1.NG2-Glia Cause Diabetic Blood-Brain Barrier Disruption by Secreting MMP-9
Xiaolong LI ; Yan CAI ; Zhu ZHONG ; Maolin LI ; Dong HUANG ; Zhifei QIAO ; Hongli ZHOU ; Zuo ZHANG ; Jiyin ZHOU
Diabetes & Metabolism Journal 2026;50(1):47-61
Background:
Disorders of the blood-brain barrier (BBB) arising from diabetes mellitus are closely related to diabetic encephalopathy. Previous research has suggested that neuron-glia antigen 2 (NG2)-glia plays a key role in maintaining the integrity of the BBB. However, the mechanism by which NG2-glia regulates the diabetic BBB remains unclear.
Methods:
Type 2 diabetes mellitus (T2DM) db/db mice and db/m mice were used. Evans-Blue BBB permeability tests and transmission electron microscopy techniques were applied. Tight junction proteins were assessed by immunofluorescence and transmission electron microscopy. NG2-glia number and signaling pathways were evaluated by immunofluorescence. Detection of matrix metalloproteinase-9 (MMP-9) in serum was performed using enzyme-linked immunosorbent assay (ELISA).
Results:
In T2DM db/db mice, BBB permeability in the hippocampus significantly increased from 16 weeks of age, and the structure of tight junction proteins changed. The number of NG2-glia in the hippocampus of db/db mice increased around microvessels from 12 weeks of age. Concurrently, the expression of MMP-9 increased in the hippocampus with no change in serum. Sixteen- week-old db/db mice showed activation of the Wnt/β-catenin signaling in hippocampal NG2-glia. Treatment with XAV-939 improved structural and functional changes in the hippocampal BBB and reduced MMP-9 secretion by hippocampal NG2-glia in db/db mice. It was also found that the upregulation of β-catenin protein in NG2-glia in the hippocampus of 16-week-old db/db mice was significantly alleviated by treatment with XAV-939.
Conclusion
The results indicate that NG2-glia can lead to structural and functional disruption of the diabetic BBB by activating Wnt/β-catenin signaling, upregulating MMP-9, and degrading tight junction proteins.
2.Clinical Safety Monitoring of 3 035 Cases of Juvenile Feilike Mixture After Marketing in Hospital
Jian ZHU ; Zhong WANG ; Jing LIU ; Jun LIU ; Wei YANG ; Yanan YU ; Hongli WU ; Sha ZHOU ; Zhiyu PAN ; Guang WU ; Mengmeng WU ; Zhiwei JING
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(10):194-200
ObjectiveTo explore the clinical safety of Feilike Mixture (FLK) in the real world. MethodsThe safety of all children who received FLK from 29 institutions in 12 provinces between January 21,2021 and December 25,2021 was evaluated through prospective centralized surveillance and a nested case control study. ResultsA total of 3 035 juveniles were included. There were 29 research centers involved,which are distributed across 12 provinces,including one traditional Chinese medicine (TCM) hospital and 28 general hospitals. The average age among the juveniles was (4.77±3.56) years old,and the average weight was (21.81±12.97) kg. Among them,119 cases (3.92%) of juveniles had a history of allergies. Acute bronchitis was the main diagnosis for juveniles,with 1 656 cases (54.46%). FLK was first used in 2 016 cases (66.43%),and 142 juvenile patients had special dosages,accounting for 4.68%. Among them,92 adverse drug reactions (ADRs) occurred,including 73 cases of gastrointestinal system disorders,10 cases of metabolic and nutritional disorders,eight cases of skin and subcutaneous tissue diseases,two cases of vascular and lymphatic disorders,and one case of systemic diseases and various reactions at the administration site. The manifestations of ADRs were mainly diarrhea,stool discoloration,and vomiting,and no serious ADRs occurred. The results of multi-factor analysis indicated that special dosages (the use of FLK)[odds ratio (OR) of 2.642, 95% confidence interval (CI) of 1.105-6.323],combined administration: spleen aminopeptide (OR of 4.978, 95%CI of 1.200-20.655),and reason for combined administration: anti-infection (OR of 1.814, 95%CI of 1.071-3.075) were the risk factors for ADRs caused by FLK. Conclusion92 ADRs occurred among 3 035 juveniles using FLK. The incidence of ADRs caused by FLK was 3.03%,and the severity was mainly mild or moderate. Generally,the prognosis was favorable after symptomatic treatment such as drug withdrawal or dosage reduction,suggesting that FLK has good clinical safety.
3.Current status and influencing factors of fear of ulcer recurrence in patients with diabetic foot
Qian WANG ; Hongjuan ZHU ; Na SHI ; Zhenhua XIA ; Hongli YU ; Liwei WANG
Chinese Journal of Nursing 2025;60(20):2486-2492
Objective To explore the fear of ulcer recurrence in patients with diabetic foot and analyze its influencing factors,so as to provide strategies for medical staff to implement comprehensive and personalized nursing interventions.Methods From February 2024 to March 2025,convenience sampling was used to select inpatients and outpatients with diabetic foot ulcers from 6 tertiary hospitals in China as the survey subjects.The general information questionnaire,ADL,MNA,PSQI,Diabetic Foot Self-Management Behavior Scale and FOP-Q-SF were used to investigate and analyze the results.Results A total of 191 questionnaires were distributed and 186 valid questionnaires were returned,with an effective recovery rate of 97.38%.The total score of ulcer recurrence fear of diabetic foot patients was(31.78±7.41).Binary Logistic regression analysis showed that nutritional status,sleep quality,duration of diabetes,other chronic diseases,family per capita monthly income and medical insurance were the influencing factors of ulcer recurrence fear in patients with diabetic foot(P<0.05).Conclusion Patients with diabetic foot have a high level of fear of ulcer recurrence.Nutritional status,sleep quality,duration of diabetes,combined with other chronic diseases,family per capita monthly income,and medical insurance are its influencing factors.Nursing staff should take targeted nursing measures according to its influencing factors to reduce the occurrence of patients' fear of ulcer recurrence.
4.Self-management dilemmas and coping strategies for home-dwelling elderly patients with diabetic foot: a qualitative study
Hongli YU ; Hongjuan ZHU ; Qian WANG ; Liwei WANG
Chinese Journal of Modern Nursing 2025;31(22):3031-3036
Objective:To deeply understand the real experiences of self-management in home-dwelling elderly patients with diabetic foot, explore the factors associated with management dilemmas, and reveal the diversity of coping strategies based on the theory of planned behavior, so as to provide a reference for development of targeted clinical nursing strategies.Methods:Purposive sampling was used to select 21 elderly patients with diabetic foot who attended the Fourth Medical Center of the Chinese PLA General Hospital from May 2023 to March 2024 for semi-structured interviews. Colaizzi 7-step analysis was used to analyze and refine the themes.Results:After collating, analyzing and summarizing the interview data, 3 themes and 9 sub-themes were extracted, namely, behavioral attitudes (lack of self-management awareness due to insufficient cognition, compromising and avoiding psychology restricting self-management behaviors, negative emotions generating and attacking confidence in self-management), subjective norms (lack of healthcare channels increasing the difficulty of accessing healthcare, increased economic burden delaying disease treatment, and poor treatment experience damaging physical and mental health) and perceived behavioral control (accumulation of knowledge to put into practice, experience of multiple management strategies, seeking external help and support) .Conclusions:The home-dwelling elderly patients with diabetic foot have multiple self-management dilemmas. Nursing staff should emphasize the patient's own and objective dilemmas, provide cognitive intervention strategies, multiple coping support, and long-term professional guidance to improve the patients' self-management ability.
5.A mixed study of factors influencing quality of life in elderly patients with minor amputations of the diabetic foot
Hongjuan ZHU ; Qian WANG ; Shujun WANG ; Dengfen ZENG ; Wanli CHU ; MUNIRE·MUTAILIPU ; Hongli YU ; Liwei WANG
Chinese Journal of Nursing 2025;60(1):83-89
Objective To investigate the current status of quality of life and its influencing factors in elderly patients with minor amputations of the diabetic foot,providing a basis for medical staff to formulate intervention strategies.Methods A convergent mixed study design was used.A single-centre cross-sectional survey research method was used to select 168 elderly patients with minor amputation of the diabetic foot admitted to the Department of Wound Repair of a tertiary-level hospital in Beijing from May 2022 to May 2024 for questionnaire surveys and multivariate linear regression analyses of factors affecting the quality of life.During the same period,15 patients were selected for semi-structured interviews using purposive sampling based on ternary interaction determinism.Results Quantitative findings:A total of 167 valid questionnaires were retrieved,and the recovery rate of valid questionnaires was 99.4%.the total quality of life score of 167 respondents was(84.22±12.49)scores;the results of multivariate linear regression analyses showed that age and self-care ability were the independent risk factors affecting the quality of life of patients with minor amputation of the diabetic foot(P<0.05).Qualitative findings:a total of 3 themes were extracted based on the triadic interactive determinism,including subject level,environmental level and behavioural level.Mixed findings:age and amputation affect the physical and mental state of patients and hinders quality of life improvement;limited work and life,and scarce external resources;the level of self-care ability restricts self-management behaviours and makes it difficult to improve quality of life.Conclusion Elderly patients with minor amputations of the diabetic foot have impaired physiological and psychological health to some degree,and healthcare professionals should be concerned about the negative impact of minor amputations on elderly diabetic foot patients,while also focusing on their individual needs and providing support.
6.The predictive value of serum HOXA6 and HOXA10 levels for endometrial receptivity in patients with diminished ovarian reserve
Clinical Medicine of China 2025;41(6):458-465
Objective:To investigate the predictive value of serum HOXA6 and HOXA10 levels in assessing endometrial receptivity in patients with diminished ovarian reserve (DOR).Methods:A total of 248 DOR patients treated at Xi'an People's Hospital from January 2021 to October 2023 were enrolled, with 200 healthy female volunteers as controls. Serum HOXA6 and HOXA10 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Endometrial thickness was assessed via transvaginal ultrasound on days 20-24 of the menstrual cycle, and endometrial receptivity was classified into high receptivity (≥8 mm), moderate receptivity (6-8 mm) and low receptivity (<6 mm) group. Follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH) levels were detected by chemiluminescence immunoassay on day 3 of the menstrual cycle. Follicle count and size were recorded via transvaginal ultrasound. Normally distributed data were expressed as Mean±SD, comparison between two groups was performed by independent samples t-test, comparison among multiple groups was performed by one-way ANOVA, pairwise comparison was performed by Tukey's HSD post hoc test. Categorical data were presented as rates or percentages and analyzed by χ2 test. Logistic regression identified independent risk factors for DOR, and Pearson correlation analyzed relationships between HOXA6/HOXA10, endometrial receptivity, and ovarian reserve. Receiver operating characteristic (ROC) curves evaluated the diagnostic value of HOXA6 and HOXA10 in predicting endometrial receptivity. Results:Serum levels of both HOXA6 [(120.34±15.16) ng/L] and HOXA10 [(98.46±12.61) ng/L] in the DOR group were significantly higher than those in the control group [(80.27±10.54) ng/L and (60.36±8.80) ng/L, respectively, t=31.70, 36.20, both P<0.001]. Endometrial thickness in the DOR group [(7.4±1.3) mm] was significantly less than that in the control group [(10.0±1.1) mm]. Serum FSH levels [(12.03±2.54) U/L] were significantly higher in the DOR group compared to the control group [(8.08±2.82) U/L], while AMH levels [(1.56±0.45) μg/L] and the number of follicles [(3.52±1.63) μg/L] were significantly lower than those in the control group [(5.07±1.05) μg/L and (10.09±2.06), respectively]. The differences between the two groups for these parameters were statistically significant ( t=22.52, 15.58, 18.10, 33.58, respectively; all P<0.001). Pearson correlation analysis revealed that serum HOXA6 and HOXA10 levels were negatively correlated with endometrial thickness, AMH levels, and the number of follicles in DOR patients (HOXA6: r=-0.773, -0.647, -0.721, respectively, all P<0.001; HOXA10: r=-0.788, -0.682, -0.834, respectively, all P<0.001), and positively correlated with serum FSH levels ( r=0.667 and 0.670, respectively, both P<0.001). Multivariate logistic regression analysis indicated that serum HOXA6 ( OR=1.179, 95% CI: 1.144-1.215, P<0.001), HOXA10 ( OR=1.223, 95% CI: 1.177-1.270, P<0.001), and FSH levels ( OR=1.827, 95% CI: 1.569-2.129, P<0.001) were independent risk factors for DOR in women. Endometrial thickness ( OR=0.264, 95% CI: 0.205-0.340, P<0.001), serum AMH levels ( OR=0.126, 95% CI: 0.078-0.205, P<0.001), and the number of follicles ( OR=0.058, 95% CI: 0.024-0.143, P<0.001) were identified as protective factors against DOR. ROC curve analysis showed that the AUCs for serum HOXA6, HOXA10, and their combination in predicting poor endometrial receptivity in DOR patients were 0.770, 0.820, and 0.864, respectively. The AUC value for HOXA10 was slightly higher than that for HOXA6, and the combined prediction model had the highest AUC value. Conclusion:Serum HOXA6 and HOXA10 levels demonstrate a statistically significant association with ovarian reserve function and endometrial receptivity. These findings suggest their potential as diagnostic biomarkers for assessing endometrial receptivity in patients with diminished ovarian reserve (DOR).
7.Construction and evaluation of a predictive model for mortality risk factors in patients with multiple trauma complicated with thoracic injuries
Sitong MOU ; Xiaoling ZHU ; Shixiong YANG ; Heyue YANG ; Ke LUO ; Xian WU ; Zhiqun ZHAN ; Hongli TENG ; Li YE ; Ming LI ; Huamin TANG
Chinese Journal of Trauma 2025;41(1):72-81
Objective:To construct a predictive model for mortality in patients with multiple trauma combined with thoracic injuries and evaluate its predictive value.Methods:A retrospective cohort study was conducted to analyze the clinical data of 184 patients with multiple trauma combined with thoracic injuries admitted to the International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese Medicine from April 2019 to December 2023, including 129 males and 55 females, aged 19-85 years [(46.1±13.7)years]. According to the prognostic outcomes at 3-month follow-up after discharge, the patients were divided into survival group ( n=145) and death group ( n=39). Data were recorded in both groups at admission, including gender, age, and cause of injury, laboratory tests such as systolic blood pressure, oxygen saturation (SaO 2), hemoglobin (Hb), neutrophil-to-lymphocyte ratio (NLR), and lactate, combined injuries such as the number of combined injuries, number of rib fracture, bilateral rib fracture, first-rib fracture, sternum fracture, thoracic vertebral fracture, bilateral pulmonary contusion, bilateral pneumothorax, subarachnoid hemorrhage, subdural hematoma, epidural hematoma, skull fracture, skull base fracture, cervical vertebral fracture, brain herniation, cerebral contusion, lumbar vertebral fracture, pelvic and abdominal cavity hematoma, liver injury, kidney injury, spleen injury, clavicle fracture, scapular fracture, femoral fracture, and pelvic fracture, and injury scores such as shock index (SI), modified shock index (MSI), injury severity score (ISS), revised trauma score (RTS), Glasgow coma score (GCS), and thoracic trauma severity (TTS) score. Univariate binary logistic regression analysis was used to screen for risk factors of death in patients with multiple trauma combined with thoracic injuries. LASSO regression and multivariate logistic regression analysis were employed to identify predictive variables and independent risk factors for mortality in those patients and to construct a regression equation. A nomogram prediction model based on the regression equation was developed using R language. Receiver operating characteristic (ROC) curves were plotted to evaluate the discrimination of the model. The ROC curves were internally validated using the Bootstrap method with 1 000 resamples. The calibration of the model was assessed using the Hosmer-Lemeshow (H-L) goodness-of-fit test. The clinical application value of the model was evaluated using decision curve analysis (DCA) and clinical impact curve (CIC) analysis. Results:There were statistically significant differences between the survival group and the death group in systolic blood pressure, SaO 2, NLR, lactate, number of combined injuries, subarachnoid hemorrhage, subdural hematoma, skull fracture, skull base fracture, brain herniation, liver injury, SI, MSI, ISS, RTS, GCS, and TTS ( P<0.05 or 0.01). The results of the univariate binary logistic regression analysis showed that the above-mentioned related variables except for systolic blood pressure were all significantly associated with death in patients with multiple trauma combined with thoracic injuries ( P<0.05 or 0.01). Five predictive variables, TTS, GCS, brain herniation, ISS, and lactate were obtained in LASSO regression analysis. The results of the multivariate logistic regression analysis showed that GCS ( OR=0.70, 95% CI 0.58, 0.83), brain herniation ( OR=46.18, 95% CI 4.27, 499.26), TTS ( OR=1.71, 95% CI 1.30, 2.24), and lactate ( OR=1.35, 95% CI 1.01, 1.80) were independent risk factors for death in patients with multiple trauma combined with thoracic injuries ( P<0.05 or 0.01). Based on the aforementioned independent risk factors, a regression formula was constructed as follows: P=e x/(1+e x), with the x=-0.36×"GCS"+3.83×"brain herniation"+0.53×"TTS"+0.30×"lactate levels"-11.03. The area under the ROC curve (AUC) of the predictive model for mortality in patients with multiple trauma combined with thoracic injuries based on the equation was 0.97 (95% CI 0.93, 1.00). The AUC was internally validated using the Bootstrap method with 1 000 samples, resulting in an AUC of 0.97 (95% CI 0.91, 1.00). The results of the H-L goodness-of-fit test showed that the bias-corrected calibration curve of the model was in good consistence with the actual curve and both of them were close to the ideal curve. In the evaluation of the clinical application value of the predictive model, the DCA results showed that the predictive model could achieve good clinical net benefit. The CIC results showed that when the threshold probability was greater than 0.7, the model-identified high-risk patients for death highly matched the patients who actually died. Conclusion:The predictive model for mortality in patients with multiple trauma combined with thoracic injuries based on GCS, brain herniation, TTS, and lactate has good predictive performance and clinical application value.
8.Clinical guideline for diagnosis and treatment of nonunion of osteoporotic vertebral fractures (version 2025)
Haipeng SI ; Le LI ; Junjie NIU ; Wencan ZHANG ; Fuxin WEI ; Jinqiu YUAN ; Qiang YANG ; Hongli WANG ; Guangchao WANG ; Shihong CHEN ; Yunzhen CHEN ; Xiaoguang CHENG ; Jianwen DONG ; Shiqing FENG ; Rui GU ; Yong HAI ; Tianyong HOU ; Bo HUANG ; Xiaobing JIANG ; Lei ZANG ; Chunhai LI ; Nianhu LI ; Hua LIN ; Hongjian LIU ; Peng LIU ; Xinyu LIU ; Sheng LU ; Shibao LU ; Chunshan LUO ; Lvy CHAOLIANG ; Lvy WEIJIA ; Xuexiao MA ; Wei MEI ; Chunyang MENG ; Cailiang SHEN ; Chunli SONG ; Ruoxian SONG ; Jiacan SU ; Honglin TENG ; Hui SHENG ; Beiyu WANG ; Bingwu WANG ; Liang WANG ; Xiangyang WANG ; Nan WU ; Guohua XU ; Yayi XIA ; Jin XU ; Youjia XU ; Jianzhong XU ; Cao YANG ; Maowei YANG ; Zibin YANG ; Xiaojian YE ; Hailong YU ; Xijie YU ; Hua YUE ; Zhili ZENG ; Xinli ZHAN ; Hui ZHANG ; Peixun ZHANG ; Wei ZHANG ; Zhenlin ZHANG ; Jianguo ZHANG ; Tengyue ZHU ; Qiang LIU ; Huilin YANG
Chinese Journal of Trauma 2025;41(10):932-945
Nonunion of osteoporotic vertebral fractures (OVF), predominantly affecting the elderly, can lead to intractable pain, vertebral collapse, progressive kyphotic deformity, and neurological impairment, significantly compromising patients′ quality of life. There exists considerable debate on diagnosis and management of OVF, encompassing key issues such as clinical diagnosis and staging criteria for nonunion, surgical indications and procedure selection, and postoperative rehabilitation planning. Currently, there lacks standardized clinical guideline and expert consensus on the diagnosis and management of OVF nonunion in China. To address this gap, Minimally Invasive Surgery Group of Chinese Orthopedic Association, Osteoporosis Committee of Chinese Association of Orthopedic Surgeons, Prevention and Rehabilitation Committee for Osteoporosis of Chinese Association of Rehabilitation Medicine and Minimally Invasive Orthopedic Surgery Branch of China Association for Geriatric Care jointly organized domestic experts in spinal surgery, endocrinology, and rehabilitation to formulate the Clinical guideline for the diagnosis and treatment for nonunion of osteoporotic vertebral fractures ( version 2025), based on existing literature and clinical experience and adhering to principles of scientific rigor and practicality. The guideline provided 13 evidence-based recommendations encompassing diagnosis and treatment of OVF nonunion, aiming to standardize its clinical management.
9.Long-term hemodialysis survivors: a case series of 8 patients on dialysis for over 30 years and literature review
Minyan HU ; Jingyi CHEN ; Feng ZHU ; Nan WANG ; Jinghui LIU ; Aomei LI ; Jiawen TIAN ; Longkai LI ; Hongli LIN
Chinese Journal of General Practitioners 2025;24(12):1541-1544
We retrospectively analyzed 8 patients who had been on hemodialysis for over 30 years from two dialysis centers in Dalian, China. A literature review was conducted by searching PubMed, CNKI, Wanfang databases,and Chinese Medical Journal Network for cases of patients on hemodialysis for over 30 years. The 8 patients had good baseline health, with chronic glomerulonephritis as the primary renal disease and no comorbidities before initiating dialysis. They started hemodialysis between 21 and 38 years of age, predominantly using arteriovenous fistulas for vascular access. Dialysis was regular and adequate (KT/V 1.23-1.88). Key laboratory parameters, including hemoglobin (88-118 g/L), albumin (27.7-39.7 g/L), calcium (1.88-2.55 mmol/L), and phosphate (0.76-1.99 mmol/L), were generally within target ranges. Body mass index ranged from 15.20 to 22.96 kg/m2. This literature review of the study included 12 case reports and 4 orginal articles. Factors influencing long-term survival included baseline health status, primary renal disease, absence of comorbidities before dialysis initiation, age at dialysis initiation, type of vascular access, dialysis adequacy, complication management, and medical support. Standardized management and timely correction of complications can significantly improve prognosis and enhance long-term survival in hemodialysis patients.
10.Analysis of the current status and countermeasures of safety content control of traditional Chinese medicine based on the revision announcement of the instruction and the national adverse drug reaction monitoring report
Jian ZHU ; Zhong WANG ; Hongli WU ; Zhiwei JING
China Pharmacy 2025;36(17):2092-2096
OBJECTIVE To provide a reference for revising the safety content of traditional Chinese medicine(TCM) instructions. METHODS A systematic analysis was conducted on the relevant announcements on the revision of TCM instruction from 2013 to 2024, including the year of publication, drug name, drug formulation, announcement release time, and the average number of revisions made to three safety contents (contraindication, adverse drug reaction, and precaution). According to the report data of national adverse drug reaction monitoring from 2013 to 2024, analyze the proportion of TCM in all adverse drug reactions, the composition ratio of adverse drug reaction of different dosage forms of drugs [TCM injection, oral TCM, other (topical) TCM]. RESULTS From 2013 to 2024, the National Medical Products Administration issued a total of 101 notices on the revision of TCM instruction, involving 241 types of TCM. Among them, there were 163 types of oral TCM, 25 types of TCM injection, and 53 types of other (topical) TCM. There were 3, 10 and 0 types of TCM injection, oral TCM, and other (topical) TCM with missing safety content, respectively. The main source of adverse drug reaction data for TCM injections was post- marketing monitoring data (accounting for 48.00%); the main source of adverse drug reaction data for oral TCM was monitoring data (accounting for 71.17%); 73.58% of other (topical) TCM did not mention the source of adverse drug reaction data. The report on national adverse drug reaction monitoring showed that the proportion of all adverse drug reactions of TCM had decreased from 17.3% in 2013 to 12.1% in 2024. Among them, the proportion of adverse drug reaction of TCM injection in the three dosage forms of TCM had decreased from 61.3% in 2015 to 24.6% in 2024, while the proportion of adverse drug reaction of oral TCM in the three dosage forms of TCM had increased from 34.7% in 2015 to 64.0% in 2024. CONCLUSIONS The risk management of TCM safety content has achieved results in China, but still faces three major challenges: strongdependence on passive monitoring, insufficient data traceability, and missing key content. It is urgent to improve safety content by dosage form, optimize data sources, and fully utilize real-world evidence to supplement safety content.

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