AIM:This study aims to investigate the sustained and stable drug release profile of the injectable hydrogel lidocaine(LDC)/betamethasone sodium phosphate hydrogel(BetP-Gel)and its effect on analgesic duration in a mouse model of acute incisional pain.METHODS:The drug-loaded hydrogel LDC/BetP-Gel was prepared through a sim-ple mixing process.Its physicochemical properties were characterized using electron microscopy,X-ray diffraction,Fouri-er-transform infrared spectroscopy,and rheological testing.In vivo gelation and injectability were evaluated through posi-tron emission tomography/computed tomography(PET-CT)imaging and pressure variation measurements.The in vitro drug release rate was determined using a direct release method,while the degradation rate was assessed using the residual weight method.A total of thirty BALB/c mice were randomly assigned to five groups:blank group,model group,4%LDC group,BetP-Gel group,and 4%LDC/BetP-Gel group.Pain behavior was assessed using the Up-Down method and Harg-reave's test.Biocompatibility was evaluated through HE staining,and the expression levels of inflammatory cytokines were measured via enzyme-linked immunosorbent assay(ELISA).RESULTS:The LDC/BetP-Gel hydrogel demonstrated ex-cellent drug encapsulation and sustained release properties.Behavioral assessments indicated that the LDC/BetP-Gel group exhibited significantly higher pain thresholds compared to the model group(P＜0.05),suggesting improved postop-erative pain relief.Furthermore,the LDC/BetP-Gel group showed a markedly prolonged analgesic effect compared to the LDC group(P＜0.05).HE staining confirmed the biocompatibility of the hydrogel.ELISA results revealed a significant re-duction in inflammatory cytokine levels in the LDC/BetP-Gel group 24 hours post-surgery(P＜0.05).CONCLUSION:The injectable hydrogel LDC/BetP-Gel possesses a dense and stable structure that enables effective drug loading and sus-tained release.Its ability to prolong anti-inflammatory and analgesic effects has been validated in a mouse model of acute incisional pain.

Thoracic anesthesia with spontaneous respiration represents a form of precision anesthesia meticulously customized to individual patients.Considering the more stringent requirements this anesthesia approach imposes on the regulation of respiratory function,the writing group of the"Consensus of Experts on the Management of Thoracic Anesthesia with Spontaneous Respiration"has formulated elaborate guidelines regarding indications and contraindications,preoperative evaluation,anesthesia implementation,common complications,and treatment strategies.This was accomplished by referencing relevant domestic and international literature and integrating it with actual clinical requirements.The objective is to standardize the rational application of this anesthesia method.

Gallbladder cancer (GBC) is the most common malignancy of the biliary system in China, characterized by high malignancy, low surgical resection rate, high postoperative recurrence, and poor responsiveness to chemotherapy and radiotherapy. Improving the prognosis of GBC relies on early diagnosis, standardized surgical treatment, and effective comprehensive therapeutic strate-gies. Achieving these goals necessitates in-depth epidemiological studies of GBC, as well as the exploration of new mechanisms involving systemic regulatory factors and the tumor microenviron-ment in the initiation and progression of GBC. It will help address the clinical challenges associated with this malignancy that improving the scope of surgical radical resection and diagnosis and treatment process for GBC in each stage and strengthening basic and translational research related to GBC to uncover its underlying biological principles.

Intrahepatic cholangiocarcinoma(ICC)is a malignant tumor originating from the epithelial cells of the intrahepatic bile ducts,with adenocarcinoma being its predominant pathological type.Due to its insidious onset and the difficulty of early diagnosis,ICC has a high mortality rate.Currently,complete resection of the tumor through surgery remains the only potential curative treatment for ICC,but only a small proportion of patients are eligible for surgery.In this context,a multidisciplinary comprehensive treatment model,centered around surgery and combined with systemic chemotherapy,targeted therapy,immunotherapy,supplemented by local interventional therapies and radiotherapy,has emerged as an effective strategy for improving the prognosis of ICC patients.This paper systematically reviews the latest research advances in chemotherapy,targeted therapy,immunotherapy,and local treatment for ICC,and summarizes the current clinical treatment strategies,aiming to provide a robust reference for the precise treatment of patients with advanced ICC.

Objective:To analyze the effects of the disease and injury spectrum on health-adjusted life expectancy (HALE) among permanent residents aged 55 and above in Shenzhen from 2016 to 2030.Methods:Based on the mortality surveillance data and the permanent resident population data in Shenzhen from 2016 to 2022, the Sullivan method was used to calculate the HALE during 2016—2022. The Bayesian age-period-cohort model and the grey system model were used to predict the HALE during 2023—2030. The HALE changes in the two periods were decomposed into the contributions of 20 categories of diseases and injuries, respectively.Results:From 2016 to 2022, the HALE increased from 31.41 years (95% CI: 30.50-32.32) to 33.57 years (95% CI: 32.47-34.67). During this period, the mortality effect of neurological disorders slowed the increase of HALE, with a reduction of 0.27 years. By 2030, it is anticipated that the HALE will reach 36.40 years (95% CI: 34.78-38.01). This is expected to be influenced by the mortality effects of nutritional deficiencies (-0.40 years) and mental disorders (-0.29 years), as well as the disability effects of musculoskeletal disorders (-0.66 years), skin and subcutaneous diseases (-0.21 years) and nutritional deficiencies (-0.13 years). Conclusion:The HALE of permanent residents aged 55 years and above in Shenzhen demonstrated an increasing trend over time. Greater attention should be paid to the adverse effects of neurological disorders, nutritional deficiencies, mental disorders, musculoskeletal disorders, and skin and subcutaneous diseases on the continuous increase of HALE in this population.

Objective·To develop a graph neural network(GNN)-based auxiliary diagnostic model for gallbladder cancer on CT images,and validate its accuracy and feasibility.Methods·From January 2010 to November 2023,1 774 contrast-enhanced CT arterial-phase images were acquired from 887 patients with normal gallbladder,benign gallbladder disease,or gallbladder cancer at Xinhua Hospital and Renji Hospital,Shanghai Jiao Tong University School of Medicine.These images were randomly divided into training and testing sets at a 4∶1 ratio to develop a hybrid GNN-convolutional neural network(CNN)model,named VJK-GIN.The model constructed a pixel-level graph in which each pixel served as a node,and spatial adjacency defined the edges,enabling extraction of local texture features.In the model architecture design,VJK-GIN integrated a three-layer graph isomorphism network,augmented with virtual nodes and jump-knowledge connections;global pooling compressed node features into a graph-level representation,which was classified by a multi-layer perceptron head.Five-fold cross-validation was used to compare VJK-GIN with GNN baselines(GCN,GraphSAGE,GAT,and GIN)and CNN baselines(ViT,EfficientNetV2,and ConvNeXt)in terms of accuracy,precision,recall,F1-score,and area under the receiver operating characteristic curve(AUC).Results·The results of five-fold cross-validation showed that VJK-GIN achieved an F1-score of 0.799(95%CI 0.775?0.823),recall of 0.795(95%CI 0.773?0.817),precision of 0.799(95%CI 0.775?0.823),AUC of 0.812(95%CI 0.792?0.832),and accuracy of 0.773(95%CI 0.748?0.798),surpassing all competing models across every metric.Conclusion·The VJK-GIN model exhibits high stability and accuracy in identifying contrast-enhanced CT images of normal,benign,and malignant gallbladder conditions.

The incidence of less common tumors is intermediate between rare tumors and high-prevalence tumors,while these less common tumors such as biliary tract cancers generate a significant regional health burden. The overall incidence of less common tumors is relatively low, and thus their clinical epidemiological studies face challenges such as recruitment difficulties,poor representation,and low standardization. Surgical center-based disease-specific cohorts have the advantages of case concentration,complete samples,and well-developed data,which are uniquely valuable in clinical epidemiological studies. Taking the disease-specific cohort of biliary tract cancers as an example,the authors combed through the relevant references and summarized the thinking in the practice of constructing disease-specific cohorts of less common tumors based on surgical centers. The architecture of the disease-specific cohort construction has been generalized as follows: the hardware includes a database, a biobank, and a platform of information synchronization, and the software follows the design principle of “high cohesion and low coupling”. The authors also recommend an orderly expansion of study size and implementation of quality control through all segments of cohort construction, and hope that these reflections could provide a reference for similar disease-specific cohorts.

Objective:To examine the safety and effectiveness of a novel domestic transcatheter aortic valve system in addressing severe aortic valve stenosis.Methods:This prospective, multicenter, single-arm target-value clinical trial enrolled patients with severe aortic stenosis meeting inclusion criteria from 13 Chinese centers between July 2021 and April 2022. The primary endpoint was all-cause mortality at 1-year post-procedure. Secondary endpoints included safety outcomes (30-day all-cause mortality, 1-year major adverse cardiovascular events, device success) and efficacy parameters (transvalvular pressure gradient, paravalvular leak severity, New York Heart Association(NYHA)class improvement, and quality of life). Survival analysis was performed using the Kaplan-Meier analysis.Results:The study included 134 patients, 85 males and 49 females, with an age of (73.6±5.6)years (range: 65.1 to 91.8 years). Bicuspid aortic valve morphology was present in 59.7% (80/134). Device success rate was 99.3%, with one case converted to open surgery due to coronary obstruction. All-cause mortality was 0.8% (95% CI: 0.1% to 5.3%) at both 30-day and 1-year follow-up, significantly lower than the 25% target value ( P<0.01). Permanent pacemaker implantation rates remained 2.2% (3/134) at both timepoints. Stroke incidence was 0.7% (1/134) at 30 days and 1.5% (2/134) at 1 year. Myocardial infarction rates were 0.7% (1/134) at both intervals. The postoperative transvalvular pressure gradient of the aortic valve was (6.6±3.1) mmHg(1 mmHg=0.133 kPa) (range: 4 to 8 mmHg). Among the patients, 32 cases (23.9%) had mild paravalvular leakage, 4 cases (3.0%) had moderate paravalvular leakage, and no severe paravalvular leakage was observed. NYHA class Ⅰ and Ⅱ patients increased from 18.7% preoperatively to 99.3% postoperatively. Conclusion:The novel domestic transcatheter aortic valve system demonstrates satisfactory 1-year safety and efficacy outcomes in treating severe aortic stenosis.

BACKGROUND:H uman pluripotent stem cell-derived cardiomyocytes offer an ideal cellular resource for studying heart diseases,conducting drug screening,developing in vitro heart models,and exploring potential cell therapies.However,human pluripotent stem cell-derived cardiomyocytes are characterized by immaturity with limited specific gene expression,low Ca2+processing levels,and underdeveloped structural,metabolic,and electrophysiological features.These limitations significantly impede the application of human pluripotent stem cell-derived cardiomyocytes.OBJECTIVE:To review the academic progress and clinical application of promoting the maturation of human pluripotent stem cell-derived cardiomyocytes by in vitro synthetic microenvironment.METHODS:CNKI,WanFang,VIP,PubMed,Web of Science,and Medline databases were searched,with"human pluripotent stem cells,human myocardial cells,hPSC-CMs,mature,OA,human pluripotent stem cell-derived cardiomyocytes,hPSC-CMs"as English search terms and"human pluripotent stem cells,cardiomyocytes,mature,OA,hPSC-CMs"as Chinese search terms.All relevant literature published from January 2002 to July 2024 was retrieved and 82 articles were included in the review.RESULTS AND CONCLUSION:(1)In recent years,in vitro synthetic microenvironments have attracted extensive attention due to their excellent intrinsic properties such as stiffness,plasticity,nanoscale morphology,and chemical functionality.(2)Human pluripotent stem cell-derived cardiomyocytes can be used as an effective platform for the treatment of cardiovascular diseases.(3)Mechanical stimulation,electrical stimulation,addition of biochemical molecules,and three-dimensional culture methods are effective methods to promote the maturation of human pluripotent stem cell-derived cardiomyocytes,which can further promote the clinical application of human pluripotent stem cell-derived cardiomyocytes.

Objective·To explore the mechanism at the atomic level by which the KRASG12D/R68G mutation induces tumor cell resistance to MRTX1133.Methods·The crystal structure data of the KRASG12D-MRTX1133 complex were obtained from the RCSB Protein Data Bank(PDB).PyMOL software was used to mutate arginine at position 68 of KRAS to glycine(R68G),constructing the initial conformations of the KRASG12D-MRTX1133 and KRASG12D/R68G-MRTX1133 complexes.The LEaP module was used to build simulation systems under periodic boundary conditions.The ff19SB force field was applied to standard amino acids in KRAS,GAFF(general AMBER force field)to MRTX1133,and TIP3P(intermolecular potential three point)to water molecules.Energy minimization was performed using the Amber software suite.The systems were then heated to 300 K,followed by NVT(constant volume and temperature)equilibration and NPT(constant pressure and temperature)production.Root mean square deviation(RMSD),root mean square fluctuation(RMSF),principal component analysis(PCA)and solvent-accessible surface area(SASA)of MRTX1133 and GDP were analyzed using cpptraj.The number of hydrogen bonds between regions and the dynamic cross-correlation matrix(DCCM)of amino acid movements were also calculated.Results·RMSD analysis showed greater structural variation in KRAS in the KRASG12D/R68G system compared to the KRASG12D system.RMSF analysis revealed significantly higher fluctuations in the Switch Ⅰ and Switch Ⅱ regions of the KRASG12D/R68G system.PCA indicated that Switch Ⅰ and Switch Ⅱ in the KRASG12D/R68G system were more frequently in an open conformation.The distances between Switch Ⅰ and the P-loop,and between Switch Ⅱ and the P-loop,were larger in the KRASG12D/R68G system,indicating an expanded binding pocket for GDP and MRTX1133 compared to the KRASG12D system.SASA analysis indicated that both GDP and MRTX1133 had increased solvent exposure in the KRASG12D/R68G system.DCCM analysis revealed more decoupled movements among the Switch Ⅰ,Switch Ⅱ and P-loop regions in the KRASG12D/R68G system.Conclusion·The KRASG12D/R68G mutation disrupts the interactions between the Switch Ⅰ and Switch Ⅱregions,leading to their separation and the opening of the MRTX1133 binding pocket.This increases the solvent exposure of MRTX1133,accelerates its dissociation,and ultimately results in KRASG12D/R68G resistance to MRTX1133.