1.Quality Evaluation of Clinical Guidelines for Acute Myocardial Infarction Based on AGREE Ⅱ
Shuyu GUAN ; Tianying CHANG ; Jiankang WANG ; Hang SHANG ; Yueying ZHANG ; Jiajuan GUO ; Yingzi CUI
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(10):201-209
ObjectiveThis paper used the AGREE Ⅱ guideline evaluation tool to evaluate the quality of 14 clinical guidelines for acute myocardial infarction,aiming to provide reference for the formulation and improvement of the guidelines. MethodsClinical guidelines and expert consensus related to acute myocardial infarction were searched by web search. The search period ranges from January 1,2019 to November 1,2024 in CNKI,VIP,Wanfang Data,SinoMed,Web of Science,OVID, the International Guidelines Collaboration Network (GIN),the UK National Institute for Health and Clinical Excellence (NICE),Yimaitong, and other platforms. Three researchers independently screened the literature and used AGREE Ⅱ to score the screening results. After ensuring that the researchers have a consistent understanding of each guideline,the quality of the guidelines was evaluated. After that,the ratings were analyzed by layer according to the issuing agency,category,method of formulation,and funding situation and compared longitudinally by rating time. The clinical guidelines and expert consensus were compared in terms of content and evidence. ResultsA total of 14 guidelines and consensus were included. The results of AGREE Ⅱ in the six areas in descending order were scope and purpose (62.82%±10.43%),rigor (62.40%±12.77%),editorial independence (62.11%±22.26%),participants (61.42%±11.65%),clarity of expression (59.98%±9.62%),and application (52.94%±16.90%) . Eleven of the guidelines were at level B, and three were at level A. In the stratified analysis,the score of the guideline formulated by the Chinese Medical Doctor Association was lower. There was little difference between the scores of Chinese/Western and Western medicine guidelines. The average score of the guidelines was higher than the consensus. Funded guidelines and consensus scores were higher. In the longitudinal comparison,the highest number of guidelines were developed in 2020 and 2021,while those developed in 2023 scored the highest. In the differential comparison analysis,the content of the guidelines was more comprehensive, and the evidence level was higher,while the content of the consensus was more novel, and the evidence was less. ConclusionThe AGREE Ⅱ score of the clinical guidelines for acute myocardial infarction is generally moderate,and there is room for improvement in terms of applicability. At the same time,the content quality of expert consensus should be improved,and more efforts should be made to develop and apply Chinese medicine guidelines for complications such as heart failure and microcirculatory obstruction after acute myocardial infarction.
2.Production of GTKO pigs and kidney xenotransplantation from pigs to rhesus macaques
Yan WANG ; Yue CHANG ; Chang YANG ; Taiyun WEI ; Xiaoying HUO ; Bowei CHEN ; Jiaoxiang WANG ; Heng ZHAO ; Jianxiong GUO ; Hongfang ZHAO ; Xiong ZHANG ; Feiyan ZHU ; Wenmin CHENG ; Hongye ZHAO ; Kaixiang XU ; Ameen Jamal MUHAMMAD ; Zhendi WANG ; Hongjiang WEI
Organ Transplantation 2025;16(4):526-537
Objective To explore the construction of α-1,3-galactosyltransferase (GGTA1) gene-knockout (GTKO) Diannan miniature pigs and the kidney xenotransplantation from pigs to rhesus macaques, and to assess the effectiveness of GTKO pigs. Methods The GTKO Diannan miniature pigs were constructed using the CRISPR/Cas9 gene-editing system and somatic cell cloning technology. The phenotype of GTKO pigs was verified through polymerase chain reaction, Sanger sequencing and immunofluorescence staining. Flow cytometry was used to detect antigen-antibody (IgM) binding and complement-dependent cytotoxicity. Kidney xenotransplantation was performed from GTKO pigs to rhesus macaques. The humoral immunity, cellular immunity, coagulation and physiological indicators of the recipient monkeys were monitored. The function and pathological changes of the transplanted kidneys were analyzed using ultrasonography, hematoxylin-eosin staining, immunohistochemical staining and immunofluorescence staining. Results Single-guide RNA (sgRNA) targeting exon 4 of the GGTA1 gene in Diannan miniature pigs was designed. The pGL3-GGTA1-sgRNA1-GFP vector was transfected into fetal fibroblasts of Diannan miniature pigs. After puromycin selection, two cell clones, C59# and C89#, were identified as GGTA1 gene-knockout clones. These clones were expanded to form cell lines, which were used as donor cells for somatic cell nuclear transfer. The reconstructed embryos were transferred into the oviducts of trihybrid surrogate sows, resulting in 13 fetal pigs. Among them, fetuses F04 and F11 exhibited biallelic mutations in the GGTA1 gene, and F04 had a normal karyotype. Using this GTKO fetal pig for recloning and transferring the reconstructed embryos into the oviducts of trihybrid surrogate sows, seven surviving piglets were obtained, all of which did not express α-Gal epitope. The binding of IgM from the serum of rhesus monkey 20# to GTKO pig PBMC was reduced, and the survival rate of GTKO pig PBMC in the complement-dependent cytotoxicity assay was higher than that of wild-type pig. GTKO pig kidneys were harvested and perfused until completely white. After the left kidney of the recipient monkey was removed, the pig kidney was heterotopically transplanted. Following vascular anastomosis and blood flow restoration, the pig kidney rapidly turned pink without hyperacute rejection (HAR). Urine appeared in the ureter 6 minutes later, indicating successful kidney transplantation. The right kidney of the recipient was then removed. Seven days after transplantation, the transplanted kidney had good blood flow, the recipient monkey's serum creatinine level was stable, and serum potassium and cystatin C levels were effectively controlled, although they increased 10 days after transplantation. Seven days after transplantation, the levels of white blood cells, lymphocytes, monocytes and eosinophils in the recipient monkey increased, while platelet count and fibrinogen levels decreased. The activated partial thromboplastin time, thrombin time and prothrombin time remained relatively stable but later showed an upward trend. The recipient monkey survived for 10 days. At autopsy, the transplanted kidney was found to be congested, swollen and necrotic, with a small amount of IgG deposition in the renal tissue, and a large amount of IgM, complement C3c and C4d deposition, as well as CD68+ macrophage infiltration. Conclusions The kidneys of GTKO Diannan miniature pigs may maintain normal renal function for a certain period in rhesus macaques and effectively overcome HAR, confirming the effectiveness of GTKO pigs for xenotransplantation.
3.Influence of antiviral treatment adjustment on the prognosis of chronic hepatitis B patients with low-level viremia
Mengwen HE ; Wucai YANG ; Chunyan WANG ; Yiming FU ; Chang GUO ; Jianjun WANG ; Dong JI
Journal of Clinical Hepatology 2025;41(6):1056-1061
ObjectiveTo investigate the incidence rate of primary liver cancer (PLC) and the progression of liver fibrosis in chronic hepatitis B (CHB) patients with low-level viremia (LLV) (HBV DNA<2 000 IU/mL but ≥20 IU/mL) after treatment adjustment, and to provide more robust evidence for clinical practice. MethodsA retrospective analysis was performed for the clinical data of LLV patients who initially received nucleos(t)ide analogue (NAs) for at least 48 weeks at the Fifth Medical Center of PLA General Hospital from August 2007 to April 2017 and subsequently underwent NAs adjustment due to LLV, and according to the virologic response after 48 weeks of treatment adjustment, the patients were divided into LLV group and complete virological response (CVR) group (HBV DNA<20 IU/mL). The patients were followed up once every 3 — 6 months till the primary endpoint event of PLC or October 2024. The incidence rate of PLC and the progression of liver fibrosis were observed, and the progression of liver fibrosis was defined as an increase of ≥1 grade in fibrosis-4 (FIB-4) index. The independent-samples t test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of continuous data with skewed distribution between two groups; the chi-square test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to calculate the cumulative incidence rate of PLC, and the Log-rank test was used for comparison between groups; the Cox regression analysis was used to investigate the risk factors for PLC, and the Logistic regression analysis was used to investigate the influencing factors for the progression of liver fibrosis. ResultsA total of 307 patients were enrolled, with a mean age of 50.0 years, and the male patients accounted for 80.5%. After 48 weeks of treatment with the adjusted NAs regimen, 254 patients (82.7%) achieved CVR, and 53 patients (17.3%) still had LLV. For the LLV group, the incidence rate of PLC was 30.2% and the rate of liver fibrosis progression was 22.6%, while for the CVR group, the incidence rate of PLC was only 13.4%, and the rate of liver fibrosis progression was 7.5%. The multivariate regression analyses showed that LLV was an independent risk factor for the onset of PLC (hazard ratio=2.623, 95% confidence interval [CI]: 1.315 — 5.234, P=0.006) and the progression of liver fibrosis (odds ratio=3.213, 95%CI: 1.385 — 7.455, P=0.007). ConclusionActive adjustment of treatment is needed immediately after the diagnosis of LLV to improve CVR, and if LLV persists after treatment adjustment, it is necessary to enhance the monitoring of liver fibrosis progression and PLC, so as to facilitate early diagnosis and treatment.
4.Modified Xiaoyaosan Alleviates Depression-like Behaviors by Regulating Activation of Hippocampal Microglia Cells in Rat Model of Juvenile Depression
Jiayi SHI ; Yun XIANG ; Ziyang ZHOU ; Dahua WU ; Feng QIU ; Chang LEI ; Hongyu ZENG ; Kaimei TAN ; Hongqing ZHAO ; Dong YANG ; Yuhong WANG ; Pengxiao GUO ; Xiuli ZHANG
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(5):46-56
ObjectiveTo investigate the mechanism of Baihuan Xiaoyao Decoction (Xiaoyaosan added with Lilii Bulbus and Albiziae Cortex) in alleviating depression-like behaviors of juvenile rats by regulating the polarization of microglia. MethodSixty juvenile SD rats were randomized into normal control, model, fluoxetine, and low-, medium-, and high-dose (5.36, 10.71, 21.42 g·kg-1, respectively) Baihuan Xiaoyao decoction groups. The rat model of juvenile depression was established by chronic unpredictable mild stress (CUMS). The sucrose preference test (SPT) was carried out to examine the sucrose preference of rats. Forced swimming test (FST) was carried out to measure the immobility time of rats. The open field test (OFT) was conducted to measure the total distance, the central distance, the number of horizontal crossings, and the frequency of rearing. Morris water maze (MWM) was used to measure the escape latency and the number of crossing the platform. The immunofluorescence assay was employed to detect the expression of inducible nitric oxide synthase (iNOS, the polarization marker of M1 microglia) and CD206 (the polarization marker of M2 microglia). Real-time polymerase chain reaction was employed to determine the mRNA levels of iNOS, CD206, pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6] and anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. Western blotting was employed to determine the protein levels of iNOS and CD206 in the hippocampus. The levels of IL-4 and IL-6 in the hippocampus were detected by enzyme-linked immunosorbent assay. ResultCompared with the normal control group, the model rats showed a reduction in sucrose preference (P<0.05), an increase in immobility time (P<0.05), decreased motor and exploratory behaviors (P<0.05), and weakened learning and spatial memory (P<0.05). In addition, the model rats showed up-regulated mRNA and protein levels of iNOS and mRNA levels of IL-1β, IL-6, and TNF-α (P<0.05). Compared with the model group, Baihuan Xiaoyao decoction increased the sucrose preference value (P<0.05), shortened the immobility time (P<0.01), increased the motor and exploratory behaviors (P<0.05), and improved the learning and spatial memory (P<0.01). Furthermore, the decoction down-regulated the positive expression and protein level of iNOS, lowered the levels of TNF-α, IL-1β, and IL-6 (P<0.01), promoted the positive expression of CD206, and elevated the levels of IL-4 and IL-10 (P<0.01) in the hippocampus of the high dose group. Moreover, the high-dose Baihuan Xiaoyao decoction group had higher sucrose preference value (P<0.01), shorter immobility time (P<0.01), longer central distance (P<0.01), stronger learning and spatial memory (P<0.01), higher positive expression and protein level of iNOS (P<0.01), lower levels of TNF-α, IL-1β, and IL-6 (P<0.05, P<0.01), lower positive expression and mRNA level of iNOS (P<0.05), and higher levels of IL-4 and IL-10 (P<0.05, P<0.01) than the fluoxetine group. ConclusionBaihuan Xiaoyao decoction can improve the depression-like behavior of juvenile rats by inhibiting the M1 polarization and promoting the M2 polarization of microglia in the hippocampus.
5.Discussion on the syndrome of toxin and blood stasis in myelodysplastic syndrome from Xuanfu theory
Jing HAO ; Jiaxin LYU ; Yanbo CHANG ; Zihan PENG ; Ziran HU ; Dongyu GUO ; Tianfeng QI ; Dandi HE ; Mingjie GAO ; Jinhuan WANG
International Journal of Traditional Chinese Medicine 2024;46(4):415-419
Myelodysplastic syndrome (MDS) is a malignant hematologic tumor, which is currently difficult to cure. The theory of Xuanfu was proposed by Liu Wansu, which is unique in the clinical evidence of Chinese medicine and is less frequently applied to hematological diseases. The application of Xuanfu theory in myelodysplastic syndrome provides new ideas for the treatment of the disease. The abnormal flow of Qi, blood and fluids caused by the occlusion of the Xuanfu is the cause of toxic stasis obstruction, which is the pathogenesis of toxic stasis obstruction. Thus, the method of dispersion of Bone from Xuanfu, the external treatment of Xuanfu, and regulation of liver qi and Xuanfu help to return to normal of opening and closing function of Xuanfu, and release toxic stasis. In this paper, we analyzed the evidence of toxin-stasis obstruction in myelodysplastic syndrome from the theory of Xuanfu, aiming to provide a feasible theoretical basis for clinical treatment of the disease.
6.Expert consensus on the evaluation and management of dysphagia after oral and maxillofacial tumor surgery
Xiaoying LI ; Moyi SUN ; Wei GUO ; Guiqing LIAO ; Zhangui TANG ; Longjiang LI ; Wei RAN ; Guoxin REN ; Zhijun SUN ; Jian MENG ; Shaoyan LIU ; Wei SHANG ; Jie ZHANG ; Yue HE ; Chunjie LI ; Kai YANG ; Zhongcheng GONG ; Jichen LI ; Qing XI ; Gang LI ; Bing HAN ; Yanping CHEN ; Qun'an CHANG ; Yadong WU ; Huaming MAI ; Jie ZHANG ; Weidong LENG ; Lingyun XIA ; Wei WU ; Xiangming YANG ; Chunyi ZHANG ; Fan YANG ; Yanping WANG ; Tiantian CAO
Journal of Practical Stomatology 2024;40(1):5-14
Surgical operation is the main treatment of oral and maxillofacial tumors.Dysphagia is a common postoperative complication.Swal-lowing disorder can not only lead to mis-aspiration,malnutrition,aspiration pneumonia and other serious consequences,but also may cause psychological problems and social communication barriers,affecting the quality of life of the patients.At present,there is no systematic evalua-tion and rehabilitation management plan for the problem of swallowing disorder after oral and maxillofacial tumor surgery in China.Combining the characteristics of postoperative swallowing disorder in patients with oral and maxillofacial tumors,summarizing the clinical experience of ex-perts in the field of tumor and rehabilitation,reviewing and summarizing relevant literature at home and abroad,and through joint discussion and modification,a group of national experts reached this consensus including the core contents of the screening of swallowing disorders,the phased assessment of prognosis and complications,and the implementation plan of comprehensive management such as nutrition management,respiratory management,swallowing function recovery,psychology and nursing during rehabilitation treatment,in order to improve the evalua-tion and rehabilitation of swallowing disorder after oral and maxillofacial tumor surgery in clinic.
7.Exploring the traditional Chinese medicine differentiation and treatment of male infertility based on the theory of"maintaining with the sweet and restoring the body fluids"
Hongyuan CHANG ; Hao WANG ; Anmin WANG ; Dongyue MA ; Ziwei ZHAO ; Dicheng LUO ; Jun GUO ; Fu WANG
Journal of Beijing University of Traditional Chinese Medicine 2024;47(7):948-952
Male infertility,a common condition in andrology,falls under the category of"no son"in traditional Chinese medicine(TCM).Unhealthy eating habits and excessive sexual activity,prevalent due to improved living standards,have contributed to the increasing incidence of male infertility.YE Tianshi proposed the theory of"maintaining with the sweet and restoring the body fluids",which emphasizes the importance of ample body fluid for the nourishment of the male essence chamber.Sufficient body fluid is crucial for normal sperm generation.In TCM,the primary pathogenesis of male infertility involves the loss of body fluids and insufficiency of yin essence.Sweet Chinese herbal medicinal is recommended as it nourishes yin,enriches essence,and replenishes male reproductive essence without producing phlegm and dampness.Therefore,when treating male infertility,attention should be given to the use of sweet Chinese herbal medicinal,adhering to the principle of"abundant body fluids nourish kidney yin,and abundant kidney yin supports semen production".Therapies such as purging fire to preserve body fluids with Zengye Decoction,nourishing yin to enrich essence with Guilu Erxian Decoction,benefiting qi to promote fluid production with Buzhong Yiqi Decoction,and warming yang and transporting fluids with Xianfu Shezi Decoction should be considered.Medication and dosage adjustments should be made based on the specific etiology,pathology,and related symptoms to improve the quality of male sperm and enhance the chances of conception.
8.Clinical Efficacy Analysis of Preconceptional Laparoscopic Cervical Cerclage in the Treatment of Cervical Incompetence
Yana LIU ; Yuxi JIN ; Meng MAO ; Qian WANG ; Xueyan LIU ; Siyu LI ; Ying ZHANG ; Lei CHANG ; Ruixia GUO
Journal of Practical Obstetrics and Gynecology 2024;40(7):572-576
Objective:To evaluate the application value of preconceptional laparoscopic cervical cerclage(LCC)in improving the pregnancy outcomes with cervical incompetence(CIC).Methods:Clinical data of 112 pa-tients with CIC who underwent preconceptional LCC in The First Affiliated Hospital of Zhengzhou University from July 1,2014 to May 31,2023 were retrospectively reviewed.The surgical indications of preconceptional LCC in-cluded:failed transvaginal cervical cerclage(TCC)(42 patients),history of cervical surgery+failed TCC(7 pa-tients),unsuitability for TCC(10 patients)and strong request from patients(53 patients).The surgical situation and pregnancy outcome of preconceptional LCC were analyzed,and the gestational age of delivery before and af-ter preconceptional LCC surgery and different surgical indications were compared in postoperative delivery pa-tients who underwent preconceptional LCC.Results:The median operation time of 112 patients was 65.5 min,the median intraoperative blood loss was 10.0 ml,and there were no intraoperative complications.The postopera-tive hospital stay was 2.9±0.6 d.108 cases were followed up after surgery,with 77 cases of pregnancy and de-livery after LCC.A total of 205 deliveries were made before surgery,and 81 deliveries were made after surgery.Successful postoperative deliveries(delivery after 28 weeks)were 78(96.3% ),with an average gestational age 37.4±1.7 weeks.The preterm birth rate was 16.7%,term birth rate was 83.3% .The delivery rate at≥28 weeks after preconceptional LCC was significantly higher than the previous delivery rate of pre pregnancy LCC(96.3% vs.10.7%,P<0.05),and the gestational age was significantly prolonged(36.4±5.5 weeks vs.19.8±7.5 weeks,P<0.05).The postoperative delivery gestational week of preconceptional LCC with different surgical indi-cations was significantly later than the previous delivery gestational week of pre pregnancy LCC(P<0.05),ex-cept for the indication of unsuitability for TCC(P>0.05).Conclusions:Preconceptional LCC surgery is highly safe and can effectively prolong the gestational age and improve pregnancy outcomes in patients with CIC.It can be an effective treatment method for patients with a history of TCC failure.
9.Clinical trial of Morinda officinalis oligosaccharides in the continuation treatment of adults with mild and moderate depression
Shu-Zhe ZHOU ; Zu-Cheng HAN ; Xiu-Zhen WANG ; Yan-Qing CHEN ; Ya-Ling HU ; Xue-Qin YU ; Bin-Hong WANG ; Guo-Zhen FAN ; Hong SANG ; Ying HAI ; Zhi-Jie JIA ; Zhan-Min WANG ; Yan WEI ; Jian-Guo ZHU ; Xue-Qin SONG ; Zhi-Dong LIU ; Li KUANG ; Hong-Ming WANG ; Feng TIAN ; Yu-Xin LI ; Ling ZHANG ; Hai LIN ; Bin WU ; Chao-Ying WANG ; Chang LIU ; Jia-Fan SUN ; Shao-Xiao YAN ; Jun LIU ; Shou-Fu XIE ; Mao-Sheng FANG ; Wei-Feng MI ; Hong-Yan ZHANG
The Chinese Journal of Clinical Pharmacology 2024;40(6):815-819
Objective To observe the efficacy and safety of Morinda officinalis oligosaccharides in the continuation treatment of mild and moderate depression.Methods An open,single-arm,multi-center design was adopted in our study.Adult patients with mild and moderate depression who had received acute treatment of Morinda officinalis oligosaccharides were enrolled and continue to receive Morinda officinalis oligosaccharides capsules for 24 weeks,the dose remained unchanged during continuation treatment.The remission rate,recurrence rate,recurrence time,and the change from baseline to endpoint of Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Clinical Global Impression-Severity(CGI-S)and Arizona Sexual Experience Scale(ASEX)were evaluated.The incidence of treatment-related adverse events was reported.Results The scores of HAMD-17 at baseline and after treatment were 6.60±1.87 and 5.85±4.18,scores of HAMA were 6.36±3.02 and 4.93±3.09,scores of CGI-S were 1.49±0.56 and 1.29±0.81,scores of ASEX were 15.92±4.72 and 15.57±5.26,with significant difference(P<0.05).After continuation treatment,the remission rate was 54.59%(202 cases/370 cases),and the recurrence rate was 6.49%(24 cases/370 cases),the recurrence time was(64.67±42.47)days.The incidence of treatment-related adverse events was 15.35%(64 cases/417 cases).Conclusion Morinda officinalis oligosaccharides capsules can be effectively used for the continuation treatment of mild and moderate depression,and are well tolerated and safe.
10.The efficacy and safety of immunotherapy combined with chemotherapy neoadjuvant in locally advanced resectable hypopharyngeal squamous cell carcinoma
Kai WANG ; Wei ZHANG ; Lin GUI ; Xiaohui HE ; Jingbo WANG ; Haizhen LU ; Dezhi LI ; Chang LIU ; Zizhao GUO ; Meng XU ; Shaoyan LIU ; Xiaolei WANG
Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2024;59(4):343-349
Objective:To explore the efficacy and safety of immunoneoadjuvant therapy with pembrolizumab combined with chemotherapy in locally advanced resectable hypopharyngeal squamous cell carcinoma patients.Methods:This study was a prospective, single arm, single center clinical study that was opened for enrollment in April 2021. Patients who met the inclusion criteria at the Cancer Hospital of the Chinese Academy of Medical Sciences were treated with neoadjuvant therapy of pembrolizumab combined with cisplatin and paclitaxel, and after treatments, received surgery and postoperative adjuvant therapy. The main endpoint of this study was postoperative pathological complete response (pCR), and other observations included adverse reactions and long-term prognoses of patients after neoadjuvant therapy.Results:By September 2023, a total of 23 patients who underwent neoadjuvant therapy and surgery were enrolled in the study and all patients were males aged 49-74 years. All patients were locally advanced stage, including 3 patients in stage Ⅲ and 20 patients in stage Ⅳ. There were 12 cases of primary lesions with posterior ring involvement accompanied by fixation of one vocal cord and 20 cases of regional lymph node metastases classified as N2. Eighteen cases received a two cycle regimen and 5 cases received a three cycle regimen for neoadjuvant therapy. The postoperative pCR rate was 26.1% (6/23), with no surgical delay caused by adverse drug reactions. The laryngeal preservation rate was 87.0% (20/23). Pharyngeal fistula was the main surgical complication, with an incidence of 21.7% (5/23). The median follow-up time was 15 months, and 3 patients experienced local recurrence.Conclusions:The immunoneoadjuvant therapy of pembrolizumab combined with chemotherapy has a high pCR rate in locally advanced resectable hypopharyngeal squamous cell carcinoma, with increased laryngeal preservation rate and no significant impact on surgical safety.

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