1.Influencing factors for the prognosis of patients with drug-induced liver injury and establishment of a nomogram model
Shimei WANG ; Shuai JIN ; Junru LI ; Na WANG ; Yan CHEN ; Ying CUI ; Mingming MA ; Xiaoli HU
Journal of Clinical Hepatology 2024;40(3):562-567
ObjectiveTo investigate the influencing factors for the clinical outcome of patients with drug-induced liver injury (DILI), and to establish a nomogram prediction model for validation. MethodsA retrospective analysis was performed for the general information and laboratory data of 188 patients with DILI who were admitted to Heilongjiang Provincial Hospital Affiliated to Harbin Institute of Technology from January 2017 to December 2022, and according to their clinical outcome, they were divided into good outcome group with 146 patients and poor outcome group with 42 patients. The independent-samples t test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. Univariate and multivariate Logistic regression analyses were used to investigate the independent influencing factors for the clinical outcome of DILI patients. R Studio 4.1.2 software was used to establish a nomogram model, and calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to perform internal validation. ResultsThe univariate Logistic regression analysis showed that liver biopsy for the diagnosis of DILI, platelet count, cholinesterase, albumin, prothrombin time activity, IgM, and IgG were associated with adverse outcomes in patients with DILI. The multivariate Logistic regression analysis showed that liver biopsy for the diagnosis of DILI (odds ratio [OR]=0.072, 95% confidence interval [CI]: 0.022 — 0.213, P<0.001), clinical classification (OR=0.463, 95%CI: 0.213 — 0.926, P=0.039), alanine aminotransferase (OR=0.999, 95%CI: 0.998 — 1.000, P=0.025), prothrombin time activity (OR=0.973, 95%CI: 0.952 — 0.993, P=0.011), and IgM (OR=1.456, 95%CI: 1.082 — 2.021, P=0.015) were independent influencing factors for clinical outcome in patients with DILI. The nomogram prediction model was established, and after validation, the calibration curve was close to the reference curve. The area under the ROC curve was 0.829, and the DCA curve showed that the model had good net clinical benefit. ConclusionThe nomogram prediction model established in this study has good clinical calibration, discriminative ability, and application value in evaluating the clinical outcome of patients with DILI.
2.Bionic design,preparation and clinical translation of oral hard tissue restorative materials
Han ZHAO ; Yan WEI ; Xuehui ZHANG ; Xiaoping YANG ; Qing CAI ; Chengyun NING ; Mingming XU ; Wenwen LIU ; Ying HUANG ; Ying HE ; Yaru GUO ; Shengjie JIANG ; Yunyang BAI ; Yujia WU ; Yusi GUO ; Xiaona ZHENG ; Wenjing LI ; Xuliang DENG
Journal of Peking University(Health Sciences) 2024;56(1):4-8
Oral diseases concern almost every individual and are a serious health risk to the popula-tion.The restorative treatment of tooth and jaw defects is an important means to achieve oral function and support the appearance of the contour.Based on the principle of"learning from the nature",Deng Xu-liang's group of Peking University School and Hospital of Stomatology has proposed a new concept of"microstructural biomimetic design and tissue adaptation of tooth/jaw materials"to address the worldwide problems of difficulty in treating dentine hypersensitivity,poor prognosis of restoration of tooth defects,and vertical bone augmentation of alveolar bone after tooth loss.The group has broken through the bottle-neck of multi-stage biomimetic technology from the design of microscopic features to the enhancement of macroscopic effects,and invented key technologies such as crystalline/amorphous multi-level assembly,ion-transportation blocking,and multi-physical properties of the micro-environment reconstruction,etc.The group also pioneered the cationic-hydrogel desensitizer,digital stump and core integrated restora-tions,and developed new crown and bridge restorative materials,gradient functionalisation guided tissue regeneration membrane,and electrically responsive alveolar bone augmentation restorative membranes,etc.These products have established new clinical strategies for tooth/jaw defect repair and achieved inno-vative results.In conclusion,the research results of our group have strongly supported the theoretical im-provement of stomatology,developed the technical system of oral hard tissue restoration,innovated the clinical treatment strategy,and led the progress of the stomatology industry.
3.Finite element analysis of three different minimally invasive fixation methods for distal tibial fractures with soft tissue injury
Mingming WANG ; Zhong ZHANG ; Jianhua SUN ; Gang ZHAO ; Hua SONG ; Huadong YAN ; Bin LYU
Chinese Journal of Tissue Engineering Research 2024;28(6):879-885
BACKGROUND:The treatment of distal tibial fractures with soft tissue injury has always been challenging,and the new retrograde tibial nailing is a new choice.Up to now,there were few reports on the biomechanical properties between the new retrograde tibial nailing,anterograde intramedullary nailing and supercutaneous locking plate. OBJECTIVE:To explore the biomechanical stability of new retrograde tibial nailing,antegrade intramedullary nailing and supercutaneous locking plate in the treatment of distal tibial fractures with soft tissue injury using finite element analysis so as to offer a scientific foundation for clinical application. METHODS:The finite element model of transverse distal tibia fracture was established by relevant software utilizing the CT data of the tibia from a 42-year-old healthy male.Retrograde tibial nailing,antegrade intramedullary nailing and supercutaneous locking plate finite element models were assembled under the principle of fracture fixation.Finally,meshing,applying loads,and data processing were accomplished with the ANSYS 2019 software.Moreover,the stress distribution and displacement of the tibia and internal fixation of each model were compared. RESULTS AND CONCLUSION:(1)The displacement of fracture end in the three groups increased with the increase of load.In all mode loads,the average displacement of the fracture end was the least in the retrograde tibial nailing group,followed by the supercutaneous locking plate group,and the highest in the antegrade intramedullary nailing group.At 800 N vertical load,the displacement difference of the fracture end was statistically significant(P<0.05).There was no statistical significance in other load modes.(2)Under different loads,the tibial stress in the three groups was the highest in the middle of the tibia,and gradually decreased to the proximal and distal ends.The stress distribution of the tibial shaft was the highest in the retrograde tibial nailing group,followed by the supercutaneous locking plate group,and the least in the antegrade intramedullary nailing group.(3)Under different loads,the stress of the tibial stress raiser in the three groups was significantly higher in the supercutaneous locking plate group than in the other two groups,with statistical significance(P<0.05).(4)Under different loads,the stress of the fixators in the three groups was the largest in the supercutaneous locking plate group,followed by the retrograde tibial nailing group,and the minimum in the antegrade intramedullary nailing group.There were significant differences in the stress of fixator stress raiser among the three groups under different loading modes(P<0.05).(5)It is indicated that all three fixation methods have the good anti-rotation ability and axial stability.Retrograde tibial nail shows better biomechanical stability.
4.Biomechanical difference of different fixation methods in bone healing of distal tibial comminuted fractures analyzed by finite element method
Huadong YAN ; Zhong ZHANG ; Gang ZHAO ; Jie LI ; Hua SONG ; Jianhua SUN ; Zhi LIU ; Mingming WANG
Chinese Journal of Tissue Engineering Research 2024;28(24):3814-3821
BACKGROUND:The treatment of distal tibial comminuted fractures with soft tissue injury has always been challenging.The new retrograde tibial nailing and supercutaneous locking plate are important treatment methods,but their strain and stress shielding at the fracture end during different periods of fracture healing and different load conditions have not been reported. OBJECTIVE:To explore the biomechanical stability of retrograde tibial nailing and supercutaneous locking plate in different periods of fracture healing by finite element analysis to offer a scientific foundation for clinical application and rehabilitation exercise. METHODS:The finite element model of distal tibial comminuted fracture was established by utilizing the CT data of the tibia from a 40-year-old healthy male.Retrograde tibial nailing,supercutaneous locking plate,and callus models were assembled in accordance with the principle of fracture fixation.The finite element analysis was performed using ANSYS software to compare the displacement of the fracture end,the stress shielding of the tibia,the stress of the callus,and the stress distribution of the tibia and the fixation device during different periods of fracture healing. RESULTS AND CONCLUSION:(1)The relative displacement of the tibial fracture decreased gradually with the healing of the fracture,and the displacement decreased significantly after 3 months.At 0 and 1 months after operation,the vertical displacement and total displacement of the supercutaneous locking plate group were higher than those in the retrograde intramedullary nail group.The Z-axis displacement(horizontal medial and lateral displacement)of the two fixation methods was more obvious than the X-axis and Y-axis,and the Z-axis displacement of supercutaneous locking plate group was the most obvious.The maximum Z-axis displacement of the two fixation methods was located on the outside of the tibia,and the minimum displacement was located on the inside of the tibia.(2)The stress shielding rate at different periods of fracture healing gradually decreased with time.The stress shielding rate of the retrograde intramedullary nail was higher than that of the supercutaneous locking plate at different stages of fracture healing.After 3 months,the stress shielding rate of the supercutaneous locking plate was reduced to about 4%,and the stress shielding rate of the retrograde intramedullary nail was reduced to about 40%.(3)The stress of the stress concentration site of the callus in the two fixation methods increased with the increase of the load,and the stress of the callus in the supercutaneous locking plate group was always greater than that in the retrograde intramedullary nail group.The maximum stress distribution of the callus was approximately equally distributed among the two modes of fixation,both in the lateral portion of the tibia.(4)As the fracture healed,the maximum stress of the tibia in the two groups decreased gradually,and the stress in the supercutaneous locking plate group was always greater than that in the retrograde intramedullary nail group.The average stress of the maximum stress area of the tibia in the supercutaneous locking plate group under 1 500 N load was 285 MPa,while that in the retrograde intramedullary nail group was 26 MPa.(5)As the fracture healed,the stress of the fixation device in the two groups decreased gradually,and the stress in the supercutaneous locking plate group was significantly higher than that in the retrograde intramedullary nail group.After 3 months,the stress of the two fixation devices decreased significantly.(6)It is indicated that in the early stage of fracture healing,the strain on the fracture end in the retrograde intramedullary nail group is small,and the maximum stress of the tibia is moderate,allowing early loaded.The fractured ends in the supercutaneous locking plate group had too large strain and too large maximum stress of the tibia,which needed to be partially loaded under protection and could not be fully loaded.In the middle and late stages of fracture healing,the tibial retrograde intramedullary nail and the supercutaneous locking plate could be completely loaded,and the stress shielding rate of the supercutaneous locking plate was significantly lower than the tibial retrograde intramedullary nail.
5.Rapid Analysis of the Chemical Composition of Zhangbang Nine Steaming Nine Sun-dying Rehmanniae Radix Based on UPLC-Q-TOF-MS Technique and Study on the Function of Solid Excipiemts in Alleviating the "Nourishing and Spleen-impairing" in Rehmanniae Radix
Xudong ZHU ; Wei YAO ; Feixia YAN ; Dong HUANG ; Song WANG ; Na ZHU ; Mingming YUAN ; Liping HUANG ; Yi WU
Chinese Journal of Modern Applied Pharmacy 2024;41(10):1332-1342
OBJECTIVE
To study the chemical composition and the function of solid excipients in relieving the "nourishing and spleen-impairing" effect of Zhangbang nine steaming nine sun-dying Rehmanniae Radix(RR) by using UPLC-Q-TOF-MS technique.
METHODS
UPLC-Q-TOF-MS was used to collect the data of Zhangbang nine steaming nine sun-dying RR, and UNIFI platform and self-built database were used for the rapid qualitative analysis and identification of the chemical components of Zhangbang nine steaming nine sun-dying RR. The effect of solid excipients on the function of RR "nourishing and spleen-impairing" was investigated by establishing a mouse model of low gastric motility and measuring its gastric residual rate and small intestine propulsion rate.
RESULTS
The UPLC-Q-TOF-MS and UNFI platforms identified 76 chemical components in nine steaming nine sun-dying RR, including 9 iridoid glycosides, 11 phenylethyl glycosides, 31 flavonoids, 6 saccharides and 19 other compounds; the results of gastric emptying and small intestinal propulsion experiments on mice showed that Zhangbang nine steaming nine sun-dying RR had gastric emptying and intestinal propulsion effects.
CONCLUSION
This method can be used for the rapid identification and analysis of nine steaming nine sun-dying RR, which has solid excipients Citri Reticulatae Pericarpium and Amomi Fructus to alleviate the "nourishing and spleen-impairing" function of RR. This study can provide a reference for quality control and elucidation of the material basis of the medicinal effects of specialty beverage of Zhangbang nine steaming nine sun-dying RR.
6.Mechanism of Sanhuang Ointment in Treatment of Haemorrhoids Based on Network Pharmacology and Experimental Verification
Wenjie LI ; Qian YU ; Yi ZHENG ; Yiliu YANG ; Xinyue ZHANG ; Guangzhe LI ; Mingming YAN
Chinese Journal of Modern Applied Pharmacy 2024;41(12):1591-1603
OBJECTIVE
To predict the core ingredients, targets and signaling pathways of Sanhuang ointment in the treatment of haemorrhoids based on network pharmacology, and preliminarily discuss the mechanism of action preliminarily by means of molecular docking and experimental verification.
METHODS
Active ingredients, targets and haemorrhoid related targets of Sanhuang ointment were obtained through literature research and database screening. Association networks were constructed and core targets were screened by Cytoscape, and gene function analysis and pathway enrichment analysis were conducted. Autodock Vina was used for molecular docking verification, and the regulatory effects of Sanhuang ointment on core targets were verified by ELISA and immunohistochemistry.
RESULTS
The 77 active ingredients and 61 potential targets of Sanhuang ointment for treating haemorrhoids were collected. KEGG showed that Sanhuang ointment could regulate calcium signaling pathways, neuroactive ligand receptor interactions, cGMP-PKG pathway, etc. Affect 6 core targets of CGRP, NK-1R, TRPV1, VEGF, IL-6 and TNF-α. Molecular docking showed that Sanhuang ointment had a good affinity with target protein, and animal experiments verified that Sanhuang ointment could inhibit the expression of IL-6, CGRP, substance P, and promote the expression of VEGF.
CONCLUSION
Sanhuang ointment may act on CGRP, NK-1R and other targets, regulate Calcium signaling pathway and PI3K-Akt pathways, and exert analgesic and anti-inflammatory effects, promoting blood circulation and removing blood stasis to treat haemorrhoids.
7.Discussion on the problems and countermeasures of human genetic resource management in the field of stomatology
Lin ZHANG ; Yanhua SHAN ; Mingming XU ; Yan LIU
Chinese Journal of Medical Science Research Management 2024;37(1):14-17
Objective:To analyze the problems in human genetic resource management in the field of stomatology and explore corresponding strategies.Methods:By organizing and analyzing stomatological projects related to the disclosure of information on human genetic resources by the Ministry of Science and Technology, combined with literature analysis and interviews with research management leaders, the problems in human genetic resource management in stomatological institutions were summarized and management strategies were proposed.Results:61 projects were approved for the utilization of human genetic resources in the field of stomatology, showing an increasing trend year by year. Among them, 43 projects were approved by stomatological institutions as the team leader unit; There are problems in the management of human genetic resources in stomatological institutions, such as insufficient resource development and utilization, urgent development of biological sample banks, and incomplete resource sharing mechanisms. The interview results show that the management of human genetic resources needs to be improved, and the management departments and professional management personnel, system construction, and training need to be strengthened.Conclusions:Stomatological colleges and institutions should comprehensively coordinate the management of human genetic resources, establish a sound management system, strengthen the construction of biological sample banks, expand shared resources through multiple channels, fully utilize human genetic resources for research, and promote the high-quality development of stomatology.
8.Preliminary study on fetal heart morphology and function in pulmonary stenosis and pulmonary atresia using fetal heart quantification
Xiaomin ZHANG ; Bowen ZHAO ; Mei PAN ; Xiaohui PENG ; Ran CHEN ; Yankai MAO ; Mingming MA ; Yuanshi TIAN ; Mingxuan ZHANG ; Yan DENG
Chinese Journal of Ultrasonography 2024;33(6):489-496
Objective:To evaluate the morphological characteristics of the fetal heart and the contractile function of the left and right ventricles in fetuses with pulmonary stenosis (PS) and pulmonary atresia (PA) using fetal heart quantitative analysis technology (fetal HQ), and to assess the impact of different degrees of right ventricular outflow tract obstruction (RVOTO) on the contractile function of the fetal left and right ventricles. To accumulate early data and explore parameters for constructing a predictive model and clinical decision-making tool for the progression of fetal PS and PA.Methods:A retrospective analysis was conducted on 42 cases of mild to moderate PS and 23 cases of severe PS or PA detected through fetal echocardiography in the Department of Ultrasound, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, from July 2020 to December 2021. A control group of 195 normal fetal cases matching gestational weeks was selected. The fetal HQ technique was employed to measure the global sphericity index (GSI), left ventricular ejection fraction (EF), left/right ventricular area change percentage (LVFAC, RVFAC), and left/right ventricular longitudinal strain (LVGLS, RVGLS). Additionally, 24-segment sphericity index (SI) and fractional shortening (FS) for both left and right ventricles were measured. Comparative analyses were performed between the case and control groups, as well as within the case group.Results:In comparison with the control group, the case group exhibited significantly decreased GSI, LVGLS, LVEF, LVFAC, RVGLS, and RVFAC.The differences were statistically significant in the mild to moderate PS group (all P<0.05) and highly significant in the severe PS/PA group (all P<0.01). In the mild to moderate PS group, the left ventricle′s 2nd segment, right ventricle′s 24th segment SI, and the left ventricle′s 1st-13th segments, right ventricle′s 1st-16th and 20th-24th segments FS showed statistically significant differences compared to the control group (all P<0.05). In the severe PS/PA group, the right ventricle′s 1st-22nd segment SI, and the left ventricle′s 6th-13th, 21st-24th segments, and the right ventricle′s 1st-14th segments FS were reduced, showing statistically significant differences compared to the control group (all P<0.05). The severe PS/PA group showed lower RVGLS, RVFAC, and SI for the right ventricle′s 1st to 17th segments when compared to the mild to moderate PS group, with statistically significant differences (all P<0.05). Conclusions:Quantitative indices derived by fetal HQ is capable of evaluating the cardiac morphology and function of fetuses with PS/PA, which may provide for reference information for comprehensive understanding of cardiac morphological and functional changes in such fetuses.
9.Quantitative evaluation of left and right atrial function and its difference in normal fetus during middle and late pregnancy using two-dimensional speckle tracking echocardiography
Limei ZHOU ; Bowen ZHAO ; Mei PAN ; Xiaohui PENG ; Ran CHEN ; Mingming MA ; Yuanshi TIAN ; Yan DENG
Chinese Journal of Ultrasonography 2024;33(8):659-666
Objective:To explore the potential application of two-dimensional speckle tracking echocardiography (2D-STE) in terms of quantification and evaluating left and right atrial function in normal fetuses, and to investigate the relevant factors affecting left and right atrial function in normal fetuses as well as differences between both atrial function.Methods:A total of 100 single fetuses underwent fetal echocardiography in the Department of Diagnostic Ultrasound & Echocardiography, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine from January 2019 to October 2022 were retrospectively enrolled. The standard basal or apical four-chamber view clips were obtained, and the left and right atrial function were quantitatively analyzed using TomTec-ARENA off-line cardiac analysis software for quantitative assessment of both atrial strain measurements including left atrial reservoir phase longitudinal strain (LASr), left atrial ductal phase longitudinal strain (LAScd), left atrial systolic phase longitudinal strain (LASct), right atrial reservoir phase longitudinal strain (RASr), right atrial ductal phase longitudinal strain (RAScd), right atrial systolic phase longitudinal strain (RASct), and the ratio of systolic longitudinal strain to conduit longitudinal strain in left and right atrial systolic display groups were calculated which was denoted as Sct/Scd.Routine fetal obstetric ultrasound measurements and fetal echocardiographic parameters in the two groups were obtained including fetal heart rate (FHR), left atrial end-systolic length (LAESL), left atrial end-systolic diameter (LAESD), left atrial end-systolic area (LAESA), left ventricular end-diastolic transverse diameter (LVEDD), right atrial end-systolic length (RAESL), right atrial end-systolic diameter (RAESD), right atrial end-systolic area (RAESA), right ventricular end-diastolic transverse diameter (RVEDD), peak blood flow velocity of mitral valve and tricuspid valve in early and late diastolic period (E, A), peak ratio of E and A: E/A (MV), E/A (TV), and the difference between the left and right atrial strain indices and the routine fetal obstetric ultrasound and fetal echocardiographic parameters, as well as the correlation between the above parameters and gestational age were analyzed. The repeatability tests were performed using the intra-class correlation coefficientt (ICC).Results:Significant differences were found in LASr and RASr, LAScd and RAScd, LASct and LAScd, Sct/Scd between the left atrium and right atrium, E/A (MV) and E/A (TV), LAESD and RAESD, LAESL and RAESL (all P<0.05), there was significant difference in FHR between the left atrial contraction display group and the no atrial contraction display group ( P=0.011), no significant difference in other parameters (all P>0.05). Correlation analysis showed that, LASr, LASct, RASr, and RASct showed moderate negative correlation with gestational age ( rs=-0.570, -0.601, -0.469, -0.568; all P<0.001). While LAScd, RAScd, E/A (MV), E/A (TV) were moderately positively related with gestational age ( rs=0.310, 0.350, 0.330, 0.343; all P<0.05). LAESL, LAESD, LAESA, RAESL, RAESD, RAESA, LVEDD and RVEDD were significantly positively related with gestational age ( rs=0.662, 0.768, 0.792, 0.728, 0.828, 0.822, 0.838, 0.802, all P<0.001). The inter-examiner ICC of fetal LASr and RASr were 0.89 and 0.84 (both P<0.05) and the intra-examiner ICC of fetal RASr and LASr both were 0.80 (both P<0.05), with good consistency. Conclusions:2D-STE is highly feasible and reproducible in assessing fetal atrial function. The corresponding variation values of fetal atria at different gestational weeks were obtained in this study, which provides a new reference index for us to further study normal fetal atria as well as comparative analysis of fetal cardiac function under prenatal pathological conditions.
10.Transabdominal-transvaginal ultrasound cervical length sequential screening to predict the risk of spontaneous preterm birth in singleton pregnancy women with low risk of preterm birth
Lan YANG ; Yuan WANG ; Yan ZHANG ; Huirong TANG ; Ya WANG ; Lianlian WANG ; Taishun LI ; Mingming ZHENG ; Yali HU ; Chenyan DAI ; Yan XU
Chinese Journal of Obstetrics and Gynecology 2024;59(9):667-674
Objective:To investigate the feasibility of predicting the risk of spontaneous preterm birth in singleton pregnancy women with low risk of preterm birth by transabdominal-transvaginal ultrasound cervical length sequential screening in the second trimester.Methods:This prospective longitudinal cohort study included singleton pregnant women at 11-13 +6 gestational weeks who were admitted to Nanjing Drum Tower Hospital from January 2023 to September 2023. Transabdominal and transvaginal cervical lengths were measured during the mid-trimester fetal ultrasound scan at 18-24 weeks, and pregnancy outcomes were obtained after delivery. A short cervix was defined as a transvaginal cervical length of ≤25 mm, and the outcomes were defined as spontaneous preterm birth occurs between 20 and 36 +6 weeks and extremely preterm birth before 32 weeks. The area under the receiver operating characteristic (ROC) curve was used to evaluate the effectiveness of predicting spontaneous preterm birth by transabdominal and transvaginal cervix length, as well as the effectiveness of predicting short cervix by transabdominal cervical length. The relationship between transabdominal and transvaginal cervical length was evaluated using a scatter plot. Results:A total of 562 cases were included in this study, comprising 33 cases of spontaneous preterm birth (7 cases occurring before 32 weeks) and 529 cases of term birth. (1) Compared to the term birth group, transabdominal cervical length (median: 37.6 vs 33.2 mm; Z=-3.838, P<0.001) and transvaginal cervical length (median: 34.0 vs 29.9 mm, Z=-3.030, P=0.002) in the spontaneous preterm birth group were significantly shorter. (2) The areas under the ROC curve for predicting spontaneous preterm birth by transabdominal and transvaginal cervical length were 0.699 (95% CI: 0.588-0.809) and 0.657 (95% CI: 0.540-0.774), respectively. The sensitivity, specificity and positive predictive value of transvaginal cervical length Conclusions:In singleton pregnancy women with low risk of preterm birth, transabdominal-transvaginal cervical length sequential screening can reduce unnecessary transvaginal ultrasounds by approximately 41% without missing the diagnosis of pregnant women with a short cervix. This method also enhances the effectiveness of transvaginal cervical length to spontaneous preterm birth.


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