[Objective] To establish a new scoring system to predict the perioperative outcomes (operation time, intraoperative blood loss, and trifecta achievement) in patients undergoing robot-assisted partial nephrectomy (RAPN) by integrating the RENAL and Mayo adhesive probability (MAP) scores. [Methods] Clinical data of 178 patients with renal cell carcinoma who underwent RAPN performed by the same surgeon in our hospital during Jan.2015 and Jan.2022 were retrospectively analyzed.The RENAL and MAP scores of all patients were calculated.Linear regression and logistic regression were used to evaluate the associations between the components of the RENAL and MAP scores (a total of 6 variables) and perioperative outcomes.The factors with significant associations were then included into logistic regression analysis to identify independent predictors for constructing an assessment system for perioperative outcomes, and the receiver operating characteristic (ROC) curve was plotted to calculate the area under the curve (AUC) to predict its efficacy. [Results] Multivariate linear regression analysis showed that tumor size (β=6.14, 95%CI: 1.93—10.34, P=0.004), exophytic rate (β=10.60, 95%CI: 3.44—17.76, P=0.004), and perinephric fat thickness (β=16.48, 95%CI: 8.52—24.45, P<0.001) were significantly associated with operation time.Tumor size (β=10.55 95%CI: 5.60—15.49, P<0.001) was associated with both intraoperative blood loss and trifecta achievement (OR=1.73, 95%CI: 1.26—2.36, P=0.001). Multivariate logistic regression analysis of these 3 factors identified tumor size (OR=9.07, 95% CI: 1.18—69.45, P=0.03) and perinephric fat thickness (OR=2.28, 95%CI: 1.86—6.04, P=0.01) as independent predictors of perioperative outcomes.Based on these findings, the tumor size and perinephric fat thickness (RP) scoring was constructed, which demonstrated better predictive ability than RENAL score or MAP score alone (RP vs.RENAL vs.MAP: 0.766 vs.0.548 vs.0.684). [Conclusion] The RP score includes fewer variables than the RENAL and MAP scores but outperforms them.

ObjectiveTo evaluate the pharmacological effect of Buzhong Yiqitang on brain development in offspring of rats with subclinical hypothyroidism （SCH） during pregnancy and explore its potential mechanism. MethodsForty-eight SPF female SD rats were divided into sham operation group （n=8） and model group （n=40）. The rat model of subclinical hypothyroidism （SCH） was constructed by total thyroidectomy combined with postoperative subcutaneous injection of levothyroxine （L-T₄）. The modeled rats were randomly allocated into model， low-， medium-， and high-dose （5.58， 11.16， 22.32 g∙kg^-1， respectively） Buzhong Yiqitang， and euthyrox （4.5×10^-6 g∙kg^-1） groups， with 8 rats in each group. These rats were co-housed with normal male rats for mating. Drug administration started 2 weeks before pregnancy and continued until delivery. Hematoxylin-eosin staining and Golgi-cox staining were used to observe pathological changes in the hippocampal tissue of offspring rats. Western blot was employed to detect the effects of Buzhong Yiqitang on the protein levels of cytochrome C oxidase subunitⅠ （COX）Ⅰ and COXⅣ in the hippocampal tissue of offspring rats. A colorimetric method was used to measure the mitochondrial adenosine triphosphate （ATP） content in the hippocampal tissue of offspring rats. For in vitro experiments， a hydrogen peroxide （H₂O₂）-induced oxidative damage model was established with rat pheochromocytoma cells （PC12）. Interventions included the DNA methyltransferase inhibitor （SGI-1027）， Buzhong Yiqitang-medicated serum， and euthyrox-medicated serum. The cell counting kit-8 （CCK-8） assay was used to examine the effect of Buzhong Yiqitang on cell proliferation. Immunofluorescence staining was performed to evaluate the effect on tubulin beta 3 class Ⅲ （TUBB3） in PC12 cells. Western blot was employed to assess the effects on the protein levels of DNA methyltransferases （TETs and DNMTs） in PC12 cells. The fluorescent probe 2′，7′-dichlorodihydrofluorescein diacetate （DCFH-DA）， luciferase assay， and JC-1 staining were employed to assess the effects of Buzhong Yiqitang on the levels of reactive oxygen species （ROS） and ATP and the mitochondrial membrane potential in PC12 cells. ResultsCompared with the sham group， the model group showed a reduction in the number of hippocampal neurons， incomplete pyramidal cell bodies， loose arrangement， shortened average dendrite length， decreased dendritic complexity and dendritic spine density， and reduced expression levels of COXⅠ and COXⅣ and content of ATP in the brain tissue （P<0.05， P<0.01）. Compared with the model group， after administration of Buzhong Yiqitang and euthyrox， hippocampal neurons exhibited regular arrangement， complete morphology， extended dendrite， increased dendritic complexity and dendritic spine density， and restored expression levels of COXⅠ and COXⅣ and content of ATP （P<0.05， P<0.01）， with the medium-dose Buzhong Yiqitang group showing the best therapeutic effect. In the PC12 cell model of oxidative damage， Buzhong Yiqitang increased the cell viability （P<0.01）， enhanced neuronal differentiation， down-regulated the expression levels of DNMTs （P<0.05）， up-regulated the expression levels of TETs （P<0.05）， decreased the ROS content （P<0.01）， and restored the ATP content and mitochondrial membrane potential （P<0.01）. ConclusionBuzhong Yiqitang protects brain development in offspring of pregnant rats with SCH. It mainly acts on the oxidative stress and mitochondrial dysfunction resulted from abnormal mtDNA methylation， with DNMTs and TETs as the key proteins for its effects.

BACKGROUND: Biomarkers-based prediction of long-term risk of acute coronary syndrome (ACS) is scarce. We aim to develop a risk score integrating clinical routine information (C) and plasma biomarkers (B) for predicting long-term risk of ACS patients. METHODS: We included 2729 ACS patients from the OCEA (Observation of cardiovascular events in ACS patients). The earlier admitted 1910 patients were enrolled as development cohort; and the subsequently admitted 819 subjects were treated as validation cohort. We investigated 10-year risk of cardiovascular (CV) death, myocardial infarction (MI) and all cause death in these patients. Potential variables contributing to risk of clinical events were assessed using Cox regression models and a score was derived using main part of these variables. RESULTS: During 16,110 person-years of follow-up, there were 238 CV death/MI in the development cohort. The 7 most important predictors including in the final model were NT-proBNP, D-dimer, GDF-15, peripheral artery disease (PAD), Fibrinogen, ST-segment elevated MI (STEMI), left ventricular ejection fraction (LVEF), termed as CB-ACS score. C-index of the score for predication of cardiovascular events was 0.79 (95% CI: 0.76-0.82) in development cohort and 0.77 (95% CI: 0.76-0.78) in the validation cohort (5832 person-years of follow-up), which outperformed GRACE 2.0 and ABC-ACS risk score. The CB-ACS score was also well calibrated in development and validation cohort (Greenwood-Nam-D'Agostino: P = 0.70 and P = 0.07, respectively). CONCLUSIONS CB-ACS risk score provides a useful tool for long-term prediction of CV events in patients with ACS. This model outperforms GRACE 2.0 and ABC-ACS ischemic risk score.

The glucagon receptor (GCGR) is a critical target for the treatment of metabolic disorders such as Type 2 Diabetes Mellitus (T2DM) and obesity. Activation of GCGR enhances systemic insulin sensitivity through paracrine stimulation of insulin secretion, presenting a promising avenue for treatment. However, the discovery of effective GCGR agonists remains a challenging and resource-intensive process, often requiring time-consuming wet-lab experiments to synthesize and screen potential compounds. Recent advances in artificial intelligence technologies have demonstrated great potential in accelerating drug discovery by streamlining screening and efficiently predicting bioactivity. In the present work, we propose DeepGCGR, a two-layer deep learning model that leverages graph convolutional networks (GCN) integrated with a multiple attention mechanism to expedite the identification of GCGR agonists. In the first layer, the model predicts the bioactivity of various compounds against GCGR, efficiently filtering large chemical libraries to identify promising candidates. In the second layer, DeepGCGR classifies high bioactive compounds based on their functional effects on GCGR signaling, identifying those with potential agonistic or antagonistic effects. Moreover, DeepGCGR was specifically applied to identify novel GCGR-regulating compounds for the treatment of T2DM from natural products derived from traditional Chinese medicine (TCM). The proposed method will not only offer an effective strategy for discovering GCGR-targeting compounds with functional activation properties but also provide new insights into the development of T2DM therapeutics.
Deep Learning ; Drug Discovery/methods* ; Humans ; Diabetes Mellitus, Type 2/metabolism* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/pharmacology*

BACKGROUND:Lumbar fixed-point rotation operation needs collaborative operation of the doctor's hands,and outputs rotation and thumb thrust.Lumbar disc herniation can be treated through disc displacement and adjusting stress distribution.However,the mechanical effects of thumb thrust and the biomechanical effects of loading direction on manipulative effects remain unclear. OBJECTIVE:To compare the biomechanical difference of lumbar fixed-point rotation manipulation for treating lumbar disc herniation under different thrust directions. METHODS:The L3-5 normal three-dimensional finite element model was constructed and validity was verified.According to the intervertebral disc degeneration Pfirrmann grade,intervertebral disc degeneration was simulated by modifying the L4/5 intervertebral space height,the volume of the nucleus pulposus,as well as the material parameters of the annulus fibrosus,nucleus pulposus,and ligament.Finally,the pathological model of L4/5 moderate disc degeneration with left para-central herniation was constructed,and then the pathological models were used as research objects.Simulation technique:spinning to the right;taking the condition on changing the direction of the thumb thrust to establish three modes of operation(M1:thumb push to the left;M2:thumb push to the right;M3:no thrust push).The protrusion displacement and the disc stress,and the stress and strain of the facet joint cartilage were compared in the three operating modes. RESULTS AND CONCLUSION:(1)Maximum displacement value of L4/5 disc herniation:displacement was 2.672 3 mm for M1,1.156 1 mm for M2,1.826 4 mm for M3,M1＞M3＞M2.(2)The maximum Von Mises stress of L4/5 discs was 1.846 7 MPa for M1,0.419 0 MPa for M2,and 1.257 9 MPa for M3,M1＞M3＞M2.(3)L4/5 bilateral small cartilage produced different degrees of contact stress changes:It was 0.485 5 MPa for M1,0.026 7 MPa for M2,and 0.441 4 MPa for M3,M1＞M3＞M2.Right cartilage contact force was 0.000 5 MPa for M1,0.025 9 MPa for M2,and 0.001 3 MPa for M3,M2＞M3＞M1;the left greater than the right,M1 had the highest value;cartilage strain was consistent with contact stress changes.(4)Different operation modes will have some biomechanical influences on the diseased intervertebral disc and accessory structure.The M1 operation mode can maximize the displacement of protrusion,disc stress and left joint cartilage contact,which can better promote disc displacement,balance stress distribution and reduce facet joint disorder,so the operation is better.

To optimize the formulation and technology of oxymatrine-astragaloside IV coloaded liposomes (Om-As-Lip) based on quality by design (QbD) principles, and further to verify the feasibility of its amplification process, Om-As-Lip was prepared by ethanol injection combined with pH gradient method. The critical material attributions of Om-As-Lip were evaluated by dual-risk analysis tools and Plackett-Burman design (PBD). The formulation of Om-As-Lip was further optimized with the Box-Behnken design (BBD). The design space was also established based on the contour plots of BBD. In order to further investigate the amplification process of Om-As-Lip, the critical process parameters of high-pressure homogenization (HPH) were optimized by single-factor test, and the quality of the final product was also evaluated. The results of risk analysis and PBD confirmed that the astragaloside concentration, cholesterol concentration, and phospholipid ratio (HSPC∶SPC) were the ctitical material attributes. The model established by BBD had a good predictability, and the optimized mass ratio of As to phospholipids was 1∶40, cholesterol to phospholipids was 1∶10, HSPC to SPC was 51∶9. The design space of Om-As-Lip was as follows: the ratio of cholesterol to phospholipids was 1∶12-1∶5 and HSPC to SPC was 1∶7-17∶3. The optimized high-pressure homogenization pressure was 600 bar, temperature was 4 ℃, and cycle times was 6 times for HPH-Om-As-Lip. The quality of Om-As-Lip prepared based on the QbD concept can meet the expected CQAs, and the formulation and technology established can provide a reliable experimental basis for its future development and applications.

Objective To explore the efficacy and safety of recombinant human anti-severe acute respiratory syn-drome coronavirus 2(anti-SARS-CoV-2)monoclonal antibody injection(F61 injection)in the treatment of patients with coronavirus disease 2019(COVID-19)combined with renal damage.Methods Patients with COVID-19 and renal damage who visited the PLA General Hospital from January to February 2023 were selected.Subjects were randomly divided into two groups.Control group was treated with conventional anti-COVID-19 therapy,while trial group was treated with conventional anti-COVID-19 therapy combined with F61 injection.A 15-day follow-up was conducted after drug administration.Clinical symptoms,laboratory tests,electrocardiogram,and chest CT of pa-tients were performed to analyze the efficacy and safety of F61 injection.Results Twelve subjects(7 in trial group and 5 in control group)were included in study.Neither group had any clinical progression or death cases.The ave-rage time for negative conversion of nucleic acid of SARS-CoV-2 in control group and trial group were 3.2 days and 1.57 days(P=0.046),respectively.The scores of COVID-19 related target symptom in the trial group on the 3rd and 5th day after medication were both lower than those of the control group(both P＜0.05).According to the clinical staging and World Health Organization 10-point graded disease progression scale,both groups of subjects improved but didn't show statistical differences(P＞0.05).For safety,trial group didn't present any infusion-re-lated adverse event.Subjects in both groups demonstrated varying degrees of elevated blood glucose,elevated urine glucose,elevated urobilinogen,positive urine casts,and cardiac arrhythmia,but the differences were not statistica-lly significant(all P＞0.05).Conclusion F61 injection has initially demonstrated safety and clinical benefit in trea-ting patients with COVID-19 combined with renal damage.As the domestically produced drug,it has good clinical accessibility and may provide more options for clinical practice.

Objective To compare the clinical efficacy and pregnancy outcomes of CO2 laser and loop electrosurgical excision procedure(LEEP)surgery in the treatment of cervical high-grade squamous intraepithelial lesion(HSIL)in women of childbearing age.Methods Patients with cervical HSIL of appropriate reproductive age(20-34 years old)who underwent satisfied colposcope,subsequently treated with laser or LEEP between Jan 2019 and Dec 2021 in Obstetrics and Gynecology Hospital,Fudan University were collected.All the patients were interpreted as transformation zone(TZ)type 1/2,and colposcopy biopsy diagnosed as cervical high-grade squamous intraepithelial lesion(HSIL)and received laser or LEEP according to the physician's advice and the patient's wishes.The effectiveness of the two surgeries was evaluated,and postoperative cytology,HPV result,and colposcopic pathology were compared.We monitored the surgical pregnancy rate,pregnancy complications,and pregnancy results after the surgery.Results A total of 566 cases,including 233 laser cases and 333 LEEP cases,were enrolled.There was no significant difference between the two groups in terms of preoperative cytology,HPV distribution,or the length of cervical canal.After 6 months of surgery,91.5%of patients who underwent laser therapy and 86.9%of those who underwent LEEP had normal cytology.The histology cure rate was 91.5%and the HPV conversion rate was 74.6%in both groups.The results of cytology,HPV,and colposcopic pathology had no significant difference between the two groups.The length of postoperative cervical canal was significantly longer in laser group than that in LEEP group[(29.09±3.15)mm vs.(27.05±3.84)mm,P<0.001].There was no statistically significant difference in postoperative pregnancy rate and pregnancy outcome between the two groups.Conclusion Laser ablation and LEEP produce comparable effects pregnancy outcomes in cervical HSIL patients with TZ types 1 and 2,while LEEP has pathologic feedback,so its misdiagnosis of invasive cancer reduce.