1.The impact of postpartum depression on maternal responsiveness in infant care
Shuzhen LI ; Fang WANG ; Ke WANG ; Su LIU ; Qian WEI ; Qing YANG ; Leilei LIU ; Huijing SHI
Shanghai Journal of Preventive Medicine 2025;37(3):271-275
		                        		
		                        			
		                        			ObjectiveTo analyze the impact of maternal postpartum depression (PPD) at 2 months postpartum on caregiving for infants aged2 to 24 months, and to provide a scientific basis for future maternal and infant healthcare services. MethodsBased on the Shanghai Maternal-Child Pairs Cohort, 1 060 mother-child pairs were selected from those fully participating in follow-up visits at 2, 6, 12, and 24 months postpartum. Pregnancy and childbirth-related information was collected using standardized questionnaire surveys and hospital obstetric and maternity records. The Edinburgh postpartum depression scale was used to assess the maternal postpartum depressive symptoms at 2 months postpartum. At 2, 6, 12, and 24 months postpartum, questionnaire survey was used to evaluate the maternal responsiveness in caregiving and the provision of early learning opportunities for infants. Scores for responsive caregiving and early learning opportunities at 2, 6, 12, and 24 months were grouped based on the 25th percentile (P25) of total scores. The mixed-effects model was used to analyze the longitudinal impact of maternal postpartum depression at 2 months on the caregiving of 2 to 24-month-old infants. ResultsThe longitudinal results from the mixed-effects model did not show an impact of maternal PPD on infant responsive caregiving within 12 months and early learning opportunities within24 months. However, cross-sectional analysis revealed that, compared to the non-PPD group, the risk of low responsive caregiving at 2 months in the PPD group was 93% higher (OR=1.931, 95%CI: 1.113‒3.364, P=0.019). The risks for low provision of early learning opportunities at2 months and 24 months increased by 59% (OR=1.589, 95%CI: 1.082‒2.324, P=0.017) and 60% (OR=1.598, 95%CI:1.120‒2.279, P=0.010), respectively. ConclusionMaternal postpartum depression increases the risk of low responsive caregiving at 2 months, but its long-term effects warrant further research. 
		                        		
		                        		
		                        		
		                        	
2.Hypoxia Exercise Mediates The miR-27/PPARγ Pathway to Improve Lipid Metabolism in Obese Rats at Target Genes and Protein Levels
Wei KONG ; Jie SHAO ; Teng ZHAI ; Qian CHENG ; Fang-Zheng HAN ; Yi QU ; Lei ZHU
Progress in Biochemistry and Biophysics 2025;52(6):1386-1400
		                        		
		                        			
		                        			ObjectiveTo explore the sequential effects of hypoxic exercising on miR-27/PPARγ and lipid metabolism target gene and protein expression levels in the obesity rats’ liver. Methods13-week-old male diet-induced obesity rats were randomly divided into three groups (n=10): normal oxygen concentration quiet group (N), hypoxia quiet group (H), hypoxic exercise group (HE). Exercise training on the horizontal animal treadmill for 1 h/d, 5 d/week for a total of 4 week, and the intensity of horizontal treadmill training was 20 m/min (hypoxic concentration was 13.6%). Comparison of the weights of perirenal fat and epididymal fat in rats across different groups and calculation of Lee’s index based on body weight and body length of rats in each group were done. And the serum concentrations of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) levels were detected. RT-PCR and Western Blot were used to detect the levels of miR-27, PPARγ, CYP7A1 and CD36. ResultsHypoxic exercise decreased the expression levels of miR-27 in the obese rats’ liver, however, the expression level of PPARγ was gradually increased. The expression levels of miR-27 in HE group were significantly lower than N group (P<0.05). The expression levels of PPARγ mRNA in N group were significantly lower than H group (P<0.05), especially lower than HE group (P<0.01). The protein expression of PPARγ protein in N group was significantly lower than that other groups (P<0.01). The expression of lipid metabolism-related genes and proteins increased in the obese rats’ liver. The expression of CYP7A1 mRNA in N group was significantly lower than H group (P<0.05), especially lower than HE group (P<0.01). The expression of CYP7A1 protein in the obese rats’ liver in N group was extremely lower than H group and HE group (P<0.01). The protein expression of CD36 in N group was significantly lower than that in HE group (P<0.05). Hypoxia exercise improved the related physiological and biochemical indexes of lipid metabolism disorder. The perirenal fat weight of obese rats in HE group was extremely lower than N group and H group (P<0.01), and the perirenal fat weight in N group was significantly higher than H group (P<0.05). The epididymal fat weight in N group was significantly higher than H group (P<0.05), and extremely higher than HE group (P<0.01). The Lee’s index in HE group was extremely lower than N group and H group (P<0.01). The serum concentration of TC in obese rats in HE group was extremely lower than N group and H group (P<0.01). The serum concentration of TG in HE group was extremely lower than N group and H group (P<0.01). The serum concentration of LDL-C in N group was extremely higher than HE group (P<0.01). The serum concentration of HDL-C in N group was extremely lower than H group (P<0.01). ConclusionHypoxia and hypoxia exercise may negatively regulate the levels of PPARγ by inhibiting miR-27 in the obese rats’ liver, thereby affecting the expression of downstream target genes CYP7A1 and CD36, and promoting cholesterol, fatty acid oxidation and HDL-C transport in the liver, and ultimately the lipid levels in obese rats were improved. The effect of hypoxia exercise on improving blood lipid is better than simple hypoxia intervention. 
		                        		
		                        		
		                        		
		                        	
3.Effects of different storage temperatures and durations on the activity of coagulation factor Ⅷ and Ⅸ in whole blood
Hehe WANG ; Tiantian WANG ; Jie WANG ; Cuicui QIAO ; Wei LIU ; Xueqin ZHANG ; Yan CHENG ; Yunhai FANG ; Xinsheng ZHANG
Chinese Journal of Blood Transfusion 2025;38(6):824-827
		                        		
		                        			
		                        			Objective: To investigate the effects of different storage temperatures and durations on the activities of coagulation factor Ⅷ (Factor Ⅷ, FⅧ) and coagulation factor Ⅸ (Factor Ⅸ, FⅨ) after whole blood collection, so as to provide data support for the optimal storage conditions. Methods: A total of 16 mL of whole blood was collected from each of the 20 healthy volunteers at our blood center and aliquoted into 8 sodium citrate anticoagulant tubes. Two tubes were immediately centrifuged for the measurement of FⅧ and FⅨ activity levels. The remaining 6 tubes of whole blood were respectively stored under room temperature and low-temperature conditions. At 2, 4, and 6 h, the whole blood samples were centrifuged and analyzed for FⅧ and FⅨ activity levels. The mean values of the two immediately tested tubes were used as the control group, while other tubes were designated as the experimental groups for comparison. Statistical analysis was performed using SPSS 26.0. Results: The activity of FⅧ in whole blood remained stable after 4 hours of storage at both room temperature and low temperature (116.53±25.95 vs 125.22±27.33, 109.77±23.23 vs 125.22±27.33) (P>0.05 for both). However, by 6 hours, FⅧ activity showed a statistically significant decline compared to the control group (108.65±22.92 vs 125.22±27.33, 100.46±20.19 vs 125.22±27.33) (P<0.05 for both), though the room temperature group results were closer to the control values. The activity of FⅨ in whole blood remained stable after 6 hours of storage under both conditions (97.14±19.48 vs 96.76±19.67, 97.10±17.45 vs 96.76±19.6) (P>0.05 for all comparisons). Conclusion: For whole blood samples after collection, storage at either room temperature or low temperature for up to 4 hours does not compromise the accuracy of test results. When stored for 6 hours, FⅨ activity remains stable, whereas FⅧ activity decreases significantly. Notably, FⅧ activity demonstrates better stability at room temperature than under low-temperature conditions within the 6-hour storage.
		                        		
		                        		
		                        		
		                        	
4.Effects of prescription pre-review system on rational drug use and off-label drug use management in outpatient and emergency department
Zhi GAO ; Lulu HAN ; Fang LIU ; Rui JIAO ; Wei ZHANG ; Yi ZHANG
China Pharmacy 2025;36(13):1666-1670
		                        		
		                        			
		                        			OBJECTIVE To explore the effects of prescription pre-review system on rational drug use and off-label drug use management in outpatient and emergency department. METHODS A retrospective analysis was conducted on outpatient and emergency department prescription data from three phases in our hospital: January to May 2023 (silent review phase, control group), June to October 2023 (systematic automatic review phase, intervention group 1), and November 2023 to March 2024 (phase combining systematic automatic review with centralized feedback from pharmacists to physicians regarding irrational prescriptions, intervention group 2). These phases followed the implementation of our hospital’s pre-prescription review software. Statistical analysis of the prompt rate of alert, rate of irrational prescriptions, registered the off-label drug use rate and false positive irrationality prescription rate were conducted. Meanwhile, the composition of irrational prescriptions was analyzed, and evidence- based evaluation of the off-label drug use proposed by clinicians was also conducted. RESULTS Compared with control group, the prompt rate of alert and the rate of irrational prescriptions in intervention group 1 were all decreased significantly after receiving pop-up notification, with statistically significant differences (P<0.05). With the help of system warning and the pharmacists feedback, the prompt rate of alert and the rate of irrational prescriptions declined further in the intervention group 2, but there was no statistically significant difference when compared with intervention group 1 (P>0.05). The main type of irrational drug use was improper administration routes. When comparing intervention group 1 with the control group, as well as intervention group 2 with intervention group 1, a significant decrease in the rate of improper administration routes was observed, with statistically significant differences (P<0.05). Compared with control group, there was no significant difference in the registered off-label drug use rate of intervention group 1 and intervention group 2 (P>0.05). The doctor’s awareness of off-label drug use registration increased due to the real-time alerts from the pre-prescription review software, along with the pharmacists’ regular summarization and feedback. Total 13 items registrations of off-label drug use were proposed by clinicians from June 2023 to March 2024, all of which were supported by evidence of varying levels; among them, 3 items received FDA approval, 4 items were included in the Micromedex database, and the remaining 6 items were supported by evidence from system reviews or randomized controlled trials. CONCLUSIONS Prescription pre-review system can improve the level of rational drug use and assist in the standardized management of off-label drug use.
		                        		
		                        		
		                        		
		                        	
5.Analysis of mental health status potential categories and related factors among primary and secondary school students in western Yunnan Province
HAN Fang, WANG Qi, WEN Yating, LI Xiaojuan, WEI Hongyu, JIAO Feng
Chinese Journal of School Health 2025;46(7):1009-1013
		                        		
		                        			Objective:
		                        			To investigate the mental health status and related factors among primary and secondary school students in western Yunnan Province, so ao to provide scientific evidences for advancing mental health education.
		                        		
		                        			Methods:
		                        			In June 2024, a stratified cluster sampling method was employed to select 4 584 students from 18 schools across Diqing Tibetan Autonomous Prefecture, Lincang City and Baoshan City three regions in western Yunnan Province. The Mental Health Test (MHT) was used for assessment. Latent class analysis (LCA) and Logistic regression were applied for data classification and related factor analysis respectively.
		                        		
		                        			Results:
		                        			The overall positive detection rate of MHT was 11.81%, with a mean total score of 40.50±19.25. The predominant issues were learning anxiety (58.4%), hypersensitivity tendency (31.1%), and self blame tendency (23.1%). LCA categorized students into four groups:severe psychological problems group (74.4% detection rate), learning anxiety hypersensitivity group ( 16.4 %), learning anxiety physical symptoms group (9.2%), and healthy group (0). Logistic regression revealed that compared with the healthy group, the severe problems group showed higher risks among females ( OR =3.01), junior/senior high school students ( OR =1.88/4.02), and those with authoritarian parenting ( OR =3.54); the anxiety hypersensitivity group had higher risks for females ( OR =1.87), senior high students ( OR =1.54), boarders ( OR =1.31), and authoritarian parenting recipients ( OR = 1.85 ); the anxiety physical symptoms group demonstrated increased risks among females ( OR =2.22), senior high students ( OR =2.58), and authoritarian parenting recipients ( OR =2.74), while lower risks were observed for students with parent/grandparent guardians ( OR =0.38) and non only children ( OR =0.58) (all  P <0.05).
		                        		
		                        			Conclusions
		                        			Mental health problems are prominent among students in western Yunnan, with gender, grade level, boarding status, guardian type, and parenting style being key determinants. Recommendations include strengthening mental health education, prioritizing left behind children s psychological well being and promoting healthy development.
		                        		
		                        		
		                        		
		                        	
6.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.
		                        		
		                        		
		                        		
		                        	
7.Interpretation of Chinese Expert Consensus on Integrated Chinese and Western Medicine Management of Wilson Disease-related Renal Damage
Wenming YANG ; Ke DIAO ; Hu XI ; Zhihong RAO ; Taohua WEI ; Yulong YANG ; Shuzhen FANG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(20):168-176
		                        		
		                        			
		                        			Wilson disease is a copper metabolism disorder caused by mutations in the ATP7B gene, which encodes a copper-transporting ATPase β, and can result in multisystem damage. The kidneys are the third most commonly affected organs after the liver and brain. In recent years, numerous diagnostic and treatment guidelines for Wilson disease have emerged. However, most of these focus primarily on hepatic and neurological manifestations and their management, with limited coverage of renal involvement. The high incidence, low awareness, and lack of clinical specificity of Wilson disease-related renal damage (WDRD) have made early detection and intervention particularly challenging in clinical practice. To further optimize the treatment of patients with WDRD, improve clinical diagnosis and management, and enhance patients' quality of life, the Neurology Committee of the Chinese Association of Integrative Medicine, in April 2024, initiated a revision of the first expert consensus on the integrated diagnosis, treatment, and management of WDRD. This effort brought together experts in hepatology, encephalopathy (neurology), and nephrology from many tertiary-level grade A hospitals and research institutions across China. Through comprehensive literature review and integration of frontline clinical experience, the expert group jointly developed Chinese Expert Consensus on Integrated Chinese and Western Medicine Management of Wilson Disease-related Renal Damage (hereinafter referred to as the "Consensus"). This article provides a detailed interpretation of the Consensus in terms of diagnostic criteria, traditional Chinese medicine (TCM) syndrome differentiation and treatment classification, and comprehensive disease management, aiming to better guide clinical application. Regarding diagnostic criteria, the Consensus integrates the latest standards in China and abroad, highlights the importance of biochemical diagnosis, and compensates for the limitations of genetic testing. In the area of TCM syndrome differentiation and treatment, the Consensus refines four major syndrome types, introduces a newly defined syndrome, i.e., phlegm, blood stasis, and heat accumulation, and elaborates on treatment principles, prescriptions, and clinical modification rules for each syndrome. For comprehensive disease management, the Consensus emphasizes multi-dimensional intervention strategies, including diet, exercise, emotional regulation, medication, and medical care, with the goal of maximally controlling the progression of renal dysfunction and helping patients achieve a better quality of life. 
		                        		
		                        		
		                        		
		                        	
8.Clinical application and research progress of artificial intelligence-assisted diagnosis of pulmonary nodules
Chen LIU ; Zemin FANG ; Zuoliang SHAO ; Ruoting YU ; Wei GAO
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2025;32(06):846-854
		                        		
		                        			
		                        			Artificial intelligence (AI) has been widely used in all walks of life, including healthcare, and has shown great application value in the auxiliary diagnosis of pulmonary nodules in the medical field. In the face of a large amount of lung imaging data, clinicians use AI tools to identify lesions more quickly and accurately, improving work efficiency, but there are still many problems in this field, such as the high false positive rate of recognition, and the difficulty in identifying special types of nodules. Researchers and clinicians are actively developing and using AI tools to promote their continuous evolution and make them better serve human health. This article reviews the clinical application and research progress of AI-assisted diagnosis of pulmonary nodules.
		                        		
		                        		
		                        		
		                        	
9.Effect of Stasis-dispelling and Detoxifying Therapy on Clinical Efficacy and JNK Signaling Pathway-related Protein Expression in Endometriosis Patients with Syndrome of Kidney Deficiency and Blood Stasis
Tingting WANG ; Zhaokang QI ; Jinxin REN ; Shuai ZHAO ; Chunxiao WEI ; Yi YU ; Fang LIAN
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(21):120-129
		                        		
		                        			
		                        			ObjectiveTo observe the clinical efficacy of the stasis-dispelling and detoxifying therapy in endometriosis (EMs) patients with the syndrome of kidney deficiency and blood stasis and the effects of this therapy on the expression levels of proteins related to the c-Jun N-terminal kinase (JNK) signaling pathway. MethodsA total of 72 patients with EMs due to kidney deficiency and blood stasis who met the criteria at the Integrated Traditional Chinese and Western Medicine Center for Reproduction and Genetics of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from March 2024 to February 2025 were selected and randomized into a treatment group and a control group, with 36 patients in each group. Another 36 patients undergoing in vitro fertilization-embryo transfer (IVF-ET) due to male factors alone were selected as the blank group. The treatment group took the Zishen Quyu Jiedu formula orally, while the control group and the blank group took placebos. The treatment course encompassed the cycle before ovarian stimulation and the oocyte retrieval cycle. The TCM syndrome score of kidney deficiency and blood stasis, as well as the serum level of cancer antigen 125 (CA125), were evaluated at the time of enrollment (before treatment) and on the trigger day (after treatment). Serum levels of sex hormones were measured on day 2 of the menstrual cycle. On the trigger day, the duration and dosage of gonadotropin (Gn) administration and the serum levels of hormones on the day of human chorionic gonadotropin (HCG) injection were assessed. Embryo outcomes were evaluated 3 days after oocyte retrieval, and clinical pregnancy rates were assessed 28 days after embryo transfer. The baseline data of three groups were observed. The TCM syndrome scores and serum CA125 levels before and after treatment were compared between the treatment and control groups. The baseline endocrine levels, Gn days, Gn dosage, hormone levels on the day of HCG administration, number of oocytes retrieved, number of 2 pronucleus (2PN) fertilizations, number of available embryos, high-quality embryo rate, and clinical pregnancy rate were also assessed in all three groups. Six patients from each group were selected for determination of the protein levels of JNK, c-Jun, and nuclear receptor subfamily 4 group A member 2 (NR4A2) in ovarian granulosa cells (GCs) on the day of oocyte retrieval by Western blot. Results(1) There were no statistically significant differences in the baseline data among three groups, indicating comparability. (2) Compared with the baseline within the same group, the treatment group showed a decrease in the syndrome score of kidney deficiency and blood stasis after treatment. After treatment, serum CA125 levels decreased in both groups (P<0.05), with a more substantial reduction in the treatment group, resulting in a difference between the two groups (P<0.05). (3) There were no significant differences among three groups in terms of baseline serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone (P), as well as the duration and dosage of Gn administration and the serum levels of LH, E2, and P on the day of HCG administration. (4) For embryo outcomes, the number of oocytes retrieved, 2PN fertilizations, available embryos, and high-quality embryo rates in the treatment group and the blank group were higher than those in the control group (P<0.05), and the treatment group and the blank group had similar 2PN fertilizations. (5) There were differences in clinical pregnancy rate among three groups (P<0.05), and the treatment group had higher pregnancy rate than the control and blank groups. (6) The protein levels of JNK, c-Jun, and NR4A2 in the GCs of the treatment group were lower than those in the control group (P<0.01) and close to those in the blank group (P<0.01). (7) No obvious adverse reactions were observed in any of the subjects during the clinical observation process. ConclusionZishen Quyu Jiedu formula can ameliorate the clinical symptoms of patients with EMs due to kidney deficiency and blood stasis, reduce the serum CA125 level, increase the number of oocytes retrieved, 2PN fertilizations, available embryos, and high-quality embryo rate, and improve pregnancy outcomes. The mechanism may involve downregulating the levels of JNK, c-Jun, and NR4A2 to reduce the apoptosis of ovarian GCs and improve the ovarian function in the patients. 
		                        		
		                        		
		                        		
		                        	
10.Relationship between Helicobacter pylori infection and disease severity and pathological type of inpatients with intestinal polyps
Wei YOU ; Dalin LU ; Yan CHEN ; Xin WANG ; Yizheng FANG ; Lunshan WANG
Journal of Public Health and Preventive Medicine 2025;36(5):85-88
		                        		
		                        			
		                        			Objective  To investigate the relationship between Helicobacter pylori (Hp) infection and disease severity and pathological type of intestinal polyps in inpatients.  Methods  The data of 303 inpatients with intestinal polyps in the hospital from August 2022 to February 2025 were collected and analyzed. The clinical characteristics of patients were analyzed, and the influencing factors of pathological types of polyps were explored.  Results  Among the 303 inpatients with intestinal polyps, there were 135 Hp positive cases and 168 Hp negative cases. The number of polyps, maximum polyp diameter, number of ileocecus/ascending colon/transverse colon polyps, number of descending colon/sigmoid colon/rectal polyps and adenomatous polyps in the Hp-positive group were higher than those in the Hp-negative group (P<0.05). Multivariate logistic regression analysis indicated that age [OR (95%CI)=1.03 (1.01-1.05)] and positive Hp[OR (95%CI)=2.61 (1.62-4.20)] were independent risk factors of occurrence of adenomatous polyps (P<0.05). ROC curve results revealed that the AUCs of age, positive HP and combination in the diagnosis of adenomatous polyps were 0.574, 0.608 and 0.646, and the 95%CI values were 0.509-0.638, 0.545-0.672 and 0.584-0.708 respectively. The efficiency of combination of the two indexes was higher than that of single diagnosis.  Conclusion  Hp infection is associated with disease severity in inpatients with intestinal polyps, and it may be involved in the occurrence and development of adenomatous polyps.
		                        		
		                        		
		                        		
		                        	
            

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