Realist synthesis is an increasingly popular approach to the review and synthesis of evidence, which focuses on understanding the mechanisms by which an intervention works (or not). There are few published examples of realist synthesis. This paper therefore fills a gap by describing, in detail, the process used for a realist review and synthesis to answer the question ‘what interventions and strategies are effective in enabling evidence-informed healthcare?’ The strengths and challenges of conducting realist review are also considered.The realist approach involves identifying underlying causal mechanisms and exploring how they work under what conditions. The stages of this review included: defining the scope of the review (concept mining and framework formulation); searching for and scrutinising the evidence; extracting and synthesising the evidence; and developing the narrative, including hypotheses.Based on key terms and concepts related to various interventions to promote evidence-informed healthcare, we developed an outcome-focused theoretical framework. Questions were tailored for each of four theory/intervention areas within the theoretical framework and were used to guide development of a review and data extraction process. The search for literature within our first theory area, change agency, was executed and the screening procedure resulted in inclusion of 52 papers. Using the questions relevant to this theory area, data were extracted by one reviewer and validated by a second reviewer. Synthesis involved organisation of extracted data into evidence tables, theming and formulation of chains of inference, linking between the chains of inference, and hypothesis formulation. The narrative was developed around the hypotheses generated within the change agency theory area.Realist synthesis lends itself to the review of complex interventions because it accounts for context as well as outcomes in the process of systematically and transparently synthesising relevant literature. While realist synthesis demands flexible thinking and the ability to deal with complexity, the rewards include the potential for more pragmatic conclusions than alternative approaches to systematic reviewing. A separate publication will report the findings of the review. The range of approaches to research review and synthesis has been growing over recent years . One appTraditional systematic review approaches have been criticised for being too specific and inflexible ,9,10. Thet al.[Realist review has emerged as a strategy for synthesising evidence and focuses on providing explanations for why interventions may or may not work, in what contexts, how and in what circumstances . For exaet al. undertooThe realist approach is philosophically rooted in realism, which combines three social science principles: causal explanations are achievable; social reality is mainly an interpretative reality of social actors; and social actors evaluate their social reality . Realismi.e., demi-regularities [The aim of a realist synthesis is ‘…to articulate underlying programme theories and then to interrogate the existing evidence to find out whether and where these theories are pertinent and productive. Primary research is examined for its contribution to the developing theory…’ . In the larities . RealistA realist synthesis follows similar stages to a traditional systematic review Table , but wit1. The focus of the synthesis is derived from a negotiation between stakeholders and reviewers and therefore the extent of stakeholder involvement throughout the process is high.2. The search and appraisal of evidence is purposive and theoretically driven with the aim of refining theory.3. Multiple types of information and evidence can be included.4. The process is iterative.5. The findings from the synthesis focus on explaining to the reader why (or not) the intervention works and in what ways, to enable informed choices about further use and/or research .The rest of this paper describes in detail the ReS-IS team’s approach to applying the realist synthesis method to a review of interventions that enable evidence-informed healthcare, including the strengths and challenges encountered in its use. A separate publication will describe the findings of the review and synthesis in detail.http://www.uofaweb.ualberta.ca/kusp/KU0Xarchive.cfm). The stakeholders are a multi-disciplinary community of researchers, practitioners, and policy makers with expertise in knowledge translation. This community served as a stakeholder reference group that were consulted at key stages in the review process: questions formulation, tool development, and evidence synthesis, providing critique and challenge to the method and emerging findings.Numerous interventions have been applied and tested to promote the use of research evidence in practice. Implementation of such interventions is often accompanied by complex strategies comprising support structures, resources and processes. While numerous systematic reviews have been conducted to determine the effectiveness of specific interventions -22, a syThis stage is fundamental to a realist synthesis because it provides the structure and framework for examining and synthesising diverse evidence . The chaA list of questions about interventions to promote knowledge use was developed and refined through extensive dialogue in small and larger group discussions. From these questions, the meaning of terms was clarified and concepts were identified. For example the meaning of terms such as ‘evidence-based,’ ‘knowledge,’ ‘strategy,’ and ‘intervention’ was discussed. It was agreed that an intervention was a broad concept, while strategies referred to mechanisms or approaches to achieve the intervention. Consensus was reached on the use of the term ‘evidence-informed,’ in preference to ‘evidence-based,’ on the grounds that decision making in practice, for good reasons, is not always research-based, but rather takes into account a range of factors in addition to empirical evidence . We alsoi.e., ‘theory areas’ emerged: change agency, technology, education and learning strategies, and systems change. These concepts were then framed to construct the theoretical framework, which underwent a number of iterations before declaration of the final framework. Figure The group then identified common concepts among the questions developed in the previous activity. Eventually four key concepts, The theoretical framework is made visible in a realist synthesis through the ‘data extraction forms.’ This is a unique feature of realist synthesis in that, unlike traditional systematic reviews, a bespoke set of data extraction forms are developed based on the content of the theoretical framework  of change agents that have an impact and connect themes to action. Overall our approach to analysis was concerned with understanding why mechanisms were having an effect (or not).In realist synthesis the literature needs to be scrutinised to identify studies related to the targeted ‘programme theories’ . This foet al.[Six online databases were searched: Medline, CINAHL, Embase, PsycInfo, Sociological Abstracts, and Web of Science. Ovid was used to execute the search within a 10-year publication period, which was considered an appropriate timeframe in the search for intervention studies. As a quality measure, one group member reviewed the indexes of 14 journals that publish articles about knowledge utilization issues. A second group member determined that relevant papers from these journals were adequately indexed in the databases selected. Additionally, using their knowledge of the literature all team members reviewed the final reference list to ensure there were no obvious omissions. Although Pawson et al. describeSearch results were saved as text files and downloaded into Reference Manager Professional Version 11.0. The content of the file was then backed-up to a secure server. Over 24,000 electronic references were returned from the change agents search strategies, which were screened through a process summarised in Figure The preliminary screen was intentionally inclusive to capture all articles potentially relevant to the review purpose, including those outside of healthcare. We erred on the side of inclusion wherever a title appeared to be even potentially relevant to the change agent/agency concept or any of the terms of reference developed in relation to the change agency component of the theoretical framework. At this stage, all seemingly relevant papers were retrieved in full-text for a more detailed relevance test: ‘Is the evidence provided in this theory area good and relevant enough to be included in the synthesis.’Using criteria for exclusion, in the next stage we undertook a preliminary screening of the article titles retrieved in the search and reduced the list of potentially relevant papers to 196. Second-level screening resulted in the exclusion of a further 144 papers, bringing the final number of papers relevant to this theory area to 52. This process was managed by two team members, in consultation with the wider group as appropriate. Our consistent reference point was the review framework and related theory area questions. Therefore decisions about what was eventually included and excluded was managed through discussions about whether the papers were of direct relevance to interventions that had been evaluated within a healthcare context.The primary reasons for exclusion of papers at this level included:i.e., demonstrating a systematic approach to inquiry).1. They were not research based .3. They were not relevant to healthcare, To test the usability and functionality of the data extraction form and to promote a consistent approach to data extraction, the tool was pre-tested, by all group members, on two purposefully selected articles. Pre-testing resulted in some minor modifications to the instrument prior to commencement of the review process. The group divided into five subgroups and the references related to the change agent theory area were divided evenly across the subgroups for appraisal.In contrast to other review processes, in a pure realist synthesis no literature is excluded (unless it does not relate to any of the theory areas). Because a paper is excluded in one theory area does not mean that it is necessarily excluded in other theory areas. Therefore, exclusion criteria at this level need to be explicit and a clear rationale needs to be documented for each article that is excluded. Consistent with Pawson’s suggestions, in this review the test for inclusion was: Is the evidence provided in this theory area ‘good and relevant enough’ to be included ?Discrepancies in opinions about the relevance of articles were resolved through discussion amongst the review group. Questions about relevance were guided by the theory area questions, and how particular pieces of evidence did or did not inform these. Final decisions erred on inclusiveness, rather than exclusion.If considered relevant, data were extracted from the article and then peer reviewed and checked by a second member of the subgroup. Even though the initial review wave comprised articles related to the change agent theory area, questions relating to each theory were applied during the extraction process because many of the articles reported aspects that were also relevant to the other theory areas. As the contents of the review’s theoretical framework were embedded in data extraction forms, these provided a template to ‘interrogate’ the papers. When extracting data, if an article did not include information relevant to a question in the form, the extractor recorded ‘Not reported.’ Direct quotations from the article were often most informative and were accompanied by the page number from which the quote was taken. Data pertaining to the target population and discipline for each study were also extracted.The aim of the data extraction process is to populate the evaluative framework with evidence. Therefore, once all subgroups had completed data extraction for the articles deemed relevant to the review purpose, the content from each group’s data extraction tables was amalgamated to form a single data extraction table including all articles addressing change agency.i.e., to determine what works, for whom, in what circumstances, in what respects and why. Pawson et al.’ publications provide little guidance on how to approach data synthesis. They suggest that synthesis should focus on four dimensions: questioning the integrity of a theory, adjudicating between competing theories, considering the same theory in comparative settings, or comparing the ‘official’ theory with actual practice [The basic task of the synthesis process is to refine the programme theory; practice ,9.In this review we developed an approach to synthesis based on the principles of realist evaluation , includi1. Organisation of extracted data into evidence tables,2. Theming by individual reviewers,3. Comparison of reviewers’ themes for a specific article and formulation of chains of inference from the identified themes,4. Linking of the chains of inference, and tracking and linking of articles5. Hypothesis formulation.This process is summarised in Additional file At a face-to-face meeting, sub-groups undertook a process of analysis, focussed on addressing the three programme theory questions , and willingness to work collaboratively.Looking for chains of inference (connections) across extracted data and themes. Through an iterative process, connections were looked for across data/themes to build up a cumulative picture. For example, were the opinion leader conditions evident in papers about other change agent roles—this resulted in a larger list factors, including, for example attitude, expert knowledge, gender, age, and cultural compatibility . The output from steps three and four resulted in a cumulative picture of potential mechanisms, contexts and outcome chains (hypotheses), which could be linked back to source evidence , but which also drew on some of the practices of traditional systematic reviewing.Our approach deviated in some respects from the approach recommended by Pawson One of the strengths of realist review is the approach’s firm roots in philosophy and social sciences ,9. RatheThe strengths of realist synthesis underpin its limitations. Realist synthesis is premised on a set of principles rather than a formula, and whilst this allows for flexibility and inclusivity, it means that the findings from a review are theoretically transferable. For example, it follows that if the appraisal and data extraction needs to be bespoke to the particular review questions that arise from the theoretical framework, these will be different for each review. Furthermore, given that the fundamental interest in realist synthesis is about finding out what works in what contexts, the recommendations one can make will not be generalisable. Rather a realist review results in findings that are theoretically transferable; ideas (‘theories’) that can be tested in different contexts, with different stakeholders.et al. [Pawson et al.  suggest Realist synthesis is a new but emerging approach to evidence review. In this paper, we have described our use and development of the approach. It is particularly appropriate for unpacking the impact of complex interventions because it works on the premise that one needs to understand how interventions work in different contexts, and why. It is not an easy option. Realist review demands much of the reviewer, including an ability to think flexibly and deal with complexity. There is not one prescribed approach to doing a realist synthesis; rather, there is a set of principles that the reviewer must particularise to the issue being explored whilst being sympathetic to the philosophy of realism. This presents unique challenges, but with it, the opportunity to develop more pragmatically insightful conclusions than those produced by some other approaches to systematic reviewing.Bridie Kent is an Associate Editor for Implementation Science; all decisions on this manuscript were made by other editors.BM and JRM led the project. All authors participated in defining the scope of the review. KD and ESC executed the search. The appraisal of evidence and data extraction were undertaken by all authors. All authors were involved in the analysis process. AMH led the documentation of the study process. KD led the development of the narrative. JRM wrote the first draft of the paper; BM, AH, and KD commented on it. All authors provided feedback on various drafts, and read and approved the final manuscript.Terms related to realist synthesis.Click here for fileReview foci and questions.Click here for fileData extraction form.Click here for fileSearch terms and strategy.Click here for fileStages of synthesis.Click here for fileHypotheses linked to themes, chains of inference and papers.Click here for file


Objectives. The aim of this randomized controlled prospective study is to evaluate the efficacy of cranberry capsules for prevention of UTI in children with neurogenic bladder caused by myelomeningocele. Patients and Methods. To be eligible for this study, patients had to be diagnosed as neurogenic bladder caused by myelomeningocele, evaluated urodynamically, followed up with clean intermittent catheterization and anticholinergic drugs. Intervention. Six months of treatment with placebo; after a week of wash-out period treatment of cranberry extract tablets (1 capsule/day) for an additional 6 months. Randomization was performed sequentially. Patients and care givers were blinded to drug assignment. Main outcome measure was infection rate. Group comparisons were performed with Wilcoxon test. Results. The study population included 20 (F/M: 13/7) patients with neurogenic bladder with the mean age of 7.25 ± 3.49  years. The median UTI rate was 0.5/year during placebo usage whereas 0/year during cranberry capsule usage. Decrease in infection rate was significant with cranberry capsule usage (P = 0.012). Decrease in the percentage of the pyuria was also recorded as significant (P = 0.000). Any adverse events or side effects were not recorded. Conclusion. We concluded that cranberry capsules could be an encouraging option for the prevention of recurrent UTI in children with neurogenic bladder caused by myelomeningocele. Cranberry juice has traditionally been used to reduce recurrent urinary tract infections (UTIs). The mechanism of action is not fully understood. The only active moieties of cranberry discovered to date are trimeric A-type proanthocyanidins. The major mechanism by which cranberry appears to prevent UTIs involves inhibition of the binding of the P-fimbria of uropathogens .In children with neurogenic bladder, UTI is a leading cause of morbidity. Symptomatic UTI and its possible association with renal damage are the greatest problems in children with neurogenic bladder . Long-te99mTcDMSA  scan, and presence of vesicoureteral reflux (VUR) in voiding cystourethrogram (VCUG).This study was a placebo-controlled crossover trial and conducted according to the Declaration of Helsinki. The Human Research Ethical Committee of Kocaeli University Hospital approved the study. Informed consent was obtained from the patient and/or from the parents of each patient. A review of the medical records and personal interviews were used to determine the age, sex, presence of scar on  Inclusion criteria were (1) children with neurogenic bladder caused by meningomyelocele, (2) age ≤ 18 years, (3) followed up with anticholinergic drugs (0.6 mg/kg oxybutinin) and clean intermittent catheterization (4/day), (4) the urodynamic finding of overactive detrusor and increased sphincter tonus. (The aim of these criteria was to form a homogenous group according to bladder pathology for prevention of causes that would lead to UTI.)4 colony-forming units/mL. The presence of urinary leukocytes, was considered significant if ≥5 WBCs/HPF were observed on microscopic examination of centrifuged urine. Each patient and parent were trained for the symptoms of symptomatic UTI. In case of symptomatic UTI, patients and parents were trained for unscheduled admission. Patients who were diagnosed as UTI were given a 10 day antibiotic course based on culture sensitivities. Elimination of the UTI was assessed after treatment. The study medications were continued throughout the period of antibiotics. Patient compliance was assessed by counting the remaining pills at each monthly visit. Infection rate for each patient was calculated before and after cranberry capsule usage as a number of infections per year. A review of the medical records was used to determine the presence of vesicoureteral reflux on VCUG and scar on DMSA scan. The results were analyzed by using SPSS for Windows 16.0, and descriptive statistics are presented as mean ± SD or median. Univariate analyses for group comparisons were performed using Mann-Whitney U, and dependent group comparisons were performed using Wilcoxon test.Twenty patients were elected from our database according to the inclusion criteria. Patients were randomized to receive 6 months placebo (1 capsule/day), after a one week wash-out period, cranberry extract capsules  were prescribed for the next 6 months sequentially. Patients and caregivers were blinded to drug assignment; however, the doctors were not. Placebo was prepared by emptying the cranberry capsules. They were followed in the pediatric nephrology out-patient clinic every month for the signs and symptoms of UTI. Symptomatic UTI was diagnosed in accordance with the European guidelines, 2003 and included signs and symptoms of infection  associated with a positive urine culture [The study population included 20 patients with the mean age of 7.25 ± 3.49  years. Seven patients were male, and 13 patients were female. Presence of VUR was recorded in 4 patients and scar in 13 patients. Follow-up time during placebo and during cranberry usage was 120, patient months for each type of medication. During that time any side effects, drop outs, or noncompliance were not recorded. Median infection rate during placebo usage was 0.5/year and during cranberry usage 0/year . DecreasE. coli adherence to biological systems of primary cultured bladder and vaginal epithelial cells in a dose-dependent manner [Cranberry, which is rich in polyphenols, including anthocyanins and proanthocyanidins, has been found to have various effects beneficial to human health, including prevention of UTI. These effects have been associated with polyphenols in the fruit. It was shown that the urinary levels of anthocyanins reached a maximum between 3 and 6 h after ingestion, and the recovery of total anthocyanins in the urine over 24 h was estimated to be 5.0% of the amount consumed [t manner .These are strong in vitro evidences confirming the hypothesis that UTI can be prevented by decreasing bacterial adherence to uroepithelial cells. For people with recurrent uncomplicated UTI, routine utilization of cranberry products may be an alternative methodology instead of antibiotic prophylaxis .For this reason, cranberries (particularly in the form of cranberry juice) have been used widely for several decades for the prevention and treatment of UTI. In the Cochrane Central Register of Controlled Trials, all randomized or quasirandomized controlled trials of cranberry juice/products for the prevention of urinary tract infections in susceptible populations of men, women, or children were included. Seven trials met the inclusion criteria  of this review. There were two good-quality randomized controlled trials that cranberry products significantly reduced the incidence of UTI at twelve months compared with placebo/control in women. Cranberry products significantly reduced the incidence of UTIs at 12 months  compared with placebo/control. Also, any significant difference was not recorded in the incidence of UTI between cranberry juices versus cranberry capsules. If it is effective for other groups such as children and elderly men and women, it is not clear in that meta-analysis [The findings of the Cochrane Collaboration support the potential use of cranberry products in the prophylaxis of recurrent UTI in young- and middle-aged women. However, in light of the heterogeneity of clinical study designs and the lack of consensus regarding the dosage regimen and formulation to use, cranberry products cannot be recommended for the prophylaxis of recurrent UTI routinely .Lactobacillu, or control in three treatment arms and followed up for 6 months. At the end, they concluded that daily consumption of concentrated cranberry juice can significantly prevent the recurrence of symptomatic UTI in children [In a study published one year later from Cochrane review, eighty-four girls aged between 3 and 14 years were randomized to cranberry, children .No consensus exists for the evaluation and management of bacteriuria in patients with spina bifida and neurogenic bladder at clinics specializing in the care of such patients, even at those with established standards of care. A clear need exists for an established, national set of evidence-based guidelines to assist medical decision making in this high-risk population and, thus, improve care .In a review by Opperman , cranberIn a multicenter survey published in 2005, 169 spina bifida clinics in the US were sent a questionnaire. Fifty-nine (39%) clinics returned the survey. Fifty-seven percent of respondents recommended cranberry to prevent UTIs. Fifty percent believed that these products were of benefit . In our clinic, we also recommended cranberry to our patients with neurogenic bladder caused by meningomyelocele with recurrent UTI. Retrospective results of cranberry usage in children with myelomeningocele were encouraging. Decrease in infection rate was significant during cranberry usage  . In this placebo-controlled crossover trial, it was shown that decrease in infection rate and decrease in frequency of pyuria was significant during cranberry usage. As far as we know this is the first prospective controlled trial with cranberry capsules in children with myelomeningocele. We concluded that cranberry capsules could be an encouraging option for the prevention of recurrent UTI in children with neurogenic bladder caused by myelomeningocele.


David Peters and Sara Bennett provide a critical perspective on a three-part series on health systems guidance that examines how evidence should be used to strengthen health systems and improve the delivery of global health interventions. PLoS Medicine:This Perspective discusses the following new Policy Forums published in doi:10.1371/journal.pmed.1001185.Bosch-Capblanch X, Lavis JN, Lewin S, Atun R, Røttingen JA, et al. (2012) Guidance for Evidence-Informed Decisions about Health Systems: Rationale for and Challenges of Guidance Development. PLoS Med 9: e1001185. In the first paper in a three-part series on health systems guidance, Xavier Bosch-Capblanch and colleagues examine how guidance is currently formulated in low- and middle-income countries, and the challenges to developing such guidance.doi:10.1371/journal.pmed.1001186.Lavis JN, Røttingen JA, Bosch-Capblanch X, Atun R, El-Jardali F, et al. (2012) Guidance for Evidence-Informed Policies about Health Systems: Linking Guidance Development to Policy Development. PLoS Med 9: e1001186. In the second paper in a three-part series on health systems guidance, John Lavis and colleagues explore the challenge of linking guidance development and policy development at global and national levels.doi:10.1371/journal.pmed.1001187.Lewin S, Bosch-Capblanch X, Oliver S, Akl EA, Vist GE, et al. (2012) Guidance for Evidence-Informed Policies about Health Systems: Assessing How Much Confidence to Place in the Research Evidence. PLoS Med 9: e1001187. In the third paper in a three-part series on health systems guidance, Simon Lewin and colleagues explore the challenge of assessing how much confidence to place in evidence on health systems interventions.PLoS Medicine, and produced by members of the World Health Organization (WHO) Task Force on Developing Health Systems Guidance, offers important contributions to improving the quality of evidence-informed decision-making in health systems The three-paper series on guidance for evidence-informed decisions about health systems, published in In recognizing the growing international consensus on the importance of strengthening health systems, particularly in low- and middle-income-countries (LMICs), the first paper argues that better guidance is needed to provide evidence-informed decisions about interventions in health systems, analogous to the methods that have been used to develop clinical guidelines, and facilitate their implementation In the first paper, Xavier Bosch-Capblanch et al. identify multiple uses of guidance on health systems from a review of national policies and plans in LMICs, but for some of the guidance identified—such as the operational guidelines for procurement, human resource management, or planning and budgeting procedures—one wonders whether research evidence is critical. The authors offer little guidance as to where health systems guidance is most needed. Given the fairly resource-intensive approach proposed to producing health systems guidance a clear sense of priorities is required, and a recognition that sometimes adherence to “best practice” may be sufficient.The papers pay relatively little attention to the well known “policy-implementation gap”, and sometimes appear to presume that getting policy right is sufficient. The WHO essential medicines program has encountered significant success in promoting the widespread adoption of an extensive set of guidelines  related to the development of evidence-based policies, institutions, and procedures p-values have little relevance to the nature of the policy question involved The authors of the third paper, Simon Lewin et al., note that systematic evidence is needed to address questions of feasibility and acceptability of interventions, as well as effectiveness, though much of the discussion in the paper addresses evidence regarding “what can work”, a question for which GRADE criteria function well. But policy makers may be more interested in questions such as “what can work in our (non-research) environment?”, “how can we make an intervention work well?”, or “how can we overcome obstacles to implementation in our situation?” They are also likely to be more concerned about the broader type of unintended consequences of an intervention  One implication of the realization that health systems, like most social systems, are actually complex adaptive systems, means that change often follows counter-intuitive and more complex patterns than is modeled through epidemiologic research on effectiveness embodied in the GRADE approach to evidence Although the papers together acknowledge that guidance needs to take account of contextual differences, the fragmented approach proposed to assess evidence on (i) effects, (ii) stakeholder views, and (iii) implementation issues suggests that the implications of context may not have been fully appreciated. From a systems perspective, stakeholder views, for example, matter in terms of how the population or other actors are likely to receive a health systems intervention proposal, and also fundamentally influence how that reform is implemented and the effects it creates. Actor resistance may lead to emergent behavior (such as seeking ways to “game” a provider payment system) that will in turn influence effectiveness. A better definition of health systems interventions than that proposed in this series would highlight the need for systems sciences and interdisciplinary inquiry and further expand the conceptualization of what comprises evidence.Finally, one key assumption behind the approach to guidance development proposed is that systematic reviews provide the best type of evidence on the effects of policy options, but this is contestable. In the first place, one could argue that the best evidence is that which is experienced, learned, and acted on by key stakeholders in their own setting. While there is very little evidence about how policy makers in LMICs understand systematic reviews, based on our personal experience, we suspect that such understanding is often quite limited, and literature instead consistently points to the importance of personal interactions with researchers and locally produced evidence in the minds of policy makers. Systematic reviews clearly have an important place in the consideration of evidence, but as previously noted, there are many types of questions about policy options that are not well addressed by systematic reviews of effects or GRADE criteria that are weighted towards simple effectiveness studies. As the authors imply, methods for alternative types of reviews are still under development and continue to be debated and to some extent contested. Finally, although it is an important scientific principle embodied in the GRADE criteria that experiments need to be repeated to gain confidence in the validity of their findings, we also need to be cautious of the “fallacy of misplaced concreteness”, and particularly the assumption that because actions have been successful in some contexts, they need be under all conditions The articles in this series point to a large agenda to better develop guidance to incorporate the different types of evidence needed for interventions in health systems, and have made a considerable contribution toward that end. Recognizing the diversity of stakeholders and complexity of health systems issues, it will be important to ensure that evidence-informed guidelines that emerge are tested with continued humility and skepticism, and that they do not become rigid models for inquiry dominated by a limited number of disciplines. They should not serve to blind us toward the need to address a wide variety of questions and incorporate the different types of evidence brought to bear by many fields of science. Further guidance is one important way to shape policy, but we must not fail to situate it in the broader context of sustained dialogue between researchers and policy makers.


Effective approaches to the prevention and treatment of substance abuse among mothers have been developed but not widely implemented. Implementation studies suggest that the adoption of evidence-based practices in the field of addictions remains low. There is a need, therefore, to better understand decision making processes in addiction agencies in order to develop more effective approaches to promote the translation of knowledge gained from addictions research into clinical practice.A descriptive qualitative study was conducted to explore: 1) the types and sources of evidence used to inform practice-related decisions within Canadian addiction agencies serving women; 2) how decision makers at different levels report using research evidence; and 3) factors that influence evidence-informed decision making. A purposeful sample of 26 decision-makers providing addiction treatment services to women completed in-depth qualitative interviews. Interview data were coded and analyzed using directed and summative content analysis strategies as well as constant comparison techniques.Across all groups, individuals reported locating and using multiple types of evidence to inform decisions. Some decision-makers rely on their experiential knowledge of addiction and recovery in decision-making. Research evidence is often used directly in decision-making at program management and senior administrative levels. Information for decision-making is accessed from a range of sources, including web-based resources and experts in the field. Individual and organizational facilitators and barriers to using research evidence in decision making were identified.There is support at administrative levels for integrating EIDM in addiction agencies. Knowledge transfer and exchange strategies should be focussed towards program managers and administrators and include capacity building for locating, appraising and using research evidence, knowledge brokering, and for partnering with universities. Resources are required to maintain web-based databases of searchable evidence to facilitate access to research evidence. A need exists to address the perception that there is a paucity of research evidence available to inform program decisions. Finally, there is a need to consider how experiential knowledge influences decision-making and what guidance research evidence has to offer regarding the implementation of different treatment approaches within the field of addictions. The treatment of substance abuse problems in women presents special challenges. Rates of substance abuse in women have been increasing  and resePromising models of integrated (or comprehensive) treatment programs that include on-site pregnancy-, parenting-, or child-related services with addiction services have been developed but not widely implemented, despite systematic reviews supporting their potential effectiveness -12. OtheAmong other health system stakeholders there is an emerging understanding that research evidence, if translated effectively, will lead to the provision of more effective programs and practices and subsequently improved health outcomes . EvidencFactors identified as impacting EIDM include individual decision makers, the system, patients, and research evidence . At the In order to advance knowledge and the practice of EIDM in the field of women's substance abuse, a program of research known as Connections was established in Canada. The focus of this five-year program of research is the development and evaluation of innovative knowledge transfer and exchange strategies to facilitate EIDM among addiction agencies serving women . For theThe principles of fundamental qualitative description, as described by Sandelowski , guided A purposeful sample of decision makers working in Canadian agencies providing addiction treatment services to women were invited to participate. A decision-maker was defined as any single individual within the organization who held formal or informal power to influence a treatment, service or program decision, including decisions related to planning, implementation, delivery, management, or evaluation. Based on past qualitative studies exploring the processes of research use by decision makers across different health fields ,32, we eTwo snowball sampling strategies were used to identify the purposeful sample: 1) researchers with expertise in the field of addiction services for women and members of the Connections Advisory Committee identified potential key informants who could provide a rich and detailed description of the types of evidence used to inform addiction treatments and program decisions; and 2) at the end of each interview, study participants were asked to identify other individuals who met the study inclusion criteria. Recruitment of new study participants continued until the data analysts determined that no new information about: the types and sources of evidence used in decision-making, how research is used in decision-making, and factors influencing EIDM was emerging from the interviews.Each study participant was invited to complete a single in-depth semi-structured telephone interview lasting approximately 60 to 90 minutes. The study was described in detail to each participant and informed consent to participate was obtained in writing. A semi-structured interview guide was developed based on Dobbins and colleagues'  theoretiAll of the interviews were transcribed verbatim, with identifying information removed to ensure participant anonymity and confidentiality, and checked for accuracy. We used a directed content analysis approach  and usedThe diversity of backgrounds and experiences among members of the research team contributed to data credibility and promoted data dependability, or the consistency of codes and findings emerging across interviews, during the analytic phase . As a grA purposeful sample of 26 decision-makers  recruited from 24 agencies providing addiction treatment services to women completed an in-depth qualitative telephone interview. Each participant was assigned a code and a number  to allow for better identification of the excerpts from the respective interviews. Of these individuals, 14 participants  completed the member checking process, which augmented and confirmed the research team's interpretations of the interview data. Participants were recruited from all ten Canadian provinces and one of three territories. Just under half of the participants indicated that they worked in agencies serving urban/rural populations, six served rural or remote populations, and five served urban populations. This purposeful sample was well positioned to provide in-depth descriptions about EIDM in the field of women's addiction services and to provide commentary about factors influencing research uptake as participants had, on average, 17 years of experiencing working in the field. Study participants had a range of educational backgrounds including addictions, education, medicine, or social work. However, all of the program managers had a professional background in social work. A summary of participant characteristics is presented in Table Across all three decision-maker groups, individuals reported locating and using multiple types of evidence to inform program or treatment decisions. The most common types of evidence used included: research evidence ; best practice guidelines; perceived best practices ; local program evaluations; client needs assessments; expert opinion; personal professional experiences; and an individual's personal experiences of addiction and recovery.At the service-provider level, participants expressed a preference for relying on perceived best practices, information from client needs assessments, and their own professional experiences when making decisions. A majority of the service providers acknowledged that research evidence has been used within their agency to inform program decisions. However, at the individual level, there was significant variability in perceptions of the value of research evidence. At one end of the spectrum, some service providers identified that research evidence is important to integrate into decision-making as it creates the opportunity to implement programs that will have a known positive effect on client outcomes. Some participants also expressed the importance of ensuring that their clinical actions would not be potentially harmful to their clients, for as one service provider (addiction counsellor) shared:It [research evidence] gives me a sense of assurance and credibility that what I'm doing is in the right direction. I mean I could be just going out there willy-nilly and waving magic wands and still get paid for it. But I want to know that what I'm doing is not going to be harmful to the people I am working with (SP011).Conversely, some service providers were more likely to place a greater value on personal and professional experiences, particularly if the research evidence contradicts "what is known to be best for the client" based on their experiences of working in the field. One counsellor with over 25 years of clinical experience expressed that:I hear my supervisor talk about best practices a lot, but the truth of the matter is - I'm going to be very honest with you - I don't really pay a lot of attention to it. Just based on my own experiences, the abstinence-based twelve-step philosophy is what works (SP007).Furthermore, some service providers gave examples of specifically locating research evidence to justify their choice of treatment model , to endorse their experiential knowledge or to validate their current professional practices.All of the service providers interviewed perceived that research evidence in the field of addictions is outdated or not relevant to their specific client populations, or that there is a gap between what researchers study and what information would be of practical value for them.Of the 12 program managers interviewed, ten managers identified expert opinion as a key type of evidence carrying significant weight in influencing their decisions. These participants identified that if a particular program or intervention was endorsed or recommended as a best practice by an individual or agency recognized as an "expert"  or perceived to be highly credible in the field, the likelihood of adopting the recommended program or intervention locally would increase.The majority of program managers and all executive directors indicated that they locate and use research evidence in their decision making, and that greater priority is placed on using research evidence and best practice guidelines to inform decisions than experiential knowledge. As one program manager noted:I think quite frankly that if we're not actually using research to inform decisions, then we assume that we are on the right path and that we're doing things that are helpful to our client population - which may in fact not be [helpful] (PM008).Participants from these two groups provided examples of using research evidence to: select an intervention or program to implement within the organization; identify trends and emerging issues in the field; develop background information on an issue for a report, presentation or grant proposal; gain new perspectives about potential strategies for addressing issues presented by women seeking service; and to endorse experiential knowledge. As one executive director explained:I'm heavily guided by research evidence. That's how I write my proposals. And it's just a way of being credible and saying that, 'Well, this is an approach that works and this is why we want to offer this program. (ED017)Furthermore, there was consensus among all levels of decision makers that once valid research evidence is located it: must be validated by program staff and clients as relevant; generally must be adapted to meet the local needs of the community and the agency's community partners before the evidence-based intervention or program can be implemented; and is only one of many types of information considered in the decision-making process.When making a decision about the types of programs, interventions or treatment modalities to use, decision makers balance the results of research studies with information about: their agency; the service providers employed by the agency; the women served by the agency; the broader social and political context in which addiction services are provided; existing programs offered by their community partners; and characteristics of the research evidence under consideration. The attributes related to each influencing factor that are considered in the decision-making process are summarized in Table Across interviews there was significant discussion about the role of individual service providers' personal experiences with addiction and recovery in informing treatment and program decision-making. Participants explained that many individuals who work in addictions have personal knowledge of the process of addiction and recovery, either from their own experiences or that of a friend or family member. However, there appears to be a tension in the field around if, and how, this experiential knowledge should be used in decision-making. Overall, study participants acknowledged that experiential knowledge could contribute to the development of mutuality and trust between the service provider and client. The small number of study participants who disclosed a personal history of addiction and recovery during the interviews reported that their experiences significantly influence their professional and clinical decisions. One clinician (SP007), in recovery from alcohol and crack addiction, acknowledged making decisions based on "what I feel is right, which is my own experience." Many program managers and executive directors identified the importance of validating counsellors' lived experiences, but highlighted the potential risks to relying solely on experiential knowledge to inform decisions.One of the risks noted is that service providers may reject evidence-based practices in favour of their personal experiences. One executive director (ED017) explained that some counsellors have the attitude that, "I've been through it [addiction and recovery] and I know all about it. I don't need to know about anything the research says 'cause what do researchers know?" There also was a belief that if a service provider chooses to disclose too much experiential knowledge, there is a risk of crossing therapeutic boundaries with the client. As one program manager (PM013) stated, "When you're trying to help a client, your job as a counsellor isn't to tell them what worked for you, but help them find what will work for them." The majority of participants concurred that experiential knowledge should not be the primary source of evidence for making agency-wide decisions regarding treatment models or interventions but recommended that it is useful in providing a deeper understanding of the issues individuals with addictions experience and for adapting best practices or research to meet the needs of women seeking services. There also was general agreement that when both experiential evidence and research evidence are taken into consideration in decision making that a more holistic understanding of the issues related to substance use and treatment is realized.Study participants reported searching for and accessing evidence for decision-making across a wide variety of sources. The most common sources included websites and from colleagues with perceived expertise in substance abuse prevention and treatment. The majority of participants identified locating information from freely accessible websites hosted by agencies affiliated or funded through provincial or federal organizations that provide access to evidence-based resources. These resources included registries of best-practices, , general information about drug prevention and treatment , and summaries of research evidence. One service provider (SP011), in describing use of the Health Canada website, commented that, "We as Canadians have an implicit trust that most of the information provided to us from a federal agency is going to be supported in research and fairly accurate."Participants also regularly access websites hosted by non-profit charitable associations  that provide information about community resources, disseminate key reports on issues such as mental health or addictions, host communities of practice, and provide links to other resources. Approximately half of the participants identified that they often conduct broad, general "Google" searches to locate websites where they can freely access evidence and resources. Through these Internet searches, a small number of participants explained that they had found and subsequently used information from websites of independent companies, most often psychologists offering workshops or training programs for counsellors. The majority of service providers and a small number of program managers and executive directors also spoke about the value of being connected to electronic mailing lists that regularly send them updates about research and information emerging in the field of addictions and substance use or being a part of a virtual community of practice .All of the service providers and just over half of the program managers and executive directors identified other individuals as a primary source of their information for decision-making. Service providers generally spoke about seeking information from colleagues working within their agency or community partners because their professional expertise was valued and their philosophies around treatment (abstinence-based vs. harm reduction) were similar. Program managers and executive directors sought information from experts, who were likely to be administrative colleagues in other agencies, researchers, or individuals from agencies with known credibility in the field. Across all levels of decision makers, study participants reported accessing research evidence through peer-reviewed journals but very few accessed research evidence in the form of systematic reviews through the Cochrane Collaboration.Study participants were asked to identify both barriers and facilitating factors to using research evidence in their decision-making. The most common barriers to using research evidence in decision making were: lack of time; a work environment with competing priorities; and the perceived gap between research evidence and practice. Decision makers highlighted specifically a lack of time to search the Internet or databases for evidence, read information or reports, critically appraise and summarize research reports, and compare findings across studies. Decision makers across all levels also described working within a field where the majority of agency resources and funds are directed towards service delivery, treatment, and educational activities and where there is little mandate to allocate resources toward conducting research or integrating research into practice. Without a mandate to focus on evidence-informed practice or policy, the decision makers identified that they then prioritize service delivery over any activities related to EIDM. Decision makers were highly critical of the current base of evidence in the field of addictions and its relevance to practice, citing that research is outdated and that it is difficult for researchers to keep up with trends emerging at the practice level. Decision makers also cited a significant gap between what researchers highlight as important to study and what practitioners identify as current practice issues requiring evaluation.One barrier that was unique to service providers was the perceived lack of interest or resistance to adopt evidence-informed interventions. One program manager (PM004) explained that:One of the interesting anomalies...in addictions services is the whole resistance to change. You know, the whole idea of 'if it ain't broke, don't fix it.' Sometimes though, it was always broke and you have to point that out [to staff] and say, 'You know, what you have been doing for the last 15 years, although it made you feel good, unfortunately has not really been effective with this particular population.'Executive directors and some program managers explained that front-line staff may be resistant to adopt evidence-based strategies when the research evidence contradicts their current professional practices or when they are put in a position to reflect on, and potentially change, their current approaches to working with clients. One executive director explained:They [front-line staff] 'know what they know.' And they don't want what they know challenged by new information. You have to acknowledge that that's a fact. People have their beliefs, they know what they know and they don't want to argue about it, they want to apply it. It's a resistance (ED015).Decision makers identified four primary facilitators to increasing the use of research evidence in practice. First, the board of directors and senior administration must support the philosophy of evidence-informed practice and provide supports for front-line staff and managers to have access to research evidence, to develop the skills required to appraise and apply evidence, and to be actively involved in primary research activities. Secondly, research is more likely to be reviewed for potential adoption if there is an individual within the agency who has the formal responsibility and skills to search for, retrieve, appraise, summarize, and interpret the research evidence for all levels of decision-makers. One executive director (ED015) explained, "To make good information palatable, often you need an emissary." This individual would also be responsible for identifying strategies for communicating the results of studies and disseminating key messages across the agency. The participant (ED015) further suggested, "You need a go-to person in each area that would talk to you and say, 'Here's some really good stuff that's coming by lately, have a look at it." Third, it was identified that research evidence is more likely to be adopted if it is translated into plain language and is accompanied by recommendations on "how-to" apply the findings into practice. The final facilitating factor was an endorsement of establishing formal partnerships between universities and addiction agencies. It was highlighted that these partnerships would create opportunities for researchers to answer practice-informed research questions and for agency staff to have access to current research evidence and individuals skilled in interpreting research jargon. One program manager concluded that:If we had partnerships with universities, right, where it would be possible to call up and say, "Okay, so this is what we're looking at. Can you just spend fifteen minutes of your time and just tell me what you know or where I can go for this information?" It'd be really helpful to have those kinds of partnerships (PM019).Within the field of addiction services for pregnant women and mothers, this is the first Canadian study to explore EIDM among service providers, program managers, and executive directors and their perceptions of what, and how, evidence is used in program decision making. Across all levels of decision making, participants consistently reported locating and using multiple types of evidence to inform treatment choices and program options for their clients. It is important to note that within these predominantly CBOs, that there is a preference for relying on locally collected information to inform decision-making processes. While research evidence is acknowledged as an important source of information, it is used in varying ways by the different levels of decision-makers. To locate evidence to inform decisions, study participants spoke to their frequent use of web-based resources or by engaging with individuals with perceived expertise in the field. Finally, decision-makers identified four key activities that are required to promote the uptake of research evidence in their agencies: 1) administrative support for creating a culture that fosters EIDM; 2) locating knowledge brokers within the agency; 3) transforming research evidence into more accessible formats; and 4) establishing partnerships and engaging with university-based academics. The findings from our study reflect similar attributes as outlined in Wilson et al's framework  for commSpecific to women's addiction services, service providers reported that their clients' perspectives were important considerations in decision making about practice -40. WhilResearch evidence is often described as being used by decision makers in three different ways: instrumentally, conceptually or symbolically ,42. The Program managers and executive directors also use research conceptually, citing examples of locating surveillance data to identify emerging trends in the field and reviewing research evidence to gain a new perspective or understanding of the issues experienced by women seeking treatment for substance abuse. In comparison, service providers reported that they did not directly use research evidence instrumentally but were more likely to provide examples of using it symbolically; they often used this type of evidence to validate their current practices or, for some, their personal experiential knowledge of addiction and recovery. The extent to which symbolic use of evidence occurs in the field is problematic and warrants further investigation. Ongoing use of research solely to validate existing practices, particularly when practices are informed by experiential knowledge, may extend the delivery of interventions with less than ideal effect on client outcomes and serve as a barrier to the development and integration of programs, services, and interventions that are known to have positive effects on client outcomesThe degree to which personal experiential knowledge of addiction and recovery is valued and used by some front-line addiction counsellors is a unique finding compared to similar studies we have conducted in the fields of child welfare , public Enkin and Jadad  suggest In this qualitative study, many decision makers highlighted the influence of an organization's treatment philosophy  on decision-making. The findings suggest an inherent tension faced by senior decision makers working in the field of addictions who must select a treatment philosophy and treatment interventions to implement within their organizations. The tension stems in part from the strong beliefs held by some regarding the effectiveness of abstinence programs compared to harm reduction models for the treatment of addictions. These firmly entrenched beliefs contradict the current best available scientific evidence on the effectiveness of 12-step approaches to influence important client outcomes. In a systematic review of eight trials (n = 3417), Alcoholics Anonymous or similar 12-step approaches were not effective in reducing alcohol dependence or other alcohol-related problems . TherefoFindings related to the attitudes about addiction and recovery held by clinical personnel with experiential knowledge are consistent with those of other studies that found that clinicians in recovery who endorsed a 12-step abstinence model were less likely to support and utilize evidence-informed motivational and behavioral treatment approaches ,25,48. TIn addition to the types of evidence used to inform decision making, this qualitative study provided insight into the sources of information. Given that the majority of funding for addiction agencies is directed toward service delivery, it was not surprising to learn that decision makers search for and locate a preponderance of their information through unstructured Google searches or by accessing websites sponsored by provincial or federal government agencies that provide free access to a range of addiction-related resources. As such, ongoing support should be provided and maintained for organizations that have the mandate, capacity, and skill to host Internet sites that contain databases of searchable evidence-informed resources relevant to addictions. Given the preference for accessing resources through these types of websites, and the acknowledgment that the decision-makers highly value programs or interventions endorsed by credible organizations, it is imperative that posted recommendations be based on the current, best available evidence such as that found in systematic reviews. This type of approach has been used in the public health sector  to support organizations in having equitable access to high-quality evidence from a reliable agency. It reduces the need for small organizations, with limited budgets, to invest locally in purchasing subscriptions to journals and other resources related to obtaining and appraising research.In addition to identifying credible sources of information on the Internet, study participants expressed a preference for seeking information for decision-making or practice recommendations from individuals and organizations with perceived expertise in the field of treating women with addictions. Flodgren and colleagues  conducteSenior decision makers shared that having the opportunity to observe the successful implementation of an intervention in another organization is a factor that would positively influence their decision to adopt the treatment or program. In his diffusion of innovations theory, Rogers  identifiIn this study, we also explored barriers and facilitators that influence the use of research evidence in decision-making. We found that the experiences of decision makers working in agencies serving women with addictions are largely congruent with the experiences of decision makers in various health care settings e.g. ,53], soc, soc53]]Given that administrators are more likely to adopt EIDM than service providers, strategies could consider program managers and executive directors as potential change agents within addictions agencies. Findings by Dobbins et al.  support Additionally, opportunities exist for capacity development within the academic arena. With increased emphasis being placed on the establishment of academic-decision maker partnerships to facilitate both the production and uptake of research evidence ,26,27, iAs part of any given knowledge transfer and exchange strategy, in addition to identifying the type of information to disseminate, researchers have a responsibility to identify the most appropriate target audience to whom the research information is transferred . It is iTo promote the overall trustworthiness  of the fThere is support among senior administrators in addiction agencies for integrating EIDM into practice. As a result, future knowledge transfer and exchange efforts should, in part, focus on targeting this specific group. Initiatives aimed at increasing the use of EIDM also should take into consideration the different value EIDM might have in the context of addiction services and particularly how EIDM can gain and maintain legitimacy among service providers. It has been argued that when the value of research evidence is low or inconsistent with the existing belief systems of professionals working in the field, the merit of available research evidence will likely remain unrecognized or contested . This leIt also is evident that researchers and decision makers focused on advancing EIDM in the field of addictions services for women need to consider the socio-political challenges of the opposing treatment philosophies of the 12-step abstinence versus harm reduction programs, and what the research evidence offers as guidance for either approach. Another important priority is for the field to address the perception that available research evidence is not relevant and does not address the needs of front-line decision makers. Ongoing support for community-university collaborations to plan and conduct practice-relevant research is required and desired.Given that approximately one third of substance abusers are women of childbearing age , substanThe authors declare that they have no competing interests.SJ, MD, SB, WS and AN contributed to the development of the study design. Sampling and data collection procedures were led by SB, SJ and WS. SB completed the initial level of data coding, SJ completed the second level of data coding and developed the data summaries and syntheses. SJ, MD, SB, WS, AN and EL participated in analytic procedures to increase data dependability. SJ wrote the first draft of the manuscript with contributions from MD and GN. All authors contributed to and have approved the final manuscript.


Leishmania infection, 54 (27%) had spleen type 1, 99 (50%) had spleen type 2, and 46 (23%) had spleen type 3. The number of clinical signs associated with visceral leishmaniasis was significantly higher in the animals with evidence of Leishmania infection and spleen type 2 or 3 than in the animals with spleen type 1. Alopecia, anemia, dehydration, dermatitis, lymphadenopathy, and onychogryphosis were all more frequent among animals with evidence of Leishmania infection and spleen type 3 than among the dogs with evidence of Leishmania infection and spleen type 1. The association between the severity of canine visceral leishmaniasis and the disorganization of the splenic lymphoid tissue was even more evident in the group of animals with positive spleen culture. Conjunctivitis and ulceration were also more common in the animals with spleen type 3 than in the animals with spleen type 1. The serum levels  of albumin  and creatinine  were significantly lower and the serum levels of aspartate aminotransferase were significantly higher  in animals with spleen type 3 than in animals with spleen type 1 . Our data confirm the hypothesis that disruption of the splenic lymphoid tissue is associated with a more severe clinical presentation of canine visceral leishmaniasis.In this work, we investigated the association between the disruption of splenic lymphoid tissue and the severity of visceral leishmaniasis in dogs. Clinical and laboratory data from 206 dogs were reviewed. Spleen sections collected during the euthanasia of these animals were analyzed, and the splenic lymphoid tissue samples were classified as well organized (spleen type 1), slightly disorganized (spleen type 2), or moderately to extensively disorganized (spleen type 3). Of 199 dogs with evidence of  The spleen is the largest secondary lymphoid organ in humans and dogs. The histological structure of the spleen is characterized by a lymphoid tissue known as white pulp, which is immersed in an entangled network of sinusoids, capillaries, and leukocyte-reticular cell cords known as red pulp. The white pulp is organized into 3 different regions: (1) a periarteriolar lymphoid sheath (PALS) around arterioles, (2) discrete nodular lymphoid follicles, and (3) a surrounding and less tightly packed marginal zone. T lymphocytes are the main constituents of the PALS, and B lymphocytes predominate in the other lymphoid areas Visceral leishmaniasis and other systemic infections  alter the histological structure of the spleen, leading to disruption of the white pulp microenvironment http://www.planalto.gov.br/ccivil_03/_ato2007-2010/2008/lei/l11794.htm) and with the manual for the surveillance and control of visceral leishmaniasis This study was performed in strict accordance with the recommendations of the Brazilian Federal Law on Animal Experimentation (Law 11794)  and sodium thiopental  and euthanized using a saturated solution of potassium chloride . Immediately following euthanasia, spleen aspirates were collected for culture, and spleen fragments were collected and frozen in liquid nitrogen for molecular biology studies or fixed in formalin and embedded in paraffin for morphological studies. The technical details of the anti-Leishmania ELISA, the LST, and the splenic culture for Leishmania isolation have been reported elsewhere The samples and clinical and laboratory data used in this study were obtained from 207 stray dogs of different breeds and different estimated ages that were collected from the streets of Jequié  between 2004 and 2010. This study was performed in collaboration with the Endemic Diseases Surveillance Program of the State Health Service as part of a program for the surveillance and control of visceral leishmaniasis. All the animals were examined clinically by at least 2 veterinarians using a clinical chart. The presence of anti-All animals were subjected to a clinical exam with an emphasis on parameters considered to be indicative of canine visceral leishmaniasis, defined as follows:Alopecia. Hairless regions at different areas of the skin.Anemia. Pale (light pink) eyes and mouth mucous membranes.Conjunctivitis. Inflammation of the conjunctiva indicated by redness or pus.Dehydration. A poor skin turgor test and/or a delayed capillary refill time.Dermatitis. Dry, exfoliative inflammation of the skin.Emaciation. Skinny, animals with ribs and pelvis evident; cachectic, animals with ribs and pelvis evident and muscle atrophy in the temporal and scapular regions.Erosion. Presence of shallow, moist, or crusted lesions caused by a loss of the epidermis.Lymphadenopathy. Lymph nodes larger than expected for the size of the animal, as follows: dogs weighing less than 5 kg with lymph nodes larger than 2 cm (large axis), dogs weighing 5–10 kg with lymph nodes larger than 3.5 cm, and dogs weighing more than 10 kg with lymph nodes larger than 4 cm.Onychogryphosis. Nails of >1 cm on all extremities.Pustules. Small (2–5 mm) skin vesicles containing pus.Splenomegaly. Animals with a palpable spleen beyond the last rib.Ulcerations. Skin lesions with loss of the epithelial layer, with a granular surface and raised edges.The animals were grouped into the following categories according to the reported clinical signs suggestive of visceral leishmaniasis: asymptomatic  and symptomatic .Spleen tissue slices transverse in orientation to the larger axis of the organ with a thickness of 3 to 4 mm were collected. The tissue slices were fixed in formalin and embedded in paraffin. Hematoxylin- and eosin-stained splenic tissue sections with a thickness of 4 to 5 µm were examined by optical microscopy. The samples were examined by 2 pathologists (LARF and WLCS) and classified into 3 categories  according to the degree of structural organization of the splenic white pulp using the criteria previously described by Santana and colleagues (2008) Blood samples for hematological and serum biochemical analyses were collected from the cephalic vein of the dogs under manual restraint. The samples were preserved in EDTA-2Na tubes  and in blood collection tubes  and were examined the same day. Total red blood cell (RBC) and white blood cell (WBC) counts were obtained using an automated cell counter . Microhematocrit tubes containing the samples were centrifuged at 12,000 rpm for 5 min, and the hematocrit was estimated. Differential blood cell counts were also performed. The serum collected by centrifugation in the Vacutainer® tubes was used for the following biochemical tests, using an enzymatic colorimetric method with an A15 auto-analyzer : total protein (TP), albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, burea, and creatinine.L. infantum kDNA to obtain a 120-bp amplicon. The reactions were performed in a final volume of 25 µL containing 5 µL of the DNA sample diluted to 30 ng/µL in deionized water and 20 µL of PCR mixture. The PCR mixture consisted of 12.5 µL of Universal Mastermix , 900 nM each of forward primer 5′-AACTTTTCTGGTCCTCCGGGTAG-3′ (LEISH-1) and reverse primer 5′-ACCCCCAGTTTCCCGCC-3′ (LEISH-2), and a fluorogenic probe (5′-AAAAATGGGTGCAGAAAT-3′), which was synthesized using a FAM reporter molecule attached to the 5′ end and a MGB-NFQ quencher linked to the 3′-end (Perkin-Elmer Applied Biosystems), at a final concentration of 200 nM. A standard curve was generated using serial dilutions of L. infantum DNA from 106 to 10−1 parasites/mL, and each dilution was performed in triplicate. The amplifications were performed in triplicate for each sample and for the negative control using an ABI Prism 5900 sequence detection system . A canine housekeeping gene (18S rRNA) was amplified to normalize the concentration of the input sample DNA. The parasite load was expressed as the number of parasites normalized to the established reference amplification value for the 18S rRNA housekeeping gene in 100 mg of host tissue.To detect parasite DNA in frozen spleen samples, a quantitative real-time PCR technique was used. DNA was extracted using a DNeasy® Blood and Tissue Kit  according to the manufacturer’s protocols. A total of 10 mg of spleen tissue was processed following the Qiagen animal tissue protocol. Once extracted, the quality and concentration of each DNA sample was determined using a digital spectrophotometer . The DNA samples were then adjusted to a concentration of 30 ng/µL, aliquoted, and stored at −20°C until use. Real-time PCR assays were performed using a previously described amplification procedure The numerical data shown in the text, tables, and graphs represent absolute values, means, or proportions as indicated. For continuous variables, the significance of the differences between groups were tested using a Mann-Whitney test when there were 2 groups and the Kruskal-Wallis test when more than 2 groups were involved. When the test was significant, the difference between 2 groups was identified using Dunn’s Multiple Comparison test. For comparisons involving proportions, the Chi-square test, the Fisher’s exact probability test, or the Chi-square test for trends were used as recommended Leishmania infection was observed in 199/203 (98%) of the animals for which the data was available  had spleen type 1, 99 (50%) had spleen type 2, and 46 (23%) had spleen type 3  had spleen type 1, and 2 (50%) had spleen type 2.Of the 199 dogs with evidence of n type 3 . Among tLeishmania infection and spleen type 3  than among the dogs with evidence of Leishmania infection and spleen type 1 . Among the 4 animals without evidence of Leishmania infection, 2 were asymptomatic, and 2 were symptomatic.The proportion of symptomatic animals was higher among the dogs with evidence of Leishmania infection and spleen type 3  or type 2  than in animals with spleen type 1  was higher in animals with evidence of Leishmania infection, some of the diagnostic tests used in this study, such as PCR and LST, may not reflect the susceptibility of these animals to visceral leishmaniasis. The LST may even reflect some degree of protection against the disease Although most of the animals had evidence of The number of clinical signs associated with visceral leishmaniasis  was higher in animals with a positive spleen culture and a type 3 spleen  than in animals with a negative spleen culture and a type 1 spleen , animals with a negative spleen culture and a type 3 spleen , or animals with a positive spleen culture and a type 1 spleen  in animals with a positive spleen culture and a type 3 spleen  was higher than that observed in animals with a positive spleen culture and a type 1 spleen  than in infected animals with spleen type 1  were lower in animals with a positive spleen culture and a type 3 spleen  than in animals from the other groups . The serL. infantum infection in dogs is endemically high in some areas of Brazil. In a recent survey of the prevalence of infection in stray dogs collected from the streets of Jequié, Bahia State, Brazil, as estimated by culture, serology, and LST (DNA techniques were not used), up to 87% of animals tested positive for infection The prevalence of Leishmania infection. However, the number of uninfected animals was low , preventing comparison between the infected and uninfected groups.Moderate to extensive disorganization of the splenic white pulp was observed in nearly 25% of the animals, all of which had evidence of Leishmania infection, the disorganization of the splenic lymphoid tissue is associated with the clinical and laboratory features of more severe disease, supporting the hypothesis of this study.Nevertheless, herein we demonstrate that in the animals with evidence of Leishmania infection and spleen type 3 had more clinical symptoms attributed to visceral leishmaniasis, including alopecia, anemia, conjunctivitis, dehydration, dermatitis, emaciation, erosion, and onychogryphosis, than infected animals with normal spleens. The association between the severity of canine visceral leishmaniasis and the disorganization of the splenic lymphoid tissue was even more evident when the group of animals with evidence of active infection (confirmed by a positive spleen culture) was considered. In these animals, the disorganization of the splenic lymphoid tissue was associated with a higher frequency of the clinical features mentioned above. These animals also had a higher frequency of lymphadenopathy and ulceration than the animals in the other groups. Furthermore, these animals had lower levels of serum albumin and creatinine and slight increases in ALT levels compared with the animals from the other groups.Animals with evidence of Leishmania is characteristic of lymphoid tissue hyperplasia Leishmania antigen and is associated with lymphocyte proliferation in the B- and T-cell areas of the lymphoid organs and with macrophage infiltration The typical pattern of lymphoid tissue changes reported in dogs, humans, and mice infected with Leishmania infection itself may be responsible for this alteration L. infantum, Carrion et al. observed an association between the size of the inoculum and lymphoid tissue disruption The factors that determine this disorganization of lymphoid tissue in visceral leishmaniasis are not completely understood. Evidence suggests that the Leishmania infection and type 3 spleens. These animals also exhibited a trend toward an increase in C-reactive protein levels. Such evidence of an inflammatory state in these animals may indicate acute infection by other pathogens, such as purulent conjunctivitis. Further work is needed to examine the contribution of these co-infections to the development of visceral leishmaniasis in Leishmania-infected dogs and the role played by lymphoid organ disorganization in this mechanism of disease.Given the characteristics of this cross-sectional study, defining a causal relationship between the observed splenic changes and the aggravation of visceral leishmaniasis in these animals is not possible. Some of the conditions, such as weight loss, that were observed in the dogs with severe canine visceral leishmaniasis in this study may lead to disorganization of the lymphoid tissue in the spleen Leishmania, and negative LST results Previous work by our group and others has shown that such disorganization of the splenic lymphoid tissue is associated with other laboratory markers of severe visceral leishmaniasis in dogs, including positive spleen culture, higher levels of serum antibodies against


H0 in terms of the posterior probability of H0 being true and the frequentist evidence against H0 in terms of the P value in testing normal means where the nuisance parameters are present. The reconcilability of evidence can be obtained both for testing a normal mean and for the Behrens-Fisher problem.The problem of reconciling the frequentist and Bayesian evidence in testing statistical hypotheses has been extensively studied in the literature. Most of the existing work considers cases without the nuisance parameters which is not the frequently encountered situation since the presence of the nuisance parameters is very common in practice. In this paper, we consider the reconcilability of the Bayesian evidence against the null hypothesis  H0, a frequentist may give evidence against H0 by the observed significance level, the P value, while a Bayesian may give it by the posterior probability that H0 is true. Lindley H0, a frBartlett , Berger Bartlett , and BerBartlett .Although many researches have been carried out to deal with the problem of reconciling the Bayesian and frequentist evidence and some of them show that evidence is reconcilable in several specific situations, most of the existing work assumes that no other unknown parameters are present except the parameters of interest. In fact, we may be confronted with the nuisance parameters in various situations. In the location-scale settings, for example, when the location parameter is unknown, so is the scale parameter, in general.P values are typically not available. Tsui and Weerahandi  → 0, as n → ∞. On the other hand, we haven, it follows that, as n → ∞,(I) We first prove that, given m → +∞, we haveSimilarly, as U and V are independent normal distributions.(II) We now show that the final conclusion holds. In fact, if we let Similarly, for , we haveC in , Φ/R) is increasing in R ∈ . Therefore, by  < 0 is equivalent to p(x) < 1/2. Therefore, by , a, at-distfore, by , the conm and n with 2 < m, n < ∞, we still obtain the reconcilability of the frequentist and Bayesian evidence.The following theorem shows that, even for fixed ν01, ν02} → ∞, the conclusion of m and n with 2 < m, n < ∞; that is, As min{ν02 → ∞,We still adopt the notations of fn(t) denote the density function of χn2. Then it is easy to see that fn(t) reaches the maximum at t = n − 2 and that maxtfn(t) = fn(n − 2) → 0, as n → ∞. Therefore, as ν02 is sufficiently large, it holds thatϵ(ν02) > 0, where ϵ(ν02) → 0, as ν02 → ∞, and Let n  (2 < n < ∞), as ν02 → ∞, we haveϵ1(ν02) → 0, as ν02 → ∞.Therefore, for any fixed n  (2 < n < ∞) and γ ≠ 0, we haveϵ0 > 0. Therefore, as ν02 → ∞, by (m  (2 < m < ∞), as ν01 → ∞, we haveν01, ν02} → ∞, for any fixed m and n with 2 < m, n < ∞, we haveOn the other hand, for any fixed  → ∞, by  and 47)n   are listed in For fixed m = 8 and n = 10 and for s12 = 1 and s22 = 4, taking different values of ν01 and ν02, we list some results of comparing P value and limκ01,κ02,σ01,σ02→0P(H0 | x) in For fixed P value and the Bayesian evidence in the one-sided hypothesis testing problem about normal means. For the problem of testing a normal mean where the nuisance parameter is present, it is shown that the Bayesian and frequentist lines of evidence are reconcilable. For the Behrens-Fisher problem, it is illustrated that if the sample sizes m and n tend to infinity, then for fixed prior parameters ν01 and ν02, both lines of evidence are reconcilable. Furthermore, it is illustrated that if the prior parameters ν01 and ν02 tend to infinity, then for any fixed sample sizes m and n, lines of evidence are reconcilable. Simulation results show that even for small and fixed values of sample sizes m and n or for small values of prior parameters ν01 and ν02, the reconcilable conclusion of the Bayesian and frequentist evidence still holds.In the presence of the nuisance parameters, we study the reconcilability of the P values as evidence in hypothesis testing problems. Furthermore, our results of the reconcilability in the one-sided testing situations may help us to come to the idea that maybe it is arbitrary to assert the irreconcilability of the evidence in the two-sided  hypothesis testing problems and perhaps we should be concerned more about the appropriateness of the methods we employ to tackle a two-sided hypothesis in both the frequentist and the Bayesian frameworks.This provides another illustration of testing situation where the Bayesian and frequentist evidence can be reconciled and may therefore to some extent prevent people from debasing or even dismissing