ObjectiveTo investigate the association of comprehensive control of multiple metabolic risk factors with the risk of all-cause mortality in patients with metabolic dysfunction-associated steatotic liver disease （MASLD） and its quantitative effect. MethodsA retrospective cohort study was conducted based on the data from National Health and Nutrition Examination Survey （NHANES） in 2003—2018. A total of 29 458 participants were enrolled， including 12 528 patients with MASLD and 16 930 non-MASLD controls. The control status of nine risk factors was assessed， i.e.， hypertension， diabetes， liver fibrosis （assessed by fibrosis-4 index ［FIB-4］）， aspartate aminotransferase （AST）/alanine aminotransferase （ALT） ratio， serum albumin， renal function （assessed by serum creatinine）， systemic inflammation （assessed by neutrophil count）， smoking， and physical activity. According to the status of comprehensive risk factor control， the patients with MASLD were further divided into low-control group with 1 107 patients， moderate-control group with 7 042 patients， and high-control group with 4 379 patients. A total of 397 participants were enrolled in the external validation cohort， among whom there were 266 participants with MASLD and 131 participants without MASLD. The Kruskal-Wallis H test was used for comparison of continuous data between multiple groups， and the chi-square test was used for comparison of categorical data between groups. The Cox proportional hazards model incorporating complex sampling weights for NHANES data were used to investigate the association between the degree of risk factor control and all-cause mortality， and the Kaplan-Meier curve， the log-rank test， restricted mean survival time （RMST）， and population attributable fraction （PAF） were used for further assessment. The robustness of the findings was validated in an independent clinical cohort （n=397）. ResultsThe cohort study based on the NHANES database showed that during the median follow-up time of 6.7 years， 1 171 deaths occurred among the 12 528 patients with MASLD. There was a significant reduction in mortality risk with the increase in the number of risk factors controlled （trend test： χ²=65.06， P<0.001）. Compared with the low-control group， the mortality risk decreased successively in the moderate-control group （hazard ratio ［HR］=0.59， 95% confidence interval ［CI］： 0.51 — 0.69） and the high-control group （HR=0.36， 95%CI： 0.27 — 0.48）， and the mortality risk was reduced by 22% for each additional risk factor controlled （HR=0.78， 95%CI： 0.74 — 0.82）. The PAF analysis showed that AST/ALT ratio control （PAF=19.2%） and physical activity （PAF=18.9%） were the largest contributors. The survival analysis of the sub-cohort constructed based on nearest neighbor matching （with a maximum follow-up time of 13.3 years） showed that there was a significant difference in cumulative survival rate between the MASLD groups with different control levels and the non-MASLD group （P<0.001）. The RMST analysis further quantified the survival benefit of each group， and the high-control group had the longest 10-year RMST （9.88 years）， which was superior to that of the non-MASLD group （9.43 years）， the moderate-control group （9.33 years）， and the low-control group （7.96 years）. The multivariable-adjusted model analysis of the complete cohort showed that compared with the non-MASLD population， the MASLD patients in the low-control group had a significant increase in mortality risk， the moderate-control group had a comparable mortality risk， and the high-control group had a significantly lower mortality risk. The subgroup analysis showed a significant protective effect of comprehensive control in both male and female individuals （P<0.05）， and the interaction analysis suggested a potentially stronger protective effect in female individuals （P_{for interaction}=0.031）. The protective effect was statistically significant in patients aged ≥60 years （P<0.05）. There was a significant difference in protective effect across the groups stratified based on waist circumference （P<0.05）， but there was no significant interaction between groups （P_{for interaction}=0.821）. In the external validation cohort， among the 397 participants， there were 72 cases of all-cause mortality （18.1%）. The survival analysis showed a significant gradient increase in the survival rate of MASLD patients with the increase in the level of control （P=0.022）. The RMST analysis showed that the moderate- and high-control groups had a better RMST than the non-MASLD group at 5 years （4.47 years vs 4.56 years vs 4.40 years）， with a more significant survival advantage at 10 years （8.67 years vs 8.95 years vs 8.44 years）. The Cox regression analysis showed that， with the low-control MASLD group as the reference， there was a significant reduction in mortality risk in the moderate-control group （HR=0.41， 95%CI： 0.21 — 0.81） and the high-control group （HR=0.32， 95%CI： 0.14 — 0.71）； with the non-MASLD population as the reference， there was a significant increase in mortality risk in the low-control group （HR=2.02， 95%CI： 1.03 — 3.95）， with a comparable mortality risk in the moderate-control group （HR=0.83， 95%CI： 0.48 — 1.44） and the high-control group （HR=0.66， 95%CI： 0.30 — 1.38）， and the point estimates of the effects were highly consistent with the main study. ConclusionAmong MASLD patients， better control of metabolic risk factors is associated with a lower mortality risk. Achieving optimal control can eliminate the excess mortality risk associated with MASLD， thereby helping patients achieve a better survival prognosis than the general population.

Objective:To investigate the efficacy and safety of sintilimab combined with the SOX regimen for adjuvant treatment of stage Ⅲgastric cancer after D2 radical resection and to provide a reference for individualized clinical treatment.Methods:The clinical data of 245 pa-tients with stage III gastric cancer who underwent D2 radical resection at the 940th Hospital of the Joint Support Force of the People's Liber-ation Army from June 2019 to May 2022 were retrospectively analyzed.The 180 patients who received only the SOX regimen were desig-nated the control group,and the 65 patients who received sintilimab combined with the SOX regimen were designated the experimental group.The 3-year disease-free survival(DFS)rate,overall survival(OS)rate,and adverse reactions among the two groups and different sub-groups(HER-2 positive,dMMR,CPS≥5)were compared.Results:The 3-year DFS(81.5%vs.59.4%)and OS(84.6%vs.70.6%)rates in the experimental group were significantly higher than those in the control group(both P<0.05).Group analysis showed that in patients with CPS≥5,the 3-year DFS(91.5%vs.67.0%)and OS(95.7%vs.71.6%)rates within the experimental group were significantly better than those in the control group(both P<0.05).Intra-group analysis within the experimental group showed that the 3-year DFS rate(91.5%vs.55.6%)and OS rate(95.7%vs.55.6%)of patients with CPS≥5 were significantly better than those of patients with CPS<5(both P<0.05).The overall and grade≥3 incidences of liver and kidney function damage,thyroid dysfunction,colitis,pneumonia,and rash in the experimental group were higher than those in the control group(all P<0.05),while the differences in other adverse reactions,including leukopenia were not statistic-ally significant(all P>0.05).Conclusions:Sintilimab combined with the SOX regimen can significantly improve 3-year DFS and OS rates in pa-tients with stage Ⅲ gastric cancer after surgery,especially in the CPS≥5 subgroup,with significant benefits and controllable safety.

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system in China. With the progress of immunotherapy research, programmed death receptor-1 (PD-1) inhibitor-based combinatory therapy offers new ideas for the treatment of advanced gastric cancer. In recent years, with the increasing status of immunotherapy in the treatment of advanced gastric cancer, a growing number of domestic and international clinical studies shown that immunotherapy could achieve better efficacy in the neoadjuvant therapy and conversion therapy for patients with advanced gastric cancer. This paper reviews the current research progress on the application of PD-1 inhibitors in the neoadjuvant therapy and conversion therapy of gastric cancer.

Objective To construct a dynamic prediction model for the risk of developing Alzheimer's disease(AD)based on baseline clinical data and longitudinal neuropsychological scores in patients with mild cognitive impairment(MCI).Methods A total of 380 MCI patients from the Alzheimer's Disease Neuroimaging Initiative 1 study from 2005 to 2011 were selected and were randomly divided into a training set and a test set in a 7∶3 randomization.The Alzheimer's disease assessment scale-cognitive 13 items(ADAS-Cog13),Rey auditory verbal learning test immediate score(RAVLT Immediate),functional activities questionnaire(FAQ),and mini-mental state examination(MMSE)were used as longitudinal neuropsychological score metrics.Random survival forests with multivariate longitudinal endogenous covariates were used to construct a dynamic prediction model of the risk of developing AD in patients with MCI in the training set.The predictive performance of the model was evaluated in the test set using time-dependent areas under the receiver operator characteristic curve(AUC)and Brier score(BS).Results For the prediction of the risk of developing AD in patients with MCI,longitudinal neuropsychological scores were more important predictors than baseline clinical data,with FAQ being the strongest predictor.The dynamic prediction model had high predictive performance in the test set,with AUC ranging from 0.7695 to 0.8987 and BS ranging from 0.1369 to 0.2184.Conclusion Random survival forests with multivariate longitudinal endogenous covariates can be used to combine multivariate longitudinal neuropsychological scores to construct a prediction model for the risk of developing AD in patients with MCI,with high predictive performance and the ability to achieve individual dynamic prediction.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Surgical resection remains the preferred treatment modality, offering the potential for cure. However, over half of HCC patients present as intermediate to advanced stages at diagnosis, with multiple factors precluding surgical resection. Conversion therapy represents an important treatment strategy by enabling tumor downstaging, offering future resectability for patients with intermediate-to-advanced HCC who are initially unresectable. This article reviews the relevant concepts and research progress in conversion therapy for HCC.

Objective To analyze the role and mechanism of Xiaoqinglong decoction in alleviating the pathological process of pulmonary arterial hypertension(PAH),and to observe the effect of Xiaoqinglong decoction on endothelial-mesenchymal transition(EMT)in human pulmonary arterial endothelial cell(HPAEC)and the involvement of the Toll-like receptor/nuclear factor-κB/hypoxia-inducible factor-1α(TLR/NF-κB/HIF-1α)pathway in this mechanism.Methods Thirty-six male Sprague Dawley(SD)rats and HPAEC were randomly divided into control group,model group,Xiaoqinglong decoction plus Earthworm group,Bosentan tablet group,dimethyl sulfoxide(DMSO)group,and monophosphoryl lipid A(MPL)group.PAH rat models and HPAEC models were established by hypoxic exposure.The Xiaoqinglong decoction plus Earthworm group received intragastric administration Xiaoqinglong decoction plus Earthworm(5 g·kg-1·d-1)or cultured with 10%corresponding drug serum,the Bosentan group received Bosentan(100 mg·kg-1·d-1)by gavage or cultured with 10%corresponding drug serum,the MPL group received 1 μg MPL,and the DMSO group received an equivalent volume of the DMSO and corn oil mixed solvent as a negative control for the MPL group.The hemodynamic parameters,including mean pulmonary arterial pressure(mPAP),right ventricular systolic pressure(RVSP),and the maximum rate of right ventricular pressure(+dp/dt max),were measured via right heart catheterization.After euthanasia,lung and heart tissues were collected to assess the right ventricular hypertrophy index(RVHI);hematoxylin-eosin(HE)staining was used to observe the degree of right ventricular cardiomyocyte hypertrophy and to calculate the average intima-media thickness(IMT)in small pulmonary arteries;Western blotting was used to detect the protein expression levels of proliferating cell nuclear antigen(PCNA),CD68,TLR4,NF-κB,HIF-1α,vascular endothelial cadherin,and vimentin;cell counting kit-8(CCK-8),Transwell,and scratch assays were used to observe cell proliferation and migration;Enzyme-linked immunosorbent assay(ELISA)was used to measure the levels of interleukins(IL-8,IL-6),tumor necrosis factor-α(TNF-α),endothelin-1(ET-1),and nitric oxide(NO).Results Compared with the model group,the Xiaoqinglong decoction plus Earthworm group showed significant reductions in mPAP,RVSP,RVHI,and IMT in PAH rats[mPAP(mmHg,1 mmHg≈0.133 kPa):22.17±1.94 vs.42.00±4.90,RVSP(mmHg):34.67±3.20 vs.52.83±3.76,RVHI:0.402±0.057 vs.0.822±0.101,IMT:(37.85±2.49)%vs.(62.06±4.52)%,all P<0.05],and a significant increase in+dP/dT max(mmHg/s:2 730.83±137.89 vs.1 718.33±148.36,P<0.05).Western blotting and ELISA results showed that compared with the model group,the Xiaoqinglong decoction plus Earthworm group had significantly lower protein expression of PCNA and CD68 in lung tissue,and levels of inflammatory factors(IL-6,IL-8,TNF-α)in rat serum[lung tissue:PCNA protein expression(PCNA/GAPDH)was 1.56±0.08 vs.2.20±0.26,CD68 protein expression(CD68/GAPDH):1.46±0.09 vs.2.60±0.23;serum:IL-8(ng/L)was 39.67±6.28 vs.149.17±7.49,IL-6(ng/L):81.00±6.63 vs.211.00±25.31,TNF-α(ng/L):213.17±24.86 vs.799.50±43.51,all P<0.05].In vitro experiments,compared with the model group,Xiaoqinglong decoction plus Earthworm inhibited abnormal proliferation(A value:2.052±0.087 vs.2.242±0.057,P<0.05)and migration[number of migrating cells(per field):101.33±12.01 vs.226.67±17.56,P<0.05]of HPAEC,and reversed the EMT process,manifested as upregulation of vascular endothelial cadherin protein expression levels(vascular endothelial cadherin/GAPDH:0.39±0.06 vs.0.12±0.03,P<0.05)and downregulation of vimentin protein expression(vimentin/GAPDH:4.96±0.33 vs.7.89±0.44,P<0.05).Western blotting results indicated that compared with the model group,the protein expression levels of TLR4,the ratio of phosphorylated p65 to total p65,and HIF-1α in both lung tissue and HPAEC were significantly reduced in the Xiaoqinglong decoction plus Earthworm group[lung tissue:TLR4 protein expression(TLR4/GAPDH)was 3.13±0.20 vs.4.38±0.30,p-p65/p65 ratio:7.11±0.81 vs.12.73±1.80,HIF-1α protein expression(HIF-1α/GAPDH):2.37±0.32 vs.4.45±0.34;HPAEC:TLR4 protein expression(TLR4/GAPDH)was 1.42±0.03 vs.2.43±0.05,p-p65/p65 ratio:6.01±1.84 vs.11.28±1.06,HIF-1α protein expression(HIF-1α/GAPDH)was 3.24±0.17 vs.5.50±0.44,all P<0.05],accompanied by upregulated vascular endothelial cadherin protein expression(vascular endothelial cadherin/GAPDH:0.66±0.03 vs.0.49±0.03,P<0.05)and downregulated vimentin protein expression(vimentin/GAPDH:1.81±0.12 vs.2.47±0.10,P<0.05),indicating that Xiaoqinglong decoction plus Earthworm inhibits the EMT process in endothelial cells by suppressing the activation of the TLR/NF-κB/HIF-1α pathway.Experiments with a TLR agonist further confirmed that activation of the TLR pathway reverses the protective effects of Xiaoqinglong decoction plus Earthworm,as shown by the MPL group compared to the DMSO group having significantly increased protein expression of the p-p65/p65 ratio and HIF-1α[p-p65/p65 ratio:2.17±0.35 vs.1.08±0.14,HIF-1α/GAPDH:3.96±0.25 vs.1.03±0.10,both P<0.05],further decreased vascular endothelial cadherin protein expression(vascular endothelial cadherin/GAPDH:0.66±0.04 vs.0.99±0.02,P<0.05),further increased vimentin protein expression(vimentin/GAPDH:1.53±0.12 vs.0.93±0.07,P<0.05),along with enhanced cell migration capacity[number of migrating cells(per field):176.67±17.50 vs.107.00±11.14;cell migration rate in scratch assay:(34.32±2.82)%vs.(22.71±2.49)%,both P<0.05]and increased proliferation activity(48 hours A value:2.156±0.044 vs.1.810±0.088,P<0.05).Conclusions Xiaoqinglong decoction combined with Pheretima not only significantly reduces pulmonary artery pressure,improves cardiac function and mitigates pulmonary vascular fibrosis in PAH rats,but also alleviates pulmonary vascular remodeling by inhibiting inflammatory responses and EMT.It can further decrease the content of ET-1,increase the level of NO,and ameliorate vascular stenosis.This result further indicates that exterior-relieving medicines exert a significant dilating and supporting effect on the narrowed meridians and collaterals.

Next generation sequencing (NGS) technology is playing an increasingly important role in the diagnosis of genetic diseases. Whole exome sequencing (WES), which targets the coding regions of the genome, has been widely used in the diagnosis of genetic diseases for its low cost and high efficiency. However, compared to conventional methods, the Next Generation Sequencing (NGS) process is intricate, and there is variability in the expertise of data analysts and variant interpreters, which may lead to inconsistencies in the outcomes. To ensure the quality of testing and enhance the diagnostic rate of diseases, this consensus has provided recommendations regarding the laboratory setup, operational procedures, data analysis, result interpretation, and quality control for WES, with an aim to standardize its application in the detection of genetic disorders.

Gastric cancer (GC) is one of the most common malignant tumors of the digestive system in China. With the progress of immunotherapy research, programmed death receptor-1 (PD-1) inhibitor-based combinatory therapy offers new ideas for the treatment of advanced gastric cancer. In recent years, with the increasing status of immunotherapy in the treatment of advanced gastric cancer, a growing number of domestic and international clinical studies shown that immunotherapy could achieve better efficacy in the neoadjuvant therapy and conversion therapy for patients with advanced gastric cancer. This paper reviews the current research progress on the application of PD-1 inhibitors in the neoadjuvant therapy and conversion therapy of gastric cancer.

Objective:To investigate the efficacy and safety of sintilimab combined with the SOX regimen for adjuvant treatment of stage Ⅲgastric cancer after D2 radical resection and to provide a reference for individualized clinical treatment.Methods:The clinical data of 245 pa-tients with stage III gastric cancer who underwent D2 radical resection at the 940th Hospital of the Joint Support Force of the People's Liber-ation Army from June 2019 to May 2022 were retrospectively analyzed.The 180 patients who received only the SOX regimen were desig-nated the control group,and the 65 patients who received sintilimab combined with the SOX regimen were designated the experimental group.The 3-year disease-free survival(DFS)rate,overall survival(OS)rate,and adverse reactions among the two groups and different sub-groups(HER-2 positive,dMMR,CPS≥5)were compared.Results:The 3-year DFS(81.5%vs.59.4%)and OS(84.6%vs.70.6%)rates in the experimental group were significantly higher than those in the control group(both P<0.05).Group analysis showed that in patients with CPS≥5,the 3-year DFS(91.5%vs.67.0%)and OS(95.7%vs.71.6%)rates within the experimental group were significantly better than those in the control group(both P<0.05).Intra-group analysis within the experimental group showed that the 3-year DFS rate(91.5%vs.55.6%)and OS rate(95.7%vs.55.6%)of patients with CPS≥5 were significantly better than those of patients with CPS<5(both P<0.05).The overall and grade≥3 incidences of liver and kidney function damage,thyroid dysfunction,colitis,pneumonia,and rash in the experimental group were higher than those in the control group(all P<0.05),while the differences in other adverse reactions,including leukopenia were not statistic-ally significant(all P>0.05).Conclusions:Sintilimab combined with the SOX regimen can significantly improve 3-year DFS and OS rates in pa-tients with stage Ⅲ gastric cancer after surgery,especially in the CPS≥5 subgroup,with significant benefits and controllable safety.

Gastric cancer is one of the most common malignant tumors in the digestive system, characterized by high incidence and mortality rates. In recent years, with the rapid develop-ment of molecular immunology, the application of immune checkpoint inhibitors (ICIs) in neoadju-vant therapy has significantly improved pathological response rates and survival outcomes for patients with resectable locally advanced gastric cancer. The authors systematically review current research progress on combination strategies involving immune checkpoint inhibitors in neoadjuvant therapy for locally advanced gastric cancer, aiming to provide an evidence for optimizing individua-lized therapeutic regimens.