Numerous clinical practice guidelines (CPGs) are published to guide management of osteoporosis. Little is known about their quality or how recommendations have changed over time.To systematically assess the quality and content of the guidelines on screening for osteoporosis, using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool, and the Institute of Medicine (IOM) standards for trustworthy guidelines.We conducted a systematic search for osteoporosis CPGs published between 2002–2016, using multiple databases and guideline websites. Two reviewers appraised the quality of eligible CPGs using the AGREE II. High quality CPGs were considered if they scored ≥ 60 in four or more domains including the domain for rigor of development. Non-parametric tests were used to test for the change of quality over time. One reviewer assessed the guidelines with IOM standards. We summarized the different evidence grading systems and extracted and compared the recommendations.A total of 33 CPGs were identified. The mean scores for AGREE II differed by domain (range: 42% to 71%). CPGs scored higher on domains for clarity of presentation, scope and purpose, and rigor of development. CPGs scored lower on domains for stakeholder involvement, editorial independence and applicability. Assessment of CPGs by IOM standards showed that CPGs scored better on standards for systematic review, establishing evidence foundation and rating strength of recommendation, articulation of recommendation, and establishing transparency. While scored lower on standards for updating, external review, and the development group composition. There was no difference in AGREE II and IOM defined guidelines’ quality before and after the introduction of the two tools . The IOM identified four more guidelines as high quality compared to the AGREE II. Examining these additional guidelines indicated that the two tools may give conflicting results especially for the rigor of development domain. Recommendations in certain areas showed substantial differences between guidelines.Osteoporosis screening CPGs are of variable quality, and their recommendations often differ. Guideline quality as measured by AGREE II and IOM standards has not improved overtime. Guideline developers should work together to improve the quality and consistency of recommendations to improve the likelihood that their guidelines will be used in practice. Osteoporosis is a disease characterised by low bone mass and deterioration of the bone tissue structure leading to increased bone fragility and liability to fractures . These fLow bone mass is a major risk factor for fractures, however, there are many other factors that contribute to osteoporosis including age, sex, previous fractures, family history of osteoporosis, use of systemic glucocorticoids, excessive alcohol and smoking . The prePatients who suffer osteoporotic fractures are at higher risk of morbidity and mortality; in the Canadian Multicentre Osteoporosis Study (CaMOS), both men and women had increased incidence of death of 23.5% (20/85) after hip fracture . The ecoOsteoporosis is usually diagnosed based on bone mineral density (BMD) measurement by dual energy x-ray absorptiometry (DXA). A T-score of -2.5 standard deviation below the expected mean value for a young white female adult, is considered diagnostic . Since lThe aim of screening is to diagnose those at risk for fractures to prevent them from occurring, in addition to prevent the risk of re-fracture in patients who sustained a previous fragility fracture. Many pharmacological and non-pharmacological treatments are available and have proven efficacy .Statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options” .Many tools have been developed by researchers incorporating many factors to estimate fractures risk over 5 or 10 years ;FRAX wasThere was a substantial variation between recommendations in whether to use a tool (FRAX) before BMD testing for risk assessment. This variation did not show any pattern of difference or similarity based on high and low quality guidelines, and mostly differed by region or country Four guidelines were not clear in their recommendations whether to use FRAX first or BMD testing  has set a threshold of intervention at each age level after 40 years, provided through a chart with or without BMD testing ,68There was little discrepancy between guidelines’ recommendation in this area.The period to assess BMD has varied between CPGs ranging between 1–2 years or 2–3 years or sometimes up to 8 years. However, most guidelines were in agreement in reporting that there is lack of evidence for the optimum period or the benefit of repeating BMD and that area is controversial.We systematically identified and assessed 33 guidelines for screening for osteoporosis published between 2002–2016 from 13 countries, using the AGREE II instrument and the IOM standards for trustworthiness, which are developed to appraise the quality of CPGs. Our findings reveal that there has been marked variability in the compliance to the criteria of the AGREE II tool and the IOM standards by these guidelines.An examination of the mean of AGREE II domain scores showed that the highest mean domain scores were for Clarity of Presentation and Scope and Purpose, while the lowest mean scores were for Applicability and Editorial Independence domains. This was consistent with other reviews in other topics ,35,82,83Regarding the domain of stakeholder involvement; most guideline developers didn’t seek the views and preferences of their target population especially patients in guidelines development and even when they did they were vague about the process. This is worth considering by all guideline developers, since a patient centred approach to health care with shared decision making is associated with better application of the guidelines and improved health care. The domBy assessing the compliance of guidelines to the criteria of the IOM standards, we found that 64%- 67% of guidelines fulfilled the standards for establishing evidence, strength of recommendations, and systematic review standards. However, most guidelines fell short in involving patients and public representatives in their guideline development and didn’t adequately describe the method for external review. Though, the IOM standards were developed in 2011, we found few studies that assessed the quality of CPGs using these standards,87,88[.TIn our study, we found that the compliance of guidelines to the criteria of both tools (AGREE II and IOM) showed no change between 2002–2010 and 2011–2016, allocating the time of the release of both tools as the comparing point. This finding aligns with previous studies evaluating CPGs over time,87,89–91In comparing the AGREE II tool with the IOM standards; the AGREE II was more comprehensive, as it covered implementation and dissemination issues of the guidelines, while IOM did not cover this area. Both instruments identified lack of compliance in domains relate to multidisciplinary development group composition with involvement of patients and public representatives. Both tools showed that the influence of funding body, and conflict of interests, is falling short in most guidelines as very few CPGs met these criteria.We used certain criteria to identify high quality guidelines; AGREE II identified less high quality guidelines compared to IOM. By examining the items or criteria for domains of rigor of development and systematic review methodology in the four extra high quality guidelines; identified by IOM; we found that the AGREE II gave lower scores for these guidelines. This is because the AGREE II has more detailed quality items for this section, While, the IOM has fewer criteria in this section, which have resulted in higher scores for the guidelines. This may have important implications for clinicians and stakeholders, in deciding which guideline to implement based on using one of the two tools to assess the quality and rigor of the guidelines.Our systematic review emphasizes the variability in the use of the different grading systems to aggregate the level of evidence and to rate the strength of recommendations. Establishing the level of evidence that underlies the recommendations is essential in guideline development. Without clarity of the system of evidence that is used, guidelines users cannot decide whether recommendations are built on strong evidence or weak evidence. Additionally, determining the strength of recommendations influences the applicability and implementation of the guideline. Different frameworks or grading systems were developed, yet, the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system is considered one of the best now, and has been adopted by many organizations . SurprisThe content analysis of selected areas of recommendations for screening of individuals without previous fractures revealed a considerable variability. This variability did not differ between high or low quality guidelines but mainly differed by region or country. In terms of their approach in screening and using BMD testing or risk assessment first, there was a huge variability between guidelines in this area. The other conflicting area relates to choosing the intervention threshold for those at risk of fracture. Some guidelines use bone mineral density T-score diagnostic criteria. Others use BMD testing with FRAX scores and not solely the T-score results, and this approach is the most adopted in more recent guidelines.Concordant recommendations were found for BMD testing sites.We expect some variation between guideline recommendations since it is based on country specific data and cost-effectiveness. However, we found even in the same country guideline recommendations differ. For instance; in Canada; British Columbia CPGs recommend using FRAX before DXA , while iThere are many limitations to this review. First; we included only CPG in English, so guidelines in other languages were not assessed. Second, the AGREE website suggests 2–4 number of reviewers, and four is preferable to increase the reliability of the study. Third; in scoring the AGREE II, only the published information about the guidelines were used in assessment, i.e. we didn’t look at the methodology documents of the organizations, which could have been on their websites. Thus, we may have underscored some domains. Fourth, assessing quality using the IOM standards was challenging because we could not find any suitable published methodology that was used in previous studies, and very few studies have used these standards to assess quality of guidelines (discussed in methods section). Thus, we are not certain about the validity of our methodology. This also may affect the results of comparison between the AGREE II and the IOM standards, which as a result of our IOM methodology, could be liable for bias.The main strength of this review is that we assessed the quality of osteoporosis screening guidelines over 14-year period to determine changes in guideline quality over time. Our search was systematic and comprehensive including all the general databases, guideline websites and major guideline developer groups, and by hand searching the references of all identified guidelines. Another strength, is that we used two recognised tools to assess guideline quality and compared the results from both tools which to our knowledge was done only by one study . We had The AGREII and IOM defined quality of CPGs for screening of osteoporosis is variable, and there is a considerable room to improve the guideline development process in this field as well as the reporting of guideline development. Guideline developers should develop their guidelines paying attention to the criteria and standards included in the AGREE II instrument and the IOM standards for trustworthy guideline. The reporting of applicability considerations of the guideline and editorial independence areas appear week. The inclusion of patients, economists, and, knowledge translation experts as well as other stakeholders should be considered as a mean of improving the quality of guidelines and their likelihood of implementation. The lack of consensus on specific guideline recommendations for osteoporosis screening is problematic and creates confusion for clinicians and patients about what exactly is best practice.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table* Items in bold font don’t have a match in the other tool.(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.


Background: Evidence-based chronic disease prevention (EBCDP) effectively reduces incidence rates of many chronic diseases, but contextual factors influence the implementation of EBCDP worldwide. This study aims to examine the following contextual factors across four countries: knowledge, access, and use of chronic disease prevention processes.Methods: In this cross-sectional study, public health practitioners (N = 400) from Australia (n = 121), Brazil (n = 76), China (n = 102), and the United States (n = 101) completed a 26-question survey on EBCDP. One-way ANOVA and Pearson's Chi-Square tests were used to assess differences in contextual factors of interest by country.Results: Practitioners in China reported less knowledge of EBCDP processes (p < 0.001) and less use of repositories of evidence-based interventions, than those from other countries (p < 0.001). Academic journals were the most frequently used method for accessing information about evidence-based interventions across countries. When selecting interventions, Brazilian and Chinese practitioners were more likely to consider implementation ease while the Australian and United States practitioners were more likely to consider effectiveness (p < 0.001).Conclusions: These findings can help inform and improve within and across country strategies for implementing EBCDP interventions. Chronic diseases are an increasing threat to the health and well-being of individuals and communities in middle- and high-income countries , and posSimilar to evidence-based medicine, evidence-based public health (EBPH), more specifically, evidence-based chronic disease prevention (EBCDP) has proven to be an effective set of processes for reducing the burden of chronic disease. These processes may vary, but include ensuring that decision-makers have up-to-date scientific evidence about the chronic disease prevention policies and programs that are effective at improving chronic disease health outcomes, using that evidence to inform health and policy agendas, and considering the environments and contextual circumstances likely to impact the application of chronic disease prevention evidence –7. When The objective of this study is to begin to describe similarities and differences in knowledge of EBCDP processes, avenues for accessing information about evidence-based interventions, factors that influence decision-making regarding planning and implementing evidence-based programs, and use of evidence-based repositories and quality improvement processes across Australia, Brazil, China, and the United States. For this study, EBCDP repositories are considered collections of evidence-based, chronic disease-related interventions . Likewise, quality improvement processes are defined as ongoing, formal assessments of the effectiveness and quality of public health chronic disease prevention efforts .For several reasons, Australia, Brazil, China, and the United States were chosen as the countries of interest for this study. First, they have a high prevalence of chronic diseases  , 17. AddN = 400) from Australia (n = 121), Brazil (n = 76), China (n = 102), and the United States (n = 101) completed a 26-question survey on EBCDP implementation. Seven questions from this survey were used in this analysis (see Appendix). This survey was conducted to assess contextual factors that influence the implementation of EBCDP in Australia, Brazil, China, and the United States. The 26-question survey was informed by the following: the development of a guiding framework based on previous work of the research team (n = 13), Brazil (n = 9), China (n = 16), and the United States (n = 12). Drafts of the survey were reviewed by 13 chronic disease prevention researchers, and were translated forward and backward to Chinese and Portuguese from English. The survey was also pilot-tested in each country to ensure contextual appropriateness. Seven response items were deemed non-applicable for China contexts, but were included in the survey for the other three countries.In this cross-sectional study, public health practitioners , five levels of contextual factors , and demographic information of the practitioners , 28. PubLevel of knowledge on evidence-based processes was assessed with the following definition and question, “Evidence-based public health is defined as: The process of integrating science-based interventions with community preferences to improve the health of populations. With this definition in mind, how knowledgeable are you with evidence-based processes?” with response options including, not at all knowledgeable, slightly knowledgeable, somewhat knowledgeable, moderately knowledgeable, and extremely knowledgeable.The channels that participants used for accessing evidence-based interventions were assessed by asking “Which avenues do you use to learn about the current study findings on evidence-based interventions?” The following question was asked to assess which avenues practitioners would like more access to, “For which avenues would you like additional access?” Both questions had the same list of response options. Respondents were prompted to select all response options that apply.Factors that influence decision-making were measured by the question, “When you make decisions about such things as program planning and implementation, which of the following are important to you?” Respondents were given a list of 12 possible factors, and prompted to select the top three that were most influential in their decisions to select an intervention.Use of repositories by self and other staff at respondents' workplace was assessed by defining repositories and asking practitioners to complete the two versions of this statement, “I/Staff have used repositories to find evidence-based interventions…” The following response options included, in none of my/their programmatic areas, in a few of my/their programmatic area, in many of my/their programmatic areas, in all of my/their programmatic areas, I don't know, and not applicable.Table 2, we present a truncated version of the survey results, where we calculated a weighted average for questions that were scalable, and presented the top response for categorical, non-scalable questions. The full list of questions included in this analysis, and subsequent results, can be found in Appendix. See Table Use of quality improvement processes by staff at the respondents' workplaces was assessed by defining quality improvement processes and asking practitioners to complete the following statement, “Staff at my agency use quality improvement processes…” Response options included, in none of my/their programmatic areas, in a few of my/their programmatic areas, in many of my/their programmatic areas, in all of my/their programmatic areas, I don't know, and not applicable. In All analyses were performed using SPSS version 23 . DescripAcross the four countries, 400 public health practitioners working in chronic disease prevention completed the survey Table . Most ofp < 0.001).Differences in knowledge of evidence-based processes, and use of and access related to evidence-based interventions, are outlined in Table p < 0.001). Compared with both Brazil and China, practitioners in Australia and the United States were significantly more likely to use email alerts, networks, and technology-based avenues including webinars and listservs/email newsletters/online forums (each significant at p < 0.001).Academic journals, conferences, evidence-based repositories, the Internet, partnerships, and trainings were among the most frequently used avenues for accessing evidence-based interventions across all countries. Practitioners from China reported significantly less frequent use of most of the avenues including the Internet, government reports, and government staff relative to all other countries (p = 0.001) more frequently than those from the other countries. Similarly, Brazilian practitioners highlighted their desire for additional access through conferences (p < 0.001), and practitioners in China cited a need for additional access to Internet search engines (p = 0.001) and Facebook (p < 0.001) more frequently compared with practitioners from the other countries.When practitioners were asked about avenues to which they needed additional access, the most frequently reported avenues across all four countries included academic journals, conferences, email alerts, evidence-based repositories, partnerships, and training/workshops/meetings within the agency. However, for avenues that practitioners needed additional access to, approximately half were not significantly different across the four countries. Practitioners in Australia requested increased access to professional networks (p < 0.001), elected officials (p < 0.001), and ease of intervention implementation (p < 0.001) compared with American and Australian counterparts. Practitioners from China were significantly less likely to make decisions based on the evidence regarding effectiveness of the interventions (p < 0.001), whereas for practitioners from Australia and the United States, evidence was commonly considered (74 and 61% respectively). In Brazil, practitioners were more likely than those from the other three countries to make decisions based on support from community partnerships (p = 0.001), recommendations from funding agencies (p < 0.001), whether their colleagues are using the intervention (p < 0.001), available resources (p < 0.001), health planning tools (p < 0.001), the relevance of the intervention to the population of interest (p < 0.001), and the seriousness of the health problem (p < 0.001).When asked to consider factors that influence their decision-making when planning and implementing evidence-based programs, practitioners from Brazil and China were more likely to report making decisions based on leadership (p < 0.001).There was a significant difference in the use of evidence-based repositories and quality improvement processes among practitioners across countries. Specifically, the majority of practitioners in China reported repository use and use of quality improvement processes in few or no programmatic areas, whereas the majority of practitioners in all three other countries reported repository use in many or all programmatic areas  and the two middle-income (Brazil and China) countries. Practitioners from both high-income countries tended to have more knowledge, access, and experience, with regard to the implementation of EBCDP, compared with practitioners from both middle-income countries.Practitioners from Brazil and China reported less knowledge of evidence-based processes than practitioners from Australia and the United States, with practitioners from China reporting the least EBCDP knowledge. This finding is consistent with the literature, citing deficiencies with regard to evidence-based practice in the field of public health in middle-income regions of the world, specifically China . In ChinAlso, postgraduate degrees were less common among practitioners from China and Brazil than among practitioners from Australia and the United States. For practitioners from Brazil, one of the most common degrees was a certificate in public health (less than a bachelor's degree); whereas consistent with the structure of the healthcare system in China, practitioners in this sample tended to have a bachelor's degree in medicine and work as physicians in community hospitals. This reflects the contextual differences between high- and middle-income countries, of practitioners working in the field of chronic disease prevention. Additionally, differences in knowledge between both of the two middle- and high-income countries could be attributed to the former having larger and better funded institutions that have the resources to fund, generate, and disseminate research on EBCDP. Fewer resources can put middle-income countries at a disadvantage when it comes to supporting the integration and adoption of evidence-based practices into the field of public health .Practitioners from China most commonly reported evidence-based repository use by themselves and by colleagues in few to no programmatic areas. One possible explanation is the less established nature of EBCDP in China, supported by a study conducted in China where researchers examined EBCDP in western countries, to inform EBCDP in China, finding that the developed western countries had a much larger evidence base for chronic disease prevention, compared to China, whose chronic disease prevention evidence base was behind due to less theoretical guidance and intervention measure development . FurtherThe two middle-income countries were more likely to value ease of intervention implementation when making decisions, which similarly could be a result of a less established commitment to EBCDP and fewer resources dedicated to this area. Similarly, China was less likely to consider the evidence regarding effectiveness of interventions when making decisions, which also aligns with their higher value on ease of implementation. This contrasts with the two high-income countries who placed high value on effectiveness of intervention and low value on ease of intervention. One potential explanation is that evidence bases produced in other countries, such as the United States, might not be applicable or transferable to countries like China, making the research base, regardless of its size, of low value to Chinese practitioners. Further, this finding may reflect the systems and policies set up for supporting and/or requiring evidence-based interventions in high-income countries . For example, in a United States study mapping the landscape of behavioral health interventions, it was found that funders of such interventions required 75% of all money spent by a program funded under the initiative be spent on evidence-based programming . If usinSimilarities across all countries also arose. Both of the two high- and middle-income countries most often used academic journals and conferences as avenues for accessing new evidence, which is consistent with literature on best practices in evidence-based public health (EBPH), directing readers to academic journals as the primary avenue for finding relevant evidence . HoweverThis study has several limitations to consider. Because the types of public health practitioners are not equivalent across the countries in this study, it is hard to control for this variable. Additionally, non-random sampling, as carried out in this study, is susceptible to selection bias, and there may be distinct differences between those who were selected and opted to take this study's survey compared with those who were not selected or opted against taking the survey. This study also did not control for potential confounders like age, job responsibilities, and culture. While the study did ask about many of these variables, small cell sizes precluded multivariable analyses in this study. Future studies should strive to have a large enough sample size to include all potentially confounding variables in the analysis. Further, because some of the chi-square analyses had cells where expected values were < 5, these results should be cautiously interpreted, even when statistically significant, and a larger, more representative study of public health practitioners in low-, middle-, and high- income country is needed, to validate study findings. Additionally, future studies should conduct country-specific research on similar variables, to validate findings from this study, and deepen the evidence-base in this area. Doing so will enable researchers to better understand, explain, and address the contextual similarities and differences of practitioner knowledge, access, and use of EBCDP, among other key contextual variables.Additionally, while this study focuses on the value of EBCDP in reducing chronic disease, the current evidence-base also supports several limitations of evidence-based practice across many fields –50, whicThe current study identified the differences of EBCDP knowledge, access, decision-making, and repository and quality improvement process use between the two middle- and two high-income countries. The distinct differences in EBCDP among the countries in this study can contribute to informing and improving global strategies for EBCDP implementation. Such efforts could take the form of cross-country conferences, as well as formal and informal partnerships where resources and knowledge could be shared. Political, administrative, and stakeholder leaders in these countries can also use these findings to glean valuable insight into areas that their public health practitioners need more assistance. Finally, findings from this study suggest that middle-income countries would benefit from increased funding, capacity building, and EBCDP infrastructure, to improve overall practitioner engagement in the implementation of EBCDP interventions.https://dataverse.harvard.edu/dataset.xhtml?persistentId=doi: 10.7910/DVN/HPJDGD.The dataset used for this study is available in the publicly available Harvard Dataverse Repository at the following link: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or National Research Committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.AD and XY contributed to the conception and design of the study, analysis and interpretation of the data, and drafting and revisions of the full manuscript. EB and KF contributed to the conception and design of the study, interpretation of data, drafting and revisions of the full manuscript. RR, ZW, PS-C, RA, TP, LB, TM, JS, TS, and RB contributed to the conception and design of the study and manuscript revisions and approval. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Using 4,094 ClinVar-curated missense variants in clinically actionable genes, we evaluated the accuracy and yield of benign and deleterious evidence in 5 in silico meta-predictors, as well as agreement of SIFT and PolyPhen2, and report the derived thresholds for the best performing predictor(s). REVEL and BayesDel outperformed all other meta-predictors , with higher positive predictive value, comparable negative predictive value, higher yield, and greater overall prediction performance. Agreement of SIFT and PolyPhen2 resulted in slightly higher yield but lower overall prediction performance than REVEL or BayesDel. Our results support the use of gene-level rather than generalized thresholds, when gene-level thresholds can be estimated. Our results also support the use of 2-sided thresholds, which allow for uncertainty, rather than a single, binary cut-point for assigning benign and deleterious evidence. The gene-level 2-sided thresholds we derived for REVEL or BayesDel can be used to assess in silico evidence for missense variants in accordance with current classification guidelines.Many  In silico prediction of variant pathogenicity is one of the eight evidence categories recommended by the American College of Medical Genetics and American College of Pathologist (ACMG/AMP) guidelines1. Many in silico algorithms have been developed to predict the degree of sequence conservation and functional impact of missense variants, each of which generates a score based on tolerance to variation. Assessment of in silico evidence based on the observed concordance of multiple scores yields a high rate of discordant predictions, even among well-classified variants, suggesting that such an approach is not ideal3. Recently, several in silico meta-predictors have been developed from analyses of multiple individual scores, and have demonstrated superior performance to that of individual predictors, although robust, systematic comparison of these approaches is lacking6.in silico meta-predictors have primarily been trained on large numbers of variants selected from genome-wide data. Yet, variants from same gene share common features and gene-level transcription facilitates the events that drive the development and progression of disease, as well as response to therapy7. Global applications of in silico scores may result in a large number of false predictions as a one-size-fits-all approach9, but gene-level thresholds for assessing benign and deleterious evidence are unavailable, in practice. In addition, while many algorithms recommend binary thresholds for assessing in silico evidence, clinical recommendations based on thresholds for “likely benign” and “likely pathogenic” are 2-sided10.Furthermore, in silico algorithms and approaches available, there is currently no standard application of these tools for variant assessment; many laboratories use different tools and thresholds for evidence of pathogenic or benign classification12. As such, the 2015 ACMG/AMP guidelines assign only a supporting level of evidence to in silico predictions1. In this study, we aimed to assess in silico evidence for pathogenicity of missense variants using gene-level and generalized  2-sided thresholds, compare prediction performance among 5 commonly used meta-predictors, and identify the thresholds corresponding to the meta-predictor(s) with the best overall prediction performance that can be used to assess in silico evidence in accordance with the ACMG/AMP guidelines.Given the wide variety of in silico scores, we compiled a dataset of 4,094 classified missense variants in 66 clinically relevant genes from ClinVar. Variants were included if reviewed by expert panel or classified by any of 6 submitters that consistently provide assertion criteria: Ambry Genetics, Emory Genetics Laboratory, GeneDx, InSiGHT, InVitae and Sharing Clinical Reports Project. For each variant, we defined its consensus class as the most supported category among benign/likely benign (B/LB), pathogenic/likely pathogenic (P/LP) and variants of uncertain significance (VUS), i.e. pathogenic/likely pathogenic if NP/LP ≥ max and NB/LB = 0 or benign/likely benign if NB/LB ≥ max and NP/LP = 0. Variants with conflicting classes  or classified as VUS by the majority of submitters ) were excluded from analysis.To evaluate the prediction performance of various In silico scores were obtained for 5 meta-predictors  and 2 individual predictors (SIFT15 and PolyPhen216) from the dbNSFP v3.5c database 17 and related websites  from 10,000 bootstrapping replicates stratified by classification status.To derive gene-level thresholds for the 20 genes with ≥10 B/LB and ≥10 P/LP variants, we fit models using Firth logistic regressionTo account for potential overfitting, the predictive performance of each meta-predictor was evaluated using leave-one-out cross-validation, in which the assigned evidence was compared to the B/LB and P/LP status from ClinVar consensus classification. Performance statistics were evaluated using positive predictive value (PPV), negative predictive value (NPV) and yield rate (YR). YR was defined as the proportion of variants received benign or deleterious evidence among all evaluated variants. To assess the joint performance of accuracy and yield, we computed overall prediction performance (OPP), defined as the root mean square of PPV, NPV and YR, i.e., OPP = mentclass2pt{minimIn an effort to minimize the overlap of variants included in this analysis and those used to train any of the 5 meta-predictor models, we also performed a sensitivity analysis in 20 genes to assess meta-predictor performance among only those variants evaluated by all submitters in ClinVar during the period from September 2015 to August 2017.in silico prediction using generalized thresholds from a combination of 20 genes and that of SIFT/PolyPhen2 agreement  and improved PPV , YR  and OPP  (Table p > 0.44 for differences between the two). For each of 5 meta-predictors in 20 genes, evidence assignment using gene-level thresholds consistently outperformed that of generalized thresholds   Table .Figure 1p < 0.32)  , supporting the robustness of gene-level thresholds ; likewise, the 90% CI around the generalized threshold estimated for pathogenic evidence overlapped with that estimated for gene-level benign evidence for 1 gene (TSC2). No overlap between the generalized threshold’s 90% CI for benign evidence and CIs estimated for gene-level pathogenic evidence was observed for any genes using BayesDel, however, the 90% CI around the generalized threshold for pathogenic evidence overlapped with that for gene-level benign evidence for TSC2.While these findings support the use of gene-level thresholds for in silico assessment in variant classification. Our results were consistent with studies that found meta-predictors better assessed variant pathogenicity than concordance of individual predictors6. Our findings suggest that REVEL and BayesDel outperform the other 3 meta-predictors (Fig. In this study, we evaluated and compared the performance of 5 well known meta-predictors often used for ors Fig. . We alsoin silico evidence using gene-level thresholds compared to generalized thresholds, which highlights the importance of gene-specific assessment of variant pathogenicity21. We further observed wide variation in gene-level thresholds, and that the 90% CI around the generalized thresholds overlapped with those of the gene-level thresholds for <50% of the 20 genes examined in this study. Taken together, our findings support the use of gene-level thresholds for clinical variant assessment, when available.The strengths of our approach include generation of gene-level thresholds for variant assessment in 20 clinically actionable genes, and comparison to generalized thresholds estimated from a broader set of 66 such genes. Both gene-level and generalized thresholds yielded NPV, PPV and overall performance statistics ≥90%, and whether estimated from REVEL or BayesDel, both outperformed SIFT/PolyPhen2 agreement. However, our results also demonstrated improved prediction performance when assigning 2. The use of 2-sided thresholds for evidence assignment is a data-driven solution to the problem of uncertainty; a single threshold necessarily assigns evidence to all variants but at the cost of high false positive or false negative rates. However, we acknowledge the trade-off between accuracy and yield, as thresholds quantified from Firth logistic regression models may be overly conservative in protecting against false predictions at the expense of the proportion of variants for which benign or pathogenic evidence can be assigned. Future methods development may include non-linear models or a weighted mechanism for adaptive balance between accuracy and yield designed to improve the overall performance of evidence assignment.An additional strength of our approach is the use of 2-sided thresholds for evidence assignment, as opposed to the current binary thresholds recommended for meta-predictors such as REVEL and BayesDelin silico scores on a gene-by-gene basis. In view of potential circularity issues arising from the testing of variants available in ClinVar that may have been previously used to train the meta-predictors we analyzed in the present study, we performed a sensitivity analysis to assess the impact of these variants. However, we were precluded from fully accounting for all such variants due to the fact that some of the variants included in our sensitivity analysis may have been deposited in ClinVar prior to 2015 and/or included in HGMD or ExAC at the time the models were developed. Nonetheless, our sensitivity analysis results were consistent with those of the larger analysis based on the full set of variants.Our findings are based on the use of ClinVar-curated variants, a rapidly growing database with confidently annotated disease-causing alterations, as a training set to calibrate in silico evidence using gene-level 2-sided thresholds from REVEL or BayesDel scores achieved higher predictive accuracy and yield compared to the use of other in silico predictors. The REVEL and BayesDel thresholds we report can serve as a viable resource for assigning in silico evidence to missense variants in the genes examined herein, to be used in conjunction with other lines of evidence in variant assessment as recommended in ACMG/AMP guidelines.Assigning Supplementary InformationSupplementary Dataset


The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine.We undertook 2 phase 1 studies assessing safety and immunogenicity of the viral vector modified vaccinia Ankara virus vectored Ebola Zaire vaccine (MVA-EBO-Z), manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with recombinant chimpanzee adenovirus type 3 vectored Ebola Zaire vaccine (ChAd3-EBO-Z) followed by MVA-EBO-Z. Adult volunteers in the United Kingdom (n = 38) and Senegal (n = 40) were vaccinated and an accelerated 1-week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events.The standard and accelerated heterologous prime-boost regimens were well-tolerated and elicited potent cellular and humoral immunogenicity in the United Kingdom and Senegal, but vaccine-induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb.MVA biomanufactured on an immortalized duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in phase 2 studies, with the 1-week prime-boost interval regimen appearing to be particularly suitable for outbreak control.NCT02451891; NCT02485912. New vaccines are needed for outbreak pathogens and novel technologies to manufacture them. We describe 2 phase 1 clinical trials demonstrating safety and immunogenicity of a novel Ebola vaccine manufactured using an improved method to reduce costs and increase yield. The largest recorded outbreak of Ebola virus disease (EVD) resulted in >11300 deaths in West Africa and highlighted the urgent need for development of an efficacious vaccine . A numbeThe use of different viral vectors, namely a replication-deficient chimpanzee adenovirus followed by a modified vaccinia Ankara (MVA) virus encoding the same glycoprotein (GP) in a heterologous prime-boost regimen is a leading strategy for developing vaccine regimens with higher potency, immediate protection, and better durability. Simian adenovirus vectors are an attractive vaccine platform as the viruses from which they are derived are not known to cause infections in humans and there is consequently a low human seroprevalence of antibodies to the chimpanzee adenovirus 3 (ChAd3) used here and to other simian vectors . ChAd3 h+ T-cell responses is potentially protective against EVD [The induction of both antibodies and CD8inst EVD , 19. ChAinst EVD . Althouginst EVD , 8, 20; inst EVD , 22. In inst EVD . Recent inst EVD , 10. A vHere we evaluate a new Ebola vaccine candidate, MVA-EBO-Z (modified vaccinia Ankara virus vectored Ebola Zaire vaccine), manufactured on an immortalized duck retinal cell line, instead of primary chick embryo fibroblast cells, which have been used to manufacture all previous MVA-vectored vaccines tested in clinical trials to date. We also compared a 1-week prime-boost interval regimen, tailored to outbreak response use, with a 4-week regimen. We conducted a phase 1, first-in-human, open-label clinical trial to assess the safety and immunogenicity of MVA-EBO-Z alone and heterologous prime-boost immunization with ChAd3-EBO-Z followed by MVA-EBO-Z at 2 doses in 40 healthy UK volunteers aged 18–50 years. After initial safety assessment in this trial, we conducted a phase 1 trial to assess the 1-week prime-boost interval in 40 Senegalese adults.ChAd3-EBO-Z consists of a recombinant replication-deficient adenovirus chimpanzee serotype 3 vector expressing wild-type (WT) Ebola GP from the Zaire strain , 7, 10. The Phase 1a study was conducted in healthy adults between the ages of 18 and 50 years at the Centre for Clinical Vaccinology and Tropical Medicine at the University of Oxford and the Wellcome Trust Clinical Research Facility at Imperial College, London, United Kingdom.Subsequently, the phase 1b study was conducted in healthy Senegalese adults aged between 18 and 50 years at the Centre Hospitalier Universitaire le Dantec, Dakar, Senegal. All participants provided written informed consent. Participant flow and study design are summarized in The study protocol and associated documents for the phase 1a trial were reviewed and approved by the UK National Research Ethics Service , the Medicines and Healthcare Products Regulatory Agency (reference 21584/0341/001-0001), and the Oxford University Clinical Trials and Research Governance team, who independently and externally monitored compliance with Good Clinical Practice guidelines. Vaccine use was authorized by the Genetically Modified Organisms Safety Committee of the Oxford University Hospitals National Health Service Trust (reference number GM462.15.82).Ethical approval for the phase 1b study was granted in the United Kingdom by the Oxford Tropical Research Ethics Committee (OxTREC reference number 27-15). Ethical and regulatory approvals for this study were also granted in Senegal by the Senegalese Comité National d’Ethique pour la Recherche en Santé and the Senegalese regulatory authority, the Ministry of Health and Social Action Department of Pharmacy and Laboratories.8 plaque-forming units (PFU) and 1.5 × 108 PFU, respectively. Subsequently, the chief investigator and local safety monitor (LSM) deemed it safe to proceed with vaccinations in groups 2 and 3 after review of the 3 volunteers in group 1a at 72 hours postvaccination. Similarly, the chief investigator and LSM deemed it safe to proceed with vaccinations in group 4 after review of the 3 volunteers in group 1b at 72 hours postvaccination. All vaccinations were administered intramuscularly into the deltoid region of the arm. Most volunteers received both vaccinations in the nondominant arm. Three volunteers (2 in group 2 and 1 in group 3) received their MVA vaccination in the contralateral arm. An independent LSM provided safety oversight. The trial was registered with ClinicalTrials.gov (NCT02451891).The phase 1a study was an open-label observational clinical trial assessing the safety and immunogenicity of MVA-EBO-Z alone and the heterologous prime-boost regimen of ChAd3- EBO-Z followed by MVA-EBO-Z. Volunteers were first enrolled into group 1a and group 1b in a staggered manner to receive vaccination with MVA-EBO-Z alone at a dose of 1 × 10The phase 1b study was a randomized, open-label clinical trial assessing the heterologous prime-boost regimen of ChAd3-EBO-Z followed by MVA-EBO-Z 1 week later, either in the same arm or in the contralateral arm, in healthy Senegalese adults. All vaccinations were administered intramuscularly into the deltoid region of the arm. The trial was registered with ClinicalTrials.gov (NCT02485912). An independent data safety and monitoring board and LSM provided oversight and reviewed preliminary safety data before vaccinations commenced. The LSM also reviewed safety data after the first 5 volunteers had been vaccinated with ChAd3-EBO-Z before the remainder of the volunteers in each group were vaccinated. The trial was monitored by an external organization . Full details regarding the study conduct are provided in the protocols, which can be found in the Supplementary Materials. Details of the safety analysis are also provided in the Supplementary Materials.Antibody responses to vaccination were measured using a standardized enzyme-linked immunosorbent assay against recombinant trimeric Zaire Ebola GP as previously detailed , as wereP values are 2-tailed. All analyses were performed in GraphPad Prism software version 7.These were observational and descriptive studies, and the sample size allowed determination of the magnitude of the outcome measures, especially of serious AEs (SAEs) and severe AEs, rather than aiming to obtain statistical significance for differences between groups. Group data show median with interquartile range (IQR) unless otherwise stated. Two groups were compared using Mann–Whitney analyses. Multiple groups were compared using Kruskal–Wallis analyses with Dunn post test for multiple comparisons. For statistical analyses, α = <.05 was considered significant and all In the phase 1a study, 70 volunteers were screened for eligibility and 40 were enrolled. Baseline demographics are shown in 8 PFU and 1.5 × 108 PFU, respectively. In groups 2, 3, and 4, 34 volunteers received priming vaccination with ChAd3-EBO-Z at a dose of 3.6 × 1010 viral particles. In group 2, 16 volunteers received vaccination with MVA-EBO-Z at a dose of 1 × 108 PFU with a prime-boost interval of 1 week. In each of groups 3 and 4, 8 volunteers were boosted with 1 × 108 PFU and 1.5 × 108 PFU MVA-EBO-Z, respectively 4 weeks after ChAd3-EBO-Z prime.Three volunteers each in group 1a and 1b received MVA-EBO-Z alone at doses of 1 × 10In the phase 1b study, 69 subjects were screened for eligibility and 40 were enrolled. Baseline demographics are shown in 8 PFU did not increase reactogenicity. No fevers or severe AEs were reported in either group.The safety profile of ChAd3-EBO-Z has been described previously , 7 and aP < .0001) and MVA-EBO-Z vaccinations . There was no reported fever or severe AEs, and there was a significantly lower proportion of moderate AEs reported. Solicited local and systemic AEs related to vaccination in the Senegalese study are shown in The reactogenicity profile was significantly milder in the Senegalese compared with the UK cohort, both after the ChAd3-EBO-Z (Unsolicited AEs in the 28 days following vaccination in the UK study were predominantly mild in nature and resolved spontaneously  and 4. TP = .0313). Responses were compared across groups at M+28 (P = .0048). There were no significant differences between boosted groups at this time point (P = .757). Titers induced by ChAd3 and MVA-EBO-Z were comparable to those previously reported for ChAd3 and MVA-BN Filo at the same time point [P = .813). Antibody responses to EBOV GP were compared between matched groups  in the United Kingdom and in Senegal split by ipsilateral or contralateral vaccination . There were no significant differences between the ipsilateral and contralateral groups within the Senegal cohort at either of these time points, or at any other time point measured.Individual antibody responses in the UK cohort peaked at either 7 or 28 days post-MVA, referred to hereafter as M+7 or M+28 . Signifi at M+28 . Titers cination  and 2D. P = .0014). ELISpot responses in prime-boost groups were still significantly higher than the MVA-only group at 3 and 6 months after MVA . Only 3 volunteers across all UK groups received vaccines in a contralateral regimen; all others received vaccines in an ipsilateral regimen. Cross-reactivity with GP peptides from the Sudan Ebola virus (SUDV) was observed at M+7. Homology between EBOV and SUDV GPs is 56% at the amino acid level [6 PBMCs, respectively, Mann–Whitney test, P < .0001). However, responses to the heterologous GPs were strongly correlated .The IFN-γ ELISpot responses in the UK vaccinees peaked 7 days after MVA vaccination in all groups and were significantly higher than the MVA-only group with median values of >1000 spot-forming cells (SFCs) per million peripheral blood mononuclear cells (PBMCs) in primed groups compared with 78 in the nonprimed group  was compared across all UK groups , while the ipsilateral group had median responses  that were not significantly different to the United Kingdom . CD8+ frequencies were similarly undetectable in the contralateral group of the Senegal cohort (0.005%), while the ipsilateral group had median responses  that were not significantly different to the United Kingdom . For both the CD4+ and CD8+ subsets, cytokine responses in the Senegal contralateral group were significantly lower than both other groups . The frequency of CD107a+CD8+ T cells was also comparable in the United Kingdom and ipsilateral group of the Senegal cohort, whereas no CD107a expression was detected in the contralateral group  and only 9 of 40 participants had a titer >200. Anti-ChAd3 neutralizing antibody titer at baseline did not correlate with any measure of postvaccination immunogenicity .8 PFU did not increase the reactogenicity compared to 1 × 108 PFU, and this vaccine showed significantly reduced reactogenicity in African adults.Monovalent MVA-EBO-Z, the first to be manufactured in an immortalized cell line and administered to humans, was safe and well tolerated in phase 1 trials in UK and West African adults. Adverse events after ChAd3-EBO-Z were predominantly mild in nature, in keeping with previous studies , 7. MVA-+ T cells) may be beneficial for long-term protection against EVD [MVA-EBO-Z given as a boost following a ChAd3-EBO-Z vaccine elicited both humoral and cell-mediated immune responses, comparable to a multivalent MVA-BN Filo expressing both Zaire and Sudan Ebola virus GPs . T-cell inst EVD . In thisinst EVD .Humoral, but not cellular, immunogenicity postimmunization was significantly reduced in Senegalese volunteers compared to the UK cohort. Reduced antibody responses to vaccination in developing countries have been observed previously, although most often in children and infants, and this phenomenon is likely multifactorial with contributing factors including an increased burden of pathogen exposure, genetic differences, microflora composition, and nutritional status . DespiteThere were no significant differences in antibody or T-cell responses measured by ELISpot between the ipsilateral and contralateral regimens. Significant differences were apparent in the cytokine responses measured by intracellular cytokine staining, with the ipsilateral regimen inducing significantly lower frequencies of antigen-specific cytokine-secreting T cells and a distinct cytokine profile. This is an intriguing observation, perhaps dependent on which lymph nodes the boosting vector drains to, and which clearly warrants further investigation in future vaccine trials in both UK and African populations.In conclusion, our study shows that the heterologous prime-boost immunization with ChAd3-EBO-Z followed by MVA-EBO-Z was safe and immunogenic and supports further testing in populations at risk of EVD in phase 2 and phase 3 studies. This was also the first trial of any MVA biomanufactured on an immortalized cell line with capacity for very large-scale manufacturing, high production yields, and lower cost of goods compared to other MVA production technologies. The AE profile was very similar to that of MVA-vectored vaccines manufactured in primary chicken embryo cells, supporting the use of this vaccine production method for other MVA-vectored vaccines.The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.Supplementary materials are available at Supplementary Figure 1Click here for additional data file.Supplementary Figure 2Click here for additional data file.Supplementary Table 1Click here for additional data file.Supplementary Table 2Click here for additional data file.Supplementary Table 3Click here for additional data file.Supplementary Table 4Click here for additional data file.Supplementary Table 5Click here for additional data file.Supplementary TextClick here for additional data file.


Clinical Practice Guidelines (CPGs) should follow an adequate methodology using an evidence-based approach in order to provide reliable recommendations. However, little is known regarding the quality of CPGs for Depression, which precludes its adequate use by stakeholders and mental health professionals. Thus, the aim of this study was to conduct a scoping review to describe the characteristics and quality of CPGs for Depression in adults.We searched CPGs for Depression in adults in eighteen databases. We included those that were published in English or Spanish between January 2014 and May 2018 and were based on systematic reviews of the evidence. Two independent authors extracted the characteristics, type and number of recommendations, and quality  of each included CPG.We included eleven CPGs, of which 9/11 did not include the participation of patients in the development of the CPG, 4/11 CPGs had a score ≥ 70% in the overall evaluation of AGREE-II, and 3/11 CPGs had a score ≥ 70% in its third domain (rigor of development). In addition, only 5/11 CPGs shared their search strategy, while only 4/11 listed the selected studies they used to reach recommendations, and 7/11 CPGs did not clearly state which methodology they used to translate evidence into a recommendation.Most of evaluated CPGs did not take into account the patient’s viewpoints, achieved a low score in the rigor of development domain, and did not clearly state the process used to reach the recommendations. Stakeholders, CPCGs developers, and CPGs users should take this into account when choosing CPGs, and interpreting and putting into practice their issued recommendations.The online version of this article (10.1186/s12888-019-2057-z) contains supplementary material, which is available to authorized users. Depression is recognized as an important public health issue. By the year 2015 it affected around 4.4% of the population [CPGs are classically defined as a set of “systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances” . CPGs caIt is of great importance that stakeholders and mental health professionals are aware of the characteristics and quality of currently used CPGs for depression. The quality of the CPGs should be taken into account when interpreting and putting in practice recommendations issued in these CPGs. However, to our knowledge, only one study has assessed the quality of CPGs for depression and anxiety in children and youth , and we We performed a scoping review of CPGs for depression in adults published in the last 5 years and evaluated characteristics regarding scope, methods used to reach recommendations, and grading the strength of recommendations. We also assessed the quality of each CPG. The PRISMA guidelines for scoping reviews (PRISMA-ScR) were used to secure adequate reporting and to guarantee the replicability of the study .A scoping review is “a form of knowledge synthesis, which incorporate a range of study designs to comprehensively summarize and synthesize evidence with the aim of informing practice, programs, and policy and providing direction to future research priorities” . It is sWe included all CPGs, defined as a document that aimed to state recommendations, that fulfilled the following criteria: assessed screening, diagnosis or management of depression in adults; were published or totally/partially updated in the last 5 years (January 2014- May 2018); full-text were available in English or Spanish; and used systematic reviews of the evidence to guide their recommendations. We decided to include only CPGs based on systematic reviews, based on the current CPG definition which states that they should be designed based on a systematic review of the evidence .We excluded those CPGs that assessed specific types of depression such as bipolar or psychotic depression, or specific types of populations such as depression in patients with cancer or in older people after a stroke.We performed a comprehensive search in eighteen databases. Our search strategy included terms related to depression and guidelines/practice guidelines. Searchers were performed by two independent researchers (JHZT and DVZ), and the last update was run in June 2018  evaluated if the CPGs met the eligibility criteria for inclusion. When there were discrepancies, a consensus was reached after debating them among all the authors.The following characteristics were extracted from the CPGs: authors; year of publication; country; involvement of patients or their representatives in the CPG development process; methodology used to reach recommendations; methodology used for grading the strength of recommendations; usage of minimally important difference (MID) when evaluating the effect of interventions; and the number of recommendations and good clinical practice (GCP).We defined a recommendation as “all the statements in favor or against an intervention based on systematic reviews of the evidence, which typically include a formal assessment of the benefits and drawbacks of available treatment options” . All theWe defined MID as a measure of the “smallest change in patient-reported outcomes of interest that patients perceive as important” .To assess the quality of CPGs we used the Appraisal of Guidelines Research and Evaluation II (AGREE-II), which has 23 items distributed in six domains . Each guideline was rated by two researchers. When a difference in two or more points in each item was found, the item was discussed to get to a consensus. Otherwise, we used the mean of the two raters for each item. Lastly, we followed the AGREE-II Instrument guideline to calculate the scores for each domain .We considered that when a CPG had a total score ≥ 70% it had adequate quality, we also used the same cutoff for each of the domains of the AGREE-II Instrument. This cutoff point was taken from a previous study that evaluated the quality of depression CPGs in children . LikewisWe found twenty CPG for depression in adults published or updated between 2014 and 2018, of which thirteen performed systematic reviews to formulate their recommendations. Two CPGs were excluded from our study given that they were not available in full-text , 17, . Regarding how the development group reached the recommendations, 3/11 did not clearly state how recommendations were reached , 4/11 used expert consensus but did not specify the criteria evaluated , and 4/11 used a well-specified methodology . All included guidelines specified the system they used for grading the strength of recommendations , 5/11 on diagnosis , 8/11 on pharmacological treatment , 9/11 on non-pharmacological treatments  Table .Table 2TTo assess the quality of guidelines, we used the AGREE II instrument. The overall assessment score ranged from 53 to 87% (mean: 70.8%), and 4/11 guidelines had an overall assessment score ≥ 70% . Regarding the third domain, scores ranged from 45 to 88% (mean: 62.9%), and 3/11 guidelines had a score ≥ 70%  , 4/11 CPGs presented the included studies , and 6/11 CPGs mentioned the risk of bias assessment as part of their methodology  Table .This study explores the characteristics, scope, and quality of CPGs for depression in adults that based their recommendations on systematic reviews and were published between January 2014 and May 2018. We included eleven CPGs from seven countries on four continents, from which two reported the patient involvement in the design or validation of the CPGs, six provided recommendations on screening, five on diagnosis, eight on pharmacological treatment, nine on psychological treatment, nine on other non-pharmacological treatments. Regarding the quality assessment, 4/11 CPGs reached a score ≥ 70% in the overall assessment of the AGREE-II instrument, and 3/11 CPGs reached a score ≥ 70% in the rigor of development domain. In addition, only 5/11 CPGs shared their search strategy, while only 4/11 listed the selected studies they used to reach recommendations, and 7/11 CPGs did not clearly state which methodology they used to translate evidence into a recommendation.The involvement of patients or their representatives in the development of CPGs is considered important as it is supposed to complement scientific evidence to reach more acceptable and implementable recommendations . Thus, mHowever, we found that 2/11 CPGs reported that patients had participated in the design or validation of the CPGs. This low patient involvement is similar to that found in other studies. One study that evaluated 62 Dutch guidelines assessed patients’ participation in the development process through three items , and found that only 1/62 CPGs fulfilled satisfactorily these items . The CPGWhen focusing on the third domain of the AGREE II Instrument (rigor of development), few CPGs (3/11 = 27%) reached a score ≥ 70%. This is similar to a systematic review of CPGs for depression in children and youth that found that only 4/17 = 17.6% achieved a score ≥ 70% in this domain . Other sOur results indicate that few of the CPGs achieve an adequate methodological quality, which could lead to recommendations that are not based on the best available evidence. This situation could be due to the fact that developing a high-quality CPG demands many financial resources, time, highly specialized personnel, and health system support –41. In aTo state a recommendation, two basic steps are needed: the selection of evidence and the methodology used to translate evidence into a recommendation . We evalRegarding the selection of evidence, only 5/11 CPGs shared their search strategy, while only 4/11 listed the selected studies they used to reach recommendations. Not sharing these information prevents the readers from adequately evaluating if there was any bias in the selection of evidence used to guide the recommendations, and prevents the replication and corroboration of the searches performed.Regarding the methodology used to translate evidence into a recommendation, 7/11 CPGs did not clearly state the methodology used. A clearly defined methodology is necessary to understand what criteria were used and how the developing group judged each criterion to reach a recommendation. This allows users to understand how subjectivity and possible competing interest of the guideline developing group may have influenced on its recommendations, and help decide if recommendations can or should be implemented in their own settings . InconsiOur study is not free from limitations. We only collected guidelines published in English or Spanish, so our findings could not be representative of CPGs published in other languages. The CGPs quality was assessed using the AGREE-II instrument, based on the reporting of the CPGs, so guidelines with inadequate reporting could be classified as deficient, despite their actual quality. Lastly, there are not validated cut-off points for the AGREE-II instrument so the discrimination between CPGs with adequate and inadequate quality could be inaccurate.However, to our knowledge, this is the first study that has evaluated the characteristics and quality of CPGs for depression in adults. This evaluation has some important strengths: we used a systematic search strategy involving eighteen databases to find available CPGs for depression in adults, we used the AGREE-II instrument that provides a standard methodology to critically appraise the quality of CPGs, and we performed independent appraisals by two researchers.We found eleven CPGs for depression in adults that used systematic reviews to guide their recommendations. Only two CGPs reported patient involvement. Regarding the quality of these CPGs, only 4/11 CPGs reached a score ≥ 70% in the overall assessment of the AGREE-II instrument, and 3/11 CPGs reached a score ≥ 70% in the rigor of development domain. In addition, only 5/11 CPGs shared their search strategy, while only 4/11 listed the selected studies they used to reach recommendations, and 7/11 CPGs did not clearly state which methodology they used to translate evidence into a recommendation. These findings should be taken into account by stakeholders, CPGs developers, and CPGs users; when choosing CPGs, and interpreting and putting into practice their issued recommendations from CPGs for depression in adults.Additional file 1:Search strategies and results for CPGs for depression. We present the list of databases or CPG repositories, the search strategy and the results from the searches. (DOCX 14 kb)Additional file 2:Flowchart of selection of CPGs. We present the flowchart of how we selected the CPGs that were included in our study. (DOCX 21 kb)


Angina pectoris with a normal coronary angiogram, termed microvascular angina (MVA), is an important clinical entity; however, its causes remain unclear. Autonomic dysfunction is one of the possible causes. Therefore, this study aimed to investigate parasympathetic dysfunction assessed by heart rate recovery (HRR) and increased sympathetic activity assessed by exaggerated blood pressure (BP) response (EBPR) to exercise in MVA.The study participants were consecutive patients with anginal chest pain who underwent both coronary angiography with an ergonovine provocation test and a treadmill exercise test between January 2008 and February 2015. Patients with significant coronary artery disease (coronary artery stenosis ≥50%) or significant coronary artery spasm (≥90%) were excluded. Based on the treadmill exercise test, patients were categorized into the microvascular angina (MVA) group (patients with uniform ST depression ≥1 mm) and the control group. HRR was defined as peak heart rate minus heart rate after a 1 min recovery; blunted HRR was defined as ≤12 beats/min. EBPR was defined as a peak exercise systolic BP ≥210 mmHg in men and ≥ 190 mmHg in women. These parameters were compared between patients with MVA and the controls.p <  0.001) compared with the control group. Moreover, the proportion of EBPR was significantly higher in the MVA group than in the control group . Multivariable logistic regression analysis showed that age (odds ratio (OR), 1.045; 95% confidence interval (CI), 1.026–1.064; p <  0.001), HRR 1 min , and EBPR  were independently associated with MVA.Among the 970 enrolled patients , 191 (20.0%) were diagnosed with MVA. In baseline characteristics, the MVA group had older participants, female predominance, and a higher prevalence of hypertension. The MVA group showed significantly lower HRR 1 min (24.9 ± 15.9 vs. 31.3 ± 22.7, HRR and EBPR were associated with MVA, which suggests a link between MVA and autonomic dysregulation. Microvascular angina (MVA) is a clinical condition characterized by exertional angina, exercise-induced myocardial ischemia, and a normal coronary angiogram . DespiteAn exercise treadmill test, easy to apply in clinical practice, can detect the presence of myocardial ischemia and changes in heart rate and blood pressure (BP) during exercise. Heart rate recovery (HRR) is a simple noninvasive measurement related to autonomic nervous system dysfunction that indicates impaired parasympathetic reactivation –9. PreviBlood pressure response during graded exercise is a useful parameter to predict hypertension,  and is aTherefore, this study aimed to investigate autonomic dysfunction as assessed by HRR and increased sympathetic activity as assessed by EBPR in MVA.This is cross-sectional, observational, single-center cohort study. We retrospectively reviewed a total of 1393 patients without significant coronary artery disease (coronary artery stenosis ≥50%) who underwent both CAG with ergonovin provocation test and treadmill test during between January 2007 and August 2015. We excluded the 300 patients with significant coronary spasm (≥90%) on ergonovin provocation test and 29 patients with other exclusion criteria as follows; any systemic disease such as significant liver disease, neurologic disorder, or malignant disease; secondary hypertension; history of heart failure; valvular heart disease; atrial fibrillation. In enrolled 998 patients, 28 patients were excluded due to outlier value in statistical analysis. MVA was defined as follows: (1) typical stable angina induced by effort, (2) a flat or downsloping depression of the ST segment > 0.1 mV below baseline and lasting longer than 0.08 s during the treadmill test, and (3) normal or near normal coronary arteries on coronary angiogram ) . DemograStandard 2-dimensional echocardiography was performed on all subjects lying in the left lateral decubitus position using a 3.5-MHz transducer , and the echocardiography examiners were blinded to patient information. Measurements of the diameter of the left ventricle (LV) cavity, the thickness of the interventricular septum and posterior wall, and the LV mass index (LVMI) were performed according to criteria outlined by the American Society of Echocardiography . Pulsed All patients underwent symptom-limited exercise stress testing  according to the protocol by Bruce et al. . BP was After diagnostic coronary angiography, incremental doses of ergonovine were injected intravenously 50, 100, 200 μg) over 10 s 0 μg over. Intracop-value < 0.05 was considered statistically significant.Statistical analyses were performed using the commercially available computer program SPSS 18.0 for Windows . Data are presented as mean ± standard deviation for continuous variables and as percentages (%) if the data are categorical. The Mann–Whitney U test was used for continuous variables, and the Chi-square test was used for categorical data. The normality of data was tested using the Kolmogorov–Smirnov test. To identify independent contributors for MVA, univariate and multivariate logistic regression analyses were performed. A A total of 970 patients were enrolled; the mean age was 53.1 years, and 59.0% were female. Among them, 191 were diagnosed with MVA, documented by no significant coronary stenosis with a positive exercise test, and 779 patients with a negative exercise test were compared as controls. In baseline characteristics, the MVA group was older, had a higher proportion of female participants, and had higher prevalence of hypertension and dyslipidemia. No significant differences were observed in BMI, office systolic/diastolic BP, and use of renin-angiotensin system blocker, beta blockers, calcium channel blockers, and statins Table . In echop <  0.001), and HRR 2 min  compared with the control group. Moreover, no differences were observed in resting systolic and diastolic BP between groups; however, the proportion of EBPR was significantly higher in the MVA group compared to the control group . Multivariable logistic regression analysis showed that age (odds ratio (OR), 1.045; 95% confidence interval (CI), 1.026–1.064; p <  0.001), HRR 1 min , and EBPR  were independently associated with MVA (Table Table The major findings obtained from this study were as follows: (1) HRR for both 1 and 2 min was lower in patients with MVA, (2) the EBPR proportion was higher in the MVA group, and (3) HRR for 1 min and EBPR were independent predictors of MVA. These findings suggest a possible link between MVA and autonomic dysregulation.Although the mechanism of MVA remains unclear and the terminology is confusing, studies have shown association with autonomic dysfunction. Lanza et al. demonstrated that metaiodobenzylguanidine (MIBI) uptake score is higher in patients with syndrome X, and impairment in cardiac MIBI uptake is associated with a reduction in HR variability indices . ParasymSympathetic activity is also an important factor of autonomic function, and BP response during exercise is an especially useful parameter. We observed that the MVA group had a higher prevalence of EBPR, suggesting that MVA might have impaired the vascular response. Vascular resistance is involved with multiple factors such as atherosclerosis, vessel spasms, and endothelial dysfunction. BP reflect the change in cardiac output during exercise or recovery can lead to changes in systolic BP . CardiovCoronary spasm is one of the major components of chest pain in patients without coronary artery stenosis and it accounts for a large number of unexplained case. Vagal withdrawal is often a component of the mechanisms leading to spontaneous coronary vasospasm . DecreasThis study has several important limitations. First, in baseline characteristics, the participants in the MVA group were older, more likely to be female, and had higher prevalence of hypertension and dyslipidemia. In particular, the higher prevalence of hypertension and trend toward higher use of anti-hypertensive medications may directly affect the BP response during exercise and change of HR. This is a major limitation of our study. Second, this was a retrospective study. Third, the definition of MVA was insufficient, and there was no evidence to suggest ischemia based on other imaging studies such as cardiac MRI or myocardial SPECT. Fourth, although we excluded patients with significant coronary spasm, we could not exclude the effect of microvascular spasms. Fifth, because this study was performed at a single tertiary care center, it is possible that biases existed with respect to patient referral and population sampling. However, we believe the results of this study show a valuable trend in MVA, especially regarding the use of HRR to evaluate this condition.Patients with MVA showed reduced HRR and greater EBPR compared with the control group, which suggest that there is a link between MVA and autonomic dysregulation.


We report a case of torsion of a wandering spleen in an 18-year-old male patient who presented with acute abdominal pain and left lower quadrant mass. The patient was initially misdiagnosed at another institution. The patient came to our hospital for further investigation. Contrast-enhanced ultrasound was performed and showed a solid hypoechoic avascular mass, which was all that remained of the spleen, located under the left kidney. Based on the ultrasound findings, CT scan and MRI of the abdomen were performed to confirm the suspicion of torsion of a wandering spleen. To the best of our knowledge, there are no case reports describing the use of contrast-enhanced ultrasound for diagnosing torsion of a wandering spleen. An 18-year-old male came to our hospital for further investigation of findings seen on ultrasound and CT scan performed at another institution because of a 12-h history of left flank bulge, nausea and slight left lower quadrant pain. The patient presented to the emergency department because of suspected differential diagnosis of vesical diverticula, mesenteric cyst or lymphangioma inferred from the finding of a very low-attenuation mass on the CT scan.3 μl-1 (150.0–450.0) and increased white blood cell count of 15.48 × 103 μl-1 (4.0–11.0).Physical examination revealed a firm and tender left lower quadrant mass. The patient denied having fever, dysuria or constipation. Laboratory tests revealed decreased platelet count of 135.00 × 10T1 and hyperintense T2 weighted images of the spleen without enhancement, which was consistent with infarction in the whole parenchyma  in which a long pedicle allows the spleen to migrate from the normal splenocolic angle to the lower abdominal cavity. The spleen is held in position by three ligaments—gastrosplenic, splenorenal and phrenicocolic.Generally, patients with wandering spleen are asymptomatic, but some patients may present with a palpable abdominal mass. Torsion is the main complication, which may lead to ischaemia and infarction, or even splenic rupture; thus prompt detection would benefit patients with this condition.2 Usually they are hypoechoic and wedge shaped, but they may be isoechoic, especially if the torsion is recent. Colour Doppler and power Doppler show areas of signal absence, which suggests perfusion defects, but Doppler ultrasound may be suboptimal in some patients; CEUS detects the smallest microvessels and obtains a perfusion map of the organs. CEUS has been shown to be a safe3 and appropriate additional tool for depicting perfusion of the splenic parenchyma and detecting repletion vascular defects.6 The microbubble contrast increases the sensitivity and specificity of the exploration, improving the capacity to diagnose splenic infarcts.6 Typically, infarcts are seen as non-enhanced areas, often as wedge shaped with the wide base orientated to the spleen surface. The border is usually well defined, although there may be a fuzzy border owing to partially ischaemic peripheral areas (watershed areas). If the infarct is complete, there is a complete absence of spleen enhancement. Often, a peripheral rim enhancement is seen on CEUS, as seen around infarcted organs, for example, the kidney.Clinical diagnosis is difficult owing to non-specific symptoms ranging from being asymptomatic to abdominal pain. Diagnosis is based on imaging findings; various imaging modalities can be used. In most cases, ultrasound is usually the first imaging technique used for making a diagnosis. The normal spleen parenchyma is very homogeneous and is more echogenic than the liver and left kidney. A wandering spleen is not seen in the upper abdomen, but is visible in the left lower quadrant or pelvis on radiological evaluation. Infarcts may be difficult to visualize on greyscale ultrasound owing to their variable appearance, depending on the timing and grade of torsion.7 Lack of parenchymal and rim enhancement of the splenic capsule is a typical finding of post-contrast imaging.CT scan and MRI confirm the suspicion of torsion of a wandering spleen, showing its ectopic position. Typically, the splenic hilum appears twisted; the whirled appearance is a very specific sign of torsion of the splenic pedicle.9 Depending on the grade of pedicle torsion, treatment can be detorsion and splenopexy, or splenectomy.10 Laparoscopic splenopexy is preferred if possible, especially in patients ≤ 30 years of age, owing to eventual infectious complications. Splenectomy is the treatment of choice in case of infarction. To the best of our knowledge, there are no case reports describing the use of CEUS in diagnosing torsion of a wandering spleen.Pre-operative diagnosis is based on radiological findings, but these are not always unequivocal; for instance, our case was initially misdiagnosed. Hence awareness of this entity allows early diagnosis and appropriate management.Wandering spleen is a rare entity; its main complication is torsion, which can be challenging to diagnose owing to non-specific symptoms. The first imaging technique for making diagnosis is ultrasound, additional CEUSincreases sensitivity to allow diagnosis of vascular patency and parenchymal viability. Recognition of wandering spleen and its complications is of utmost importance for deciding on proper surgical treatment options.Wandering spleen torsion is a rare cause of acute abdomen with significant morbidity and mortality if misdiagnosed.CEUS is a rapid and sensitive technique for diagnosing infarction with certainty and has an impact on patient management.Treatment options are splenopexy or splenectomy, depending on the grade of torsion of the pedicle.Written informed consent for the case to be published  was obtained from the patient.


Personality disorders (PD) are common and burdensome mental disorders. The treatment of individuals with PD represents one of the more challenging areas in the field of mental health and health care providers need evidence-based recommendations to best support patients with PDs. Clinical guidelines serve this purpose and are formulated by expert consensus and/or systematic reviews of the current evidence. In this review, European guidelines for the treatment of PDs are summarized and evaluated. To date, eight countries in Europe have developed and published guidelines that differ in quality with regard to recency and completeness, transparency of methods, combination of expert knowledge with empirical data, and patient/service user involvement. Five of the guidelines are about Borderline personality disorder (BPD), one is about antisocial personality disorder and three concern PD in general. After evaluating the methodological quality of the nine European guidelines from eight countries, results in the domains of diagnosis, psychotherapy and pharmacological treatment of PD are discussed. Our comparison of guidelines reveals important contradictions between recommendations in relation to diagnosis, length and setting of treatment, as well as the use of pharmacological treatment. All the guidelines recommend psychotherapy as the treatment of first choice. Future guidelines should rigorously follow internationally accepted methodology and should more systematically include the views of patients and users. Individuals with PD often suffer extreme distress and social impairment. Compared to those without a PD, they lead shorter lives, and their quality of life is often significantly reduced , 2. Treawww.gradeworkinggroup.org) provides guidance on how to link the body of evidence with the degree of strength of the recommendation . GRADE emphasizes the importance of phrasing recommendations using active language and of avoiding ambiguous or unclear wording, such as ‘if clinically appropriate’ or ‘if necessary’ [Guidelines vary in methodological approach and quality, and most guidelines differentiate between evidence and practice-based recommendations. Guideline quality can be assessed and quantified using the AGREE system , where a guideline is assessed across six domains . See Tabcessary’ . Guidelicessary’ . Thus, iIn this paper we provide an overview of the European guidelines that we are aware of and highlight key recommendations for improvement. For each guideline we considered the AGREE domains and especially the rigour in the development and applicability of the guidelines. In reviewing the guidelines, ultimately our aim was to identify areas of convergence as well as divergence with a view to assisting the refinement of future iterations of guidelines.We first provide a general overview of identified guidelines based on geographical location and with emphasis on organizational background, rigour of development and perceived applicability.Clinical guidelines for personality disorders in 2006, which were recently updated (2017) [The earliest European guidelines that we were able to identify derived from The Swedish Psychiatric Society. The Society developed d (2017) .The current, revised clinical guidelines were developed based on existing research evidence. They do not include a method section outlining a systematic evaluation of the empirical support underlying different recommendations, but rather rely heavily on guidelines from other countries, e.g., The National Institute for Health and Care Excellence  and the the goal of the Swedish guidelines appears to have been to develop guidelines with a ‘clinical foundation’, focusing on the daily work with patients and their families. The guideline takes into account a range of clinical issues regarding the evaluation and treatment of patients with PDs at different levels of healthcare. It discusses dynamics and requirements at an organizational level as well as the need for interventions and care at the community level, including work support.The Finnish Current Care Guidelines for BPD were developed by the Finnish Medical Society Duodecim in cooperation with the Finnish Psychiatric Association in 2015 . This isThe Finnish Medical Society Duodecim is one of the founding members of the Guidelines International Network (G-I-N), so the BPD guideline has been assessed according to the G-I-N guideline standards . Workinghttp://www.kaypahoito.fi/web/kh/suositukset/suositus?id=hoi50064), and patient versions are available for use by the public.The guidelines are intended to be used by physicians and healthcare professionals, and therefore focus on questions relating to diagnosis, psychotherapy in general and are somewhat more specific with regard to medication. They are made publicly available , and include an English quick-guide translation.The working group consisted of members from several professional associations and of method consultants from the National Health Authority. In addition, the working group was overseen by a reference group consisting of experts, consumers and individuals in senior management positions. The GRADE system was used in developing the recommendations. The working process, methods and analyses behind the recommendations are publicly available on the National Health Authority website  has recently sent an inquiry to the Norwegian health authorities recommending the development of national clinical guidelines to stimulate the establishment of treatment programmes, sound evaluation practices and adequate referral criteria to various levels of the healthcare system.In Germany, the AWMF  is responsible for the development of guidelines by the scientific medical societies.Treatment guidelines for PD were first developed in 2009 by a committee of experts as delegated by a variety of professional societies and associations . A systeDue to the lack of efficacy studies, with the exception of BPD, recommendations in the 2009 guideline for the treatment of PD subtypes are based primarily on clinical expertise or published expert opinions. This is a major limitation as guidelines based on consensus are likely to have limited impact.In the Netherlands, the first Multidisciplinary Guideline for PD was published in 2008 .The guideline was developed by an expert workgroup and is based on the results of scientific research critically and systematically appraised according to the level of evidence and completed with professional expertise. However, the connection between evidence and strength of recommendations is not fully transparent and many recommendations were based on very low levels of evidence.The guideline was developed to improve the treatment of individuals with PDs. Questions concerning the role of the patient and the family, diagnosis, therapeutic interventions, nursing care, vocational therapies, pharmacological interventions, co-morbidity, cost effectiveness and organization of care, guided the discussions of a Working Group that was responsible for the result. The major limitation of the guideline concerned implementation, especially in regard to systematically considering barriers and monitoring progress. Furthermore, the guideline has been criticized for being too focused on patients receiving specialist psychotherapy and neglectful of other types of care e.g. psychiatric management and vocational therapy. This perspective has now been covered in a standardized procedure of care for patients with BPD published in 2017 . This Sthttps://www.nice.org.uk/). NICE commissions the National Collaborating Centre for Mental Health to set up working groups to develop guidelines. In 2009, the Guidelines on BPD [In the United Kingdom, National Institute of Health Care and Excellence (NICE) is an independent public body that provides national guidance and advice to improve health and social care in the United Kingdom  [In Switzerland, the Swiss Association for Psychiatry and Psychotherapy set up a task force consisting of personality experts with the aim of coming up with practical and relevant clinical treatment recommendations for BPD rather than a new guideline. The task force published recommendations in 2018 (utiques) . The recThe guideline has several strengths in addressing important clinical questions and in considering national particularities but may be criticised in terms of a lack of transparency in using multiple levels of evidence without defining how this is reflected in the strength of recommendations.Recommendations were based on a consensus view giving weight to scientific evidence, good clinical practice and national applicability. However, a lack of diverse representation in the guideline development group may have limited the utility of these recommendations.In Spain, a clinical practice guideline for BPD was developed in 2011 by the Catalan Agency for Health Information, Assessment and Quality.Methodologically, the guideline was developed using the system SIGN (Scottish Intercollegiate Guidelines Network) . The guiThe guideline is oriented towards specialists in mental health who are responsible for the treatment and care of individuals with BPD, including: psychiatrists, clinical psychologists, nurses, social workers, educators, occupational therapists, and other professionals of the NHS. Clinical areas included in the guideline are: prevention, diagnosis and interventions in both psychological and psycho-social domains as well as in pharmacological treatment, organization of services and programs for primary health care services, community care services, hospitalization services, partial hospitalization services / day hospital, community rehabilitation services, continuation of care program, and care itinerary. Issues pertaining to applicability and implementation were, similarly to other guidelines, only addressed sparsely.In evaluating the different guidelines, we focused on three main areas: diagnosis, psychological treatment and pharmacological treatment. These areas were chosen because recommendations in diagnosis and general treatment should be independent of national health systems and thus be generalizable to the whole of Europe. It is clear that there are both similarities and discrepancies across guidelines.Regarding diagnoses  and long-term treatments, while the British guidelines specifically warn against the use of psychotherapy treatments lasting less than 3 months. Also, few guidelines mention specific theoretical approaches, such as Mentalization-Based Therapy (MBT), Dialectical Behaviour Therapy (DBT), Transference-focused Psychotherapy (TFP), or Schema Therapy. One noteworthy exception, however, is the German guideline, which specifically state that DBT has better empirical evidence than other types of specialized psychotherapy for BPD. However, in a recent meta-analysis it was concluded that both DBT and psychodynamic approaches  are effective for BPD symptoms .Finally, recommendations on pharmacological treatment are in overall agreement that, based on sparse trial evidence, medication should not be considered the primary intervention for PD, but should be used mainly for treating comorbid disorders and in some cases used briefly during times of crisis . This would mean that guideline authors should adhere to harmonised standards for reporting their recommendations in a complete and transparent way. Unfortunately, currently, we are far from such practices. Although the number of RCTs has considerably increased since the development of the first BPD Guideline [Although national variations in the context of mental health service delivery and varying needs of the populations could justify some variation between national guidelines, the differences we have identified are probably due to, to a large extent, the lack of methodological rigour with which guidelines have been developed along with the paucity of evidence for many of the clinical questions addressed by the guidelines. Since guidelines should base their recommendations on an evidence-based paradigm, and since their strongest recommendations stem from randomized controlled trials, it would be reasonable to expect guideline authors to adopt the same strict practices required when reporting such trials   a more systematic approach of capturing the views and values of patients and carers is needed in the process of developing new guidelines; this will help make the guidelines more clinically relevant and have greater utility of clinicians and patients alike, b) since guidelines have so far focused almost exclusively on BPD and guidelines for other PDs are either outdated or missing completely, there is a strong need for future guidelines to include these other PDs, c) future guidelines need to have a stronger focus on how their recommendations will be audited and brought into practice and, finally d) the issue of severity is generally neglected in existing guidelines, hence there is a need for future guidelines to take this dimension into consideration and align with the forthcoming ICD-11. Collaboration between researchers working across Europe is needed to speed up this important development work and, in this respect, the ESSPD provides a helpful platform for dialogue and development on this topic and will support initiatives directly aimed at strengthening future collaboration on PD guidelines across Europe.