1.Prognosis and influencing factors analysis of patients with initially resectable gastric cancer liver metastasis who were treated by different modalities: a nationwide, multicenter clinical study
Li LI ; Yunhe GAO ; Liang SHANG ; Zhaoqing TANG ; Kan XUE ; Jiang YU ; Yanrui LIANG ; Zirui HE ; Bin KE ; Hualong ZHENG ; Hua HUANG ; Jianping XIONG ; Zhongyuan HE ; Jiyang LI ; Tingting LU ; Qiying SONG ; Shihe LIU ; Hongqing XI ; Yun TANG ; Zhi QIAO ; Han LIANG ; Jiafu JI ; Lin CHEN
Chinese Journal of Digestive Surgery 2024;23(1):114-124
		                        		
		                        			
		                        			Objective:To investigate the prognosis of patients with initially resectable gastric cancer liver metastasis (GCLM) who were treated by different modalities, and analyze the influencing factors for prognosis of patients.Methods:The retrospective cohort study was conducted. The clinicopathological data of 327 patients with initially resectable GCLM who were included in the database of a nationwide multicenter retrospective cohort study on GCLM based on real-world data from January 2010 to December 2019 were collected. There were 267 males and 60 females, aged 61(54,68)years. According to the specific situations of patients, treatment modalities included radical surgery combined with systemic treatment, palliative surgery combined with systemic treatment, and systemic treatment alone. Observation indicators: (1) clinical characteristics of patients who were treated by different modalities; (2) prognostic outcomes of patients who were treated by different modalities; (3) analysis of influencing factors for prognosis of patients with initially resectable GCLM; (4) screening of potential beneficiaries in patients who were treated by radical surgery plus systemic treatment and patients who were treated by palliative surgery plus systemic treatment. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M( Q1, Q3), and comparison between groups was conducted using the rank sum test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. The Kaplan-Meier method was used to calculate survival rate and draw survival curve, and Log-Rank test was used for survival analysis. Univariate and multivariate analyses were conducted using the COX proportional hazard regression model. The propensity score matching was employed by the 1:1 nearest neighbor matching method with a caliper value of 0.1. The forest plots were utilized to evaluate potential benefits of diverse surgical combined with systemic treatments within the population. Results:(1) Clinical characteristics of patients who were treated by different modalities. Of 327 patients, there were 118 cases undergoing radical surgery plus systemic treatment, 164 cases undergoing palliative surgery plus systemic treatment, and 45 cases undergoing systemic treatment alone. There were significant differences in smoking, drinking, site of primary gastric tumor, diameter of primary gastric tumor, site of liver metastasis, and metastatic interval among the three groups of patients ( P<0.05). (2) Prognostic outcomes of patients who were treated by different modalities. The median overall survival time of the 327 pati-ents was 19.9 months (95% confidence interval as 14.9-24.9 months), with 1-, 3-year overall survival rate of 61.3%, 32.7%, respectively. The 1-year overall survival rates of patients undergoing radical surgery plus systemic treatment, palliative surgery plus systemic treatment and systemic treatment alone were 68.3%, 63.1%, 30.6%, and the 3-year overall survival rates were 41.1%, 29.9%, 11.9%, showing a significant difference in overall survival rate among the three groups of patients ( χ2=19.46, P<0.05). Results of further analysis showed that there was a significant difference in overall survival rate between patients undergoing radical surgery plus systemic treatment and patients undergoing systemic treatment alone ( hazard ratio=0.40, 95% confidence interval as 0.26-0.61, P<0.05), between patients undergoing palliative surgery plus systemic treatment and patients under-going systemic treatment alone ( hazard ratio=0.47, 95% confidence interval as 0.32-0.71, P<0.05). (3) Analysis of influencing factors for prognosis of patients with initially resectable GCLM. Results of multivariate analysis showed that the larger primary gastric tumor, poorly differentiated tumor, larger liver metastasis, multiple hepatic metastases were independent risk factors for prognosis of patients with initially resectable GCLM ( hazard ratio=1.20, 1.70, 1.20, 2.06, 95% confidence interval as 1.14-1.27, 1.25-2.31, 1.04-1.42, 1.45-2.92, P<0.05) and immunotherapy or targeted therapy, the treatment modality of radical or palliative surgery plus systemic therapy were independent protective factors for prognosis of patients with initially resectable GCLM ( hazard ratio=0.60, 0.39, 0.46, 95% confidence interval as 0.42-0.87, 0.25-0.60, 0.30-0.70, P<0.05). (4) Screening of potentinal beneficiaries in patients who were treated by radical surgery plus systemic treatment and patients who were treated by palliative surgery plus systemic treatment. Results of forest plots analysis showed that for patients with high-moderate differentiated GCLM and patients with liver metastasis located in the left liver, the overall survival rate of patients undergoing radical surgery plus systemic treatment was better than patients undergoing palliative surgery plus systemic treatment ( hazard ratio=0.21, 0.42, 95% confidence interval as 0.09-0.48, 0.23-0.78, P<0.05). Conclusions:Compared to systemic therapy alone, both radical and palliative surgery plus systemic therapy can improve the pro-gnosis of patients with initially resectable GCLM. The larger primary gastric tumor, poorly differen-tiated tumor, larger liver metastasis, multiple hepatic metastases are independent risk factors for prognosis of patients with initial resectable GCLM and immunotherapy or targeted therapy, the treatment modality of radical or palliative surgery plus systemic therapy are independent protective factors for prognosis of patients with initially resectable GCLM.
		                        		
		                        		
		                        		
		                        	
2.Multi-parametric MRI combined with 68Ga-PSMA PET/CT for the diagnosis of clinically significant prostate cancer
Xiaoli MENG ; Fei KANG ; Zhiyong QUAN ; Mingru ZHANG ; Min WANG ; Tingting HAN ; Jun SHU ; Jing REN ; Weidong YANG ; Jing WANG
Chinese Journal of Nuclear Medicine and Molecular Imaging 2024;44(1):25-29
		                        		
		                        			
		                        			Objective:To explore whether multi-parametric MRI (mpMRI) combined with 68Ga-prostate specific membrane antigen (PSMA) PET/CT can improve the detection efficiency of clinically significant prostate cancer (csPCa). Methods:Clinical and imaging data of 152 patients (age (68.5±8.5) years) who underwent mpMRI and 68Ga-PSMA PET/CT examination for suspected prostate cancer in the First Affiliated Hospital of the Air Force Medical University from January 2021 to November 2022 were retrospectively analyzed, with the histopathological results from transrectal ultrasound guided biopsy as reference. Lesions with Gleason scores (GS) ≥3+ 4 from the biopsy were diagnosed with csPCa, and lesions with negative biopsy or GS 6 were diagnosed with non-csPCa. MpMRI was evaluated independently by two radiologists according to the Prostate Imaging Reporting and Data System (PI-RADS) version 2.1. The radioactive uptake of 68Ga-PSMA PET/CT in prostate lesions was evaluated by SUV max. The independent-sample t test, Mann-Whitney U test and χ2 test were used to compare differences between the two groups, and then multivariate logistic regression analysis was performed. ROC curves analysis was used to analyze the diagnostic efficacies of individual and combined factors and Delong test was used. Results:There were 85 csPCa and 67 non-csPCa confirmed. Prostate specific antigen (PSA), PI-RADS score and SUV max were significantly different between the csPCa group and the non-csPCa group ( χ2=68.06, U values: -7.66, -8.98, all P<0.001). Multivariate logistic regression analysis indicated that PI-RADS score (odds ratio ( OR)=3.424, 95% CI: 1.651-7.100) and SUV max ( OR=1.931, 95% CI: 1.403-2.658) were independent predictors of csPCa (both P<0.001). ROC curves analysis revealed that the cut-off value for diagnosing csPCa was 4 for PI-RADS score and 5.6 for SUV max. The accuracy of mpMRI and PET/CT alone in csPCa diagnosis was 80%(122/152) (AUC of 0.789(95% CI: 0.711-0.866) with the sensitivity and specificity of 91%(77/85) and 67%(45/67)), and 87%(132/152) (AUC of 0.876(95% CI: 0.817-0.936) with the sensitivity and specificity of 81%(69/85) and 94%(63/67)), respectively. Several joint models incorporating 68Ga-PSMA PET/CT with mpMRI data were investigated, the model of PI-RADS 5 or PI-RADS 3-4 and SUV max>5.6 showed better performance than mpMRI and PET/CT alone and other joint models ( z values: 2.01-3.64, all P<0.05), with the accuracy of 91%(138/152) (AUC of 0.910(95% CI: 0.857-0.962) with the sensitivity and specificity of 89%(76/85) and 93%(62/67)). Conclusion:MpMRI combined with 68Ga-PSMA PET/CT can significantly improve the detection efficiency of csPCa, with the principal effect being improved in risk stratification of PI-RADS 3-4 lesions in mpMRI.
		                        		
		                        		
		                        		
		                        	
3.Effect of shared medical appointments on blood glucose levels and self-management behavior in patients with gestational diabetes mellitus
Wanying WANG ; Tingting HAN ; Xiaofan LU ; Chong XU ; Ying ZHANG ; Yalan QI ; Huaping YIN ; Huiling ZOU ; Yu SUN
Journal of Clinical Medicine in Practice 2024;28(16):109-113
		                        		
		                        			
		                        			Objective To investigate the impact of the Shared Medical Appointment (SMA) model on blood glucose levels and self-management behaviors in patients with gestational diabetes mellitus (GDM). Methods A total of 87 pregnant women diagnosed with GDM at the Obstetrics and Gynecology and Endocrinology Outpatient Departments of the Affiliated Suqian Hospital of Xuzhou Medical University from October 2021 to October 2022 were enrolled and divided into treatment group (
		                        		
		                        	
4.Current Situation,Existing Problems and Solving Strategies of the Assessment of Medical Ethics and Styles in the Examination of Doctors' Qualification
Hua GUO ; Yu HAN ; Kai REN ; Zhihao ZHOU ; Mingjie ZI ; Yujiao SONG ; Min ZHU ; Lili XYU ; Yi LI ; Tingting WANG ; Linyong YU
Journal of Traditional Chinese Medicine 2024;65(12):1292-1295
		                        		
		                        			
		                        			This paper discussed the current education status on medical ethics and styles and the assessment condition in the examination of doctors' qualification, as well as the existing problems and potential solutions by reviewing domestic and foreign literature and summarizing the practice experience. Traditionally, medical ethics and styles have always been integrated into clinical medical practice in China. However, under the modern medical education system, it is challenged to integrate traditional education on medical ethics and styles with the rules of modern medical knowledge. By summarizing the education and assessment status of medical ethics and styles in the examination of doctors' qualification, it is found that the current examination is relatively poor in the evaluation content, and the way of evaluation is not diverse, with lack of curriculum of medical humanities. The solutions suggested are enriching relevant examination content, introducing more and comprehensive evaluation method, and establishing more medical humanities-related courses. 
		                        		
		                        		
		                        		
		                        	
5.MicroRNA-141-5p/ABCG1 reverses imatinib resistance in K562 chronic myeloid leukemia cells
Han Xu ; Tingting Xu ; Wanjie Wang ; Jing Bao
Acta Universitatis Medicinalis Anhui 2024;59(11):1887-1896
		                        		
		                        			Objective:
		                        			To explore the mechanism of miR-141-5p and its effect on Imatinib(IM) resistance in CML.
		                        		
		                        			Methods:
		                        			qRT-PCR was used to detect miR-141-5p mRNA levels in IM resistant and sensitive patients.Western blot was used to detect the expression of proteins such as MMP-3,MMP-9,and Bcl-2 before and after transfection in K562 and K562/G01 cells.CCK-8 was used to detect of K562 and K562/G01 cell activity;Flow cytometry assay was used to detect the binding of miR-141-5p with ABCG1;Nude mice were used to validate the effect of miR-141-5p on tumors in vivo.
		                        		
		                        			Results:
		                        			The results showed that miR-141-5p was downregulated in IMresistant CML patients and IM-resistant CML cells and overexpression of miR-141-5p could inhibit the growth of IMresistant CML cells and promote their apoptosis.Research on tumor bearing mice had shown that miR-141-5p inhibits tumor growth in vivo.Finally,it was found that miR-141-5p could directly target ABCG1 in IM-resistant CML cells to regulate CML occurrence.
		                        		
		                        			Conclusion
		                        			miR-141-5p and ABCG1 form a competing endogenous RNA(ceRNA) network to function in IM resistance,thus facilitating CML progression.
		                        		
		                        		
		                        		
		                        	
6.The application of health education with the combination of hospital WeChat platform and teach-back method in improving the quality of life of patients with prostate cancer after operation
Tingting GU ; Huiling WANG ; Yuanyuan SHEN ; Han JIANG ; Ying GU ; Jihui SHI ; Wei FENG
Chinese Journal of Practical Nursing 2024;40(18):1403-1410
		                        		
		                        			
		                        			Objective:To explore the application of 'hospital WeChat' platform combined with feedback method in improving the quality of life of patients with prostate cancer after operation, to provide suggestions for health education of patients with prostate cancer after operation.Methods:A randomized controlled trial was conducted. A total of 80 male patients who underwent radical prostatectomy in the Third People's Hospital of Yancheng City from June 2022 to July 2023 were selected by convenient sampling method. They were divided into control group and experimental group by random number method, with 40 cases in each group. The control group used routine nursing health education, the experimental group used the 'hospital WeChat' platform combined with feedback method for health education. The severity of urinary incontinence, quality of life, and satisfaction with health education after discharge were compared between the two groups.Results:Forty patients in each group completed the study. The age of the control group was (73.40 ± 4.02) years old, and the age of the experimental group was (73.25 ± 4.02) years old. The urinary incontinence scores of the experimental group at 1 week, 1 month and 3 months after discharge were (14.00 ± 1.41), (11.90 ± 1.34) and (5.13 ± 3.45) points, respectively, which were significantly different from those of the control group (16.10 ± 2.04), (15.00 ± 1.20) and (10.90 ± 3.70) points, the differences were statistically significant ( t=-5.36, -10.93, -7.23, all P<0.05). The total scores of quality of life in the experimental group at 1 and 3 months after discharge were (77.51 ± 6.11) and (79.53 ± 5.42) points, which were significantly higher than (67.70 ± 6.62) and (69.05 ± 6.92) points in the control group, the differences were statistically significant ( t=6.89, 7.62, both P<0.05). The satisfaction scores of health education mode, attitude and evaluation items in the experimental group after discharge were (5.03 ± 0.70), (4.95 ± 0.81) and (5.33 ± 0.86) points, respectively, which were higher than those in the control group (3.93 ± 1.00), (3.65 ± 1.10) and (3.80 ± 0.72) points, the differences were statistically significant ( t=5.72, 6.01, 8.59, all P<0.05). Conclusions:The 'hospital WeChat' platform combined with feedback method can effectively improve the urinary incontinence of patients after prostate cancer surgery, and improve the quality of life and satisfaction of health education for patients. This study is hopeful to provide specific measures for health education for clinical prostate cancer patients.
		                        		
		                        		
		                        		
		                        	
7.Determination of sodium hyaluronate injection by enzymatic hydrolysis-HPLC
Jing ZHANG ; Tingting QIN ; Xiaojie HAN
Drug Standards of China 2024;25(5):495-500
		                        		
		                        			
		                        			Objective:To establish a determination method for sodium hyaluronate injection.Methods:Sodium hyaluronate was specifically hydrolyzed by hyaluronidase,and the optimal enzymolysis conditions were enzymolysis at 37 ℃ for 4 h at 100 IU·mg-1 of enzyme reaction concentration.The analysis was performed on a of Shodex sug-ar SH1011 column(300 mm ×8 mm,6 μm)with a mobile phase of 1%H3PO4 at a flow rate of 0.6 mL·min-1.The eluent was detected at 230 nm.Results:Linear ranges were 101.38-1 013.76 μg·mL-1(r=0.999 5),RSDs of precision,stability and repeatability tests were lower than 1%,and average recovery was 100.4%,RSD=2.0%(n=9).The RAD of determination results of this method and colorimetric was 0.1%-1.2%.Conclusions:The method is accurate and reproducible,and can be used for the determination of sodium hyalur-onate injection.
		                        		
		                        		
		                        		
		                        	
8.Construction and Verification of Differential Diagnosis Model of Mycobacterium Avium-Intracellular Complex Group Lung Disease and Primary Pulmonary Tuberculosis Based on CT Features and Machine Learning
Jiacheng ZHANG ; Tingting HUANG ; Xu HE ; Dingsheng HAN ; Qian XU ; Fukun SHI ; Dailun HOU ; Lan ZHANG
Chinese Journal of Medical Imaging 2024;32(10):1007-1013,1039
		                        		
		                        			
		                        			Purpose To construct and validate a machine learning-based diagnostic model for distinguishing between Mycobacterium avium-intracellular complex pulmonary disease(MAC-PD)and pulmonary tuberculosis(PTB)via chest CT images.Materials and Methods Retrospective data from patients diagnosed with MAC-PD and PTB between May 2021 and August 2022 at Beijing Chest Hospital,Capital Medical University,which were collected as the training set.The prospective external validation set was obtained from patients at the First Affiliated Hospital of Henan University of Chinese Medicine between September 2022 and May 2023.Clinical and radiological data were analyzed,and multivariable logistic regression,random forest and support vector machine(SVM)models were established and externally validated using the validation set.The diagnostic performance of models were evaluated using receiver operating characteristic curve and precision-recall curve,and the differences of the areas under the curve of various models were compared via the Delong test.Results There were significant differences in age and hemoptysis rate between the two groups(t=30.414,P<0.001;χ2=6.186,P=0.013).There were statistically significant differences in cavity types and morphology between the two groups(χ2=6.546,P=0.011;χ2=24.113,P<0.001),but there was no significant difference in the distribution and characteristics of cavitary lesions(P>0.05).There were significant differences in the types and distribution of bronchiectasis between the two groups(χ2=4.634,P=0.031;χ2=23.145,P<0.001).Compared with logistic regression and random forest models,the SVM model had better differential diagnostic performance,and the area under the receiver operating characteristic curve,sensitivity,specificity,accuracy,positive predictive value and negative predictive value were 0.960(95%CI 0.935-0.985),85.7%,93.6%,90.5%,93.3%,88.0%and 0.885(95%CI 0.803-0.967),respectively,76.7%,80.0%,78.3%,79.3%,77.4%.The precision-recall curve showed that the SVM model had high precision and low recall,that was,the model performs well.Conclusion The machine learning-based models exhibits excellent diagnostic performance and can assist in differentiating MAC-PD and PTB.
		                        		
		                        		
		                        		
		                        	
9.Study on Mechanism of Zuogui Jiangtang Jieyu Prescription in Modulating Dopamine Receptors to Ameliorate Neuroinflammation in Rats of Diabetes Mellitus Complicated with Depression
Ping LI ; Manshu ZOU ; Tingting WANG ; Haipeng GUO ; Tingting REN ; Yingxi LIU ; Yingjuan TANG ; Ying HE ; Yuhong WANG ; Yuanshan HAN
Chinese Journal of Information on Traditional Chinese Medicine 2024;31(12):112-119
		                        		
		                        			
		                        			Objective To explore the effect and related mechanism of Zuogui Jiangtang Jieyu Prescription on neuroinflammation of nucleus accumbens in rats with diabetes mellitus(DM)complicated with depression based on dopamine receptor.Methods DM,depression and DM complicated with depression models were respectively established through a combination of high-fat feeding and streptozotocin intraperitoneal injection,as well as chronic unpredictable mild stress+solitary cage feeding.The rats were divided into control group,depression group,DM group,DM complicated with depression group,positive group,D1R agonists group,D2/3R agonists group and Zuogui Jiangtang Jieyu Prescription group.Depression and learning and memory abilities in rats were assessed using open field experiments,forced swimming experiments and water maze experiments.Neuronal damage in nucleus accumbens was detected through HE and Nissl staining.Serum contents of 5-hydroxytryptamine(5-HT),dopamine(DA),interleukin(IL)-1β and IL-18 were detected by ELISA.The expressions of D1R,D2R,D3R and Iba1/NLRP3 in nucleus accumbens were detected by immunofluorescence.The protein expressions of D1R,D2R,D3R,NLRP3,ASC,Caspase-1 p20 and IL-1β in nucleus accumbens were detected by Western blot.Results Compared with the control group,the changes of fasting blood glucose(FBG)in rats of DM complicated with depression group significantly increased(P<0.01),the total distance and number of activities in the open field experiment,the time ratio of staying in the original platform quadrant and the number of times crossed the original platform in the water maze experiment significantly decreased(P<0.05,P<0.01),the forced swimming immobility time and the escape latency period in the water maze experiment were prolonged(P<0.05,P<0.01),the contents of serum 5-HT and DA significantly decreased(P<0.01),the contents of IL-1β and IL-18 significantly increased(P<0.05,P<0.01),neurons in the nucleus accumbens showed nuclear condensation,degeneration,and increased necrotic cells,with loss of Nissl bodies,the expressions of D1R,D2R and D3R were significantly decreased(P<0.01),while the expressions of NLRP3,ASC,Caspase-1 p20 and IL-1β protein significantly increased(P<0.05,P<0.01).Compared with the DM complicated with depression group,the changes of FBG significantly decreased in the Zuogui Jiangtang Jieyu Prescription group,learning and memory abilities were enhanced,depression-like behavior was improved,and the damage to neurons in the nucleus accumbens was reduced,the contents of serum 5-HT and DA significantly increased(P<0.01),the contents of IL-1β and IL-18 significantly decreased(P<0.01),the expressions of D1R,D2R and D3R in the nucleus accumbens increased(P<0.05,P<0.01),and the expressions of NLRP3,ASC,Caspase-1 p20 and IL-1β protein decreased(P<0.05,P<0.01).Conclusion The dopaminergic system dysfunction and neuroinflammation are the key mechanisms of DM complicated with depression.Zuogui Jiangtang Jieyu Prescription may improve neuroinflammation by regulating the dopamine receptor to inhibit the activation of microglial NLRP3 signaling in the nucleus accumbens.
		                        		
		                        		
		                        		
		                        	
10.Utility of lactate dehydrogenase,creatine kinase,and neuron-specific enolase levels in cerebrospinal fluid in differential diagnosis of purulent meningitis and tuberculous meningitis
Yali WANG ; Lining CHONG ; Tingting WANG ; Guomei MA ; Jingzhe HAN
Chinese Journal of Infection and Chemotherapy 2024;24(3):265-270
		                        		
		                        			
		                        			Objective To compare the differences in the levels of lactate dehydrogenase(LDH),creatine kinase(CK),and neuron-specific enolase(NSE)in the cerebrospinal fluid(CSF)between the patients with purulent meningitis(PM)and those with tuberculous meningitis(TBM)and evaluate the utility of the three biomarkers in the differentiation of PM and TBM.Methods Thirty-five PM patients and 45 TBM patients who attended the Department of Neurology from December 2019 to December 2021 were enrolled in this study.The CSF samples were collected from the patients before treatment.The levels of LDH,CK,NSE,and glucose,protein,and chloride in CSF were measured and compared between PM and TBM patients.The correlation between the biomarkers in CSF was analyzed by Pearson correlation coefficient.Linear regression analysis was performed to analyze the risk factors for the occurrence of TBM.Receiver operating characteristic(ROC)curves were plotted to evaluate the discriminative value of CSF LDH,CK,NSE alone or in combination in differential diagnosis of PM and TBM.Results Patient age,gender,clinical features such as fever,pathological signs,vomiting,limb twitching,and CSF levels of glucose and protein did not show significant difference between TBM patients and PM patients(P>0.05).TBM was associated with significantly higher LDH and NSE levels in CSF and significantly lower CK level and chloride in CSF compared to PM(P<0.05).Pearson correlation analysis showed that LDH level in CSF was negatively correlated with CK and chloride(r<0,P<0.05),and positively correlated with NSE(r>0,P<0.05).CK was negatively correlated with NSE(r<0,P<0.05),and positively correlated with chloride(r>0,P<0.05).NSE was negatively correlated with chloride(r<0,P<0.05).Linear regression analysis showed that LDH,CK,NSE,and chloride levels in CSF were all associated with the occurrence of TBM(P<0.05).ROC curves demonstrated that the AUCs of CSF levels of LDH,CK,NSE alone and in combination for differentiation between PM and TBM were 0.849(95%CI:0.768-0.930),0.858(95%CI:0.779-0.937),0.851(95%CI:0.771-0.931),and 0.954(95%CI:0.911-0.996),respectively.Conclusions The clinical features are similar for PM and TBM patients.However,the levels of LDH,CK,and NSE in CSF are different between PM and TBM.LDH,CK,NSE in combination may improve the differential diagnosis between PM and TBM.
		                        		
		                        		
		                        		
		                        	
            

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