Disseminated intravascular coagulation (DIC) is a common complication in sepsis. Since DIC not only promotes organ dysfunction but also is a strong prognostic factor, its diagnosis at the earliest possible timing is important. Thrombocytopenia is often present in patients with DIC but can also occur in a number of other critical conditions. Of note, many of the rare thrombocytopenic diseases require prompt diagnoses and specific treatments. To differentiate these diseases correctly, the phenotypic expressions must be considered and the different disease pathophysiologies must be understood. There are three major players in the background characteristics of thrombocytopenia: platelets, the coagulation system, and vascular endothelial cells. For example, the activation of coagulation is at the core of the pathogenesis of sepsis-associated DIC, while platelet aggregation is the essential mechanism in thrombotic thrombocytopenic purpura and endothelial damage is the hallmark of hemolytic uremic syndrome. Though each of the three players is important in all thrombocytopenic diseases, one of the three dominant players typically establishes the individual features of each disease. In this review, we introduce the pathogeneses, symptoms, diagnostic measures, and recent therapeutic advances for the major diseases that should be immediately differentiated from DIC in sepsis. Of note, even if the PT ratio and the level of fibrin/fibrinogen degradation products are elevated, the possible coexistence of other diseases should be considered when the changes in patients’ coagulation status do not correlate with their clinical courses of infection. If patients have a normal PT ratio or level of fibrin/fibrinogen degradation products but show the findings of MAHA, i.e., elevated levels of LDH, total bilirubin, decreased haptoglobin, and schistocytosis, the presence of TMA is suspected. The patient should be evaluated for presence of STEC-HUS by assessing symptoms of enterocolitis and by examining for presence of STEC using a culture-based assay, serological assessment, or polymerase chain reaction. While, if the patients do not show abdominal symptoms and fever, aHUS, TTP, and secondary TMAs are differentiated. With respect to the usefulness of this algorithm, since this diagnostic approach has just been proposed, the validation should be performed in the future study. When the presence of MAHA is ruled out, diseases other than TMA, such as HIT, ITP, and others, are the candidates for the consideration; if the presence of MAHA is confirmed, the likelihood of TMAs is high and the initiation of plasma exchange will be considered. In severe cases, plasma exchange is recommended to be initiated within 4–8 h; however, if the response is not sufficient, diseases other than TTP, such as aHUS or secondary TMA, will be suspected again. For the discrimination in secondary TMA, the use of check sheet is helpful (Fig. A provisional diagnostic algorithm was constructed based on the above review Fig. . First, Besides DIC, thrombocytopenia can occur in response to various backgrounds in patients with sepsis. For the appropriate management of thrombocytopenia, early diagnosis and the urgent initiation of proper treatments are crucial. Therefore, we have proposed a new diagnostic algorithm that enables a rapid diagnosis. Since recent advances in diagnostic tests and therapeutics have been remarkable, it is now mandatory to recognize the pathophysiology of individual diseases correctly. We also emphasize that we have to keep in mind that since most of the differential diseases are quite rare, the high-quality evidence that supports the therapeutics is still lacking. Future study is warranted in this area. This review summarized the pathogenic and clinical features of the major thrombocytopenic conditions.


Rating the quality of a body of evidence is an increasingly common component of research syntheses on intervention effectiveness. This study sought to identify and examine existing systems for rating the quality of a body of evidence on the effectiveness of health and social interventions.We used a multicomponent search strategy to search for full‐length reports of systems for rating the quality of a body of evidence on the effectiveness of health and social interventions published in English from 1995 onward. Two independent reviewers extracted data from each eligible system on the evidence domains included, as well as the development and dissemination processes for each system.Seventeen systems met our eligibility criteria. Across systems, we identified 13 discrete evidence domains: study design, study execution, consistency, measures of precision, directness, publication bias, magnitude of effect, dose‐response, plausible confounding, analogy, robustness, applicability, and coherence. We found little reporting of rigorous procedures in the development and dissemination of evidence rating systems.We identified 17 systems for rating the quality of a body of evidence on intervention effectiveness across health and social policy. Existing systems vary greatly in the domains they include and how they operationalize domains, and most have important limitations in their development and dissemination. The construct of the quality of the body of evidence was defined in a few systems largely extending the Grading of Recommendations Assessment, Development, and Evaluation approach. Grading of Recommendations Assessment, Development, and Evaluation was found to be unique in its comprehensive guidance, rigorous development, and dissemination strategy. While assessing risks of bias in each Systems for rating the quality of a body of evidence typically involve an examination of various characteristics of evidence that ultimately results in a rating of that body of evidence. For example, in the GRADE approach, the process of rating starts with a consideration of the designs of included studies: If the body of evidence contributing to an outcome consists of randomized controlled trials (RCTs), the quality of a body of evidence is initially given a rating of “high,” while a body of evidence consisting of nonrandomized studies is initially given a rating of “low.”As use of evidence rating systems has increased, so have reports of challenges faced by those attempting to use these systems—particularly for research syntheses on social and public health interventions, which are often described as “complex.”1.1In view of the challenges reported in applying quality of a body of evidence rating outside of biomedical settings and interventions,The key objectives of this systematic review therefore are to (1) identify existing systems for rating the quality of a body of evidence on intervention effectiveness across health and social policy, (2) examine how these systems describe the construct of the quality of a body of evidence and map out discrete domains they use to rate that quality, and (3) describe the reported procedures used to develop and disseminate the systems.The resultant “state of the field” map of the systems can be used by any reviewer to identify and adopt systems and domains for rating the quality of a body of evidence that are relevant for their specific needs.22.1body of evidence, derived from evidence synthesis that integrates results across individual studies on the effectiveness of health or social interventions, and (2) be published in English from 1995 onward, when evidence rating was first proposed as a stage of research synthesis.Methods of this systematic review are described in detail in an a priori developed protocol see . To be i2.2We used a multicomponent search strategy with multiple sources in an attempt to maximize the sensitivity of the search. First, we updated search strategies used in previous systematic reviewsScreening of all titles, abstracts, and full‐text documents was conducted by the first author (AM) by using the Rayyan web application for systematic reviews.2.3We extracted data on 4 types of information. First, we extracted descriptive information about included systems, namely, the author, year, title, publication source, and eligibility criteria. We then extracted information from each system on how its authors defined the construct of the quality of a body of evidence. We further extracted details of specific domains within the system used to rate the quality of a body of evidence, how these domains were defined, and how ratings of the quality of a body of evidence were categorized . Extending the prespecified domains for development and dissemination of research reporting guidelines,The first author (AM) and a second independent reviewer (either JD or a research assistant) extracted information about the content, development, and dissemination of the included systems into a Microsoft Excel spreadsheet. Three independent reviewers  piloted the data extraction form on the same evidence rating system before continuing with the remaining systems.2.4We employed a 3‐step procedure to describe the domains of evidence for rating the quality of a body of evidence in the included systems. First, we created an inventory of all identified domains by using cross‐case tables.3We identified 11,758 records after duplicates were removed. After title and abstract screening, we assessed the full texts of 141 records, from which 28 records were found to be eligible for inclusion in this review. Overall, these 28 records describe 17 evidence rating systems . Twenty‐nine records described procedures and domains for categorizing interventions on websites of different “what works” organizations, also known as evidence clearinghouses or evidence‐based program registers.3.2Fourteen of the included systems were developed for healthcare, including general clinical and public health interventions  of a preventive service is correct.”the extent of confidence that an estimate of the effect is adequate to support a particular decision or recommendation.”Only 6 systems—3 of which are largely based on the GRADE approach—provided a definition for the construct of the quality of a body of evidence on intervention effectiveness.chain of evidence” diagrams to map out the specific linkages in the overall chain of evidence that must be present for a preventive service to be considered effective.coherence of evidence assessment in the GEPHI system.To assess the net benefit of a preventive service, the USPSTF system uses analytic frameworks, also called “3.4The evidence domains used to rate the quality of a body of evidence were often similar in concept across systems yet different in how they were described and operationalized. We encourage readers to use Table 3.4.1Twelve systems included an evidence domain related to the design of the individual studies constituting the body of evidence. All but 4 of these systems3.4.2quality of study execution, risk of bias, study limitations, and study quality). In most instances, however, systems mainly included criteria to assess risks of bias or threats to the internal validity for assessing study execution. A few systems, however, also included specific criteria for assessing the generalizability of the study results, that is, criteria related to the external validity of the individual studies in the body of evidence.Fifteen systems included an evidence domain related to assessing how well studies constituting the body of evidence were executed to minimize threats to internal and external validities  and events (for dichotomous outcomes) that would be needed to regard a body of evidence as having adequate power.”Eleven systems included an evidence domain that we have classified as relating to 3.4.5directness, applicability, and generalizability of evidence interchangeably and inconsistently—often without providing clear definitions or specific criteria to guide the assessment.In general, the systems used concepts of 3.4.6publication bias as a domain for rating the quality of a body of evidence.a failure to identify studies as a result of studies remaining unpublished or obscurely published.”Five systems included 3.4.7magnitude of effect as a distinct domain to rate the quality of a body of evidence on the effectiveness of health or social interventions.We identified 7 systems, which included 3.4.8dose‐response as a distinct domain of evidence when rating the quality of a body of evidence on the effectiveness of health or social interventions.pattern of a larger effect with greater exposure to an intervention.”Overall, 5 systems considered 3.4.9if all plausible residual biases would diminish the observed effect, or if all plausible residual biases would suggest a spurious effect when no effect is observed.”All systems that followed the structure of the GRADE approach  considered counteracting confounding, as a domain to upgrade the quality of a body of evidence, when a body of evidence is mainly composed of observational studies.3.4.10Only 1 system—the GEPHI system—included an evidence domain related to analogous evidence. The GEPHI system operationalized analogous evidence as supporting evidence from similar or “analogous” interventions that are known to operate through the same or similar mechanisms, which, if present, could lead to a higher quality of a body of evidence rating.3.4.11confidence intervals of the last three cumulative, random‐effects meta‐analyses remain fully on the same side of zero after removing of the study with the smallest weight.”Robustness of evidence was described as a domain to rate the quality of a body of evidence by one system.3.4.12how closely the available measures an outcome of interest” and relies on 2 judgmentsFour systems described applicability as a domain of evidence measuring the extent to which evidence may be applicable in a specific context.3.4.13coherence of evidence) regarding the evidence informing each individual link in the causal pathway.if the theoretical basis is not known, the strength of evidence will be less convincing.”Only 3 systems included an evidence domain related to assessing the coherence of the causal pathway of an intervention3.5Figure Regarding the write‐up and dissemination activities, only 3 systems described how the publication introducing the system was developed,44.1This systematic review set out to describe the content, development, and dissemination of the systems for rating the quality of a body of evidence on intervention effectiveness across health and social policies. The review identified 17 systems that have made useful contributions to rating the quality of a body of evidence in health and social research synthesis. While this review identified domains of evidence that were commonly reported across the systems, there was significant variation in the specifications for these domains. The systems used different terminology to denote similar constructs of evidence when rating the quality of a body of evidence. The systems also varied in how they operationalized the domains of evidence, that is, in whether they described specific criteria and provided guidance for assessing each domain in an operationalizable manner. This review also identified domains of evidence that were found only in a few systems  included in the body of evidence. There are, however, concerns that this approach only partly reflects the central tenet of scientific method, specifically that findings are replicable across “a variety of situations and techniques.”the true effect for a specific outcome lies on one side of a specified threshold or within a chosen range.”Our review identified very few instances where the systems provided a definition for the construct of the quality of the body of evidence (see section Regarding the activities underpinning the development and dissemination of the included systems, our review found that most systems did not report a comprehensive literature review or a consensus‐based procedure for developing the system (see Figure 4.2This review's unique contribution may lie in its thorough exploration of the content, development, and dissemination of the existing systems for rating the quality of a body of evidence across a range of policy areas, following systematic searches of bibliographic databases and sources of gray literature. Consequently, this review provides a comprehensive inventory of evidence domains considered when assessing quality of a body of evidence in research syntheses on intervention effectiveness across not just health, but social policy as well. Considering the acknowledged challenges associated with locating evidence rating systems through formal literature searches,We note several limitations worth considering when interpreting our findings. First, we had to limit the scope of our review because of practical considerations. For instance, we included documents published in English only and therefore might have missed relevant work from the non‐English literature. Furthermore, given the identified variation in the terminology of the evidence domains, the mapping of these domains necessarily involved a degree of interpretation. It is therefore possible that another team of reviewers might have produced a different mapping of the domains with different conceptual categories. For example, another review team may have interpreted the broad evidence domain of the “efficacy data” of the Highest Attainable Standard of Evidence system4.3The mapping of evidence domains presented in this review aims to clarify how domains of evidence for rating the quality of a body of evidence on intervention effectiveness have been specified, developed, and disseminated across health and social policies. We see 2 broad applications of our mapping of evidence domains. First, it can serve as an aid for researchers to help choose the evidence rating system and corresponding domains of evidence most suitable for their research focus and context of work. Second, by delineating important gaps in the content, development, and dissemination of current systems, it can indicate areas that may need further methodological development. It is worth noting that our mapping of domains should not be regarded as an expert advice on the best system for assessing the quality of a body of evidence on intervention effectiveness, but rather should be considered as a “state of the field” description and interpretation of the content and the processes of development and dissemination based on the information reported in the included systems.File S1. Review protocolFile S2. Specification of the evidence domains in the included evidence rating systemsClick here for additional data file.


Hardly any other medical intervention is as directly relevant for life-and-death outcomes as cardiopulmonary resuscitation (CPR). One would have expected, therefore, extensive evidence from rigorous randomized controlled trials (RCTs) for fine-tuning best approaches that maximize CPR effectiveness. However, this is not the case. Professional guidelines reflect little tangible progress, and recommendations are not driven by strong effects seen in RCTs.To map the landscape of meta-analyses of RCTs on CPR, we searched PubMed  for “cardiopulmonary resuscitation AND meta-analysis AND (randomized OR randomised).” We screened 114 retrieved items for meta-analyses of RCTs in real patients (not education or simulation/manikins), addressing aspects pertaining to CPR per se rather than interventions done afterwards  and using survival and/or neurologically intact survival as outcomes. Whenever multiple overlapping meta-analyses existed, we kept all of them if they were published after 2013, to examine consistency of results.The available evidence Table  suggestsp value. However, this precision is misleading because potential bias may completely invalidate this conclusion.This rather disheartening evidence pertains largely to short-time follow-up. Longer-term outcomes are essential to make informed choices, but these data are rarely available from RCTs. One can try to supplement the evidence gap with observational datasets, and this is becoming increasingly convenient as large datasets become routinely available. However, for what are likely to be modest or subtle differences, it is unlikely that observational data will be sufficiently error-free to be conclusive. Many observational studies in this field claim sizeable survival differences, but their credibility is questionable—they need to be validated in carefully done RCTs . For exaIn contrast to massive observational datasets, the RCTs done to-date and even their meta-analyses have usually had rather limited sample sizes. Clinically meaningful differences between the tested interventions may still have been missed, e.g., 20% relative risk differences in survival cannot be completely excluded for anything that has been tested to-date. This suggests that we need much larger RCTs in this field. Given that CPR is so commonly required, large simple trials should be feasible to do in large enough health care structures. It is important to instill in the future research agenda a strong element of pragmatism, so that the results would be more directly applicable to real-life circumstances. CPR is a good example where “point of care” randomization should be feasible without obtaining consent first given the nature of the intervention. Randomization should be the default option for CPR encounters if a protocol has been approved and set in place. RCTs with sample sizes in the tens of thousands of participants should be the goal.A challenge in conducting such large-scale pragmatic RCTs is to avoid diluting the potential therapeutic effects by poor choices in the background management of the resuscitated patients. For example, an intervention may be effective by itself, but whatever benefit it produces may be lost if the patients undergo low-quality chest compressions or if they are then sub-optimally managed in the intensive care setting, e.g., improper choices are made for hypo- or hyper-ventilation. Meeting both pragmatism and some essential quality standards needs careful design and proper background training of the resuscitating and managing teams.Another challenge is selecting the proper dose of various interventions to be tested. Several standard choices in the CPR ritual have little evidence to support that the dose, intensity, timing, or frequency used is optimized. For example, the standard dose of adrenalin (1 mg) is largely based on an experiment done over a century ago in 10-kg dogs, in which adrenaline was given at a dose of 0.1 mg/kg. While we have some randomized evidence on higher doses, we have no evidence on lower than standard doses. Timing may also be important. For example, another high-profile recent trial  administFinally, single interventions may have very limited efficacy and effectiveness, but their combination may manage to achieve a breakthrough in success rates. Testing this hypothesis would require running factorial trials, where two randomizations are performed concurrently. Then, one can assess both interventions as well as their joint effect in a statistically efficient manner.CPR may save lives, and optimizing it should not be left to chance. A rigorous agenda of large pragmatic RCTs is long due. With simple design, the cost of these trials can be minimized, since data collection would pertain to only the most relevant information. Health care systems, insurances, and public agencies could make excellent investments in funding such trials.


Background: Evidence suggesting adverse drug reactions often emerges unsystematically and unpredictably in form of anecdotal reports, case series and survey data. Safety trials and observational studies also provide crucial information regarding the (un-)safety of drugs. Hence, integrating multiple types of pharmacovigilance evidence is key to minimising the risks of harm.Methods: In previous work, we began the development of a Bayesian framework for aggregating multiple types of evidence to assess the probability of a putative causal link between drugs and side effects. This framework arose out of a philosophical analysis of the Bradford Hill Guidelines. In this article, we expand the Bayesian framework and add “evidential modulators,” which bear on the assessment of the reliability of incoming study results. The overall framework for evidence synthesis, “E-Synthesis”, is then applied to a case study.Results: Theoretically and computationally, E-Synthesis exploits coherence of partly or fully independent evidence converging towards the hypothesis of interest (or of conflicting evidence with respect to it), in order to update its posterior probability. With respect to other frameworks for evidence synthesis, our Bayesian model has the unique feature of grounding its inferential machinery on a consolidated theory of hypothesis confirmation (Bayesian epistemology), and in allowing any data from heterogeneous sources , and methods  to be quantitatively integrated into the same inferential framework.Conclusions: E-Synthesis is highly flexible concerning the allowed input, while at the same time relying on a consistent computational system, that is philosophically and statistically grounded. Furthermore, by introducing evidential modulators, and thereby breaking up the different dimensions of evidence , E-Synthesis allows them to be explicitly tracked in updating causal hypotheses. The United States Department of Health and Human Services reports that although medications help millions of people live longer and healthier lives, they are also the cause of approximately 280,000 hospital admissions each year and an estimated one-third of all adverse events in hospitals . The provia the aggregation of evidence is rapidly growing. The recent focus has been on various aspects of causal assessment based on heterogeneous evidence. Some examples include work on aggregating human and animal data  reviews and comparisons of evidence synthesis methods . A numbeTraditional approaches supporting drug-licensing decisions are reviewed in  and the However, the number of approaches that attempt to tackle the issues of aggregating different types of evidence to facilitate causal assessment of adverse drug reactions (assessing whether a drug causes an adverse reaction) straight on is rather small. One such approach is an epistemological framework based on Bradford Hill’s well-known guidelines , which cOur work is rooted in the tradition that draws on statistical information and probabilsitc (in)dependence for the purpose of causal assessment. Challenges to Bayesian causal assessment have been raised by This paper is a first step towards translating the philosophical approach to causal assessment of suspected adverse drug reactions of  towards Here, we are mainly concerned with further developing the framework and how to – in principle – operationalise our approach. Delineated functional forms and some  probabilities serve only illustrative purposes. The focus is on how to determine them in principle and highlight roles and interactions of relevant concepts. Hence, significant further work is required before the framework is a ready-to-use tool.E-Synthesis is a theoretical framework for causal assessment based on , we brieThe framework in  aims to E in population U.” To facilitate the inference from all the available evidence, indicators of causality are used. These indicators are based on Hill’s nine viewpoints for causal assessment  and see  and study duration (D)], and systematic error; attenuated by adjustment or stratification (A), randomisation (R), blinding (B), placebo (Pl) and sponsorship bias (SB).The causal hypothesis represented by © is a root node.This framework also allows for the incorporation of evidential modulators related to external validity [called “relevance” in ], howeveA probability function consistent with the conditional independencies of the Bayesian network is selected which expresses our uncertainties in the tradition of Bayesian epistemology . Unlike While a certain degree of subjectivity is undeniable, there is a good argument to be made that some subjectivity is unavoidable in any approach to statistical/uncertain inference  and thatConcepts of interest fall into two classes: i) a class of causal concepts comprising the hypothesis of interest and the indicators of causation and ii) a class of evidential concepts comprising evidential modulators and reports (data).E in a population U – given the available evidence. Although the hypothesis space could be in principle subdivided into three hypotheses: 1) 𝒟 causes E, 2) 𝒟 hinders E, and 3) 𝒟 does not cause E, we divide it here for simplicity’s sake into two alternative hypotheses: 1) 𝒟 causes E and 2) 𝒟 does not cause E, which consists of the disjunct of 2 and 3 above. To shorten notation, we use the symbol © in order to denote causation, such as in 𝒟©E, or simply ©.We are interested in determining the probability of the causal hypothesis that a drug 𝒟 causes a particular adverse effect Causal inference is mediated in the framework by “indicators of causation” in line with the Bradford Hill Guidelines for causation. As Hill puts it :“None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non. What they can do, with greater or less strength, is to help us make up our minds in the fundamental question – is there any other way of explaining the set of facts before us, is there any other equally, or more, likely than cause and effect?”In epistemic terms, causal indicators can be considered as observable and testable consequences of causal hypotheses, albeit non-deterministic consequences (with one exception); that is, they are more likely to be observed in the presence of a causal relationship and less likely in its absence, The first indicator “difference-making,” Δ, is a perfect one, in that it entails causation. However, note that in our framework Δ is not entailed by causation. All other indicators are related only probabilistically to the hypothesis of causation, as we now explain.E stand in a difference-making relationship, then changes in 𝒟 make a difference to E (while the reverse might not hold). In contrast with mere statistical measures of association, the difference-making relationship is an asymmetric one. Probabilistic dependence can go in both ways ; the same does not hold for difference making, which provides information about its direction. This explains why experimental evidence is considered particularly informative with respect to causation; the reason is exactly that in experiments, putative causes are intervened upon, in service of establishing whether they make a difference to the effect.If 𝒟 and Mutatis mutandis, this convention applies to the following three indicators as well.Consistent with our choice of modelling “positive” causation only (that is instances of causation where X fosters rather than inhibiting Y), we shall understand this difference-making indicator as being true, if and only if the difference made is a positive one. PD encodes whether 𝒟 and E are probabilistically dependent or not – such dependence naturally increases our belief in some underlying causal connection  monotonic growth for a significant portion of the range . The indicators of causality RoG, DR, PD are independent of the causal structure, in the sense that they could be equally observed either in cases where 𝒟 causes E, or in cases where E causes 𝒟, or when 𝒟 and E have a common cause. All that matters is whether there is a (certain) systematic relationship between 𝒟 and E. RoG, DR, PD are semantically and epistemically related and we refer to them as statistical “black-box” indicators, denoted by Σ.This indicator refers to the presence of a steep slope in the dose-response relationship. Hence, M represents the proposition: “there is a mechanism for 𝒟 to E”: by which we mean a “linkage between a direct molecular initiating event [..] and an adverse outcome at a biological level of organization relevant to risk assessment” , which can refer to temporal order, distance, or duration. If 𝒟 causes E, T must hold (as a necessary condition): © ⇒ T. T remains an imperfect indicator, nevertheless, because temporal precedence is also compatible with ¬(𝒟 causing E) when 𝒟 and E are connected by a common cause or through reversed causation. Hence T ⇒ © does not necessarily hold.PD, DR, RoG, M, T) provide support for the causal hypothesis © once concrete studies provide concrete evidence for these indicators. As mentioned above, since they are observable consequences of ©, the causal indicators . This reflects our intention to demarcate the conceptual divide between purely observational (symmetric) and genuinely interventional (asymmetric) indicators. Moreover, M entails T in that if there exists a mechanism linking the drug and the side effect, then it must be the case that drug administration and side effect stand in the right temporal order.The presence of a high rate of growth, The model in  was deveEvidential Modulators: Study Design and Application of the Model: Does Paracetamol Cause Asthma?, we show how the current model can be applied to the debated causal connection between paracetamol and asthma.In this paper, we allow for continuous variables taking values in the entire unit interval  ⊂ ℝ, discuss and model in detail the inferential roles of evidential modulators and thereby improve on the model of reliability , or vice versa . Indeed, a plausible interpretation of the criterion underpinning the evidence hierarchies is the maximisation of internal validity, see also .However, in our view, study design also determines the kind of information that the evidence is able to provide, hence we evaluate the evidence also on the level of the kind of information it delivers: that is, the causal indicator it is able to “speak to.”Following point 1, we associate distinct types of study design as potential carriers of causal indicators as follows:Randomised Controlled Trials (RCTs) provide information about difference making, time course, possibly also dose-response relationship and rate of growth.Cohort studies provide evidence of time course and statistical association (Σ).Case-control studies provide information about Σ only.Individual case studies cannot provide information about statistical association, but they provide very detailed information about time course and, possibly, difference-making, whenever this can be established with confidence [see for instance the Karch-Lasagna or Naranjo algorithm ]. HoweveCase series can possibly help delineate a reference class, where the putative causal link holds.in vitro, or in silico), and in vivo studies, are generally the main source for evidence on the mechanisms underpinning the putative causal link.Basic science studies  is the innovative point of our approach with respect to the standard view, in which these aspects are conflated, or, at least, remain implicit, in evaluating and using evidence in order to make decisions. The reason for adopting such an approach is twofold:To avoid conflation of distinct ways in which the available evidence bears on the hypothesis of interest. Among others, this characterization, makes more explicit what distinguishes one method from another in terms of relevant causal information, rather than of the degree to which it avoids systematic error;In our framework, evidence supports the causal indicators which in turn support the causal hypothesis of interest, each to a different degree. Hence, downgrading the evidential value of studies that feed into the weaker indicators just because of the kind of information they cannot provide, would amount to double-downgrading such evidence. For instance, evidence coming from observational studies is uninformative with respect to the Δ indicator, but may be highly informative with respect to statistical association (Σ).Therefore, the kind of study from which the evidence derives is directly specified by the kind of indicators to which it speaks, which be found on the right side of the conditional probability (see Section 2 in the SS) and Study Duration (D). Control for systematic error is operationalised differently for experimental vs. observational studies. We assume that for pure observational studies, signal-tracking is limited to getting the statistical indicators right. We consider adjustment/stratification as relevant procedures in this respect.Additionally, studies are weighted by their degree to which they control for systematic and random error. Control for random error is operationalised in terms of Sample Size . In the following, we discuss these evidential modulators in more detail.Instead, for experimental studies, signal-tracking relates to getting the E-Synthesis, sponsorship bias shifts probabilities towards reports of greater safety. (Sub-conscious) biases may instead push researchers in both directions, with a higher prevalence towards reporting more publishable results: this means statistically significant evidence and/or counter-intuitive and surprising results.In the future, we hope to analyse and incorporate further modulators such as dropouts, missing data, protocol violations, whether analysis was by intent to treat and the presence or absence of further biases into our approach. For example, regarding harm assessment, which is the focus of the present study and the main goal for developing Our Bayesian model is sufficiently powerful to capture uncertainties arising from inherent difficulties in assessing the degree to which studies are controlled for systematic and random error.A large sample size helps to reduce confidence in the hypothesis that an observed effect (or lack thereof) is due to chance/noise/random error. The larger the sample size, the less defeasible the inference one may draw from reported results (modulo systematic error).Most drugs produce their beneficial effects within a time horizon that is well-understood at the time of drug prescription. Instead, some adverse drug reactions, such as stroke, heart attack, and cancer, may be noted only a long time after the end of the treatment. A priori, it is not clear after how long the adverse effects will materialise. Infamous examples are the DES tragedy of causing vaginal adenocarcinoma in pubertal and adult children of treated pregnant mothers  and antiIn principle, the longer the follow up, the more likely adverse drug events will be detected. Studies with a short follow up period may thus fail to detect medium to long term effects of drugs, hence they tend to produce false negatives. A study with a short follow-up period, which does not detect an adverse effect, can only count as very weak evidence against the causal hypothesis, since the adverse reaction may occur only after the end of the follow-up period see . Howeverrandom error but short studies lead to a systematic under-reporting of harms. This explains the position of the duration node in So, study duration affects not excluded other factors that may have caused the results. For example, consider a large study that is biased in an important respect, then – when evidence is taken at face value – one may become even surer that one has nailed down the effect size of the phenomenon of interest, erroneously so , that the treatment and the control group are comparable with respect to all these possible additional causal influences, and therefore that the observed effect is due to the treatment and only to it, see , since evidence for these indicators draws on the observed effect difference putative causes are compared against each other, without any knowledge as to their causative status, and no absolute benchmark , then such relative comparison against each other only provides information about relative difference making, that is, one is not able to establish whether e.g. 1) drug 𝒜 produces an improvement of symptoms, 2) or it is drug ℬ that worsens the situation by the same amount, 3) or else, both drug 𝒜 and ℬ have opposite effects with respect to such symptoms .In fact, if the effects of distinct E in some way, while the former can be taken as benchmark(s).There are cases that can be disambiguated though, for instance when at least one of the arms but not all of them show a dose-response relationship. In this case, the very fact that some drugs do not exhibit such dose-response relationship, and some do, is taken as a sign that the latter do contribute to Even when no such disambiguation is feasible, there is still a possibility to glean some information about Δ in experimental studies, by comparing the study outcomes to the base rate incidence of the same outcome measure in the sampled population. Like many other steps in causal inference this step is fraught with risks. The more tenuous the connection between study outcome and the base rate, the more risky the step. In our framework, this risk is captured by employing different values of the evidential modulator representing the quality of the implementation of placebo control.for the right covariates, in a sufficient causal set leads us to detecting non-spurious statistical associations, whereas conditioning on the wrong variables leads us astray and increases the chance of false positives and negatives, see, e.g., , still, well-known incentives to the distortion of evidence may arise through vested interests, and compromise the reliability of the evidence at different stages of evidence collection, interpretation and evaluation quite independently of the methodology adopted . Other tbias produces “more accurate” data when no side-effects are present in reality.One persistent bias in medical research is the sponsorship bias due to the interests of the organisations funding medical research, see, e.g., . One draRegulatory constraints on medical methodology have evolved with such sources of bias in mind, see . HoweverThis section lists three possible evidence types which may be observed with respect to causal hypotheses in medicine. A certain  measure as to the effect size, evidence regarding the possible mechanisms underpinning the “phenotypic” effect, and evidence of time course (which can only come jointly with one of the other two).The medical community has developed various popular measures of the strength of observed effects: relationships between the odds ratio, hazard ratio and the relative risk are discussed in .19These measures all refer to the average observed effect difference in the study groups. However, other measures of causal strength refer to the systematic pattern that relates treatment and effect (dose-response relationship) and to the rate at which increase in dosage increases the observed effect (rate of growth).Evidence speaking for or against a mechanistic hypothesis stems from basic science or animal studies, and previously established pharmacological/biochemical knowledge. It is rarely the case that a study confirms or establishes a complete mechanism of action  given the evidential modulators. We assess the modulators for this study as follows: A = 0.5, SS = 1, D = 0, SB = 1, B = 1, R = 1, Pl = 0.5. We use This formula captures the idea that, if a study is good at tracking the signal, then the probability of observing the effect, given that the related statistical indicator holds, tends to 1. Instead, the worse the study is, the smaller the probability becomes. See Section 2 of the DR and T . For the modulators we have SS = 1, D = 1, SB = 0, A = 1 and thusM1 and M2) by which paracetamol may cause asthma.To focus the exposition, we only consider two possible mechanisms (M1: Paracetamol is metabolised to NAPQI (N-acetyl-p-benzoquinone imine) , NAPQI stimulates transient receptor potential ankyrin-1 (TRPA1)  [reported in µ1,3) [reported in M2: Paracetamol depletes Gluthatione  [reported in µ2,2) [reported in M to:We set the conditional probabilities of a mechanism given M1 and M2 to be likely, if M holds; M1 was assessed to be the more likely of the two. If M does not hold, then all Mi have to fail to hold and are hence assigned zero probability.We assessed µ1,k given M1 and given Mi entails µi,k and henceWe now turn to setting conditional probabilities of the µ1,1, µ1,2, µ1,3 and M1 fails to hold, then we are indifferent about µ1,3 and µ1,2 – independently of µ1,1 .If M1 holds or not) and hence putIn general, almost all effective drugs have toxic metabolites. We here take it as established that paracetamol is metabolised to NAPQI  as an example of a sensitivity analysis investigating the output (posterior probability of ©) on the input parameters.We computed the posterior probability of © using the Bayes Net Toolbox in Matlab R2012a and report the posterior probabilities in The  probabilities introduced above are a general example which may reflect the judgements of expert opinions. In concrete applications, these probabilities can and should heavily draw on real-world evidence and data. There is some work on how to determine such probabilities in this way, as we now briefly outline.DR, given the available dose-response evidence and its related modulators. The MCP-Mod algorithm  existence of a dose-response.Theoretically and computationally, E-Synthesis exploits coherence of partly or fully independent evidence converging towards the hypothesis (or of conflicting evidence with respect to it), in order to update its posterior probability. Propagation of probabilities hence work in a totally different sense than for causal DAGs . ProbabiWith respect to other frameworks for evidence synthesis , our BayBy introducing evidential modulators, and thereby breaking up the different dimensions of evidence  E-Synthesis allows them to be explicitly tracked in the body of evidence. This makes it possible to parcel out the strength of evidence from the method with which it was obtained.within one model, rooting in one hypothesis, but E-Synthesis allows for going beyond the network limits and for embedding it in an even larger network to trace the hypothesis relation with other potentially concurring hypotheses. The mechanics of Bayesian epistemology are flexible enough to permit such an augmentation for the purposes of tracing further inference patterns.via expert elicitation and the general formulae for the conditional probabilities of evidential variables (Section 2 in the This paper focuses on inference Discussion) and/or based on expert opinions, applications to further case studies to demonstrate the versatility of the framework, analysis and incorporation of further evidential modulators , analysis and incorporation of further biases , comparing E-Synthesis to other frameworks of causal assessment via applications to the same case study , the Marche Polytechnic University  and the Munich Center for Mathematical Philosophy . JL and FP worked at the paper as 100% research fellows within the project, whereas BO is the project PI. For the final phase of writing this manuscript JL gratefully acknowledges funding from the German Research Foundation for the grant agreements LA 4093/2-1 (Evidence and Objective Bayesian Epistemology) and LA 4093/3-1 . JL gratefully acknowledges funding from the Deutsche Forschungsgemeinschaft  - 432308570 and 405961989.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.


Recent systematic reviews and editorials suggest that many organizations that produce nutritional guideline recommendations do not adhere to internationally recognized standards set forth by the Institute of Medicine (IoM), Guidelines International Network (GIN), Appraisal of Guidelines Research and Evaluation (AGREE), and Grading Recommendations, Assessment, Development and Evaluation (GRADE).BMJ Rapid Recommendations project has recently demonstrated the feasibility and utility of this approach. Here, we are proposing trustworthy nutritional guideline recommendations based on internationally accepted guideline development standards, recommendations that will be informed by rigorous and novel systematic reviews of the benefits and harms associated with nutritional exposures, as well as studies on the values and preferences related to dietary behaviors among members of the international community.The potential solution is an independent group with content expertise and skilled in the methodology of systematic reviews and practice guidelines to produce trustworthy guideline recommendations, recommendations that are supported by publication in a top tier journal. The Adhering to international guideline standards, conducting high quality systematic reviews, and actively assessing the values and preferences of key stakeholders is expected to improve the quality of nutritional guidelines and their relevance to end-users, particularly patients and community members. We will send our work for peer review, and if found acceptable, we will publish our nutritional recommendations in top-tier general medicine journals. Globally, chronic non-communicable illnesses represent the largest burden of disease, and healthy eating habits may be a cornerstone to the prevention and management of chronic disease , 2. EvidDespite the evidence that nutrition may play a major role in curbing the burden of chronic disease, clinicians typically do not emphasize nutrition in their interactions with patients . The knoClinicians, including registered dietitians, require primary research and systematic evidence synthesis, including meta-analyses, to understand the available evidence; nutrition practice guidelines to provide appropriate interpretation of evidence and direction in its application; and user-friendly presentations and access to facilitate efficient uptake. Systematic syntheses of evidence are often, however, not available, or the syntheses that do exist are of limited rigor. For example, in systematic reviews and nutrition practice guidelines, important health outcomes  are often not optimally identified and synthesized, thus limiting our understanding of the impact of interventions on patient and community members’ lives .Evidence-based nutrition involves the integration of the best available evidence summaries, clinical and public health practice experience, and patient and community values and preferences , 11 , Appraisal of Guidelines Research and Evaluation (AGREE), the Grading Recommendations, Assessment, Development and Evaluation (GRADE) working group –16, and Despite these widely accepted standards for trustworthy guidelines and vastly improved methods and processes for their production, systematic surveys of over 1100 practice guidelines across a wide range of health topics indicate that guidelines continue to suffer from important limitations –19. An eIn the field of nutrition, previous systematic evaluations show similar methodological limitations , 20–22. Not only are conflicts of interest an issue in nutritional guideline recommendations, but also in systematic reviews and primary studies , 25. Altn = 296,707) revealed no evidence to support antioxidant supplements for primary or secondary prevention of diseases ) and on factors that may have a causal relation to cardiovascular outcomes (hypertension and cholesterol), or other adverse outcomes (haemoglobin)?With respect to red and processd meat consumption, most dietary guidelines suggest limited consumption of meat because of the reported association with cancer –40. Therhttps://www.crd.york.ac.uk/prospero/).Using the GRADE approach we will begin by working with our NutriRECS panelists to structure and refine our health care questions in terms of the population of interest, and the alternative dietary strategies (e.g. restricted versus unrestricted dietary patterns) based on the most important outcomes to the target audience. For all NutriRECS projects, the target outcomes will be selected based on importance to patients and members of the general community, and will be elicited prior to our conducting the systematic reviews of the literature based on discussions with our NutriRECS panel. Each NutriRECS project panel will have patients and members of the general community to ensure selected outcomes are of importance. Unlike dietary guidelines we are aware of, we will also work with NutriRECS panel to identify subgroups of interest  and will register the research question and systematic review protocol, including the subgroups of interest, in PROSPERO , typically presented by generating relative or absolute differences between high consumers (e.g. quantile 5) and low consumers (e.g. quantile 1) of a target exposure will be summarized and evaluated seperately from observational studies that assess dietary patterns . Subsequently, as a novel method, we will use the summary estimates for each to further asssess etiologic causal inferences. To do so, among outcomes with a statistically significant effect for a food or nutrient, if there is also a significant effect (with similar estimates) based on the dietary pattern data, this will be seen as evidence that undermines the casual inference for the target food or nutrient (e.g. processed meat).After consultation with the NutriRECS panel members, our research question, subgroups of interest and systematic review methods for red and processed meat and health outcomes has been publically registered with PROSPERO (ID=CRD42017074074).Subsequently, in duplicate, we will use GRADE methods to rate the certainty of evidence for each outcome across all eligible studies according to study design  and five factors that can reduce certainty of evidence  and three that can increase certainty . The certainty of evidence will reflect our confidence in the estimate of the effect.Our certainty in the potential desirable and undesirable effects of the interventions based on the body of evidence will then be considered in making a recommendation.Optimal nutritional guideline development requires consideration of patient and community values and preferences associated with dietary patterns. By values and preferences we refer to individuals’ predisposition to either favour (like) or not favour (dislike) something such as red meat . ModifyiWe will start by conducting a systematic review of the literature for evidence regarding peoples’ values and preferences in regards to red meat.For moving from the evidence to recommendations we will use the Evidence to Decision (EtD) frameworks. The purpose of Evidence to Decision (EtD) frameworks is to help people use evidence in a structured and transparent way to inform decisions in the context of clinical and public health recommendations. These frameworks summarize evidence, and its certainty, for benefits, harms and burdens, values and preferences, cost considerations, as well as equity, acceptability, and feasibility Table . This apThe EtD frameworks have a common structure that includes formulation of the question, an assessment of the evidence for each criterion, and drawing conclusions. EtD frameworks make explicit the criteria that are used to assess interventions or options, the judgments made by each panel member for each criterion, and the research evidence and additional considerations used to inform each judgment. Research evidence refers to facts  used to inform the panel’s judgments that are derived from studies that used systematic and explicit methods. Additional considerations include other evidence, such as routinely collected data, assumptions, and logic used to make a judgment. As a novel innovation in the field of nutrition guideline development, using EtD frameworks we will survey and collect the anonymous judgements of each panel member prior to making the recommendations and use these judgements for the purpose of panel discussions prior to making the final recommendations. This way, panel members who may be afraid to voice dissenting views during panel meetings will have an opportunity to make their views known. For instance, panel members may make different judgments for one or more subgroups (such as patients who are older or who have more severe disease) in relation to some or all of the criteria.Afterwards, panels review the judgments they have made for all of the criteria in their assessment and consider the implications of those judgments for the recommendation or decision. Based on their assessment, the panel draws conclusions about the strength of recommendation or type of decision; for example, a strong or weak  recommendation for or against an intervention or option.Finally, the panel states the recommendation or decision in a concise, clear and actionable manner, and provides the justification for their recommendation or decision. The conclusions also include relevant considerations about subgroups, implementation, monitoring and evaluation, and research priorities.We have formed an international NutriRECS Executive made up of systematic review and nutrition/public health experts , experts in guideline methods , and a community member with guideline experience . The Executive will determine the nutrition topics, the systematic review and practice guideline methods, review and approve conflicts of interest statements and decide whether they are acceptable and, if acceptable, how they will be managed.www.nutrirecs.com) and seek feedback from members of the public.Each NutriRECS question will be addressed by a panel including a chair, a methods editor, and upwards of 15 additional panel members from around the world. The chair will be responsible for the management of the NutriRECS guideline panel meetings, while the methods editor will be responsible for assembling the panel and review team, summarizing conflicts of interest for final assessment by the NutriRECS Executive, and creating relevant content . To produce the systematic reviews, Evidence Profiles, Evidence to Decision frameworks, and user-friendly multi-layered presentation formats , we will use relevant software that has been developed and user tested via randomized trials, surveys and consensus processes –50. PrioNutritional guidelines and the supporting systematic reviews will be widely disseminated via publication in a high-impact general medicine journal. As well, using GRADE summary of findings tables and decision aids, we will produce user-friendly outputs for clinicians, patients and the community members, including plain language summaries in multiple languages , and work to ensure these outputs are open-access.NutriRECS and corresponding systematic reviews will bring together patients and community members as well as international experts in nutrition and evidence synthesis and translation. Patients, community members and research experts will have the opportunity to reflect on the values and preferences of the communities for which the recommendations are intended in the context of the summary evidence and arrive at nutritional guideline recommendations. Subsequently the guidelines will be sent for peer-review, and recommendations will be publically available via open-access publication.The strength of our proposed methods includes our commitment to internationally accepted guideline standards from IoM, GRADE, AGREE and GIN. Our core NutriRECS group includes leading members of these organizations, including GRADE and AGREE. Adherence to these standards will ensure that our recommendations are based on high quality, novel systematic reviews of the literature. Our nutritional recommendations will be put forward by a group of community representatives and experts in nutrition and epidemiology from around the world, representatives and experts with limited to no intellectual or financial conflicts of interest.www.magicapp.org) which, based on GRADE evidence summaries, provide decision aids to clinicians, patients and the community on all electronic devices . Should we be successful with our funding applications, we will link the scientific journal articles directly to the content in MAGICapp.Potential limitations of our NutriRECS work include the current lack of resources to ensure that our recommendations remain fully accessible around the world to all potential end-users, including patients and members of the general community, via multiple platforms, and that our systematic reviews and nutritional recommendations remain updated. We are currently seeking funds to regularly update our NutriRECS work, and to have full access to the MAGIC authoring and publication platform , Spain (Iberoamerican Cochrane Centre) and Poland (Cochrane Poland). Among the four centres, we have access to an extensive number of local, national, multi-national grant funding opportunities . As with almost all independent research programs, we do not have permanent funding for the NutriRECS program. To secure ongoing funding, our team of investigators and trainees consistently write operational grants, career grants and trainee grants. We also sustain ourselves through a large network of research volunteers in exchange for methods training and publication.A third limitation of our effort is that we have not yet been in contact with organizations producing nutrition guidelines to try and forge a collaboration. Our strategy is to show what can be accomplished in producing trustworthy guidelines by an independent group with limited resources. Having achieved that goal, we believe that this will place us in a more credible position when interacting with established organizations.The implications of the NutriRECS project include the promotion of better-informed decision-making by patients, members of the community, clinicians, and public health policy-makers on the desirable and undesirable effects of alternative dietary patterns, as well as foods and nutrients on important health outcomes.


The temporal modulation structure of speech plays a key role in neural encoding of the speech signal. Amplitude modulations  in speech are encoded by neuronal oscillations  that oscillate at matching temporal rates. To date, however, all neural studies have investigated adult-directed speech (ADS) as produced and perceived by highly literate adults. Whether temporal features of ADS vary with the skills of the speaker, for example literacy skills, is currently unknown. Here we analyse the temporal structure of ADS spoken by illiterate, low literate (≤ 4 years of literacy) and highly literate (≥ 12 years of literacy) adults. We find that illiterates produce speech differently. Spontaneous conversational speech produced by illiterate adults showed significantly less synchronised coupling between AM bands (less phase synchronisation) than conversational speech produced by low literate and highly literate adults, and contained significantly fewer syllables per second. There was also a significant relationship between years of literacy and the amount of theta-band energy in conversational speech. When asked to produce rhythmic proverbs learned in childhood, all groups could produce speech with similar AM phase synchronisation, suggesting that the differences in spontaneous conversational speech were not caused by physiological constraints. The data suggest that the temporal modulation structure of spoken language changes with the acquisition of cultural skills like literacy that are usually a product of schooling. There is a cultural effect on the temporal modulation structure of spoken language. Tukey tests showed that high literates produced more syllables per second than illiterates (p = .001) and low literates (p < .001). This would be expected, as a group of highly literate individuals are likely to produce more complex syntax and polysyllabic words , 41. No Using the modulation phase synchronisation analysis approach in , we foun2 = .219]. Post-hoc Tukey tests showed lower delta-theta AM phase synchronisation for illiterates when compared to both low literates (p < .001) and high literates (p = .001), and also lower theta-beta/low-gamma phase AM synchronisation between illiterates and high literates (p = .01), but not between illiterates and low literates (p > .2). This suggests that literacy affects the regularity of the temporal spacing of different phonological units in conversational speech. No group differences were found for the MANOVA for rhythmic speech , showing that all participating adults could produce temporally synchronised speech if required. Accordingly, there were no physiological constraints underpinning the differences in temporal modulation structure found for conversational speech.To explore the effects of literacy on phase synchronisation, and given the speech rate differences for conversational speech but not rhythmic speech, separate MANOVAs were computed for conversational speech and rhythmic speech respectively. In each case, delta-theta PSIs and theta-beta/low gamma PSIs were the dependent variables, with literacy group as the independent variable. The MANOVAs revealed an effect of literacy in conversational speech for both the magnitude of delta-theta and of theta-beta/low gamma phase synchronisation 22], dyslphoneme awareness may appear surprising. In multi-time resolution models of speech processing, faster oscillatory information is thought to support phoneme awareness . Howeveion, see . Changesion, see . AccordiOne limitation of the current study is the relatively old age of the participants, who were screened for general cognitive impairments (via the MMSE) but not specifically matched for hearing. It could be important to access other illiterate populations, ideally younger than the population studied here. This would also enable investigation of whether the growing literature on the core role of theta entrainment for neural speech encoding ,5 is an In conclusion, our data suggest that future neural imaging studies of features of spoken language performance in both perception and production must take into account the literacy skills of participants. Literacy has long been known to change the brain ,13,16. HS1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S4 Fig(TIF)Click here for additional data file.


New York Times reported the drug’s promise as a ‘modern miracle’ in the treatment of rheumatoid arthritis (RA). Given its high profile, it is unsurprising that historians of medicine have been attracted to study the innovation of cortisone. It arrived at the end of a decade of ‘therapeutic revolutions’, kicked off by penicillin transforming the treatment of bacterial infections and ending with hopes of a revolution in the treatment of non-infectious, chronic inflammatory diseases. Despite these studies of cortisone’s introduction, few historians have taken the story forward and considered how cortisone was adopted and adapted into clinical practice. This article tells the longer of how the drug and its derivatives were taken from research laboratories and integrated into clinical practice; what has in recent decades become known as translational medicine (TM). In exploring cortisone’s first decade in Britain, we focus specifically on its role in the treatment of RA. Our approach is always to consider cortisone’s use in the context of other treatments available to clinicians, and at local and national institutional settings. We do not discuss the many other therapeutic uses of cortisone, which ranged for topical applications for skin diseases to the management of cancers, especially childhood leukaemia, nor do we discuss its close analogue ACTH—AdenoCorticoTropic Hormone. We think there are lessons in our study for TM policies today.Cortisone, initially known as ‘compound E’ was the medical sensation of the late 1940s and early 1950s. As early as April 1949, only a week after Philip Hench and colleagues first described the potential of ‘compound E’ at a Mayo Clinic seminar, the  New York Times reported the drug’s promise as a ‘modern miracle’ in the treatment of rheumatoid arthritis (RA)  Marks .1 When ccs’ Anon , b.Given these claims, it is unsurprising that historians of medicine have been attracted to development and introduction of cortisone Kendall . However[M]astery of the “implementation science” of fielding and evaluating interventions in real-world settings and of the disciplines that inform the design of those interventions, such as clinical epidemiology and evidence synthesis, communication theory, behavioral science, public policy, financing, organizational theory, system redesign, informatics, and mixed methods/qualitative research.  Cantor . By the The principal pathology of RA is damaged joints, where cartilage becomes inflamed, eroded and degenerates, causing swelling, pain and immobility. The adjective ‘rheumatoid’ indicates that it is a systemic disease, as the humour ‘rheum’ was historically associated with inflammation that could spread throughout the body. The systemic character of RA differentiated it from osteoarthritis, which is localised and largely due to wear and tear to specific joints, and from the less common condition ankylosing spondylitis, which affects the spine. By contrast, RA typically extends from the hands and feet, on to other joints, and then possibly even to affect the heart, lungs and eyes, producing general debility in sufferers. In the most severe cases, the damage produced leads to adhesion and the fusion of joints, all of which causes swelling in surrounding tissues, chronic pain and physical disabilities. These crippling consequences gave RA a fearsome reputation. It was often a ‘disaster for the individual’, and in the public mind the sufferer was imagined as ‘a severely crippled patient in a bath-chair being wheeled along and quite incapable of walking and needing help in all the usual daily activities.’ , with varied doctor-patient relationships, and multiple types of intervention .Davidson’s views on aetiology were typical in suspecting that the onset was triggered by infection, a claim supported by the experience that sufferers were known to benefit from regimes similar to those used for ‘other chronic diseases of infective origin.’ His assumption was that infection had produced persistent ‘disordered immunological processes,’ which in turn led to inflammation and stiffness, along with fatigue that was exacerbated by persistent pain. Davidson was typical in making an explicit parallel with tuberculosis, one form of which affected the bones and joints and some treatments echoed sanatorium regimes of rest, fresh air, sunshine, cheerful surroundings and a full diet.Davidson set out the accepted figures for prognosis in a typical patient population: ‘if treated early and efficiently’ a quarter of those treated could be restored to normal health, while ten percent would become ‘completely crippled’ despite adequate treatment. The remaining sixty-five percent of patients could be expected to show ‘functional improvement’ varying ‘from mild to good.’ In sum, the situation was, he suggested, better than generally believed, but interventions needed to be early and given with a ‘a hopeful outlook.’ Pain relief was the cornerstone of treatment, and maximum relief required a careful balancing of analgesics such as aspirin, phenacetin, codeine and barbiturates, and ensuring patient compliance. Next in importance was physiotherapy, which included both the local manipulation of joints by trained professionals and a programme of general exercise that would allow the patient to maintain overall mobility. Complementing pain relief and physiotherapy was occupational therapy, which would occupy the mind of the sufferer and counter possible adverse psychological factors. While Davidson admitted that there were no ‘controlled investigations’ to support the idea that emotional strain could lead to arthritis, he nonetheless suggested that ‘the clinical impressions of experienced physicians must not be discarded lightly.’When it came to specific treatments, especially drugs that were claimed to have specific therapeutic effects, Davidson was scathing: ‘Of the hundreds of remedies which have been recommended in the treatment of rheumatoid arthritis, the majority are useless’ Davidson , p. 137.Gold salts are of value in the treatment of rheumatoid arthritis, particularly when used in conjunction with general, physiotherapeutic, and orthopaedic measures. On account of their toxicity they should only be employed by those with experience in their use. Fraser , p. 75 Lord Horder, then chair of the ERC, made no mention this study in his Annual Report for 1945 and the tenor of his remarks was there was nothing new to say on treatment (Horder The only specific drug treatment that Davidson and his peers endorsed for treating RA (as opposed to simply relieving the pain associated with it) was chrysotherapy, the injection of gold salts . The modern use of gold compounds in therapy began with Robert Koch, who tried them as antibacterial agents with tuberculosis in the late 1880s. As Rodnan and Benedek  have shoDavidson’s views in 1948 were similar, namely that ‘gold salts must be considered merely a part of—and not a substitute for—a general plan of treatment carefully arranged for each particular patient’ Davidson . None thAnnals of Internal Medicine  reported that Hench opened by saying ‘he had nothing striking or wonderful to bring before his audience’ and spent most of the lecture criticising current remedies. He began by stating that in his experience, general supportive measures led to 15% of patients being cured and a further 35% improved. He then argued that this could be raised to 75% with special measures such as gold therapy. However, he warned physicians of the range of remedies of dubious value, showing a slide in which a remedy was listed for every letter of the alphabet, even including Z—“zero-therapy”(do nothing). The lecture ended with ‘mention’ of remissions induced by spontaneous jaundice and pregnancy, where over 90% of patients improved. In a clear trailer for soon to be announced ‘compound E.’ he argued that ‘there was an unrealized potential in these conditions’ to make RA ‘potentially reversible’ and eventually ‘therapeutically controllable.’Philip Hench was already a celebrity rheumatologist when he announced ‘compound E’ in April 1949. He had been appointed head of the Mayo Clinic’s rheumatology service in 1928 and was a founding member of the American Association for the Study and Control of Rheumatology  was in cortisone trials from an early stage  This intervention was apparently sufficient to convince Committee members that the publication of the results of the trial would need to be carefully handled. .The wording of the report on the trial was that ‘For practical purposes … there appears to have been surprisingly little to choose between cortisone and aspirin in the management of the 61 patients in the early stages of rheumatoid arthritis.’ The results had been first presented to the Joint Committee of the MRC and Nuffield Foundation on 26 January 1954, not by a rheumatologist, but by Bradford Hill ; Hill But another member of the Committee, Ian Duthie, broke ranks and revealed the findings of a preliminary report at a meeting of the Royal Society of Medicine that very evening. He only described the results at 3 months, not the full year, but nonetheless concluded that ‘long-continued administration of cortisone to patients suffering from RA was not to be recommended until complications which cannot be foreseen or prevented at present can be avoided with certainty’Duthie . In suppBMJ on 29 May 1954, offering its now famous conclusion on the seeming equivalence of cortisone and aspirin. In the same journal, just a fortnight previously, Copeman too indicated his dissent by rushing out the more positive results of his study on prolonged administration of cortisone at the West London Hospital  and Squibb (Kenacort) in 1957; methyl-prednisone (Medrol) and fluprednisolone (Alphadrol) by Upjohn in 1957; and dexamethasone (Decadron) by Merck in 1958 Benedek . HoweverThe business of finding, testing, synthesizing, upscaling to production, marketing and selling these new drugs became controversial in the United States in 1957 because of alleged price-fixing and profiteering. This led to investigations by the Senate Antitrust and Monopoly Subcommittee, led by Senator Estes Kefauver, which began his interest in drug regulation, and in 1962 the famous Kefauver-Harris Amendments Nossiter Throughout the year of the trial the patients remaining on cortisone showed, on the average, no material change for better or worse. The prednisone group, on the other hand, showed improvement in the following characteristics—strength of grip, blood sedimentation rate, haemoglobin level, general capacity, and disease activity. At the end of the year the disease was judged to be inactive in five of this group but in none of the patients on cortisone. (Joint Committee  Improvements were greatest in the early months and over the trial period a number of side effects were reported, which were attributed to the higher dosage allowed with prednisone. A follow-on trial that compared prednisolone and aspirin over 2 years also had positive results (Joint Committee [T]he administration of prednisolone instead of, or in addition to, analgesics, such as aspirin, to certain patients with rheumatoid arthritis for a period of 2 years will, on average, improve their functional capacity and general well-being and reduce the incidence of erosive joint damage. (Joint Committee  Moreover, though side effects were again present, they had proved manageable by reducing the dosage and retaining some benefits. In the following year, the Committee reported on a further year’s trial, the improvements for patients had been maintained, ‘though to slightly lower degree.’ (Joint Committee In Britain the assessment of the new corticosteroids remained with the Joint Committee of the MRC and Nuffield Foundation. As early as 1956, they set up trials to compare prednisone and cortisone. (Joint Committee Steroids should not be prescribed to the exclusion of other measures. A sound comprehensive program should be employed concomitantly; this would consist of well-regulated rest and exercise, properly balanced diet, avoidance of undue emotional stress, physiotherapeutic procedures and graded muscle exercises, careful handling of affected joints with proper supports and splints, occupational and rehabilitative measures, and simple analgesics. Boland , p. 888Ending therapy needed careful management too: ‘treatment must be gradually discontinued or “tapered off’’—not suddenly withdrawn. ’The physician’s goal, as ever, was to balance benefits and risks: ‘to promote and uphold that degree of disease suppression that is feasible with dosages that are well tolerated on a long-term treatment basis.’ In his review a year later, Boland’s verdict was that results with the new corticosteroids had been mixed.Some possess advantages in one respect or another, but none is divested of the major deterrent features of corticosteroid therapy, and some produce peculiar objectionable reactions of their own. Because of a lack of published comparative data and misleading promotional pharmaceutical advertising, physicians have been confused regarding the relative merits, special properties, and tendencies to unwanted reactions of these newer preparations. Boland , p. 888With experience and the use of clinical acumen, informed by trials and case reports, rheumatologists could adopt the new drugs selectively, finding them niches in their multi-strand therapies, adjusted to individual patients and their disease.By the end of the 1950s, leading Californian rheumatologist Edward Boland, who had been one of the five participants in the early cortisone trials in the United States, wrote influential reviews of the ‘relative therapeutic efficiencies’ of chemically modified adreno-corticosteroids in RA Boland ; 1960. IIn Britain in 1960, Dudley Hart .Textbook of Rheumatic Disease, published in 1964, Ian Duthie wrote the chapter on rheumatoid arthritis. He was critical of both old and new therapies.In recent years the results of adequately controlled clinical trials have shown that many remedies popular in the past are without effect on symptoms or the course of the disease. It has also been shown that although a number of drugs can make a useful contribution to treatment, none that proved predictably effective or harmless. Remissions induced by these have not been sustained and the ultimate course of the disease does not appear to have been significantly altered for the better and may even have been made more severe. An example of this, seen only too frequently, is the markedly increased severity of both arthritis and constitutional symptoms which may follow the injudicious withdrawal of corticosteroids. Fatal complications have also been induced by other remedies such as gold and phenylbutazone, which were given in good faith and in the absence of known contraindications. If follows that simple conservative measures should be used in the first place with the great majority of patients. Duthie , p. 208 Duthie was direct on cortisone and its analogues. He wrote that ‘It is clear that corticosteroids have a distinctly limited role in the treatment of rheumatoid arthritis’ and that derivatives ‘share the major deterrent features of earlier corticosteroids.’ He only recommended drug treatment for patients with ‘disease of longer duration and in whom activity has not been controlled by an adequate trial of … conservative measures.’ The drugs discussed were, in order: aspirin; phenylbutazone and oxyphenylbutazone; corticosteroids and ACTH; chloroquine and hydrochloroquine; and gold. It might have surprised many readers that gave most attention to gold therapy, concluding ‘In spite of its obvious limitations and dangers, the majority of experienced observers consider that chrysotherapy is of value in the treatment of rheumatoid arthritis’ (Duthie In the Third Edition of Copeman’s It is clear that corticosteroids have a distinctly limited role in the treatment of rheumatoid arthritis. Their use should never be considered until conservative measures applied over an adequate period of time have failed to control progressive and crippling disease. Copeman , p. 223 Thus, the wonder drugs of the 1950s were second line therapies, and then that had to be closely monitored and of limited duration due to safety concerns.In 1964, William Copeman, by then head of the ERC, summed up the position thus:Steroid Drugs, published in 1962, the editor, Norman Applezweig, suggested that ‘The Cortisone Era’ was over and that modifications of its molecule had produced drugs with improved properties. (Applezweig In the Introduction of a book entitled The history of cortisone’s first decade can be read as showing that as a treatment for RA was ‘lost in transition’ twice. First, in the early 1950s, though rapidly taken from bench to bedside in trials with a select group of clinicians, its spread into hospital and general practice was very limited. Its adoption and uptake were checked by shortages of supply, high cost, uncertainties over dosage and worries about side effects. Second, from the mid-1950s and paradoxically just as the problems of supply and price were solved, pharmaceutical companies had begun to produce new and different variants of cortisone, in a new class of drugs—the corticosteroids (Bunim et al. Yet, the very naming of NSAIDs as ‘Non-Steroidal’ shows that cortisone had not been lost. It continued to define, albeit negatively, a pharmacologically-based, anti-inflammatory therapeutic strategy for the treatment of RA. Moreover, it was one that accepted that such drugs offered relief of symptoms rather than a cure. The initial hope of a’miracle cure’ for rheumatic diseases had had the effect of stimulating therapeutic innovations with established treatments as well as new pharmaceuticals. Thus, clinicians had a greater range of combinations of physical and medical treatment, even setting up RCT comparisons. The ‘messiness’ of translations identified by Steven Woolf was evident in the ways that cortisone and its derivatives were typically used in combination or alternatively with physical treatments, physiotherapy, splints, etc. and other chemotherapeutic methods.Our discussion of cortisone has shown the limitations of focussing on a single innovation and the advantages of the socio-technical systems approach of Thomas Hughes. For while over the 1950s as a whole, cortisone was little used in the treatment of RA, it had a wider translational impact on treatment, institutions and the public profile of the disease. First and foremost, it stimulated the search for other drugs to treat RA and the reassessment of existing treatments, all of which combined to transform the experience of sufferers. Second, its profile and promise helped remake rheumatology, aiding its move from spas and physical methods, to hospitals and medical measures. Thirdly, such developments stimulated rheumatology as an academic specialism, with investment in research and the proliferation of trials, which produced the new corticosteroids in the 1950s and NSAIDs in the 1960s Dixon . These n


The publication rate of neurosurgical guidelines has increased tremendously over the past decade; however, only a small proportion of clinical decisions appear to be based on high-quality evidence.The aim was to evaluate the evidence available within neurosurgery and its value within clinical practice according to neurosurgeons.A Web-based survey was sent to 2552 neurosurgeons, who were members of the European Association of Neurosurgical Societies.P<.001). Also, more neurosurgeons with formal training believed they could understand, criticize, and interpret statistical outcomes presented in journals than those without formal training .The response rate to the survey was 6.78% (173/2552). According to 48.6% (84/173) of the respondents, neurosurgery clinical practices are based on less evidence than other medical specialties and not enough high-quality evidence is available; however, 84.4% (146/173) of the respondents believed neurosurgery is amenable to evidence. Of the respondents, 59.0% (102/173) considered the neurosurgical guidelines in their hospital to be based on high-quality evidence, most of whom considered their own treatments to be based on high-quality (level I and/or level II) data (84.3%, 86/102; significantly more than for the neurosurgeons who did not consider the hospital guidelines to be based on high-quality evidence: 55%, 12/22; According to the respondents, neurosurgery is based on high-quality evidence less often than other medical specialties. The results of the survey indicate that formal training in evidence-based medicine would enable neurosurgeons to better understand, criticize, and interpret statistical outcomes presented in journals. Evidence-based neurosurgery is a paradigm of neurosurgical practice in which the best available evidence is consulted to establish the principles of diagnosis and treatment. These principles are applied considering the neurosurgeon’s training and experience, as well as being informed by the patient’s individual circumstances and preferences, to produce the best possible health outcomes . AlthougIn 2011, a new rating system, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), was developed, which offers an outcome-centric system for rating the quality of evidence derived from different types of studies . The GRARothoerl et al . and YarThese studies suggest that surgeons are increasingly turning their backs on research. Further evidence indicates that compared with a decade or two ago, surgeons apply for and receive fewer grants, publish less, and—perhaps most perniciously—feel that research is not part of their role . InvolveThe goal of this study is to investigate the opinion of neurosurgeons about the evidence available in neurosurgical practice and the extent to which this evidence is implemented in clinical practice.Evaluation by an ethical committee was not necessary for this study. A survey was conducted among 2552 members of the European Association of Neurosurgical Societies (EANS). The survey asked the opinion of neurosurgeons regarding the levels of evidence generated in neurosurgical studies, their understanding of the levels of evidence, and to what extent neurosurgeons implement evidence in clinical practice. The survey was emailed directly to the members of the EANS by the society’s administrative personnel. Data were collected over a period of 3 weeks from the date of the first mailing. Two reminders, each 1 week apart, were sent to the cohort.The survey  was madeMost questions consisted of a five-item Likert scale, which was chosen because each item is of equal value, so the respondents were scored rather than the items. The Likert scale was also likely to yield highly reliable answers and is easy to read and complete . Some qut tests were used, whereas chi-square tests were used to analyze categorical data. Some values, for example the number of years as a neurosurgeon, were categorized before being statistically examined. Comparisons were made between different groups of neurosurgeons. Multiple groups were formed based on the answers to the questions asked and their opinions on different aspects, and consisted of respondents responding with a positive answer , a negative answer , or an indecisive answer (“indifferent”) to particular questions. Afterwards, comparisons were made between the answers and opinions of certain groups for different aspects of neurosurgery. Values are presented as a mean ±95% confidence interval (CI).IBM SPSS version 22  was used for the statistical analyses. For the continuous data, Student The response rate was 6.78% (177 respondents) of the 2552 EANS members surveyed. All completed surveys contained complete data and had no partial or missing responses. Four respondents were excluded: three were still residents and one response was sent twice. A final total of 173 completed surveys (6.78%) were analyzed.The remaining 36 respondents  worked in one of 18 non-European countries, particularly in countries in the Middle East , such as Saudi Arabia , Pakistan , and Iraq . The remaining respondents came mainly from Mexico , India , and the United States .Every participant indicated the guidelines they used most often, to a maximum of three guidelines . The levP=.048). Of the most-used neurosurgical guidelines (According to 84.4% of the neurosurgeons (146/173), neurosurgery is amenable to evidence ; howeveridelines , only 9.P=.02).Of the 129 respondents who believed their treatments were based on high-quality evidence, 50.4% (65/129) considered level I and/or level II to be high-quality evidence, whereas significantly fewer  of the respondents who did not consider their treatments to be based on high-quality evidence considered level I and/or level II to be high quality (P=.02).Most respondents  were involved in the process of setting up the neurosurgical guidelines in their hospital. More than half  of the respondents considered the neurosurgical guidelines of their hospital to be based on high-quality evidence. Of those who were involved in their establishment, 65.9% (83/126) considered the guidelines of their hospital to be based on high-quality evidence, compared with just 43% (20/47) of those who were not involved (P<.001).Of the 59.0% (102/173) of respondents who considered the neurosurgical guidelines in their hospital to be based on high-quality evidence, 84.3% (86/102) considered their own treatments to be based on level I and/or level II evidence, whereas 55% (12/22) of the respondents who did not consider hospital guidelines to be based on high-quality evidence considered their own treatments to be based on level I and/or level II evidence (P=.03).Only 34.7% (60/173) of the respondents said they had received formal training in EBM. Of those who received formal training, 76% (46/60) considered their own treatments to be based on level I and/or level II evidence, whereas 85% (71/84) of those without formal training believed their treatments were based on this level of evidence (P<.001). There was no difference between the number of respondents with and without additional academic qualifications who stated that they could understand, criticize, and interpret statistical outcomes .The majority of respondents  said they could understand, criticize, and interpret statistical outcomes in medical research. This response was more common for respondents who received formal training  than for those without formal training  considered either level I or levels I and II to be high quality. Moreover, all levels of evidence seem to be used by the majority of neurosurgeons. Several neurosurgeons commented that the lack of evidence is an important issue in neurosurgery.Indisputable advancements in neurosurgery have been traditionally based on technical innovations advocated by pioneers without rigid assessment in clinical trials; therefore, changes in clinical practice have frequently been technology-driven rather than strictly evidence-based . EverydaSince 1970, the rate of increase in the publication of guidelines in all specialties has outpaced neurosurgery ; howeverP<.001).Of the respondents who participated in this study, 25.4% (44/173) did not think that, or know whether, the treatment options they use are based on high-quality evidence. Ducis et al  investigOne participant commented that neurosurgery is currently based more on eminence than on evidence. Eminence refers to a clinical decision that is made solely by relying on the opinion of a medical specialist or any prominent health professional rather than the critical appraisal of the scientific evidence available . EvidencAnother neurosurgeon commented that the current definition of evidence-based neurosurgery is in dire need of rigorous update and expansion. A common misunderstanding of EBM is that a lack of available evidence means a lack of RCTs . EBM evaThe differences in the confidence of neurosurgeons with and without formal training in EBM to adequately interpret the statistical outcomes presented in the literature was striking. Only 35% of the responding neurosurgeons (60/173) had received formal training in EBM and although it seems low, it is similar to that described in orthopedic surgery . The lacA major strength of this study is the broad representation of the opinions of neurosurgeons worldwide through the involvement of the EANS. EANS has a large number of members all over the world. The membership of EANS is primarily located in Europe, but neurosurgeons from all countries are permitted to join. However, some potential limitations should also be discussed. First, due to the low response rate, selection bias cannot be precluded, which hampers the generalizability of our results. For external email surveys, a response rate between 10% to 25% is usually considered the average ,36. The The transition from using levels of evidence to the GRADE system is an important change in all medical specialties, including neurosurgery. The literature available about the evaluation of evidence in neurosurgery does not include the new system and is, therefore, in need of expansion and updating. The GRADE guidelines offer some major advantages over the levels of evidence, as they enable the rating of evidence in systematic reviews and guidelines and the grading of the strength of recommendations made in guidelines. Moreover, the GRADE system offers a transparent and structured process for developing and presenting summaries of evidence in systematic reviews and guidelines in health care, and for carrying out the steps involved in developing recommendations .There are major gaps between the current definition of high-quality evidence (level I and level II) and neurosurgeons’ opinions of evidence. Neurosurgeons are willing to base their clinical decisions on more than just RCTs, relying on lower-quality evidence. The transition to the GRADE system is one way to overcome this issue because these guidelines are outcome-centric and do not rate each study as a single unit. In the GRADE approach, RCTs are initially considered to be high-quality evidence and observational studies are initially considered low-quality evidence supporting estimates of intervention effects. Five factors may lead the ratings to be decreased, whereas three other factors may lead to an increased rating. Ultimately, the quality of evidence for each outcome falls into one of four categories, from high to very low .EBM is important when choosing between treatments for patients; however, shared decision making (SDM) was also developed alongside the introduction of EBM. According to 71.7% (124/173) of the respondents of this study, knowledge gained from patients and carers was an important factor in the selection of a treatment, whereas 22.5% of the respondents 39/173) were indifferent and 5.8% (10/173) did not believe that the knowledge of patients and carers was an important factor when choosing a treatment. Evidence from trials has shown that engaged patients consume less health care resources ,38; furt/173 wereUnderstanding EBM is key to using it correctly in practice. This study shows that relatively few neurosurgeons have received formal training in EBM; thus, more training in EBM, both in the medical curriculum for residents and at neurosurgical departments, would enable neurosurgeons to improve their abilities to better facilitate the implementation of statistical results into clinical practice. It would be interesting to perform this research on a larger scale, including a wider multinational sample in the future.According to the respondents, neurosurgery is less commonly based on high-quality evidence than other medical specialties. The results of the survey suggest that providing more formal training in EBM is desirable, enabling neurosurgeons to better understand, criticize, and interpret the statistical outcomes presented in journals.