Textural statistics for each sample were calculated using grey-level co-occurrence matrices (GLCMs). Standard 2-D GLCM analysis was found to be slice-dependent while 3-D GLCM contrast and homogeneity analysis resulted in separation of the vehicle and ZD6126-treated cohorts over a range of length scales.Methods of monitoring drug toxicity in off-target organs are very important in the development of effective and safe drugs. Standard 2-D techniques, such as histology, are prone to sampling errors and can miss important information. We demonstrate a novel application of optical computed tomography (CT) imaging to quantitatively assess, in 3-D, the response of adult murine spleen to off-target drug toxicity induced by treatment with the vascular disrupting agent ZD6126. Reconstructed images from optical CT scans sensitive to haemoglobin absorption reveal detailed, high-contrast 3-D maps of splenic structure and microvasculature. A significant difference in total splenic volume was found between vehicle and ZD6126-treated cohorts, with mean volumes of 61 ± 3 mm  •Murine spleen imaged in 3-D using optical computed tomography•Endogenous haemoglobin-sensitive contrast revealed detailed internal structure.•Toxicity effect of treatment with vascular disrupting agent ZD6126 characterised•Significant ZD6126 treatment-induced shrinkage of 28% of total spleen volume found•Microvascular ZD6126 treatment-induced changes characterised via textural analysis Toxicity is an important consideration in drug development and off-target effects are common, with potentially significant adverse side-effects. Methods that provide informative, accurate and rapid assessment of drug-induced toxicity to major target organs, such as the liver, kidneys and spleen, can either positively impact and accelerate the development of promising new agents, or force early closure of a programme that ultimately will not deliver a safe drug. They also inform design of subsequent clinical trials, ensuring that imaging protocols are optimised to include potentially critical normal tissues.In the treatment of cancer, a number of agents designed to specifically target the tumour vasculature have been and continue to be developed. Given the hypervascular nature of the spleen, its essential role as a blood filter and the unique presence of acute endothelial contractility , the effin vivo microscopy  is an emerging imaging modality. Although initially introduced in 1996 to solve problems in the physical sciences , the firendogenous , or exogenous in the form of optical stains which are well characterised in the field of histopathology. Previously OPT has been used to probe developing spleens in embryos  ZD6126. A previous 2-D assessment, using fluorescence microscopy of Hoechst 33342 uptake , demonstO-phosphate, Angiogene Pharmaceuticals Ltd.) was formulated in 20% of 5% sodium carbonate and 80% phosphate-buffered saline (PBS).ZD6126  Act 1986, the United Kingdom National Cancer Research Institute guidelines for the welfare of animals in cancer research  and kept in 70% ethanol in PBS overnight at room temperature. The samples were then dehydrated with three washes of 100% ethanol over three days. Optical clearing was achieved with a graded series of ethanol and 1:2 benzyl benzoate:benzyl alcohol (BABB) solutions , with washes of 30% and 70% 1:2 BABB in ethanol, each for one day, followed by two washes of 100% 1:2 BABB over a one week period.Imaging was performed using an in-house optical CT system, shown in 3-voxel volume. Dataset 1 had a FOV of (13.3 mm)3 and isotropic voxels of size (26 μm)3, while Dataset 2 had a FOV of (5.3 mm)3 and isotropic voxels of size (10.4 μm)3.Two datasets were acquired for each optically cleared spleen, each based on a raw dataset of 1000 projection images of 512 × 512 pixels, acquired over 180° rotation and reconstructed to a 512The first scan encompassed the entire spleen height, enabling accurate total volume measurements. The second scan had a reduced FOV to enable acquisition of higher resolution data over a limited height, providing more detailed images of the internal tissue structure. Dataset 1 was acquired using a wavelength of 630 nm . For increased contrast between the red and white pulp regions, a wavelength of 430 nm was chosen for Dataset 2 , which is near the peak absorption wavelength of deoxyhaemoglobin and also strongly absorbed by oxyhaemoglobin.3. This method is advantageous over threshold-based segmentation as highly attenuating artefacts were excluded. The volume results for each cohort were tested for significant difference using a non-parametric one-tailed Mann–Whitney U test at the 95% confidence limit.Volume measurements were carried out by segmenting spleen from background in each slice and counting the total number of spleen voxels. Segmentation was done in OsiriX . For eacQuantitative analysis of internal structures was performed by comparing various textural statistics between samples. Due to the irregular size and shapes of the spleens, regions-of-interest (ROIs) of size 200 × 200 × 30 pixels in similar positions were analysed for each sample, as shown in 16 elements, compared to 264 elements for a 32-bit image, which is on the order of exabytes. Therefore, scaling to 8-bit is customary to give a tractable computation time, 75 min in our case using a Dell PC with 256 GB RAM. Additionally, it was found that a linear scaling of optical CT image intensity to grey-level value suppressed image contrast due to the presence of some highly attenuating artefacts. Histogram equalisation was therefore employed to maintain intra-sample contrast despite sacrificing inter-sample comparability of absolute values. This process can amplify noise, so a median filter with a kernel width of 3 was applied prior to analysis to improve the signal-to-noise ratio (SNR). This width was chosen given the interest in long-range textural features, such as red and white pulp boundaries that change over larger pixel distances.The grey-level co-occurrence matrix (GLCM) is a standard method of calculating textural features in 2-D images . ROI voxx–y slice in the sample ROIs for a range of pixel displacements and averaged over four angular directions . Contrast and homogeneity were calculated from these 3-D GLCMs according to equations adapted from . The analysis was not blinded and these endpoints were decided after data acquisition.3-D matrices were calculated for a range of ted from  . The red pulp areas of the spleen transport and trap some RBCs making these areas highly absorbing on our optical CT scans. White pulp areas including lymph nodes do not usually contain RBCs and are therefore far less absorbing. The marginal zone between red and white pulp can trap RBCs to a lesser extent than the red pulp giving it intermediate absorption.Simulated spleen images were generated incorporating these three tissue types. Each simulated image had four ‘features’ made up of a simulated lymph node and surrounding simulated marginal zone. The lymph nodes were simulated as circles, with constant grey level value of 0. The marginal zone was represented as a circular disc around the lymph node with uniform grey level value of 128 and the surrounding areas simulated the red pulp, with a grey level value of 256. Four simulated spleen images were generated with different lymph node and marginal zone radii, changing the total size of the features and the ratio of marginal zone area within each feature. 2-D contrast was calculated for each case.High contrast data were successfully acquired for each spleen, and all animals were included in analysis. 3–63.9 mm3, while the ZD6126-treated group volumes ranged from 40.6 mm3–45.8 mm3 demonstrating a ZD6126-induced median shrinkage of 28% with significance of p = 0.05.The total volume of each spleen is plotted in Our initial 2-D GLCM analysis, calculated as specified by , was fouAfter analysis of 2-D simulations of splenic features it was found that features with smaller radii resulted peak contrast occurring at smaller pixel displacements and simulations with decreased marginal zone area had increased 2-D contrast .In this study, we were able to demonstrate the use of endogenous optical CT contrast to provide distinct images of murine spleen microstructure, and its sensitivity to treatment-induced effects on spleen function following administration of the VDA ZD6126. Differences in spleen structure between the two groups were clearly observed via optical CT and changes in total spleen volume, 3-D contrast and homogeneity were determined.Owing to the distortions induced by physical sectioning of the samples and the other difficulties described in the introduction, assessment of volume is problematic using standard 2-D histology techniques. Thus, the volume difference between ZD6126-treated and vehicle spleens may not have been detected using conventional histology due to the irregularity of spleen shapes. The changes in volume observed in our optical CT images may not be linearly related to actual changes in vivo due to the nature of the clearing process. Dehydration causes tissue shrinkage and the amount of shrinkage may depend on original tissue size and density. Nevertheless, given our observations and the results of previous studies using ZD6126 and another VDA, AVE8062 , it is hDirect biological interpretation of textural feature statistics is difficult given that many factors contribute to the final result. Qualitatively we noticed that the ZD6126-treated samples appeared to have a steeper gradient of grey values between white and red pulp areas a.. The rIn previous findings, ZD6126 was found to reduce spleen perfusion, associated with red pulp areas as measured by uptake of Hoechst 33342 . The reaThe effects of the VDA ZD6126 on the spleen were detected and characterised in 3-D, using an optical CT anatomical scan sensitive to haemoglobin absorption contrast. In the future this could be extended using optical stains providing additional functional information. For example, India ink would provide detail of perfused vessels and fluorescent micro-particles can indicate the degree of RBC trapping in the red pulp and marginal zones of the spleen. Indeed, there are plenty of data from these initial scans that could be extracted with further computational analysis.We have shown that spleen imaging using optical CT is potentially a very useful measure of spleen structure in 3-D, complementary to ultra-high resolution 2-D methods such as SEM and TEM. This method can be more straightforward than microvascular-corrosion cast methods, which involve many more preparatory steps prior to imaging and can be susceptible to practical problems in delivering resin down to the capillary level. Further investigation is continuing, including testing different functional stains and characterising the effect of the clearing process on this contractile organ. The promising results of this proof-of-concept study suggest a useful role for optical CT in assessment of drug-induced changes. Future studies with a larger cohort to enable robust statistical testing will establish the significance of the quantitative changes and the sensitivity of the technique.


Evidence-Based System of Innovation Support (EBSIS) as a framework to guide research and thereby strengthen the evidence base for building practitioners’ capacity. The purpose of this review was to contribute to further development of the EBSIS by systematically reviewing empirical studies of capacity-building interventions to identify (1) the range of strategies used, (2) variations in the way they were structured, and (3) evidence for their effectiveness at increasing practitioners’ capacity to use evidence-based prevention interventions.Numerous agencies are providing training, technical assistance, and other support to build community-based practitioners’ capacity to adopt and implement evidence-based prevention interventions. Yet, little is known about how best to design capacity-building interventions to optimize their effectiveness. Wandersman et al.  proposed the PubMed, EMBASE, and CINAHL were searched for English-language articles reporting findings of empirical studies of capacity-building interventions that were published between January 2000 and January 2014 and were intended to increase use of evidence-based prevention interventions in non-clinical settings. To maximize review data, studies were not excluded a priori based on design or methodological quality. Using the EBSIS as a guide, two researchers independently extracted data from included studies. Vote counting and meta-summary methods were used to summarize findings.n = 10 of 12 studies) and implementation (n = 9 of 10 studies) of evidence-based interventions. Findings were mixed for interventions’ effects on practitioners’ capacity or intervention planning behaviors. Both the type and structure of capacity-building strategies may have influenced effectiveness. The review also identified contextual factors that may require variations in the ways capacity-building interventions are designed.The review included 42 publications reporting findings from 29 studies. In addition to confirming the strategies and structures described in the EBSIS, the review identified two new strategies and two variations in structure. Capacity-building interventions were found to be effective at increasing practitioners’ adoption  contains supplementary material, which is available to authorized users. Public health and other community-based practitioners have access to a growing menu of evidence-based interventions (EBIs) to promote health and prevent disease. These EBIs include a range of programs, policies, and practices that have been shown to be effective at improving environments, behaviors, and health outcomes . Practitprevention synthesis and translation systems that disseminate EBIs , (2) prevention delivery systems that use EBIs to promote health , and (3) prevention support systems that bridge the gap between the two other systems by disseminating tools and providing training and technical assistance (TA) to build prevention delivery system capacity to effectively use EBIs in practice ), ), TA as  et al., ), evaluaools n = . Among t et al., ). Only tning n =  and toolentation .Opportunities for peer networking included bringing practitioners together to learn from each other via in-person trainings and TA sessions [incentives to motivate practitioners to participate in the capacity-building intervention or to adopt and implement EBIs, such as scholarships to participate in trainings [The review identified two capacity-building strategies not described by the EBSIS: opportunities for peer networking and incentives. sessions , 30–32, sessions , and websessions . Many ofrainings , mandatirainings , or provrainings .orientation was towards “pushing” one or two specific EBIs . In the remaining 19 studies, capacity building was oriented towards building practitioners’ capacity to “pull” EBIs from a wider range of options. Dosage varied widely, with authors often providing only limited information. In 19 of the studies, authors provided information on training dosage, typically in the format of number of trainings and their duration . Authors provided almost no information on TA dosage in 15 studies. Authors did provide data on TA frequency  but noti-weekly ) in fivei-weekly ). Authorcollaborative design of capacity-building interventions also varied. The review revealed multiple related dimensions across which variation occurred in the collaborations between those providing and those receiving the capacity-building intervention. Those providing the intervention may work directly with delivery systems or may use a two-level or train-the-trainer model to build the capacity of intermediaries  who thedinators ) versus dinators ). In mosdelivered within the context of an overall planning model . Planning models walk delivery systems through an overall planning process that includes stages such as assessing the context, selecting an EBI, implementing the EBI, and evaluating processes and outcomes. The most commonly used planning models were variations on Getting to Outcomes (n = 5 studies) [n = 2 studies) [The review identified an additional dimension of variation in the structure of capacity building not specified by EBSIS. Capacity-building interventions varied in whether or not they were studies) , 37, 38,studies) , 39, andstudies) , the Heastudies) , STAR [3studies) , the Strstudies) , and a lstudies) .n = 12) or implementation (n = 11) than they were to report the effect that capacity building had on practitioners’ capacity (n = 7) or planning behaviors (n = 7)  and Lit[n = 50, ). Resear[n = 50,  and know[n = 50, ) and in [n = 50,  and beli[n = 50, ). Neithe[n = 50,  and self[n = 50,  and self[n = 50, ).In one study, researchers analyzed the role that capacity played as both a mediator and moderator of capacity building’s effects on implementation . They fon = 24, [n = 134, schools [n = 30 programs, [The review found mixed evidence for the effects that interventions had on practitioners’ collective EBI planning behaviors  and one schools ); and onrograms, ). In fourograms, , 38, 46.adoption, four found a significant within group difference [implementation, all but one reported that capacity building had a positive effect. In five group trials (four of which were randomized), researchers compared differences between groups and found that the intervention group had better implementation outcomes than the comparison. In one of the five trials, findings were mixed and the intervention group performed significantly better on only some of the outcomes [The review found evidence that capacity building affects delivery system adoption and implementation of EBIs  [EBIs with more components and less prescriptive implementation guidance are more difficult or require more effort to support than other EBIs [fit a particular setting’s funding streams, values, or their clients’ cultures [planning process  , 41, 48 dership) . In prevdership) , which fdership) . In a sedership)  found thdership) . In two her EBIs , 32. Stucultures , 48. Muln et al. ).Wandersman et al.  created Similar to prior reviews, we found that capacity-building interventions can be effective at increasing EBI adoption and implementation , 7, 10. One of the review’s central purposes was to describe capacity-building strategies and synthesize evidence related to variations in their types and structures. The lack of information that authors provided about their capacity-building strategies and the way they were structured make it difficult to transfer successful strategies to new settings or to develop guidance for how best to structure capacity building. The need for specific guidance on how to structure capacity building is evidenced by findings that TA providers often experience their role as vague and ill-defined . The lacThe review of the literature was systematic but not comprehensive. Searches for literature related to implementation science are difficult because the field is still in the early stages of development, and consistent terminology has not been adopted , 56. BecThe EBSIS and our refined framework both move the field towards a more standardized approach to conceptualizing the types and structures of capacity-building strategies. This standardization will assist in synthesizing findings across studies and building the evidence base for what works under which circumstances. However, for findings to contribute to the evidence base, it is essential that researchers provide complete descriptions of how they designed and delivered their capacity-building interventions. Capacity building is a complex, behavioral change intervention. The prevention support field could benefit from guidance that the United Kingdom’s Medical Research Council and others have developed to facilitate the development, testing, and translation of complex interventions , 59. Of EBSIS and the refined framework could also advance the field towards the development of theory. Since capacity is hypothesized as the primary causal mechanism, further research is needed to better understand the capacities that practitioners require to successfully adopt and implement EBIs and to develop measures of those capacities. Additional research is also needed to identify salient contextual factors that moderate the effects of prevention support and the best approaches to customizing prevention support contingent on those factors. The framework’s depiction of prevention support as a linear process is an oversimplification, and more research is needed to understand bi-directional interactions between support providers and practitioners and their effects.The number of researchers and agencies providing technical assistance and other capacity-building strategies to promote the use of evidence in practice is on the rise. However, the science to guide the design of prevention support is nascent. Only a limited number of researchers have taken a rigorous approach to designing, describing, and testing capacity-building strategies. As a result, little is known about how capacity-building strategies may vary across projects and how those variations may affect outcomes. This review contributes to the understanding of the types of capacity-building strategies and their effects thereby building the knowledge base on how to build practitioners’ capacity to use EBIs.


Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence  of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity.Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs.When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible.The online version of this article (doi:10.1186/s12940-016-0156-6) contains supplementary material, which is available to authorized users. Endocrine disrupting chemicals (EDCs) have received significant attention by scientists across numerous disciplines and risk assessors since the term was first coined in the 1990s . Concernevidence of an (adverse) effect, evidence of endocrine disrupting activity evidence of a plausible link between the observed adverse effect and the endocrine disrupting activitySince the term ‘endocrine disruptor’ was first used, numerous definitions have been proposed by various groups and agencies. The 2002 report by the International Programme on Chemical Safety and World Health Organization (IPCS/WHO) defined an EDC as “an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse effects in an intact organism, or its progeny, or (sub)populations” . This deWe have focused on the IPCS/WHO definition in this manuscript for a number of reasons. First, the use of this definition by the WHO and other international organizations suggests that it is relevant across the globe. Second, this definition provides a framework for testing, as it is the strictest definition requiring detailed data to address specific points. As discussed later in this manuscript, the selection of other definitions for an EDC may be appropriate in specific contexts, and we provide suggestions for how a decision-making framework would be adapted for these definitions.State of the Science of Endocrine Disrupting Chemicals – 2012” , or by complying with human-subjects guidelines for a clinical study” ensures that the research was conducted using high standards . HoweverSeveral new evaluation methods have been developed that better target internal validity of in vivo or in vitro toxicity studies, and provide more structured support for determining a study’s adequacy for hazard and risk assessments. Additional file in silico methods are limited to those that predict the potential for a particular chemical structure to cause “endocrine disruption”. These often include computational methods that derive structure-activity relationships (SAR) and thus predict potential EDC activity for a given chemical structure. SAR methods can also provide an understanding of the variations in chemical structures that contribute to variations in EDC activity. Table in silico data. The REACH legislation provides guidance for use of quantitative SAR (QSAR) models [in silico data [For the purpose of this review, ) models , dictatiico data .Table 3EThe development of the SYRINA framework considered the viewpoints proposed by Austin Bradford Hill , which win silico). If using the IPCS/WHO definition of an EDC [Association between chemical exposure and (adverse) effect (Step 5a)Association between the chemical and endocrine disrupting activity (Step 5b)The purpose of this step is to summarize relevant data from the individual studies evaluated in Step 4, and to synthesize the evidence within each stream  theWe recommend that the initial rating for experimental laboratory animal studies should be set as “high” based on the approach in clinical medicine, where randomized clinical trials (i.e. controlled and randomized exposure studies with the inclusion of a relevant control group) are rated “high”. For epidemiology studies, the choice of the initial confidence rating for the GRADE-based methods is an issue that is undergoing research and review. “Medium”, has been recommended for an initial rating of observational (epidemiology) studies , 85; anolimitations in methodological quality of the research in the stream (including risk of bias across studies)important and unexplained inconsistency in study results within the streamimprecise or sparse dataFollowing this initial rating, evidence streams are up- or down-graded according to specified features of the body of evidence. The following factors should be considered to downgrade confidence in a stream of evidence:large magnitude of effectconsistency across different study designs or speciesdose response gradients observed in similar studiesconfounding is minimizedThe following factors can be considered to upgrade confidence in a stream of evidence:These adjustment factors are not scored numerically  but shouAs part of the analysis of consistency and to aid in the interpretation of the quality of the evidence, if possible, a meta-analysis of some or all of the studies within a stream of evidence should be conducted to calculate a summary effect estimate. This summary estimate can provide a more precise estimate of the magnitude of effect than an estimate from an individual study. For the purpose of hazard identification, however, a single effect estimate may not be needed, as the focus is on examining patterns and variability (consistency) across studies. If a meta-analysis is conducted, the validity of the assumption that the studies are examining a common effect estimate must be carefully considered; this consideration requires more than a statistical test of heterogeneity , 86. Stustrength of evidence for each evidence stream. Confidence descriptors can also be used to summarize studies that conclude that no effect was observed. The confidence descriptor produced in this step designates conclusions related to the association between exposure and adverse effects: e.g. “We have high/medium/low confidence that exposure to compound X is associated with adverse outcome Y in humans .” Confidence descriptors can also be used to summarize studies that indicate that no effect was observed. Confidence descriptors should not be used to characterize the strength of the effect associated with exposure to the compound .After conducting this process, a confidence descriptor  is generated for the A similar process to that described in Step 5A can be used for the synthesis of studies aimed at addressing endocrine mechanisms; a set of considerations are applied to conclusions drawn from a group of studies. Again, we propose the same four-level rating system to summarize the strength of evidence in each stream: “high”, “medium”, “low” and “absent” (no studies available) Table .“We have low/medium/high confidence that compound X is associated with Y endocrine disrupting activity in experimental animal studies.”After conducting this process, a confidence descriptor  is again generated for the strength of evidence for each evidence stream, but this descriptor is related to the association between the chemical and endocrine disrupting activity: e.g. The purpose of this step is to integrate the streams of evidence that were assessed in Steps 5A and 5B to come to a conclusion about the overall strength of the evidence for endocrine disruption. First, the individual streams of evidence need to be integrated to assess the strength of the evidence relating to the association between exposure and an adverse effect (Step 6A). Second, the strength of the evidence for each of the conclusions from Steps 5A and 5B are integrated to reach a conclusion about endocrine disrupting activity (Step 6B).in silico and in vitro studies. Explanations of the terms “strong”, “moderate” and “weak” should be developed as part of the systematic review framework.The aim of this step is to assess the overall strength of evidence that exposure to a potential endocrine disruptor is associated with a health outcome. This is a function of the combined certainty of each stream of evidence. The first step in the process is to use a matrix Fig.  to assig“We have strong evidence that exposure to compound X causes adverse outcome Y” even if no information about endocrine disrupting properties of compound X is available. Outside of the framework of the IPCS definition of an EDC, it may not be necessary to identify the mechanism by which a chemical acts prior to regulating its use. Thus, a systematic review that solely identifies the strength of evidence linking a compound to a health outcome may be sufficient to implement a public health response.Most importantly, the result of this assessment can potentially yield a health hazard classification independent of any endocrine disrupting effects of the compound under review, i.e. this step can allow for a conclusion that The main aim of integration at this stage is to qualitatively assess evidence of endocrine disrupting activity. In Step 5, individual streams of evidence were evaluated and assessed with respect to this feature. Again, the overall strength of the evidence achieved from integrating multiple streams of evidence will be at least as high as the highest strength of evidence obtained for any single stream Fig. . The samThe IPCS/WHO definition of an EDC requires an integration of: 1) the health outcome; 2) the endocrine activity; and 3) the plausibility of the link between the outcome and endocrine activity. To complete the SYRINA process, a final integration step can be accomplished using a matrix Fig. . ConfideIn this final step, consideration is given to the plausibility of the link between endocrine disrupting activity and outcome. The strength of the link can be used in relatively unusual cases to up- or down-grade the preliminary conclusions. Situations where the preliminary conclusions can be downgraded include those where the outcome is multifactorial  and the evidence for the endocrine disrupting activity  is only ‘probable’ or ‘possible’. Similarly, it may be appropriate to upgrade the preliminary conclusion when the evidence of an outcome  has an acknowledged strong link to endocrine activity, but data are limited to support conclusions on endocrine activity for that particular chemical.potential hazards. Based on the results obtained during Step 6, these conclusions will usually take the form of statements such as “Chemical A is a known/probable/possible endocrine disrupting chemical based on strong/moderate/weak evidence from human and non-human studies.”The objective of a SYRINA is to provide a scientifically supported evidence base for others to act in order to avoid or minimise potential adverse effects, rather than waiting to observe adverse effects in humans or the environment before any actions are taken. The conclusions of a SYRINA will therefore include statements about As noted in Step 1, the conclusions that will be reached about the likelihood that a chemical is an EDC will depend on how the PECO statement is framed. For this reason, we caution against drawing overly broad conclusions about the lack of endocrine disrupting properties of a chemical based on the results of a narrow analysis; using the SYRINA framework, one could conclude that a chemical is not classifiable as an EDC based on one PECO statement but could conclude that the same chemical is a known EDC based on another PECO statement that evaluates different literature. For example, a review that is focused on the anti-androgenic effects of a suspected EDC would likely not assess the same literature as a review focused on the thyroid hormone disrupting properties of the same compound.The SYRINA framework described here was designed specifically to address evidence of endocrine disruption as it is defined by the IPCS/WHO . Yet, thIt is important to note that, regardless of which definition is used, the use of the SYRINA framework requires participation from individuals with a range of expertise. Not only are experts in aspects of study design for each evidence stream needed, scientific experts that understand the biological processes implicated in the PECO statement are needed ; generalized toxicology or endocrinology knowledge is not likely to be sufficient. Without such subject matter experts, the conclusions that are drawn may be incomplete or inaccurate.evaluation of evidence about the potentially adverse effects of an EDC is a different activity from deciding how to act on the basis of that evidence. Who evaluates the evidence and who then recommends action, based on the available evidence, depends on the issues and practices involved in different domains of activity and regulatory contexts. In many regulatory agencies tasked with addressing chemical safety, the evaluation of evidence is performed by “risk assessors” whereas the recommendations for action are made by “risk managers”. Recommendations are typically based on both the evidence of risk (or hazards), and on the availability, feasibility, and cost of the options for action.The .As Bradford Hill and others have addressed, there is no direct link between the strength of evidence about a threat  and the strength of recommendations about how to minimise or avoid it. For example, information may be available only from epidemiology studies with designs in which bias and confounding may be impossible to resolve, yet an intervention may be strongly recommended given the serious consequences of inactionmechanism of action is not required . Mechanistic data can take decades to collect and to be agreed upon by experts in the field [Some groups may prefer to use a modified version of the SYRINA framework where direct evidence for he field , 87. DecIn each step of the SYRINA, as in the assessment of chemical hazards and risk in general, there are sources of scientific uncertainties and the possibility for error that could contribute to false-positive or false-negative conclusions. There are, for example, uncertainties associated with assumptions made while formulating the problem or review question, as well as how the PECO statement is framed. Uncertainties also arise when extrapolating from data that is only indirectly relevant to the target population, e.g. toxicity data in other species, or exposure scenarios that differ from actual exposure. Incomplete or lack of data also contribute to uncertainties in the final conclusions.p that the study results deviate from expectation under the null hypothesis is less than a limit of 5 %. However, this limit may rule out many potentially causal associations, e.g. because the study was too small to reach statistical significance [negative conclusions [positive findings in environmental health and toxicology, very few such cases have been found [A specific source of uncertainty is the reliance on “statistics” in individual studies to make conclusions about the strength of evidence. “Statistical significance” is generally achieved when the probability ificance . While aificance , 90. Pubificance . For exaificance . The “unclusions . In conten found , 94. ThuSources of uncertainty related to any of the steps in the systematic review should be disclosed and characterized as far as possible in order to inform risk managers. Guidance for evaluating and expressing uncertainty in hazard and risk assessment is available from the International Programme on Chemical Safety (IPCS) . GuidancThere is often an intermediate step between evidence evaluation/integration and taking action and this is the evaluation of the consequences of being wrong about either the evaluation or the threat. For example, at this stage it is important to consider the consequences of being wrong about a chemical being hazardous, or the consequences of a failure to act following evidence that an EDC is hazardous. As the consequences of being wrong in both cases can be serious, and sometimes irreversible, they may need to be evaluated and reported by evidence evaluators whose expertise contributes to such consequence analyses.confidence that evaluators have placed in their conclusions. We propose that this confidence can be increased by using transparent and reproducible methods that acknowledge uncertainties during the process of completing a SYRINA.The plausibility and likelihood of being wrong with an evaluation of evidence is related to the in silico data. We note the need for a case study which would also shed light on important procedural issues, including the number and types of experts needed to evaluate evidence from different scientific fields. Such a case study would also be important to identify the time required to complete Steps 1–6 of SYRINA based on examples with many relevant studies versus other examples with minimal available data. We anticipate that the completion of Steps 1–6 could take more than a year to conduct if a relatively large dataset is identified; importantly, this could lead to further delays in the already lengthy processes for regulatory decision-making and other public health oriented actions. We also note that some risk assessment groups will need to make concrete decisions about how PECO statements are written and which risk of bias tools are used in evaluation of studies within evidence streams, as this level of consistency is needed to produce harmonized evaluations.The SYRINA framework described in this manuscript provides methods to critically evaluate scientific literature. Like the methods on which it is based (OHAT and Navigation Guide), there is a need to explore and evaluate the best use of these tools in hazard identification and regulatory contexts and from these experiences, and improve these methods for greater efficiency and transparency. Several areas have been identified in this review as short-term needs including the development of methods for evaluating in vitro and In fall 2015, the US National Academy of Sciences convened a panel specifically to evaluate the data in support of “low dose effects” for environmental chemicals including EDCs.  ThThe IPCS/WHO definition of an EDC raises another important future research need: the delineation of effects as adverse (or not) has been a source of significant debate , 17. In A number of recent analyses of the EDC literature were criticized for failing to use systematic review methods to draw their conclusions. Importantly, systematic review processes specific to EDCs were not yet available for use in these reports. Here, we have developed a seven-step framework for the systematic review and integrated assessment of EDC studies; this framework has a direct application to the IPCS/WHO definition for EDCs. It is also amenable for use in the context of other definitions of an EDC or, with some minor modifications, it could be used to conduct systematic reviews of environmental chemicals that are not EDCs. The SYRINA framework can be used in hazard assessment, which encompasses the first step of the risk assessment process.The implementation of the SYRINA framework will enhance the assessment of the EDC literature, allowing for transparent and reproducible analyses to be conducted. Case studies using this framework are needed to demonstrate its use and identify any flaws. Importantly, frameworks for systematic reviews should be robust enough to adapt to future needs, and the SYRINA framework was designed with this objective in mind.DRAGON, Dose Response Analytical Generator and Organizational Network; EDC, endocrine disrupting chemicals; FDA, Food and Drug Administration; GLP, Good Laboratory Practices; HAWC, Health Assessment Workspace Collaborative; IARC, International Agency for Research on Cancer; IPCS, International Program on Chemical Safety; MeSH, Medical Subject Headings; NTP, National Toxicology Program; OECD, Organization for Economic Cooperation and Development; OHAT, Office of Health Assessment and Translation; ORoC, Office of the Report on Carcinogens; PECO, Populations, Exposures, Comparators, Outcomes; PICO, Populations, Interventions, Comparators, Outcomes; QSAR, quantitative structure-activity relationship; ROBINS-I, Risk of Bias In Nonrandomized Studies - of Interventions; SAR, structure-activity relationships; SAREC, State-of-the-Art Report to the European Commission; SciRAP, Science in Risk Assessment and Policy; SYRINA, systematic review and integrated assessment; UNEP, United Nations Environment Programme; US EPA, US Environmental Protection Agency; WHO, World Health Organization


Hyponatremia is a common electrolyte disorder. Multiple organizations have published guidance documents to assist clinicians in managing hyponatremia. We aimed to explore the scope, content, and consistency of these documents.We searched MEDLINE, EMBASE, and websites of guideline organizations and professional societies to September 2014 without language restriction for Clinical Practice Guidelines (defined as any document providing guidance informed by systematic literature review) and Consensus Statements (any other guidance document) developed specifically to guide differential diagnosis or treatment of hyponatremia. Four reviewers appraised guideline quality using the 23-item AGREE II instrument, which rates reporting of the guidance development process across six domains: scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. Total scores were calculated as standardized averages by domain.We found ten guidance documents; five clinical practice guidelines and five consensus statements. Overall, quality was mixed: two clinical practice guidelines attained an average score of >50% for all of the domains, three rated the evidence in a systematic way and two graded strength of the recommendations. All five consensus statements received AGREE scores below 60% for each of the specific domains.The guidance documents varied widely in scope. All dealt with therapy and seven included recommendations on diagnosis, using serum osmolality to confirm hypotonic hyponatremia, and volume status, urinary sodium concentration, and urinary osmolality for further classification of the hyponatremia. They differed, however, in classification thresholds, what additional tests to consider, and when to initiate diagnostic work-up. Eight guidance documents advocated hypertonic NaCl in severely symptomatic, acute onset (<48 h) hyponatremia. In chronic (>48 h) or asymptomatic cases, recommended treatments were NaCl 0.9%, fluid restriction, and cause-specific therapy for hypovolemic, euvolemic, and hypervolemic hyponatremia, respectively. Eight guidance documents recommended limits for speed of increase of sodium concentration, but these varied between 8 and 12 mmol/L per 24 h. Inconsistencies also existed in the recommended dose of NaCl, its initial infusion speed, and which second line interventions to consider.Current guidance documents on the assessment and treatment of hyponatremia vary in methodological rigor and recommendations are not always consistent.The online version of this article (doi:10.1186/s12916-014-0231-1) contains supplementary material, which is available to authorized users. Hyponatremia is the most common electrolyte disorder in clinical medicine; it represents an excess of water relative to total body solute . HyponatDespite the frequency and severity of some of the associated complications, research suggests hyponatremia is often neglected by clinicians . If acquHyponatremia may be managed clinically by different specialists, such as endocrinologists, nephrologists, geriatricians, or intensivists, and, accordingly, management strategies often vary . AlthougClinical practice guidelines and consensus statements provide recommendations to help evidence-based practice by suggesting the most appropriate diagnostic tests and the most appropriate treatments. Over the years, multiple organizations have developed recommendations to assist clinicians in the management of hyponatremia. To be reliable, these recommendations must be based on a systematic review of the evidence, and have a transparent and multidisciplinary development process . InconsiWe included evidence-based clinical practice guidelines and consensus statements on the diagnosis and treatment of hyponatremia. We defined clinical practice guidelines as statements that included recommendations intended to optimize patient care informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options . We defiWe searched MEDLINE  and EMBASE (1980 to September 2014), combining vocabulary terms and text words for hyponatremia with terms related to clinical practice guidelines and consensus statements. We also searched guideline databases and websites of organizations as well as of selected professional specialist societies in nephrology, endocrinology, and intensive care medicine. A list of the databases and websites along with the full search strategies are outlined in Additional file We developed a draft data extraction form which was piloted and modified as necessary. The extracted data included document characteristics , recommendations related to the diagnosis and assessment of hyponatremia, and recommendations related to the treatment of hyponatremia. EN and JV extracted all data using the standardized data extraction form  instrument . AGREE IThe minimum possible score for each domain equaled the number of questions multiplied by the number of reviewers, multiplied by 1 (strongly disagree). The maximum score for a domain equaled the number of questions multiplied by the number of reviewers, multiplied by 7 (strongly agree). To ensure standardization of each reviewer’s approach, all reviewers completed the online training tutorial  before sIn a consensus meeting among the reviewers, we discussed every item for which scores differed by more than 1 point  on the original 7-point scale. Reviewers in turn explained the rationale for their score and had the opportunity to revise their score when they considered this appropriate. We audiotaped the consensus meeting to reliably record the underlying reasons for changing scores.We conducted a textual descriptive synthesis to analyze the scope, content, and consistency of the included recommendations. EN inductively coded the text manually to identify domains covered by the guidelines. These were cross-tabulated with the guidelines and recommendations were inserted into the corresponding cell. For each domain, we compared guideline recommendations to identify similarities and discrepancies. Consistent with the scope of this review, we only tabulated the information on diagnosis and treatment of hyponatremia.We identified 1,402 citations, of which we excluded 1,367 after screening titles and abstracts because they did not meet our eligibility criteria  and clarity of presentation , and lowest scores for applicability  and editorial independence .Initial appraisal results differed more than one point on the Likert scale between two or more reviewers for 143/230 items (62%). The majority of discrepancies were found in the domain ‘Clarity of Presentation’, with 90% of items differing more than one point. Group discussion resulted in 287/920 (31%) of individual entries being changed. Finally, no scores differed more than two points and for 82% of items, scores were the same or within one point of each other. Major reasons for changing an entry were a change of own opinion after clarification of the opinion of other reviewers during the group discussion ; aiming for consistency between entries given same available data ; re-evaluation of the score in light of a noted comment during the appraisal process ; correction for available data that were overlooked during the initial appraisal ; misinterpretation of the question during the initial appraisal ; adjusting for arbitrary scoring of items that were felt to be inapplicable for some reason ; adjusting for inconsistent approach to deal with the assumption that a criterion was fulfilled even if this was not clearly mentioned ; and data entry error . Overall, this resulted in 29/60 (48%) of standardized domain scores being downgraded by a maximum of 10% and 10/60 (17%) of standardized domain scores being upgraded with a maximum of 10%; the remaining 35% remained unchanged.The included guidance documents addressed three major themes: diagnosis, treatment, and speed of correction.Seven guidance documents covered diagnosis and differential diagnosis of hyponatremia -22. TablGuidance documents differed somewhat in their recommended threshold for starting diagnostic assessment. Six recommended starting diagnostic assessment when the serum sodium concentration dropped below 135 mmol/L ,19-23 anMost guidance documents proposed additional laboratory tests that could be of value to identify the underlying disorder, but they varied substantially regarding which tests to use in what situation and which reference values to use. Only two explicitly recommended taking a history of drug intake and symptoms as part of the assessment ,22. FourTable Patients without symptoms of hyponatremia were assumed to have chronic onset hyponatremia, and treatment suggestions were mostly dependent on the classification hypovolemic, euvolemic, or hypervolemic. Only three guidance documents specifically advised treating the underlying condition ,22. SeveFor euvolemic asymptomatic hyponatremia, the majority recommended fluid restriction as the first-line treatment -25. FiveFor hypervolemic asymptomatic hyponatremia, seven guidance documents recommended fluid restriction as the first-line treatment ,17,19-23Table Seven guidance documents provided targets or aims for the increase in serum sodium concentration in case of symptomatic and/or acute hyponatremia ,19-22,25We found five clinical practice guidelines and five consensus statements covering the diagnostic approach to and treatment of hyponatremia. Although most used serum osmolality, volume status, urinary sodium, and urinary osmolality to guide differential diagnosis, they differed in classification thresholds, what additional tests to consider, and when to initiate diagnostic work-up. Most advocated hypertonic NaCl in severely symptomatic, acute onset hyponatremia and NaCl 0.9%, fluid restriction, and cause-specific therapy for hypovolemic, euvolemic, and hypervolemic hyponatremia, respectively. However, they somewhat differed in the limits for speed of increase in serum sodium concentration and which specific medications to use. The reasons for offering different recommendations are undoubtedly multifactorial. They may in part be explained by the fact that recommendations were issued by organizations differing in context and scope. It is also very likely that some variability in guidance arose through limitations in the evidence available for guideline developers to base their recommendations on . In the However, it is also possible that discrepancies between guidance documents may in part be explained by differences in underlying methods of development. Quality, as assessed by AGREE II, was suboptimal at best, with only two documents obtaining a score >50% for each of the six quality domains ,20. The Only half of the guidance groups stated they had conducted a systematic review of the evidence. Save one, the reviews would not have met the Institute of Medicine’s criteria for reporting high-quality systematic reviews ,27, becaSix groups included healthcare professionals from different specialties ,22,24,25Low scores for applicability mostly reflect the absence of describing barriers to guideline implementation and failure to provide tools for putting the recommendations into practice. In part, guidelines are designed to deal with the challenges of increasing knowledge and time-pressure. They are designed to help make decisions at the point of care. However, being often lengthy publications without layered presentation of information, it is likely that the majority of the guidance documents may not reach their target audience or stimulate implementation. Four guidance documents provided algorithms for diagnosis or treatment ,18,20,25To our knowledge, this is the first attempt to systematically synthesize and appraise clinical guidelines on the diagnosis and treatment of hyponatremia In accordance with the Prisma statement, we conducted a comprehensive literature search and searched an additional 337 websites of specialist societies and guideline organizations  Additio. We usedThis study has its limitations. We based our assessment on what guideline organizations actually reported. Reporting by guideline developers may not wholly reflect what occurred in practice with respect to the AGREE criteria, and we did not seek additional clarification. However, contacting guideline developers is not standard practice when using AGREE as the instrument specifically aims to provide a framework for assessing the quality of reporting of recommendations. We aimed to summarize the existing recommendations on diagnosis and treatment of hyponatremia as formulated by other guideline development groups and to evaluate the quality of the guideline development process. We did not aim to summarize or critically appraise the evidence base itself. Consequently, it is difficult to assess to what extent differences between guidance documents stem from differences in development procedures rather than important limitations in the evidence base that underpin individual recommendations. Secondly, the purpose of using the AGREE instrument was not to accuse guideline development groups of being biased, but rather to highlight both strengths and weaknesses of existing guidance to suggest on how we could make improvements in the future.Calculation of summary scores for each domain across reviewers required summing up all the scores of the individual items in a domain for each reviewer and then standardizing this total as a percentage of the maximum possible score for that domain. In doing so, the originally semi-qualitative Likert scale was converted to a quantitative score. This may have introduced numeric differences between the guidance documents that were beyond the discriminatory ability of the tool and possibly negligible in practice. Finally, we acknowledge that four of the authors of this paper also authored one of the guidelines included in this review. Although we aimed to judge all guidance documents fairly against the criteria outlined by the AGREE instrument, we cannot rule out that a subconscious intellectual competing interest unduly influenced the scoring.Current guidelines on the assessment and treatment of hyponatremia often fail to meet methodological criteria for development and reporting as described by AGREE II. Despite many similarities, recommendations are sometimes inconsistent, but to what extent this is attributable to the underlying development process remains unclear.


Health is influenced by determinants beyond the traditional conception of the health sector. Increasingly, global actors are targeting policymakers at global and national levels to take an intersectoral approach to health issues. Multilateral organizations in the health and transport communities have published policy reports targeting policymakers to address the burden of road traffic injuries. However, these reports stem from sectors grounded in different disciplinary perspectives. We investigate whether sectors have differing evidentiary traditions by analyzing differences regarding author networks, type of evidence cited, recommendations, and indicators.We selected global policy reports on road traffic injury prevention based upon expert opinion and categorized them by sector according to their institutional publisher. For each report, we i) conducted an authorship analysis by sectoral affiliation; ii) analyzed the types of research evidence cited and categorized the evidence type and institutional nature of the publisher; iii) analyzed key recommendations by extracting recommendations presented in the concluding sections of the documents; and iv) examined the use of indicators. Descriptive statistics were used to determine whether dimensions differed by the sectoral affiliation of the policy report.Authorship was dominated by the sector from which the report was published, while reports that involved both sectors often showed clustering of authors in one sector or another, depending on the subject addressed. Reports originating from different sectors preferentially cited different types of evidence; notably, health sector reports emphasized observational studies and reviews, while transport sector reports drew heavily on government agency reports. There were no differences in recommendations and indicators used.Notions of knowledge validity and valuations of evidence vary depending on the field’s historical development. Such differences in valuing evidence within sectors may have the potential to undermine the application of evidence in intersectoral policymaking. Strategies to address this challenge include the identification of key individuals to connect separate sectors, knowledge translation activities that take account of sectoral differences, and the tailoring of messages to different audiences. Future analyses on other intersectoral issues may provide clarity on points of tension and differing types of evidence used in intersectoral work. RTIP is an appropriate case for our analysis given the fact that i) it represents a leading cause of death among adolescents worldwide, accounting for the loss of approximately 1.2 million lives and between 20 to 50 million injuries every year, creating economic burdens of up to 2% of GDP annually . ii) It Through an analysis of prominent international reports on RTIP published by major health and transport organizations, we sought to investigate whether there are differences between the health and transport reports with respect to i) author networks; ii) interventions and types of evidence cited; iii) recommendations; and iv) indicators used.We examined the nature of research evidence by selecting influential policy documents on global RTIP and categorizing them based on the mission and orientation of the publishing organization. Through discussions with an expert in the RTIP field (KB) who straddles both the health and engineering communities, we identified the major organizational players in the field and selected one major organization stemming from each of the fields of health, transport, and mixed.We selected documents from the WHO, World Bank (WB), and the Organization for Economic Cooperation and Development (OECD), as they represent the most prominent organizations operating within the health, transport, and economic fields on an international level. The WHO is the premier international agency responsible for health within the UN system and is responsible for coordinating all RTIP work within it. The WB is an international development bank, with a mandate that encompasses both public health and infrastructure development (including transport); it therefore represents a mixed  perspective on RTIP. The WB takes behavior change, capacity building, and systems engineering approaches to address RTIP and its associated economic consequences. The OECD collaborates with the International Transport Forum (ITF) to contribute to international co-operation on road accidents. While the OECD does have a division for health under the Directorate for Employment, Labour and Social Affairs, to date, its work on road traffic injury has been driven largely by the ITF. The ITF was created under a Declaration issued by the Council of Ministers of the European Conference of Ministers of Transport, and thus has a predominantly transport perspective. From these three organizations, we included all reports that were i) aimed at policymakers; ii) included an evidentiary basis utilizing research evidence on RTIP interventions that were included in the landmark 2004 Report on Road Traffic Injury Prevention ; iii) foFor each report, we first conducted an authorship analysis to study formations of authorship networks ,32. We eOur sampling yielded 12 reports published by WHO, WB, and OECD between 2002 and 2013. Of the reports, two were categorized as health  ,33, six Author affiliations on health and transport sector reports were strongly aligned with the sector from which the report was published. In health sector reports, main authors were unnamed, but named contributors had primary affiliations in the public health sector . In transport sector reports, the majority of authors had primary affiliations in the transport sector . For the mixed sector reports, there was a clear majority grouping of authors from either within the health or transport sector, depending on the report subject topic. For example, report M1 and M2  had a clear majority of authors originating from the health sector while M3 and M4 (addressing speed management and drinking and driving) had a clear majority of authors originating from the transport sector. M5 covered all of the aforementioned topics, but had a majority of authors from the health sector  and its organizational affiliation  for each citation. A summary on the proportion of evidence cited by sector can be found in Table There was a stark difference in the types of prevailing evidence cited across the health and transport reports. Evidence in the health sector was split amongst reports (32.4%), observational studies (26.5%), and systematic and non-systematic reviews (19.1%), while evidence cited from the transport sector was dominated by agency and organizational reports (69.1%). Approximately 7.4% of citations from the health sector were systematic reviews, while the transport sector cited none.Institutional affiliations of evidence cited also varied considerably by the sector from which the report was published. The transport sector had the highest proportion of government agencies (44.4%) and multilateral organization (22.2%) reports, while the health sector had the highest proportion of evidence from peer-reviewed academic journals (39.7%). Though government agencies were strongly present in all sector reports, the striking difference arises in the presence of peer-reviewed literature in health, but not the transport sector.By and large, despite the differing make-up of evidence types that informed reports across the health and transport sectors, recommendations and conclusions across the reports were similar. The conclusions of all reports were non-specific and focused on the process of implementing RTIP policies and programs, rather than recommending specific interventions. The conclusions generally stated that policymakers should first examine their own country/district’s situation through suggested activities and processes . Only after assessing their own situation, should they utilize the evidence on interventions included in the reports, match the evidence to their own situation, and implement accordingly.. Despite the reports being published from organizations rooted in different sectors, with differing focus in the types of evidence cited, we saw no substantive difference in the use of indicators across sectors.Seven indicators were tracked across the 12 reports  in peer-reviewed journals, while transport sector reports drew on government agency reports. Third, despite substantive differences in the types of evidence cited, concluding recommendations of these reports were similar, focusing on generic policy processes rather than specific interventions. Fourth, indicators were used consistently across reports from different sectors. We reflect on the nature of our findings, limitations in study design, and the implications of the findings for future action and further research.The clustered nature of author networks on transport and health reports aligns with Haas’ concept of epistemic communities, whereby networks of professionals with recognized expertise share i) causal beliefs which serve as the basis for possible policy actions and desired outcomes and ii) notions of validity for weighing and validating information within the domain of expertise . ReportsThe differing valuations of evidence across the two communities may stem from their respective field’s historical development. The emphasis in the health community on observational studies and systematic reviews matches with common valuations of evidence within the biomedical/epidemiological tradition , and indRecent literature has heavily emphasized the importance of interdisciplinarity and transdisciplinarity in public health research ,51. The This was an exploratory study designed to investigate an issue on which there has been very little prior research. The study has a number of limitations. First, sampling of reports from each of the sectors was based on expert opinion and potential for replicability is accordingly limited. While we originally intended to use citation counts as a measure of prominence to select reports, limitations in the scope of grey literature citation tracking prevented this and hence expert consultation was used instead. Second, our study targeted global reports, and perhaps as a consequence of this and the great heterogeneity in country contexts across the world, the recommendations presented in each report were quite generic. A similar analysis at national or sub-national level may have identified more specific policy recommendations. This is important as it is impossible to conclude whether the non-specific recommendations are more reflective of country heterogeneity or of lack of agreement on strategies across transport and health sector actors. Third, our study considers only one intersectoral topic area; it is possible that findings may differ considerably for other topics and other sectors where evidentiary paradigms differ. Finally, while we have classified people according to their current institutional affiliation, it is possible that some researchers trained in one paradigm  may have crossed over to work in the other sector. We do not have empirical data on how common this is, but based on both our own experience and a scan of the online CVs of authors of the reports studied in this paper it appears relatively rare.Given the exploratory nature of this study, it would be inappropriate to draw hard and fast conclusions about the implications of this work; nonetheless, a number of points are worth reflecting on.First, the author analysis helped identify individuals (such as the one transport and one mixed sector author on the WHO report ) who forWith increasing emphasis on research dissemination to bridge the evidence-to-practice gap, researchers are engaging in ‘push’ activities to identify actionable messages from their research, tailor them to specific audiences, and work with groups to deliver them . Our finFinally, while we started this study with some notions of the likely differences in evidence between the health and transport sectors regarding RTIP, the analysis forced us to think more deeply and reach a refined understanding of the historical evolution of the transport sector and the different disciplinary perspectives that inform thinking within the sector. In turn, this has led to a clearer understanding of the likely points of tension between the two sectors in terms of which types of evidence are valued. It seems likely that similar analyses for other intersectoral issues may be valuable in promoting improved mutual understanding across sectors.This study focused on one intersectoral issue (RTIP) and two primary fields  that have informed the development of this policy area. As noted in the section on study weaknesses, findings may vary substantially in other intersectoral fields and the global nature of policy reports reviewed likely contributed to the relatively generic policy recommendations found in both sectors, despite apparently substantive differences in use of evidence. In light of this, we would encourage others to undertake similar reviews for other intersectoral policy issues, as well as to extend analyses of this nature to the national level. It would be particularly interesting to contrast findings for highly contested intersectoral policy issues with less contested ones.There are many further questions about the process of evidence use around intersectoral policies that could shed light on how significant a barrier evidentiary traditions are to collaboration and good practices supporting evidence use across sectors. For example, qualitative studies could explore the role of research evidence in the intersectoral policy process: are both sectors equally responsible for providing the evidentiary basis for policy decisions and what determines this? How is research evidence valued from one sector to another when it does not meet their community’s notion of knowledge validity? Further, social network analysis could cast light on the constituent communities within each sector, how they relate, and which individuals are well situated to play a broker role between communities. Finally, further research could be conducted to investigate the nature of recommendations among other intersectoral issues where there is less fragmentation of the policy community.Intersectoral action for health has tremendous potential but little research has been done on how research evidence is used when sectors from different scientific paradigms come to work together. Through documentary analysis of reports originating in the health and transport sectors, we demonstrated that, for road traffic injury prevention, the health and transport communities exist in separate scientific paradigms and within their own, albeit connected, epistemic communities. The health and transport sectors valued and drew on different types of evidence to support their recommended interventions. For road traffic injury prevention, the two communities have managed to create a sufficiently coherent problem statement and vision for the issue to have received a relatively high level global recognition. However, translating this commitment to address the problem into practical strategies for intersectoral action may require even greater collaboration, and shared understanding of the relevance of evidence from both sectors.


Evidence-based, expert-driven, practical statements improve quality and effectiveness of the diagnostic and therapeutic process of patient care. Although the effectiveness of physiotherapy treatment strategies in ICU patients has been described, statements or guidelines of physiotherapy for ICU patients are not available . GuideliFor the development of this evidence statement, we used the EBRO method, as recommended by the Dutch Evidence Based Guideline Development Platform . This meThree expert-based relevant clinical questions were formulated within the physiotherapy clinical reasoning process and were classified according to the International Classification of Functioning, Disability and Health. In a systematic literature search, 129 studies were identified and assessed for methodological quality and classified according to the level of evidence. The final Evidence Statement consisted of recommendations for physiotherapy in ICU patients including safety criteria, a core set of instruments to assess impairments and activity restrictions and effective interventions.The Evidence Statement for physiotherapeutic diagnostics and intervention in ICU patients will contribute to the quality of clinical practice by supporting the clinical decision-making process.


Finding current best evidence for clinical decisions remains challenging. With 3,000 new studies published every day, no single evidence-based resource provides all answers or is sufficiently updated. McMaster Premium LiteratUre Service - Federated Search (MacPLUS FS) addresses this issue by looking in multiple high quality resources simultaneously and displaying results in a one-page pyramid with the most clinically useful at the top. Yet, additional logistical and educational barriers need to be addressed to enhance point-of-care evidence retrieval. This trial seeks to test three innovative interventions, among clinicians registered to MacPLUS FS, to increase the quantity and quality of searching for current best evidence to answer clinical questions.In a user-centered approach, we designed three interventions embedded in MacPLUS FS: (A) a web-based Clinical Question Recorder; (B) an Evidence Retrieval Coach composed of eight short educational videos; (C) an Audit, Feedback and Gamification approach to evidence retrieval, based on the allocation of `badges’ and `reputation scores.’We will conduct a randomized factorial controlled trial among all the 904 eligible medical doctors currently registered to MacPLUS FS at the hospitals affiliated with McMaster University, Canada. Postgraduate trainees (n = 429) and clinical faculty/staff (n = 475) will be randomized to each of the three following interventions in a factorial design (A x B x C). Utilization will be continuously recorded through clinicians’ accounts that track logins and usage, down to the level of individual keystrokes. The primary outcome is the rate of searches per month per user during the six months of follow-up. Secondary outcomes, measured through the validated Impact Assessment Method questionnaire, include: utility of answers found (meeting clinicians’ information needs), use (application in practice), and perceived usefulness on patient outcomes.Built on effective models for the point-of-care teaching, these interventions approach evidence retrieval as a clinical skill. If effective, they may offer the opportunity to enhance it for a large audience, at low cost, providing better access to relevant evidence across many top EBM resources in parallel.ClinicalTrials.Gov NCT02038439.The online version of this article (doi:10.1186/s13012-014-0125-9) contains supplementary material, which is available to authorized users. Translation of new knowledge from research into evidence-informed health care is a shared obligation of the clinical and the scientific communities. Unfortunately, studies investigating quality of care continue to show that this goal is substantially unrealized. Clinicians’ uptake of validated best care procedures remains stubbornly around 50% or less for most advances in therapeutics ,2]. Com. Com2]. One main barrier to achieving evidence-based care by clinicians is lack of quick and easy identification, appraisal and synthesis of current best evidence. Clinicians’ information needs are considerable - with an average of five to eight questions about individual patients per daily shift -6], thu, thu6], e.g., DynaMed, UpToDate, Best Practice, ACP Smart Medicine), then pre-appraised research in the middle layers . This novel resource provides a unique one-stop simultaneous search of multiple current best EBM resources for use at the point of care (see Table elevance ), and fielevance  and unfielevance  (similarelevance ), as wele.g., lack of awareness of the `architecture’ of evidence and limits of non-federated single resources, lack of knowledge and experience of what federated searches can offer, limited searching skills, and lack of reference standards among peers for finding best evidence) -. We. We37]. We recruited eight independent testers , who underwent 12 full user-tests. We also performed numerous shorter usability tests on four team members. This process identified 34 significant issues - mainly around accessibility, usability, understandability, usefulness, and desirability - which resulted in 38 modifications of the prototype, across 5 major iterations (4 to 11 issues and 3 to 13 changes made per iterations). Consistently fewer refinements were necessary as use of the recorder became more intuitive and users were more satisfied. Final remote usability testing did not identify any remaining issues.The main features of the final Clinical Question Recorder are listed in Table The purpose of this intervention is to facilitate the retrieval of current best evidence by providing guidance, `small bites’ of knowledge and skills through short videos. These videos are both embedded in MacPLUS FS and sent via e-mails according to each the clinician’s specific patterns of utilization and search.We started this development by identifying specific teaching content that may help clinicians to benefit from available EBM resources in finding current best evidence. For that, we built on the strong expertise of our multi-disciplinary team in the Health Information Research Unit (HiRU), which has been one of the leading groups in evidence processing and retrieval, has contributed to many top EBM information resources over the past two decades, and has conceived MacPLUS FS. We wrote short scripts and mock-ups, and worked closely with an instructional designer (MP) to optimize language and presentation and produce the short videos.We then asked our eight user-testers to provide independent feedback, particularly on understandability, usefulness, and satisfaction with the content and presentation. After two iterations, the videos were implemented in MacPLUS FS. We then asked our testers to check online usability while using the platform remotely.e.g., to translate clinical questions and rapidly get reliable answers).The main features and the content of the videos within the Evidence Retrieval Coach are listed in Table Moreover, the display of the videos is tailored to clinician’s individual patterns of behaviors, according to predefined triggers , with feedback being more effective when baseline performance is low and when it is provided regularly . In lighWe designed the online interface, badges and graphical presentation with the help of a user experience designer (AC). After internal usability testing of the features implemented, we asked our eight user-testers to evaluate the intervention while using the platform remotely, and provide independent feedback on usability, understandability, and satisfaction with the content and presentation.The main features of the final audit, feedback and gamification interventions are listed in Table Each badge was assigned a reputation score based on the desirability of the behavior it reinforces. Badges pop-up online after a specific behavior Figure E, award We will conduct the trials described in this protocol in the teaching hospitals and clinics affiliated with McMaster University, Ontario, Canada. This amounts to 2 major academic hospital systems, operating 10 hospitals in the Hamilton area, as well as 2 regional campuses in Niagara and Waterloo, Ontario.Currently about 2,800 clinicians and students are registered in MacPLUS FS. The first trial will be conducted among all postgraduate trainees, and the second trial among all faculty registered in MacPLUS FS at the beginning of the trials, after exclusion of those no longer physically working at McMaster University affiliated hospitals. We will also exclude registrants who have never interacted with MacPLUS FS, either by logging in to read email alerts or to perform a search, during the last 12 months counting back from the beginning of the trials, regardless of how long they have been registered. These broad eligibility criteria reflect our choice to perform pragmatic effectiveness trials, rather than focusing only on high-frequency users. Indeed, our objective is precisely to increase the quantity and quality of searches among low-frequency users in real clinical practice. Nevertheless, we are excluding registrants with a very high probability of being unexposed or insensitive to our web-based interventions, either because they are no longer at our institution or have repeatedly ignored MacPLUS FS over a prolonged period.By December 31, 2013, these eligibility criteria were met by 904 clinicians - 429 postgraduate and 475 faculty MDs (see Table 3 = 8 groups), balancing on blocks of 16 within each stratum (=2 - 8). Our information technology programmers, in charge of MacPLUS FS system administration, will perform randomization using a computer-based pseudo-random number generator. They will maintain a secure master list of the randomization codes and assignments, and conceal allocation from the analysts.Participants will be randomized to our three web-based interventions in a factorial design , waiting time features displaying all resources searched in parallel in MacPLUS FS . This will be measured by (i) rate of searches/month/user, (ii) and corresponding proportions of `super-searchers’ (>five searches/month), `regular-searchers’ (one to five searches/month), `occasional-searchers’ (<one search/month), and `alert-only-users’ (no searches/month). The primary outcome will be averaged over six months, but continuously recorded as participants will be signed on through their individual user account that tracks logins and use of EBM resources, down to individual keystrokes.Our primary question is whether each intervention increases the quantity of searches to answer questions - Table The utilization patterns were different for Faculty MDs (n = 475) who searched MacPLUS FS half as much, about 423 times in total, corresponding to about 0.20 searches/month/user, whereas they accessed almost twice as many alerts to new evidence, 7,092 alerts in total, corresponding to 2.54 alerts/month/user, and consulted other web-resources in MacPLUS FS 0.32 times/month/user. About 78.9% of faculty used were `alert-only-users,’ while 5.1% were `regular-searchers’ and 0.8% `super-searchers.’.We will assess whether each intervention can increase the utility of the evidence retrieved , the use of the evidence (the extent of use when caring for a specific patient), and its perceived usefulness in patient care and outcomes (perceived benefits of applying the evidence for a specific patient). Utility, use and usefulness of the evidence retrieved will be assessed using an adapted version of the Impact Assessment Method (IAM) -43], wh, wh43], e.g., persistent, transient, increasing or decreasing effect), and whether the interventions have an impact on non-searching utilization of MacPLUS FS .Other secondary questions that we plan to address include whether each intervention efficacy varies across time within the six-month trial . The effect of each intervention will be tested by regressing the average number of searches per month over the trial’s six-month time period for each user onto dummy variables for each intervention, controlling for search frequency at baseline. The distribution of the number of searches per user is not known at present, but baseline data suggests excess zeros with extra-Poisson variation. We will attempt to capture the distribution parametrically, but in the event that it is not possible to do this accurately, we will use ordinary least squares to estimate the regression coefficients together with heteroscedasticity-robust standard errors.e.g., more effective in clinicians practicing internal medicine than family medicine or other specialties - and according to baseline frequency of search during the six months prior to the trial - e.g., higher frequency searchers would tend to be more responsive to each intervention . We cannot formally exclude any synergistic interaction (beyond additivity), but we have no reason to expect it a priori. Th. Th48]. Our trials have also inherent limitations. First, although MacPLUS FS includes most top EBM resources currently widely used by clinicians  requires clinicians to actively record their questions. To maximize the chances they engage, we focused our efforts upstream in the user-centered design, implementation and testing of the recorder. Actual use in real life settings remains uncertain, although simply offering the intervention may also have some indirect effect on searches.e.g., holidays, vacation days, or exam periods) may affect the assessment of the interventions, although utilization averaged over six months of follow-up should allow a reasonable comparison between study arms.Finally, baseline data showed that search rates heavily fluctuate across time. Lower rates at certain periods , and enhance the access to current best evidence for a large audience, across many top EBM resources in parallel, and tied directly to clinical questions.In conclusion, the trials will answer whether these innovations have the potential of enhancing knowledge translation through a clinician’s timely access to current best evidence. The MacPLUS FS interface allows a broad implementation for registrants, in a sustainable way, with limited additional costs. If effective, these interventions can further be broadly implemented beyond the McMaster community, using the twin version of MacPLUS FS - called ACCESSSS FS : TA and NH. Specific design of intervention B : TA, MP, EI and PR. Specific design of intervention C : TA, NC, AC. IT programming: NH, RP and CC. Conduct of the user-testing: TA. Analysis of baseline data: TA and EI. Statistical analysis plan: TA and EP. Overall supervision: BH. Draft of the manuscript: TA. Critical revision of the manuscript for important intellectual content: EI, NH, NC, AC, PR, MP, CC, RP, EP, NW, AI and BH. All authors read and approved the final manuscript. TA had full access to all the data presented in the manuscript and takes responsibility for its integrity and accuracy.Additional file 1: User-testing interview guide for the development of the Clinical Question Recorder.(PDF 262 KB)Additional file 2: Evidence Retrieval Coach: tailoring the educational videos to clinicians pattern of use.(PDF 77 KB)Additional file 3: Online administration of Impact Assessment Method (IAM) questionnaire.(PDF 191 KB)Additional file 4: Power curves for the primary outcome.(PDF 48 KB)Authors’ original file for figure 1Authors’ original file for figure 2Authors’ original file for figure 3Authors’ original file for figure 4Below are the links to the authors’ original submitted files for images.