1.Correlation between ultrasound parameters of internal carotid artery blood flow and regional cerebral oxygen saturation in elderly patients undergoing coronary artery bypass grafting under CPB
Ying HAN ; Wanlin LI ; Yamei ZHAO ; Haiyan WEI ; Jialin YIN ; Zhonghong SU ; Yali GE ; Hongwei SHI
Chinese Journal of Anesthesiology 2024;44(2):214-219
		                        		
		                        			
		                        			Objective:To evaluate the correlation between ultrasound parameters of internal carotid artery blood flow and regional cerebral oxygen saturation (rScO 2) in elderly patients undergoing coronary artery bypass grafting (CABG) under cardiopulmonary bypass (CPB). Methods:Sixty-four elderly patients undergoing elective CABG under CPB, aged 60-80 yr, regardless of gender, with body mass index of 18.1-28.9 kg/m 2, of American Society of Anesthesiologists Physical Status classification Ⅱ or Ⅲ, with New York Heart Association class Ⅱ or Ⅲ, with left ventricular ejection fraction≥50%, were selected. The rScO 2 and ultrasonic parameters of internal carotid artery including peak systolic velocity (PSV-ICA), end-diastolic velocity (EDV-ICA), diameter (D-ICA) and blood flow volume (Q-ICA) were recorded before anesthesia induction (T 0), at surgical skin incision (T 1), at 30 and 60 min of CPB (mean value was calculated, T 2), and at 30 and 60 min after termination of CPB (mean value was calculated, T 3). The ratio of unilateral internal carotid artery blood flow to cardiac output (Q/CO) was calculated. The receiver operating characteristic curve was used to analyze the accuracy of ultrasound parameters of internal carotid artery blood flow in predicting rScO 2 < 60%. Results:PSV-ICA was positively correlated with rScO 2 at T 0, T 1 and T 3 ( P<0.05), but no correlation was found between PSV-ICA and rScO 2 at T 2 ( P>0.05). There was no correlation between EDV-ICA and rScO 2 at each time point ( P>0.05). Q-ICA was positively correlated with rScO 2 at each time point ( P<0.05). Q/CO was not correlated with rScO 2 at T 1 ( P>0.05), but Q/CO was positively correlated with rScO 2 at T 2 and T 3 ( P<0.05). During the non-CPB period (T 0, T 1, T 3), the cutoff values of PSV-ICA and Q-ICA in predicting rScO 2< 60% were 51.35 cm/s and 283.5 ml/min respectively, the sensitivity was 0.900 and 0.900 respectively, and the specificity was 0.610 and 0.857 respectively (AUC=0.761, P=0.006; AUC=0.903, P< 0.001). During the CPB period, the cutoff values of Q-ICA and Q/CO in predicting rScO 2<60% were 296.5 ml/min and 5.84% respectively, the sensitivity was 0.900 and 0.800, and the specificity was 0.545 and 0.659 (AUC=0.764, P=0.001; AUC=0.748, P=0.002), respectively. Conclusions:PSV-ICA and Q-ICA are positively correlated with rScO 2 during the non-CPB period, and Q-ICA and Q/CO are positively correlated with rScO 2 during the CPB period in elderly patients undergoing CABG. PSV-ICA, Q-ICA and Q/CO can accurately predict rScO 2<60%.
		                        		
		                        		
		                        		
		                        	
2.TCM Guidelines for Diagnosis and Treatment of Chronic Cough in Children
Xi MING ; Liqun WU ; Ziwei WANG ; Bo WANG ; Jialin ZHENG ; Jingwei HUO ; Mei HAN ; Xiaochun FENG ; Baoqing ZHANG ; Xia ZHAO ; Mengqing WANG ; Zheng XUE ; Ke CHANG ; Youpeng WANG ; Yanhong QIN ; Bin YUAN ; Hua CHEN ; Lining WANG ; Xianqing REN ; Hua XU ; Liping SUN ; Zhenqi WU ; Yun ZHAO ; Xinmin LI ; Min LI ; Jian CHEN ; Junhong WANG ; Yonghong JIANG ; Yongbin YAN ; Hengmiao GAO ; Hongmin FU ; Yongkun HUANG ; Jinghui YANG ; Zhu CHEN ; Lei XIONG
Journal of Nanjing University of Traditional Chinese Medicine 2024;40(7):722-732
		                        		
		                        			
		                        			Following the principles of evidence-based medicine,in accordance with the structure and drafting rules of standardized documents,based on literature research,according to the characteristics of chronic cough in children and issues that need to form a consensus,the TCM Guidelines for Diagnosis and Treatment of Chronic Cough in Children was formulated based on the Delphi method,expert discussion meetings,and public solicitation of opinions.The guideline includes scope of application,terms and definitions,eti-ology and diagnosis,auxiliary examination,treatment,prevention and care.The aim is to clarify the optimal treatment plan of Chinese medicine in the diagnosis and treatment of this disease,and to provide guidance for improving the clinical diagnosis and treatment of chronic cough in children with Chinese medicine.
		                        		
		                        		
		                        		
		                        	
3.An analysis of the meaning of"diet as usual"in Treatise on Cold Pathogenic and Miscellaneous Diseases
Jialin CHENG ; Changxiang LI ; Zilin REN ; Xin LAN ; Yuxiao ZHENG ; Jinhua HAN ; Xueqian WANG
Journal of Beijing University of Traditional Chinese Medicine 2024;47(7):934-938
		                        		
		                        			
		                        			In Treatise on Cold Pathogenic and Miscellaneous Diseases,there are five articles concerning"diet as usual".When many doctors annotate such articles,they mostly interpret"diet as usual"as normal diet or because of stomach qi not affected by disease,ignoring the true significance of"diet as usual"and its role in clinical differential diagnosis.Through sorting out and summarizing the relevant provisions of"diet as usual",combining with the comments of Shuowen Jiezi and various ancient and modern doctors on the relevant provisions of"diet as usual"to explore the meaning behind it,the author believes that"diet as usual"can only be understood as"diet as before".Because it exists in a variety of diseases,it cannot be blindly extended to"normal diet"."Diet as usual"has two functions in clinical differential diagnosis:on the one hand,the stomach is empty,and no solid no drink blocks the qi movement,or there is stagnant heat in the stomach and intestines,but has not yet formed dry feces;on the other hand,when the middle jiao becomes one of the pathogenic factors of the disease,"diet as usual"can exclude the influence of the middle jiao.
		                        		
		                        		
		                        		
		                        	
4.Effects of esketamine on ventricular function and internal carotid artery blood flow in patients un-dergoing cardiac surgery under cardiopulmonary bypass
Wanlin LI ; Jieqiong MENG ; Ying HAN ; Yamei ZHAO ; Jialin YIN ; Haiyan WEI ; Zhonghong SU ; Tao SHI ; Yali GE ; Hongwei SHI
The Journal of Clinical Anesthesiology 2024;40(10):1039-1045
		                        		
		                        			
		                        			Objective To assess the impact of intravenous esketamine administered prior to car-diopulmonary bypass(CPB)initiation on ventricular function and internal carotid artery blood flow in pa-tients undergoing heart valve replacement surgery.Methods Sixty patients underwent elective CPB heart valve replacement,38 males and 22 females,aged 18-75 years,BMI 18.5-30.0 kg/m2,ASA physical status Ⅱ or Ⅲ,NYHA cardiac function classification Ⅰ-Ⅲ,and a left ventricular ejection fraction(LVEF)of≥45%,were selected.The patients were randomly divided into two groups:esketamine group(group E)and normal saline group(group C),30 patients in each group.Total intravenous anesthesia was used during the operation.Following the initiation of CPB,group E received an intravenous infusion of es-ketamine at a rate of 0.5 mg·kg-1·h-1 until the conclusion of the procedure,while group C received an equivalent volume of normal saline concurrently at the same rate.HR,MAP,CVP,and cardiac output index(CI)were recorded before anesthesia induction,during skin resection,and within 60 minutes after stopping CPB.LVEF,left ventricular global longitudinal strain(GLS),global longitudinal time-to-peak strain standard deviation(GLTSD),global circumferential strain(GCS),global circumferential time-to-peak strain standard deviation(GCTSD),right ventricular ejection fraction(RVEF),right ventricular GLS,and GLTSD were obtained during skin resection,within 40 minutes of CPB,and 60 minutes after stopping CPB.rScO2,BIS,concentrations of Hb and lactic acid(Lac),peak systolic flow velocity(SPV),quantity of flow-internal carotid artery(Q-ICA),and blood flow resistance index(RI)were recorded before anesthesia induction,during skin resection,within 40 minutes of CPB,and within 60 minutes after stopping CPB.Concentrations of cardiac troponin Ⅰ(cTnⅠ),alanine aminotransferase(ALT),creatinine(Cr),and neuron-specific enolase(NSE)were recorded before anesthesia induction and 6 hours after operation.Spon-taneous resuscitation after CPB,postoperative extubation time,duration of ICU stay,total hospital stay,in-cidence of adverse cardiac events,and 30-day postoperative mortality were recorded.Results Compared with group C,group E exhibited a significant increase in CI within 60 minutes after stopping CPB(P<0.05).The LVEF,RVEF,and right ventricular GLS demonstrated significant increases within 60 minutes after stopping CPB in group E compared with group C(P<0.05).The left ventricular GLS and left ven-tricular GCTSD displayed significant increases 30 minutes after stopping CPB in group E compared with group C.The RI exhibited a significant increase within 40 minutes of CPB in group E compared with group C(P<0.05).There were no significant differences in cTnⅠ,ALT,Cr,NSE,spontaneous resuscitation affter CPB,postoperative extubation time,duration of ICU stay,total hospital stay,incidence of cardiac adverse events,and 30-day postoperative mortality between the two groups.Conclusion Administration of esket-amine following the onset of CPB in patients undergoing cardiac surgery demonstrates a significant elevation in CI post-CPB cessation.Furthermore,it may augment ventricular longitudinal strain,thereby enhancing myocardial contraction,leading to increased postoperative ventricular ejection fraction,and sustaining hemo-dynamic stability.
		                        		
		                        		
		                        		
		                        	
5.Progress on mechanical circulatory support in the treatment of fulminant myocarditis in children
Chinese Pediatric Emergency Medicine 2024;31(5):349-352
		                        		
		                        			
		                        			Fulminant myocarditis is a severe heart inflammatory disease caused by a variety of causes,which are so insidious and deteriorative rapidly,with atypical early clinical symptoms,and that the patients are prone to obstinately cardiogenic shock,heart failure and fatal arrhythmia with high mortality.In recent years,the development of mechanical circulatory support(MCS)has brought light to the rescue of critically ill children.Due to factors such as technological limits and economic level,children MCS can only be carried out in a minority of superior medical establishment,which developmental stage is still lagging far behind that of adults.This review summarized the recent progress of MCS in children with fulminant myocarditis from the perspective of the multifold types of MCS for providing theoretical support for further clinical improment.
		                        		
		                        		
		                        		
		                        	
6.Clinical efficacy of allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome-evolved acute myeloid leukemia
Shulian CHEN ; Yuanyuan SHI ; Lining ZHANG ; Ming GONG ; Xiaoyu ZHANG ; Xiaoli ZHAO ; Mengze HAO ; Jialin WEI ; Yi HE ; Sizhou FENG ; Mingzhe HAN ; Erlie JIANG
Chinese Journal of Hematology 2024;45(4):364-369
		                        		
		                        			
		                        			Objective:The outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndromes-evolved acute myeloid leukemia (MDS-AML) were explored.Methods:A retrospective review was conducted for 54 patients with MDS-AML treated with allo-HSCT in the Institute of Hematology and Blood Disease Hospital from January 2018 to August 2022. The clinical effects after transplantation were observed, and the related risk factors influencing prognosis were explored.Results:Of the total 54 patients, 26 males, 28 females, and 53 patients achieved hematopoietic reconstruction. After a median follow-up of 597 (15-1 934) days, the 1 year overall survival (OS) rate, disease-free survival (DFS) rate, relapse rate (CIR) and non-relapse mortality (NRM) rate were 75.8%±5.8%, 72.1%±6.1%, 12.7%±4.9%, and 17.1%±5.2%, respectively. The 3 year estimated OS, DFS, CIR, and NRM rates were 57.8%±7.5%, 58.1%±7.2%, 23.2%±6.6%, and 23.7%±6.6%, respectively. The cumulative incidence of acute graft-versus-host disease (aGVHD) was 57.5%±6.9%, and the cumulative incidence of chronic graft-versus-host disease (cGVHD) was 48.4%±7.7%. Hematopoietic cell transplantation comorbidity index (HCT-CI) before transplantation was ≥2, minimal residual disease (MRD) was positive on the day of reconstitution, grade Ⅲ/Ⅳ aGVHD, bacterial or fungal infection and no cGVHD after transplantation were adverse prognostic factors for OS ( P<0.05). COX regression model for multivariate analysis showed that HCT-CI score before transplantation, bone marrow MRD on the day of response, grade Ⅲ or Ⅳ aGVHD, and cGVHD after transplantation were the independent adverse factors for OS ( P=0.001, HR=6.981, 95% CI 2.186-22.300; P=0.010, HR=6.719, 95% CI 1.572-28.711; P=0.026, HR=3.386, 95% CI 1.158-9.901; P=0.006, HR=0.151, 95% CI 0.039-0.581) . Conclusion:For patients with MDS-AML and high risk of relapse, allogeneic transplantation must be considered as soon as possible. The enhanced management of post-transplantation complications and maintenance treatment should be provided whenever possible after transplantation.
		                        		
		                        		
		                        		
		                        	
7.Analysis of therapeutic effects of allogeneic hematopoietic stem cell transplantation in 12 patients with DEK-NUP214 fusion gene positive acute myeloid leukemia
Yuyan SHEN ; Donglin YANG ; Yi HE ; Aiming PANG ; Xin CHEN ; Qiaoling MA ; Rongli ZHANG ; Jialin WEI ; Weihua ZHAI ; Mingzhe HAN ; Erlie JIANG ; Sizhou FENG
Chinese Journal of Hematology 2024;45(4):383-387
		                        		
		                        			
		                        			Twelve DEK-NUP214 fusion gene-positive patients with acute myeloid leukemia and on allo-HSCT treatment at the Hematology Hospital of the Chinese Academy of Medical Sciences from November 2016 to August 2022 were included in the study, and their clinical data were retrospectively analyzed. The patients comprised five men and seven women with a median age of 34 (16-52) years. At the time of diagnosis, all the patients were positive for the DEK-NUP214 fusion gene. Chromosome karyotyping analysis showed t (6;9) (p23;q34) translocation in 10 patients (two patients did not undergo chromosome karyotyping analysis), FLT3-ITD mutation was detected in 11 patients, and high expression of WT1 was observed in 11 patients. Nine patients had their primary disease in the first complete remission state before transplantation, one patient had no disease remission, and two patients were in a recurrent state. All patients received myeloablative pretreatment, five patients received sibling allogeneic hematopoietic stem cell transplantation, and seven patients received haploid hematopoietic stem cell transplantation. The median number of mononuclear cells in the transplant was 10.87 (7.09-17.89) ×10 8/kg, and the number of CD34 + cells was 3.29 (2.53-6.10) ×10 6/kg. All patients achieved blood reconstruction, with a median time of 14 (10-20) days for neutrophil implantation and 15 (9-27) days for platelet implantation. The 1 year transplant-related mortality rate after transplantation was 21.2%. The cumulative recurrence rates 1 and 3 years after transplantation were 25.0% and 50.0%, respectively. The leukemia free survival rates were (65.6±14.0) % and (65.6±14.0) %, respectively. The overall survival rates were (72.2±13.8) % and (72.2±13.8) %, respectively.
		                        		
		                        		
		                        		
		                        	
8.Analysis of the efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome with blastomycosis and survival comparison of different subtypes after the WHO 2022 reclassification
Hui WANG ; Runzhi MA ; Aiming PANG ; Donglin YANG ; Xin CHEN ; Rongli ZHANG ; Jialin WEI ; Qiaoling MA ; Weihua ZHAI ; Yi HE ; Erlie JIANG ; Mingzhe HAN ; Sizhou FENG
Chinese Journal of Hematology 2024;45(5):445-452
		                        		
		                        			
		                        			Objective:To evaluate the efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myelodysplastic syndrome accompanied by myelodysplasia (MDS-EB) and to compare the prognosis of different subtypes of patients classified by World Health Organization (WHO) 2022.Methods:A total of 282 patients with MDS-EB who underwent allo-HSCT at the Hematology Hospital of the Chinese Academy of Medical Sciences from October 2006 to December 2022 were included in the study. The WHO 2022 diagnostic criteria reclassified MDS into three groups: myelodysplastic tumors with type 1/2 of primitive cell proliferation (MDS-IB1/IB2, 222 cases), MDS with fibrosis (MDS-f, 41 cases), and MDS with biallelic TP53 mutation (MDS-biTP53, 19 cases). Their clinical data were retrospectively analyzed.Results:① The median age of 282 patients was 46 (15-66) years, with 191 males and 91 females. Among them, 118 (42% ) and 164 (58% ) had MDS-EB1 and MDS-EB2, respectively. ②Among the 282 patients, 256 (90.8% ) achieved hematopoietic reconstruction after transplantation, with 11 (3.9% ) and 15 (5.3% ) having primary and secondary implantation dysfunctions, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) 100 days post-transplantation was (42.6±3.0) %, and the cumulative incidence of grade Ⅱ-Ⅳ acute GVHD was (33.0±2.8) %. The cumulative incidence of chronic GVHD 1 year post-transplantation was (31.0±2.9) %. Post-transplantation, 128 (45.4% ), 63 (22.3% ), 35 (12.4% ), and 17 patients (6.0% ) developed cytomegalovirus infection, bacteremia, pulmonary fungal infection, and Epstein-Barr virus infection. ③The median follow-up time post-transplantation was 22.1 (19.2-24.7) months, and the 3-year overall survival (OS) and disease-free survival (DFS) rates were 71.9% (95% CI 65.7% -78.6% ) and 63.6% (95% CI 57.2% -70.7% ), respectively. The 3-year non-recurrent mortality rate (NRM) is 17.9% (95% CI 13.9% -22.9% ), and the 3-year cumulative recurrence rate (CIR) is 9.8% (95% CI 6.7% -13.7% ). The independent risk factors affecting OS post-transplantation include monocyte karyotype ( P=0.004, HR=3.26, 95% CI 1.46-7.29), hematopoietic stem cell transplantation complication index (HCI-CI) of ≥3 points ( P<0.001, HR=2.86, 95% CI 1.72-4.75), and the occurrence of acute gastrointestinal GVHD of grade Ⅱ-Ⅳ ( P<0.001, HR=5.94, 95% CI 3.50-10.10). ④The 3-year OS and DFS rates in the MDS-IB1/IB2 group post-transplantation were better than those in the MDS-biTP53 group [OS: 72.0% (95% CI 63.4% -80.7% ) vs 46.4% (95% CI 26.9% –80.1% ), P=0.020; DFS: 67.4% (95% CI 60.3% -75.3% ) vs 39.7% (95% CI 22.3% -70.8% ), P=0.015]. The 3-year CIR was lower than that of the MDS-biTP53 group [7.3% (95% CI 4.3% -11.4% ) vs 26.9% (95% CI 9.2% -48.5% ), P=0.004]. The NRM at 3 years post-transplantation in the MDS-IB1/IB2, MDS-f, and MDS-biTP53 groups were 16.7% (95% CI 12.1% -22.1% ), 20.5% (95% CI 9.4% -34.6% ), and 26.3% (95% CI 9.1% -47.5% ), respectively ( P=0.690) . Conclusion:Allo-HSCT is an effective treatment for MDS-EB, with monomeric karyotype, HCI-CI, and grade Ⅱ-Ⅳ acute gastrointestinal GVHD as independent risk factors affecting the patient’s OS. The WHO 2022 classification helps distinguish the efficacy of allo-HSCT in different subgroups of patients. Allo-HSCT can improve the poor prognosis of patients with MDS-f, but those with MDS-biTP53 have a higher risk of recurrence post-transplantation.
		                        		
		                        		
		                        		
		                        	
9.Exploration of the pathogenesis of metabolic syndrome based on the theory of "yang transforming qi and yin shaping up body"
Chunyu WANG ; Jialin CHENG ; Jinhua HAN ; Haojia ZHANG ; Liyang DONG ; Xueqian WANG ; Qingguo WANG ; Fafeng CHENG
Journal of Beijing University of Traditional Chinese Medicine 2024;47(9):1217-1222
		                        		
		                        			
		                        			The theory of "yang transforming qi and yin shaping up body" comes from Huangdi Neijing (Inner Canon of Yellow Emperor),which describes the basic form of human metabolism dominated by "yang transforming qi":the effect of " yang transforming qi" leads the energy metabolism of human body,while the effect of "yin shaping up body" leads the material metabolism. Metabolic syndrome is a clinical syndrome with metabolic disorders of protein,fat and carbohydrate. The theory of "yang transforming qi and yin shaping up body" has a strong guiding value for the pathogenesis analysis and clinical differentiation and treatment of metabolic syndrome. Yin and yang represent the two basic trends of the change and development of things,and the functions of "transforming qi" and "shaping up body" are the main manifestations of them in metabolism. From this perspective,this paper suggests that the key pathogenesis of metabolic syndrome should be "insufficiency of yang transforming qi and impairment of yin shaping up body" based on the mutual assistance of yin and yang. On this basis we take "coordinating yin-yang and promoting the reproduction of them" as the main directions of therapy,which provides a new idea for the treatment of metabolic syndrome.
		                        		
		                        		
		                        		
		                        	
10.Clinical analysis of 76 patients with severe aplastic anemia treated with haploid hematopoietic stem cell transplantation
Ying ZHANG ; Guixin ZHANG ; Aiming PANG ; Donglin YANG ; Rongli ZHANG ; Weihua ZHAI ; Jialin WEI ; Yi HE ; Erlie JIANG ; Sizhou FENG ; Mingzhe HAN
Chinese Journal of Hematology 2023;44(3):202-210
		                        		
		                        			
		                        			Objective:The purpose of this study is to determine the efficacy of haploidentical donor hematopoietic stem cell transplantation in the treatment of severe aplastic anemia.Methods:The clinical data of 76 patients with severe aplastic anemia (SAA) patients who underwent haplo-HSCT from December 2014 to October 2020 were selectively analyzed. There were 50 males and 26 females with a median age of 16 (3-52) years old. There were 49 SAA-Ⅰ patients, 18 SAA-Ⅱ patients, and 9 patients with hepatitis-associated aplastic anemia. There were 15 cases of bone marrow put together with peripheral blood stem cell transplantation and 61 cases of peripheral blood stem-cell transplantation. Conditioning regimens were Cyclophosphamide (CY) + Fludarabine (Flu) + ATG for 46 patients and Busulfan (Bu) + CY+Flu+ATG for 30 patients.Results:Three patients died during the myelosuppressive phase following transplantation, and 73 patients had a median time of neutrophil engraftment of 12 (9-21) days; in addition to 3 patients who died early, 8 patients did not obtain platelet reconstruction after transplantation, and 65 patients had platelet engraftment with a medium time of 14 (9-90) d. The incidence of primary graft failure was 10.9% and the incidence of secondary graft failure was 5.5%. The incidence of Ⅱ-Ⅳ acute graft-versus-host disease (aGVHD) was 38.4%, the incidence of Ⅲ-Ⅳ aGVHD was 16.4%, the incidence of chronic graft anti-host disease (cGVHD) was 35.8%, and the incidence of extensive cGVHD was 22.4%. The medium follow-up time was 19.5 (1-75) months, the prospective overall survival (OS) for 2 years was (78.6±5.0) %, the failure-free survival (FFS) was (75.9±5.1) %, and the transplant-related mortality was (20.2±4.9) %. Multi-factor analysis revealed that the patient older than 35 years old, Ⅲ/Ⅳ aGVHD, HCT-CI≥3, the pre-transplant ferritin ≥1 500 μg/L, the number of neutrophils >1×10 9/L at the time of onset were risk factors affecting OS ( P=0.008, 0.008, 0.014, 0.004, 0.027) . Patients with graft failure had lower OS and FFS than other patients ( P<0.001) . Conclusion:Haplo-HSCT is an effective method for treating SAA in children, adolescents, and young patients, and the occurrence of severe aGVHD and severe infection, as well as graft failure, are the main causes of survival rate. The prevention and treatment of severe aGVHD and infection are essential to improve efficacy.
		                        		
		                        		
		                        		
		                        	
            
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