OBJECTIVE To systematically review the pharmacoeconomic evaluation literature about proprotein convertase subtilisin/kexin type 9 （PCSK9） inhibitors for the prevention of cardiovascular disease in patients with hypercholesterolemia， and to provide a reference for clinical treatment， health decision-making and future follow-up research. METHODS Retrieved from English and Chinese databases such as PubMed and CNKI， the pharmacoeconomic literature about PCSK9 inhibitors （evolocumab and alirocumab） for the prevention of cardiovascular disease in patients with hypercholesterolemia was collected from the establishment of the database to October 8， 2023. The quality of the included literature was assessed with Consolidated Health Economic Evaluation Reporting Standards 2022 （CHEERS 2022） scale. The descriptive analysis was performed for basic information， model structure， related parameters， sensitivity analysis and the results of included studies. RESULTS & CONCLUSIONS A total of 29 literature were included， with overall good quality. The evaluation mainly adopted the Markov model from the healthcare system， payer and societal perspective. The effectiveness and utility data mainly came from the previous studies； the direct cost was mainly considered with a discount rate of 1.5%-5.0% per year， while the willingness-to-pay threshold was often set at 1-3 times the gross domestic product per capita. Most health output indicators were measured in life years and quality-adjusted life years. The sensitivity analysis of most studies demonstrated the robustness and the main influential factor was the drug cost. Most Chinese studies showed that PCSK9 inhibitor was not cost-effective for the prevention of cardiovascular disease in patients with acute coronary syndrome， myocardial infarction and atherosclerotic cardiovascular disease. It was cost-effective to use PCSK9 inhibitors for the prevention of cardiovascular disease only in specific groups， such as patients with triple vessel disease， patients with newly diagnosed acute coronary syndrome and low-density lipoprotein cholesterol≥100 mg/dL. Future research should refer to the CHEERS 2022 scale to improve the design， and strive to select large-scale， high-quality data to enhance the quality of reports and the transparency of health decisions， so as to more accurately assess the cost-effectiveness of PCSK9 inhibitors.

ObjectiveTo investigate the impact of icariin （ICA） on autophagy in glucocorticoid-induced bone microvascular endothelial cells （BMECs） mediated by the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin （PI3K/Akt/mTOR） signaling pathway. MethodBMECs were isolated and cultured from femoral heads obtained during total hip arthroplasty and identified using immunofluorescence staining. The experimental cells were divided into four groups： A control group， a glucocorticoid group （100 mg·L^-1 hydrocortisone）， an ICA group （100 mg·L^-1 hydrocortisone+6.7×10^-3 mg·L^-1 ICA）， and a Rapamycin group （100 mg·L^-1 hydrocortisone+6.7×10^-3 mg·L^-1 ICA+1 mg·L^-1 rapamycin）. Autophagy in BMECs was induced using 100 mg·L^-1 hydrocortisone. LC3 fluorescence staining was used to observe the peak of autophagy at different time points. Western blot analysis was employed to analyze the expression of autophagy-related proteins and PI3K/Akt/mTOR pathway proteins in each group. Electron microscopy was used to observe autophagosomes and autolysosomes in the cells. ResultHydrocortisone at 100 mg·L^-1 induced autophagy in BMECs， reaching a peak at around 5 hours， which then declined with further intervention. Compared to the control group， the glucocorticoid group showed cell membrane damage， disordered organelle arrangement， and a large number of autophagosomes and autolysosomes. Compared to the glucocorticoid group， the ICA group had more intact cell membranes， sparser organelle arrangement， and fewer autophagosomes and autolysosomes. Compared to the ICA group， the Rapamycin group showed cell membrane damage， disordered organelle arrangement， and more autophagosomes and autolysosomes. Compared to the control group， the glucocorticoid group had significantly increased expression of light chain 3B （LC3B）， Atg4B， and p62 （P<0.01）. Compared to the glucocorticoid group， the ICA group showed significantly decreased expression of LC3B， Atg4B， p62， and Beclin-1 （P<0.01）. Compared to the ICA group， the Rapamycin group had significantly increased expression of Atg4B and p62 （P<0.01）. Compared to the control group， the glucocorticoid group had significantly decreased expression of p-PI3K/PI3K， p-Akt/Akt， and p-mTOR/mTOR （P<0.01）. Compared to the glucocorticoid group， the ICA group showed significantly increased expression of p-PI3K/PI3K， p-Akt/Akt， and p-mTOR/mTOR （P<0.01）. Compared to the ICA group， the Rapamycin group had significantly decreased expression of p-PI3K/PI3K， p-Akt/Akt， and p-mTOR/mTOR （P<0.01）. Ubiquitination levels were significantly decreased in the glucocorticoid group compared to the control group （P<0.01）. Compared to the glucocorticoid group， ubiquitination levels were significantly increased in the ICA group （P<0.01）， and significantly decreased in the Rapamycin group compared to the ICA group （P<0.01）. ConclusionThe glucocorticoid-induced autophagy in BMECs is time-dependent. ICA inhibits glucocorticoid-induced autophagy in BMECs， and this effect may be related to the regulation of the PI3K/Akt/mTOR pathway.

Objective To develop an intelligent model for differential diagnosis of atrioventricular nodal re-entrant tachycardia(AVNRT)and atrioventricular re-entrant tachycardia(AVRT)using 12-lead wearable electrocardiogram devices.Methods A total of 356 samples of 12-lead supraventricular tachycardia(SVT)electrocardiograms recorded by wearable devices were randomly divided into training and validation sets using 5-fold cross validation to establish the intelligent classification model,and 101 patients with the diagnosis of SVT undergoing electrophysiological studies and radiofrequency ablation from October,2021 to March,2023 were selected as the testing set.The changes in electrocardiogram parameters before and during induced tachycardia were compared.Based on multiscale deep neural network,an intelligent diagnosis model for classifying SVT mechanisms was constructed and validated.The 3-lead electrocardiogram signals from Ⅱ,Ⅲ,and V1 were extracted to build new classification models,whose diagnostic efficacy was compared with that of the 12-lead model.Results Of the 101 patients with SVT in the testing set,68 were diagnosed with AVNRT and 33 were diagnosed with AVRT by electrophysiological study.The pre-trained model achieved a high area under the precision-recall curve(0.9492)and F1 score(0.8195)for identifying AVNRT in the validation set.The total F1 scores of the lead Ⅱ,Ⅲ,V1,3-lead and 12-lead intelligent diagnostic models in the testing set were 0.5597,0.6061,0.3419,0.6003 and 0.6136,respectively.Compared with the 12-lead classification model,the lead-Ⅲ model had a net reclassification index improvement of-0.029(P=0.878)and an integrated discrimination index improvement of-0.005(P=0.965).Conclusion The intelligent diagnostic model based on multiscale deep neural network using wearable electrocardiogram devices has an acceptable accuracy for classifying SVT mechanisms.

Background and aim:A genome-wide association study has indicated the association of numerous genes in the 6p21.3 region with chronic hepatitis B virus(HBV)infection.In this study,we screened 12 representative single-nucleotide polymorphisms(SNPs)from the 6p21.3 region and investigated their association with the risk of chronic hepatitis B(CHB)to better understand the molecular etiology un-derlying CHB risk in the Han Chinese population. Methods:Between March 2021 and November 2022,we included 183 patients with CHB(case group)and 196 with natural HBV clearance(control group).Allele typing of the selected SNPs was performed using snapshot technology.The correlation between the 12 chosen SNPs and the risk of chronic HBV infection was examined using binary logistic regression analysis.Interacting genes of the variants were identified,and expression quantitative trait loci(eQTL)were analyzed using the 3DSNP database. Results:We validated 12 previously reported CHB susceptibility sites,including rs1419881 of tran-scription factor 19(TCF19),rs3130542 and rs2853953 of human leukocyte antigen(HLA)-C,rs652888 of euchromatic histone-lysine-methyltransferase 2(EHMT2),rs2856718,rs9276370,rs7756516,and rs7453920 of HLA-DQ,rs378352 of HLA-DOA,and rs3077,rs9277535,and rs9366816 of HLA-DP.Logistic regression analyses revealed that polymorphisms such as rs9276370,rs7756516,rs7453920,rs3077,rs9277535,and rs9366816 were positively correlated with natural HBV clearance in the dominant model.Conversely,rs3130542 and rs378352 were identified as risk factors for CHB.Haplotype analysis revealed that rs9276370,rs7756516,and rs7453920 in HLA-DQ were TTG and GCA haplotypes.Although the TTG haplotype was positively correlated with a higher risk of CHB,the GCA haplotype significantly influenced the natural clearance of HBV.Bioinformatics analysis demonstrated that rs378352,rs3077,and rs9366816 were located within enhancer states;rs3077 and rs9366816 overlapped with nine tran-scription factor-binding sites,whereas rs378352 altered five sequence motifs.Furthermore,eQTL analysis demonstrated the functional tendencies of eight statistically significant SNPs(rs3130542,rs9276370,rs7756516,rs7453920,rs378352,rs3077,rs9277535,and rs9366816). Conclusions:Genetic variations within the 6p21.3 region were associated with chronic HBV infection in the Han Chinese population in southern China.Furthermore,the GCA haplotype including rs9276370,rs7756516,and rs7453920 of HLA-DQ contributed significantly to natural HBV clearance,implying that multiple SNPs exert a cumulative allelic effect on HBV infection.

Objective To develop an intelligent model for differential diagnosis of atrioventricular nodal re-entrant tachycardia(AVNRT)and atrioventricular re-entrant tachycardia(AVRT)using 12-lead wearable electrocardiogram devices.Methods A total of 356 samples of 12-lead supraventricular tachycardia(SVT)electrocardiograms recorded by wearable devices were randomly divided into training and validation sets using 5-fold cross validation to establish the intelligent classification model,and 101 patients with the diagnosis of SVT undergoing electrophysiological studies and radiofrequency ablation from October,2021 to March,2023 were selected as the testing set.The changes in electrocardiogram parameters before and during induced tachycardia were compared.Based on multiscale deep neural network,an intelligent diagnosis model for classifying SVT mechanisms was constructed and validated.The 3-lead electrocardiogram signals from Ⅱ,Ⅲ,and V1 were extracted to build new classification models,whose diagnostic efficacy was compared with that of the 12-lead model.Results Of the 101 patients with SVT in the testing set,68 were diagnosed with AVNRT and 33 were diagnosed with AVRT by electrophysiological study.The pre-trained model achieved a high area under the precision-recall curve(0.9492)and F1 score(0.8195)for identifying AVNRT in the validation set.The total F1 scores of the lead Ⅱ,Ⅲ,V1,3-lead and 12-lead intelligent diagnostic models in the testing set were 0.5597,0.6061,0.3419,0.6003 and 0.6136,respectively.Compared with the 12-lead classification model,the lead-Ⅲ model had a net reclassification index improvement of-0.029(P=0.878)and an integrated discrimination index improvement of-0.005(P=0.965).Conclusion The intelligent diagnostic model based on multiscale deep neural network using wearable electrocardiogram devices has an acceptable accuracy for classifying SVT mechanisms.

Objective To analyze the dynamic changes in serum adiponectin (APN) levels after acute myocardial infarction (AMI) and its relationship with heart failure (HF) and major adverse cardiovascular events (MACE). Methods A total of 124 AMI patients who underwent percutaneous coronary intervention (PCI) in our hospital from January 2021 to December 2023 were enrolled as AMI group. Additionally, 30 patients with non-AMI coronary artery disease and 30 healthy individuals were included in non-AMI coronary artery disease group and healthy group, respectively. General information such as age, gender, smoking, alcohol consumption, hypertension, diabetes, and blood lipids were recorded for all subjects. Serum APN levels were measured using the enzyme-linked immunosorbent assay (ELISA) method; plasma brain natriuretic peptide (BNP) levels were determined by immunofluorescence; and left ventricular ejection fraction (LVEF) was assessed using echocardiography. Changes in serum APN levels and its relationship with BNP, LVEF, and MACE were recorded during a one-year follow-up period. Results AMI patients had lower serum APN levels than those in the non-AMI coronary artery disease group and the healthy group, while levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C); Lipoprotein-associated phospholipase A2 (Lp-PLA2), and the proportions of smokers and diabetics were higher(P < 0.05). A one-year follow-up of AMI patients revealed an upward trend in serum APN and BNP levels and a downward trend in LVEF levels at one week, one month, three months, six months, and one year postoperatively (P < 0.05). APN and BNP levels peaked one month after PCI, while LVEF reached its lowest level at the same time point. However, there were no statistically significant changes in these indicators in the subsequent 11 months (P>0.05). The incidence of MACE in AMI patients at one, three, six, and twelve months postoperatively was 2.8%, 3.2%, 4.6%, and 8.8%, respectively. Both preoperative and one-month postoperative serum APN levels had high predictive value for the occurrence of HF and MACE within one year in AMI patients, and the area under the curve for predicting HF and MACE one month postoperatively was larger than that preoperatively (P < 0.05). Conclusion Serum APN levels in AMI patients show an upward trend after PCI, peaking one month postoperatively. At this time point, serum APN levels have the highest predictive value for the occurrence of HF and MACE.

Purpose: Erectile dysfunction (ED) is a common postoperative complication of pelvic surgery for which there is currently no effective treatment. This study investigated the therapeutic effects and potential mechanisms of adipose derived mesenchymal stem cells-derived mitochondria (ADSCs-mito) transplantation in a rat model of bilateral cavernous nerve injury (CNI) ED. Materials and Methods: We isolated mitochondria from ADSCs and tested their quality. In vivo, twenty male Sprague Dawley rats were randomly divided into four groups: sham operation group and CNI groups that received intracavernous injection of either phosphate buffer solution, ADSCs-mito or ADSCs. Two weeks after therapy, the erectile function of the rats was evaluated and the penile tissues were harvested for histologic analysis and western blotting. In vitro, the apoptosis rate, reactive oxygen species (ROS), mitochondria derived active oxygen (mtROS) and adenosine triphosphate (ATP) levels were detected in corpus cavernosum smooth muscle cells (CCSMCs) after the incubation with ADSCs-mito. In addition, intercellular mitochondrial transfer was visualized by co-culture of ADSCs and CCSMCs. Results: The ADSCs, ADSCs-mito and CCSMCs were isolated and identified successfully. ADSCs-mito transplantation notably restored the erectile function and smooth muscle content of CNI ED rats. Moreover, the levels of ROS, mtROS and cleaved-caspase 3 were reduced and the levels of superoxide dismutase and ATP were increased after ADSCs-mito transplantation. In CNI ED rats, the mitochondrial structure of cells in penile tissues was destroyed. ADSCs could transfer its own mitochondria to CCSMCs. Pre-treatment with ADSCs-mito could significantly decrease apoptosis rate, ROS levels and mtROS levels as well as restore the ATP level in CCSMCs. Conclusions ADSCs-mito transplantation significantly ameliorated ED induced by CNI, with similar potency to ADSCs treatment. The ADSCs-mito might exert their effects via anti-oxidative stress, anti-apoptosis and modulating energy metabolism of CCSMCs. Mitochondrial transplantation should be a promising therapeutic method for treating CNI ED in the future.

Methcathinone (MCAT) belongs to the designer drugs called synthetic cathinones, which are abused worldwide for recreational purposes. It has strong stimulant effects, including enhanced euphoria, sensation, alertness, and empathy. However, little is known about how MCAT modulates neuronal activity in vivo. Here, we evaluated the effect of MCAT on neuronal activity with a series of functional approaches. C-Fos immunostaining showed that MCAT increased the number of activated neurons by 6-fold, especially in sensory and motor cortices, striatum, and midbrain motor nuclei. In vivo single-unit recording and two-photon Ca²⁺ imaging revealed that a large proportion of neurons increased spiking activity upon MCAT administration. Notably, MCAT induced a strong de-correlation of population activity and increased trial-to-trial reliability, specifically during a natural movie stimulus. It improved the information-processing efficiency by enhancing the single-neuron coding capacity, suggesting a cortical network mechanism of the enhanced perception produced by psychoactive stimulants.
Mice ; Animals ; Reproducibility of Results ; Neurons ; Sensation ; Perception

Objective:To investigate the association between preterm birth, low birth weight and the risk of hypospadias.Methods:According to the search strategy of Cochrance Collaborative Network, the China National Knowledge Internet (CNKI), VIP, Wanfang, Pubmed, Cochrance and Embase were searched from the establishment of the database to April 2022. The literature on the relationship between preterm birth, low birth weight and the risk of hypospadias was included. Meta analysis was conducted on the relationship between preterm birth, low birth weight and the risk of hypospadias.Results:A total of 13 articles were included, including cases from Asia, Europe, Australia and America. Newcastle-ottawa Scale was used for evaluation, and the scores were all above 6. There were 10 articles on the relationship between preterm birth and the risk of hypospadias, all of which were case-control studies. Heterogeneity test I2=46%, P=0.05. There were 3 521 cases in the case group and 95 816 cases in the control group. Compared with the control group, preterm birth was a risk factor for hypospadias ( OR: 2.13, 95% CI: 1.89-2.41), and the difference was statistically significant ( Z=12.21, P<0.01). There were 11 articles on the association between low birth weight and the risk of hypospadias, all of which were case-control studies. Heterogeneity test I2=47%, P=0.04. There were 2 460 cases in the case group and 94 260 cases in the control group. Compared with the control group, low birth weight was a risk factor for hypospadias ( OR: 3.29, 95% CI: 2.57-4.22), and the difference was statistically significant ( Z=9.40, P<0.01). Conclusions:Based on meta-analysis of published literature, preterm birth and low birth weight increase the risk of hypospadias.

Bone defects caused by different causes such as trauma, severe bone infection and other factors are common in clinic and difficult to treat. Usually, bone substitutes are required for repair. Current bone grafting materials used clinically include autologous bones, allogeneic bones, xenografts, and synthetic materials, etc. Other than autologous bones, the major hurdles of rest bone grafts have various degrees of poor biological activity and lack of active ingredients to provide osteogenic impetus. Bone marrow contains various components such as stem cells and bioactive factors, which are contributive to osteogenesis. In response, the technique of bone marrow enrichment, based on the efficient utilization of components within bone marrow, has been risen, aiming to extract osteogenic cells and factors from bone marrow of patients and incorporate them into 3D scaffolds for fabricating bone grafts with high osteoinductivity. However, the scientific guidance and application specification are lacked with regard to the clinical scope, approach, safety and effectiveness. In this context, under the organization of Chinese Orthopedic Association, the Expert consensus for the clinical application of autologous bone marrow enrichment technique for bone repair ( version 2023) is formulated based on the evidence-based medicine. The consensus covers the topics of the characteristics, range of application, safety and application notes of the technique of autologous bone marrow enrichment and proposes corresponding recommendations, hoping to provide better guidance for clinical practice of the technique.