Several guidelines on the evaluation of patients with suspected cervical spine trauma in the Emergency Department (ED) exist. High heterogeneity between different guidelines has been reported. Aim of this study was to find areas of agreement and disagreement between guidelines, to identify topics in which further research is needed and to provide an evidence-based cervical spine trauma algorithm for ED physicians. The three most relevant guidelines published on cervical spine trauma in the last 10 years were selected screening websites of the main scientific societies and through the comparison of a normalized Google Scholar and SCOPUS citation index. We compared the selected guidelines through seven a-priori defined questions. In case of disagreement between the guidelines or if the quality of evidence appeared low, evidence from published systematic reviews on the topic was added to build an evidence-based algorithm for approach to spinal trauma in the ED. The three selected guidelines were: NICE 2016, Eastern Association for the Surgery of Trauma 2009 and American Association of Neurological Surgeons and Congress of Neurological Surgeons 2013. We found complete agreement on one question, partial agreement for one questions, no agreement for two questions, while agreement was not assessable for 3 questions. The agreement between different guidelines and the evidence on which recommendations are based is low. An attempt to build an evidence-based algorithm has been made. More studies are needed on many topics. Trauma is one of the main reasons for patient assessment in emergency departments. Many patients with trauma are suspected of having lesions of the cervical spine . The evaGuidelines should help physicians to take decisions that are evidence-based, appropriate and with an explicit evaluation of the risk–benefit ratio. However, guidelines have been deeply criticized. Previous studies have shown that many guidelines are not evidence-based and can be influenced by conflicts of interest. Furthermore, there is often no consensus on the evaluation of the evidence and the suggested recommendations among the various guidelines . The conThe aim of this paper was to systematically compare the most important guidelines on cervical spine trauma, to find areas of agreement and disagreement between guidelines, to identify topics in which further research is needed and to provide an evidence-based algorithm with which to approach patients with cervical trauma in the ED.This study is a systematic comparison of secondary evidence.PubMed database for key terms referring to guidelines on this topic and choosing the most cited. We lastly asked to experts and looked the references to find further guidelines.Briefly, we initially screened the websites of the main medical scientific society interested on the topic, searching for proposed guidelines. Then, a systematic search of the all the available guidelines on cervical spine trauma published in literature was performed, screening the We decided in advance to select up to a maximum of three guidelines for comparison.Moreover, a search of literature was performed to find any systematic review and metaanlysis on spinal trauma.The guidelines were selected and compared in terms of seven a-priori emergency department questions. The concordance between different guidelines was evaluated and, in case of discrepancy, the presence of published systematic reviews on the topic was verified in order to find more evidence on the topic. Finally, an algorithm for the management of these patients in the ED was proposed, emphasizing the quality of evidence and the strength of recommendations.We initially searched and included guidelines on the websites of medical scientific societies related to the topic. In particular, we screened the National Institute for Health and Care Excellence (NICE) website, the American College of Physicians (ACP) website, the American College of Emergency Physicians (ACEP) website to include in our study any guideline on cervical spine trauma.We decided in advance to select up to a maximum of three guidelines for comparison, the number of three has been a-priori chosen to equilibrate the possibility of comparison among them and to permit the readability of the manuscript. Such number has been previously adopted by similar studies .We also decided in advance to perform a guideline search in literature in case of less than three guidelines on the topic were found on medical societies’ websites.PubMed database to find any other guideline on the topic published in the past 10 years. In case of multiple versions of the same guideline, the most recent was considered.In such case, we then searched the A systematic search of the literature was performed, screening MEDLINE database for the following terms:(((((spine)AND((injury) OR trauma)))AND((guideline*) OR guidelines)))OR(((spine)AND((injury) OR trauma))ANDPractice Guideline[ptyp]).Among the results, we included the most cited guidelines in order to reach the number of three guidelines selected for comparison. To compare the citations between guidelines we analysed the guidelines citations on Google Scholar and SCOPUS. We normalized the total number of citations based on the year of publication (number of citations on SCOPUS and Google Scholar divided by the difference between the year of the literature search and year of publication). This method has been previously adopted by similar studies .We lastly asked to experts and looked at references of studies to find any additional relevant guideline.Two different researchers (EG and PB) independently screened all titles and abstracts. In case of disagreement, a consensus was reached through the consultation of a third researcher (GC).Last guidelines search was performed in January 2021.PubMed the following keywords “(spine) AND ((injury) OR (trauma))”, filtering results by “systematic reviews” and “metanalysis.A search aimed to find systematic review and metanalyses on cervical spine trauma was performed, entering in Seven questions, thought to be the most clinically relevant on the topic, were pre-defined as follows: (1) Which patients should be evaluated for traumatic cervical injury? (2) Who should not have cervical spine imaging performed? (3) Who should undergo cervical spine imaging? (4) Which kind of imaging should be performed as an initial investigation? (5) How many and which segments of the cervical spine need to be investigated? (6) Within what timeframe should the imaging report be received? (7) When should the cervical collar be removed?Two reviewers (PB and EG) independently extracted from the guideline data regarding article title, journal, year of publication, first author, medical society, search strategy, setting of guidelines’ applications, system used to grade the guidelines’ recommendations and the reported references. The answer for each question and the quality of evidence/level of recommendation, according to the method used by the guideline, was extrapolated—if possible—for each stated point.no agreement when the guidelines stated different recommendations; (2) agreement when the guidelines suggested the same diagnostic measures or a similar patients’ management strategy; (3) partial agreement when different guidelines agreed, with some differences; (4) not available when at least one of the guidelines did not address the topic.Differences and similarities between the selected guidelines were evaluated. Agreement between the guidelines was defined as follows: (1) In order to facilitate the comparison between the guidelines, the quality of evidence and the strength of recommendation declared from every guideline for each recommendation were extrapolated, if possible, and expressed through the GRADE  system, considering what was expressed by the guidelines’ authors and briefly re-evaluating the references.If the GRADE system was already used to rank the evidence by the authors, we confirmed their statement.Briefly, the GRADE system allows grading of the quality of evidence and strength of recommendations. It has the advantages of providing a clear separation between judging confidence in the estimated effect and strength of recommendations and providing a clear, pragmatic interpretation of strong versus weak recommendations. Therefore, unlike many other grading systems, the GRADE approach emphasizes that the strength of a recommendation is affected by factors other than quality of evidence  , 5.Two different reviewers  independently assessed agreement between guidelines. In case of discrepancy between the two reviewers, a consensus was reached with the contribution of a third reviewer (GC).In case of agreement between guidelines we provided a pooled rating of recommendations using the GRADE system  Practice Management Guidelines were published in 2009 as an update to the previous EAST guidelines, published in 1998 and 2000. The American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS) guidelines were published in 2013 and are an update to the original guideline of 2002. All three guidelines were developed for the ED setting.In the NICE guidelines, the evidence for outcomes from the included studies was evaluated and presented using an adaptation of the GRADE toolbox developed by the international GRADE working group .In the EAST guidelines, articles were classified as Class I, II, or III, as described in the EAST primer on evidence-based medicine: Class I: Prospective, randomized clinical trials; Class II: Clinical studies in which data were collected prospectively or retrospective analyses based on clearly reliable data; Class III: Studies based on retrospectively collected data. The guideline recommendations were then classified as Level 1 ; Level 2 ; Level 3 .In the AANS/CNS, the quality of evidence was assessed as Class I ; Class II , and Class III (case series and expert opinion). The strength of recommendations is classified as Level I, Level II and Level III.Considering all the seven questions, we found some recommendations for all the items. Complete agreement was found only for 1 question. For 3 question agreement was not assessable, while there was no agreement on 2 questions and partial agreement on 1 question. Overall, most of the recommendations were judged as strong through the GRADE system, although mainly founded on low quality of evidence (see Tables Agreement between the three guidelines was not assessable because only one of the reviewed guidelines (NICE) answers this question, suggesting that all adults who present with suspected spinal column or spinal cord injury secondary to a traumatic event should be evaluated for traumatic cervical injury. Neither the strength of recommendation, the quality of evidence on which this recommendation is based nor the references were clearly reported in the guideline for this indication.Guidelines do not provide a definition of cervical spine trauma. A traumatic event involves multiple variables, which cannot be standardized under a specific definition. Therefore, the clinician should define whether an event can be considered relevant and harmful to the patient. It is unlikely that future studies could evaluate which kinds of patient should be screened for traumatic cervical spine lesions.It would be reasonable to state that every trauma patient, with the exception of minor isolated limb lesions, should be clinically evaluated for cervical injuries. It could be assumed that any patient suspected of having cervical spine trauma is eligible for cervical injury screening, from trivial to high-energy traumas. The selection of patients eligible for evaluation for cervical spine trauma remains a decision for the clinician.All the reviewed guidelines answer this question, but there is no agreement between the three guidelines. Two guidelines  agreed in recommending not to perform imaging in the awake, alert, asymptomatic patient without neurological deficit, without neck pain or tenderness, without distracting injury, who is able to complete a functional range of motion examination. The EAST and the AANS/CNS guidelines refer to the NEXUS  algorithm  plus evaAll the guidelines define the strategies on this topic as a strong recommendation. However, the NICE guidelines state that the recommendation is based on very low to low-quality of evidence, EAST guidelines are based on low quality of evidence, while the level of evidence is not assessable in the AANS/CNS guidelines. Of the three guidelines, only the EAST clearly states the references on which the recommendations are based.Several rules have been proposed for the screening of patients who present in the ED with cervical spine trauma and identification of those who really require imaging investigations. The NEXUS and CCR, the two most important rules on this topic, were published in 2000 and 2001 , 10. TheThere is not enough evidence to identify a single rule to be applied for patients with cervical spine trauma.However, we suggest consideration of CCR in addition to clinical judgement to identify which patients with cervical spine trauma should undergo CT scan. Further validation studies on this topic would be useful.Table 2All the reviewed guidelines answer this question, but there is no agreement between the three guidelines. For this query, between two guidelines (EAST and AANS/CNS) there is substantial agreement recommending imaging in all patients considered difficult to evaluate  or symptomatic . One guideline (EAST) also recommends imaging in patients with distracting injury. The NICE guideline recommends imaging in all patients with GCS < 15, or at high risk for cervical spine injury according to the CCR or patients at low risk for cervical spine injury according to the CCR but unable to actively rotate their neck 45 degrees left and right. All the guidelines define the strategies on this topic as strong a recommendation. However, the NICE guidelines declare that the recommendation is based on very low to low quality of evidence; the EAST guideline is based on low quality evidence, while the level of evidence is not assessable in the AANS/CNS guideline. None of the three guidelines clearly state the references on which the recommendations are based.This answer is similar to the previous one. The NICE guidelines set 65 years of age as the cut-off for performing the diagnostic test. Setting an age cut-off could be problematic. While it is reasonable to assume that older age is related to higher risk, further studies should be performed to evaluate the increase in risk of cervical spine injury with age and to assess whether using different age thresholds could be feasible and useful.Considering that an ideal rule is not available, it could be considered reasonable to perform a CT scan in patients younger than 65 years at high risk, considering CCR and clinical judgment, in polytraumatized patients, in patients older than 65 years that had a cervical spine trauma considered not to be trivial based on clinical judgement (even if asymptomatic).This suggestion should be considered based on low-quality evidence and future studies are needed to evaluate this topic.All the reviewed guidelines answer this question and there is agreement between the three guidelines. All the reviewed guidelines agree recommending CT scan as the first-choice imaging investigation for cervical spine trauma, because of the better sensitivity if compared with X-ray imaging. The AANS/CNS guideline also specifies that if high-quality CT imaging is not available, a 3- view cervical spine series  is recommended. This should be supplemented with CT (when available) if necessary.All the guidelines define the strategies on this topic as a strong recommendation. However, the NICE guideline states that the recommendation is based on very low to low quality of evidence; the EAST guidelines are based on low quality of evidence, while the level of evidence is not assessable in the AANS/CNS guideline. Of the three guidelines, only the EAST clearly states the references on which the recommendations are based.Holmes’ meta-analysis showed that CT has better sensitivity than X-ray in patients at high risk . HoweveMoreover, the cervical spine rules, on which we have already commented, are based on radiography as the reference standard, and we do not know if replacing radiography with CT could be useful. In conclusion, more studies are needed on the comparison between radiography and spinal CT, setting patient outcomes as the reference standard rather than an abnormality found in the imaging.Considering the evidence available in the literature, if imaging is considered necessary, CT scan should be performed.This suggestion should be considered based on low quality evidence.Agreement between the three guidelines is not assessable because two of the reviewed guidelines (NICE and AANS/CNS) do not answer this question. The EAST guideline recommends imaging from the occiput to T1. This strategy is defined as a strong recommendation based on low quality of evidence. The references on which the recommendations are based are not clearly stated.Based on the literature, the most common sites of injury are the second cervical vertebra  and the region of the three vertebrae C5, C6, and C7 (50%) , 12. TheIf imaging of the cervical spine is necessary, investigation from the occiput to T1 should be performed. This suggestion is based on high-quality evidence and should be considered as a strong recommendation.Agreement between the three guidelines is not assessable because only the NICE guideline answers this question, recommending that images should be interpreted immediately by a healthcare professional with training and skills in this area. This strategy is defined as a strong recommendation based on very low to low quality of evidence. The references on which the recommendations are based are not clearly stated.From a clinical point of view, maintaining a cervical collar is associated with negative side effects  and discomfort for the patient ; moreoveA CT report should be obtained as soon as possible . This suggestion is based on low-quality evidence and should be considered as a weak recommendation.All the reviewed guidelines answer this question and there is partial agreement between the three guidelines. Two guidelines (EAST and AANS/CNS) agree in recommending to remove the cervical collar in the awake, alert, asymptomatic patient without neurological deficit, without neck pain or tenderness, without distracting injury, who is able to complete a functional range of motion examination. These two guidelines agree even in recommending to consider continuing cervical immobilization until the patient is asymptomatic or to remove the cervical collar after a negative MRI or after adequate flexion–extension X-ray, in the awake, symptomatic patient with a negative CT scan. Moreover, the AANS/CNS guideline suggests possibly discontinuing cervical immobilization at the discretion of the treating physician. Only one guideline (EAST) considers the obtunded patient with a negative CT scan and gross motor function of all four extremities, recommending to continue cervical collar immobilization until a clinical examination can be performed or to remove the cervical collar on the basis of CT alone or plus MRI and, if MRI shows nothing abnormal, to remove the cervical collar. The NICE guidelines require patients to have low- risk factors for cervical spine injury as identified and indicated by the CCR, to be pain free and ableto actively rotate the neck 45 degrees left and right. The strength of the recommendations and quality of evidence on which these are based are shown in Table It is safe to remove the cervical collar if the patient is asymptomatic and the imaging examination is negative. The literature is not clear about which management strategy could be the best in patients who are still symptomatic but have negative imaging..In clinical practice, the cervical collar can probably be safely removed in asymptomatic patients and in patients who are clinically evaluable, with have no neurological deficits and with negative CT imaging. In special situations the clinician should evaluate case-by-case if maintaining cervical collar and/or perform more investigations. In doubtful situations, spine specialist consultation may be considered. This suggestion is based on low-quality evidence and should be considered as a weak recommendationThe aim of this paper was to compare the main guidelines in the literature on cervical spine trauma evaluation and management, to identify topics in which further research is needed, to extrapolate recommendations on several topics of interest and to provide, if possible, a univocal pathway that can help clinicians in approaching patients with suspected cervical trauma/injury. Evaluating the answers to our a-priori questions in the selected guidelines, it emerged that there was very scarce agreement between different guidelines. In particular, for only one question  there was complete agreement in the answer. For one other question there was only partial agreement, for two questions there was no agreement, while for three questions it was not possible to establish any agreement because some guidelines did not cover the topic. This underlines that between the different guidelines there is wide inhomogeneity, not only between what is recommended but also in the covered topics. This fact could perhaps be explained by the fact that even when the same question is answered, the cited references often differ or, if the references are similar, the grade of recommendation can differ. Moreover, most of the recommendations are judged to be of low quality.The guidelines use different criteria to evaluate the quality of evidence (QoL) and to state the strength of recommendation. In particular, the NICE guidelines state that they used the GRADE method, while the other two use their own tailored criteria. The GRADE, among those currently available, is a codified and reproducible evaluation system for the quality of the evidence and strength of the recommendations, but was published in 2013, after the AANS/CNS and the EAST guidelines.The inhomogeneity between the grading system for QoL and strength of recommendations could represent an obstacle for the clinician examining several different guidelines and needing to identify the most useful one.The analysis of the guidelines and the subsequent search of the available literature highlight that further studies are needed for multiple fields of research. In particular, more studies would be useful for the following: (1) comparing the available tools to screen high-risk patients for cervical spine injury with the purpose of identifying the most accurate one and definitively validating it, setting CT scan as the reference standard; (2) evaluating the increase in risk of cervical spine injury with age and the utility of different age thresholds; (3) comparing the diagnostic accuracy of spinal CT and X-ray, setting some fixed outcome  as the reference standard; (4) evaluating the best management for patients who are still symptomatic after negative imaging.We ultimately proposed an evidence-based algorithm for the management of patients with cervical spine trauma.This study has several limitations. Our comparison approached only three guidelines—the most cited—which were published in different years with a time interval of 9 years between the oldest and the newest.We selected the three most-cited guidelines, but these criteria do not necessarily guarantee that the suggested recommendations are the best available.Our protocol is an attempt to help the clinician based on these guidelines, the available evidence-based information and our clinical experience and should be validated in the future.There is scarce agreement between the guidelines addressing cervical spine trauma in the ED. Further research is needed to evaluate the best management of these patients and to identify patients that need to undergo specific diagnostic evaluation. Based on our comparison of the guidelines and literature search, we have proposed an evidence-based algorithm for the management of cervical spine trauma patients in the ED Fig. . Fig. 2P


Background: The myopia is a public health issue that attracts much attention. However, limited attention has been paid to the effect of primary school students' acceptance of health messages. Previous studies have found that framing effects and evidence types influence the persuasive effect of messages.Purpose: This study explored whether framing effects and evidence type influence the persuasive effect of myopia prevention messages among elementary school students and the influence of children's myopia prevention cognition was considered.Methods: A cross-sectional study was conducted among 1,493 elementary school students aged 9 to 13 in China from May to July 2020 by convenience sampling. Wilcoxon signed-rank test and multinomial logistic regression were used for data analysis.Results: Significant differences were found in the persuasive effect between statistical and non-statistical evidence messages (p < 0.001). Among non-statistical evidence messages, gain-framed messages showed a greater persuasive effect than loss-framed messages (p < 0.001). Among statistical evidence messages, loss-framed messages performed better than gain-framed messages (p < 0.001). Children's myopia prevention cognition exerted no significant effect on the persuasive effect of the messages (p > 0.05).Conclusion: This study demonstrated the influence of framing effect on the persuasive effect of myopia prevention messages among children aged 9 to 13 in China. Non-statistical evidence messages showed a better persuasive effect than statistical evidence messages. Different types of evidence influenced the persuasive effect of gain- and loss- framed messages. These findings have implications for strategies more or less likely to work in making myopia prevention messages for children. Studies estimated that the global prevalence of myopia and high myopia will increase significantly by 2050, affecting nearly 5 billion people and 1 billion people, respectively .A large number of studies showed that the causes and influencing factors of myopia are complex and diverse, and genetic and environmental factors can affect the incidence of myopia., Lack of time for outdoor activities  and incrCOVID-19 has spread worldwide since December 2019. In China, the isolation policy prevents students from returning to school, although some schools have begun organizing students to return to school when the epidemic was brought under control around April. Most students have spent a long period of online learning. During the COVID-19 outbreak, increased electronic use  and reduced outdoor activities among children and adolescents increase the risk of myopia development and progression. In June 2020, the Ministry of Education of the People's Republic of China investigated the vision changes among primary, middle, and high school students in nine provinces  during the epidemic. Compared with the data at the end of 2019, the myopia rate of primary and middle school students increased by 11.7% in the 6 months  × two types of evidence . We also investigated whether or not children's myopia prevention cognition affects the persuasive effect of the message.The following are the inclusion criteria. The participants must be primary school students aged 9–13 years old because of their ability to read health information and it is an important period to prevent myopia before the age of 14 .From several primary schools in Chongqing and Guangxi, China, a total of 1,493 participants were recruited using online and offline surveys, and the effective rate was 61.5%, the final valid questionnaires were 918.The questionnaire was developed in accordance with existing literature and technical services specification for vision health management of primary and middle school students (T/CHAA 008-2019) , and theDemographic characteristics included the child's gender, age and grade. Information about the regular visual examination or not, average daily screen time, have eye exercises or not, myopia status and myopia of parents were collected.The children's myopia prevention cognition was assessed by five questions: “Do you know that myopia will have a bad effect on your study and life? ”; “What you think is the best reading distance for your eyes from a book? ” ; “How loThe content of framed messages in this study was designed based on previous studies, and relevant service specifications were referred to . FirstlyDemographic questions were answered by the participants. In the myopia prevention message framing materials, participants ranked four pieces of messages under each theme, with the first representing the most agreeable, the second representing the second most agreeable, the third representing the third most agreeable and the fourth representing the least agreeable. We assign the score for a persuasive effect to the ranking results . Therefore, the higher the score is, the better the persuasive effect is. The online questionnaire data were automatically recorded by the system, and the paper questionnaire data were input into the computer by the interviewers.The study protocol was approved by the Ethics Committee of Chongqing Medical University (The record number is 2018011). Participants provided informed consent before completing the questionnaire.p-value not more than 0.01 was considered statistically significant.Data were processed using Excel software before entry into the database. Data analysis was performed using SPSS 25.0 software . In the demographic characteristics of children, frequencies and percentages were calculated for categorical variables. We used the mean score to represent the persuasive effect of a certain type of message. Wilcoxon signed-rank test was performed to assess whether or not a significant difference exists between different types of messages. Multinomial logistic regression analysis was performed to investigate the factors that affect the persuasive effect of myopia prevention messages. Independent variables were evidence type, frame type, demographic characteristics, have a regular visual examination or not, average daily screen time, have eye exercises or not, myopia status, the myopia of parents and myopia prevention cognition. We have divided the messages into four groups  according to the persuasive effect of the messages. The higher the number, the better the persuasive effect and group 1 served as the control group. A The questionnaire was modified several times after expert interviews and a pilot survey. The investigators received standardized training, had a detailed understanding of the purpose and methodology of the study and had extensive experience in dealing with potentially sensitive issues. In online surveys, the quality of questionnaire responses can be controlled by setting rules .The demographic characteristics of the participants are presented in p < 0.001), and the persuasive effect of a message with non-statistical evidence was higher than that of a message with statistical evidence. However, no significant difference in persuasive effect was found between gain- and loss-framed messages (p = 0.517).Two features of the messages were experimentally manipulated: goal framing and non-statistical vs. statistical evidence type. As shown in p < 0.001, p < 0.001). However, differences were found between messages with non-statistical and statistical evidence. Among the non-statistical evidence messages, the gain-framed messages showed a better persuasive effect than the loss-framed messages. However, among the statistical evidence messages, the opposite was true. Among the gain-framed messages, the non-statistical evidence messages showed a better persuasive effect than the statistical evidence messages.Furthermore, we analyzed the moderating effects between evidence types and framing effects. As shown in Except for evidence type and framing type, no other independent variables in this study had a significant effect on the persuasive effect of myopia prevention messages. In particular, evidence type had a great impact on the persuasive effect of myopia prevention messages. As shown in In this study, we aimed to explore how to improve the persuasive effects of myopia prevention messages on children aged 9–13 years. No significant difference was found between the persuasive effect of gain-framed and loss-framed messages, but a significant difference was found between messages with non-statistical and statistical evidence, for example, when we describe that “the probability of suffering from myopia will greatly increase,” the persuasive effect of messages is better than “the probability of suffering from myopia will increase by 70%”. The design of the questionnaire referred to previous studies , 12 and Different from some previous studies, in the present study we found that the framing effect did not affect the persuasive effect of the messages. Previous studies found that gain-framed messages might be more persuasive than loss-framed messages for some prevention behaviors and loss-framed messages might be more persuasive than gain-framed messages for some health detection behaviors –33. HoweNon-statistical evidence messages showed a better persuasive effect in our study. Empirical studies found that statistical evidence can improve the persuasiveness of messages and that statistical evidence messages can enhance systematic and heuristic processing , 36, 37.Furthermore, a moderating effect was found between evidence type and the framing effect. To further investigate the relevance of the framing effect and evidence type, we divided the messages into two groups according to evidence type and then investigated the difference in persuasive effect between gain-and loss-framed messages. We have found that in the messages containing different types of evidence, the influence of goal framing will change. This difference may be due to a change in evidence type. Different from some previous studies , this stWe also investigated whether or not children's myopia prevention cognition influences the persuasive effect of messages. As shown in This study has certain limitations. Firstly, we used a convenient sampling method in the experimental design to ensure that the participants in the study are willing to read our information materials. However, we increased the contingency and reduced the representativeness of the sample. Secondly, the participants were between 9 and 13 years old, and they were not representative of children of all ages. Thirdly, other factors that may affect vision (beyond screen exposure time and near work) were not included in the study because the length of the questionnaire was limited, and parents' education level may be a confounder variable that was not considered in the study. Finally, the study relied on self-report, which can introduce bias because of dishonesty, over-reporting, under-reporting and measurement flaws. Limitations of this study would provide interesting avenues for further research. Despite these limitations, this study provided insights into the development of myopia prevention messages for children aged 9–13 in China.Messages with non-statistical evidence had a better persuasive effect than messages with statistical evidence. Further analysis revealed that evidence type exerted a moderating effect on the framing effect. The gain-framed messages showed a better persuasive effect than the loss-framed messages among the messages with non-statistical evidence, whereas the loss-framed messages had a better persuasive effect than the gain-framed messages among the messages with statistical evidence. Children's myopia prevention cognition exerted no significant impact on the persuasive effect of messages. The results of this study will contribute to the formulation of children's myopia prevention messages and improve the persuasive effect of children's myopia prevention messages.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Chongqing Medical University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.XH, ZZ, QR, TC, and LB designed the experiments. XH, ZZ, QR, CY, and MJ performed the experiments. ZZ wrote the paper and analyzed the data. YL helped analyse the data. XH and YL helped draft the manuscript. All authors have read and approved the final manuscript.This research was funded by the Ministry of Education in China Project of Humanities and Social Sciences (Grant No. 20YJCZH043); the Intelligent Medicine Research Project of Chongqing Medical University in 2019 (Grant No. ZHYX2019006); Chongqing Medical University, China, the Intelligent Medical Foundation of Chongqing Medical University (Grant No. YJSZHYX202016); the College of Medical Informatics, Chongqing Medical University, China, Student Research and Innovation Experiment Project (Grant No. 2019C009); Chongqing Municipal Education Commission, China, Chongqing Graduate Scientific Research Innovation Project (Grant No. CYS20225).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.


The gelatin mats presented different physicochemical properties due to the inherent differences in the chemical structure of the added BAs and their interaction with the gelatin chains. The conductivity, surface tension, and viscosity of gelatin dopes changed with the presence of the BAs, yet the electrospun nanofibers showed defect‐free uniform morphology as confirmed by electron microscopy, with no significant change in the chemical structure of gelatin. The melting temperature of gelatin mats remained in the range of 187–197°C. The mats presented lower tensile strength and elongation at break by the addition of BAs compared with the pristine gelatin mat. The highest radical scavenging (90%) was yielded by mats with EEO, while mats with CEO depicted better antibacterial activity with an inhibition zone of 18.83 mm. However, a dose‐dependent increase in the antifungal properties was noticed for all the mats. The mats retained almost 50% of BAs after 60 days of storage at 45% relative humidity. Electrospun gelatin mats inhibited the aerobic bacteria (81%) and yeast and molds (61%) in preservative‐free bread after 10 days of storage.In the current study, fish gelatin‐based nanofiber mats were embedded with different bioactive agents (BAs) such as cinnamaldehyde (CEO), limonene (LEO), and eugenol (EEO) at 1, 3, and 5%  Fish gelatin‐based nanofiber mats were embedded with bioactive agents (BAs) such as cinnamaldehyde (CEO), limonene (LEO), and eugenol (EEO) at 1, 3, and 5% via electrospinning. The BAs added in the mats being different in the chemical structure were interacted differently with gelatin and manipulated the gelatin mat properties. Electrospun gelatin mats presented a good inhibition of aerobic bacteria (81%), and yeast and molds (61%) in preservative‐free bread after 10 days of storage. Microbial proliferation on the food surface is one of the principal reasons of food spoilage. At the same time, addition of antimicrobial preservatives causes food components to lose their effectiveness besides compromising the food organoleptic properties. Thus, the development of active packaging by incorporating antimicrobial preservatives in the polymeric carrier is a suitable alternative where the polymer matrix acts as a reservoir and tailors the release of these bioactive agents  are natural BAs found in plants that have been widely employed in developing antimicrobial active packaging systems , limonene , and eugenol , were embedded in fish gelatin mats 22.13.6H2O), ferrous sulfate (Fe2SO4), and sodium acetate trihydrate were supplied by Merck Millipore (USA). Nutrient broth, nutrient agar, Mueller‐Hinton agar, and potato dextrose agar were bought from HiMedia (India).Fish gelatin type‐A (Bloom number 210 g) was obtained from SIM Company . Gas chromatographic grade BAs, cinnamaldehyde (CEO: 99.5%), limonene (LEO: 99.8%), and eugenol (EEO: 99.7%), were obtained from R & M Chemicals (UK). Analytical grade glacial acetic acid, hydrochloric acid, ethanol, and methanol were procured from QRec Chemicals . Free radical, 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH), and 2,4,6‐tripyridyl‐s‐triazine (TPTZ) were purchased from Sigma (USA). Ferric chloride hexahydrate (FeCl2.2Spinning dope of fish gelatin (30% w/v) was prepared in acetic acid (30% v/v) by stirring the preweighed gelatin powder at 50°C for 6 h according to Mahmood et al. . The CEO2.3®, Thermo Fisher Scientific) was used to measure the apparent surface tension (dyne/cm) by the du‐Noüy ring method. The cleaned ring was immersed (1 cm) deep into the dope filled in a 15‐ml glass beaker and slowly removed and detached from the surface of the dope. The viscosity (Pa.s) was measured by a rheometer  employing a flat plate geometry  at a shear rate of 0–200 s−1. The dope (0.5 ml) was applied on the Peltier plate of the rheometer and equilibrated before shearing. All measurements were made at 25 ± 1°C.The electrical conductivity (mS/cm) of gelatin dope was measured by using a waterproof conductivity meter . The dope was filled in a 25‐ml glass beaker, and the electrode was equilibrated for 3 s before taking the readings. A semiautomatic tensiometer (Tensiomat2.4The electrospinning setup was comprised of three main components: (1) a high‐voltage power supply (Spellman CZE100r), (2) a syringe pump (New Era 1000), and (3) a static plate collector. The electrospinning process was carried out at 17 kV, 0.5 ml/h, and 15 cm of voltage, flow rate, and spinneret tip‐to‐collector distance, respectively. Electrospinning was conducted at ambient conditions at 40 ± 2% relative humidity. The electrospun fibers were collected as a mat on a grounded plate collector covered with aluminum foil.2.53 mbar by a sputter coater (Quorum‐Q150 TS) and photographed at 10,000× magnification by an FEI Quanta SEM  at a voltage of 15 kV. The diameter of six randomly selected fibers was measured and averaged.The shape and diameter of fibers were assessed by using a field emission scanning electron microscope (FESEM). The sample was attached to the stub using a double tape and coated with gold for 60 s at 20‐mA current and pressure of 1 × 102.6−1 at transmittance mode with 64 scans at a resolution of 4 cm−1. IR® solution software was used to analyze the spectra of gelatin mats.Structural changes in the electrospun gelatin mat with BAs were assessed using attenuated total reflectance Fourier transform infrared spectrometer (ATR‐FTIR) equipped with a Zn/Se laser . The sample was scanned from 400 to 4000 cm2.7® analysis software to obtain glass transition (Tg) and melting temperature (Tm). The sample (3–5 mg) was weighed in a standard aluminum pan (#900786.901) and sealed using the pan crimper. The sample was heat scanned in the range of 30–250°C with a heating rate of 10°C/min. An empty aluminum pan was used as a reference.Thermal properties of electrospun gelatin mats were evaluated by using a calibrated differential scanning calorimeter  under nitrogen environment, and the thermograms were analyzed by TA‐universal2.82), and the double tape was used to stick the sample between grips of the tensile tester. The initial separation of grips was maintained at 10 mm, and the test was carried out at a crosshead speed of 10 mm/min. The tensile strength (TS), elongation at break (EAB), and Young's modulus (Y) were calculated from the stress–strain curve.The mechanical properties of mats were determined using a tensile tester . The rectangular‐shaped sample (20 mm ×5 mm) was conditioned for 48 h at 40 ± 2% relative humidity at ambient temperature. The sample was prepared by using two layers of graph paper  was mixed with the DPPH reagent (150 μl) and allowed to react at room temperature for 30 min in the dark. The absorbance of the reaction mixture was measured at 517 nm. The RSA was computed by the following equation:RSA of the gelatin mat was estimated through the DPPH method  solution at a 10:1:1 ratio. The supernatant (150 μl) was mixed with 150 μl of the FRAP reagent and thoroughly vortexed. The mixture was incubated at room temperature in the dark for 30 min, and the absorbance was measured at 593 nm. Ferrous sulfate (FeSO4.7H2O) was used as standard, and the results were expressed as μmol eq Fe+2/g mat.The FRAP assay was conducted according to Tongnuanchan et al.  with sli2.10Encapsulation efficiency (EE%) of gelatin mats for BAs was estimated by the ratio of FRAP value of nonencapsulated BAs to the encapsulated counterparts according to Torkamani et al. .2.11Staphylococcus aureus) and a gram‐negative bacterium (Escherichia coli). Cultures of both the bacterial strains were adjusted to 0.5 McFarland, and 100 μl was swabbed on Mueller‐Hinton agar. Gelatin mat disks (8 mm) were then fixed on to the cultured plates of bacteria and incubated at 37°C for 16–24 h. The growth inhibition zones (mm) for bacteria were measured to observe the antibacterial efficiency of the mats.Antibacterial activities of mats were tested by the disk diffusion method against a gram‐positive bacterium  of the gelatin mat were then placed on to the cultured plates and incubated for 72 h at 25°C. The zone of fungal growth inhibition (mm) was measured in triplicate to estimate the antifungal efficiency of gelatin mats.For evaluation of antifungal activity of gelatin mats, 2.13Stability of mats was estimated under storage at ambient temperature for 60 days at 45 ± 2% relative humidity. The retention of BAs in the mats was estimated through the FRAP assay (as mentioned in 2.9.2) with an interval of 10 days. The FRAP value was correlated with the amount of active compounds retained within the mats and further converted into the release (%) by subtracting the retention from 100 and plotted as a cumulative release against time (days).2.14−1 to 10−5. Almost 100 μl of the homogenate was poured on nutrient agar and potato dextrose agar for counting total aerobic bacteria, and yeast and molds, respectively. The Petri plates were incubated at 37°C and 25°C for 16–24 h and 72–96 h for counting bacteria, and yeast and molds, respectively. The efficiency of the mat in preserving the bread was determined by the following equation:The gelatin mats were tested for improving the shelf stability of preservative‐free wheat bread. The following ingredients were added for bread preparation based on the weight percentage of wheat flour: (1) 4% instant dry yeast, (2) 4% of shortening, (3) 8% sucrose, (4) 2% salt, and (5) 60%–64% distilled water. After baking, the bread was cooled before slicing and stored in polyethylene bags for further analysis. The bread crumb (10 ± 0.5 g) was placed in the sterile Petri plate (110 mm × 25 mm), and the mat (40 mg) was placed within the Petri plate without direct contact with bread. The Petri plate was sealed with parafilm and incubated at room temperature for 10 days. A control sample was prepared by using gelatin film without BAs. To estimate the microbial load, the bread sample was homogenized in peptone water (0.1%) in a stomacher at a ratio of 1:10, and serial dilutions were made from 102.15p < .05 was considered statistically significant.Analysis of variance (ANOVA) was performed using SPSS‐23.0 (IBM), and for mean comparison, the Duncan multiple range test (DMRT) was applied. 33.1p < .05); however, the dope with LEO presented the least conductivity. This reduction in conductivity could be correlated with the low polarity of the BAs where LEO is least polar due to its terpene‐like nature. Karami et al. .Similarly, a reduction in viscosity of spinning dope was seen in the presence of BAs compared with the control, which suggests the reduced intermolecular interaction of gelatin chains. Almost 30%–40% reduction in viscosity was noticed for dopes with BAs. This outcome is in line with a previous study where EO addition resulted in lowering of dope viscosity  along with in‐phase bending vibrations of the N‐H bond refers to the amide‐I group in gelatin.In electrospun mats, the chemical structure of gelatin and interaction between gelatin polypeptide chains and BAs were estimated by attenuated total reflectance Fourier transform infrared spectroscopy (ATR‐FTIR). The mats with different BAs presented somewhat similar spectra for major bands Figure . The pea−1 is credited to the N‐H bend and C‐N stretching deformations. The small peak at 1242 cm−1 is a complex peak and is attributed to the N‐H bending and C‐N stretching, labeled as amide‐III  in BAs, respectively. Moreover, peaks from 1000 to 1500 cm−1 and 750 to 900 cm−1 in the spectrum of CEO correspond to the C‐H bending of the benzene ring , sharp peaks were seen at 1636, 1606, and 1510 cm−1  and melting temperature (Tm). Tg is a second‐order transition, which represents the chain mobility of the amorphous polymeric regions under heat; however, Tm is correlated with the melting or destruction of partial crystallites in polymeric structures held by various interactions and is considered as a first‐order transition. Thermal analysis could be a good estimation of the successful encapsulation of BAs within the polymeric matrix  versus strain (deformation) curve, the slope represents the Young's modulus (Y) and the height of the curve indicates TS, while the point of maximum strain is an indicator of EAB. The mechanical properties of gelatin mats are tabulated in Table The mats with EEO presented the highest EAB (44.08%), suggesting greater flexibility. The least elasticity (EAB 27.15%) of mats with LEO is related to the highest TS. However, surprisingly, the lower concentrations of BAs  provided significant change in the tensile property while an increase in the concentration of BAs  could not bring a dose‐dependent increase in the observed properties. This type of mechanical behavior could be related to the saturation effect at gelatin/BA interface, where an increase in the concentration of BAs above a certain level did not result in any further change in tensile properties of gelatin mats. In line with current results, Said and Sarbon  reportedThe mechanical properties of biodegradable polymeric mats are greatly dependent on the type and concentration of BAs added and the specific interactions existing at the polymer/BA interface  of gelatin mats was in the range of 63.86%–89.33% Table .The observed pattern of RSA% is very true to the chemical structure‐based antioxidant activity of the BAs. The phenolic group in the molecule of EEO resulted in better RSA compared with CEO  and LEO (terpenes). In previous report, gelatin mats added with lavender and oregano EOs presented lower RSA%, which was correlated with the interactions between EOs and gelatin chains  was observed in mats with 1% LEO. In other words, EEO has the strongest reducing capacity and 1 g of the mat can change 1685 μmol of Fe+3‐TPTZ to Fe+2‐TPTZ. The better FRAP activity of EEO than others could be correlated with the presence of the phenolic group, which is a well‐known reducing agent. In a study, the FRAP values of tuna‐skin gelatin and bovine‐hide gelatin mats incorporated with rosemary and oregano extracts were measured. The oregano extract showed better antioxidant activity due to the phenolic group in its structure compared to films with rosemary  and a gram‐negative bacterium (E. coli). The growth inhibition zone (mm) was significantly enhanced in the presence of BAs, and a greater inhibition was observed for mats with 5% BAs. However, CEO at 5% presented the highest growth inhibition of both S. aureus and E. coli. The least inhibition activity was seen for the mats with LEO, whereas the activity in EEO was comparable to that of CEO ; however, a comparable antifungal activity was noticed at a higher concentration (5%). Overall, with an increase in the concentration of BAs in electrospun mats, a stronger fungal inhibition was observed with bigger inhibition zones.The growth inhibition data of Antifungal activity of the gelatin mats could be due to the disruption of fungal cell membrane and the associated enzymes by the BAs. The carbonyl functional group in CEO binds cell membrane proteins and damages the cell membrane  inhibition of aerobic bacteria was observed (Table Freshly baked bread is perishable and only has a shelf life of 3–4 days (Jideani & Vogt, In the case of yeast and molds, mats with 5% EEO provided the best control over growth with 61% inhibition. In line with the antibacterial data, mats with LEO remained the least potent in hindering fungal proliferation. No fungal growth was noticed on the surface of the crumbs when stored with electrospun gelatin mats embedding 5% BAs, corroborating the effectiveness of mats as antifungal active packaging. The gelatin mats with different BAs presented variable inhibition of the microbial growth. These variations in the antimicrobial activity of mats could be due to different chemical structure, polarity and hydrophobicity of the added BAs. Altan et al.  employed4In this study, three BAs were embedded within the gelatin mats by electrospinning. The incorporation of BAs in gelatin spinning dopes modified conductivity, surface tension, and viscosity differently, which resulted in variations in the diameter of the nanofibers. The thermal stability of the mats was improved in the presence of BAs. However, the mechanical strength and flexibility of mats were impaired in the presence of BAs, except for LEO. Gelatin mats with EEO provided the best antioxidant properties, while mats with CEO excelled in antimicrobial activities against bacterial and fungal strains. The slower release of BAs validated the stability and suitability of the electrospun gelatin matrix in the retention of BAs over a sufficiently long period. Moreover, the absence of fungi on preservative‐free bread crumbs holds promise for the application of electrospun mats as antimicrobial active packaging for low‐to‐intermediate moisture foods.The authors have no relevant financial or nonfinancial interests to disclose.This study does not involve any human or animal testing.


Health technology assessment (HTA) aims to be a systematic, transparent, unbiased synthesis of clinical efficacy, safety, and value of medical products (MPs) to help policymakers, payers, clinicians, and industry to make informed decisions. The evidence available for HTA has gaps—impeding timely prediction of the individual long-term effect in real clinical practice. Also, appraisal of an MP needs cross-stakeholder communication and engagement. Both aspects may benefit from extended use of modeling and simulation. Modeling is used in HTA for data-synthesis and health-economic projections. In parallel, regulatory consideration of model informed drug development (MIDD) has brought attention to mechanistic modeling techniques that could in fact be relevant for HTA. The ability to extrapolate and generate personalized predictions renders the mechanistic MIDD approaches suitable to support translation between clinical trial data into real-world evidence. In this perspective, we therefore discuss concrete examples of how mechanistic models could address HTA-related questions. We shed light on different stakeholder's contributions and needs in the appraisal phase and suggest how mechanistic modeling strategies and reporting can contribute to this effort. There are still barriers dissecting the HTA space and the clinical development space with regard to modeling: lack of an adapted model validation framework for decision-making process, inconsistent and unclear support by stakeholders, limited generalizable use cases, and absence of appropriate incentives. To address this challenge, we suggest to intensify the collaboration between competent authorities, drug developers and modelers with the aim to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders. Health technology assessment (HTA) is a systematic and multidisciplinary process that summarizes medical evidence, social and economic impact, and ethical issues related to the use of health technology. HTA addresses both the direct and intended effects of this technology, as well as its indirect and unintended consequences—with the goal of informing decision making. A major feature of the collective output of a HTA process is the reimbursement by the health insurance system of the medical product (MP).In general, two levels of decision-making regarding health care should be informed by HTA:  for the HTA seeks to couple the available evidence on the MP and the disease with the decision-making process itself, and thus has similarities to evidence-based health care and evidence-based policymaking . By evidThe COVID-19 pandemic has disrupted global healthcare systems and created significant challenges for the HTA and payer communities . The COVEspecially in light of the COVID-19 pandemic, the importance of the assessment for the individual cannot be underestimated. While some patients do not suffer from any symptoms, others do not survive, or are affected on long timescales. Clinical data on COVID-19 prophylaxis and treatment currently under-represents the individual course of the disease due to the diversity and time dependency of the interactions between the virus and the patients' bodies. Here, the inherent limitation of HTA—being centered around population-based approaches—is aggravated. Issues related to better guiding economic evaluation of personalized medicine interventions—e.g., how study questions are developed, how populations are characterized, how comparators are defined, how effectiveness is evaluated, how outcomes are valued and how resources are measured —need urgThe COVID-19 pandemic has also raised the bar for communication around HTA. There has been divergence of opinion among international HTA agencies on how to deal with evidence for early COVID-19 treatments . This diAs a response to the urgency to address these challenges, we wish to advocate using mechanistic models to bridge clinical MP development and HTA thanks to their capability for evidence generation, synthesis, and stakeholder communication alike.A key issue for HTA of a new MP is the number of limitations regarding the representativeness and validity of the evidence that is available. For conclusions useful for patients and public health, more quantitative knowledge and valid answers to questions need to be found .A first reason for the limited use of data generated during development lies in the results provided by randomized clinical trials (RCT) which are the gold standard for clinical evidence. An RCT is an instrument built to determine if the new treatment is effective or not by statistical testing. The frequentist inference paradigm  is stillA second limitation in HTA is the fact that currently population (and sometimes stratified) medicine is pursued during clinical development while for HTA, the benefit for individual patient (groups) becomes important. RCTs, done either separately for different strata for the population or analyzed for different subgroups of one larger study population are currently the only tool available to “individualize” a MP efficacy estimate. As it is the central focus of an RCT to robustly estimate the average effect in a given population, cannot be obtained easily and hence, detailed information at patient level and the mean estimated effect is “applied equally” to each patient. Frequently, patients enrolled during clinical development are not entirely representative of the future target population because of the way they are selected to enter the trials. And they are furthermore limited in number and diversity. Reliably quantifying the effect for individuals from this evidence is therefore limited as well.The advent of personalized medicine puts the “mean efficacy” approach in question  and callFor sponsors, there are increased barriers to conducting randomized trials after registration. Availability of a treatment with proven efficacy may pose ethical problems for placebo-controlled trials. Additional information about the effect of a treatment often needs to rely on observational studies and RWD . The fact that RWD contains routinely collected information and low accessibility but high heterogeneity of data , 30 doesIn summary, gold-standard evidence for HTA (RCTs) can be regarded as more qualitative than quantitative, it has a domain of validity restricted to the context tested in clinical trials during clinical development and does not answer a number of important questions see . It is nModel-informed drug development (MIDD) applies drug exposure-based, (systems) biological and statistical models derived from preclinical and clinical data sources to inform drug development and decision-making . It intein vitro, preclinical, omics, clinical) data can be used for  calibration  to introduce interpatient variability. A VPop is a set of virtual patients, each one being characterized by its own set of descriptors  that follow pre-defined joint distributions –43. Simuelopment , 45. RunMechanistic models thus can bring biological plausibility, equity of clinical and mechanistic evidence as well as individual predictions  to the table of evidence synthesis and generation.Modeling in HTA is conducted during  the evidFor evidence synthesis, different data-driven modeling approaches are commonly used. Pairwise and network meta-analyses (NMA)  using fiFor extrapolating a clinical effect into longer-term economic impact there exists quite a variety of methods, which are used for HTA and can be classified as cost-benefit analysis, cost-effectiveness analysis, and cost-utility analysis , 51. SimMechanistic models can bridge the gap between development and HTA. Given that validation can establish the credibility of a model for regulatory decision making, exploration of a much larger number of situations than in RCTs  might be feasible. Such digital evidence supporting RCT data alleviates several difficulties such as power, representativeness, costs to run the trials, and ethical issues. For the consideration of such evidence in HTA one should consider the following unique benefits of mechanistic model that statistical ones cannot provide. First, mechanistic models possess biological plausibility by design—using biological, chemical, and physical processes as “blueprint”—and are therefore well suited for extrapolations. Second, the VPop can be set up to assess the very same patient under various conditions and scenarios (such as treatment arms) which corresponds to an idealized crossover design and allows to assess clinical benefit for every individual.A concrete list of examples of how mechanistic models can address unanswered questions left in the MA dossier is given in HTA is a multi-stakeholder activity that should shed light on more facets of an MP than just a technical analysis. Especially in the appraisal phase, “complex calculations, arbitrary assumptions, debatable choices of whose perspectives to pursue, difficult-to-understand methods, research designs and underlying philosophy/concepts, and time-consuming processes” are at risk of narrowing the HTA findings . It has There are still barriers dissecting modeling in the HTA space and modeling in the clinical development space. These barriers are conceptually similar to the known barriers to bring HTA to policy making . Specifidrug developers could generate more HTA-relevant data during Phase III, the resulting pivotal trials would be more complex and risk missing the statistical target. Drug developers should therefore consider mechanistic models to bridge this gap and report HTA-relevant modeling outcomes, validated with Phase III results.While Competent authorities will have a special role in facilitating model-based stakeholder engagement. They should issue more precise and dedicated guidance so that more modeling is included in MA. They should intensify the reporting of mechanistic modeling studies in benefit-risk assessment reports.The modeler needs to embrace the fact that non-experts will also be exposed to the  model and its results. There is a lot of work being done concerning the communication and reporting of clinical trial results to patients and the public which are also applicable for simulated trials. There are EU Commission recommendations on the content of a lay summary (wording and layout) its development and dissemination—Good Lay Summary Practice , but a strong mechanistic background can be approved. The implications of this paradigm shift for HTA still need to be fully understood. In this article, we have advocated that mechanistic models can be used to reproduce, support and extrapolate clinical trials and could constitute a new type of evidence. Mechanistic models can provide causal and quantitative links between patient characteristics, personalized/realistic drug regimen or other extrinsic factors and individual benefit—under consideration of alternative treatment scenarios. They can therefore help to overcome barriers for a more quantitative appraisal of clinical data in HTA and they should also be considered to inform and educate special populations and individuals from a bottom-up perspective. Generation and uptake of The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.EC, J-PB, AK, EP, JM, and RK wrote the manuscript. All authors discussed and reviewed the manuscript.EC, J-PB, RK, MH, EP, and AK are employed by Novadiscovery. The remaining 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.


We undertook an analysis of the Canadian Agency for Drugs and Technologies in Health (CADTH)’s health technology assessments (HTAs) of systemic therapies for solid tumour indications to determine if a mechanism to re-evaluate HTA decisions is needed based on the level of certainty supporting the original recommendation. To measure the certainty in the evidence, we analysed if: (1) overall survival (OS) was the primary endpoint in the pivotal trial, (2) median OS was available at the time of the recommendation, and (3) the expert review committee explicitly identified gaps in the evidence. There were 96 drugs approved by Health Canada that met our eligibility criteria between 1 January 2017 and 31 October 2021. Median OS was not estimable at the time of the recommendation in 57% of the positive recommendations, and the uncertainty in the magnitude of clinical benefit was identified by the expert review committee in 21% of the positive recommendations. There is uncertainty at the time of the HTA recommendation for many drugs, and thus a need to implement a process to re-evaluate drugs in Canada to allow patients timely access to promising therapies while ensuring long-term value of therapies to patients and the healthcare system. Every year, new therapies become available to Canadians through the provincial and territorial universal healthcare systems. As in many other countries, the processes of reviewing drugs for public reimbursement are complex ,2. In adDrugs entering the Canadian market require regulatory approval from Health Canada. Health Canada has three review streams: standard review (300-day timeline), a priority review (180-day timeline) . When a After regulatory approval is granted, a drug is submitted for health technology assessment (HTA) to review its value compared to existing therapies and make recommendations to the public drug plans on whether it should be reimbursed. Canada has two HTA agencies  and Institut National d’Excellence en Santé et Services Sociaux ). The HTA agencies have expert committees that review the clinical benefit, economic value, patient perspectives, and implementation considerations for the drug in order to make recommendations for reimbursement. CADTH has an expert review committee specifically to review drugs for cancer indications called the pan Canadian Oncology Drug Review (pCODR) Expert Review Committee (pERC). If a drug receives a positive HTA recommendation, the next step in the process is for the public drug plans to collectively negotiate a price for the drug with the pharmaceutical company through the pan Canadian Pharmaceutical Alliance (pCPA). The final step in the process is for each province, territory, or federal drug plan to make its own funding decision for the drug under review based on their budget and other priorities .There is ongoing tension between population health and individual health, which results in tension among clinicians, patients, public payers, and the pharmaceutical industry regarding rigour and timeliness. There needs be a balance in how quickly a drug is added to a public formulary and confidence in the value that the drug offers patients and the healthcare system. Clinicians have obligations to society, the healthcare system, and most importantly, patients. Timely access is essential because patients could potentially benefit from these novel therapies, and some may die while waiting for them ,6.Currently, there is no clear mechanism to re-evaluate drugs once they are added to provincial formularies, the inert designs of which are barriers to re-evaluation. Once a drug is added to the formulary, it is not easily removed unless there is a clear signal that it is not safe. There has been discussion for several years that there should be a mechanism to re-evaluate drugs. This is sometimes referred to as a lifecycle approach , wherebyThere are several outcomes important to patients and clinicians in the treatment of cancer, including overall survival, disease-free survival, progression-free survival, quality of life, and severity and frequency of adverse events ,10. DespWe undertook this analysis of drugs for solid tumour indications to understand if a mechanism for re-evaluation is needed based on the certainty in the evidence available at the time of the HTA recommendations. To measure the certainty in the evidence, we analysed three key factors, if: (1) OS was the primary endpoint in the pivotal trial, (2) median OS from the pivotal trial was available at the time of the HTA recommendation, and (3) CADTH’s pERC explicitly identified gaps in the evidence.All drugs with completed new approvals or completed supplementary approvals were extracted from the Health Canada website from 1 January 2017 to 31 October 2021 . The lisWe then assessed how many Health Canada-approved drugs had been reviewed by CADTH . We extrOur descriptive analysis examined trends in regulatory approvals and HTA recommendations by tumour site, pivotal study design, and primary and secondary outcomes. In order to measure the certainty in the evidence at the time of the CADTH HTA recommendation, we extracted details on whether overall survival (OS) was measured and if OS was available at the time of the HTA recommendation. In addition, we reviewed each of pERC’s recommendations to determine if they had explicitly identified gaps in the evidence. Until recently, pERC included a section in their recommendations called “Potential Next Steps for Stakeholders” which would outline factors that would need to be considered upon the introduction of the drug to the healthcare system. These ‘next steps’ could include references to pricing or administration considerations, and when applicable, pERC would identify gaps in the evidence not addressed in the HTA review. We analysed these ‘next steps’ to identify gaps in evidence flagged by pERC. The ‘next steps’ are less consistently reported for negative HTA recommendations because there is an implicit assumption that public reimbursement is unlikely.We conducted an additional analysis to explore if there may be a signal to trigger a re-evaluation based on the European Society of Medical Oncology’s Magnitude of Clinical Benefit Scale (ESMO-MCBS version 1.1) score. The MCBS was designed to assist in the prioritisation of medicines for cancer care . The ESMWe used the results of the descriptive analysis on the uncertainty at the time of the HTA recommendation as the basis to determine whether there is merit in having a mechanism to confirm the value of the therapy at a subsequent time point.n = 29), followed by gastrointestinal cancers (n = 17) and breast cancers (n = 16)  . NotablyMost of the drugs approved by Health Canada have been submitted to CADTH for HTA review . However, nearly 1/4 of the Health Canada-approved drugs in our analysis have not been submitted to CADTH for an HTA recommendation. Of the drugs submitted to CADTH, about 70% (51/73) received a positive HTA recommendation. For the drugs in our analysis, CADTH issued 14 negative HTA recommendations, and as of 31 October 2021 there were 7 ongoing HTA reviews. One drug was withdrawn from the HTA review in 2019 (atezolizumab for triple-negative breast cancer). There are more drugs in the not submitted category for 2021 than for the other years, and this is likely due to the fact that some of these drugs will be submitted for HTA review in 2022 now that they have regulatory approval from Health Canada .About 46% of the drugs in our analysis followed the standard review stream at Health Canada (44/96), and there was nearly an even split of priority reviews and accelerated NOC/c reviews . Approvals based on the accelerated NOC/c review stream were less likely to be submitted to CADTH than approvals that followed the other streams .While the majority of Health Canada approvals for drugs in our analysis were based on phase III randomised controlled trials (RCT) , about one-third of the Health Canada approvals were based on phase II trials . Of the 30 approvals based on phase II pivotal trials, 4 approvals were based on comparative phase II trials, while the remainder of the approvals were based on phase II non-comparative trials.There were more positive HTA recommendations issued based on drugs where the pivotal trial was an RCT compared to drugs where the pivotal trial was a phase II study. However, there were still more positive HTA recommendations than negative HTA recommendations issued in drugs where the pivotal trial was a phase II study (8 positive recommendations vs. 6 negative recommendations).Overall survival was an endpoint in 82% of the pivotal trials for drugs with Health Canada approval; of these, OS was the primary endpoint in about 40% (31/78). Notably, all of the positive HTA recommendations were for drugs where the pivotal trials measured OS as a primary or secondary endpoint. There were no positive HTA recommendations where OS was not measured in the pivotal trial, and one negative HTA recommendation where OS was not measured. About half (12/23) of the studies for the drugs that were not submitted for an HTA review did not measure OS as an outcome .Overall survival was not estimable at the time of the HTA recommendation in 41/73 (56%) where OS was an endpoint (either primary or secondary) of the pivotal trial. When analysing just the positive HTA recommendations, median OS was not estimable at the time of the HTA recommendation in 29/51 (57%) of the recommendations. Median OS was not estimable at the time of the HTA recommendation in a similar proportion of negative recommendations (8/14 (57%)) .When the “Potential Next Steps for Stakeholders” section was analysed in each of the positive HTA recommendations, 39 gaps in evidence were identified in 35 recommendations. Some recommendations had more than two gaps identified. We categorised the evidence gaps into three groups: (i) uncertainty in the magnitude of clinical benefit, (ii) uncertainty in sequencing the new drug with other currently available therapies, and (iii) uncertainty in treatment duration. The most common gap identified was uncertainty in sequencing with other available therapies. Uncertainty in the magnitude of clinical benefit compared to other relevant therapies was identified in 21% (11/51) of positive HTA recommendations.Of the drugs with HTA recommendations, there were 15 drugs that met all 3 certainty criteria . That is, there were 15 drugs that used median OS as the primary endpoint, OS was measurable at the time of the HTA recommendation, and there were no gaps in evidence identified by pERC. There were 11 positive HTA recommendations and 4 negative HTA recommendations that met all 3 certainty criteria. Conversely, there were 29/73 (40%) of the drugs with HTA recommendations that met none of the 3 certainty criteria. Of these, 18 resulted in positive HTA recommendations and 11 resulted in negative HTA recommendations .There were 14 negative HTA recommendations issued for the drugs included in our analysis. The rationale for the negative recommendations was largely due to uncertainty in the magnitude of clinical benefit. The pivotal trial was a non-comparative phase II study for five of these negative recommendations leading to uncertainty in clinical benefit compared to current standards of care. The pivotal trial was an RCT in seven of these recommendations, but the reimbursement request focused on a subgroup in four of these reviews, raising concerns in the confidence in the results. There were two reviews where the demonstrated lack of meaningful clinical benefit seemed to form the basis of the negative recommendation. In comparison, there were 12 reviews where the uncertainty in the magnitude of clinical benefit due to study design or immaturity of results led to a negative recommendation.When we examined the ESMO Magnitude of Clinical Benefit Scale (MCBS) scores for the drugs in our analysis, we found that 76/96 (79%) were scored using the non-curative MCBS, 10/96 (10%) were scored using the curative MCBS, and 10/96 (10%) did not have an ESMO MCBS score on the ESMO website. About 37% (28/76) of the drugs scored with the non-curative MCBS scored a ‘4’ or ‘5’. There was one drug that was assessed as a ‘4’ but received a negative CADTH HTA recommendation. This recommendation was for lenvatinib with everolimus for renal cell carcinoma . CADTH’sOf the 10 drugs scored using the curative MCBS, 9 of 10 drugs received an ‘A’ score, and 1 received a score of ‘C’. There were three negative HTA recommendations in this ‘curative’ group, all for breast cancer indications .We performed an analysis of systemic therapies for solid tumour indications to understand if a mechanism for re-evaluation is needed based on the certainty in the evidence available at the time of the HTA recommendation. Our analysis focused on three key factors to measure the certainty in the evidence in the HTA recommendations, i.e., if: (1) OS was the primary endpoint in the pivotal trial, (2) median OS from the pivotal trial was available at the time of the HTA recommendation, and (3) CADTH’s pERC explicitly identified gaps in the evidence.At the time of the HTA recommendation, 21% (15/173) of drugs met all 3 certainty criteria, 8% (6/73) met 2 of 3 certainty criteria, 22% (16/73) met 1 of 3 criteria, and 40% (29/73) met none of the criteria. About 1/3 of the positive HTA recommendations did not meet any of the criteria, suggesting a high level of uncertainty in the recommendation. It is important that even though there is uncertainty in the evidence at the time of the HTA recommendations, there is a pathway for patients to receive therapies.Nearly 3/4 of the negative HTA recommendations did not meet any of the certainty criteria. Based on these findings, we wonder if there should be a delineation between negative recommendations based on a definitive lack of clinical benefit vs. those with uncertainty in clinical benefit? The extent that there is considerable uncertainty at the time of both the positive and negative HTA recommendations highlights the need for opportunities for further evaluation at a subsequent time point to ensure that value is being met. It is important to strike the balance between timely access because there is an urgency for patients to receive therapies and confirmation of clinical value.There is an awareness that knowledge evolution is important to clinical practice and optimal patient care, as was recently highlighted by Bayoumi and Laupacis . HoweverCanada is well-positioned to develop its own process to re-evaluate drugs. There are rich sources of data in Canada to draw upon and strengthen to enable the generation of evidence to demonstrate value, such as the BC Cancer Registry  and the Canada already has some experience with re-evaluations. In 2011, Ontario established their Evidence Building Program to provide time-limited coverage for drugs while data were collected . The firIn addition, there is a precedent in Canada for accepting drugs based on conditions through Health Canada’s Notice of Compliance with conditions (NOC/c) regulatory approvals. One potential starting point is to look at aligning Health Canada’s existing process for conditional approvals (NOC/c) with conditional HTA approvals where there is promise of value but uncertainty . AlternaOne of CADTH’s strategic priorities is to “implement programs for reassessment and disinvestment” . SimilarIn recent years, there has been an increase in global regulatory alignment through Project ORBIS  with theOur analysis has some limitations. Our analysis looked for Health Canada approvals up to the end of 31 October 2021, potentially limiting the possibility of finding a subsequent CADTH HTA review. The more recent Health Canada approvals are less likely to have a CADTH recommendation. However, CADTH does allow for submissions to be made while Health Canada is conducting their review , at the very least a HTA review could be ongoing at the time of Health Canada approval. In 2021, CADTH changed their HTA recommendation template and no longer included a section for “Potential Next Steps for Stakeholders”. This is a limitation because we relied on this section to identify the evidence gaps flagged by pERC. In addition, a limitation to the ‘next steps’ is that they may not have been included consistently in all HTA recommendations. The ‘next steps’ are dependent on the deliberations of pERC. The ‘next steps’ are less consistently reported for negative HTA recommendations because there is an implicit assumption that public reimbursement is unlikely. Our analysis focused only on the endpoint of overall survival because it is considered the gold standard endpoint for clinical trials. There are many other important outcomes to patients beyond survival that were not analysed. Surrogate endpoints such as progression-free survival or disease-free survival were the most common primary endpoints in our analysis. This is expected because the utility of OS may be limited due to a few factors. Surrogate outcomes such as PFS or DFS may be less time-consuming to generate compared to OS, and these surrogate outcomes also have the potential to contribute information about quality of life and treatment failure. Nonetheless, we looked primarily at median OS because it is often considered the ‘gold standard’ for trial outcomes in oncology . FinallyIn the future, it would be worthwhile to conduct a similar analysis on drugs for haematology indications to evaluate if there are any common themes with these therapies. In addition, it would be important to explore how the cost-effectiveness analyses and the timelines for reimbursement relate to the uncertainty in the evidence. Finally, a future analysis could take a more comprehensive exploration into other endpoints and how it relates to drug reimbursement in Canada.There is frequently some degree of uncertainty in the evidence at the time of the HTA recommendation. Therefore, there is a need to implement a process to re-evaluate drugs in Canada in order to balance the urgent need for patients to access therapies and the sustainability of the healthcare system. Through broad stakeholder collaboration and a mindset of continuous improvement, Canada could successfully enable a mechanism to allow patients earlier access to promising therapies while ensuring long-term value of therapies to patients and the healthcare system.


This article studies how different systems of policy advice are suited to provide relevant knowledge in times of acute crisis. The notion of evidence-based policymaking (EBP) originated in the successful 1997 New Labour program in the United Kingdom to formulate policy based not on ideology but on sound empirical evidence. We provide a brief overview of the history of the concept and the current debates around it. We then outline the main characteristics of the policy advisory systems in Germany, Switzerland, and Italy through which scientific knowledge—in the form of either person-bound expertise or evidence generated through standard scientific processes—was fed into policy formulation processes before the COVID-19 crisis. Whereas EBP takes place in the form of institutionalized advisory bodies and draws on expertise rather than on evidence in Germany, the system in Switzerland focuses more on the use of evidence provided through external mandates. Italy has a hybrid politicized expert system. The article then analyzes how this different prioritization of expertise vs. evidence in the three countries affects policymakers’ capacity to include scientific knowledge in policy decisions in times of acute crisis. The comparison of the three countries implies that countries with policy advisory systems designed to use expertise are better placed to incorporate scientific knowledge into their decisions in times of acute crisis than are countries with policy advisory systems that relied primarily on evidence before the COVID-19 crisis.The online version of this article (10.1007/s11615-022-00382-x) contains supplementary material, which is available to authorized users. This article studies how different systems of policy advice are suited to provide relevant knowledge in times of acute crisis. The notion of evidence-based policymaking (EBP) became popular in the 1990s, particularly with the Labour government under Tony Blair in the United Kingdom  in noncrisis times and what form that scientific knowledge takes. We then analyze how policy advisory systems operate under situations of “creeping crises”  , and experts from other disciplines  are not represented, it can be assumed that representativeness is restricted. If there is a balance of different disciplines, however, representativeness can be high.As defined by Ledermann , expertiSalience: Salience is expected to be less strongly emphasized by evidence because generating knowledge through processes following scientific standards can take a long time. This delays the provision of evidence , which may come too late to satisfy the need for policymakers’ advice . Accordingly, the logic of the credibility of scientific knowledge tends to be low or moderate in times of acute crisis.Representativeness: The generation of unbiased scientific knowledge that includes all relevant interests is also limited by the short-term nature of the decisions for which the knowledge is to be used. A targeted consideration of different perspectives is often possible only in later phases of crisis management, which is why representativeness is rated as low to moderate.Parviainen et al. , p. 236 To sum up, Table Table The analysis builds on a comparative case study design by contrasting Germany, Switzerland, and Italy. The case selection was motivated by the very different institutionalization of the use of scientific knowledge before the pandemic. As outlined before, scientific knowledge is primarily used in the form of expertise by commissions or cabinets in the policy formulation process in Germany and Italy, whereas this happens mainly through evidence provided by short mandates in Switzerland. Moreover, while having different policy advisory systems, these countries were exposed to the same context conditions during the pandemic. This is the case regarding access to international expert recommendations such as those of the World Health Organization or the possibilities of cross-country policy learning given the rapid spread of the COVID-19. They are therefore considered as independent cases, and the analysis can focus on the way each country’s expert advisory system mediates the available evidence. Comparing these contrasting policy advisory systems constitutes a “diverse case” selection strategy  credibility, and low representativeness.These decisions serve as a basis to assess the specific nature of EBP during the second wave (expertise vs. evidence). In Germany, the way in which scientific knowledge was used to inform decision-making at the joint meetings is characterized by From the beginning of the pandemic, the federal government could quickly rely on scientific input from a variety of its own internal-to-government advisors. These included the standing commission on vaccinations, the national ethics council, and the national academy of science (Leopoldina), as well as its own scientific institutes—most importantly, the Robert Koch Institute and the Paul Ehrlich Institute. The heads of these institutes played a central role in communicating developments to the public and suggesting measures to fight the virus, often in the form of direct policy advice. In particular, eight individual experts, who are the heads of the most important scientific institutes and leading university researchers, can be considered close to policymakers.5Although expertise was generally produced in compliance with scientific standards, the high complexity and uncertainty that characterized the fight against COVID-19 required personal assessments of the experts consulted—for instance, if evidence was not in line with more general experiences or if evidence was itself contradictory. For example, policymakers followed the expertise of virologist Christian Drosten, physicist Viola Priesemann, and others to keep schools and nurseries closed after the January 5 meeting. This decision was taken even though the head of the University Hospital Dresden (Reinhard Berner) referred to a study by his institute that concluded that schools could be reopened.German policymakers could rely on the scientific advice of research institutes and the national academy of science, which cover a variety of academic disciplines but have a clear focus on the natural sciences.13In sum, the high salience, the low to medium credibility, and the low representativeness in which scientific knowledge has been produced in the German case indicates that it can be best described as an expertise-based system.To examine whether this expertise was actually considered by policymakers, we tracked the core policy decisions made during the three major government meetings and show how they align with expert recommendations. Table A3 in the online annex details the most prominent expert recommendations and compares them with the core decisions made at the three conferences.In Switzerland, the second wave lasted from mid-October 2020 to mid-January 2021  representativeness.Switzerland is a highly decentralized federal country, with strong decision-making capacities of the cantons . During the first wave, however, pandemic management was centralized at the national level. In fall 2020, the Federal Council refused to take the lead again and shifted the blame for the bad epidemic situation to the cantons, arguing that they had to enact their own restrictions depending on the local situation Mavrot . In thisThe Swiss National COVID-19 Science Task Force was rapidly established in March 2020 to ensure the provision of up-to-date medical expertise to the federal authorities. Members were nominated by the Federal Department of Home Affairs and the Federal Office of Public Health (FOPH) upon the proposition of the task force itself. Its members are top-level medical experts, active at universities and public hospitals. They serve on a voluntary basis. The structure and composition of the task force varied over time, but during the second wave, it included 10 expert thematic groups , amounting to a total of 70 scientists Mavrot . The misStrikingly, the expert system was strongly fitted for a centralized management of the pandemic at the national level, as Switzerland experienced during the first wave. However, with the partial shifting of pandemic management to the cantonal governments during the second wave, the system showed some limitations. The task force’s analyses of the epidemiological situation were mainly national, without differentiation of the regional situations.The credibility of the task force in the political and media scene was high. The task force was made up of the country’s top scientists, active both in research and in hospital practice, with a large majority being university professors. They were credited with a high degree of theoretical and frontline field knowledge throughout the crisis, which was not questioned in the public debates. The evaluation of the epidemiologic situation and the scientific reports of the task force complied with scientific standards and procedures . Similarly, the policy briefs proposed recommendations based on projections or offered meta-analysis of the available scientific literature. The production of the task force relied on ad hoc studies and data analysis and not on general empirical assessments of the situation. The Federal Council and the federal health administration also gave consequent credit to the task force by regularly citing its work and recommendations during press conferences.On the one hand, the representativeness of the task force’s scientists was high when considered from a strictly medical perspective. The large number of included experts allowed internal deliberations of the various dimensions of the pandemic within the scientific community. The collegial and internal deliberation of experts within the task force’s thematic groups allowed scientists to present a quite united front in their reports and policy papers. Because of the integrative nature of this system, there was little external criticism of the task force’s opinions from other scientists in the media. This collegial functioning was in line with the politico-institutional culture of the Swiss consensus-based democracy Mavrot . On the The medium salience, the high credibility, and the medium to low representativeness as well as the composition of the task force puts it in the category of an evidence-based advice system. There were recurrent frictions between some scientists in the task force and national political authorities. While the Federal Council essentially followed the experts’ recommendations at the beginning of the first wave, the politics of the pandemic took another path at the end of the first lockdown with the reopening of economic activities , the national executive was entrusted with substantial emergency management powers, although with leeway for regions to adopt more restrictive measures , however, are not necessarily crucial for the way the three countries came through the second wave at large . However, those differences in integrating scientific advice in policy decisions during the pandemic do tell us something if we observe the knowledge dimensions’ departures from our expectations, namely in terms of credibility. They indicate that credibility can be a matter of perception in relation to the preexisting policy advice system: In systems in which scientific evidence (with high credibility) had rarely been embedded in policymaking before the pandemic, its comparatively higher usage in times of crisis might generate a perception of high credibility. Consequently, policymakers might use that knowledge to legitimize their own actions, as occurred in the cases of Italy and Germany. In Switzerland, policymakers also strongly used scientific advice during the COVID-19 crisis to legitimize their decisions when needed, but such strategic use of evidence is also usual in noncrisis times with policy evaluations.These findings bear important practical insights. It is well known that EBP does not come out of the blue. The three cases show how institutional structures can foster both the provision and the use of scientific advice. Established cooperation between experts and politicians makes it easier to refer to these routines in times of acute need for knowledge in times of sudden uncertainty. On the downside, this means that EBP that only refers to the production of tailored evidence for specific policy questions does not suffice as a structure firm enough for knowledge transfer in times of acute crisis. The expert–politician nexus is a social interface that needs established forms of exchange and a good fit with the politico-institutional features of the system. In order to establish these structures, institutions are the adequate way to build and maintain a routine that decision-makers can refer to in times of acute crisis.The online annex provides detailed information on the sources analyzed in the case studies. Table A1 summarizes the newspapers consulted in each country. Additionally, the annex includes a list of all press and media sources consulted. Table A2 outlines the indicator questions asked to operationalize the three logics of scientific knowledge . Table A3 summarizes the alignment of expert recommendations with decisions taken at governmental meetings in Germany.