1.Analysis of abnormal ALT in blood donors in five Zang autonomous prefectures of Qinghai Province, China: characteristics and screening strategies
Yingnan DANG ; ; Rong TANG ; Liqin HUANG ; Hailin WU ; Tingting CHEN ; Shengju LI ; Yanli SUN ; Xin ZHENG ; Yanxia LI ; Xianlin YE ; Jinfeng ZENG
Chinese Journal of Blood Transfusion 2025;38(4):502-507
[Objective] To investigate the factors associated with alanine aminotransferase (ALT) abnormalities in multi-ethnic blood donors across five Zang autonomous prefectures in the plateau regions of Qinghai Province, and to provide evidence for ensuring blood safety and formulating screening strategies. [Methods] A retrospective analysis was performed on the ALT abnormal test results of blood donors in the Zang autonomous prefectures of Qinghai from 2022 to 2024. The correlations between ALT levels and factors including gender, age, altitude, and infectious markers were investigated. [Results] The overall ALT unqualified rate among blood donors in this region was 9.01%. Significant differences in ALT levels were observed across genders and age groups (P<0.05). Variations in ALT abnormality rates were also noted among different plateau regions (P<0.05). Overall, ALT values exhibited an increasing trend with rising altitude. The average ALT unqualified rates were 11.19% in Zang donors, 7.96% in Han donors, and 4.79% in donors from other ethnic groups (P<0.05). No statistically significant association was observed between ALT abnormality and the presence of HBV/HCV infectious markers (P>0.05). [Conclusion] In the plateau areas of Qinghai, multi-ethnic blood donors have a relatively high ALT levels and ALT unqualified rates, showing distinct regional characteristics. ALT elevation in voluntary blood donors is related to non-pathological factors such as gender, age, and dietary habits, but not to infectious indicators.
2.Effects of KCNQ1OT1 Gene Knockout Combined with Bruceine D on Proliferation, Migration, and Invasion of Breast Cancer MDA-MB-231 Cells
Feng LONG ; Yu ZHAO ; Yong HUANG ; Xiaoyan LIU ; Xuan ZHOU ; Xue LI ; Hailin YE
Cancer Research on Prevention and Treatment 2023;50(11):1066-1074
Objective To explore the effect of KCNQ1OT1 gene knockout combined with bruceine D on the proliferation, migration, and invasion of breast cancer MDA-MB-231 cells. Methods Cell Counting Kit-8, wound healing, and Transwell invasion assay were used to detect the effects of bruceine D and siKCNQ1OT1 on the viability, migration, and invasion of MDA-MB-231 cells. Effect of bruceine D and siKCNQ1OT1 on the expression of KCNQ1OT1 in MDA-MB-231 cells was detected by qRT-PCR. Western blot was used to detect the effect of bruceine D and siKCNQ1OT1 on the expression of EMT-related proteins and CDC42, p-MKK7, MKK7 proteins in MDA-MB-231 cells. Results Bruceine D and siKCNQ1OT1 could significantly inhibit the viability, migration, and invasion of MDA-MB-231 cells, and the inhibitory effect was enhanced when they were combined (all
3.Influence of Huayu xiaozhong decoction on inflammatory response in rats with deep vein thrombosis
Ye MAI ; Daobin LIN ; Hailin LIU ; Yaoyao LIN ; Qingqing XU ; Yong GU
China Pharmacy 2023;34(14):1697-1702
OBJECTIVE To investigate the influence of Huayu xiaozhong decoction (HXD) on inflammatory response in rats with deep vein thrombosis (DVT). METHODS The male SD rats were divided into control group (CK group), model group (Model group), HXD low-dose group (HXD-L group, HXD 10.86 mg/kg), HXD medium-dose group (HXD-M group, HXD 21.71 mg/kg), HXD high-dose group (HXD-H group, HXD 32.57 mg/kg), positive control group (LMWHS group, low molecular weight heparin sodium 600 IU/kg), silent information regulator 2 (SIRT2) inhibitor group (AK-7 group, AK-7 20 mg/kg), HXD-M+AK-7 group (HXD 21.71 mg/kg+AK-7 20 mg/kg), with 12 rats in each group. Except for the CK group, the DVT rat was induced by the Reyers method in other groups; after modeling, administration groups were given relevant medicine intragastrically/intraperitoneally, once a day, for consecutive 2 weeks. Twenty-four hours after the last medication, the coagulation function indexes [activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), fibrinogen (FIB)] and inflammatory indexes in serum and inferior vena cava tissue [interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α)] of rats were detected. The formation of thrombus was observed, and the wet and dry masses of the thrombus were weighed. The protein expressions of tissue factor (TF) and SIRT2 as well as the phosphorylation and acetylation levels of nuclear factor kappa B (NF-κB) p65 in inferior vena cava tissue were detected. RESULTS Compared with CK group, APTT, TT and PT of rats in Model group were shortened significantly(P<0.05); the content of FIB, the levels of IL-1β, IL-6 and TNF-α, wet weight and dry weight of venous thrombus, TF protein staining score, the phosphorylation and acetylation levels of NF-κB p65 protein increased significantly (P<0.05); the inferior vena cava was full of thrombus, and the protein expression of SIRT2 decreased (P<0.05). Compared with Model group, above indexes of HXD-L group, HXD-M group, HXD-H group and LMWHS group were improved, while the improvement effects of HXD-M group, HXD-H group and LMWHS group were significantly better than those of HXD-L group (P<0.05). The trends of the corresponding indicators in AK-7 group were opposite to the above (P<0.05); AK-7 attenuated the inhibitory effect of medium-dose HXD on the inflammatory response in model rats (P<0.05).CONCLUSIONS HXD may inhibit the inflammatory response of DVT rats by activating SIRT2/NF-κB signaling pathway.
4.Anti-tumor Mechanisms of Bruceine D: A Review
Yu ZHAO ; Feng LONG ; Xiaoyan LIU ; Xuan ZHOU ; Xue LI ; Hailin YE
Chinese Journal of Experimental Traditional Medical Formulae 2023;29(12):274-282
Malignant tumors seriously threaten human life and health. Radiotherapy and chemotherapy are the conventional methods for the clinical treatment of advanced tumors. The prognosis and efficacy are still far from satisfactory due to the radiotherapy has serious adverse effects on the body and the chemotherapy often causes problems such as tumor resistance and cell proliferationinhibition. Therefore, the search for new, safe, and effective anti-tumor drugs and the elucidation of their molecular mechanisms are effective measures for clinical treatment of tumors and improvement of patients' quality of life. Active ingredients derived from Chinese herbal medicines and natural products have gradually become a hot spot in the research and development of anti-tumor drugs due to their multi-target and multi-channel anti-tumor pharmacological activity characteristics and their advantages such as less adverse reaction on the body. Bruceine D is a class of tetracyclic triterpenoids extracted from the fruit of the Chinese herbal medicine Bruceae Fructus, with anti-inflammatory, anti-malarial, anti-parasitic, and other pharmacological activities, and its anti-tumor activity is particularly significant. Pharmacological studies have found that bruceine D can regulate various cellular physiological activities such as proliferation, apoptosis, invasion, and migration of lung cancer, liver cancer, pancreatic cancer, intestinal cancer, and other cancer cells by targeting different signaling pathways. Bruceine D can be used in combination with other chemotherapeutic drugs to improve the sensitivity of tumor cells to chemotherapeutic drugs, thereby reducing the adverse effect of chemotherapy. Clinical application practice has shown that Bruceae Fructus oil emulsion injection containing bruceine D has significant advantages in the efficacy and safety of tumor treatment. Although there are many studies on the antitumor pharmacological activity of bruceine D and its clinical efficacy is significant, the specific antitumor molecular mechanism of bruceine D is still unclear, and there is a lack of systematic review on the existing antitumor mechanism of bruceine D. Therefore, based on the research on bruceine D in China and abroad in recent years, this paper reviewed the anti-tumor effect and related molecular mechanisms of bruceine D from six aspects, namely, tumor cell proliferation, apoptosis, metastasis and invasion, glucose metabolism process, autophagy, and chemotherapy sensitivity. This paper is expected to provide a pharmacological basis and scientific reference for the antitumor drug development and clinical application of bruceine D.
5.Whole brain dynamic volume CT angiography and CT perfusion imaging in middle cerebral artery occlusion animal models
Juan YE ; Zhifu QIU ; Hailin SHEN ; Hailong SHANG ; Hongdi DU ; Lelin YU ; Fanghui ZHENG ; Ying CAO ; Fanghong ZHAO ; Ying WANG
Chinese Journal of Neuromedicine 2022;21(2):119-125
Objective:To investigate the evaluation value of one-stop whole-brain dynamic volume CT angiography and CT perfusion imaging (CTA-CTP) in the cynomolgus monkeys models of middle cerebral artery occlusion (MCAO).Methods:Ten adult cynomolgus monkeys were selected and examined by head and neck CTA-CTP and craniocerebral MRI to rule out craniocerebral space-occupying lesions or cerebrovascular malformation. Under guidance of digital substraction angiography (DSA), the right femoral artery was dissected and monkey autologous thrombosis was injected into the right middle cerebral artery (MCA) through microcatheter to prepare MCAO models. Whole brain DSA was performed intraoperatively to observe whether the model was successfully prepared, and head and neck CTA-CTP was performed 24 h and 7 d after modeling to determine the locations and brain blood flow changes of ischemic lesions. The monkeys were sacrificed 8 d after modeling, and the brain tissues were stained with 2,3,5-triphenyltetrazolium chloride (TTC).Results:Among the 10 cynomolgus monkeys, one was excluded because of preoperative cerebrovascular malformation, and one died of cerebral hernia caused by cerebral hemorrhage during the experiment. The remaining 8 MCAO models were successfully prepared. Intraoperative DSA orthography showed unclear M1 segment and distal branch of MCA. Brain CT scan 24 h and 7 d after modeling showed obvious cerebral ischemic lesions in the right MCA blood supply area, and the infarct extent 7 d after surgery was more obvious than that 24 h after surgery. CTA examination showed obvious blood flow interruption imaging in the in M1 segment of MCA on the right side, the distal vessels were not clearly displayed and the distal branches of the infarct side 7 d after surgery were obvious decreased as compared with those 24 h after surgery. CTP scan showed that the cerebral blood volume of the right cerebrum was obviously reduced as compared with that of the left cerebrum, which was consistent with the blood supply area of MCA; and the infarct cores and penumbra areas 7 d after surgery were obvious increased as compared with those 24 h after surgery. TTC staining showed that the ischemic lesions of the brain tissue on the slices were gray and involved multiple layers, and the range was roughly consistent with the infarction sites shown by DSA and CT imaging.Conclusion:One-stop whole brain dynamic volume CTA-CTP has good evaluation value in imaging findings in MCAO animal models.
6.Chinese experts′ consensus statement on diagnosis, treatment and prevention of Group A Streptococcus infection related diseases in children
Dingle YU ; Qinghua LU ; Yuanhai YOU ; Hailin ZHANG ; Min LU ; Baoping XU ; Gang LIU ; Lin MA ; Yunmei LIANG ; Ying LIU ; Yaoling MA ; Yanxia HE ; Kaihu YAO ; Sangjie YU ; Hongmei QIAO ; Cong LIU ; Xiaorong LIU ; Jianfeng FAN ; Liwei GAO ; Jifeng YE ; Chuanqing WANG ; Xiang MA ; Jianghong DENG ; Gen LU ; Huanji CHENG ; Wenshuang ZHANG ; Peiru XU ; Jun YIN ; Zhou FU ; Hesheng CHANG ; Guocheng ZHANG ; Yuejie ZHENG ; Kunling SHEN ; Yonghong YANG
Chinese Journal of Applied Clinical Pediatrics 2022;37(21):1604-1618
Group A Streptococcus (GAS) is a very important pathogen, especially for children.On a global scale, GAS is an important cause of morbidity and mortality.But the burden of disease caused by GAS is still unknown in China and also has not obtained enough attention.For this purpose, the expert consensus is comprehensively described in diagnosis, treatment and prevention of GAS diseases in children, covering related aspects of pneumology, infectiology, immunology, microbiology, cardiology, nephrology, critical care medicine and preventive medicine.Accordingly, the consensus document was intended to improve management strategies of GAS disease in Chinese children.
7.A comparative study of selective decongestive devascularization of gastrosplenic region and hassab devascularization in the treatment of patients with portal hypertension
Jianwen DUAN ; Huajun YU ; Hailin YE ; Yongsheng CHEN ; Qiyu ZHANG
Chinese Journal of Hepatobiliary Surgery 2021;27(7):525-528
Objective:To determine the clinical efficacy of selective decongestive devascularization of gastrosplenic (SDD-GSR) and splenectomy combined with pericardial vascularization in the treatment of portal hypertension in cirrhosis.Methods:A total of 134 patients with cirrhosis portal hypertension admitted to the First Affiliated Hospital of Wenzhou Medical University were enrolled in the study, including 102 males and 32 females, with an average age of 51 years. Of 61 cases of SDD-GSR were included in the SDD-GSR group, and 73 cases of splenectomy combined with pericardial vascularization were included in the control group. Preoperative and postoperative white blood cell count, platelet count, Child-Pugh grade of liver function, free portal pressure (FPP) and postoperation tomplication were analyzed in the two groups. Operation time, intraoperative blood loss, free portal pressure (FPP), Child-Pugh grade of liver function, preoperative and postoperative white blood cell count, platelet count, and postoperative complications were analyzedin the two groups.Results:The operation time and intraoperative blood loss of SDD-GSR group were 165 (110, 198) min and 280 (100, 650) ml, which were lower than those of control group [190 (135, 605) min and 895 (300, 3 500) ml], the differences were statistically significant ( P<0.05). Postoperative FPP of SDD-GSR group and control group was 39 (35, 44) cmH 2O (1 cmH 2O=0.098 kPa) and 38 (34, 44) cmH 2O, respectively, which were lower than those before operation, with statistical significance (both P<0.05). Postoperative platelet count and white blood cell count in SDD-GSR group were lower than those in control group, and the differences were statistically significant (all P<0.05). The Child-Pugh grading of recent postoperative liver function in SDD-GSR group was better than that in control group, with statistical significance ( P<0.05). The complication rate (abdominal infection and portal vein thrombosis) of control group was higher than SDD-GSR group. Conclusion:SDD-GSR is better than splenectomy combined with pericardial vascularization since it has less intraoperative bleeding, obvious improvement of liver function and fewer complications, and it may be an effective surgical option for the treatment of portal hypertension of cirrhosis.
8.Clinical application of transbronchial cryotherapy in the diagnosis and treatment of tracheobronchial tuberculosis in children
Huishan ZHANG ; Xipo CHEN ; Leping YE ; Guangfa WANG ; Yangming ZHENG ; Hailin ZHANG ; Changchong LI ; Xiaodong XIA
Chinese Journal of Pediatrics 2021;59(11):963-967
Objective:To explore the clinical utility of bronchoscopy and transbronchial cryotherapy in children with tracheobronchial tuberculosis (TBTB).Methods:Retrospective study was conducted to collect the clinical data of 10 hospitalized children who underwent bronchoscopy and were diagnosed as TBTB and in the Department of Pediatrics of Peking University First Hospital and the Department of Pediatric Respiratory Medicine of the Second Affiliated Hospital and Yuying Children′s Hospital of Wenzhou Medical University from January 2011 to October 2019. The clinical characteristics of TBTB in children, and the efficacy and safety of bronchoscopy and transbronchial cryotherapy were summarized through descriptive analysis.Results:The onset age of 10 children (6 males and 4 females) ranged from 1-14 years. The clinical manifestations included fever (8/10), cough (7/10) and hemoptysis (2/10). Purified protein derivative test and interferon-γ release assay were performed in 9 and 10 patients respectively, the results were all positive. Chest CT examination was performed in all patients, and 8 patients had hilar and mediastinal lymphadenopathy. All patients underwent pediatric bronchoscopy in time, in 9 patients bronchus was found to be blocked in varying degrees by granulation tissue and caseous necrosis and in the remaining patient, obvious congestion and edema in bronchial mucosa. The bronchoscopic manifestations included 8 cases of lymph node fistula type, 1 case of granulation proliferative type and 1 case of inflammatory infiltration type. Pathological biopsies were performed in 7 cases, the findings were consistent with the pathological characteristics of tuberculosis. Nine patients were treated by pediatric bronchoscopic intervention, with 8 transbronchial cryotherapy by flexible bronchoscopy, and among them, 2 patients were treated by simultaneous rigid bronchoscopy. After 1-3 times of transbronchial cryotherapy, the blocked bronchial lumina in 8 cases were all recanalized, and the curative effect was significant without any serious complications.Conclusions:Bronchoscopy plays an important role in the diagnosis of TBTB in children and is helpful for its classification. Also, transbronchial cryotherapy has good efficacy and safety for TBTB in children, especially for the granuloproliferative type or lymph node fistula type.
9.Influence of body shape on the short-term therapeutic effects of laparoscopic distal gastrectomy: a multicentre retrospective study (A report of 506 cases)
Hexin LIN ; Su YAN ; Zhijian YE ; Jian ZHANG ; Lisheng CAI ; Jinping CHEN ; Guoqiang SU ; Guowei ZHANG ; Jinbo FU ; Chuanhui LU ; Liang WANG ; Weiping JI ; Wencheng KONG ; Jiang GONG ; Ping CHEN ; Rongjie HUANG ; Hailin KE ; Xian SHEN ; Jun YOU
Chinese Journal of Digestive Surgery 2019;18(1):65-73
Objective To investigate the risk factors of perioperative complications of laparoscopic radical distal gastrectomy and influence of body shape on the short-term therapeutic effects.Methods The retrospective case-control study was conducted.The clinicopathological data of 506 patients (328 males and 178 females,average age 60 years with the range of 24-85 years) who underwent laparoscopic radical distal gastrectomy+D2 lymph nodes dissection in the 8 clinical centers between March 2016 and November 2018 were collected,including 143 in the First Affiliated Hospital of Xiamen University,66 in the Affiliated Hospital of Qinghai University,66 in the Second Affiliated Hospital of Wenzhou Medical University,64 in the Zhongshan Hospital of Xiamen University,54 in the Affiliated Hangzhou First people's Hospital of Zhejiang University School of Medicine,48 in the Zhangzhou Affiliated Hospital of Fujian Medical University,35 in the Affiliated Quanzhou First Hospital of Fujian Medical University,30 in the Second Affiliated Hospital of Xiamen Medical College.The maximum thickness of subcutaneous fat at the level of umbilicus (USCF),the maximum vertical distance between the anterior abdominal skin and the back skin at the level of the umbilicus (UAPD),the maximum horizontal distance between the anterior abdominal skin and the back skin at the level of the umbilicus (UTD),the maximum verticaldistance between the anterior abdominal skin and the back skin at the level of the xiphoid bone (XAPD),the maximum horizontal distance between the.anterior abdominal skin and the back skin at the level of the xiphoid bone (XTD),the distance between the anterior abdominal skin and the root of celiac artery (CAD) and the maximum horizontal distance at a right angle to CAD (CATD) were measured using preoperative imaging examinations.Observation indicators:(1) intraoperative and postoperative situations;(2) follow-up situations;(3) risk factors analysis of perioperative complications;(4) influence of body shape related indexes on intraoperative situations and postoperative recovery:① Pearson univariate correlation analysis,② liner regression model analysis.Followup using outpatient examination and telephone interview was performed to detect the postoperative survival and tumor recurrence or metastasis up to December 2018.Measurement data with normal distribution were represented as Mean±SD.Measurement data with skewed distribution were described as M (range).Comparisons of count data were analyzed using the chi-square test.Comparisons of ordinal data were analyzed by Mann-Whitney U nonparametric test.Risk factors of perioperative complications of laparoscopic distal gastrectomy were analyzed by Logistic regression model.Influence of body shape related indexes on intraoperative situations and postoperative recovery was analyzed by Pearson univariate correlation analysis and liner regression model.Results (1) Intraoperative and postoperative situations:all the 506 patients underwent successful laparoscopic distal gastrectomy,including 103 with Billroth Ⅰ anastomosis,140 with Billroth Ⅱ anastomosis,201 with Billroth Ⅱ + Braun anastomosis,62 with Roux-en-Y anastomosis.The operation time,volume of intraoperative blood loss,number of lymph nodes dissected,time to postoperative anal exsufflation,time for initial fluid diet intake,time for initial semi-fluid diet intake and duration of postoperative hospital stay were (233±44)minutes,(102±86)mL,34±13,(3.6±1.5)days,(5.8±3.3)days,(8.3±3.8)days,(12.2±5.7)days respectively in the 506 patients.Of 506 patients,196 were defined as pathological stage Ⅰ,122 were defined as pathological stage Ⅱ and 188 were defined as pathological stage Ⅲ postoperatively.Of 506 patients,93 had 106 times of perioperative complications,including 33 times of pulmonary and upper respiratory infection,12 times of incisional infection,11 times of anastomotic leakage,11 times of abdominal infection,8 times of intestinal obstruction,8 times of gastroplegia,6 times of abdominal hemorrhage,5 times of bacteremia,3 times of anastomotic hemorrhage,3 times of lymph fluid leakage,2 times of pancreatic leakage,1 time of urinary infection,1 time of anatomotic stenosis,1 time of deep venous thrombosis and 1 time of pulmonary embolism;the same patient can merge multiple complications.Eleven patients were in the Clavien-Dindo classification ≥ Ⅲ.(2) Follow-up situations:465 of 506 patients were followed up for 1-32 months with a median time of 12 months.During the follow-up,451 had postoperative survival and 38 had tumor recurrence or metastasis.(3) Risk factors analysis of perioperative complications.① Results of univariate analysis showed that age,body mass index (BMI),preoperative hemoglobin,preoperative serum albumin and XAPD were related factors affecting perioperative complications of laparoscopic distal gastrectomy (x2 =10.289,7.427,5.269,5.481,4.285,P< 0.05).② Results of multivariate analysis showed that age,BMI,preoperative serum albumin were independent related factors affecting perioperative complications of laparoscopic distal gastrectomy (odds ratio =1.033,1.118,0.937,95% interval confidence:1.011-1.057,1.025-1.219,0.887-0.990,P<0.05).(4) Influence of body shape related indexes on intraoperative situations and postoperative recovery.① Results of Pearson univariate correlation analysis showed correlations between UAPD,XAPD,CAD,CATD and volume of intraoperative blood loss (r=0.107,0.169,0.179,0.106,P<0.05),between UAPD,XAPD,CAD and the number of lymph nodes dissected (r=-0.137,-0.143,-0.173,P<0.05),between USCF,XAPD and time to postoperative anal exsufflation (r =0.122,0.109,P<0.05),between USCF,XAPD,CAD and time for initial fluid diet intake (r=0.132,0.108,0.132,P<0.05),between USCF,XAPD and duration of postoperative hospital stay (r=0.116,0.100,P<0.05).② Results of liner regression model analysis showed a positive correlation between CAD and volume of intraoperative blood loss (r =6.776),a negative correlation between CAD and the number of lymph nodes dissected (r =-0.841),with statistically significant differences (t =2.410,-1.992,P< 0.05);a positive correlation between USCF and time to postoperative anal exsufflation (r=0.170),between USCF and time for initial fluid diet intake (r=0.365),between USCF and duration of postoperative hospital stay (r=0.636) respectively,with statisticallysignificant differences (t =2.188,1.981,2.107,P< 0.05).Conclusions Abdominal shape can influence intraoperative situations and postoperative recovery of laparoscopic distal gastrectomy,but cannot increase risks ofperioperative complications.Age,BMI and preoperative serum albumin are independent related factors affecting perioperative complications of laparoscopic distal gastrectomy.
10.Influence of social supports on frailty in elderly maintenance hemodialysis patients
Liqin YE ; Ying ZHOU ; Hailin ZHANG ; Lixia YIN ; Yongping ZHANG
Chinese Journal of Geriatrics 2019;38(1):72-75
Objective To investigate the current situations of the frailty and the perceived social support and explore the influence of social support on the frailty in elderly maintenance hemodialysis patients.Methods The 237 elderly patients with maintenance hemodialysis were investigated by the Fried frailty phenotype and the perceived social support scale in this cross-sectional study.Results The prevalence of frailty was 163 (68.8%)in 237 patients.The level of perceived social support was low.The frailty was negatively correlated with the social supportscore,family support,friends support,and other support(r =-0.326,-0.129,-0.301 and-0.230,respectively,all P <0.05).Multiple logistic regression analysis showed that friends support,dialysis vintage,Charlson comorbidity index(CCI)score and activities of daily living(ADL)score were the main influential factors for frailty in elderly maintenance hemodialysis patients.Conclusions Medical staff should evaluate the frailty in elderly patients with maintenance hemodialysis,and the frailty can be alleviated by improving the support of friends.

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