In this study, total lesion glycolysis (TLG) on positron emission tomography images was estimated by a trained and validated CT radiomics model, and its prognostic ability was explored among lung cancer (LC) and esophageal cancer patients (EC).Using the identical features between the combined and thin-section CT, the estimation model of SUVsum  was trained from the lymph nodes (LNs) of LC patients (n = 1239). Besides LNs of LC patients from other centers, the validation cohorts also included LNs and primary tumors of LC/EC from the same center. After calculating TLG  based on the model, the prognostic ability of the estimated and measured values was compared and analyzed.In the training cohort, the model of 3 features was trained by the deep learning and linear regression method. It performed well in all validation cohorts (n = 5), and a linear regression could correct the bias from different scanners. Additionally, the absolute biases of the model were not significantly affected by the evaluated factors whether they included LN metastasis or not. Between the estimated natural logarithm of TLG (elnTLG) and the measured values (mlnTLG), significant difference existed among both LC  and EC patients . However, for both cancers, the overall shapes of the curves of hazard ratio (HR) against elnTLG or mlnTLG were quite alike.Total lesion glycolysis can be estimated by three CT features with particular coefficients for different scanners, and it similar to the measured values in predicting the outcome of cancer patients. Therefore, this study was designed to explore its feasibility.Radiomics has gained attention recently due to the quantitative information extracted from medical images and derived features, which are associated with cancer phenotype, patient outcome, treatment response, and other classification data , 2. Howein vivo can be imaged by a positron emission tomography scanner (PET). Because the resolution of PET images is lower than other medical imaging modalities, an additional CT (combined CT) scan is conventionally acquired to accurately locate the abnormal uptake of tracer. Therefore, commercial scanners are simultaneously equipped with PET and CT scanners, and the images are successively acquired. In PET/CT image analysis, standard uptake value (SUV) is the most frequently used semi-quantitative parameter for measuring FDG uptake and is a unitless value of a single pixel in a lesion. There are several types of SUV, for example, maximal SUV (SUVmax) and sum SUV (SUVsum) means the maximum and total value of a primary tumor (or a lymph node), respectively (Radioactive 18F labeled Fluorodeoxyglucose (18F-FDG) is an analog of glucose, and its distribution ectively –5.SUVmax of the primary tumor is commonly used in various PET/CT reports, and is related to the prognosis of myeloma, lymphoma, and other cancers –5; howevIn this study, we trained and validated a CT radiomic model to estimate the SUVsum of each lymph node or primary tumor on PET images. The prognostic ability of the estimated TLG was then evaluated and compared to the measured value.ClinicalTrials.gov (NCT03648151). For a retrospective study, the two review boards waived the requirement for informed consent.From January 2015 to December 2019, pathologically confirmed lung cancer (LC) patients were screened from the First Affiliated Hospital of Shanxi Medical University (SMU), the First Affiliated Hospital of Anhui Medical University (AMU), and the RIDER Lung PET-CT dataset . AdditioEligible patients had accepted PET/CT scans (PET and combined CT), and at least one LN (short-axis diameter > 3mm) was visible on CT images identified by two experienced radiologists. For the lung cancer patients from SMU (SMU LC), besides PET/CT images, an additional thin-section chest CT scan was acquired. The excluded patients had a history of diabetes, chronic heart diseases, or chronic renal failure. The inclusion criteria of LNs were (1): in the regions (1-14) defined by the International Association for the Study of Lung Cancer (IASLC) guidelines , 12 (2);The study design is presented in In brief, lymph nodes and primary tumors on the combined or thin-section CT images were semi-automatically segmented. The lymph nodes (LNs) of SMU LC were the training cohort. Predictable features for estimating the SUVsum of each LN were selected and sorted by deep learning method. The candidate features were the same between the top 20 features on the combined and thin-section CT images. The estimation model was trained by the partial least squares (PLS) and the linear regression of Passing & Bablok and validated using the cohorts outlined in For each SMU cancer patient, the total SUVsum of the primary tumor and lymph nodes was calculated by trained model, and its prognostic power was evaluated and compared with the measured TLG on PET images. The patients were followed to the end of November 2019 by medical records or communications. Overall survival (OS) was defined from the day of PET/CT scan to death for any reason. The patients were staged according to the Seventh Edition of the Union for International Cancer Control American Joint Committee on Cancer System (UICC-AJCC). Age was stratified by the median age of the cohort. Treatment modalities after PET/CT scans were stratified into no treatment, chemotherapy only, radiotherapy only, and combined chemo-radiotherapy. Target drug administration was also followed, included signal transduction inhibitors, gene expression modulators, immunotherapy drugs, and others.Right censored survival data, and model training and validation were analyzed by the R software . Besides the basic packages of the R package, others included ggplot2, Hmisc, survcomp, h2o, and et al. Two sides of P<0.05 were considered as a significant level.The results of model training and validation are presented in the In the validations of the images acquired by the same scanner  and esophageal cancer (n=56) patients were 64y (range: 38-88y) and 65.5y (range: 44-83y), respectively. Between the two cancers, the characteristics of pathology, TNM stage, and treatment modalities had significant differences Table 2;To evaluate the prognostic ability of the values estimated by the model, the accumulated SUVsum of the primary tumor and lymph nodes in each patient of the SMU cohort was calculated. Between the estimated natural logarithm of TLG (elnTLG) and the measured values (mlnTLG), significant difference existed among both lung cancer  and esophageal cancer patients . Because the slight difference might not have a significant influence on their prognostic ability, they were analyzed as continuous variables in the following Cox regression.After PET/CT examinations, 7 and 49 esophageal cancer patients (n=56) received surgery and combined therapy, respectively. Among the lung cancer patients, 18 did not accept any treatment, and 14, 23 and 82 individuals received surgery, chemotherapy, and combined therapy, respectively. Additionally, target drugs were administered to 34 lung cancer and 11 esophageal cancer patients. The treatment modalities had no significant difference between the pathology types of lung cancer  or esophageal cancer .During the observation time from 30m to 106m (median: 43m), 91 lung cancer and 44 esophageal cancer patients died in the range of 0-40m (median 11 m) and 1-60m (median 15m), respectively. In the univariate Cox regression analysis Figure 3After integrating mlnTLG or elnTLG as continuous variables, all C-index of basic models were significantly deteriorated Figure 4According to the method from Liu et al. , the corIn this study, among the lung cancer and esophageal cancer patients, the CT radiomics model trained from lymph nodes could be used to calculate the natural logarithm of SUVsum of primary tumors and lymph nodes. Furthermore, in predicting the outcome of lung cancer patients, total lesion glycolysis (TLG) calculated by the model was similar to those measured on PET images. It should be noted that, for different scanners and protocols, a simple linear regression rather than deep learning analysis could be used to correct the bias. Additionally, the model was seldom affected by the evaluated factors of injected dose, acquisition time, LN volume, pathology, and even lymph nodes metastasis or not. Above all, our results illustrated the possibility of estimating quantitative values by radiomic models.With the development of computer science and technology, hundreds of radiomics features can be extracted from medical images. A previous study from Giesel et al.  indicateRecently, TLG was proposed as a better prognostic index than SUVmax among most cancer patients , 16, 17.In molecular imaging-guided radiation therapy (MIGRT), the delineation of gross target volumes (GTV) on CT is improved by molecular imaging technology, such as PET and SPECT images. The simple way is to manually delineate CT GTV and revise its boundary by visual interpretation of PET . HoweverTo train a repeatable model, as pre-described in the The advantage of the logarithmic estimation was that it was seldom affected by the evaluated factors, did and did not include lymph node metastasis. Because pathological evidence for LNs was not easy to prove, we alternately used the SUVmax=2.0 (or 2.5) as the threshold of benign and malignant ones. The correlation coefficients between the measured and estimated values were not changed according to the stratifications. Additionally, no different serial scatters appeared on the Bland-Altman and scatter plots of Model 1 Figure 2in vivo. Although the method needed to preset radiomics models for different equipment, it was easily performed by researchers or even equipment vendors through a simple linear regression. The advantage of the method was that the changes of the content could be repeatedly observed in vivo, and would widen the application range of radiomics.Additionally, our data suggested that it was possible to estimate the content of lesions by a radiomics model In summary, our study indicated that several CT radiomic features can be used to estimate the logarithm of SUVsum acquired by the same scanner, and the coefficients of the models could be corrected by a simple linear regression for different scanners or protocols.Total lesion glycolysis can be estimated by three CT features with particular coefficients for different scanners, and it similar to the measured values in predicting the outcome of cancer patients.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 First Affiliated Hospital of Shanxi Medical University and the First Affiliated Hospital of Anhui Medical University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Conceptualization, SL. Methodology, HS and XH. Software, LZ. Validation, XX and JC. Investigation, PW and LL. Resources, ZW. Data curation, CZ. Writing—original draft preparation, HS. Writing—review and editing, SL. Supervision, S.L. Project administration, S.L. Funding acquisition, H.S. All authors contributed to the article and approved the submitted version.The work was funded by grants from Collaborative Innovation Center for Molecular Imaging, Precise D&T Center (Grant No. MP201604) and Research Project of Health Commission of Anhui Province (Grant NO. AHWJ2021b148). Funding organizations had no role in the design, implementation, interpretation, and publication of the study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Sarcopenia is a muscle disease in loss of muscle strength, mass, and function associated with aging. Although protective effects of exercise on muscle mass and function are generally recognized, research findings in sarcopenic adults are inconsistent. It is necessary to conduct a systematic review to determine the effects of exercise on muscle strength, body composition, and physical performance in older adults with sarcopenia, and to examine the potential moderators including sociodemographic characteristics and exercise-related factors.Methods: Six electronical academic databases  were used to retrieve the eligible studies from inception to May 2020. Two reviewers independently selected and extracted the data from each included study, and effect sizes were calculated by employing random-effect models with 95% confidential interval (CI). The Physiotherapy Evidence Database (PEDro) scale was used to assess study quality.Results: Seventeen studies  were included in this review study. The meta-analytic results showed significant improvements in muscle strength , in physical performance , and in body composition . However, there were no significant differences in other body composition (SMD = 0.20–0.36). Additionally, meta-regression revealed that the higher percent of female participants was significantly associated with improved gait speed  and decreased skeletal muscle mass index .Conclusions: The current meta-analysis suggests that exercise is a beneficial therapy, which has protective effects for older adults with sarcopenia. Some beneficial effects may be moderated by gender and exercise intensity. One of the major public health challenges is to preserve older adults' physical ability and quality of life, to achieve successful aging in the whole society  in older adults –14. MoreAdditionally, it is important for sarcopenic older adults to have optimized exercise programs that can promote their physical health. A previous study has found that the exercise modalities  were not met to counteract sarcopenia . DenisonTherefore, the current study was conducted: 1) to determine the effects of exercise on muscle strength, physical performance, and body composition in older adults with sarcopenia and 2) to investigate whether the potential moderators including sociodemographic characteristics and exercise-related factors that influence the intervention effects, as these moderators have been found affecting the sarcopenia-related health outcomes .https://www.crd.york.ac.uk/) and performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  “sarcopenia” OR “sarcopenic” OR “dynapenia” OR “muscular atrophy” OR “muscular weight” OR “grip strength”; AND 3) “older adults” OR “aged” OR “elder*”; AND 4) “randomized controlled trials” OR “clinical trial” OR “random allocation.” To retrieve more eligible articles, manual searching was conducted from the bibliographies of the included studies.This systematic review was prospectively registered at PROSPERO  Participants aged over 65 years were diagnosed as sarcopenia based on the definition of EWGSOP, Asia Working Group for Sarcopenia (AWGS) or other clinical diagnosis. (ii) The study was designed as an RCT. (iii) Exercise  was used in the intervention group. (iv) No exercise intervention  was given in the control group. (v) The outcomes were muscle strength, body composition , and physical performance (gait speed and timed up and go test). (vi) The study was published in the English language.in vitro with an animal trial, (ii) participants with sarcopenia obesity, (iii) insufficient information for calculating the effect size (ES), And (iv) case-study, observational studies, editorials, or review articles.Exclusion criteria were: (i) Detailed information was extracted from each study through a pre-created extraction table by two authors (YZ and LZ). The presenting information included the author and year of publication, study design, participants' characteristics, interventions, sarcopenia diagnostic criteria, assessment tool for body composition, outcomes, and safety.Assessment of study quality was conducted using the Physiotherapy Evidence Database (PEDro) scale  by two aI2 test, which was classified as three levels: low, moderate, and high heterogeneity with cutoff points . We assessed the publication bias using Egger's regression test and Funnel plot. The Duval and Tweedie's trim and fill method was used to assess the potential impact of this publication bias. A two—side analysis with a significant level of 0.05 was used in all analyses.The Comprehensive Meta-Analysis program (version 2.2) was used for analyzing the extracted data. Since all extracted outcome data were continuous variables with variability between studies, standard mean differences (SMDs) were used for representing the ESs by calculating the mean change from baseline to post-intervention for the intervention and control groups. If there were two exercise groups (or control group) in one study, we halved the number of participants in the control group (or exercise group), while the mean and SD were unchanged. The random effects model, which can avoid the high risk of false-positive results,  was usedAdditionally, the continuous and categorical moderator analyses were performed using random effects model to investigate the influences of potential moderators on the overall ESs. Continuous moderators included mean age, exercise duration, and dose of exercise intervention . Potential categorical moderators included sex, diagnosis criteria, and exercise characteristics . The coding of diagnosis criteria was categorized as the AWGS and EWGSOP. According to the classification of exercise prescription in a previous study , the typThe characteristics of the included 17 studies are summarized in The results for methodological quality assessment are summarized in I2 = 6%, p < 0.01). Pooled results from eight trials revealed a significant improvement in chair and stand  compared with the control group. Moreover, pooled analysis from 11 parallel trials showed a significant improvement in knee extension in favor of exercise intervention , and gait speed  compared with the control group.In terms of physical performance , the pooI2 = 16%, p < 0.01] and ASM  compared with the control group, but there were no significant differences on lean mass , body fat , and fat-free mass  between the exercise group and control group.In terms of body composition , the metQ = 4.45, df = 1, p = 0.04) and SMI  were significantly moderated by exercise intensity. Moderate–vigorous intensity  of exercise significantly improved TUG compared with the high intensity  of exercise. The high intensity  and moderate intensity  of exercise significantly improved SMI compared with the light-to-moderate intensity  of exercise.To investigate the moderator effects of exercise on interested outcomes, moderator analyses were conducted according to the categorical and continuous variables in p = 0.03) (p = 0.01)   and skel = 0.01) . In addip < 0.05), the Duval and Tweedie's trim and fill showed that five studies were missing on the left side of the mean effect. The adjusted value was SMD = 0.35, 95% CI , which was substantially lower than our estimation (SMD = 0.59). There seems to be evidence for publication bias in this meta-analysis since studies with smaller effect sizes are not provided.Publication bias was evaluated using Egger's test in  and FunnThe present systematic review and meta-analysis consisting of 17 RCTs  investigated the effects of exercises on muscle strength, physical performance, and body composition. The main findings of this systematic review with meta-analysis showed that exercises had significant benefits on muscle strength , physical performance , and body composition  compared with the control group in older adults with sarcopenia. The effects of exercise on gait speed and SMI were moderated by sex in the study and exercise intensity. These results may be important for implementing exercise interventions for sarcopenic older adults in clinic.Since the differences in diagnostic criteria for sarcopenia, according to different organizations, the EWGSOP updated the definition and diagnostic criteria in 2008. This definition highlights that muscle strength is a principal element in sarcopenia diagnosis and is a useful predictor of adverse outcomes in people with sarcopenia , 50, exeIn regard to physical performance, the common testing tools include gait speed and TUG. Previous studies have demonstrated that poor physical performance, similar to low muscle strength, is associated with a higher risk of death in older adults , 54. TheWith reference to the body composition, in particular, the use of DXA or BIA to measure skeletal muscle mass and appendicular skeletal muscle mass has been considered as an important approach to assess the muscle quantity or quality to identify sarcopenia in the latest consensus . On thisIn addition, the moderator analyses revealed that moderate to vigorous intensity exercise (ES = 0.81) could produce greater effects on TUG than did vigorous intensity exercise (ES = 0.23). This result may be inconclusive due to the small number of included studies investigating vigorous intensity exercise and the different methods on coding intensity exercise in the subgroup. Actually, a recent systematic review study has documented that both moderate and vigorous intensity exercises can improve functional ability in frail older adults . Future Additionally, the meta-regression revealed gender-specific effects on exercise-related changing in gait speed and SMI, implying a tendency that female participants had more improvements in gait speed and SMI than male participants after practicing exercise. The explanations for this findings may be attributed to external confounding  that might affect the results . Based oOur systematic review and meta-analysis have some strengths that should be noted. All studies included in this meta-analysis were RCTs, which provided the empirical data for understanding the evidence of a treatment's efficacy. Furthermore, participants in this present study were only sarcopenic older adults without other physical conditions, like not being obese; so our research findings can be applied to the prevention or treatment in this sarcopenia population. Additionally, other potential confounders were examined to find whether they had any influence on the effects of exercise. This novelty could provide more information for future research to look at the influences of these confounders.There are, however, several limitations in our study. First, as there were no consistent assessment criteria for sarcopenia, participants who met the initial sarcopenia defined by the EWGSOP and AWGS were included in our study. It may result in publication bias. Herein, according to the latest operational definition of sarcopenia , uniform cutoff points are expected to diagnose the subject and measure the outcomes in the future study. Second, the included studies used different instruments to measure the interested outcomes such as body composition , which will contribute to the effect size of outcomes. While both of them used to examine the sarcopenia in clinical research, which is suggested by EWGSOP and AWGS, the multifrequency BIA equivalent to the DEXA measurements could be used in future research so as to ensure the accuracy of the diagnosis. Moreover, confirming the effect of exercise on interested outcomes by analyzing different instruments used to measure muscle mass separately is warranted. Third, studies using a sole exercise intervention to treat sarcopenia were included, excluding studies combing exercise intervention and nutrition. As a source of muscle synthesis, nutrient intake methods are important for the prevention and treatment of sarcopenia. There is a need for further research that examines the effect of combined exercise and nutrition intervention on sarcopenia. Four, the percentage of the female participants  was considerably high compared with male participants, and the findings may not generalize all populations. As a result, further study may benefit from investigating the effects of exercise on sarcopenia in males and females separately due to physical difference in gender.These meta-analysis results suggest that exercise interventions have positive effects on muscle strength, physical performance, and skeletal muscle mass for sarcopenic elderly, but no effect is found in body composition . Further researches need to use the latest consensus criteria proposed by EWGSOP or AWGS to identify the sarcopenia, and a larger number of studies are recommended to confirm our findings. Meanwhile, the effective exercise protocol should be designed as promoting strategies in treating sarcopenia.The original contributions generated for the study are included in the article/YZ and WS conceptualized the study. YZ, LZ, JB, and XL handled the methodology. YZ, S-TC, DK, and XL were in charge of the software. DK, XL, and WS did the validation. YZ, LZ, and S-TC performed the formal analysis. YZ, LZ, S-TC, and JB conducted the investigation. YZ and XL were in charge of the resources. YZ, JB, and XL did the data curation. YZ, LZ, and XL prepared and wrote the original draft. LZ and WS reviewed, edited, and wrote the manuscript. YZ, S-TC, and DK did the visualization. WS was in charge of the supervision and project administration. All authors have read and agreed to the published version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In contrast, the self-report did not reveal any differences between the two groups in terms of PA (p ≥ 0.572). Subsequent correlation analyses indicated that accelerometry data for mild PA and total PA were significantly correlated in couples , but MVPA was not . The self-reported PA data, on the other hand, did not indicate any significant correlation . The presented results give a first indication that an alignment of PA between osteoarthritis patients and their spouses is most likely to be detected by accelerometry, but not by self-report.This study examined whether an alignment of physical activity (PA) between osteoarthritis patients and their spouses, which was previously proven by accelerometry, might also be revealed by self-report. The PA of 28 cohabitating couples (58–83 years) was assessed by means of synchronous accelerometry (ActiGraph wGTX3-BT) and compared to their according self-reports in the German Physical Activity, Exercise, and Sport Questionnaire (BSA-F). Both methods were used to quantify the average weekly light PA, moderate to vigorous PA (MVPA), and total PA. Accelerometry revealed no differences in weekly light PA and total PA ( Osteoarthritis (OA) of the hip and knee is one of the most common orthopedic conditions that increases with age and is characterized by structural changes of the affected joints, causing pain, functional disability, and a significant loss of autonomy in patients ,2. As OAWhen the adherence to therapeutic guidelines by patients with chronic diseases is investigated, the influence of the social environment is often ignored. Most PA studies primarily focus on the affected patients, neglecting the role of their partners , althougNevertheless, for patients who are in a relationship, the partner is the primary coping resource . ParticuThere are a variety of methods to measure PA in daily life. Probably the most appropriate method is the use of accelerometers , as theyThe intention of the present study was to examine whether questionnaire data on PA collected from older couples consisting of OA patients and their spouses also show a correlative association. Despite the already-known discrepancies between self-reports and objective measurements, this could be the case if both partners equally over- or underestimate their own PA.The presented data were obtained in a cross-sectional, exploratory study conducted to assess PA by means of accelerometry and self-report in a sample of German end-stage OA patients and their cohabitating partners. Since all partners were married to the patients, the term spouse is used.The criteria for inclusion of patients were symptomatic hip or knee OA (according to the guidelines of the American College of Rheumatology ), age beSelf-reported characteristics that were associated with levels of PA in the published literature, including age, body mass index, gender, and education , were coAs datasets were selected from a larger collective, which had already been reported in a previous study, details on the recruitment of the volunteers can be found elsewhere . Data ofAccelerometry. PA was assessed by tri-axial ActiGraph wGTX3-BT (Firmware 1.9.2) activity monitors  that were worn on the waist using elastic belts. The couples were instructed to wear the monitors simultaneously and remove them only for water-based activities, such as bathing and swimming. The monitors were initialized per the manufacturer’s manual. Data were downloaded using the ActiLife Software  with normal filter settings. The minimum wear time was set to 10 h per day for at least four days, as this number is minimally needed to obtain reliable PA estimates . FurtherPatient-reported outcome measure. The Lequesne Index (LI) covers specific symptoms and physical functional disability in patients with hip or knee OA . It aggrQuestionnaire. The individual self-assessment of everyday PA (corresponds to light PA) and sport activities (corresponds to MVPA) in OA patients and spouses was conducted using the German Physical Activity, Exercise, and Sport Questionnaire (BSA-F: derived from German: Bewegungs- und Sportaktivität Fragebogen), which was designed to address the F.I.T.T.  dimensions of PA. By means of the BSA-F basic PA  in everyday life, at work, and during leisure time are quantified by nine items . In addition, individual sport activities  are assessed. For this purpose, the frequency and duration of every specific activity during the last four weeks is queried and reported as cumulative indices  for PA (here referred to as the everyday activity index) and sports (the sport and exercise index) . In viewt-tests, chi-square tests, or Mann–Whitney U-tests were used to examine differences between the patients and their spouses. The correlation of data obtained by self-report and accelerometry was investigated with Pearson or Spearman rank correlations per group . The correlation of data obtained by the same test in both groups was investigated by partial correlations correcting for the difference in the BMI between the partners. An a priori sample size calculation for correlation analyses indicated that a minimum sample size of N = 19 subjects was required to achieve a significant strong (r = 0.6 according to the working hypothesis) correlation between data quantifying the patients’ PA and their spouses’ data with a statistical power of 0.80 and an error probability of 0.05. All statistical analyses were performed using SPSS , with the significance level set at α = 0.05.All subject data were pseudonymized. Results were presented as means (M) ± standard deviation (SD) or as median (Mdn) and interquartile range (IQR). Data were checked on a normal distribution by means of the Shapiro–Wilk test. In the case of a violation of the normality assumption, non-parametric methods were used. Either N = 28 OA patients, N = 28 spouses) who were selected for the study provided data. The sociodemographic characteristics of the subjects are summarized in All 56 participants (knee: 11.63 ± 3.13) and hip osteoarthritis (LIhip: 10.00 ± 2.80) (p = 0.161).On average, the patients were diagnosed with OA 7.2 ± 6.7 years ago . The initial degree of OA-related restrictions under everyday conditions was determined by the according LI for the hip or knee . There wp = 0.638), and the duration of measurement was significantly correlated in both groups . Data obtained by accelerometry were approximately normally distributed , whereas data of the BSA-F questionnaire were not normally distributed .In total, accelerometric data from OA patients and their spouses were recorded in 5.98 ± 0.84 days. There was no significant difference between the valid days collected (p ≥ 0.187). Cumulative MVPA, on the other hand, was significantly higher among the spouses by 200 min per week (p = 0.015). The data collected by the BSA-F questionnaire did not reveal any differences between the patients and their spouses, neither for the everyday activity index, the sport and exercise index, nor for the total activity index (p ≥ 0.572)  .p ≤ 0.005) and their spouses’ data . Only the correlation between the patients’ sedentary time and their light PA failed to meet the significance criteria . Contrasting that, the everyday activity indices and the sport and exercise indices of the questionnaire were not correlated, neither in patients nor in their spouses . However, both indices were correlated with the total activity index .Correlation analyses were carried out to investigate the interrelationship of the investigated parameters within and between the two used instruments. First, it could be shown that most parameters of accelerometry  were significantly correlated, both for the patients’ data  and their spouses . Sport and exercise indices, on the other hand, were not correlated with any accelerometry parameter, neither for the patients’ data nor for their spouses’ data   .p = 0.046), between their weekly time spent in light PA , and their weekly total PA . Only the time in MVPA per week was not correlated between the patients and their spouses  (p = 0.409), the sport and exercise indices , nor the total activity indices of the questionnaire  reached significance criteria  A. On thecriteria B.In this study, we described the levels of weekly PA using both self-reported and objectively measured PA among middle-aged and elderly German couples affected by OA. Previous studies have shown that there is an alignment of health-related behavior between healthy couples in particular with regard to PA and sedentary behavior . ReducedExamining the correlation between self-reported and objectively measured PA is particularly important in individuals with OA, because they may have a different lifestyle and are often recommended to engage in specific activities, such as low-impact aerobic exercise . The OA Both methods showed broad agreement in that no differences were seen between the investigated groups in terms of weekly light PA and total PA. However, a comparison of the number of active minutes per week recorded by the two methods showed massive differences. The light PA determined by accelerometer was about twice as high as the self-reported everyday activity index, and the total PA was about three times as high as the total activity index. These differences could be explained by known problems with PA questionnaires in general, as self-reported levels of PA are based on a persons’ perception of his or her own quantity of PA, and are therefore prone to misinterpretation and social desirability, and are reliant on accurate recall of the type, intensity, frequency, and duration of activities . On the The investigation of PA often focuses on MVPA because it is the recommended intensity to meet national physical activity guidelines for aerobic activity . MVPA isWhen analyzing the PA data collected by means of the two methods, corresponding correlations were found within the two groups of subjects. In both groups, light PA was correlated with the everyday activity index, and total PA was correlated with the total activity index, suggesting a good fit between the two methods in determining PA in these activity domains. The range of correlation within the spouses’ data was weak to moderate, which is similar to previous findings in healthy adults ,45,46. MHowever, the main aspect of this study was the comparative investigation of the PA alignment between OA patients and their spouses using objective and subjective methods. Both methods were aimed at assessing light PA, MVPA, and total PA. Accelerometry showed that at least two of the three parameters were significantly correlated between the partners, whereas self-reported data revealed no significant correlations. In addition, sedentary behavior quantified by accelerometry was also correlated between the partners, but, unfortunately, the corresponding assessment was missing in the used questionnaire. On the one hand, these findings largely confirm previous results regarding the behavioral alignment between couples in general  and betwThe relatively low correlation and large differences between accelerometer-measured and self-reported data observed in this study, as well as in others, is not surprising given that they do not measure the same constructs . QuestioTo our knowledge, this study is the first to investigate the differences between accelerometric and questionnaire-based assessment of PA alignment in OA patients and their spouses. The synchronous measurements, which lasted four to seven days, fulfilled the requirements for an objective recording of habitual PA using accelerometry . The datSome limitations of this study must be acknowledged. There are aspects that limit PA measurement by accelerometry, such as the devices not being able to cover stationary activities, cycling, or water-based activities . In addiSelf-reported and accelerometer-measured PA differs largely in couples with one partner suffering from OA. While self-reported everyday activity, sport and exercise activity, as well as total activity were uncorrelated between patients and spouses, significant correlations of the couples’ light PA and total PA were demonstrated using accelerometry. Self-reported PA does not seem to be suitable to study behavioral alignment in this population.


Glioblastoma (GBM) is the most common primary intracranial tumor and originates from the small pool of adult neural stem and progenitor cells (NSPCs). According to the World Health Organization (WHO) classification of brain tumors, gliomas are classified into grades I–IV, and GBM is defined as the highest grade (IV). GBM can be disseminated by cerebrospinal fluid (CSF), but extracranial metastasis is rare. Additionally, the pathway and mechanism involved remain unclear.We report a rare case of left temporal lobe GBM with multiple bone metastases and soft tissue metastasis. This 49-year-old right-handed man who was diagnosed with GBM underwent surgery on May 9, 2017, followed by radiochemotherapy in June 2017. On August 13, 2019, local relapse was found. Then, the patient received a second surgery but not radiochemotherapy. In November 2019, the patient was reported to be suffering from low back pain for nearly 1 month. On December 6, 2019, magnetic resonance imaging (MRI) of the thoracolumbar vertebrae and abdominal computed tomography (CT) confirmed metastases on the ninth posterior rib on the right, the third anterior rib on the left, and the T7 and T10 vertebrae and their appendages. CT-guided rib space-occupying puncture biopsy was performed, and GBM was identified by pathology.We should pay attention to extracranial metastasis of GBM. Timely detection and early treatment improve overall quality of patients’ life. The extracranial metastasis in this patient may have occurred through the spinal nerve root or intercostal nerve. Further clinical observations are required to clarify the pathway and mechanism involved. Malignant brain tumors are among the most feared types of cancer, not only because of their poor prognosis but also because of their direct repercussions on quality of life and cognitive function. Glioblastoma (GBM) is the most notorious intracranial tumor in adults ; after s2/day) as an adjunct to radiotherapy and then sequentially  between June 5, 2017, and December 9, 2017. There were no obvious signs of recurrence or metastasis on craniocerebral MRI every 3 months after the operation.On first admission (May 2017), a 47-year-old man presented with a 3-month history of headache, nausea, vomiting, and memory loss. On May 7, 2017, craniocerebral magnetic resonance imaging (MRI) revealed space-occupying lesions in the left temporal lobe Figure 1On second admission , MRI demonstrated recurrence of the tumor in the postoperative residual cavity Figure 32/day). Oral analgesics were recommended during treatment from December 2019 to January 2020. At the end of treatment, the patient’s symptoms were slightly relieved, but there was still pain, with an NRS score of 2. The patient did not come for further consultation for personal reasons. According to a telephone follow-up, the patient’s pain worsened again in August 2020, and he received analgesic treatment at a local hospital. He eventually developed cachexia and died of systemic failure in December 2020. The progression-free survival (PFS) period was 27 months, and the overall survival (OS) period was 43 months.On third admission (November 2019), the patient presented with a 1-month history of back pain affecting sleep and aggravating in the recumbent position, with a numerical rating scale (NRS) score for the first 24 h of 4. On December 4, 2019, he underwent brain MRI. The intracranial conditions are shown in via neurosurgical management  tumors and 47.7% of all primary malignant CNS tumors . Surgerynagement . GBM hasnagement , 16, andnagement .via the movement of CSF through shunts to the peritoneum or pleura (via the CSF, lymph drainage that ends in the lymph nodes or blood, and invasive procedures increase the access of tumor cells to metastasize (Although GBM cells can pass through the BBB and be disseminated throughout the peripheral blood , extracrr pleura . Previour pleura , 28. Addastasize . Howeverastasize . Later sastasize . Malte Mastasize . GBM metastasize .via multiple possible pathways, including those described above. However, interestingly, the two metastases that were seen on imaging in December 2019 and the soft tissue metastasis in the ninth posterior costal ribs and T10 metastasis (Approximately 10.5% of extracranial metastases of GBM involve multiple metastases, with or without intracranial recurrence . The mostastasis Figure 6tastasis , so the The survival time of GBM patients is related to many factors. Research has shown that GBM with extracranial metastases most often involves the temporal lobe, either coincidentally or factually . For IDHAlthough the number of reports of GBM metastases has increased over time, the pathogenesis of such metastases remains elusive, and this diagnosis remains rare , 46. OurThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the Ethics Committee of Weifang People’s Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.WZ, YYC, and FRH performed the chemoradiotherapy in this case. WZ, XLW, and XXW drafted the manuscript and performed the literature review. YL and YJC retrieved the clinical and the image information, GYH and YXZ retrieved and analyzed the pathological information. FRH and YXZ conceived, designed, and supervised this study. The paper properly credits the meaningful contributions of the coauthors and coresearchers. All authors have been personally and actively involved in substantial work leading to the publication of paper and take public responsibility for its content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: The purpose of the research is to identify the main active ingredients in Coptidis Rhizoma (CR) and explore the possible molecular mechanisms in the treatment of Kawasaki disease (KD).Materials and Methods: A total of 58 children with KD were randomly divided into a control group and a Berberine treatment group. The therapeutic indicators of the two groups before and after treatment were compared. Then, compounds and drug targets of CR from the TCMSP, SWISS, SEA, and the STITCH were collected, and targeted KD genes were retrieved from the DisGeNET, DrugBank, and GeneCards databases. The network pharmacology approach involved network construction, target prediction, and module analysis. GO and KEGG enrichment analysis were performed to investigate the possible pathways related to CR for KD treatments. Finally, protein expression was determined to verify the core targets using Western blotting in the cell experiment.Results: In total, nine compounds, 369 relative drug targets, and 624 KD target genes were collected in the above database. The network analysis revealed that 41 targets might be the therapeutic targets of CR on KD. GO and KEGG enrichment analysis revealed that the biological processes, namely, response to hormone, response to inorganic substance, and enzyme-linked receptor protein signaling pathway, and Pathways in cancer, Toll-like receptor signaling pathway, and Pancreatic cancer are the most significant. Protein expression of CASP3, PTGS2, and SRC was upregulated and AKT1 and ERK were downregulated.Conclusion: We provided useful resources to understand the molecular mechanism and the potential targets for novel therapy of KD. Kawasaki disease (KD) is a systemic inflammatory vasculitis predominantly affecting children younger than 5 years of age  and is nRanunculaceae. The Isoquinoline Alkaloids in Coptis Chinensis, namely Berberine (BBR), Coptis Chinensis, and Rhizopine, are the main effective components of CR. Data have proved that CR has anti-inflammatory (via the Phosphatidyl Inositol 3-kinase (PI3K)/serine/threonine protein kinase B/endothelial nitric oxide synthase signaling pathway (Coptidis Rhizoma (CR), called Huang Lian (HL) in Chinese, belongs to perennial herbs of ammatory , antibacammatory , antitumammatory , antidiaammatory , and pha pathway . In addi pathway .Network pharmacology is a part of bioinformatics based on the concept of “disease–gene–target–drug” , which iTo investigate the clinical effects of BBR on patients with KD and its pharmacological mechanisms, a randomized and case–control study was performed in Shenzhen Children's Hospital and a comprehensive network pharmacology approach was established to probe the appliances of CR on KD by network pharmacology analysis.g for 10 min and aliquots were stored at −80°C.The sample group of this study is formed by 20 children with KD  admitted to the Department of Cardiology and 20 healthy children  from Child Health Section, Shenzhen Children's Hospital from October 2018 to May 2019. They have randomly divided them into the routine treatment group and the routine treatment + BBR group. All children were typical KD patients and the diagnostic criteria were in line with the AHA and American Academy of Pediatrics 2004 guidelines . The KD http://lsp.nwu.edu.cn/tcmsp.php)  Database (msp.php) , a systemsp.php) . In addihttps://www.drugbank.ca/) (https://www.genecards.org/) (http://www.disgenet.org/home/)  , GeneCards.org/)  and DisGg/home/) . It is nvia targets. The target fishing was used to search for or predict the potential targets of small molecules and the small molecular structure information of the active ingredients in CR by TCMS could also be predicted by applying the Similarity Ensemble Approach (http://sea.bkslab.org/), STITCH (http://stitch.embl.de/), and Swiss Target Prediction (http://www.swisstargetprediction.ch/).The active ingredients of drugs play an important role in related biological functions Approach   to draw the Venny map and also to obtain the common target genes of the intersection. Then, the online tool STRING (http://string-db.org) was used to construct the target protein–protein interaction (PPI) network of CR acting on KD. The network construction was established, first, with a network between active compounds and targets of CR and also with PPI network of compounds and targets developed by linking the compound targets and predicted targets of other human proteins. Another PPI network of KD targets was also constructed by linking the known KD-related target.In this phase, the CR targets and the acquired KD targets were screened by the online tools Venny2.1.0  and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enriched by GSEA  with FDRg for 10 min and aliquots were stored at −80°C.In our cell experiment, a total of 28 subjects, including 14 normal children and 14 KD patients, were recruited from Shenzhen Children's Hospital. Serum samples were separated by centrifugation at 1,000 × 2. Cells were then stimulated with culture medium containing 15% serum [15% (V/V)] from KD patients or healthy donors for 24 h. The cells were then used in subsequent studies. Each measurement was performed in triplicate (n = 3). The BBR was dissolved in sterile ultrapure water. The stock solution of BBR was 40 μm, which can be diluted into final concentration (20 μm) with cell culture medium.HCAECs were brought form ScienCell  and cultured with endothelial cell growth medium containing growth factors, supplements, and 10% fetal bovine serum at 37°C in 5%COThe protein samples of the three groups were extracted and measured through a BCA protein assay. We loaded and separated the proteins through 4 and 10% SDS-PAGE and then transferred them onto PVDF membranes. The membranes were washed and then blocked using 5% skimmed milk powder blocking solution for 2 h. The antibody  was diluted at 1:1,000, diluted with 5%BSA TBST, and incubated overnight at 4°C. After washing three times with TBST for 4 min each, the membranes were incubated with secondary antibodies  for 2 h at room temperature. Then, the membranes were washed four times with TBST for 4 min each. Finally, the image is collected and analyzed.p-values were calculated by t-test and chi-square, as appropriate. p < 0.05 was regarded as having statistical significance.Here, all quantitative data are presented as means ± SEM. For pairwise comparison of two or more groups of quantitative data, One of the first things to be observed in this phase is that no statistically significant differences were found in baseline data and hematologic indicators between the two groups. The BBR group was able to reduce the values of C-reactive protein (CRP), neutrophils/lymphocytes (NLR), and platelets/lymphocytes (PLR) shown in , and theOverall, nine target compounds were collected from TCMSP and 369 target genes in the whole formula in total were retrieved from TCMSP, SWISS, SEA, and STITCH database . The valTo further determine the target of CR on KD, a compound-target network was built with an online tool Cytoscape3.6, representing a compound-target gene network including nine compounds and 41 target genes shown in . CompounTo investigate the biological functions of the direct targets of CR for KD, the target genes GO and KEGG pathway function enrichment was performed by GSEA. As shown in The KEGG pathway enrichment is shown in Cytoscape3.6.0 software was used to demonstrate the enrichment of the 21 proteins of the above five pathways shown in . Most ofFor this part of the study, the String online server was the main tool that helped to build the PPI network, containing 41 nodes in total shown in . The sigWe selected the top 5 genes according to the degree of PPI, including PTGS2, CASP3, ERK, AKT1, and SRC. After the treatment of berberine, the expressions of CAPS3 and PTGS2 were extremely significantly decreased, and the difference was statistically significant. While the expression of SRC was decreased, the expression of ERK and AKT1 was increased, and there was no statistically significant difference .KD is a systemic inflammatory syndrome of small and medium vessels. In recent years, more and more evidence has shown that the pathogenesis of this condition is related to infectious factors, susceptibility genes and autoimmune activation. Traditional Chinese medicine is suitable for treating diseases with complex mechanisms because of its multiple curative effects and minimal side effects. The effects of BBR on KD in clinical practice were tested based on some previous findings regarding this topic . The preIn the clinical trial stage, C-reactive protein (CRP) and peripheral blood cell parameters were also used as markers of systemic inflammation. Among them, CRP plays a role in promoting phagocytosis and immune regulation. Data have shown that during the course of KD, the increase of CRP level is related to coronary artery dilatation and is a high-risk factor of complication with coronary artery injury for KD . NLR andAKT1, CASP3, TP53, MAPK3/8/14, PTGS2, SRC, RELA, and MTOR were found and set as top 10 target genes as well.To investigate the mechanisms of BBR on KD, network pharmacology was used. Nine target compounds of CR were collected from TCMSP; 369 target genes of CR were collected from TCMSP, SWISS, SEA, and STITCH database; and a total of 624 target genes of CR were obtained by searching related databases together with 41 target genes obtained by the intersection of CR and KD. By further screening this sample of genes, AKT1, a serine/threonine protein kinase, is widely expressed in various tissues. It is known that activated AKT plays a regulatory role in the cell cycle, apoptosis, and proliferation by activating downstream factors. Also, the specific activation of AKT1 in vascular endothelial cells can alleviate the injury after carotid artery ligation by increasing the expression of nitric oxide and protecting the function of the endovascular cortex . By initMAPK, an intracellular serine/threonine protein kinase, is an important signaling system for cell-mediated extracellular signals to intracellular responses and plays a key role in cell proliferation, apoptosis, inflammation, immunity, and angiogenesis . StudiesSRC encodes tyrosine protein kinase also has to be mentioned since it is a member of the non-receptor protein tyrosine kinase family. This protein is constantly associated with multiple signaling pathways in cells and its related genes are involved in important biological processes such as growth, differentiation, adhesion, and transcription. Studies have confirmed that the SRC-1 gene is related to the susceptibility to coronary artery aneurysm of KD complications , indicatAdditionally, CASP3 is a key apoptotic protease in the final pathway of apoptotic cell death, mediating exogenous and endogenous cell death signaling pathways. CASP3 leads to transcriptional activation of inflammatory genes by activating the NF-κB pathway in the mechanism of KD. As a genetic variation of genes may also cause damage and remodeling of vascular structures, TP53 is considered to be an important tumor suppressor gene that can affect cell cycle, DNA repair, apoptosis, signal transduction, transcription, and autophagy, as well as regulate the growth, differentiation, and senescence of cells. PTGS2 contains 10 exons and 9 introns, encoding cyclooxygenase 2 (Cox-2). Cox-2, in this case, is expressed in vascular smooth muscle, monocytes, and fibroblasts, and is a cardinal inflammatory mediator in the process of atherosclerosis . In addiRELA is a member of the NF-κB family. NF-κB plays a key role in inflammatory and immune responses in cells. Studies have shown that in the pathological process of KD, the NF-κB signaling system regulates transcription of almost all genes involved in inflammatory mediators and cell proliferation and activation. Activation of the NF-κB signaling pathway is linked to the occurrence of KD vasculitis in the acute phase, which is likely to aggravate KD vasculitis response and participate in the formation of coronary artery injury . ICAM-1 In addition, the GO enrichment analysis in this study showed that response to hormone, response to inorganic substance, enzyme-linked receptor protein signaling pathway, and immune effector process are the major biological processes for CR treatment of KD. The disturbance of these biological processes is likely the cause of KD vasculitis. Accordingly, CR may be important in the regulation of different biological functions of KD.Finally, the enrichment analysis of the KEGG pathway found that the five signaling pathways closely related to CR and KD prevention and treatment included Pathways in cancer, Toll-like receptor signaling pathway, Pancreatic cancer, Neurotrophin signaling pathway, and MAPK signaling pathway. The Toll-like receptor signaling pathway is a family of receptors composed of members of multiple receptors and has a key function when it comes to inflammatory and immune injuries of endothelial cells caused by pathogen infection and immune response . ClinicaThis study systematically explored the putative bioactive compounds in CR and pharmacological targets of CR for KD prevention and treatment through network pharmacology and Western blotting. All the ingredients of CR were extracted from edible plants, and they were all claimed safe in previous applications. Therefore, this study provides a new way to explore the mechanism of CR in treating KD. However, the examinations here conducted have certain limitations. It is suggested for the future that relevant experiments are carried out to better explain the mechanisms of CR in the treatment of KD.After conducting this examination, we postulated that BBR is effective in the treatment of young children with KD and can be considered as an alternative treatment for KD. This study has preliminarily revealed the possible mechanism of CR in the treatment of this disease by regulating multi-targets with multi-components. Furthermore, the outcomes demonstrated that a network pharmacology-based approach was useful for elucidation of the interrelationship between complex diseases and interventions of Chinese herbal medicines, potentially providing references for further research on its mechanisms of action in the future.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Shenzhen CHildren Hospital. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.MX conceived and designed the research, and reviewed and revised the manuscript. XF wrote the manuscript. XG and YL performed a preliminary analysis. All authors read and approved the final version of the manuscript.This study was supported by the National Nature Science Foundation of China (81870364), Shenzhen Sanming Project (SZSM20162057), Shenzhen Scientific Plan (JCYJ20190809164004023), and Guangdong Province High Level Clinical Key Specialties (SZGSP012) .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This review aimed to comprehensively assess the efficacy and safety of oral East Asian herbal medicine (EAHM) for overall peripheral neuropathy (PN). In addition, an Apriori algorithm-based association rule analysis was performed to identify the core herb combination, thereby further generating useful hypotheses for subsequent drug discovery. A total of 10 databases were searched electronically from inception to July 2021. Randomized clinical trials (RCTs) comparing EAHM with conventional analgesic medication or usual care for managing PN were included. The RCT quality was appraised using RoB 2.0, and the random effects model was used to calculate the effect sizes of the included RCTs. The overall quality of evidence was evaluated according to the Grading of Recommendations Assessment, Development, and Evaluation. By analyzing the constituent herb data, the potential association rules of core herb combinations were explored. A total of 67 RCTs involving 5753 patients were included in this systematic review. In a meta-analysis, EAHM monotherapy and combined EAHM and western medicine therapy demonstrated substantially improved sensory nerve conduction velocity, motor nerve conduction velocity, and response rate. Moreover, EAHM significantly improved the incidence rate, pain intensity, Toronto clinical scoring system, and Michigan diabetic neuropathy score. The evidence grade was moderate to low due to the substantial heterogeneity among the studies. Nine association rules were identified by performing the association rule analysis on the extraction data of 156 EAHM herbs. Therefore, the constituents of the herb combinations with consistent association rules were Astragali Radix, Cinnamomi Ramulus, and Spatholobi Calulis. This meta-analysis supports the hypothesis that EAHM monotherapy and combined therapy may be beneficial for PN patients, and follow-up research should be conducted to confirm the precise action target of the core herb. Peripheral neuropathy (PN) is one of the most common causes for a patient to visit the clinic . The preSeveral epidemiological studies have reported that the treatment results for PN patients are unsatisfactory ,6. This Several EAHMs with pharmacological activities against PN have been reported. A previous study has reported that various herbs, including EAHM, relieve neuropathy symptoms through serotonin 5-HT1A receptors, inhibit axonal degeneration, improve axonal transport, and suppress TNF-α and NO in CIPN . In contIn the past decade, numerous randomized controlled trials (RCTs) have been conducted to assess the efficacy and safety of EAHM for PN. In addition, studies on drug discovery, which can regulate neuropathic pain based on EAHM, are actively conducted . SeveralTherefore, the aim of this study was to comprehensively assess the efficacy and safety of oral EAHM in overall PN with multiple underlying causes. Additionally, an Apriori algorithm-based association rule analysis was performed on the various herb data to identify the core herb combination, thereby further generating useful hypotheses for subsequent drug discovery.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021252277, accessed on 9 October 2021).This study was conducted in accordance with the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions , as wellA comprehensive electronic search through four English databases , four Korean databases , one Chinese database , and one Japanese database (CiNii) were performed from inception to July 2021 by two investigators. The following Boolean format was used for the search:  AND  AND . In the Korean, Chinese, and Japanese databases, these search terms were appropriately modified to perform a search. The detailed search strategy has been explained in Only RCTs evaluating the efficacy and safety of oral EAHM administration for PN were included. There were no restrictions on language or publication time. A few studies were excluded if they met the following criteria: (a) Not an RCT or quasi-RCT; (b) the control group was not used or was inappropriate; (c) unrelated to PN; (d) animal studies; (e) review; and (f) not published in peer-reviewed scientific journals, including postgraduate theses or dissertations.All of the adults (age > 18 years) diagnosed with PN were included without restrictions on gender and nationality. The types of PN were classified into diabetic, chemotherapy-induced, postherpetic, and other causes, according to the underlying pathology.All of the EAHM forms, such as decoction, granules, capsules, and a combination of EAHM and another active treatment for PN management were included. The mode of delivery was restricted to the oral intake. Studies in which East Asian medical interventions, such as acupuncture, massage or non-drug therapy, were only combined in the treatment group were excluded. Studies in which the comparators included other EAHMs were excluded. Moreover, studies that exemplify the details of herbs constituting the revealed EAHM prescriptions were excluded.Primary OutcomesNCV: Improvement in NCV measured in each body part.Response rate: Rate of improvement or no improvement in symptoms, such as NCV, pain, numbness, tingling, and weakness.Secondary OutcomesIncidence rate: Occurrence rate of PN due to multiple underlying causes.Pain intensity: Intensity of PN related to pain symptoms, as measured by instruments, such as the visual analog scale (VAS) or numerical rating scale (NRS).Toronto clinical scoring system (TCSS) .Michigan diabetic neuropathy score (MDNS) .Adverse events (AEs).Two review investigators (H.-G.J. and D.L.) extracted the following information: (1) First author and year of publication; (2) type of underlying cause; (3) patient characteristics, including sample size, gender distribution, age range, and disease duration; (4) intervention group; (5) control group; (6) treatment duration; (7) main outcome measures and intergroup differences; (8) AEs; and (9) detailed EAHM composition.Two review investigators (H.-G.J. and D.L.) independently evaluated the RoB of the included studies according to the revised tool for risk of bias in randomized trials, RoB 2.0 . Disagre2 test and I2 statistics. Heterogeneity was considered statistically significant when the p-value based on the χ2 test was <0.10 or I2 was ≥50%. If heterogeneity was identified, a subgroup analysis was performed to explore the possible causes. Statistical synthesis of individual research results was performed using R version 4.1.0, with the default settings of the ‘meta’ package and the ‘metaprop’ function [For continuous outcomes, the mean difference (MD) was calculated with a 95% confidence interval (CI). A standardized MD (SMD) of 95% CI was used to express the intervention effect when the same outcome was measured using different scales. Risk ratios or odds ratios with 95% CI were applied to represent results for dichotomous outcomes. Statistical heterogeneity across the included studies was tested using the χfunction . Only thfunction . For theBy analyzing the constituent herb data of EAHM collected from the included studies, the potential association rules of core herb combinations were explored. Furthermore, prior to the association rule analysis, the frequency of individual herbs used in this analysis was checked. The R studio program  was used for the Apriori association rule analysis and plot production. A data fit was performed using the R-package “arules” and the R-package “arulesViz”was applied to generate plots and charts according to the results ,32. The Support, confidence, and lift are the main metrics used to measure associations using the Apriori algorithm. The metric support evaluates the usefulness of the association rule and is the proportion of prescriptions containing a specific herb combination in the total EAHM prescription. This can be expressed as P(A∩B). The metric confidence indicates the likelihood that the consequent herb set will be included when an antecedent herb set is specified as an EAHM prescription. Therefore, support is the entire set of standard EAHM prescriptions, whereas confidence limits reference prescriptions to those that include a specific herb combination and is expressed as P(A∩B)/P(A) = P(B|A). The metric lift compensates for the fact that it is not known whether confidence is useful or a random result. The confidence of herbs A and B is divided by the confidence under the independent assumption that A does not affect B, and is expressed as P(A∩B)/P(A)·P(B) = P(B|A)/P(B). When the confidence is approximately 1, herbs A and B are considered irrelevant since they are close to independence in probability. Conversely, if the lift value is large, the correlation is interpreted as strong. In this review, the association rules were identified based on the minimum values for support and confidence of 20 and 80%, respectively. Among them, the core herb combination showing the most distinct association and its constituent herbs was searched.The overall quality of evidence for each outcome was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) pro . The GRAA total of 903 studies were selected through an electronic database search, of which 37 duplicates were removed. After screening for titles and abstracts, 743 studies were excluded for at least one of the following reasons: (i) No clinical trial, (ii) studies unrelated to EAHM, (iii) case reports or reviews, and (iv) irrelevant to PN. A full text assessment was performed on the remaining 123 studies, and 56 studies were excluded for the following reasons: (i) No clinical trials or quasi-RCTs; (ii) no oral administration; (iii) undisclosed herb ingredients; (iv) combination of interventions other than oral administration of EAHM; (v) inappropriate control groups; (vi) not related to PN; (vii) duplicated. A total of 67 studies were identified. The screening process is summarized in n = 2898) and the control group (n = 2855). The treatment duration ranged from 2 to 26 weeks. The characteristics of the included 67 studies are summarized in Four RCTs were published in English, and the rest were published in Chinese. Four studies were conducted in Japan, whereas the others were conducted in China. The etiology of PN included studies of 50 DPNs, 11 CIPNs, one HPN, one occipital neuralgia, one trigeminal neuralgia, and one supraorbital neuralgia. The sample size of the included studies ranged from 29 to 247, and a total of 5753 participants were separated into the experimental group  1.30, 95% CI 1.21–1.40, p < 0.0001; heterogeneity chi-square = 39.53, df = 20, p < 0.01; I2 = 49%; n = 1997, RR 1.20, 95% CI 1.15–1.25, p < 0.0001; heterogeneity chi-square = 26.03, df = 24, p = 0.35; I2 = 8%; n = 227, RR 1.19, 95% CI 1.03–1.37, p < 0.01). A visual summary of the confidence level for individual studies and pooled estimates using the response rate is presented through a drapery plot  and Begg’s test (p < 0.0001).The contour-enhanced funnel plot analysis was performed to explore the publication bias through the response rate, which is an outcome of most of the included studies . The patIn the comparison between the combination EAHM and WM therapy and WM monotherapy, the overall quality of evidence according to all of the outcome measures was low to moderate. Meanwhile, the overall quality of evidence according to all of the outcome measures was low to moderate in EAHM monotherapy compared with WM monotherapy. The results of the GRADE assessment are listed in In this systematic review, 67 RCTs including 5753 PN patients were obtained and analyzed. The main finding of this study is that EAHM monotherapy or combined EAHM and WM therapy was superior to the control group without EAHM in improving nerve conduction velocity, response rate, incidence rate, pain intensity, and other overall symptoms. Additionally, EAHM is generally safe and tolerable for PN patients. Therefore, EAHM can be considered a recommended option for PN treatment in clinical practice based on the evidence presented in this study. On the contrary, in the association rule analysis of various EAHM prescription data included in this study, Astragali Radix, Cinnamomi Ramulus, and Spatholobi Calulis were identified as components constituting the core herb combination. It may be worthwhile to conduct further studies on whether EAHM containing the three individual herbs or their combination can exert a remarkable effect in the PN-treated group.This review has various limitations. Therefore, caution is required before using the results. First, most of the studies were conducted in China. As a result, additional well-designed multicenter clinical trials in East Asia are needed to generalize the positive results identified by the analysis. Second, the methodological quality of the clinical trials included in this study was generally poor. The overall risk of evaluated bias according to RoB 2.0 reported that only four included studies have a ‘low risk of bias.’ All of the other studies have a ‘high risk of bias’ due to methodological flaws in domains, such as the randomization process, deviations from the intended intervention, and missing outcome data. Therefore, it is difficult to draw firm conclusions, even though the review contains relatively large sample data and primary trials. Rigorous conclusions regarding EAHM can be drawn only in well-designed clinical trials to minimize the risk of future bias. Third, a high level of heterogeneity was observed in the meta-analysis of NCV, which is one of the primary outcomes of this study. This high heterogeneity is a problem that cannot be overlooked, as it reduces the significance of the synthesized evidence. In this study, the cause of heterogeneity could not be identified, even though a subgroup analysis was performed according to the underlying disease and treatment duration. It is estimated that the cause of the estimated troubleshooting is that the NCV at the basement and the amount of change in participants are different for each included study. This reflects the difficulty in diagnosing and measuring PN severity. Another possible cause of heterogeneity is the extreme diversity in the composition and dose of EAHMs used in individual clinical trials. This leads to inconsistency among interventions, except for the commonality of ‘the combination of herbal medicines in East Asia.’ In this review, the association rule analysis was performed on herb data to overcome this heterogeneity and derive useful information. The potential heterogeneity may be partially overcome in similar future systematic reviews by actively utilizing data mining methods. Fourth, the goal of this study was to identify valuable candidates for drug discovery or locate material information that may be employed in direct patient treatment in the clinic. Therefore, it was not possible to focus on quality control in the manufacturing process, such as pre-treatment, active ingredient extraction methods, and moisture content assessment, all of which significantly impact the efficacy of specific goods. Moreover, this was suspected to have influenced the heterogeneity of the results. In the future, an animal study meta-analysis on the same issue will be used to compensate for these flaws.The evidence related to the use of EAHM therapy for PN supported by this study is consistent with the results of previous studies on similar subjects. A study analyzing the clinical data for DPN after using 216 EAHM prescriptions found that the combination of Astragali Radix-Cinnamomi Ramulus and Ligusticum Chuanxiong-Moutan Radicis Cortex highly correlated with MDNS improvement . MoreoveThe characteristic of EAHM to treat complex diseases by stimulating many networks of human interaction systems at the systematic level through a multi-targeted approach is being investigated . TherefoInformation on the pharmacological action of individual herbs is also important for achieving the above purpose. Research on various pharmacotherapeutic targets is required for an effective drug treatment for diseases in which the overall pathology, such as PN, is not fully understood. Combining this basic study with the action-related information of the individual active ingredient of EAHM will make it possible to clearly predict the direction of the synergistic effect expected from multiple herb combinations. Even for DPN, research on several molecular targets, including the polyol pathway, hexamine pathway, PKC signaling, oxidative stress, AGEs pathway, PARP pathway, MAPK pathway, NF-κB signaling, TNF-α signaling, and cyclooxygenase pathway is conducted . In thisThe following problems must be considered until the aforementioned discoveries are meaningfully exploited in clinical practice and medication discovery. Natural medicines, including EAHM and synthetic drugs, have significantly distinct modes of action, target pathways, and pharmacologically active components from a macroscopic point of view. The most well-known difference is that multiple compounds present in herbal medicine operate on many targets and single compound synthetic medications work on single targets . As demoFirst, this review was undertaken with the goal of finding EAHM materials that may provide prospective advantages to PN patients, and it does not go into detail regarding the formulation process of the materials. However, as mentioned above, estimating a consistent impact even for the same herb material in a condition where there is a lack of adequate consensus and discussion on the processing technique, pre-treatment, and extraction method of individual EAHM materials may be challenging ,130. SinThis meta-analysis supports the hypothesis that EAHM monotherapy may be beneficial for PN patients. Moreover, the combined EAHM and WM therapy may be recommended for these patients. EAHM monotherapy improves severe pain intensity and abnormal sensations, such as tingling, burning, and numbness, which impair the quality of life in PN patients. Additionally, unlike the PN treatment with WM alone, which has a poor prognosis, a combination of EAHM and WM treatment alleviated the symptoms of PN including tingling, burning, and numbness and prevented chronic PN. However, high quality RCTs evaluating the effects of EAHM are needed due to limitations, such as heterogeneity, to understand this result clearly. In addition, it is worth conducting a follow-up study to verify the specific action target of the core herb combination derived from the present review and the hypothesis of superiority in clinical practice.


Rationale: Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) have been identified as independent risk factors for cardiovascular diseases. However, the impact of COPD and OSA overlap syndrome (OS) on cardiovascular outcomes remains to be elucidated.Objective: To determine the prevalence of cardiovascular events and their risk factors in OS patients.Methods: Seventy-four patients who had OS between January 2015 and July 2020 were retrospectively enrolled, and 222 COPD-only patients and 222 OSA-only patients were pair-matched for age and sex from the same period and served as the OS-free control group. The prevalence rates of coronary heart disease (CHD), arrhythmia, heart failure, and pulmonary arterial hypertension (PAH) were compared among the three groups, and multivariable logistic regression models were used to screen the risk factors for specific cardiovascular events.Results: OS patients had higher prevalence rates of heart failure  and PAH  than those with OSA alone or COPD alone . The CHD prevalence was also significantly higher in the OS group than in the COPD-alone group . There was no significant difference in the prevalence of arrhythmia among the three groups . In OS patients, risk factors for CHD included hypertension, diabetes, body mass index, lactate dehydrogenase level, and tidal volume; risk factors for heart failure included diabetes, partial pressure of oxygen, partial pressure of carbon dioxide, maximum ventilatory volume, and neutrophilic granulocyte percentage; and risk factors for PAH included minimum nocturnal oxygen saturation, partial pressure of carbon dioxide, and brain natriuretic peptide and lactate dehydrogenase levels.Conclusions: OS patients have a higher prevalence of cardiovascular events, which is associated with hypoxemia, hypercapnia, and impaired lung function in these patients. Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are among the most prevalent chronic diseases and represent a major reason for health-care utilization, imposing a heavy health burden worldwide –3. The pCOPD is characterized by incomplete reversible airflow obstruction that increases the risk of cardiovascular disease through increased sympathetic nervous activity and persistent low-grade systemic inflammation , 11. ObsUnder the synergistic effect of COPD and OSA, patients with OS have lower nocturnal oxygen saturation, more profound oxidative stress, more serious systemic inflammation, more severe vascular endothelial dysfunction, and accelerated atherosclerosis –17, all This is a cross-sectional study, and anonymized clinical data were collected from the Biobank of the First Affiliated Hospital of Xi'an Jiaotong University from January 2015 to July 2020. The Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University approved this study (no. XJTU1AF2020LSK-187), and informed consent was obtained. All methods were carried out in accordance with the relevant guidelines and regulations according to the principles expressed in the Declaration of Helsinki.The medical records of all patients who were diagnosed with COPD or OSA were retrospectively analyzed. The diagnoses were based on clinical expert consensus documents. COPD should have been considered in any patient with dyspnea, chronic cough or sputum production, a history of exposure to risk factors for the disease, and a post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.70 as measured by spirometry. OSA was defined as symptoms such as excessive daytime sleepiness, recurrent awakenings from sleep, daytime fatigue, and impaired concentration, as well as overnight monitoring demonstrating five or more obstructed breathing events per hour during sleep (apnea/hypopnea index > 5). OS was defined as the simultaneous occurrence of COPD and OSA in the same patient , 18, 19.All data, including medical history, personal history, and laboratory examination, were obtained from the electronic medical record system of the hospital and recorded using a standardized protocol. Pulmonary function tests were performed according to the guidelines of the American Thoracic Society , and fulThe primary endpoint in this study was to explore the prevalence rates of four specific types of cardiovascular diseases—coronary heart disease (CHD), heart failure, arrhythmia, and pulmonary arterial hypertension (PAH)—and whether there was any difference in prevalence between patients with OS and those with OSA alone or COPD alone. The secondary endpoint was to screen the risk factors for these diseases.post-hoc test was used if the data were normally distributed for continuous variables. The chi-squared test was used for categorical variables. When the ratio of variables to missing values was less than 5, the median of quantitative variables or the most common attribute values of qualitative data were used as simple assignments. Univariable logistic regression models were used to characterize OS compared with COPD alone or OSA alone, and multivariable logistic regression was used to explore the risk factors for cardiovascular diseases. Statistical analyses were conducted with SPSS v18.0.0. P < 0.05 were considered statistically significant.The Kolmogorov–Smirnov test was used to test the normality of each data distribution. Categorical variables are reported as counts and percentages, whereas continuous variables are reported as the mean (X) and standard deviation. When comparing groups, the Kruskal–Wallis test was used if the data were not normally distributed, and analysis of variance with a Of the 6,295 patients initially recruited to the study, 4,412 had COPD as the main diagnosis, and 2047 had OSA. Through a detailed screening, 74 consecutive patients identified to have overlap syndrome were enrolled in the OS group; 222 patients paired-matched for age and sex were enrolled in the OSA-alone group, and the same method was used to form the COPD-alone group .P < 0.05), body mass index (BMI) (P < 0.01), and partial pressure of carbon dioxide (PCO2) (P < 0.01) were higher, and the partial pressure of oxygen (PO2) (P < 0.01) and oxygen saturation (SaO2) (P < 0.01) were lower in subjects with overlap syndrome than in those from the other two groups. The patients with OS had higher serum levels of brain natriuretic peptide (BNP), lactate dehydrogenase (LDH), and neutrophil granulocytes than the patients with OSA alone . However, the serum troponin levels and the number of patients who smoked or drank alcohol were similar between the three groups , and the prevalence rate of OSA in COPD patients was 3.72% (164/4412). The clinical characteristics of the study subjects with OS, OSA alone, and COPD alone are described in e groups .P < 0.01), and the number of patients using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers in the OS group was significantly higher than that in the COPD-alone group (P < 0.01). The use of medications such as amiodarone, warfarin, or rivaroxaban was not significantly different among the three groups . Six common comorbidities in these cohorts were evaluated: the prevalence of hypertension and pulmonary thromboembolism (PTE) in the OS group was significantly higher than that in the other two groups (P < 0.01); the prevalence of stroke in the OS group was higher than that in the COPD-alone group (P < 0.05); and the prevalence of venous embolism of the extremities in the OS group was higher than that in the OSA-alone group (P < 0.05). However, no significant difference was observed in the prevalence of diabetes among the three groups , and the mean oxygen saturation  was much lower in the OS group than in the OSA-alone group, whereas the minimum SpO2 and sleep architecture were not different between the two groups.In the overlap syndrome population, most patients were categorized as having mild/moderate OSA , whereas, in the OSA-alone group, nearly half of the patients (42.68%) had severe OSA . In the P > 0.05), and FEV1% predicted was also comparable in both groups (P > 0.05). However, the FEV1/FVC ratio was significantly lower in the OS group than in the COPD alone group. Vital capacity and maximum ventilatory volume (MVV), which represent lung volume and pulmonary ventilation function, were lower in patients with overlap syndrome than in those with COPD alone , and the prevalence of CHD in subjects with OS was higher than in those with COPD alone (P < 0.01). However, the prevalence of arrhythmias  was not significantly different between the OS group and OSA or COPD groups , and the prevalence of CHD was also higher in the OS group than in the COPD-alone group (P < 0.01). In patients with OS, risk factors for CHD included hypertension, diabetes, stroke, BMI, LDH level, and tidal volume; risk factors for heart failure included diabetes, PTE, PO2, PCO2, MVV, and neutrophilic granulocyte percentage; and risk factors for PAH included PTE, PCO2, minSpO2, PCO2, and BNP and LDH levels. To the best of our knowledge, this study initially identifies the prevalence and risk factors for cardiovascular events in OS patients in an Asian population compared with both OSA-alone patients and COPD-alone patients.In this study, a significant increase in the prevalence of cardiovascular events was observed in the OS population. Patients with OS had a higher prevalence of heart failure and PAH than those with COPD alone or OSA alone . The patients/participants provided their written informed consent to participate in this study.MT and YL: methodology, writing, and original draft preparation. MT, SL, and XY: data curation and investigation. TS: supervision, writing, reviewing, and editing the manuscript. All authors provided critical review of the manuscript and approved the final draft for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cystatin C is indicated to be involved in the pathogenesis of Alzheimer's disease (AD) and cognitive impairment. Our objective is to examine the serum Cystatin C levels, and to clarify the correlations between serum Cystatin C and cognitive performance in Chinese AD patients.The serum Cystatin C concentrations in AD patients and age, sex, and body mass index (BMI) matched-healthy controls were measured. The cognitive functions of the AD patients were evaluated by using the Mini-mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). The severity of dementia was determined with clinical dementia rating (CDR).A total of 463 AD patients and 1,389 matched healthy subjects were included. AD patients had higher serum Cystatin C than healthy controls. Serum cystatin C levels were correlated with MoCA scores in AD patients. In an ordinal logistic regression model, AD patients with higher serum cystatin C levels had increased odds of severe cognitive dysfunction.Our study suggested that AD patients had higher levels of serum cystatin C than age/sex/BMI-matched normal control subjects. Higher serum cystatin C may be associated with worse cognitive performance, but more studies are required to verify such association. Cystatin C is highly expressed in the brain and cerebrospinal fluid (CSF) . APOE haplotypes were determined according to the manufacturer's instruction with the use of ViennaLab ApoE Strip Assay .This study was performed at the Department of Neurology, Sichuan University West China Hospital, Chengdu, China. From Jan 2014 to Dec 2019, a total of 463 patients with probable AD were enrolled. The diagnosis of AD was based on the criteria issued by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) The individual, semistructured interviews were conducted with participants and their close informants. Demographic data, including sociodemographic characteristics, lifestyle, medical history, current medications, and family history, were collected. Clinical data related to cognitive impairments, including time of onset, possible triggers, course of condition, impact on daily activities, changes in mood or behavior, and treatment and its effects, were also recored. Last, standardized general and neurological examinations were performed. The diagnoses were made at the end of each interviews according to the NINCDS-ADRDA criteria  is an informant-based global assessment scale with established reliability and validity, and it is utilized as a severity-ranking scale in AD patients in the present study. The cognitive performance was rated in six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated according to one of five levels of impairment, and the cognitive dysfunction was defined as follow: mild (CDR = 0.5 or 1), moderate (CDR = 2) and severe (CDR = 3).t-test. The Kolmogorov-Smirnov test was applied in all continuous variables to verify the presence of normality. A χ2 test was used to compare the categorical variables. One-way ANOVA was performed for three group comparisons of normally-distributed continuous variables. Pearson's non-parametric correlation was applied to investigate the existence of linear association of the serum cystatin C levels and eGFR values to the cognitive performance. The association between cystatin C levels with CDR grading was assessed using ordinal logistic regression model, which was used to predict the CDR stage using serum cystatin C levels in a single model, potential confounders, including age of onset, sex, disease duration, and carriage of the APOE4 allele were allowed in the analyses. This method makes the parallel regression assumption for all variables across the grading of CDR stage. All data were presented in the form of mean ± standard deviation, and they were analyzed using SPSS 17.0. A p-value of <0.05 was considered to be statistically significant.Comparisons of continuous variables between two groups were made using Student's p = 0.0362). The cognitive performances evaluated by MMSE or MoCA were poorer in AD patients compared to those in HCs  and 232 (50.1%) females], and 1,389 healthy subjects [693 males (49.9%) and 696 females (50.1%)]. The MRI scan supported the diagnosis of the included AD patients, who had medial temporal 146 lobe atrophy, and the Fazekas scale of white matter lesions was <2. The mean age at examination of the AD patients and HCs were 69.00 ± 11.31 and 69.08 ± 11.28 years, respectively. Serum cystatin C levels in AD patients were significantly higher than those in normal subjects . In addition, the correlation analyses were utilized to investigate the correlations between serum cystatin C levels and cognitive performance assessed by MMSE and MoCA . However, the correlation analyses showed that serum cystatin C levels were not correlated to the cognitive performance in HCs . Serum cystatin C levels was also found to be significantly associated with age at examination in both AD patients and HCs . The ordinal logistic regression stratified by CDR grade was conducted, and the results of the model for predicting CDR grade using cystatin C level showed age at onset, sex, disease duration and presence of APOE ε4 allele were not significant risk factors in this model. However, serum cystatin C levels were slightly associated with severity of cognitive impairment . With regard to the cognitive predictors, AD patients with a 1-point increase in cystatin C levels were 48% more likely to have a higher CDR grade, indicating the AD patients with higher cystatin C levels may have increased odds of severe cognitive dysfunction.In order to determine the association between serum cystatin C levels and cognitive impairment, we stratified the cohort based on the CDR grade . The one-way ANOVA analyses showed that the serum cystatin C levels were not significantly different among AD patients with different severities of dementia  the genetic CST3 genotypes were not considered; (2) the results of the present cannot be extrapolated to other populations since our patients were recruited from a single specialized unit. On the other hand, some of the strengths of our study are the strict inclusion criteria, the examination of APOE genotype, and the fact that the specialized neurologists conducted all the data collections and manifestation assessments.In summary, the findings of the current study support the idea that cystatin C plays an essential role in the pathogenesis of AD. Our results suggest AD patients had higher levels of serum cystatin C when compared to age/sex/BMI-matched normal controls, and higher serum cystatin C levels were weakly associated with worse cognitive performance in AD patients. Our findings strengthen the evidence that serum cystatin C may be involved in modulating the clinical expression of cognitive decline. Further longitudinal studies in larger cohorts and distinct ethnic groups will be needed to validate our findings, and to determine the mechanisms underlying this association.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.HS conceived this study. YH, TB, RO, QW, YC, JL, and JY did the patient evaluation and data collection. FJ did the statistical analysis. XC and HS wrote the manuscript while all authors revised and discussed to the final edition. All authors contributed to the article and approved the submitted version.This study was supported by grant from National key Research and development program of China (Grant No. 2017YFC09007703), grant from science and technology planning project in Sichuan Province (Grant No. 2020YJ0281), grant from 1·3·5 project for disciplines of excellence West China Hospital Sichuan University (Grant No. ZYJC18038), and the grant from cadres health care project in Sichuan Province (Grant No. 2019-112).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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