1.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. 
		                        		
		                        		
		                        		
		                        	
2.The correlation between vitamin D level and liver fibrosis in patients with metabolic dysfunction-associated fatty liver disease
Huajuan WANG ; Shujun SHI ; Xuelian XIONG
Chinese Journal of Clinical Medicine 2025;32(3):327-333
		                        		
		                        			
		                        			Objective To investigate the correlation between different forms of serum vitamin D levels and liver fibrosis in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). Methods Data from the National Health and Nutrition Examination Survey in 2021–2023 were analyzed. Logistic regression models were used to evaluate the relationship between serum total vitamin D, 25(OH)D3 levels, and liver fibrosis in the MAFLD patients. Results A total of 2 628 patients were included. There were significant differences between MAFLD patients with liver fibrosis and those without fibrosis in age, smoking history, waist circumference, body mass index, high-density lipoprotein cholesterol, total cholesterol, fasting plasma glucose, hypertension history, vitamin D, and 25(OH)D3 levels (P<0.05). Logistic regression analysis revealed that compared to the low total serum vitamin D group (11.2-61.8 nmol/L), MAFLD patients with high total vitamin D levels (89.1 nmol/L<vitamin D≤290 nmol/L) exhibited a 22% reduced risk of liver fibrosis (OR=0.78, 95%CI 0.64-0.94, P=0.015). Similarly, compared to the low 25(OH)D3 group (4.1-57.0 nmol/L), those with high 25(OH)D3 level [84.7 nmol/L<25(OH)D3≤288 nmol/L] showed a 23% lower risk of liver fibrosis (OR=0.77, 95%CI 0.62-0.95, P=0.021). After adjusting for covariates, high total vitamin D levels remained significantly associated with reduced liver fibrosis risk (OR=0.63, 95%CI 0.42-0.94, P=0.036). Conclusions Elevated serum total vitamin D and 25(OH)D3 levels are protective factors against early liver fibrosis in MAFLD patients.
		                        		
		                        		
		                        		
		                        	
3.Analysis of pharmaceutical clinic service in our hospital over the past five years
Li FAN ; Shuyan QUAN ; Xuan WANG ; Menglin LUO ; Fei YE ; Lang ZOU ; Feifei YU ; Min HU ; Xuelian HU ; Chenjing LUO ; Peng GU
China Pharmacy 2025;36(6):748-751
		                        		
		                        			
		                        			OBJECTIVE To summarize the current situation of pharmaceutical clinic service in our hospital over the past five years, and explore sustainable development strategies for service models of pharmaceutical clinics. METHODS A retrospective analysis was conducted on the consultation records of patients who registered and established files at the pharmaceutical clinic in our hospital from January 2019 to December 2023. Statistical analysis was performed on patients’ general information, medication- related problems, and types of pharmaceutical services provided by pharmacists. RESULTS A total of 963 consultation records were included, among which females aged 20-39 years accounted for the highest proportion (66.04%); obstetrics and gynecology- related consultations accounted for the largest number of cases. Additionally, 80 patients attended follow-up visits at our hospital’s pharmaceutical clinic. A total of 1 029 medication-related issues were resolved, including 538 cases of drug consultations (52.28%), 453 medication recommendations (44.02%), 22 medication restructuring(2.14%), and 16 medication education (1.55%); the most common types of medication-related problems identified were adverse drug events(70.07%). CONCLUSIONS Although the pharmaceutical clinic has achieved recognition from clinicians and patients, challenges such as low awareness among healthcare providers and the public persist. Future efforts should focus on strengthening information technology construction, enhancing pharmacist training, and establishing various forms of outpatient pharmaceutical service models.
		                        		
		                        		
		                        		
		                        	
4.Process Optimization and Health Risk Assessment of Calcined Haematitum Based on QbD Concept
Yue YANG ; Jingwei ZHOU ; Jialiang ZOU ; Guorong MEI ; Yifan SHI ; Lei ZHONG ; Jiaojiao WANG ; Xuelian GAN ; Dewen ZENG ; Xin CHEN ; Lin CHEN ; Hongping CHEN ; Shilin CHEN ; Yuan HU ; Youping LIU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(13):187-196
		                        		
		                        			
		                        			ObjectiveTo investigate the processing technology of calcined Haematitum based on the concept of quality by design(QbD) and to assess its health risk. MethodsTaking whole iron content, Fe2+ dissolution content and looseness as critical quality attributes(CQAs), and calcination temperature, calcination time, spreading thickness and particle size as critical process parameters(CPPs) determined by the failure mode and effect analysis(FMEA), the processing technology of calcined Haematitum was optimized by orthogonal test combined with analytic hierarchy process-criteria importance through intercriteria correlation(AHP-CRITIC) hybrid weighting method. The contents of heavy metals and harmful elements were determined by inductively coupled plasma mass spectrometry, and the health risk assessment was carried out by daily exposure(EXP), target hazard quotient(THQ) and lifetime cancer risk(LCR), and the theoretical value of the maximum limit was deduced. ResultsThe optimal processing technology for calcined Haematitum was calcination at 650 ℃, calcination time of 1 h, particle size of 0.2-0.5 cm, spreading thickness of 1 cm, and vinegar quenching for 1 time[Haematitum-vinegar(10:3)]. The contents of 5 heavy metals and harmful elements in 13 batches of calcined Haematitum were all decreased with reductions of up to 5-fold. The cumulative THQ of 2 batches of samples was>1, while the cumulative THQ of all batches of Haematitum was>1. The LCR of As in 1 batches of Haematitum was 1×10-6-1×10-4, and the LCR of the rest was<1×10-6, and the LCRs of calcined Haematitum were all<1×10-6, indicating that the carcinogenic risk of calcined Haematitum was low, but special attention should still be paid to Haematitum medicinal materials. Preliminary theoretical values of the maximum limits of Cu, As, Cd, Pb and Hg were formulated as 1 014, 25, 17, 27, 7 mg·kg-1. ConclusionThe optimized processing technology of calcined Haematitum is stable and feasible, and the contents of heavy metals and harmful elements are reduced after processing. Preliminary theoretical values of the maximum limits of Cu, As, Cd, Pb and Hg are formulated to provide a scientific basis for the formulation of standards for the limits of harmful elements in Haematitum. 
		                        		
		                        		
		                        		
		                        	
5.Process Optimization and Health Risk Assessment of Calcined Haematitum Based on QbD Concept
Yue YANG ; Jingwei ZHOU ; Jialiang ZOU ; Guorong MEI ; Yifan SHI ; Lei ZHONG ; Jiaojiao WANG ; Xuelian GAN ; Dewen ZENG ; Xin CHEN ; Lin CHEN ; Hongping CHEN ; Shilin CHEN ; Yuan HU ; Youping LIU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(13):187-196
		                        		
		                        			
		                        			ObjectiveTo investigate the processing technology of calcined Haematitum based on the concept of quality by design(QbD) and to assess its health risk. MethodsTaking whole iron content, Fe2+ dissolution content and looseness as critical quality attributes(CQAs), and calcination temperature, calcination time, spreading thickness and particle size as critical process parameters(CPPs) determined by the failure mode and effect analysis(FMEA), the processing technology of calcined Haematitum was optimized by orthogonal test combined with analytic hierarchy process-criteria importance through intercriteria correlation(AHP-CRITIC) hybrid weighting method. The contents of heavy metals and harmful elements were determined by inductively coupled plasma mass spectrometry, and the health risk assessment was carried out by daily exposure(EXP), target hazard quotient(THQ) and lifetime cancer risk(LCR), and the theoretical value of the maximum limit was deduced. ResultsThe optimal processing technology for calcined Haematitum was calcination at 650 ℃, calcination time of 1 h, particle size of 0.2-0.5 cm, spreading thickness of 1 cm, and vinegar quenching for 1 time[Haematitum-vinegar(10:3)]. The contents of 5 heavy metals and harmful elements in 13 batches of calcined Haematitum were all decreased with reductions of up to 5-fold. The cumulative THQ of 2 batches of samples was>1, while the cumulative THQ of all batches of Haematitum was>1. The LCR of As in 1 batches of Haematitum was 1×10-6-1×10-4, and the LCR of the rest was<1×10-6, and the LCRs of calcined Haematitum were all<1×10-6, indicating that the carcinogenic risk of calcined Haematitum was low, but special attention should still be paid to Haematitum medicinal materials. Preliminary theoretical values of the maximum limits of Cu, As, Cd, Pb and Hg were formulated as 1 014, 25, 17, 27, 7 mg·kg-1. ConclusionThe optimized processing technology of calcined Haematitum is stable and feasible, and the contents of heavy metals and harmful elements are reduced after processing. Preliminary theoretical values of the maximum limits of Cu, As, Cd, Pb and Hg are formulated to provide a scientific basis for the formulation of standards for the limits of harmful elements in Haematitum. 
		                        		
		                        		
		                        		
		                        	
6.Formulation and interpretation of the Guidelines for the Pharmacist-managed Clinics Service and Document Writing and Usage(Reference)
Lijuan YANG ; Quanzhi LI ; Kejing WANG ; Xiaofen YE ; Zining WANG ; Xuelian YAN ; Liang HUANG ; Juan LI ; Jiancun ZHEN
China Pharmacy 2025;36(11):1301-1305
		                        		
		                        			
		                        			The writing of pharmacist-managed clinics documents (hereinafter referred to as “outpatient medication record”) is a necessary part of pharmacist-managed clinics service. Outpatient medication record is an important carrier to reflect the quality of pharmacist-managed clinics service. The Chinese Hospital Association Pharmaceutical Specialized Committee was entrusted by the Pharmaceutical Administration Department of the National Health Commission to lead the formulation of the Guidelines for the Pharmacist-managed Clinics Service and Document Writing and Usage (Reference) (hereinafter referred to as Guidelines) according to the compilation method of group standards and the technical route of “documentation combing→framework establishment→draft writing→opinion collection→Guidelines formation”. The Guidelines standardizes the basic requirements of pharmacist-managed clinics record management and the basic content of record, and provides a general template and two specialized templates including pregnant and lactating pharmacist-managed clinics record template and cough and asthma pharmacist-managed clinics record template, which provides a reference for medical institutions to write pharmacist-managed clinics record. This paper introduces the formulation process of Guidelines and analyzes the key contents of Guidelines, which is helpful for the application practice of Guidelines and further improves the quality of pharmacist-managed clinics work.
		                        		
		                        		
		                        		
		                        	
7.SARS-CoV-2 antibody level one month after COVID-19 infection in healthcare workers in Pudong New Area of Shanghai
Shaohua GUO ; Xuelian FU ; Yaojun LYU ; Yifeng SHEN ; Xiao WANG ; Dan LIU ; Laibao YANG
Shanghai Journal of Preventive Medicine 2024;36(2):128-133
		                        		
		                        			
		                        			ObjectiveTo investigate the levels of serum antibodies against novel coronavirus (SARS-CoV-2) in healthcare workers after one month of natural infection, to explore the influencing factors and their correlations with the levels of antibodies, and to provide reference for strengthening the protection of healthcare workers and preventive intervention in Pudong New Area in Shanghai. MethodsVenous blood samples were collected from 1 102 medical staff in Pudong hospitals one month after infection. The serum levels of new coronavirus specific antibodies IgM, IgG and neutralizing antibodies were detected by chemiluminescent immunoassay. The information of gender, age, position, infection severity, vaccination, basic diseases and use of immunosuppressants were obtained by questionnaire to explore the influencing factors and their correlation with the antibody level. ResultsOne month after natural infection, 99.00% (1 091/1 102) of the subjects were found to be positive for IgG antibody against the new coronavirus, 17.79% (196/1 102) of the subjects were IgM antibody positive, and 99.00% (1 091/1 102) of the samples were positive for the neutralizing antibody. The level of antibody might be influenced by the severity of infection, the time of the last dose of vaccination, and the long-term use of immunosuppressants. The more severe the disease, the stronger the neutralizing antibody response. The antibody level in the people who received the final dose of vaccine within 6 months was higher than that of the people who received the vaccine 6 months ago, and the difference was statistically significant. The antibody levels were low in the subjects who received long-term immunosuppressants. ConclusionThe specific IgM, IgG and neutralizing antibody were found, one month after infection, in the medical workers in Pudong New Area, Shanghai, and the antibody titers were high, which had a good protective effect. The antibody level of the people who were vaccinated within 6 months was higher, it is recommended that people who receive the last vacination more than 6 months should be re-vaccinated with the booster vaccine, to improve the autoimmunity against the novel coronavirus. 
		                        		
		                        		
		                        		
		                        	
8.Evidence-based practice of non-invasive mechanical ventilation related pressure injury prevention guided by the integrated promoting action on research implementation in health services framework
Xia WANG ; Haiyan WANG ; Kui SONG ; Xuelian WANG ; Shengxiao NIE ; Hong GUO
Chinese Journal of Practical Nursing 2024;40(8):568-575
		                        		
		                        			
		                        			Objective:To use the best evidence of noninvasive mechanical ventilation related pressure injury prevention in the clinic guided by integrated promoting action on research implementation in health services framework (i-PARIHS) and evaluate its effect.Methods:This study is an unsynchronized before and after control study. Convenience sampling method was used to select patients receiving non-invasive mechanical ventilation from 7 wards of Beijing Hospital from October 2019 to September 2021. A total of 575 patients receiving non-invasive mechanical ventilation from October 2019 to September 2020 were included in the control group and 602 patients from October 2020 to September 2021 were included in the trial group. The control group adopted the usual care measures, and the trial group applied the prevention program for noninvasive ventilation related facial pressure injuries. The incidence of pressure injury was compared between the two groups. Nurses in 7 wards were investigated before and after the intervention program to compare the changes of knowledge level.Results:In the control group, there were 354 males, 221 females, aged (77.13 ± 14.49) years old; in the trial group there were 392 males, 210 females, aged (75.60 ± 14.27) years old. The incidence of pressure injury in the trial group was lower than the control group, but showed no significant difference ( P>0.05). In the control group, 11 cases suffered pressure injury, including 5 cases in stage 2, 6 cases in stage 3 and above. There were 9 cases in the trial group, including 8 in stage 2 and 1 in stage 3 and above. The severity of pressure injury in the trial group was lower than that in the control group, and the difference was significant ( χ2 = 3.83, 4.11, both P<0.05). The scores of the nurse′pressure injury knowledge increased from (6.77 ± 1.53) points to (7.15 ± 1.47) points, with a significant difference ( t = -2.31, P<0.05). Conclusions:Management of the prevention of noninvasive mechanical ventilation related facial pressure injury through evidence-based practice can reduce its incidence, reduce its severity, and it is beneficial to improve the clinical nurses' prevention knowledge and clinical practice level of facial pressure injury related to non-invasive mechanical ventilation.
		                        		
		                        		
		                        		
		                        	
9.Association between triglyceride-glucose index and arterial stiffness progression:A retrospective cohort study
Xiaoling ZHU ; Jia CHEN ; Xuelian LIU ; Yaqin WANG
Journal of Central South University(Medical Sciences) 2024;49(6):951-960
		                        		
		                        			
		                        			Objective:Insulin resistance(IR)is closely associated with atherosclerosis and adverse cardiovascular events.The triglyceride-glucose(TyG)index is an effective indicator for assessing IR.This study aims to explore the relationship between the TyG index and the risk of arterial stiffness progression. Methods:This retrospective cohort study included adults who had undergone at least 2 health examinations with arteriosclerosis testing at the Health Management Medical Center of the Third Xiangya Hospital,Central South University,between January 2012 and December 2022.Clinical data were collected.The TyG index was calculated using the formula of ln(triglyceridesxfasting blood glucose/2).The baseline TyG index was assessed as both a continuous variable and as a quartile-based categorical variable.The progression of arteriosclerosis was evaluated by the annual change rate of brachial-ankle pulse wave velocity(baPWV)and the new onset of increased arterial stiffness.Linear regression model and Cox proportional hazard model were used to explore whether the TyG index is an independent risk factor for arterial stiffness progression.Subgroup analyses were performed based on age,gender,body mass index(BMI),and the presence of type 2 diabetes,hypertension,or hyperlipidemia to determine the characteristics of the association between the TyG index and arterial stiffness progression. Results:A total of 4 971 participants were included,with a follow-up period of(3.01±1.98)years.During follow-up,the annual baPWV change rate was(24.94±81.15)cm/s,and 278 cases of new onset of increased aterial stiffness were recorded.After fully adjusting for confounding factors,the baseline TyG index was independently positively correlated with both the annual baPWV change rate(β=17.5,95%CI 9.00 to 25.94,P<0.001)and the risk of new onset of increased aterial stiffness[hazard ratio(HR)=1.43,95%CI 1.18 to 1.74,P<0.001]when the TyG index was treated as a continuous variable.When treated as a categorical variable,higher TyG index quartiles were associated with progressively higher baPWV change rates and new onset of increased arterial stiffness(all P<0.055).In subgroups of participants aged ≥45 years,males,BMI<28 kg/m2,those with or without hypertension,and those without type 2 diabetes or hyperlipidemia,the baseline TyG index(both continuous and categorical)was significantly associated with new onset of increased arterial stiffness(all P<0.05),with no significant interactions observed across subgroups(all P>0.05). Conclusion:The TyG index is independently associated with an increased risk of arterial stiffness progression and may serve as a useful indicator for assessing arterial stiffness progression risk in health check-up populations.
		                        		
		                        		
		                        		
		                        	
10.Expression of connexin 43 in hippocampus of post-stroke depression model rats and its effect on cell apoptosis
Jinmei CHEN ; Yu WANG ; Jie WANG ; Xuelian LUO ; Gongjun WANG ; Chengzheng BAO ; Xuebin LI
Chinese Journal of Behavioral Medicine and Brain Science 2024;33(6):487-493
		                        		
		                        			
		                        			Objective:To explore the expression of connexin 43 (Cx43) in hippocampus of post-stroke depression (PSD) model rats and its effect on cell apoptosis and depressive-like behavior.Methods:Sixty SPF-grade male SD rats aged 6-8 weeks were randomly divided into five groups (12 rats in each group): normal group, stroke group, depression group, PSD group and carbenoxolone(CBX) group. The stroke model was established by injection of endothelin-1.Chronic unpredictable mild stress (CUMS) combined with solitary rearing was used to establish a depression model. Rats in PSD group were given CUMS and raised alone on the seventh day of stroke modeling.Rats in CBX group were given intraperitoneal injection of CBX(20 mg/kg) on 14th day after PSD modeling. The depressive-like behavior of rats was evaluated by sugar water preference test and open field test. The expression of Cx43 mRNA in hippocampus of rats was detected by RT-PCR, the expression levels of Cx43, caspase-3, Bax and Bcl-2 were detected by Western blot, and the changes of apoptosis rate were detected by TUNEL staining. SPSS 23.0 software was used for statistical analysis, the behavioral data were analyzed by repeated measurement ANOVA, the remaining data were analyzed by one-way ANOVA, and the LSD- t test was used for further pairwise comparison. Results:(1)As for the preference rate of sugar water and the times of crossing the grid, the interaction effects between time and group were significant among the 5 groups( Finteraction=35.57, 111.43, both P<0.05). On the 28th day after operation, the preference rate of sugar water and the times of crossing grid in depression group and PSD group were lower than those in stroke group (all P<0.05), while the preference rate of sugar water and the times of crossing grid in CBX group were both lower than those in PSD group (both P<0.05). (2) The levels of Cx43 mRNA and Cx43 protein in the five groups were significantly different ( F=273.57, 64.56, both P<0.05). The levels of Cx43 mRNA and Cx43 protein in depression group ((0.59±0.05), (0.69±0.08)) and PSD group ((0.61±0.07), (0.63±0.12)) were lower than those in stroke group ((1.01±0.03), (1.05±0.08)) (all P<0.05). The levels of Cx43 mRNA and Cx43 protein in CBX group ((0.30±0.01), (0.37±0.09)) were lower than those in PSD group (both P<0.05). (3) The protein levels of caspase-3, Bax, Bcl-2 and Bcl-2/Bax and the apoptosis rate of the five groups were significantly different ( F=102.40, 90.27, 47.42, 159.99, 115.21, all P<0.05). The levels of caspase-3, Bax protein, apoptosis rate in stroke group ((0.44±0.06), (0.54±0.07), (29.16±5.03)) and depression group ((0.45±0.07), (0.59±0.09), (27.00±4.93)) were higher than those in normal group ((0.21±0.08), (0.33±0.07), (4.83±3.18)) (all P<0.05), the levels of Bcl-2 protein and Bcl-2/Bax in stroke group ((0.80±0.04), (1.51±0.20)) and depression group ((0.60±0.09), (1.03±0.09)) were lower than those in normal group ((1.04±0.13), (3.14±0.38)) (all P<0.05).The levels of caspase-3, Bax protein and apoptosis rate in PSD group ((0.76±0.05), (0.84±0.02), (44.50±3.83)) were all higher than those in stroke group and depression group (all P<0.05), and the levels of Bcl-2 protein and Bcl-2/Bax in PSD group ((0.50±0.14), (0.59±0.17)) were lower than those in stroke group and depression group (both P<0.05). The levels of caspase-3 and Bax protein and the apoptosis rate in CBX group ((1.03±0.10), (1.02±0.05), (56.00±4.81)) were higher than those in PSD group (all P<0.05).The levels of Bcl-2 protein and Bcl-2/Bax in CBX group((0.26±0.08), (0.25±0.08)) were lower than those in PSD group (both P<0.05). Conclusion:The expression level of Cx43 in the hippocampus of PSD model rats is downregulated, which can promote cell apoptosis and exacerbate depressive behavior.
		                        		
		                        		
		                        		
		                        	
            
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