1.Herbal Textual Research and Modern Research Progress of Ostreae Concha
Hongyi ZHANG ; Bin WANG ; Jiawen LIU ; Yuan HU ; Lin CHEN ; Youping LIU ; Hongping CHEN
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(3):223-234
By consulting relevant literature of ancient herbal books and processing specifications, this paper made a systematic research and analysis of Ostreae Concha, including the name, producing area, harvesting, quality, historical evolution of processing, relevant processing specifications, modern processing technology, and changes in chemical composition and pharmacological effects before and after processing, in order to provide documentary evidence for the research on processing technology and the establishment of quality standards. According to the textual research, it is known that Ostreae Concha has a long history of being used in medicine, and there have been many aliases and local names in each historical period. Shennong's Classic of the Materia Medica(Shennong Bencaojing) began to use Muli as the correct name, which has continued to use to today, and there were also aliases such as Muge, Zuogu Muli and Haoke. Ostreae Concha has a wide range of localities and irregular harvesting periods. The ancients believed that its left shell was of superior quality, but this has not been seen in modern. And there were many kinds of processing methods of Ostreae Concha, such as grinding, roasting, calcining, frying, simmering, quenching and so on, and the calcining was still in use. The different editions of Chinese Pharmacopoeia from 1963 to 2020 contain only calcined Ostreae Concha, and the local processing specifications mainly include three kinds of processed products(calcined products, salt-soaked products and vinegar-soaked products). Modern processing research mainly focuses on process optimization, changes in chemical composition and pharmacological effects, and the research methods are relatively single. Overall, there are currently issues such as inconsistent processing standards, unclear process parameters and imperfect quality standards, which are not conducive to the quality control and standardized clinical use of Ostreae Concha. Therefore, it is necessary to further investigate the pharmacological substance basis of Ostreae Concha and its processed products in order to elucidate the processing mechanism, standardize the processing technology and improve the quality standard.
2.Finite element analysis of various root shield thicknesses in maxillary central incisor socket-shield technique
Guangneng CHEN ; Siyang LUO ; Mei WANG ; Bin YE ; Jiawen CHEN ; Yin LIU ; Yuwen ZUO ; Xianyu HE ; Jiajin SHEN ; Minxian MA
Chinese Journal of Tissue Engineering Research 2025;29(10):2052-2060
BACKGROUND:Socket-shield technique can effectively maintain labial soft and hard tissues,but the incidence of postoperative complications such as exposure and displacement of root shield is relatively high.It is speculated that the root shield may be exposed and displaced due to excessive load after long-term function of dental implants. OBJECTIVE:Through three-dimensional finite element analysis,we aim to study the influence of varying root shield thicknesses on the stress distribution,equivalent stress peaks,and displacement in the root shield,periodontal ligaments,implant,and surrounding alveolar bone under normal occlusal loading.We also attempt to analyze the correlation between the thickness of the root shield and occurrence of mechanical events such as root shield exposure,displacement,and fracture. METHODS:Cone-beam CT data of a patient who met the indication standard of socket-shield technique for maxillary central incisor were retrieved from database.Reverse engineering techniques were used to build models of the maxillary bone and root shield,while forward engineering was used to create models for the implant components based on their parameters.Models depicting various root shield thicknesses(0.5,1.0,1.5,and 2.0 mm)were created using Solidworks 2022 software.ANSYS Workbench 2021 software was then used to simulate and analyze the effects of varying root shield thicknesses on stress distribution,equivalent stress peaks,and displacement of the root shields,periodontal ligaments,implants,and surrounding alveolar bone under normal occlusion. RESULTS AND CONCLUSION:(1)In all root shield models,the stress was concentrated on the palatal cervical side,both sides of the edges and the lower edge of the labial side.As the thickness of the root shield increased,the equivalent stress peak and displacement showed a decreasing trend.The 0.5 mm thickness model produced a stress concentration of 176.20 MPa,which exceeded the yield strength(150 MPa)of tooth tissue.(2)The periodontal ligament stress in each group was concentrated in the neck margin and upper region.With the increase of root shield thickness,the equivalent stress peak and displacement of periodontal ligament showed a decreasing trend.(3)Implant stress in all models was concentrated in the neck of the implant and the joint of the implant-repair abutment,and the labial side was more concentrated than the palatal side.With the increase of root shield thickness,the equivalent stress peak of the implant in the model showed an increasing trend.(4)In each group of models,stress of cortical bone concentrated around the neck of the implant and the periphery of the root shield,and the labial side was more concentrated than the palatal side.With the increase of the thickness of the root shield,the equivalent stress peak around the root shield decreased;the peak value of the equivalent stress of the bone around the neck of the implant showed an increasing trend.In the model,the stress of cancellous bone was mainly concentrated around the neck of the lip of the implant,the top of the thread,the root tip and the lower margin of the root shield,and the labial side was more concentrated than the palatal side.With the increase of the thickness of the root shield,the peak value of the equivalent stress of the bone around the root shield in the model showed a decreasing trend.The minimum principal stress of cortical bone in each group of models was concentrated around the neck of the implant,exhibiting a fan-shaped distribution.As the thickness of the root shield increased,the minimum principal stress of cortical bone showed an increasing trend.(5)These results indicate that different thicknesses of the root shield have different biomechanical effects.The root shield with a thickness of 0.5 mm is easy to fracture.For patients with sufficient bone width,the root shield with a thickness of 2.0 mm is an option to reduce the risk of complications such as root shield exposure,fracture,and displacement.Meanwhile,it should be taken into account to protect the periodontal ligament in the preparation process,and rounding treatments ought to be carried out on both sides and the lower edge of the root shield.
3.Research on the value of narrative medicine in bridging differences in shared decision-making
Shan LUO ; Dabin WANG ; Jiawen ZHANG ; Fang XIE ; Hong LIU
Chinese Medical Ethics 2025;38(6):679-686
Shared Decision-Making (SDM) is a crucial concept in modern medicine, emphasizing the joint participation of doctors and patients in the medical decision-making process. However, the authoritative position of doctors and the passive role of patients in traditional medical models often overlook the personal wishes and needs of patients, leading to tense doctor-patient relationships and medical disputes. By listening to and understanding their stories, narrative medicine helps doctors gain a more comprehensive understanding of patients’ situations and balances medical advice with patient needs in the decision-making process. Through systematic literature analysis and theoretical exploration, this paper investigated the application effects and mechanisms of narrative medicine in different medical contexts, as well as analyzed its specific role in the process of SDM. The aim is to explore the value of narrative medicine in bridging differences in SDM, revealing its role in promoting doctor-patient communication, enhancing decision-making participation, and improving medical outcomes. Researches had found that narrative medicine enhanced doctors’ “narrative ability”, promoted emotional communication and trust between doctors and patients, reduced conflicts and misunderstandings in decision-making, and improved patients’ sense of participation and trust, thus playing an important role in SDM. Therefore, by enhancing doctor-patient communication and understanding, promoting SDM and treatment selection between doctors and patients, personalized care and treatment optimization, advocating for doctor-patient co-construction, improving consultation efficiency, restoring the patient’s subject position, and other methods, it can bridge doctor-patient differences, promote communication and enhance decision-making participation, and improve medical outcomes and patient satisfaction.
4.Research on the mediating effect of clinicians’ empathy ability between medical narrative competence and humanistic care quality
Ziqi LI ; Jiawen LIU ; Zixuan LI ; Yun LIU
Chinese Medical Ethics 2025;38(10):1365-1372
ObjectiveTo explore the mediating effect of empathy ability on clinicians’ medical narrative competence and humanistic care quality, and to provide data support for the improvement of clinicians’ empathy ability, narrative competence, and humanistic care quality. MethodsEmploying a convenience sampling method, a questionnaire survey was conducted among clinicians in Hebei province using a general data questionnaire, the Chinese Physician Narrative Behavior Scale, the Chinese version of the Jefferson Scale of Empathy, and the Humanistic Care Quality Scale. SPSS 21.0 software was used to analyze the current situation and correlation of clinicians’ medical narrative competence, empathy ability, and humanistic care quality. Amos 26.0 software was utilized to construct the structural equation model, and the Bootstrap method was adopted to test this model. ResultsThe scores of clinicians’ medical narrative competence, empathy ability, and humanistic care quality were (84.436±11.939), (106.058±18.936), and (117.652±14.087), respectively. There were significantly positive correlations between clinicians’ medical narrative competence and humanistic care quality (r = 0.530, P<0.01), between empathy ability and humanistic care quality (r=0.416, P < 0.01), as well as between medical narrative competence and empathy ability (r=0.176, P<0.01). Clinicians’ medical narrative competence had a positive predictive effect on humanistic care quality (β = 0.649, P < 0.001). The empathy ability of clinicians played a partial mediating role between medical narrative competence and humanistic care quality (β = 0.061, P < 0.001), with a mediating effect size of 0.068, accounting for 8.59% of the total effect. ConclusionClinicians’ medical narrative ability, empathy ability, and humanistic care quality are all at a moderately high level. Empathy ability plays a partially mediating role between medical narrative ability and humanistic care quality. It is suggested that clinicians’ medical narrative competence should be improved through various ways, thereby improving their humanistic care quality.
5.Molecular Mechanism of Danshen Tongluo Formula in Intervention of Coronary Artery Disease-dominated Panvascular Disease
Jiawen CHENG ; Chao LIU ; Jie WANG ; Yongmei LIU ; Wenjing LIAN ; Chengzhi HOU ; Chenyang ZHU ; Cheng MA
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(24):86-93
ObjectiveEndothelial cell dysfunction being the core link. This study explores the molecular mechanism of Danshen Tongluo formula in treating coronary artery disease-dominated panvascular disease with endothelial cell changes as the core through animal experiments and single-cell transcriptome sequencing. MethodsA rat model of coronary artery disease-dominated panvascular disease was established by ligating the left anterior coronary artery. Rats were randomized into a blank group, a model group, and a Danshen Tongluo formula (28 mg·kg-1·d-1) group. The efficacy was evaluated by examining the cardiac ultrasound, determination of the plasma level of N-terminal pro-brain natriuretic peptide, and pathological staining. After single-cell sequencing, SingleR package, public datasets, and related literature were used for annotation of the cells. Cell chat was used for intercellular communication and ligand-receptor analysis, and scmetabolism was used for metabolic analysis of endothelial cells. ResultsAnimal experiments showed that Danshen Tongluo formula reduced the N-terminal pro-brain natriuretic peptide ( NT-proBNP ) level (P<0.05), ameliorated myocardial cell damage and fibrosis, and increase left ventricular ejection fractions (LVEF) in the rat model of heart failure after myocardial infarction(P<0.05). Single-cell sequencing results showed that Danshen Tongluo formula increased the proportion of arterial endothelial cells, venous endothelial cells, and capillary-arterial endothelial cells, while reducing the proportion of capillary-venous endothelial cells. In addition, this formula increased the interaction intensity of endothelial cells with cardiomyocytes and M1 macrophages and reduced the interaction intensity of endothelial cells with fibroblasts and T cells. Danshen Tongluo formula upregulated CXCL12-CXCR4 signaling in endothelium-B cells and Ptprm-Ptprm signaling in endothelial endothelial cells, while downregulating Mif-(CD74+CXCR44) signaling in endothelium-M1 macrophages and Mif-(CD74+CD44) signaling in endothelium-M2 macrophages. It reduced the citric acid cycle, oxidative phosphorylation, and glycolysis and increased the glycolysis/oxidative phosphorylation ratio in endothelial cells. GO and KEGG enrichment analysis showed that arterial endothelial cells, venous endothelial cells, and venous capillary endothelial cells can all regulate oxidative phosphorylation, cell adhesion molecules, and tyrosine metabolism. Lymphatic endothelial cells regulate immunity and vascular constriction to participate in the metabolism of various amino acids and fatty acids. ConclusionDanshen Tongluo Formula can ameliorate coronary artery disease-dominated panvascular disease by changing the composition of endothelial cells and regulating the communication between myocardial endothelial cells and non-endothelial cells.
6.Comparative study of different treatment methods for peroneus longus tendon stump in anterior cruciate ligament reconstruction.
Peng WANG ; Zhiwei LIU ; Zhonghua SHI ; Fan ZHAO ; Jiawen WANG ; Huan LI
Chinese Journal of Reparative and Reconstructive Surgery 2025;39(12):1526-1531
OBJECTIVE:
To compare the impact of different peroneus longus tendon (PLT) stump management techniques on ankle function following arthroscopic anterior cruciate ligament (ACL) reconstruction with autologous PLT grafts.
METHODS:
A retrospective analysis was conducted on 60 patients with ACL rupture who met the inclusion criteria between August 2020 and July 2024. All patients underwent arthroscopic ACL reconstruction using the autologous PLT grafts. Patients were assigned to group A [PLT stump sutured to peroneus brevis tendon (PBT), n=30] or group B (no stump intervention, n=30). The two groups showed no significant difference ( P>0.05) in baseline data, including gender, age, body mass index, injury mechanism, affected side, preoperative American Orthopaedic Foot and Ankle Society (AOFAS) score, ankle muscle strength, ankle range of motion, and arch-related angles. Postoperative outcomes were assessed using the AOFAS score, ankle muscle strength (eversion and first-ray plantar flexion), arch-related angles (medial/lateral longitudinal and anterior/posterior arch), ankle range of motion (eversion, inversion, dorsiflexion, plantarflexion), and limb symmetry index (LSI). Change values in muscle strength, arch-related angles, and range of motion from preoperative to 12 months postoperatively were calculated for intergroup comparison.
RESULTS:
Groups A and B had comparable PLT graft lengths and diameters ( P>0.05). All patients were followed up 13-16 months (mean, 14.5 months). Postoperative complications included 1 case of incision infection, 1 case of deep vein thrombosis, and 1 case of knee stiffness in group A, 1 case of knee stiffness in group B. There was no significant difference in the overall complication incidences between groups ( P>0.05). No significant difference was found in the AOFAS scores between different time points and between groups ( P>0.05). At 12 months after operation, neither group showed significant changes from preoperative baseline in ankle strength, range of motion, or arch-related angles, and there was no significant difference in these change values between groups ( P>0.05). There was no significant difference in LSI between the two groups at 6 or 12 months postoperatively ( P>0.05).
CONCLUSION
Both suturing and leaving the PLT stump untreated during arthroscopic ACL reconstruction provided comparable ankle outcomes and well-preserved foot and ankle function.
Humans
;
Anterior Cruciate Ligament Reconstruction/methods*
;
Male
;
Retrospective Studies
;
Female
;
Adult
;
Anterior Cruciate Ligament Injuries/surgery*
;
Tendons/transplantation*
;
Range of Motion, Articular
;
Arthroscopy/methods*
;
Young Adult
;
Treatment Outcome
;
Muscle Strength
;
Transplantation, Autologous
;
Ankle Joint/surgery*
;
Middle Aged
;
Adolescent
7.Prognosis-guided optimization of intensity-modulated radiation therapy plans for lung cancer.
Huali LI ; Ting SONG ; Jiawen LIU ; Yongbao LI ; Zhaojing JIANG ; Wen DOU ; Linghong ZHOU
Journal of Southern Medical University 2025;45(3):643-649
OBJECTIVES:
To propose a new method for optimizing radiotherapy planning for lung cancer by incorporating prognostic models that take into account individual patient information and assess the feasibility of treatment planning optimization directly guided by minimizing the predicted prognostic risk.
METHODS:
A mixed fluence map optimization objective was constructed, incorporating the outcome-based objective and the physical dose constraints. The outcome-based objective function was constructed as an equally weighted summation of prognostic prediction models for local control failure, radiation-induced cardiac toxicity, and radiation pneumonitis considering clinical risk factors. These models were derived using Cox regression analysis or Logistic regression. The primary goal was to minimize the outcome-based objective with the physical dose constraints recommended by the clinical guidelines. The efficacy of the proposed method for optimizing treatment plans was tested in 15 cases of non-small cell lung cancer in comparison with the conventional dose-based optimization method (clinical plan), and the dosimetric indicators and predicted prognostic outcomes were compared between different plans.
RESULTS:
In terms of the dosemetric indicators, D95% of the planning target volume obtained using the proposed method was basically consistent with that of the clinical plan (100.33% vs 102.57%, P=0.056), and the average dose of the heart and lungs was significantly decreased from 9.83 Gy and 9.50 Gy to 7.02 Gy (t=4.537, P<0.05) and 8.40 Gy (t=4.104, P<0.05), respectively. The predicted probability of local control failure was similar between the proposed plan and the clinical plan (60.05% vs 59.66%), while the probability of radiation-induced cardiac toxicity was reduced by 1.41% in the proposed plan.
CONCLUSIONS
The proposed optimization method based on a mixed objective function of outcome prediction and physical dose provides effective protection against normal tissue exposure to improve the outcomes of lung cancer patients following radiotherapy.
Humans
;
Lung Neoplasms/radiotherapy*
;
Radiotherapy Planning, Computer-Assisted/methods*
;
Prognosis
;
Radiotherapy, Intensity-Modulated/methods*
;
Carcinoma, Non-Small-Cell Lung/radiotherapy*
;
Radiotherapy Dosage
;
Female
;
Male
;
Middle Aged
8.The impact of iron overload and ferroptosis on the development and progression of autoimmune hepatitis and their mechanism of action
Bolin WANG ; Ling LI ; Jinxia ZHU ; Jiawen ZHANG ; Zhigao LUO ; Guangwei LIU
Journal of Clinical Hepatology 2025;41(11):2384-2389
Autoimmune hepatitis (AIH) is an inflammatory disease caused by immune dysfunction, and its pathogenic mechanism remains unclear. In recent years, a large number of studies have shown that iron homeostasis imbalance and ferroptosis are closely associated with the pathogenesis and progression of AIH. This article reviews the pathological mechanism and impact of iron overload and ferroptosis in AIH, in order to provide new insights and theoretical bases for research on the mechanism and clinical treatment of AIH.
9.Effect of Liangxue Tuizi Formula (凉血退紫方) on RAF/MEK/ERK Pathway in Skin Tissue and Serum NETs Biomarkers in Henoch-Schönlein Purpura Model Rats with Blood Heat Syndrome
Yingying JIANG ; Manxiang YANG ; Zhenhua YUAN ; Leying XI ; Mingyang CAI ; Diya MA ; Yifan LI ; Yuhang NIU ; Runze LIU ; Jiawen CAO ; Xilin CHEN ; Xianqing REN
Journal of Traditional Chinese Medicine 2025;66(23):2475-2483
ObjectiveTo investigate the potential mechanism of Liangxue Tuizi Formula (凉血退紫方, LXTZF) in treating Henoch-Schönlein Purpura (HSP) by examining its regulatory effect on neutrophil extracellular trap (NETs) dysregulation via the rapidly accelerated fibrosarcoma kinase (RAF)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway. MethodsSeventy Wistar rats were randomly allocated into a blank control group (n=14) and a modeling group (n=56). Rats in the modelling group underwent an eight-week modelling period to establish HSP rat models with blood-heat syndrome via modified ovalbumin (OVA) induction method combined with oral administration of heat-property Chinese herbal medicine. Fifty successfully modeled rats were subsequently randomly divided into five groups (n=10 per group), model group, compound glycyrrhizin group, LXTZF group, RAF inhibitor group, and LXTZF + RAF agonist group. Additionally, 10 rats were selected from the original blank control group for the final experiment. From the 11th week of modelling, rats in the blank control group and the model group received 1 ml/(100 g·d) ultrapure water via oral administration, in addition to 0.5 ml/(kg·d) 0.9% sodium chloride solution via intraperitoneal injection. The LXTZF group and the compound glycyrrhizin group received 7.5 g/(kg·d) LXTZF granule suspension via gavage, 13.5 mg/(kg·d) compound glycyrrhizin suspension via gavage, respectively. The RAF inhibitor group received 1 mg/(kg·d) GW5074 suspension via intraperitoneal injection and ultrapure water via oral administration; the LXTZF + RAF agonist group received 7.5 g/(kg·d) LXTZF granule suspension via gavage and 1 mg/(kg·d) paclitaxel suspension via intraperitoneal injection. All administrations were performed once daily for 4 weeks. After intervention, skin tissue histopathology was examined by hematoxylin and eosin (H&E) staining, immunoglobulin A (IgA) deposition was assessed via immunofluorescence, serum levels of neutrophil elastase (NE), tumor necrosis factor-α (TNF-α), and vascular cell adhesion molecule-1 (VCAM-1) were measured using enzyme-linked immunosorbent assay (ELISA), serum myeloperoxidase (MPO) level was determined by a colorimetric assay; the mRNA expression levels of RAF, MEK, and ERK in skin tissue were detected by real-time quantitative polymerase chain reaction (RT-qPCR); and the protein expression of RAF, MEK, ERK, as well as phosphorylated MEK (p-MEK) and phosphorylated ERK (p-ERK), were analyzed by Western Blot. ResultsSkin tissue in the blank control group rats remained normal, whereas the model group exhibited neutrophil infiltration and haemorrhage with red blood cell rupture. In all drug intervention groups, neutrophil infiltration and haemorrhagic exudation reduced markedly, with LXTZF group demonstrating the most pronounced improvement. Compared with the blank control group, rats in the model group exhibited enhanced IgA fluorescence intensity in skin tissue, elevated serum levels of NE, MPO, TNF-α and VCAM-1, increased mRNA expression of RAF, MEK, ERK1 and ERK2, as well as heightened RAF protein levels and p-MEK/MEK and p-ERK/ERK ratios (P<0.05). Compared with the model group, the drug intervention groups exhibited reduced IgA fluorescence intensity in skin tissue, along with decreased serum levels of NE, MPO, TNF-α, and VCAM-1 (P<0.05). In LXTZF group and RAF inhibition groups, reduced mRNA expression of RAF, MEK, ERK1, and ERK2 was observed in rat skin tissue, alongside decreased RAF protein levels and reduced p-MEK/MEK and p-ERK/ERK ratios (P<0.05). Compared with LXTZF + RAF agonist group, the compound glycyrrhizin group, LXTZF group, and RAF inhibitior group exhibited reduced IgA fluorescence intensity in skin tissue, decreased serum NE, MPO, TNF-α, and VCAM-1 levels, and decreased MEK mRNA expression and p-MEK/MEK ratio (P<0.05). ConclusionThe potential mechanism by which LXTZF treats Henoch-Schönlein purpura with blood heat syndrome may involve blocking the RAF/MEK/ERK signaling pathway in skin tissue, and suppressing excessive formation of NETs, thereby reducing IgA deposition in dermal microvessels and attenuating systemic inflammatory responses.
10.Study on pharmacodynamic substances of anti-inflammatory effect of Zhuang medicine Stahlianthus involucratus based on metabolism in rats
Xingchen LIU ; Jie LIANG ; Chunyan HUANG ; Jiayi CHEN ; Jiawen PENG ; Jingjing XIE ; Yuming MA ; Sisi CHEN ; Jiali WEI
China Pharmacy 2024;35(19):2358-2364
OBJECTIVE To provide reference for basic analysis of the pharmacodynamic substance in Stahlianthus involucratus. METHODS Overall 24 SD male rats were randomly divided into blank group (purified water), and administration group (ethanol extract of S. involucratus, 15.75 g/kg, calculated by crude drug), with 12 rats in each group. They were given drug liquid/purified water intragastrically, twice a day, every 6-8 h, for consecutive 3 days. After medication, the blood, urine and fecal samples were collected from two groups of rats. UPLC-Q-Exactive-MS technology was used to identify the chemical constituents in the ethanol extract of S. involucratus, and metabolites in the blood, urine and fecal of rats after intragastrical administration of the ethanol extract of S. involucratus. Multivariate statistical analysis was employed to screen various serum metabolites. Metabolic pathways were analyzed by MetaboAnalyst 5.0 platform. RESULTS A total of 38 chemical constituents were identified from the ethanol extract of S. involucratus, including fourteen prototype components and three metabolites identified from 5 urine samples, nine prototype components identified from fecal samples, and ten prototype components and one metabolite identified from serum samples. A total of 71 differential metabolites were screened from two groups of rat serum samples, of which 44 differential metabolites, such as ferulic acid, glycyrrhizin, were up-regulated and 27 differential metabolites, such as arachidonic acid, phenylacetylglutamine, were down-regulated. The 71 differential metabolites were mainly enriched in 11 metabolic pathways, including phenylalanine metabolism, linoleic acid metabolism, arachidonic acid metabolism, and tryptophan metabolism. CONCLUSIONS Ferulic acid, liquiritigenin, isofraxidin and formononetin may be the material basis that directly exert pharmacological effects of S. involucratus. S. involucratus may exert anti-inflammatory effects by affecting metabolic pathways, including arachidonic acid metabolism and tryptophan metabolism.

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