1.Compilation Instructions for Expert Consensus on Clinical Application of Dieda Huoxue Capsules
Yuhang MENG ; Jinghua GAO ; Minshan FENG ; Quan JI ; Jin JIN ; Ting CHENG ; Yongyao LI ; Yuanyuan LI ; Xin CUI ; Yanming XIE
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(20):177-183
The Compilation Instructions for Expert Consensus on Clinical Application of Dieda Huoxue capsules systematically expound the development methods and evidence-based basis of this consensus. In view of the weak clinical application evidence and ambiguous indications of Dieda Huoxue capsules, the Institute of Basic Research in Clinical Medicine of the China Academy of Chinese Medical Sciences and Wangjing Hospital took the lead and collaborated with 33 experts from 28 medical institutions nationwide. They strictly followed the World Health Organization (WHO) guideline-making norms and the Grading of Recommendations Assessment, Development and Evaluations (GRADE) evidence-grading system and completed the compilation through multidisciplinary cooperation. The workflow included constructing clinical questions (19 items were screened by the nominal group technique), retrieving evidence (from Chinese and English databases and grey literature), assessing safety (integrating drug monitoring data and clinical investigations), and forming recommendations and consensus suggestions (3 recommendations were reached via the GRADE grid method, and 16 consensus suggestions were reached by the majority vote rule). The results indicate that the consensus clearly states that this medicine (Dieda Huoxue capsules) is applicable to conditions like traumatic injury, blood stasis-induced pain, and sudden lumbar sprains. The recommended dose is 6 capsules each time, twice a day. Combining oral administration with external application can enhance the efficacy, and elderly patients should take the medicine at intervals. Safety monitoring suggests that it should be used with caution in people with a bleeding tendency and those with an allergic constitution. The compilation process involved three rounds of reviews by internal and external experts. Literature analysis, the Delphi method, and clinical applicability tests were employed to ensure methodological rigor. The compilation instructions comprehensively present key aspects such as project approval and registration, conflict-of-interest statements, and evidence evaluation through 12 appendices, providing methodological support for the clinical translation of the consensus. In the future, it will be continuously improved through a dynamic revision mechanism.
2.Surveillance of antifungal resistance in clinical isolates of Candida spp.in East China Invasive Fungal Infection Group from 2018 to 2022
Dongjiang WANG ; Wenjuan WU ; Jian GUO ; Min ZHANG ; Huiping LIN ; Feifei WAN ; Xiaobo MA ; Yueting LI ; Jia LI ; Huiqiong JIA ; Lingbing ZENG ; Xiuhai LU ; Yan JIN ; Jinfeng CAI ; Wei LI ; Zhimin BAI ; Yongqin WU ; Hui DING ; Zhongxian LIAO ; Gen LI ; Hui ZHANG ; Hongwei MENG ; Changzi DENG ; Feng CHEN ; Na JIANG ; Jie QIN ; Guoping DONG ; Jinghua ZHANG ; Wei XI ; Haomin ZHANG ; Rong TANG ; Li LI ; Suzhen WANG ; Fen PAN ; Jing GAO ; Lu JIANG ; Hua FANG ; Zhilan LI ; Yiqun YUAN ; Guoqing WANG ; Yuanxia WANG ; Liping WANG
Chinese Journal of Infection and Chemotherapy 2024;24(4):402-409
Objective To monitor the antifungal resistance of clinical isolates of Candida spp.in the East China region.Methods MALDI-TOF MS or molecular methods were used to re-identify the strains collected from January 2018 to December 2022.Antifungal susceptibility testing was performed using the broth microdilution method.The susceptibility test results were interpreted according to the breakpoints of 2022 Clinical and Laboratory Standards Institute(CLSI)documents M27 M44s-Ed3 and M57s-Ed4.Results A total of 3 026 strains of Candida were collected,65.33%of which were isolated from sterile body sites,mainly from blood(38.86%)and pleural effusion/ascites(10.21%).The predominant species of Candida were Candida albicans(44.51%),followed by Candida parapsilosis complex(19.46%),Candida tropicalis(13.98%),Candida glabrata(10.34%),and other Candida species(0.79%).Candida albicans showed overall high susceptibility rates to the 10 antifungal drugs tested(the lowest rate being 93.62%).Only 2.97%of the strains showed dose-dependent susceptibility(SDD)to fluconazole.Candida parapsilosis complex had a SDD rate of 2.61%and a resistance rate of 9.42%to fluconazole,and susceptibility rates above 90%to other drugs.Candida glabrata had a SDD rate of 92.01%and a resistance rate of 7.99%to fluconazole,resistance rates of 32.27%and 48.24%to posaconazole and voriconazole non-wild-type strains(NWT),respectively,and susceptibility rates above 90%to other drugs.Candida tropicalis had resistance rates of 29.55%and 26.24%to fluconazole and voriconazole,respectively,resistance rates of 76.60%and 21.99%to posaconazole and echinocandins non-wild-type strains(NWT),and a resistance rate of 2.36%to echinocandins.Conclusions The prevalence and species distribution of Candida spp.in the East China region are consistent with previous domestic and international reports.Candida glabrata exhibits certain degree of resistance to fluconazole,while Candida tropicalis demonstrates higher resistance to triazole drugs.Additionally,echinocandins resistance has emerged in Candida albicans,Candida glabrata,Candida tropicalis,and Candida parapsilosis.
3.Effect of linear echoendoscope guided precise endoscopic sphincterotomy on function of gallbladder in patients with calculus of common bile duct after endoscopic retrograde cholangiopancreatography
Xiao CHEN ; Zhaohui ZHANG ; Shenqiang GAO ; Jinghua JIANG ; Bin YANG
China Journal of Endoscopy 2024;30(6):8-16
Objective To investigate the effect of linear echoendoscope guided precise endoscopic sphincterotomy(EST)on positive rates of bile amylase(BA)and bile bacteria as well as occult pancreaticobiliary reflux(OPBR)in patients with calculus of common bile duct after endoscopic retrograde cholangiopancreatography(ERCP).Methods The subjects of this study,146 patients with calculus of common bile duct who underwent EST for ERCP from June 2021 to February 2023,were divided into two groups based on EST type,each with 73 cases.Observation group was administrated with linear echoendoscope guided precise EST,control group was administrated traditional EST.The operation conditions of both groups were observed.Liver function indexes[total bilirubin(TBiL),conjugated bilirubin(CB)and alanine aminotransferase(ALT)],inflammatory and stress indicators[C-reactive protein(CRP),high mobility group box-1 protein(HMGB1),cortisol(Cor),norepinephrine(NE)],and the positive rates of BA and bile bacteria were compared between the two groups before operation and 1,3 days after operation.The postoperative complications and recurrence rate 12 months after operation were recorded.Results There was no significant difference in the success rate of lithotomy and operation time between the two groups(P>0.05).The intraoperative blood loss in the observation group was less than that in the control group,and the hospital stay was shorter than that in the control group,and the differences were statistically significant(P<0.05).1 and 3 days after surgery,TBiL,CB and ALT in two groups were lower than those before surgery,the differences were statistically significant(P<0.05),but there was no statistically significant difference between groups(P>0.05).1 and 3 days after surgery,serum CRP,HMGB1,Cor and NE levels and BA concentration in two groups were higher than those before surgery,and observation group was lower than control group,with statistical significance(P<0.05).The positive rate of biliary bacteria 1 and 3 days after surgery in the control group was higher than that before surgery,the difference was statistically significant(P<0.05);the positive rate of biliary bacteria in the observation group was not significantly different at different time points before and after surgery(P>0.05);the positive rate of biliary bacteria in the observation group was lower than that in the control group 1 and 3 days after surgery(P<0.05).The incidence of OPBR and postoperative recurrence rate at 12 months in the observation group(15.07%and 1.37%)were lower than those in the control group(57.53%and 10.96%),and the differences were statistically significant(P<0.05).Conclusion Linear echoendoscope guided precise EST is more effective in mitigating duodenal papillary sphincter injury,preventing duodenal-biliary reflux,inhibiting BA secretion and bacterial proliferation,and reducing the risk of OPBR than traditional EST.
4.Application of gallbladder plate approach using Laennec membrane based on APR triangle region in laparoscopic anaphylactic right lobe hepatectomy
Shengqiang GAO ; Min YU ; Bin YANG ; Jinghua JIANG ; Jiansheng LUO ; Shi'an YU
China Journal of Endoscopy 2024;30(11):82-88
Objective To investigate the safety and clinical efficacy of the combined gallbladder plate approach using Laennec membrane based on APR triangle in laparoscopic anaphylactic right lobe hepatectomy.Methods Clinical data of 27 patients underwent laparoscopic anaphylactic of right lobe hepatectomy based on the APR triangle combined with the gallbladder plate approach using Laennec membrane were collected from January 2021 to December 2023.The relevant data of patients were statistically analyzed,including operation time,intraoperative blood loss,postoperative complications,and postoperative hospital stay.Results All the 27 patients underwent laparoscopic anatomic hepatectomy,and no perioperative death occurred.Among them,segment Ⅴ was resected in 4 cases,segment Ⅵ in 3 cases,segment Ⅴ+Ⅷ in 6 cases,segment Ⅴ+Ⅵ in 4 cases,segment Ⅵ+Ⅶin 5 cases,segment Ⅴ+Ⅵ+Ⅶ in 3 cases,and segment Ⅴ+Ⅵ+Ⅷ in 2 cases.All cases belonged to the China Liver Cancer(CNLC)clinical staging,stage Ⅰa in 15 cases,stage Ⅰb in 8 cases and stage Ⅱa in 4 cases.The operative time was(258.3±62.3)min,the intraoperative blood loss was(168.8±48.1)mL,and there was no transfusion.The patients were given liquid diet on the first day after surgery,and were active in bed on the second day after surgery.The mean postoperative length of hospital stay was(6.5±1.7)d after removal of abdominal drainage tube.There were 5 cases of Clavien-Dindo Ⅰ and Ⅱ complications(3 cases of abdominal effusion,1 case of pleural effusion,1 case of pulmonary infection),and no complications such as bile leakage and abdominal hemorrhage occurred.Postoperative pathology:21 cases of hepatocellular carcinoma,4 cases of hepatociliary duct carcinoma,2 cases of liver metastasis.Patients with liver malignant tumor were followed up for 2 months to 2 years,and all patients survived during the follow-up period without tumor recurrence.Conclusion The gallbladder plate approach based on APR triangle combined with Laennec membrane is a safe and effective surgical method for laparoscopic anaphylactic right lobe hepatectomy,which is worthy of clinical application.
5.Value of preoperative vascular ultrasound parameters in predicting postoperative lower extremity deep venous thrombosis in patients with gynecological malignant tumors
Wenhui GAO ; Weiwei ZHANG ; Nirong WANG ; Jiaqi ZHANG ; Jinghua DAI ; Xinhui LI ; Jian-Feng WEI ; Shuzhen YU
Chinese Journal of Anesthesiology 2024;44(8):937-940
Objective:To evaluate the value of preoperative vascular ultrasound parameters in predicting the postoperative lower extremity deep venous thrombosis (DVT) in patients with gynecological malignant tumors.Methods:Ninety-nine patients with gynecological malignant tumors, aged>18 yr, with body mass index<30 kg/m 2, of American Society of Anesthesiologists Physical Status classification Ⅱ or Ⅲ, scheduled for elective surgery under general anesthesia, were selected. Vascular ultrasound examination was performed before surgery. The flow velocity and diameter of common femoral vein (CFV), deep femoral vein (DFV), popliteal vein (POV), and intermuscular vein (IMV) were recorded. Ultrasound examination of lower limb veins (including anterior tibial vein, posterior tibial vein, IMV, CFV, DFV, POV) were conducted at 1-8 days after surgery to determine whether a DVT occurred. The receiver operating charcateristic curve was used to evaluate the accuracy of each indicator in predicting the lower extremity DVT, and the cut-off value was determined based on the maximum principle of Jorden index. Results:The incidence of lower extremity DVT was 13.1%. The area under the curve (95% confidence interval) of the preoperative CFV flow velocity and diameter, DFV flow velocity and diameter, POV flow velocity and diameter, IMV flow velocity and diameter in predicting the lower extremity DVT were 0.769 (0.616-0.923) and 0.800 (0.644-0.950), 0.797 (0.641-0.954) and 0.771 (0.596-0.945), 0.806 (0.645-0.968) and 0.754 (0.606-0.903), 0.764 (0.615-0.914) and 0.818 (0.645-0.990), respectively ( P<0.05), and the predicted cut-off values were 27.13 cm/s and 11.93 mm, 19.31 cm/s and 10.15 mm, 16.04 cm/s and 8.79 mm, 14.39 cm/s and 8.68 mm, respectively, and the sensitivity and specificity were 90.0%, 71.4% and 90.0%, 74.3%; 90.0%, 74.3% and 90.0%, 68.6%; 90.0%, 82.9% and 90.0%, 72.9%; 90.0%, 70.0% and 80.0%, 87.1%, respectively. Conclusions:Preoperative vascular vascular ultrasound parameters can accurately predict the occurrence of postoperative lower extremity DVT in patients with gynecological malignant tumors.
6.Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis.
Shuran FAN ; Ming QI ; Qi QI ; Qun MIAO ; Lijuan DENG ; Jinghua PAN ; Shenghui QIU ; Jiashuai HE ; Maohua HUANG ; Xiaobo LI ; Jie HUANG ; Jiapeng LIN ; Wenyu LYU ; Weiqing DENG ; Yingyin HE ; Xuesong LIU ; Lvfen GAO ; Dongmei ZHANG ; Wencai YE ; Minfeng CHEN
Acta Pharmaceutica Sinica B 2024;14(2):682-697
Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.
7.Platinum-Based Nanoplatforms in the Application of Medical Multimodal Imaging
Heying LI ; Jingpi GAO ; Pengshan GUO ; Qinghao HE ; Manping LIN ; Shuo GU ; Jinghua LI
Chinese Journal of Medical Imaging 2024;32(1):105-108,112
Platinum-based nanoplatforms can enhance the absorption of X-ray due to the presence of high atomic number element of platinum and are applied to computed tomography imaging.Meanwhile,platinum-based nanomaterials have good near-infrared light absorption properties and photothermal conversion efficiency,which make them capable of photothermal imaging and photoacoustic imaging.In addition,by reducing transverse and longitudinal relaxation time,platinum-based nanoplatforms can mediate MRI imaging.In this paper,we report a multimodal imaging system based on platinum-based nanoplatforms for guiding the development of cancer treatment and diagnosis platform and medical application research,and also summarize the prospects of multimodal imaging technology in cancer diagnosis and treatment,report the research progress of platinum-based nanoplatforms in improving the contrast of medical images and enhancing cancer treatment.
8.Clinical Study on Zhuanyaotang Granules for the Treatment of Degenerative Lumbar Spinal Stenosis
Daiyuan LIU ; Chunyu GAO ; Luguang LI ; Kexin YANG ; Wu SUN ; Jie LUO ; Minshan FENG ; Jianguo LI ; Lei LI ; Peng FENG ; Minrui FU ; Haibao WEN ; Jinghua GAO
Chinese Journal of Information on Traditional Chinese Medicine 2024;31(1):159-163
Objective To observe the clinical efficacy of Zhuanyaotang Granules for the treatment of degenerative lumbar spinal stenosis(DLSS).Methods Using a randomized double blind controlled design,104 DLSS patients were divided into an experimental group and a control group using a random number table method,with 52 patients in each group.The treatment group took oral Zhuanyaotang Granules,methylcobalamin tablets and celecoxib capsule simulants.The control group used Zhuanyaotang Granules simulants,methylcobalamin tablets and celecoxib capsules.The course of treatment was 3 weeks for both groups.The follow-ups were conducted at 1 month and 3 months after treatment.The intermittent claudication distance,visual analogue scale(VAS)score and JOA efficacy rating criteria for low back pain score were observed in both groups before treatment,1,2,3 weeks of treatment and 1 month after treatment and 3 months after treatment.Adverse reactions during treatment were recorded.Results There were 5 cases of detachment and 2 cases of exclusion in the experimental group,and 5 cases of detachment and 1 case of exclusion in the control group.Compared with before treatment,there were statistically significant differences in intermittent claudication distance,VAS score,and JOA score between the two groups of patients at various time points during treatment and follow-up(P<0.05);there was no statistically significant difference in intermittent claudication distance,VAS score,and JOA score between the experimental group and the control group before treatment and 1 and 2 weeks of treatment(P>0.05);compared with the two groups at 3 weeks of treatment and 1 and 3 months after treatment,the intermittent claudication distance and JOA score in the experimental group were lower than those in the control group(P<0.05);There was no significant difference in VAS score between the two groups and the control group after 3 weeks of treatment(P>0.05).There were 2 adverse reactions(4.4%)in the experimental group and 5 adverse reactions(10.8%)in the control group,without statistical significance(P>0.05).Conclusion Zhuanyaotang Granules can effectively relieve pain and improve lumbar function in patients with DLSS,which is more effective and safer than oral celecoxib capsules and methylcobalamin tablets.
9.A Multicenter, Randomized, Double-blind, and Placebo-parallel Controlled Trial of Tibetan Medicine Ruyi Zhenbaowan in Treatment of Knee Osteoarthritis
Chunquan SUN ; Yanming XIE ; Jinghua GAO ; Weiheng CHEN ; Lianxin WANG ; Shangquan WANG ; Xiangdong TIAN ; Zujian XU ; Yuxin ZHENG ; Mingwang ZHOU ; Chungen LI ; Zhanwang XU ; Jiayi GUO ; Shuangqing DU ; Qigang CHEN ; Quan JI ; Zhiqiang BAI ; Jing XIAO ; Wanli QI ; Weiyi YANG ; Jingxiao ZHANG
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(24):57-67
ObjectiveThis study aimed to evaluate the clinical efficacy of Ruyi Zhenbaowan(RYZBW)in the treatment of initial and early knee osteoarthritis (KOA) through a prospective multicenter,randomized,double-blind,and placebo-parallel controlled trial. MethodFrom October 13th, 2021 to December 25th, 2021, 240 KOA subjects meeting the acceptance criteria were enrolled in 15 sub-centers including Wangjing Hospital, Chinese Academy of Chinese Medical Sciences, and they were randomly divided into observation group and control group, with 120 cases in each group. The intervention measures for the observation group were RYZBW + health education, and the intervention measures for the control group were RYZBW placebo + health education. The intervention period in both groups was four weeks, and they were followed up for four weeks after the intervention. The primary outcome measure was the total score of Western Ontario and McMaster University Osteoarthritis Index score (WOMAC score), and the secondary outcome measures were the response rate of visual scale (VAS) pain score, WOMAC sub item scores (joint pain, joint stiffness, and joint function), quality of life (SF-12) score, and traditional Chinese medicine (TCM) syndrome score. Result(1) Efficacy evaluation. The marginal model results showed that the observation group was better than the control group in improving the WOMAC total score and WOMAC pain score in the treatment of KOA with RYZBW, and the difference was statistically significant (P<0.05). There was no significant difference between the two groups in improving VAS score response rate, WOMAC function score, WOMAC stiffness score, SF12-PCS (quality of life-physical health) score, SF12-MCS (quality of life-mental health) score, and TCM syndrome score. (2) Subgroup analysis. ① In terms of VAS score response rate, the response rate of the observation group was higher than that of the control group for subjects with baseline VAS score of (4, 5], and the difference was statistically significant (P<0.05). ② In terms of TCM syndrome score, for subjects aged [56, 60] and [61, 65], the decrease in total TCM syndrome score in the observation group was better than that in the control group, and the difference was statistically significant (P<0.05). ConclusionTibetan medicine RYZBW has good clinical efficacy in improving WOMAC total score, VAS score response rate, WOMAC pain score, WOMAC function score, and TCM syndrome score for patients with initial and early KOA, which can fill the lack of Tibetan medicine RYZBW in the treatment of KOA and make a demonstration study for the inheritance and development of ethnic medicine.
10.Effect of Baizhu Zhuanyao decoction on rats with fibrosis of lumbar ligamentum flavum and TGF-β1 mediated inflammation in M2 macrophages
Haibao WEN ; Ying CHE ; Luguang LI ; Jianguo LI ; Chunyu GAO ; Jinghua GAO ; Peng FENG
Journal of Beijing University of Traditional Chinese Medicine 2024;47(6):782-791
Objective Zhuanyao decoction is a traditional Chinese herbal compound prescription orignated from Bianzhenglu in Ming Dynasty;Baizhu Zhuanyao decoction(BZZYD),adding spatholobus suberectus,sappanwood,and cyathula root,is intended to enhance the therapeutic effects on the waist and hips.We aimed to investigate the effects of BZZYD on lumbar ligamentum flavum fibrosis and its possible immune regulation mechanism.Methods(i)By using a random number table method,twenty-four male SD rats were divided into the normal,model,chlorophosphate,and BZZYD groups,with six rats per group.The rats in all groups,except for the normal group,were used to establish a rat model of lumbar ligamentum flavum fibrosis using lumbar instability method.The rats in the BZZYD group received Baizhu Zhuanyao decoction through gavage(13.6 g/kg),and the other groups were administered the same amount of saline by gavage once a day for 30 days.The rats in the chlorophosphate group were subcutaneously injected with disodium chlorophosphate liposome(5 g/L,0.5 mL)at the original incision immediately after surgery and at Day 9,18,and 27.After 30 days,the rats were sarcrificed through excessive anesthesia,and the ligamentum flavum was histologically evaluated using HE and Masson staining.The collagen volume fraction(CVF)was calculated.Transforming growth factor-β1(TGF-β1),tumor necrosis factor-α(TNF-α),and interleukin-1β(IL-1β)protein expressions in the ligamentum flavum were detected using immunohistochemical staining.CD163 and TGF-β1 protein expression in M2 macrophages were detected using the immunofluorescence double-labeling method.(ⅱ)M2 macrophage and fibroblast were cultured in the three ways:separately,co-culture,and co-culture of pre-treatment of BZZYD containing serum on M2 macrophage and fibroblast.TGF-β1,TNF-α,and IL-1β mRNA expressions in M2 macrophage and fibroblast were compared using RT-qPCR.Results(ⅰ)Compared with those in the normal group,the ligamentum flavum fibers were dense and twisted,immune cells infiltrated,and the CVF was increased in the model group.TGF-β1,TNF-α,and IL-1β protein expression in the ligamentum flavum tissues of the model group were increased,and TGF-β1 and TNF-α protein expression in the BZZYD group were increased(P<0.05).Compared with that of the model group,extracellular matrix accumulation decreased in the chlorophosphate and BZZYD groups,the CVF was decreased,and TGF-β1,TNF-α,and IL-1β protein expressions in ligamentum flavum tissue were decreased(P<0.05).Compared with that of the chlorophosphate group,extracellular matrix accumulation increased,the CVF was increased,TGF-β1 and IL-1β protein expressions in ligamentum flavum tissue were increased(P<0.05).CD163 and TGF-β1 proteins were not expressed in the normal and chlorophosphate groups.CD163 and TGF-β1 proteins were expressed and co-localized in the model group,and CD163 protein expression was observed in the BZZYD group,however,TGF-β1 expression was low.(ⅱ)The co-culture system increased mRNA expressions of TGF-β1 and IL-1β in M2 macrophages,TNF-α and IL-1β in fibroblasts,compared to the two kinds of cells cultured separately.And after pre-treatment on M2 macrophages,the mRNA expressions all decreased compared co-culture system(P<0.05).Conclusion BZZYD can significantly inhibit lumbar ligamentum flavum fibrosis,reduce TGF-β1 and IL-1β expression in M2 macrophages,affect TNF-α and IL-1β expression in fibroblasts,and inhibit the positive feedback of ligamentum flavum inflammation-fibrosis.

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