ObjectiveTo explore the effects of the Tibetan medicine Sanwei Doukoutang （SWDK） on cognitive dysfunction in mice suffering from Alzheimer's disease （AD） and its related mechanism. MethodsFifty SPF 5 × FAD mice were randomly divided into model group， total ginsenoside group（0.04 g·kg^-1）， high-， medium-， and low-dose groups of SWDK （32.60， 16.30， 8.15 g·kg^-1）， with 10 mice in each group， and ten wild-type mice of the same age were used as the normal group， male and female in 1∶1. Gavage administration was performed once daily for 8 weeks. The Morris water maze test and contextual fear memory experiment were used to observe learning and memory function. Hematoxylin-eosin （HE） staining was utilized to observe the changes in the pathomorphology of brain tissue in mice. The levels of synaptophysin （SYP） and postsynaptic dense substance 95 （PSD95） in mice serum were detected by enzyme-linked immunosorbent assay （ELISA）. The positive expression of brain-derived neurotrophic factor（BDNF） in the dentate gyrus （DG） region of mouse brain tissue was observed by immunohistochemistry （IHC）. The protein levels of BDNF， Wnt family member 3A（Wnt3a）， and β-catenin were detected in the hippocampus of mice by Western blot. ResultsCompared with the normal group of mice， the model group of mice had significantly more complex swimming routes and lower swimming speed （P<0.01）， significantly lower percentage of time spent in the target quadrant （P<0.01）， and a significantly lower percentage of freezing time （P<0.05）. The number of neurons in the hippocampal region of mice was obviously reduced and unevenly arranged. The levels of SYP and PSD95（P<0.01） in the serum of mice were reduced， and the positive expression of BDNF in the DG region of the brain tissue of mice was reduced. The levels of hippocampal BDNF， Wnt3a， and β-catenin proteins in the hippocampus of mice were obviously reduced （P<0.05， P<0.01）. Compared with the model group， the mice in the SWDK group and the total ginsenoside group had significantly shorter swimming routes， the high- and medium- dose SWDK groups significantly higher swimming speeds （P<0.01）， significantly higher percentage of time spent in the target quadrant （P<0.01）， obviously higher percentage of Freezing time （P<0.05）， and obviously more neurons in the hippocampal region of the mice with tighter arrangement. The mice had elevated levels of serum SYP （P<0.05， P<0.01）， PSD95 （P<0.01）， increased BDNF-positive cells in the DG region of brain tissue， and obviously elevated levels of BDNF， Wnt3a， and β-catenin proteins in the hippocampus of mice （P<0.05， P<0.01）. ConclusionSWDK can significantly improve the cognitive dysfunction of AD mice， and its mechanism may be related to regulating the Wnt/β-catenin signaling pathway， which promotes BDNF expression and thereby enhances synaptic plasticity， allowing neuronal signaling to be restored.

ObjectiveTo explore the effects of the Tibetan medicine Sanwei Doukoutang （SWDK） on cognitive dysfunction in mice suffering from Alzheimer's disease （AD） and its related mechanism. MethodsFifty SPF 5 × FAD mice were randomly divided into model group， total ginsenoside group（0.04 g·kg^-1）， high-， medium-， and low-dose groups of SWDK （32.60， 16.30， 8.15 g·kg^-1）， with 10 mice in each group， and ten wild-type mice of the same age were used as the normal group， male and female in 1∶1. Gavage administration was performed once daily for 8 weeks. The Morris water maze test and contextual fear memory experiment were used to observe learning and memory function. Hematoxylin-eosin （HE） staining was utilized to observe the changes in the pathomorphology of brain tissue in mice. The levels of synaptophysin （SYP） and postsynaptic dense substance 95 （PSD95） in mice serum were detected by enzyme-linked immunosorbent assay （ELISA）. The positive expression of brain-derived neurotrophic factor（BDNF） in the dentate gyrus （DG） region of mouse brain tissue was observed by immunohistochemistry （IHC）. The protein levels of BDNF， Wnt family member 3A（Wnt3a）， and β-catenin were detected in the hippocampus of mice by Western blot. ResultsCompared with the normal group of mice， the model group of mice had significantly more complex swimming routes and lower swimming speed （P<0.01）， significantly lower percentage of time spent in the target quadrant （P<0.01）， and a significantly lower percentage of freezing time （P<0.05）. The number of neurons in the hippocampal region of mice was obviously reduced and unevenly arranged. The levels of SYP and PSD95（P<0.01） in the serum of mice were reduced， and the positive expression of BDNF in the DG region of the brain tissue of mice was reduced. The levels of hippocampal BDNF， Wnt3a， and β-catenin proteins in the hippocampus of mice were obviously reduced （P<0.05， P<0.01）. Compared with the model group， the mice in the SWDK group and the total ginsenoside group had significantly shorter swimming routes， the high- and medium- dose SWDK groups significantly higher swimming speeds （P<0.01）， significantly higher percentage of time spent in the target quadrant （P<0.01）， obviously higher percentage of Freezing time （P<0.05）， and obviously more neurons in the hippocampal region of the mice with tighter arrangement. The mice had elevated levels of serum SYP （P<0.05， P<0.01）， PSD95 （P<0.01）， increased BDNF-positive cells in the DG region of brain tissue， and obviously elevated levels of BDNF， Wnt3a， and β-catenin proteins in the hippocampus of mice （P<0.05， P<0.01）. ConclusionSWDK can significantly improve the cognitive dysfunction of AD mice， and its mechanism may be related to regulating the Wnt/β-catenin signaling pathway， which promotes BDNF expression and thereby enhances synaptic plasticity， allowing neuronal signaling to be restored.

AIM:To evaluate the effectiveness of EYESI binocular indirect ophthalmoscope simulation system as a training platform for fundus examination skills of general practitioner.METHODS:Prospective randomized study. A total of 40 general practitioners who received clinical ophthalmology training at Shenzhen Eye Hospital from January 2021 to December 2024 were selected and randomly divided into two groups by random number table method, with 20 cases in the study group and 20 cases in the control group. The study group was trained by EYESI binocular indirect ophthalmoscope simulation system and the control group was trained by conventional teaching. Training effects of the two groups were analyzed.RESULTS: The general information of the two groups was comparable. Through training with the EYESI binocular indirect ophthalmoscope simulator, the study group showed significant improvements in total examination and drawing scores compared to pre-training results(all P<0.001). Additionally, examination duration, retinal light exposure time, and drawing time were all significantly shorter than those before training(all P<0.001).The study group achieved significantly higher total examination and drawing scores than the control group during the EYESI binocular indirect ophthalmoscope simulator assessment(all P<0.001). Furthermore, examination duration, retinal light exposure time, and drawing time were all significantly shorter in the study group compared to the control group(all P<0.001). Moreover, ratings for the novelty of the training method and overall satisfaction with the training were significantly higher in the study group than in the control group(all P<0.001); while the perceived psychological stress during training was significantly lower in the study group(P<0.001).CONCLUSION:The EYESI binocular indirect ophthalmoscope simulaton system effectively enhances both the proficiency in fundus examination skills and overall training satisfaction among general practitioners.

Background::Ainuovirine (ANV) is a new generation of non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus (HIV) type 1 infection. This study aimed to evaluate the population pharmacokinetic (PopPK) profile and exposure-response relationship of ANV among people living with HIV.Methods::Plasma concentration-time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the PopPK model. Exposure estimates obtained from the final model were used in exposure-response analysis for virologic responses and safety responses.Results::ANV exhibited a nonlinear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (relative standard error [%]) for clearance adjusted for bioavailability (CL/F) was 6.46 (15.00) L/h, and the clearance of ANV increased after multiple doses. The exposure-response model revealed no significant correlation between the virologic response (HIV-RNA <50 copies/mL) at 48 weeks and the exposure, but the incidence of adverse events increased with the increasing exposure ( P value of steady-state trough concentration and area under the steady-state curve were 0.0177 and 0.0141, respectively). Conclusions::Our PopPK model supported ANV 150 mg once daily as the recommended dose for people living with HIV, requiring no dose adjustment for the studied factors. Optimization of ANV dose may be warranted in clinical practice due to an increasing trend in adverse reactions with increasing exposure.Trial registration::Chinese Clinical Trial Registry https://www.chictr.org.cn (Nos. ChiCTR1800018022 and ChiCTR1800019041).

Objective:To explore the prognostic value of systemic immune-inflammatory index(SII)combined with tumor burden score (TBS) (hereinafter referred to as STS) in patients with intrahepatic cholangiocarcinoma (ICC) after radical resection, and to construct a nomogram model.Methods:The clinical data (including the degree of tumor differentiation, vascular cancer thrombus, and lymph node metastasis, etc.) of 258 ICC patients who received radical resection at People′s Hospital of Zhengzhou University (170 cases, training set) and Cancer Hospital of Zhengzhou University (88 cases, validation set) from January 1, 2016 to January 31, 2020 were retrospectively analyzed and graded by SII, TBS and STS. Multivariate Cox regression analysis were used to identify independent factors affecting the prognosis of patients with ICC. Kaplan-Meier survival curve and receiver operating characteristic curve (ROC) were drawn to evaluate the predictive efficiency of SII, TBS and STS in the overall survival of patients with ICC after radical resection. The nomogram prediction model was constructed and evaluate the performance of nomogram model using consistency index (C-index) and calibration curve.Results:Among 170 ICC patients in the training set, there were 106 cases of SII grade 1 and 64 cases of SII grade 2; 137 cases of TBS grade 1 and 33 cases of TBS grade 2; and 98 cases of STS grade 1, 47 cases of STS grade 2, and 25 cases of STS grade 3. Among 88 ICC patients in the validation set, there were 33 cases of SII grade 1 and 55 cases of SII grade 2; 66 cases of TBS grade 1 and 22 cases of TBS grade 2; and 30 case of STS grade 1, 39 cases of TBS grade 2, and 19 cases of TBS grade 3.The multivariate Cox regression analysis showed that tumor differentiation degree (highly differentiated vs. moderately differentiated HR=0.157, 95% confidence interval(95% CI) 0.045 to 0.546, highly differentiated vs. poorly differentiated HR=0.452, 95% CI 0.273 to 0.750), STS (grade 3 vs. grade 2 HR=1.966, 95% CI 1.148 to 3.469; grade 3 vs. grade 1 HR=1.405, 95% CI 0.890 to 2.216), vascular cancer thrombus ( HR=2.006, 95% CI 1.313 to 3.066), nerve invasion ( HR=1.865, 95% CI 1.221 to 2.850), and lymph node metastasis ( HR=1.802, 95% CI 1.121 to 2.896) were independent influencing factors of overall survival in ICC patients after radical resection (all P<0.05). The Kaplan-Meier survival curve showed that SII, TBS, and STS were independent influencing factors of overall survival in ICC patients (all P<0.05). The results of ROC analysis showed that the areas under the curve of SII, TBS and STS in predicting overall survival of ICC patients after radical resection were 0.566 (95% CI 0.479 to 0.652), 0.585 (95% CI 0.499 to 0.672), and 0.657 (95% CI 0.522 to 0.692), respectively. Tumor differentiation, vascular tumor thrombus, nerve invassion, lymph node metastasis, and STS were included to constract the nomogram model. The C-indexes of the training set and validation set based on the nomogram model were 0.792 (95% CI 0.699 to 0.825) and 0.776 (95% CI 0.716 to 0.833), respectively. The calibration curves of the survival rate of the training set and the validation set were close to the reference lines, and the nomogram model had better predictive ability in both the training set and the validation set. Conclusions:Preoperative STS grading is an effective and practical predictor of overall survival in ICC patients after radical section. Compared with SII and TBS alone, it has better predictive value for the prognosis of patients with ICC.

Objective:To analyze the clinical phenotypes and genotypes of a family with posterior segment microphthalmia-retinoschisis and drusen syndrome.Methods:A pedigree investigation study was conducted.A family with four members across two generations treated at Shenzhen Eye Hospital in July 2021 was enrolled.Detailed ophthalmic examinations, including best corrected visual acuity (BCVA), intraocular pressure, slit-lamp microscopy, color fundus photography, optical coherence tomography (OCT), anterior segment OCT, fundus fluorescein angiography (FFA), and visual field tests were performed in the four members.Peripheral venous blood samples were collected from members for whole exome sequencing and data analysis.The pathogenicity of novel variant sites was assessed according to the ACMG guidelines.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Shenzhen Eye Hospital (No.22KYPJ018).Written informed consent was obtained from each subject or the guardian.Results:The proband is a 14-year-old female with high hyperopia since childhood, BCVA of + 9.75 DS-0.75 DC×150°=0.9 and + 11.75 DS-1.25 DC×30°=0.7, corneal transverse diameters of 12.1 and 12.2 mm, anterior chamber depths of 2.56 and 2.92 mm, lens thicknesses of 3.92 and 3.94 mm, and axial lengths of 17.47 and 17.01 mm in the right and left eyes, respectively.Fundus photography revealed diffuse yellow-white drusen-like lesions with unclear borders in the mid-peripheral retina, while OCT showed retinoschisis in the inner nuclear layer and homogeneous mound-like elevations with hyperreflective dense spots under the retinal pigment epithelium.FFA demonstrated diffuse punctate transilllumination of the mid-peripheral retina in both eyes, and visual field tests revealed a general decrease in visual acuity.The proband's 8-year-old brother exhibited similar signs to the proband.The consanguineously married parents were phenotypically normal.Whole exome sequencing identified compound heterozygous mutations in the membrane frizzled-related protein ( MFRP) gene in the proband and her brother, c.1150_1151insC (p.His384Profs*8) in exon 5 and c. 498_499insC (p.Asn167Glnfs*34) in exon 10.The father carried the c. 498_499insC mutation, while the mother carried the c.1150_1151insC mutation.Both were frameshift mutations predicted to alter gene function.These novel mutations had not been reported in the ESP, 1 000 Genomes (Phase 3), or ExAC databases, indicating they are novel variants.The variants co-segregated with the disease and both were classified as pathogenic according to ACMG guidelines.Based on the clinical and genetic findings, the family was diagnosed with posterior segment microphthalmia-retinoschisis and drusen syndrome, inherited in an autosomal recessive manner. Conclusions:The MFRP gene mutations c. 1150_1151insC and c. 498_499insC are the pathogenic variants for the posterior segment microphthalmia-retinoschisis and drusen syndrome in this family, and these compound heterozygous mutations are reported for the first time.

By combining the ability of SMOTE data augmentation method to process complex audio data with the accurate prediction ability of GA-SVM,a GA-SVM model based on SMOTE data augmentation algorithm is proposed and applied to the diagnosis of thyroid diseases.The results demonstrate the excellent performance of the proposed method in the classification and diagnosis of thyroid diseases.Compared with other methods,the proposed method has better diagnostic efficacy and higher applicability in the classification and diagnosis of thyroid diseases.

OBJECTIVE To investigate the effects of anlotinib on the malignant phenotype of glioma cells by regulating the nuclear factor-κB （NF-κB） signaling pathway. METHODS Human glioma T98G cells were cultured in vitro， and 5-fluorouracil was used as positive control to investigate the effects of different concentrations of anlotinib （5， 10， 20 μmol/L） on the ability of proliferation， adhesion， migration and invasion， the expressions of epithelial-mesenchymal transition （EMT） related proteins [E-cadherin， N-cadherin， vimentin and fibronectin （FN）]. NF- κB signaling pathway inhibitor （BAY 11-7082） and activator （prostratin） were additionally used to verify the possible mechanism of the above effects of anlotinib. RESULTS Anlotinib with 5， 10， 20 μmol/L could significantly decrease the activity of cell proliferation （except for 5 μmol/L anlotinib group）， migration rate， and the number of adherent cells and invasive cells， could significantly up-regulate the expression of E-cadherin protein while down-regulate the expressions of N-cadherin， vimentin and FN protein （P＜0.05）； the effect of 20 μmol/L anlotinib was similar to that of positive control （P＞0.05）. Compared with 10 μmol/L anlotinib， pathway inhibitor could significantly decrease the ability of proliferation， adhesion， migration and invasion， and the expressions of N-cadherin， vimentin， FN and phosphorylated NF-κB p65 protein， while could significantly up-regulate the expression of E-cadherin protein （P＜0.05）； above indexes were reversed significantly by pathway activator （P＜0.05）. CONCLUSIONS Anlotinib may inhibit the proliferation， adhesion， migration and invasion of human glioma T98G cells， which may be associated with the inhibition of the NF-κB signaling pathway， thus inhibiting cell EMT-like processes.

Objective:To construct and validate a machine learning model for preoperative prediction of perineural invasion (PNI) status in intrahepatic cholangiocarcinoma (ICC).Methods:Clincial data of 329 patients, including 245 admitted to Zhengzhou University People's Hospital from January 2018 to June 2023 and 84 admitted to the Affiliated Cancer Hospital of Zhengzhou University from January 2013 to January 2020 were retrospectively analyzed. Patients were divided into a training set ( n=231) and a validation set ( n=98). Clinicopathological data including age, gender, hepatitis B virus (HBV) infection status were collected. Predictive variables were determined using least absolute shrinkage and selection operator (LASSO) regression analysis. Six machine learning algorithms including random forest (RF), logistic regression, and linear kernel-based support vector machine were selected to construct the preoperative prediction model for PNI in ICC. Performance metrics of the model were calculated using a confusion matrix, and the final model was selected. The model performance was evaluated in the validation set. Calibration curves were plotted to evaluate the final model, and a Pareto chart was used to visualize the importance of predictive variables. Results:LASSO regression identified nine predictive variables included in the prediction model, including carbohydrate antigen 19-9 (CA19-9), HBV infection status, alkaline phosphatase, alanine aminotransferase, prothrombin time, total bilirubin, albumin, neutrophil times gamma-glutamyl transferase to lymphocyte ratio, and tumor burden score. Among the trained six models, the area under the curve (AUC) of the RF model was 0.909, with a sensitivity of 0.842 and an accuracy of 0.870. Compared with the AUC of the RF model, the AUCs of the other 5 models were lower (all P<0.05). The AUC of the RF model for predicting PNI in ICC in validation set was 0.736. Calibration curves showed good fit of the RF model's prediction of PNI in ICC in both training and validation sets. The Pareto chart showed that CA19-9 was the most important predictive variable in the model, followed by HBV infection status. Conclusion:The machine learning model based on the RF algorithm has a high accuracy in preoperative prediction of PNI status in ICC.

ObjectiveTo investigate the current status and high-risk factors of chromosomal aberrations in peripheral blood lymphocytes （PBL） of radiation workers in Hainan Province. MethodsA total of 200 radiological workers who underwent occupational health examination in Hainan Provincial Hospital of Traditional Chinese Medicine from January 2021 to December 2021 were selected to collect the occupational health examination data and the rate of PBL chromosomal aberrations. The influencing factors of PBL chromosomal aberrations were analyzed by logistic regression model. The predictive value of logistic regression prediction model on PBL chromosomal aberrations were determined by using the reciver operator characteristic （ROC） curve. ResultsA total of 20 000 cells （100 cells/person） were tested. The chromosomal aberration rate was 0.37% （74/20 000） and the PBL chromosomal aberration rate in the subjects was 6.00% （12/200）. Univariate analysis showed that PBL chromosomal aberrations in radiological workers were related to age， length of service， type of work and education （all P<0.05）， but not to gender （P>0.05）. The logistic regression prediction model was constructed based on the influencing factors， with χ²=9.413， df=9， P=0.852， suggesting a good model fit. The logistic regression prediction model predicted the area under the curve （AUC） for the occurrence of PBL chromosomal aberrations in radiation workers was 0.914 （95%CI： 0.866‒0.949）， with a cut-off value of 3.05， corresponding to a prediction sensitivity and specificity of 100.00% and 75.98%， respectively. ConclusionThe incidence of PBL chromosomal aberrations in radiological workers in Hainan Province was 6.00%， with age， working age and job type as high-risk factors and education level as a protective factor. The prediction model constructed by the above factors can provide a reliable basis for clinical prediction of PBL chromosomal aberrations in radiological workers.