Objective To investigate the clinical effectiveness and safety of apatinib mesylate combined with gemcitabine+cisplatin(GC)and camrelizumab in the treatment of advanced gallbladder cancer,and to provide evidence for the clinical treatment of patients with advanced gallbladder cancer.Methods A total of 75 patients with advanced gallbladder cancer admitted to Henan Provincial People's Hospital and The Affiliated Cancer Hospital of Zhengzhou University from January 2022 to December 2023 were retrospectively included.According to treatment plans,they were divided into study group(apatinib mesylate combined with GC+camrelizumab)and control group(GC+camrelizumab).The 1-year survival rate,objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),overall survival(OS),and adverse reactions were compared between the two groups.Inter-group comparisons were performed using the chi-square test/Fisher's exact test,the t-test,and the Mann-Whitney U test for categorical data,continuous data in normal distribution,and continuous data in non-normal distribution,respectively.The Kaplan-Meier survival curves were generated and compared using the log-rank test.Results The ORR and DCR of the study group were 35.0%and 80.0%,respectively,which were not significantly different from those of the control group(bothP>0.05).The 1-year survival rate of the study group differed significantly from that of the control group(45.0%vs 20.0%,P<0.05).The median PFS was 7.73(95%confidence interval[CI]:4.39-11.01)months in the study group and 4.17(95%CI:3.48-4.85)months in the control group,and the difference was statistically significant(P<0.01).The median OS was 11.77(95%CI:8.07-15.47)months in the study group and 7.97(95%CI:5.84-10.09)months in the control group,which were not statistically significant(P>0.05).Across all grades of adverse reactions,the study group showed significantly higher incidence rates of hand-foot syndrome(62.5%vs 34.3%,χ2=5.945,P<0.05)and elevated blood pressure(42.5%vs 20.0%,χ2=4.343,P<0.05)than the control group.There were no significant differences in the incidence rates of adverse reactions of grade Ⅲ or above between the two groups(all P>0.05).Conclusion Apatinib mesylate combined with GC+camrelizumab is superior to GC+camrelizumab in prolonging the PFS but not in terms of the OS,with controllable toxic side effects,which is a safe and effective treatment regimen.

BACKGROUND:Studies have found that massage can reduce blood sugar,promote myogenic factor expression,and increase skeletal muscle content.The extracellular matrix is an important component of skeletal muscle,and association between massage and extracellular matrix and their mechanism of action are still unclear.OBJECTIVE:To explore the effect of massage on extracellular matrix collagen deposition in type 2 diabetic sarcopenia rats.METHODS:Totally 24 Wistar male rats were randomly divided into blank group,model group,and massage group.High-fat diet combined with the streptozotocin method was used to establish a type 2 diabetes mellitus and sarcopenia model.After successful model establishment,the massage group used abdominal massage combined with hind limbs.After 8 weeks of treatment,the fasting blood glucose and serum insulin levels of the rats were measured.The skeletal muscle mass was detected by dual-energy X-ray.The exhaustion time was measured by small animal treadmill.The sliding angle was measured by inclined board test.The pathological changes of skeletal muscle tissue were observed by hematoxylin-eosin staining.The skeletal muscle collagen deposition was observed by Masson staining.The mRNA and protein expressions of type Ⅰ and type Ⅲ collagen in skeletal muscle were detected by qPCR and western blot assay.RESULTS AND CONCLUSION:(1)Compared with the model group,the blood glucose(P＜0.05)and serum insulin(P＜0.01)decreased in the massage group.(2)Compared with the model group,the skeletal muscle mass,running exhaustion time,and the angle of inclined plate experiment were increased in massage group(P＜0.05).(3)Compared with the model group,the skeletal muscles of the massage group were arranged neatly,muscle atrophy was improved,and collagen fiber deposition was reduced.(4)Compared with the model group,the expression levels of type Ⅰ and type Ⅲ collagen mRNA and protein in skeletal muscle were decreased in the massage group(P＜0.05).(5)The results suggest that massage can enhance insulin sensitivity,lower blood sugar,improve skeletal muscle mass,strength and function,and diminish collagen deposition in rats with type 2 diabetes,and may be a potential target for massage to exert its therapeutic effects.

Objective:To report the follow-up status of patients participating phase Ⅲ clinical trial (ZGDD3) of Donafenib tosilate (abbreviated as Donafenib) in the treatment of progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), and to explore its efficacy, safety and prognostic factors.Methods:This study was a randomized controlled trial, and the clinicopathological data and follow-up results of 29 patients (16 males, 13 females, age 40-68 years) who participated in the clinical trial ZGDD3 between August 2018 and March 2021 were analyzed. Patients were divided into Donafenib group and placebo group using the central dynamic randomization method with the ratio of 2∶1. Adverse reactions (AE) during the trial were observed. Independent-sample t test, Mann-Whitney U test and Fisher exact test were used to analyze the differences of baseline characteristics between the two groups. Progression-free survival (PFS) and overall survival (OS) were followed up. Kaplan-Meier method was used to draw the survival curve (log-rank test) and Cox regression analysis was used to analyze the prognostic factors. Results:There were 22 patients in Donafenib group and 7 patients in placebo group. There were no significant differences of baseline characteristics between the two groups ( t values: -0.68, Z values: from -1.47 to -0.56, all P>0.05). The follow-up was 32.07(21.07, 49.85) months. During the trial, drug-related AEs occurred in all patients in Donafenib group, mostly was grade Ⅰ-Ⅱ, no grade Ⅳ or Ⅴ AEs were found. The median PFS was significantly longer in Donafenib group than that in placebo group (13.23 vs 4.03 months; χ2=9.68, P=0.002), and the median OS was 55.00 and 24.30 months respectively ( χ2=2.07, P=0.150). Metastasis to less common sites was the independent risk factor for OS (hazard ratio ( HR)=6.789, 95% CI: 1.272-36.246, P=0.025). Conclusions:Donafenib shows good clinical application in the treatment of RAIR-DTC, demonstrating good safety and efficacy. Metastasis to less common sites is closely related to OS.

Objective:To investigate changes in the density and spatial distribution of CD69 + T cells within hepatocellular carcinoma tissues following immune checkpoint blockade (ICB) therapy, and to explore their correlation with tumor infiltrating immune cell. Methods:Tumor specimens were collected from 12 patients with hepatocellular carcinoma who were admitted to the Department of Hepatobiliary and Pancreatic Surgery of People's Hospital of Zhengzhou University and the First Affiliated Hospital of Zhengzhou University from July 2023 to July 2024. There were 10 males and 2 females, aged (58.5±5.6) years. Of the 12 patients, 6 cases underwent radical surgery directly and 6 underwent radical surgery after immunotherapy. The maximum tumor diameter and tumor volume of the immunotherapy group were measured by imaging. The density and distribution of immune cells such as CD8 + CD69 + T, CD4 + CD69 + T and programmed death-1 (PD-1) were detected by immunohistochemistry and immunofluorescence. The number of immune cells around the target cells was calculated to evaluate the effective score, and the intercellular distance was measured to evaluate the intercellular interaction. Results:The maximum tumor diameter and tumor volume of 6 patients after immunotherapy were lower than before treatment, and the differences were statistically significant (all P<0.05). The density of PD1 + cells in the immunotherapy group was 36.6 (25.9, 55.9) cells/mm 2, which was less than that in the control group 53.9 (38.3, 84.5) cells/mm 2, and the difference was statistically significant ( Z=-2.66, P=0.008). In the control group, the number of CD8 + CD69 + T cells was positively correlated with CD8 + PD1 + T cells and CD8 + PD1 + CD103 + T cells, and the correlation coefficients were 0.42 and 0.40, respectively ( P=0.001, 0.002). The effective scores of CD8 + CD69 + T cells and CD8 + PD1 + T, CD4 + CD103 + T, CD4 + PD1 + CD103 + T and CD8 + PD1 + CD103 + T cells in the above three areas in the immunotherapy group were lower than those in the control group, with statistical significance (all P<0.05). The distance between CD8 + CD69 + T and CD4 + CD69 + CD103 + T cells in the interface area of the control group was closer than that of the immunotherapy group, and the difference was statistically significant ( t=2.67, P=0.009). Conclusion:After immunotherapy in hepatocellular carcinoma patients, PD-1+ cells and immune cells around CD8 + CD69 + T cells decreased, and this change was related to the distance between CD8 + CD103 + T cells.

Objective:To analyze the risk factors for clinically relevant delayed gastric emptying (CR-DGE) following laparoscopic pancreaticoduodenectomy (LPD) and to develop a model to predict the postoperative CR-DGE after LPD using the machine-learning approach with multi-model comparison.Methods:Clinical data of 278 patients with tumors located in the pancreatic head and periampullary region undergoing LPD at People’s Hospital of Zhengzhou University from January 2019 to December 2023 were retrospectively analyzed, including 167 males and 111 females, aged 59 (53, 66) years. According to the occurrence of DGE, patients were divided into the CR-DGE group ( n=94) and the non-CR-DGE group ( n=184). Main clinical characteristics were compared between the groups, including pancreatic duct diameter, intraoperative blood loss and operative time. The perioperative indicators were selected using the least absolute shrinkage and selection operator (LASSO) algorithm. Following variable selection, 278 patients were allocated into a training set ( n=222) and a validation set ( n=56) in an 8∶2 ratio. Eight machine learning models were selected to model the training set: random forest, adaptive boosting, light gradient boosting, multilayer perceptron, support vector machine, K-nearest neighbor algorithm, decision tree and complementary set plain bayes. The area under the curve (AUC) of receiver operating characteristic curve of the validation set was utilized to identify the optimal model. The predictive performance of the optimal model was evaluated using calibration plots and decision curve analysis (DCA). The contribution of each feature to the prediction is assessed using Shapley additive explanation (SHAP). Results:Univariate analysis showed statistically significant differences between the CR-DGE and non-CR-DGE groups in terms of age [66(62, 69) years vs. 56(51, 60), years], diabetes [42.6%(40/94) vs. 11.4%(21/184)], level of fibrinogen [3.43(2.74, 4.18) g/L vs. 3.84(3.19, 4.68) g/L], pancreatic duct diameter [2.00(1.50, 2.70) mm vs. 3.40(1.60, 5.00) mm], intraoperative blood loss [300(200, 600) ml vs. 200(150, 300) ml], operative time [472(430, 502) min vs. 430(365, 475) min], clinically relevant postoperative pancreatic fistula [34.0%(32/94) vs. 3.8%(7/184)], abdominal fluid accumulation [46.8%(44/94) vs. 12.5%(23/184)], postoperative hemorrhage [20.2%(19/94) vs. 3.3%(6/184)], abdominal infection [28.7%(27/94) vs. 11.4% (21/184)] and duration of postoperative gastrointestinal decompression [4.00 (2.00, 6.00) d vs. 3.00 (2.00, 5.00) d] (all P<0.05). The eleven variables selected via LASSO were incorporated into each of the eight machine learning models. Results demonstrated that the random forest model achieved the highest performance in the validation set, with an AUC of 0.894 (95% CI: 0.800-0.985), accuracy of 0.820 and sensitivity of 0.606. Calibration plots and DCA confirmed the robustness of the random forest model. SHAP analysis indicated that age, pancreatic duct diameter and preoperative aspartate aminotransferase were important predictors in the random forest model. Conclusion:The random forest model developed in this study demonstrated a good predictive performance for CR-DGE after LPD and may assist in the early identification of high-risk patients in clinical practice.

Objective To investigate the differences in neurite density index(NDI),neurite orientation dispersion index(ODI),and volume fraction of isotropic water molecule(Viso)of subcutaneous white matter fiber tracts in patients with cerebral small ves-sel disease(CSVD),and the effect of the glymphatic system(GS)on NDI,ODI,and Viso values of white matter fiber tracts in patients with CSVD.Methods A total of 69 CSVD patients(CSVD group)were retrospectively selected.All patients underwent conventional plain MRI scans[3D-T1,T2WI,3D-T2 fluid attenuated inversion recovery(FLAIR)],spin echo-echo planar imaging(SE-EPI),and susceptibility weighted imaging(SWI)scans.The NDI,ODI,and Viso values of 29 white matter fiber tracts in the brain were meas-ured using post-processing software.Thirty-five healthy volunteers were recruited as the control group,and the independent sample t test was used to compare the differences of NDI,ODI,and Viso values between the two groups.Multiple linear regression was used to evaluate the relationship between along the perivascular space(ALPS)index and NDI,ODI,and Viso values of 29 white matter fiber tracts in CSVD patients.Results Compared with control group,CSVD group showed a statistically significant increase in Viso values in 26 white matter fiber tracts and decrease in NDI values in 14 white matter fiber tracts(PFDR<0.05).In multiple linear regression,the decrease of ALPS index in CSVD patients was found to be statistically different from that of NDI values in certain white matter fiber tracts(PFDR<0.05)and primarily located in the frontal and temporal lobes.Conclusion Neurite orientation dispersion and density imaging(NODDI)technology is more effective in identifying the biological differences,which impact the integrity of white matter fiber tracts in patients with CSVD.Furthermore,it reflects the pathophysiological changes of the brain GS on different white matter fiber tracts in CSVD patients.This provides valuable insights for recognizing the clinical manifestations of CSVD and developing appropri-ate treatment plans.

Objective: To analyze the bioinformatics of domestic Clostridium difficile toxin B(TcdB) and prepare it to provide data support for the development of effective vaccines. Methods: Using bioinformatics software such as Snippy, Blast, Muscle, and the dist.alignment() and hclust() functions in R, 1 355 strains of Clostridium difficile from NCBI GenBank in China were compared and analyzed, and TcdB were grouped. The maximum likelihood tree and phylogenetic tree were beautified and displayed using iTOL. An online bioinformatics analysis website was used to predict and analyze the spatial structure and antigenic epitopes of the two largest subgroups, TcdB1 and TcdB2. The antigen protein TcdB was expressed and purified by prokaryotic system. Results: According to the genotype of toxin B, the 1 355 prevalent strains of Clostridium difficile in China could be roughly divided into 12 subtypes, among which TcdB1 and TcdB2 were the main subtypes, accounting for more than 93.94% of all isolated strains, and about 17.20% of the strains were nontoxigenic or lack TcdB. The antigen epitope prediction of TcdB1 and TcdB2 showed that their antigen epitope distributions were basically the same, and many of them were distributed outside the C-terminal combined repetitive oligopeptides domains. Conclusion A specialized typing system for C. difficile TcdB in China has been established, and its main subtypes have been predicted for antigenic epitopes. The screened TcdB has been expressed for recombinant preparation.

With the continuous advancement and innovation in medical equipment technology, the transition between high-flow oxygen therapy, non-invasive ventilation, and invasive ventilation can be easily achieved by adjusting the ventilation mode of ventilators. During the weaning phase for tracheotomized patients, it is necessary to disconnect the ventilator circuit, change the ventilator mode, and gradually extend the weaning time to achieve complete ventilator liberation. During the weaning process, due to patients' excessive dependence on the ventilator, there may be situations where respiratory endpoints and Y-connectors of the ventilator are reconnected for invasive ventilation. However, during the weaning process, the Y-connector and expiratory end connectors are exposed to the air, which cannot ensure the tightness of the ventilator circuit, easily increasing the probability of ventilator circuit contamination and subsequently the risk of ventilator-associated pneumonia (VAP). To overcome these issues, the research team of department of critical care medicine of Zhongda Hospital Southeast University has designed a ventilator circuit interface protective device for weaning and has obtained a National Utility Model Patent of China (ZL 2023 2 1453385.8). The main body of the protective device is a Y-connector plug, consisting of multiple components, including a sealing piece, a protective cover, a sealing plug, an interface 1 (connects with the patient's tracheal tube), an interface 2 (connects with the respiratory branch of the ventilator), and an interface 3 (connects with the expiratory branch of the ventilator), featuring a unique design and easy operation. During the patient's weaning training process, the interface 1 and interface 2 is disconnected from the patient's tracheal tube and respiratory branch, respectively. The interface 1 is plugged with a stopper, and the interface 2 is covered with a protective cover to ensure the tightness of the expiratory branch and Y-connector of the ventilator. During the period when the patient is using the ventilator, the protective cover and plug are removed, and connecting them together ensures the tightness of the device itself, reducing the incidence of VAP caused by ventilator circuit contamination, avoiding nosocomial infections, and shortening the prolonged use of invasive ventilation, increased complication rate, extended hospital stay, and increased medical cost associated with weaning.
Humans ; Ventilator Weaning/methods* ; Equipment Design ; Ventilators, Mechanical ; Respiration, Artificial/instrumentation* ; Pneumonia, Ventilator-Associated/prevention & control*

Objective To investigate the cardiac protective effect of Taohong Tongluo granules on coronary microvascular dysfunction(CMD)rats.Methods SD rats were randomly assigned to sham-operated group,CMD group,nicorandil group(5 mg/kg),or Taohong Tongluo granule group(50 mg/kg).Animals were administered corresponding drugs for 7 d according to the grouping,and the CMD model was prepared 2 h after the last administration.The rat CMD model was induced by injecting embolization microspheres(diameter 40-120 μm,approximately 1 000 microspheres)into the left ventricular cavity.Twenty-four hours after modeling,echocardiography was performed to measure the left ventricular ejection fraction(EF),fractional shortening(FS),and end-diastolic volume(EDV).The damaged myocardial area was assessed by 2,3,5-triphenyltetrazolium chloride(TTC)staining.Myocardial morphological changes were observed by hematoxylin-eosin(H-E)staining.The protein expression levels of NOD-like receptor family pyrin domain containing protein 3(NLRP3),apoptosis-associated speck-like protein(ASC),and cysteine aspartic acid specific protease(caspase)-1 in rat myocardial tissue were detected by immunohistochemical staining and Western blotting.Results Echocardiography showed that the EF and FS values in the Taohong Tongluo granule group,CMD group,and nicorandil group were significantly lower than those in the sham-operated group(all P＜0.001).The EF and FS values in the Taohong Tongluo granule group and nicorandil group were significantly higher than those in the CMD group(all P＜0.01).However,there were no significant differences in EDV among the groups(all P＞0.05).H-E staining showed no abnormalities in the myocardium in the sham-operated group.The CMD group exhibited microsphere embolism in the myocardium,myocardial cell dissolution and rupture,and inflammatory infiltration.The lesions in the nicorandil group and the Taohong Tongluo granule group were relatively milder,and the number of thrombi in both groups was lower than that in the CMD group(both P＜0.01).The results of TTC staining indicated that the areas of damaged myocardial regions in both the nicorandil group and the Taohong Tongluo granule group were smaller than that in the CMD group(P＜0.05 or P＜0.01).Moreover,the area in the Taohong Tongluo granule group was smaller than that in the nicorandil group(P＜0.05).The results of immunohistochemical staining showed that in the CMD model,the expression of ASC and caspase-1 proteins,as well as the number of positive cells for these proteins,was increased and was distributed in myocardial and interstitial cells.The numbers of ASC and caspase-1 positive cells in the Taohong Tongluo granule group were lower than that in the CMD group(both P＜0.01).The Western blotting showed that the expression levels of NLRP3,ASC,and caspase-1 proteins in the Taohong Tongluo granule group were all lower than those in the CMD group(all P＜0.05).Conclusion Taohong Tongluo granules can improve cardiac function,ameliorate hemodynamic parameters,and reduce myocardial infarction area in rats with CMD induced by microsphere embolism.The mechanism is related to the inhibition of myocardial inflammasome activation,thereby attenuating the myocardial injuries.

AIM: To investigate the influence of relevant inflammatory markers in peripheral blood on the progression of neovascular glaucoma(NVG)secondary to diabetic retinopathy(DR)patients.METHODS: Retrospective case-control study. Patients were categorized into two groups based on the presence or absence of NVG: those with proliferative diabetic retinopathy(PDR)alone(PDR group, n=148)and those with NVG secondary to PDR(NVG secondary to PDR group, n=142). Peripheral blood inflammatory markers were evaluated, including white blood cell-related indices, neutrophil-to-lymphocyte ratio(NLR), platelet-to-lymphocyte ratio(PLR), monocyte-to-lymphocyte ratio(MLR), and systemic immune-inflammation index(SII). The distinctions in peripheral blood inflammatory markers between the two groups of patients and their relationships with NVG secondary to PDR were analyzed.RESULTS:No statistically significant differences were observed in basic characteristics between the two groups, confirming their comparability. However, significant differences were found in eosinophil percentage and MLR between the PDR group and the NVG secondary to PDR group(all P<0.05), with both values being significantly higher in the NVG secondary to PDR group. Multivariate Logistic regression analysis revealed that the eosinophil percentage and the MLR were factors influencing the development of patients with NVG secondary to PDR.CONCLUSION: Eosinophil percentage and MLR may be associated with the progression of PDR to NVG, and could serve as potential predictive markers for NVG development in PDR patients.