P < .05). Under the MDT model of emergency trauma, the combination of mind mapping and PBL teaching can improve the comprehensive clinical ability of the trainees more than participating in the traditional lecture-based learning teaching, which is worth promoting and implementing in the clinical standardized training.Explore the feasibility and effectiveness of accepting mind mapping combined with problem-based learning (PBL) teaching method in the standardized training of emergency surgery residents in the multi-disciplinary team (MDT) model of emergency trauma. Eighty-nine doctors under training who rotated in the Department of Emergency Surgery of the First Affiliated Hospital of Anhui Medical University from January 2021 to January 2022 were selected as the study subjects, and randomly divided into a group receiving mind mapping combined with PBL teaching and a group receiving traditional lecture-based learning teaching. Mini-clinical evaluation exercise (Mini-CEX), direct observation of procedural skills (DOPS), teaching adherence, and satisfaction assessments were completed at the time of discharge from the department. There were no significant differences between the observation and control group trainees in terms of gender, age, education, and entry grades. Both groups of doctors were better able to participate in their respective teaching modes and made significant progress. The participants in the observation group had significantly higher Mini-CEX, DOPS, and teaching satisfaction scores than the control group ( Its training and teaching work has now become another important work content after clinical medical treatment, medical research, and undergraduate teaching. Therefore, combining the common emergency trauma cases in the department, adopting scientific and effective teaching methods, and developing a reasonable and fair assessment system is of outstanding significance to improve the emergency diagnosis and treatment level of the standardized clinical residents.Standardized residency training is the first mandatory stage of post-graduation education for clinical medical students. By receiving systematic and standardized training of comprehensive clinical competence as a resident in a nationally recognized hospital with training qualifications, the aim is to develop the 4 major job competencies of resident’s professional ethics, professional and technical skills, teamwork and communication skills, and teaching and research skills. This type of training is currently the mainstream way of training physicians around the world.,5 This approach is now widely used in our emergency surgery department. By participating in the MDT process of emergency trauma, it can establish a standardized and individualized treatment concept for the trainees and then cultivate their all-around and multi-dimensional treatment thinking ability. On this basis, further optimization of the teaching program will have a multiplier effect on the cultivation of qualified emergency medicine trainees. In the process of teaching practice at home and abroad, it is found that the problem-based learning (PBL) can effectively develop students’ ability to identify, analyze and solve problems.–8 It is characterized by student-centered, case-oriented, and problem-based teaching and learning tasks in the form of group discussions. However, PBL teaching alone cannot make students form a systematic understanding of the learning content. In contrast, mind maps use a combination of text and graphics to make abstract problems concrete and simplify complex problems by linking fragmented knowledge together, so they are a good supplement to PBL teaching mode.Emergency trauma patients, especially those with combined multiple injuries, are characterized by complex injuries, rapid changes in condition, many comorbidities, and easy misdiagnosis and underdiagnosis. In such cases, the multi-disciplinary team (MDT) mode is usually used to formulate targeted treatment plans by experts from different specialties and perform early controlled surgical interventions when necessary, which can significantly improve the patient’s outcome and prognosis.We selected 89 standardized clinical residents who rotated in the Department of Emergency Surgery of the First Affiliated Hospital of Anhui Medical University from January 2021 to January 2022 as the study population. We introduced the symptom-based mind maps combined with PBL teaching method into the emergency trauma training teaching in MDT mode and applied the mini-clinical evaluation exercise (Mini-CEX) and direct observation of procedural skills (DOPS) assessments as formative evaluation tools, and achieved satisfactory teaching results, which can provide a basis for promoting the clinical training teaching method of emergency surgery in the future, which is reported as follows.Among the 89 doctors in the department of emergency surgery who participated in the teaching study, 54 were male, and 35 were female. The age ranged from 22 to 29 years old, with an average of 24.21 ± 1.77) years old. Forty-seven had a bachelor’s degree, 32 had a master’s degree, and 10 had a doctoral degree. The randomized data table method was applied to divide the study population into observation and control groups, and theoretical performance was assessed after admission to the department. There were no significant differences between the members of the 2 groups in terms of general information  teaching in the emergency trauma MDT model. Each cohort of trainees had a 4-week learning and assessment period in the emergency surgery department. The Mini-CEX and DOPS assessments were conducted in the 1st and 4th weeks after admission to the department, respectively. The assessment was scored by 3 non-instructors with intermediate or higher titles, and the average was taken as the final score. The differences in scores between the members of 2 groups while before and after enrollment were analyzed, and finally, the participants were surveyed for teaching adherence and satisfaction. The above research contents have been approved by the Clinical Medical Research Ethics Committee of the First Affiliated Hospital of Anhui Medical University (Quick-PJ2022-04-42).The MDT model is now widely used in the context of medical specialty integration and exchange. Through multidisciplinary coordination, the injury condition of emergency trauma patients is evaluated to provide appropriate treatment plans. If necessary, emergency surgery is carried out by the corresponding department according to the severity of each organ damage. In the MDT mode, the success rate of emergency trauma treatment can be significantly improved by reevaluating the injury condition and determining the subsequent treatment or surgery plan after the patient’s vital signs have stabilized. We involve the trainees in the MDT discussion and medical treatment process, during which the teachers of each specialty guide the participants to think about the problems that may arise, aiming to cultivate the trainees’ ability of comprehensive and integrated analysis of emergency trauma. Based on the selected emergency trauma PBL cases combined with problem-oriented, the training participants extracted keywords to construct the basic framework of mind maps. By using lines, characters, and pictures, they can link the relevant knowledge points from the center to the periphery. At the same time, the contents of the mind maps are expanded with the help of textbooks, clinical guidelines, and domestic and international literature. Trainees are encouraged to discuss during the process of making symptom-based mind maps, actively ask questions to the instructor to avoid discussion bias, and enhance their sense of teamwork.The observation group trainees applied X-Mind software to draw mind maps of emergency trauma under the guidance of their instructors, focusing on the principles of mapping: Place the injured organ in the center with symptoms as the core theme. The secondary issues are arranged in a radial pattern, concise, and clearly layered. Use different colors or pictures to express the content as much as possible to enhance the visual impact. The diagram should reflect the holistic thinking of trauma and be easy to understand and remember.The instructor applied the PBL teaching content and mind maps to the teaching of the observation group. The case materials were distributed after the teaching of basic theory and clinical training of emergency trauma in small groups. At the same time, 4~5 questions were set from the diagnosis, treatment, surgical management, and doctor-patient relationship of the disease. Each group coordinates with each other to consult tools and literature, and after independent study, they compile an outline of the presentation and draw mind maps. Participants will first discuss the issues involved in the case within the group. Then the group representative will present the case analysis conclusion according to the content of the mind maps. And finally, the instructor will make a summary evaluation after the group discussion. The instructor can organize the trainees to select some typical emergency trauma cases for simulation training. The group members will play different roles to deepen their understanding of the knowledge. The Mini-CEX evaluation form we developed according to the characteristics of emergency trauma includes 7 aspects such as interrogation ability, communication skills, professionalism, physical examination, clinical judgment, operational ability, and overall evaluation, etc.,13 Each item adopts a stanine scale in 3-level, with 1~3 being substandard, 4~6 being qualified, and 7~9 being excellent. The DOPS evaluation form judged the trainees’ performance in the clinical practice activities of trauma. The assessment is drawn from routine surgical operations such as debridement and suturing, suture removal, abdominal puncture, catheterization, and gastric tube insertion. The criterion is based on an internationally accepted 6-point scale in 4-level, with 1 to 2 being below the expected standard, 3 being close to the expected standard, 4 being at the expected standard, and 5 to 6 being above the expected standard. The degree of cooperation of the trainees with the respective teaching mode is classified into full compliance, basic compliance, partial compliance, and noncompliance according to the level. The results are used as important indicators for evaluating the final teaching effect. The teaching satisfaction assessment is conducted by means of a questionnaire out of the department, which mainly includes stimulating learning interest, deepening knowledge understanding, improving clinical thinking and recognizing the teaching mode, etc. Participants are rated from 0 to 10 points according to their actual experience.The Mini-CEX and DOPS were used as formative evaluation tools for teaching effectiveness, with the assessment period being the first and fourth week of admission, respectively. The Mini-CEX focused on assessing the trainees’ receiving and handling skills, while the DOPS focused on assessing the trainees’ clinical operation skills.s, while t test was used for comparison between groups. Count data were expressed as the number of cases or percentages, while χ2 test was used for comparison between groups, and P < .05 indicated that the difference was statistically significant.All data were statistically analyzed using SPSS 23.0 software, and the measurement data were expressed as χ ± The observation group of trainees attending the basic trauma theory training in the department was able to participate in the MDT treatment and teaching process actively. This has a certain depth in understanding of the assessment of emergency trauma, consultation and treatment process, treatment principles, surgical selection, and postoperative rehabilitation, and has the ability to complete the reception and initial treatment of patients with multiple and compound injuries under the guidance of teachers in MDT. Most of the trainees in the observation group could correctly grasp the principles of drawing mind maps and the application of X-Mind software, review the literature through teamwork to make symptom-based emergency trauma mind maps and complete the summarization of the whole consultation process of trauma patients in the guide map Fig. .Under the guidance of the instructors, the observation group of trainees showed high enthusiasm for the PBL teaching format. They were able to take the initiative to identify, analyze and solve problems based on the distributed case materials. Group members developed appropriate treatment plans for emergency trauma patients by reviewing literature and participating in discussions, and correctly played the roles chosen in the situational simulation exercises. The participants of the observation group introduced the method of drawing mind maps, which had been mastered in the previous period, into the PBL case analysis, so that the symptoms, auxiliary examinations, diagnosis, and treatment of the disease were presented in an orderly manner as holistic thinking, making the clinical decision-making process easy to understand and remember, and we used the case of emergency trauma in Figure 9/L, NEU% 90.5%, RBC 3.02 × 109/L, Hb 87g/L; electrocardiogram showed sinus tachycardia. Questions in the first act: What parts of the physical examination should be focused on? What are the indifference of expression and cold extremities suggest? What emergency tests should be performed on this patient? What is the diagnostic sequence and treatment plan based on the patient’s condition?The basic situation of the case: The patient was a male, 36 years old, who accidentally caught his right upper limb and abdominal clothes in a machine at work, resulting in crushing crush injury of the right hand, large skin avulsion injury of the abdomen and open abdominal injury, and was transferred to a higher level hospital after dressing the trauma at the local hospital. The patient was admitted with an indifferent expression, wet and cold extremities, total defect of the median abdomen with intestinal exenteration, severe crush injury of the right forearm, and comminuted fracture of the metacarpal. Blood pressure was 106/52 mm Hg, emergency blood count: WBC 16.4 × 10An abdominal exploration in MDT mode revealed a ruptured transverse colon and mesenteric contusion, with no significant abdominal other organ abnormalities, and a post-repair transverse colostomy was performed. Some of the skin and soft tissues of the middle abdomen were missing. However, it was still possible to close the abdominal cavity with sutures, and the incision was drained with vacuum sealing drainage. The crushed fracture of the right hand could not be repaired, so a wrist amputation was performed, and a full-thickness skin flap graft was made on the skin defect of the right forearm. Questions in the second act: Principles of selecting the surgical plan? What is the sequence of surgical exploration? Why did the patient undergo external transverse colon surgery?The patient was treated with symptomatic treatment such as anti-inflammatory, nutritional rehydration, etc. After the intestinal function was restored, the gastric tube was removed, and the diet was gradually resumed. The right upper limb flap was observed for abnormal blood flow 1 week after surgery during the hospitalization. At 2 weeks postoperatively, the abdominal incision was confirmed to be well-healed, and then the vacuum sealing drainage was removed. The external transverse colon was placed back into the abdominal cavity under local anesthesia at 4 weeks postoperatively. Questions in the third act: How to observe the recovery of bowel function? What are the precautions after flap grafting? What should be done if the patient develops a postoperative abdominal wall hernia?In the discussion session, the trainees introduced the whole case analysis process in the form of mind maps and chose the corresponding roles to conduct scenario simulation exercises, in which the summary points of concern include: What is the definition of open and closed abdominal injuries? What are the principles of treatment for multiple injuries? What is the clinical application of damage control surgery?The Mini-CEX and DOPS assessments were administered before and after the residents from observation and control groups participated in the teaching study. By analyzing the changes in the performance of the members of the 2 groups before and after admission to the department, the progress of their receiving and handling abilities and clinical operation skills during the study in the department of emergency surgery was assessed. The results of the study confirmed that the post-teaching Mini-CEX and DOPS scores of the 2 groups of trainees were significantly higher than the pre-teaching scores. There were significant differences in their overall scores and most individual scores, suggesting that within the emergency trauma MDT model, both the acceptance of mind maps combined with PBL teaching and the traditional LBL teaching can improve the overall level of the trainees, as detailed in Figure The residents from observation and control groups were evaluated before and after the teaching study in terms of receiving and handling abilities and clinical operation skills, and the differences in their teaching effects under different training modes were assessed by analyzing the Mini-CEX and DOPS scores before and after the members of the 2 groups were admitted to the department. The results of the study confirmed that there was no significant difference between the Mini-CEX and DOPS scores of the 2 groups of trainees before teaching. Still, after teaching, the observation group had significantly higher overall scores and most individual scores than the control group, suggesting that within the emergency trauma MDT model, receiving mind maps combined with PBL teaching could improve the overall level of the trainees compared with the traditional LBL teaching, as detailed in Figure The adherence of the both groups of trainees to participate in different teaching modes has an important influence on the final teaching effect. Therefore, they were evaluated comprehensively in terms of the initiative of learning, the standardization of practice, and the cooperation of assessment, respectively. According to the level of compliance, they were classified as fully compliant, basically compliant, partially compliant, and non-compliant. The study identified full compliance and basic compliance as better compliance. The results confirmed that both the observation and control groups of participants showed better compliance in their respective teaching activities, with no significant differences between them Table .The teaching satisfaction evaluation of the both groups of trainees before they left the department was carried out using our homemade questionnaire, which included stimulating learning interest, deepening knowledge understanding, improving clinical thinking, enhancing teamwork, recognizing the teaching mode and overall satisfaction, and all the members who participated in the study completed the questionnaire. The summary results of the questionnaire showed that the observation group had significantly higher overall scores and all individual scores than the control group, suggesting that the participants were more satisfied with receiving mind maps combined with PBL teaching in the emergency trauma MDT model Table .–17 Emergency medicine is a very distinctive emerging clinical medicine specialty whose level reflects to a certain extent of the comprehensive medical level of a hospital or even a country. As an inseparable part of emergency medicine, emergency surgery has become an independent discipline with rapid development. The training of qualified emergency surgeons is an important part of our clinician training. Therefore, we have participated in a number of clinical teaching training activities organized by society and the hospital, hoping to improve the effect of training and teaching in emergency surgery through the adoption of appropriate teaching methods. By combining the characteristics of the common emergency trauma patients in the department, we decided to carry out the teaching of emergency trauma MDT in the mode of receiving mind maps combined with PBL teaching and traditional LBL teaching, so as to provide a theoretical basis for further promoting the experience of training and teaching in the future.In the 21st century, medical science is rapidly developing and facing serious challenges. Medical educators are proposing a variety of teaching reforms for medical students at all stages of theoretical teaching, clinical practice, and residency training in order to produce qualified clinical medical personnel for society. As a basic treatment model for modern diseases, MDT is conducive to the development of a multidisciplinary mindset, and trainees can integrate theoretical medical knowledge and clinical specialty practice by participating in the treatment process of emergency trauma patients.,22 In our teaching study, we found that both groups of trainees had significantly improved their assessment scores after participating in the MDT model of emergency trauma teaching, suggesting that this method is practical and feasible to be applied to the training teaching. The trainees in the observation group introduced PBL teaching on the basis of MDT through discovering, analyzing, and solving problems in typical cases, which prompted standardized clinical residents to deepen their understanding of theoretical knowledge in teaching practice. It aims to stimulate learning interest, improve self-learning ability, cultivate clinical thinking and strengthen teamwork spirit. As a good complement to PBL teaching, the mind map is a note-taking method created by Tony Buzan, a famous British psychologist, to record the thinking process through lines, images, and markers in a radioactive way.,24 Emergency trauma patients mostly have obvious clinical symptoms, so the symptom-based mind maps can adopt the technique of combining graphics and text to connect the topics of disease occurrence, progression, treatment, and prognosis at all levels with hierarchical diagrams, so as to improve the ability of participants to integrate clinical information and deal with clinical problems, thus effectively promoting their enthusiasm and efficiency of independent learning.The intervention of emergency trauma patients in MDT mode and damage control surgery when necessary can significantly reduce the mortality rate and improve the prognosis of patients. In this study, we found that the post-teaching Mini-CEX and DOPS assessment scores of both groups were significantly higher than the pre-teaching scores. The post-teaching assessment scores of the observation group were higher compared with the control group, suggesting that within the emergency trauma MDT model, receiving mind maps combined with PBL teaching can improve the comprehensive clinical competence of the trainees more than participating in the traditional LBL teaching. If the participants are not able to cooperate with the teaching activities or see them as a burden, it will directly affect the final learning performance. In our practice, we found that both groups of trainees were able to adapt well to their respective teaching methods. All participating doctors completed the satisfaction questionnaire before they left the department. The results confirmed that the trainees had higher recognition and interest in learning under the MDT model of emergency trauma with the combination of mind maps and PBL teaching, so this teaching model has better prospects for clinical promotion.The development of a reasonable and fair assessment system in standardized training can help to evaluate the teaching effect objectively. Mini-CEX and DOPS can assess the trainees’ performance and give feedback at the same time, prompting them to recognize the shortcomings in learning and make targeted improvements.In summary, the clinical teaching of resident doctors is an important part of carrying out teaching reform, and the selection of appropriate teaching methods is the key to cultivating high-quality medical talents. This study found that the acceptance of mind maps combined with PBL teaching in the emergency trauma MDT model as a new teaching tool for emergency surgery trainees can both motivate participants to learn and improve clinical practice in a multi-dimensional way. Its good feedback was obtained in the teaching evaluation system, and it is worth being promoted and implemented in the standardized residency training of hospitals around the world.The authors are thankful to all staff members of Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, for their help in instructing the work.Zhou-Wei Xu contributed to the conception of the study and wrote the manuscript; Jian-Lin Zhang, Xue-Sheng Wu, and Jia Chen participated in the teaching study as the instructors; Jia-Wei Chang and Bai-Cheng Ding performed the teaching effectiveness evaluation; Na-Na Liu, Yu-Nuo Wu, and Jia-Peng Wang helped perform the data collection and analysis; Wei-Dong Chen and Xing-Yu Wang contributed to the research program and constructive discussions.Data curation: Jia-Wei Chang.Formal analysis: Jia-Wei Chang.Funding acquisition: Zhou-Wei Xu.Investigation: Na-Na Liu, Jia-Wei Chang.Project administration: Jian-Lin Zhang, Xue-Sheng Wu, Jia Chen, Wei-Dong Chen.Resources: Bai-Cheng Ding, Yu-Nuo Wu, Jia-Peng Wang.Supervision: Wei-Dong Chen, Xing-Yu Wang.Validation: Jia Chen, Bai-Cheng Ding.Writing – original draft: Zhou-Wei Xu, Yu-Nuo Wu, Jia-Peng Wang.Writing – review & editing: Xing-Yu Wang.


Medical education has emphasized the importance of integrating medical humanities training into the curriculum to benefit medical and nursing students' future practice, featuring in the list of national funding priorities for healthcare education research in Taiwan for many years. However, the extent to which this drive has resulted in medical humanities training, what rationales underpin its inclusion, and its efficacy is largely unknown. This study aims to address these issues across medical humanities programs within the Taiwanese context.We conducted a systematic review. Inclusion criteria included studies in English or Mandarin reporting outcomes of medical humanities courses in healthcare education settings in Taiwan between 2000 and 2019. We searched across five electronic databases , following PRISMA guidelines. The Best Evidence Medical Education (BEME) Global Scale and Kirkpatrick Levels are used for identifying the strength of evidence.17 articles were extracted from the 134 identified. Intrinsic and instrumental rationales for the inclusion of medical humanities education were common, compared with epistemological-based and critical-based approaches. Several positive impacts were identified in relation to participation including modification of attitudes, knowledge, and skills. However, the highest level  of evidence characterized by effects on students' behaviors or ongoing interaction with colleagues and patients is lacking.Findings suggest that although medical humanities education is widely implemented in Taiwan, no clear consensus has been reached regarding the rationale for inclusion or how it is localized from Western to Asian contexts. Future research still needs to explore the long-term impact of medical humanities education for medical and nursing students and its impact on patient care.https://www.crd.york.ac.uk/PROSPERO, identifier: CRD42019123967. The inclusion of the medical humanities into medical curricula has to date been driven by four key rationales: instrumental, intrinsic, critical, and epistemological  rationale focuses on the potential counterbalancing effect of bringing a humanistic perspective into the curriculum :RQ1: How are the medical humanities defined in Taiwan and what rationales are used for their inclusion in medical and nursing curricula?RQ2: What types of medical humanities interventions are employed in the Taiwan medical and nursing curricula?RQ3: How are the medical humanities outcomes assessed across Taiwan's medical and nursing curricula?RQ4: On what type of evidence is the successful delivery of the medical humanities in Taiwan based?RQ5: To what extent are medical humanities curricula successful in delivering specific outcomes?We conducted a systematic review focusing on medical humanities education interventions in medical and nursing education in Taiwan. We used the Best Evidence Medical Education (BEME) Global Rating Scale and Kirkpatrick-based outcomes Online  to evaluBEME is defined as: “the implementation by teachers and educational bodies in their practice, of methods and approaches to education based on the best evidence available.” BEME can be considered as a spectrum ranging from 100% opinion-based education where there is no useful evidence, to 100% evidence-based education where there is adequate evidence .reaction (1), learning (2), behavior (3), and results (4). The first level of evaluation, reaction, typically involves trainees completing a post-course evaluation of their impressions of the program. Such evaluation does not measure what participants have learned, but gauges the interest, motivation, and attention levels of participants. The second level, learning, involves measuring what participants have learned in terms of both knowledge and/or skills. Learning evaluation can include trainees participating in written assessments or role-plays to demonstrate their skills. This level of evaluation allows participants to demonstrate their understanding of specific skills and/or knowledge within the learning program. The third level is behavior or performance. This involves assessment of the trainee's ability to use their newly learned knowledge or skills in the workplace. This level of evaluation attempts to determine whether participants  use their new skills when they return to the work environment. The fourth level, described as results, is a measure of the impact that the training has had overall, including financial or morale impacts. This might include improvement in, for example, staff–resident interaction, decreased incidents of challenging behavior, and staff turnover (The Kirkpatrick (1996) model , additioturnover .This study focused on the implementation of medical humanities into undergraduate medical and nursing education curricula in Taiwan . Specifically, in Taiwan, most medical and nursing schools adopt definitions of the medical humanities that have been developed in Anglo-American contexts, such as the mission statement developed by New York University (NYU), which defines medical humanities as “an interdisciplinary field of humanities , social science , and the arts  and their application to healthcare education and practice” , 29. FolOur systematic review was executed in two phases: first, we searched electronic databases; second, the authors then manually searched reference lists for relevant articles. Articles in the first phase were obtained from the following electronic databases: PubMed, Embase, ERIC, PsycInfo, and Web of Science See . We limiAll researchers independently identified relevant articles for full-text review in Endnote by scanning the titles and abstracts on the basis of the inclusion and exclusion criteria set out in Box 1Inclusion criteriast January 2000 - 31st May 2019Date range: 1Population: Medical Student , Medical Teacher , Nursing Student, Nursing Course, Medical School , Medical CourseExposure: Medical Humanities, Narrative Medicine, Health Humanities,Outcome: Participants' inter-professional collaboration skills, patient-centered decision on professional issues, Participants' cognition on medical humanities, Participants' improvement of doctor-patient communication, cultural competence, critical thinking and in-field clinical performance after medical humanities trainingLanguage: English, MandarinGeographic location: TaiwanSetting: Medical School , Nursing School, HospitalStudy design: All studies with empirical dataExclusion criteriast January 2000Date range: Before 1Population: Continuing Student, Continuing Trainee, Professional NurseExposure: Continuing Education, Post-graduate StudentLanguage: Other than English and MandarinGeographic location: Other than TaiwanStudy design: Systematic reviews or reviewsData extraction comprised the following process: We managed the coding of articles in ATLAS.ti (version 8.0) software. After all seventeen studies were imported to the library, BLH screened them once again to ensure all inclusion and exclusion criteria had been applied correctly. Following this, the coding began: noting firstly the author(s) name(s), year of publication, and language. A second-team member (CDH) double-checked the database. BLH then coded for study design, research period, stages of the training, type of participants, research specific outcomes, and other specific information required to answer the research questions. Another team member (LVM) then checked the ATLAS.ti database as an independent review, in addition to whole-team discussions on process during our regular meetings online and on-site. Discussions regarding the rationales used for medical humanities inclusion in the curricula taken within each article occurred online, via emails. Discrepancies were communicated and resolved. Evidence grading was undertaken by BLH who categorized articles according to the Best Evidence Medical Education (BEME) Global Rating Scale and Kirkpatrick-based outcomes Online . The samTo answer the key research questions, data were deductively coded according to the following criteria: (1) presence and origin of definitions for medical humanities; (2) rationales for implementation of the medical humanities (outlined earlier).We present the main body of our results section according to the research questions. In terms of study participants, we note that fourteen articles comprised only medical students as participants and two articles had both medical and nursing students , 34 crean = 6; 35.30%)   did not clearly specify the definition they used  , 36–40 u.30% , 36 47,05%) –44 applihey used , 45, 46.In terms of rationales for applying the medical humanities to medical and nursing education, we identified studies that could be classified into the four rationales (as outlined earlier) , albeit Six articles were classified according to an intrinsic rationale , 44, 46.Only one article was classified to the critical rationale : valuingThe epistemological rationale was also represented by a single paper . In thisFor articles based on the instrumental rationale, exposure to visual arts , 26, narWithin the intrinsic articles, fieldwork , memoriaThe outcomes of medical humanities interventions are assessed via a range of methods. Self-assessments about participants' medical humanities skills development/professional development , facultyAs for the evaluation of participants' medical humanities skills development/professional development, while self-assessment of students' own perceptions on their development was used in two articles , 40, twoWe considered the type of research study that was undertaken. In terms of methodology, two studies used mixed methods with pre-test and post-test outcomes and collection of written feedback , 44. FivQuality of the research evidence available, the Utility of the evidence, the Extent of the evidence, the Strength of the evidence, the Target or outcomes measured, and the Setting or context. In this section we report on the extent to which the included studies met the quality criteria using the BEME Strength of Evidence Scale , rating We now consider the outcome levels for each of the articles, noting that some studies addressed more than one outcome at different levels see .All articles addressed level one outcomes reporting student reactions and responses to medical humanities courses , 33–46. Six studies  reporteIn terms of improvement in perceptions about study, specifically, in Fan et al.'s study (BEME level 3) in which the post-course outcome comprised students' grades in their fourth-year general psychiatry performance, it was found that students who had attended the course had scores that were significantly higher compared to those who did not. The authors attributed this to a more creative and fresher mind in critical thinking .The second study used an experimental, non-randomly controlled design with a field visit, group writing report, and group assignment as the interventions , and wasIt should also be noted that there were some articles (BEME level 1) that sought to achieve level 2a outcomes, including , 43, 46 Four studies were categorized at this level (across BEME levels 3 and 4) in which participants demonstrated modifications in terms of clinical treatment knowledge and skills via relevant humanities activities, such as critical thinking , 26, refThere were no articles in our review that aligned with this level.There were also no articles in our review that aligned with this level.Our findings suggest that all four rationales outlined in the literature  are reprseeSimilarly, narrative/storytelling, coursework, and fieldwork are the most frequently employed interventions when incorporating the Medical Humanities into Taiwanese medical curricula. Again, we feel that this reflects the nascent nature of the field in Taiwan. As the Medical Humanities gain more traction in the country and become part of the core curricula educators will likely seek out more novel approaches, such as seen in the few studies which explored the use of community-based experiences, exposure to art, and the “silent mentor” program see. As for Our review found that medical humanities outcomes in Taiwan are assessed in a variety of ways, including (and in approximate order of frequency): self-assessments; written methods such as assignments, reflective writing and clinical/field reports; faculty observation/judgment; and content tests or presentations. Other studies used alternative measures, such as academic grades, clinical notes, course surveys, interviews, and a mental health survey. The frequency of self-assessments or reports is reflected in the predominance of outcomes at Level 1 on Kirkpatrick's model (see below for further discussion). On one level, this plurality of methods suggests that Taiwanese medical schools have implemented medical humanities education quite comprehensively. However, it may also suggest a continuing search for appropriate and valid methods of assessing what is recognized as challenging skills and outcomes to assess , 51, 52.The majority of studies in this review reported findings based on participant reactions to the intervention, that is, Level 1 of Kirkpatrick's model. A small number of studies reported a higher level of outcomes , although no study was found which claimed observable changes in the students' themselves in terms of application to daily life after their newly acquired knowwledge/attitude, and at organizational or patient levels. In terms of strength of evidence, there was a spread of studies across Levels 1-4 of the BEME strength of evidence scale, with many using either quantitative or qualitative methods, rather than the approaches necessary for a Level 4 classification, such as mixed methods, diversified participant groups, and more longitudinal and better-aligned assessments such as portfolios. Furthermore, the focus of most of the studies were participants' attitudes, feelings, and knowledge about intended learning outcomes, with few aiming to elicit or evaluate broader changes in participants' real behaviors or impact.The overall strength of evidence and levels of outcomes of these studies lead us to two broad conclusions: first, students have generally learned the expected skills in accordance with common goals and purposes of the medical humanities as outlined by course designers; second, students generally appreciate the goals and purpose of the course they have taken. While stronger conclusions relating to changes in organizational or patient outcomes are not warranted at this stage, these are nevertheless positive results for the relatively recent adoption of medical humanities in Taiwan. This is also consistent with Ousager and Johannessen  findingsFinally, we found a dominance of western definitions of the medical humanities being used in the studies we reviewed. While a useful definition in practical curricular terms, the reliance on western conceptualizations of the medical humanities may have an unintended consequence in overly constraining notions and applications of the medical humanities in non-western contexts. This may be problematic, as it often emerges in practice in a “quasi-Western” form through the use of Western cultural artifacts , potentially marginalizing local expressions of cultural diversity not only for patients and society but also for clinical practitioners and students' themselves . It is tWe acknowledge several limitations of our study. Firstly, the lack of clear articulation or attribution of definitions of medical humanities in many studies has meant that details of the curricular intervention were not always clear, so we adopted an inclusive approach. Similarly, the lack of explicit rationales for the use of the medical humanities in many studies meant that we as authors have had to infer what these might be from the details provided of the curriculum, and our inferences may not accord with the (unstated) intentions of the educators. Finally, as we did not search the gray literature  our study may not have identified all potentially relevant studies of the medical humanities outcomes, particularly with the practice of medical humanities in Taiwan.Despite these limitations, we believe our study offers important insights, such as data on the alignment between the expected outcomes of medical humanities education and the actual outcomes, as reflected in the relevant academic literature. This focus has enabled us to confirm that most evaluations of the medical humanities continue to target student perceptions or knowledge while identifying some studies which do appear to address higher outcome levels and/or provide a stronger basis for claims of impact. At the same time, our focus on a specific national context has enabled us to provide a relatively comprehensive survey of the outcomes and practices related to a relatively homogeneous curriculum, an important factor for a highly contextual educational domain as reflected by medical humanities pedagogy.Medical humanities education appears to be growing in importance in Taiwan and the results of this systematic review reflect this development. Nevertheless, a clear and locally produced consensus about the nature and practice of the medical humanities in the Taiwan context remains to be reached. There is also considerable scope to expand the focus of research in the medical humanities from intrinsic and instrumental rationales to critical and epistemological rationales for its adoption in medical education. The main approaches and interventions for delivering the medical humanities in Taiwan include narrative/storytelling, coursework, and fieldwork, along with several other related interventions. The ways medical humanities outcomes are assessed in Taiwan's medical curricula are currently heavily dependent on soliciting the students' perspective. In line with the higher levels of the BEME strength of evidence scale, more diversified participants' backgrounds, mixed methods, and assessments aligned with the outcomes of interest are recommended to produce more compelling evidence of the impact of medical humanities programs. Similarly, studies exploring higher-level outcomes according to Kirkpatrick's model would further advance our understanding of the impact of medical humanities curricula, in particular, the long-term impacts of medical humanities education for the medical students, practitioners to patients, and patient care remain unclear. Longitudinal studies thus should also be encouraged as they should provide clearer evidence of participants' behavioral change. Finally, future studies which broaden the evidence base, such as interviews with clinicians, policymakers, and patients, should shed more light on the implementation and evaluation of humanities education in medical schools.The original contributions presented in the study are included in the article/BLH, C-DH, and LVM contributed to the development of the study, analysis and interpretation of the data, writing, reviewing and finalizing of the manuscript. K-SC and S-CC participated in the study conceptualization, analyzed the data, and critically revised the manuscript. NC participated in the interpretation of the data and critically revised the manuscript. YSM participated in the analysis and interpretation of the data and critically revised the manuscript. All authors read and approved the final version of the manuscript.This study was supported by the Ministry of Science and Technology, ROC [MOST 107- 2511-H-182-013], [MOST 109-2511-H-182-006] and Chang Gung Memorial Hospital, Taiwan [CDRPG 3J0051].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.


Pancreatic cancer is deadly cancer characterized by dense stroma creating an immunosuppressive tumor microenvironment. Accumulating evidences indicate that the microbiome plays an important role in pancreatic cancer development and progression via the local and systemic inflammation and immune responses. The alteration of the microbiome modulates the tumor microenvironment and immune system in pancreatic cancer, which affects the efficacy of chemotherapies including immune-targeted therapies. Understanding the role of microbiome and underlying mechanisms may lead to novel biomarkers and therapeutic strategies for pancreatic cancer. This review summarizes the current evidence on the role of the microbiome in pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with little improvement in outcomes in recent decades, although the molecular and phenotypic characterization of PDAC has contributed to advances in tailored therapies. PDAC is characterized by dense stroma surrounding tumor cells, which limits the efficacy of treatment due to the creation of a physical barrier and immunosuppressive environment. Emerging evidence regarding the microbiome in PDAC implies its potential role in the initiation and progression of PDAC. However, the underlying mechanisms of how the microbiome affects the local tumor microenvironment (TME) as well as the systemic immune system have not been elucidated in PDAC. In addition, therapeutic strategies based on the microbiome have not been established. In this review, we summarize the current evidence regarding the role of the microbiome in the development of PDAC and discuss a possible role for the microbiome in the early detection of PDAC in relation to premalignant pancreatic diseases, such as chronic pancreatitis and intraductal papillary mucinous neoplasm (IPMN). In addition, we discuss the potential role of the microbiome in the treatment of PDAC, especially in immunotherapy, although the biomarkers used to predict the efficacy of immunotherapy in PDAC are still unknown. A comprehensive understanding of tumor-associated immune responses, including those involving the microbiome, holds promise for new treatments in PDAC. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer worldwide, and it has a five-year survival rate of less than 9% for all the stages combined . More thBRCA1 and BRCA2 mutations, benefit from platinum-based therapy and poly (ADP-ribose) polymerase (PARP) inhibitors [KRAS (KRASWT) often have alternative oncogenic mutations, such as BRAF [According to the development of the genetic and molecular characterization of PDAC, tailored therapies have emerged. Recent studies have suggested that up to 25% of PDACs have actionable genetic mutations [hibitors ,5,6,7,8.hibitors . Patient as BRAF ,5, and mAlthough ICB is a promising therapy in many types of cancers as well as PDAC, biomarkers for the efficacy of treatment are still unknown in PDAC. Clinical trials showed that MMR-D patients in PDAC are resistant to ICB therapies compared to other types of cancer ,9. PDAC The microbiome is now known to be associated with cancer development and progression in many types of cancer . SeveralIn this review, we summarize the role of the microbiome in the development and progression of PDAC and discuss the potential role of the microbiome in the design of new therapeutic strategies, especially in immunotherapy. A comprehensive understanding of the microbiome-associated immune response in tumors holds promise for new treatments in PDAC.Helicobacter pylori in gastric cancer [Enterotoxigenic Bacteroides fragilis [Fusobacterium nucleatum [For many types of cancer, the microbiome is now recognized to be involved in the development and progression of cancer , includic cancer  and Entefragilis  and Fusoucleatum ,21 in coucleatum .In recent years, many papers have reported the association of microbiome and PDAC . The micNeisseria elongata and Streptococcus mitis were significantly reduced in patients with PDAC relative to healthy controls. Fan et al. [Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were associated with a higher risk of PDAC. Michaud et al. (2013) reported that high levels of antibodies against the oral bacteria Porphyromonas gingivalis were also associated with a twofold increased risk of PDAC [Porphyromonas gingivalis in plasma was measured up to 10 years prior to PDAC diagnosis, which suggested a potential role for the measurement of plasma antibody levels of Porphyromonas gingivalis in the early detection of PDAC. Fecal metagenomic classifiers [Bacteroidetes and a decrease in Firmicutes in PDAC patients. At taxonomic levels, Anaerostipes and genera belonging to Erysipelotrichaeceae and Clostridiaceae decreased in PDAC, while genera belonging to Veillonellaceae increased in PDAC. Pushalkar et al. [Proteobacteria constituted more than half of the gut microbiome in PDAC patients, while it comprised only 8% of the bacteria in normal pancreata. The authors reported that Synergistetes and Euyarchaeota were similarly enriched in the gut microbiome in patients with PDAC. In addition, smoking is a well-described risk factor for PDAC, and smoking cessation results in an increase in Firmicutes and Actinobacteria and a decrease in Proteobacteria and Bacteroidetes species within the intestine [Streptococcus and Veillonella spp and a depletion of Faecalibacterium prausnitzii in oral and fecal samples in PDAC patients, which are commonly observed in German and Spanish cohorts [Many similar observational results have been reported comparing the microbiome between PDAC patients and healthy controls using oral and fecal samples. Farrell et al.  analyzedn et al.  reported of PDAC . In addissifiers  were repssifiers  analyzedr et al.  analyzedntestine . A recen cohorts .Gammaproteobacteria being the most abundant in PDAC.Geller et al.  analyzedProteobacteria dominated the microbiome of PDAC, similarly to the normal duodenal microbiome. Fusobacterium was more abundant in gastrointestinal (GI) cancers, such as colorectal cancers, stomach cancers, cholangiocarcinoma and PDAC, compared to non-GI cancers [Fusobacterium nucleatum was enriched in PDAC as well as breast cancer. Interestingly, a distinct microbiome was observed according to subtypes of breast cancer.Nejman et al.  analyzed cancers ,32. FusoPseudoxanthomonas, Streptomyces, Sacchropolyspora, and Bacillus clausii was associated with favorable survival in multiple patient cohorts, while no predominant microbiome was identified in patients with short survival [Riquelme et al.  showed tsurvival .Consequently, dysbiosis of the oral, gut, and intratumor microbiomes is associated with the development of PDAC, and microbe-induced inflammation modifies a systemic immune response, which supports the progression of PDAC ,15. The Early detection of PDAC is an important strategy to improve outcomes because PDAC is highly resistant to conventional chemotherapies and molecularly targeted reagents. Chronic pancreatitis and pancreatic cysts, especially IPMN, are recognized as risk factors for PDAC as well as smoking, diabetes, obesity, and a family history of PDAC. Efforts have been made to find biomarkers that distinguish between precursor diseases and PDACs, but efficient biomarkers are still unknown. Accumulating evidence indicates the association between microbiota and PDAC as well as the potential role of microbiota as a biomarker for early detection of PDAC.Chronic pancreatitis (CP) is a disease of the pancreas in which ongoing inflammation leads to atrophy and fibrosis of the pancreas and loss of endocrine and exocrine secretion. Possible causes include toxic factors such as alcohol, smoking, diabetes mellitus, idiopathic, heredity, autoimmune reactions, and obstructive mechanisms. CP can cause recurrent abdominal pain, diabetes mellitus (endocrine dysfunction), and indigestion (exocrine dysfunction). Fibrosis and calcification of the pancreatic parenchyma as well as dilatation of the pancreatic ducts were observed at the late stage, and CP is known to be a risk for PDAC. It is important to understand the biology of CP and mechanisms of carcinogenesis from CP patients as well as to discover biomarkers for the early detection of PDAC in CP patients.Klebsiella, Enterococcus, and Sphingomonas). A lower abundance of Faecalibacterium was observed in ACP compared to both A-HC and sAH patients. A decrease in the abundance of Faecalibacterium prausnitzii was also observed in patients with CP [Faecalibacterium prausnitzii and Ruminococcus bromii from controls compared to those with CP. Faecalibacterium prausnitzii is the most abundant commensal in the human intestine [Ruminococcus bromii is associated with starch degradation harvesting butyrate in the human colon [Faecalibacterium prausnitzii and Ruminococcus bromii may contribute to the disruption of the intestinal mucosal barrier. Zhou et al. [Proteobacteria were observed in CP patients compared to the HC group. A high abundance of Escherichia/Shigella and a low abundance of Faecalibacterium were observed in CP patients. In these studies, the microbial diversity was decreased in patients with CP compared to HC [Faecalibacterium, were decreased in CP compared to HC [Proteobacteria was increased in CP compared to HC [Recent analyses compared the gut microbiome in patients with CP and healthy controls (HC). Ciocan et al.  analyzed with CP . Jandhya with CP  evaluatentestine , which intestine ,36,37. Ran colon . Therefou et al.  reporteded to HC ,33,39. Sed to HC ,33, and ed to HC ,39. In aThese observations suggest the association of the microbiome with CP. However, it remains unclear whether dysbiosis in CP is a cause or consequence of pancreatitis.Faecalibacterium prausnitzii was negatively correlated with glycemic control [Pancreatic exocrine insufficiency and diabetes mellitus have been associated with the incidence of CP. The abundance of  control ,39. Bifi control ,39. ThesAkkermansia muciniphila I and Lactobacillus reuteri, which are beneficial bacteria, was observed after the administration of pancreatic digestive enzymes in mice [Regarding autoimmune pancreatitis (AIP), which is another type of CP, Hamada et al.  reported in mice , suggestNeisseria elongata and Streptococcus mitis were significantly decreased in patients with PDAC compared to HC. Additionally, the levels of one increased species  and one decreased species (Streptococcus mitis) were significantly different between PDAC and CP. As such, the microbiome provides the potential to detect early cancer in CP patients  of the pancreas have been recognized as precursor lesions to PDAC. IPMNs have been categorized into main-duct and branch-duct types according to the location of the lesions, such as cystic dilatation of the ducts. As main-duct-type IPMNs have high malignant potential, surgical resection is recommended at the time of diagnosis. In patients with branch-type IPMNs, the size of the cystic lesions and the diameter of the main pancreatic duct were associated with the incidence of IPMN-derived carcinoma, whereas they are not associated with the concomitant occurrence of PDAC . SimilarBacteroides, Escherichia/Shigella, and Acidaminococcus as predominant genera and did not find significant differences in the diversity of bacterial microbiota between the cyst types. The authors indicated the unique bacterial ecosystem in pancreatic cyst fluid and identified 17 potentially pro-cancerous bacteria including Bifidobacterium, Faecalibacterium, Escherichia/Shigella, and Bacteroides. Olson et al. [Firmicutes and HC had higher levels of Proteobacteria. The differences between patients with PDACs and IPMNs were similar with those between PDACs and controls. This may be due to the small difference between PDACs and IPMNs and the smaller sample size of IPMNs than controls.Previously, Li et al.  analyzedn et al.  found noProteobacteria, while IPMN HGD and cancer were generally diverse and dominated by Firmicutes or Proteobacteria. Despite the large individual variation, the authors found that IPMN HGD was enriched in Fusobacteria, Granulicatella, and Serratia, suggesting the potential role of these bacteria in the progression of pancreatic precursors to PDAC. Kohi et al. [Fusobacteria and Rothia bacteria in duodenal fluid were enriched in PDAC patients with short survival. However, the authors reported that the microbiome profiles in duodenal fluid were not significantly different between HC and pancreatic cysts.Recently, Gaiser et al.  analyzedi et al.  analyzedMorgell et al.  identifiAlthough there are many reports suggesting a correlation between IPMN and the microbiome, further studies are needed to detect a relevant biomarker for the early detection of PDAC from pancreatic precursor diseases. Combining a multi-omics approach with microbiome analysis may lead to clinically accessible methods for the early detection of PDAC. Furthermore, the role of the microbiome in tumorigenesis is still unknown. As seen in the analysis of PDAC, microbiome-induced inflammation or TME modulation may contribute to the tumorigenesis and progression of pre-cancerous lesions to PDAC.Regarding the underlying mechanisms, a major role of microbiota in PDAC development may be microbiome-induced inflammation and modification of the immune program. PDAC is characterized by an abundant stroma with desmoplasia creating an immunosuppressive environment. The desmoplasia, which creates a physical barrier around the tumor cells and prevents appropriate vascularization and delivery of chemotherapeutic agents, was previously thought to promote cancer , and manAccumulating evidence suggests that the microbiome modulates innate and adaptive immune programs and contributes to the formation of an immunosuppressive tumor microenvironment. Understanding the underlying mechanisms of how microbiota affect the tumor microenvironment can lead to new therapeutic strategies.In recent years, intense genomic analyses have been performed to reveal the mutational landscape of PDAC ,56,57,58Acinetobacter, Pseudomonas, and Sphingopyxis in basal-like human PDAC, and the analysis of microbial genes suggested the potential of the microbiome in inducing pathogen-related inflammation [An association between the molecular subtypes and microbiome was recently reported, identifying a high abundance of ammation .In recent studies, single-cell RNA sequencing has been used to reveal the heterogeneity of stromal components ,52,53,54Dense stroma with desmoplastic reaction may act as a physical barrier and affect the infiltration of MDSCs and T cells in TME ,79. In aAs an association between microbiome and CAF subtypes was not clear, the microbiome was associated with the inflammatory and immunosuppressive TME in mice.The association of the mycobiome with the complement system has been reported . The mycGamma Proteobacteria are reported to present in PDAC tumors and induce resistance to gemcitabine via cytidine deaminase [Microbiota-induced activation of toll-like receptors (TLRs), especially TLR9, activate pancreatic cancer stellate cells and attract immunosuppressive T regulatory cells and MDSCs to the tumor environment, which contribute to the suppression of innate and adaptive immunity in PDAC progression in mice . Lipopoleaminase . TherefoThus, the microbiome plays a pro-tumorigenic role via inflammation, immune response, and metabolic pathways . These rThe curative therapy for localized PDAC is surgical resection with neoadjuvant and/or adjuvant therapies, but only approximately 20% of PDAC cases are resectable at diagnosis. For advanced PDAC, FOLFIRINOX and gemcitabine plus nab-paclitaxel ,105 are MLH1, PMS2, MSH2, MSH6) due to hereditary germline mutations, known as Lynch syndrome, and biallelic somatic mutations of MMR genes. MMR-D and MSI-H are commonly associated with a high tumor gene mutation burden (TMB). High TMBs are thought to increase the number of neoantigens that are recognized by the host immune system, and activated tumor-infiltrating lymphocytes (TILs), especially CD8 + T cells, migrate into TME and play an important role in antitumor response [ICB therapies represent an effective treatment for patients with MMR-D/MSI-H regardless of the tumor type, but their activity depends on the tumor type. MMR-D is caused by the loss of function of MMR genes  of PDACs were mainly positive for gamma Proteobacteria.As mentioned above, using a colorectal cancer model, Geller et al.  found thTo elucidate the role of the microbiome in PDAC treatment, mouse models are commonly used. Fecal microbiota transplantation (FMT) was performed in immunocompetent mice after antibiotic treatment to analyze the role of fecal microbiota of interest in tumor formation ,115,117.G12D/+;PTENlox/+ mice depleted of microbes via antibiotics had a reduced percentage of poorly differentiated tumors compared to KrasG12D/+;PTENlox/+ mice with intact microbes. Sethi et al. [Proteobacteria, Euyarchaeota, and Synergistetes than normal pancreases, and ablation of the microbiota showed an enhanced effect of ICB in PDAC. The authors reported that the removal of the microbiome suppresses the development of both pre-invasive and invasive PDAC but the transfer of bacteria from tumor-bearing hosts promotes tumors. Bacterial removal was associated with immunogenic reprogramming of the TME in PDAC, including a decrease in MDSCs and an increase in M1 macrophage, which promoted Th1 differentiation of CD4+ T cells and activation of CD8+ T cells. These data suggest that endogenous microbes promote the immunosuppressive TME of PDAC and that microbial ablation is a promising approach to inhibit the progression of PDAC. However, a contrary effect of microbial ablation has been reported in other types of cancer [The impact of microbiome ablation on PDAC development has been tested by antibiotic therapy as well as the activation of pattern recognition receptors (PRRs), such as TLR4 , TLR7 1, Dectin i et al.  reportedi et al.  reportedf cancer ,131,132,Riquelme et al.  performeThe role of the microbiome in PDAC is summarized in In pancreatic precursors, such as IPMN and chronic pancreatitis, the microbiome may play a role in a pro-tumorigenic effect including inflammation and immunomodulation. Whether differences in the microbiome in pancreatic cancer precursors are a cause or a consequence remains unclear. Regarding its role as a biomarker, comprehensive analyses of multi-omics, including the microbiome, are expected to detect PDAC at an early stage. Therapeutic strategies targeting PDAC-associated microbiomes include the elimination of pro-tumorigenic bacteria with antibiotics or transplantation of bacteria to induce an immune-activated tumor microenvironment. The microbiome could also be a biomarker for the prediction of an immunogenic tumor microenvironment and immune-targeted therapies. A number of clinical trials are underway, and we look forward to the information from them as well as further studies for microbiome-based medicine.


Fluorescence guided surgery, augmented reality, and intra-operative imaging devices are rapidly pervading the field of surgical interventions, equipping the surgeon with powerful tools capable of enhancing the surgical visualisation of anatomical normal and pathological structures. There is a wide range of possibilities in the adult population to use these novel technologies and devices in the guidance for surgical procedures and minimally invasive surgeries. Their applications and their use have also been increasingly growing in the field of paediatric surgery, where the detailed visualisation of small anatomical structures could reduce procedure time, minimising surgical complications and ultimately improve the outcome of surgery. This review aims to illustrate the mechanisms underlying these innovations and their main applications in the clinical setting. The field of surgery faces an ever-increasing need for real-time intraoperative visualisation of small anatomical structures, such as vessels and nerves. In the last decade, there has been a great effort to develop novel technologies and devices that could better visualise vital organs, with the final aim to minimise surgical complications and improve outcomes. Technological innovations, such as fluorescence-guided surgery and augmented reality, are developing the broad field of image-guided surgery with the aid of more responsive and artificial intelligence enhanced robots , 2], , , 5], , , 8], , ..in uteroFluorescence-guided surgery, augmented reality, iMRI, UHFUS, and PAI represent an exciting novel opportunity to enhance surgical practice, with the potential to yield significant advantages in specific challenges faced with paediatric patients. Further testing of these novel intraoperative techniques together with the use of robotic instruments will determine their role in surgical precision and visualisation, which should lead to highly precise resection of targeted tissues, revolutionising surgery.Supplementary MaterialClick here for additional data file.


Research on the effects of videogames (VGs) on health has produced mixed results. Here, we assess the relationships of VG playing with sleep; chronotype; sleepiness; and levels of depression, anxiety, and stress; and how they are modulated by the level of exposure to VGs. Four hundred-and two adult participants  completed an online survey including questions on VG use and a set of standardized questionnaires. The sample was divided into three groups: habitual gamers , nonhabitual gamers , and non-gamers . No between-group differences emerged in sleepiness  or Pittsburgh Sleep Quality Index measures except the sleep disturbances subscore, which was higher in NHGs. HGs showed delayed bed- and risetimes and higher eveningness (reduced Morningness–Eveningness Questionnaire). HGs and NHGs showed higher depression subscores  but remained in the subclinical range. Moreover, hours/week of VG playing predicted delayed sleep timing, lower daytime dysfunction, and lower sleepiness. Our data suggest that VG playing does not necessarily compromise sleep quality and may even benefit daytime functioning, underlining the need to reconsider the relationships between VG use and health by taking into account possible modulating factors such as habitual VG exposure. It has been a while since the first video game (from here on we will refer to the term as VG), a basic form of the famous game Tris, was created by Alexander S. Douglas in 1952. Since then, the impact and popularity of VGs have grown exponentially to make for one of the most profitable multimedia industries. The Entertainment Software Association (ESA) reported that over 226 million United States citizens, with an average age of 31 years, play VGs )In conclusion, our findings show that VG use in the general adult population is not detrimental to important aspects of wellbeing such as sleep quality and daytime functioning and is not associated with clinical levels of depression, anxiety, or stress. In addition, they suggest that VG playing could even benefit daytime functioning in terms of alertness and cognitive efficiency. Thus, our pattern of results encourages the reconsideration of the previous literature on the negative effects of VG use and prompts further research aimed at better clarifying the role of possible modulating factors such as the degree of practice, the violent vs. nonviolent nature of the VG in question, complexity of the VG, age, and associated psychopathological characteristics . In this regard, it is worth noting, for instance, that most experimental studies documenting negative consequences of VG exposure  have use


Human papillomavirus (HPV) infection represents the most diffuse sexually transmitted disease of the lower genital tract, with an estimated risk of infection in the general population of 80% over the course of the lifetime . In the HPV is able to establish a latent infection, implementing an immunological escape mechanism; after the initial vegetative infection, it is not eradicated by the cell-mediated system and humoral immune response . MoreoveRecent data confirm that natural HPV infection gives the host a specific immune response (acquired antibodies) to specific genotypes. These antibodies are able to recognize the L1 protein with neutralizing activity and protect against infection, but their production is slow and reported in only a few subjects . For thiGardnerella, Prevotella and Atopobium, and a reduction in Lactobacilli. On the other hand, Lactobacillus spp. represent a marker of vaginal health, increasing the production of bacteriocins, biosurfactants, and other protective factors [Nowadays, the possible role of the vaginal microbiome in the evolution of CIN caused by HR-HPV infection represents an interesting approach. Indeed, changes in the normal vaginal microenvironment create a perturbation of local innate immunity and biochemical and structural vaginal and cervical tissue, promoting viral proliferation and reducing clearance . In addi factors . Moreove factors . Analyzi factors .Improvements in research on the strong connection between HPV infection, the vaginal microenvironment and host immune response, as well as knowledge of viral escape mechanisms, represent the basis of a new approach to reduce HPV-related lesions and promote antiviral strategies able to prevent the infection and transmission of HR-HPV globally.


Functional and smart biomaterials are biomaterials that have controllable properties and can perform beneficial treatment and repair effect in human body . Due to In this Research Topic, we have collected a total of seven papers, which cover the preparation, characterization, evaluation and current research progress of the functional and smart biomaterials in various biomedical fields. We thus have briefly introduced the papers published in the Research Topic as follow.Xie, et al. introduced the preparation of wood patches coated with rhodamine and rapamycin, and evaluated their effect by implanting into the rat subcutaneous tissue, the abdominal cavity, or the inferior vena cava (IVC). Wood patches became soft after processing with Na2SO3 (>98%) and NaOH (>98%), and showed biocompatibility after implantation into the subcutaneous tissue or the abdominal cavity. The natural microstructure in the wood patch facilitated attachment and migration of neointimal endothelial progenitor cell, as well as therapeutic drug loading and continuous release in vivo. The study showed that the wood-derived scaffolds could be used successfully as vascular patches and a drug delivery system, suggesting the potential application of plant-derived materials in vascular applications.The first article of this Research Topic by Zhang, et al., three gelatin methacrylate-based scaffolds loaded with transforming growth factor (TGF)-β1 (GelMA-T) were prepared, and their repair effect on nasal septum cartilage defects was examined. They proved that at 4, 12, and 24 weeks post surgery, the nasal septum cartilage defects exhibited more complete repair in rabbits treated with the 10% GelMA-T/BMSC scaffold according to hematoxylin and eosin, safranine-O, and toluidine blue staining, which could be applied for the physiological and structural repair of defects in the nasal septum cartilage, thus providing a potential strategy for repairing cartilage defects in the clinic.Hydrogel-based tissue engineering has been widely used to repair cartilage injury. However, whether this approach can be applied to treat nasal septum cartilage defects remains unclear. In the study by Yasin, et al.highlighted and summarized the recent progress in converting HA to smart formulation, such as multifunctional coatings, targeted nanoparticles, or injectable hydrogels, which are used in advanced biomedical application. The relationship between the molecular properties of HA and the advances in biomedical applications was systematically explored. The future application of HA on composite biomedical platform systems was summarized. This review provided a comprehensive knowledge relevant to the development of the composite biomedical platform systems of HA.Hyaluronic acid (HA) and its derivatives have played an increasingly important role in tissue engineering, wound healing, cancer treatment, ophthalmology, and cosmetics. Shang, et al. systematically evaluated the corrosion behaviors of Mg-based vascular stent materials include pure Mg, AZ31, and WE43 in a dynamic environment and studied the effect of their degradation products on the behavior of vascular cells. The results showed that the corrosion rate of different Mg based materials was related to the composition of the elements. The effect of corrosive products on vascular cells was beneficial to re-endothelialization and inhibition of smooth muscle cell proliferation at the implantation site of vascular stent materials, which may have potential application as a potential vascular stent material.In another study, Yue, et al. analyzed and summarized existing biomaterial delivery and restoring platforms, and the therapeutic strategies based on biomaterial platforms, including general strategies to block the fibrosis process and new strategies to promote cellular restoring effects. They proposed that the development of structures with the ability to block further fibrosis progression as well as to promote cardiomyocytes viability should be the main research interests in myocardial fibrosis, and the reestablishment of structures necessary for normal cardiac function was central to the treatment of myocardial fibrosis. Further on, the future application of biomaterials for myocardial fibrosis was also conducted.Tan et al. described direct visual evidence for the involvement of dynamic changes in macrophages and the chronic inflammatory microenvironment in human NONFH. They proved that macrophage M1/M2 imbalance facilitated the progression of NONFH, osteonecrosis and tissue fibrosis in the local lesion. Inhibiting inflammation, promoting the resolution of inflammation, switching macrophages to an M2 phenotype, or inhibiting their adoption of an M1 phenotype, which may be useful therapeutic strategies against NONFH in future.Non-traumatic osteonecrosis of the femoral head (NONFH) remains a common refractory disease with poorly understood pathogenesis. Xu et al. constructed a radiomics model to predict cognitive dysfunction in patients with Type 2 diabetes mellitus (T2DM) in terms of MRI-based radiomics features. Compared with the Support Vector Machine (SVM) and k-NearestNeighbor (KNN), the Logistic Regression (LR) algorithm for the construction of the model showed better performance. Thus, the model may serve as a potential tool to guide personalized treatment.etc. Here, seven top quality articles have been published in this collected Research Topic on Functional and Smart Biomaterials: Development and Application in Regenerative Medicine-Volume II. In prospectively, we hope this Research Topic would be meaning for development and application of novel functional and smart biomaterials, such as the design, the evolution of advanced manufacture techniques, and biomedical applications in the field of regenerative medicine and tissue engineering.In summary, the functional and smart biomaterials have been broadly studied in various regenerative medicines, including wound treatment, tissue culture, targeted therapy of diseases, and tissue regeneration,


According to the result released by the World Health Organization (WHO), non-communicable diseases have occupied four of the top 10 current causes for death in the world. Cancer is one of the significant factors that trigger complications and deaths; more than 80% cancer patients require surgical or palliative treatment. In this case, anesthetic treatment is indispensable. Since cancer is a heterogeneous disease, various types of interventions can activate oncogenes or mutate tumor suppressor genes. More and more researchers believe that anesthetics have a certain effect on the long-term recurrence and metastasis of tumors, but it is still controversial whether they promote or inhibit the progression of cancer. On this basis, a series of retrospective or prospective randomized clinical trials have been conducted, but it seems to be difficult to reach a conclusion within 5 years or longer. This article focuses on the effects of anesthetic drugs on immune function and cancer and reviews their latest targets on the tumor cells, in order to provide a theoretical basis for optimizing the selection of anesthetic drugs, exploring therapeutic targets, and improving the prognosis of cancer patients. Anesthetics are a diverse group of drugs that are used in the management of pains and are generally categorized into two classes according to their functions, namely, general anesthetics and local anesthetics . GeneralAnti-tumor immunity includes innate and adaptive immunity. Anesthetic drugs can affect human body immune function. Normally, the immune system can recognize and remove mutated cells. However, some tumor cells have altered antigens, which help them escape from immune surveillance, resulting in their sustainable growth and metastases.in situ or infiltration , to promote degranulation of immune cells like NK cells and macrophages and consequently decrease their killing abilities and inhibit anti-tumor effects , 7. It hby cells . By doseby cells , 12, whivia the mitochondrial pathway, and inhibits the maturation of dendritic cells. However, thiopental inhibits T-lymphocyte apoptosis by inducing heat shock proteins (HSPs)  , 13. Pros (HSPs) . Regardis (HSPs) .Immunocytes, such as neutrophils, macrophages, and T cells, can secrete endogenous opioid peptides (EOP), combine with the peripheric opioid receptor, and relieve inflammation and neuropathic pains . MeanwhiSurgical traumas can activate the hypothalamic–pituitary–adrenal axis (HPA) of patients, which contributes to the change in neuroendocrine function and then inhibits immune functions. The use of local anesthetics can alleviate the stress reaction after operation and lower the inhibiting effect of stress on the immune system by blocking the signaling to nerves. Blocking peripheral nerves or intraspinal anesthesia can lower the conduction of stimulation caused by surgical injuries to the central nervous system and then reduce the immune suppression resulting from the activated HPA . Apart fBased on the previous research, different anesthetics and methods can affect the immune function positively or negatively, and immune balance plays a role in tumor dissemination and recurrence. Depending on existing evidence, sevoflurane and isoflurane mostly play a negative role in anti-tumor immunity, but it is relatively vague for propofol. Local anesthetics can block neurotransmission from afferent nerves to the central nervous system, thus preventing surgical pains and reducing surgically induced neuroendocrine stress so that the HPA axis and SNS reactions are avoided. Toxicity that local anesthetics have on the cardiovascular system and the central nervous system, particular types of local anesthetics function, and their safe concentrations that effectively regulate the function of immune cells all need to be further studied.The major review is that the influence of inhalation anesthetics on the OS of patients with cancers is stronger than that of intravenous anesthetics.Sevoflurane, a kind of inhalation anesthetics which is widely used in clinical practices, has many advantages, such as rapid recovery, strong controllability, and organ protection. The influence of evoflurane on tumors is currently being disputed.Ru Li et al. made a comparative analysis between the respective use of sevoflurane and propofol in the mouse model of breast cancer and found that the mice with the adoption of sevoflurane had increased proinflammatory cytokines, which were related to tumor metastasis. On the first day after the operation, the volume of IL-6 and VEGF in the mouse serum with sevoflurane was higher than that in the group with propofol. Particularly, by increasing the expression of IL-6, sevoflurane activated the signaling pathway of IL-6/JAK/STAT3, induced the aggregation of CD11b bone marrow stromal cells in lung tissues, and promoted the metastasis of tumor cells to the lung. AZD1480, a JAK inhibitor, can be used to significantly reduce the number of metastasized tumors in the lung of the mice narcotized with sevoflurane and to reduce the level of p-STAT3 .via miR-203 , which stimulates the development of tumors. With isoflurane use, an increased expression of IGF-1 and IGF-1 RSKOV3 was found in ovarian tumor cells, which accelerated the cell cycle and proliferation , 39. Thrigration , but theigration .Combined with statistical results of clinical samples, it is found that compared to total intravenous anesthesia, the use of isoflurane increases the risk of death in tumor patients, which indicates that propofol is more applicable to anesthesia in tumor excision surgeries. The anti-immune effect of isoflurane may not be applied to the population with low immunity but can be potentially used in the organ transplantation or patients with host immunity response stimulated by infection.Propofol, an alkyl acid intravenous anesthetic with short-term effects which is widely used for intravenous injection in clinical practices, realizes sedative effects by enhancing the neurotransmission of central inhibition (the GABA pathway) and decreasing that of central excitation (the NMDA pathway) and is commonly used as an anesthetic in tumor resection operations. It is worthy of exploring whether propofol affects tumors when generating central sedation.P < 0.05) (N-methyl-D-aspartate receptor (NMDAR), a subset of ionic glutamic acid receptor which is controlled by the membrane potential as well as by other neurotransmitters, plays an important role in the synaptic transmission and plasticity regulation in the central nervous system . By inhi < 0.05) , but the < 0.05) . Sub-typ < 0.05) . Similar < 0.05) . A recen < 0.05) .via the specific signal transduction pathway. Recent research indicates that except for the existence of GABA and GABAR (the receptor of GABA) in the central nervous system, with their expressions in some tumor tissues, they regulate tumor proliferation, invasion, and metastasis and engage in the development and progression of tumors via specific signal transduction pathways. The research suggests GABA is significantly expressed in tumor tissues such as neuroglioma, prostate cancer, and colorectal cancer, but the expression of GABAR is significantly increased in liver cancer and breast cancer , GABAR(B), and GABAR(C). By combining with receptors of different subtypes, GABA will produce different regulatory effects t cancer –54, whict cancer  studied t cancer –58 the aDue to differences of the structure and function between tumor cells and neuronal cells, the GABAR pathway in neuronal cells is different from that in tumor cells. It needs to be further explored by researchers with regard to whether the expression of GABA and GABAR in tumor tissues is a tumor promoter or a protective response of the body, what kind of receptor pathway is adopted to play the regulatory role, and what is the signal transduction pathway.Etomidate, a kind of non-barbiturate intravenous anesthetics and a derivant of imidazole, produces analgesic effects by activating GABAR , 60. It A research indicated that with the adoption of etomidate in resection operation of lung adenocarcinoma, the quantity of CD8 + T cells in patients’ blood after the operation was lower than in that in the propofol group but higher than that in the propofol group 24 hours after the operation, which illustrated that etomidate had smaller effects on the immune system of patients with lung adenocarcinoma , and itsAs one of the most commonly used intravenous anesthetics, only a few studies have shown that propofol can promote the proliferation of some cancer cells, and clinical data show that propofol has no great influence on long-term prognosis. But most cytological and animal studies suggest that propofol seems to have a tumor-suppressive effect by decreasing cancer cell migration, invasion, proliferation, and angiogenesis and by inducing apoptosis, as demonstrated in many experimental studies. At present, few research studies are found on the effects of etomidate on tumors. It is still necessary to further reveal the regulatory effect and molecular mechanism of propofol and etomidate in different types of cancers. Clinical studies are also needed to confirm their effects and provide a reference for the rational selection of propofol or etomidate.The opioid receptor, a kind of G-protein-coupled receptors (GPCRs) with seven transmembrane domains (TMDs), mainly exists in the central nervous system with four subtypes , namely, MOR, KOR, DOR, and ORL1 receptors. With approximately 60% of amino acids are structurally identical, these receptors of different types could have analgesic, sedative, and other effects after being activated , 66. EmeMorphine is the agonist of MOR, KOR, and DOR, which has gradually decreased effects on subtypes of the aforementioned three receptors. It is currently believed that the effect that morphine has on tumor development is contradictory, and both its promoting and inhibiting effects are reported. Based on a cytological study, it was found that morphine could activate the MOR in lung cancer cells, induce phosphorylation of the epidermal growth factor receptor (EGFR), lead to activation of the lower MAPK/ERK/Akt pathway, and promote cell proliferation and invasion. Increasing expressions of the EGFR and MOR in lung cancer could promote growth of tumor cells, trigger angiogenesis mediated by the vascular endothelial growth factor (VEGF), increase vascular permeability, accelerate tumor progression, and increase the risk of micrometastasis .in vivo and in vitro research on nude mice that a 24-hour incubation of 10 μM morphine could significantly increase the apoptosis rate of Hep3B/HepG2  was 5∼10 times increased, which was consistent with that in the NSCLC cell line, which indicates that high expression of the MOR may have regulated a series of biological characteristics including cell proliferation and differentiation , 76. A rAlthough most of the research results revealed that the activated MOR could promote tumor progression, for patients with advanced tumors, the effect of the MOR agonist on the opioid receptor in the central nervous system could effectively relieve their pains, reduce inflammatory reactions caused by tumors, inhibit angiogenesis, and alleviate tumor recurrence and metastasis . ResearcThe major metabolite of butorphanol tartrate activates KOR and has double actions on the MOR particularly, as the activator and the inhibitor. It majorly plays its pharmacological role indirectly by combining with the receptor in the central nervous system.via the PKC or Bcl-2 pathway  and had demethylation effects, which was potentially a candidate drug for liver cell cancer  could significantly reduce the expression of the EGFR and the tumor volume . By incrl cancer . The asstentials . The apptentials .RARβ and RASSF1A, and increase the sensitivity of cisplatin to breast cancer cells  and inhibit the proliferation of tumor cells , 102. HoBupivacaine is a kind of long-term amide local anesthetic, which has strong combination with plasma proteins. The toxicity of bupivacaine is four times greater than lidocaine, its cardiotoxicity should be noticed especially, and the rate between circulatory collapse and convulsions (CC/CNS) induced by is low.via intrinsic and extrinsic pathways of mitochondria (The degree of apoptosis induced by lidocaine and bupivacaine in MCF-7 (breast cancer cell line) was significantly higher than that in MCF-10A , both of which could activate caspase 7, caspase 8, and caspase 9 in MCF-7 and promote the lysed nucleosome and thus induced the apoptosis of MCF-7 chondria . Chang echondria  proved ichondria . Lidocaivia migration of anti-tumor cells, and improved the prognosis of patients with tumors, which was possibly an ideal adjuvant drug in the treatment of cancers. However, it should be further verified by clinical research on how it can be clinically used.Current literature has pointed out that the intravenous infusion of lidocaine provides an antiproliferative tumor suppressive effect. Many molecular pathways/mechanisms are described. Local anesthetics could directly act on tumor cells and induce apoptosis of tumor cells through intrinsic and extrinsic pathways . LidocaiCancer is a disease with high heterogeneity. Various factors contribute to the activation of oncogenes or mutation of tumor suppressor genes, which results in great differences between the therapeutic effectiveness of cancers.Surgical stress and immunosuppression are unevadable topics. With the activation of the HPA axis and SNS, neuroendocrine regulators are increased, which promotes the metastasis of residual or circulating tumor cells to regional lymph nodes and distant sites. We can reduce the noxious stimulus as much as possible by prioritizing the selection of local anesthetics. In the perioperative period, anesthetics and analgesics are inevitable environmental exposure factors for patients with tumors. As shown in Furthermore, it is necessary for scientists of clinical medicine to conduct a series of retrospective or perspective and stochastic clinical trials to explore the effect that anesthetics have on long-term recurrence and metastasis of tumors, such as to provide a theoretical basis for optimizing the selection of anesthetics, exploring therapeutic targets, and improving the life quality and prognosis of tumor patients.HW, JW, and CL designed and supervised the review. TL and YL searched the literature and wrote the manuscript. LS and SX searched the literature and reviewed the manuscript. All authors contributed to the article and approved the submitted version.