Pressures to contain health care costs, personalize patient care, use big data, and to enhance health care quality have highlighted the need for integration of evidence at the point of care. The application of evidence-based medicine (EBM) has great promise in the era of electronic health records (EHRs) and health technology. The most successful integration of evidence into EHRs has been complex decision tools that trigger at a critical point of the clinical visit and include patient specific recommendations.The objective of this viewpoint paper is to investigate why the incorporation of complex CDS tools into the EMR is equally complex and continues to challenge health service researchers and implementation scientists. Poor adoption and sustainability of EBM guidelines and CDS tools at the point of care have persisted and continue to document low rates of usage. The barriers cited by physicians include efficiency, perception of usefulness, information content, user interface, and over-triggering.Building on the traditional EHR implementation frameworks, we review keys strategies for successful CDSs: (1) the quality of the evidence, (2) the potential to reduce unnecessary care, (3) ease of integrating evidence at the point of care, (4) the evidence’s consistency with clinician perceptions and preferences, (5) incorporating bundled sets or automated documentation, and (6) shared decision making tools.As EHRs become commonplace and insurers demand higher quality and evidence-based care, better methods for integrating evidence into everyday care are warranted. We have outlined basic criteria that should be considered before attempting to integrate evidenced-based decision support tools into the EHR. Pressures to contain health care costs, personalize patient care, use of big data, and enhance health care quality have highlighted the need for integration of evidence at the point of care -5. In thWith the onset of Health Information Technology for Economic and Clinical Health Act and Meaningful Use initiatives in 2009, researchers have been hopeful that health technology will be the solution to bringing EBM to the point of care. Substantial investments of funding, intellect, and energy have yielded an array of EHRs and electronic clinical decision support (CDS) tools to improve patients’ quality of care and reduce inappropriate use of critical resources.The most successful integration of evidence into EHRs has been complex decision tools that trigger at a critical point of the clinical visit and include patient specific recommendations. In contrast, most of the CDS tools being launched are uni-dimensional and not incorporated into the physicians’ workflow. For the purpose of this article, we have designated these forms of evidence integration as “flat reminders”: one-dimensional alerts that are typically triggered by one or two EHR components such as an element of patient history -11. ExamComplex, multidimensional forms of CDS are patient-specific, provide specific recommendations for rapid frontline decision making, and therefore have had a greater impact on patient outcomes and resource utilization. CPRs are forms of complex CDS. Based on real-time patient data points such as medical history, physical examination, and laboratory data, CPRs are EBM based algorithms that are able to personalize the patient’s diagnosis, prognosis, and likely response to treatment . CPRs weIncorporating complex CDS tools, such as CPRs, into an EHR holds great promise for finally realizing their potential by standardizing their application, reinforcing their application, and documentation. The caveat is that incorporation of complex CDS tools into the EMR is equally complex and continues to challenge health service researchers and implementation scientists. Poor adoption and sustainability of CDS tools at the point of care has persisted and continues to have low rates of usage -18. The Over the past five years, our research team has been working to improve the integration and adoption of complex CDS tools. Similar to the EBM cycle, we see CDS integration as a step wise process of: identifying a clinical problem, reviewing the evidence, usability testing of the tool, integration and deployment of the tool into the EHR, incorporation of shared decision making, and continuous monitoring and maintenance for sustained effectiveness  the quality of the evidence, (2) the potential to reduce unnecessary care, (3) ease of integrating evidence at the point of care, (4) the evidence’s consistency with clinician perceptions and preferences, (5) incorporating bundled sets or automated documentation, and (6) shared decision-making tools.The first consideration to successful adoption of CDS tools is assessing the quality of the evidence. This may seem an obvious step, but this critical element is often overlooked, with inaccurate assumptions about evidence and impeding the hoped-for results. Therefore, a formal process of evaluating and grading the evidence of the CDS prior to integration is critical. In order for the CDS tool to have a significant impact on health care outcomes, it must be based on high-quality evidence .The quality of CPRs is determined by how well they have been validated and tested. CPRs are typically developed in a three-step process: (1) derivation of the rule and creation of a model, usually with a retrospective database; (2) validation of the rule, in which the model is tested, preferably in a prospective fashion in several different sites to demonstrate that it is transportable and stable; and (3) impact analysis, when the rule’s impact on clinical behavior is assessed  and reduce unnecessary usage of antibiotics.A key to both clinician adoption of CDS tools at the point of care and successful integration is how it easy it is to meld the CPR into workflow and how the patient specific data are entered into the tool. Some CDS tools are extremely complex, requiring multiple data points that may not be automatically integrated into the CDS tool and thus require manual entry. In some practice settings, the EHR may not automatically interface with required data such as x-ray results in the emergency departments or rapid point-of-care test results in primary care clinics. Busy clinicians are unlikely to adopt tools that require them to manually derive, obtain, or enter data. Examples of overly complex tools are the Pneumonia Severity Index (PSI) used in emergency departments to help providers decide to admit patients. The rule has over 20 data elements . AttemptA related issue to ease of integration is “triggering” of the tool. To be truly effective, CDS tools need to be an active (automatic) trigger and seamlessly integrated into the flow of care. Providers should not have to activate the decision support, but rather be automatically offered it in the appropriate setting and related to the appropriate patient. Certain phrases or orders and combinations can act as trigger points in the EMR, such as chief complaint or diagnosis. For a trigger to be successful, it needs to trigger accurately (when truly needed) and not be overly sensitive. In our study on using a CPR for pneumonia, entering cough in the chief complaint section was one method of automatically triggering the complex decision support tool. Ideally, decision support is triggered infrequently and is targeted to the specific condition where it can most assist the provider. If there is no method for accurate triggering, the decision tool may not be effective in changing clinicians’ behavior.Clinicians are most likely to adopt decision support tools or act on evidence guidelines that align with their predispositions about care. Literature suggests providers’ understand the value of CPRs and state they utilize them in decision making, but CPR adoption rates continue to be low and vary across CPRs ,18,29,30CPRs that can stratify risk and have a corresponding management plan or diagnostic testing, which can be streamlined and bundled into order sets, will likely have more buy in by physicians, leading to higher usage and therefore larger impact on patient outcomes. The largest incentive we have witnessed through our usability testing is how the CPR and CDS tools can streamline clinical practice instead of impeding and slowing it. By incorporating order sets or automated documentation in progress notes of the EMR and automated documentation in progress notes of the EMR, physicians see the CDS as a facilitator rather than a burden. Therefore, we work to develop CDS tools that offer some incentive to using the tool. In our models, we embedded patient education material in both English and Spanish for patients to take home ,22,37. WThe final piece of completing the evidence cycle, which has yet to be sufficiently studied, is the integration of shared decision making when it’s appropriate and as long as it’s based on the best available evidence. Shared decision making (SDM) is becoming an integral part of patient centered care and is seen as a method to improve patient-clinician communication ,39. SDM As EHRs become commonplace and insurers demand higher quality and evidence-based care, better methods for integrating evidence into everyday care are warranted. We have outlined basic criteria that should be considered before attempting to integrate evidenced-based decision support tools into the EHR. First and foremost, this process emphasizes a critical appraisal of the quality of the evidence behind the decision support. Second, CDS tools should be evaluated for their ability to perform and impact clinical care through assessments of providers’ perception of utility. Finally, usability testing and integration into workflow need to be thoroughly evaluated prior to attempts to integrate evidence. Evaluation of the evidence and usability testing, however, are often lacking in research design, implementation methodology, and training of researchers in this area. If the federal government, EHR vendors, or health care institutions do not support research in these areas, the integration of successful CDS tools will continue to lag in creating change in patient outcomes. At this critical juncture of widespread EHRs and pressure to bend the cost curve, incentives to help industry, government, and academic health centers to support these research areas is urgent.


The context is a complex and important influence on decision-making, affecting degree of responsiveness and people-centred health systems. Although theoretical frameworks to understand context are available, limited empirical research exists exploring contextual influences on evidence-informed health policymaking. This presentation compares contextual influences on the role of evidence in health policy development within two large countries within their continents: India and Nigeria.In each country, the contextual influences on the development of three specific health policies were explored. The study was guided by a conceptual framework, developed from the literature. Context includes factors at three levels: macro , meso (e.g. organisation’s roles and practices) and micro . Data was collected using 72 in-depth interviews with key policy actors and document reviews, and analysed using framework approach.All policies were perceived as evidence-informed. Both formal (e.g. research) and informal (e.g. experiences) evidence was used in India; in Nigeria reliance was mostly on formal evidence. Key macro-level facilitators of evidence-informed decisions were international treaties driving reform agendas, leadership changes and political will. Key constraints included limited resources and opposition from powerful actors. At meso-level, civil society was particularly influential in India; whereas international agencies had greater role in policy decisions, including evidence use, in Nigeria. At micro-level, individuals had different understandings of what constitutes ‘robust’ evidence for policymaking, shaping their evidence preferences and decision-making practices.Understanding context is essential in ensuring responsiveness of policy decisions to the needs of key policy actors within people-centred systems, for example through recognising actors’ agendas and interests. Powerful civil society can catalyse greater recognition of citizens voice through communicating informal evidence, as we found in India; and influential donors can favour costly surveys, thus undermining use of evidence from government health information systems, as in Nigeria.


Background: The Navigation Guide is a novel systematic review method to synthesize scientific evidence and reach strength of evidence conclusions for environmental health decision making.Objective: Our aim was to integrate scientific findings from human and nonhuman studies to determine the overall strength of evidence for the question “Does developmental exposure to perfluorooctanoic acid (PFOA) affect fetal growth in humans?”a) rate the quality of the scientific evidence as “high,” “moderate,” or “low”; b) rate the strength of the human and nonhuman evidence separately as “sufficient,” “limited,” “moderate,” or “evidence of lack of toxicity”; and c) integrate the strength of the human and nonhuman evidence ratings into a strength of the evidence conclusion.Methods: We developed and applied prespecified criteria to systematically and transparently Results: We identified 18 epidemiology studies and 21 animal toxicology studies relevant to our study question. We rated both the human and nonhuman mammalian evidence as “moderate” quality and “sufficient” strength. Integration of these evidence ratings produced a final strength of evidence rating in which review authors concluded that PFOA is “known to be toxic” to human reproduction and development based on sufficient evidence of decreased fetal growth in both human and nonhuman mammalian species.Conclusion: We concluded that developmental exposure to PFOA adversely affects human health based on sufficient evidence of decreased fetal growth in both human and nonhuman mammalian species. The results of this case study demonstrate the application of a systematic and transparent methodology, via the Navigation Guide, for reaching strength of evidence conclusions in environmental health.http://dx.doi.org/10.1289/ehp.1307923Citation: Lam J, Koustas E, Sutton P, Johnson PI, Atchley DS, Sen S, Robinson KA, Axelrad DA, Woodruff TJ. 2014. The Navigation Guide—evidence-based medicine meets environmental health: integration of animal and human evidence for PFOA effects on fetal growth. Environ Health Perspect 122:1040–1051;  Evidence-based decision making in environmental health requires synthesizing research from human and nonhuman  evidence to reach overall strength of evidence conclusions, and is an integral part of hazard identification and risk assessment . HoweverIn the clinical sciences, methods of research synthesis—which integrate transparent and systematic approaches to evidence collection and evaluation—have been developed and refined over the past three decades and have played a transformative role in evidence-based decision making for medical interventions . For exaHowever, methods of research synthesis used in the clinical sciences are not fully applicable to environmental health, primarily because of the differences in evidence streams and decision contexts between the two . In parta) PFOA has been in widespread use for > 50 years . PossibRisk of bias across studies: Evidence streams were rated down if most of the relevant evidence came from studies that had high risk of bias, although review authors were instructed to be conservative in the judgment of rating down. In other words, review authors were instructed to rate down only if they judged that there was a substantial risk of bias in the body of available evidence. Furthermore, review authors were instructed not to assess factors by averaging across studies .Indirectness: Following GRADE guidelines , evidenca) point estimates varied widely across studies; b) confidence intervals (CIs) showed minimal or no overlap for similar studies of comparable size; c) the statistical test for heterogeneity had a low p-value (p < 0.05); or d) the I2 was large  . The following considerations were used to indicate potential inconsistency: n of I2) . Review Imprecision: Evidence streams were rated down if most studies had small sample sizes and few events, thus leading to wide CIs.a) the body of evidence was dominated by early studies with negative results, particularly studies that were small in size; b) studies were uniformly small (particularly when sponsored or funded by industry); c) empirical examination of patterns of results  suggested publication bias; d) we were able to obtain results of unpublished studies that demonstrated results different from those of published studies; or e) a comprehensive search of the literature was not performed.Publication bias: Evidence steams were rated down if we thought that studies were missing from the body of evidence that might result in an overestimate or underestimate of true exposure effects. We used considerations from GRADE guidance for evaluating publication bias, with modifications to reflect the Navigation Guide’s primary concern with underestimating the true effects of existing chemical exposure, in contrast to GRADE’s primary concern of overestimating the true effect of treatments or pharmaceuticals . These mFurthermore, the rating of each factor was considered in the context of other limitations. For instance, if the review authors found that two quality issues received borderline decisions , at least one of the two factors was rated down, as suggested by GRADE .The instructions to review authors also contained information on how to evaluate the human body of evidence for upgrading based on consideration of three factors ; for details, see Supplemental Material, “Instructions for rating the quality and strength of human and nonhuman evidence.” Possible ratings were 0 (no change), +1 (one-level upgrade), or +2 (two-level upgrade):Large magnitude of effect: GRADE  recommenDose–response gradient: The evidence stream was rated up if there were consistent dose–response gradients within one or more studies and/or evidence of dose response across the studies in the overall body of evidence.Confounders minimize the demonstrated effect: The evidence stream was rated up if consideration of plausible residual confounders or biases would only reduce the magnitude of the observed effect, or would suggest a spurious effect when results show no effect. GRADE provides an illustrative example of rating up observational evidence that showed a lack of association between vaccination and autism, which occurred despite empirically confirmed bias that parents of autistic children may be more likely to remember their vaccine experience . The negConsistent with GRADE’s approach to evaluating risk of bias across studies , the revRating the strength of the evidence across studies. In systematic reviews in the clinical sciences, only human evidence is considered in a decision, and so there exists no corollary step for integrating multiple streams of evidence in Cochrane or other methods of systematic review in the clinical sciences. We followed guidance from a) quality of body of evidence , b) direction of effect estimates, c) confidence in effect estimates (likelihood that a new study would change our conclusion), and d) other compelling attributes of the data that may influence certainty  qualertainty . We compertainty .The review authors independently evaluated the strength of the evidence according to the four considerations specified above to form their opinion of the final rating of strength of evidence for the human and nonhuman evidence as a way to initiate the group discussion and gather all perspectives for consideration. All authors collectively discussed their evaluations in a meeting until a consensus was reached. Specifically, this final rating did not involve a “majority vote” or other tallying of perspectives. It was prespecified that discrepancies between the review authors’ judgments that could not be resolved through consensus would be resolved by the senior author (T.J.W.). However, for this case study, review authors were able to agree on a collective consensus for the final rating for strength of evidence and the arbiter was not necessary. The rationale for our collective decision on each of the criteria and overall ratings was documented and recorded.The final step of our review was to integrate the strength of the human and nonhuman streams of evidence into a final concluding statement about PFOA toxicity. We compared the strength of the human and nonhuman evidence ratings from step 3 of the Navigation Guide , which wBy determining the intersection of the ratings assigned to the human evidence in step 3 with those of the nonhuman evidence , we cameIncluded studies. Our database and hand searches of human literature retrieved a total of 3,024 unique records; of these, we identified a total of 18 relevant studies (which contributed 19 data sets) for analysis . Additional meta-analyses demonstrated that PFOA exposure was also slightly associated with decreases in other fetal growth measures at birth, such as length , ponderal index , and head circumference   .Fifteen of the 21 nonhuman studies were conducted on mammalian species (11 in mice and 4 in rats) and 6 were conducted on nonmammalian species  . From anI2 test statistic was 0%, indicating no observed statistical heterogeneity between studies that could not be explained by chance; this conclusion was further supported by the Q statistic (p = 0.73).We used the mean pup body weight at birth (± SE) from each of the data sets for all doses < 5 mg/kg BW/day. The dose was limited to focus on effects at lower tested doses and minimize adverse impacts from responses at higher doses, such as litter loss, on the overall estimate. We initially attempted to transform doses tested in animals to human-equivalent serum concentrations for more direct comparisons to the human data; however, a review of the available scientific data produced minimal data that would support such extrapolation. We felt that our limitation to doses < 5 mg/kg BW/day was adequate to ensure relevance of the animal dose–response estimates to humans. Furthermore, by using the slope of the dose–response model for animals, our interpretation assumes that similar increases in exposure would result in the same relative changes in birth weights compared with humans, which we considered reasonable. From the meta-analysis, we found an overall estimate of –0.023 g BW per 1-mg/kg BW/day increase in PFOA dose to pregnant dams  . The I2 We also visually inspected scatter plots of dose–response data for all mammalian and nonmammalian animal data, including data excluded from the meta-analysis (those with study characteristics determined to be too variable to combine) to investigate effects . The dosSensitivity analysis of the human studies demonstrated little change in the overall effect estimate when removing one included study at a time or adding in one excluded study, although the heterogeneity statistics did increase. Sensitivity analysis of the nonhuman studies demonstrated little change in the overall effect estimate or heterogeneity statistic when removing one included study at a time. We originally planned to produce funnel plots of the estimated effects to visually assess the possibility of publication bias, but we did not due to the small number of included studies.Quality of the body of evidence. We evaluated each of the five quality downgrade factors separately for human, nonhuman mammalian, and nonmammalian streams of evidence. We concluded that there was no indication of substantial risk of bias across studies for the available human evidence, particularly when evaluating the studies included in the meta-analysis; thus, we did not downgrade the human evidence for this factor. The majority of nonhuman mammalian studies had “probably high” risk of bias for the allocation concealment and blinding domains. The nonmammalian studies had “probably high” risk of bias for the sequence generation, allocation concealment, and blinding domains. Because these components have been shown empirically to influence study outcomes in experimental animal studies  between humans and the nonmammalian model systems. Therefore, we downgraded the nonmammalian evidence one quality level (–1) for indirectness.We concluded there was no indication of substantial indirectness in either the body of available human or nonhuman mammalian evidence. The human studies assessed the population, exposure, and outcomes of interest, as did the nonhuman mammalian evidence, based on empirical evidence that mammalian data can be used as direct evidence for human health inference . HoweverWe concluded there was no indication of inconsistency in any of the three bodies of evidence. With the exception of two small studies , resultsWe concluded there was no indication of imprecision in any of the three bodies of evidence. We judged the CIs for both the human and nonhuman mammalian meta-analysis to be sufficiently narrow so as not to warrant downgrading the evidence. Similarly, CIs for the nonmammalian evidence were either sufficiently narrow or, if none were given, the data showed statistically significant responses at high doses, indicating small confidence bounds. The group consensus after evaluating this factor was to not downgrade the quality level for any of the bodies of evidence for imprecision.We concluded there was no indication of publication bias in any of the three bodies of evidence. The literature search was comprehensive and included strategies to search the grey literature, such as conference abstracts, reports, or other non–peer-reviewed literature. Although we could not ensure that we had identified all unpublished studies, the studies we found had varying sample sizes and funding sources, and none of the unpublished studies we found presented results out of the range of estimates reported by published studies. Without a sufficient number of studies to produce an informative funnel plot to derive evidence about potential missing data, the group consensus was that we did not have substantial evidence to warrant downgrading the quality level for any of the bodies of evidence for publication bias.We evaluated each of the three upgrade quality factors for human evidence only. We found no compelling evidence to warrant upgrading the evidence based on our prespecified definitions for the three considered factors. We evaluated the human effect estimates judiciously and agreed that the magnitudes of the effect estimates were not compelling enough to justify upgrading the evidence. Although several studies showed some evidence of a dose–response relationship, we agreed that the evidence was not compelling enough across the body of evidence as a whole. We also agreed that there was no evidence to suggest that consideration of plausible residual confounders or biases would reduce the estimated effect. The group consensus after evaluating these factors was to not upgrade the quality level for the human evidence.A summary of our final decisions for each upgrade/downgrade factor for each of the three bodies of evidence is shown in Strength of the body of evidence rating. We rated the overall strength of the human and nonhuman bodies of evidence separately based on the four considerations: a) quality of the body of evidence, b) direction of effect estimates, c) confidence in effect estimates (likelihood that a new study would change our conclusion), and d) other compelling attributes of the data that may influence certainty. Because the quality of the nonmammalian evidence was rated “low,” whereas the nonhuman mammalian data were rated “moderate,” we made the decision to carry forth only the higher quality nonhuman mammalian body of evidence for evaluating strength of evidence. This is consistent with GRADE recommendations: When high-quality data are available for decision making, one does not need to incorporate low quality data  our findings met the definitions for “sufficient evidence of toxicity” ; b) the available evidence included results from one or more well-designed, well-conducted studies; and c) the conclusion was unlikely to be strongly affected by the results of future studies.A summary of our strength of evidence determinations for each consideration for human and nonhuman evidence is reported by a) our findings for the nonhuman  studies met the definitions for “sufficient evidence of toxicity” ; b) the available evidence included results from one or more well-designed, well-conducted studies; and c) the conclusion was unlikely to be strongly affected by the results of future studies.Our consensus for the nonhuman studies was that the overall body of evidence was “moderate,” and we had a high level of confidence in an association between decreased birth weight and increased exposures to PFOA. We agreed that Our final conclusion for the overall strength of evidence was that there was “sufficient evidence of toxicity” in humans and “sufficient evidence of toxicity” in nonhuman mammals to support a judgment that exposure to PFOA affects fetal growth.Integrating the evidence across evidence streams. We integrated our evidence rating of “sufficient evidence of toxicity” for the human and the nonhuman evidence and concluded that PFOA should be classified as “known to be toxic.”The application of the Navigation Guide systematic review methodology demonstrated a novel method for integrating diverse sources of toxicity data to reach strength of evidence conclusions for noncancer health effects in environmental health. Application of the method produced a clear and concise conclusion by the authors of this review: that exposure to PFOA is “known to be toxic” to human reproduction and development based on sufficient evidence of decreased fetal growth in both human and nonhuman mammalian species.a) a transparent collective rating of the evidence as “moderate” quality; b) a meta-analysis estimating a reduction in birth weight in relation to PFOA exposure for which confidence bounds were sufficiently narrow and did not include zero; and c) our confidence that it would be unlikely for a new study to have an effect estimate that could substantially change the overall effect estimate of the meta-analysis (a) a transparent collective rating of the available nonhuman mammalian evidence as “moderate” quality; b) a meta-analysis showing a reduction in birth weight in relation to PFOA dose for which confidence bounds were narrow and did not include zero; and c) our confidence that the conclusion was unlikely to be strongly affected by the results of future studies , and during the analysis, we had to interpret the heterogeneity and relevance of these data to human health. In another example, in following recommendations from GRADE, we defined the factor for upgrading the quality of evidence based on large magnitude of effect as associations with an RR > 2 (+1 upgrade to the evidence) or an RR > 5 (+2 upgrade to the evidence). However, the data from the human evidence were more amenable to a meta-analysis performed on a continuous scale; therefore, we did not have RRs to compare using this definition. Furthermore, RRs on a scale of 2 or 5 for nonoccupational studies are a rarity in the field of environmental health because of the relatively low levels of exposure to environmental contaminants . AlthougFor this case study, we decided beforehand to define the “inconsistency” factor to rate down each body of evidence if studies showed widely different estimates of effect, but we did not include a consistency factor to rate up each body of evidence for the converse scenario. Our goal was to ensure that all bodies of evidence would be evaluated for consistency; therefore, because the nonhuman evidence was not assessed for upgrade factors because it started at “high,” we included inconsistency as a downgrade. This is consistent with GRADE recommendations for evaluating inconsistency for human evidence . This deIn recent years, several scientists have hypothesized that maternal and fetal physiology may influence measured blood levels indicating an exposure; in particular for PFOA and reduced birth weight, these associations may be due to reverse causality whereby women who have smaller babies have higher measures of PFOA as a result of a lower glomerular filtration rate caused by lower plasma volume expansion . If thisWe considered this hypothesis and its supporting scientific evidence in the context of the final conclusion of our review and decided that it did not undermine our findings for two reasons. First, this hypothesis is not relevant to associations found in animal studies. In our review of PFOA, the experimental animal evidence was robust and mirrored the human evidence, lending support for the association between PFOA exposure and low birth weight . Second,Ultimately, our application of the Navigation Guide approach led to a clear and concise concluding statement, resulting from a systematic and transparent review of the literature developed from comprehensive and transparent methods used in the clinical sciences that have been demonstrated to reduce bias . This isAdami et al. proposed a framework to combine the toxicological and epidemiological evidence to establish causal inference . AlthougOne benefit of our adoption of the IARC approach is that it was transparent and simple to integrate the evidence from human and nonhuman bodies of available evidence once we rated each stream’s strength of evidence separately. However, this meant that quantitative evaluations of the effect estimates for each body of evidence were kept separate and not integrated earlier on in the process. There has been much discussion recently in several research fields to utilize quantitative methods that can integrate diverse sources of data, such as human and nonhuman toxicity evidence, into a single quantitative model that can account for the different sources of data and expected contribution of each data set to the evidence for human toxicity . Future The nomenclature of the overall strength of the human evidence  generally had differing connotations among review authors despite agreement on the underlying definitions that supported the final conclusion. Some of the review authors found “known to be toxic” to be an accurate descriptor of the body of evidence, whereas others felt the descriptor “probably toxic” was more appropriate. Our discussions of the variability of our own subjective reactions to “known” and “probably” emphasized the need for further delineation of prespecified objective criteria for the strength of the evidence definitions.Our different subjective reactions over terminology were resolved by focusing our discussion on the definitions we had established for each strength of evidence rating . From thAddressing a lack of consensus in the interpretation of scientific evidence reinforced a key methodological strength of systematic reviews—transparent definitions and documentation of the basis of a conclusion—so the rationale for the final toxicity statement can be readily interpreted and/or contested by outside entities. In particular, it is critical to provide both a final recommendation and the documentation and justification leading to this conclusion. In addition, we anticipate that readers will have their own subjective connotations and reactions to our concluding statement. Although our nomenclature  was developed by modifying the nomenclature used by Specifically, there is currently no consensus in environmental health on how to name and communicate the strength of the evidence, and indeed there are many examples of similar terms that are commonly used to characterize varying strengths of evidence; for example, terms used to describe “moderate” evidence include “balance of evidence,” “balance of probabilities,” “reasonable grounds of concern,” and “strong possibility” . Researcin vitro studies and other modern methods of toxicology testing into the reviewed evidence stream. It is critical to develop such approaches because in vitro and other model systems and types of data will play an increasingly important role in the regulatory sphere as advances in technology allow for the rapid production of large quantities of data, such as those used in high-throughput screening  PDFClick here for additional data file.


A major challenge in updating clinical guidelines is to efficiently identify new, relevant evidence. We evaluated the efficiency and feasibility of two new approaches: the development of restrictive search strategies using PubMed Clinical Queries for MEDLINE and the use of the PLUS (McMaster Premium Literature Service) database.We evaluated a random sample of recommendations from a national guideline development program and identified the references that would potentially trigger an update (key references) using an exhaustive approach.We designed restrictive search strategies using the minimum number of Medical Subject Headings (MeSH) terms and text words required from the original exhaustive search strategies and applying broad and narrow filters. We developed PLUS search strategies, matching Medical Subject Headings (MeSH) and Systematized Nomenclature of Medicine (SNOMED) terms with guideline topics. We compared the number of key references retrieved by these approaches with those retrieved by the exhaustive approach.The restrictive approach retrieved 68.1 % fewer references than the exhaustive approach , and identified 89.9 % (62/69) of key references and 88 % (22/25) of recommendation updates. The use of PLUS retrieved 88.5 % fewer references than the exhaustive approach  and identified substantially fewer key references  and fewer recommendation updates .The proposed restrictive approach is a highly efficient and feasible method to identify new evidence that triggers a recommendation update. Searching only in the PLUS database proved to be a suboptimal approach and suggests the need for topic-specific tailoring.The online version of this article (doi:10.1186/s12874-015-0058-2) contains supplementary material, which is available to authorized users. Clinical guidelines, like systematic reviews and other evidence summaries, require periodic reassessment of research evidence to remain valid –4. CurreA major challenge for guideline developers is to efficiently screen for new, relevant evidence that justifies a clinical guideline update. Unfortunately, little empirical work has been conducted to date to test the effectiveness and efficiency of searching processes . More thSimilarly, researchers are testing alternative search strategies to update systematic reviews –13. HaynWe designed a study to evaluate the efficiency and feasibility of two approaches to identify the need to update clinical guidelines recommendations: 1) restrictive search strategies using PubMed Clinical Queries search filters for MEDLINE and 2) the use of PLUS database.We conducted a descriptive study of search strategies to identify the references that update recommendations from clinical guidelines. We developed three search strategies to identify the need to update the recommendations: an exhaustive approach, a restrictive approach, and a PLUS approach.The sample was obtained from a previous study and included a stratified random sample of recommendations from the Spanish National Health System Clinical Guidelines Program , 16. ThePertinent references: Randomised controlled trials or systematic reviews related to the topic of the clinical guideline; 2) Relevant references: pertinent references that could be used when considering an update to a recommendation, but that would not necessarily trigger a potential update; and 3) Key references: relevant references that would potentially trigger an update because of their impact on the population, the intervention, the comparison, the outcome, the quality of the evidence, the direction and/or the strength of the recommendation. Using the results of the reference screening we classified recommendations as: 1) need for updating: with one or more key references linked; or 2) still valid: without key references linked.Guideline methodologists with experience designing search strategies developed exhaustive literature search strategies for each clinical question: 1) based on the original searches; and 2) applying the filters of the original study. An example of the exhaustive search strategy is available in Additional file A more complete description of this approach is available in the previously published protocol and survival analysis results , 16.www.ncbi.nlm.nih.gov/pubmed/clinical), and a systematic review filter ).The restrictive approach  retrieved 68.1 % fewer references than the exhaustive approach, and identified most of the key references  and recommendations updates . We developed search strategies for each clinical question but obtained better results by considering the results across all questions included in a clinical guideline. The restrictive approach proved to be relatively simple to develop, not needing the expertise of information retrieval specialists. Over half of the very few missing key references with this approach were systematic reviews. Three references were missed due to a mistake in the design of restrictive searches, and one was missed by the filter used , reflectpost-hoc analysis). This poor performance was mainly due to most of these key references (80.4 %) being from journals not included in PLUS database.Our results show that PLUS approach retrieved 88.5 % fewer references than the exhaustive approach but identified a substantially lower number of key references  and potential updates  than the restrictive approach. These results were similar independently of the searches being performed by a PLUS information specialist (using search strategies) or directly using the PLUS interface using topic synonyms (The PLUS approach performed differently across topics with major depression performing best (66.7 % of key references retrieved) and prostate cancer worst 14.3 %). This poor performance in the prostate cancer guideline is explained by the fact that the PLUS database does not include a large number of urology journals. This resource includes a limited number of journals with a stronger focus on a limited number of specialties and health topics. Given these findings and building on previous research in the systematic reviews and clinical guidelines fields, post-hoc we explored a potential approach of tailoring the PLUS approach by adding a limited number of journals for each specialty (e.g. those with a higher impact factor) , 12, 13..3 %. ThiThe two search strategies we tested were far less time consuming than the exhaustive search strategy. The restrictive approach needs initial tailoring and takes each original guideline, question, search and references into account. In contrast, the PLUS approach could be potentially executed directly in its interface simply using topic synonyms from clinical guidelines.Only one previous study of clinical guidelines compared a different type of restrictive approach versus an exhaustive approach . HoweverA recent evaluation of NICE clinical guidelines for interventional procedures also showed that updated recommendations that required a modification generally had a greater increase in their evidence base  than non-updated recommendations . Our resThere is indirect evidence about the performance of PLUS for clinical guidelines from a previous study that evaluated the updating of systematic reviews . Only 13The same study by Hemens et al. confirmed the high sensitivity of Clinical Queries filters for MEDLINE and EMBASE in detecting randomized controlled trials . This isWe used a rigorous and explicit methodology building on previous research in this area, improving its deficiencies, and implementing an innovative solution. We also used the exhaustive approach as a standard, improving the validity of the results and, hence, the strength of our inferences. We independently screened and extracted the data in pairs and included methodologists and panel members from the original guidelines as far as possible. Finally, we laid out a structured framework  that could prove useful in the future for other researchers in the field.Our study has some limitations. We did not assess all references retrieved by each alternative approach, so we were not able to evaluate whether other key references were identified by any of these approaches. Our sample is limited to recommendations from four guidelines topics. However, this potential limitation is mitigated because our sample covers broad areas such as cancer, cardiovascular diseases, mental health and lifestyle and behavioural issues. Additionally, we based our exhaustive search strategies on searches specifically designed during the original guidelines development. A post-hoc analysis revealed several mistakes and inconsistencies in search strategies that could have been avoided through peer review process . HoweverOur results have important implications both for the updating of guidelines and for future research in this field. The proposed method of developing restrictive search strategies, using PubMed Clinical Queries filters in the MEDLINE database, provides a feasible and efficient method for guideline developers to identify significant new studies that are likely to trigger a recommendation update. Searching only in the PLUS database was a suboptimal approach that needs topic specific tailoring.Our results highlight the need for additional methodological research in this field. For this future work, investigators are likely to find our framework helpful.


Background. Several international groups develop asthma guidelines. Conflicting recommendations across guidelines have been described in several disease areas and may contribute to practice variability. Accordingly, we compared the latest Canadian Thoracic Society (CTS) asthma guideline with contemporaneous international asthma guidelines to evaluate conflicting recommendations and their causes. Methods. We identified the latest CTS asthma guideline update (2012) and the following societies which also updated their guidelines in 2012: the British Thoracic Society and Scottish Intercollegiate Guidelines Network and the Global Initiative for Asthma. We compared these three guidelines on (1) key methodological factors and (2) adult pharmacotherapy recommendations. Results. Methods used and documentation provided for literature search strategy and dates, evidence synthesis, outcomes considered, evidence appraisal, and recommendation formulation varied between guidelines. Criteria used to define suboptimal asthma control varied widely between guidelines. Inhaled corticosteroid dosing recommendations diverged, as did recommendations surrounding use of budesonide/formoterol as a reliever and controller and recommendations in the subsequent step. Conclusions. There are important differences between recommendations provided in contemporaneous asthma guidelines. Causes include differences in methods used for interpreting evidence and formulating recommendations. Adopting a common set of valid and explicit methods across international societies could harmonize recommendations and facilitate guideline implementation. Asthma is the third most common chronic disease in adults, affecting 8.1% of the population, or 2.4 million Canadians, and increasing in prevalence  and a diEffective therapies for asthma exist and well-controlled asthma is achievable in most patients. Several international groups have developed and regularly update evidence-based guidelines aimed at improving asthma control and outcomes. The Canadian Thoracic Society (CTS) published the first Canadian Asthma Guideline in 1990, the US National Heart, Lung and Blood Institute (NHLBI) first issued an asthma guideline in 1991, the Global Initiative for Asthma (GINA) has produced guidelines since 1995, and the British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN) produced their first joint British guideline in 2001.However, despite these high-quality guidelines, over half of the patients with asthma remain poorly controlled –8. This Given the important consequences of conflicting guideline recommendations, we sought to perform a comparative analysis of the latest Canadian Asthma Guideline with contemporaneous asthma guidelines from around the world.We identified the latest CTS asthma guideline, published in April 2012 , and theWe compared these guidelines on the following key methodological factors: literature search strategy and dates; evidence synthesis; outcomes considered; evidence appraisal; recommendation formulation; and overlaps in guideline committee memberships.Next, we analyzed and compared adult pharmacotherapy recommendations provided in each guideline, in the following three areas: (1) criteria for controller initiation and escalation (asthma control criteria); (2) recommendations for therapeutic escalation of baseline medications  (“stepping up” therapy); and (3) recommendations for therapeutic deescalation of baseline medications (after achieving good control) (“stepping down” therapy). We did not compare nonpharmacotherapy recommendations, as these were not reviewed in the 2012 CTS guideline. We also believed that the high quality of evidence for pharmacotherapy choices would minimize the chances of expert opinion-related differences between guidelines.For comparison of controller escalation recommendations, to account for differences in naming conventions for therapeutic “steps” between guidelines, we designated “step 1” as first-line therapy and steps 2–4 as the subsequent sequential therapeutic intensification recommendations. We did not consider steps beyond “step 4” because they applied to only a small percentage of asthma patients with “difficult-to-treat” asthma, and because evidence is less well-established for these steps , 28. FurFor each of the above-described content areas, we also documented the level of evidence attached to each recommendation and compared the references used to support each recommendation, between guidelines. When recommendations and supporting references differed between guidelines, we determined whether the observed differences in references could simply be explained by differences in literature search dates between guidelines.The 2012 CTS guideline was not presented as a comprehensive, independent guideline statement but rather addressed four very specific PICO questions and reiterated recommendations from the 2010 CTS guideline in other areas. However, this guideline did address therapeutic escalations directly, enabling appropriate comparisons to contemporaneous guidelines. Although it did not revisit asthma control definitions, it reiterated prior definitions, which was the case for the other two guidelines as well.Literature search strategies varied slightly between guidelines. Search dates were similar for BTS/SIGN and CTS guidelines. The BTS/SIGN guideline had the least current literature review (December 2009), whereas the GINA guideline had the most current (June 2012). Methodological approaches, their documentation, and usage of validated tools varied greatly between guidelines.With respect to guideline committee membership, there were several common members  between both the GINA and BTS/SIGN guidelines and the GINA and CTS guidelines. The GINA Science Committee included one participant who was cochair of the BTS/SIGN Pharmacological Management Committee and on the BTS/SIGN executive and steering group. The GINA Board of Directors included two participants who were on the 2012 and 2010 CTS Guideline committees (including one who was the Chair of the GINA Board of Directors), and the GINA Science Committee included one participant who was on the 2012 and 2010 CTS Guideline committees and one participant who was on the 2010 CTS Guideline committee.The highest age category to which recommendations were made applicable was similar between guidelines, as follows: BTS/SIGN > 12 years; GINA “adolescents and adults;” and CTS ≥ 12 years (unless otherwise specified for certain recommendations).All three guidelines presented criteria for suboptimal control; however, these varied considerably. The GINA guideline recommended using a four-week look-back period to characterize “average” control according to criteria, whereas neither the BTS/SIGN nor the CTS guidelines provided a recommended duration for criterion evaluation. These criteria seemed to apply to both initiation and escalation of controller therapy, as none of the guidelines explicitly recommended distinct criteria for each of these situations.The CTS guideline was unique in that it presented an “Asthma Management Continuum” diagram, suggesting that management should be approached as more of a continuum than as a series of distinct steps. However, specific recommendations for stepwise therapeutic intensifications were also clearly presented in the text and formed the basis for this comparative analysis.All three guidelines recommended that all patients start therapy with a short-acting inhaled beta-2-agonist used as needed in step 1. For comparative purposes, the most recent citation for this recommendation in each guideline was published prior to the least current literature review , as follows: CTS, 2009; BTS/SIGN, 1999; and GINA, 1997. Next, all guidelines recommended inhaled corticosteroids (ICSs) in step 2; however, recommended doses were higher in the BTS/SIGN guideline. The CTS and BTS/SIGN guidelines did not provide specific references for their initial ICS dose recommendation, and the most recent citation for this in the GINA guideline was from 2005. In step 3, all three guidelines recommended addition of a LABA; however, the GINA and BTS/SIGN guidelines also allowed for use of a single inhaler of budesonide/formoterol as a reliever and a controller (SMART), whereas the CTS guideline did not, concluding that there was insufficient evidence to make this recommendation. Most recent citations for recommendations at this step were as follows: CTS, 2011; BTS/SIGN, 2009; and GINA, 2006. Seven of the references used in the CTS guideline for this step were published after the end-date of the BTS/SIGN literature search. Finally, in step 4, the GINA and BTS/SIGN guidelines suggested increasing the ICS dose (with the BTS/SIGN uniquely suggesting to discontinue the LABA if ineffective), whereas the CTS guideline recommended adding a leukotriene receptor antagonist or switching to the SMART approach. Most recent citations for recommendations at this step were as follows: CTS, 2011; BTS/SIGN, 2007; GINA, 2004. Three of the references used in the CTS guideline for this step were published after the end-date of the BTS/SIGN literature search.Although all three guidelines recommended reducing to the lowest possible therapeutic dose and regimen after achieving good control, only the GINA guideline provided guidance on each sequential deescalation. However, two of these five recommendations provided in the GINA guideline were derived through panel consensus judgment.We compared the latest Canadian Asthma Guidelines with two other contemporaneous international guidelines and found major differences between guideline methodologies, asthma control criteria, and recommendations for deescalation of therapy and more minor differences  between recommendations for escalation of therapy. To our knowledge, this is the first detailed comparative analysis of contemporaneous asthma guidelines presented in the literature.Previous authors have described varying degrees of interguideline variability in COPD and asthma. Iqbal and colleagues  describeReasons for the differences that we have observed between asthma guidelines are likely multifactorial. One of the most important causes is likely the observed difference in the evidence used (cited) by each guideline group for each recommendation. In turn, there are several possible explanations for this. Search strategies did differ slightly between guidelines; howeve, each was reasonably comprehensive and would not be expected to miss any major studies . Search  completely independent, as there were overlapping guideline committee members and leaders between both GINA and BTS/SIGN and GINA and CTS guidelines. Although one would have expected overlapping committee members to bring common perspectives to the different guideline processes and/or to reconcile major differences in recommendations, this may have been hampered by fundamental differences in process between guidelines. Next, nonvalid factors such as inadequate critical appraisal and/or a failure to consider all relevant outcomes (particularly patient-relevant outcomes) may also have contributed [Differences in evidence interpretation might have occurred for both valid and nonvalid reasons. Perfectly valid differences in judgment may have occurred regarding which studies were relevant, the risk of bias in individual studies, and the relative balance of demonstrated benefits and adverse effects. Such differences are an inevitable product from the “human” aspect of evidence interpretation, whereby it may be unrealistic to expect two independently produced guidelines to provide identical recommendations in each area. Interestingly, these guideline committees were nottributed . In all tributed . These ftributed , 31. Fintributed . Accorditributed .Differences between methods used for formulating recommendations may also have played a role in the observed variability. The GINA guideline sought full committee consensus, the BTS/SIGN guideline sought unanimity within a small working group, and the CTS guideline sought a majority in a full committee vote . In a prA myriad of other factors may also have contributed to the variability in recommendations. The relative paucity of available evidence in certain areas, such as the definition of asthma control, required increased use of subjective expert judgments, which are inherently variable , 19. Het time they occurred or on each day that they occurred , and whether rescue beta agonist use should be counted by number of doses or by number of times the rescue puffer was required , and whether use prior to exercise was included. The practical impact of these differences was demonstrated in a review of primary care electronic medical records which compared asthma control according to CTS and GINA guidelines and noted interguideline discordance between asthma control ratings in more than half of the patients deemed “in control” by at least one guideline [The major consequence of disagreement between guidelines is variability in practitioner behavior , which muideline . The criuideline .There is also a theoretical concern that the observed guideline variability may contribute to the poor uptake of asthma guidelines, which has been noted particularly in the areas of asthma control determination  and escaFinally, studies have found that conflicting recommendations can lead to more test ordering  and resuWe have demonstrated important differences in the basic recommendations surrounding adult asthma care between contemporaneous international guidelines. This has important effects on the consistency of clinical asthma care and may possibly impact overall guideline uptake. Given that this variability appears to have been driven by methodological differences in areas such as evidence interpretation and recommendation formulation, universal acceptance and application of a single, transparent, and explicit set of standards for these processes would likely reduce the observed differences , 49. A c


Pophyromonas gingivalis (PPAD). However, the precise mechanism by which PPAD could generate potentially immunogenic peptides has remained controversial due to lack of information about the structural and catalytic mechanisms of the enzyme.Periodontitis (PD) is a known risk factor for rheumatoid arthritis (RA) and there is increasing evidence that the link between the two diseases is due to citrullination by the unique bacterial peptidylarginine deiminase (PAD) enzyme expressed by periodontal pathogen By solving the 3D structure of PPAD we aim to characterise activity and elucidate potential mechanisms involved in breach of tolerance to citrullinated proteins in RA.C351A were crystallised and their 3D structures solved. Key residues identified from 3D structures were examined by mutations. Fibrinogen and α-enolase were incubated with PPAD and P. gingivalis arginine gingipain (RgpB) and citrullinated peptides formed were sequenced and quantified by mass spectrometry.PPAD and a catalytically inactive mutant PPADHere, we solve the crystal structure of a truncated, highly active form of PPAD. We confirm catalysis is mediated by the following residues: Asp130, His236, Asp238, Asn297 and Cys351 and show Arg152 and Arg154 may determine the substrate specificity of PPAD for C-terminal arginines. We demonstrate the formation of 37 C-terminally citrullinated peptides from fibrinogen and 11 from α-enolase following incubation with tPPAD and RgpB.PPAD displays an unequivocal specificity for C-terminal arginine residues and readily citrullinates peptides from key RA autoantigens. The formation of these novel citrullinated peptides may be involved in breach of tolerance to citrullinated proteins in RA. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by inflammation and destruction of the joints. The current hypothesis of disease development involves a combination of environmental risk factors in genetically predisposed individuals. Periodontitis (PD) is one such environmental risk factor. The prevalence of PD is increased approximately twofold in RA,Porphyromonas gingivalis (PPAD) has been implicated in the aetiology of RA.P. gingivalis are found in individuals at high-risk of developing RA, and in established disease where an increased anti-PPAD response is also observed.2+ ions during catalysis,P. gingivalis enzyme, the arginine specific protease arginine gingipain (Rgp).P. gingivalis.P. gingivalis cultures did not autocitrullinate.The discovery of ACPA in RA and the involvement of citrullination in a number of other diseases have resulted in a rapidly expanding field of research into the structure and function of peptidylarginine deiminase (PAD) enzymes, which mediate citrullination by conversion of arginine to citrulline. Of the five human PAD isoforms (PAD1–4 and PAD6) PAD2 and PAD4 are of particular interest as they are often found at sites of pathology, including the RA jointAs a potential candidate for breaking tolerance in RA,WT amino acid sequence 49-484 was amplified from the full-length PPAD coding sequence of P. gingivalis strain W83 using forward (5′AATCCCCCTGCAGGTCCTG) and reverse (5′GGCGTTGAACCATGCACGAA) primers with upstream (5′TACTTCCAATCCATG) and downstream (5′TATCCACCTTTACTGTCA) 5′ extensions to enable ligation independent cloning into pNIC28-Bsa4 vector , Oxford. GenBank Accession No. EF198106) generating an N-terminal His6-tagged fusion protein. Recombinant proteins were expressed in Escherichia coli BL21(DE3)-R3-pRARE2 cells (inhouse SGC) and purified from protein soluble fraction using Talon (Clontech) Co2+-nitrilotriacetic acid (NTA) affinity chromatography before further purification by size exclusion chromatography on an S200 column on the ÄKTAxpress system. His-fusion tags were removed by Tobacco Etch Virus cleavage (inhouse SGC) using 1 mg/20 mg protein and incubated overnight (o/n) before Co2+-NTA affinity chromatography was repeated to remove free fusion tag.tPPADC351A, Cys351 was replaced with Ala and to generate tPPADR152A and tPPADR154A, Arg152 and Arg154 were replaced with Ala. Further cloning and purification strategies for tPPADC351A, tPPADR152A and tPPADR154A remained the same as tPPADWT. Constructs were sequenced to confirm insertion of DNA segments and that mutations were successful.Site-directed mutagenesis using the megaprimer method was carried out as describedPPAD was crystallised by vapour diffusion at 20°C. Diffraction data were collected at the Diamond Light Source. Structures of PPAD were solved by molecular replacement.Recombinant human PAD2 and PAD4 were cloned, expressed and purified as previously described.23Protein concentrations of all PPAD and PAD enzymes were standardised using Bradford assay and NanoDrop A280 module.The colorimetric assay for citrullination activity was used as previously described,Following in vitro citrullination, proteins were precipitated using chloroform/methanol.More detailed materials and methods can be found in online supplementary information.E. coli. Among them, a His6-tagged truncated construct , encoding CD and IgLF but lacking NtSP and CTD, yielded highly soluble and crystallisable protein, with significantly increased catalytic activity towards the in vitro arginine substrate Nα-Benzoyl-L-arginine ethyl ester hydrochloride (BAEE) as compared with full length PPAD (C351A) with the essential catalytic nucleophile among GMEs Cys351PPAD is organised into four domains: the N-terminal signal peptide , catalytic/deiminase domain , Ig-like fold  and C-terminal domain A. A librgth PPAD B. An equWT and tPPADC351A by molecular replacement (see online supplementary information table S1), which reveal identical and superimposable conformations (root mean square deviation (RMSD)∼0.09 Å), suggesting that the Cys351Ala substitution did not perturb protein integrity. The visible PPAD structure comprises aa 49-463 arranged into the CD and IgLF regions  and Arg-Gly-Gly (p=0.015). PAD2 displayed a similar trend to PAD4 although did not reach significance due to significantly lower activity overall. tPPADC351A did not display activity on any of the substrates.To examine the substrate specificities of PPAD compared with human PAD2 and PAD4, colorimetric detection of citrulline was used with three short peptides containing either N-terminal (Arg-Gly-Glu), internal (Met-Arg-Phe) or C-terminal (Gly-Arg) arginine residues following incubation with tPPAD or PAD4 A. As expR152A and tPPADR154A) as per tPPADWT. Using BAEE as substrate in the colorimetric assay, the activity of tPPADR152A is significantly reduced compared with tPPADR154A (p<0.001) and tPPADWT (p=0.004). There was no significant difference between tPPADR154A and tPPADWT . All enzymes retained activity on C-terminal arginine peptide Gly-Arg only , the latter equivalent to the baseline measurement level for inactive tPPADC351A  and tPPADR154A (p=0.003). tPPADR154A was also significantly less active than tPPADWT on FibA-R (p=0.002). In addition, activity of tPPADWT, tPPADR152A and tPPADR154A was lower on longer fibrinogen peptides than short synthetic peptides, with 86%, 39% and 86% less citrulline produced, respectively.To examine this result in a more physiologically relevant context, two peptides from the fibrinogen α-chain with a C-terminal (FibA-R: CESSSHHPGIAEFPS-R), or an internal arginine residue (FibA-R-XX: CESSSHHPGIAEFPS-R-GK) were used in the assay. First, level of activity of tPPADPADC351A A. Using l groups B. As befWT was also highly efficient, citrullinating 21 of the 25 peptides formed from the fibrinogen α-chain  family, characterised by the dependence on CTD processing for enzyme translocation.P. gingivalis in vesiclesE. coli may have caused insolubility in the recombinant expression of CD-alone constructs. The truncated form of PPAD secreted from P. gingivalis lacks the N-terminal 43 amino acids and CTD, and so has similar N-terminal/C-terminal boundaries to our tPPADWT construct. If the secreted form is the virulent form of PPAD, the truncation may also increase activity, explaining the increased enzyme activity level compared with full-length PPAD, as we observed.The crystallised tPPADP. gingivalis cultures.P. gingivalis PPAD and Rgp knockout strains, implying a necessity for both enzymes. The current study confirms this directly and increased the number of C-terminally citrullinated peptides observed, to 37 from fibrinogen and 11 from α-enolase. It has also been shown that many of the citrullinated arginine residues identified in this study from fibrinogen and α-enolase can be citrullinated by PAD2 and PAD4 in vitro when in internal positions in the peptide.32Using synthetic peptides, we showed that PPAD only citrullinates C-terminal arginine residues, whereas PAD2 and PAD4 both preferentially citrullinated internal arginine residues. In our assays using short synthetic peptides Arg-Gly-GLu, Met-Arg-Phe and Gly-Arg activity of PAD2 was significantly lower than that of PAD4. We suggest this may be due to a preference of PAD2 for longer peptides, which has been observed in our lab (data not shown). We extended this investigation to demonstrate the generation of novel C-terminally citrullinated peptides from key RA autoantigens fibrinogen and α-enolase in combination with RgpB. In a previous study from our laboratory four C-terminally citrullinated peptides from fibrinogen and one from α-enolase were generated by incubating purified proteins with + phenotype indicates a key role for T cells in RA. Previous studies have examined the preferential binding of citrullinated peptides to major histocompatibility (MHC) shared epitope alleles, leading to T cell activation.The strong association of the human leukocyte antigen DRB1 (HLA-DRB1) shared epitope (SE) alleles with an ACPA52DYGILQINSRW62, with a C-subterminal citrulline at position 61 is bound to the P10 pocket of the mouse MHC. Interestingly, the resulting antibodies in these mice bound to separate epitopes on native (uncitrullinated) hen egg lysozyme protein. This mechanism could explain why, although patients with PD have a significantly elevated frequency of ACPA, the reaction is not citrulline specific.40Perhaps the most compelling evidence to support the T cell antigenicity of citrullines located at or near the C-terminus is the murine model of autoimmunity in mice transgenic for hen egg lysozyme.By solving the crystal structure of the unique pathogen enzyme PPAD, we have elucidated the mechanisms that may cause tolerance breakdown in patients with PD who go on to develop RA. We propose the bacterial origins of PPAD and lack of homology to human PADs make it an ideal target for inhibition.


For flashed stimuli presentations, it is known that the latency of the first spike of retinal ganglion cells (RGC) encodes information about the stimulus. This was shown at the level of individual neurons but also at the population level by considering the relative latency between certain pairs of RGC . In thisInterestingly, due to the presence of a high spontaneous activity, we did not find any RGC pair showing a clear relation between the relative latencies and stimuli as in . So we eWe first showed that the FWS is specific to each stimuli. To do so, we defined a distance between the FWS of a reference grating and the gratings with similar spatial frequency and varying phases. This distance was correlated to the phase difference between gratings.Then, to estimate quantitatively the coding efficiency of the FWS, we performed a discrimination task where the aim was to identify the phase among gratings of identical spatial frequency. We compared the performance  of the FWS under classical Bayesian decoders to independent response latency of each recorded RGC. Results showed the FWS decoder which is based on the relative rank of latencies only, was as efficient as the pure latency decoder based on absolute latency values (~73% of FCP for both).Finally, as the spikes from the output of the retina are conveyed and processed by higher neural structure such as the Lateral Geniculate Nucleus (LGN), we investigated the possible effects of an a posteriori processing stage on the neural code. We fed a simulated LGN-like layer  with the


The publication of the guideline by the European Renal Best Practice (ERBP) group has helped stimulate a debate on this important cause of morbidity and mortality Therefore, it seems to be unusual that tolvaptan, the only licensed vasopressin receptor antagonist (vaptan) for hyponatraemia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Notably, some of the recommendations of the ERBP guideline are in contrast to those of the other publications mentioned above, particularly in patients with SIADH Unusually, the authors have chosen to analyse four vaptans  within the same meta-analysis Although there is a paucity of evidence to support evidence-based recommendations for most available therapies in hyponatraemia The authors also expressed concern with the hepatotoxicity associated with the use of particularly high doses of tolvaptan in autosomal dominant polycystic kidney disease (ADPKD) The vaptan meta-analysis also suggested a signal indicating a possibly increased risk of death for hypervolaemic patients treated with vaptans compared with placebo With the rigour afforded to the analyses of the risk–benefit profile for vaptans, it is surprising that the same in-depth analyses do not seem to have been conducted for any treatments the ERBP guideline recommends for SIADH. The authors acknowledge that there are no systematic reviews or randomised controlled trials evaluating the benefits and harms of fluid restriction, urea or loop diuretics Yet the authors' recommendation for first-line treatment with fluid restriction fails to acknowledge that it may be inappropriate for many patient populations (e.g. in patients with cancer where it may delay chemotherapy n=9), with the remaining studies using NaCl intravenously The guideline recommends second-line treatment with urea or the combination of loop diuretics with oral sodium chloride (NaCl), despite extremely limited efficacy data Tolvaptan has a proven benefit–risk profile, which is supported by randomised controlled trials and over 4 years of real-world use, and we urge the authors to take a more consistent and measured approach towards evidence-based recommendations.A response to this letter European Journal of Endocrinology and Nephrology Dialysis Transplantation.This letter will be co-published in the


Dirofilaria immitis and Angiostrongylus vasorum are increasingly reported in dogs and are responsible for two diseases with overlapping endemic areas, especially in Europe: dirofilariosis and angiostrongylosis. The reasons for their apparent emergence are unknown, but several factors  may play a role in the recent rise in reports of infection in the various countries of Europe. The aim of this study was to investigate the seroprevalence of D. immitis (by DiroCHECK® ELISA) and the fecal presence of first stage larvae (L1) of A. vasorum (by FLOTAC) in dogs from 68 kennels of the Campania region . The fecal samples were collected from pooled samples using the box as epidemiological unit. To the authors’s knowledge, this is the first cross-sectional survey conducted at regional-scale in Italy and in Europe on the contemporaneous detection of D. immitis antigens and A. vasorum L1 in kennels.The cardiopulmonary nematodes D. immitis were detected in 24/537  dogs in 6 out of the 68 kennels . The 24 positive samples for D. immitis antigen were tested also with AngioDetect® and only 1 sample was seropositive for A. vasorum with a prevalence of 4.2 %. A. vasorum L1 were detected in dogs from 9 out of the 68 kennels . Pooled fecal samples from 25 boxes out of the 1360 analyzed resulted positive to A. vasorum L1 .Antigens of The present study indicates that cardiopulmonary nematodes are present in Campania region in symptomatic dogs as well as in asymptomatic ones. Therefore, regular parasitological surveillance, appropriate treatment strategies and high quality standard of hygiene are required to guarantee the health and welfare of kennel dogs. Dirofilaria immitis and Angiostrongylus vasorum are increasingly reported in dogs and are responsible for two diseases with overlapping endemic areas, especially in Europe: angiostrongylosis and dirofilariosis [D. immitis [A. vasorum [The cardiopulmonary nematodes lariosis –3. The rlariosis –7. In pa immitis  and coul vasorum , 10.D. immitis and A. vasorum are both localized in the Arteria pulmonalis and the right heart of their definitive hosts [D. immitis and A. vasorum cause different respiratory signs and severity may change in accordance to the parasite burden and host-related factors [The adult stages of ve hosts . D. immi factors –14. Age, factors , 14.D. immitis in Italy, as observed in the rest of Europe [D. immitis is present not only in the hyperendemic area of the Po River Valley [Current epidemiological data confirm the expanding trend of f Europe , 15. Todr Valley , 16, butr Valley , includir Valley  where thA. vasorum is undoubtedly spreading from northern to southern Italy, especially in the central regions that offer ideal environmental and epidemiological conditions for the expansion of this parasite and the establishment of further new endemic foci [A. vasorum has grown in the last 20 years and is correlated especially with increased urbanization of the red fox (Vulpes vulpes) which acts as a reservoir host representing a potential infection for dogs [Similarly, mic foci , 20. Knofor dogs , 22.D. immitis and A. vasorum prevalence have been conducted in many countries; however, no studies investigated the simultaneous detection of these cardiopulmonary nematodes in kenneled dogs. Therefore, the aim of this study was to investigate the distribution of D. immitis and A. vasorum in kenneled dogs of the Campania region of southern Italy. Noteworthy, to the authors’ knowledge, this is the first cross-sectional survey conducted at regional-scale in Italy and in Europe on the contemporaneous detection of D. immitis antigens and A. vasorum first stage larvae (L1) in kennels.In recent years, epidemiological surveys on www.anagrafecaninacampania.it). The region  which extends over an area of 13,590 km2 is mainly hilly and extends from 0 to 1890 m above sea level. The climate is Mediterranean with dry summers and rainy winters.The survey was conducted between June 2012 and August 2013 in the 68 public kennels located in the Campania region of southern Italy  provides for setting up specific kennels to collect and re-home roaming and abandoned animals; for many disowned dogs, the kennel becomes a permanent shelter . These kD.immitis using DiroCHEK® ELISA  according to the manufacturer’s instructions (sensitivity = 85–100 % and specificity = 100 %) [In the 68 kennels, 537 blood samples (from 5 to 10 per each kennel) were collected. In each kennel we selected the dogs that were hosted for 2 years at least. The samples were transported to the laboratory and centrifuged at 3000 rpm for 10 min to obtain sera, then stored at -20 °C until testing for seroprevalence of = 100 %) .D. immitis were also tested with the antigenic test AngioDetect®   [After the analysis with DiroCHEK® ELISA, the dog sera resulted positive to = 100 %) . The bloA. vasorum [In each of the 68 studied kennels, the box  was considered as the epidemiological unit of the study for practical reasons as reported in Rinaldi et al. . In each vasorum .D. immitis were detected in dogs from 6 out of the 68 kennels . Specifically, 24/537  dogs of 6 kennels were positive to D. immitis .Antigens of eactions . Only 1 A. vasorum (L1) were detected in dogs from 9 out of the 68 kennels . Pooled fecal samples from 25 boxes out of the 1360 analyzed resulted positive to A. vasorum L1 . The mean number of A. vasorum positive boxes/kennel was 2.8 (min 1- max 7).D. immitis antigens (8.8 %) and A. vasorum L1 (13.2 %) in kennels conducted by a cross-sectional survey at regional-scale.The strength of the present study was the contemporaneous detection of D. immitis infection were recently reported in owned dogs from the same region [A. vasorum found in this study (13.2 %) cannot directly be compared with prevalence of other study based on individual samples.However, also some limits emerged from our study. First, the lack of knowledge of the history of the kenneled dogs; we did not know if they were all natives of the Campania Region, even if autochthonous foci of canine e region . Second,The main findings of the present survey confirm that polyparasitism is the rule in the studied kennels in southern Italy as already described by Rinaldi et al.  concerniD. immitis has spread in the last years in Europe due to climate change, the spreading of mosquito Aedes albopictus and the introduction of new vector Aedes koreicus [D. immitis infection has been widely studied in dogs from central and northern Italy, epidemiological data on the occurrence of D. immitis infection in southern Italy are scant and limited to sporadic case reports. The prevalence of D. immitis reported in this study was 8.8 %. This prevalence is higher than the previous study conducted in the Vesuvius area (0.6 %) of the same region confirming the spread of this parasite [D. immitis was found in autochthonous dogs [koreicus . These fkoreicus , 30. Whiparasite . Similarous dogs .D. immitis spread and the temperature increase into previously infection free areas as demonstrated also in a questionnaire survey by Genchi et al., [D. immitis was detected in non- endemic area (10 %) and in endemic- area (12 %) of Europe.Different predictive studies, conducted using Geographical Information Systems (GIS) tools , 16, con et al.,  where anA. vasorum infection is considered endemic in certain areas of Europe, including regions of Denmark, Germany, Hungary, Finland, France, Ireland, Italy, the Netherlands, Poland, Slovakia, Spain, Sweden, Switzerland, Turkey and the United Kingdom. The country list is growing as the A. vasorum geographic distribution continues to evolve in several countries of Europe [f Europe .A. vasorum infection in the same region. Also in the same region a prevalence of 33.3 % was found in red foxes at post-mortem examination [A. vasorum infection is the red fox (Vulpes vulpes) [Our present study expands on that recently published by Rinaldi et al  which demination  and the  vulpes) , 22. A p vulpes) .A. vasorum infection is alarming if we consider the clinical signs can be severe: respiratory dysfunctions, bleeding, neurological, ocular, cardiovascular and gastrointestinal symptomatology, skin lesions [A. vasorum infection may be also asymptomatic, especially in the early stages and so affected dogs can develop clinical signs after months to years from the infection [The positive percentage found in our present study 13.2 %), even if is not comparable with the prevalence of the other study because of the different epidemiological unit considered, is very high if compared other studies , 34. The lesions , 33. Eve.2 %, eveD. immitis. The reasons of the lack of a prophylaxis for D. immitis are: the unawareness of the severity of this parasite, the economic issue and the difficulties of managing and monitoring of the kenneled dogs.Kennel dogs are at the highest risk of infection with helminths, for this reason anthelmintics or combinations of anthelmintics with a broad spectrum activity, as suggested in a previous study , are reqD. immitis and A. vasorum circulate in the kennels of the Campania region of southern Italy. Therefore, regular parasitological surveillance, appropriate diagnostic tools, treatment strategies and high quality standard of hygiene are required to guarantee the health and welfare of kennel dogs as recommended by the European Scientific Counsil for Companion Animals Parasites (www.esccap.org).In conclusion, the present study indicates that the cardiopulmonary nematodes


The guideline in this issue, “The Society of Thoracic Surgeons, The Society of Cardiovascular Anesthesiologists, and The American Society of ExtraCorporeal Technology: Clinical practice guidelines for cardiopulmonary bypass—Temperature management during adult cardiopulmonary bypass” represents the first multidisciplinary effort to develop guidelines for the practice of cardiopulmonary bypass (CPB) . In the When this process began, individuals were selected by the Society of Thoracic Surgeons, the Society of Cardiovascular Anesthesiologists, and the American Society of ExtraCorporeal Technology to form a multidisciplinary writing group and construct a series of guidelines. The group agreed to review the appropriate literature relative to CPB from 2001 through 2014. John W. Hammon was selected to represent the Society of Thoracic Surgeons, Linda Shore-Lesserson was selected to represent the Society of Cardiovascular Anesthesiologists, and Timothy A. Dickinson was selected to represent the American Society of ExtraCorporeal Technology. We have expanded and formed a large team of experts in this field to review the relevant literature, assess the levels of evidence, and synthesize the recommendations into appropriate and actionable clinical practice guidelines.Robert A. Baker, PhD, and his group at Flinders University, Adelaide, South Australia, Australia, has developed a tool to facilitate the guideline development process. The tool, known as “Guideliner,” is an Internet-based program that stores literature searches and literature reviews, creates work lists, and directs the user through a very conservative evidence-review process. Thus far, the Guideliner has guided our multidisciplinary group through the review of 3,321 abstracts and 935 complete articles. Articles published from 2001 through 2014 have been carefully screened to find the most relevant and scientifically sound evidence. These would be combined with older high-quality publications to form future guidelines for CPB.Dr. Richard Engelman and his team have produced a comprehensive statement regarding the best practices in CPB temperature management to date. Subsequently, we hope other guidelines will be presented, including renal protection, neurologic protection, anticoagulation management, equipment selection, and interdisciplinary collaboration; the final guideline would address the conduct of CPB and perfusion safety. Our expectation is that this series of guidelines will be used by clinical teams to facilitate the assessment and improvement of care for the patients whom we collectively serve.


The management of neuropathic pain (NP) is challenging despite it being the recent focus of extensive research. A number of clinical practice guidelines (CPGs) for the management of NP have been published worldwide over the past 2 decades. This study aimed to assess the quality of these CPGs.We performed a systematic review of published CPGs for the management of NP. Three reviewers independently assessed the quality of the CPGs using the Appraisal of Guidelines Research and Evaluation II (AGREE-II) instrument, and recommendations of CPGs were also appraised.A total of 16 CPGs were included. Thirteen CPGs were developed using an evidence-based approach, and the remaining CPGs were produced by consensus panels. None of CPGs obtained a score greater than 50 % in all six AGREE II instrument domains mainly owing to poor performance in the “Applicability” domain. The highest score of the CPGs was achieved in “Clarity and Presentation” domain, followed by “Scope and Purpose” and “Editorial Independence” domains, and the lowest scores were found the in “Applicability” domain. The majority of the CPG recommendations on the management of patients with NP were relatively consistent, especially regarding the recommendation of stepwise treatment with medication.Greater efforts are needed not only to improve the quality of development and presentation of the CPGs, but also to provide more efficacy evidence for the management of patients with NP.The online version of this article (doi:10.1186/s12871-015-0150-5) contains supplementary material, which is available to authorized users. Clinical practice guidelines (CPGs), defined as “statements that include recommendations intended to optimize patient care that are informed by a systematic review of the evidence and an assessment of the benefits and harms of alternative care options”, have been expected to facilitate more consistent, effective and efficient medical practice, and ultimately improve health outcomes , 2. ManyNeuropathic pain (NP), caused by a somatosensory lesion or various diseases, comprises a wide range of heterogenous conditions . NP affeIn the present study, we systematically reviewed the available CPGs for NP, focusing on their methodological quality, using the Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument, and also assessed the consistency of the CPG recommendations.Two experienced systematic reviewers searched relevant studies to identify CPGs for the management of NP. The following electronic databases were searched: MEDLINE, Embase, the National Guideline Clearinghouse, the Guidelines International Network, and Canadian Medical Association Infobase. Additionally, we searched the websites of the related associations, institutes, societies, and communities, including EFNS, the Canadian Pain Society, IASP, and the South African Society of Anaesthesiologists.The following terms and Boolean operators were used in Mesh and free-text searches: (Practice Guideline OR Guideline OR Consensus OR Recommendation) and neuropathic pain. Finally, we also scanned the reference lists of relevant published articles not identified in the database searches.Two reviewers independently examined and selected the CPGs according to inclusion and exclusion criteria. The inclusion criteria were as follows: (1) explicit statement identifying itself as a “guideline”; (2) CPGs that included recommendations concerning screening, diagnosis, and/or management for neuropathic pain; (3) CPGs that included a systematic review of the evidence; (4) CPGs produced by the related associations, institute, societies, or communities; (5) CPGs published in English. The exclusion criteria were as follows: (1) consensus statements, which were derived from the collective opinion of an expert panel not based on a systematic review of the evidence; (2) articles including primary studies, narrative reviews, text-like documents on development methods, documents on comments related to CPGs; (3) documents focused entirely on a unique condition, such as cancer-related neuropathic pain, postherpetic neuralgia, diabetic neuropathy, among others.Following completion of all searches, references were merged and duplicates were removed. By reading titles and abstracts, two reviewers independently scanned the references to verify their eligibility using the pre-defined inclusion and exclusion criteria listed above. Additionally, two reviewers independently scanned the full-text to further verify their eligibility according to the eligibility criteria after the full-text article was obtained. If needed, disagreements were resolved by discussion with a third reviewer.The AGREE II instrument, an updated version of the original AGREE instrument, is an international, rigorously developed, and validated instrument used widely to assess CPGs . It consP < 0.05.Descriptive and statistical analyses were performed for each domain of the AGREE II instrument. Inter-rater reliability within each domain was examined using the intra-class correlation coefficient (ICC) with a 95 % confidence interval. The degree of agreement was classified according to the scale proposed by Landis and Koch, as follows: poor (<0.00), slight (0.00–0.20), fair (0.21–0.40), moderate (0.41–0.60), substantial (0.61–0.80) and very good or almost perfect (0.81–1.00) . All staAs shown in Fig. Table Three reviewers evaluated the 16 included CPGs using the AGREE II instrument. Table The results of the inter-rater reliability assessments among the three reviewers are presented in Table As shown in Table In the present study, we evaluated the quality of CPGs and consistency of the recommendations of CPGs for the management of NP to assist physicians in the selection of the appropriate recommendations. Our review demonstrated that the overall quality of the CPGs based on the AGREE II instrument was poor. However, we found consistency in the recommendations stated in the 16 CPGs with respect to drug treatment.The AGREE II instrument allows the evaluation of various aspects of the guidelines, including integrity, reproducibility, and transparency of guidelines among six domains. Each domain has a different value and concern. Domain 1, “Scope and Purpose,” is concerned with the overall aim of the guideline, the specific health questions being addressed, and the target population (items 1–3). Domain 2, “Stakeholder Involvement,” focuses on the extent to which the guideline was developed by the appropriate stakeholders and represents the views of its intended users (items 4–6). Domain 3, “Rigor of Development,” relates to the process used to gather and synthesize the evidence, the methods to formulate the recommendations, and update them (items 7–14). Domain 4, “Clarity of Presentation,” deals with the language, structure, and format of the guideline (items 15–17). Domain 5, “Applicability” pertains to the likely barriers and facilitators to implementation, strategies to improve uptake, and resource implications of applying the guideline (items 18–21). Domain 6, “Editorial Independence” is concerned with the formulation of recommendations not being unduly biased with competing interests (items 22–23).Our study showed that four domains concerning “Stakeholder Involvement”, “Rigor of Development”, “Applicability”, and “Editorial Independence” had serious shortcomings because the related information was poor provided. The remaining domains, including “Scope and Purpose” and “Clarity of Presentation” tended to more precisely reported because most of the included guidelines described in detail the specific and focused clinical questions they aimed to address, the target population, specific and unambiguous presentation, different management options for different presentations, and easily identifiable presentation.Although the AGREE II instrument provides six independent domains, the “Rigor of Development” domain is considered the strongest indicator of quality of all the domains because it evaluates the integrity of the guideline development process. Among the included CPGs, low scores in the “Rigor of Development” domain were partly because of poor performance in this aspect, including the literature search and selection methods, lack of external review prior to publication, and lack of guideline updating mechanisms. Among the six domains, the quality of the “Applicability” domain also plays a significant role. A guideline developed systematically with clear recommendations based on the best available evidence could improve the healthcare practice . HoweverGuidelines need to be evaluated not only for methodological quality but also for validity of their content in terms of recommendations. Thus, this study also analyzed the recommendations of these guidelines for the management of NP. In general, these recommendations were consistent on the diagnosis, assessment and pharmacological management despite scoring poorly in their rigor of development. It was difficult to tell whether we obtained these results because there was insufficient evidence to develop the guidelines or because the CPG authors did not search and make use of the best evidence available.A large number of the drug development research has been devoted to the field of NP. A large number of analgesic agents have shown efficacy for the treatment of NP. However, no more than 40–60 % of patients have obtained sufficient pain relief with medications alone and in combination , 17. ThuIn general, the guidelines for the management of NP vary considerably in terms of quality, because of the apparently low standards. To reduce the variability of the CPGs, guideline development groups should have standard methodology and strategy. Further, it would be helpful to become familiarized with the AGREE II instrument domains to know what information should be reported and how it ought to be reported in the CPGs. Here, we also give some pointers to reduce the variability among the CPGs:1) The study should describe the specific health question it aims to address, such as prevention, screening, diagnosis, or treatment, and target population, including sex, age clinical condition, severity stage of the disease, comorbidities, and others. 2) The guideline development group should include individuals from all relevant professional groups, not only or mainly health care providers. Competing interests of guideline development group members should be fully recorded and addressed. 3) In the guideline development process, appropriate methodologies and rigorous strategies are important for successful implementation of the resulting recommendations, such as the systematic methods and criteria for selecting the evidence, methods for formulating the recommendations, health benefits, side effects considered in formulating the recommendations, links between the recommendations and the evidence. Additionally, guidelines should be externally reviewed prior to their publication, and a procedure for guideline updating should be planned and described. 4) The different options for the management of the condition or health issue should be clearly presented and the recommendations should be specific and unambiguous. 5) The views of the funding body and interests of the development group should been recorded and addressed.Additional file 1:PRISMA 2009 checklist. (DOC 63 kb)Additional file 2:PRISMA 2009 flow diagram. (DOC 60 kb)