1.TIPS with bare stents and covered stents for the treatment of portal hypertension:analysis of its long-term efficacy
Shengli YANG ; Linqiang LAI ; Jingjing SONG ; Dengke ZHANG ; Zhongwei ZHAO ; Jianfei TU ; Jiansong JI ; Yingjun BAO ; Junpeng GU ; Weixin REN
Journal of Interventional Radiology 2024;33(3):295-299
		                        		
		                        			
		                        			Objective To evaluate the long-term efficacy of transjugular intrahepatic portosystemic shunt(TIPS)with bare stents and Fluency covered stents in the treatment of portal hypertension,and to discuss its clinical value.Methods The clinical data of 29 patients with intractable ascites or esophagogastric fundus varices rupture and hemorrhage caused by cirrhotic portal hypertension,who received TIPS with bare stents and covered stents at the First Affiliated Hospital of Xinjiang Medical University of China(25 patients)and the Lishui Municipal Central Hospital of China(4 patients)between August 2012 and December 2017,were retrospectively analyzed.The patients were regularly followed up to check the survival status.The postoperative cumulative shunt patency rate and cumulative survival rate of the patients were analyzed by Kaplan-Meier method.Results The technical success rate of TIPS was 100%.The mean portal vein pressure was decreased from preoperative(40.21±3.24)cmH2O to postoperative(24.55±3.55)cmH2O(P<0.05).The patients were followed up for 5.1-10.5 years.The postoperative 1-,3-,5-,7-year primary cumulative patency rates of the shunt were 89.7%,75.9%,75.9% and 52.5%,respectively.The postoperative 5-,7-,9-and 10-year cumulative survival rates were 100%,66.9%,66.9% and 33.4%,respectively.The incidence of hepatic encephalopathy was 13.8%(4/29).Conclusion Using bare stents combined with Fluency covered stents for TIPS is clinically safe and effective in the treatment of portal hypertension.This technique carries higher long-term shunt patency rate and low incidence of hepatic encephalopathy.Therefore,it can be used as a substitute for Viatorr stent when necessary.(J Intervent Radiol,2024,33:295-299)
		                        		
		                        		
		                        		
		                        	
2.Comparative study of medical tissue glue in the treatment of acute hemoptysis by bronchial arterial embolization
Jingjing SONG ; Shengli YANG ; Zhongwei ZHAO ; Jianfei TU ; Jiansong JI
Journal of Practical Radiology 2024;40(11):1884-1887
		                        		
		                        			
		                        			Objective To evaluate the clinical application value of medical tissue glue in the treatment of acute hemoptysis by bronchial arterial embolization(BAE).Methods The clinical data of 78 patients who underwent emergency BAE for hemoptysis were retrospectively collected.Among them,18 patients who underwent embolization with medical tissue glue were selected as a study group,and other 18 patients who underwent embolization with absorbent gelatin sponge particles and spring coil were selected as a control group.The technical success rates,average surgical operation time,average surgical cost,postoperative hemoptysis recur-rence rate,and incidence of adverse reactions of the two groups were compared and analyzed.Results The technical success rates of the two groups were both 100%.There were no statistically significant differences in recurrence rate of postoperative hemoptysis and incidence of adverse reactions between the two groups(P>0.05).The average surgical operation time of study group and control group were 53.4 min[(53.4±2.2)min]and 65.4 min[(65.4±2.8)min],and the average surgical cost were 3 651 yuan[(3 651±102.7)yuan]and 5 094 yuan[(5 094±136.3)yuan],respectively.Compared with the control group,the average surgical operation time and aver-age surgical cost of the study group were shorter,and the differences were statistically significant(P<0.05).Conclusion Compared with absorbent gelatin sponge particles combined with spring coil embolization,the use of medical tissue glue for embolization is also safe and effective in the treatment of acute hemoptysis patients by BAE.The average surgical operation time is shorter,and the surgical cost for patients is lower.It is worth promoting in clinical practice.
		                        		
		                        		
		                        		
		                        	
3.Application value of cone beam CT in accurate diagnosis of submandibular gland calculi
Xiaofeng YANG ; Xiaojuan SUN ; Guangwei QIAO ; Zhongwei ZHOU ; Huixia LAN
Academic Journal of Naval Medical University 2024;45(8):1041-1045
		                        		
		                        			
		                        			Objective To compare the detection rates of X-ray,ultrasound,computed tomography(CT)and cone beam CT(CBCT)for submandibular gland calculi in different positions,and to explore the auxiliary value of 3-dimensional visualization technology in diagnosis and treatment of submandibular gland calculi.Methods The X-ray,ultrasound,CT and CBCT examination data of 113 patients with submandibular gland calculi at General Hospital of Ningxia Medical University from Nov.2014 to Mar.2021 were retrospectively analyzed.The detection rates and overall detection rates of the 4 imaging methods for calculi in different positions were compared.Mimics 19.0 software and CBCT data were used for 3D reconstruction imaging,visually displaying the location,size,morphology,and number of calculi from a visual perspective.Results There was no significant difference in the total detection rate of submandibular gland calculi between CBCT and CT(98.2%[111/113]vs 95.6%[108/113],P>0.05),but both were significantly higher than that of X-ray(65.5%,74/113)and ultrasound(73.5%,83/113).The detection rates of ultrasound for calculi in the anterior and middle ducts were the lowest(63.6%[21/33]and 72.2%[26/36],respectively),which were significantly different from those of CBCT(97.0%[32/33]and 100.0%[36/36],respectively)and CT(93.9%[31/33]and 97.2%[35/36],respectively)(all P<0.05).The detection rate of X-ray for calculi in the posterior duct was significantly lower than that of ultrasound,CBCT,and CT(40.9%[18/44]vs 81.8%[36/44],97.7%[43/44],and 95.5%[42/44],all P<0.01).After CBCT data were imported into Mimics 19.0 software,submandibular gland calculi with different sizes,shapes,or numbers were successfully visualized and reconstructed.The reconstructed image was clear,and anatomical position relationship between the calculi and the mandible was visualized.Conclusion CBCT has good application value in the diagnosis of submandibular gland calculi and can replace traditional CT for the diagnosis of sialolithiasis.Clinically,CBCT examination can be directly performed for accurate diagnosis of calculi in the posterior duct which are not detected by double coincidence diagnosis but are indicated by ultrasound.For calculi in the anterior and middle ducts,X-ray and CBCT are preferred.Visualization technology helps clinical patient education and the development of personalized preoperative treatment plans.
		                        		
		                        		
		                        		
		                        	
4.Application of 3D printed model combined with visual surgical simulation in clinical teaching of extremity bone defects
Bingchuan LIU ; Xingcai LI ; Zhongwei YANG ; Guojin HOU ; Fang ZHOU ; Yun TIAN
Chinese Journal of Medical Education Research 2024;23(9):1286-1291
		                        		
		                        			
		                        			Objective:To investigate the application effect of the comprehensive innovative teaching model with "3D printed model combined with visual surgical simulation" as the core in the clinical teaching of extremity bone defects.Methods:The physicians who participated in the clinical management of patients with extremity bone defects in Department of Orthopedics, Peking University Third Hospital, from March 2019 to December 2021 were selected as subjects and were divided into standardized training group with 52 physicians and refresher physician group with 58 physicians. Teaching and training was performed for the special disease of extremity bone defects, including basic knowledge teaching, dressing change for infected wounds, multidisciplinary discussion, digital surgical simulation, and practical surgical operation. The assessment indices for teaching quality included the assessment of theoretical knowledge and clinical skills, the objective evaluation of the clinical ability of patient management, and an investigation of the degree of satisfaction. SPSS 22.0 was used for the t-test and the chi-square test. Results:After training, both groups had significant increases in the assessment scores of theoretical knowledge [(32.4±6.7)and (42.2±3.8)] and clinical practice skills [(19.6±2.0), (20.8±2.2), (20.5±2.5), (21.5±2.3)]( P<0.05). After training, the standardized training group had significant increases in the scores of six objective evaluation indicators [(8.3±0.8) vs. (6.9±1.1), (7.4±0.7) vs. (6.3±1.5), (7.2±1.3) vs. (5.0±1.4), (7.9±1.2) vs. (4.0±1.5), (8.4±0.8) vs. (6.4±1.6), (40.3±2.6) vs. (28.6±2.4)]( P<0.01), while the refresher physician group had significant improvements in four aspects, i.e., the understanding of extremity bone defects [(8.1±0.9) vs. (7.2±1.1)], the self-confidence in facing complex extremity bone defects [(8.1±1.2) vs. (6.6±0.9)], spatial thinking ability in repair surgery for bone defects [(8.6±0.8) vs. (7.3±0.9)], and overall clinical performance in actual management of patients with bone defects [(41.4±2.3) vs. (37.3±1.8)] ( P<0.01). The satisfaction score for this comprehensive innovative teaching model was (95.3±3.2) points in the standardized training group and (94.8±2.8) points in the refresher physician group. Conclusions:The comprehensive innovative teaching model with "3D printed model combined with visual surgical simulation" as the core can significantly improve the basic knowledge and clinical skills of physicians in a short period of time and meet the needs for learning surgical techniques and advanced diagnosis and treatment concepts among refresher physicians.
		                        		
		                        		
		                        		
		                        	
5.Application of post competency-oriented "TECK" teaching model in clinical pathology internship teaching
Wei DOU ; Dongxu WANG ; Zhongwei AI ; Fan YANG ; Yonghong HUANG ; Dandan CUI ; Haiying DONG
Chinese Journal of Medical Education Research 2024;23(10):1384-1389
		                        		
		                        			
		                        			Objective:To investigate the effects of the "TECK" (theoretical class, experimental course, case discussion, and knowledge reinforcement) teaching model oriented by post competency in clinical pathology internship teaching.Methods:The intern students from 2015 to 2019 in the pathology direction of clinical medicine in the School of Pathology, Qiqihar Medical College, who were enrolled in the internship from 2019 to 2023, were selected as the research objects.We enrolled 32 medical students from grades 2017, 2018, and 2019 (research group) and 24 medical students from grades 2015 and 2016 (control group) who would participate in pathology internships. The control group adopted the traditional internship mode, while the research group adopted the competency-oriented "TECK" teaching mode. After the internship, the two groups were compared for internship assessment score and surveyed for post competency. With the use of SPSS 18.0 statistical software. Continuous data were presented as (mean±standard deviation) and t-test was used for comparison between groups. Count data were expressed in the number of cases, and chi-square test was used for comparison between groups.The significance level α was 0.05. Results:The research group showed significantly higher scores of skill assessment (82.81±4.20 vs. 79.58±5.09) and pathological diagnosis assessment (80.28±4.23 vs. 76.21±4.58) than the control group (both P<0.05), with no significant difference in the score of theoretical knowledge ( P>0.05). In terms of post competency, the research group was superior to the control group in clinical skills and medical care ability (12.38±0.94 vs. 11.35±0.76), disease prevention and health promotion ability (6.28±0.92 vs. 4.48±0.93), interpersonal communication and information management ability (19.81±1.09 vs. 17.00±1.28), and teamwork and scientific research ability (11.44±1.27 vs. 9.25±0.87; all P<0.05). There were no significant differences between the two groups in core values and professional literacy and medical knowledge and lifelong learning (both P>0.05). Conclusions:In undergraduate internships, the competency-oriented "TECK"teaching mode can significantly improve students' clinical operation and pathological diagnosis ability, and effectively cultivate their abilities of clinical skills and medical care, disease prevention and health promotion, interpersonal communication and information management, teamwork and scientific research.
		                        		
		                        		
		                        		
		                        	
6.Tildrakizumab for moderate-to-severe plaque psoriasis in Chinese patients: A 12-week randomized placebo-controlled phase III trial with long-term extension
Chen YU ; Songmei GENG ; Bin YANG ; Yunhua DENG ; Fuqiu LI ; Xiaojing KANG ; Mingye BI ; Furen ZHANG ; Yi ZHAO ; Weili PAN ; Zhongwei TIAN ; Jinhua XU ; Zhenghua ZHANG ; Nan YU ; Xinsuo DUAN ; Shuping GUO ; Qing SUN ; Weiquan LI ; Juan TAO ; Zhijun LIU ; Yuanyuan YIN ; Gang WANG
Chinese Medical Journal 2024;137(10):1190-1198
		                        		
		                        			
		                        			Background::There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients.Methods::In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12.Results::At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P <0.001) and Physician’s Global Assessment (60.9% [67/110] vs. 10.0% [11/110]; difference, 49.1% [95% CI, 38.64, 59.62]; P <0.001) compared to placebo. PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups, reaching maximal efficacy after 28 weeks (86.8% [92/106] vs. 82.4% [89/108]) and maintained up to 52 weeks (91.3% [95/104] vs. 87.4% [90/103]). Most treatment-emergent adverse events were mild and not related to tildrakizumab. Conclusion::Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.Trial registration::ClinicalTrials.gov, NCT05108766.
		                        		
		                        		
		                        		
		                        	
7.Heterozygous CARD9 mutation favors the development of allergic bronchopulmonary aspergillosis.
Xia XU ; Haiwen LU ; Jianxiong LI ; Jielin DUAN ; Zhongwei WANG ; Jiawei YANG ; Shuyi GU ; Rongguang LUO ; Shuo LIANG ; Wei TANG ; Fengying ZHANG ; Jingqing HANG ; Juan GE ; Xin LIN ; Jieming QU ; Xinming JIA ; Jinfu XU
Chinese Medical Journal 2023;136(16):1949-1958
		                        		
		                        			BACKGROUND:
		                        			Previous research demonstrated that a homozygous mutation of g.136372044G>A (S12N) in caspase recruitment domain family member 9 ( CARD9 ) is critical for producing Aspergillus fumigatus -induced ( Af -induced) T helper 2 (T H 2)-mediated responses in allergic bronchopulmonary aspergillosis (ABPA). However, it remains unclear whether the CARD9S12N mutation, especially the heterozygous occurrence, predisposes the host to ABPA.
		                        		
		                        			METHODS:
		                        			A total of 61 ABPA patients and 264 controls (including 156 healthy controls and 108 asthma patients) were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA. A series of in vivo and in vitro experiments, such as quantitative real-time polymerase chain reaction, flow cytometry, and RNA isolation and quantification, were used to illuminate the involved mechanism of the disease.
		                        		
		                        			RESULTS:
		                        			The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients, regardless of Aspergillus sensitivity. Relative to healthy controls without relevant allergies, the mutation of p.S12N was associated with a significant risk of ABPA (OR: 2.69 and 4.17 for GA and AA genotypes, P = 0.003 and 0.029, respectively). Compared with patients with asthma, ABPA patients had a significantly higher heterozygous mutation (GA genotype), indicating that p.S12N might be a significant ABPA-susceptibility locus ( aspergillus sensitized asthma: OR: 3.02, P = 0.009; aspergillus unsensitized asthma: OR: 2.94, P = 0.005). The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9S12N , which contributes to its functional alterations to facilitate Af -induced T H 2-mediated ABPA development. In terms of mechanism, Card9 wild-type ( Card9WT ) expression levels decreased significantly due to Af -induced decay of its messenger RNA compared to the heterozygous Card9S12N . In addition, ABPA patients with heterozygous CARD9S12N had increased Af -induced interleukin-5 production.
		                        		
		                        			CONCLUSION
		                        			Our study provides the genetic evidence showing that the heterozygous mutation of CARD9S12N , followed by allele expression imbalance of CARD9S12N , facilitates the development of ABPA.
		                        		
		                        		
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Aspergillosis, Allergic Bronchopulmonary/complications*
		                        			;
		                        		
		                        			Aspergillus fumigatus/genetics*
		                        			;
		                        		
		                        			Asthma/genetics*
		                        			;
		                        		
		                        			Aspergillus
		                        			;
		                        		
		                        			Mutation/genetics*
		                        			;
		                        		
		                        			CARD Signaling Adaptor Proteins/genetics*
		                        			
		                        		
		                        	
8.A novel biodegradable polymer-coated sirolimus-eluting stent: 1-year results of the HELIOS registry.
Bo ZHENG ; Yi LIU ; Ruining ZHANG ; Wangwei YANG ; Fangju SU ; Rutao WANG ; Dapeng CHEN ; Guidong SHEN ; Yumin QIU ; Lianmin WANG ; Chang CHEN ; Zhongwei WU ; Fei LI ; Jiayi LI ; Chengxiang LI ; Chao GAO ; Ling TAO
Chinese Medical Journal 2023;136(15):1848-1854
		                        		
		                        			BACKGROUND:
		                        			The HELIOS stent is a sirolimus-eluting stent with a biodegradable polymer and titanium oxide film as the tie-layer. The study aimed to evaluate the safety and efficacy of HELIOS stent in a real-world setting.
		                        		
		                        			METHODS:
		                        			The HELIOS registry is a prospective, multicenter, cohort study conducted at 38 centers across China between November 2018 and December 2019. A total of 3060 consecutive patients were enrolled after application of minimal inclusion and exclusion criteria. The primary endpoint was target lesion failure (TLF), defined as a composite of cardiac death, non-fatal target vessel myocardial infarction (MI), and clinically indicated target lesion revascularization (TLR) at 1-year follow-up. Kaplan-Meier methods were used to estimate the cumulative incidence of clinical events and construct survival curves.
		                        		
		                        			RESULTS:
		                        			A total of 2998 (98.0%) patients completed the 1-year follow-up. The 1-year incidence of TLF was 3.10% (94/2998, 95% closed interval: 2.54-3.78%). The rates of cardiac death, non-fatal target vessel MI and clinically indicated TLR were 2.33% (70/2998), 0.20% (6/2998), and 0.70% (21/2998), respectively. The rate of stent thrombosis was 0.33% (10/2998). Age ≥60 years, diabetes mellitus, family history of coronary artery disease, acute myocardial infarction at admission, and device success were independent predictors of TLF at 1 year.
		                        		
		                        			CONCLUSION:
		                        			The 1-year incidence rates of TLF and stent thrombosis were 3.10% and 0.33%, respectively, in patients treated with HELIOS stents. Our results provide clinical evidence for interventional cardiologists and policymakers to evaluate HELIOS stent.
		                        		
		                        			CLINICAL TRIAL REGISTRATION
		                        			ClinicalTrials.gov, NCT03916432.
		                        		
		                        		
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Middle Aged
		                        			;
		                        		
		                        			Sirolimus/therapeutic use*
		                        			;
		                        		
		                        			Drug-Eluting Stents/adverse effects*
		                        			;
		                        		
		                        			Prospective Studies
		                        			;
		                        		
		                        			Cohort Studies
		                        			;
		                        		
		                        			Treatment Outcome
		                        			;
		                        		
		                        			Risk Factors
		                        			;
		                        		
		                        			Time Factors
		                        			;
		                        		
		                        			Percutaneous Coronary Intervention/adverse effects*
		                        			;
		                        		
		                        			Cardiovascular Agents/therapeutic use*
		                        			;
		                        		
		                        			Coronary Artery Disease/therapy*
		                        			;
		                        		
		                        			Myocardial Infarction/etiology*
		                        			;
		                        		
		                        			Thrombosis/complications*
		                        			;
		                        		
		                        			Polymers
		                        			;
		                        		
		                        			Registries
		                        			
		                        		
		                        	
9.MLL4 Regulates the Progression of Non–Small-Cell Lung Cancer by Regulating the PI3K/AKT/SOX2 Axis
Yang YANG ; Rongfang QIU ; Qiaoyou WENG ; Ziwei XU ; Jingjing SONG ; Siyu ZHAO ; Miaomiao MENG ; Dengke ZHANG ; Chunli KONG ; Hailin WANG ; Min XU ; Zhongwei ZHAO ; Jiansong JI
Cancer Research and Treatment 2023;55(3):778-803
		                        		
		                        			 Purpose:
		                        			Mixed-lineage leukemia protein 4 (MLL4/KMT2D) is a histone methyltransferase, and its mutation has been reported to be associated with a poor prognosis in many cancers, including lung cancer. We investigated the function of MLL4 in lung carcinogenesis. 
		                        		
		                        			Materials and Methods:
		                        			RNA sequencing (RNA-seq) in A549 cells transfected with control siRNA or MLL4 siRNA was performed. Also, we used EdU incorporation assay, colony formation assays, growth curve analysis, transwell invasion assays, immunohistochemical staining, and in vivo bioluminescence assay to investigate the function of MLL4 in lung carcinogenesis. 
		                        		
		                        			Results:
		                        			We found that MLL4 expression was downregulated in non–small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues and tended to decrease with disease stage progression. We analyzed the transcriptomes in control and MLL4- deficient cells using high-throughput RNA deep sequencing (RNA-seq) and identified a cohort of target genes, such as SOX2, ATF1, FOXP4, PIK3IP1, SIRT4, TENT5B, and LFNG, some of which are related to proliferation and metastasis. Our results showed that low expression of MLL4 promotes NSCLC cell proliferation and metastasis and is required for the maintenance of NSCLC stem cell properties. 
		                        		
		                        			Conclusion
		                        			Our findings identify an important role of MLL4 in lung carcinogenesis through transcriptional regulation of PIK3IP1, affecting the PI3K/AKT/SOX2 axis, and suggest that MLL4 could be a potential prognostic indicator and target for NSCLC therapy. 
		                        		
		                        		
		                        		
		                        	
10.Correlation of Preoperative Anemia Types with Pathological Features and Prognosis in Patients with Colorectal Cancer
Houji GUO ; Mei YANG ; Zhongwei QIN ; Zhanyi HUANG
Journal of Kunming Medical University 2023;44(12):165-170
		                        		
		                        			
		                        			Objective To analyze the correlation between different types of anemia(small cell anemia and nor-mal cell anemia)before operation and pathological features and prognosis of colorectal cancer patients.Methods The clinical data of 130 patients with colorectal cancer who underwent radical surgery in our hospital from March 2018 to February 2021 were retrospectively analyzed.According to the morphology of red blood cells,the patients were divided into group A(70 cases without anemia),group B(18 cases with small cell anemia)and group C(42 cases with normal cell anemia).Pathological features and postoperative 2 a survival rate of the 3 groups were compared.The correlation between preoperative anemia types and pathological features of colorectal cancer was analyzed by Phi coefficient test,and Kaplan-Meier survival curve was drawn to compare the survival rate of the 3 groups.Results There were significant differences in gender,tumor site,tumor diameter and TNM stage distribution among the three groups(P<0.05).The Phi coefficient test showed that preoperative anemia type was correlated with gender,tumor site,tumor diameter,and TNM stage(r = 0.238,0.255,0.266,0.331,P = 0.025,0.015,0.010,0.001).Multivariate Logistic regression analysis showed that tumor diameter≥5 cm,TNM stage Ⅲ-Ⅳ,distant metastasis,lymph node metastasis,preoperative small cell anemia,preoperative normal cell anemia were the risk factors for the prognosis of colorectal cancer after radical surgery(OR>1,P<0.05).The overall survival rate of 2a in group A was higher than that in group C>that in group B(P<0.05).Log-rank test showed that the postoperative survival rate of the three groups was significantly different(P<0.05).Conclusion Preoperative anemia types were correlated with tumor site,tumor diameter,TNM stage and postoperative survival time of colorectal cancer patients,among which preoperative small-cell anemia patients had the lowest survival rate.
		                        		
		                        		
		                        		
		                        	
            
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