Systematic reviews (SRs) are widely recognized as the best means of synthesizing clinical research. However, traditional approaches can be costly and time-consuming and can be subject to selection and judgment bias. It can also be difficult to interpret the results of a SR in a meaningful way in order to make research recommendations, clinical or policy decisions, or practice guidelines. Samueli Institute has developed the Rapid Evidence Assessment of the Literature (REAL) SR process to address these issues. REAL provides up-to-date, rigorous, high quality SR information on health care practices, products, or programs in a streamlined, efficient and reliable manner. This process is a component of the Scientific Evaluation and Review of Claims in Health Care (SEaRCH™) program developed by Samueli Institute, which aims at answering the question of “What works?” in health care.The REAL process (1) tailors a standardized search strategy to a specific and relevant research question developed with various stakeholders to survey the available literature; (2) evaluates the quantity and quality of the literature using structured tools and rulebooks to ensure objectivity, reliability and reproducibility of reviewer ratings in an independent fashion and; (3) obtains formalized, balanced input from trained subject matter experts on the implications of the evidence for future research and current practice.Online tools and quality assurance processes are utilized for each step of the review to ensure a rapid, rigorous, reliable, transparent and reproducible SR process.The REAL is a rapid SR process developed to streamline and aid in the rigorous and reliable evaluation and review of claims in health care in order to make evidence-based, informed decisions, and has been used by a variety of organizations aiming to gain insight into “what works” in health care. Using the REAL system allows for the facilitation of recommendations on appropriate next steps in policy, funding, and research and for making clinical and field decisions in a timely, transparent, and cost-effective manner. Evidence is the basis from which we tell truth from fiction in the natural world and determine value in health care claims. Millions of articles are published in thousands of biomedical journals worldwide . PubMed,Effective health care decisions should be evidence-based rather than rely solely on clinical judgment. Such judgments are often made under conditions of uncertainty , and useMastering and managing the recent explosion of medical information is a difficult task, and evidence-based problem solving skills are essential for responsible decision-making, maintaining quality health care and ensuring good outcomes. As stated, SRs form the foundation for evidence-based medicine by collating all empirical evidence that fit pre-specified eligibility criteria in order to answer a specific research question. While expert opinions and narrative reviews are popular means for organizing data, and can be informative and produced faster and more easily than SRs, they are often subjective and prone to bias. Thus, during a time characterized by large amounts of information and the critical need to make evidence-based decisions, the shift from these analyses towards SRs is not only becoming prominent, but also necessary. Indeed, high quality SRs that clearly summarize evidence have become a crucial component in helping clinicians, patients, and policymakers make accurate decisions about clinical care . SR methSR methodology used to assess the quality of available literature has gradually improved over the years, with several groups receiving international attention for the development of standards and advancing the science in SRs. Despite this progress, SR methodologies can still present challenges. First, many still vary considerably, and as such, outside reviewers often have difficulty replicating such methodologies. There is a need for improved standardized and reliable protocols and procedures to ensure transparency and produce meaningful information. Second, research questions and data extraction can be chosen without the input of diverse stakeholders, resulting in a narrow scope of the review, and sometimes minimal relevance or utility for making clinical decisions. Third, the subjective nature of quality assessment of research can leave SRs open to bias, resulting in unreliable results. Finally, while SRs help to provide a summary of the evidence, not all provide informative syntheses, perhaps because they lack a structured approach for obtaining expert input on the implications of the evidence for recommendations.SRs can be cumbersome to execute and quite costly, requiring large amounts of personnel time and budget. Many people grossly underestimate the amount of time needed to perform a comprehensive, rigorous, and evidence-based SR, and subsequently choose to rely on less reliable methods such as expert opinions or narrative reviews. Protocol development, search strategy formation and literature searching, quality assessment and data extraction, discussion of disagreements for study inclusion, coding and quality assessments, acquisition of missing data from authors, and data analysis are all time consuming steps requiring specific skills, training and effort. A large team trained in specific roles/responsibilities at each phase of the review is needed to perform a SR most efficiently. Because lack of resources is sometimes a challenge, training, explicit processes, and the application of online systems can enhance efficiency and decrease cost. The methodology described below incorporates such methods and in turn reduces costs while enhancing the quality of the review.©). This method utilizes specific tools  and standard procedures  to rigorously deliver more reliable, transparent and objective SRs in a streamlined fashion, without compromising quality and at a lower cost than other SR methods.In order to overcome these challenges and maximize efficiency in the execution and dissemination of good evidence, there is a need for more objective, high quality and up-to-date syntheses provided in a more streamlined manner regarding health care interventions. To fill this need, Samueli Institute has developed a SR process known as the Rapid Evidence Assessment of the Literature  the rapid identification of literature relevant to a particular subject matter area ; (2) the use of one or more grading systems to assess the quality and strength of evidence for the topic; (3) a summary of that evidence and; 4) subject matter experts (SMEs) input and assessments of implications for the current use of the intervention in practice. This rapid methodology requires a team-based approach to capitalize on resources and ensure maximum meaning, impact and utility; efficient and consistent review methodologies aimed at reducing time while maintaining quality; careful creation of objective protocols describing how to execute SR processes to ensure both reliability and reproducibility; as well as thoughtful synthesis and interpretation of the data to form a foundation for future work. Consequently, SRs that utilize this more streamlined process  are more efficient and reliable than some other traditional SR methods. Figure  the rapi subject Efficiency is of great importance when stakeholders need immediate, evidence-based answers for “what works”. Many review teams are small in size and reviews can take years to complete. Conversely, to maximize efficiency, Samueli Institute REALs are executed by several well-trained team members, each with specific roles and responsibilities, and often take approximately 3–6 months, from question development to manuscript delivery.Principal Investigator to oversee the entire project; (2) a Review Manager with SR methodology expertise to guide the review process from start to finish; (3) a Search Expert to assist with literature search strategy development and execution; (4) at least two trained Reviewers to screen, extract data and review the quality of the literature; (5) a Reference Manager/Research Assistant to provide administrative and project support; (6) a Statistician to provide guidance regarding the interpretation of complex results or meta-analyses; and (7) at least two SMEs with diverse perspectives related to the review topic to provide guidance and synthesize the overall literature pool. It is important to note, that while Samueli Institute has designed the REAL process to be executed by individuals within these roles/responsibilities, some organizations and entities may be more limited in terms of available personnel. As such, it is reasonable for individuals to be trained to take on multiple roles, although doing so may delay the review process. The division of labor allows for more efficient, accurate and reliable execution of the review steps and reduction of time needed by any one individual. Further, it allows for better compliance with the Institute of Medicine (IOM) recommendations for managing bias and conflicts of interest (COI) when producing reviews and recommendations [Specifically, a REAL Review Team includes: (1) a  finish;  a SearchSteering Committee comprised of 4–6 diverse stakeholders  chosen by the client and Principal Investigator, who provide guidance throughout the review process. This ensures that the review’s focus stays relevant to the end-user of the SR results and allows for translation to practice to occur more effectively. The Steering Committee seeks to address the “so what” question that so often occurs after a standard SR in which simply “more and better research is needed.” Though integral to the review, the Steering Committee is not involved in the review’s technical steps. This guards against bias during the independent evidence assessment process. Once the Steering Committee and the SMEs review and approve the team’s plans and progress at each review phase the Review Team is then solely focused on conducting the review and analyses in an independent and objective fashion.One of the most frequent complaints by clinicians and patients about systematic reviews is that their conclusions have little relevance to daily clinical decisions and so are not of much use. The REAL has built in a process to obtain continuous input from any stakeholder involved in these decisions. In addition to the Review Team, REALs also include a Once assembled, it is imperative that both the Review Team and Steering Committee work together to formulate the review’s research question, scope, definitions, and eligibility criteria using the PICO(S) process  , as wellAdapting and Developing of Quality Assessment Tools).The REAL process requires search expertise to build robust literature search strategies as well as iterative input from both the SMEs and Steering Committee members for guidance. REALs do not “exhaustively” search the literature by including grey and non-English language literature, unless essential to the specific research question . Instead, they usually include only peer-reviewed literature published in the English language. While the traditional SR considers the inclusion of only English-language studies as a limitation, doing so rarely compromises the outcome or implication for the majority of interventions and claims . There hREALs are more efficient due to not only their focus on English and peer-reviewed literature, but also their use of readily available software systems to automate the review process. These systems have been customized for use with a REAL and streamline many of the review steps including automated article processing and management, eliminating the need for data transcription, automated reliability estimation, real time error and quality checking, and reduction of post-review data collation. Using a specific review system and rulebooks allows researchers to deliver results faster, with improved accuracy and reliability, and provides a complete audit trail of all changes to ensure transparency. Such systems can also be accessed remotely and include messaging features that allow the review team to interact virtually, thereby considerably decreasing costs associated with travel, materials, supplies, and meeting facilities.©) [Most groups using SRs to develop recommendations and guidelines rely on subject matter experts (SMEs) to evaluate the quality of the research. However, SMEs almost always have a particular point of view (bias) and also are rarely trained in the proper use of quality assessment tools. REALs avoid the use of SMEs in applying quality assessment tools and instead rely on trained review teams. This way, higher standards for accuracy and reliability are obtained. There are many well-accepted quality assessment rating systems available to researchers for evaluating quality and risk of bias. These tools typically focus on internal validity, or whether the results are due to attributional bias issues. These tools are usually quite subjective and variable in how quality criteria are interpreted. Samueli Institute has adapted some of these rating systems to improve their use and objectivity. In addition, we have also developed, validated and incorporated an External Validity Assessment Tool (EVAT©)  into theDue to the inherently subjective nature of interpreting research results, Samueli Institute has created rulebooks to ensure that review teams are: (1) objectively evaluating and “scoring” each included article for quality; and, (2) consistently extracting data in a specific, consistent format, thereby reducing time needed for post-review data cleaning. Reviewers utilize these rulebooks and so provide transparent data extraction as well as a consistent and sufficient inter-rater reliability Cohen’s Kappa , indicating a low level of conflict and high level of agreement between reviewers. These rulebooks are essential for managing and minimizing bias and ensuring the quality of any review. For example, should someone question the basis for any results in a SR, the team can refer to the rulebooks to explain and demonstrate specifically why and how particular articles were scored.Just as the criteria and parameters whereby reviewers conduct the review are explicitly detailed in rulebooks, all decisions, processes and outcomes relating to each step of the review are maintained in a Review Documentation Checklist throughout the review process. Because this Checklist was developed to adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines , it not The REAL process is designed to provide a basis for SMEs to identify current implications for research and practice based on the evidence as a whole. In fact, once all individual studies included in the review have been evaluated, SMEs assess the overall literature pool according to the researched outcomes relevant to the research question in order to: (1) determine the quality of the research as a whole; (2) identify gaps in the literature; (3) assess the effectiveness of the intervention or claim as well as the confidence in that effectiveness estimate; and (4) judge the appropriateness for clinical use of the intervention. This is done in the following way. A roundtable is convened with the review team, Steering Committee and SMEs to evaluate the review’s results, the overall literature pool analyses, identified gaps, as well as outline next steps for the particular field of research. Several tools are used to organize the goals and discussion at this roundtable. A synthesis report is produced from this roundtable that is reviewed and modified by the REAL team based on feedback from all participants. These syntheses form a foundation for researchers, clinicians and patients to be better informed about the current state-of-the-science for any intervention, and determine next steps needed in the field of research and practice for use and impact. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) working group has developed methods for going about synthesizing the literature as a whole that should be used standardly across all systematic reviews .REALs are constructed in a way that lays a foundation for future stakeholders to use quality evidence for decision making in multiple areas—research, practice, personal and policy areas. These foundational elements include the evaluated dataset (which can be further updated and added to), effect size estimates, meta-analyses (when possible), and other elements that go into the report such as the quality tools previously described and synthesis and interpretation assessments.Meta-analyses combine the actual quantitative results  of separate studies included in a review, use statistical techniques to determine the overall effect size and confidence in the effect of the intervention, and employ analytic techniques to quantify possible publication bias. They are often costly and time-consuming, and only appropriate when the existing literature suggests that there are sufficient studies with enough homogeneity in outcomes. REALs are designed to form the foundation for subsequent meta-analyses to be conducted, if appropriate. REALs can therefore be utilized as an effective tool for rapidly determining the current state of the literature, and what gaps should be addressed to conduct an effective meta-analysis.all parties in ways that allow them to make medical decisions and so do not maximize impact of reviews. The REAL process is one of three components of Samueli Institute’s Scientific Evaluation and Review of Claims in Health Care (SEaRCH) Program and is a key step to forming a foundation upon which the other two SEaRCH components can be used for determining the clinical impact and relevance of evidence. SEaRCH is comprised of the REAL, Claim Assessment Profile (CAP) and Expert Panel Processes  processes as described in this journal issue [There is a considerable barrier to rapidly translating evidence into decision making for clinicians, patients, researchers and policy makers. Although authors of SRs disseminate results through various routes of publication, results often do not reach al issue , 25. TogSimilar to the REAL, expert panels and the CAP employ specific processes and safeguards to reduce variability and bias and promote collaboration and efficient delivery of meaningful results. The CAP can be conducted prior to the REAL to inform the REAL toward specific definitions about a particular claim, or can be conducted in tandem with the REAL for informing the expert panel process. While expert panels can be organized once the REAL process is completed it is important that the review and expert panel processes both remain independent of each other to manage bias and maintain a focus on clinical and patient relevance. To do this properly, SME input and the REAL process need to be carefully managed even as they are linked to the expert panel process. The SEaRCH program is designed to allow for complete interaction between the SR and expert panel process in a manner that remains both impartial and informative in the interaction between SMEs and the trained reviewers . This prThe REAL is a process that streamlines and organizes many elements of systematic reviews in order to insert high quality, rigorous evidence in a more rapid, objective, relevant and cost-efficient manner into decision making processes. Specifically, the REAL (1) follows a team-based approach; (2) utilizes specific search strategies; (3) automates review processes to ensure efficient use of time and skill; (4) involves key stakeholders to guarantee the right questions are being asked and addressed; (5) outlines and adheres to a transparent protocol to ensure objectivity and the management of bias; and (6) forms a foundation for subsequent analyses and expert panels to guide gaps and relevance, particularly when tied into other elements of the SEaRCH process. These features not only increase efficiency, but also assure adherence to reliable and reproducible protocols that provide a more consistent, transparent SR process for evidence-based medicine and decision making by the multiple stakeholders in health care.By providing background and information on the existing literature, research gaps, and the weaknesses and strengths of current evidence, systematic reviews utilizing the REAL process provide a solid and consistent foundation for making clinical, patient and policy decisions. The, objectivity and efficiency of the REAL process make it a valuable for a variety of organizations and entities that need good evidence for decisions about products, practices or programs currently in use or those being explored for potential use. Decision makers as diverse as a health insurance or regulatory company/agency wanting to know what the evidence is for an intervention in order to decide whether or not it should be covered, or a clinical practice wanting to know if implementing a certain practice would benefit their patients are examples of decisions that can be aided by a REAL.Samueli Institute has shared their REAL methodology with others in the SR field and continues to extend outreach and support to those interested in using this approach for evidence assessment. The Institute has developed a workshop that teaches participants how to conduct SRs in the step-wise fashion used by the REAL. This workshop is currently offered 2–3 times a year and provides participants with a comprehensive workbook covering theoretical material , practical instructions and guidelines on how to conduct SRs using the REAL process, and allows participants to receive individual coaching on review projects they are developing or conducting. The course and assistance is also offered through an online, self-paced platform (Black Board) complemented by didactics, mentorship, and in person workshops. Samueli Institute also collaborates with other organizations wishing to evaluate a topic using the REAL methodology, and offers guidance and mentorship throughout the review process. These workshops have been done for government and private groups and can be customized for use by any organization interested in applying evidence to health care decision making.There is a need for reliable, rapid, and transparent evidence to guide effective health care decision-making. The REAL approach was developed to ensure high quality SRs are conducted in a rapid, streamlined, transparent and valid fashion. It has been shown to: (1) reduce the cost of generating reviews for those making informed decisions regarding health care; and, (2) inform the public in a time sensitive, cost-effective and objective manner about the state of the evidence for any health care area.Detailing the challenges of current SR methodology and the ways in which this rapid SR process addresses those challenges highlights the need for investigators to ensure that reviews are objective, transparent, scientifically valid, and follow a common language and structure for characterizing the strength of evidence across reviews. Adapting an approach like the REAL into current SR processes will not only decrease the variability and improve the quality of SRs, but also allow health care decision makers, including clinicians, patients and policy makers to play a crucial role in developing relevant research questions and for making sound, evidence-based decisions in all of heath care.For those interested in utilizing the REAL approach and learning more about conducting SRs, training workshops and collaboration opportunities, please visit the Samueli Institute website .


B. divergens infected erythrocytes on spleen histopathology, cell cycle alteration, and the presence of oxidative stress. Mongolian gerbils were challenged with 5 × 106  Babesia divergens infected erythrocytes. Parasitemia reached approximately 77% at day 5 postinfection. Infection also induced injury of the spleen. This was evidenced with (i) increases in cellular damage of the spleen, (ii) decrease in antioxidant capacity as indicated by decreased glutathione, catalase, and superoxide dismutase levels, (iii) increased production of malondialdehyde and nitric oxide derived products (nitrite/nitrate), and (iv) increased lactic acid dehydrogenase activity and protein carbonyl content in the spleen. Infection interfered with normal cell cycle of the spleen cells at G0/G1, S, and G2/M phases. On the basis of the above results it can be hypothesized that B. divergens infected erythrocytes could alter the spleen histopathology and cause cell cycle alteration and induce oxidative stress in splenic tissue.Babesiosis is caused by intraerythrocytic protozoan parasites transmitted by ticks and affects a wide range of domestic and wild animals and occasionally humans. The current study aimed to investigate the effect of  Babesia organisms from a vertebrate reservoir to humans; the infection is incidental in humans [ Babesia. Fever, hemolytic anemia, and hemoglobinuria may result from Babesia infection [Babesiosis is a zoonotic infection in which ticks transmitn humans . The clinfection . B. divergens is transmitted by Ixodes ricinus, a member of the family of hard ticks (Ixodidae). Recently, worldwide interest in B. divergens has increased as a result of human cases caused by identical or similar parasites outside areas where bovine babesiosis is endemic [Members of the genus Babesia are intraerythrocytic protozoan parasites, and many species are of considerable economic importance in the livestock industry. Additionally, some species affect human health . B. dive endemic . As with endemic .Many parasites including protozoa are sensitive to oxidative stress. Sensitivity to oxidative stress has been reported in malaria , hepatoz B. divergens genotoxicity. The current study aimed to investigate the effect of B. divergens infected erythrocytes on spleen histopathology, cell cycle alteration, and the presence of oxidative stress.Although some parasites can induce DNA damage, there are no enough data onBabesia divergens was kindly provided by Professor Mehlhorn . This strain has been maintained in our laboratory in Mongolian gerbils (Meriones unguiculatus) by intraperitoneal injection of infected blood. M. unguiculatus aged from 9 to 11 weeks old were used. They were bred under specific pathogen-free conditions in the animal facilities of King Saud University, Riyadh, Saudi Arabia. They were housed in plastic cages and fed on standard diet and given water ad libitum.Male6 B. divergens-parasitized erythrocytes. Parasitaemia was evaluated using Giemsa-stained smears, which were prepared daily using blood taken from the tail veins, and the total number of parasitized erythrocytes per mL was estimated by counting in a Neubauer chamber. To study the spleen injury induced by the parasite in gerbils, it was necessary to allow infections to progress until parasitaemia had reached 60–70%. Eight animals that had been infected with 5 × 106 B. divergens-parasitized erythrocytes were anaesthetized with ether and then killed by cervical dislocation on day 5 postinfection (p.i.), along with 8 noninfected control animals. Parasitemia was evaluated in Giemsa-stained blood smears from the tail veins. The experiments were approved by the state authorities and followed Saudi Arabian rules on animal protection (Project number RGP-198).To determine the extent of parasitaemia and survival of gerbils, 12 animals were inoculated with 5 × 10μm paraffin sections were cut and stained with hematoxylin and eosin for histological study. A semiquantitative scoring system [Small pieces of spleen were fixed in 10% neutral buffered formalin. Specimens were then routinely dehydrated with ethanol and embedded in paraffin, and then 5 g system  was usedSpleen was weighed and homogenized immediately to give 50% (w/v) homogenate in ice-cold medium containing 50 mM Tris-HCl and 300 mM sucrose . The homGlutathione (GSH) was determined chemically in spleen homogenate using Ellman's reagent . The met2O2. The reaction is stopped after exactly one minute with a catalase inhibitor. In the presence of horseradish peroxidase, remaining H2O2 reacts with 3,5-dichloro-2-hydroxybenzenesulfonic acid and 4-aminophenazone to form a chromophore with a color intensity inversely proportional to the amount of catalase in the original sample, measured at 240 nm. Superoxide dismutase activity in plasma was assayed by the method of Nishikimi et al. [Catalase activity was assayed by the method of Aebi . Catalasi et al. . This asLipid peroxidation in spleen homogenate was determined according to the method of Ohkawa et al.  by usingThe assay of nitrite in spleen homogenate was done according to the method of Berkels et al. . In acid+ is accompanied by a decrease in absorbance (A) at 340 nm, which correlates with the LDH activity. The change of absorbance, in the absence or presence of parasite, was recorded over a 0.5 to 4.5 min period, and the relative ΔA/min was calculated. The change in absorbance was converted to LDH international units per liter (U/l) by the following calculations: ΔA/min , where tV is the total volume, EMC is the NADH extinction micromolar coefficient (6.22 cm2μmol at 340 nm), l is the light path length (1 cm), and sV is the sample volume. The final activity was expressed as U/g protein.Lactate dehydrogenase (LDH) assay was performed in the spleen homogenate by using a commercial kit based on the transformation of pyruvate to lactate by LDH, at pH 7.5, in the presence of NADH coenzyme. The transformation of NADH to NAD−1 cm−1.Protein carbonyl content was determined as described by Levine et al. , with slμg mL−1 PI, and 50 μg mL−1 DNase-free RNase A. The suspension was incubated for 30 min at room temperature in the dark and filtered through 200 μm nylon mesh. The DNA fluorescence of PI-stained cells was analyzed by excitation at 488 nm and monitored through a 630/22 nm band-pass filter using a FACScan flow cytometer . A minimum of 10000 cells was counted per sample, and the DNA histograms were evaluated further using cell Quest software on a PC workstation to calculate the percentage of cells in various phases of the cell cycle.The cell cycle and DNA damage were evaluated with propidium iodide (PI) staining and flow cytometry according to the method previously described by Hishikawa et al. . Propidit-test using a statistical package program (SPSS version 17.0). P values are ≤0.05 considered as significant for all statistical analyses in this study.Statistical analyses were performed by Student's 6 B. divergens infected erythrocytes induced a lethal outcome of the infection. No gerbils survived after day 5 p.i.  due to B. divergens infection  is the main, fully susceptible experimental model used to study B. divergens infections [The Mongolian gerbil  are destroyed by the same mechanisms which the spleen uses to remove senescent and other aberrant erythrocytes from circulation. Basically, pRBC are eliminated by phagocytes in the red pulp areas of the spleen, specifically in extravascular beds. These form an open circulation through which blood is percolated on the way from arterioles to venules [Histologic examination of spleen tissue of gerbils infected with venules . The spl venules  and incr venules ; the mac venules . B. rossi infection, there was a marked decrease in haematocrit long before parasites were detectible in peripheral blood. This early change was hypothesized to be caused by hemodilution, splenomegaly, and sequestration in the spleen [ Babesia, Leishmania, Hepatozoon, Ehrlichia, Theileria, and Plasmodium parasites [ B. divergens. MDA is excreted in urine, blood, and other body fluids and therefore serves as a marker of lipid peroxidation and the presence of oxidative stress [P < 0.01) in gerbils with diagnosed babesiosis versus the healthy control group. Increased levels of MDA have been reported in B. gibsoni infection [ Ehrlichia canis and B. gibsoni [The quantity of the destroyed erythrocytes is usually much higher than the degree of parasitaemia, suggesting that nonparasitized erythrocytes may also be damaged . In expee spleen . This mee spleen , reducede spleen , and ince spleen , 31. Alse spleen . The reae spleen . Highly arasites , 31, 32.e stress . The resnfection , 27 and Babesia infection induced oxidative stress in spleen as evidenced by the decreased GSH, CAT concentration as well as increased formation of lipid peroxidation, and nitrite/nitrate. GSH is an excellent and potent endogenous antioxidant, which by scavenging various types of reactive radicals protects the cell from oxidative insults [ B. divergens infection depleted cellular GSH content. Decrease in cellular GSH content thus indicates generation of large quantity of ROS [ insults . On encoy of ROS . This fay of ROS . B. divergens significantly increased the formation of protein carbonyl; a measure of oxidative damage also correlated well with the percentage of parasitemia [Also, lactate dehydrogenase is a cytoplasmic enzyme present in essentially all major organ systems. The extracellular appearance of LDH is used to detect cell damage or cell death . Moreoveasitemia , 18.0, G1, G2, and S phases was significantly altered due to infection.Infection with some pathogens could alter the cell cycle . Our stuIn Conclusion. B. divergens infected erythrocytes could alter the spleen histopathology, cause cell cycle alteration, and induce oxidative stress in splenic tissue. Understanding of the pathogenesis induced in the spleen due to infection with Babesia is useful for both the management and the prevention of the infection.


To assess the quality of the currently available clinical practice guidelines (CPGs) for hepatocellular carcinoma, and provide a reference for clinicians in selecting the best available clinical protocols.The databases of PubMed, MEDLINE, Web of Science, Chinese Biomedical Literature database (CBM), China National Knowledge Infrastructure (CNKI), WanFang, and relevant CPGs websites were systematically searched through March 2014. CPGs quality was appraised using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument, and data analysis was performed using SPSS 13.0 software.A total of 20 evidence-based and 20 expert consensus-based guidelines were included. The mean percentage of the domain scores were: scope and purpose 83% , 81% to 86%), clarity of presentation 79% , stakeholder involvement 39% , editorial independence 58% , rigor of development 39% , and applicability 16% . Evidence-based guidelines were superior to those established by consensus for the domains of rigor of development (p<0.001), clarity of presentation (p = 0.01) and applicability (p = 0.021).The overall methodological quality of CPGs for hepatocellular carcinoma and metastatic liver cancer is moderate, with poor applicability and potential conflict of interest issues. The evidence-based guidelines has become mainstream for high quality CPGs development; however, there is still need to further increase the transparency and quality of evidence rating, as well as the recommendation process, and to address potential conflict of interest. Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide The Institute of Medicine (IOM) has established the definition of clinical practice guidelines (CPGs) as “systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances” et alSchmidt The available guidelines on the treatment of primary or metastatic liver cancer published in English or Chinese were included.a) HCC guidelines for diagnosis ); b) The Chinese version or other versions of oversea CPGs; c) Quality improvement guidelines, position statements or guideline summaries; d) National Institute for Health and Excellence interventional procedure guidance (NICE IPG) or overview; e) Conference abstracts, overviews, primary studies, systematic reviews or letters.The electronic databases of PubMed, MEDLINE, Web of Science, Chinese Biomedical Literature database (CBM), China National Knowledge Infrastructure (CNKI), and WanFang were systematically searched through March 2014. The MeSH terms with free-text terms were as follows:  AND (Guideline OR Practice Guideline OR Consensus). We also searched the relevant CPG websites, including Guideline-International Network (G-I-N), National Guideline Clearinghouse (NGC), Clinical Practice Guideline Network (CPGN), National electronic Library for Medicines (NeLM), and NICE.The PRISMA  statement was followed to search and select guidelines If a guideline has clearly stated the quality of evidence on which a recommendation is based or grading for recommendation and statements, then the guideline is judged as evidence-based. If a guideline is developed based on consensus , without illustrating the source of evidence and grade of recommendation, the guideline is judged as consensus-based.Three appraisers  independently rated the included CPGs using the AGREE II instrument that consisted of 23 key items organized within six quality domains followed by two global rating items . Each of the items was rated on a 7-point scale (1-strongly disagree to 7-strongly agree). The appraisers scored each guideline independently using the rating scale. If the three appraisers rated items with a difference of more than two points, a consensus discussion was held to obtain the final rating .A domain score of 60% was considered a threshold value of the AGREE instrument for rating the overall quality of CPGs. A guideline was ‘strongly recommended’ if the majority of domains (more than five) were scored above 60%. A guideline was ‘weakly recommended’ if more than four domains were scored above 30%. A guideline was ‘not recommended’ if more than three domains were scored below 30% The mean score and 95% confident intervals (CI) were calculated for each domain using AGREE II. Kendall's coefficient of concordance A total of 1,686 records were obtained after systematically searching the database and relevant websites. After an initial screening, 99 records of potential interest were identified. Of these, 59 were removed after viewing the full texts for the following reasons: a) Twelve were guidelines for non-HCC or only for diagnosis of HCC; b) Twelve were primary studies or systematic reviews; c) Ten were guidelines written in French, Korean, Spanish, etc; d) Eight were guideline summaries or letters; e) Seven were quality improvement guidelines or position statements; and f) Five were NICE IPGs or overviews. Finally, 40 guidelines published between 1999 and 2013 were included, of which 20 were evidence-based The number of guidelines has risen dramatically over the years, and the proportions of consensus-based guidelines are rising in 2010 and 2011.However, evidence-based guidelines are predominant in 2012 .et alet alet alet alet alAmong the 40 guidelines, 30 (75%) were developed for HCC Guideline evaluation results using the AGREE II instrument are detailed in Among the six domains of AGREE II, 40 guidelines were scored ≥60% with a mean of 79% to 83% for two domains, namely scope and purpose, and clarity of presentation. Sixteen guidelines were scored ≥60% for the stakeholder involvement domain and the remaining twenty-four had scores ranging from 33% to 59%. For the rigor of development domain, eight guidelines were scored ≥60% with a range of 63% to 90%, sixteen were scored 30% to 59% and the last sixteen were scored 3% to 22%. For the domain of applicability, only three guidelines were scored ≥60% with a range of 64% to 76%, and four others ranged from 39% to 53%, with 33 being scored below 30%. For the domain of editorial independence, nine guidelines were scored from 61% to 100%, and thirteen ranged from 33% to 58%, while the other eighteen were scored below 30%. Therefore, five guidelines were ‘strongly recommended’ according to AGREE II including three for HCC Evidence-based guidelines were superior to those established by consensus for the domains of rigor of development (p<0.001), clarity of presentation (p = 0.01), and applicability (P = 0.021). However, there was no significant difference for the other three domains (p>0.05) .http://www.g-i-n.net/library), and the National Guideline Clearinghouse (NGC) currently includes 2,549 individual guideline summaries (http://www.guideline.gov). However, there is a great discrepancy among guidelines established by varied governments, associations, and companies or other organizations, especially with respect to their quality et alThere has been a sharp increase in the number of CPGs worldwide since the 1980s et alet alZheng et alIn this study, it was found that the domain scores that received the highest marks as measured with AGREE II were ‘scope and purpose’  and ‘clarity of presentation’ , which is similar to the research of Schmidt However, there were some disappointing results regarding evidence-based guidelines in the domain of ‘stakeholder involvement’. Although the average quality score measured with AGREE II is 58%, there were 24 guidelines (60%), including eleven evidence-based guidelines that were scored less than 60%, which reflected the dearth of multidisciplinary teams and lack of accounting for views and experiences of the targeted patient population during the development of these guidelines The quality of a guideline largely depends on whether or not its methodology is rigorous and scientific. However, most guidelines received a lower score (39%) for the domain of ‘rigor of development’. Five consensus-based guidelines scored less than 30% for this domain. Although evidence-based guidelines are superior to consensus-based ones with respect to evidence gathering, quality assessment or strength of recommendations, there are still 12 evidence-based guidelines which were only scored between 30% and 60%. It is common that guidelines include references to published studies, but few of them clearly describe the searching strategy, the methodology used to formulate the final recommendations, or the dates on which guidelines were updated The domain of applicability mainly evaluates implementation barriers, cost factors, and monitoring criteria et alSimilarly, the domain of editorial independence addresses whether the recommendations are impacted by the funding body and conflict of interests (COIs) issues which may arise from within the guideline-developing organization We based our recommendations of the guidelines on the AGREE II instrument as previously described The ultimate goal of the present guideline evaluation is to recognize the faults of existing guidelines so that the necessary steps are taken to improve their quality. We found that most authors had increasingly emphasized evidence gathering and synthesis, and formulated the final recommendations when they developed their guidelines. The evidence-based guideline has become a mainstream for high quality guideline development. However, the transparency of guidelines in aspects of quality appraisal of evidence, formulation of recommendations, and the COI of authors are still insufficient, and this has become a prominent problem affecting the quality of guidelines. Some guidelines have simply classified evidence according to the study design, ignoring quality assessment of evidence, therefore making it difficult to know on which one or type of specific evidence the recommendation was based.Although some guidelines use GRADE  as a tool for evaluating the quality of evidence and formulating the final recommendations, GRADE evidence profiles and summary of finding (SoF) tables were not presented or linked in the guidelines. Therefore, the GRADE working group has suggested that the guideline-developing committee should summarize evidence in simple, transparent and informative SoF tables and evidence profiles that provide detailed information about the reason for the quality of evidence rating Before developing a guideline, it is necessary to limit funding sources coming from industries or other institutions, or provide a formal process for discussion and public disclosure of financial COIs for authors The study is based on published guidelines in Chinese and English journals. However, most institutions have local guidelines or rely on national guidelines , none of which is published. Thus the quality of guidelines used in most clinical settings might be of lower quality than published guidelines, hence causing some degree of selection bias. The AGREE II tool mainly focuses on methodology and quality of reporting, but not on the nature of the supporting evidence. Therefore, the quality of evidence on which the recommendations are based in the ‘strongly recommended’ guidelines still needs to be systematically reviewed and amended accordingly.Although much progress has been achieved with respect to the quality of HCC and metastatic liver cancer guidelines, the overall methodological quality is moderate with poor applicability and potential conflict of interests (COIs). The evidence-based guidelines has become mainstream for high quality guideline development, such as the Japanese Ministry of Health (JMH) guideline, American Association for the Study of Liver Disease (AASLD), and European Association for the Study of Liver/European Organization for Research and Treatment of Cancer (EASL-EORTC) guideline; however, there is still a need to further increase transparency, quality of evidence rating, and the recommendation process and to address COIs issues.Checklist S1(DOCX)Click here for additional data file.


Background. Circumsporozoite protein (CS) is the antigenic target for RTS,S, the most advanced malaria vaccine to date. Heterologous prime-boost with the viral vectors simian adenovirus 63 (ChAd63)-modified vaccinia virus Ankara (MVA) is the most potent inducer of T-cells in humans, demonstrating significant efficacy when expressing the preerythrocytic antigen insert multiple epitope–thrombospondin-related adhesion protein (ME-TRAP). We hypothesized that ChAd63-MVA containing CS may result in a significant clinical protective efficacy.Methods. We conducted an open-label, 2-site, partially randomized Plasmodium falciparum sporozoite controlled human malaria infection (CHMI) study to compare the clinical efficacy of ChAd63-MVA CS with ChAd63-MVA ME-TRAP.Results. One of 15 vaccinees (7%) receiving ChAd63-MVA CS and 2 of 15 (13%) receiving ChAd63-MVA ME-TRAP achieved sterile protection after CHMI. Three of 15 vaccinees (20%) receiving ChAd63-MVA CS and 5 of 15 (33%) receiving ChAd63-MVA ME-TRAP demonstrated a delay in time to treatment, compared with unvaccinated controls. In quantitative polymerase chain reaction analyses, ChAd63-MVA CS was estimated to reduce the liver parasite burden by 69%–79%, compared with 79%–84% for ChAd63-MVA ME-TRAP.Conclusions. ChAd63-MVA CS does reduce the liver parasite burden, but ChAd63-MVA ME-TRAP remains the most promising antigenic insert for a vectored liver-stage vaccine. Detailed analyses of parasite kinetics may allow detection of smaller but biologically important differences in vaccine efficacy that can influence future vaccine development.Clinical Trials Registration. NCT01623557. P. falciparum malaria remains a major public health concern ) , using tP. falciparum strain 3D7–infected Anopheles stephensi mosquitoes. This took place at the Alexander Fleming Building, Imperial College , and mosquitoes were supplied by the Department of Entomology, Walter Reed Army Institute of Research . Healthy, malaria-naive men and non-pregnant women aged 18–45 years were invited to participate in the study. All volunteers gave written informed consent prior to participation, and the study was conducted according to the principles of the Declaration of Helsinki and in accordance with good clinical practice. There was no selection of volunteers on the basis of preexisting neutralizing antibodies to the ChAd63 vector before enrollment. The full list of inclusion and exclusion criteria is given in the Supplementary Materials.The study was conducted at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford , and at the National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility, part of the University of Southampton and University Hospital Southampton National Health Service (NHS) Foundation Trust . The challenge procedure was performed as previously described , using 5All necessary approvals for the study were granted by the United Kingdom National Research Ethics Service, Committee South Central–Oxford A (reference 12/SC/0037), and the United Kingdom Medicines and Healthcare Products Regulatory Agency (reference 21584/0293/001-0001). The study was additionally reviewed by the Western Institution Review Board  at the request of the PATH Malaria Vaccine Initiative and was approved. The Genetically Modified Organisms Safety Committee of the Oxford University Hospitals NHS Trust (reference GM462.11.65) authorized recombinant vaccine use. The trial was registered with ClinicalTrials.gov (reference NCT01623557). The local safety committee provided safety oversight, and good clinical practice compliance was independently monitored by an external organization .P. falciparum strain T9/96 ; group 2: Spearman r = −0.3 [P = .34]; Figure 7A and 7B). A marginal negative correlation was seen in group 2 between IgG antibody responses to ME-TRAP and qPCR findings 7.5 days after CHMI . No significant correlation was seen between IFN-γ ELISPOT findings for CS or ME-TRAP and qPCR findings 7.5 days after CHMI for group 1 or 2 , in concordance with previous data in which ELISPOT-determined responses did not correlate with vaccine efficacy [In group 1 but not group 2, IgG antibody responses to CS correlated significantly and negatively with qPCR-determined densities 7.5 days after CHMI  and a delayed time to diagnosis in 33% (5 of 15). This efficacy is slightly less than that recently reported in another CHMI study of ChAd63-MVA ME-TRAP , despiteChAd63-MVA CS induced moderate to high IFN-γ–expressing T-cell responses, but anti-CS IgG levels were markedly lower than that seen with in a sporozoite CHMI trial assessing RTS,S, in which 50% of vaccinees 18 of 36) receiving RTS,S/AS01B and 32% (14 of 44) receiving RTS,S/AS02A achieved sterile protection  . The cor of 36 reKaplan–Meier analysis of time to diagnosis between vaccinees and unvaccinated controls and numerous analyses of the qPCR data demonstrated significant efficacy for ChAd63-MVA ME-TRAP alone. There was no such statistically significant difference for the ChAd63-MVA CS vaccines using the same analysis. However, the AUC analysis, comparison of parasitemia at 7.5 days after CHMI, the evidence of sterile protection, and a delay to diagnosis in certain vaccinees all support the view that ChAd63-MVA CS led to a reduction  in the number of parasites released from the liver. Because ChAd63-MVA ME-TRAP was, by use of the same measures, estimated to reduce the liver parasite burden by 79%–84%, it appears that relatively large reductions in liver-stage infection are required to significantly influence clinical outcomes after mosquito bite CHMI, as suggested previously , 35. As Our data, importantly, compare the efficacy of ChAd63-MVA containing CS or ME-TRAP and, together with previous data comparing these antigens in DNA-MVA  and fowlWe suggest that detailed analyses of parasite kinetics should be routinely performed in future CHMI vaccine studies to allow detection of smaller but biologically important differences in vaccine efficacy that could influence future vaccine development.Supplementary materials are available at The Journal of Infectious Diseases online . Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.


Thus, it is not possible to "put in thesame bag'' all of the different lesion types and clinical imaging categorization, whichare clear factors that contribute to a misinterpretation of the results. Third, no one method of monitoring byitself can influence the outcome of a particular entity. It is the process ofcollecting, broadly analyzing and, finally, making choices based on data that willultimately have a real impact. Whenthe authors introduce and then discuss their paper, they engage in a major misconceptionthat is worth mentioning. The Best Trip Trial, despite being published in a high-impact journal, hassignificant limitations. It has been subject to various criticisms and has raisedcontroversy of all kinds.-9 The study was not designed to assessintracranial pressure (ICP) monitoring; instead, the aim of the trial was to analyze twodifferent approaches to the same problem: intracranial hypertension. However, Ferreira et al. did notinclude any data related to ICP measurements. In my opinion, to achieve statisticalpower, the study's sample size (n) should account for the number of episodes of ICPincrease, not the number of patients. Fourth, the previous progress in understanding thepathophysiology of severe traumatic brain injury using modern multimodal monitoringtechniques allows us today to reflect on some issues. Several questions remainunanswered. When should therapy for intracranial hypertension begin? Which measurementsto treat according to lesion type? What is the period of evolution of the pathology?Which variables can influence its measurements?I read with great interest the work of Ferreira et al., which deserves some reflectionsand commentary. First, the findings should be interpreted with great caution. Althoughthe statistical methodology is valid and correct, it has many limitations that have beenexplained perfectly both by the authors and in Prof. Biestro's editorialcomments.,11 Although there are other issues to analyze andreflect on, I would like to make one last point. Konstantin Tsiolkovsky, a Sovietphysicist and fervent believer in the presence of life on other planets, coined thephrase ''the absence of evidence does not mean evidence of absence''. It has been over 60 years since theclose correlation between intracranial hypertension and death was established in casesof severe traumatic brain injury.Since then, a significant amount of ''water has passed under the bridge'', and althoughwe do not have high-quality studies that follow the standards of evidence-basedmedicine, the published data are overwhelming. Thus, until today, there have not beenvalid reasons to question the role of ICP monitoring in the management of severetraumatic brain injury.It is important to note and understand that ICP is only another number in a largeequation, and its control is one way, but not the only way, to achieve the finalgoal.Daniel Agustín GodoyIntensive Care Unit, San Juan Bautista Hospital - Catamarca, Argentina andNeurointensive Care Unit, Sanatorio Pasteur - Catamarca, Argentina.Mario Di NapoliNeurological Service, San Camillo de' Lellis General Hospital - Rieti, Italy andNeurological Section, SMDN-Center for Cardiovascular Medicine and CerebrovascularDisease Prevention - Sulmona, L'Aquila, Italy.


Health technology assessment and healthcare decision-making are based on multiple criteria and evidence, and heterogeneous opinions of participating stakeholders. Multi-criteria decision analysis (MCDA) offers a potential framework to systematize this process and take different perspectives into account. The objectives of this study were to explore perspectives and preferences across German stakeholders when appraising healthcare interventions, using multi-criteria assessment of a heart pulmonary sensor as a case study.An online survey of 100 German healthcare stakeholders was conducted using a comprehensive MCDA framework (EVIDEM V2.2). Participants were asked to provide i) relative weights for each criterion of the framework; ii) performance scores for a health pulmonary sensor, based on available data synthesized for each criterion; and iii) qualitative feedback on the consideration of contextual criteria. Normalized weights and scores were combined using a linear model to calculate a value estimate across different stakeholders. Differences across types of stakeholders were explored.The survey was completed by 54 participants. The most important criteria were efficacy, patient reported outcomes, disease severity, safety, and quality of evidence (relative weight >0.075 each). Compared to all participants, policymakers gave more weight to budget impact and quality of evidence. The quantitative appraisal of a pulmonary heart sensor revealed differences in scoring performance of this intervention at the criteria level between stakeholder groups. The highest value estimate of the sensor reached 0.68  for industry representatives and the lowest value of 0.40 was reported for policymakers, compared to 0.48 for all participants. Participants indicated that most qualitative criteria should be considered and their impact on the quantitative appraisal was captured transparently.The study identified important variations in perspectives across German stakeholders when appraising a healthcare intervention and revealed that MCDA can demonstrate the value of a specified technology for all participating stakeholders. Better understanding of these differences at the criteria level, in particular between policymakers and industry representatives, is important to focus innovation aligned with patient health and healthcare system values and constraints.The online version of this article (doi:10.1186/s12961-015-0011-1) contains supplementary material, which is available to authorized users. Its aim is to inform the formulation of safe, effective, health policies that are patient focused and seek to achieve best value” [Health technology assessment (HTA) is defined by the European Network for HTA as a “t value” . AccordiHTA and policy decisions are usually complex due to the multiple aspects considered and the extensive amount of evidence. Frequent gaps in the evidence and associated uncertainty also contribute to the challenges faced by decision makers. Complex interventions complicate this problem further. The implementation aspects of complex health interventions are an essential link to the desired health outcomes ,3. In tuIn addition, the current approaches in HTA and healthcare decision-making have some limitations regarding the integration of the diversity of stakeholders’ preferences and perspectives in their processes. On the one hand, patient and public involvement is gaining more and more attention from health policymakers . On the www.evidem.org), and includes a set of relevant criteria to explore stakeholders perspectives and preferences regarding evaluation and decision making for healthcare interventions. The framework consists of a core quantitative MCDA model and a qualitative contextual tool, with a comprehensive range of criteria and sub-criteria, which allows for adaptation to context.Comprehensive multi-criteria decision analysis (MCDA) provides a tool in this direction. Its methodological basis enables the exploration of stakeholders’ preferences and perspectives and to explicitly structure the broad range of criteria on which real life evaluations and decisions are based . MCDA prThe objectives of this study were to explore perspectives and preferences, in the German context and across different types of stakeholders, when appraising healthcare interventions using multi-criteria assessment of a heart pulmonary sensor as a case study.The EVIDEM (EVIdence based Decision-Making) framework, designed to assess interventions in healthcare using quantitative and qualitative decision criteria, was selected. This established framework proposes a comprehensive range of criteria fulfilling the methodological requirements of MCDA models. Additionally, we provided synthesized data on the heart sensor for each of these criteria to make the online survey feasible and to allow exploration of perspectives from a broad range of stakeholders. The framework, which includes normative  and feasibility (what can be done?) criteria, was adapted for this study in the German context including its translation. The EVIDEM core model used in this study consisted of 14 universal, quantitative criteria, while the contextual tool included 8 qualitative criteria. A definition of all criteria and scales used in the survey is provided in the Additional file In the first part of the survey, individual perspectives on what matters most in HTA, i.e., which criteria contribute the most to the value of healthcare interventions, was captured by weight elicitation independently of the intervention. Participants were asked to provide relative weights for each criterion of the MCDA core model from their individual perspective, but in the context of coverage decision for healthcare interventions in general. For this survey, we selected a 5-point weighting scale. Participants provided a relative weight for each decision criterion of the quantitative core model, using a 5-point scale . They were also asked whether the contextual criteria should be considered for coverage decisions  available scientific and colloquial data obtained from a literature review supplemented by data analyses and ii) quantitative performance scores of this intervention for each criterion of the core model and qualitative impacts for each contextual criterion.Participants scored the performance of the pulmonary sensor using a scoring scale with defined anchors for each criterion ranging from 0 to 3, except for the intervention outcomes criteria  which also had a negative scale (−3 to +3) to capture worse outcomes. An additional box for every criterion was available for participants to indicate if the data was not sufficient to understand the performance of the sensor, which corresponded to a zero score . For qualitative contextual criteria, participants indicated whether consideration of a given criterion had a positive, neutral, or negative influence on the decision about the sensor. The estimated value of the heart sensor was elicited by the performance scores.The online survey was tested in advance by six participants to ensure optimal responses and understanding of the process and of the criteria to be considered.CardioMEMS, the assessed pulmonary heart sensor, enables the permanent surveillance of patients with chronic heart failure (New York Heart Association III), based on telemonitoring, using a microelectromechanical system. This intervention was selected as a relevant case study given the current developments and the need to guide future research and development in the field of cardiology and telemedicine . The impThe MCDA evidence matrix was populated with available data for each criterion identified through an extensive literature review supplemented by additional analyses due to the scarcity of data. The clinical efficacy for the sensor was identified by searching healthcare databases, including PubMed, ScienceDirect (EMBASE), and Scopus, as well as websites of HTA and regulatory agencies. Since the device is relatively new, available data was limited. The study team drafted the relevant HTA report, which served as background for the MCDA questionnaire. Clinical data was obtained from one high-quality randomized controlled trial  and a FoIn total, 100 stakeholder representatives were contacted by email to participate in the survey (20 from each group) with an emailed invitation letter describing the project. The five key responder groups represented key healthcare stakeholders including health professionals, health policymakers, including from the Federal Joint Committee (GBA), Institute for Quality and Efficiency in Health Care, Statutory Health Insurance (GKV-Spitzenverband), industry, citizens, and researchers. Participants were identified through personal and business networks of the research group and were asked to take their own perspective into account when providing the relative importance of decision criteria and appraising the selected intervention for reimbursement decisions.Weights, scores, and impact obtained from the participations were analyzed in Excel. Descriptive statistics were applied and mean and standard deviations (SD) calculated in Excel. Normalized weights and scores were combined for each criterion  and summed using a linear additive model to calculate the MCDA value estimates for each participant, for each group of stakeholders, and for all participants .Descriptive statistics  are reported for those criteria for which largest differences across groups were observed. The cut-off value for reporting differences between mean for stakeholders and the mean for the whole population were set at 0.008 for normalized weights (distributed to sum up to 1) and 0.2 difference for scores .In total, 54 participants completed the survey (54% response rate) as illustrated in Table Regarding relative weights provided by survey participants, Figure The largest variations in weights across participants were observed for ‘Size of population’  and the criteria ‘Type of medical service’ , ‘Budget impact’ , and ‘Impact on other spending’ . The smallest variations were observed for ‘Improvements in effectiveness/efficiency’  and the criteria ‘Public health interest’ , ‘Improvement in patient-reported outcomes’ , and ‘Completeness and consistency of the reported evidence’ .Regarding differences in weights between stakeholder groups, policymakers weighted the criteria ‘Budget impact’ and ‘Relevance and validity of evidence’ higher  compared to all participants; they reported a lower relative weight for ‘Type of medical service’ (−0.011) and ‘Severity of disease’ (−0.008)  and ‘Impact on other spending’ . The largest variations in scores across all stakeholders were observed for the criteria ‘Improvements in safety and tolerability’  and ‘Clinical guidelines’ , ‘Budget impact’ , and ‘Cost-effectiveness’ .These results were also reflected in the MCDA value estimate of 0.48  individual preferences and values on what matters most, or in other words, which criteria contribute the most to the worth of healthcare interventions in general (captured by weights independently of the intervention), and ii) understanding the value of a heart sensor measured by the contribution of a comprehensive range of criteria (elicited by performance scores).are used to weight decision criteria” [Firstly, values and preferences provided the base for statements about the relative importance of assessment criteria. Other MCDA studies used DCEs to elicit preferences ,15,17,20riteria” . ConsequSecondly, stakeholders need to perceive and understand the complex evidence about health technologies, i.e., CardioMEMS. However, the perception and understanding of the provided evidence can be very different depending on the professional background of each stakeholder. As highlighted in our study, stakeholders scored the evidence very differently, depending on their personal background. Finally, the qualitative feedback contains both aspects: preferences and values as well as perception and understanding of the evidence.Better understanding of these differences across stakeholders at the criteria level is important to focus innovation aligned with patient health and healthcare system values and constraints .Participants representing all types of stakeholders across the healthcare decision continuum in Germany indicated that the most important criteria for reimbursement decision making were ‘Improvement of efficacy/effectiveness’ , ‘Improvements in patient reported outcomes’ , ‘Disease severity’ , ‘Improvement in safety’ , and ‘Quality of evidence’ (relative weight >0.075 each). These results are to some extent in agreement with results of an international survey of decision criteria which indicated that most important decision criteria included ‘Clinical efficacy’ , ‘Safety’ , ‘Quality of evidence’ , ‘Disease severity’ , and ‘Impact on healthcare costs’ , a majorThis survey reveals the primary importance to German stakeholders related to the three criteria of the cluster ‘Intervention outcomes’ , including ‘Improvement in efficacy/effectiveness’ , ‘Improvement in safety’ , and ‘Improvement in patient reported outcomes’ , as well as the consensus on this point, revealed by the lowest SD across participants on their relative importance. This is in agreement with the current HTA approach in place in Germany through the GBA, which gives a high importance to ‘Incremental efficacy’ , ‘Incremental safety’ , and ‘Incremental patient reported outcomes’. Indeed, patient relevant outcomes  are the only criteria used in the assessment of the benefit of medical interventions .However, the criterion ‘Disease severity’ was ranked third in this survey, revealing the importance of one of the fundamental objectives of healthcare to alleviate suffering in those who are worst off. However, current health policy does not actively take severity of disease into account . The levFor policymakers, the criterion ‘Quality of the evidence’ was more important than for other stakeholders, revealing the value of evidence based decision-making in the German context. The GBA emphasizes the quality of evidence which needs to clearly demonstrate any claimed benefit .For all participants, weights for economic criteria were generally lower than for other clusters of criteria, and ‘Budget impact of the intervention’ had the lowest weight of all criteria. Still, the highest SD (0.024) across all criteria indicated a poor agreement on the importance of economic issues. Across groups of stakeholders, the lowest weights on economic criteria were observed from the responses of health professionals, which reveal their wish to help patients without focusing on economic constrains -51. ThesRegarding the qualitative assessment, a majority of stakeholders reported that criteria alignment of interventions with the ‘Goal of healthcare’ , ‘Fairness and priorities’ , ‘Opportunity costs and feasibility’ , ‘System capacity and implementation’ , and ‘Regulatory status’ should be considered in reimbursement processes. These qualitative but sometimes critical elements of decisions need a more formal integration into existing processes. Regarding the criteria ‘Political and historical context’ and ‘Pressures/barriers from stakeholders’ , full awareness of these aspects may be critical to make provisions to ensure acceptability and implementation of decisions ,54, althAppraisal of the pulmonary heart sensor revealed that the major contributors to the value of this innovation were ‘Size of population’ , ‘Severity of disease’ , and ‘Comparative intervention limitations’ , highlighting the health need for the management of heart failure. ‘Improvement in efficacy/effectiveness’ was also a major contributor but limited data   was critAlthough stakeholder groups were too small to perform comparative statistical tests, a quantitative appraisal of the pulmonary heart sensor revealed large differences in scores between stakeholder groups. Health professionals scored ‘Improvement of efficacy/effectiveness’ for the heart sensor higher  while health policymakers scored this criteria lower . This suggests a more stringent judgment on what constitutes an improvement from health policymakers. The scoring scales of the MCDA framework used in the survey capture the judgment made on evidence, which results from an objective interpretation of evidence and a more subjective definition of what constitutes a major, moderate, minor, absence of improvement, or worsening of efficacy/effectiveness. Despite the caveats discussed above, this difference appears to quantitatively confirm the different viewpoints on the value of new interventions between innovation-oriented manufacturers and policymakers and purchasers of innovation in Germany .This value estimate of 48% is of interest as far as it represents the contribution of each criterion to value, but the absolute value has limited interest in the absence of a frame of reference. Comparisons to other MCDA studies are not appropriate due to different sets of decision criteria and the application of other technical approaches, e.g., AHP. The comparison to other EVIDEM studies concludes certain reliability across different cultural, societal, and economic settings. MCDA estimates were 41% for growth hormone for Turner syndrome patients , 44% forAs recommended by Baltussen et al. , MCDA esStudy results should be considered in light of their limitations. We selected the 5-point weight elicitation technique and used linear scoring scales to keep the survey simple and to shorten time commitment. Still, it would be of interest to explore other weighting techniques and different types of scales as a follow-up to this exploratory study. In particular, the fact that differences in criteria weights had only limited influence on the overall value estimates raises some questions. The discriminatory power of the 5-point scale might be limited regarding the large number of criteria. As this was the first application of the EVIDEM framework to explore differences in criteria weights across stakeholder groups, this limitation should be taken into account for further research. Preston et al.  highlighOur sampling approach  has to be taken into account carefully when interpreting the presented results. However, this systematic sampling approach ensured a high response rate of 54%. Comparisons across groups of stakeholders are exploratory given the small sample size and the stochastic nature of the data, but nonetheless revealed differences. The lack of appropriate evidence, for most criteria, and difficulties in understanding the complex information resulted in lower scores and higher SDs, reflecting uncertainty on data and limitations in appraisal. Lay participants felt overtaxed by scientific evidence which is also true for patient representatives in other studies . For staThis study provided important insights into the current decision-making landscape in Germany and revealed that MCDA can demonstrate the value of a specified technology for all participating stakeholders. The application of a multi-criteria framework allowed to identify perspectives across German stakeholders when appraising a healthcare intervention at the criteria level, both quantitatively and qualitatively. A better understanding of these differences at the criteria level, in particular between policymakers and industry representatives, is important to focus innovations aligned with healthcare system values and constraints. The appraisal of the pulmonary heart sensor highlighted the health need for the management of heart failure. Multi-criteria frameworks provide a basis of dialogue between all stakeholders, which is beneficial for all parties , and whi


The uncreative mind can spot wrong answers. It takes a creative mind to spot wrong questions. — Anthony Jay, British writer and journalistWhen practitioners take an evidence-based approach to chronic disease prevention, they undertake several important processes : 1) makiPreventing Chronic Disease provide some of the best examples to date showing how practice–academic partnerships can produce new scientific information that is timely and relevant for practitioners as they seek to take a more evidence-based approach to chronic disease prevention. This collection builds on recent work from Jacobs and colleagues  Mentorship Program has a set of competencies that are closely aligned with this concept of evidence-based public health (EBPH)  is then handed off to practitioners and policy makers who are charged with implementing a program or policy (the “pull”). As noted by Green, if we are seeking to foster evidence-based practice, we need more practice-based evidence   and adaptation (the ability to fit the community or setting of interest). Adapting interventions from one setting to another requires considerations regarding the extent to which the determinants of the issue are comparable (which determines whether the intervention focus is or is not appropriate) and how contextual differences  may affect the intervention. Lee and colleagues developed a useful approach for planned adaptation that includes 4 steps: 1) examining the evidence-based theory of change, 2) identifying population differences, 3) adapting the program content, and 4) adapting evaluation strategies .Participatory research methods have the potential to address chronic diseases by involving community members and stakeholders in the decision-making processes, thus enhancing the relevance and overall quality of research. Within community and public health settings, participatory research builds trust, respect, capacity, empowerment, accountability, and sustainability , all of Effective dissemination and implementation of evidence-based interventions is a formidable challenge. In part, this is due to differing priorities. For researchers, the priority is often on discovery (not application) of new knowledge; whereas for practitioners and policy makers, the priority is often on practical ways of applying these discoveries in their settings. Research on how to disseminate evidence-based interventions has now taught us several important lessons: 1) multicomponent, active strategies are often the most effective; 2) leadership matters but is not sufficient; 3) provider behavior is difficult to change and (when changed) is even harder to sustain; and 4) systems are complex and change is recursive. Yet most of these lessons have been learned from studies with early adopters in high-resource settings. We have yet to learn the lessons of how to change public health in more challenging settings. Several articles in this collection take on that challenge.These articles lead to areas where additional research is warranted, for example —How to emphasize building strategic partnerships early in the research process.New and more rapid methods for determining when a new program or policy is ready for adoption in a nonresearch setting .Ways of ensuring that an intervention is developed in ways that match well with adopters’ needs, assets, and time frames.Many of these challenges need particular attention in settings with high health-related disparities where system and resource constraints are great and where delivery systems are underdeveloped.Public health history teaches us that a long latency period often exists between the scientific understanding of a viable disease control method and its widespread application on a population basis. By expanding the evidence base for public health and applying the evidence already in hand, we can shorten the latency period and begin to fully achieve the promise of prevention. In the current era of level or shrinking public health budgets, it is more important than ever to increase the effectiveness and efficiency of public health services by applying the principles of EBPH.


This study aims to identify “best practice” at the population-level on the basis of existing quasi-experimental natural experiments and cost effectiveness, with small scale emerging and promising evidence comprising “good practice”. At the community-level, using expert consensus, the ACE (Assessing Cost-Effectiveness in Prevention Project) grading system was used to differentiate “best practice” interventions with sufficient evidence from “good practice” interventions with limited but promising evidence.A narrative review was conducted given the wide range of relevant interventions. Expert consensus was used to identify “best practice”. Child protection laws, improved control of neurocysticercosis and mass awareness campaigns were identified as “good practice”. At the community level, socio-emotional learning programmes in schools and parenting programmes during infancy were identified as “best practice”. The following were all identified as “good practice”: Integrating mental health promotion strategies into workplace occupational health and safety policies; mental health information and awareness programmes as well as detection of MNS disorders in schools; early child enrichment/preschool educational programs and parenting programs for children aged 2–14 years; gender equity and/or economic empowerment programs for vulnerable groups; training of gatekeepers to identify people with MNS disorders in the community; and training non-specialist community members at a neighbourhood level to assist with community-based support and rehabilitation of people with mental disorders.At the population-level, laws and regulations to control alcohol demand and restrict access to lethal means of suicide were considered “Interventions provided at the population- and community-levels have an important role to play in promoting mental health, preventing the onset, and protecting those with MNS disorders. The importance of inter-sectoral engagement and the need for further research on interventions at these levels in LMICs is highlighted.The online version of this article (doi:10.1186/s13033-016-0060-z) contains supplementary material, which is available to authorized users. Over two thirds of people with mental, neurological and substance use (MNS) disorders do not receive the care they need worldwide . This isIn addition to strengthening services for mental health care provided by the health care system, for example, through programmes such as the Mental Health Gap Action Programme (mhGAP) , 4; inteIn pursuit of reducing the burden of mental disorders in LMICs, identifying interventions that can be effectively and feasibly delivered at these levels is helpful to decision-makers as it highlights where resources should be allocated, besides in the health care sector . It also enables potential opportunities, synergies and efficiencies to be identified across multiple sectors.This paper provides an overview of the evidence for interventions at the population- and community-levels in LMICs along the continuum of care from interventions that promote positive mental health, and primary preventative interventions which strive to prevent the onset of MNS disorders; through to identification and case detection; as well as treatment, care and rehabilitation. The evidence presented for each level is structured around these core elements of the continuum of care. The review was informed by the chapter on population and community ‘platforms’ or levels of care in the mental health volume of Disease Control Priorities (third edition)  as well best practice” on the basis of whether evidence from quasi-experimental natural experiments was available in LMICs as well as evidence of cost-effectiveness in LMICs. “Good practice” interventions were identified on the basis of whether there was limited but promising local small scale studies in LMICs, and where further research was still needed.Population level interventions are rarely evaluated using the gold standard of randomized controlled trials. More commonly used approaches are quasi-experimental natural experiments, with before-and-after data obtained from archival analysis of official statistics or surveys, and comparisons with populations who have not been exposed to the intervention, where possible. A narrative review approach was used given the need to cover a wide range of study designs and issues which do not lend themselves to a systematic review . Availabsufficient evidence is when there is at least one systematic review of randomized control trials (RCTs), as well as several good quality RCTs or several high-quality pseudo-RCTs using alternate allocation or another method, or non-RCTs with comparative groups to exclude chance. Limitedevidence is when the effect is probably not due to chance, but bias cannot be ruled out as a possible explanation for the effect. We have classified this evidence as promising. Inconclusive evidence is when there is no evidence of systematic reviews or RCTs, although there may be a few poor quality pseudo-randomized/non-RCTs with comparative groups or cohort studies.Studies on interventions at the community level in LMICs were identified on the same basis as for the population-level. Many of these interventions have a prevention and promotion focus, and expert consensus by the authors of this manuscript was used to evaluate effectiveness using the ACE-Prevention framework . The ACEBest-practice” interventions were identified on the basis of whether there was sufficient evidence of their effectiveness in LMICs using the ACE grading system, evidence of their cost-effectiveness in HICs, and evidence of their feasibility in relation to cultural acceptability and capacity for scale-up in resource-constrained settings in LMICs. “Good practice” interventions were identified on the basis of sufficient evidence of their effectiveness in HICs and limited but promising evidence of their effectiveness in LMICs, using the ACE framework.“Details of the specific studies reviewed can be found in Additional file Reducing demand for alcohol productsThe prevention of harmful alcohol use in adults provides benefits across diseases. It can help prevent the development of alcohol use disorder and unipolar depression; other chronic non-communicable diseases, such as cardiovascular disease, diabetes, and cirrhosis of the liver; and help prevent accidental and intentional injuries or death .best practice”. Raising taxes is, however, less effective in countries with lower levels of alcohol consumption where other targeted interventions, such as enforcing drunk-driving legislation and brief screening and intervention (BSI), are more effective [Evidence from HICs and LMICs indicates that the most cost-effective strategy for reducing alcohol consumption is increased taxation and/or pricing of alcohol products, followed by bans on alcohol advertising, restrictions on access to alcohol, and enforcement of drinking and driving legislation , 10. Lawffective . RegulatRestricting access to means of suicidebestpractice”. The impact of the introduction of pesticide regulations on the reduction of suicides in Sri Lanka provides an example of how this strategy has been effectively applied in LMICs, where the suicide rate of 47 deaths per 100,000 in 1995 was halved from 1996 to 2005, with a reduction of 19 769 suicides, as a result of the banning of all WHO toxicity Class pesticides in 1995 and the banning of endosulfan, a Class II toxicity pesticide in 1998 [Three quarters of the 804,000 deaths by suicide that are estimated globally for 2012 were from LMICs . Regulat in 1998 Other multi-sectoral public policies with promising evidence to promote mental health and prevent MNS disorders in children and adultsgood practice” at the population level.During childhood, child maltreatment is a risk factor for the development of MNS disorders . SufficiInformation and public awareness campaigns employ broad strategies and messages to promote mental health literacy, defined as knowledge and beliefs about mental disorders to aid their recognition, management, and prevention ; as wellMost information and awareness programs represent low-intensity interventions aimed at large numbers of people, often through print media, recordings, radio, television, cinema, mobile phones, and the Internet , 21. TheWith regard to anti-stigma interventions specifically, a systematic review of interventions in HICs by Clement and colleagues showed that mass media awareness programmes may reduce prejudice; although fewer studies have investigated their effects on actual discrimination . A revieThere is a paucity of evidence for the effectiveness of mass awareness programmes to improve mental health literacy and reduce stigma in LMICs. One study in the Russian Federation investigated the effectiveness of an anti-stigma computer program for improving knowledge and attitudes as well as reducing social distance among university students . Studentgood practice”; with more research in LMICs being particularly needed.Based on sufficient evidence from HICs and emerging evidence from LMICs, mass public awareness campaigns are recommended as “Evidence of the impact of legislation and regulations for improved identification, treatment and care is lacking from both HICs and LMICs. It would, however, be reasonable to assume that up-to-date mental health laws and regulations that are in line with the best practice and human rights standards such as those outlined by the WHO QualityRights  would prgood practice”, given limited but promising evidence, with a recommendation that more robust evidence be generated from LMICs.Workplace settings provide an ideal setting for the provision of promotion and prevention interventions for adults. Evidence from HICs indicates that individual and organizational level interventions improve and maintain mental health in the workplace, including screening and cognitive behavioral therapy (CBT) for preclinical symptoms of depression and anxiety to prevent the onset of these disorders , 38. TheEvidence is available from HICs on the identification and case detection of MNS disorders in the workplace. An evaluation of the APPRAND program in France found that individuals on sick leave who were screened and identified as having anxiety and depressive disorders by company health physicians, and who received an awareness-raising and referral intervention, displayed higher remission and recovery rates, compared to individuals in other centres who were not screened and who did not receive the intervention . PositivInterventions for the treatment, care, and rehabilitation of people with MNS disorders in the workplace have been shown to be effective in HICs. For people with common mental health problems, individual therapies rather than organizational interventions have been the most effective; in particular, CBT –46  interventionsStudies from HICs and LMICs indicate that universal SEL programs that promote social and emotional competencies can improve social and emotional functioning and academic performance in exposed children, as well as reduce risk behaviour. Systematic reviews from HICs show that universal SEL interventions in primary and post-primary schools promote children’s social and emotional functioning and academic performance, including evidence of long-term benefits –67. InteA systematic review , as wellTargeted/indicated interventions for high-risk children  that promote coping and resilience, including cognitive skills training have been found to help prevent the onset of anxiety, depression, and suicide in HICs –78. Sevebest practice” interventions in LMICs, and targeted school-based interventions as “good practice”, with more research on the role of individual and contextual variables on mental health outcomes required.Economic analyses from HICs indicate that SEL interventions in schools are cost-effective, resulting in savings from better health outcomes, as well as reduced expenditures in the criminal justice system , 86. BasMany people with MNS disorders have their onset during childhood and adolescence, and these early difficulties are likely to be present in the school context. Teachers have a critical role in identifying emerging problems and taking appropriate action, with RCTs from HICs providing evidence for training in indicated screening of developmental and behavioral disorders in schools. Mental health first aid for high school teachers has been tested using a cluster RCT . While dgood practice”; with further research in LMICs required.Given sufficient evidence from HICs as well as emerging promising evidence from LMICs, identification and case detection in schools of children with MNS disorders are recommended as “There is sufficient research evidence of the effective treatment and management of people with some types of MNS disorders in schools in HICs. A meta-analysis that examined the effectiveness of various types of school-based CBT for young people with anxiety and depression showed significant reductions in symptoms overall . School-Evidence from HICs indicates that children with emotional and behavioural disorders benefit from classroom environments that are predictable and consistent, with clear structures and rules; such settings are associated with improved classroom, peer behavior, and enhanced learning . InterveEvidence from LMICs for treatment, care and rehabilitation for children with MNS disorders is equivocal. An RCT of a universal school-based intervention in reducing depressive symptoms was conducted in Chile. Using CBT techniques delivered by non-specialists, this intervention comprised 11 1-h weekly and two booster classroom sessions. Although it was a universal intervention, the study analysed subgroups of young people with high depression scores. It showed no clinically significant difference between the intervention and control groups, and no evidence of effect modification by severity of symptoms . There hChild enrichment and preschool educational programsgood practice”.Robust evidence from HICs demonstrates the effectiveness and cost-effectiveness of early child enrichment and preschool educational programs  on children’s social and emotional wellbeing, cognitive skills, problem behaviors, and school readiness , 104; asParenting interventionsbest practice” [good practice”.The effectiveness of parenting interventions for promoting child emotional and behavioral adjustment in HICs, particularly in infants and younger children, has been demonstrated , as wellractice” , 111–116ractice”  with proractice” , 118–120Gender equity and/or economic empowerment interventionsgood practice”.A growing body of research indicates the feasibility and benefits for vulnerable adolescents and adults of gender equity and/or economic empowerment programs in LMICs –127. MicThere is an array of primary prevention and promotion interventions delivered in neighbourhood settings or through community groups. These include programs on early child enrichment/preschool educational programmes, community-based parenting, and gender and/or economic empowerment interventions.good practice”; with further research in LMICs recommended.Mental health first aid training at the community level involves training members to identify when a person is developing a mental disorder, is suicidal, or is in crisis; to know how to manage the situation; and to know appropriate facilities for referral . EvidencPolicy shifts to deinstitutionalization and decentralized care in many LMICs are heightening the need for community-based treatment and rehabilitation for mental disorders. There is emerging evidence of the effectiveness of collaborative community-based care interventions using a task-sharing approach in LMICs. The Community Care for People with Schizophrenia in India (COPSI) intervention compared the effectiveness of facility-based care with a collaborative community-based approach using a multicentre RCT. Findings demonstrated that the collaborative community-based approach in combination with facility-based care was most effective and was associated with improvements in disability and symptoms . Observabest practice” and “good practice” are summarized in Table Interventions identified as being “Interventions at the population level have a broad reach, promoting and protecting the mental health of the entire population through legislation, regulations, and public campaigns. There is good evidence that legislation and regulations to control alcohol demand can reduce alcohol consumption in LMICs at minimal cost, and laws and regulations restricting access to lethal means of suicide that are region-specific can reduce suicide rates in LMICs. There is also promising evidence of the benefits of mass public awareness campaigns on reducing stigma and discrimination; as well as the mental health benefits of child protection laws, and laws and regulations for improved control of neurocysticercosis in reducing epilepsy specifically.At the community level, there is evidence from LMICs that neighbourhoods are an important setting for the delivery of primary prevention and promotion interventions. In particular, there is strong evidence that parenting programs during infancy, that promote mother–child interaction, are beneficial for long term mental health. There is also promising evidence of the mental health benefits of early child enrichment/preschool educational programs, parenting programs for older children, and gender equity and/or economic empowerment programs for vulnerable groups. Neighbourhoods are also important settings for the identification of people with MNS disorders, using trained community gatekeepers.Schools are a particularly important setting for mental health promotion and prevention interventions in children; as well as identification. In particular, there is sufficient evidence of universal SEL programs for improving mental health outcomes in children and to a lesser degree targeted programmes in LMICs. Schools can also be used for the delivery of information and awareness programmes.Finally, the workplace presents an opportune setting for mental health promotion and prevention activities for adults, with emerging evidence in LMICs of the benefits of integrating stress reduction programmes and awareness-raising, particularly of alcohol and drug misuse.Although much attention has historically been paid to the health sector for the delivery of mental health services, greater consideration of interventions at the population- and community-levels are necessary, particularly for the delivery of mental health promotion and prevention interventions, as well as for the early identification of mental disorders, especially in children and adolescents, and to a lesser degree, care and rehabilitation. This review has identified “best practice” and “good practice” interventions at the population and community levels; providing evidence of potential opportunities and synergies for the strengthening of mental health and human capital development across multiple sectors in LMICs. Harnessing these opportunities, however, requires awareness of mental health as a public health and social development priority and political will to engage in collaborative arrangements across different sectors.