Peer victimization is a harmful experience that contributed to one's psychological problems, physical health deterioration, and so on. Quality of life (QoL) is an important indicator of adolescent health assessment. To identify potential pathways of positive experiences in preventing peer victimization's detrimental effects and then provide intervention ideas for adolescent health, this study was conducted to examine the relationship between peer victimization and QoL in Chongqing adolescents and discover whether resilience plays a mediating role and positive childhood experiences (PCEs) act as a moderating role in the relationship.Data were the first follow-up of a cohort study conducted in four complete middle schools in two districts of Chongqing, China. Self-designed peer victimization items, the Connor–Davidson Resilience Scale, the Adolescent Quality of Life Scale, and the Benevolent Childhood Experiences Scale were used. We investigated the differences and correlations in peer victimization, QoL, and resilience between the two PCEs groups. Mplus version 8.3 was used to analyze the mediating role of resilience and the moderating role of PCEs in peer victimization and QoL.P < 0.001). Peer victimization negatively correlated with QoL and resilience, while resilience positively correlated with QoL (P < 0.001). In the models with total QOL as the dependent variable, the indirect effect was −0.431  in the low-PCEs group vs. −2.077  in the high-PCEs group. In the models with four dimensions of QOL as the dependent variable, the indirect effects ranged from −0.054 to −0.180  in the low-PCEs group and from 0.295 to −0.823 in the high-PCEs group . Both total and indirect effects were significant (P < 0.05). In addition, the differences in indirect effects were significant between the two PCEs groups (P < 0.05), while differences in total and direct effects were almost not apparent.Peer victimization, resilience, and QoL differed between the two PCEs groups (Resilience partially mediated the effect of peer victimization on QoL in Chongqing adolescents, and PCEs moderated this mediation. Schools, families, and society should focus on resilience intervention and prioritize the enhancement of PCEs for improving adolescent QoL. Adolescence is an important transitional stage in life. Interactions with the social environment shape an individual's capabilities to enter adult life smoothly at this stage. Individuals also gain physical, cognitive, emotional, social, and economic resources from this period to provide the foundation and benefits for their present and future and the wellbeing of the next generation  interact to affect the course of development, and resilience itself is constantly evolving within individuals and systems  refer to the individual's positive experiences of perceived internal and external safety, security, and support, and positive and predictable QoL before the age of 18 years  scores of QoL/dimensions of QoL, peer victimization, and resilience will be different across two levels of PCEs; (2) QoL/dimensions of QoL, peer victimization, and resilience will be correlated across two levels of PCEs; and (3) resilience will show a mediating effect in the association between peer victimization and QoL/dimensions of QoL, and the path coefficients will be different in the high-PCEs group vs. the low-PCEs group.The cross-sectional data were the first follow-up part in May 2022 of the Adolescent Behavior and Health Survey Cohort Study conducted in four complete middle schools (the schools include middle and high school students) in two districts of Chongqing. According to the administrative and economic development level of Chongqing, it is divided into central urban areas and districts. Then, Yubei District and Qijiang District were selected in two areas, and two schools were chosen for each region according to the principle of convenient sampling. Since the study lasted for 2 years, the loss of follow-up due to further education needed to be considered. Therefore, we chose students in 7th and 10th grade to follow. According to the use of a random number table, four to five classes in each grade were chosen for the survey. The inclusion criteria were that students could independently understand and complete the questionnaire.The sample size for the first follow-up section was 1,747 (including 7th and 10th graders). The participants were investigated with a self-reported questionnaire, which mainly included scales for general demographic variables, peer victimization, resilience, QoL, and PCEs. Cases with missing demographic variables , complete absence of one or more instruments , and apparent logical anomalies in variable values  were first eliminated to obtain a sample of 1,706. The retention rate was 97.71%.The general demographic variables were collected using self-made items: school location (Qijiang/Yubei), gender , grade (grade 7th/10th), family residence (countryside/township/urban), whether single child (yes/no), and whether living in school (yes/no).The three items were designed for measuring peer victimization referring to Marsh et al.  descriptThe Connor–Davidson Resilience Scale (CD-RISC) in the Chinese version was used in our study  in the Chinese version , and Tucker–Lewis index (TLI) above 0.90 .The details for general demographic variables grouped by PCEs are shown in P < 0.001). Resilience and peer victimization were also found to be different in the two PCEs groups (P < 0.001). The mean score of resilience was 45.892 (SD = 18.007) in the low-PCEs group vs. 65.441 (SD = 19.471) in the high-PCEs group. The mean score of peer victimization was 3.803 (SD = 1.698) in the former vs. 3.361 (SD = 1.046) in the latter.The scores of QoL and its four dimensions, resilience, and peer victimization were also compared between the two PCEs groups as shown in P < 0.001). It is worth mentioning that peer victimization and resilience in the two groups had correlation coefficients below 0.5, and there was little multicollinearity between the two groups .Grade, gender, and family residence were found to be associated with QoL and its dimensions, resilience, and peer victimization in this study. So the three general demographic variables were included as covariates in the mediation models for control. All unconstrained mediation models were saturated . Similarly, in models with the four dimensions of QoL as the dependent variables, the constrained models also showed poorer fit results . It might show that the PCEs did affect the relationship among peer victimization, resilience, and QoL. Therefore, we ultimately chose the unconstrained models for analysis. The mediation mechanisms under the two-level PCEs are shown in For the mediation model with QoL as the dependent variable in the two PCEs groups, the model comparison test showed a significant deterioration in the model with constrained path coefficients compared to the unconstrained model , and the indirect effect was −0.431 . In the high-PCEs group, the direct effect of peer victimization was −2.872 , and the indirect effect through resilience was −2.077 .P < 0.05). The direct path coefficients in the high-PCEs group ranged from −0.134 to −1.242, where all direct path coefficients were significant (P < 0.05) except the path coefficient of pubertal QoL. The indirect effect values for the low-PCEs group ranged from −0.054 to −0.180 (P < 0.05), accounting for 6.07–12.95% of the total effect, while the high-PCEs group had indirect effect values ranging from −0.295 to −0.823 (P < 0.001), accounting for 35.89–68.76% of the total effect.c) were not significantly different between the two PCEs groups in all models (P > 0.05). Except for psychological QoL, the direct effect coefficients (path c') of the mediation models were not significantly different between the two PCEs groups (P > 0.05). The differences in path a (peer victimization to resilience) between the two groups were significant in all models (P < 0.05). The difference in path b (resilience to QoL) was significant only in the model with pubertal QoL as the dependent variable (P < 0.05). Differences in indirect effects (path a*b) were significant in all models (P < 0.05).Finally, the results of the differences in path coefficients between the two PCEs groups are shown in Our study was the first to examine the effects of peer victimization on adolescents' QoL and the potential mediating mechanisms from the perspective of PCEs. The results showed that peer victimization had a negative correlation with adolescents' QoL, four dimensions of QoL, and resilience, while resilience had a positive correlation with QoL and four dimensions of QoL. These correlations remained significant across different PCEs groups. It was shown that resilience could partially mediate the link between peer victimization and QoL at two levels of PCEs, with similar direct effects and different indirect effects. Overall, these findings were consistent with our hypothesis that traumatic experiences such as peer victimization negatively affect QoL. Resilience partially mediated this relationship. PCEs moderated the relationship among the three.via decreasing resilience. Similar to previous studies  have increased in the high-PCEs group, which meant the PCEs mainly affect this pathway. The specificity of the association between peer victimization and resilience had similar results in previous literature. Several studies showed that there were significant negative associations between ACEs and numerous physical, psychological, and social health outcomes and life satisfaction at higher PCEs, whereas these relationships were not significant at lower PCEs  in the high-PCEs group were slightly larger than those in the low-PCEs group. Although the difference was not significant except for the model of pubertal QoL. Higher PCEs could be used as a promoting variable to develop resilience . At the same time, schools need to supervise whether there is any bullying behavior on campus through students and teachers and impose appropriate punishments on the perpetrators of bullying. Parents could actively seek knowledge about adolescent mental health from schools and the media, not engage in risky behaviors such as gambling or excessive drinking, and foster open and comprehensive communications within the family. For society, it may be a good choice to report the negative effects and prevention methods of peer bullying. During the promotion process, attention should be paid to protecting the reputation and privacy of teenagers to prevent secondary harm.The raw data supporting the conclusions of this article will be made available by the corresponding author, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Chongqing Medical University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.LD participated in work design, research investigation, data collection and analysis, and original manuscript drafting and revising. YL participated in work design, data analysis, and critically revising important intellectual content. HW contributed to work design, critically revising important intellectual content, and funding acquisition. JY and LL participated in work design, research investigation, and data collection. All authors read and approved the final manuscript.


The association between serum uric acid (UA) and spontaneous hemorrhagic transformation (HT) has been seldom studied, and the role of UA in spontaneous HT remains unclear. This study aims to investigate the sex-dependent association between UA and spontaneous HT in patients with ischemic stroke.We retrospectively included patients with ischemic stroke in a tertiary academic hospital between December 2016 and May 2020. Patients were included if they presented within 24 h after the onset of symptoms and did not receive reperfusion therapy. Spontaneous HT was determined by an independent evaluation of neuroimaging by three trained neurologists who were blinded to clinical data. A univariate analysis was performed to identify factors related to spontaneous HT. Four logistic regression models were established to adjust each factor and assess the association between UA and spontaneous HT.P < 0.05 (model A) in the univariate analysis, the ratio of UA and its interquartile range (RUI) was independently associated with spontaneous HT in male patients , but not in female patients . In models B–D, the results remain consistent with model A after the adjustment for other potential confounders.A total of 769 patients were enrolled . After adjusting the confounders with a Higher serum UA was independently associated with a higher occurrence of spontaneous HT in male patients who were admitted within 24 h after the stroke onset without receiving reperfusion therapy. Spontaneous hemorrhagic transformation (HT) is defined as the blood stain of an infarcted cerebral area formed by the overflow of red blood cells and other blood components from blood vessels to the infarcted brain tissue, which is a part of the natural course of ischemic stroke and a crucial complication of treatment . SpontanUric acid (UA) is an endogenous antioxidant produced by purine metabolism , 4. If tNevertheless, reperfusion injury and blood–brain barrier damage after infarction are considered the two major causes of spontaneous HT, and the reactive oxygen species (ROS)-mediated oxidative stress response has an important role in these two mechanisms . Many stThere is no consensus on the association between UA and spontaneous HT in patients with acute ischemic stroke. Studies of the relationship between UA levels and spontaneous HT are contradictory. Positive and negative in the male population or both positive in men and women have been described , 13, 14.We retrospectively reviewed the medical records of patients with ischemic stroke admitted to the Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, from December 2016 to May 2020. For this analysis, the patients were included if they: (1) met the diagnostic criteria of acute ischemic stroke (AIS) in the Guidelines for Early Management of Patients With Acute Ischemic Stroke (2019) of the American Heart Association (AHA) , (2) werThe clinical data were collected from each patient by two researchers: (1) demographic characteristics, such as age and sex; (2) medical histories, such as the history of smoking, alcohol consumption, hypertension, diabetes, dyslipidemia, and atrial fibrillation (AF); (3) clinical variables, such as National Institute of Health Stroke Scale (NIHSS), the Trial of ORG 10172 in Acute Stroke classification (TOAST), systolic blood pressure (SBP), diastolic blood pressure (DBP), and time from the stroke onset to admission; (4) laboratory tests, such as platelet count, activated partial thromboplastin time, serum UA, estimated glomerular filtration rate (eGFR), serum creatinine, low-density lipoprotein cholesterol (LDL-C), and hemoglobin A1c (HbA1c); (5) radiological characteristics, such as large hemispheric infarction (LHI) and spontaneous HT; and (6) treatment, such as anticoagulants, antiplatelet drugs, antihypertensive drugs, and antidiabetic drugs. Among them, eGFR was calculated by the serum creatinine level according to the formula of the Chronic Kidney Disease Epidemiology Collaboration . The cerSerum UA concentration was tested by the enzymatic method (Roche Cobas C701) or the dry chemistry method . The diagnosis of spontaneous HT is based on the following criteria: abnormal hyperdensity within the area of low attenuation (CT) or abnormal hypointensity within the identified ischemic area (MRI) . The imat-test or Mann–Whitney U-test, whereas the comparison of categorical variables was made by performing the chi-square test or Fisher's exact test. In addition, the factors with a P < 0.05 in the univariate analysis and other factors that potentially could affect the study results were included in the subsequent logistic regression analysis. UA levels are lower in female patients, and a sex-dependent association between UA and cardiovascular disease was reported. Therefore, sex-dependent analysis was performed to investigate the impact of UA levels on HT occurrence. In total, four logistic regression models were built, and the association between UA and spontaneous HT was determined by dividing patients into two subgroups of male and female. These variables were chosen based on their known associations with the occurrence of HT, and their demonstrated link to HT in the logistical regression: Model A is adjusted for variables with a P < 0.05 in male  patient subgroup univariate analysis; model B is adjusted for variables with a P < 0.05 in both subgroup univariate analysis; model C is adjusted for variables in model B, antiplatelet treatment, and anticoagulant treatment; model D is adjusted for variables in model C, smoking, alcohol consumption, systolic blood pressure, and eGFR. A P < 0.05 was considered statistically significant. Data analysis of the present study was performed by using SPSS Statistics Software  and GraphPad Prism .Since there is no clinical significance of a 1-unit (1 μmol/L) change in UA in clinical practice, in this study, the ratio of UA and its interquartile range  was used to replace UA in the statistical analysis, for increasing the practicability of the conclusions in clinical diagnosis and treatment. Continuous variables were expressed as the mean and standard deviation, and categorical variables were expressed as frequency and percentage. The comparison of continuous variables between groups was made by performing the P < 0.001), RUI , drinking, smoking, creatinine level, and eGFR and antiplatelet drug use rate. Female patients were older  and have higher occurrences of AF  and anticoagulant use than those of men , age, admission NIHSS score, higher occurrence of AF and LHI, and shorter time from the onset to admission compared to patients without. However, there was no significant association between UA/RUI and spontaneous HT in the female patients (P = 0.336) , RUI  .P < 0.05 (model A) in the univariate analysis of each group by logistic regression, the ratio of UA/IQR was found to be independently associated with spontaneous HT in male patients , but not in female patients . Furthermore, in the other three multivariate logistic regression models, the statistical results were consistent with model A after being adjusted for the factors with a P < 0.05 in the univariate analyses of both subgroups (model B), anticoagulant use and antiplatelet drug (model C), and smoking, alcohol consumption, SBP, and eGFR (model D) (After adjustment for factors with a model D) .In this study, the RUI was independently associated with spontaneous HT in male patients admitted within 24 h after the onset, and the incidence of spontaneous HT increased by 85.0% for each IQR increase in the UA level. Interestingly, no similar association between the UA level and spontaneous HT was found in female patients.Furthermore, we reported that UA levels were associated with spontaneous HT in male patients with acute ischemic stroke. However, this association was not found in female patients. UA levels are commonly available in medical settings, and the results of our study suggested that UA may be a potential target for interventions. Several previous studies have investigated the sex differences of UA in patients with cerebrovascular diseases , 20. RecIn previous studies, reperfusion treatment is one of the mechanisms of spontaneous HT, subsequently affecting the outcome. Previous studies regarding the relationship between UA and spontaneous HT have shown conflicting results in the thrombolysis population and non-thrombolysis group. Thrombectomy, the restoration of blood flow to the salvageable ischemic brain tissue, is consistent with the aforementioned mechanism of spontaneous HT, and a higher incidence of spontaneous HT was reported in previous studies. The reason for these contradictory results may partly be due to the modifying effect of reperfusion strategies on spontaneous HT in these studies. Thus, we excluded those patients from this study.The exact underlying mechanism of UA levels on spontaneous HT remains unknown. Generally, UA is an abundant antioxidant in humans and is supposed to play a protective role in cardio-cerebral vascular diseases. The possible explanation of sex-dependent differences in UA levels on spontaneous HT was the uricosuric effect of estrogen , the inhIt should be noted that our study had some limitations. First, it was a single-center retrospective study with a relatively small sample size. The impact of UA on spontaneous HT seems to be limited in the sex-specific subgroups, and this clinical relevance may not be generalizable to patients with reperfusion treatment. In addition, a multicenter prospective study with a large sample size is required to further confirm and explore the association between UA and the subtypes of HT. Second, UA levels have been found to change over time in patients with stroke , whereasIn conclusion, among the non-reperfusion patients with acute ischemic stroke within 24 h after admission, the level of UA was independently and positively associated with the occurrence of spontaneous HT in male patients. More prospective research is needed to confirm these results.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Board of the First Affiliated Hospital of Chongqing Medical University. The patients/participants provided their written informed consent to participate in this study.YT and M-SL: study concept and design. YT, M-SL, and CF: acquisition of data. YT: statistical analysis and drafting of the manuscript. G-QL: critical revision of the manuscript for important intellectual content and study supervision. Analysis and interpretation of data were done by all authors. All authors contributed to the article and approved the submitted version.


Quality and risk of bias assessments were conducted according to the Quality Assessment Tool For In Vitro Studies. A meta-analysis was performed using mean difference and standard deviation for each outcome, and heterogeneity (I2) was estimated. p < 0.05 was considered significant. (4) Results: One-hundred and forty-six studies were identified following duplicate removal, and nine were included in the systematic review and meta-analysis. The overall risk of bias was classified as low. The DNS was found to be more accurate and efficient than the FH approach was, resulting in a significantly shorter operation time (p < 0.00001) and less angular (p ≤ 0.0001) and linear deviation (p ≤ 0.01). For substance loss, the advantage of the DNS was significant only for microsurgery . A reduced risk of iatrogenic failure using the DNS was observed for both expert and novice operators. (5) Conclusions: The DNS appears beneficial for non-surgical and microsurgical endodontics, regardless of the operator’s experience. However, appropriate training and experience are necessary to access the full advantages offered by the DNS.(1) Background: A Dynamic Navigation System (DNS) is an innovative tool that facilitates the management of complex endodontic cases. Despite the number of advantages and limitations of this approach, there is no evidence-based information about its efficiency in comparison with that of the traditional method in endodontics. (2) Objectives: We aimed to explore any beneficial effects of the DNS and compare the outcomes of DNS vs. free-hand (FH) approaches for non-surgical and microsurgical endodontics. (3) Methods: A literature search was conducted in August 2023 to identify randomized, experimental, non-surgical, and microsurgical endodontic studies that compared the DNS with FH approaches. The procedural time , substance loss (ΔV, mm The main methods of pulp disease therapy are aimed at preventing periodontal complications. Non-surgical types of treatment are performed through gaining coronal access into the system of root canals. In the few clinical cases when direct coronal access is not performable due to risk of tissue loss, coronal blocks, or other indications, a microsurgical type of endodontic treatment could be the chosen treatment. In this case, access to root apexes is gained retrograde through the jaw bone structure. In both positions, tissue preservation (dentine and bone) is critical for a better prognosis and long-term outcome.A Dynamic Navigation System (DNS) is an innovative tool that facilitates the management of complex endodontic cases  ,3,4,5,6.Despite the undeniable practical advantages of the DNS, there are associated limitations , and ovePrevious reviews examining the DNS vs. FH approaches have reported high data heterogeneity and low-level evidence from in vitro studies, thereby confounding any subsequent meta-analysis ,29. Howe0) that there would be no differences between the DNS and FH approaches.This systematic review and meta-analysis aimed to compare the accuracy and efficacy of DNS with FH approaches for non-surgical and microsurgical endodontic procedures, testing the null hypothesis (Hhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=348725 (accessed on 4 August 2022).This study was written in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  on human teeth  using the dynamic navigation system (DNS) in comparison with a free-hand (FH) approach. Review question: Does the DNS increase the accuracy and efficacy of performing endodontic and microsurgical procedures vs. an FH approach?3), angular deviation (degrees), coronal (platform) linear deviation (mm), and apical linear deviation (mm); Study design: in vitro randomized experimental studies.The methodology was carried out according to the Cochrane PICOS formula  This is A systematic literature search of PubMed, Cochrane Library, Wiley Online Library, and Scopus electronic databases was conducted in August 2023 to include all randomized experimental (in vitro) studies that evaluated endodontic procedures  utilizing the DNS (test) in comparison with FH (control) approaches on human teeth. Studies were excluded if they did not include an FH control group. The search was limited to articles published in journals over the last five years, without any other restriction. The search terms used were the following: “Dynamic navigation” and “Endodontics”, which are also MeSH terms, and they were combined using the Boolean operator AND. They were entered in the fields for title, abstract, and key words. The search query was adapted to each database.In addition, the references cited in each selected study were screened, and any that met the inclusion criteria were added to the list.The literature search, study screening, and data extraction were independently performed by two reviewers (EM and MDF). Any disagreements were resolved through a discussion. More specifically, the studies initially retrieved through electronic plus manual searches were added to a reference manager software program (Zotero 6.0.26), which was also used to exclude duplicate articles. The titles and abstracts of the remaining studies were then screened to form a list of eligible studies. The full text of all eligible studies was obtained and assessed to make sure that the studies met the inclusion criteria. All studies excluded at this stage were listed in a separate table, indicating the reason for exclusion. The included studies underwent data extraction for the subsequent steps of the review .3), angular deviation , coronal (platform) linear deviation , and apical linear deviation . The following information was collected in addition to the outcome measures listed above: author names, study title, year of publication, country, study design, quality and quantity of prepared teeth, techniques (DNS and FH), and the number and experience of operators performing the study. In the event of missing data, the study’s authors were contacted via email. The respective study was excluded if no response was received after three attempts within three weeks.The following outcomes were extracted from the included studies and expressed as the difference (Δ) between the DNS and FH groups: procedural time , substance volume loss , mean differences for continuous data were combined using fixed-effects models. A random-effect model was adopted when I2 > 60%, and p < 0.05.Separate meta-analyses were performed for each outcome measure  linear deviation, and apical linear deviation) using the software Review Manager 5.4 . Data heterogeneity was evaluated using funnel plots. In the instance of there being no significant heterogeneity  was used to assess the risk of bias of the included studies ). Two reThe literature search yielded 146 articles following the removal of duplicates. The subsequent screening of the titles and abstracts led to the exclusion of 124 publications which were not relevant to this analysis. The remaining 22 studies underwent full-text evaluation, which led to the exclusion of a further 13 articles that did not meet the inclusion criteria. A flowchart of the selection process is shown in A summary of the included studies is presented in Five of the nine studies used natural, extracted human teeth  ,43,44,46The subgroup sizes ranged from 10  to 36 2 teeth. TGenerally, nine selected studies reported that the DNS was more accurate and more efficient than an FH approach for access preparation, canal location, and fiber post removal. Compared with an FH approach, the DNS resulted in significantly reduced substance loss and a shorter operation time. The DNS was also considered to minimize the potential risk of the iatrogenic weakening of critical portions of the crown and reduce negative influences on shaping procedures ). AccordThe criteria of the Quality Assessment Tool For In Vitro Studies (QUIN Tool) are reported in p < 0.00001) and in the non-surgical and microsurgical subgroups . The effect was comparable across the two subgroups and appeared independent of operator’s experience in the two microsurgical studies that were stratified by experience. It is noteworthy that almost all the included studies defined the procedural time as the in-chair time only, excluding any preoperative time required for CBCT scanning, digital planning, sensor calibration, and other procedures not required for an FH approach. Due to the nature of the studies that included expert and novice operator subgroups, it was not possible to compare the procedural time spent by the expert and novice operators [All nine studies were included in a random-effect meta-analysis on procedural time ,44,45,46ubgroups A. A highperators ,44,45. Iperators  did not p = 0.65, I2 = 99%). In the microsurgical group, separate novice and expert data both favored the DNS, with significant difference between the subgroups .Three non-surgical studies and two subgroups of one microsurgical study were included in an analysis of substance loss .Angular deviation was reported in six studies. According to p < 0.00001, p = 0.01, I2 = 0%), high heterogeneity was identified in the surgical studies (I2 = 99%), primarily due to one study which reported a significantly greater benefit of the DNS when used by novice operators compared with experts (41).Following p = 0.0008; I2 = 0%) and microsurgical  procedures , and that the time required to prepare access cavities was significantly reduced for expert vs. novice operators (p < 0.05). The DNS was also associated with a decreased access preparation time  vs. an FH approach . Jain et al. (2020) reported significantly faster access preparation with the DNS compared with that of the FH approach , while Connert et al. (2021) [p > 0.05). According to Janabi et al. (2021) [p < 0.05). This is supported by Martinho et al. (2022) [p < 0.05). Only Tang et al. (2022) [Time is an important consideration when planning a treatment and also to ensure a comfort relationship between the patient and doctor. This meta-analysis found that the DNS was associated with a significantly reduced procedural time  compared with that of the FH approach. It is noteworthy that almost all the included studies defined procedural time as the in-chair time only, excluding any preoperative time required for CBCT scanning, digital planning, sensor calibration, and other procedures not required for an FH approach. Due to the nature of the studies that included expert and novice operator subgroups, it was not possible to compare the procedural times spent by expert and novice operators ,44,45. I. (2021)  reported. (2021) , the ave. (2022)  also fou3, p < 0.05). Data reported by Connert et al. (2021) [3, p < 0.001). These results were further supported by Janabi et al. (2021) [Jain et al. (2020)  reported. (2021)  also fav. (2021) , who dem. (2021) , who comp < 0.05). This was further confirmed by Martinho et al. (2022) [p < 0.005) and verified that expert operators achieved a higher accuracy with the DNS than novice operators did. Finally, Dianat et al. (2020) [p < 0.001) and angular deflection (p < 0.0001) with the DNS vs. FH approaches. According to Tang et al. (2022) [Linear and apical deviations can be used to determine the precision and accuracy of a navigation approach. In this regard, Gambarini et al. (2020)  determin. (2022)  who repo. (2020)  also obs. (2022) , the DNSIn summary, this systematic literature search and meta-analysis suggests that the DNS is associated with significantly reduced substance loss  and shorter operation times than those of an FH approach, while also minimizing the potential risk of the iatrogenic weakening of critical portions of the crown and reducing negative influences on shaping procedures. Overall, the data indicate that the DNS is a highly accurate and efficient tool for difficult clinical cases where extreme precision is required ,43,45,46The key strength of this systematic review and meta-analysis is the strict eligibility criteria that were used to identify the comparative studies of the DNS and FH approaches, which minimized the risk of selection bias. The low overall risk of bias of the included studies further strengthens these analyses.Given the relative limitations of this systematic review and meta-analysis, more studies are needed to fully determine the appropriate use of the DNS vs. FH approaches. Future studies should consider using standardized procedures for separated teeth groups and well-defined time measurements, while taking into account individual clinical case characteristics and operators’ training and expertise.According to the results of this systematic review and meta-analysis, the DNS approach for non-surgical and microsurgical endodontic procedures appears to yield better results when compared with those of an FH approach in almost every subgroup examined. The benefits of the DNS range from a reduced operating time to a reduction of substance loss and a lessened probability of iatrogenic complications, and it also improves accuracy of the treatment. However, until recently, the use of the DNS was optional and often dependent on personal experience, training, and manual skills to derive the full advantages of the technique. With limited available evidence, there is a need for high-quality trials to fully determine the benefits offered by the DNS approach for non-surgical endodontics and microsurgery.


Response surface analyses were calculated via R statistics. The explained variance was high for the model predicting depression severity  and physical health . Additive incongruence effects of pain and physical activity on depression severity, mental, physical, and overall health were found . In our study, physical activity and pain synergistically influenced physical, mental, and overall health. The pain not only led to low mental health but also interfered with the valuable potential of engaging in physical activity in lipedema patients.Lipedema is a widespread disease with painful accumulations of subcutaneous fat in the legs and arms. Often, obesity co-occurs. Many patients suffer from impairment in mobility and mental health. Obesity and mental health in turn can be positively influenced by physical activity. In this study, we aimed to examine the interrelations between pain and physical activity on mental health in lipedema patients. In total, 511 female lipedema patients (age M = 40.16 ± 12.45 years, BMI M = 33.86 ± 7.80 kg/m Lipedema is a widespread disease characterized by large accumulations of subcutaneous fat that primarily affects the legs and limbs. The distribution pattern is mostly bilaterally and symmetrically ,2,3 and Lipedema can lead to secondary complications such as lymphedema, osteoarthritis, massive impairment in mobility, and aesthetic and psychosocial problems ,13. For Pain is known to be the leading symptom of lipedema and has many facets. As with the disease itself, the pathogenesis and etiology of pain in lipedema patients are not yet fully understood . The paiPatients often suffer from obesity as a comorbidity, accentuating the high relevance to enhance weight loss ,19. It iy levels . Thus, ty levels . Moreovey levels . DespitePatients suffering from lipedema reported significant impairment in their quality of life (QoL) ,27. QoL In addition, not only reduced QoL but also elevated depression levels have been reported in lipedema patients ,31. DeprThe current state of evidence indicates that pain, physical activity, and aspects of mental health such as symptoms of depression and QoL stand in a compound interaction. Physical inactivity and the continuous perception of pain could result in a vicious circle-like negative synergy that negatively influences aspects of mental health ,27,34. RHypothesis 1 (main effect). Higher levels of pain lead to lower levels of mental health.Hypothesis 2 (main effect). Higher levels of physical activity lead to higher levels of mental health.Hypothesis 3 (synergy effect). High levels of pain and low levels of physical activity are synergistically associated with lower levels of mental health.This study was approved by the Ethics Committee of the Medical Association Westphalia-Lippe and the University of Muenster. Approval Code: 2021-684-f-S. Approval Date: 9 March 2022. Informed consent was obtained from all subjects and/or their legal guardian(s). All methods were carried out in accordance with relevant guidelines and regulations. Participation in this study was voluntary. All patients with suspected lipedema visiting our specialized clinic for an initial consultation were asked to fill in the paper-pencil questionnaires assessing general baseline information. Therefore, age, height, weight, age of symptom onset/diagnosis, family history and stage of lipedema, location and symptoms of pain, previous therapies, comorbidities, QoL, symptoms of depression, and physical activity behavior were assessed. Each patient filled in an individually designed questionnaire prior to their consultation. Only patients later diagnosed with lipedema were included. Patients who had already received a liposuction or any bariatric surgery prior to the consultation were excluded from the study.Patients were asked to rate their pain in the specific areas  that were affected by lipedema. Therefore, a single-item questionnaire was used (“Do you have pain in the affected areas?”). The response was rated on a ten-point Likert scale ranging from one (“none”) to ten (“very strong”). For analysis, the raw score of the single item was used.Physical activity was assessed via a questionnaire consisting of seven items that were specifically designed for the purpose of this study. Each item represents one dimension . The patients were asked to define the number of sporting activities per week. For analysis, a sum score of hours per week was calculated.Mental health  was assessed via the World Health Organization Quality of Life-BREF (WHOQOL-BREF) and the PHQ-9 ,38 questα = 0.84 . The PHQα = 0.84 . It entaThe WHOQOL-BREF is a proven self-report tool with high validity to assess general QoL. It comprises twenty-six items that are rated on a six-point Likert scale ranging from one  to five (“fully agree”) . The WHO to 0.85 . Thus, i2) and physical activity (Y2), and the cross-product of pain and physical activity (XY). b0 to b5 represent the unstandardized regression weights. Within the full model described above, more parsimonious  models can be identified that fit the data better and that are nested within the full model [RR model), a shifted and tilted ridge (SRR model), or a shifted and tilted ridge with an additional rotation (SRRR model). The flat ridge model does not allow a main effect, but a mismatch of the predictor variables, again without a tilted but with a shifted ridge (SSQD model), or with a shifted and rotated ridge (SRSQD model). Furthermore, the additive model, interaction model (IA model), and models with single effects of the X-variable (onlyX or onlyX2 models) or Y-variable (onlyY or onlyY2 models) can be identified.Data analyses were performed via the programming language R  with thell model . The ris2R were assessed to evaluate absolute model fit. According to Cohen [R2adj = 0.26), moderate (R2adj = 0.13), or weak (R2adj = 0.02). Practically equivalent models were defined by ΔAICc < 2 and Implausible models were defined by a cumulative weight > 0.95. The models showing the best fit indices were selected for analysis.To test and select the best fitting model, model fit indices were compared and evaluated . Therefoto Cohen , values Within the three-dimensional visualization of the RSA, the shape of the surface is guided by the lines of congruence and incongruence. Effects of congruence  on the outcome variable are made visible via a line of congruence (LOC). Similarly, the effects of incongruence between the two predictor variables on the outcome variable are visualized via the line of incongruence (LOIC). Regarding the congruence effects described by the LOC, the coefficients a1 and a2 are interpreted. The slope of the LOC is defined as Prior to the main analysis, the stage of lipedema was entered as a moderator variable into linear regression analyses, regressing the outcome variables on pain and physical activity. Therefore, we could examine whether the severity of lipedema  influenced the relationship between the predictor variables and the outcome variable. As high values of PHQ-9 represent lower levels of health and high levels of WHOQOL-BREF represent higher levels of health, the colors in the RSA visualization were selected as follows. In all analyses, the green color represents higher levels of health, whereas the red color represents lower levels of health.f2 = 0.05 based on results of previous studies [n = 193 [n = 386–579 was required to conduct the RSA.For RSA analyses, it has been recommended to use a sample size that is two or three times as large as the required sample size for a regression analysis with two predictors . Definin studies , a desir[n = 193 . Thus, an = 511) were female. Descriptive statistics of the demographic data and results are presented in p > 0.005).All patients enrolled in this study  negatively affected physical health, hence indicating the presence of incongruence effects.With regard to the physical health scale of the WHOQOL-BREF, the onlyXSRSQD model indicated weak explained variance and main effects of both pain and physical activity on mental health. No congruence effects were found. In terms of incongruence effects, a mismatch of the predictor variables  negatively affected mental health.In the analysis of the mental health scale of the WHOQOL-BREF, the onlyY model indicated no explained variance. No main effect, congruence, or incongruence effect were found. In the analysis of the environmental health scale of the WHOQOL-BREF, the onlyX2 model indicated weak explained variance and a main effect of only pain but not of physical activity on environmental health. A significant curvilinear additive effect on the line of congruence was present. Looking at the incongruence effects, a mismatch of the predictor variables could be identified but the degree of mismatch on environmental health was not significant.Regarding the social health scale of the WHOQOL-BREF, the SRR model indicated weak to moderate explained variance and main effects of both pain and physical activity on overall health. A significant linear additive effect on the line of congruence was detectable. In terms of incongruence effects, a mismatch of the predictor variables was found, yet the degree of mismatch on the outcome variable was not significant.Concerning the overall health scale of the WHOQOL-BREF, the In this study, we hypothesized that higher levels of pain led to lower levels of mental health (Hypothesis 1), that higher levels of physical activity led to higher levels of mental health (Hypothesis 2), and that high levels of pain and low levels of physical activity were synergistically associated with lower levels of mental health (Hypothesis 3). The results of the present study in female lipedema patients provide evidence that pain was the leading entity to all aspects of mental and physical health. Specifically, the remarkable negative effects of pain on physical, mental, environmental, and overall health were found. Also, considerable effects of physical activity on mental health and overall health were found. Thus, Hypotheses 1 and 2 could be confirmed. The results indicate that both pain and physical activity are important influencing factors to explain mental health in lipedema patients. Going beyond these two-dimensional effects, physical activity and pain seem to stand in a synergetic relationship influencing physical, mental, and overall health, confirming Hypothesis 3.No causal treatment option for lipedema has been identified yet. Thus, potential treatment options focus on improving the symptoms that are associated with lipedema . To imprThe support of physical activity in lipedema patients can have beneficial effects on several levels. First, engagement in physical activity can support mobility and weight loss in obesity that often co-occurs in lipedema patients . Second,However, the present findings of this study imply that exercise regimens and physical therapy can be significantly constricted due to massive impairment in mobility and pain. In addition, dietary treatment has been shown to be of limited effectiveness, as lipedemic tissue has hardly been influenced by weight loss intervention ,11. TherFollowing the current State of the Art to reduce lipedemic tissue, most lipedema patients receive conservative therapy . SpecifiTargeting reduced QoL and elevated depression levels in lipedema patients, psychological counseling has been suggested . On one Taken together, pain in the lipidemic tissue can interfere with the opportunity to engage in physical activity. Vice versa, a low pain conception and higher levels of physical activity synergize and lead to higher levels of mental, physical, and overall health. Therefore, pain reduction via reduction in lipidemic tissue appears to be a key aspect in enhancing physical activity, physical health, and mental health in lipedema patients ,11.This study has several methodological strengths. The first is to analyze and contextualize the complex interrelations between physical activity and pain and their effects on aspects of mental health in lipedema patients. Yet, it is based on cross-sectional data and cannot address potential causal relations between the variables. Longitudinal studies are required to further investigate interactions between pain, physical activity, and mental health in lipedema patients.In this study, physical activity was measured via a tool assessing the number of units per week. This tool provides general information about the amount of physical activity the participants were engaging in per week. Thus, a more detailed assessment of the intensity or differentiation between exercise and physical activity was not possible. The data was obtained from patients presenting in our specialized clinic. The application of such convenience sampling can potentially lead to specific biases in results .Pain was substantially related to lower levels of mental, physical, environmental, and overall health, whereas physical activity positively affected mental, physical, and overall health. Thus, physical activity and pain stand in a complex, vicious circle-like synergetic relationship, influencing physical, mental, and overall health in lipedema patients.So far, studies focusing on the understanding of treatment and effectiveness, including the complex interrelations between physical and mental health symptoms and health behaviors, are of very high relevance. This study, using sophisticated methodology, had been developed to support filling this gap. Going beyond this study, pain relief and improved mobility resulting from liposuction may provide patients with the novel opportunity to engage in physical activity, and thus to benefit from the overarching and long-term positive effects of physical activity on physical and mental health. Also, the high relevance of supporting psychological consultation is outlined. The results of this study point out that the treatment of lipedema requires a complex and multi-component approach. Responding to this awareness, the inclusion of interventions targeting mental health and pain can have a high impact on the way to best practice treating lipedema patients.


Drawing on Wigfield and Eccles’s motivational theory, which is acclaimed for explaining individual behavioral intentions, this study investigated the extent to which different forms of motivation  predicted student behavioral feedback engagement  in English learning. The participants were 276 male and female students who were enrolled in a second-year full-time English language and literature program at two Chinese universities. Multiple regression analyses showed that task value emerged as the only motivational variable that significantly predicted both students’ action on teacher feedback and feedback seeking. Intrinsic motivation significantly predicted action on teacher feedback, whereas extrinsic motivation and self-efficacy significantly predicted feedback seeking. Pedagogical implications for endeavors to support students in their engagement with feedback in learning English as a foreign language in China are discussed. While the benefits of feedback are frequently mentioned in articles about learning and teaching, a major challenge for productive feedback processes is the difficulty of generating student engagement with the feedback they receive, which may limit student learning opportunities and undermine their confidence and motivation, leading to disengagement and even withdrawal from the feedback processes . AlthougMeanwhile, some researchers investigating second language feedback have explored individual learner differences underlying students’ preferences for different kinds of corrective feedback e.g., ,6,7). Th,7. Th6,7Following prior research on self-regulated language learning e.g., ,12,13), ,13, 12,11. What are the relationships between four motivational variables  and student action on teacher feedback in the context of an English language and literature program at a Chinese university?2. What are the relationships between four motivational variables  and student feedback seeking in the context of an English language and literature program at a Chinese university?An important theoretical framework to understand individuals’ motivational beliefs and their learning behavior in the literature is the expectancy–value model ,17. FromIn the Chinese culture, education is regarded as the path to success and meaningful participation in society throughout life . ChineseFrom a social cognitive theory perspective, self-efficacy represents people’s beliefs in their capabilities to organize and execute a given course of action to solve a problem or accomplish a task . Self-efIn the expectancy–value theory, task value refers to students’ perceptions of how important, how interesting, and how useful a particular task is. Task value, thus, differs from goal orientation in that goal orientation concerns the reasons why students are participating in a particular task , whereasIt is recognized in research that learners tend to work harder to achieve understanding and make greater progress when they are motivated to learn something . ResearcIn general terms, a very useful way of organizing conceptualization about engagement in learning in the field of education is the three-category taxonomy of engagement proposed by Fredricks et al. . Accordiaction on teacher feedback, which was defined in this study as students processing and using the feedback information offed by their teacher, and (2) feedback seeking, which was defined in this study as students proactively soliciting information in relation to their learning performance.In second-language acquisition, Ellis  applied In the field of organizational psychology, Ashford and Cummings  proposedApplying the model of Ashford and Cummings  on feedbTEM-4) and the Test for English Majors—Grade 8 (TEM-8) in their second and fourth year, respectively, in the program. These two English proficiency tests are developed and organized every year by the Chinese Ministry of Education.The sample comprised 276 second-year university students majoring in English language and literature from two universities that are located in central China. Students are admitted into the English language and literature program based on their assessment results from the National College Entrance Examination. The English language and literature program offers a range of courses, such as English vocabulary and grammar, speaking and writing, and English literature, which are intended to help students develop the understanding, knowledge, and skills they need to use English to communicate effectively in a variety of professional communication contexts. An institution-wide requirement that is worth noting is that students studying in the English language and literature program should take the Test for English Majors—Grade 4  males and 243 (88%) females. The age of the participants ranged from 17 to 22 years old (two participants did not state their age), with Items in the English language self-efficacy questionnaire were adapted from . The parBased on Pintrich et al. , the tasTo assess the participants’ intrinsic and extrinsic motivations in English learning, we modified eight items from Pintrich et al.’s  intrinsiAs discussed in the earlier section, the behavioral feedback engagement scale used in this study includes two factors: (1) action on teacher feedback and (2) feedback seeking. Items on the two factors were adapted from . The actdf), along with the associated p-value; the Comparative Fit Index ; the Tucker–Lewis Index ; the Root Mean Square Error of Approximation ; and the Standardized Root Mean Squared Residual (SRMR) . Second, descriptive analyses and correlation analyses were conducted. Third, two sets of multiple regression analysis were performed to explore the relative strength of different forms of motivational variables in predicting students’ behavioral feedback engagement in English learning.In this study, confirmatory factor analysis (CFA) was first conducted to test the fit to the data to all univariate models that represent the respective constructs. The following model fit indices were used for evaluating the model fit : the chiSince each of the instruments used in this study had a clear theoretical lineage, CFA was conducted to examine the construct validity. The CFA results provided evidence of the satisfying model fit of the English language self-efficacy scale, with factor loadings ranging from 0.67 to 0.86: χ2 = 233.28, df = 98; CFI = 0.96; TLI = 0.95; RMSEA = 0.07 ; and SRMR = 0.03. The CFA results also indicated that the two-factor motivational scale generally fit the data well: χ2 = 61.70, df = 14; CFI = 0.95; TLI = 0.91; RMSEA = 0.11 ; and SRMR = 0.07, with the factor loadings of the items ranging from 0.46 to 0.95. With regard to the task value scale, the CFA results confirmed that the measurement model had a good fit with the data: χ2 = 11.41, df = 6; CFI = 0.99; TLI = 0.99; RMSEA = 0.06 ; and SRMR = 0.02, and the factor loadings of the items ranged from 0.63 to 0.89. Finally, with regard to the behavioral feedback engagement scale, two items were deleted because of their strong correlations with other constructs. The CFA results for the remaining 13 feedback behavior items, which factor loadings ranged from 0.52 to 0.88, revealed a good model fit: χ2 = 172.76, df = 57; CFI = 0.96; TLI = 0.94; RMSEA = 0.08 ; and SRMR = 0.06.The Cronbach’s alpha values for the factors shown in M = 4.82, SD = 1.06) than they engaged in feedback seeking . With regard to the motivational variables, the results show that the highest rating was given to task value beliefs . This was followed by extrinsic  and intrinsic motivations , and then English language self-efficacy . The students reported roughly identical levels of extrinsic and intrinsic motivations, and their rating of English language self-efficacy was the lowest. The correlation matrix in r = 0.70), and the lowest is between extrinsic motivation and action on teacher feedback (r = 0.42). Overall, the higher levels of perceived task value, intrinsic and extrinsic motivations, and English language self-efficacy, the more students act on teacher feedback and engage in feedback seeking.The descriptive statistics for the variables and the correlations between these variables are also provided in p < 0.001) and intrinsic motivation , are significant predictors. With feedback seeking as the outcome variable, the model accounts for 46% of the variance, and three motivational variables, self-efficacy , task value beliefs , and extrinsic motivation , are significant predictors.Multiple regression analyses were conducted to investigate the relationships between self-efficacy, task value beliefs, intrinsic and extrinsic motivations, and feedback engagement. As demonstrated in In this study, task value beliefs emerged as the only motivational variable that significantly predicted both action on teacher feedback and feedback seeking. Task value beliefs refer to learners’ evaluation of how important, useful, and interesting a learning task is . The resIntrinsic motivation refers to the situation where the actor is free of coercion, demand, or persuasion to engage in, or not engage in, a particular task . In thisThe missing link between intrinsic motivation and feedback seeking in this study is somewhat not expected because, according to the self-regulated learning theory, intrinsically motivated students are both persistent and resourceful in that they not only act upon teacher feedback but also actively seek external feedback, for example, from teachers and peer classmates or other external sources . HoweverIn this study, extrinsic motivation had a significant relation with feedback seeking but not with action on feedback. Ashford and Northcraft  argued tSelf-efficacy reflects a student’s contextually specific judgments of their abilities or confidence to perform an academic task successfully ,67. Reseintrinsic and extrinsic motivations) predicted two types of behavioral feedback engagement  in English learning within the context of a tertiary-level English language and literature program. Understanding what keeps students engaged with feedback is of great importance if the inherent power of feedback is to be harnessed [The present investigation examined the extent to which four motivational variables .This study contributes to the literature by providing empirical evidence that feedback is not simply a cognitive process involving only the transfer of information, but feedback is regulated by multiple forms of motivation; however, some limitations to the present study should be acknowledged and direction for future research needs to be provided. First, this investigation was a cross-sectional study and the findings of our study only indicate the associations or relationships between the variables. As such, conclusions about the causal direction of effects, which requires careful experiments, could not be established. In future research, longitudinal design is needed to confirm the direction of the relationships tested. Second, as is the case with other survey-based investigations, this investigation’s use of self-reported data is likely to be subjected to bias. Although self-report has been widely utilized as a valid approach for measuring student perceptions and intra-psychic processes, responses from student self-report might not accurately reflect their true feelings. Future studies could adopt additional objective measures, such as teacher reports or classroom observations, to corroborate the statistical evidence reported in this study. Third, this study represents the first attempt to empirically operationalize action on teacher feedback and feedback seeking to investigate their relations to students’ English-language self-efficacy, task value beliefs, and intrinsic and extrinsic motivations. As the items used for measuring these two types of student feedback behavior are relatively newly proposed, further assessment with other populations is needed to provide evidence from external aspects regarding the construct validity of the two scales. Fourth, most of the participants in this study were females as a consequence of the trend across language and literature programs that female students tend to outnumber male students, which limits the generalizability of the current research findings. Fourth, although this study provided insight into the dynamic relationships between motivational processes and student feedback experience in the context of a university-level English language and literature program, the models in this study should be replicated and further examined in other academic subject areas. It is critical to administer the instruments more widely to other languages or other subjects in order to further illuminate the generalizability of the role of motivational factors in students’ feedback engagement across different academic subjects and demonstrate the utility of such instruments. In particular, we suggest that future research replicates this study to examine the generalizability of our findings to different social and cultural contexts and different age or gender groups. Finally, our study is limited in terms of a relatively small sample size. Future studies are encouraged to include a larger sample of students to achieve better generalizability.


We estimated that about 2% of the CA were located in the immediate vicinity of the vessels or in the peri-vascular space. While CA in the ependymal lining of the cerebral aqueduct was rare, the sub-pial tissue of the anterior and posterior midbrain contained several CA. In the sample with the highest CA density, quantitative maps obtained with MRI revealed high R2* values and a diamagnetic shift in a region which spatially coincided with the CA dense region.Corpora amylacea (CA) are polyglucosan aggregated granules that accumulate in the human body throughout aging. In the cerebrum, CA have been found in proximity to ventricular walls, pial surfaces, and blood vessels. However, studies showing their three-dimensional spatial distribution are sparse. In this study, volumetric images of four human brain stems were obtained with MRI and phase-contrast X-ray microtomography, followed up by Periodic acid Schiff stain for validation. CA appeared as hyperintense spheroid structures with diameters up to 30 μm. An automatic pipeline was developed to segment the CA, and the spatial distribution of over 200,000 individual corpora amylacea could be investigated. A threefold—or higher—density of CA was detected in the dorsomedial column of the periaqueductal gray (860–4,200 CA count/mm Corpora amylacea (CA) are polyglucosan aggregates that tend to accumulate in several organs throughout aging  and the effective transversal relaxation rate (R2*) have been used to measure calcifications and iron content, and high resolution QSM has been used to detect paramagnetic shifts likely originating from iron-binding beta amyloid plaques in Alzheimer's disease , CA-dependent alterations of the T1 and T2 weighted signals have been reported 3 and 5 × 5 × 5 μm3. Finally, the specimens were prepared for histology to verify the presence of CA. By using automated segmentation on SR PhC-μCT images with 1 μm isotropic voxels, we could identify a large number of CA in the midbrain and investigate their spatial distribution. A higher number of CA were found along the midline of the mesencephalon, corresponding to the dorsomedial periacqueductal gray (dmPAG). MRI of the sample with the highest CA density showed increased R2* and more diamagnetic QSM values in the dmPAG area than in the surrounding tissue. The proposed methodology opens up novel prospects for studying CA in ex vivo brain tissue.In the present study, we used three techniques to study the CA in human brain stems. First, gradient echo images were acquired using a high field MRI scanner to visualize the anatomy of the samples prior to paraffin embedding and to obtain quantitative MRI parameters. To be able to resolve individual CA which have diameters <30 μm  were collected through the body donor program at the Institute of Clinical Anatomy and Cell Analysis, Department of Anatomy, Eberhard Karls University of Tübingen. The donors provided their informed consent in line with the declaration of Helsinki for research purposes. The ethics commission at the Medical Department of the University of Tübingen approved the procedure. The donors had no history of neurological disease. The samples were fixed in formaldehyde solution  for a minimum of 4 weeks and kept at room temperature throughout this study  during the MRI acquisition. Multi-echo gradient echo images were acquired at 14.1T . The samples were positioned at the center of the magnet and the radio-frequency (RF) coil followed by global shimming, frequency adjustment, reference power optimization, and receiver gain adjustment using the automatic set-up method provided by the manufacturer (software: Paravision 6.0.1). We used a BFG240-120-S14 gradient system and an in-house built quadrature volume transceiver RF coil. Scanning parameters are provided in *) were generated by fitting a mono-exponential decay curve to the square of the magnitude using least square procedure. Quantitative susceptibility mapping image was calculated from the first echo after ROMEO unwrapping  axis, dehydrated in increasing ethanol concentration, transferred to Xylene, and embedded in paraffin for SR PhC-μCT. Data acquired from the paraffin blocks covering the midbrains are presented here. For sample 1, 3, and 4, two blocks were measured, where one included the midbrain section covering the superior colliculus and the other included the inferior colliculus. For sample 2, the midbrain was smaller and a single block covered the entire midbrain.11 photon/s/mm2 during the first two beam times, and about 24% lower flux during the third. Using a half-acquisition mode . For subjects 1, 3, and 4, every 10th section was stained with the luxol fast blue—cresyl violet method, and for subject 2, serial sections were stained with luxol fast blue—cresyl violet. Furthermore, selected slides were stained using periodic-acid Schiff–hematoxylin method for subject 1, 3, and 4 and additional hematoxylin and eosin stain for subject 4. Stained slices were digitized using a Zeiss Axio scan microscope .We used ImageJ software  and a sphericity >0.85  where σ is the standard deviation of the Gaussian function, which we set to 50 μm. For each coordinate, Gaussian weights for the five nearest neighboring CA were added. The unit for the resulting metric is arbitrary. Different pairs of parameters are known to lead to similar density maps -filled spaces, such as the ependymal or subpial regions Alder, . Since tExamining the midbrain in an axial plane , there aThere has been contradicting claims on the relationship between blood vessels and CA. Navarro et al.  found blIn order to investigate the co-localization of CA and blood vessels, we developed a segmentation method that separates blood vessels from CA located in the blood vessel boundaries . The resSeveral CA were observed in the anterior medial vessel in all four subjects. * values and a diamagnetic shift in quantitative susceptibility maps concomitant with the CA distribution in this region . Periodic acid Schiff reaction was used to validate these granules as CA. There are three novel findings in regard to the distribution of CA in the present work: (1) dmPAG accumulates high numbers of CA, (2) not all pial surfaces accumulate CA in the midbrain, and (3) only 2 percent of the CA are located in immediate proximity to the vessels and the perivascular space. Furthermore, in one of the samples we found indications that CA can cause prominent local field inhomogeneities in MRI which lead to alterations in gradient-echo images and quantitative maps. Below, these findings are discussed in more detail.We investigated the brain stem of four subjects and found the dmPAG to accumulate large numbers of CA. In two of our specimens, we could investigate additional brain regions more caudally . We checPrior studies report observing abundant CA in the vicinity of CSF-filled spaces, such as the ependymal or subpial regions Alder, . In the postmortem tissue, remains a challenge. Furthermore, the contribution of the intramural periarterial drainage pathway should also be assessed as a potential clearance process , previously reported in Wilson's disease, implausible. Other content like calcium is more likely but would require further analysis to be ascertained. A diamagnetic shift in MRI can also occur in myelin-rich areas, where CA also can be found. Dependent on the magnetic properties of the surroundings, it may thus be difficult to distinguish between MRI signal changes driven by CA, that are much smaller than the voxel size used, and other tissue components. Future studies could take CA isolated from CSF as done in Riba et al. (in vivo scanning of aging populations.Corpora amylacea have been investigated previously using X-ray microanalysis (Singhrao et al., a et al.  to obtaiIt is also possible that the components of CA differ in neuropathology. If the current hypothesis of CA serving as a general waste container is true, then CA in patients might contain different components. It has already been shown that molecules observed in CA in Alzheimer patients are different from the normal aging brain (Singhrao et al., Collectively, we show that SR PhC-μCT is a suitable method for understanding the three-dimensional distribution of CA. MRI can be used to obtain additional information regarding their magnetic properties, albeit at a coarser spatial scale. In order to fully understand their distribution in the human nervous system, it will be ideal to obtain high resolution PhC-μCT of the entire brain including cerebrum, cerebellum, and brain stem. The Human Organ Atlas (Walsh et al., In conclusion, we used state of the art biomedical imaging techniques coupled with classical histology methods to study CA within the human brain stem. CA were present throughout the entire midbrain. We found that the dmPAG region of the midbrain had exceptionally high numbers of CA. For the subpial surfaces, not the entire surface but only the anterior and posterior medial parts seem to collect CA. The subependymal region of the aqueduct did not accumulate CA. Further studies should be conducted to understand why CA tend to accumulate in certain regions.The original contributions presented in the study are included in the article/The studies involving humans were approved by Medical Department of the University of Tübingen. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.JL: investigation, data curation, methodology, software, formal analysis, writing—original draft, and writing—review and editing. AM and UM: resources, investigation, validation, and writing—review and editing. SD: investigation, methodology, data curation, and writing—review and editing. RL: investigation, methodology, and writing—review and editing. GT: investigation, software, and writing—review and editing. TS: resources and writing—review and editing. KS: funding acquisition, data curation, and writing—review and editing. GH: conceptualization, investigation, methodology, software, data curation, formal analysis, supervision, writing—original draft, project administration, writing—review and editing, and funding acquisition. All authors contributed to the article and approved the submitted version.


P for nonlinearity < 0.001). Similar trends were found across three time-windows . Compared with those with both low LPA (<3.89 h/day) and low MVPA (<0.27 h/day), the adjusted HR (95% CI) of PD risk was 0.49 (0.36–0.66), 0.19 (0.36–0.66) and 0.13 (0.09–0.18), respectively, for participants with high MVPA only, high LPA only, and both high LPA and high MVPA. Moreover, participants with both low LPA and high sedentary time (≥9.41 h/day) , and those with both low MVPA and high sedentary time  had the highest risk of incident PD. In conclusion, regardless of exercise timing , there was an inverse association for accelerometer-measured MVPA and LPA, and a positive association for sedentary time, with incident PD.Evidence regarding the association between physical activity and Parkinson’s disease (PD) risk is generally limited due to the use of self-report questionnaires. We aimed to quantify the separate and combined effects of accelerometer-measured light physical activity (LPA), moderate-to-vigorous physical activity (MVPA), sedentary time and exercise timing with incident PD. 96,422 participants without prior PD and with usable accelerometer data were included from UK Biobank. Time spent in sedentary activity, LPA, MVPA, and exercise timing were estimated using machine learning models. The study outcome was incident PD. Over a median follow-up duration of 6.8 years, 313 participants developed PD. There was a L-shaped association for LPA and MVPA, and a reversed L-shaped association for sedentary time, with the risk of incident PD (all  PD affects 2 to 3% of the global population aged over 65, and the incidence of PD continues to rise in almost every part of the world with the increase of aging population4. In the absence of effective drugs to halt or retard neurodegeneration, developing non-pharmacological strategies  to prevent the onset of PD is essential.Parkinson’s disease (PD) is the second most common neurodegenerative disease (after Alzheimer’s disease) characterized by the progressive loss of dopaminergic neurons in the substantia nigra and in other neuronal systems5, has long been known to reduce mortality and lower the risk of other neurodegenerative diseases such as Alzheimer’s disease and cognitive decline9. Although intensive PA has been reported to be associated with neuroprotective and neurorestorative effects in the nigrostriatal dopaminergic system10, previous cohort studies designed to examine the relationship between PA and the risk of PD have yielded inconsistent results. A recent meta-analysis of previous prospective studies showed that there was an inverse dose-response association of total PA and moderate-to-vigorous PA (MVPA) with PD risk in men, but not in women11, while a subsequent study reported that higher total PA was significantly associated with a lower PD incidence in women12. Of note, all of these studies used self-reported measures of PA, which are more prone to recall bias and, therefore, a weak surrogate to measure activity and capture the true magnitude and nature of the association between PA and PD risk. Moreover, due to the inability of self-reported questionnaires to accurately measure light intensity PA (LPA)14, there is limited evidence for the association between LPA and PD risk, despite LPA being the predominant form of activity in daily life and a more feasible behavioral goal for middle-aged and older adults15.Physical activity (PA), defined as any bodily movement produced by skeletal muscles resulting in energy expenditure16, so there is a need to further clarify whether the health benefits of PA depend on the temporal distribution of PA throughout the day. While previous studies have suggested that PA at specific times may be beneficial in lowering blood glucose levels and activating PA metabolic pathways18, there is no consistent evidence that equivalent amounts of PA in the morning, midday-afternoon, and evening may have different effects on health outcomes19. More importantly, few studies have assessed the relationship between PA at different times of the day  and PD risk.In addition, there is growing evidence that almost all physiological and biochemical processes in the human body follow circadian rhythms15 and is thought to impair glucose and lipid metabolism20, both of which are risk factors for PD21. Nevertheless, there is little direct evidence of the association between sedentary time and PD risk. Furthermore, given that different combinations of PA and sedentary time are reasonable during waking times, and may potentially lead to a gradient of health consequences23, it is important to assess the role of the interrelationship between PA and sedentary time on PD risk.Moreover, sedentary time is another major part of daily activities for the general populationOverall, due to the recall bias of traditional self-reported PA measurements and limitations such as the inability to accurately collect LPA, exercise time, and sedentary time, using new digital and mobile technologies to accurately address the above gaps in knowledge becomes a necessary option. Of note, embedded sensors in wearable technology can capture data remotely, passively, and continuously, and various algorithms may then be applied to the acceleration signal to more accurately estimate LPA, MVPA, exercise time and sedentary time. However, no studies have fully evaluated the relationship between these various objective accelerometer-generated PA information and the risk of incident PD.As such, using data from the UK Biobank, we aimed to examine the individual and combined effects of accelerometer-measured LPA, MVPA, sedentary time and exercise timing on the risk of incident PD.Of the 96,422 participants included , 313 (0.3%) participants developed incident PD, of which 98.4% were ascertained by hospital admissions recodes. As shown in Table P for nonlinearity < 0.001).As shown in Fig. Consistently, when PA and sedentary time were assessed as quartiles, compared with participants in the first quartile, those in the second , third , and fourth  quartiles of LPA, and those in the second , third , and fourth  quartiles of MVPA, had a significantly lower risk of incident PD, while those in the third  and fourth  quartiles of sedentary time had a significantly higher risk of incident PD , but not multiplicative interaction (P for interaction = 0.168) between LPA and MVPA on PD risk  of PD risk was 0.49 0.36,0.66), 0.19  and 0.13 , respectively, for participants with high MVPA only, high LPA only, and with both high LPA and high MVPA  or multiplicative scales  and sedentary time were considered, compared with those with high LPA and low sedentary time, participants with both low LPA and high sedentary time had the highest risk of incident PD , there was an inverse association for MVPA and LPA, and a positive association for sedentary time, with the risk of PD. More importantly, participants with both high LPA (≥3.89 h/day) and high MVPA (≥0.27 h/day) had the lowest risk of PD, while participants with both low PA (LPA < 3.89 h/day and MVPA < 0.27 h/day) and high sedentary time (≥9.41 h/day) had the highest risk of PD.29 found an inverse dose-response association of total PA and MVPA with PD risk in men, but not in women11. Subsequently, the E3N Cohort Study observed a significant inverse association between total PA and PD in women12. In contrast, the few previous studies28 did not observe a significant association between LPA and PD risk. It is important to note that all of the above studies have common limitations in that they used self-reported questionnaires to assess PA, which are more prone to recall bias and have lower validity and accuracy. What’s more, the ubiquitous presence and sporadic nature of LPA makes it impossible to accurately assess through recall by self-reported questionnaires30. Therefore, to date, the relationship of LPA and MVPA and PD risk remains unknown. At the same time, few studies have examined the association between sedentary time and PD risk.A recent meta-analysis of previous prospective studies31. Moreover, we further observed an additive interaction between LPA and MVPA, suggesting that high LPA and MVPA synergistically decrease the risk of PD, and therefore, promotions targeting both LPA and MVPA may be more effective in preventing PD. Our results also suggest that participation in LPA may have a greater benefit relative to participation in MVPA. In addition, in the 1st quartile population, only a modest increase in either LPA or MVPA to 3.89 h or 0.27 h daily was associated with a substantially lower risk of PD. Since such an increase in activity is achievable in humans, our study emphasizes the potential benefits of a modest increase in MVPA to reduce the risk of PD, and further provides an alternative strategy of increasing LPA to reduce the risk of PD, as LPA is more feasible and reasonable for inactive individuals or middle-aged and elderly people. Further work is needed to confirm our results and determine causality.Based on accelerometer-derived PA, sedentary time and exercise timing , our study provides some unique contributions. First, we found that objectively quantified PA, regardless of LPA or MVPA, was associated with a significantly reduced risk of PD. These findings are consistent with evidence from animal and human data that physical exercise has neuroprotective effects by promoting the expression of neuroprotective growth factors, increasing the release of neurotrophic factors, reducing damage to dopaminergic neurons in motor circuits, and reducing cellular inflammation and oxidative stress32. Although PA has been reported to eliminate the increased risk of death associated with high sedentary time33, and our study also showed that the combination of low PA and high sedentary time led to the highest risk of incident PD, we found that PA and sedentary time had neither a significant additive nor a significant multiplicative interaction effect on PD risk. It suggests that PA and sedentary time are two key and independent behavioral pathways that modify the risk of incident PD.Second, given that most adults spend most of their waking time inactive, the effect of sedentary time on health is gaining widespread attention. To our knowledge, no other studies have examined the association of sedentary time with PD risk. We found a nonlinear positive association between sedentary time and PD risk, with a threshold of approximately 9.4 h per day, which is similar to the threshold, 9 h per day, between daily sedentary time and all-cause mortality risk, beyond which the risk of all-cause death increases19, little is known about the effect of timing of exercise on PD risk. Our study showed that regardless of exercise timing , higher MVPA and LPA levels were associated with a lower risk of PD, while high sedentary time was associated with a higher risk of PD. Of note, we observed a slightly lower PD risk associated with moderate sedentary time in the evening period. One possible explanation is the heterogeneity in the types of sedentary behavior, as specific components of sedentary behavior may have different effects on cognition. The mentally active types of sedentary behavior (such as reading and computer using) immediately affects cerebral hemodynamics, leading to higher blood flow velocities and higher cerebral metabolism35, and thereby contributing to improved cerebrovascular health. Consistently, in our sensitivity analysis, there was a U-shaped association between non-occupational computer using with the risk of incident PD.Third, although a growing recognition of the importance of exercise timing on healthOverall, the contribution of our study in terms of digital medicine is as follows: Based on the objectively measured time of different movement behavior in a free-living setting, which could be better interpretable and easier to be translated into recommendations, our study explores the individual and combined effects of accelerometer-measured LPA and MVPA and sedentary time on the risk of incident PD, suggesting that the digitization of wearable sensors may have practical value in the primary prevention of PD. Moreover, we introduced a timing phenotype of activity and found that increasing PA and decreasing sedentary time in any time windows  was associated with a lower risks of PD. Our findings suggest that clinicians and healthcare systems may consider using accelerometer-measured PA and sedentary time to guide and improve strategy development and practice for prevention of PD.36, the single time-point limits any potential inferences related to within-person changes or variability in PA and sedentary time over time. Thirdly, the participants in our study were predominantly of European descent and healthier than the UK general population37, which may limit the generalizability of the findings to other populations. Nevertheless, a representative population is not required to validly assess the relationship between exposure and disease37. Due to these limitations, further studies to confirm our findings are necessary.This study has some limitations. Firstly, due to the nature of observational studies, despite comprehensive adjustments for a range of covariates, residual confounding cannot be completely ruled out and causality cannot be determined. Secondly, although 7-day monitoring periods have been routinely used in previous studies because they provide an opportunity to sample PA and sedentary time on both weekdays and weekend days, and achieve a greater than 80% intra-class correlations in most populationsIn conclusion, we found that regardless of exercise timing , higher accelerometer-measured MVPA (≥0.27 h/day) and LPA (≥3.89 h/day) were associated with a lower risk of PD, while higher sedentary time (≥9.41 h/day) was associated with a higher risk of PD. Moreover, participants with both high LPA and high MVPA had the lowest risk of PD, and participation in LPA may have a greater benefit relative to participation in MVPA. If further confirmed, our study suggested that increasing participation in PA, regardless of intensity and exercise timing, and controlling sedentary time should be prioritized throughout one’s lifetime to prevent PD incidence. Clinicians and healthcare systems may consider the use of accelerometer-measured PA and sedentary time as a metric of health evaluation and promotion.38, the UK Biobank is a large, observational, population-based cohort recruiting half a million adult residents, aged 37–73 years, from 1 of 22 assessment centers across the United Kingdom  between 2006 and 2010. At baseline, participants were asked to complete a comprehensive questionnaire assessing sociodemographic, lifestyle, and health related information, receive physical examinations and provide biological samples. The UK Biobank was approved by the North West Research Ethics Committee (11/NW/0382) and all participants signed an informed consent.As previously described40. Additionally, we excluded participants who had been diagnosed with dementia or PD before the end of their accelerometer wear, resulting in 96,422 participants for the final analysis , if the average acceleration was implausibly high (>100 milli-gravity), or if the file failed to process40. Participants were instructed to wear the device on their dominant wrist continuously for 1 week while continuing with their usual activities. The accelerometer captures triaxial acceleration data over 7 days at 100 Hz with a dynamic range of ±8 gravity. Time spent in sedentary activity , LPA , and MVPA  were estimated using machine learning models that were trained using wearable cameras and time-use diaries among 152 individuals in free-living conditions39.Between February 2013 and December 2015, participants who provided a valid email address to UK Biobank were invited at random to wear a wrist-worn accelerometer (Axivity AX3). The response rate was 45%, but participants who received accelerometry measurements showed similar baseline demographic and health-related characteristics as those who declined the measurementshttps://biobank.ndph.ox.ac.uk/ukb/ukb/docs/alg_outcome_pdp.pdf). The follow-up for each participant was calculated from the final date of accelerometer wear until the first date of PD diagnosis, date of death, date of loss to follow-up, or the end of follow-up, whichever came first.The study outcome was incident PD. Ascertainment of PD was based on self-reported data, diagnosis in the hospital admissions data, or cause of death recorded in the national death register, whichever was the earliest. The UK Biobank study conducted a validation study on the accuracy of code sources for identification of PD cases, which achieved a positive predictive value (PPV) of 0.91 , income, education levels, employment, smoking, and alcohol drinking. Body mass index (BMI) was also measured and calculated as weight (in kilograms (kg)) divided by the square of height (in meters (m)). Pre-existing hypertension, diabetes, and cardiovascular disease (CVD) were diagnosed by baseline self-reported medical history or health records taken before the time of accelerometer measurement.Population characteristics, presented as mean (SD) for continuous variables or proportions for categorical variables, according to incident PD status, were compared using t-tests for continuous variables and chi-square tests for categorical variables.Restricted cubic spline (RCS) Cox regression was performed to test for linearity and explore the shape of the dose-response relationship of PA and sedentary time with incident PD. Cox proportional hazards models were used to estimate hazard ratio (HR) and 95% confidence interval (CI) for incident PD according to the quartiles of exposures  throughout the day and at different time-windows , without and with adjustments for demographics , anthropometric and lifestyle factors , pre-existing chronic conditions , and the season of accelerometer wear. The proportional hazards assumption was checked using the Schoenfeld residuals, and no violation was found.To test the robustness of our findings, several sensitivity analyses were also performed. First, participants within 2 years of follow-up were excluded. Second, the Fine-Gray competing risk model was used to examine the association while accounting for death as a competing risk. Third, we further explore the association between sedentary behaviors  and incident PD. At baseline, the durations of sedentary behaviors were collected using a touchscreen questionnaire by asking “In a typical day, how many hours do you spend watching TV/using the computer (do not include using a computer at work)”.41. Interactions on a multiplicative scale were also tested by adding a cross-product term between PA and sedentary time to the multivariable Cox models.In addition, the adjusted Cox proportional hazards model was used to examine the combined effect of LPA and MVPA (categorized to four groups), and PA (LPA and MVPA) and sedentary time  on PD risk. The relative excess risk due to interaction (RERI) was calculated to evaluate the interaction between PA and sedentary time on an additive scale, where an RERI equal 0 means no additive interaction and > 0 means a positive interaction2), smoking status (never or ever), alcohol drinking (<1 or ≥ 1 times/week), and TDI (<median or ≥ median).As additional exploratory analyses, RCS Cox regression was used to determine the dose-response relationship of PA and sedentary time within three time-windows  with incident PD. Furthermore, possible modifications of the association of PA and sedentary time with incident PD were also assessed for the following variables: age (<60 or ≥60 years), sex , BMI .A two-tailed Further information on research design is available in the Reporting SummarySupplementary Information