1.Effect of outdoor activities and short-distance use of eyes on myopia among primary and secondary school students in Yunnan minority areas
LI Peiqian, HUANG Dafeng, ZHANG Jinjiao, MA Zixue, LI Xixi, LUO Xiao, XIAO Jie, HUANG Ying
Chinese Journal of School Health 2025;46(1):34-38
		                        		
		                        			Objective:
		                        			To understand the prevalence of myopia among primary and secondary school students in minority areas of Yunnan Province, and to explore the influence of outdoor activities and short-distance use of eyes, so as to provide a basis for early myopia intervention.
		                        		
		                        			Methods:
		                        			In October 2020, the survey was conducted among 1 782 primary and secondary school students in three cities of Yunnan through a multi stage random cluster sampling method. All subjects underwent a questionnaire survey and the visual acuity examination at baseline. The first follow-up was conducted in October 2021 to obtain 1 691 valid samples, and the second follow-up was conducted in May 2023 to obtain 1 367 valid samples. Factors associated with myopia among primary and secondary school students were explored by using generalized estimating equations.
		                        		
		                        			Results:
		                        			The prevalence rates of myopia in 2020, 2021 and 2023 were 52.64%, 61.62% and 69.35%, respectively, showing an increasing trend ( χ 2 trend =91.77,  P <0.05). The results of multivariate regression analysis on the generalized estimation equations showed that age at baseline ( OR =1.31), girls ( OR =1.76), Hani ethnicity ( OR =0.75), Bai ethnicity ( OR =0.69), parental myopia ( OR =1.97-2.29), parents often reducing children s exercise time for homework or tutoring ( OR =1.35), less than 1 time or 2-3 times of ball sports per week ( OR =1.27,  1.20 ), reading and writing in the classroom during the break ( OR =1.27), reading in direct sunlight occasionally ( OR =1.20), using only desk lamp for writing at home ( OR =0.71), more than 1 hours of short-distance eye use for a break once ( OR =1.23) were associated with myopia among primary and secondary school students ( P <0.05).
		                        		
		                        			Conclusions
		                        			Outdoor activities and short-distance use of eye among primary and middle school students in minority areas in Yunnan province are suboptimal. Enhancing the related environmental and behavioral factors can effectively mitigate the occurrence and progression of myopia.
		                        		
		                        		
		                        		
		                        	
2.Practice of PIVAS operation cost-benefit management in a hospital based on lean Six Sigma management
Lei HUANG ; Hui ZHANG ; Zhou GENG ; Aiming SHI ; Jie PAN
China Pharmacy 2025;36(1):13-18
		                        		
		                        			
		                        			OBJECTIVE To explore the practice and application effect of lean Six Sigma (LSS) management in the cost- benefit management of PIVAS operation in a tertiary comprehensive hospital (hereinafter referred to as “S Hospital”), providing reference for the operation and management of PIVAS in hospitals. METHODS The five steps (define, measure, analyze, improve and control, i.e. DMAIC) of LSS management were implemented for PIVAS operation cost-benefit of S Hospital, and lean management was implemented for its cost-benefit management elements (human resource cost, medical and health material cost, and all-in-one parenteral nutrition preparation income). Several intervention measures including personnel training and performance assessment, refined management system of consumables, and doctor’s advice package of full parenteral nutrition were developed. Finally, the overall improvement effect was evaluated by the total benefit, total cost and net benefit of PIVAS. The effects of human resource allocation optimization and improvement were evaluated by the work efficiency, work quality, job satisfaction, turnover rate and accumulated rest days. The effects of consumables cost management were evaluated by the amount of medical and health materials cost. The improvement effects of all-in-one parenteral nutrition preparation income were evaluated by the profit amount, quantity and the proportion of single bottle of parenteral nutrition. RESULTS After implementing DMAIC in S Hospital, the total benefit of PIVAS was increased from (471 366.50±9 201.5) yuan/month to (479 679.50±14 320.14) yuan/month (P> 0.05), the total cost was decreased from (305 878.88±3 201.75) yuan/month to (294 610.59±5 007.33) yuan/month (P<0.05), and the net benefit of PIVAS was increased by 11.83% compared with that before the improvement. The work efficiency, work quality and job satisfaction of employees were significantly improved, the accumulated rest days were significantly reduced, and the turnover rate of third-party employees was reduced from 15.0% before the improvement to 7.5% after the improvement. The cost of medical and health materials significantly decreased from (67 826.42±2 812.76) yuan/month before improvement to (56 384.33±4 607.67) yuan/month after improvement (P<0.05). The quantity of all-in-one parenteral nutrition was significantly increased from (1 263.75±135.83) group/month before improvement to (2 061.25±89.04) group/month after improvement (P<0.05), and the proportion of users of single bottle of parenteral nutrition in total users decreased from 93.25% before improvement to 58.75% after improvement. The profit of all-in-one parenteral nutrition was 63.18% higher than that before implementing DMAIC. CONCLUSIONS The implementation of PIVAS operation cost-benefit management based on DMAIC is conducive to strengthening the cost control of PIVAS and promoting the healthy development of PIVAS.
		                        		
		                        		
		                        		
		                        	
3.Cost-utility analysis of ciclesonide and budesonide in the treatment of mild to moderate bronchial asthma
Jie ZOU ; Jieying HUANG ; Lina WANG ; Wenwen DU ; Wei XU
China Pharmacy 2025;36(2):203-207
		                        		
		                        			
		                        			OBJECTIVE To evaluate the cost-utility of ciclesonide (CIC) versus budesonide (BUD) for the maintenance treatment of mild to moderate bronchial asthma. METHODS From the perspective of Chinese health service system, a Markov model was established based on the data from a clinical trial in China and some literature. The cycle length was 1 week, the time horizon was 60 years. A discount rate of 5% per year was applied. Cost-utility analysis was performed on therapeutic scheme of CIC and BUD using three times of China’s per capita gross domestic product (GDP) in 2023 as the threshold of willing-to-pay (WTP). One-way sensitivity analysis, probabilistic sensitivity analysis and scenario analysis were applied to test the uncertainty of basic analysis. RESULTS Compared with BUD scheme, the incremental cost of the CIC scheme was 9 401.67 yuan, and the incremental quality-adjusted life years(QALYs) were 0.001 3; incremental cost-effectiveness ratio (ICER) was 6 928 868.26 yuan/QALY, far beyond the threshold of WTP 268 074 yuan/QALY. One-way sensitivity analysis showed that the usage, dosage and unit price of CIC and BUD were parameters that had a significant impact on ICER; probabilistic sensitivity analysis showed that the basic analysis results were relatively robust; scenario analysis showed that, when the price of CIC reduced to 159.95 yuan/branch, the probability of CIC scheme having economics was similar to that of BUD scheme. CONCLUSIONS At the current price, CIC is not economical compared with BUD for the maintenance treatment of mild to moderate asthma, using three times of China’s GDP in 2023 as the threshold of WTP.
		                        		
		                        		
		                        		
		                        	
4.Cost-utility analysis of ciclesonide and budesonide in the treatment of mild to moderate bronchial asthma
Jie ZOU ; Jieying HUANG ; Lina WANG ; Wenwen DU ; Wei XU
China Pharmacy 2025;36(2):203-207
		                        		
		                        			
		                        			OBJECTIVE To evaluate the cost-utility of ciclesonide (CIC) versus budesonide (BUD) for the maintenance treatment of mild to moderate bronchial asthma. METHODS From the perspective of Chinese health service system, a Markov model was established based on the data from a clinical trial in China and some literature. The cycle length was 1 week, the time horizon was 60 years. A discount rate of 5% per year was applied. Cost-utility analysis was performed on therapeutic scheme of CIC and BUD using three times of China’s per capita gross domestic product (GDP) in 2023 as the threshold of willing-to-pay (WTP). One-way sensitivity analysis, probabilistic sensitivity analysis and scenario analysis were applied to test the uncertainty of basic analysis. RESULTS Compared with BUD scheme, the incremental cost of the CIC scheme was 9 401.67 yuan, and the incremental quality-adjusted life years(QALYs) were 0.001 3; incremental cost-effectiveness ratio (ICER) was 6 928 868.26 yuan/QALY, far beyond the threshold of WTP 268 074 yuan/QALY. One-way sensitivity analysis showed that the usage, dosage and unit price of CIC and BUD were parameters that had a significant impact on ICER; probabilistic sensitivity analysis showed that the basic analysis results were relatively robust; scenario analysis showed that, when the price of CIC reduced to 159.95 yuan/branch, the probability of CIC scheme having economics was similar to that of BUD scheme. CONCLUSIONS At the current price, CIC is not economical compared with BUD for the maintenance treatment of mild to moderate asthma, using three times of China’s GDP in 2023 as the threshold of WTP.
		                        		
		                        		
		                        		
		                        	
5.Constructing rabbit intervertebral disc degeneration models by different methods under X-ray guidance:a comparative study
Zhili DING ; Jie HUANG ; Qiang JIANG ; Tusheng LI ; Jiang LIU ; Yu DING
Chinese Journal of Tissue Engineering Research 2025;29(5):995-1002
		                        		
		                        			
		                        			BACKGROUND:Scholars at home and abroad consider New Zealand rabbits to be an ideal model animal because of the similar anatomical morphology of the lumbar spine to that of the human lumbar spine.There is a lack of systematic comparison of different ways to establish rabbit intervertebral disc degeneration models under X-ray guidance. OBJECTIVE:To establish a rabbit model of lumbar disc degeneration using X-ray guided acupuncture,end-plate injection and combined method,and to compare the modeling effects of these three methods. METHODS:Eighteen 6-month-old New Zealand white rabbits were randomly selected and divided into four groups:acupuncture group,endplate injection group,combined group and blank control group.In the acupuncture group,three consecutive segments of the intervertebral discs(L2/3,L3/4,L4/5)were needled and modeled;in the endplate injection group,50 μL of anhydrous ethanol was injected at a single point on the endplates of the three consecutive segmental discs;in the combined group,three consecutive segmental intervertebral discs were needled and injected with 50 μL of anhydrous ethanol at four azimuthal points on the endplates of the corresponding segmental discs;and the blank control group received no interventions.X-ray examination was performed to measure the disc height index at 2,4,and 8 weeks after surgery.The intervertebral disc tissues were then taken for anatomical observation and pathological examination. RESULTS AND CONCLUSION:(1)Anatomical examination showed that fibrous annulus rupture,nucleus pulposus degeneration,and total disc structure disorder were the main manifestation in the acupuncture group,endplate injection group,and combined group,respectively.(2)X-ray examination showed that the disc height index showed the most obvious reduction in the acupuncture group at 2 weeks after operation,significant reductions in the endplate injection group at 2 and 4 weeks after operation,and significant reductions in the combined group at 2,4,and 8 weeks after operation.(3)Pathological examination showed that the fibrous ring structure was damaged and the inner annulus fibrosus protruded inward in the acupuncture group;endplate fissure,disordered arrangement and nucleus loss were observed in the endplate injection group;total disc structure disorder with the nucleus pulposus losing water and shrinking and no obvious border with the broken annulus fibrosus was found in the combined group.To conclude,acupuncture,endplate injection and the modified endplate injection method can establish the rabbit intervertebral disc degeneration model.Compared with the single method,the modified endplate injection method can greatly accelerate and aggravate the degeneration of the intervertebral disc,and can effectively shorten the experiment period.
		                        		
		                        		
		                        		
		                        	
6.Eucommia ulmoides promotes alveolar bone formation in ovariectomized rats
Lin ZHENG ; Wenjun JIN ; Shanshan LUO ; Rui HUANG ; Jie WANG ; Yuting CHENG ; Zheqing AN ; Yue XIONG ; Zipeng GONG ; Jian LIAO
Chinese Journal of Tissue Engineering Research 2025;29(6):1159-1167
		                        		
		                        			
		                        			BACKGROUND:Eucommia ulmoides has a certain osteogenic effect,which can promote the proliferation and differentiation of osteoblasts.However,it is unclear whether Eucommia ulmoides has effects on alveolar bone formation and Wnt/β-Catenin signaling pathway. OBJECTIVE:To investigate the mechanism by which Eucommia ulmoides promotes alveolar bone formation in ovariectomized rats based on the Wnt/β-Catenin signaling pathway. METHODS:Sixty female Sprague-Dawley rats were selected and randomly divided into five groups:blank control group,sham-operation group,model group,low-dose group Eucommia ulmoides group,and high-dose Eucommia ulmoides group,with twelve rats in each group.Osteoporosis animal models were constructed by bilateral oophorectomy in the model group and the low-dose and high-dose Eucommia ulmoides groups.The sham-operation group underwent the same method to remove adipose tissue of equal mass around the bilateral ovaries.Three months after surgery,the low-and high-dose Eucommia ulmoides groups were given 2.1 g/kg/d and 4.2 g/kg/d Eucommia ulmoides by gavage,respectively.The sham-operation group and model group were given the same amount of physiological saline by gavage.After 12 weeks of drug intervention,the changes in alveolar bone mass of rats in each group were observed through Micro-CT;hematoxylin-eosin staining was used to observe the pathological structural changes of alveolar bone in rats;enzyme linked immunosorbent assay was used to detect the expression levels of alkaline phosphatase and osteocalcin in the serum of rats;western blot was used to detect the expression levels of β-Catenin and Frizzled9 receptor proteins in the alveolar bone of rats;and real-time fluorescence quantitative PCR was used to detect the expression of osteocalcin,Runt-related transcription factor 2(Runx2),alkaline phosphatase,β-catenin,and frizzled9 mRNAs in alveolar bone tissues of rats. RESULTS AND CONCLUSION:Compared with the blank control group,bone volume fraction,trabecular number,trabecular thickness,and bone mineral density were reduced in the model group(P<0.05),and trabecular separation was elevated(P<0.05).Pathological observation showed that the arrangement of trabeculae was disordered and irregular,the trabeculae were thinned or broken,and the marrow cavity was enlarged in the model group,with a significant reduction in bone volume;the level of alkaline phosphatase in the serum was increased(P<0.05),and the level of osteocalcin was decreased(P<0.05);mRNA expression of alkaline phosphatase,osteocalcin,Runx2,β-catenin,and frizzled9 were decreased(P<0.05);protein expression of β-Catenin and Frizzled9 was decreased(P<0.05).Compared with the model group,the low-and high-dose Eucommia ulmoides groups showed an increase in bone volume fraction,trabecular number,trabecular thickness,and bone mineral density(P<0.05)and a decrease in trabecular separation(P<0.05).In the low-and high-dose Eucommia ulmoides groups,bone trabeculae were slightly aligned and thickened,with a significant increase in bone mass.Compared with the model group,the serum level of alkaline phosphatase was reduced(P<0.05)and the serum level of osteocalcin was elevated(P<0.05)in the low-and high-dose Eucommia ulmoides groups.Compared with the model group,the mRNA expression of alkaline phosphatase,osteocalcin,Runx2,β-catenin,and frizzled9 were increased in the low-and high-dose Eucommia ulmoides groups(P<0.05).Compared with the model group,the protein expression of Frizzled9 was increased in the low-dose Eucommia ulmoides group(P<0.05),while the protein expression of β-Catenin and Frizzled9 was increased in the high-dose Eucommia ulmoides group(P<0.05).Compared with the low-dose Eucommia ulmoides group,the high-dose Eucommia ulmoides group had a more significant improvement in the above indexes.To conclude,Eucommia ulmoides can effectively promote the alveolar bone formation,and its mechanism of action might be related to the activation of the Wnt/β-catenin signaling pathway.
		                        		
		                        		
		                        		
		                        	
7.Target of neohesperidin in treatment of osteoporosis and its effect on osteogenic differentiation of bone marrow mesenchymal stem cells
Zhenyu ZHANG ; Qiujian LIANG ; Jun YANG ; Xiangyu WEI ; Jie JIANG ; Linke HUANG ; Zhen TAN
Chinese Journal of Tissue Engineering Research 2025;29(7):1437-1447
		                        		
		                        			
		                        			BACKGROUND:Previous studies have found that neohesperidin can delay bone loss in ovariectomized mice and has the potential to treat osteoporosis,but its specific mechanism of action remains to be explored. OBJECTIVE:To explore the key targets and possible mechanisms of neohesperidin in the treatment of osteoporosis based on bioinformatics and cell experiments in vitro. METHODS:The gene expression dataset related to osteoporosis was obtained from GEO database,and the differentially expressed genes were screened and analyzed in R language.The osteoporosis-related targets were screened from GeneCards and DisGeNET databases,and the neohesperidin-related targets were screened from ChEMBL and PubChem databases,and the common targets were obtained by intersection of the three.The String database was used to construct the PPI network of intersection genes,and the key targets were screened.The DAVID database was used for GO and KEGG enrichment analysis.The AutoDock software was used to verify the molecular docking between the neohesperidin and the target protein.The effect of neohesperidin on osteogenic differentiation of C57 mouse bone marrow mesenchymal stem cells was detected.Complete medium was used as blank control group;osteogenic induction medium was used as the control group;and osteogenic induction medium containing different concentrations of neohesperidin(25,50 μmol/L)was used as experimental group.The expression of alkaline phosphatase,the degree of mineralization,the expression of osteogenic-related genes and target genes during osteogenic differentiation of cells were measured at corresponding time points. RESULTS AND CONCLUSION:(1)9 253 differentially expressed genes,2 161 osteoporosis-related targets,and 326 neohesperidin-related targets were screened.There were 53 common targets among the three.All 53 genes were up-regulated in osteoporosis samples.The PPI network screened the target gene PRKACA of research significance.GO function and KEGG pathway enrichment analysis showed that neohesperidin's treatment of osteoporosis through PRKACA target mainly depended on biological processes such as protein phosphorylation and protein autophosphorylation,acting on endocrine resistance,proteoglycan in cancer,and estrogen signaling pathway to play a therapeutic role.Molecular docking results showed that neohesperidin had a certain binding ability to the protein corresponding to the target PRKACA.(2)The results of alkaline phosphatase staining showed that neohesperidin could promote the expression of alkaline phosphatase in the early stage of osteogenic differentiation of mesenchymal stem cells.Alizarin red staining showed that neohesperidin could promote the mineralization of osteogenic differentiation of mesenchymal stem cells.RT-qPCR results showed that neohesperidin could increase the mRNA expression of alkaline phosphatase,PRKACA,and osteocalcin.(3)These results indicate that neohesperidin may promote osteogenic differentiation through PRKACA target on the estrogen signaling pathway to prevent and treat osteoporosis.
		                        		
		                        		
		                        		
		                        	
8.Research progress on the anti-tumor effects of traditional Chinese medicine through intervention in the Nrf2/GPX4 signaling pathway
Jie HUANG ; Si LIN ; Chunjuan JIANG ; Ling WEI
China Pharmacy 2025;36(4):507-512
		                        		
		                        			
		                        			Nuclear factor-erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway plays a key role in the occurrence and development of tumors, and is involved in tumor cell proliferation, apoptosis, ferroptosis, invasion, migration, and drug resistance. Based on the Nrf2/GPX4 signaling pathway, this paper summarizes the research progress of the anti- tumor effects of traditional Chinese medicine. It is found that flavonoids (ginkgetin, luteolin, etc.), terpenoids (atractylenolide, cucurbitacin B, etc.), saponins (polyphyllin Ⅰ, polyphyllin Ⅶ), ester (brusatol) and other effective components, and traditional Chinese medicine extracts (total coumarins in Pileostegia tomentella and total flavonoids of Pterocarya hupehensis Skan), traditional Chinese medicine compounds (Fushao diqin fang, Xiaoai jiedu fang, etc.) can promote ferroptosis in tumor cells by inhibiting Nrf2/GPX4 signaling pathway and the expressions of its upstream and downstream factor proteins, as well as by increasing Fe2+ levels and lipid peroxidation, thereby exerting an antitumor effect.
		                        		
		                        		
		                        		
		                        	
9.Analysis of changes and influencing factors of activation rate of peripheral blood monocytes after liver transplantation
Yu GONG ; Hui WU ; Jie ZHU ; Ting WANG ; Xiaowu HUANG
Chinese Journal of Clinical Medicine 2025;32(1):101-107
		                        		
		                        			
		                        			Objective To analyze the effect of the activation rate of peripheral blood monocytes on the recovery of patients after liver transplantation and to initially explore the possible influencing factors for differences in monocyte activation rates. Methods A total of 139 patients who underwent orthotopic liver transplantation from September 2020 to June 2023 at Department of Liver Surgery and Transplantation of Zhongshan Hospital, Fudan University were selected. The proportion of CD14+HLA-DR+ monocytes in peripheral blood was defined as the monocyte activation rate. The difference in monocyte activation rates between postoperative day 7 (POD7) and postoperative day 1 (POD1) was calculated as Δ, and patients were divided into Δ>0 group (n=73) and Δ<0 group (n=66). The two groups were compared in terms of complete blood count, liver and kidney function, coagulation indicators, infection indicators, ICU length of stay, total length of hospitalization, and 90-day mortality. Changes in the proportions of different monocytes subsets (Mo0, Mo1, Mo2, and Mo3) and HLA-DR expression in peripheral blood on POD1 and POD7 were detected using flow cytometry. Results The ICU length of stay in the Δ<0 group was significantly longer than that in the Δ>0 group (18[12, 26] days vs 14[10, 20.5] days, P=0.018). On POD1, the proportion of Mo0 in the Δ>0 group was significantly lower than that in the Δ<0 group (P<0.05); on POD7, the proportion of Mo0 in the Δ>0 group was significantly lower than that in the Δ<0 group (P<0.001), while the proportions of Mo1, Mo2, and Mo3 were significantly higher than those in the Δ<0 group (P<0.001). Compared to POD1, the HLA-DR expression level of Mo0 in peripheral blood of patients with liver transplantation significantly decreased on POD7 (P<0.01), while there was no significant difference in HLA-DR expression levels of Mo1, Mo2, and Mo3. Conclusions Increased proportion of Mo0 (CD14lowCD16−HLA-DRlow) among peripheral blood monocyte subsets may be one of the influencing factors for the differences in monocyte activation rates in patients with liver transplantation. The difference in monocyte activation rate can serve as a new clinical indicator for assessing changes in the immune status and postoperative recovery of patients with liver transplantation.
		                        		
		                        		
		                        		
		                        	
10.Distribution characteristics, source apportionment, and health risk assessment of metals and metalloids in PM2.5 in a southern city in 2019
Yaxin QU ; Suli HUANG ; Chao WANG ; Jie JIANG ; Jiajia JI ; Daokui FANG ; Shaohua XIE ; Xiaoheng LI ; Ning LIU
Journal of Environmental and Occupational Medicine 2025;42(2):196-204
		                        		
		                        			
		                        			Background Metals and metalloids in fine particulate matter (PM2.5) may cause damage to the respiratory and circulatory systems of the human body, and long-term exposure is prone to causing chronic poisoning, cancer, and other adverse effects. Objective To assess the distribution characteristics of metals and metalloids in outdoor PM2.5 in a southern city of China, conduct source apportionment, and evaluate the associated health risks, thereby providing theoretical support for further pollution control measures. Methods PM2.5 samples were collected in districts A, B, and C of a southern China city, and the concentrations of 17 metals and metalloids were detected by inductively coupled plasma-mass spectrometry (ICP-MS). Pollution sources were assessed through enrichment factor and principal components analysis, and the main pollution sources were quantified using absolute principal component scores-multivariate linear regression (APCS-MLR). Health risks were evaluated based on the Technical guide for environmental health risk assessment of chemical exposure (WS/T777—2021). Results The ambient air PM2.5 concentrations in the city were higher in winter and spring, and lower in summer and autumn. The annual average concentrations of ambient PM2.5 in districts A, B, and C were 36.7, 31.9, and 24.4 μg·m−3, respectively. The ambient PM2.5 levels in districts B and C were below the second-grade limit set by the Ambient air quality standards (GB 3095—2012). The enrichment factors of cadmium (Cd), aluminum (Al), and antimony (Sb) were greater than 10, those of copper (Cu), lead (Pb), arsenic (As), nickel (Ni), mercury (Hg), and molybdenum (Mo) fell between 1 and 10, and those of manganese (Mn), vanadium (V), chromium (Cr), cobalt (Co), barium (Ba), beryllium (Be), and uranium (U) were below or equal to 1. The comprehensive evaluation of source analysis showed that the main pollution sources in districts A and C and the whole city were coal-burning. In district B, the main pollution source was also coal combustion, followed by industrial process sources and dust sources. The carcinogenic risks of As and Cr were between 1×10−6 and 1×10−4. However, the hazard quotients for 15 metals and metalloids in terms of non-carcinogenic risk were below 1. Conclusion Cr and As in the atmospheric PM2.5 of the city present a certain risk of cancer and should be paid attention to. In addition, preventive control measures should be taken against relevant pollution sources such as industrial emission, dust, and coal burning.
		                        		
		                        		
		                        		
		                        	
            

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