Surgical ward rounds are key element to point-of-care interprofessional postoperative treatment and technical and communicational aspects are relevant for the patient’s safety and satisfaction. Due to COVID-19 restrictions, the training opportunity of experiencing a face-to-face surgical ward round was massively hampered and thus, we developed a digital concept. This study aims to investigate the feasibility of video-transmitted ward rounds integrating surgical and communicational aspects with live streaming from wards. Further, medical students were asked for their satisfaction and their subjective learning success.The proof-of-concept study consisted of self-reported subjective evaluation of competences in ward round skills. Qualitative feedback was collected to gain deeper insight and students’ empathy was rated by using the student version of the Jefferson Empathy Scale (JES).p < .001, Mpre = 3.00, SD = 0.77; Mpost = 3.76, SD = 0.75). The surgeon was rated as empathic . In the qualitative feedback they named helpful aspects like including an expert for communication. However, they preferred the face-to-face setting in comparison to the digital concept.One hundred three medical students participated. The students were satisfied with the video-transmitted ward round . In the subjective evaluation students’ ward round competencies rose significantly (It was feasible to implement a video-transmitted ward round within a pandemic. The format worked technically, was well-accepted and also led to a subjective rise in the students’ competencies. Video-transmitted ward rounds may be integrated to support the medical education, though, they cannot replace the face-to-face setting. Surgical ward rounds are key element to point-of-care interprofessional postoperative treatment of surgical patients, which warrants central importance in medical education, too . AlthougDue to COVID-19 restrictions, the training opportunity of experiencing a face-to-face surgical ward round was massively hampered since summer term 2020 as students were not allowed any direct patient contact in teaching , 13. On Thus, to the best of our knowledge, there hasn’t been any attempt to preserve the traditional surgical ward round to teach medical students this complex skill in a time where direct patient contact was prohibited.At our surgical department, teaching started as a complete virtual course with asynchronous and synchronous elements but without any patient contact. In 2021, at least seminar teaching was allowed in presence although direct face-to-face patient contacts were still prohibited. We thus created a video-transmitted ward round concept including surgical and communicational aspects of ward rounds with live streaming from wards. With this study, we wanted to prove that such a setting was feasible to perform, worked in its hybrid form, was well-accepted by students, and showed a positive subjective learning effect regarding key elements of ward round competencies.We conducted a proof-of-concept study with self-reported evaluation of the acquired competences in ward round skills as well as satisfaction with its implementation. Additionally, we collected qualitative feedback to gain deeper insight. Furthermore, we examined the physician–patient interaction using the Jefferson Empathy Scale.th and 10th semester taking part in the course earlier or later than regularly scheduled. Eligibility criteria were being medical students attending courses of clinical examination and understanding German.In total, 103 Students participated in the study. Of these were 69.9% female and 30.1% male which corresponds to the general gender relation at the Medical Faculty of Tübingen. 92.9% of the students were in the 9. Semester forming the regular target group while 2.9% and 3.9% were in the 8The ward round teaching took place within the regular surgical class in year 5 on a weekly basis. On the introductory day, there was a 45min seminar on theoretical background followed by the practical teaching on day 4. It lasted 150min and was taught as a face-to-face seminar by one surgeon and one liaison psychiatrist to reflect on technical as well as non-technical skills within a ward round. The corresponding ward round streamed to the students was performed on a regular ward of the department of visceral surgery, University Hospital Tübingen, Germany. The ward round team included the class surgeon and a nurse, as well as potentially other health care professionals and/or nurses in training or final-year medical students. The liaison psychiatrist stayed with the students in the seminar room the whole time. During the surgeon’s absence she discussed with the students topics regarding communication and interaction on the one hand and moderated the communication between the observing students group and the ward group  could see and interact with each other. The Students could especially ask questions to the team and the patient.At the end of the face-to-face teaching seminar students filled in a questionnaire containing questions on their subjective rating of ward round competencies as well as satisfaction with and helpfulness of the course. Additionally, structural and technical aspects of the video-transmitted ward round  were assessed. All items ranged on a Likert Scale from 1  to 5 (“very”). An example item was “how satisfied were you with the general organization of the ward round.”. Furthermore, students rated the surgeon’s empathy in the observed ward round using the student version of the Jefferson Empathy Scale (JES). The JES is a standardizedquestionnaire and consists of 20 items ranging from 1  to 7 (“completely agree”) . The JESp < 0.05. Qualitative feedback was evaluated in thematic content analysis based on Braun & Clark (2006) using Microsoft Excel, and themes in the dataset were identified, analysed and documented [Quantitative data were evaluated by using IBM SPSS Statistics version 27. Frequencies, percentages, mean values (M) and standard deviations (SD) were calculated. Data was tested normally distributed by using Kolomogrow Smirnow-test. T-test for dependent samples were used to test for differences in the competencies before and after the course. The level of significance was set to cumented . Based ocumented .The study was approved by the Ethics Committee of the University Clinic of Tübingen, Project Nr. 272/2021BO2. It was conducted in accordance to the relevant guidelines and regulations and in accordance to the Declaration of Helsinki. Participation was voluntary, and all participants gave their informed written consent. All patients involved were thoroughly informed beforehand and gave their written consent. Patients below the age of 18 or with a limited understanding of German were excluded from participation in the study.Overall, students were satisfied with the video-transmitted ward round course rating it with M = 3.54 (SD = 1.22). The Helpfulness of the course was rated with M = 3.92 (SD = 1.01).p < 0.001) from M = 3.0 (SD = 0.77) to M = 3.76 (SD = 0.75) in a pre-post comparison.In the subjective evaluation students’ ward round competencies rose significantly . The ward round itself was considered highly efficient . They were also very happy with the explanation of the bedside examination within the ward round . Regarding the interprofessional ward team, the involvement of the nurse was rated relatively high with M = 3.84 (SD = 0.93) reflecting standard operational procedures on the ward. The ward round surgeon was rated as highly empathic by the students with M = 119.05 (SD = 10.09).Also, the rating of technical aspects was generally positive  if allowed again. The following thematic topics could be found based on the qualitative analysis: helpful aspects of the video-transmitted ward round, room for improvement, content to be kept after the pandemic and reasons for preference of format (online versus face-to-face). Please see Table With this study, we could show that it was feasible to implement a video-transmitted ward round into regular training of undergraduate medical students within a pandemic. The format worked technically, was well-accepted by the target group and also led to a subjective significant rise in surgical ward round competencies of medical students deemed necessary for adequate treatment of surgical inpatients .Due to a structured educational model, explicit teaching of usually implicitly taught skills like communication aspects of a ward round, was implemented and appreciated by students. This was in line with literature stating the importance of communicational aspects of a ward round for patient care and safety as well as the surgeon’s role as a communicator –31. The The ward round is also a central point for interprofessional care, where crucial aspects of patients are discussed in the team of healthcare professionals . InterprDigital formats for teaching within the pandemic had so far focussed either on the care of actual COVID-19 patients, created specific designs for ward round teaching, or simply let students sit by routine telemedical encounters –19, 21. A well-known issue in ward round teaching is, that students lack a structure as also mirrored in our study. Although checklists have shown to be helpful for basic structure, its value to improve the actual communication and interaction on the ward is still unclear , 37–39. In this study, the performing surgeon was rated as very empathic. This is particularly important in light of the fact that physicians are eagerly observed by students and act as role models . AwareneA big issue with digital teaching is the technical component and possible failure of devices or transmission . In thisUnderstandably, students in our study were currently more inclined to have a face-to-face ward round than a digital one which is in line with other findings on bedside teaching settings , 49. HowHaving one perspective on the situation enabled also a better postexposure discussion as all participants had watched the same footage this corresponds to the helpfulness of videos as a reflexive instrument . Due to There are some limitations to this study. First, it was within one semester and one medical faculty only which may limit generalisability. Second, we only measured the students’ subjective gain in competency. Future studies should evaluate skills acquired through video-transmitted ward rounds in either real war round settings or simulated sessions objectively. Finally, it was not possible to compare the digital concept to a face-to-face setting due to the Covid-19 restrictions, we only asked the medical students’ perspective. Further research should investigate this comparison to confirm our finding on students’ preference of a face-to-face setting. Furthermore, the patient’s perspective was not assessed in the study. So, we could not compare the patient’s and students’ perspective regarding the physician’ s empathy. Future research should also involve the patient’s perspective. In this study, we decided us against the patient’s perspective as we focused on the feasibility. However, despite these limitations we feel confident that this study contributes significantly to the insights of digital teaching concepts with regards to surgical ward rounds.This study showed that it is possible to transfer the powerful tool of ward round teaching successfully into a digital format. Further studies should focus on more detailed and specific components of the ward round and the patients’ perception of such an offer as well as on the transfer potential of digitally helpful elements in a face-to-face ward round structure. Moreover, the communications aspects and the integration of ward nurses should be focused more specifically in future research as, in this study, they might be addressed as implicit manners.


Visual research receives less attention compared to text-based research, especially in evaluating projects for physical activity (PA). This is surprising, since empowering individuals and communities to engage in the assessment tasks, and take decisions about the evaluation process has shown to have a positive impact on outcomes .NU-BIG[1] set out to involve women in difficult life situations[2] (n = 6) in creating a video to reflect upon the long-term effects of a PA program. It implies “a collaborative approach in which people create a video about themselves to open spaces for learning, enable change and transformation” .We conducted a qualitative study using a semi-standardized monitoring protocol, semi-structured interviews (n = 12), field notes (n = 4), and a reflexive focus group interview (n = 1) to investigate the process of making the video.The video-making process lasted from November 2021 to July 2023. Along the way, researchers and the women involved faced numerous challenges.For the women, deciding on doing a video resulted in insecurities and often seemed to rather inhibit their active participation. They needed sustained support and guidance from scientists , as well as the help of a media professional to handle practical aspects. However, in later stages of the process, they also experienced dynamic learning, which improved their general media literacy, self-confidence and critical awareness.The women clearly voiced that the video was to be done on their terms. This put the involved researchers in a challenging situation. Researchers were forced to continuously reflect on their own role and identity in the process, and had to relinquish control. This required them to be flexible in e.g. the facilitation of meetings and a permanent ability to adapt to spontaneous situations and demands.The video enabled women to share how PA had influenced their lives, allowing them to reclaim their voices and combat feelings of marginalization. As an evaluation method, it can enable relevant stakeholders to gain valuable data, which can contribute to social change. Visual research methods should be given more importance, particularly in community-based projects with vulnerable population groups.


IntroductionWard rounds are vital clinical processes that facilitate an opportunity for daily review and management of thoracic surgery inpatients. The aim of this study was to compare thoracic surgery ward round documentation against locally agreed standards and design a template to improve the detail and uniformity of this process to enhance patient care.Materials and methodsData for this audit was collected retrospectively and prospectively. Data was collected during three auditing periods and managed on Microsoft Excel. Descriptive statistics were used for its analysis. Chi-square and Fisher’s Exact tests were used to test for differences in reporting rates.Results and discussionInitially, a total of 199 ward round notes were reviewed. Imaging results (19%) and discharge planning (23%) were not reported. eCARE  was developed to ensure that all aspects of patient evaluation recommended by the guidelines were included. Reporting rates significantly improved after such changes. We analysed the effect of the new ward round note on discharge planning , complication rates , post-surgical length of stay (LOS) .ConclusionOver a year, we audited the Thoracic Surgery Department's ward round documentation against locally agreed standards in line with national recommendations. Several important items were not regularly reported. Using closed-ended questions improved reporting rates, and patient care was optimised. Further research should explore the impact of this new documentation method on patient care and postoperative outcomes in our Trust as well as other cardiothoracic centres. Ward rounds are complex clinical processes that provide an opportunity for daily review and management of surgical inpatients . HoweverThe National Institute for Health and Care Excellence (NICE) issued in 2017 the Structured Ward Rounds for Emergency and Acute Medical Care in adults . These aThe documentation of surgical ward rounds is crucial not only for medico-legal reasons but also to ensure continuity of care. Pucher et al. reported that less thorough ward rounds resulted in delayed diagnoses and preventable complications, and negatively affected outcomes . Other aThe aim of this study was to ensure a safer and more uniform ward round in our Thoracic Surgery Department. To this objective, we audited compliance for our service with the guidelines and recommendations issued by the General Medical Council (GMC) and RCP/RCN and developed a system to improve adherence to national ward round strategies.This article was previously posted to the Research Square preprint server on 6 February 2023.Data for this audit was collected retrospectively and prospectively. The thoracic surgical ward round entries were reviewed from the medical notes by two independent observers. The data was collected during three auditing periods.From October to November 2021, ward round notes were reviewed without any previous modification. With the help of our IT department, we developed and created eCARE  including all mandatory items according to the GMC and RCP/RCN for a high-quality ward round with mostly open-ended questions.From March to April 2022, we conducted a satisfaction survey amongst members of the thoracic surgical team on the use of the new thoracic surgery ward round note. Taking this feedback into consideration, we designed a new note that would remain user-friendly. Based on previous literature and good outcomes we implemented several checklists to allow more efficient and less time-consuming information gathering during thoracic surgery ward rounds.From June to July 2022, we reviewed the modified ward round notes and the reporting rates of relevant information and compliance with the guidelines.Over the three auditing periods, data was managed on Microsoft Excel and descriptive statistics were used for its analysis. Chi-square and Fisher’s Exact tests were used to test for differences in reporting rates. This audit was registered under ID number 004887 in our Cardiothoracic Centre.During the first auditing period, a total of 199 patient notes were reviewed and patient details, location, date, time, and ward round lead were reported. All notes were documented chronologically. All notes were signed and the bleep carried by the medical team for further contact was provided. The observations and physical findings were documented in 84% and 80% of the notes. Remarks were added in 92% of the notes. Pain and chest drain observations were reported in 53% and 30% of the notes. The surgical wound was assessed in 16% of all notes. Microbiology results, plan for antibiotics and blood results were reported in 5%, 15% and 24% of all notes respectively. Imaging results (19%) and discharge planning (23%) were often not reported. None of the healthcare professionals documenting the ward rounds included their GMC number .However, when we compared mortality the difference between the two periods was not significant. This could be due to a possible delay in the uptake of this new method on long-term results. Additionally, the time through which we evaluated mortality in the second group was shorter than the first group (as patients were followed up from operation day to present) and this could therefore limit the interpretation of our results.Based on the benefits of systematic ward rounds and checklists presented by previous research ,20 and cOver a year, we audited the thoracic surgery departments' daily ward round documentation against locally agreed standards in line with national guidelines. Several important items were not regularly reported during ward rounds. We created eCARE, a new thoracic ward round note to comply with such standards. Although these changes were satisfactory with improvement in patient care and experience, we hypothesised that using closed-ended questions format would improve reporting rates for surgical notes documentation. Using this format, reporting rates improved, and patient care and safety were optimised. Further research should explore the impact of these new documentation methods and the usage of checklists on patient care and postoperative outcomes in our Trust as well as other cardiothoracic centres.


Given the infrequency of this combination, there is currently no established management strategy available. (2) Case Description: A 49-year-old male patient with multiple symptoms including headaches, tinnitus, and visual impairment diagnosed with the coexistence of an arteriovenous malformation with the involvement of dural arteries and moyamoya syndrome was admitted to the national tertiary hospital. The patient underwent surgical management through embolization of the AVM from the afferents of the dural arteries, which has resulted in positive clinical outcomes. However, this approach may not be suitable for all cases, and a multidisciplinary team approach may be required to develop an individualized treatment strategy. (3) Conclusion: The contradictory nature of the treatment approaches in cases of combined AVM with the involvement of dural arteries and MMD highlights the complex nature of this condition and the need for further research to identify the most effective treatment strategies. The combination of arteriovenous malformation (AVM) with moyamoya syndrome and dural involvement of afferent arteries is an exceptionally rare vascular pathology with severe complications and potentially fatal outcomes . ArteriaManaging arteriovenous malformation involving dural arteries, in addition to moyamoya syndrome, in patients presenting with non-hemorrhagic neurological deficits such as visual impairment and pulsatile tinnitus is a challenging and controversial task.High-flow AVMs with dural components can become symptomatic and cause secondary ischemic neurological deficits due to chronic venous hypertension and compromised vascular flight in adjacent tissues. This can lead to progressive or abrupt focal deficits, seizures, cognitive decline, and other neurological symptoms that can mimic dementias or neurodegenerative diseases .Moyamoya disease (MMD) is believed to be caused by a combination of angiogenic factors and hemodynamic stress that leads to the development of arteriovenous malformations (AVMs) ,8,9. WhiA 49-year-old right-handed man was admitted to the hospital with a history of headaches and blurred vision that had persisted for three months. Approximately one year prior, he had experienced transient ischemic attacks that caused temporary motor weakness in his right arm and leg. Upon admission, a neurological examination did not reveal any neurological deficits, except for visual impairment and tinnitus. The patient’s visual acuity (thereafter–VA) was 4/10 in the right eye and 10/10 in the left eye.An MRI of the brain revealed a 35 × 33 × 30 mm nidus of malformed vessels with an enlarged draining vein in the left occipital region, primarily draining into the superior sagittal sinus A–F.In addition, MR angiography demonstrated restricted blood flow in the cavernous segment of the patient’s left internal carotid artery (ICA), with occlusion observed in the supraclinoidal segment, followed by the reconstitution of blood flow in the distal branches A–F.The cerebral angiography A–D reveaBecause of the small caliber and tortuosity of the afferents from the intracranial vessels and the extended length of the left middle meningeal artery that supplied the territory of the left MCA, an endovascular embolization of the AVM with a liquid embolic agent was performed via left-side occipital craniotomy closer to the AVM and a direct afferent  puncture A–C.After the surgical procedure, the patient’s symptoms gradually improved during the postoperative period. The visual impairment, which was initially at VA 4/10, improved to 8/10 in the right eye, and the tinnitus also regressed. After a week of hospitalization, the patient was discharged for dynamic monitoring to ensure continued improvement. The cerebral angiography performed 10 months after surgery demonstrated embolized superior, inferior, and lateral parts of the AVM. Many small afferents are seen from the occipital, superficial temporal, and meningeal arteries from both sides, as well as cortical vein drainage to the superior sagittal sinus .This case is a rare combination of three cerebral lesions. The primary goal of treatment was to determine the necessity of intervention and select the most appropriate treatment options for each pathology. It is essential to note that MMD and AVM with the involvement of dural arteries are two distinct forms of cerebral lesions with unique pathological processes. The incidence rate of AVM combined with MMD is relatively low at 1.7 per 1000 people, which is ten times lower than the incidence rate of each condition separately in the general population. The prevalence of AVM with involvement of dural arteries linked with MMD is uncertain, with only two previously reported cases of concomitant MMD and dAVF and only two patients characterized as having concurrent MMS and dAVF ,9. AccorIn this case, moyamoya syndrome, in combination with an arteriovenous malformation fed by dural arteries, can present with an acute course of symptoms such as pulsatile tinnitus and visual disturbance. Symptoms and signs may present with periods of remission and relapse due to changes in venous drainage.Pulsatile tinnitus can be considered a sign of a serious and potentially life-threatening condition  and causManaging arteriovenous malformation involving dural arteries, in addition to moyamoya syndrome, in patients presenting with non-hemorrhagic neurological deficits such as visual impairment due to vascular steal phenomenon is a challenging and controversial task. High-flow AVMs with dural components may become symptomatic and cause ischemic neurological deficits secondary to chronic venous hypertension and vascular steal from adjacent compromised tissue. The symptoms may present as progressive or abrupt focal deficits, seizures, and cognitive decline, which can resemble dementias or neurodegenerative diseases .Palliative embolization is performed when radiosurgery is not suitable. It is used in cases where long-standing venous hypertension or vascular steal has resulted in ischemic neurological deterioration and morbidity. The goal of palliative embolization is to alleviate symptoms caused by vascular steal syndrome, improve quality of life, and reduce the risk of further complications . It is iHemodynamic stress explains the process through which AVM initially develops and is followed by MMD. According to the limited research, an ischemia environment and subsequent angiogenesis have been postulated to play crucial roles in the development of AVFs. High blood flow to the AVM causes turbulent flow in the ICA, affecting the endothelial protection mechanisms and leading to gradual occlusion of the afflicted ICA. MMD collateral vessels form in order to protect brain tissue from hypoxia ,16.The concepts of treating AVM in conjunction with MMD are clearly contradictory, which is the most fascinating aspect of this condition. The challenge of choosing the optimal sequence of surgical treatment for cases that involve both AVM and MMD, along with dural afferents, remains an unresolved issue with conflicting arguments in the literature.In cases where an arteriovenous malformation (AVM) is combined with moyamoya disease (MMD), treatment recommendations are based on the patient’s symptoms and cerebral perfusion status. In such cases, bypass surgery for MMD is recommended. However, revascularization interventions, which improve blood flow to the brain, may lead to the growth of the AVM nidus due to the collateral blood vessels ,17. TherNevertheless, it is important to note that in rare cases, gamma knife radiosurgery may initiate MMS and worsen the patient’s condition. Therefore, treatment decisions must be made on a case-by-case basis, considering the risks and benefits associated with each option. Additionally, close follow-up after any intervention is necessary to control the patient’s progress and make adjustments to the treatment plan as needed ,9. In thEmbolization is a potential treatment option for patients with AVM and AVF, especially when there is an increasing steal effect as was observed in the present case. Lo Presti et al. reported the successful treatment of a case of AVF with MMD using Onyx transarterial embolization . HoweverThe contradictory nature of treatment approaches in cases of combined AVM involving dural arteries and MMD highlights the complex nature of this condition and the need for further research to identify the most effective treatment strategies. Surgery may be considered as a treatment option for patients with MMS and associated AVM or AVF depending on the patient’s clinical characteristics and cerebral hemodynamic condition.


Since its implementation in July 2021, the “double reduction ” policy (“the Policy”), which aims to foster a sound environment for extracurricular education, has attracted much social attention. At the preliminary stage where data and cases are insufficient, it is of theoretical and practical significance to evaluate extracurricular tuition and its effect mechanism before the Policy was implemented. This study analyzed the said question based on the data from the China Education Panel Survey between 2014 and 2015 (CEPS2014–2015) by virtue of propensity score matching (PSM) and the intermediate effect. The research found that: (1) extracurricular tuition (ET) is positively correlated with academic performance (AP); (2) high and low extracurricular tuition intensities (ETIs) show no difference in improving academic performance, and the group analysis shows that extracurricular tuition is influenced by the “optimal starting zone (OSZ)”; and (3) psychological resilience (PR) is an intermediate variable of extracurricular tuition, which acts as a “conversion valve”. Based on the above findings, the research raised the following suggestions. Firstly, we suggest to emphasize the promotion effect of after-class service on students’ academic performance and switch the functions of extracurricular tuition to after-sale service. Then, pay attention to the reverse effect of high extracurricular tuition intensity on students’ physical and psychological health and their academic performance. In practice, explore the effective “optimal starting zone” of extracurricular tuition for students. Lastly, cultivate students’ psychological resilience by shifting the core of education quality improvement from simple stacking of disciplinary knowledge to psychological health development. In recent years, as academic pressure has increased, the demand for extracurricular teaching and tutoring is on the rise. Extracurricular tuition  has become popular among students and parents . Known aConcerning extracurricular tuition and its effect mechanism, the academia widely recognizes that extracurricular tuition affects academic performance. Nevertheless, many studies focus on whether the effect is affected by external factors. Additionally, scholars share different opinions and there is a lack of research with casual inference. As for questions such as, “Are there any differences between extracurricular tuition intensities?” and “Does and how does extracurricular tuition affect academic performance?”, such a research area remains a “black box” due to existing insufficient theories and empirical studies. Therefore, our study utilized CEPS2014-2015 to construct the framework of the ET-AP effect mechanism. With the controlled heterogeneity of junior middle school students, we discussed the causal correlation between extracurricular tuition and academic performance, and the intermediate effect of student individuals’ psychological factors. We hoped our study could offer a reference for the effective implementation of the Policy.yi kao ding zhongshen” (one exam in a lifetime) prevails among the public . Bo. Bo31]. Based on the above theory, along with the traits and nature of extracurricular tuition, our study invented the extracurricular tuition-psychological resilience-academic performance effect mechanism (the ET-PR-AP effect mechanism) see . The extH2: Psychological resilience has an intermediate effect in the ET-AP effect mechanism.To explore the ET-AP effect mechanism, we categorized extracurricular tuition intensity into high and low. We then discussed their effects on academic performance and the intermediate effect of psychological resilience on the two categories separately. Finally, we built the ET-AP effect mechanism from the perspective of behavioral public policy see .To investigate the ETI-AP effect heterogeneity and the effect of psychological resilience in this pathway, our study borrowed and analyzed data on school administrators, teachers, students, and parents from 112 junior high schools in China from CEPS2014-2015. Considering the data in the second-wave longitudinal study, namely the data on students in the eighth grade (formerly seventh grade) which were optimized compared with the previous year, we screened out and analyzed them to keep sample consistency.To reflect the effect of extracurricular tuition (ET) on the dependent variable, we defined academic performance (AP) as a student’s overall score (OS) in the name of a proxy variable—his/her standardized overall score of the Chinese, Math, and English disciplines in 2014. This step aimed to explore the ETI-AP effect and the disciplinary heterogeneity of the effect pathway.For the independent variables, we selected the CEPS question “Does a student participate in extracurricular tuition courses?” as the indicator of ET. If a student participates in extracurricular tuition courses, then ET is 1, otherwise it is 0. To study whether the time and intensity of extracurricular tuition will influence the dependent variable, we established two variables: extracurricular tuition time (ETT) and extracurricular tuition intensity (ETI). ETT was established according to a student’s weekly extracurricular tuition time. ETI, a categorical variable, was established as follows. In need of categorization, we set an equation: ETI = ETT/20. According to the distribution of data on ETT of the CEPS samples in descriptive statistics, we set ETI = 0.2 (namely ETT = 4) as the high-low critical point. We defined ETI > 0.2 as high, assigning the value 2, and 0.2 ≥ ETI > 0 as low, assigning the value 1.As for the intermediate variable, by referring to previous research , we inclConcerning control variables, by referring to previous research , we seleThe specific descriptive statistical results are shown in Our data analysis focused on the ET-AP effect mechanism and the intermediate effect of psychological resilience therein. We adopted the fixed-effect (FE) model, the regression analysis, the propensity score matching (PSM) method, and the intermediate effect model in our study. The study consisted of the following three steps:Firstly, we set academic performance as a dependent variable and extracurricular tuition as independent variables. We also included different control variables. Then, we controlled the fixed effects of school and conducted a regression analysis. Based on the regression results, we tested the ET-AP influence by virtue of PSM. We put “non-ET” in the control group and “ET” in the experimental group. Then, we explored the treatment effect of extracurricular tuition on academic performance while controlling other endogenous variables.Next, we probed into the effect mechanism of different extracurricular tuition intensities on academic performance. To be specific, we put “non-ET” in the control group and “ET” in the experimental group; and put “Low-ETI” in the control group and “High-ETI” in the experimental group. From the two group pairs, we acquired different extracurricular tuition intensity-academic performance effects (ETI-AP effects). Then, we further segmented and compared the extracurricular tuition intensities to identify an “optimal starting zone (OSZ)”.Lastly, we referred to the analysis in the research on the “carbon reduction” policy by Kang et al., which did not extend the endogeneity issues in the intermediate mechanism . Having In the study on extracurricular tuition and academic performance, one can observe the internal mechanism with the traditional ordinary least squares regression (OLS) which was adopted in previous studies ,39,40. Np > 0.1) of regression on academic performance. This illustrates that with extracurricular tuition provided, the rise of extracurricular tuition time (extracurricular tuition intensity) cannot further promote academic performance. For Models (4) and (5), we discussed the effects of extracurricular tuition time with low and high extracurricular tuition intensities on academic performance, respectively. The results show that extracurricular tuition time with either low or high extracurricular tuition intensity does not have a significance of regression on academic performance. Therefore, for samples with extracurricular tuition, there is not much difference between high and low extracurricular tuition intensities.The bi-grouping test of low and high extracurricular tuition intensities may not comprehensively reveal the marginal changes of the extracurricular tuition effect. Therefore, with reference to previous studies , we furtFor Model (6), the results show an insignificant group difference, indicating no significant difference in extracurricular tuition effect between Group 1 and 2. For Model (7), the difference between Group 1 and 3 is significantly positive, reaching a significance level of 0.01. This indicates that the extracurricular tuition effect with ETI = 0.3–0.4 is higher than that with ETI = 0–0.2. When the extracurricular tuition intensity falls in this zone, extracurricular tuition has a stronger effect on academic performance than that with low extracurricular tuition time. This accords with the process from quantitative to qualitative changes. A small rise of extracurricular tuition intensity hardly improves the extracurricular tuition effect. Only when extracurricular tuition intensity increases continuously beyond a certain scope can it significantly improve the extracurricular tuition effect. For Model (8), the regression coefficient is negative, and the regression does not reach a significance level of 0.10. This shows that the extracurricular tuition effect does not improve as extracurricular tuition time continues to increase. When ETI = 0.4, the extracurricular tuition effect is, on the contrary, not higher than the effect with low extracurricular tuition intensity. This indicates that beyond the OSZ, excessive extracurricular tuition time will backfire. Thus, the OSZ should be that in Group 3, with an ETI of 0.3–0.4.Our study discussed the influence of extracurricular tuition on academic performance. To test the robustness of the ET-AP effect mechanism, we adopted PSM to verify the above conclusions based on OLS. Firstly, to minimize the omitted variables of the regression model, we regarded factors affecting academic performance as control variables and included them in the logit regression equation to calculate the propensity score. The score is shown in p < 0.01). With one-to-one matching, ATT = 5.36 and T = 3.05 (p < 0.01). With radius matching, ATT = 16.80 and T = 12.88 (p < 0.01). With kernel matching, ATT = 4.77 and T = 3.20 (p < 0.01). With nearest neighbor matching, ATT = 5.36 and T =2.75 (p < 0.01). Evidently, the matched ATT values are lower than that before matching and reach the significance level of 1%. To sum up, although the ET-AP effect before matching is overestimated, it is still significant. In other words, H1a is tenable. However, the ETI-AP correlation and its effect mechanism should be further explored.To produce more reliable PSM results, we calculated the data with one-to-one matching, radius matching, kernel matching, and nearest neighbor matching. The ATT values calculated are shown in Next, our study tested the ETI-AP effect. The above research indicated that extracurricular tuition has a significant effect on academic performance. However, as extracurricular tuition intensity increases, can the effect maintain its robustness, or will it follow the law of diminishing marginal utility? This question is still to be answered. Therefore, by simulating Models (6)–(8), we conducted the robustness test by comparing the effects of different extracurricular tuition intensities with PSM. The process is as follows. Firstly, to minimize the omitted variables of the regression model, we regarded factors affecting academic performance as control variables and included them in the logit regression equation to calculate the propensity score. Then, we conducted a balancing test on each control variable to ensure the heterogeneity of the matched results. The results before and after matching are consistent, namely the extracurricular tuition effects of Groups 1 and 2, and of Group 1 and 4, have no significant difference. The extracurricular tuition effects of Groups 1 and 3 have significantly positive difference, namely the OSZ falls into Group 3 (with an ETI of 0.3–0.4). The regression results based on OLS are robust. To sum up, the matched results demonstrate that extracurricular tuition does significantly improve academic performance. However, high and low extracurricular tuition intensities have similar effects on academic performance. That is to say, high extracurricular tuition intensity has no significance for academic performance and may even weaken or eliminate the extracurricular tuition effect on academic performance. H1b is tenable.p < 0.01), the ET-PR-AP intermediate effect is 1.045 , the direct effect of extracurricular tuition is 5.402 (p < 0.01), and the proportion of intermediate effect of psychological resilience is 16.21%. This indicates that psychological resilience plays an intermediate role in the ET-AP effect mechanism. In other words, extracurricular tuition itself can improve academic performance by cultivating a student’s psychological resilience.To further explore the ET-AP effect mechanism, we built an intermediate model to identify the mechanism’s two indirect effects. To verify the effect of psychological resilience in the ET-PR-AP pathway, we set “ET” and “ETT” as independent variables, “PR” as intermediate variable, and “AP” as dependent variable. We also added a series of control variables to the model. In the aspect of extracurricular tuition, the results are shown in Taking advantage of PSM, we studied the ET-AP effect mechanism of junior middle school students and the intermediate effect of psychological resilience therein. We found that: (1) extracurricular tuition does improve academic performance; (2) high and low extracurricular tuition intensities have a similar effect on academic performance, and there is an “optimal starting zone” of extracurricular tuition; and (3) considering the result (yes–no), or the degree (high–low), psychological resilience has different intermediate effects in the mechanism. Based on these findings, we concluded our discussion as follows.Having controlled other influence factors, our study discovered that students who take extracurricular tuition courses do have better academic performance than those who do not. In other words, extracurricular tuition promotes academic performance. Theoretically, the implementation of the “double reduction” policy is a powerful way to alleviate coursework burden, hence reducing students’ academic stress. Practically, however, in the current education environment that is directed by zhongkao (senior high school entrance exam) and gaokao, extracurricular tuition is a spontaneous behavior of students and parents in the competition environment.There are many reasons for the need of extracurricular tuition. First, the traditional school classroom education is oriented to class teaching, and it is difficult to carry out targeted management on the learning situation of each student. Compared with school classroom teaching, extracurricular tuition in the form of one-to-one or small-class teaching can more accurately find out the knowledge points that each student fails to grasp in classroom learning and provide targeted guidance to fill in the gaps. Secondly, in traditional Chinese culture, education has been endowed with the moral and political functions of cultivating personal accomplishment and educating the people: “jade is not polished, it is not a tool; people do not learn, he is ignorant. It is therefore the ancient king who establishes the country and the people, teaching is the first”  (“Learning Record”). The Chinese Imperial Examination System closely links the level of education with personal career development and the rise of social class . The modNevertheless, this objective demand has become the rooted obstacle against the implementation of the Policy to some extent. According to the theories of the behavioral public policy, to successfully implement the Policy, policymakers should put themselves in the shoes of students and parents. Only when students and parents understand and accept the care for students’ physical and psychological health behind the policy will they obey it. Currently, the demand for further study is the barricade against people’s recognition of the Policy. In our opinion, albeit the proposal of regulating discipline-based extracurricular tuition, policymakers should also recognize the positive effect of extracurricular tuition and transplant it into school education and after-class service. The multiple channels built therefrom will satisfy students and parents’ demands and boost school education. Such is a necessity to implement the “double reduction” policy.We compared high and low extracurricular tuition intensities, as well as cases with and without extracurricular tuition. It is known that extracurricular tuition can improve academic performance. Nonetheless, such is not a purely linear relationship—there exists an “optimal starting zone”. In other words, to make extracurricular tuition effective, one should respect the law of the transformation of quantity into quality. More importantly, s/he should pay attention to excessive extracurricular tuition  and mainWe believe the above discussion will enlighten the policy implementation. Although extracurricular tuition has switched from off-campus to on-campus, in nature, it is still a supplementary form of after-class learning, with an “optimal starting zone” to improve academic performance. Students should maintain a certain learning intensity off the campus to improve their academic performance. However, the intensity should fall into an optimal zone to take effect. Compared with senior middle schools, junior middle schools emphasize more on cultivating students’ learning habits and attitudes . Low extSince the implementation of the fourteenth five-year plan, educational development with quality has become an urgent core task in China’s elementary education. To achieve this goal, it is necessary to understand the education mechanism. According to our ET-PR-AP effect mechanism, extracurricular tuition is an education form with the nature of academic stress event, whereas psychological resilience is the “conversion valve” of the effect of extracurricular tuition. From the perspective of behavioral public management, psychological resilience is an indicator of the effectiveness of an individual student’s stress tackling in the inner- and outer-environmental interaction. It determines whether the “double reduction” policy can benefit students and parents.In the ET-PR-AP effect mechanism, extracurricular tuition as an additional learning event is an academic stress event from the inner- and outer-environments for students, which has the possibility to cause dysfunction. In this context, psychological functioning may be reconstructed in three directions, namely, consolidating, maintaining, or damaging the psychological resilience. The reconstruction direction depends on an individual’s psychological resilience and the level of the stress event. With psychological resilience unchanged, low extracurricular tuition intensity will cultivate students’ psychological resilience and thus improve their academic performance. High intensity, however, will impose a heavier academic burden, hurting the psychological resilience of students who have not developed sound psychological adjustment. This may damage students’ body and mind and do little good to their academic performance. In an interview, a parent of a junior middle school student expressed similar views, acknowledging the promotion effect of extracurricular tuition while worrying about the psychological stress brought by high extracurricular tuition intensity (20200924Z). Much evidence proves that whatever the stage of extracurricular tuition, psychological resilience is the prerequisite to improve academic performance with extracurricular tuition. Cultivating students’ psychological resilience, therefore, is a feasible way to develop China’s elementary education with quality.According to the above data analysis and discussion results, we raised three suggestions on the “double reduction” policy against extracurricular tuition.Firstly, replace extracurricular tuition with after-class service to improve students’ learning quality. Since the Policy was implemented, most primary and junior middle schools in China have begun to offer “5 + 2 ” after-class tutoring service. Nevertheless, the arrangement for schoolteachers and curricula have not been standardized, which results in deficiencies in after-class service. For example, shift teachers find it hard to tutor students; students lack sufficient materials to fulfill their two-hour learning demand. Thus, in the forthcoming reform, it is suggested that such problems be solved to ameliorate the system of after-class service as an alternative to extracurricular tuition.In terms of teaching technology, this study helps to improve the after-school service system of the school, introduce the teaching method represented by Universal Design for Learning, develop a flexible teaching environment, accept teaching feedback to solve the differences of students’ individual learning conditions, and help all students achieve efficient learning  so as toSecondly, pay attention to the negative effect of high extracurricular tuition intensity on students’ physical and psychological health as well as their academic performance and explore the “optimal starting zone” of extracurricular tuition in teaching practice. At present, discipline-based extracurricular tuition at the stage of elementary education is increasing, which lays a heavy burden on families and students. This is one of the reasons why the central government strengthens the regulations on extracurricular tuition. Our study proved that there exists an “optimal starting zone”, beyond which extracurricular tuition may be less effective on academic performance. Academic performance may not be necessarily better as extracurricular tuition increases. Nonetheless, from the investigation within Guangdong province, we knew that in some regions, junior high schools vie with each other. They join academic races, secretly offering tuition courses to students with no intention to stop. Such a prisoner’s dilemma hinders schools from following the “double reduction” policy. Therefore, schools themselves should seek to terminate such vicious contests. They should explore the “optimal starting zone” of the time of after-class service and extracurricular tuition that fits them best in the teaching practice; replace the increase of tuition with quality teaching, raise parents’ awareness of the objective restriction of tuition as well as the importance of moderate tuition and learning. In addition, the government should standardize the ecology of the education and training industry, regulate the length of extracurricular tuition, guide after-school tuition institutions to transform into non-disciplinary training institutions, and encourage the provision of quality education services that promote the comprehensive development of education.Thirdly, strengthen the multi-party cultivation of psychological resilience and provide psychological support. The issuing of the Opinion implies that the improvement of education quality has become an urgent issue in China’s elementary education. Our study indicated that education quality can be improved by not only deepening and improving disciplinary knowledge, but also promoting students’ psychological development. Psychological resilience is an indispensable factor for students to make academic progress from extracurricular tuition. It is also crucial for their academic and professional development. While restricting extracurricular tuition, the government should also encourage family education and peer company. It is suggested to enrich the education environment through multi-party interaction and communication. For example, at present, some schools have integrated mental health education into after-school services and carried out team psychological counseling activities. This practice provides psychological counseling and help during after-school services so as to reduce “negative” feelings and “pressure” among students. This will broaden the channels for students to access psychological resources, improve their psychological resilience, and promote their psychological development, all of which helps cultivate all-round talents.


Compounds 1, 3, 10, and 15 showed hCA I inhibition, whereas 1, 4, and 10 showed hCA II inhibition at nanomolar concentrations. Among these compounds, 1 displayed potent inhibitory activity against the hCA I (Ki = 28.5 nM) and hCA II (Ki = 2.2 nM), being 10 and 6 times more potent than acetazolamide, a standard inhibitor (Ki = 250 nM and 12 nM), respectively. Furthermore, this compound displayed 14-fold selectivity towards the hCA II isoform compared to hCA I. Molecular docking and MD simulations were performed to understand the atomic level interactions responsible for the selectivity of compound 1 towards hCA II.A series of phthalimide-capped benzene sulphonamides (  Several CA isoenzymes are involved in critical physiological processes, such as biosynthetic reactions,,Carbonic anhydrases (CAs) are metalloenzymes that contain Zn2+) coordinated to three histidine residues  and a water molecule or hydroxide ionAll CA families catalyse the reversible hydration of carbon dioxide. The active site of α-CAs consists of a zinc ion coordinated to three histidine residues and a water molecule. The water molecule acts as a nucleophile and attacks the carbon dioxide molecule, forming bicarbonate and a proton. The proton is then released into the solvent through a network of hydrogen bonds involving other amino acid residues such as glutamate and asparagine. The active site of carbonic anhydrase is highly conserved among different isoforms and species, indicating its functional importance,,,Various studies have been performed on CA inhibitors belonging to a variety of classes. A literature survey revealed that a diverse structural class of compounds had been reported as potent CA inhibitors50 value of 48.2 µM. Further optimisation was not performed because the scaffold was not a potent antiviral. Later, our team was tempted to explore this series of compounds for their ability to inhibit CA because of: (i) the presence of a sulphonamide group, an essential pharmacophore for CA inhibitors; (ii) reports and reviews on neurological manifestations associated with dengue viral infection,,Aedes aegypti belong to α-CAs, and hCAs inhibitors available in the market have shown some effectiveness against A. aegypti CA, opening a potential for their use in vector controlA. aegypti. Inhibiting carbonic anhydrase activity in A. aegypti may negatively affect the insect’s development, reproduction, or survival, thereby reducing the transmission of mosquito-borne diseases. Considering the potent inhibition of human CAs (hCA I and hCA II), it is reasonable to investigate their potential as inhibitors of A. aegypti carbonic anhydrase. A potential inhibitor of CA from this series will provide a starting point for optimising a candidate effective against dengue viral infection and addressing associated neurological issues. It is also expected that the effective concentration of a drug candidate in the blood of treated infected populations may also increase the sensitivity of mosquitoes  to insecticides and also exert larvicidal activity.Our group  reported novel sulphonamides as dengue protease inhibitorsUsing a stopped-flow Applied Photophysics assay, we evaluated our previously synthesised inhibitors targeting human carbonic anhydrase isoenzymes I and II for their inhibitory activities. This assay provided valuable data on the potency and selectivity of the inhibitors, which helped assess their potential as therapeutic agents. Additionally, molecular docking and molecular dynamics simulations were employed to investigate the molecular basis of inhibition by examining the binding modes and complex stability between the inhibitors and target enzymes. These in silico analyses, combined with experimental bioassays, provide a comprehensive understanding of the inhibitory mechanisms and potential of the synthesised inhibitors as carbonic anhydrase inhibitors. These findings may facilitate the development of novel therapeutic agents targeting carbonic anhydrase and lay the groundwork for their potential cross-application in vector control.The CA isoenzyme assay was performed using a stopped-flow Applied Photophysics  instrument using Khalifah’s techniqueA. aegypti carbonic anhydrase II . The AlphaFold structure did not contain a zinc ion present in the active site of the crystal structures obtained from the PDB. To address this, we used AlphaFillThe molecular docking study was conducted using AutoDock 4.2 software supplemented by MGLTools 1.5.7The docking parameters were set as follows. A ga_pop_size of 150 was used to ensure accurate results while maintaining a reasonable computation time. A maximum of 2,500,000 energy evaluations were performed to explore sufficient conformational space for obtaining reliable results. The maximum number of generations allowed for the genetic algorithms during the docking simulation was set to 27,000 to ensure convergence and generation of reliable results. A total of 100 runs were performed, which provided a sufficient sampling of conformational space to obtain reliable results. The ligand was initially set to the bound state using the ‘unbound_model bound’ parameter, which is a common starting point for docking simulation. The docked structures were visualised using UCSF Chimaera 1.6+ or Cl−) using the GROMACS Genion module. The simulation was performed using an NPT ensemble with periodic boundary conditions, temperature of 300 K, and pressure of 1 atm. The equations of motion were integrated using the leapfrog algorithm, with a time step of 2 fs. Long-range electrostatic interactions were calculated using the particle mesh Ewald method, with a cut-off distance of 12 Å. The simulations were run for 300 ns, and the coordinates and velocities were saved every 10 ps for analysis.For molecular dynamics simulations, the GROMACS package 1–22) were synthesised according to a previously reported procedureThe compounds . The study revealed ZBG-dependent inhibition of CA I and CA II enzymes because of the free sulphamoyl group in the most potent molecule, 1. Other derivatives in which the sulphamoyl group is substituted have been reported to be inactive or poorly active.The CA inhibitory activities of all synthesised compounds 1–22 against hCA I and hCA II1, identified in this study was previously reported by our group to be inactive against dengue viral protease. The potent dengue protease inhibitor 19 reported by our group was inactive against hCA I and hCA II in the current study. Furthermore, the lead optimisation strategy should consider exploring the chemical space around the phenyl ring of phthalimide and benzene sulphonamide, keeping the sulphamoyl amino group unsubstituted for multi-target directed ligand (MTDL) design.The potent CA Inhibitor, in vitro studies, compound 1 was the most potent inhibitor of hCA I and hCA II among the 22 compounds evaluated. In terms of selectivity, 1 displayed ∼10-fold more selectivity towards hCA II than towards hCA I. Accordingly, molecular docking was performed using AutoDock 4.2 to investigate the binding interactions of a small molecule ligand and reference molecule acetazolamide with its target proteins. We also conducted molecular docking studies of compound 1 against CA from A. aegypti to explore the potential of the compound as an inhibitor of mosquito-borne diseases such as dengue fever, Zika virus, or chikungunya. These studies could help establish a relative correlation between humans and A. aegypti CAs, providing insight into potential applications in vector control, which could also help develop novel strategies for combating mosquito-borne diseases.In the 1 showed good docking scores, with the 1 having a lower score and, therefore, higher predicted affinity. Compound 1 interacted with the active site histidine residues , as well as other key residues such as Thr199, Gln92, Phe91, and His200. Hydrophobic interactions were observed with Leu198, Trp209, Val143, Ala121, and Phe131  simulation studies to validate the ligand-protein complexes. The Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and % interaction between the ligand and protein atoms were analysed based on the results. Additionally, the interactions observed during docking studies were verified to determine their retention over the 300 ns MD simulation. Conformational changes throughout the simulation were measured as RMSD values, with the initial frame serving as the standard backbone, and the deviation at the end was compared to the starting point. The system was stabilised and equilibrated when RMSD values ranged from 1 to 3 Å. More significant fluctuations were associated with lower complex stability.The biophysical interactions between docked complexes of The RMSD analysis revealed that all three complexes start with a high RMSD, indicating the flexibility and structural adjustments of the complexes, and gradually stabilise over time. At 100 ns, hCA I and hCA II stabilise, while the AlphaFold version of carbonic anhydrase shows a jump in RMSD. All complexes eventually stabilise at 250 ns and show a decline thereafter. The trend suggests the stability of the protein-ligand complexes over the simulation time .On the RMSF plots, a significant variation was observed between C-alpha residues 110 to 130 and between 190 to 210, which was common for all three complexes. This variation could be representative of the spatial adjustment of the active site residues, especially the histidines and hydrophobic threonine and leucine residues .The radius of the gyration plot shows an initial increase in the size of the protein-ligand complex, indicating conformational changes during the simulation, followed by a reduction and stabilisation near 250 ns after a few periodical spikes, indicating some level of structural stabilisation and the formation of stable interactions between the protein and the ligand .An overall increasing SASA trend for all three complexes indicated that the protein-ligand interaction becomes more solvent-exposed overtime during the simulation . An RMSDin vitro experimental data highlights the validity of the computational approach employed in this study and provides deeper insights into the molecular mechanisms. This indicates that the MD simulations effectively captured the dynamic behaviour of the protein-ligand complexes and their interactions, providing insights into the underlying molecular mechanisms. Furthermore, the strong correlation with experimental data reinforces the reliability of the predicted binding affinities and key residues involved in protein-ligand interactions.In this study, MD simulations of carbonic anhydrase-ligand complexes revealed fluctuations in protein-ligand interactions over time. The RMSF plots showed significant variation in the active site residues, especially the histidines and hydrophobic threonine and leucine residues, indicating their dynamic behaviour in the protein-ligand complex. These results suggest that the protein-ligand interaction in carbonic anhydrase is dynamic and fluctuates during the MD simulation. The observed correlation between the docking results, MD simulation data, predicted Ki values, and docking scores with the 1 in hCA II and AF-A0A1S4EX12 but not in hCA I. The similarity in π–π stacking interactions between compound 1 and both hCA II and AF-A0A1S4EX12, which are carbonic anhydrase II enzymes from different species, indicated the potential conservation of binding site features between these enzymes. This conservation indicated that the binding pocket of the carbonic anhydrase II isoform is structurally and functionally conserved across species, implying a similar role in their respective organisms.Comparing the docking scores and predicted Ki values between hCA I and hCA II with AF-A0A1S4EX12, it is evident that both ligands exhibit higher affinities for hCA I and hCA II than for AF-A0A1S4EX12. The differences in binding affinities can be attributed to variations in the interacting residues and their types, as observed in hydrogen bonding, π–π stacking, and hydrophobic interactions. While hCA I and hCA II share a common set of histidine and threonine residues involved in hydrogen bonding, mosquito carbonic anhydrase exhibits a different pattern of interactions involving unique residues such as His131 and Thr213. Furthermore, π–π stacking interactions were observed for In terms of drug development, conservation presents both challenges and opportunities. On the one hand, the similarity in binding interactions may make it challenging to design highly selective inhibitors that target only the mosquito carbonic anhydrase (AF-A0A1S4EX12) without affecting the human isoform (hCA II). Consequently, achieving selectivity in drug design might necessitate focusing on subtle differences in the binding sites or exploiting allosteric sites that may be unique to the mosquito enzyme. On the other hand, this conservation also provides an opportunity to leverage the extensive knowledge and understanding of human carbonic anhydrase II for drug development. Researchers can utilise existing data and establish strategies for the development of inhibitors against mosquito enzymes, potentially accelerating the discovery process. Additionally, this conservation could help to identify broad-spectrum inhibitors that target carbonic anhydrase II enzymes in multiple species, which might be useful in addressing a variety of vector-borne diseases.1–22) and screened against CA isoforms, such as CA I, which are cytosolic and associated with GI and CA II related to glaucoma. The synthesised derivatives displayed ZBG-dependent inhibition of the hCA I and hCA II enzymes. Compounds 1, 3, 10, and 15 inhibited hCA I, whereas compounds 1, 4, and 10 inhibited hCA II. Among these compounds, 1 displayed potent inhibitory activity at low nanomolar concentrations against hCA I (Ki = 28.5 nM) and hCA II (Ki = 2.2 nM) enzymes. In hCA II, 1, was six times more potent than ACTZ (Ki = 12 nM), and in the case of hCA I, it was 10 times more potent than ACTZ (Ki = 250 nM). Moreover, the identified lead compound displayed 14 folds selectivity towards the hCA II isoform compared to hCA I. The in silico results also confirmed a similar binding pattern for 1 and ACTZ, where the free sulphamoyl group acted as a zinc-binding group. The incorporation of hydrophobic rings increased the potency of the synthesised molecules. Compound 1 can be further optimised to obtain more potent molecules and can be used in further stages of the drug design process.Our drug design hypothesis was validated by synthesising a small library of sulphonamides incorporating phthalyl moieties with free and N-substituted sulphamoyl groups (


Monitoring drinking behavior allows producers to assess the health and well-being of their beef cattle. Changes in regular drinking behavior can serve as an indicator of potential health issues. Detecting these issues early on enables the application of timely interventions, mitigating the likelihood of severe complications and enhancing the prospects for prompt and efficient treatments. In the current study, we used computer vision techniques to study and analyze the drinking behavior of beef cattle. Two different camera positions were used to identify the drinking behavior. Our proposed method was able to successfully identify both the drinking behavior and drinking time of beef cattle.Monitoring the drinking behavior of animals can provide important information for livestock farming, including the health and well-being of the animals. Measuring drinking time is labor-demanding and, thus, it is still a challenge in most livestock production systems. Computer vision technology using a low-cost camera system can be useful in overcoming this issue. The aim of this research was to develop a computer vision system for monitoring beef cattle drinking behavior. A data acquisition system, including an RGB camera and an ultrasonic sensor, was developed to record beef cattle drinking actions. We developed an algorithm for tracking the beef cattle’s key body parts, such as head–ear–neck position, using a state-of-the-art deep learning architecture DeepLabCut. The extracted key points were analyzed using a long short-term memory (LSTM) model to classify drinking and non-drinking periods. A total of 70 videos were used to train and test the model and 8 videos were used for validation purposes. During the testing, the model achieved 97.35% accuracy. The results of this study will guide us to meet immediate needs and expand farmers’ capability in monitoring animal health and well-being by identifying drinking behavior. The US is the world leader in annual beef production value, and maintains the third-largest cattle herd and the largest cattle industry globally; it produced USD 86.1 billion in gross income in 2022 . Based oDifferent deep learning techniques have been developed to automate animal behavior detection methods using computer vision and video analysis technologies. Tsai et al.  investigRecently, in identifying and classifying livestock activity, different artificial neural networks have been used to improve the performance of recognition tasks. Chen et al.  investigDeep learning and vision analysis play significant roles in the automated recognition of livestock behavior, as highlighted in the previously mentioned works . AlthougThe University of Tennessee (UT) Animal Care and Use Committee (IACUC) approved the experiment on the use of cattle subjects under the following protocol title: Computer vision characterization of respiration as an indicator of cattle health; Protocol #: 2932-0922.The experiment was conducted at the University of Tennessee, Middle Tennessee AgResearch and Education Center (MTREC), between 5 October 2022 and 12 October 2022. The experiment involved four purebred black Angus cattle, all of which were 1 year old at the time. The cattle were kept in a barn equipped with a roof and automatic fans that activated when the temperature reached predefined conditions, ensuring they were protected from direct sunlight, rain, wind, and muddy conditions when needed. An open space was connected to the barn, offering plenty of room for the animals to move about without restraint. Surrounding both the open space and the barn were wooden fences, ensuring that the animals remained within their designated boundaries. MTREC staff diligently supervised the well-being and health of all animals during the experiment, adhering to the farm’s standard operating procedures and following veterinary recommendations.The waterer was placed in the open space to provide free access to drinking water. The vision system was installed over the top of the waterer. The vision system consisted of a mainframe, a ball waterer, and a sensing camera unit . The senIn this study, animal drinking behavior was recorded from two camera positions. This was to ensure that our algorithm was not sensitive to a specific camera position and could potentially handle flexible camera mounting options. A total of 78 videos, including 39 videos of each position, were recorded. The videos were recorded as H264 files. After that, the MP4 (RGB) and Hierarchical Data Format (HDF) files were extracted from each H264 file. The MP4 (RBG) files were used to track the key body points. A total of five key points were used to observe the pose skeleton . Each skBased on the literature review, key body points and pose were identified using the DeepLabCut CNN-based pose estimation tool . DeepLabThe LSTM-based model was used to classify drinking and non-drinking behavior. This model used the output from the previous DeepLabCut model, which were the coordinates of the key body parts, as the input, and produced either drinking or non-drinking classes as the output. The input included coordinates from 30 consecutive frames (1 s of video). In this study, 30-frame sequences were constantly sampled and predicted, and a 30-frame step size was set to make sure that the video sequence was repetitive each time. Therefore, after setting the fixed window size to 30 and sliding the window with a step size of 30, the proposed LSTM algorithm was used to detect the drinking behavior from small video segments obtained from the sequence. −5 and 1 × 10−7, respectively. The input dimension of the LSTM was 30 × 10, which represented 30 frames × 5 key points in each frame × 2 coordinates (x and y) per point.In deep learning studies, the augmentation of data is a very useful method to enhance the efficiency of the model training process by reducing over-sampling and augmenting random transformations . TherefoEvaluation indices including accuracy, precision, recall, specificity, F1 score, and AUC were used to validate the proposed algorithm. The evaluation indices were calculated as shown in Equations (1)–(5) :(1)AccurEight 1-minute-long individual videos were used for validation of the proposed LSTM model. The videos were collected from both camera positions. Efforts to develop automated dairy cattle drinking behavior models have been underway by various research groups. Most researchers were mainly focused on automatic basic behavior recognition methods including for drinking, ruminating, walking, standing, and lying. Among them, Tsai et al.  developeIn contrast to the previous research, the proposed method in this study was a rapid and non-invasive technique. The DeepLabCut pose-estimation-based model accurately categorized the drinking behavior and could analyze drinking time tracked through videos with different lengths. Addressing the continuous detection and tracking of key points on constantly moving cattle, without the need for expert pre-marking, is an essential challenge. In this study, the focus was on tracking the key points of interest in the head area. DeepLabCut has the capability to effectively acquire body part information, even when faced with challenges such as a complex and changing background, uneven lighting conditions, or distortions caused by the camera. DeepLabCut also offers several key benefits, including cost reduction in manual behavior analysis, achieving high accuracy with a minimal number of training images, and eliminating the necessity of placing visible markers on specific locations of interest . CreatinThis study proposed a skeleton-based computer vision method for beef cattle drinking behavior recognition. It used cameras from different positions and orientations for beef cattle pose estimation using DeepLabCut with a ResNet50 backbone. A dataset containing 70 videos was evaluated using the model to create the sequential key body points data. After that, an LSTM model was used to classify the drinking and non-drinking behaviors. The accuracy of the model was 98.25%, which was higher than the previous studies using other computer vision methods. We are currently conducting a preliminary study focused on addressing a significant and practical challenge within the field of livestock farming. This research has the potential to be applied to various livestock species, including but not limited to beef cattle, sheep, horses, and more. By employing the same vision system and pose estimation techniques, we can additionally quantify the respiration rates of animals. Currently, our group is collecting more video data from different farms using different camera positions. More collected data will further increase the accuracy of the LSTM model as well as different classification models. They will also help prepare the vision system as a practical tool for beef farms worldwide.


The aim of this study is to review the available literature investigating the relationship between hikikomori, a pathological condition characterized by severe social withdrawal or isolation, autism spectrum disorder (ASD) and Internet gaming disorder (IGD). Studies on the relationship between ASD and IGD have found significant positive correlations between these two conditions. Individuals with ASD would appear to be at risk of developing a problematic use of the Internet, which, to the right extent, would represent a useful tool for social interaction and cognitive development. Even subjects with hikikomori, in whom rarefied interpersonal relationships and social isolation could be balanced by the use of online connections, appear to be at high risk of developing IGD. On the other hand, the finding of significant autistic traits in populations with hikikomori could lead to considering this psychopathological condition as a particular presentation of autism spectrum, a hypothesis that requires further investigation. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and a restricted, repetitive pattern of behaviors, interests, or activities, caused by both genetic and environmental factors affecting the developing brain ,2. ASD iIn this framework, the recent literature has reported a possible association between autism spectrum features and a specific psychopathological condition called “hikikomori” .Hikikomori is a form of pathological social withdrawal or social isolation lasting longer than 6 months, associated with a significant functional impairment or distress ,15. ThisHikikomori is known to be comorbid with various mental disorders including anxiety disorder, depression, personality disorders, and specifically, Internet gaming disorder (IGD) ,36,37,38This association was also confirmed by experimental studies. In two large samples of young adults evaluated for the presence of IGD and Hikikomori, an association was reported between symptoms of the two conditions, especially when longer game-playing times were implied ,44. MoreIn this regard, it should be noted that one of the populations at greatest risk of isolation due to difficulties in communication and social interaction is individuals with ASD. However, studies about hikikomori and autism are still very scant. Hikikomori has been found to co-occur in around a third of people diagnosed with ASD , who areDespite the above-reported evidence and the theoretical hypothesis about how autism spectrum, IGD, and hikikomori seem to be linked, studies about the relative relationships between these conditions are still limited in number, while no study have yet investigated the association between autism spectrum, IGD, and hikikomori in the same sample. In order to pave the way for further research in the field, the aim of the present work was to review all available studies about the relationship between autism spectrum and hikikomori, hikikomori and IGD, IGD and autism spectrum, highlighting possible overlapping features and traits.Furthermore, considering that within the general population, the characteristics of autism are variably distributed along a continuum of severity, from subthreshold manifestations or autistic traits (ATs) to full-blown disorder (ASD), it would be interesting to explore the presence of ATs in individuals with IGD and hikikomori, through the use of specific spectrum questionnaires, such as the Adult Autism Subthreshold Spectrum (AdAS Spectrum).The interest in the possible relationship between autism spectrum conditions and hikikomori has increased only recently.In the late 2000s, Kondo and colleagues highlighted the presence of developmental disabilities in at least about a third of hikikomori subjects. The authors also stressed that the association with neurodevelopmental disorders should not surprise, considering that subjects with aloof personality, social difficulties, and withdrawal could have likely be diagnosed with autism spectrum conditions before the development of the hikikomori construct . Tateno Although the close relationship between these conditions have been variously described in theoretical studies , data frIndividuals at risk for hikikomori were also found to have longer internet usage time and higher scores on both IAT and SAS. Moreover, correlation analyses revealed that HQ-25 and IAT scores had a relatively strong relationship, although HQ-25 and SAS-SV had a moderately weak one. Lastly, those who used the Internet for gaming were at higher risk for the development of hikikomori than those who used the Internet for social networking. According to the authors, these data could be possibly explained by the fact that gaming, especially when competitive, is an activity better performed on the computer than on the smartphone, inducing the subject to spend more time in their room to have a better gaming experience. However, this may enhance a reduction of outside social activities. Another study of interest was carried out in the USA and Australia  on two sn = 179). Parents completed the measures of evaluation of extracurricular activities and on the screen of children. Children with ASD spent about 62% more time watching TV and playing video games than all activities not on the screen. Compared to children with typical development, it was shown that children with ASD played video games more frequently and were therefore more likely to demonstrate a problematic use of video games, including difficulties in stopping the gaming activity when necessary, anger when interrupted, and excessive amounts of play, with no gender differences [ASD people have often been reported to show a problematic and excessive video game use, spending most of their free time on screens, social media, television, or computers . Orsmondferences . The samn = 56), attention deficit hyperactivity disorder (ADHD) (n = 44) and controls (n = 41) aged between 8 and 18 years . A significant difference between the ASD group and controls was found on the daily hours of video games played, the family income, and the marital status of parents. Results suggested that the ASD group had higher PVGT scores than controls. However, symptoms of GD were not related to autistic traits in the ASD group. The ASD diagnosis was assessed clinically by a physician and/or psychologist and by the use of standardized tools, including the ADOS or ADI-R. The questionnaires assessed hours of video game use per day, access to in-room video games, video game genres, problematic video game use, ASD symptoms, and ADHD symptoms. Boys with ASD spent more time than controls playing video games (2.1 vs. 1.2 h/d). Both the ASD and ADHD groups had greater access to in-room video games and more problematic use of video games than controls. Symptoms of inattention predicted problem gambling for both the ASD and ADHD groups, and role-playing preferences predicted problematic game use only in the ASD group. Video game use was assessed using a questionnaire specifically designed for the study. Parents reported the number of hours per day their children spent “playing videos or video games” during extracurricular hours. Parents also listed the top three most played video games by their kids in the past month. Problematic video game use was assessed using a modified version of the PVGT. Current ASD symptoms were assessed using the Social Communication Questionnaire-Current (SCQ). Symptoms of inattention and hyperactivity/impulsivity were assessed using the Vanderbilt Attention Deficit/Hyperactivity Disorder Parent Rating Scale (VADPRS).Mazurek and Engelhardt  conducteMacMullin et al.  evaluateIn a further study, Arcelus et al.  investigLiu et al.  instead Similarly, Engelhardt  and PaulIn a study conducted by Finke et al.  on a samFinally, Murray et al.  mined whThe aim of this work was to review the available literature about comorbidity and overlaps among autism spectrum, hikikomori, and IGD. First of all, as anticipated, the literature in the field, although promising, is still scant. To date, the most investigated relationship remains that between ASD and IGD. Studies on the relationship between ASD and IGD included in this review, conducted on samples of children, adolescents, and adults with ASD ,51,70,71Regarding the association between hikikomori and IGD, the limited available literature suggests the presence of a significant overlap. On one hand, the rarefaction of interpersonal relationships and social withdrawal characteristic of hikikomori may be compensated through the use of the Internet and the online connections established through it . The useWhile, as reported above, both ASD and hikikomori subjects seem to be at greater risk of developing IGD, these two conditions also seem to significantly overlap. Despite the limited studies available, since the early investigations on psychiatric conditions among hikikomori subjects, a significant association with developmental disabilities has been reported . Further