1.Da Chaihutang for Treatment of Sepsis with Yang Syndrome:A Randomized Controlled Trial
Na HUANG ; Guangmei CHEN ; Xingyu KAO ; Zhen YANG ; Weixian XU ; Kang YUAN ; Junna LEI ; Jingli CHEN ; Mingfeng HE
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(1):55-63
		                        		
		                        			
		                        			ObjectiveTo explore the clinical efficacy and safety of Da Chaihutang (DCH) for the treatment of sepsis with Yang syndrome. MethodsA total of 70 patients suffering from sepsis with Yang syndrome were randomly divided into an observation group and a control group, with 35 cases in each group. They both received standard Western medicine treatment. The observation group was additionally given a dose of DCH, which was boiled into 100 mL and taken twice. The control group was additionally given an equal volume and dosage of warm water. The intervention lasted for three days. The 28-day all-cause mortality and the changes in the following indicators before and after intervention were compared between the two groups, including sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score,white blood cell (WBC),the percentage of neutrophils (NEU%),C-reactive protein (CRP),procalcitonin (PCT),alanine transaminase (ALT),aspartate transaminase (AST),total bilirubin (TBil),creatinine (Cr),blood urea nitrogen (BUN),acute gastrointestinal injury (AGI) grade,gastrointestinal dysfunction score (GDS),serum intestinal fatty acid-binding protein (iFABP), citrulline (CR),platelet (PLT),prothrombin time(PT),activated partial thromboplastin time (APTT),fibrinogen (Fib),international normalized ratio (INR),and D-dimer (D-D). ResultsThere was no significant difference between the two groups regarding 28-day all-cause mortality. After the intervention,SOFA,WBC,PCT,and Cr were significantly decreased, and PLT was significantly increased in the control group (P<0.05). SOFA,APACHE Ⅱ,NEU%,CRP,PCT,ALT,AST,Cr,BUN,AGI grade,GDS,and serum iFABP and CR were significantly improved in the observation group (P<0.05). After the intervention,APACHE Ⅱ,PCT,AGI grade,GDS,and serum iFABP in the observation group were significantly lower than those in the control group ,while CR and PLT were higher (P<0.05,P<0.01). There were significant differences regarding the gap of SOFA,APACHE Ⅱ,AST,TBil,AGI grade,GDS,iFABP,CR, and PLT between the two groups (P<0.05,P<0.01). There were slight differences regarding PT,APTT,Fib,INR,and D-D between the two groups,which were in the clinical normal range. ConclusionOn the basis of Western medicine, DCH helped to reduce sepsis severity and improved multiple organ dysfunction with high clinical efficacy and safety, but further research on its impact on the prognosis of patients with sepsis is still required. 
		                        		
		                        		
		                        		
		                        	
2.Health risk assessment of fluoride and trichloromethane in drinking water in rural schools in Guizhou Province
JIAN Zihai, ZHANG Jianhua, SU Minmin, CHEN Xuanhao, YUAN Minlan, YANG Dan, CHEN Gang
Chinese Journal of School Health 2025;46(1):134-137
		                        		
		                        			Objective:
		                        			To analyze the distribution characteristics of fluoride and trichloromethane in drinking water in rural schools in Guizhou Province and assess their health risks, so as to provide a scientific basis for ensuring the safety of drinking water in rural schools.
		                        		
		                        			Methods:
		                        			During the dry season (March to May) and wet season (July to September) of 2020 to 2022, 788 rural primary and secondary schools in agricultural counties (districts) in Guizhou Province were selected for investigation by using a direct sampling method. A total of 1 566 drinking water samples were collected from these schools, and the mass concentrations of fluoride and trichloromethane in the water samples were detected. The Mann-Whitney  U  test was used for intergroup comparison, and a health risk assessment model was employed to evaluate the health risks of students oral intake of fluoride and trichloromethane.
		                        		
		                        			Results:
		                        			From 2020 to 2022, the mass concentrations of fluoride and trichloromethane in the drinking water of rural schools in Guizhou Province all met the standards, and the ranges were no detection to 0.99 mg/L and (no detection to 0.06)×10 -3  mg/L, respectively. The mass concentrations of fluoride in dry and wet seasons were 0.05(0.05,0.10), 0.05(0.05,0.10) mg/L, the mass concentrations of trichloromethane were [0.02(0.02,1.00)]×10 -3 , [0.02(0.02,1.00)]×10 -3  mg/L, the mass concentrations of fluoride in factory water and terminal water were 0.05(0.05,0.05), 0.05(0.05,0.10) mg/L, and the differences were not statistically significant ( Z=-0.04, -0.88, - 0.98 , P >0.05). There was a statistically significant difference in the mass concentration of trichloromethane between factory water and peripheral water [0.02(0.02,0.02)×10 -3 , 0.02(0.02,1.05)×10 -3  mg/L]( Z=-2.16, P < 0.05 ). The non-carcinogenic risk assessment values for students  oral exposure to fluoride and trichloromethane were in the range of 0.01(0.01,0.03)-0.03(0.03,0.06) and [0.26( 0.26 ,14.54)]×10 -4 -[0.52(0.52,48.62)]×10 -4 , respectively, all of which were at acceptable levels; the carcinogenic risk assessment values for oral exposure to trichloromethane were in the range of [0.08(0.08, 4.51 )]×10 -7 -[0.16(0.16,15.07)]×10 -7 , indicating a low risk.
		                        		
		                        			Conclusions
		                        			The health risks of students  expore to fluoride and trichloromethane in drinking water in rural schools of Guizhou Province are low. It is necessary to strengthen the standardized management of disinfection in some rural drinking water projects and the monitoring of fluoride in water sources to reduce the exposure risk to children.
		                        		
		                        		
		                        		
		                        	
3.An animal model of severe acute respiratory distress syndrome for translational research
Kuo‑An CHU ; Chia‑Yu LAI ; Yu‑Hui CHEN ; Fu‑Hsien KUO ; I.‑Yuan CHEN ; You‑Cheng JIANG ; Ya‑Ling LIU ; Tsui‑Ling KO ; Yu‑Show FU
Laboratory Animal Research 2025;41(1):81-92
		                        		
		                        			 Background:
		                        			Despite the fact that an increasing number of studies have focused on developing therapies for acute lung injury, managing acute respiratory distress syndrome (ARDS) remains a challenge in intensive care medicine.Whether the pathology of animal models with acute lung injury in prior studies differed from clinical symptoms of ARDS, resulting in questionable management for human ARDS. To evaluate precisely the therapeutic effect of trans‑ planted stem cells or medications on acute lung injury, we developed an animal model of severe ARDS with lower lung function, capable of keeping the experimental animals survive with consistent reproducibility. Establishing this animal model could help develop the treatment of ARDS with higher efficiency. 
		                        		
		                        			Results:
		                        			In this approach, we intratracheally delivered bleomycin (BLM, 5 mg/rat) into rats’ left trachea via a needle connected with polyethylene tube, and simultaneously rotated the rats to the left side by 60 degrees. Within sevendays after the injury, we found that arterial blood oxygen saturation (SpO2 ) significantly decreased to 83.7%, partial pressure of arterial oxygen (PaO2 ) markedly reduced to 65.3 mmHg, partial pressure of arterial carbon dioxide (PaCO2 )amplified to 49.2 mmHg, and the respiratory rate increased over time. Morphologically, the surface of the left lung appeared uneven on Day 1, the alveoli of the left lung disappeared on Day 2, and the left lung shrank on Day 7. A his‑ tological examination revealed that considerable cell infiltration began on Day 1 and lasted until Day 7, with a larger area of cell infiltration. Serum levels of IL-5, IL-6, IFN-γ, MCP-1, MIP-2, G-CSF, and TNF-α substantially rose on Day 7. 
		                        		
		                        			Conclusions
		                        			This modified approach for BLM-induced lung injury provided a severe, stable, and one-sided (left-lobe) ARDS animal model with consistent reproducibility. The physiological symptoms observed in this severe ARDS animal model are entirely consistent with the characteristics of clinical ARDS. The establishment of this ARDS animal model could help develop treatment for ARDS. 
		                        		
		                        		
		                        		
		                        	
4.Causal Relationship Between Colorectal Cancer and Common Psychiatric Disorders: A Two-sample Mendelian Randomization Study
Yuan YAO ; Mingze YANG ; Chen LI ; Haibo CHENG
Cancer Research on Prevention and Treatment 2025;52(6):496-501
		                        		
		                        			
		                        			Objective To elucidate the causal relationships between colorectal cancer (CRC) and prevalent psychiatric disorders through a two-sample Mendelian randomization approach. Methods Utilizing publicly available genome-wide association study data, we explored the connections between CRC and various psychiatric disorders, including depression, anxiety, bipolar disorder, and schizophrenia. We applied three statistical analyses: inverse variance weighting, MR-Egger, and median weighting. Sensitivity analyses were conducted to ensure the reliability and validity of the results. Results Inverse variance weighting analysis showed no significant links between CRC and depression (P=0.090), anxiety (P=0.099), or schizophrenia (P=0.899). Conversely, a significant inverse relationship was found with bipolar disorder (P=0.010). Conclusion No causal connection exists between CRC and the psychiatric conditions of depression, anxiety, or schizophrenia. However, CRC may have a causal association with a reduced risk of bipolar disorder, further supporting the existence of the gut-brain axis.
		                        		
		                        		
		                        		
		                        	
5.Enhancement of Microglial Phagocytosis by Scaffold Protein PDLIM5 and Its Role in Multiple Sclerosis
Hailian CHEN ; Yuge WANG ; Yu CUI ; Suning PING ; Yuan CHEN
Journal of Sun Yat-sen University(Medical Sciences) 2025;46(2):179-185
		                        		
		                        			
		                        			ObjectiveTo investigate the expression of scaffold protein PDLIM5 in multiple sclerosis (MS) patients and the mouse microglial cell line BV2, and to explore its effects on the phagocytosis of microglial cells. MethodsPeripheral blood samples were collected from 24 MS patients and 6 healthy volunteers as controls. The expression levels of PDLIM5 were detected by real-time quantitative PCR. A neuroinflammation cell model was established by treating the mouse microglial cell line BV2 with lipopolysaccharide (LPS, 1 µg/mL). The expression levels of PDLIM5 were measured by Western Blot. The effect of PDLIM5 expression on phagocytosis was analyzed by transfecting BV2 cells with PDLIM5 shRNA plasmids or PDLIM5 overexpression plasmids. ResultsReal-time quantitative PCR results showed that compared with the healthy control group, the expression level of PDLIM5 from the MS patients was significantly increased in monocytes [2.78 (0.70-6.86) vs. 0.54 (0.39-1.51), P=0.036] and lymphocytes [1.62 (0.90-2.26) vs. 0.11 (0.05-0.21), P<0.001]. Western Blot results indicated that PDLIM5 expression was significantly upregulated in BV2 cells following LPS stimulation (P<0.05). Plasmid transfection experiments demonstrated that knockdown of PDLIM5 inhibited the phagocytic capacity of BV2 cells as measured by trypan blue uptake (P<0.05), while overexpression of PDLIM5 enhanced the phagocytic ability of BV2 cells (P<0.001). ConclusionUnder neuroinflammatory conditions, PDLIM5 expression is elevated, and this upregulation promotes the phagocytosis of microglial cell. 
		                        		
		                        		
		                        		
		                        	
6.Mechanism of Huanglian Wendantang on Damp-heat Type Diabetes Enteropathy Rats Based on TGR5/GLP-1 Signaling Pathway and Intestinal Flora
Yujin WANG ; Yulong QIE ; Hua JIANG ; Chen YUAN ; Xirui DENG ; Xuelian MENG ; Wenli WANG ; Yanjin SU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(15):10-18
		                        		
		                        			
		                        			ObjectiveTo explore the mechanism of Huanglian Wendantang on damp-heat type diabetes enteropathy rats based on the G protein coupled bile acid receptor 5/glucagon like peptide-1 (TGR5/GLP-1) signaling pathway and intestinal flora. MethodsA total of 72 male Sprague Dawley (SD) rats were adaptively fed for one week. Twelve SD rats were randomly selected as a blank group and fed with an ordinary diet. The rest of the SD rats were fasted for 12 hours without water. A rat model with damp-heat type diabetes enteropathy was made by left intraperitoneal injection of streptozotocin (55 mg·kg-1) and high sugar and high fat diet (20% sucrose solution + high fat diet) in a humid and hot environment (artificial climate box: temperature 30-34 ℃, relative humidity: 85%-95%). After successful modeling, the rats were randomly divided into a model group, a metformin group (200 mg·kg-1), low-dose, medium-dose, and high-dose Huanglian Wendantang groups (7.10, 14.20, 28.39 g·kg-1), with 12 rats in each group. The normal group and the model group were orally administered with physiological saline once a day for 6 consecutive weeks. During the observation period, the weight and blood glucose levels of rats were measured and recorded weekly. After the administration, fresh feces were collected from rats, and 16S rRNA sequencing technology was used to study the differences and changes in intestinal flora among different groups. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the serum of rats were detected by enzyme-linked immunosorbent assay (ELISA), and the pathological morphological changes of colon tissue were examined. The expression of TGR5 and GLP-1 in colon tissue was detected by immunohistochemistry, and the expression of TGR5 and GLP-1 proteins in colon tissue was measured by Western blot. ResultsCompared with the blank group, the model group showed a decrease in body weight, an increase in blood glucose, and significant damp-heat symptoms. The levels of IL-6 and TNF-α in serum were significantly increased (P<0.01). The expression of TGR5 and GLP-1 was decreased (P<0.01), and the pathogenic bacteria were increased. Compared with the model group, the treatment groups exhibited improvements in body weight, blood glucose levels, and damp-heat syndrome in rats. Among them, the high-dose group of Huanglian Wendantang displayed the most significant improvement effect, with significantly reduced inflammation levels (P<0.01) and elevated expression of TGR5 and GLP-1 (P<0.01). Colonic pathological sections showed that Huanglian Wendantang could effectively ameliorate colonic pathological changes. The 16S rRNA sequencing result indicated a significant increase in beneficial bacteria in the treatment groups. ConclusionHuanglian Wendantang can effectively ameliorate the damp-heat symptoms and blood glucose levels in rats with damp-heat type diabetes enteropathy, and it may exert an effect by regulating the TGR5/GLP-1 signaling pathway and intestinal flora disorder. 
		                        		
		                        		
		                        		
		                        	
7.Anti-atherosclerosis Effect and Mechanism of Siegesbeckiae Herba Water Decoction via Regulation of NF-κB Signaling Pathway
Tengyue WANG ; Mingyue ZHAO ; Xiaonan YUE ; Yuan CHEN ; Changqing LU ; Huan WANG ; Kaifang FAN
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(15):106-114
		                        		
		                        			
		                        			ObjectiveTo investigate the therapeutic effect of Siegesbeckiae Herba water decoction (SWD) at different doses on atherosclerosis (AS) in a mouse model induced by a high-fat diet and analyze its potential mechanism of action. MethodsThirty-six male ApoE-/- mice were randomly divided into six groups: blank control group, model group, low-dose, medium-dose, and high-dose SWD groups, and positive control group. Firstly, the AS mouse model was created by feeding mice a high-fat diet. After successful modeling, the low-, medium-, and high-dose SWD groups were intragastrically administered with SWD at 0.65, 1.3, 2.6 g·kg-1, respectively. The positive control group was intragastrically administered with 30 mg·kg-1 of atorvastatin calcium aqueous solution, while the blank and model groups received an equal volume of 0.9% sodium chloride solution via oral gavage, all administered for 12 weeks. During the administration period, the general condition of the mice was observed and recorded daily. Before sampling, color Doppler ultrasound was performed to observe the pathological changes in atherosclerotic plaques in the aortic wall of mice. Hematoxylin-eosin (HE) staining was used to observe the pathological changes in aortic tissue in mice, and oil red O staining was used to detect the atherosclerotic plaque area in the aorta. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum lipid indices and the levels of interleukins (IL-1β, IL-4, IL-6, and IL-10) and tumor necrosis factor-α (TNF-α) in mice. Protein expression levels of IKKα, IKKβ, and NF-κB p65 in mouse aortic tissue were detected by Western blot. ResultsCompared with the blank control group, the model group showed a significant increase in body weight. The results of color Doppler ultrasound showed enhanced vascular wall echo, suggesting the presence of atherosclerotic plaques. HE staining showed foam cell aggregation, fibrous connective tissue proliferation, and vascular intima injury in the aortic tissue. Oil red O staining showed a significant increase in the plaque area in the aortic tissue (P<0.01). ELISA results indicated significantly elevated levels of IL-1β, IL-6, TNF-α, total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) in mouse serum (P<0.01), as well as significantly decreased levels of IL-4, IL-10, and high-density lipoprotein (HDL) (P<0.01). Western blot results showed that the expression of IKKα, IKKβ, and NF-κB p65 in mouse aortic tissue increased significantly (P<0.01). Compared with those in the model group, mice in the middle- and high-dose SWD groups showed significant weight loss. In the high-dose group, the aortic vascular wall echoes were weakened, and the atherosclerotic plaques were reduced. The aortic lesions of mice in the medium- and high-dose SWD groups were significantly alleviated. The plaque area percentage showed an inverse correlation with the administered dose in all groups treated with SWD (P<0.05). In the medium-dose SWD group, serum levels of IL-1β, IL-6, TNF-α, TC, TG, and LDL were significantly decreased (P<0.05, P<0.01), while those of IL-4 and IL-10 were significantly increased (P<0.01). In the high-dose SWD group, levels of IL-1β, IL-6, TNF-α, TC, TG, and LDL were significantly decreased (P<0.01), while IL-4, IL-10, and HDL were significantly increased (P<0.01). The IKKα and IKKβ expression was significantly decreased in the low-dose SWD group (P<0.05), and IKKα, IKKβ, and NF-κB p65 were significantly decreased in the medium- and high-dose SWD groups (P<0.05, P<0.01). ConclusionSWD may exert therapeutic effects on AS by regulating the expression of related inflammatory factors through the NF-κB signaling pathway, thereby reducing inflammation, plaque area, and lipid content in the body. 
		                        		
		                        		
		                        		
		                        	
8.Influencing factors, clinical manifestations and preventive strategies of hypercoagulable state after kidney transplantation
Rentian CHEN ; Zehua YUAN ; Hongtao JIANG ; Tao LI ; Meng YANG ; Liang XU ; Yi WANG
Organ Transplantation 2025;16(4):640-647
		                        		
		                        			
		                        			Hypercoagulable state (HCS) after kidney transplantation is one of the common and serious complications in kidney transplant recipients, which has attracted increasing attention in recent years. HCS refers to the abnormal and excessive activation of blood coagulation function, leading to the increased risk of thrombosis. After kidney transplantation, the combined effects of hemodynamic changes, surgical trauma and severe rejection increase the incidence of HCS, not only raising the risk of thrombosis but also potentially causing graft failure and affecting the postoperative survival rate of patients. This article reviews the influencing factors, clinical manifestations, diagnostic methods and preventive strategies of HCS after kidney transplantation, aiming to provide a theoretical basis for optimizing perioperative management and improving the prognosis of patients.
		                        		
		                        		
		                        		
		                        	
9.Differential Analysis on Chemical Composition and Pharmacodynamic Effect Between Combined Decoction and Single Decoction of Famous Classical Formula Huaganjian
Yang WANG ; Gaoju ZHANG ; Ling LI ; Liping CHEN ; Li ZHANG ; Xiao LIU ; Yuyu ZHANG ; Yuan CUI ; Minglong LI ; Chaomei FU ; Xin YAN ; Yuxin HE ; Qin DONG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(16):199-207
		                        		
		                        			
		                        			ObjectiveThrough qualitatively and quantitatively analysis of the differences in chemical composition between the combined decoction and single decoction of Huaganjian and comparison of their core efficacy, to explore the rationality of the flexible clinical application of Huaganjian compound preparations and single-flavored dispensing granules. MethodsUltra performance liquid chromatography-quadrupole-electrostatic field orbitrap high resolution mass spectrometry(UPLC-Q-Exactive Orbitrap MS) was used to qualitatively analyze the combined decoction and single decoction samples of Huaganjian, and meanwhile, the contents of four index components(geniposide, paeoniflorin, hesperidin and paeonol) were quantitatively analyzed by high performance liquid chromatography(HPLC). Nonalcoholic fatty liver disease(NAFLD) rat model induced by high-fat diet was applied to compare the efficacy of combined decoction and single decoction of Huaganjian. A total of 30 male SD rats were randomly divided into the control group, model group, lovastatin group(1.8 mg·kg-1), combined decoction group(1.26 g·kg-1) and single decoction group(1.18 g·kg-1). After successful modeling, lovastatin group, combined decoction group and single decoction group were given corresponding doses of drugs by intragastric administration every day, and the control group and model group were given equal amounts of normal saline by intragastric administration, after 4 weeks of administration, the serum and liver tissues were collected, and the contents of alanine aminotransferase(ALT), aspartate aminotransferase(AST), total cholesterol(TC), triglyceride(TG), low-density lipoprotein cholesterol(LDL-C) and high-density lipoprotein cholesterol(HDL-C) in serum of rats were detected, and the liver pathological examination was carried out by hematoxylin-eosin(HE) staining and oil red O staining, so as to compare differences of their efficacy. ResultsSeventy chemical components were initially identified and attributed from the lyophilized powder of the combined decoction and single decoction samples of Huaganjian, and there was no obvious difference in composition between the two. Further quantitative analysis showed that the contents of geniposide, paeoniflorin, hesperidin and paeonol in the combined decoction samples were significantly increased when compared with those of the single decoction samples(P<0.01). The pharmacodynamic results showed that compared with the model group, both the combined and single decoction groups of Huaganjian could improve the liver index of NAFLD rats, reduce the serum levels of AST, ALT, TC, TG and LDL-C, increase the serum level of HDL-C, and ameliorate the pathological changes of liver cell steatosis and fat accumulation. However, there was no significant difference in pharmacodynamic effects between the combined decoction group and the single decoction group. ConclusionThere is no significant difference between the combined decoction and single decoction of Huaganjian in terms of chemical composition, but the contents of the four index components show significantly difference. Both of them can significantly improve the fat accumulation and liver function in NAFLD rats. This study provides a reference basis for the rational clinical application and evaluation of famous classical formula compound preparations and single-flavored dispensing granules. 
		                        		
		                        		
		                        		
		                        	
10.Modern Clinical Application and Mechanism of Action of Chaihu Guizhi Ganjiangtang: A Review
Miaomiao MENG ; Zibo YUAN ; Kaili CHEN ; Jun ZHANG ; Zixuan YU ; Wei DENG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(16):266-277
		                        		
		                        			
		                        			Chaihu Guizhi Ganjiangtang (CGG)is a classic prescription in the Treatise on Cold Damage,which has the effects of clearing and relieving stagnation heat in Shaoyang,warming and dissolving water drink,and relieving the pivot mechanism. It is a classic prescription for treating spleen deficiency and liver depression and stopping internal stagnation caused by water drink. The formula is exquisite and well-matched and is often modified and used by ancient and modern medical practitioners to treat various miscellaneous diseases of internal and external medicine,with significant therapeutic effects. In recent years,with the rapid development of modern pharmacology,research on the micro mechanism of CGG has been continuously developed and deepened,providing new ideas for the treatment of diseases with CGG. Therefore,the authors systematically searched databases such as China National Knowledge Infrastructure,Wanfang Data Knowledge Service Platform,VIP Database, and PubMed for literature on the clinical application and pharmacological mechanism of CGG published by Chinese and foreign scholars in recent years. This article summarized the literature from two aspects:the modern clinical application and mechanism of action of CGG and elaborated on the diseases treated by CGG in modern literature,involving digestive system,respiratory system,nervous system,endocrine system,circulatory system,urinary system,gynecology,as well as its application in reducing the side effects of radiotherapy and chemotherapy, gynecology, dermatology, ophthalmology, and orthopedics. At the same time,the mechanism of CGG in treating diseases may be related to anti-inflammatory,anti-oxidative stress, regulation of immunity, anti-fibrosis, anti-tumor, improvement of gastrointestinal flora and motility, protection of liver tissue, reduction of blood lipids and blood sugar, and regulation of hormone levels. 
		                        		
		                        		
		                        		
		                        	
            

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