1.Protective Effect of Xuebijing on Lung Injury in Rats with Severe Acute Pancreatitis by Blocking FPRs/NLRP3 Inflammatory Pathway
Guixian ZHANG ; Dawei LIU ; Xia LI ; Xijing LI ; Pengcheng SHI ; Zhiqiao FENG ; Jun CAI ; Wenhui ZONG ; Xiumei ZHAO ; Hongbin LIU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(1):113-120
		                        		
		                        			
		                        			ObjectiveTo explore the therapeutic effect of Xuebijing injection (XBJ) on severe acute pancreatitis induced acute lung injury (SAP-ALI) by regulating formyl peptide receptors (FPRs)/nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammatory pathway. MethodsSixty rats were randomly divided into a sham group, a SAP-ALI model group, low-, medium-, and high-dose XBJ groups (4, 8, and 12 mL·kg-1), and a positive drug (BOC2, 0.2 mg·kg-1) group. For the sham group, the pancreas of rats was only gently flipped after laparotomy, and then the abdomen was closed, while for the remaining five groups, SAP-ALI rat models were established by retrograde injection of 5% sodium taurocholate (Na-Tc) via the biliopancreatic duct. XBJ and BOC2 were administered via intraperitoneal injection once daily for 3 d prior to modeling and 0.5 h after modeling. Blood was collected from the abdominal aorta 6 h after the completion of modeling, and the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in plasma was measured by enzyme-linked immunosorbent assay (ELISA). The amount of ascites was measured, and the dry-wet weight ratios of pancreatic and lung tissue were determined. Pancreatic and lung tissue was taken for hematoxylin-eosin (HE) staining to observe pathological changes and then scored. The protein expression levels of FPR1, FPR2, and NLRP3 in lung tissue were detected by the immunohistochemical method. Western blot was used to detect the expression of FPR1, FPR2, and NLRP3 in lung tissue. Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) was used to detect the mRNA expression of FPR1, FPR2, and NLRP3 in lung tissue. ResultsCompared with the sham group, the SAP-ALI model group showed significantly decreased dry-wet weight ratio of lung tissue (P<0.01), serious pathological changes of lung tissue, a significantly increased pathological score (P<0.01), and significantly increased protein and mRNA expression levels of FPR1, FPR2, and NLRP3 in lung tissue (P<0.01). After BOC2 intervention, the above detection indicators were significantly reversed (P<0.01). After treatment with XBJ, the groups of different XBJ doses achieved results consistent with BOC2 intervention. ConclusionXBJ can effectively improve the inflammatory response of the lungs in SAP-ALI rats and reduce damage. The mechanism may be related to inhibiting the expression of FPRs and NLRP3 in lung tissue, which thereby reduces IL-1β and simultaneously antagonize the release of inflammatory factors IL-6 and TNF-α. 
		                        		
		                        		
		                        		
		                        	
2.Effect of different blood transfusion threshold on the prognosis of elderly patients with anemia in intensive care unit
Feihuan HU ; Heng YANG ; Pushan ZHANG ; Jun LI ; Hanshen YE
Chinese Journal of Blood Transfusion 2025;38(6):782-787
		                        		
		                        			
		                        			Objective: To evaluate the clinical effect of blood transfusion treatment in elderly critically ill patients under different blood transfusion initiation thresholds. Methods: A total of 144 elderly critically ill patients aged >70 years who underwent red blood cell transfusion in the elderly intensive care unit (ICU) of our hospital from January 2021 to January 2023 were included. According to different blood transfusion initiation thresholds, the patients were divided into restrictive blood transfusion group (n=77, Hb<70 g/L before blood transfusion) and liberal blood transfusion group (n=67, Hb 70-100 g/L before blood transfusion). Acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score, estimated mortality and general data collection were performed when the two groups of patients entered the ICU. Blood transfusion details of these patients in the ICU were collected and documented, including pre-transfusion Hb levels, volume and number of red blood cell transfusion, and post- transfusion Hb levels. Propensity score matching (PSM) was used to match the baseline data of the two groups of patients, and the clinical outcomes were compared and analyzed after matching. Results: After PSM matching, 52 pairs of patients were successfully matched. The matched restrictive and liberal transfusion groups showed comparable characterists, including age, APACHE Ⅱ score, the number of cases with APACHE Ⅱ score >20, estimated mortality, incidence of comorbidities and primary diseases (P>0.05). The number of red blood cell transfusions and transfusion volume (U) in the ICU of the two groups were 7.77±4.73 vs 12.19±10.41, 11.64±7.65 vs 19.14±16.14 (all P<0.05), and the Hb levels (g/L) before and after red blood cell transfusion in the ICU was 59.92±5.98 vs 77.44±8.60,77.88±17.21 vs 87.56±15.23 (all P<0.05). In terms of clinical outcomes, there was no significant difference between the two groups (all P>0.05): ICU length of stay (d) 39.56±36.80 vs 40.10±49.29, three-week mortality rate (%) 21.2 vs 21.2, in-hospital mortality rate (%) 46.2 vs 53.9, mortality rate in subgroup with APACHE Ⅱ score ≤ 20 (%) 11.5 vs 1.9, the incidence of severe infection (%) 78.8 vs 73.1, the incidence of heart failure (%) 57.7 vs 44.2, and the incidence of pulmonary edema (%) 26.9 vs 19.2. Conclusion: Elderly ICU patients can tolerate lower blood transfusion thresholds. Therefore, the restrictive transfusion strategy can reduce the total amount of blood transfusion, save valuable blood resources, and achieve the same blood transfusion effect as the liberal transfusion strategy.
		                        		
		                        		
		                        		
		                        	
3.Association between herbicide exposure and liver enzyme levels in a middle-aged and elderly population
Weiya LI ; Zhuoya ZHAO ; Xu CHENG ; Jun AN ; Shiyang ZHANG ; Chengyong JIA ; Meian HE
Journal of Environmental and Occupational Medicine 2025;42(6):699-705
		                        		
		                        			
		                        			Background The widespread use of herbicides has led to environmental contamination and has implications for human health. The liver is an important organ for the detoxification of environmental pollutants; however, studies on the association between herbicide exposure and liver function are limited. Objectives To investigate the association between baseline serum herbicide levels and changes in liver enzyme levels and liver enzyme abnormalities over a 5-year period in middle-aged and older adults. Methods This study was based on a nested case-control population of type 2 diabetes established in the Dongfeng-Tongji cohort, with a total of 
		                        		
		                        	
4.Distribution characteristics of bacterial communities in central air-conditioning ventilation systems of a Grade 3A hospital in Shanghai based on 16S rRNA sequencing
Jun NI ; Haiyun ZHANG ; Jian CHEN ; Lijun ZHANG ; Yongping LIU ; Xiaojing LI ; Yiming ZHENG ; Liping ZHANG
Journal of Environmental and Occupational Medicine 2025;42(6):732-739
		                        		
		                        			
		                        			Background A diverse cohort of patients and susceptible individuals congregate in healthcare facilities, where exposure to pathogenic microorganisms associated with respiratory infectious diseases constitutes a significant risk factor for cross-infection. Central air-conditioning ventilation systems improve some indoor environment indicators while exacerbating the risk of transmission of respiratory infectious diseases. Objective To investigate the distribution characteristics of microbial communities in the central air-conditioning ventilation systems of hospitals, providing a scientific basis for the selection of microbial indicators in hygiene standards for hospital central air-conditioning ventilation systems and for hospital risk early warning systems. Methods In October 2023, two central air-conditioning ventilation systems were selected from a Grade 3A hospital in Shanghai: one was an all-air air-conditioning system serving the waiting area on the ground floor, and the other was a fan coil plus fresh air system serving the outpatient area on the third floor. Samples from four different components of the ventilation systems—air outlets, filters, surface coolers, and condensate trays—were collected for high-throughput sequencing of the 16S rRNA gene to analyze bacterial communities. Alpha-diversity and beta-diversity analyses were performed to investigate the microbial community composition and diversity characteristics of the hospital central air-conditioning ventilation systems. Functional analysis was conducted to determine the relative abundance of bacterial functions in these systems.Results A total of 528 operational taxonomic units (OTUs) were identified, encompassing 20 bacterial phyla, 37 classes, 79 orders, 123 families, and 240 genera. The analysis revealed that the bacterial community was predominantly composed of Proteobacteria, Gemmatimonadates, Bacteroidetes, and Actinobacteria. The diversity analysis indicated that bacterial community richness and diversity were highest in the condensate trays, while no statistically significant differences (P > 0.05) were observed in the bacterial community composition among the air outlets, filters, and surface coolers. The functional analysis showed that the bacterial communities in the central air-conditioning ventilation systems primarily exhibited chemoheterotrophic, oxidative energy-dependent heterotrophic, and ureolytic functional characteristics. Conclusion The dominance of Proteobacteria suggests that this phylum exhibits strong adaptability in the central air-conditioning ventilation systems, possibly related to its ability to survive and reproduce under varying environmental conditions. The diversity analysis indicates that the condensate tray is a critical area for bacterial proliferation in the central air-conditioning ventilation systems. The similarity in environmental conditions among the air outlets, filters, and surface coolers result in similar bacterial community structures. The functional analysis reveals that the bacterial communities possess robust energy conversion and metabolic capabilities, potentially contributing to processes such as organic matter decomposition and nitrogen cycling within the central air-conditioning ventilation systems.
		                        		
		                        		
		                        		
		                        	
5.Investigation of Effect of Different Drying Conditions on Appearance Characteristics and Internal Indicators of Pinelliae Rhizoma Based on Standardization
Suqing LIU ; Xueli ZHANG ; Jing ZHANG ; Cong YANG ; Changfu YANG ; Jun YU ; Bingpeng ZHENG ; Huiwu LI ; Yanhua JIANG ; Chang LIN
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(16):208-215
		                        		
		                        			
		                        			ObjectiveTo explore the effect of different drying conditions on the appearance and intrinsic quality indicators of Pinelliae Rhizoma for screening suitable drying conditions, so as to provide reference for its standardized production and quality evaluation. MethodsDifferent dried samples of Pinelliae Rhizoma were prepared by lime-assisted sweating method and intermittent drying method. Visual analysis was employed to measure the color brightness values(L*) of the surface, cross-section and powder of the samples, texture analyzer was used to determine the hardness of the samples under different drying conditions. The total starch content was calculated by measuring the contents of amylose and amylopectin in the samples with ultraviolet-visible spectroscopy. High performance liquid chromatography(HPLC) was used to determine the contents of seven nucleoside components(uracil, hypoxanthine, uridine, inosine, guanosine, β-thymidine and adenosine) in the samples. Pearson correlation analysis was conducted to explore the correlation between the external characteristics and intrinsic indicators of the different dried samples. Principal component analysis(PCA) was used to comprehensively rank the data of various indicators, and partial least squares-discriminant analysis(PLS-DA) was used to screen differential components with variable importance in the projection(VIP) value>1. Furthermore, the difference between the optimal drying condition for Pinelliae Rhizoma and the traditional sun-drying method was explored by independent samples t-test. ResultsWith the increase of temperature, the color of the intermittently dried samples gradually deepened, while their hardness gradually decreased. Concurrently, the contents of extract, total starch, uridine and adenosine exhibited an upward trend, whereas the contents of uracil, hypoxanthine and inosine displayed a downward trajectory. Compared with the intermittent drying group, the content of extract in the samples subjected to lime-assisted sweating increased. With the increase of lime dose, the hardness and the total content of nucleoside components in the samples showed a downward trend, while the total starch content showed an upward trend. Correlation analysis showed that the comprehensive score of L* was negatively correlated with the contents of uracil, hypoxanthine and inosine, and positively correlated with the contents of uridine, guanosine and adenosine. Hardness was negatively correlated with adenosine content, and positively correlated with the contents of inosine, uracil and hypoxanthine. Through comprehensive consideration and comprehensive score of principal components, the method of 5% lime-mixed sweating for 6 days emerged as the top-ranking approach. Except for the extract, the results of independent samples t-test showed that there was no significant difference between the 5% lime-mixed sweating for 6 days and the traditional sun-drying in terms of other content indicators. ConclusionThe whiteness and firmness of Pinelliae Rhizoma exhibit significant correlations with its chemical composition, while uridine, uracil, guanosine, adenosine and inosine are the key constituents responsible for the quality difference of Pinelliae Rhizoma under different drying conditions. The lime-assisted sweating method optimized in this study can be proposed as a viable alternative to the traditional sun-drying method. This method not only ensures the quality of the medicinal material but also effectively reduces the drying time and prevents mold contamination, which provides a valuable reference for the standardization of drying conditions and the establishment of quality evaluation criteria for Pinelliae Rhizoma. 
		                        		
		                        		
		                        		
		                        	
6.Effects of Cldn14 gene knockout on the formation of calcium oxalate stones in rats and its mechanism
Peiyue LUO ; Liying ZHENG ; Tao CHEN ; Jun ZOU ; Wei LI ; Qi CHEN ; Le CHENG ; Lifeng GAN ; Fangtao ZHANG ; Biao QIAN
Journal of Modern Urology 2025;30(2):168-173
		                        		
		                        			
		                        			Objective: To explore the effects of Cldn14 gene knockout on renal metabolism and stone formation in rats,so as to provide reference for research in the field of urinary calium metabolism and stone formation. Methods: Cldn14 gene knockout homozygous rats and wild-type rats of the same age were randomly divided into 4 groups:wild-type control (WC) group,wild-type ethylene glycol (WE) group,gene knockout control (KC) group and gene knockout ethylene glycol (KE) group,with 10 rats in each group.The WE and KE groups were induced with ethylene glycol + ammonium chloride to form kidney stones,while the WC and KC groups received normal saline gavage.After 4 weeks of standard maintenance feeding,the urine samples were collected to detect the venous blood.The kidneys were collected for HE,Pizzolatto's staining and transmission electron microscopy.The protein in renal tissues was extracted to detect the expressions of Claudin16 and Claudin19. Results: Crystal deposition was observed in the renal tubular lumen of the WE and the KE groups,and more crystals were detected in the KE group.The WE group had a large number of intracytoplasmic black crystalline inclusions observed in renal tubular epithelial cells under transmission electron microscope,followed by the KE and KC groups.Compared with WC and WE groups,KC and KE groups had significantly decreased serum calcium and magnesium levels but significantly increased urinary calcium level.In addition,the urinary calcium level was higher in the WE group than in the WC group and higher in the KE group than in the KC group.The KE group had lower level of Claudin16,but there was no significant difference in the level of Claudin19 among the 4 groups(P>0.05). Conclusion: Knockout of Cldn14 gene alone cannot effectively reduce urinary calcium excretion or reduce the risk of stone formation in rats,which may be related to the decrease of Claudin16 level.
		                        		
		                        		
		                        		
		                        	
7.Association between medium to long term ambient PM 2.5 exposure and overweight/obesity among primary and secondary school students
Chinese Journal of School Health 2025;46(7):937-940
		                        		
		                        			Objective:
		                        			To investigate the association between medium  to long term PM 2.5  exposure around school areas and overweight/obesity among primary and secondary school students in Guangxi, providing data support and theoretical foundations for scientifically addressing overweight and obesity in primary and secondary school students.
		                        		
		                        			Methods:
		                        			From September to November 2023, a stratified cluster random sampling method was employed to select 251 183 students aged 7-18 years (grade 1 to grade 12) from 14 prefecture level cities (111 districts and counties) in Guangxi. PM 2.5  mass concentration data were obtained from the Tracking Air Pollution in China (TAP) dataset. Preliminary comparative analysis was conducted using the Mann-Whitney  U  test, while binary Logistic regression models were applied to quantify the relationship between PM 2.5  exposure and overweight/obesity. Restricted cubic spline analysis was further utilized to examine the nonlinear association between PM 2.5  concentration and overweight/obesity risk.
		                        		
		                        			Results:
		                        			The detection rate of overweight/obesity among Guangxi students in 2023 was 19.5%. The median PM 2.5  concentration in the year prior to the study was higher in the overweight/obesity group (23.22 μg/m 3) compared to the non overweight/obesity group (22.63 μg/m 3) ( Z=-15.66, P <0.01), and consistent trends were observed across gender (male/female) and educational stage (primary/junior/senior high school) subgroups (all  P <0.01). Binary Logistic regression revealed that for every 10 μg/m 3 increase in the annual average PM 2.5  concentration, the risk of overweight/obesity increased by 12% ( OR=1.12, 95%CI=1.09- 1.15 , P <0.01). Restricted cubic spline analysis indicated a nonlinear relationship between monthly PM 2.5  levels and overweight/obesity risk ( P trend <0.01). Below 22.68 μg/m 3, PM 2.5  exposure showed no significant association with obesity risk; above the threshold, the risk increased with rising PM 2.5  levels.
		                        		
		                        			Conclusion
		                        			Medium  to long term PM 2.5  exposure around school environments is significantly associated with overweight/obesity among primary and secondary school students.
		                        		
		                        		
		                        		
		                        	
8.Correlation Between Cardiovascular Events and Traditional Chinese Medicine Syndrome in Patients with Rheumatoid Arthritis:A Cross-Sectional Study
Fuyuan ZHANG ; Quan JIANG ; Jun LI ; Yuchen YANG ; Xieli MA ; Tian CHANG ; Congmin XIA ; Jian WANG ; Xun GONG
Journal of Traditional Chinese Medicine 2025;66(15):1572-1578
		                        		
		                        			
		                        			ObjectiveTo explore the correlation between the occurrence of cardiovascular events in rheumatoid arthritis(RA) and traditional Chinese medicine(TCM) syndrome. MethodsThe cross-sectional study selected 6713 RA patients from 122 centres nationwide, in which general information such as name, gender, age, height, body weight, and course of disease were collected by completing a questionnaire; patients were classified into eight types of syndrome according to the information of their four examinations,i.e. wind-dampness obstruction syndrome, cold-dampness obstruction syndrome, dampness-heat obstruction syndrome, phlegm-stasis obstruction syndrome, stasis-blood obstructing collateral syndrome, qi-blood deficiency syndrome, liver-kidney insufficiency syndrome, and qi-yin deficiency syndrome. According to the occurrence of cardiovascular events, they were divided into the occurrence group and the non-occurrence group, and the condition assessment data and laboratory examination indexes were recorded. The test of difference between groups was used to analyse the possible risk factors for the occurrence of RA cardiovascular events, and binary logistic regression was used to analyse the correlation between TCM syndromes and RA cardiovascular events. ResultsA total of 6713 RA patients were included, including 256 cases in occurrence group and 6457 in non-occurrence group. There was no statistically significant difference between groups in terms of height, gender, insomnia, appetite, white blood cell(WBC), hemoglobin(HGB), platelets(PLT), rheumatoid factor(RF), anti-cyclic peptide containing citrulline(CCP), alanine aminotransferase(ALT), aspartate aminotransferase(AST), γ-glutamyl transpeptidase(GGT), urea creatinine(CREA), and glucose(GLU)(P>0.05). The TCM syndromes between groups showed significant statistic differences(P<0.05). Patients in occurrence group had longer disease duration, heavier body weight, and older age; more severe conditions such as disease activity(DAS-28), number of painful joints(TJC), number of swollen joints(SJC), health questionnaire scores(HAQ), visual analog scores(VAS), restlessness, and fatigue; higher blood sedimentation rate(ESR), low-density lipoprotein(LDL-C), triglyceride(TG), total cholesterol(TC), D-Dimer, and lower high-density lipoprotein(HDL-C)(P<0.05). The distribution of syndrome types showed that dampness-heat obstruction syndrome accounted for the largest proportion of patients in both groups and was higher in RA cardiovascular events. Logistic regression analysis showed that the occurrence of RA cardiovascular events was strongly associated with dampness-heat obstruction syndrome[OR=5.937, 95%CI (4.434, 7.949), P<0.001]. ConclusionThe occurrence of RA cardiovascular events were associated with TCM syndromes, and the probability of cardiovascular events in the RA patients with dampness-heat obstruction syndrome was 5.937 times higher than patients with other TCM syndromes. 
		                        		
		                        		
		                        		
		                        	
9.Quality evaluation of Sanzi powder based on quantitative analysis of multi-component combined with chemical pattern recognition and entropy weight-TOPSIS method
Rongjie LI ; Qian ZHANG ; Wei ZHANG ; Xinkui LI ; Yuxia HU ; Mengdi ZHANG ; Jing LIU ; Fang WANG ; Fengye ZHOU ; Jun LI
China Pharmacy 2025;36(15):1846-1851
		                        		
		                        			
		                        			OBJECTIVE To comprehensively evaluate the quality of Sanzi powder from different batches based on 12 components quantitative analysis combined with chemical pattern recognition and entropy weight-TOPSIS method. METHODS The contents of 12 components in 15 batches of Sanzi powder (No. S1-S15) were determined by HPLC-MS/MS, such as ethyl gallate, gallic acid, ferulic acid, corilagin, genipin-1-O-β-D-gentiobioside, toosendanin, geniposide, caffeic acid, methyl deacetylated coumarinate, tannic acid, rutin, quercetin. Cluster analysis (CA), principal component analysis (PCA), and orthogonal partial least squares-discriminant analysis (OPLS-DA) were conducted on the assay results. Using variable importance projection (VIP) value>1 and P<0.05 as the evaluation criteria, the quality differential markers in Sanzi powder were screened. The entropy weight method was used to calculate the weight value, and TOPSIS method was used to rank the quality of 15 batches of Sanzi powder from superior to inferior. RESULTS The contents of the 12 components were 13.494-24.292, 2 069.608-3 188.100, 1.410-3.616, 1 065.030-2 630.584, 1 404.704-1 838.078, 101.640-354.268, 9 193.720-14 777.854, 1.240-5.060, 148.028-5 541.990, 4 261.422-5 607.438, 107.560- 195.512, 2.226-4.192 μg/g, respectively. The results of CA, PCA and OPLS-DA indicated that 15 batches of Sanzi powder could be clustered into two groups. Specifically, batches S3, S7, S10 and S15 were grouped into one category, and remaining batches were grouped into one category. VIP values of geniposide, quercetin, caffeic acid, and methyl deacetylated coumarinate were all greater than 1, with corresponding P-values less than 0.05. The results of the entropy weight-TOPSIS analysis revealed that methyl deacetylate exhibited the smallest information entropy and the highest weight. The relative closeness degrees of samples S3, S7, S10 and S15 ranged from 0.789 to 0.973, while the remaining samples ranged from 0.054 to 0.172. CONCLUSIONS The contents of 12 components in Sanzi powder could be determined accurately by using HPLC-MS/MS technology. Methyl deacetylated coumarinate, geniposide, quercetin and caffeic acid were identified as the quality differential markers. It was found that the overall quality of samples S3, S7, S10 and S15 were superior to that of other batches. Notably, the quality of Gardeniae Fructus decoction pieces emerges as a critical factor in ensuring the consistency of the preparation’s quality.
		                        		
		                        		
		                        		
		                        	
10.Clinical Practice of Coronary Microvascular Disease with the Integrated Approach of Traditional Chinese and Western Medicine
Aolin LI ; Xinnong CHEN ; Lerong YU ; Jun GE ; Wei ZHOU ; Kangzheng GUO ; Junping ZHANG
Journal of Traditional Chinese Medicine 2025;66(16):1662-1667
		                        		
		                        			
		                        			This paper analyzed the traditional Chinese medicine (TCM) and western medical understanding of coronary microvascular disease (CMVD) from the three dimensions of "disease-syndrome-symptom". In western medicine, by summarizing the suspected diagnosis and understanding of CMVD, it is believed that inflammatory responses and vascular endothelial damage are the key mechanisms of the pathogenesis. From the perspective of TCM, the disease location is at blood, vessels and heart, and the fundamental cause is spleen and kidney depletion, closely realted to phlegm, stasis, toxin, wind and qi. Integrating the understanding of both TCM and western medicine, clinical treatment advocates taking the CMVD pathology as the base, and the TCM understanding of pathogenesis as the main focus. The properties of Chinese herbal medicinals is used as the guidance for medication, and the pharmacological understanding as the assisstance of treatment, with the medical history and the severity of the condition are additionally considered. It is finally proposed that during the acute phase, the methods of nourishing yin and resolving toxins, softening hardness and dissipating masses, dispelling wind and unblocking collaterals should be applied to alleviate the emergency. In the subacute phase, the focus should be on raising and lifting qi promote its movement, with flexible use of medicinals that can unblock yang. In the remission phase, the method of tonifying spleen and fortifying kidney should be used to maintain the stability of the condition. 
		                        		
		                        		
		                        		
		                        	
            

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