Individuals with Friedreich ataxia (FRDA) can find it difficult to access specialized clinical care. To facilitate best practice in delivering healthcare for FRDA, clinical management guidelines (CMGs) were developed in 2014. However, the lack of high-certainty evidence and the inadequacy of accepted metrics to measure health status continues to present challenges in FRDA and other rare diseases. To overcome these challenges, the Grading of Recommendations Assessment and Evaluation (GRADE) framework for rare diseases developed by the RARE-Bestpractices Working Group was adopted to update the clinical guidelines for FRDA. This approach incorporates additional strategies to the GRADE framework to support the strength of recommendations, such as review of literature in similar conditions, the systematic collection of expert opinion and patient perceptions, and use of natural history data.A panel representing international clinical experts, stakeholders and consumer groups provided oversight to guideline development within the GRADE framework. Invited expert authors generated the Patient, Intervention, Comparison, Outcome (PICO) questions to guide the literature search (2014 to June 2020). Evidence profiles in tandem with feedback from individuals living with FRDA, natural history registry data and expert clinical observations contributed to the final recommendations. Authors also developed best practice statements for clinical care points that were considered self-evident or were not amenable to the GRADE process.Seventy clinical experts contributed to fifteen topic-specific chapters with clinical recommendations and/or best practice statements. New topics since 2014 include emergency medicine, digital and assistive technologies and a stand-alone section on mental health. Evidence was evaluated according to GRADE criteria and 130 new recommendations and 95 best practice statements were generated.Evidence-based CMGs are required to ensure the best clinical care for people with FRDA. Adopting the GRADE rare-disease framework enabled the development of higher quality CMGs for FRDA and allows individual topics to be updated as new evidence emerges. While the primary goal of these guidelines is better outcomes for people living with FRDA, the process of developing the guidelines may also help inform the development of clinical guidelines in other rare diseases.The online version contains supplementary material available at 10.1186/s13023-022-02568-3. Friedreich ataxia (FRDA) is a multisystem autosomal recessive disease affecting approximately 1 in 29,000 individuals with Caucasian ancestry . The onsDespite significant progress in the search for disease modifying agents, the chronic, progressive course of FRDA cannot yet be significantly slowed. Disease progression continues to have a profound impact on the health and well-being of people with FRDA. Given the rarity of the condition, individuals with FRDA often find it difficult to access experienced specialist multi-disciplinary care for long-term, evidence-based management. Rare diseases present a unique set of challenges in evidence based clinical care. In particular, the lack of adequately powered studies means that many management recommendations are based on low-certainty evidence. Specifically, the developmental and degenerative issues related to FRDA and the need for clinical care across childhood and adulthood requires a diverse approach to clinical management . Recommehttp://www.g-i-n.net/). Recommendations were established according to the criteria developed by the National Health and Medical Research Council (NHMRC) Australia. In the absence of robust evidence, most (62%) of the 142 recommendations in these guidelines were based on the collective expertise of the clinicians and were thus presented as good practice points.In 2014, identifying the requirement for FRDA-specific clinical management guidelines, 39 international expert clinicians wrote the first iteration of the Consensus Clinical Management Guidelines for Friedreich ataxia . In thisGiven the time that had elapsed since 2014, an update of the guidelines was required; however, the challenge of developing guidelines for rare diseases remained. Paucity of available evidence, the predominance of low-quality studies and the inconsistency in metrics used to measure outcomes in FRDA make it challenging to apply standard comparative effectiveness strategies to this and other rare diseases . In partThe time between the first and second iteration of the guidelines provided an opportunity to consider alternative methods of grading the evidence and establishing the strength of the recommendations. The RARE-Bestpractices Working Group has provided a framework for developing guidelines using the Grading of Recommendations Assessment and Evaluation (GRADE) system . Pai andFigure The key stakeholders in the development of the guidelines were:Guideline panel. An executive guideline panel comprising seven international clinicians provided oversight of the guideline development process and endorsed the final recommendations.Project coordinator. The panel was supported by a project coordinator and administrative support.Expert authors. International expert clinicians and researchers were invited by the guideline panel to author chapters and develop recommendations for their designated topic.Methods experts. Expert authors were assisted by two methodological experts who completed the literature searches and summarized and synthesized the evidence using the GRADE structure.Individuals with FRDA and/or their families. In contrast to the preceding iteration of the guidelines, individuals with FRDA and/or their families were included throughout the development of the guidelines to provide a lived perspective of FRDA on the development of topics and the final recommendations, in particular the lay summaries of recommendations.Figure The guideline panel reviewed the topic list from the previous CMG iteration, identified gaps in the available topics and suggested new topics for inclusion.Expert authors were allocated topics relevant to their expertise and were asked to define the scope of their designated topic. Authors were instructed that each recommendation should answer a focused and sensible healthcare question designed according to the Patient, Intervention, Comparator, Outcome (PICO) framework. Individuals with FRDA and/or their families provided feedback on the PICO questions. The PICO questions guided the literature review and generation of other evidence if required.https://www.gradepro.org), including the evidence table, summary of findings table and evidence to recommendation table, was used to generate the guidelines. The bespoke structured observation forms used to develop these guidelines were based on those presented in the GRADE tool  for publications from January 2014 to June 2020, including only English-language publications. Reference lists and the authors’ personal libraries were searched for further publications. Randomized, non-randomized controlled and observational studies were included. Papers identified in the 2014 guidelines (published prior to 2014) were included in the review if not superseded by more recent, higher quality literature.The populations included adults and/or children with FRDA. However, when there was minimal published evidence, populations with like conditions (such as spinocerebellar ataxia and multiple sclerosis) were included in the search.For each PICO, the review of the literature was summarized and presented to expert authors via the GRADE evidence table and summary of findings table.In instances where there was limited published evidence on the PICO question, authors had the opportunity to interrogate registry data from two international natural history registries of clinical information from individuals with FRDA: the Friedreich’s Ataxia Clinical Outcomes Measures (FACOMS) and the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS). The information provided was descriptive only; for example, frequency of use of a medication in individuals with a specific impairment related to FRDA.If the expert authors anticipated there was limited or no published evidence on the PICO question, structured observation forms were used to systematically document clinical observations by experienced clinicians that could contribute to the strength of the recommendation. In the first instance, the expert authors (clinicians) working on that topic completed the form/s independently. If responses showed large discrepancies, all expert authors were invited to complete the structured observation forms. The questions were targeted at clinicians known to provide healthcare to individuals with FRDA.GRADE Evidence to Recommendation tables were used to provide the structure for expert authors to decide the strength of the recommendation and the level of evidence. The evidence base related to each question was evaluated according to the criteria of: problem (is the issue a significant problem?); desirable effects (of the intervention); undesirable effects (of the intervention); certainty of evidence; values; balance of effects; and acceptability (of the intervention). Based on the responses to these criteria, the type  and strength of the recommendation  were generated. For the rating of the strength of the recommendation, in addition to evidence from studies in FRDA, evidence from like conditions, clinical experience and expert consensus were taken into account when published evidence was not available. In this situation, the level of evidence was rated as “low” or “very low”. Table For strong recommendations, consistent with the GRADE working group we suggested authors should use terminology such as "we recommend…" or "clinicians should…", “clinicians should not…” or “do…”, “don’t…” For conditional recommendations, we suggested less definitive wording, such as "we suggest…" or "clinicians might…" or “we conditionally recommend…” or “we make a qualified recommendation that…”.Along with each recommendation, authors provided clinical and research justification for the recommendation and a description of subgroups that might need particular consideration in implementing the recommendation, if any.Best practice statements were included when application of the GRADE framework was not appropriate. This was in circumstances where the reverse would not be credible; for example, ambulant individuals with FRDA who are falling frequently should be offered a detailed assessment of balance and gait. In addition if recommendations from the 2014 guidelines were deemed still relevant, yet not incorporated into a new PICO thus enabling scrutiny from a GRADE framework, they were included as best practice statements.For each topic, expert authors were asked to write a chapter elaborating on the evidence and providing background and context to the best practice statements and recommendations. For chapters that did not include recommendations or best practice statements, expert authors provided an evidence-based overview of the topic.Expert authors wrote a lay summary of the recommendations related to the topic. Given the target audience for this section is individuals living with FRDA, review of the lay summaries by individuals with FRDA and their families was a crucial component of the guideline development.Each of the expert authors needed to agree on the grading of recommendations. In the case of not achieving consensus we proposed the authors use a Delphi survey to achieve consensus.The executive panel reviewed the chapter content and recommendations and responded to a set of questions via an online survey . New topics (since 2014) include emergency medicine, digital and assistive technologies and a separate topic (with 3 sub-topics) dedicated to mental health . Three of the chapters  provide overviews of topics that did not generate PICOs, and consequently do not contain recommendations, although chapter 12 contains best practice statements. For the other 14 main topics, expert authors used the GRADE rare-diseases process to assess the evidence for 130 PICOs, generating 130 recommendations. Authors were able to achieve consensus on all recommendations without the use of a Delphi survey. In addition to the 130 new recommendations, there are 95 best practice statements included across the 17 chapters.Based on the contents of the previous iteration of the guidelines and identified gaps, the guidelines panel defined 17 overall topics for inclusion in the new guidelines, resulting in 17 separate chapters. As shown in Table https://frdaguidelines.org/).Table against the intervention, while the rest (n = 91) were conditional or strong recommendations for the intervention.Table FRDA presents with a unique, heterogeneous phenotype that spans both childhood and adulthood. As such, CMGs for FRDA need to provide expedient clinical guidance for clinicians, particularly those less familiar with the condition. The diverse manifestation and complexity of FRDA mandates appropriate CMGs developed in a transparent manner, via a process able to synthesize available evidence and delivered in a clear and concise manner . ConsistThe addition of new topics was crucial to this iteration. For example, a consistent theme in the development of these guidelines was the frustration of both affected individuals and clinicians alike regarding the experience of someone with FRDA presenting to the emergency room. By most accounts, many emergency room physicians have scarce clinical experience with FRDA and as such may be unsure how to manage issues such as chest pain, trauma or urinary tract infection in the context of FRDA. These CMGs now specifically address this knowledge gap by providing an additional resource to the clinician. Inclusion of such topics reflects the importance of incorporating those who have a lived experience of FRDA and the challenges of navigating the health system, into each step of the development of these guidelines. The inclusion of the lived experience of FRDA provided an important differentiation from the 2014 guidelines and was pivotal in identifying the gaps in those guidelines that required attention. In addition, the inclusion of lay summaries of the recommendations was a significant new initiative. Whilst the target audience of the guidelines is healthcare professionals, provision of a lay summary of the clinical recommendations will assist individuals with FRDA and their families in understanding how best to manage their health and well-being and support shared decision-making with healthcare providers. Lay summaries underwent comprehensive scrutiny by individuals living with FRDA to ensure they address this requirement.Ensuring the contemporaneous nature and sustainability of recommendations is an important component of guideline development . As new A further critical component to developing guidelines is dissemination and ensuring the guidelines are openly available and easily accessed by clinicians and others in need of the information. Again, the opinions of clinicians and individuals with a lived experience of FRDA was sought in deciding the best repository and process of dissemination of the CMGs. An important component of dissemination is ensuring transparency, access to the evidence to recommendation tables that underscore the recommendations and the opportunity for future work such as translation into languages other than English. Incorporating suggestions from stakeholders, a dedicated website has been designed to house the CMGs, including chapter content, lay summaries, recommendations, best practice statements and the evidence to recommendation tables. Ongoing review of this process of dissemination will occur via the website.Finally, it is important to reiterate these CMGs are intended to assist healthcare professionals to make informed treatment decisions about the care of individuals with FRDA. They are not intended as a sole source of guidance in managing issues related to FRDA. Rather, they were designed to assist clinicians by providing an evidence-based framework for decision-making. Ultimately, healthcare professionals must make their own treatment decisions about care on a case-by-case basis, after consultation with individuals living with FRDA, consideration of local or geographical issues including fiscal issues, and using their clinical judgement, knowledge and expertise. Developing guidelines for rare diseases such as FRDA is challenging; however, we believe the blueprint we have provided for this process will be applicable to other clinicians striving, as we are, to provide the best possible clinical care to people who live with rare conditions.Additional file 1. Example of a structured observation form.Additional file 2. Recommendations review survey.


Evidence theory by Dempster-Shafer for determination of hormone receptor status in breast cancer samples was introduced in our previous paper. One major topic pointed out here is the link between pieces of evidence found from different origins. In this paper the challenge of selecting appropriate ways of fusing evidence, depending on the type and quality of data involved is addressed. A parameterized family of evidence combination rules, covering the full range of potential needs, from emphasizing discrepancies in the measurements to aspiring accordance, is covered. The consequences for real patient samples are shown by modeling different decision strategies. The Dempster-Shafer theory of evidence (DST) is a generalized framework in probability theory. First introduced by Dempster between 1966  in the cIn 1988 Smets  (ChapterOne common approach to DST is via the “transferable belief model” (TBM), which Smets introduced in 1990 . In the Among others, an important elaboration of DST is given by the “Theory of Hints”, which was outlined by Kohlas in 1995 . In 1991While in probability theory the calculus with probabilities is inherent, in DST the exertion of influence between pieces of evidence opens a wide field of facilities. Combining two pieces of evidence to improved evidence is, in general, accomplished by evidence combination rules (ECR). There is certainly a large variety of meaningful ECRs. Dempster’s original suggestion, which distributes inconsistent BBMs equally among others, was the most obvious Dempster ECR . The rulAs an alternative to Dempster’s ECR and to overcoming the problem of conflicting evidence, Shafer suggested  to manipThe TBM gives a procedure of how to convert evidence into probabilities. However, there is a push for decision making based on evidence. An axiomatic approach was given in 1990 . The incThere are many use cases for DST. An obvious one can be found in robotics for “Simultaneous Localization and Mapping” (SLAM) by combining data from different sensors . Every sAnother important application is in combining classifiers as outlined in 2002 by Al-Ani . ElementThe described procedure is very close to our approach with the crucial difference, that in our model not the full feature space is mapped to categories, but leaves the option of a feature vector being mapped to an additional category labeled as “undecidable”.A. Blue, Red and Green, thus Evidence theory by Dempster-Shafer (DST) is based on combining pieces of evidence rather than dealing with probabilities. An evidence can be seen as a generalization of a probability function. The essential difference is, that while in the former the sample space The function We currently restrict ourselves to normalized evidence, but we will discuss the origin and opportunities of open world models later in the context of evidence combination rules (ECR) and vague FOD.S.For every set This is why DST is also called the theory of belief functions.For a normalized evidence we have One strength of DST is the flexibility in combining pieces of evidence with various ECRs in adjustment of necessities. We will show how to take advantage of this by customizing ECRs, depending on the origin of the data. Put simply, an ECR is a binary operator ⊕ that combines two mass functions Basically, such an operator does not need to fulfill any properties, except Most ECRs are commutative, but only in very rare cases are they associative, not even pseudo-associative in terms of . There igiven in .Obviously, an inverse function al magma .An easy way to combine pieces of evidence is by simply multiplying the intersecting mass functions .(3)m1. How to transform this data into appropriate iscussed ,33.Putting these together into our existing model, the BBM Missing data are represented by the vacuous mass function. On the basis of the Formula  ⊕1 stand Formula .(8)αhorHowever, this model suffers from a couple of shortcomings. The following list of improvements addresses the problems and provides credible results.The operator ⊗, as defined in Formula , is not The operator us paper  we introCombining gene expression evidence with IHC evidence, the operator In the past it turned out that the optimal choice for the co-gene of progesterone is mostly estrogen itself. If so, although Respecting all these issues above we suggest an improved model such asThe operators ribed in . GraphicA further detailed explanation is required for the shift from ⊗ to  Formula  will faiMoreover, there is a strong connection between the two receptor genes. A progesterone positive sample will almost always be estrogen positive while an estrogen negative sample is very likely to be progesterone negative. However, the approach given in Formula  is basedCombining receptor evidence with The data set for the following results consists of 2559 freely available breast cancer samples from the Gene Expression Omnibus . For eacIn the first example (sample id 881 from the data set), gene expression data and IHC measurements are contradicting each other. In addition, gene expression of progesterone is not very accurate, and can be seen from the differing measurements. This leads to a final very diffuse evidence, and therefore no decision can reliably be made.In the second example (sample id 1980 from the data set), there is strong conformity in the data. Although one IHC measurement is missing, pieces of evidence accumulate to a strong belief in hormone receptor positive, see left panel in The last example (sample id 2365 from the data set) is a very contradictory example concerning the data at hand. Large amounts of the final mass are distributed to lack of knowledge, which can be seen from the large central circles in As can be seen in stead of  only hasThe left panel of A as “true” if the belief in it has more mass than the plausibility of its complement We will not change our strategy for decision making as proposed in our previous work ,33. ThisIn this very simplified case with Note that In DST, the dogma “a (machine learning) model is only as good as the data it is fed” can be understood from a different perspective. This guiding principle is still valid, but lack of data quality can be coped with in the BBMs and ECRs by adequate parametrization. Here DST offers additional flexibility.In our model with only two possible outcomes this is simple. The best example is the modeling of the BBM for the IHC status. The less confidence there is in the data, the more mass is assigned to subsets of This issue was the subject of our earlier papers ,33 and wThe most important is to consider the possibility of erroneous gene expression values by keeping masses significantly smaller than 1. A welcome side effect is to avoid some rare numerically problematic cases.The conversion of IHC measurements into BBM is again realized as described in ,33. We aWe introduced the parameter On the other hand, if the data sources are homogeneous, a large Theoretically, it would also be possible to choose uggested . That woThere is even more potential in the variation of (Formula ) is chooThe parameter Due to a lack of clean training data of sufficient high quality we have done simulations to train There are many ECRs available and existing ones are constantly being developed further. However, none of these developments could state with certainty or explain conclusively which ECR is beneficial for which application. Therefore we proposed to set the parameter In any case, the parameterized ECR introduced in this way covers a very wide range of possible combinations of evidence. Unfortunately, it is difficult to assess whether certain additional mathematical requirements for an ECR, such as commutativity, (pseudo-) associativity, idem-potency, invertibility or other characteristics of binary operators could provide additional value.The larger the expected contradiction between the two BBMs, the smaller one will usually choose The net effect of this strategy would be to reduce the variability of This approach can be pursued particularly elegantly if one assumes the resulting mass of total ignorance as an a priori constant, i.e., For the special case Our FOD consists of only two outcomes, “positive” and “negative”, i.e., The first is a refined model. Here, the refinement lies in subdividing “+” further into The second is to adapt the “open world assumption”. There are patients for whom it is basically impossible to make a serious choice for the most suitable treatment method based on the receptor status–even if it is measured precisely and reliably. The outcome for such patients is therefore not covered by the FOD. Such a model can be implemented by allowing a strictly positive BBM of the empty set, ergo Finally, another open point is the need for a risk function. Wrong decisions regarding therapy are not symmetrical. Adjuvant chemotherapy is often vital, even if only hormone therapy is applied. Some preliminary investigations have already been carried out , but conDempster–Shafer theory of belief functions represents a generalization of Bayes’ probabilities. It provides a powerful framework to proactively involve the outcome “uncertain” in case of insufficient data availability to make confident decisions. Instead of probabilities pieces of evidence, represented by basic belief masses, are concatenated by evidence combination rules.In this paper, we presented a manner to parameterize evidence combination rules to adjust models to the nature of the incoming measurements. Data with high potential to be contradictory  is linked in a more conservative manner than data which is more likely expected to be in consent. Thus, evidence theory avoids several well-known problems with decisions based on conventional statistics.As a major advancement, our work introduces flexible evidence-combination-rules offering the potential of adaptable risk. Changing the parameters for concatenating pieces of evidence (respectively data) alters the probability for a sample to be classified as “well-defined” or as “uncertain”. This is especially helpful to adapt the Dempster-Shafer algorithm to possible different types of risks and directly related possibilities of a treatment decision. Examples are possible over- and under-treatment of particular patients.To illustrate the strength of evidence theory we used a case study of hormone receptor status determined for breast cancer samples. As a key outcome we estimate that slightly too many patients have been classified as hormone receptor positive by conventional clinical-decision-making in comparison to our approach. We do not advocate overruling clinical decisions, but rather flagging questionable samples as “uncertain” and suggesting further investigations for these particular patients.Drawing on flexible evidence combination rules in our approach we see great potential for the advancement in personalized medicine.


The authors discuss functional characterization of Mousterian tools on the basis of their use-wear and residue analysis of five lithic tools from Mezmaiskaya cave and Saradj-Chuko grotto in the North Caucasus. The results represent the first comprehensive use-wear and residue analysis carried out on Mousterian stone artefacts in the Caucasus. This study unequivocally confirms the use of bitumen for hafting stone tools in two different Middle Paleolithic cultural contexts defined in the Caucasus, Eastern Micoquian and Zagros Mousterian. Homo . Our understanding of the use of composite tools by the Middle Palaeolithic (MP) Neanderthals in Eurasia relies on evidence of hafting and adhesives4. Most ideas on the development of Palaeolithic composite tool technologies are based on microscopic use-wear, including diagnostic impact fractures (DIFs) and other traces of use15, and diagnostic characteristics of hafting traces10 , and the morphology of tools . However, the exact hafting significance of use-wear traces and morphological features is not always clear16, and this evidence alone are not an exhausted indication of the presence of hafting technology. Also, some studies indicate that the interpretative potential of some impact fractures proposed as having diagnostic value for the identification of projectiles is still unclear18.The development of composite technology using adhesive materials is often seen as a hallmark of cognitive sophistication that played an important role in the social and technological development of the genus 20, two lumps of birch tar that were probably attached to a bifacial knife from Königsaue (Germany)21, and nine tools and flakes with pine resin, and one scraper with pine resin and beeswax from Fossellone and Sant’Agostino caves 22 in Europe, as well as 14 tools and flakes with bitumen from the sites of Umm El Tlel and Hummal (Syria) in the Levant26. These studies document that adhesive technology was used in both Europe and south-west Asia by varied Neandertal populations and the MP production of adhesives was complex. Neandertals mixed pine resin with beeswax22 and bitumen with quartz and gypsum24, and distilled tar from birch bark20.The lithic residue analysis provides direct information that the lithic artefacts were hafted, as well as allows precise identifying the adhesive materials involved in the manufacture of these composite tools. The currently known unambiguous evidence of the securely dated, and chemically and spectrometrically identified MP hafting adhesives includes three flakes with birch tar from Campitello Quarry  and Zandmotor (Netherlands)20], the level of adhesive technology applied for manufacturing composite tools among different Neanderthal groups is problematic given the lack of relevant data from the majority of MP regional contexts. This state of research demonstrates the need for detailed modern studies about the role of adhesives in hafting and the level of hafting technology in various MP regions.Despite the MP adhesive evidence is being increasingly documented in Europe and Asia  established the methodological framework for examination of archaeological residues in our study. The absorption bands corresponding to specific bitumen bands were defined after75. Band assignments for Raman peaks were made based on36.The good preservation of the analyzed lithic artefacts allowed us to identify use-wear traces and residues on all archaeological samples. Various articles focused on the characterization and identification of common materials found in various applications


N = 430). The questionnaire measured five variables: news media literacy, xenophobia, blind patriotism, perceived threat, and intellectual humility. Confirmatory factor analysis (CFA) was used to validate this five-variable survey, and the analyses indicated satisfactory construct validity. Results from structural equation modeling indicated that intellectual humility was a significant predictor of news media literacy, and blind patriotism and perceived threat mediated the relationship between news media literacy and xenophobia. This study provides insights for researchers and instructors who are promoting news media literacy education in schools.The dissemination of misinformation and disinformation has increased the need for news media literacy. This study administered a self-developed questionnaire to measure the relationship between news media literacy and xenophobia among college students in China ( News media literacy is an important form of literacy in the post-truth era in which social media are rife with various kinds of misinformation, and some news agencies work with politicians to advance their respective agendas. The post-truth era has not only threatened individuals’ ability to explore what is true , but theAt present, although there is still a lack of clarity regarding the differences between the concepts of misinformation and disinformation, some preliminary consensus has been reached . AccordiGiven the complexity of misleading information, people need to be careful with the information they receive. Affected by misleading information, people could be emotionally clouded and hence engage in behaviors that endanger themselves and others. Xenophobia might be one of the consequences. Previous studies on xenophobia have suggested its tremendous psychological impact on individuals and communities . People The relationship between obtaining and perceiving information and some irrational behaviors or cognition is complex and could be influenced by multiple factors. The factors identified so far include hate speech exposure , inherenConsidering these issues, the importance of news media literacy is clear. However, published studies have analyzed only a limited number of factors that contribute to people’s news media literacy. Only need for cognition and media locus of control were found to be significant predictors . ConsideAs a virtue, intellectual humility may promote news media literacy. According to To clarify the situation and the underlying sociopsychological mechanisms involved in the relationship, this study focuses on the above three factors, namely intellectual humility, blind patriotism, and perceived threat. We gained empirical data from young adults in China to investigate: (1) whether intellectual humility may act as a predictor of news media literacy, (2) the relationship between news media literacy and xenophobia, and (3) whether the relationship between news media literacy and xenophobia is mediated by blind patriotism and perceived threat.News media literacy refers to the knowledge and abilities needed to identify and engage with news . Having The significance of studying news media literacy has also been highlighted. As Given the importance of news media literacy, researchers have found some educational ways to enhance it, such as integrating news and current affairs into instruction . Hobbs . The sample consisted of 104 top QS 500 university students, 107 middle-class university students, and 219 unranked university students. Of the 430, 191 were bachelor students, 217 were master’s students, and 22 were doctoral students. They were invited to complete an online survey at their own pace, and were compensated with a small monetary reward at the end of the study.A total of 430 participants  volunteered to take part in this research ; their aAge, gender, degree, and academic performance were selected as background factors. Although GPA has been widely used in defining students’ academic performance, the grading schemes of universities are different and hard to unify and standardize . In ordeThe news media literacy scale developed by With reference to and modification of a prior research scale , xenophoDrawing from Each participant responded to the perceived threat scale to self-report their perception of threat from foreigners. This survey was developed and validated by The general intellectual humility scale of As the original scales shown above were all written in English, we asked English major students to help translate them into simplified Chinese. The scales were reviewed by two professors who majored in Chinese and English language, respectively. We also provided items in both English and Chinese to ensure the accuracy and minimize the errors. Then five university students were recruited to take part in a pilot test. They were required to give comments on the statement of each item, including the differences in expressions between the Chinese and English versions and the clarity of the translations. After that, we revised the statements according to their feedback. Finally, five more university students were recruited to take part in the second round of the pilot test; they all gave positive feedback on the Chinese version.1 a well-known data service platform in China. Participants could open the survey link directly in WeChat, which created a convenient environment for our investigation.An online survey was conducted to help us verify the double mediator hypothesized model we proposed. On the first page of the questionnaire, participants signed a consent form (IRB Reference No. EDU2022-055), and they were fully informed of the purpose, hypotheses, and conditions of this research. In addition, we emphasized that this survey was for academic research only, participation was completely voluntary, and participants might withdraw at any time. We collected data by using the Tencent Survey Platform,2/df, the adjusted goodness-of-fit statistic (AGFI), root mean square error of approximation (RMSEA), the non-normed fit index (NNFI), the comparative fit index (CFI), and the incremental fit index (IFI) were employed to assess the comprehensive goodness of fit of the research model. Next, User-defined estimands were used to test our hypothesized model.A series of statistical analyses was performed to examine the data. Firstly, Pearson correlation and Spearman’s rank correlation analysis were used to analyze the relationships between the factors. With reference to Before the analyses, univariate and multivariate normality tests were conducted. Firstly, we noted that both skewness (range: from –0.46 to 0.10) and kurtosis (range: from –1.07 to –0.60) were satisfied with the required range. Secondly, to test the multivariate normality, we noted that the standardized multivariate kurtosis was –0.961, which means that the data conformed to multivariate normal distribution .Pearson correlation coefficients were calculated to investigate the correlations among continuous variables, such as news media literacy, xenophobia, blind patriotism, intellectual humility, and perceived threat. Spearman’s rank correlation coefficient was also used to investigate the correlations between ordinal variables (university and degree) and other variables. As noted in The measurement model of this study was examined through convergent validity and reliability see . The sta2/df = 1.54, GFI = 0.92, AGFI = 0.91, IFI = 0.97, TLI = 0.97, CFI = 0.97, and RMSEA = 0.035 were acquired. The fit scale showed a sufficient fit for this model as these indices were approaching the criterion of a good fit according to some researchers , and both are positively correlated with xenophobia . As for news media literacy, it is negatively correlated with xenophobia , blind patriotism  and perceived threat . Intellectual humility was the positive predictor for explaining news media literacy . In summary, the above results indicate that the hypotheses in the model were all verified.The path analysis results are presented in 2/df, AGFI, RMSEA, NNFI, CFI, and IFI were employed to assess the comprehensive goodness of fit of the research model ], and news media literacy showed an indirect effect of −0.07 on xenophobia via perceived threat . Regarding the serial mediation analysis, we found a significant indirect effect serially via blind patriotism and perceived threat , and the path serially via blind patriotism and perceived threat contributed slightly more than the Ind 1 path but had no significant difference from the Ind 2 path. Thus, the mediation effects in the hypothesized model existed. In addition, as the direct effect of news media literacy on xenophobia is significant, the mediated effect and direct effect both exist and point in the same direction. According to To further validate the structural relationships of our model, we assessed the serial mediation with blind patriotism and perceived threat serially mediating the relationship between news media literacy and xenophobia by plugin PROCESS 4.1 in SPSS 24.0 see . The 95%News plays a role in establishing public agendas, while misinformation presented as news can contribute to severe social consequences and influence people’s perceptions of outgroup or specific events . AlthougAlthough news media literacy has received much attention in the current complex media environments, and xenophobia has become more intensive with the Covid-19 pandemic, the relationship between the two factors among college students has rarely been explored, especially in the Asian context. As previous research has suggested, although contemporary young adults are always considered to be digital natives or cyber experts, they are vulnerable media users, which places them in a paradoxical situation . ConsideIn this study, we investigated the relationship between news media literacy and xenophobia based on Chinese university students. Considering that news media literacy would affect how people obtain information, which further influences their perceptions of the outside world, this study also investigated the mediating role of blind patriotism and perceived threat. In addition, since news media literacy is about reviewing and processing information rationally, we also hypothesized that intellectual humility would be positively associated with news media literacy. Findings from 430 college students in China indicated that the relationship between news media literacy and xenophobia was mediated by blind patriotism and perceived threat. Specifically, people with higher news media literacy might perceive less threat and would not be so blindly patriotic. Therefore, they might have less xenophobic beliefs. In addition, blind patriotism was positively associated with perceived threat, and intellectual humility was a positive predictor of news media literacy. The results of this study are consistent not only with studies indicating that news media literacy affects individuals’ perceptions , but alsFirstly, this study employed Amos 24.0 to establish a valid and reliable five-variable structural equation model that measures the relationship between news media literacy and xenophobia among college students, and which integrates intellectual humility, blind patriotism, and perceived threat into the model. More interestingly, this study confirmed the mediating role of blind patriotism and perceived threat and the predicting role of intellectual humility. To the best of our knowledge, this is the first model that incorporates these variables to examine the relationship between news media literacy and xenophobia. Our model implies that the students’ news media literacy played a role in their acquisition and review of online information. Intellectual humility is significant , and theThe current results imply that the way students process information influences their views about outgroups, which also corresponds to the cognitive behavioral theory, indicating that one’s cognition would shape one’s behavior and vice versa . From a Secondly, this study enriches the research on news media literacy and xenophobia by broadening the samples to include data from China. Also, it helps better understand the news media literacy of college students from mainland China. Moreover, the results show that students with a higher level of news media literacy had positive perceptions of outgroup relationships, which is the same as the previous findings in western samples. It implies that news media literacy should also be promoted for Chinese students to reduce the chances of them developing negative outgroup perceptions.Furthermore, In conclusion, the emergence of the Internet and social media has changed the spread of information, and people must learn how to face this complex situation to avoid being emotionally affected by misinformation and disinformation. Students should develop news media literacy, which will form knowledge for their future decision making and allow them to examine information critically and to understand group relationships objectively. We also recommend that educators pay attention to the impact of intellectual humility on news media literacy and emphasize the danger of blind patriotism and perceived threats in the formation of xenophobia. This would help people to navigate an increasingly convoluted information ecosystem, promote harmonious relationships, and prevent violent extremism.Study limitations and areas for continued research are important to note. Firstly, this study did not consider the influence of some underlying reasons, such as news bias and political bias. In addition, as The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was conducted by The Chinese University of Hong Kong (IRB Reference No. EDU2022-055). Written informed consent for participation was approved by The Chinese University of Hong Kong and signed by each participant in accordance with the national legislation and institutional requirements.ML and CC contributed to the conception and design of the study. ML performed the statistical analysis and wrote the first draft of the manuscript. CC and J-CL contributed to manuscript revision, read, and approved the submitted version. All authors contributed to the article and approved the submitted version.


Rigorous evidence is vital in all disciplines to ensure efficient, appropriate, and fit-for-purpose decision-making with minimised risk of unintended harm. To date, however, disciplines have been slow to share evidence synthesis frameworks, best practices, and tools amongst one another. Recent progress in collaborative digital and programmatic frameworks, such as the free and Open Source software R, have significantly expanded the opportunities for development of free-to-use, incrementally improvable, community driven tools to support evidence synthesis . Despite this, evidence synthesis  practitioners and methodologists who make use of R remain relatively disconnected from one another. Here, we report on a new virtual conference for evidence synthesis and meta-analysis in the R programming environment (ESMARConf) that aims to connect these communities. By designing an entirely free and online conference from scratch, we have been able to focus efforts on maximising accessibility and equity—making these core missions for our new community of practice. As a community of practice, ESMARConf builds on the success and groundwork of the broader R community and systematic review coordinating bodies (e.g. Cochrane), but fills an important niche. ESMARConf aims to maximise accessibility and equity of participants across regions, contexts, and social backgrounds, forging a level playing field in a digital, connected, and online future of evidence synthesis. We believe that everyone should have the same access to participation and involvement, and we believe ESMARConf provides a vital opportunity to push for equitability across disciplines, regions, and personal situations. The recent pandemic forced many research community activities and conferences online. Here, we report on a new online conference for evidence synthesis and meta-analysis in the R programming environment (ESMARConf), which focuses on accessibility and equity as core missions. ESMARConf is an event series geared towards a novel community of practice of tool developers and users working with evidence synthesis and meta-analysis in R. We believe this conference has the power to curate a vital community of practice across disciplines, raising awareness, fostering capacity sharing, and developing free and Open Source, efficient and rigorous needs-based tools to support evidence synthesis. ESMARConf builds on the success and groundwork of the broader R community and systematic review coordinating bodies (e.g. Cochrane), but fills an important niche; catering to a variety of audience types including developers, users and learners. Here, we introduce ESMARConf and its core values, calling for the evidence synthesis and R communities to fully embrace both the conference and this style of event in an effort to maximise accessibility and equity.Rigorous evidence is vital across disciplines for efficient, appropriate, and fit-for-purpose decision-making with minimised risk of unintended harm, and to make the best use of available resources . RigorouTo date, however, disciplines have been slow to share evidence synthesis frameworks, best practices, and tools amongst one another. Instead, evidence synthesis paradigms are borrowed but largely reinvented for new disciplines wishing to learn from other fields. This exceptionalism and limited collaboration undoubtedly results in inefficiencies and unnecessary teething problems , 6. HoweThe importance of communities of practice has also been recognised for some time in existing interdisciplinary contexts. Developments in collaborative digital and programmatic frameworks, such as the free and Open Source software R, have significantly expanded the opportunities for development of free-to-use, incrementally improvable, community-driven tools to support evidence synthesis. Examples of such R-based evidence synthesis tools include: EviAtlas for visualising cartographic evidence maps ; robvis tool developers is not well connected with users of evidence synthesis tools. This means that many needed tools may go undeveloped, and tools that could have a broad applicability may not end up being as widely used because end users are not aware of their existence or because certain use cases and needs may not be met.Although the community of R tool (i.e. package) developers is active and strong across disciplines, evidence synthesis  practitioners and methodologists who make use of R remain relatively disconnected from one another, often also existing outside and potentially unaware of systematic review coordinating bodies, such as Cochrane, the Campbell Collaboration, and the Collaboration for Environmental Evidence. Furthermore, the R community of Clearly, then, there is a need to develop a community of practice of evidence synthesis tool developers and users. Such an active and well-connected, interdisciplinary community would facilitate the production of fit-for-purpose, needs-driven tools that conformed to rigorous standards in evidence synthesis best practice. A community would also facilitate capacity sharing and awareness raising across the use of evidence synthesis tools and methods. Furthermore, as some have argued (e.g. ), this mhttps://www.eshackathon.org/), an organisation that aims to produce Open Source evidence synthesis tools, initiated planning of the first Evidence Synthesis and Meta-Analysis in R Conference , held on 21st and 22nd January 2021. The event consisted of 39 presentations of 7 min, 10 panel discussions, and 4 workshops. During the 4 days of the conference, the conference received 514 registrations, with 650 unique viewers during the conference and > 3500 video views.In 2020, active members of the Evidence Synthesis Hackathon .ESMARConf is a purely online conference, designed to be as accessible and equitable as possible see Fig. , whilst Importantly, we aim to combine presentations of existing tools and frameworks in R with capacity building and training both around the use of R in evidence synthesis and rigorous evidence synthesis methodology itself. By leveraging R as an open and widely used platform for statistics and data visualisation, we have the opportunity to connect a large and disciplinarily diverse audience of graduate students and earlier stage researchers with best practices in rigorous evidence synthesis. Indeed, our post-event evaluations demonstrate the importance of these career stages, but also demonstrate continued engagement from more senior researchers Fig. .Fig. 2DiWe developed a mission for ESMARConf that builds on the principles and values of R both as a coding platform and a community of practice, and the communities leading and promoting rigorous systematic reviews .Conference fees should not be a barrier to participation. High conference fees are a huge financial barrier to those who most need access to information and networking. We believe that online events should not be costed at the same rate as traditional, in-person conferences. We believe that running online events using free and low-cost software  is vital for enabling low/no registration fees and facilitating equitable participation. We now have the experience of running two large, global conferences entirely for free for participants. We aim to ensure ESMARConf is free forever, but there are costs to ensuring these events are accessible , and so we welcome voluntary donations and registrations where participants’ budgets allow. We are also striving to develop Open Source automated pipelines for ESMARConf to minimise burden on conference organisers, and we welcome others who may wish to use them for the same purposes .Online conferences remove barriers to physical attendance. By holding the conference online and recording all live content, participants can digest the content at a time that works for them. Around 67% of the more than 9500 views of the ESMARConf2021 videos on our YouTube Channel were for individual pre-recorded talks (as opposed to the live stream), and 73% of all views occurred after the end of the conference  are continually evolving and central to all our events. We mention them at the start of each live session and clearly link to them on our website. Some 83% of participants responding to an evaluation of ESMARConf2022 said that they felt personally welcome . In future years, we hope to be able to allow presenters to present in the language of their choice in pre-recorded talks, providing subtitles that can be translated into the viewer’s preferred language.Access should not be restricted by geographical location. By running the event as an exclusively online conference, we aim to allow anyone with access to an internet connection (including mobile or satellite internet) and a charged/mains powered electronic device that can display a YouTube video to join. In particular, we aim to facilitate participation from people in traditionally underrepresented regions and countries. ESMARConf2022 was attended by participants from across 86 countries . However, these costs are not excessive for a conference that can easily be scaled up in participation without additional costs. In our evaluation of ESMARConf2022, 75% of presenters and 37% of participants supported the idea of a voluntary registration fee to support attendance by those with accessibility and resource constraints. For participants, the median voluntary registration fee people were willing to pay was 50 USD. This indicates that an annual budget of c. 15,000 USD might be possible . This is a promising indication that an objective to break even in the long term might be feasible, considering that our costs for ESMARConf2022 were c. 7000 USD.ESMARConf aims to provide for three key audience groups and their objectives: (1) coders producing evidence synthesis tools wishing to collaborate; (2) current/potential R users wishing to conduct an evidence synthesis in R and learn more about the tools available; (3) non-R users with expertise/experience in evidence synthesis wishing to use free tools via non-coding user interfaces. As a result, collaboration, awareness raising, capacity building and sharing, and matching users to developers are core objectives of the conference: more generally speaking, developing a community of practice in tool use and development.The core values in our mission are important to ensuring engagement by all three audience groups, but we recognise several important factors that differ between groups. Firstly, we aim to support interested tool developers by matching their skills with other coders and specific projects, valuing all backgrounds and abilities, and also attempting to integrate opportunities for continued learning: all expertise are valued and everyone is learning. Secondly, we aim to make it easy to find relevant ESMARConf content for participants wishing to find tools for specific tasks. We do this by hosting an interactive database of all ESMARConf content indexed by review stage  and type  that can be searched and filtered Fig. . ThirdlyWe call on members of our three audiences to join the evidence synthesis and meta-analysis in R community of practice by embracing ESMARConf. Whatever your background in evidence synthesis, meta-analysis or R, you can play a vital role in ensuring that free and Open Source tools are developed that are fit-for-purpose, widely used and accessible to all. By joining and supporting the community, you can help us to raise awareness, build and share capacity and improve the rigour of evidence syntheses across disciplines. Support us by registering for ESMARConf2023 next year and engaging with presenters and colleagues, by presenting your work and sharing your skills, and by helping to develop needs-driven tools to improve accessibility, efficiency, and rigour of evidence syntheses across disciplines. Where possible, donations and voluntary registration fees can ‘pay it forwards’, helping to support those with constraints to break down barriers and participate in a global community.By supporting ESMARConf, you can help to maximise accessibility and equity across regions, contexts, and social backgrounds, helping to aim for a level playing field in a digital, connected, and online future of evidence synthesis. Welcome to ESMARConf!


Systematic reviews that synthesize safety outcomes pose challenges (e.g. rare events), which raise questions for grading the strength of the body of evidence. This is maybe one reason why in many potentially inappropriate medication (PIM) lists the recommendations are not based on formalized systems for assessing the quality of the body of evidence such as GRADE.In this contribution, we describe specifications and suggest adaptions of the GRADE system for grading the quality of evidence on safety outcomes, which were developed in the context of preparing a PIM-list, namely PRISCUS.We systematically assessed each of the five GRADE domains for rating-down  and the criteria for rating-up, considering if special considerations or revisions of the original approach were indicated. The result was gathered in a written document and discussed in a group-meeting of five members with various background until consensus. Subsequently, we performed a proof-of-concept application using a convenience sample of systematic reviews and applied the approach to systematic reviews on 19 different clinical questions.We describe specifications and suggest adaptions for the criteria “study limitations”, imprecision, “publication bias” and “rating-up for large effect”. In addition, we suggest a new criterion to account for data from subgroup-analyses. The proof-of-concept application did not reveal a need for further revision and thus we used the approach for the systematic reviews that were prepared for the PRISCUS-list.We assessed 51 outcomes. Each of the proposed adaptions was applied. There were neither an excessive number of low and very low ratings, nor an excessive number of high ratings, but the different methodological quality of the safety outcomes appeared to be well reflected.The suggestions appear to have the potential to overcome some of the challenges when grading the methodological quality of harms and thus may be helpful for producers of evidence syntheses considering safety.The online version contains supplementary material available at 10.1186/s12874-022-01715-5. Clinical practice recommendations (for example in guidelines) that are based on the best available evidence can improve quality of care , 2. ListTo grade the quality/levels of evidence for practice recommendations grading systems have been developed , 6. The Usually, the evidence is weaker for safety than for effectiveness outcomes because of inconsistent measurement, imprecision  and poor reporting of harms , 8. OtheOne might argue that the quality of evidence on safety is just the way it is and no specific rating criteria for quality of evidence are necessary. However, if rating proceeds in the standard way some problems may come up. First, it bears the risk that the certainty of evidence between benefit and harms is unbalanced per se because benefits tend to get higher methodological quality ratings (e.g. because only NRS are available for a very rare harm). Second, there may be the methodological problem that a difference in the quality of evidence on different safety outcomes could not be differentiated because of floor effects, i.e. all studies are classified as low or very low quality of evidence. This is because in the GRADE system evidence from NRS always starts at low quality and thus only one additional criterion for rating down (e.g. imprecision) would result in a very low quality of evidence rating .Some older evidence level classifications schemes, such as the oxford level of evidence use different criteria for harms and benefits, but there is no specific GRADE guidance for assessing the quality of evidence for safety outcomes .In this contribution, we describe specifications and adaptions of the GRADE system for grading the quality of a body of evidence on safety outcomes and report our first experience of applying these for the development of a PIM-list.This project was part of the update of a PIM-list for older people in Germany, namely the PRISCUS list . GRADE iThe research team consisted of five members; two experienced methodologists, one senior clinical pharmacologist, one senior general practitioner, and one pharmacist. The members assessed each of the five GRADE domains for rating down  and the criteria for rating up, considering whether special considerations or revisions of the original GRADE approach were indicated. We judged a specification or adaption as indicated, if it could be expected that one of the challenges quoted in the introduction affect the original GRADE criteria . A revision of an original GRADE criterion was only made if it could be methodologically justified, this means it was supported by statistical/epidemiological reasoning and could be supported by methodological articles. The results were gathered in a written document  and discussed in a group meeting with the whole project team. To facilitate the discussion, we illustrated the different challenges using example cases. If necessary, we refined the criteria until a consensus was reached. Note, no formalized consensus procedure was applied.Subsequently, we performed a proof-of-concept application using a convenience sample including six systematic reviews focusing on safety known to us and for which we assumed that all specifications and adaptions would come into effect. These systematic reviews were not part of PRISCUS. In this phase, we checked our approach for any problems with a focus on inconsistencies and tendencies of overestimating the strength of evidence. In the proof-of-concept application, no reasons for revision of the criteria were recognized.After this development phase, we used our approach for evidence syntheses prepared as basis for expert-rated recommendations on the PRISCUS-list. The GRADE assessment was performed by TM. All members of the team checked the final ratings for inconsistencies. In the pilot study, we assessed 51 outcomes for 19 clinical questions see  from 13 Table NRS usually start as low quality of evidence because of the risk of confounding bias . The appapplied. Than all studies must be assessed for risk of confounding or participant selection bias. An adequate critical appraisal tool could be used or guide this assessment. As suggested for ROBINS-I, it might be useful to have a well-designed target trial in mind as the reference for evaluation. Furthermore, in the case that other bias in addition to confounding and selection bias are present it is possible to rate down three levels for study limitations (risk of bias) when using this approach [Recently a new approach was suggested when using the ROBINS-I tool for assessing the risk of bias of NRS by the GRADE working group . It suggapproach . Clearlyapproach . Second,approach , 18. TheIn our review on safety of tramadol in older people all evidence on falls risk was observational and consequently would have started at low quality of evidence, when assessed in the standard way. Based on the methodological quality assessment, the outcome was rated-down one level for confounding bias and one level for imprecision, which would have resulted in a very low quality of evidence rating because of double counting confounding and selection bias. Noticeable, in this case even only one criterion for rating-down would have led to a very low rating. In contrast, if assessed in the adapted way the evidence starts high and rating-down two levels resulted in a low quality of evidence rating.Precision of an effect is usually assessed based on the 95% CI . HoweverIn a systematic review of artemethere lumefantrine versus Amodiaquine plus sulfadoxinee pyrimethamine for treating uncomplicated malaria the authors found 34 severe adverse events (SAEs) and calculated a risk ratio (RR) of 1.08 (95%-KI 0.56 to 2.08). The SAEs were observed in in >2.700 participants resulting in an absolute risk difference of 1% with (95%CI 0.6% less to 1.4% more) . The exaThe quality of evidence is usually rated down one level when publication bias is detected . The criIn one of our reviews that was performed to inform experts on oral anticoagulants in older people all studies were industry sponsored, the expected harms were not reported for all studies , or harms were grouped uncommonly , and the funnel-plot was slightly asymmetric. Therefore, we rated-up the quality of evidence for bleeding one level, from low to moderate.The evidence usually can be rated-up by one level if the magnitude of the effect is large, whereby large is defined as an RR of >2 (<0.5). This threshold is based on the assumption that confounding alone is unlikely to cause such an large effect . This thIn our review on proton pump inhibitors compared to no proton pump inhibitors, we found a RR of 1.97 (95%CI 1.44 to 2.70) for dementia. The risk of bias for this estimate was low. Therefore, we rated-up the quality of evidence one level, from low to moderate, which would not have been done if applied in the original way.Risk of experiencing harms often varies between subgroups . TherefoIn our review on oral anticoagulants in older people we extracted data from well performed  within study subgroup-analyses for major bleeding. Most of these suggested that the risk of experiencing major bleeding increases with increasing age and that the risk of major bleeding is in particularly high in the very older people. For that reason, we rated-up the quality of evidence one level (from low to moderate) for bleeding risk in the very older people.We found RCTs  for only 9 of the 19 clinical questions. Each of the proposed adaptions was applied. Nevertheless, the ratings were well balanced. We rated 14 outcomes as high quality, 7 as moderate quality, 17 as low quality and 13 as very low quality. As expected, most “high methodological quality” ratings were made for clinical questions for which RCTs were available.A review of PIM-lists found that the applied methods were very heterogeneous and a look in these PIM-lists revealed that almost none appears to apply formalized methods to assess the quality of the underlying body of evidence for recommendations using formalized systems such as GRADE as it is standard for preparing clinical practice guidelines . Only thThe initial results of the application for preparing a PIM-list suggests that the ratings were quite well balanced. There were neither floor-effects (excessive number of low and very low ratings) nor ceiling effects (excessive number of high ratings), but the different methodological quality of the safety outcomes seems to be well reflected. The adaptions might have the potential to overcome some of the challenges when grading the methodological quality of harms and thus may be helpful for producers of evidence syntheses considering safety . Although the adaptions were developed for evidence syntheses focusing on drug safety, we think that the adaptions might also be useful for evidence syntheses in general  because basically all systematic reviews considering harms face the same challenges when grading the quality of evidence. Future research is desirable for developing refined GRADE guidance for evidence syntheses on harms.The adaptions were not developed in a GRADE working group because the timeline of the project required that the evidence syntheses start immediately. Therefore, the suggested adaptions should only be regarded as a first step for stimulating further discussion and development of guidelines specifically for grading the quality of evidence on safety. This is in particular true for the suggestion that all NRS start high irrespective of the applied critical appraisal tool. Here, further research is needed that evaluates the impact of using different critical appraisal tools on the GRADE ratings. Likewise, the cut-off for (very) large effects remains controversial and require further evaluation .Additional file 1.


This retrospective study aimed to introduce a novel method for simultaneous Y-shape osteotomy combined with subtalar arthrodesis for calcaneus malunion and to evaluate the feasibility of this method.Y-shape osteotomy and subtalar arthrodesis who were admitted to our hospital from June 2018 to October 2020. The patients included 9 males and 2 females aged from 24 to 69 years old, with an average age of 42.18 years. The clinical and radiological results were assessed with the Visual Analogue Scale (VAS) pain score and American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score. In addition, functional recovery and general quality of life were evaluated using the 12-Item Short-Form Survey (SF-12).We retrospectively analysed the clinical and imaging data of 11 patients with calcaneus malunion treated using p < 0.05). The mean AOFAS and VAS scores at the last follow-up improved compared with those preoperatively, from 34.18 ± 9.53 to 84.18 ± 11.59 and from 6.90 ± 1.22 to 1.90 ± 1.13, respectively (p < 0.05). The SF-12 physical and mental health scores were 49.65 ± 6.84 and 52.68 ± 7.88, respectively. Furthermore, the early postoperative complications included skin necrosis in one and sural neuralgia in one patient, and the late postoperative complication included ankle pain in one patient. No other complications, such as implant discomforts, malunion, nonunion and re-fracture, were presented.All radiological parameters were significantly improved at the last follow-up, with increases of 14.37°, 9.18°, and 4.51 mm in the Böhler’s angle, calcaneal pitch angle, and talocalcaneal height, respectively, and decreases of 6.39 mm and 6.18° in the calcaneal width and Hindfoot alignment angle (These results indicate that Y-shape osteotomy combined with subtalar arthrodesis is an effective new method for the treatment of calcaneal malunion. Advantages include improvement of the anatomic shape of the calcaneus and union rates for subtalar arthrodesis. Calcaneus fracture is very common in the clinic, accounting for approximately 2% of systemic fractures and 60% of all tarsal fractures, usually as a result of high-energy trauma, such as traffic accidents or falling . Due to Sanders et al.  reviewedSubtalar arthrodesis is the best treatment for traumatic subtalar arthritis, but the complex pathological features brought by calcaneal malunion should not be ignored.At present, depending on the type of deformity, many authors have advocated different reconstructive strategies. The mainstream techniques for calcaneal malunions include lateral wall decompression, in situ subtalar arthrodesis, arthroscopic subtalar arthrodesis, distraction subtalar arthrodesis, corrective calcaneal osteotomy with arthrodesis, and triple arthrodesis, among which distraction subtalar arthrodesis and in situ subtalar arthrodesis are the most popular –8.The goThis study was approved by the Ethics Committee of Honghui Hospital Affiliated to Xi'an Jiaotong University (NO. 202111002), and all patients provided written informed consent to participate in the study and for all operative procedures performed.-up > 12 months, a calcaneus malunion of type II or III according to the Stephens–Sanders classification, extensive subtalar joint degeneration on imaging, significantly collapsed arches. The exclusion criteria were as follows: bilateral calcaneal fractures, poor skin healing at the original incision site, diabetes with blood glucose that was not well controlled, history of systemic osteoarticular diseases such as rheumatoid arthritis and Charcot’s joint, and incomplete follow-up data. We retrospectively analysed 11 patients that met the inclusion and exclusion criteria from June 2018 to October 2020. All patients underwent Y-shaped calcaneal osteotomy and subtalar arthrodesis, and the operations were performed by the same physician. The patient information is shown in Table The inclusion criteria were as follows: calcaneus malunion > 6 months, last followThe patients were placed on a radiolucent operating table in the contralateral decubitus position of the injured limb, and they were placed under general anaesthesia and had epidural anaesthesia. An L-shaped extended lateral incision was made to expose the subtalar joints and fractured fragments. Three 2.0 mm Kirschner wires were used to drill into the distal fibula, talus neck, and cuboid through the incision, and the full-thickness flap was lifted by bending the Kirschner wires to expose the lateral wall of the calcaneus and the subtalar joint. The lateral wall of the calcaneus was repaired with a pendulum saw, and the remaining bone fragments were saved Fig. A. At 1 cAfter cold compression for 24 h, routine second-generation cephalosporin antibiotics were administered postoperatively for 48 h to prevent infection, and the drainage tube was removed. Passive and active motion exercises of the metatarsophalangeal joint without weight bearing were initiated the day after surgery. The wounds healed without infection, and all stitches were removed after 2 weeks. In addition, non-weight-bearing functional training, such as cycling, was encouraged while the patient was in bed. The patient would apply a removable boot for 6–8 weeks and remain non-weight bearing. At 6 weeks, the patient was seen in the office and radiographs were obtained. And they may begin to walk with the walking boot, depending upon their level of discomfort. And partial weight-bearing (20–30 kg) was allowed as soon as the patient tolerated it. Stationary bicycle training could be carried out, and resistance training could be gradually increased after 8–10 weeks. Gradual weight-bearing exercises were started, and X-rays taken 12 weeks after the operation showed complete fracture healing and enabled clearance for bearing weight.X-ray and CT scans were obtained in all patients before surgery, after the operation and at the latest follow-up. The patients underwent clinical assessment and were analysed. The functional assessment was performed preoperatively and at the latest follow-up clinic visit based on the American Orthopaedic Foot and Ankle Society (AOFAS), visual analogue score (VAS) and SF-12 . MoreoveStatistical analyses were performed with SPSS 25.0 software. A Shapiro‒Wilk test for normality was conducted on all continuous data, and continuous variables were presented as the mean ± standard deviation. If the results revealed a normal data distribution, the paired sample t test was used for intragroup comparison. If the data were abnormally distributed, the nonparametric Wilcoxon signed-rank test was used for intragroup comparisons. The level of significance was set at 0.05 for all analyses.p < 0.05). Meanwhile, the mean AOFAS score increase was 50; the mean VAS score decrease was 5. The SF12-PCS and SF12-MCS scores were significantly improved at the last follow-up, with increases of 20.55 and 15.98, respectively . A representative case is shown in Fig. Compared to the preoperative values, the calcaneal width and Hindfoot alignment angle had decreased by the last follow-up, whereas the Böhler angle, Calcaneal Pitch angle and Talocalcaneal height had increased by the last follow-up  and sural neuralgia . Of the patients, one patient had skin incision necrosis that resolved with dressing changes. The other patient had sural nerve injury and was administered neurotrophic drugs. At the last follow-up, the patient complained that there was still a sense of numbness in the dorsal foot during the aggravation of daily activities, but it was significantly less than that before the operation. The late postoperative complications (1 year or more) included ankle pain , which intensified after activity. However, the patient could almost resume his daily activities without crutches. We suggested strengthening his rehabilitation program to alleviate the pain.The pathological anatomy of calcaneal malunion is complex and diverse, but there are some commonalities. First, under high-energy trauma, as little as 2 mm of displacement along the articular surface of the subtalar joint can greatly alter the contact pressure, while conservative, non-anatomical reduction and irreversible damage to the cartilage by primary violence may further develop into posttraumatic arthrosis . Severe Determining the efficacy of different surgical treatments can help doctors formulate different treatment plans according to the patient's condition. Agren et al.  performeCarr et al.  first adt = 1.131, P = 0.284; t = 0.168, p = 0.870), suggesting that the study population in this group recovered to ideal physical and mental health. Subjectively, the patients were very satisfied with the fusion results, all patients returned to their daily life and work, and 4 patients could even perform high-intensity mountain climbing exercises.Huang et al.  performeFletcher et al.  systematWound healing problems and infections are a frequent complication, reported around 20–45% of patients when extensile lateral approach has been used .Sinus taTherefore, we believe that Y-shaped osteotomy and subtalar arthrodesis may have the following advantages: (1) by sliding the posterior osteotomy to the plantar side, problems such as calcaneal height and traumatic flatfoot are improved. (2) By internal/external sliding of the posterior calcaneal osteotomy block, the angulation deformity of the calcaneal axis is improved, and the lower limb force line is better restored. (3) Through the lateral calcaneal incision, it is convenient to fully remove the lateral wall of the calcaneal bulge so that the calcaneal width can be restored to normal, and the peroneal tendinopathy caused by subfibular impingement can be solved. At the same time, the lateral wall bone fragment can be implanted into the calcaneus "Y"-shaped osteotomy, which reduces the loss of the calcaneal length. (4) By adjusting the middle osteotomy block, not only is the contact of the collapsed subtalar articular surface more sufficient and matched, additional allograft filling is unnecessary. The subtalar articular surface can also be clearly exposed during the operation, which is convenient for the surgeon to thoroughly clean the damaged subtalar cartilage. Both of these abilities further improve the bony fusion rate of the subtalar joint. However, the method is accompanied by obvious shortcomings: (1) Although the calcaneus length problem is alleviated by filling the calcaneal body with lateral wall fragments, the calcaneal length may not be fully restored. (2) Due to Y-shaped osteotomy, there is a large amount of skin tension, and complications such as delayed wound healing and infection can easily occur.There are several limitations to this study. First, this was a single-centre retrospective case series with inherent limitations of the study design, further prospective studies are needed. Second, the number of cases was limited, and the follow-up duration was short, which could have an impact on the results. Third, our study did not involve a control group. It may be interesting to compare the clinical and radiologic changes following our technique versus the changes seen following distraction subtalar arthrodesis.In summary, Y-shaped calcaneal osteotomy and subtalar arthrodesis have a significant clinical effect on calcaneal malunion and can effectively restore the calcaneal height, width and alignment. At the same time, the matching degree of the subtalar joint is adjusted without bone grafting, which effectively reduces the formation of nonunion after subtalar joint arthrodesis and adds a new surgical method for the treatment of complex calcaneal malunion.