This study aims to explore the mechanism of Jiaotai Pills in treating depression based on metabolomics and network pharmacology. The chemical constituents of Jiaotai Pills were identified by UHPLC-Orbitrap Exploris 480, and the targets of Jiaotai Pills and depression were retrieved from online databases. STRING and Cytoscape 3.7.2 were used to construct the protein-protein interaction network of core targets of Jiaotai Pills in treating depression and the "compound-target-pathway" network. DAVID was used for Gene Ontology(GO) function and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses of the core targets. The mouse model of depression was established with chronic unpredictable mild stress(CUMS) and treated with different doses of Jiaotai Pills. The behavioral changes and pathological changes in the hippocampus were observed. UHPLC-Orbitrap Exploris 120 was used for metabolic profiling of the serum, from which the differential metabolites and related metabolic pathways were screened. A "metabolite-reaction-enzyme-gene" network was constructed for the integrated analysis of metabolomics and network pharmacology. A total of 34 chemical components of Jiaotai Pills were identified, and 143 core targets of Jiaotai Pills in treating depression were predicted, which were mainly involved in the arginine and proline, sphingolipid, and neurotrophin metabolism signaling pathways. The results of animal experiments showed that Jiaotai Pills alleviated the depression behaviors and pathological changes in the hippocampus of the mouse model of CUMS-induced depression. In addition, Jiaotai Pills reversed the levels of 32 metabolites involved in various pathways such as arginine and proline metabolism, sphingolipid metabolism, and porphyrin metabolism in the serum of model mice. The integrated analysis showed that arginine and proline metabolism, cysteine and methionine metabolism, and porphyrin metabolism might be the key pathways in the treatment of depression with Jiaotai Pills. In conclusion, metabolomics combined with network pharmacology clarifies the antidepressant mechanism of Jiaotai Pills, which may provide a basis for the clinical application of Jiaotai Pills in treating depression.
Animals ; Drugs, Chinese Herbal/chemistry* ; Depression/genetics* ; Mice ; Network Pharmacology ; Metabolomics ; Male ; Disease Models, Animal ; Humans ; Protein Interaction Maps/drug effects* ; Antidepressive Agents

Jiuwei Xifeng Granules have become a Chinese patent medicine in the market. Because the formula contains Os Draconis, a top-level protected fossil of ancient organisms, the formula was to be improved by replacing Os Draconis with Ostreae Concha. To evaluate whether the improved formula has the same effectiveness and safety as the original formula, a randomized, double-blind, parallel-controlled, equivalence clinical trial was conducted. This study enrolled 288 tic disorder(TD) of children and assigned them into two groups in 1∶1. The treatment group and control group took the modified formula and original formula, respectively. The treatment lasted for 6 weeks, and follow-up visits were conducted at weeks 2, 4, and 6. The primary efficacy endpoint was the difference in Yale global tic severity scale(YGTSS)-total tic severity(TTS) score from baseline after 6 weeks of treatment. The results showed that after 6 weeks of treatment, the declines in YGTSS-TSS score showed no statistically significant difference between the two groups. The difference in YGTSS-TSS score(treatment group-control group) and the 95%CI of the full analysis set(FAS) were-0.17[-1.42, 1.08] and those of per-protocol set(PPS) were 0.29[-0.97, 1.56], which were within the equivalence boundary [-3, 3]. The equivalence test was therefore concluded. The two groups showed no significant differences in the secondary efficacy endpoints of effective rate for TD, total score and factor scores of YGTSS, clinical global impressions-severity(CGI-S) score, traditional Chinese medicine(TCM) response rate, or symptom disappearance rate, and thus a complete evidence chain with the primary outcome was formed. A total of 6 adverse reactions were reported, including 4(2.82%) cases in the treatment group and 2(1.41%) cases in the control group, which showed no statistically significant difference between the two groups. No serious suspected unexpected adverse reactions were reported, and no laboratory test results indicated serious clinically significant abnormalities. The results support the replacement of Os Draconis by Ostreae Concha in the original formula, and the efficacy and safety of the modified formula are consistent with those of the original formula.
Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Male ; Double-Blind Method ; Drugs, Chinese Herbal/therapeutic use* ; Tic Disorders/drug therapy* ; Treatment Outcome

Quality control is a key link in the modernization process of traditional Chinese medicine(TCM). Studies have shown that the effects of active components in TCM depend on not only their chemical composition but also their suitable physical forms and states. The physical phase structures, such as micelles, vesicles, gels, and nanoparticles, can improve the solubility, delivery efficiency, and targeting precision of active components. These structures significantly enhance the pharmacological activity while reducing the toxicity and side effects, demonstrating functional activity surpassing that of active components and highlighting the key effects of "structures" on "functions" of active components. Taking the physical phase structure as a breakthrough point, this paper outlines the common types of TCM physical phase structures. Furthermore, this paper explores how to realize the quality upgrading of TCM through the precise regulation of physical phase structures based on the current applications and potential of TCM physical phase structures in processing to increase the efficacy and reduce the toxicity, compounding and decocting processes, drug delivery systems, and quality control, aiming to provide novel insights for the future quality control of TCM.
Quality Control ; Drugs, Chinese Herbal/standards* ; Medicine, Chinese Traditional/standards* ; Humans ; Drug Delivery Systems

OBJECTIVE: To investigate the effects of acupuncture on the neurotransmitter levels and gut microbiota in a mouse model of Tourette syndrome (TS). METHODS: Thirty-six male C57/BL6 mice were randomly divided into 4 groups using a random number table method: 3,3'-iminodipropionitrile (IDPN) group, control group, acupuncture group, and tiapride group, with 9 mice in each group. In the IDPN group, acupuncture group, and tiapride group, mice received daily intraperitoneal injections of IDPN (300 mg/kg body weight) for 7 consecutive days to induce stereotyped behaviors. Subsequently, in the acupuncture intervention group, standardized acupuncture treatment was administered for 14 consecutive days to IDPN-induced TS model mice. The selected acupoints included Baihui (DU 20), Yintang (DU 29), Waiguan (SJ 5), and Zulinqi (GB 41). In the tiapride group, mice were administered tiapride (50 mg/kg body weight) via oral gavage daily for 14 consecutive days. The control group, IDPN group, and acupuncture group received the same volume of saline orally for 14 consecutive days. Stereotypic behaviors were quantified through behavioral assessments. Neurotransmitter levels, including dopamine (DA), glutamate (Glu), and aspartate (ASP) in striatal tissue were measured using enzyme-linked immunosorbent assay. Dopamine transporter (DAT) expression levels were additionally quantified through quantitative polymerase chain reaction (qPCR). Gut microbial composition was analyzed through 16S ribosomal RNA gene sequencing, while metabolic profiling was conducted using liquid chromatography-mass spectrometry (LC-MS). RESULTS: Acupuncture administration significantly attenuated stereotypic behaviors, concurrently reducing striatal levels of DA, Glu and ASP concentrations while upregulating DAT expression compared with untreated TS controls (P<0.05 or P<0.01). Comparative analysis identified significant differences in Muribaculaceae (P=0.001), Oscillospiraceae (P=0.049), Desulfovibrionaceae (P=0.001), and Marinifilaceae (P=0.014) following acupuncture intervention. Metabolomic profiling revealed alterations in 7 metabolites and 18 metabolic pathways when compared to the TS mice, which involved various amino acid metabolisms associated with DA, Glu, and ASP. CONCLUSIONS Acupuncture demonstrates significant modulatory effects on both central neurotransmitter systems and gut microbial ecology, thereby highlighting its dual therapeutic potential for TS management through gut-brain axis regulation.
Animals ; Tourette Syndrome/metabolism* ; Gastrointestinal Microbiome ; Neurotransmitter Agents/metabolism* ; Acupuncture Therapy ; Male ; Mice, Inbred C57BL ; Mice

Objective To compare the effects of 20 mg qd and 10 mg bidadministration of iprrazole enteric-coated tablets on the control of gastric acid in healthy subjects.Methods A randomized,single-center,parallel controlled trial was designed to include 8 healthy subjects.Randomly divided into 2 groups,20 mg qd administration group:20 mg enteric-coated tablets of iprrazole in the morning;10 mg bid administration group:10 mg enteric-coated tablets of iprrazole in the morning and 10 mg in the evening.The pH values in the stomach of the subjects before and 24 h after administration were monitored by pH meter.The plasma concentration of iprazole after administration was determined by HPLC-MS/MS.The main pharmacokinetic parameters were calculated by Phoenix WinNonlin(V8.0)software.Results The PK parameters of iprrazole enteric-coated tablets and reference preparations in fasting group were as follows:The Cmax of 20 mg qd group and 10 mg bid group were(595.75±131.15)and(283.50±96.98)ng·mL-1;AUC0-t were(5 531.94±784.35)and(4 686.67±898.23)h·ng·mL-1;AUC0-∞ were(6 003.19±538.59)and(7 361.48±1 816.77)h·ng·mL-1,respectively.The mean time percentage of gastric pH＞3 after 20 mg qd and 10 mg bid were 82.64％and 61.92％,and the median gastric pH within 24 h were 6.25±1.49 and 3.53±2.05,respectively.The mean gastric pH values within 24 h were 5.71±1.36 and 4.23±1.45,respectively.The correlation analysis of pharmacokinetic/pharmacodynamics showed that there was no significant correlation between the peak concentration of drug in plasma and the inhibitory effect of acid.Conclusion Compared with the 20 mg qd group and the 10 mg bid group,the acid inhibition effect is better,the administration times are less,and the safety of the two administration regimes is good.

Objective To explore the optimal image-guided verification mode by using combined cone-beam CT(CBCT)and ExacTrac X-ray(ETX)image-guided system for the position verification during the first and remaining fractionated radiotherapy of high-grade glioma patients.Methods Twenty high-grade glioma patients undergoing intensity-modulated radiotherapy at some hospital from January 2018 to June 2020 were analyzed retrospectively.CBCT image-guided system was used for the patients treated for the first time to determine the corresponding position of the treatment center on the body surface and to reset and mark the treatment center,then on-line auto registration of the CBCT images with CT positioning images was carried out,and the residual setup errors were verified with ETX image-guided system;position verification of the setup errors was performed with ETX image-guided sysem during the remaining fractionated treatment.The setup errors and their interval distributionswere calculated for the patients in six directions including left-right direction(Lat),head-foot direction(Lng),anterior-posterior direction(Vrt),rotation around left-right(Pitch),rotation around head-foot(Roll)and rotation around anterior-posterior(Yaw).SPSS 22.0 statistical software was used for data analysis.Results There were 75％patients treated for the first time and 78.62％ones undergoing the remaining fractionated radiotherapy only needed one time of setup error corre-ction.Combined CBCT and ETX image-guided resetting during the first radiotherapy met clinical requirements;during the remaining fractionated radiotherapy there were significant differences between the setup errors in the six directions before and after calibration(P＜0.05).The interval distribution of setup errors showed the error values in the six directions were all restricted within 0 to 1 mm and within 0° to l °during the first and remaining fractionated radiotherapy.Conclusion Involve-ment of combined CBCT and ETX image-guided system in the first and remaining fractionated radiotherapy of high-grade glioma patients after operation contributes to determining and resetting the treatment center rapidly and accurately,decreasing setup errors and enhancing the accuracy and repeatability of radiotherapy.[Chinese Medical Equipment Journal,2024,45(8):57-62].

Objective To investigate the distribution of pathogens and change of homology of Acinetobacter bau-mannii(AB)in intensive care units(ICUs)of partial medical institutions in Shanghai before and after the pandemic of coronavirus disease 2019(COVID-19).Methods Pathogens were isolated and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF MS),the whole genome of AB was sequenced using Illumina Miseq sequencing platform,and its genetic relationship was explored based on multilocus sequence typing(MLST)and core genome multilocus sequence typing(cgMLST).Results The total detection rate of patho-gens in ICU environment after the pandemic was lower than before the pandemic([6.10％,101/1 656]vs[10.77％,181/1 680];P＜0.05).Before and after the pandemic,the proportion of AB detected on the surface of bedding in the ICU environment remained at the highest level.After the pandemic,the ST types showed a diverse distribution.MLST_Pasteur results showed that 162 strains of AB were divided into 20 ST types,with ST2(80.25％,n=130)being the main type.MLST_Oxford results showed that there were 19 ST types among 162 strains,with ST208(37.04％,n=60)being the main type.The clustering analysis based on cgMLST showed that ST208_Oxford had closer genetic relationship with ST540_Oxford and ST369_Oxford after the pandemic.ST164_Pasteur clone changed from ST234_Oxford before the pandemic to ST1418_Oxford after the pandemic,and 2 new types of ST_Pasteurr and 11 new types of ST_Oxford were discovered.Conclusion The detection rate of pathogens from ICU environment after the pandemic is lower than before the pandemic,and the distribution of ST types is slightly different at the same detection sites before and after the pandemic.ST2_Pasteur/ST208_Oxford is still the dominant epidemic clone before and after the pandemic,but some alleles have changed.cgMLST is more accurate than MLST_Oxford and MLST_Pasteur in homology analysis,evolution,spread,and outbreak analysis.

Objective:To investigate the efficacy of posterior reduction and fixation combined with pedicle subtraction osteotomy (PSO) in the treatment of ankylosing spondylitis (AS) kyphotic deformity complicated by upper cervical spine injury.Methods:A retrospective case series study was conducted to analyze the clinical data of 8 patients with AS kyphotic deformity complicated by upper cervical spine injury, who were admitted to First Affiliated Hospital of Xinjiang Medical University from October 2010 to December 2022. All were males, aged 32-58 years [(46.9±8.7)years]. Acute injury was found in 1 patient and chronic injuries in 7 patients, including 3 with cervicothoracic kyphotic deformity and 5 with thoracolumbar kyphotic deformity. Five patients were complicated by odontoid fractures, 1 by C 2-C 3 fracture and 2 by atlantoaxial dislocation. According to American Spinal Injury Association (ASIA) scale, 2 patients were with grade C, 3 with grade D, and 3 with grade E. The patients were treated with posterior upper cervical reduction and fixation combined with cervicothoracic PSO or thoracolumbar PSO respectively according to the location of the deformity. The operation time and intraoperative blood loss were recorded. Neck disability index (NDI), visual analogue scale (VAS), C 0-C 2 angle, C 1-C 2 angle, cervical lordosis angle (CL), head tilt angle (HT), chin-brow vertical angle (CBVA), cervical sagittal vertical axis (CSVA), and sagittal vertical axis (SVA) were compared before surgery, at 1 week and 3, 6, 12 months after surgery, and at the last follow-up. The healing of fractures and fusion of osteotomy site were recorded at 12 months after surgery. Recovery of neurological function was observed at the last follow-up. Incidence of complications was observed. Results:Patients were all followed up for 12-24 months [(17.0±5.4)months]. The operation time was 5.5-7.2 hours [(6.2±0.6)hours] and the intraoperative blood loss was 480-800 ml [(629.4±124.0)ml]. The NDI scores at 1 week and 3, 6, 12 months after surgery, and at the last follow-up were (14.6±2.6)points, (13.6±2.8)points, (12.8±2.4)points, (12.8±2.7)points, and (12.8±2.6)points respectively, significantly lower than (29.6±8.5)points preoperatively ( P<0.01). There were no significant differences in NDI scores at various time points after surgery ( P>0.05). The VAS scores were 2.0(1.0, 3.0)points, 1.5(1.0, 2.0)points, 0.5(0.0, 1.8)points, 0.5(0.0, 1.7)points, and 0.5(0.0, 1.8)points respectively, significantly lower than 3.5(3.0, 4.8)points preoperatively ( P<0.01). The VAS score at 3 months postoperatively was lower than that at 1 week postoperatively ( P<0.05), and the VAS score at 6 months postoperatively was lower than that at 3 months postoperatively ( P<0.05). There were no statistically significant differences in VAS scores at 6, 12 months postoperatively, and at the last follow-up ( P>0.05). There were no statistically significant differences between C 0-C 2 angle and C 1-C 2 angle preoperatively and at different time points postoperatively ( P>0.05). At 1 week and 3, 6, 12 months postoperatively and at the last follow-up, the CL values were -8.5(-5.3, -11.9)°, -8.6(-5.5, -11.9)°, -8.4(5.2, -12.1)°, -8.8(-5.6, -12.4)°, and -8.7(-5.3, -12.5)° respectively, significantly higher than 1.2(9.5, -4.8)° preoperatively ( P<0.01); the HT values were 6.1(4.5, 9.6)°, 6.1(4.3, 9.4)°, 6.0(4.2, 8.9)°, 6.0(4.2, 9.2)°, and 6.1(4.3, 9.2)° respectively, significantly lower than 17.0(10.3, 22.0)° preoperatively ( P<0.01); the CBVA values were (23.2±5.0)°, (23.1±4.8)°, (23.0±4.7)°, (23.1±4.7)°, and (23.1±4.9)° respectively, significantly lower than (44.1±9.8)° preoperatively ( P<0.01); the CSVA values were 5.2(4.2, 7.5)cm, 5.4(4.1, 7.1)cm, 4.7(4.0, 7.4)cm, 5.4(4.1, 7.0)cm, and 5.1(4.3, 6.5)cm respectively, significantly shorter than 9.0(7.8, 9.3)cm preoperatively ( P<0.01); the SVA values were 7.7(6.2, 13.7)cm, 7.5(6.0, 13.4)cm, 7.6(6.2, 13.2)cm, 7.4(6.3, 13.1)cm, and 7.5(6.2, 13.2)cm respectively, significantly shorter than 16.8(8.2, 27.2)cm preoperatively ( P<0.05). There were no statistically significant differences among CL, HT, CBVA, CSVA, and SVA values at different time points after surgery ( P>0.05). All the fractures healed at 12 months after surgery and Bridwell grade I healing was achieved at all the osteotomy sites. At the last follow-up, all the patients were classified as ASIA grade E, significantly improved compared with preoperatively ( P<0.01). One patient had transient C 8 nerve paralysis after surgery and recovered after 4 weeks′ treatment. The remaining patients did not develop any infection or internal fixation-related complications, such as broken rods, broken screws, or loose screws. Conclusion:For AS kyphosis deformity complicated with upper cervical injury, posterior reduction and fixation combined with cervicothoracic or thoracolumbar PSO can effectively promote functional recovery, relieve pain, maintain overall trunk balance, improve neurological symptoms, and reduce the incidence of complications.

OBJECTIVE: This study aimed to determine the HIV-1 subtype distribution and HIV drug resistance (HIVDR) in patients with ART failure from 2014 to 2020 in Hainan, China. METHODS: A 7-year cross-sectional study was conducted among HIV/AIDS patients with ART failure in Hainan. We used online subtyping tools and the maximum likelihood phylogenetic tree to confirm the HIV subtypes with pol sequences. Drug resistance mutations (DRMs) were analyzed using the Stanford University HIV Drug Resistance Database. RESULTS: A total of 307 HIV-infected patients with ART failure were included, and 241 available pol sequences were obtained. Among 241 patients, CRF01_AE accounted for 68.88%, followed by CRF07_BC (17.00%) and eight other subtypes (14.12%). The overall prevalence of HIVDR was 61.41%, and the HIVDR against non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) were 59.75%, 45.64%, and 2.49%, respectively. Unemployed patients, hypoimmunity or opportunistic infections in individuals, and samples from 2017 to 2020 increased the odd ratios of HIVDR. Also, HIVDR was less likely to affect female patients. The common DRMs to NNRTIs were K103N (21.99%) and Y181C (20.33%), and M184V (28.21%) and K65R (19.09%) were the main DRMs against NRTIs. CONCLUSION The present study highlights the HIV-1 subtype diversity in Hainan and the importance of HIVDR surveillance over a long period.
Humans ; Reverse Transcriptase Inhibitors/therapeutic use* ; HIV-1/genetics* ; Cross-Sectional Studies ; Phylogeny ; Anti-HIV Agents/therapeutic use* ; Drug Resistance, Viral/genetics* ; HIV Infections/epidemiology* ; Mutation ; China/epidemiology* ; Prevalence ; Genotype

Objective: Compare and analyze the results of the domestic Lanyi AH600 glycated hemoglobin analyzer and other different detection systems to understand the comparability of the detection results of different detectors, and establish the best cut point of Lanyi AH600 determination of haemoglobin A1c (HbA1c) in the diagnosis of diabetes. Methods: Multi center cohort study was adopted. The clinical laboratory departments of 18 medical institutions independently collected test samples from their respective hospitals from March to April 2022, and independently completed comparative analysis of the evaluated instrument (Lanyi AH600) and the reference instrument HbA1c. The reference instruments include four different brands of glycosylated hemoglobin meters, including Arkray, Bio-Rad, DOSOH, and Huizhong. Scatter plot was used to calculate the correlation between the results of different detection systems, and the regression equation was calculated. The consistency analysis between the results of different detection systems was evaluated by Bland Altman method. Consistency judgment principles: (1) When the 95% limits of agreement (95% LoA) of the measurement difference was within 0.4% HbA1c and the measurement score was≥80 points, the comparison consistency was good; (2) When the measurement difference of 95% LoA exceeded 0.4% HbA1c, and the measurement score was≥80 points, the comparison consistency was relatively good; (3) The measurement score was less than 80 points, the comparison consistency was poor. The difference between the results of different detection systems was tested by paired sample T test or Wilcoxon paired sign rank sum test; The best cut-off point of diabetes was analyzed by receiver operating characteristic curve (ROC). Results: The correlation coefficient R² of results between Lanyi AH600 and the reference instrument in 16 hospitals is≥0.99; The Bland Altman consistency analysis showed that the difference of 95% LoA in Nanjing Maternity and Child Health Care Hospital in Jiangsu Province (reference instrument: Arkray HA8180) was -0.486%-0.325%, and the measurement score was 94.6 points (473/500); The difference of 95% LoA in the Tibetan Traditional Medical Hospital of TAR (reference instrument: Bio-Rad Variant II) was -0.727%-0.612%, and the measurement score was 89.8 points; The difference of 95% LoA in the People's Hospital of Chongqing Liang Jiang New Area (reference instrument: Huizhong MQ-2000PT) was -0.231%-0.461%, and the measurement score was 96.6 points; The difference of 95% LoA in the Taihe Hospital of traditional Chinese Medicine in Anhui Province (reference instrument: Huizhong MQ-2000PT) was -0.469%-0.479%, and the measurement score was 91.9 points. The other 14 hospitals, Lanyi AH600, were compared with 4 reference instrument brands, the difference of 95% LoA was less than 0.4% HbA1c, and the scores were all greater than 95 points. The results of paired sample T test or Wilcoxon paired sign rank sum test showed that there was no statistically significant difference between Lanyi AH600 and the reference instrument Arkray HA8180 (Z=1.665,P=0.096), with no statistical difference. The mean difference between the measured values of the two instruments was 0.004%. The comparison data of Lanyi AH600 and the reference instrument of all other institutions had significant differences (all P<0.001), however, it was necessary to consider whether it was within the clinical acceptable range in combination with the results of the Bland-Altman consistency analysis. The ROC curve of HbA1c detected by Lanyi AH600 in 985 patients with diabetes and 3 423 patients with non-diabetes was analyzed, the area under curve (AUC) was 0.877, the standard error was 0.007, and the 95% confidence interval 95%CI was (0.864, 0.891), which was statistically significant (P<0.001). The maximum value of Youden index was 0.634, and the corresponding HbA1c cut point was 6.235%. The sensitivity and specificity of diabetes diagnosis were 76.2% and 87.2%, respectively. Conclusion: Among the hospitals and instruments currently included in this study, among these four hospitals included Nanjing Maternity and Child Health Care Hospital in Jiangsu Province (reference instrument: Arkray HA8180), Tibetan Traditional Medical Hospital of TAR (reference instrument: Bio-Rad Variant Ⅱ), the People's Hospital of Chongqing Liang Jiang New Area (reference instrument: Huizhong MQ-2000PT), and the Taihe Hospital of traditional Chinese Medicine in Anhui Province (reference instrument: Huizhong MQ-2000PT), the comparison between Lanyi AH600 and the reference instruments showed relatively good consistency, while the other 14 hospitals involved four different brands of reference instruments: Arkray, Bio-Rad, DOSOH, and Huizhong, Lanyi AH600 had good consistency with its comparison. The best cut point of the domestic Lanyi AH600 for detecting HbA1c in the diagnosis of diabetes is 6.235%.
Pregnancy ; Child ; Humans ; Female ; Glycated Hemoglobin ; Cohort Studies ; Diabetes Mellitus/diagnosis* ; Sensitivity and Specificity ; ROC Curve