The cerebellum’s anatomical and functional organization and network interactions between the cerebellum and the cerebral cortex and subcortical structures are dynamic across the lifespan. Executive, emotional and social (EES) functions have likewise evolved during human development from contributing to primitive behaviors during infancy and childhood to being able to modulate complex actions in adults. In this review, we address how the importance of the cerebellum in the processing of EES functions might change across development. This evolution is driven by the macroscopic and microscopic modifications of the cerebellum that are occurring during development including its increasing connectivity with distant supra-tentorial cortical and sub-cortical regions. As a result of anatomical and functional changes, neuroimaging and clinical data indicate that the importance of the role of the cerebellum in human EES-related networks shifts from being crucial in newborns and young children to being only supportive later in life. In early life, given the immaturity of cortically mediated EES functions, EES functions and motor control and perception are more closely interrelated. At that time, the cerebellum due to its important role in motor control and sequencing makes EES functions more reliant on these computational properties that compute spatial distance, motor intent, and assist in the execution of sequences of behavior related to their developing EES expression. As the cortical brain matures, EES functions and decisions become less dependent upon these aspects of motor behavior and more dependent upon high-order cognitive and social conceptual processes. At that time, the cerebellum assumes a supportive role in these EES-related behaviors by computing their motor and sequential features. We suspect that this evolving role of the cerebellum has complicated the interpretation of its contribution to EES computational demands. The cerebellum has been assigned many crucial roles beginning with motor control but more recently it has been deemed crucial for higher-order cognitive, emotional, and even social processing . HoweverIn this review, we will suggest that the role of the cerebellum in human EES-related networks shifts from being crucial in newborns and young children to being only supportive later in life. Here, we propose, based on evidence from both the child and adult literatures, a dynamic framework for this shifting importance of the cerebellum in executive, emotional and social processing across the lifespan.Children have to learn and then practice skilled movements and behavior in order to perform them without conscious attention whereas in adults, cognitive and motor behavior are coordinated, often unconsciously, and often become automatically expressed ensuring efficient performance.EES behaviors that are acquired and eventually executed automatically are essential in real-life, otherwise, EES actions would impose a significant cognitive load. These automatic EES behaviors are not always sufficient when slower high-order cognitive regulation and adaptation is mandatory. Children and adults are often engaged in EES behaviors that elicit automatic or higher-order control. Sensorimotor-based perception and agency and high-order control are two distinct means of EES behavioral control that rely upon complex anatomical and functional networks that evolve during human development.In adults, multiple task-based imaging studies report healthy volunteer cerebellar activation across a wide range of tasks, depending on task demands  are closely intermingled with other brain functions such as motor skills, cognition, and sensory processes. The core of the system that processes emotion includes the PFC, the hippocampus, the amygdala, the hypothalamus, the pituitary gland and the insula. Others subcortical regions such as the basal ganglia  are connected to these regions by circuits known as Cortico-Striato-Thalamo-Cortical loops . These lSocial functions are also supported by an extended brain network, including dorsomedial PFC, premotor cortex, intraparietal sulcus, temporoparietal junction, posterior cingulate cortex, and ventro medial PFC, dorso lateral PFC, Orbito Frontal Cortex, and the anterior temporal lobe .These EES functions closely interact, therefore several overlapping brain networks involve these functions. All these cortical and subcortical supra tentorial regions are known to be anatomically and functionally connected either directly or indirectly to the cerebellum forming a larger distributed network concerned with EES functions.EES networks including the cerebellum can be considered both functionally and anatomically as “closed-loop” systems. These integrated systems have been continuously evolving throughout anthropoid evolution as species acquired complex skills. Almost every cortical area has a reciprocal, segregated connection with the cerebellum although these connections may traverse polysynaptic circuits . The thaTaken together, the reported findings suggest that the role of the cerebellum in EES function changes across the lifespan. In the following section, we propose that the cerebellum participates in a complex dynamic network that allows humans to acquire, develop and execute properly EES behaviors in real life. However, the significance of the cerebellum’s contribution to EES behavior is diminished in adults compared to children.In healthy children, they are few task-based imaging studies related to EES functions , 42. TheOne study compared children and adult brain and cerebellar activation, using fMRI during a working memory task . They reSince the latter part of the last century, cognitive deficits including EES functions were described following cerebellar injuries in children, leading to the launch of the Cerebellar Cognitive Affective Syndrome (CCAS) , and theThe CCAS is characterized by impairments in EF , often with perseveration, distractibility or inattention; visual–spatial disorganization and impaired visual–spatial memory; personality change with blunting of affect or disinhibited and inappropriate behavior; and by impairments in language production such as dysprosody, agrammatism and mild anomia. The CMS is a condition that encompasses speech and language dysfunction (from complete mutism to mild dysfunction), behavioral/emotional changes with cerebellar motor signs , cognitive (including EF), and sometimes brainstem dysfunction including long tract signs and cranial nerve impairment. This syndrome has been extensively studied in children  especialThe pathophysiology of CMS is unclear . It occuHowever, the impairment of a function after cerebellar damage may also reflect the remote effect of the cerebellar malfunction to the cerebral cortex. Perfusion Imaging studies are helpful to explore the distant consequence (s) of a cerebellar injury and therefore in understanding the role of the cerebellum in children . In chilUp until recently, it was debatable whether a younger age at the time of a cerebellar injury predicted worse motor and cognitive outcomes. Does a cerebellar injury impair EES function in the same way across development? It has been shown that complex congenital cerebellar anomalies such as cerebellar agenesis may be linked to developmental diaschisis . Others This concept has been previously suggested by some authors. In a consensus paper on the role of the cerebellum in movement and cognition, most of the authors described the cerebellum as a structure that acquires internal models that govern both movement and thinking . SchmahmStructurally, the cerebellum and the cerebrum undergo major changes during human development, as a consequence of brain maturation and adaptation. Functionally, networks evolve from spatially close anatomical hubs to large-scale but integrated network communities .Most of the brain’s macroscopic changes  are completed by the age of 2 . NeverthCerebellar macroscopic changes reaches peak later in development . InteresUsing resting-state functional magnetic resonance image (rs-fMRI), it was reported that functional connectivity (FC) is already present in utero from 24 weeks gestation age and increases with full-term age . HoweverIt had been thought that long-range network connections between the cerebellum and cortical areas developed only after birth . Yet, thMoreover, Kipping et al. assessed cerebellar GM volume and white matter (WM) tract integrity [Fractional Anisotropy (FA)] in children from 6 to 10 years of age. First, they showed that there was an evolution across development of both parameters. Compared to older children, younger children had lower GM volumes and higher WM FA of the anterior cerebellum, while compared to younger children, older children had higher GM volumes and lower WM FA in the posterior cerebellum. Moreover, they correlated these findings with increasing cognitive planning capacity .The evidence reviewed above indicates significant morphological, microstructural and functional reorganization of human cortical and cerebellar structural networks from infancy to adulthood. As this occurred, EES functional processing became more efficient and organized indicating that the relevance of each component of the network to EES changes over development. We will address later in this article the implication of these changes for the shifting role of the cerebellum in EES functions.Having identified the cerebellum as an important anatomical hub does not mean that its role in a network is necessarily crucial. Indeed, every functional network is built on regional nodes some of which can be considered crucial to the network’s assigned functional role(s) whereas other network nodes can be considered supportive. For example, even if the primary visual cortex (V1) is a member of an extended network that reaches into the prefrontal cortex, it would be hard to argue that V1 has a crucial role in decision-making or social cognition. In this example, V1 may provide visual information contributing to a decision or social interaction but is not likely to be computing the higher-order representations that are crucial to the decision . Likewise, higher-order decision making can bias how we process visual information  but is not likely to be computing the molecular aspects of visual information processing.Movement and cognition are human behaviors that are deeply intermingled in our daily life. In newborns, both motor and cognitive behaviors are relatively “primitive”. In late childhood, our motor abilities are approaching their peak of performance, but our cognitive behaviors continue to mature—especially EES-related behaviors—into young adulthood. We propose that EES-related behaviors are more dependent upon motor processing in newborn and younger children given their cognitive immaturity.Clinical studies reporting the outcome of patients with acute cerebellar injury or chronic neurodegeneration have shown that the degree of cognitive impairment and the long-term effect of the injury is worse in younger children , 6. PretWhen damaged, inflow and outflow pathways to/from the cerebellum, especially via the thalamus, not only play a role in both ataxic movement and impaired fine motor skills, but also EES dysfunction, particularly after childhood cerebellar injury . This isTwo other observations support this hypothesis. The first one is that, in children, the PFC is not increasingly recruited when performing an EF task when the cerebellum is damaged in contrast to what is observed in adults . In an iFor every function, different cortical and sub-cortical regional nodes can be considered crucial to any network they belong to or the nodes can simply be supportive, supplying information for, or biasing, decision-making and agency. To complicate matters, the relative importance of cerebellar participation in the network(s) evolves during development. This evolution is driven by the macroscopic and microscopic modifications of the cerebellum that are occurring during development including its increasing connectivity with distant supra-tentorial cortical and sub-cortical regions.As a result of these anatomical and functional changes, neuroimaging and clinical data indicate that the importance of the role of the cerebellum in human EES-related networks shitfs from being crucial in newborns and young children to being only supportive later in life. In early life, given the immaturity of cortically mediated EES functions, EES functions and motor control and perception are more closely interrelated. At that time, the cerebellum due to its important role in motor control and sequencing makes EES functions more reliant on these computational properties that compute spatial distance, motor intent, and assist in the execution of sequences of behavior related to their developing EES expression. As the cortical brain matures, EES functions and decisions become less dependent upon these aspects of motor behavior and more dependent upon high-order cognitive and social conceptual processes. At that time, the cerebellum assumes a supportive role in these EES-related behaviors by computing their motor and sequential features Fig. . We suspHowever, in order to truly understand this shift in nodal network responsibility, future longitudinal cohort studies are needed that follow healthy participants from in utero to later in adulthood, using repeated functional and morphological imaging and neuropsychological testing to monitor the developmental relationship between cerebellar structure and cognition including EES functions. Moreover, longitudinal cohort studies in cerebellar patients are also needed to compare long term sequelae across all age but also to evaluate the pattern of recovery depending on age.


Among almost millions of children asylum seekers registered in the EU in 2015-2017, there were one-fifth unaccompanied children. These children are facing many challenges, including substance use while at the same time the recommendations for prevention are underdeveloped in many countries. To address the issue of substance use among migrant children in Serbia, the Institute of Public Health of Serbia with the support of the UNICEF and in cooperation with other partners developed recommendations for preventive activities in 2022 based on the migrant needs and country-specific situation. In the first phase of development, a desk review of current legislation and available relevant data was done. In the second phase, in order to gain in-depth view of the challenges and opportunities, workshops were conducted in two migrant centers with medical and other staff. Based on the findings and consultation process, feasible, evidence-based interventions were recommended. Several barriers to the implementation of evidence-based prevention activities in migrant centers were identified. To address the knowledge gap on the management of acute intoxication and the current referral system, guidelines were developed. The diversity of professional backgrounds of staff in migrant centers was identified as a barrier and recommendations for further training were made. There are several barriers that need further action and solutions such as short periods of stay in centers that hinder the provision of structured programs, language barriers, and ethical issues for minors, especially unaccompanied children. Prevention activities in migrant centers need to consider the specific needs of migrants, such as language barrier, capacities, and relevant knowledge of available staff and country-specific situations. The development of guidelines and a flowchart for a referral system for migrants at risk for substance abuse and dependence can be a useful tool for staff in migrant centers.• Substance use prevention among migrants should be evidence-based and in line with migrant needs and country-specific situations.• Guidelines for prevention should be available to migrant centers’ staff.


The European Society for Organ Transplantation (ESOT) has created a platform for the development of rigorous and regularly updated evidence based guidelines for clinical practice in the transplantation field. A dedicated Guideline Taskforce, including ESOT-council members, a representative from the Centre for Evidence in Transplantation, editors of the journal Transplant International has developed transparent procedures to guide the development of guidelines, recommendations, and consensus statements. During ESOT’s first Consensus Conference in November 2022, leading experts will present in-depth evidence based reviews of nine themes and will propose recommendations aimed at reaching a consensus after public discussion and assessment by an independent jury. All recommendations and consensus statements produced for the nine selected topics will be published including the entire evidence-based consensus-finding process. An extensive literature review of each topic was conducted to provide final evidence and/or expert opinion. High-quality, evidence-based clinical practice guidance documents to support best practice in solid organ transplantation along with improving the quality of life are increasingly needed. These are statements that include recommendations intended to optimize patient care, lead to better clinical outcomes, and improve cost effectiveness. Furthermore, they provide the opportunity to identify areas requiring further research and serve an educational scope. Clinical Practice Guideline statements are informed by a systematic review of evidence and an assessment of the benefits of alternative care options. The multidisciplinary and multiprocedural nature of organ transplantation, the intrinsic difficulty in designing and carrying out numerically and methodologically sound comparative studies, and the ever-changing landscape of knowledge and therapeutics, challenge the realization of a solid evidence framework in some crucial areas of the field. Solid organ transplants, therefore, more than other clinical areas, need implementation of a systematic, continuous expert work dedicated to guideline and consensus production to help clinicians with framing evidence and expert opinions into clinical practical approaches –3.The European Society of Organ Transplantation (ESOT) is recently giving high priority to the development of clinical practice guidelines launching a structured and continuous dedicated action plan. In January 2022, ESOT created a guideline taskforce (GT) composed of ESOT leadership and Transplant International editorial board members. The GT has the fundamental commitment to promote methodologically homogeneous guideline and consensus activities and to warrant trustworthiness, transparency and continuity of the processes. Furthermore, the GT selects cutting edge topics, initiates and realizes consensus processes among experts, draws guidelines and promotes dissemination of the compiled products.via social media. Patients and their representatives will play an active role in the consensus development processes and will be targets of the dissemination activities according to the principles and concepts of value-based health care (VBHC). When appropriate, the GT will involve stakeholders including those in health care management and economics, organ sharing organizations, and health care policy makers.Guideline and consensus related material will undergo widespread dissemination within the transplant community through publications in Transplant International, ESOT congresses, and platforms as well as through networking Besides drafting a uniform methodology for ESOT guidance/guideline production and promoting topic selection, the GT created a platform for the development of methodologically solid and up-to-date evidence-based guidelines for clinical practice in the transplantation field. This platform guarantees procedural and logistical continuity to ESOT activities in the field of consensus processes and guideline production.The first edition of the Transplant Learning Journey (TLJ) 3.0, after several months of preparatory work, is there to produce systematic reviews of evidence and to grade evidence followed by drafting and sharing recommendations. During TLJ 3.0 in Prague 13th–15th November 2022, the 3-day consensus conference, a series of consensus-based clinical guidance documents comprising research topics considered as cutting-edge will be established.The main purpose of the TLJ 3.0 ESOT GT and the consensus conference is to provide methodologically solid evidence-based and best-practice recommendations reflecting the latest knowledge.While creating clinical guidance through expertise and knowledge from all stakeholders involved in organ transplantation within the ESOT community and beyond, a further goal is to provide resources in the form of reference databases on an available platform maintained and updated continuously to lead the way in organ transplantation.The present report is intentionally submitted for publication and it will be freely available prior to TLJ 3.0 event, to make publicly available and report fully with trustworthiness and transparency , 2 the nA dedicated ESOT GT established a methodologic action plan in January 2022 and elaborated a handbook formalizing the processes associated with the preparation of ESOT Clinical Practice Guidelines, including selection of topics for new guidelines, writing, reviewing, approval, dissemination, and update. The document also defines the governance of the process and the roles of the various committees. This handbook has been open to be consulted on the ESOT website since the end of September 2022.In line with the established action plan, the ESOT GT launched the event “Transplant Learning Journey (TLJ) 3.0” as an in-person consensus conference, designed as a modified NIH  model consensus development conference –6. Such The platform, and its future developments, will represent ESOT’s permanent operative tool to regularly elaborate and deliver rigorous and homogenous consensus statements and publications. Due to the known limitations related to face-to-face consensus conferences, particular attention has been given to methods for topic selection, selection and number of steering committee members, and review of evidence.The Delphi method will be applied to arrive at a group opinion by surveying the expert panels including SC, conference attendees and jury members. The final result will reflect a solid consensus of experts in the field , 8.In the setting of the ESOT TLJ consensus conferences, the Delphi method is an appropriate technique as it can help to come to a conclusion under several circumstances which have been described in the late 1970s already  rating the proposal from 1 to 10; 2) recommending the topic yes/no; 3) marking the proposed group members 1) good proposition, 2) good but unbalanced, i3) needs to be discussed.In a joint meeting, the GT reviewed and prioritized all submitted proposals and selected nine that met the following criteria: 1) cutting edge topics for which a consensus would have an impact on healthcare; 2) lack of similar guidelines or recommendations for this topic or an urgent need for an update of a previous version; 3) identification of barriers or data gaps requiring consensus recommendations to progress the field; 4) feasibility in the context of TLJ 3.0 meeting including minimal availability of published evidence; 5) completion of previous activated ESOT consensus processes; 6) collaborative forum of European and international leaders to exchange experience and knowledge.For each of the selected topics, a specific steering committee (SC) was composed. The SC consists of a chair and co-chair, expert-members in the topic field, the Centre for Evidence in Transplantation (CET) , a YPT-rThe GT had the final responsibility to nominate the SC members for each topic, though it did invite the topic proposers to suggest expert members. Depending on the balance of the proposed group representatives , the GT did either accept or request a modification of the member composition.Each SC is led by a chair and a co-chair to warrant independency between topic proposers and guideline developers and to avoid bias and imbalances ; selectiSome of the consensus topics are developed jointly with other international organizations. In those cases, representatives suggested by the partner organization were included as members of the SC and involved throughout the entire process.The composition of the nine SC, including roles, is illustrated in Steering committee members participate on a voluntary basis and are not paid for their contribution. Travel and accommodation costs for meetings are reimbursed according to the relevant ESOT travel and meetings policy.A number of virtual meetings were held by the SC to define the scope and aims of their topics and to work on their particular consensus process. Further meetings are scheduled in the upcoming months. Key issues were identified and implemented in the process to be worked on. The agreed clinical questions were formulated according to the PICO methodology  . All PICFollowing the definition of the PICOs, for each topic, literature searches were developed by expert staff from the CET who have expertise in conducting systematic reviews. The searches were conducted in the Transplant Library, Medline, and Embase with or without a date limit (dates differed for each of the groups) and the exact search date of each search was recorded (and will be reported in each consensus-dedicated publication). Bibliographic searches consisted of a combination of Medical Subject Headings and keywords. Search terms and strategies will be provided in the specific topic related publications. Searches, excluding grey literature (some SC included congress abstracts upon request) and following removal of duplicate references, resulted in unique references which were selected for title/abstract screening. If titles/abstracts appeared relevant to the PICO question, corresponding full texts were acquired and reviewed for possible inclusion and interactive reading, and to support the development of consensus statements. Due to the breadth of topics included, a full systematic review process for article review was not performed at this time. Rather, titles and abstracts were reviewed by CET members.PRISMA flowcharts describing the number of studies identified by the literature search and number of studies selected for inclusion in the consensus statement will appear in the following topic-specific publications.A short summary of the evidence addressing each key question by the included studies was prepared in an evidence table. The workgroup proposed a recommendation for each key question, based on the quality of evidence rated using the GRADE approach, with high quality rated as A, medium quality as B, and low quality as C; very low quality of evidence was not considered. In particular, in the evaluation of the quality of evidence according to GRADE the following features were considered: study design, risk of bias, inconsistency, indirectness, imprecision, number of patients, effect, importance . Strengtvia the ESOT webpage  SC leaders will introduce and present their topic to an extended panel composed of all working group members in addition to conference participants registered to participate in the in-person consensus discussion; 2) a single SC member, will provide an overview of the evidence for each key question and present the proposed recommendations; 3) feedback will be provided by working group members and conference participants with particular attention to the generation of clear and concise consensus statements taking into account the suggestions emerged by the discussion 4) the following day the consensus recommendations will undergo the jury vote. Consensus will be considered achieved will be considered as reached if an agreement rate of >80% is achieved; topic lectures and proposed consensus statements will be presented to the entire TLJ 3.0 audience in a dedicated session on the last day of the in-person meeting in Prague.Consensus conference participants are selected and distributed amongst the working groups by the GT members. Complete information including the list of consensus conference working group domains, processes regarding consensus conference participant selection, development and refinement of consensus statements, and modified Delphi methodology including consensus polling will be also reported in Transplant International after the face-to-face meeting in Prague.A validation committee, including experts in validation procedures, will be formed after the jury members have been finalized. Consensus and recommendations will be reviewed by experts in validation according to the AGREE II guidelines: Appraisal of guidelines for research and evaluation II , 17. TheThe 2022 ESOT Consensus Conference, as part of TLJ 3.0, will be the first consensus and guideline conference initiated by ESOT covering the entire field of organ transplantation including organ-specific as well as cross-cutting, inter- and multidisciplinary topics. This in-person event represents the impetus for the foundation of an ongoing consensus, recommendation, and guideline production process which launches also a permanent area, like a standing committee, within ESOT. All guidelines and recommendations produced and published by ESOT and its involved representatives will undergo a continuous review process to stay up to date. Pre-meeting responsibilities and activities included constitution of a taskforce, steering committees and their working group members, opening of the jury applications and their selection process. The guideline development process started with the identification of the topics of interest, formulation of PICO questions and the identification of the relevant evidence.The consensus conference during the TLJ 3.0 consists out of discussion session on statements and generating recommendations including Delphi rounds in some cases, as well as a voting and a discussion session, on the last day during the in-person meeting . The TLJAll recommendations and consensus statements produced for the nine selected topics will be published including the entire evidence-based consensus-finding process.


Nutrition literacy is having the skills and abilities required to prepare food, make healthy food preferences, and understand its effects on health, environment, and economy. Inadequate nutrition literacy can lead to an unhealthy diet, overweight, or obesity. Along with inadequate nutrition literacy, gender is also a risk factor for obesity. In this regard, it is seen that women’s level of nutrition literacy has an important role in gaining healthy eating habits and preventing chronic diseases related to nutrition such as obesity. This study aims to determine the level of nutrition literacy of adult Turkish women and the factors affecting.In this comparative descriptive research, 239 women were selected into 2 groups by their BMI, from Public Education Centers in Istanbul, Turkey, by using simple random sampling method. Data were collected using Introductory Characteristics Form and Adult Nutrition Literacy Assessment Tool. For statistical analysis, Pearson Chi-Square, Mann Whitney U and logistic regression were used.In the study, adequate numerical literacy and food label reading rates in overweight/obese women were found lower (p = 0.000) than non-overweight/obese women. It was found that the number of main meals increases the nutrition literacy level of non-overweight/obese women 2.628 times (p = 0.012). In the overweight/obese group, it was found that number of children (p = 0.040), waist circumference (p = 0.048), snack amount (p = 0.022) and Youtube usage (p = 0.041) increase nutrition literacy levels.The nutrition literacy of both groups was found to be high. However it is highly affected by YouTube usage which provides a new perspective in terms of public health practices and policies. It is recommended for public health professionals to:• use social media platforms and provide evidence-based information• monitor the height, weight and BMI of individuals in the risk group• organize interventions to strengthen nutritional literacy• Adequate numerical literacy and food label reading sub-dimension mean scores of overweight/obese women was lower than the non-overweight/obese women.• Spending time on Youtube increases the nutrition literacy levels in overweight/obese women by 91,116 times which points to the relationship between nutritional literacy and social media use.


In this study, we reported a methodological framework for the development of a guideline for establishing a regulatory science system for supervising the application of artificial intelligence for traditional Chinese medicine (TCM). It introduced all of the key steps for developing the guideline as follows: the composition of the guideline expert groups, summary steps, agency, purpose, targeted population, writing, publishing, updating, dissemination, dynamic monitoring, and evaluation. The guideline will provide the basis for national authorities to effectively regulate artificial intelligence technology and enrich the supervisory system for TCM, and it will be of great significance to TCM. Traditional Chinese medicine (TCM) is a medical and pharmaceutical system with a long history, unique theory, and technical methods, which made great contributions to human health . As a reAs a result of the development of computer science, the application of artificial intelligence (AI) can effectively transform the combined online and offline medical model to achieve multidisciplinary integration, multipath diagnosis, and treatment of the wisdom of the Internet medical, which can improve the efficiency of diagnosis, treatment, and management , 10. In As a result of the wide application of AI technology in the construction of an evaluation system, disease model construction, medical device innovation, and public health crisis response, the establishment of a regulatory science system for supervising the application of AI has become a potential research topic , 15. UntThe guideline's development will follow the latest definitions of guidelines provided by the United States Institute of Medicine , which aThe development of the guideline consists of four phases . In phasTCM : traditiAI : artificRegulatory science : regulatLiving guideline : A livinThe guideline will not require ethical approval because no data linked to individual patient information will be used in our study. Additionally, the findings will be disseminated through peer-reviewed journals or conferences.The guideline will be developed by members from editorial boards of the Journal of Evidence-Based Medicine and the Chinese Journal of Evidence-Based Medicine, in collaboration with a large number of institutions in China, and we will invite experts from multiple units outside of China.The guideline teams consist of a guideline steering committee, guideline expert group, guideline secretariat group, and external review group. To ensure the authority and comprehensiveness of the guideline, the guideline teams will include experts from main cities around China. Additionally, we will invite regulatory science experts from countries out of China to participate. Members of the guideline steering committee, guideline expert group, guideline external review group, and secretariat group should complete a declaration of interest and declare any conflict of interests before formally participating in the work related to the development of the guideline. All members' statements of interest will be reported in the final guideline document.The current study is a methodological study, and patient and public involvement is not needed.The purpose of the guideline is to establish a regulatory science system for supervising the application of AI to TCM. The guideline will focus on the scientific regulatory approach, comprehensive evaluation, and dynamic updating of the application of AI to TCM. This guideline applies to personnel at all levels who conduct regulatory science research on the application of AI to TCM, including policy-makers, medical device managers, clinicians, nurses, computer scientists, and journal editors.X), standard deviation (SD), coefficient of variation (CV), and R value will be calculated for each attribute.Guiding questions will be designed by the guideline steering committee using the relevant literature and study objectives. A three-round Delphi study will be conducted to determine the issues that refer to the guidance and the development method of the regulatory scientific system. Each item will be rated by using a five-point Likert scale . The mean value  will be assessed using ROB 2.0 for RCTs . The NewThe candidate items in the guideline will be developed using the Delphi method. We will develop the candidate items before sending them the questionnaire. A two-round Delphi questionnaire and a final consensus meeting will be employed , 36. An http://right-statement.org) reporting standard. The draft guideline will be submitted to the steering committee for review and approval. Then, the introduction and announcement of the guideline will be published. The guideline will also be presented and discussed at relevant professional society academic meetings and through publication in scientific journals. We will establish the regulatory scientific evidence systematic based on the guideline. The guideline will be updated according to the feedback on the actual operation of the guideline and the latest research results in relevant fields.Once the recommendations are approved, the guideline steering committee will write the guideline according to the RIGHT (Developing a guideline for establishing a regulatory science system for supervising the application of AI to TCM is urgent because the development of AI is so fast. The future guideline will be developed by a multidisciplinary team of experts. To help the guideline, opinions will be obtained from experts, policy-makers, and users. The guideline developers will establish an update and evaluation process to update the guideline and finally help supervise the application of AI in TCM. The guideline will not only track new evidence in real time, promote the practical application of the best research evidence, and implement scientific regulation but also save a large number of resources and optimize the guideline formulation and evaluation process. The guideline will be a new innovation in TCM.In conclusion, the current study describes the steps of formulating a guideline for the application of AI to TCM. The guideline will be developed in strictly accordance with the standards of an evidence-based guideline. The results will be used as a context for analyzing general strengths and gaps in the current quality of evidence in the application of AI to TCM.


To develop a summary format of clinical practice guideline (CPG) recommendations to improve understandability among health care professionals.We developed a summary format based on current research and used the “Think Aloud” technique in one-on-one cognitive interviews to iteratively improve it. Interviews of health care professionals from Children’s Oncology Group-member, National Cancer Institute Community Oncology Research Program sites were conducted. After every five interviews (a round), responses were reviewed, and changes made to the format until it was well understood and no new, substantive suggestions for revision were raised. We took a directed (deductive) approach to content analysis of the interview notes to identify concerns related to recommendation summary usability, understandability, validity, applicability and visual appeal.During seven rounds of interviews with 33 health care professionals, we identified important factors that influenced understandability. Participants found understanding weak recommendations more challenging than strong recommendations. Understanding was improved when the term ‘conditional’ recommendation was used instead of ‘weak’ recommendation. Participants found a Rationale section to be very helpful but desired more information when a recommendation entailed a practice change. In the final format, the recommendation strength is clearly indicated in the title, highlighted, and defined within a text box. The rationale for the recommendation is in a column on the left, with supporting evidence on the right. In a bulleted list, the Rationale section describes the benefits and harms and additional factors, such as implementation, that were considered by the CPG developers. Each bullet under the supporting evidence section indicates the level of evidence with an explanation and the supporting studies with hyperlinks when applicable.A summary format to present strong and conditional recommendations was created through an iterative interview process. The format is straightforward, making it easy for organizations and CPG developers to use it to communicate recommendations clearly to intended users. Many organizations dedicate time and resources to develop clinical practice guidelines (CPGs). Guideline development groups spend countless hours crafting the recommendations and supporting materials, with the goal of improving uptake and implementation. Despite these efforts, implementation has proved challenging across many professions and disciplines. While much of the literature has focused on how to implement recommendations in practice (such as through auditing and providing feedback to practitioners), there has been increasing interest in determining the inherent features of the recommendations themselves and their format that could influence implementation , 2. The With respect to usability, the layout and choice of wording of the recommendation, as well as the supporting evidence, could influence how well the recommendation’s message is textually communicated. Some guidance exists to improve the communication of the intended action of the recommendation. The National Academy of Science’s (formerly known as the Institute of Medicine) Standards for Developing Trustworthy Clinical Practice Guidelines indicate that recommendations should clearly describe the action and the strength of the recommendation: whether the recommendation should be in the affirmative (i.e. ‘to do something’) or the negative (i.e. ‘not do something’) and how to frame the level of obligation to follow the recommendation . When usBased on these guidance statements for recommendation development, the wording of any recommendation should convey its strength intrinsically. However, the choice of word or wording to convey this strength has proven to be challenging. Investigators have evaluated ‘recommend’ versus ‘suggest’ and ‘should’ versus ‘might’, and found that no word or wording was superior in communicating the recommendation strength . Others It is also unclear how much information should accompany recommendations to ensure understanding and acceptance. Some research supports the need for more explanation when a recommendation is based on a close balance of the evidence, or when its implementation requires that other factors be considered . These fWe undertook this qualitative study to develop a summary format to communicate CPG recommendations  to healtWe conducted one-on-one interviews to develop a CPG recommendation summary format that is well understood. We used the “Think Aloud” (TAL) technique of cognitive interviewing in multiple rounds (groups) to iteratively improve the format by exploring participants’ understanding of the recommendation summaries and preferences for the presentation. We applied a directed content analysis to explore multiple themes from within the interviews. We used the Standards for Reporting Qualitative Research  to guideAll 37 COG-member NCORP sites were invited to participate in the primary study. We invited health care professionals who provided direct care for children with cancer at participating sites to be interviewed. Trainees were excluded. Potential participants submitted their demographic characteristics and were purposively sampled to ensure variability by type of health care professional, years in pediatric oncology practice, self-professed level of familiarity with CPGs (from not very to very aware), NCORP site location, and proportion of time devoted to direct patient care.Ethics approval for the study was obtained from the National Cancer Institute Pediatric Central Institutional Review Board (OMB# 0925–0753). Participants gave verbal consent to be interviewed; the need for documentation of consent was waived.www.decide-collaboration.eu) and on formats for different audiences freely available in the GRADEpro online software (www.gradepro.org). We considered the quantity of text , the type of information , formatting , use of symbols, and use of color. From recommendations available from COG-endorsed supportive care CPGs [The initial recommendation summary format  was deveare CPGs , we chos™) lasting approximately 30 to 60 minutes. Five members of the team conducted interviews  who had experience in health research methodology and guideline development, and/or paediatric oncology. Each session was recorded, and interviewers took notes during and after the interview—all without identifying the interviewee.We conducted one-on-one, semi-structured interviews via video chat  and shown two recommendation summaries on that topic  in random order. The formats were provided via email to each participant as a PDF document which could be viewed on screen or printed. At the beginning of the interview, we described a short clinical scenario related to the recommendation topic to place the following recommendations in context. Using the TAL technique, we asked each participant for their initial reactions to the recommendation summary, and then continually prompted the participant to think aloud while he/she interpreted each section of the recommendation summary . To evaluate understanding, we asked the participant to choose from four possible courses of action suggested by the recommendation summary: to provide care (or not) as per the recommendation (strong recommendations) or likely provide care (or not) as per the recommendation . Next, the interviewer disclosed the correct course of action according to the interview guide and asked the participant to reflect upon which parts of the recommendation summary enhanced or detracted from the correct understanding, and to suggest modifications to improve understanding. The interview guide is available in The interviews were conducted in rounds of five, but each round could be stopped prior to completion of five interviews if feedback indicated that immediate revision to the recommendation summary format was needed. Interviews were conducted until the tested recommendation summary format was well understood (defined as correctly choosing the action recommended) by at least four of five interviewees, and until saturation of ideas  was achieved. We planned to interview 25 participants at minimum and estimated that up to 50 interviews could be required.Feedback about the format was categorised as positive (not requiring a modification), obstructive (preventing use of the recommendation), major (interviewee able to solve independently), minor (cosmetic), and suggestions for modification/improvement. In addition, we calculated the number of participants per round who correctly interpreted the course of action for the recommendation summary. The team met virtually after each round of interviews to review the interview notes and agreed by consensus about which revisions should be made. The recommendation summary format was then revised prior to the next round of interviews. In order to identify other concerns related to recommendation summary understandability, two investigators (NS and LLD) conducted a directed content analysis of the notes taken during and after each interview based on the implementability framework . To ensuTwenty-six of the 37 NCORP sites (70%) were involved in the primary study and participants were selected from 15 of these sites. Five investigators conducted a total of 33 interviews in seven rounds from February 1, 2019 through September 3, 2020. Participants included physicians, nurses, pharmacists and other health care professionals. Almost all reported that they were fairly or very aware of CPGs. Demographic characteristics of participants and their institutions are provided in Seven rounds of interviews were conducted in total. The first round was closed after three interviews because feedback on the initial format required immediate revision . Overall, we found that major changes were made to the format for both the strong and weak/conditional recommendation summaries up to round 3 but there were few changes made in the subsequent rounds. In addition, during the first three rounds, we asked about understanding of the format based on a clinical scenario for an individual patient, but in subsequent rounds, we asked participants to respond from the perspective of their institution to encourage the participant to focus on the general application of the recommendation summary. By the sixth round of interviews, the strong recommendation summary format met criteria for both understanding and saturation. Therefore, only the weak/conditional format was discussed in the seventh round of interviews. Understanding of the recommendation summaries by participants in each round of interviews is presented in Throughout the interview a tension was noted between providing too much or too little information. During the first rounds when most of the information was presented in paragraphs of text, it became clear that interviewees found the provided information difficult to read. One participant stated, “because it’s too wordy I wouldn’t know where to start and would have to read every line.” Therefore, the format was changed to bulleted lists. Conversely, many participants wanted more and specific information about drugs that were recommended, such as brand and generic names, contraindications, and dosages. To address these conflicting requests, hyperlinks to additional information were embedded within the recommendation summaries. However, additional information provided in the Rationale section was well-liked and was, therefore retained: “I like the rationale—like in general—physicians like to see that rationale.” The positioning of the rationale on the left and then more details about the evidence on the right also made sense to interviewees.In the early rounds of interviews, interviewees commented on the specific format of the recommendation summaries. Most comments were related to emphasizing key elements in the text, such as bolding the strength of the recommendation and the words used to denote the strength , and changing the title of the document to include the strength of the recommendation. Participants also stated that strong and weak/conditional recommendation summaries should be presented in the same general format—a ‘consistent’ presentation.strong or weak. Strong recommendations are generally understood as meaning that the recommendation should be followed and were correctly interpreted by the majority of participants even in the early rounds of interviews .Participants also suggested that the rationale could be communicated to a patient/patient’s family to explain why a medication or approach was being offered. In addition, they indicated that this section would be more useful if it described how institutional differences have or could have an impact on the recommendation. Since participants identified multiple roles for the Rationale section, it was divided into two sections in the third round to better meet these needs: Supporting Evidence and Rationale. The Rationale section describes the balance of benefits, and then harms, and provides information about additional factors, such as implementation, that were considered by the CPG panel when making the recommendation. The Supporting Evidence section explains the level of evidence with hyperlinks to supporting studies when applicable, and the quality of the evidence. Key words are hyperlinked to explanatory or supplementary information.Similar to comments about needing a rationale , participants noted that they wanted more information when a recommendation entailed an institutional practice change. Some acknowledged that a recommendation would be more easily accepted if it matched current practice: “this recommendation is standard practice, so I would do it.” Other factors related to acceptance were trust in the group who developed or endorsed the CPG and the level of supporting evidence. Even though the level of evidence is not correlated with the strength of the recommendation , participants indicated that they would find it harder to accept a recommendation if it were based on low or very low-quality evidence. In addition, a participant stated that “…if it supports what I’m already doing, it doesn’t matter so much what the level of evidence is.”To improve implementation of a recommendation, many participants requested more details, including information about the specific population to which the recommendation pertains and the circumstances. Suggestions included clearly indicating the population to which the recommendation applied in the recommendation statement and in the rationale; providing links to websites with additional descriptions or information, such as about drug doses; and providing brand names of the drugs mentioned. These changes were made after each round and improved understanding of the recommendation summary. Interviewees also expressed a desire for a care pathway or specific instructions, most notably when recommendations offered a choice . In later rounds, we changed the perspective by asking participants what the institutional standard of care should be based on the recommendation, i.e., using the recommendation to create care pathways which would apply to an individual patient. Still, there were some physician participants who indicated that they may not follow recommendations when deciding how to care for their own patients.After six rounds, 28 interviews, the final format for a strong recommendation summary was reached whereas seven rounds and 33 interviews were required before the format for a conditional recommendation summary was finalised . These fBased on feedback from health care professionals in pediatric oncology, we created a summary format for the presentation of supportive care recommendations to improve recommendation usability, understandability, validity, applicability and visual appeal. In doing so, we obtained valuable insight into the preferences of users with respect to recommendation summary presentation and content as well as the challenges faced by users as they attempted to interpret the recommendations. We incorporated these findings into the final format. Recommendations in this summary format are intended to accompany a fully published CPG as an implementation tool.weak to conditional, providing a rationale for the recommendation, and including a summary of supporting evidence and factors for users to consider when implementing conditional recommendations. Despite the breadth of its content, the final recommendation summary format is brief.One of the most striking issues that we uncovered was the misunderstanding of and discomfort with weak recommendations. This supports anecdotal evidence that practitioners may have difficulty understanding and applying recommendations that are weak, and that strong recommendations are more easily understood. Our final recommendation summary format successfully addressed this concern by including clear definitions of strong and weak recommendations, changing the word We had also hypothesised that symbols might improve the understandability of recommendations, as they could be a way to distinguish the strength of the recommendation. We, however, did not find that the use of symbols or different shading had an impact on understanding and therefore removed symbols from the format early in the process.We tested recommendations on three different supportive care topics with different levels of evidence associated with different strengths of recommendations. We were, therefore, able to explore participants’ understanding when the level of evidence did not intuitively match the strength of the recommendation—for example, a weak/conditional recommendation that was supported by moderate or high-quality evidence. These cases seemed the most confusing to the interviewees. However, by including some details about the evidence, (such as the limitation of the studies or the participants in the studies) interviewees understood the level of evidence and the strength of the recommendation. However, caution in describing the evidence is needed, as participants might use the description of the evidence to determine their own level of evidence, instead of considering the level assessed by the CPG developers.An interesting finding of this study was the initial desire of many participants in early interviews for clinical pathways instead of recommendations. Clinical pathways are defined as tools that standardize care over a course of treatment by translating evidence into a structured, multidisciplinary care plan within a specific context . A cliniwould do if given the recommendation summary. Some indicated that they may not provide CPG-consistent care. In future, we could evaluate changes in practice when CPGs using the new recommendation summary format are published are explore reasons for care choices that are not CPG-consistent. The format was also presented to participants in a package of materials, but not within a website or other electronic platform, such as an electronic order entry system. Although the recommendation summary format was tested on screen during most interviews, further exploration of the format within a platform could provide additional insight to its contribution to CPG-consistent care. We also focused only on a few key components of the implementability framework, but work continues to develop more tools to optimize communication of CPG content [One of the strengths of this study was our use of the TAL interview technique, which allowed us to glean valuable information about how people interpreted what we presented and consequently enabled us to modify the recommendation summary format to improve understanding. Further, inclusion of a broad range of health care professionals who provide direct care to pediatric oncology patients gave voice to users at all levels of the CPG implementation process: from those who select a CPG for implementation to those who deliver direct care. According to our protocol, the recommendation summary format was tested until it was well understood, defined as achieving saturation of ideas and having at least four out of five interviewees choose the correct action based on the recommendation. The former criterion is subjective. However, our research team of more than five members had to agree on this judgement, ensuring our results were reliable. Despite the many strengths of this study, there are limitations to consider. Our findings apply only to summaries of published CPG recommendations . Expert  content , 16.We provide a format to present a summary of strong and conditional recommendations that can be used to convey recommendations to health care professionals. The format is straightforward, making it easy for organizations and CPG developers to use it to summarize and communicate their recommendations clearly to intended users. Ideally, the implementability of this format could be assessed in a larger group of multi-disciplinary and multi-professional users. Once refined and integrated into CPGs, its influence on CPG-consistent care delivery should be assessed.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.


Bleeding and thrombosis frequently occur in pediatric patients with extracorporeal membrane oxygenation (ECMO) therapy. Until now, most patients are anticoagulated with unfractionated heparin (UFH). However, heparin has many disadvantages, such as binding to other plasma proteins and endothelial cells in addition to antithrombin, causing an unpredictable response, challenging monitoring, development of heparin resistance, and risk of heparin-induced thrombocytopenia (HIT). Direct thrombin inhibitors (DTIs), such as bivalirudin and argatroban, might be a good alternative. This review will discuss the use of both UFH and DTIs in pediatric patients with ECMO therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly used in pediatric patients with life-threatening cardiac and/or respiratory failure. Very recently, the extracorporeal life support organization (ELSO) reported 154,106 ECMO runs by 521 participating centers worldwide since 1990 . They coUntil recently, all patients with ECMO were anticoagulated with UFH, mainly because of the long-term experience with the anticoagulant, the lack of better alternatives, and the ability to rapidly reverse with protamine sulfate when complications occur. UFH is a sulfated mucopolysaccharide. Heparin molecules range in molecular weight and have a mean molecular weight of 15,000 kDa, corresponding to about 45 saccharide units .International surveys have shown large variation in the management of anticoagulation during ECMO , 6. The A recent literature review investigated the association between coagulation tests and hemostatic complications, such as bleeding and thrombotic events . In nineAlthough UFH has been used for years in patients with ECMO, it has various important limitations, especially in neonates and young infants . As mentvia both the active/catalytic site and the exosite 1/fibrinogen binding site, independent of antithrombin. It is a small peptide, with a molecular weight of approx. 4,000 Da, which is cleaved by proteases that includes thrombin  and diluted thrombin time (dTT). A recent study by Beyer et al. demonstrated a significant discordance between the aPTT and the ECA and dTT with a higher rate of bleeding complications in patients whose DTI dose was titrated exclusively based on the aPTT . It appeEcarin is a metalloprotease isolated from viper venom, which directly activates thrombin and is therefore not affected by other factor deficiencies or lupus anticoagulants. The measured clotting time (CT) is theoretically directly proportional to the concentration of the DTI. However, studies showed that it was only suitable for bivalirudin but not lepirudin or argatroban due to the sensitivity of the chromogenic substrate chosen . The dTTGlobal coagulation assays TEG and thromboelastometry (ROTEM) are 2 whole blood coagulation assays that are currently being studied for their utility in monitoring the anticoagulation of patients on mechanical circulatory devices. They are able to measure the changes in viscosity of dynamics of clot formation. It remains an assay that is utilized in major centers and therefore has limited data. Studies have shown a good correlation between the anti-factor II assay and an ecarin-modified TEG . SimilarThere are no guidelines for dosing of bivalirudin in ECMO. Dosing strategies vary significantly by institutions. In adults, the majority of the studies report doses varying from 0.025 to 0.05 mg/kg/h with the average rate of bivalirudin infusion required to maintain therapeutic aPTT or ACT levels varying from 0.028 to 0.5 mg/kg/h . There iIt has also been shown that bivalirudin requirements increase with time. Hamzah et al. indicated that improved renal function with ECMO, upregulation of proteases that cleave thrombin resulting in increased thrombin levels, increased clot burden over time in the circuit, and increasing levels of fibrinogen over time resulting in increased competition for thrombin binding as possible reasons for this phenomenon. They also reported a dose-dependent increase in PT/INR, which may be suggestive of effects on other coagulation factors beyond thrombin.n = 2,059, UFH n = 2,039). Bivalirudin showed no benefit over UFH with regards to the primary composite outcome of any of the following hospital and procedural complications: death, myocardial infarction, the abrupt closure of the dilated vessel, or rapid clinical deterioration of cardiac origin requiring bypass surgery, intra-aortic balloon counter-pulsation, or repeated coronary angioplasty  (p < 0.001). Follow-up analysis that included an intention to treat the model with the 214 patients not included in the original analysis showed similar results with regard to ischemic and hemorrhagic complications, with some slight increase in benefit seen with bivalirudin based on an adjusted primary end point of death, myocardial infarction, and revascularization  , i.e., patients with or at risk for having HIT or heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Initial US Food and Drug Administration (FDA) approval was based on results from the Hirulog Angioplasty Study (HAS) where 4,098 patients were randomized to receive bivalirudin or UFH during angioplasty for unstable angina or post-infarct angina  . However= 0.039) . Thus, bn = 6,010) successfully met the non-inferiority end point as compared to heparin with regards to the composite outcome of death, myocardial infarction (MI), urgent revascularization, or in-hospital major bleeding within 30 days . Bivalirudin was also found to have lower rates of major bleeding  and fewer patients treated with bivalirudin experienced a decline in platelet count below < 100 × 10/9l .Several subsequent studies expanded the use of bivalirudin to PCI in the setting of glycoprotein IIB/IIIa antagonists. The pilot trial, Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET) established the proper dosing regimen for bivalirudin for PCI in this setting  . This doBivalirudin for PCI in patients with HIT was investigated in the anticoagulation therapy with bivalirudin to assist in the performance of PCI in patients with heparin-induced thrombocytopenia trial (ATBAT) . Fifty-tBivalirudin has increasingly been used off-label in part because it has a relatively short half-life and predominantly non-organ-independent clearance with less need for reduction in the setting of mild or moderate renal function. Additionally, it is not dependent on a co-factor and therefore less likely to result in drug resistance as can be seen with heparin and low levels of antithrombin . For alln = 16) established pediatric dosing for bivalirudin of a bolus dose (0.125 mg/kg) followed by continuous infusion (starting at a rate of 0.125 mg/kg/h) to target 1.5–2.5 times the patient’s baseline aPTT. Two patients suffered from a major bleeding event. No patient had thrombus progression at 48–72 h and 6 patients (37.5%) had complete or partial resolution of the thrombus at 72 h. This was followed by the Utilization of Bivalirudin on Clots in Kids (UNBLOCK) study; an open-label, single-arm, dose-finding, pharmacokinetic, safety, and efficacy study conducted in children aged 6 months to 18 years with a deep venous thrombosis (n = 110)  . In thisn = 50). Bivalirudin dosing in this study was extrapolated from approved weight-based dosing in adults. Children receiving UFH achieved higher ACT levels at first bolus and 30 min after the onset of CPB  and a shorter duration of post-CPB ACT increment . Bivalirudin also prolonged the duration of surgery mostly due to the need for additional bolus doses each of which prolonged the surgery by 10–13 min. There was no difference, however, in chest tube output or need for transfusions between the two groups.There is only 1 randomized trial of bivalirudin use in children to our knowledge. In this trial, bivalirudin was compared to UFH in children with acyanotic aged 1–12 years who underwent open-heart surgery  (n = 50)Robust randomized or prospective data for the use of bivalirudin in mechanical support devices, such as ECMO circuits, and ventricular assist devices (VADs) are lacking. A systemic review from 2005 to 2017 looking at bivalirudin and ECMO found only 8 relevant publications ; 2 retrospective case-control studies, 1 case series, and 5 case reports; highlighting the knowledge gap in this area . In the n = 295), Rivosecchi et al. showed a decrease in circuit-related thrombotic events  with the use of bivalirudin in patients placed on veno-venous (VV)-ECMO (p = 0.0126] (n = 429) failed, however, to demonstrate a significant difference in the composite outcome of circuit intervention rate and oxygenator/pump change-out rate (n = 72) (n = 32) found no difference in time within the therapeutic range between UFH and bivalirudin -ECMO . These r 0.0126] . It is iout rate . One add(n = 72) . The autalirudin . In thisThere is potential that the short half-life of bivalirudin, while desirable, may not be ideal for mechanical support devices where areas of stasis or non-systemic blood flow may result. This may result in disproportionately low bivalirudin concentrations and thrombus formation. With ECMO, there is no contractile force on blood flow allowing for cardiac blood stagnation and possible formation of intracardiac thrombus, especially in the setting of a very large right or left atrium with insufficient venous drainage or with very poor ventricular systolic function .Bivalirudin is just one of the DTIs and it has the most expansive label indication. Intravenous DTIs represent a class of medications that can be either synthetic hirudin fragments  or low-molecular-weight inhibitors that interact at the active site of thrombosis . To our knowledge at this time, only a few case reports have described the use of lepirudin with the primary indication being HITT in the majority of the cases , 49. Lepn = 13) reporting on argatroban use in 307 patients with ECMO found considerable variation in dosing practice and target anticoagulation goals with either the aPTT or ACT. These differences are likely related to patient differences with regards to disease severity, end-organ function, and institutional aPTT or ACT goals. Across the included studies, bleeding and thromboembolic event rates were similar to UFH  overcoming the potential limitation of bivalirudin in areas of stagnation addressed above. Agatroban undergoes liver metabolism and dosing is not renal dependent. Argatroban has successfully been used in the setting of ECMO. In propensity score-matched observational study of 78 adult patients who received UFH were matched to 39 patients who received argatroban. A composite primary outcome of major thrombosis and/or major bleeding was seen in 83% of patients with UFH and 79% of the patients who received argatroban. The authors concluded that argatroban was found to be non-inferior to UFH regarding bleeding and thrombosis rates. While argatroban drug costs were higher, they were balanced when accounting for blood product support and HIT testing associated with UFH use . A syster to UFH .Prevention of bleeding and thrombosis in the setting of the inherent variability in ECMO circuits, cannulation, and patient populations is extremely challenging. The choice of anticoagulants, which was limited to heparin, has now increased with the new parenteral anticoagulants. Bivalirudin is being increasingly explored for anticoagulation in patients with ECMO for its obvious advantages of short half-life and ability to bind to both free and clot-bound thrombin, but the lack of a reversal agent is a primary disadvantage. Although data are limited, there appears to be increasing evidence that this may at least be an equally efficacious. It also has the potential to avoid the use of antithrombin replacement and reduce lab monitoring. Current potential benefits are mostly extrapolated from adult data in the setting of PCI and additional studies are needed for specific ECMO to determine the true impact on clinical outcomes, such as transfusion needs, circuit-related thrombosis, and hemolysis. Randomized controlled trials are extremely difficult to conduct in this diverse population of patients and continued data collection on the safety and efficacy of the use of bivalirudin in ECMO will be required to determine if this can be considered a first-line anticoagulant in ECMO.CN, MC, and CO reviewed the literature, wrote, edited, and revised the manuscript. All authors agreed with the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Evidence briefs for policy (EBP) draw on best-available data and research evidence  to help clarify policy problems, frame options for addressing them, and identify implementation considerations for policymakers in a given context. An increasing number of governments, non-governmental organizations and research groups have been developing EBP on a wide variety of topics. However, the reporting characteristics of EBP vary across organizations due to a lack of internationally accepted standard reporting guidelines. This project aims to develop a STandard reporting guideline of Evidence briefs for Policy (STEP), which will encompass a reporting checklist and a STEP statement and a user manual.We will refer to and adapt the methods recommended by the EQUATOR  network. The key actions include: (1) developing a protocol; (2) establishing an international multidisciplinary STEP working group (consisting of a Coordination Team and a Delphi Panel); (3) generating an initial draft of the potential items for the STEP reporting checklist through a comprehensive review of EBP-related literature and documents; (4) conducting a modified Delphi process to select and refine the reporting checklist; (5) using the STEP to evaluate published policy briefs in different countries; (6) finalizing the checklist; (7) developing the STEP statement and the user manual (8) translating the STEP into different languages; and (9) testing the reliability through real world use.Our protocol describes the development process for STEP. It will directly address what and how information should be reported in EBP and contribute to improving their quality. The decision-makers, researchers, journal editors, evaluators, and other stakeholders who support evidence-informed policymaking through the use of mechanisms like EBP will benefit from the STEP.Registration We registered the protocol on the EQUATOR network. (https://www.equator-network.org/library/reporting-guidelines-under-development/#84) The need for evidence-informed policies and decisions to achieve the Sustainable Development Goals (SDGs) and other global-development targets is increasingly and widely recognized among policymakers, managers, providers, the public, researchers, and other stakeholders –4. As anNowadays, more and more health and non-health EBPs are being prepared to address different issues by international organizations or academic groups, such as the Evidence-Informed Policy Network (EVIPNet). Moreover, related theories, methodologies, and practical handbooks about the development and usage of EBP are continuously evolving as experience grows.However, the reporting format, characteristics, and lengths of EBP varies greatly across the organizations preparing them , 9. AdamReporting guidelines are an important method to promote scientific research and developing guidelines for research-derived products such as EBP would similarly promote more systematic and transparent approaches to the development and reporting in these increasingly common documents. A clear, accurate, and complete EBP can not only help decision-makers and other stakeholders correctly understand the contents of the brief, but also help users make more evidence-informed decisions. Moreover, as one popular evidence-packaging document that addresses policy issues and provides policy options for policymakers, it is necessary to develop a widely accepted reporting guideline for EBP. The STandard reporting of Evidence briefs for Policy (STEP) project aims to develop a reporting guideline which will encompass a reporting checklist, a STEP statement & a user manual.We will refer to and adapt the methods recommended by the EQUATOR network . Table 1To identify the need for developing the STEP checklist, we searched the peer-reviewed literature and related documents on EBP and found there is no internationally accepted standard reporting checklist for EBP in health and non-health sectors. Moreover, our several interactions with different groups of decision-makers reaffirmed the need to develop a STEP checklist through a systematic and transparent process.Our project is funded by the major project of the National Social Science Foundation of China: “Research on the Theoretical System, International Experience and Chinese Path of Evidence-based Social Science” (Project No. 19ZDA142). The funder will not interfere in the design of the study, in any aspect of data collection, analysis or interpretation, or in the writing and publication of the output.https://www.equator-network.org/library/reporting-guidelines-under-development/#84). The protocol will be published in the peer-reviewed journal and the development of STEP will be initiated after publication of the protocol.To enhance the transparency and quality of the STEP development process, we drafted a research protocol and registered it on the EQUATOR network (Coordination Team (CT)The STEP working group consists of two subgroups: the Coordination Team (CT) and the Delphi panel (DP). We will collect both direct and indirect disclosures for all participants at the start of the STEP project and before publication.2.Delphi Panel (DP)The members of the CT represent skills and experience covering project coordination, Delphi technique, development of EBP, reporting guidelines, guideline development, and implementation science. The roles of the CT are to coordinate the project; recruit the DP; draft the protocol and potential items; organize the Delphi process; collect and analyze data from the Delphi process; and draft the final checklist, statement, and explanatory document.Considering the diversity of methodological expertise, gender equality and wide geographic representation, we will invite 10–20 individuals to the DP group, based on a review of the main authors in the field, as well as the recommendations from our working group. We will include experts with technical expertise in EBP development and implementation; EIP; health and non-health sectors; policy research; practice guideline development and implementation; knowledge translation; and reporting guidelines. To reflect the views and perspective of EBP target users and population, representatives of policymakers and other decision-makers , researchers and the public  will be also invited into this group. The roles of the DP group are to contribute to the protocol and development of checklist; and provide the comments on the final STEP checklist.We will conduct a literature search to extract potential reporting items. The search strategy, including the search sources and terms, will be developed with the help of an information scientist. We will mainly search six electronic databases: Web of Science, PubMed, EBSCO, PIE, Health Systems Evidence, and Social Systems Evidence. Also, we will additionally search related websites: 3IE International Initiative for Impact Evaluation, European Observatory on Health Systems and Policies, Evidence for Action (E4A), Evidence-Informed Policy Network (EVIPNet), Health Affairs, Health Systems Global (HSG), World Health Organization (WHO), and United Nations (UN). Moreover, we will search Google and Google Scholar for first 200 records and check the references of included studies and papers recommended by experts. The search strategy for PubMed is presented in Table We will include the publications with the following characteristics: (1) publicly available, which clearly mentions one of EBP characteristics in both health and social science sectors between 2017 and 2021; and (2) publicly available research literature and/or documents related to EBP methodology, including development, reporting, use or implementation of EBP. We will exclude conference abstracts, editorials, commentaries, letters, opinions, correspondence, and news. Two reviewers will independently conduct the screening for literature and documents and the discrepancies will be resolved through discussions and consulting a third reviewer (if necessary).We will develop a standardized form to extract the characteristics of each included document, including title, publication year, journal or development organization, and country focus (if applicable). We will extract and code the reporting characteristics  from included documents, and conduct a thematic analysis based on the coding. Two reviewers will independently conduct the data extraction and coding for documents and the discrepancies will be solved through discussions and consulting a third reviewer (if necessary). During the process, iterative discussion and feedback among the research team members will be undertaken. Through the virtual meeting among research team, a list of potential items for reporting EBP will be developed and refined.To achieve consensus on reporting items in the final STEP checklist, considering the possible attrition and participant fatigue , we willThe questionnaire will be piloted among the CT. The content and format of the questionnaire will be adjusted through discussion. We will send the initially prepared items in Microsoft Word format to score each item of the initial STEP checklist and collect suggestions and modifications. We will use a 7-point scale  to rate each potential item –16.Participants will be provided with the opportunity to suggest refinements and modifications to each of the candidate items and to suggest additional items not addressed in the list. The responses for each round will be analyzed using Microsoft Excel. For the scored quantitative data, we calculate the median score. The definition of agreement and consensus are presented in Table After the second or third round of Delphi surveys is completed, we will generate a draft version of the STEP checklist. To validate the utility, applicability, and reliability of the STEP checklist, we plan to use the STEP checklist to evaluate a sample of policy briefs published in different languages  in the last three years. Through the evaluation of a sample of EBP, we hope to identify current deficiencies and weaknesses in the tool, record them and use them to inform the final updates and improvements to the STEP checklist. CT will collect and analyze results, and discuss them with DP in the next phase .Due to the COVID-19 pandemic, we will organize a virtual (rather than in-person) conference including representatives of the CT and DP groups to present and discuss the results of the Delphi process and evaluation results, then will draft the final checklist. We will send it to the representatives of the CT and DP for their review to ensure accuracy.The CT will develop STEP statement and user manual, including rationale for developing the checklist, development process, and the checklist. A purposive sample of participants will be recruited to for pilot testing. We will not limit participants according to their experience and exposure to EBP development and/or use, which will help us better estimate of the usability of the guideline among its expected users. We will seek feedback by pilot testing, which will include contacting individuals and groups involved in developing EBP, asking them to use the checklist to inform the preparation of their EBP, followed by the collection of feedback (by online survey) from them about any further revisions that need to be made to the guideline. We will publish the STEP in a peer-reviewed journal.We will welcome and collaborate with other EBP developers who want to translate this guideline into other languages.We will test the reliability of the checklist through continuous collection, comparison and analysis of user data using a feedback mechanism by emails. Moreover, we plan to update the STEP every 3–5 years.The main output of our project is a STandard reporting guideline of Evidence briefs for Policy (STEP), which will encompass a checklist of reporting items for EBP in health and non-health sectors, a STEP statement, and a user manual. The STEP will directly address what and how information should be reported in EBP. We also hope to reach a consensus on the term of EBP in this project. Moreover, policy makers, decision-makers, researchers, users, journal editors, and evaluators will benefit from the STEP statement.The main strength of our research is the systematic, transparent and rigorous methods that will be applied to identify EBPs not only in the health sector, but also in the social sciences. The multi-layered approach to developing a checklist through systematic literature review followed by refining the list through a Delphi process will enhance the transparency and credibility of our findings. STEP working group members have years of experience in developing and evaluating EBP and publishing them  in academic journals. However, there some challenges may exist: first, EBP that are not in the public domain will not be included for obvious reasons; second, we do not plan to conduct a quality assessment for all included EBP because there are no appraisal tools widely accepted.We will collaborate with some organizations, institutions, and groups who are preparing and/or using EBP to implement STEP, and continuously seek feedback from developers, users, and stakeholders. We will disseminate the STEP by publishing into a peer-reviewed journal, presenting to relevant stakeholders and translating into different languages. We will update the checklist based on the continuous feedback and new relevant research evidence.


Entrustable Professional Activities (EPAs) assessments measure learners’ competence with an entrustment or supervisory scale. Designed for workplace-based assessment EPA assessments have also been proposed for undergraduate medical education (UME), where assessments frequently occur outside the workplace and may be less intuitive, raising validity concerns. This study explored how assessors make entrustment determinations in UME, with additional specific comparison based on familiarity with prior performance in the context of longitudinal student-assessor relationships.A qualitative approach using think-alouds was employed. Assessors assessed two students (familiar and unfamiliar) completing a history and physical examination using a supervisory scale and then thought-aloud after each assessment. We conducted a thematic analysis of assessors’ response processes and compared them based on their familiarity with a student.Four themes and fifteen subthemes were identified. The most prevalent theme related to “student performance.” The other three themes included “frame of reference,” “assessor uncertainty,” and “the patient.” “Previous student performance” and “affective reactions” were subthemes more likely to inform scoring when faculty were familiar with a student, while unfamiliar faculty were more likely to reference “self” and “lack confidence in their ability to assess.”Student performance appears to be assessors’ main consideration for all students, providing some validity evidence for the response process in EPA assessments. Several problematic themes could be addressed with faculty development while others appear to be inherent to entrustment and may be more challenging to mitigate. Differences based on assessor familiarity with student merits further research on how trust develops over time.The online version contains supplementary material available at 10.1186/s12909-022-03402-x. Competency-based, time-variable education is a hotly debated topic in medical education , 2. In rEPA assessments are typically done in the clinical workplace and resemble the decisions supervisors make frequently regarding their trainees . They arWhile initially intended for residency training, there has also been interest in using EPAs in early medical training . To thatscoring (translating an observation into a score or scores); generalization (interpreting the score or scores as a reflection of test performance); extrapolation , and implications (making an advancement decision based on the score or scores)  than when they were unfamiliar student’s prior performance (3–4).When an assessor was familiar with the student, they provided on average 8.6 entrustment determinations and think-alouds per 20-min video (range: 5–22) compared to an average of 9.2 determinations (range: 5–22) when they had not observed the student previously. As listed in Table The average length of each transcript was approximately 1500 words and each think-aloud was 150–300 words in length. Three rounds of iterative coding of four transcripts were required to develop an initial codebook. No new codes emerged after these initial four transcripts, confirming our sample size of 18 transcripts was likely to achieve thematic saturation (34). Fifteen subthemes emerged 764 times during the coding process, which were further organized into four themes. Definitions for each theme/subtheme are available in Table [These questions] assure me that [the student is] thinking about potentially red flag issues that might have brought the patient in.or when the assessor questions the students’ clinical reasoning:I'm not sure where [this is] all going.Student rapport related to how the assessor understood the patient to be relating to the student. This code had two variants: patient response,The patient seems comfortable with him as well. and student effort:The student [is] using active listening and summarizing to build rapport. Observable or inferred student activities - often described as skills. This theme included “student behaviors,” “inferred clinical reasoning,” and “patient rapport.” and represented two-thirds of transcribed content (66%). Student behavior, as a subtheme, indicated that assessors was commenting on something they observed the student doing. This was frequently described in neutral terms,  but was also occasionally described as correct  or incorrect . Clinical reasoning was typically inferred from what the student was doing:I would have wanted to be in the room and at least initially to be able to jump in. .Occasionally, however, they discussed levels of supervision in the future tense – indicating they were considering what level of supervision the student would require in the future:She'd have to work with a supervisor before she could conduct this stuff in an independent fashion.Assessor preference/self was used when the assessor referred to themselves as frame of reference:I would have put this patient in the chair and done the interview in the chair to make it a little more relaxing. Assessors’ affective response appeared to manifest as disappointment, pain, feeling good/better, discomfort and surprise:In the past I’ve seen her do this incredibly well so I’m a little surprised that she didn’t do as well on this [case]. Phase of training represented when entrustment decisions were informed by where the student was in training rather than just their performance:But there's part of me that also is inhibited by the fact that he's a second-year medical student.An exemplar of how familiarity with a student’s prior performance can influence entrustment was:[My rating is] based partly on my past-experience with her and what I've observed this time. Conversely, a lack of familiarity also impacted entrustment:Right now, I'm putting low confidence just because I don't know the student and I'm realizing that does make an impact.Assessors occasionally compared the student in the second video to the student from the first video. Of note, the order of the videos was randomized (familiar/unfamiliar) and this subtheme did not appear more often for either type of relationship.So, she's doing a better job than the last student characterizing the complaint - she seems to be more methodical. The curriculum was evoked as a frame of reference for what the assessors expected. Occasionally, it was referenced as an “excuse” for the student not performing as expected. For example, this assessor is referencing a perceived inadequacy in the curriculum, despite assessing a student they longitudinally instructed:Based on what I know about the curriculum here [...] I wonder if she may not have the ability to form a broad differential for that [chief complaint].How the assessor understands the task at hand to include personal context or differences in understanding related to the purposes of the assessment. The next most common theme included seven different subthemes: “future training requirements,” “Assessor preference/self,” “affective reactions” to the student’s performance, the “student’s phase of training,” “previous exposure to student performance,” “comparison with other students,” and “the curriculum.” Future training requirements revealed assessors were considering what supervision was needed in the future versus what supervision was required during the current encounter. For example, most of the time the assessors commented on what supervision the student currently required:I still don't know what his level of knowledge is… and I don't know about his clinical decision making…so I think he's able to conduct the interview, but not necessarily. (Assessor G-Familiar student)In contrast, compromised information had to do with an inability to observe what the student was doing, typically due to the camera angle of the video:I can’t tell, but it does not look to me like the bed is at a 45 degree angle… it looks much flatter because we’re looking down. (Assessor H-Unfamiliar student)Insufficient number of assessments referred to an entrustment score being limited because of a single observation and the need for further exposure to the student:Given the opportunity to observe [the student] several more times, I might be willing to fairly quickly move him up in the in the supervisory level scheme. But just with one […] single observation, [I] wouldn't go any higher just yet. (Assessor A-Unfamiliar Student)When the assessor questions that their ability to observe the student adequately. The third theme included “assessor confidence” in their ability to assess, “compromised information,” and concern regarding an “insufficient number of assessments.” Assessor confidence was commonly expressed near the end of the student’s performance and reflected their uncertainty about their own ability to assess aspects of a student’s performance without giving an explicit explanation:. This least common theme related to “patient safety” and “patient characteristics.” These subthemes did not relate to the quality of the student’s performance. For example, if a student neglected to ask a critical question, failed to complete an important part of the physical exam, or neglected a diagnostic option that might threaten patient safety, these errors were considered student performance. Patient safety, as a subtheme, was noted regardless of student performance:The patient wasn't in extremis, so I don't think that the supervisor needed to be in the room.(Assessor F-Familiar student)Similarly, “patient characteristics” had little to do with student performance, but instead typically highlighted an assessor’s desire to see “such a complicated patient” before they “left the clinic.”Details specific to the patient, like acuity and risk associated with careComparison of the subthemes we identified when assessors observed students with whom they were familiar with to those they were unfamiliar with revealed several key differences Table . When asstudent performance. While it is reassuring that student performance played a large role in how assessors arrived at an entrustment score, our assessors also employed several other considerations that went beyond the observed behavior and were outside a student’s realm of control. When assessors’ considerations do not directly relate to a student’s observed performance, evidence that entrustment scores are fair and accurate may be compromised.We examined the thought processes of assessors who were tasked with making an entrustment determination while they observed a student completing a history and physical examination with a standardized patient and identified four themes and fifteen subthemes that represent the assessors’ response processes. Subthemes represented all three phases of the rating process: observing, processing, and integrating . The preSeveral of the subthemes in this theme represent challenges associated with observation-based clinical assessment . The useOne potentially problematic subtheme influencing rater cognition that appeared to be unique to entrustment assessments was “future training needs.” Assessors appeared to have varying interpretations regarding what they were assessing – the student’s current supervisory requirements versus their future supervisory requirements. The Modified Chen Scale is intended to assess future supervision requirements, as indicated by the typical preamble to the scale: “If you were to supervise this student again in a similar situation, which of the following statements aligns with how you would assign the task?” . WithoutAssessor familiarity with a student appeared to directly influence several aspects of rater cognition: “previous exposure to the same student,” “affective response,” and “accessor uncertainty.” It has previously been hypothesized that assessors need to consider previous observations of a student in order to develop grounded trust , 13 and As previously theorized , 13, patThis study has several limitations. First and foremost, it was done in a research setting and thus may not wholly represent the actual thinking that occurs as faculty are observing their students in real practice. Second, think-alouds have not been shown to be effective at detecting unconscious processing , so the Work remains to be done to determine if EPA assessments outside of the workplace “ask the right questions, in the right way, about the right things” . The mosAdditional file 1.Additional file 2.