation of public health issues within the research evidence, which failed to address broad research questions of interest when setting policy and commissioning services.So it’s not all about having the same population – it’s about what was in place before you introduced this intervention. So here for example, we’ve got a really comprehensive stop smoking service and in [the next Local Authority] they don’t. So saying ‘if you reduced smoking by this much this is the impact you’re going to have’…. it just doesn’t mean the same thing because here to reduce smoking by that much it’s going to be really hard and it’s going to be the really hardcore smokers and if you do get it you’re going to get a bigger benefit. In [the next Local Authority] it could be people who were going to give up anyway – there aren’t any actual savings.”“One participant also described the focus within evaluation studies on comparing outcomes of intervention participants with usual care or no intervention, and the failure to take into account existing health systems, unhelpful.have then fallen to the wayside sort of thing because it’s not necessarily the highest priority on people’s to do list and the day job gets in the way in the council and then the attendance drops off and then it becomes a bit pointless.”“[These fora] Participants across sites appeared to value links with research and academic institutions and, when asked, could describe examples of when partnerships had worked well. Mixed fora of evidence generators and users were viewed as a valuable opportunity where both evidence generators and users could collaborate and share knowledge. However, one participant described how such groups were viewed as idealistic and were often started with good intent, only for this effort to fall behind at a later date.One participant described his efforts to improve collaborations with researchers, particularly in terms of obtaining support around the implementation of research evidence, but found that these efforts were often thwarted by a lack of sustained funding.…So that makes it more complex because the research of perspective is arguably over-funded and the implementation aspect is under-funded. So you [end up] doing a very robust evaluation of a very under-funded intervention which both researchers and those who have implemented the intervention will be aware of but they wouldn’t be any kind of resource to prevent that.”“The transition of public health from the National Health Service to local government control has had an impact on decision-making and evidence use patterns, although the nature of this is not uniform across LAs and not across PHP accounts.At its most basic level, the change to local government control has meant that locally elected council members now have ultimate decision-making power, and may be directly involved in policy-setting and commissioning decisions, particularly those involving large budgets. PHPs have responded accordingly in order to ensure that locally elected officials are informed in making decisions. This has included the repackaging of certain forms of evidence into a format that is more acceptable for locally elected officials, in line with broader debates around ensuring that research and evidence is open and accessible to broader public interest and scrutiny . It has PHPs also divulged that the involvement of local politicians in public health decision-making also entailed being mindful of their evidence use styles and preferences. This included engaging local politicians to look beyond the face validity of ideas and instead to engage more closely with the evidence base, responding to preferences for economic evidence, as well as offsetting a tendency for overreliance on anecdote. PHP responses to these demands were often sympathetic, and in many ways these preferences perhaps embody the democratic principles that increased political involvement at a local level would be expected to bring in terms of innovation, scrutiny and accountability in public health decisions and decision-making . For exaThe results of this study point towards local patterns of evidence needs that are unmet from the perspective of PHPs. Political involvement at the local level has reinforced an appetite for local knowledge and evidence. Research evidence needs to demonstrate its local salience if it is to contribute to decision-making alongside competing sources, particularly anecdotal information collected by local decision-makers from their electorate. Habitually, PHPs seek evidence that reflects the smallest possible geographic unit of ‘local’ in an attempt to locate evidence that is useful and implementable, although also describe several evidence requirements that are currently unmet. These unmet needs include evidence that can attest to its local credentials as well as evidence that is ‘mutlifactorial’ in nature and recognises the interdependencies in the way in which public health issues emerge and the actions that need to be taken in response to these. To better meet decision-making needs, a shift in the scope of public health evidence is required, and particularly at a systematic review level, through moving away from producing evidence that reflects broad global generalisations about narrow and simple questions, and rather towards a form of evidence that has local applicability and can support complex policy-focussed decisions.While this study is based on research conducted in the United Kingdom, and in England specifically, the experiences documented here may be generalisable to other settings where there has been a shift towards devolution of decision-making or a re-organisation of decision-making structures. Many countries have increasingly devolved or partially devolved healthcare systems; for example, in Europe, healthcare systems in Spain, Sweden, Denmark, Norway, and the Netherlands have notably high levels of devolved decision-making –28. SimiLimitations to the findings include that these data are based on practitioners’ own perceptions with no verification from other sources  and on a small sample of PHPs working across different roles across three areas. The breadth of the sample in terms of the different PHP roles across three different sites does potentially increase its generalisability in some ways, although it raises the possibility that depth of understanding was compromised for any one public health function and/or setting. The use of template analysis helped to identify when saturation was reached, and although new codes were generated as the template was applied to each new transcript, the number of new codes generated dropped substantially with each successive transcript analysed. Finally, our role as academic researchers enquiring about the use of evidence within public health decision-making could theoretically have influenced some responses .One of the intentions of moving public health (back) into LAs was that PHPs would be in a better position to influence the social determinants of health across other areas of LA responsibility . We are New models of evidence production, which recognise public health interventions and challenges as ‘complex systems’ composed of many different components that interact to produce an outcome, and attempt to identify the actions needed to change the system in favourable way , are an Alongside the shift in perspectives and methods described above, our research also signals that public health researchers should be prepared to, and be funded to, spend much more of their time working with PHPs to understand how their evidence can be implemented in local settings, avoiding the current ‘publish and run’ model of evidence production. Our findings also suggest that, while the efforts of organisations such as Public Health England to provide training and enhance the capacity of PHPs to interpret evidence are welcome , some ofResearch evidence is only one of many sources that contribute to public health decision-making , as echo


The aim of this study was to assess the quality of clinical practice guidelines of traumatic brain injury (TBI) and investigate the evidence grading systems.A systematic search of relevant guideline websites and literature databases  was undertaken from inception to May 2018 to identify and select TBI guidelines. Four independent reviewers assessed the eligible guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. The degree of agreement was evaluated with intraclass correlation coefficient (ICC).From 1802 records retrieved, 12 TBI guidelines were included. The mean scores for each AGREE II domain were as follows: scope and purpose (mean ± SD= 74.2 ± 9.09); stakeholder involvement (mean± SD= 54.6 ± 11.6); rigor of development (mean ± SD=70.1 ± 13.6); clarity and presentation (mean ± SD=78.4 ± 11.5); applicability (mean ± SD= 60.5 ± 13.6); and editorial independence (mean ± SD=61.7 ± 14.8). Ten guidelines were rated as “recommended.” The ICC values ranged from 0.73 to 0.95. Seven grading systems were used by TBI guidelines to rate the level of evidence and the strength of recommendation.Most TBI guidelines got a high-quality rating, whereas a standardized grading system should be adopted to provide clear information about the level of evidence and strength of recommendation in TBI guidelines. However, TBI guidelines vary in quality, comprehensiveness, and grading system, leading to difficulties with standardization of care, adaptation, and implementation. Despite this, a major criticism of the TBI guidelines is that they may not be appropriate for use in all locations due to differences in available resources. Although some previous studies have evaluated quality of existing TBI guidelines, they just have focused on the subsets of TBI severity such as mild TBI only–5 or reviewed only a limited number of TBI guidelines, and none of them focused on the grading systems of TBI guidelines adopted, which actually is very important to help guideline users, readers, and stakeholders to understand the confidence of estimate of the effects and the strength of recommendations. Moreover, according to Institute of Medicine (IOM) statement of guideline, some old TBI guidelines (published before 2007) evaluated by these studies had been abandoned in clinical practice as the recommendations were outdated.During the past 20 years, >30 TBI guidelines have been developed and updated from different organizations. We also compared the codes of evidence quality and strength of recommendation among different TBI guidelines.Hence, we conducted this study to assess and summarize the quality of all currently available international TBI guidelines by conducting a systematic review using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument.22.1This study conducted a comprehensive review of clinical guidelines using the AGREE II instrument. This study was performed in accordance with the guidelines from preferred reporting items for systematic reviews and meta-analyses (PRISMA).2.2https://www.nice.org.uk/guidance) and SIGN (http://www.sign.ac.uk/), and guideline databases such as GIN (http://www.g-i-n.net/) and NGC (https://www.guideline.gov/). Besides, we searched Google Search Engine as well as the references of all the obtained guidelines to include more potential guidelines.Systematic searches were performed in PubMed database from inception to May 31, 2018, combining the term “traumatic brain injury OR TBI” and a filter to identify guideline documents . We also searched the websites of guideline development organizations, NICE (Two reviewers (DBS and WKP) independently evaluated search results to determine inclusion or exclusion of references and extracted the general characteristics of each guideline. Disagreements were resolved by consensus or by consulting the third expert adjudicator (GTK).2.3The inclusion criteria were as follows: complete guideline text is available in English; guideline contains recommendations regarding TBI interventions; and the guideline should be published after 2007. If the guideline had updates, only the most recent version was assessed. For every guideline ultimately included, we thoroughly searched for accompanying technical and supporting documents to better inform our assessments. The following literatures will be excluded: duplicate guidelines, guidelines for patients, editorials, translations of guidelines, secondary or multiple publications, and short summaries. For multiple versions of guidelines, only the newest guidelines were included in the analysis and the older versions were excluded.2.4We used the latest version of the AGREE II instrument to evaluate each TBI CPG meeting our inclusion criteria. According to AGREE II handbook, each CPG was scored on 23 items within 6 domains. Domain 1 (scope and purpose) is divided into 3 items: guideline objectives, health questions, and population application. Domain 2 (stakeholder involvement) is based on 3 items: guideline development group, preferences of target population, and target users. Domain 3 (rigor of development) includes 8 items: systematic methods used to search evidence, criteria for selection, strengths and limitations of the evidence, methods for formulating the evidence, health benefits and side effects of recommendations, explicit links between recommendation and supporting evidence, expert reviewers, and updating guideline for future use. Domain 4 (clarity and presentation) includes 3 items: recommendations are specific and unambiguous, different options for management, and key recommendations. Domain 5 (applicability) includes 4 items: facilitators and barriers, advice/tools to implement recommendations into practice, resources for implications, and auditing criteria. Domain 6  is based on 2 items: editorial independence from the funding body and conflicts of interest of the guideline development members.,10 DBS and WKP were trained to use the AGREE II instrument through the online tutorials on the AGREE website.In this study, each TBI guideline was scored by 4 independent reviewers  according to AGREE II user manual. Among the 4 reviewers, DBS and WKP are senior doctors of neurosurgery; MWJ and LY are methodologists in guideline development. Besides, YL had rich experiences in the application of AGREE II and published a study about using AGREE II to assess clinical guidelines,The user manual defines each item and assists the user in determining a guideline's score for that item. Items were scored based on a scale ranging from 1 (absence of item) to 7 . Domain scores were calculated by summing item scores within each domain from each reviewer, and then standardizing them as a percentage of the maximum possible score. AGREE II protocol states that no overall score is calculated to determine if a CPG is recommended or not recommended. Instead, guidelines in this study were recommend if the guidelines have >4 domains scoring >50%.2.5The strength of recommendations and level of evidence of each TBI guideline were extracted if these guidelines adopted evidence grading systems.2.6 According to a previous study, the degree of agreement between 0.01 and 0.20 was deemed minor, 0.21 to 0.40 fair, 0.41 to 0.60 moderate, 0.61 to 0.80 substantial, and 0.81 to 1.00 very good. A value of P <.05 denoted statistical significance. All tests were 2-sided. Statistical analyses were conducted using SPSS version 19.0 .We performed a descriptive statistics analysis using the calculation of the total score by each reviewer and the score per domain. The number of recommendations and the percentage distributions among quality of evidence and strength of recommendation classes were determined. Agreement between each reviewer's scores was tested using a 2-way ANOVA with single-rater 2-way intraclass correlation coefficients (ICCs) with 95% confidence interval (CI) for each domain across all guidelines.33.1–24 met inclusion criteria  of CPGs focused on the early management of TBI.,16,20–23 Of the 24 assessed CPGs, 4 were developed by professional organizations,,15,23,24 2 were developed by nonprofit organizations,,20 2 by international committees,,21 and another 4 by national institutes or government organizations.,17,19,22 The detailed information of included guidelines was shown in Table Overall, 12 TBI guidelines were included in this analysis . The highest score was 88.9, from Brain Trauma Foundation and American association of Neurological Surgeons .3.3.3This domain contains items on the involvement degree of professional members, consideration of the views and preferences of the target population, and the definition of target users. Scores fluctuated remarkably with a mean score±SD of 54.6 ± 11.6. Five (38%) TBI guidelines scored <50%, of which the lowest was 40.2 from China .3.3.4This domain investigates the method and process of evidence search, grading, summary, and the formulation of the recommendations. The mean score and SD for this domain was 70.1 ± 13.6. All TBI guidelines scored >50%, of which the lowest was 51.3 from China .3.3.5This domain addresses the presentation and format of guidelines. The mean score and SD in this domain was 78.4 ± 11.5. The lowest score was 57.4 from Brain Trauma Foundation .3.3.6This domain evaluates the consideration of facilitators or barriers when implementing the guidelines and the monitoring criteria. The mean score and SD of this domain was 60.5 ± 13.6, among which 3 TBI guidelines scored <50, with the lowest score of 39.1 from Brain Trauma Foundation .3.3.7This domain considers funders and competing interests of experts involved in guideline development. The mean score and SD of this domain was 61.7 ± 14.8 and 3 scored <50%. The score among these guidelines varied a lot, the lowest score of 38.5 points came from China  and the highest score was 82.7, from Brain Trauma Foundation and American association of Neurological Surgeons .3.3.8This assessment concerns “the rating of body quality of the guidelines and whether the guideline would be recommended for use in practice.” According to the appraisal of the individual domains and overall scores, 10 TBI guidelines had >4 domains scored >50, and rated as “recommended” by the appraisers Table .3.3.9–24 adopted GRADE system , 2,18 used SIGN system , 1 used NHMRC system , 1 used USPSTF system , 1 used PNLG system , 1 used AAN system  and 1 used ACEP system . However, the codes of level of evidence and strength of recommendation in different grading systems varied a lot , Scandinavian Neurotrauma Committee , and Eastern Association for the Surgery of Trauma  were the 3 CPGs with best results. All of the TBI guidelines evaluated in this study were developed by high-income countries (HICs) and are therefore minimally applicable in resource-limited settings. Besides, the distribution of level of evidence and strength of recommendations varied significantly among different TBI guidelines.,29–30 This is likely attributed to the scientific rigor of developing a guideline, which typically involves a highly methodical approach. In general, the guidelines that were more recently developed or updated, and those that had undergone numerous updates, most consistently demonstrated the highest quality by AGREE II scores.Overall, the strong scores in the clarity and presentation, scope and purpose, and rigor of development domains have been reported in other systematic reviews evaluating TBI CPGs.–24 In a 2011 critical review of mild TBI guidelines by Tavender et al, the NSW 2006 TBI guideline got a worse score of AGREE II in all domains with the exception of scope and purpose domain when compared with the updated 2011 version. It is noteworthy to mention that new version of TBI guidelines also has the advantage of newer and more rigorous evidence-based medicine in addition to the availability of designing guidelines around the AGREE II format. Nevertheless, a frequently criticized area in our results, within the rigor of development domain, was the lack of procedures for updating the guidelines for quality improvement. Given the trend toward improved guideline quality with newer revisions, development of a quality improvement list may help to ensure quality of future TBI guidelines.Our analysis indicates an overall improvement in the above domains in the most current CPGs, consistent with other studies. which might be referred by TBI guidelines developers in the future.The AGREE II result may also associate with reporting of key information in guidelines, which indicated more attention should be paid to improve the reporting quality of guidelines. In 2016, the AGREE working group developed a new checklist for improving the reporting quality of CPGs,,33 Although there have been progressive improvement in guideline development, the domains of stakeholder involvement, applicability, and editorial independence remain weak, specifically when it comes to piloting interventions, addressing potential costs, barriers to implementation, and auditing for quality improvement. Recent studies suggested that successful implementation of guidelines could improve patient outcomes–36; however, applicability of guidelines to a given locale based on factors, such as availability and cost of resources, provider skills, and population needs and values, is critically important for successful implementation of guidelines in a manner that will improve patient care. Consideration of stakeholder involvement and applicability are imperative considering these domains are intrinsically associated with CPG implementation and translation to other settings such as LMICs.Older reviews have demonstrated limited stakeholder involvement in TBI guideline development, a trend that persisted in new versions. However, the various codes of evidence level and strength of recommendation could bring challenges to reach the target. As we know, most guidelines, especially evidence-based guidelines, applied grading systems to communicate clear message, quickly and concisely so as to help guideline users, readers, and stakeholders to understand the confidence of estimate of the effects and the strength of recommendations easily. The confidence of estimate of the effects reflects the extent to which confidence in an estimate of the effect is adequate to support a particular recommendation. And the strength of guideline recommendation reflects the extent of collective confidence that adherence to the recommendation will do more good than harm.,39 However, in our study, different grading systems with various systems of codes were used to communicate grades of evidence and recommendations in TBI guidelines, which could confuse the guideline users when using these guidelines. Therefore, a standardized grading system should be established to provide a clear information about the level of evidence and the strength of recommendation for TBI guidelines users, and the good news is that we find some guideline organizations such as Scottish Intercollegiate Guidelines Network (SIGN) and National Health and Medical Research Council (NHMRC) begin to adopt GRADE system instead of old systems in their new version of guideline development handbooks.,41It has been suggested that adaptation of existing guidelines to local situations may be a more valid and cost-effective means of achieving high-quality guidelines worldwide.4.1,43 Furthermore, our study could not establish the causality between the poor performance and the characteristics of TBI guidelines, matching current guidelines to future guideline updates (in a cohort study) would allow for better assessment of guideline quality than did our cross-sectional assessment.Our overall findings have some strengths. First, our authors were from different background consisting of clinical experts and methodologists with extensive experience in evaluating clinical guidelines, which improved the reliability of our findings. Second, different domains have been appropriately weighed to derive overall assessment and recommendation. Nonetheless, our study also has limitations. Exclusion of guidelines published in languages other than English, or other forms , might have resulted in under-representation of guidelines from less developed countries. Third, AGREE II instrument focused on methods of guideline development and the transparency of reporting, but could not assess potential impacts of recommendations on patient's outcomes.5Most TBI guidelines got a high-quality rating. The high-quality domains were achieved in clarity and presentation, scope and purpose, and rigor of development. Our findings called for a standardized grading system to provide a clear information about the level of evidence and the strength of recommendation in TBI guidelines.We thank Jinhui Tian and Kehu Yang (Evidence-Based Medicine Center of Lanzhou University) for supporting the methodology and Liang Yao (Hong Kong Baptist University) for providing assistance with editing the final article.LAQ and WKP had full access to all of the data in the study and taken responsibility for the integrity of the data and the accuracy of the data analysis. CN and GTK contributed to drafting and critical revision of the article; DBS, WKP, and MWJ contributed to the data collection, AGREE process, and data analysis; DBS and GTK contributed to the study design and critical review. All authors contributed to the interpretation of study data and critically reviewed and approved the article before submission.Conceptualization: Anqi Lu.Data curation: Baoshan Di, Kongping Wei, Wenjuan Ma.Methodology: Tiankang Guo.Project administration: Yang Niu.Resources: Qi Zhang.Software: Kongping Wei, Wenjuan Ma.Supervision: Anqi Lu, Hu Wang, Nong Cao, Tiankang Guo.Writing – original draft: Baoshan Di.Writing – review and editing: Baoshan Di, Kongping Wei, Wenjuan Ma, Tiankang Guo.


The spleen is a secondary lymphoid organ responsible for immune surveillance against blood-circulating pathogens. Absence of the spleen is associated with increased susceptibility to systemic spread and fatal infection by different pathogens. Severe forms of visceral leishmaniasis are associated with disorganization of spleen compartments where cell interactions essential for splenic immunological function take place. White pulp atrophies, secondary lymphoid follicles and marginal zones vanish, and the boundaries separating white and red pulp blur. Leukocyte populations are reduced or disappear or are replaced by plasma cells. In this paper, we review the published data on spleen disorganization in severe forms of visceral leishmaniasis and propose a histological classification to help the exchange of information among research groups. Leishmania infantum (syn. Leishmania chagasi) or Leishmania donovani that affects both humans and dogs. Visceral leishmaniasis is distributed in Central and South America, Asia, parts of Africa and the Mediterranean basin, with an estimated burden of 2.1 million DALY (disability adjusted life years)  is a severe parasitic disease caused by infection by The spleen, bone marrow, and liver are the main organs involved in VL. The spleen is affected in all cases of the disease. Furthermore, while some control of infection is observed in the liver, the infection acquires a progressive character in the spleen throughout the course of the disease  and a proliferation-inducing ligand (APRIL) in a T-cell independent (TI) response, which plays an important role against microbial antigens , cytokines and adhesion molecules , more frequently altered laboratory biochemistry and hematological tests  and more frequently negative leishmanin skin test than animals with active Leishmania infection and type 1 spleen (Lima et al., Spleen disorganization is associated with more severe VL presentations. Dogs with active infection by In humans who died with severe VL, Veress et al.  found WPLeishmania and other pathogens. In fact, bacterial infection is among the main causes of death in patients with VL (Andrade et al., In this review, we draw attention to the marked changes in the organization of spleen compartments in severe forms of VL. These changes combine an increase in the size and altered distribution of cell components. The cell populations undergo change, and the appropriated sites of cell interactions and differentiation disappear or are substantially disrupted. Secondary lymphoid follicles, a site of development and refinement of antibody immune response, are no longer observed and MZs, homing sites for a variety of memory B cells are almost nonexistent. Since the spleen changes are usual in the whole course of VL, we may consider the role played by the disease in the genesis of these alterations. Furthermore, these changes in the spleen are associated with severe/terminal disease in dogs and in humans. Given the role of spleen in the protection against bloodborne pathogens the change in cell postulations and cytokine expression pattern in disorganized spleen may contribute to the progression of the disease by increasing host susceptibility to WD-S, GO, MH conceived the manuscript. MH, CM, IL wrote the text. WD-S, GO revised the text. WD-S, MH, produced the figures.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.


Candida and Cryptococcus sp. both in vitro and in vivo. To evaluate if sertraline has activity against Coccidioides, the minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) of sertraline for four clinical isolates of C. immitis were determined. Sertraline was observed to have an MIC range of 4–8 µg/ml and MFC also of 4–8 µg/ml for Coccidioides. These MIC and MFC results for C. immitis are similar to those reported for Cryptococcus sp. suggesting sertraline may potentially have utility for the treatment of coccidioidomycosis.Coccidioidomycosis causes substantial morbidity in endemic areas. Disseminated coccidioidomycosis is an AIDS defining condition and treatment often requires lifelong antifungal therapy. Sertraline, a widely used serotonin-reuptake inhibitor anti-depressant, has demonstrated activity against  Coccidioides species are dimorphic fungi prevalent in arid regions of the Western Hemisphere. Infections with Coccidioides sp. cause substantial morbidity and mortality in endemic areas  of 2–6 µg/ml . These C. immitis colonies were then grown on Sabouraud-dextrose agar slants prior to MIC testing. None of the isolates were stored or further subcultured.Laboratory work was carried out in the biosafety level-3 microbiology laboratory of Community Regional Medical Center, a tertiary care hospital located in an endemic region for coccidioidomycosis . Fungal isolates from four distinct individual’s clinical specimens were identified as C. immitis colonies were scraped from the agar slants, suspended in sterile water and vortexed with sterile glass beads to disaggregate the fungal colonies. The suspended C. immitis was then further diluted with sterile water to a concentration of 0.5 McFarland units (530 nm wavelength) and then further diluted 1:100 in Roswell Park Memorial Institute (RPMI) culture medium ).The MIC for each of these four clinical isolates was determined for each drug (or combination) following the reference protocol Clinical and Laboratory Standards Institute M27-S4 and M38-A2 CLSI . C. immiStock solutions of sertraline  and fluconazole (Santa Cruz Biotechnology sc-205698) were made at 5 mg/mL in dimethyl sulfoxide (DMSO) (Corning Cellgro DMSO MT23950CQC), and then diluted to 10× the desired final concentration using RPMI and filtered using a 0.22-micron syringe filter (Whatman Puradisc cellulose acetate 0.2 µM).To measure MICs, again, following the reference protocol Clinical and Laboratory Standards Institute M27-S4 and M38-A2 CLSI , a totalC. immitis testing, using Candida krusei (ATCC 6258) and Candida parapsilosis (ATCC 20019) with MIC results obtained for fluconazole within the acceptable MIC range for these quality control organisms.Standard quality control for yeast susceptibility testing was also performed in parallel with Drug interaction was defined based on the fractional inhibitory concentration (FIC): FIC =  + . A drug combination with an FIC ≤0.5 was considered synergistic, FIC >0.5 and ≤1.0 additive, and FIC >1 and ≤2 to be indifferent.C. immitis isolates. The MIC of fluconazole for these C. immitis isolates ranged from 4 to 32 µg/mL and for sertraline from 4 to 8 µg/mL  . While the serum drug level of sertraline at standard approved dosing is significantly lower than the MIC concentrations seen here, sertraline is concentrated in tissues and in the CNS reaches concentrations similar to the MIC for C. immitis (Wille et al. The potential clinical utility of sertraline for treatment of coccidioidomycosis will depend on the drug levels achievable C. immitis is similar to the reported MIC of sertraline for Cryptococcus neoformans (Zhai et al. C. immitis would suggest sertraline would have potential as an additional agent for the treatment of coccidioidal meningitis and possibly other forms of coccidioidal infection.The MIC of sertraline for


We assessed adherence to WHO publication requirements and the reporting of guideline development processes associated with trustworthiness. In the absence of quality appraisal tools for guidelines developed under compressed timeframes, we applied the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool.We included 21 guidelines (13 de novo and 8 updates). Six guidelines used a formal evidence review process. Most guidelines involved external experts in the development process and collected declarations of interest. Peer review was reported in six documents. Most emergency guidelines included updating plans. The highest scoring AGREE II domain was clarity of presentation (median score 78%); the lowest scoring domain was applicability (median score 18%).WHO developed moderate‐ to high‐quality emergency guidelines in the challenging context of a PHEIC. We found improvement opportunities for WHO guideline development teams in the use of evidence to formulate recommendations, the collection of declarations of interest, reporting of conflicts of interest, and the use of existing WHO organizational quality assurance processes. As of February 2018, 86 countries had evidence of ongoing or past vector‐borne ZIKV transmissionThere is no treatment available for ZIKV infection,in utero exposure to ZIKV and congenital abnormalities was unclearIn the early phases of the 2015‐2016 ZIKV disease outbreak in the Americas, the causal association between The objective of this study was to describe the characteristics related to trustworthiness of WHO ZIKV guidelines published in response to the ZIKV Public Health Emergency of International Concern (PHEIC) in 2016, and to assess their quality in terms of stakeholder involvement, rigor of development, clarity of presentation, inclusion of implementation considerations, and management of conflicts of interests.2We examined WHO guidelines developed and published by WHO headquarters specifically for the ZIKV outbreak response in 2016. We defined the study period, 1 February to 18 November 2016, based on WHO's declaration that the association of ZIKV infection with clusters of microcephaly and other neurological disorders constituted a PHEIC on 1 February 2016, and the end of the PHEIC on 18 November 2016.We extracted guideline characteristics and information on publication format. In addition, we tracked updates throughout the study period, identified translations to regionally important languages, and described guideline quality assurance and control efforts such as external peer review, Guidelines Review Committee (GRC) approval  or presence in e‐Pub.We also identified and extracted data on the characteristics, format and related text for discrete recommendations within each included guideline. WHO defines recommendations as statements that tell end‐users what to do in specific situations to achieve the best health outcomes.All data were extracted by one coauthor and independently checked by a second one. This study did not undergo ethics review.2.1Although validated quality assessment tools specific for emergency guidelines are not available in the medical literature,In addition, four independent appraisals of each guideline were performed using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument.We report the prevalence of key characteristics and present AGREE II scores for each of the six domains for each guideline  and then report scores across guidelines using the median value and the interquartile range for each domain. All statistical analyses were conducted using Stata 12.1 .3We identified 21 WHO ZIKV guidelines published during the study period, of which 13 were developed for the first time (de novo) and 8 were updates  were rarely described. All six guidelines (29%) that reported using a systematic or rapid review were updates; none of the de novo guidelines mentioned a systematic or rapid review. The majority (57%) of the guidelines referenced other WHO guidelines and all cited at least one other document or publication Table .Most guidelines involved external experts in many functions; 62% of guidelines included external experts as members of guideline development group  with their names listed in the document. Of the 21 guidelines reviewed, 17 (81%) reported collecting declarations of interest (DOI). Of the four guidelines that did not report collecting DOI, three did not include external experts in the formulation of recommendations, involving them rather as peer reviewers. Four guidelines (20%) reported funding sources. External peer review was reported in six (29%) guidelines and 81% included an expiration date or plan for updating. One guideline (5%) was reviewed and approved by the WHO Guidelines Review Committee.The highest scoring AGREE II domains were clarity of presentation (median score 78% (interquartile range [IQR] 71%‐86%). The lowest scoring domain was applicability (18% [IQR 6%‐31%]). There was substantial variability in most of the domains, most notably for rigor of development Figure .For the recommendation‐level assessment, we identified 58 discrete recommendations contained in 6 of the 13 guidelines that were current at the time of data extraction (November 2016) Table . The rem4Our study suggests that WHO can efficiently and effectively develop and publish timely, moderate‐ to high‐quality guidelines in the very challenging context of a biologic threat leading to a PHEIC. Most of the guidelines produced by WHO in response to the 2016 ZIKV disease outbreak used the organizational template and complied with publication and reporting requirements. These guidelines performed particularly well on key aspects of trustworthiness such as reporting of DOI and management of conflicts of interest and scored high in the AGREE II quality domains of “scope and purpose” and “clarity of presentation”. Nonetheless, we identified opportunities for improvement in many components of the guideline development process pertaining to trustworthiness: the use of evidence such as from systematic reviews, collection DOI and transparent management of conflicts of interest of all contributors, reporting the role of funders, more inclusive and explicit consideration of decision elements beyond benefits and harms , consistent peer review of draft final guidelines, the development of tools for implementation in the local context and the uniform use of quality assurance processes. WHO guidelines produced in the context of the ZIKV disease outbreak were rarely submitted to the GRC or its Secretariat: some form of quality assurance is essential for all of WHO's information products, regardless of the context, whether this is the GRC or some other closely related process. In addition, all WHO information products should be registered in the publication clearance and approval system. These are thus important areas for improvement which WHO is currently addressing.Significant challenges when evaluating emergency guidelines include the poor reporting of development methods in these documents and the lack of validated and widely accepted standards and quality assessment tools.Standards for the assessment of guideline quality such as the components for trustworthy guidelinesThe high scores in the AGREE II quality domains of “scope and purpose” and “clarity of presentation” are similar to those reported in a previous evaluation of WHO emergency guidelines.The results of the AGREE II quality domain of “applicability” showed significant room for improvement, however. This domain covers the barriers and facilitators to implementation, strategies to improve uptake, cost and implementation tools.WHO ZIKV disease emergency guidelines also had suboptimal performance on the AGREE II domain of “rigor of development.” This finding is likely due to the infrequent use and availability of scientific evidence, and the failure to use a structured decision‐making process for formulating recommendations. These components of guidelines are corner‐stones of trustworthiness, and actions to improve them need to be prioritized in future iterations of the templates and development processes.We did not evaluate many important questions such as how to prioritize topics for guideline development during an emergency, how to assess existing guidelines for relevance and applicability, optimal dissemination methods and tools, the uptake by end‐users, and most importantly, the impact on health outcomes of the affected populations. We also did not address the validity of the recommendations issued in the emergency context. As new data and updated guidelines become available, the validity of the previous recommendations and the robustness of the processes used to formulate them should be assessed and the results used to improve processes and methods in future.WHO has an intentionally broad definition for guidelines, which may have resulted in misclassification of some information products as guidelines when the purpose of the document was not to provide normative guidance. However, we had a clear operational definition and eligibility criteria for guidelines and 90% of the included documents used the emergency interim guidance template, suggesting that misclassification was likely rare. Another potential limitation was our reliance on information that was reported in guidelines; we did not query guideline authors for additional information. We chose to focus primarily on rigor of quality of development as well as WHO's reporting requirements; we did not apply the CheckUp checklist for reporting of updated guidelines although many of its items were encompassed by our evaluation.5WHO developed moderate‐ to high‐quality emergency guidelines in the challenging context of a PHEIC. We found improvement opportunities for WHO guideline development teams in the use of evidence to formulate recommendations, the collection of DOI, reporting and management of conflict of interest, and the use of existing WHO organizational quality assurance processes. It is important to ensure that the lessons learned in this evaluation are translated into WHO's standard operational procedures and made available to technical units responsible for developing emergency guidelines in the future. Equally important is the establishment and continuous refinement of emergency guideline development methods and accompanying tools to facilitate production of the best possible guidance in a timely and trustworthy manner.SLN is a member of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group and has published numerous papers related to GRADE. GRADE is the guideline process used by her employer, the World Health Organization, to develop guidelines. MF is currently an employee of Bristol Myers Squibb and owns company stock as part of his remuneration plan; a family member was employed by Bristol Myers Squibb at the time this study was performed. YHAL is currently an employee at Genentech and owns company stock as part of her renumeration; she had no affiliation with Genentech at the time the study was performed. The other authors declare no competing interests.The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated.Online AnnexureClick here for additional data file.Supporting MaterialClick here for additional data file.