1.Pharmacokinetic study of 3 blood-absorbed components of Xiangshao sanjie oral liquid in rats with hyperplasia of mammary gland
Yu ZHANG ; Jiaming LI ; Dan PENG ; Ruoqiu FU ; Yue MING ; Zhengbi LIU ; Jingjing WANG ; Shiqi CHENG ; Hongjun XIE ; Yao LIU
China Pharmacy 2025;36(6):680-685
OBJECTIVE To explore the pharmacokinetic characteristics of 3 blood-absorbed components of Xiangshao sanjie oral liquid in rats with hyperplasia of mammary gland (HMG). METHODS Female SD rats were divided into control group and HMG group according to body weight, with 6 rats in each group. The HMG group was given estrogen+progesterone to construct HMG model. After modeling, two groups were given 1.485 g/kg of Xiangshao sanjie oral liquid (calculated by crude drug) intragastrically, once a day, for 7 consecutive days. Blood samples were collected before the first administration (0 h), and at 5, 15, 30 minutes and 1, 2, 4, 8, 12, 24 hours after the last administration, respectively. Using chlorzoxazone as the internal standard, the plasma concentrations of ferulic acid, paeoniflorin and rosmarinic acid in rats were detected by UPLC-Q/TOF-MS. The pharmacokinetic parameters [area under the drug time curve (AUC0-24 h, AUC0-∞), mean residence time (MRT0-∞), half-life (t1/2), peak time (tmax), peak concentration (cmax)] were calculated by the non-atrioventricular model using Phoenix WinNonlin 8.1 software. RESULTS Compared with the control group, the AUC0-24 h, AUC0-∞ and cmax of ferulic acid in the HMG group were significantly increased (P<0.05); the AUC0-24 h, AUC0-∞ , MRT0-∞ , t1/2 and cmax of paeoniflorin increased, but there was no significant difference between 2 groups (P>0.05); the AUC0-24 h and MRT0-∞ of rosmarinic acid were significantly increased or prolonged (P<0.05). C ONCLUSIONS In HMG model rats, the exposure of ferulic acid, paeoniflorin and rosmarinic acid in Xiangshao sanjie oral liquid all increase, and the retention time of rosmarinic acid is significantly prolonged.
2.Relationship between psychological abuse and neglect and suicidal ideation in left-behind adolescents: the mediating role of negative affect and the moderating role of different stages of adolescence
Lu PAN ; Yuhang WU ; Yuqin SONG ; Cen LIN ; Yu CEN ; Jiarui SHAO ; Cailin XIE ; Mengqin DAI ; Qiuyue FAN ; Lei TANG ; Jiaming LUO
Sichuan Mental Health 2025;38(4):374-380
BackgroundPrevious studies have identified a close relationship among psychological neglect and abuse, negative affect, different stages of adolescence, and suicidal ideation. However, the mechanisms underlying the impact of psychological abuse and neglect on suicidal ideation among left-behind adolescents remain unclear, and this field of research is still in its relative infancy. ObjectiveTo explore the relationship between psychological neglect/abuse and suicidal ideation among left-behind adolescents, as well as the mediating role of negative affect and the moderating effect of different stages of adolescence, so as to provide insights for preventing and intervening suicidal ideation in this population. MethodsFrom November 2021 to May 2022, a cluster random sampling technique was utilized to select 2 309 left-behind adolescents in western China. Assessments were conducted using the Child Psychological Abuse and Neglect Scale (CPANS), the Positive and Negative Suicide Ideation (PANSI) and the Positive and Negative Affect Schedule for Children (PANAS-C). Spearman correlation coefficients were calculated across all samples, and Process 4.1 was employed to test the mediating role of negative affect and the moderating role of different stages of adolescence in the pathway linking psychological abuse/neglect to suicidal ideation. ResultsA total of 2 119 left-behind adolescents (mean age: 14.94±1.20 years) completed the study, with males comprising 51.34% (1 088/2 119) and females 48.66% (1 031/2 119).Among left-behind adolescents, scores on CPANS psychological neglect subscale showed positive correlations with both psychological abuse subscale scores and PANAS-C negative affect subscale scores (r=0.446, 0.496, P<0.01). Additionally, CPANS psychological neglect and psychological abuse subscale scores were also positively correlated with PANSI scores (r=0.487, 0.508, P<0.01). Furthermore, PANAS-C negative affect subscale scores demonstrated a positive correlation with PANSI scores (r=0.499, P<0.01). Negative affect partially mediated the relationship between psychological abuse/psychological neglect and suicidal ideation, with effect sizes of 0.166 (95% CI: 0.141~0.191) and 0.131 (95% CI: 0.112~0.152). Different stages of adolescence moderated the latter part (negative emotion → suicidal ideation) of the indirect mediation path from psychological neglect to suicidal ideation through negative affect (β=-0.066, P<0.01). ConclusionBoth psychological neglect and psychological abuse may influence suicidal ideation among left-behind adolescents via negative affect. Moreover, different stages of adolescence may moderate the indirect path from psychological neglect to suicide ideation through negative affect.
3.Progress of Pulpal Disease Treatment in Young Permanent Teeth
Jiaming WAN ; Chun XIE ; Jiarong LIU
Acta Medicinae Universitatis Scientiae et Technologiae Huazhong 2024;53(1):129-132
Young permanent teeth are not fully developed due to their short eruption,characterized by a relatively large pulp cavity,high and pointed pulp horns,and open apical foramina.Due to caries,abnormal tooth development or trauma,the dental pulp may be damaged or infected,which may lead to pulp necrosis and directly affect the normal tooth root formation.Therefore,the treatment of dental pulp disease in young permanent teeth poses a huge clinical challenge.The goal of clinical treatment is to promote continued root development of the affected tooth,thicken the root canal walls,and close the api-cal foramina.This article reviews the treatment options for reversible and irreversible pulpitis caused by pulp exposure,aiming to provide a reference for the treatment of pulp lesions in young permanent teeth,focusing on preserving healthy pulp and pro-moting pulp repair and regeneration.
4.Effect of combined use of midazolam and remifentanil without muscle relaxants on tracheal intubation in female patients undergoing breast surgery
Lijun FU ; Zuying LIU ; Jiaming FAN ; Yanle XIE ; Xiaoyin XU ; Xiaochong FAN
Chinese Journal of Primary Medicine and Pharmacy 2024;31(4):570-573
Objective:To investigate the effect of combined use of midazolam and remifentanil without muscle relaxant on tracheal intubation in female patients undergoing breast surgery.Methods:A retrospective analysis was performed on 40 female patients with breast disease who underwent tracheal intubation and general anesthesia at The First Affiliated Hospital of Zhengzhou University between January 2023 and June 2023. These patients were divided into a control group ( n = 20) and an observation group ( n = 20) based on whether muscle relaxants were applied at the time of intubation. The control group received intravenous rocuronium bromide, whereas the observation group did not use muscle relaxants. Both groups were intravenously administered midazolam (0.1 mg/kg) and remifentanil (4 μg/kg) prior to tracheal intubation. The intubation conditions were evaluated based on factors such as the ease of inserting the laryngoscope and the patient's response to intubation, including coughing. Results:There were no statistically significant differences in age, height, and body mass between the two groups (all P > 0.05). The excellent rate of intubation conditions was significantly lower in the observation group compared with the control group [45% (9/20) vs. 85% (17/20), χ2 = 7.03, P = 0.008). The good rate of intubation conditions was significantly higher in the observation group compared with the control group [40% (8/20) vs. 5% (1/20), χ2 = 7.03, P < 0.05]. There was no statistically significant difference in the excellent and good rates of intubation conditions between the observation and control groups [85% (17/20) vs. 90% (18/20), χ2 = 0.23, P > 0.05]. No significant difference in intraoperative awareness score was observed between the observation and control groups [(2.59 ± 0.44) points vs. (2.61 ± 0.31) points, P > 0.05]. None of the patients in either group exhibited any episodes of arrhythmias. Furthermore, no adverse reactions such as muscle stiffness, nausea, vomiting, or skin itching were observed in either group following the surgical procedure. Conclusion:Without the use of muscle relaxants, intravenous administration of midazolam at 0.1 mg/kg and remifentanil at 4 μg/kg for tracheal intubation in female patients undergoing breast surgery can offer excellent intubation conditions, ensuring that the patient remains unconscious throughout the surgical procedure.
5.Preliminary application of three-dimensional ultrasound fusion imaging visualization technology guiding precise needle placement for thermal ablation of hepatocellular carcinoma
Yueting SUN ; Yuqing GUO ; Jiaming LIU ; Ming LIU ; Longfei CONG ; Baoxian LIU ; Xiaoyan XIE ; Guangliang HUANG
Chinese Journal of Ultrasonography 2024;33(2):158-164
Objective:To preliminarily explore the clinical value of three-dimensional ultrasound fusion imaging(3DUS FI) visualization technology in guiding precise needle placement during thermal ablation of hepatocellular carcinoma (HCC).Methods:A total of 56 HCC patients (59 lesions)who underwent 3DUS FI guided thermal ablation were retrospectively analyzed in the First Affiliated Hospital of Sun Yat-sen University from November 2019 to December 2021. All patients were collected with three-dimensional ultrasound volume image before ablation which were fused with real-time two-dimensional ultrasound image for registration, and then the tumor and the safety margin of 5 mm were segmented and marked. Finally, the thermal ablation was performed under three-dimensional visualization. Contrast-enhanced CT/MRI was performed 1 month after thermal ablation to evaluate whether the lesion was completely ablated and measure the ablative margin, and the relationship between ablative margin and the incidence of local tumor progression (LTP) was also analyzed.Results:During the ablation, all lesions could be successfully registered and displayed in three-dimension. Postoperative contrast-enhanced ultrasound showed that all lesions were completely ablated. A total of 37 lesions could be evaluated for ablative efficacy and ablative margin based on contrast-enhanced CT/MRI 1 month after themal ablation, of which 32 (86.5%) lesions achieved complete ablation and obtained at least 5 mm ablative margin. During the follow-up period, LTP was occurred in 4 lesions, 3 of the lesions occurred at the ablative margin< 5 mm. Both 1-year and 2-year cumulative LTP rates were all 7.1%. None of patients had serious complications or deaths associated with thermal ablation.Conclusions:3DUS FI real-time guidance technology is feasible and safe in visually guiding precise needle placement during thermal ablation of HCC.
6.A comparative study of clinical features and lymph node metastasis risk between early multi-primary and singlee pulmonary adenocarcinoma nodules
Jiaming YANG ; Shi XIE ; Haishen ZHOU ; Jiaqing ZHANG
The Journal of Practical Medicine 2024;40(22):3208-3214
Objective To investigate the clinical characteristics and risk of lymph node metastasis in patients with multiple primary lung adenocarcinoma nodules compared to those with a single lung adenocarcinoma nodule.Methods Retrospective analysis was conducted on 212 patients who underwent thoracic surgery at Zhujiang Hospital of Southern Medical University from 2022 to 2023.This included 149 cases of single lung adenocarcinoma nodules and 63 cases of multiple primary lung adenocarcinoma nodules.After propensity score matching,a comparison was made between the two groups in terms of imaging features,tumor serological indicators,pathological immunohis-tochemistry,and lymph node metastasis rate.Additionally,binary logistic regression was employed to explore the differences in lymph node metastasis rate between single and multiple nodules.Results After propensity score matching,statistically significant differences were observed in the Avr value of CT(P=0.001),KI-67 expression level(P<0.001),PD-L1 expression level(P=0.002),and lymph node metastasis rate(P=0.030)between the two groups.However,there were no statistically significant differences in nodule type,imaging features such as lobula-tion and vascular clustering,tumor serological indicators including CEA and NSE,ALK positive rate,and SYN posi-tive rate.The variables with significant differences(Avr,Ki-67,PD-L1)were identified through Spearman test for correlation analysis.Binary logistic regression analysis was performed using lymph node metastasis as the dependent variable and single or multiple nodules as categorical covariates along with the three correlated variables included as independent variables interactively.The results showed that the probability of lymph node metastasis in multiple primary lung adenocarcinoma nodules was 80.8%lower than that in single lung adenocarcinoma nodules(RR=0.192,P=0.042).Conclusions Multiple primary adenocarcinoma nodules exhibit a less aggressive biological behavior compared to solitary adenocarcinoma nodules,resulting in a reduced likelihood of lymph node metastasis.For cases involving multiple primary lung adenocarcinoma nodules,the implementation of aggressive surgical protocols is not advisable;instead,personalized treatment plans should be developed based on comprehensive evaluations including intraoperative frozen pathology and imaging.
7.Vonoprazan 10 mg or 20 mg vs. lansoprazole 15 mg as maintenance therapy in Asian patients with healed erosive esophagitis: A randomized controlled trial
Yinglian XIAO ; Jiaming QIAN ; Shutian ZHANG ; Ning DAI ; Jai Hoon CHUN ; Chengtang CHIU ; Fung Chui CHONG ; Nobuo FUNAO ; Yuuichi SAKURAI ; D. Jessica EISNER ; Li XIE ; Minhu CHEN
Chinese Medical Journal 2024;137(8):962-971
Background::Erosive esophagitis (EE) is a gastroesophageal reflux disease characterized by mucosal breaks in the esophagus. Proton pump inhibitors are widely used as maintenance therapy for EE, but many patients still relapse. In this trial, we evaluated the noninferiority of vonoprazan vs. lansoprazole as maintenance therapy in patients with healed EE. Methods::We performed a double-blind, double-dummy, multicenter, phase 3 clinical trial among non-Japanese Asian adults with endoscopically confirmed healed EE from April 2015 to February 2019. Patients from China, South Korea, and Malaysia were randomized to vonoprazan 10 mg or 20 mg once daily or lansoprazole 15 mg once daily for 24 weeks. The primary endpoint was endoscopically confirmed EE recurrence rate over 24 weeks with a noninferiority margin of 10% using a two-sided 95% confidence interval (CI). Treatment-emergent adverse events (TEAEs) were recorded.Results::Among 703 patients, EE recurrence was observed in 24/181 (13.3%) and 21/171 (12.3%) patients receiving vonoprazan 10 mg or 20 mg, respectively, and 47/184 (25.5%) patients receiving lansoprazole (differences: -12.3% [95% CI, -20.3% to-4.3%] and -13.3% [95% CI, -21.3% to -5.3%], respectively), meeting the primary endpoint of noninferiority to lansoprazole in preventing EE recurrence at 24 weeks. Evidence of superiority (upper bound of 95% CI <0%) was also observed. At 12 weeks, endoscopically confirmed EE recurrence was observed in 5/18, 2/20, and 7/20 of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. TEAEs were experienced by 66.8% (157/235), 69.0% (156/226), and 65.3% (158/242) of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. The most common TEAE was upper respiratory tract infection in 12.8% (30/235) and 12.8% (29/226) patients in vonoprazan 10 mg and 20 mg groups, respectively and 8.7% (21/242) patients in lansoprazole group.Conclusion::Vonoprazan maintenance therapy was well-tolerated and noninferior to lansoprazole for preventing EE recurrence in Asian patients with healed EE.Trial Registration::https://clinicaltrials.gov; NCT02388737.
8.Effects of acute normovolemic hemodilution on target-controlled infusion of etomidate blood concen-trations and adrenocortical function
Yinghui CUI ; Jiaming XU ; Tong LIU ; Haiyong TAO ; Xi-Aoyi XIE ; Shejun HU ; Xuefei WANG ; Jinghuo WANG ; Jianrong GUO
The Journal of Clinical Anesthesiology 2024;40(8):814-819
Objective To observe the effects of acute normovolemic hemodilution(ANH)on target-controlled infusion(TCI)of etomidate blood drug concentration and adrenal cortical function.Methods Sixty patients who undergo elective multisegmental spine surgery,35 males and 25 females,aged 30-60 years,BMI 20-25 kg/m2,ASA physical status Ⅰ or Ⅱ,were divided into two groups using random number table method:ANH group and control group,30 patients in each group.Both groups used a target-controlled infusion of etomidate for anesthesia induction and anesthesia maintenance.In the ANH group,ANH was performed after steady anesthesia induction,ideal Hct 28%to 30%,and transfused within 1 hour after surgery;the control group was routinely treated.The dosage of etomidate was recorded.Liquid chroma-tography-tandem mass spectrometry(LC-MS/MS)was used to detect etomidate blood concentrations at the immediate postoperative,10,20,and 30 minutes postoperative periods in the two groups,and the immedi-ate moment autologous blood collected into the storage bag,preserved in the storage bag for 1 hour,and the immediate moment transfused back in the ANH group.Plasma concentrations of cortisol(Cor),adrenocorti-cotropic hormone(ACTH),and aldosterone(ALD)were measured by chemiluminescence immunoassay(CLIA)before the induction of anesthesia,immediately after the operation,and at 1 day and 2 days postop-eratively.Results There was no significant difference in the total dosage of etomidate between the two groups.Compared with the immediate postoperative period,the plasma etomidate concentration was signifi-cantly decreased 10,20,and 30 minutes after surgery(P<0.05).Compared with the control group,the concentration increased significantly 10 minutes after surgery in the ANH group(P<0.05).The plasma concentrations of etomidate were(547.8±119.4)ng/ml at the immediate moment autologous blood collected into the storage bag,(536.7±107.8)ng/ml at the preserved in the storage bag for 1 hour,and(522.8±91.7)ng/ml at theimmediatemoment transfusedbackinthe ANHgroup.Comparedwithbeforein-duction of anesthesia,the concentration of Cor and ALD immediately after the operation decreased signifi-cantly(P<0.05)and the concentration of ACTH was significantly higher(P<0.05).There were no sta-tistically significant differences in the concentrations of Cor,ALD,and ACTH between the two groups before induction of anesthesia 1 day and 2 days postoperatively.Conclusion In the orthopedic surgery of TCI eto-midate,return transfusion of collected autologous blood transiently(about 10 minutes)increases etomidate blood concentrations,the function of adrenal cortical will recover to the preoperative level within 24 hours after the operation.
9.Comparative Study of Quality of Life Assessment Scales for Bronchiectasis and Thinking of Development of Scales Based on the Mode of Combination of Disease and Syndrome
Jiaming REN ; Yang XIE ; Nannan GUO
Journal of Traditional Chinese Medicine 2023;64(18):1872-1876
This paper summarized the current status of the commonly used quality of life assessment scales of bronchiectasis (BE) at home and abroad, and compared the characteristics and differences of each scale from the basic framework, domain, item pool, application status and quality assessment, so as to provide a basis for the development and application of scales based on the mode of combination of disease and syndrome. There are currently 12 assessment tools for evaluating the quality of life in BE with good reliability, validity, and responsiveness, but only quality of life - bronchiectasis (QOL-B) and bronchiectasis health questionnaire (BHQ) are specifically developed for BE patients. The development process of these scales is mostly rooted in western culture and modern medicine, making it difficult to highlight the characteristics and advantages of traditional Chinese medicine (TCM). The content of the scales lacks the outcome indicators that BE patients are most concerned about, and cannot fully reflect the subjective feelings of patients. The development and assessment of scales lacks clinical research data and methodological support. Under the guidance of TCM syndrome differentiation and treatment, the development of scales based on the mode of combination of disease and syndrome can emerge the characteristics of TCM, reflect the true feelings of patients, and make up for the limitations of the existing scales of BE. Therefore, based on domestic and international scales, factors of China's national conditions and cultural characteristics of TCM should be considered to develop the scale suitable for Chinese people, which requires the construction of a theoretical model for the combination of disease and syndrome, by taking patients as the center and evaluating the performance and quality of the scale.
10.Application value of choledochoscopy in the diagnosis of cholelithiasis related diseases
Wei LI ; Jiaming XIE ; Zhenyu YE ; Zhenyu FENG ; Jun PAN ; Dekang GAO ; Shaohua WEI ; Wei CHEN
Chinese Journal of Digestive Surgery 2020;19(8):882-888
Objective:To investigate the application value of choledochoscopy in the diagnosis of cholelithiasis related diseases.Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 111 patients with cholelithiasis related diseases who were admitted to the Second Affiliated Hospital of Soochow University between January 2018 and April 2019 were collected. There were 45 males and 66 females, aged (55±16)years, with the range from 20 to 89 years. The mucosal course of biliary system and the submucosal vascular density of the 111 patients were observed by choledochoscopy during operation. Observation indicators: (1) patient examinations; (2) specific case analysis. Measurement data with normal distribution were represented as Mean± SD. Count data were described as absolute numbers or percentages. Results:(1) Patient examinations: 111 patients underwent intraoperative choledochoscopy examination, and 5 patients underwent pathological examination. Five of the 111 patients had the results of intraoperative choledochoscopy examination inconsistent with results of preoperative imaging examination. (2) Specific case analysis. Case 1: the patient was diagnosed with intrahepatic and extrahepatic bile duct stones preoperatively by computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) examination. Results of intraoperative choledochoscopy examination and electronic staining under choledochoscope showed abnormal mucosa at the opening of the original cholecyst duct in the common bile duct, thickened and disordered blood vessels, which indicated the possibility of malignant transformation. Results of intraoperative rapid frozen histopathological examination showed inflammatory cell infiltration in gallbladder neck and focal glandular epithelial high-grade intraepithelial neoplasia. Results of postoperative pathological examination showed high-grade intraepithelial neoplasia of the wall of gallbladder cervical ducts, focal infiltrating myowall carcinoma and strongly positive of Cytokeratin 7 diaminobenzine staining. Case 2: results of preoperative doppler ultrasonography and MRCP showed gallbladder polyps. Intraoperative choledochoscopy examination showed gallbladder polyps with adenoma and a blood vessel at polyp root, which was diagnosed as gallbladder polyp combined with adenoma. Results of electronic staining in narrow band imaging (NBI) showed gallbladder polyps with adenoma and thick blood vessels at polyp root. Results of intraoperative rapid frozen histopathological examination showed cholesterol polyps and focal adenomatous hyperplasia. Results of postoperative pathological examination showed chronic cholecystitis with cholesterol polyps and adenomatous hyperplasia of focal glands. Case 3: results of preoperative MRCP examination showed choledocholithiasis and intrahepatic bile duct stones. Results of intraoperative choledochoscopy examination showed intrahepatic bile duct stones of large size. The patient underwent holmium laser lithotripsy and mucosal hyperplasia with soft lesion and smooth mucous epithelium was found after the stone was broken. Results of NBI and methylene electron staining showed multiple submucosal tortuous vessels in proliferative lesions behind bile duct stone. Results of intraoperative rapid frozen histopathological examination showed adenoma with high-grade intraepithelial neoplasia. Case 4: results of preoperative MRCP examination showed intrahepatic and extrahepatic bile duct stones combined with dilatation of bile duct. Results of CT examination showed multiple soft tissue density shadows of intrahepatic and extrahepatic bile ducts, which was considered as biliary papillomatosis. Results of intraoperative choledochoscopy showed small stones in the lower common bile duct and multiple segmental proliferative flocculent hyperplasia lesions on the wall of the intrahepatic and extrahepatic bile ducts. Results of electronic staining in NBI showed multiple proliferative lesions in intrahepatic and extrahepatic bile ducts and multiple curved vascular shadows under the mucosa of the lesions. Results of intraoperative rapid frozen histopathological examination showed a denomatous hyperplasia with low-grade intraepithelial neoplasia. Results of postoperative pathological examination showed adenoma with low-grade intraepithelial neoplasia. Case 5: results of preoperative magnetic resonance imaging examination showed silt-like stones in the lower part of bile duct accompanied with dilatation of intrahepatic and extrahepatic bile ducts, neck of pancreatic duct was narrowed and the remaining areas were thickened. Results of CT examination showed multiple stones in the neck of the gallbladder and in the common bile duct, accompanied by dilatation of the intrahepatic and extrahepatic bile ducts and the main pancreatic duct, and the lower end of the common bile duct was slightly narrow which mean the possibility of ampulla space occupying could not be excluded. Results of preoperative endoscopic ultrasonography examination showed soft tissue occupation at the lower end of the common bile duct which considering as the possibility of entophytic adenoma, and small stones in the common bile duct. Results of preoperative endoscopic ultrasonography biopsy showed chronic inflammation of duodenal papilla. Results of intraoperative rapid frozen histopathological examination showed chronic inflammation of duodenal papilla. Results of intraoperative choledochoscopy examination and electronic staining under choledochoscope showed smooth mucosa of duodenal papilla, without lesion. Results of intraoperative choledochoscopy examination with endobronchial ultrasonography showed clear structure of mucosa and submucosal of duodenal papilla, without lesion.Conclusion:Choledochoscopy can be used in the auxiliary diagnosis of cholelithiasis related diseases.

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