1.Predicting Postoperative Progression of Ossification of the Posterior Longitudinal Ligament in the Cervical Spine Using Interpretable Radiomics Models
Siyuan QIN ; Ruomu QU ; Ke LIU ; Ruixin YAN ; Weili ZHAO ; Jun XU ; Enlong ZHANG ; Feifei ZHOU ; Ning LANG
Neurospine 2025;22(1):144-156
		                        		
		                        			 Objective:
		                        			This study investigates the potential of radiomics to predict postoperative progression of ossification of the posterior longitudinal ligament (OPLL) after posterior cervical spine surgery. 
		                        		
		                        			Methods:
		                        			This retrospective study included 473 patients diagnosed with OPLL at Peking University Third Hospital between October 2006 and September 2022. Patients underwent posterior spinal surgery and had at least 2 computed tomography (CT) examinations spaced at least 1 year apart. OPLL progression was defined as an annual growth rate exceeding 7.5%. Radiomic features were extracted from preoperative CT images of the OPLL lesions, followed by feature selection using correlation coefficient analysis and least absolute shrinkage and selection operator, and dimensionality reduction using principal component analysis. Univariable analysis identified significant clinical variables for constructing the clinical model. Logistic regression models, including the Rad-score model, clinical model, and combined model, were developed to predict OPLL progression. 
		                        		
		                        			Results:
		                        			Of the 473 patients, 191 (40.4%) experienced OPLL progression. On the testing set, the combined model, which incorporated the Rad-score and clinical variables (area under the receiver operating characteristic curve [AUC] = 0.751), outperformed both the radiomics-only model (AUC = 0.693) and the clinical model (AUC = 0.620). Calibration curves demonstrated good agreement between predicted probabilities and observed outcomes, and decision curve analysis confirmed the clinical utility of the combined model. SHAP (SHapley Additive exPlanations) analysis indicated that the Rad-score and age were key contributors to the model’s predictions, enhancing clinical interpretability. 
		                        		
		                        			Conclusion
		                        			Radiomics, combined with clinical variables, provides a valuable predictive tool for assessing the risk of postoperative progression in cervical OPLL, supporting more personalized treatment strategies. Prospective, multicenter validation is needed to confirm the utility of the model in broader clinical settings. 
		                        		
		                        		
		                        		
		                        	
2.Predicting Postoperative Progression of Ossification of the Posterior Longitudinal Ligament in the Cervical Spine Using Interpretable Radiomics Models
Siyuan QIN ; Ruomu QU ; Ke LIU ; Ruixin YAN ; Weili ZHAO ; Jun XU ; Enlong ZHANG ; Feifei ZHOU ; Ning LANG
Neurospine 2025;22(1):144-156
		                        		
		                        			 Objective:
		                        			This study investigates the potential of radiomics to predict postoperative progression of ossification of the posterior longitudinal ligament (OPLL) after posterior cervical spine surgery. 
		                        		
		                        			Methods:
		                        			This retrospective study included 473 patients diagnosed with OPLL at Peking University Third Hospital between October 2006 and September 2022. Patients underwent posterior spinal surgery and had at least 2 computed tomography (CT) examinations spaced at least 1 year apart. OPLL progression was defined as an annual growth rate exceeding 7.5%. Radiomic features were extracted from preoperative CT images of the OPLL lesions, followed by feature selection using correlation coefficient analysis and least absolute shrinkage and selection operator, and dimensionality reduction using principal component analysis. Univariable analysis identified significant clinical variables for constructing the clinical model. Logistic regression models, including the Rad-score model, clinical model, and combined model, were developed to predict OPLL progression. 
		                        		
		                        			Results:
		                        			Of the 473 patients, 191 (40.4%) experienced OPLL progression. On the testing set, the combined model, which incorporated the Rad-score and clinical variables (area under the receiver operating characteristic curve [AUC] = 0.751), outperformed both the radiomics-only model (AUC = 0.693) and the clinical model (AUC = 0.620). Calibration curves demonstrated good agreement between predicted probabilities and observed outcomes, and decision curve analysis confirmed the clinical utility of the combined model. SHAP (SHapley Additive exPlanations) analysis indicated that the Rad-score and age were key contributors to the model’s predictions, enhancing clinical interpretability. 
		                        		
		                        			Conclusion
		                        			Radiomics, combined with clinical variables, provides a valuable predictive tool for assessing the risk of postoperative progression in cervical OPLL, supporting more personalized treatment strategies. Prospective, multicenter validation is needed to confirm the utility of the model in broader clinical settings. 
		                        		
		                        		
		                        		
		                        	
3.Multidimensional Analysis of Mechanisms of Nuciferine Against Cerebral Ischemia Based on Transcriptomic Data
Yingying QIN ; Peng LI ; Sha CHEN ; Yan LIU ; Jintang CHENG ; Qingxia XU ; Guohua WANG ; Jing ZHOU ; An LIU ; Chang CHEN
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(9):184-191
		                        		
		                        			
		                        			ObjectiveStudies have shown that nuciferine has anti-cerebral ischemia effect, but the specific mechanism of action has not been elaborated. Based on the transcriptome results, the pharmacological mechanism of nuciferine against cerebral ischemia was analyzed from multiple dimensions including tissue, cell, pathological process, biological process and signaling pathway. MethodsThirty SD rats were randomly divided into the sham group, model group and nuciferine group(40 mg·kg-1) according to weight. Except for the sham group, the model of middle cerebral artery occlusion(MCAO) was established by thread embolization method after 30 min of administration in the other two groups. Twenty-four hours after surgery, transcriptome sequencing was used to detect the gene expression profiles in the cortex penumbra of rat cerebral tissue, and gene ontology(GO) and kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis were performed for differentially expressed genes. The mechanismof nuciferine against cerebral ischemia was analyzed from 5 dimensions of tissue, cell, pathological process, biological process and signaling pathway by the transcriptome-based multi-scale network pharmacology platform(TMNP). ResultsTranscriptome sequencing and gene quantitative analysis showed that 667 genes were significantly reversed by nuciferine. Further enrichment analysis of KEGG and GO suggested that the pathways of nuciferine involved regulating stress response, ion transport, cell proliferation and differentiation, and synaptic function. TMNP research found that at the tissue level, nuciferine could significantly improve the cerebral tissue injury caused by ischemia. At the cellular and pathological levels, nuciferine could play an anti-cerebral ischemia role by improving the state of various nerve cells, mobilizing immune cells, regulating inflammation. And at the level of biological processes and signaling pathways, nuciferine mainly acted on the processes such as vascular remodeling, inflammation-related signaling pathways, and synaptic signaling. ConclusionCombined with the results of transcriptome sequencing, gene quantitative analysis and TMNP, the mechanism of nuciferine against cerebral ischemia may be related to processes such as intervening in stress response and inflammation, affecting vascular remodeling and regulating synaptic function. These results can provide a basis and reference for further study of the pharmacological mechanism of nuciferine against cerebral ischemia. 
		                        		
		                        		
		                        		
		                        	
4.Propensity score matching analysis of the impact of left behind experience on the mental health of secondary vocational school students
ZHOU Quanxiang, SHE Fuqiang, WAN Yan, HE Xuehua, YANG Jingyuan, CAO Xianming, XU Xiangyang
Chinese Journal of School Health 2025;46(3):353-357
		                        		
		                        			Objective:
		                        			To understand the impact of left behind experience on the mental health of  secondary vocational school students, so as to provide theoretical basis for the psychological health education of secondary vocational school students.
		                        		
		                        			Methods:
		                        			From  September to December in 2019, a total of 3 401 students from Duyun, Guiding and Pingtang County were selected by multi stage cluster random sampling method. Self designed questionnaire and Symptom Check List-90(SCL-90) were used to investigate mental health status. A total of 1 415 left behind students and 1 415 non left behind students were matched by using propensity score matching (PSM). Wilcoxon test and Logistic regression analysis were conducted.
		                        		
		                        			Results:
		                        			Before the matching of propensity score, there were statistically significant differences in the distribution of family structure, mother s educational level, family residence,family harmony and children s past health among the students with or without left behind experience ( χ 2=28.17, 52.40, 96.31,  29.75 , 19.10,  P <0.05). After the matching, there were no statistically significant differences in the distribution of the above variables among the students with or without left behind experience ( χ 2=0.02-4.32,  P >0.05). Before the matching of propensity scores, there were significant differences in the scores of 10 dimensions of SCL-90, including somatization (1.67,1.58), interpersonal sensitivity (2.00,1.89), anxiety (1.90,1.70), obsessive compulsive symptoms (2.20, 2.10), depression (2.00, 1.85), hostility (1.83, 1.67), terror (1.85, 1.71), paranoia (1.83, 1.67), psychotic (1.70, 1.60) and other (1.85, 1.71) dimensions among secondary vocational school students with or without left behind experience ( Z=-5.15  to  -2.84, P <0.05). After propensity score matching, there were significant differences in scores remained only in three factors for interpersonal sensitivity [(2.00(1.56,2.67),2.00(1.44,2.56)], paranoia [1.83(1.33,2.50),1.83(1.33,2.33)] and psychoticism [1.70(1.30,2.30),1.70(1.20,2.20)] in  SCL- 90 among secondary vocational students with or without left behind experience ( Z=-2.45, -2.12, -2.23, P <0.05).
		                        		
		                        			Conclusion
		                        			The impact of left behind experience on the mental health of vocational school students is mainly reflected in interpersonal sensitivity, paranoia, and psychoticism, which should be identified as key areas of psychological education for secondary vocational school students.
		                        		
		                        		
		                        		
		                        	
5.Analysis of characteristics of adverse drug reactions in a hospital from 2021 to 2023
Yan WANG ; Ming FANG ; Hongwei SONG ; Chao ZHONG ; Feng XU ; Ting ZHOU
Journal of Pharmaceutical Practice and Service 2025;43(4):200-204
		                        		
		                        			
		                        			Objective To analyze the characteristics of adverse drug reactions (ADR) reported in Sixth People’s Hospital South Campus, Shanghai Jiaotong University from 2021 to 2023, to provide reference for promoting rational clinical drug use. Methods ADR data reported in our hospital were collected retrospectively, including patients’ basic information, drugs causing adverse reactions, types of adverse reactions and outcomes. Descriptive analysis methods were used to summarize and analyze the data. Results A total of 979 cases of ADR were reported in our hospital from 2021 to 2023. The highest proportion of patients with ADR occurred in the age range of 31 to 50, and more male patients (63.5%). The top five drugs involved with adverse reactions were antibiotics (48.8%), Chinese medicine injections(19.2%), vitamins(7.5%), Chinese traditional medicine(7.2%), equine tetanus immunoglobulin(6.3%). Among antibiotics, cefuroxime, ceftazidime and cefotiam were the majority. The organs/systems involved in all ADR were mainly skin and accessories damage (55.4%). The clinical manifestations were rash, itching, and maculopapular rash. Conclusion From 2021 to 2023, the most common drugs causing adverse drug reactions in our hospital were mainly antibacterial drugs, and the rational clinical use of antibacterial drugs still needs to be concerned.
		                        		
		                        		
		                        		
		                        	
6.Dynamics of eosinophil infiltration and microglia activation in brain tissues of mice infected with Angiostrongylus cantonensis
Fanna WEI ; Renjie ZHANG ; Yahong HU ; Xiaoyu QIN ; Yunhai GUO ; Xiaojin MO ; Yan LU ; Jiahui SUN ; Yan ZHOU ; Jiatian GUO ; Peng SONG ; Yanhong CHU ; Bin XU ; Ting ZHANG ; Yuchun CAI ; Muxin CHEN
Chinese Journal of Schistosomiasis Control 2025;37(2):163-175
		                        		
		                        			
		                        			 Objective To investigate the changes in eosinophil counts and the activation of microglial cells in the brain tissues of mice at different stages of Angiostrongylus cantonensis infection, and to examine the role of microglia in regulating the progression of angiostrongyliasis and unravel the possible molecular mechanisms. Methods Fifty BALB/c mice were randomly divided into the control group and the 7-d, 14-d, 21-day and 25-d infection groups, of 10 mice in each group. All mice in infection groups were infected with 30 stage III A. cantonensis larvae by gavage, and animals in the control group was given an equal amount of physiological saline. Five mice were collected from each of infection groups on days 7, 14, 21 d and 25 d post-infection, and 5 mice were collected from the control group on the day of oral gavage. The general and focal functional impairment was scored using the Clark scoring method to assess the degree of mouse neurological impairment. Five mice from each of infection groups were sacrificed on days 7, 14, 21 d and 25 d post-infection, and 5 mice from the control group were sacrificed on the day of oral gavage. Mouse brain tissues were sampled, and the pathological changes of brain tissues were dynamically observed using hematoxylin and eosin (HE) staining. Immunofluorescence staining with eosinophilic cationic protein (ECP) and ionized calcium binding adaptor molecule 1 (Iba1) was used to assess the degree of eosinophil infiltration and the counts of microglial cells in mouse brain tissues in each group, and the morphological parameters of microglial cells (skeleton analysis and fractal analysis) were quantified by using Image J software to determine the morphological changes of microglial cells. In addition, the expression of M1 microglia markers Fcγ receptor III (Fcgr3), Fcγ receptor IIb (Fcgr2b) and CD86 antigen (Cd86), M2 microglia markers Arginase 1 (Arg1), macrophage mannose receptor C-type 1 (Mrc1), chitinase-like 3 (Chil3), and phagocytosis genes myeloid cell triggering receptor expressed on myeloid cells 2 (Trem2), CD68 antigen (Cd68), and apolipoprotein E (Apoe) was quantified using real-time quantitative reverse transcription PCR (RT-qPCR) assay in the mouse cerebral cortex of mice post-infection. Results A large number of A. cantonensis larvae were seen on the mouse meninges surface post-infection, and many neuronal nuclei were crumpled and deeply stained, with a large number of bleeding points in the meninges. The median Clark scores of mouse general functional impairment were 0 (interquartile range, 0), 0 (interquartile range, 0.5), 6 (interquartile range, 1.0), 14 (interquartile range, 8.5) points and 20 (interquartile range, 9.0) points in the control group and the 7-d, 14-d, 21-d and 25-d groups, respectively (H = 22.45, P < 0.01), and the median Clark scores of mouse focal functional impairment were 0 (interquartile range, 0), 2 (interquartile range, 2.5), 7 (interquartile range, 3.0), 18 (interquartile range, 5.0) points and 25 (interquartile range, 6.5) points in the control group and the 7-d, 14-d, 21-d and 25-d groups, respectively (H = 22.72, P < 0.01). The mean scores of mice general and focal functional impairment were all higher in the infection groups than in the control group (all P values < 0.05). Immunofluorescence staining showed a significant difference in the eosinophil counts in mouse brain tissues among the five groups (F = 40.05, P < 0.000 1), and the eosinophil counts were significantly higher in mouse brain tissues in the 14-d (3.08 ± 0.78) and 21-d infection groups (5.97 ± 1.37) than in the control group (1.00 ± 0.28) (both P values < 0.05). Semi-quantitative analysis of microglia immunofluorescence showed a significant difference in the counts of microglial cells among the five groups (F = 17.66, P < 0.000 1), and higher Iba1 levels were detected in mouse brain tissues in 14-d (5.75 ± 1.28), 21-d (6.23 ± 1.89) and 25-d infection groups (3.70 ± 1.30) than in the control group (1.00 ± 0.30) (all P values < 0.05). Skeleton and fractal analyses showed that the branch length [(162.04 ± 34.10) μm vs. (395.37 ± 64.11) μm; t = 5.566, P < 0.05] and fractal dimension of microglial cells (1.30 ± 0.01 vs. 1.41 ± 0.03; t = 5.266, P < 0.05) were reduced in mouse brain tissues in the 21-d infection group relative to the control group. In addition, there were significant differences among the 5 groups in terms of M1 and M2 microglia markers Fcgr3 (F = 48.34, P < 0.05), Fcgr2b (F = 55.46, P < 0.05), Cd86 (F = 24.44, P < 0.05), Arg1 (F = 31.18, P < 0.05), Mrc1 (F = 15.42, P < 0.05) and Chil3 (F = 24.41, P < 0.05), as well as phagocytosis markers Trem2 (F = 21.19, P < 0.05), Cd68 (F = 43.95, P < 0.05) and Apoe (F = 7.12, P < 0.05) in mice brain tissues. Conclusions A. cantonensis infections may induce severe pathological injuries in mouse brain tissues that are characterized by massive eosinophil infiltration and persistent activation of microglia cells, thereby resulting in progressive deterioration of neurological functions. 
		                        		
		                        		
		                        		
		                        	
7.Predicting Postoperative Progression of Ossification of the Posterior Longitudinal Ligament in the Cervical Spine Using Interpretable Radiomics Models
Siyuan QIN ; Ruomu QU ; Ke LIU ; Ruixin YAN ; Weili ZHAO ; Jun XU ; Enlong ZHANG ; Feifei ZHOU ; Ning LANG
Neurospine 2025;22(1):144-156
		                        		
		                        			 Objective:
		                        			This study investigates the potential of radiomics to predict postoperative progression of ossification of the posterior longitudinal ligament (OPLL) after posterior cervical spine surgery. 
		                        		
		                        			Methods:
		                        			This retrospective study included 473 patients diagnosed with OPLL at Peking University Third Hospital between October 2006 and September 2022. Patients underwent posterior spinal surgery and had at least 2 computed tomography (CT) examinations spaced at least 1 year apart. OPLL progression was defined as an annual growth rate exceeding 7.5%. Radiomic features were extracted from preoperative CT images of the OPLL lesions, followed by feature selection using correlation coefficient analysis and least absolute shrinkage and selection operator, and dimensionality reduction using principal component analysis. Univariable analysis identified significant clinical variables for constructing the clinical model. Logistic regression models, including the Rad-score model, clinical model, and combined model, were developed to predict OPLL progression. 
		                        		
		                        			Results:
		                        			Of the 473 patients, 191 (40.4%) experienced OPLL progression. On the testing set, the combined model, which incorporated the Rad-score and clinical variables (area under the receiver operating characteristic curve [AUC] = 0.751), outperformed both the radiomics-only model (AUC = 0.693) and the clinical model (AUC = 0.620). Calibration curves demonstrated good agreement between predicted probabilities and observed outcomes, and decision curve analysis confirmed the clinical utility of the combined model. SHAP (SHapley Additive exPlanations) analysis indicated that the Rad-score and age were key contributors to the model’s predictions, enhancing clinical interpretability. 
		                        		
		                        			Conclusion
		                        			Radiomics, combined with clinical variables, provides a valuable predictive tool for assessing the risk of postoperative progression in cervical OPLL, supporting more personalized treatment strategies. Prospective, multicenter validation is needed to confirm the utility of the model in broader clinical settings. 
		                        		
		                        		
		                        		
		                        	
8.Predicting Postoperative Progression of Ossification of the Posterior Longitudinal Ligament in the Cervical Spine Using Interpretable Radiomics Models
Siyuan QIN ; Ruomu QU ; Ke LIU ; Ruixin YAN ; Weili ZHAO ; Jun XU ; Enlong ZHANG ; Feifei ZHOU ; Ning LANG
Neurospine 2025;22(1):144-156
		                        		
		                        			 Objective:
		                        			This study investigates the potential of radiomics to predict postoperative progression of ossification of the posterior longitudinal ligament (OPLL) after posterior cervical spine surgery. 
		                        		
		                        			Methods:
		                        			This retrospective study included 473 patients diagnosed with OPLL at Peking University Third Hospital between October 2006 and September 2022. Patients underwent posterior spinal surgery and had at least 2 computed tomography (CT) examinations spaced at least 1 year apart. OPLL progression was defined as an annual growth rate exceeding 7.5%. Radiomic features were extracted from preoperative CT images of the OPLL lesions, followed by feature selection using correlation coefficient analysis and least absolute shrinkage and selection operator, and dimensionality reduction using principal component analysis. Univariable analysis identified significant clinical variables for constructing the clinical model. Logistic regression models, including the Rad-score model, clinical model, and combined model, were developed to predict OPLL progression. 
		                        		
		                        			Results:
		                        			Of the 473 patients, 191 (40.4%) experienced OPLL progression. On the testing set, the combined model, which incorporated the Rad-score and clinical variables (area under the receiver operating characteristic curve [AUC] = 0.751), outperformed both the radiomics-only model (AUC = 0.693) and the clinical model (AUC = 0.620). Calibration curves demonstrated good agreement between predicted probabilities and observed outcomes, and decision curve analysis confirmed the clinical utility of the combined model. SHAP (SHapley Additive exPlanations) analysis indicated that the Rad-score and age were key contributors to the model’s predictions, enhancing clinical interpretability. 
		                        		
		                        			Conclusion
		                        			Radiomics, combined with clinical variables, provides a valuable predictive tool for assessing the risk of postoperative progression in cervical OPLL, supporting more personalized treatment strategies. Prospective, multicenter validation is needed to confirm the utility of the model in broader clinical settings. 
		                        		
		                        		
		                        		
		                        	
9.Predicting Postoperative Progression of Ossification of the Posterior Longitudinal Ligament in the Cervical Spine Using Interpretable Radiomics Models
Siyuan QIN ; Ruomu QU ; Ke LIU ; Ruixin YAN ; Weili ZHAO ; Jun XU ; Enlong ZHANG ; Feifei ZHOU ; Ning LANG
Neurospine 2025;22(1):144-156
		                        		
		                        			 Objective:
		                        			This study investigates the potential of radiomics to predict postoperative progression of ossification of the posterior longitudinal ligament (OPLL) after posterior cervical spine surgery. 
		                        		
		                        			Methods:
		                        			This retrospective study included 473 patients diagnosed with OPLL at Peking University Third Hospital between October 2006 and September 2022. Patients underwent posterior spinal surgery and had at least 2 computed tomography (CT) examinations spaced at least 1 year apart. OPLL progression was defined as an annual growth rate exceeding 7.5%. Radiomic features were extracted from preoperative CT images of the OPLL lesions, followed by feature selection using correlation coefficient analysis and least absolute shrinkage and selection operator, and dimensionality reduction using principal component analysis. Univariable analysis identified significant clinical variables for constructing the clinical model. Logistic regression models, including the Rad-score model, clinical model, and combined model, were developed to predict OPLL progression. 
		                        		
		                        			Results:
		                        			Of the 473 patients, 191 (40.4%) experienced OPLL progression. On the testing set, the combined model, which incorporated the Rad-score and clinical variables (area under the receiver operating characteristic curve [AUC] = 0.751), outperformed both the radiomics-only model (AUC = 0.693) and the clinical model (AUC = 0.620). Calibration curves demonstrated good agreement between predicted probabilities and observed outcomes, and decision curve analysis confirmed the clinical utility of the combined model. SHAP (SHapley Additive exPlanations) analysis indicated that the Rad-score and age were key contributors to the model’s predictions, enhancing clinical interpretability. 
		                        		
		                        			Conclusion
		                        			Radiomics, combined with clinical variables, provides a valuable predictive tool for assessing the risk of postoperative progression in cervical OPLL, supporting more personalized treatment strategies. Prospective, multicenter validation is needed to confirm the utility of the model in broader clinical settings. 
		                        		
		                        		
		                        		
		                        	
10.Phosphatidic acid-enabled MKL1 contributes to liver regeneration: Translational implication in liver failure.
Jiawen ZHOU ; Xinyue SUN ; Xuelian CHEN ; Huimin LIU ; Xiulian MIAO ; Yan GUO ; Zhiwen FAN ; Jie LI ; Yong XU ; Zilong LI
Acta Pharmaceutica Sinica B 2024;14(1):256-272
		                        		
		                        			
		                        			Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function. In the present study we investigated the contribution of megakaryocytic leukemia 1 (MKL1), a transcriptional modulator, to liver regeneration. We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients. Mice with MKL1 deletion exhibited defective regenerative response in the liver. Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription. MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1. Of interest, phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid (PA). PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure. Finally, PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients. In conclusion, our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration. Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.
		                        		
		                        		
		                        		
		                        	
            

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