ObjectiveTo reveal the mechanism of Zuogui Jiangtang Jieyu prescription against damage to hippocampal synaptic microenvironment via suppressing glutamate receptor 2 （GluR2）/Parkin signal-mediated mitophagy in rats with diabetes-related depression （DD）. MethodsEighty male SD rats underwent adaptive feeding for 5 days before the study. Ten rats were randomly assigned to the normal group. The model of DD rats was established with the rest by 2-week high-fat diet + streptozotocin （STZ） tail intravenous injection + 28 days of chronic unpredictable mild stress （CUMS） combined with isolation. The rats were randomly divided into a normal group， a model group， a GluR2 blocker group （5 μg·kg^-1）， a GluR2 agonist group （10 μg·kg^-1）， a metformin + fluoxetine group （0.18 g·kg^-1 metformin + 1.8 mg·kg^-1 fluoxetine）， and high- and low-dose Zuogui Jiangtang Jieyu prescription groups （20.52 and 10.26 g·kg^-1， respectively）. The rats in the GluR2 blocker group and the GluR2 agonist group were continuously injected with CNQX and Cl-HIBO in the dentate gyrus of the hippocampus once a week starting from stress modeling， respectively， while the metformin + fluoxetine group and the high- and low-dose Zuogui Jiangtang Jieyu prescription groups were continuously given intragastric administration for 28 d at the same time of stress modeling. Depression-like behavior was evaluated by open field and forced swimming experiments. The levels of serum insulin and adenosine triphosphate （ATP） in hippocampus were detected by biochemical analysis. The levels of 5-hydroxytryptamine （5-HT） and dopamine （DA） in hippocampus were detected by enzyme-linked immunosorbent assay （ELISA）. The autophagosomes of hippocampal neurons were observed by transmission electron microscopy. The morphology and structure of dendrites and spines of hippocampal neurons were evaluated by Golgi staining. Western blot detected the expression levels of GluR2 and Parkin proteins in hippocampus. The expression levels of GluR2， Parkin， regulating synaptic membrane exocytosis protein 3 （RIMS3）， and postsynaptic density protein 95 （PSD95） in the dentate gyrus of the hippocampus were detected by immunofluorescence. ResultsCompared with the normal group， the model group exhibited reduced total activity distance in the open field and increased immobility time in forced swimming （P<0.01）， lowered levels of serum insulin and ATP， 5-HT， and DA in hippocampus （P<0.01）， increased autophagosomes of hippocampal neurons， significantly damaged morphology and structure of dendrites and spines of hippocampal neurons， decreased expression levels of GluR2， RIMS3， and PSD95 in hippocampus， and an increased Parkin expression level （P<0.05， P<0.01）. Compared with the model group， the GluR2 blocker group and the GluR2 agonist group showed aggravation and alleviation of the above abnormal changes， respectively （P<0.05， P<0.01）. The above depression-like behavior was significantly improved in the high- and low-dose Zuogui Jiangtang Jieyu prescription groups to different degrees. Specifically， the two groups saw elevated levels of serum insulin and ATP， 5-HT， and DA in hippocampus （P<0.05， P<0.01）， restrained increase in autophagosomes and damage to morphology and structure of dendrites and spines of hippocampal neurons， up-regulated protein expression levels of GluR2， RIMS3， and PSD95， and down-regulated Parkin expression level （P<0.05， P<0.01）. ConclusionZuogui Jiangtong Jieyu prescription can ameliorate the mitophagy-mediated damage to hippocampal synaptic microenvironment in DD rats， the mechanism of which might be related to the regulation of GluR2/Parkin signaling pathway.

Abstract: Heterologous boost COVID-19 vaccination can solved the problem of decreased efficacy caused by single dose of vaccine. Heterologous booster with adenoviral-vectored COVID-19 vaccine (Ad5-nCoV) following primary immunization with inactivated COVID-19 vaccines is a widely-used vaccination strategy in clinic, while different routes of Ad5-nCoV administration exist and pose a question which route could be more optimal. In this study, we comprehensively evaluated and compared the vaccine immunity induced in mice immunized according to three different vaccination regimens: “3×phosphate buffered solution(3× PBS)”, “2×inactivated vaccine + 1×inactivated vaccine (3×INA)”, “2×inactivated vaccine + 1×Ad5-nCoV (intramuscular)[2×INA+Ad5(im)]”and“2×inactivated vaccine + 1×Ad5-nCoV (intranasal)[2×INA+Ad5(in)]”. We found that heterologous booster with Ad5-nCoV, irrespective of the route of administration, induced significantly higher levels of anti-Spike IgG and subclasses (IgG1and IgG2c), Spike-specific T cells, class-switched Spike+ memory B cells (MBCs) than homologous booster with 3rd dose of inactivated COVID-19 vaccine. Of note, compared with the intramuscular given, intranasal given of Ad5-nCoV as a booster dose clearly induced higher levels of serum and bronchoalveolar bavage fluid anti-spike immunoglobulin A, and moreover, induced stronger infiltration of major innate effector cells like neutrophils, natural killer cells and dendritic cells into the lung tissue, which suggested that mucosal vaccine responses are generated upon intranasal booster with Ad5-nCoV. Altogether, our study analyzed the vaccine immunity induced by different COVID-19 vaccines administered using different regimens, which may guide the clinical use of other types of prophylactic vaccines aiming to mount improved vaccine responses.

Objective:To analyze the safety and efficacy of PD-1 inhibitors versus chemotherapy or ipilimumab in advanced melanoma.Methods:PubMed,CNKI,VIP and Wanfang databases were searched to collect randomised controlled trials of PD-1 inhibi-tors in treatment of advanced melanoma.The search time was from the establishment of the database to May 1,2022.Two reviewers independently screened the literature,extracted data,and assessed risk of bias of included studies.Meta-analysis was performed using RevMan5.4 and STATA16 software.Results:A total of 7 studies were included.Meta-analysis results show that:①Safety:Compared with chemotherapy,PD-1 inhibitor treatment had fewer adverse events,especially in the blood system;compared with ipilimumab alone,PD-1 inhibitor combined with ipilimumab had more adverse events,especially liver function indicators;there was no signifi-cant difference in the incidence of total adverse events between PD-1 inhibitor monotherapy and ipilimumab monotherapy.②Efficacy:The PFS,OS and ORR of PD-1 inhibitor versus chemotherapy or ipilimumab were HR=0.54,95%CI(0.45,0.62),P<0.05,HR= 0.69,95%CI(0.58,0.80),P=0.03 and OR=3.16,95%CI(2.59,3.86),P<0.05,respectively.Conclusion:PD-1 inhibitors have good efficacy in treatment of advanced melanoma,while different combination methods and different control treatments may have different efficacy.Limited by the quantity and quality of included studies,more research evidence is needed to support this.

Objective:To investigate the risk factors of pleural effusion after spinal separation surgery for patients with spinal metastatic tumors.Methods:A total of 427 patients with spinal metastatic tumors from January 2014 to January 2022 in the Second Affiliated Hospital of Zhejiang University School of Medicine were retrospectively analyzed. There were 252 males and 175 females, with an average age of 59±12 years (range, 15-87 years). All patients underwent separation surgery. Based on the chest CT within 1 month after surgery, the volume of pleural effusion was measured individually by reconstruction software. Pleural effusion was defined as small volume (0-500 ml), moderate volume (500-1 000 ml), and large volume (above 1 000 ml). Baseline data and perioperative clinical outcomes were compared between the groups, and indicators with statistically significant differences were included in a binary logistic regression analysis to determine the independent risk factors for the development of pleural effusion after isolation of spinal metastatic cancer. Receiver operating characteristic (ROC) curves were conducted to calculate the area under the curve (AUC) for each independent risk factor.Results:All patients successfully completed the operation. Among the 427 patients, there were 35 cases of large pleural effusion, 42 cases of moderate pleural effusion, and 350 cases of small pleural effusion. There were significant differences in tumor size (χ 2=9.485, P=0.013), intraoperative blood loss ( Z=-2.503, P=0.011), blood transfusion ( Z=-2.983, P=0.003), preoperative total protein ( Z=2.681, P=0.007), preoperative albumin ( Z=1.720, P= 0.085), postoperative hemoglobin ( t=2.950, P=0.008), postoperative total protein ( Z=4.192, P<0.001), and postoperative albumin ( t=2.268, P=0.032) in the large pleural effusion group versus the small and moderate pleural effusion group. Logistic regression analysis showed that decreased preoperative albumin ( OR=0.89, P=0.045) and metastases located in the thoracic spine ( OR=4.01, P=0.039) were independent risk factors for the occurrence of large pleural effusion after separation surgery. The ROC curve showed that the AUC and 95% CI for preoperative albumin, lesion location, and the combined model were 0.637 (0.54, 0.74), 0.421 (0.36, 0.48), and 0.883 (0.81, 0.92). The combined predictive model showed good predictive value. Conclusion:The volume of pleural effusion can be measured individually and quantitatively based on chest CT. Decreased preoperative albumin and metastases located in the thoracic spine are independent risk factors for the occurrence of large pleural effusion after separation surgery. The combined prediction of the two factors has better predictive efficacy.

Objective:To analyze the correlation between serum glycated hemoglobin (HbA 1c), γ-glutamyltranspeptidase(γ-GT) and intercellular adhesion factor-1 (ICAM-1) levels and cognitive impairment in elderly patients with hyperlipidemia complicated with cardiovascular disease. Methods:In this retrospective cohort study, 158 elderly patients who underwent examination and were diagnosed with hyperlipidemia complicated with cardiovascular disease at Beijing Anzhen Hospital Affiliated with Capital Medical University from January to December 2022 were selected as study subjects. The simple mental state scale (MMSE) was assessed in the subjects in combination with the subject′s level of education. Illiteracy≤17 points, primary school≤20 points, middle school and above≤24 points were classified as cognitive impairment group (67 cases), the rest were were classified into the non-cognitive impairment group (91 cases); and another 50 healthy elderly people who received physical examination in the same period were selected as the control group. The blood samples in the three groups were extracted to measure serum HbA 1c, γ-GT and ICAM-1. The correlation between HbA 1c, γ-GT and ICAM-1 levels with cognitive impairment were analyzed. Results:The serum levels of HbA 1c, γ-GT and ICAM-1 in the cognitive impairment group were all significantly higher than those in the non-cognitive impairment group and the control group [5.41%±1.04% vs 4.82%±0.95%, 4.39%±0.86%; (52.01±10.96) vs (41.28±9.23), (25.03±7.17) U/L; (336.61±85.36) vs (286.93±72.53), (143.52±64.20) g/ml], and the MMSE score was significantly lower [(20.19±2.85) vs (25.30±1.24), (27.14±1.56) points] (all P<0.05). Serum levels of HbA 1c, γ-GT and ICAM-1 were all significantly negatively correlated with MMSE score ( r=-0.512, -0.498, -0.563) (all P<0.05). The areas under the receiver operating characteristic curves (AUCs) for serum HbA 1c, γ-GT, and ICAM-1 levels in the assessment of cognitive dysfunction were 0.657, 0.816, and 0.691, respectively (all P<0.05). The optimal cut-off values were 5.115%, 47.65 U/L, and 304.58 g/ml, respectively. Conclusion:Serum HbA 1c, γ-GT and ICAM-1 levels in elderly patients with hyperlipidemia complicated with cardiovascular disease are negatively correlated with cognitive impairment, and have certain value for the evaluation and early diagnosis of cognitive impairment.

Objective To explore the regulatory mechanism of the interaction between trigeminal ganglion neurons and satellite glial cells （SGCs） in migraine and to identify key factors mediating this interaction. Methods The trigeminal ganglia of eight 2-to 3-day-old Wistar rats were cultured in vitro for 3 days. A migraine cell model was established using sensory nerve action potential （SNAP） with nitric oxide （NO） donor. The in vitro migraine simulation group was treated with SNAP at concentrations of 0.25 mmol/L， 0.5 mmol/L， and 1 mmol/L for 2 hours. The inhibitor group received intervention with AR-A014418 （10 μmol/L）， followed by SNAP （1 mmol/L） 30 min later， allowing for 2 hour intervention. The intervention-free group served as a control. The levels of calcitonin gene-related peptide （CGRP）， substance P（SP）， and prostaglandin E2 （PGE2） in the cultured cells from each group were measured using enzyme-linked immunosorbent assay （ELISA）. The positive and negative regulatory sites of glycogen synthase kinase-3β （GSK-3β） and the changes in the expression of CX3CL1/CX3CR1 proteins were evaluated using immunofluorescence assay. The expression of GSK-3β and CX3CL1/CX3CR1 was semi-quantitatively analyzed using Western blotting. Results The expression levels of CGRP， PGE2， and SP in the SNAP （1 mmol/L） group were significantly higher than those in the control group， while the expression levels in the inhibitor group was significantly lower than those in the SNAP （1 mmol/L） group （both P<0.05）. Immunofluorescence assay showed that the SNAP （1 mmol/L） group exhibited decreased expression of pGSK-3β Ser9 and increased expression of GSK-3β Try216 and CX3CL1/CX3CR1 in trigeminal ganglion cells when compared with the control group. In contrast， the inhibitor group exhibited increased expression of pGSK-3β Ser9 and decreased expression of pGSK-3β Try216 and CX3CL1/CX3CR1 when compared with the SNAP （1 mmol/L） group. Conclusion NO enhances the expression of GSK-3β in trigeminal ganglia， up-regulates CX3CL1/CX3CR1， and activates SGCs to produce inflammatory factors. This signaling pathway represents a regulatory mechanism of the development and progression of migraine.

[摘 要] 目的：系统评估经动脉化疗栓塞（TACE）和酪氨酸激酶抑制剂（TKI）联合（TT）联合或不联合PD-1抗体（PD-1Ab）治疗晚期肝细胞癌（aHCC）的疗效与潜在不良反应（AE）。方法：检索PubMed、中国知网（CNKI）、Embase、Web of Science等数据库，时限为各数据库建库始至2024年1月31日。由2位评价员独立筛选文献、提取资料并评价纳入研究的偏倚风险后，采用Stata16.0软件进行Meta分析。结果：纳入17项研究，共2 334例aHCC患者。Meta分析结果显示，与TT疗法相比，PD-1Ab的加入能显著改善aHCC患者的总生存期（OS）[HR = 0.44，95% CI（0.36，0.51），P < 0.000 01]和无进展生存期（PFS）[HR = 0.47，95% CI（0.42，0.52），P < 0.000 01]，同时提高aHCC患者的客观缓解率（ORR）[HR = 1.65，95% CI（1.46，1.86），P < 0.000 01]和疾病控制率（DCR）[HR = 1.26，95% CI（1.15，1.38），P < 0.000 01]；不同基线资料如ECOG-PS、肝外转移与否、BCLC分期、肿瘤大小、Child-Pugh评分及肝门静脉侵犯与否等aHCC患者均可从TT PD-1Ab疗法中获益；两治疗方案间全级别与 ≥3级AE的总发生率无显著差异，但高血压、甲状腺功能减退及反应性皮肤血管增生等症状在接受TT PD-1Ab治疗的患者中更为常见。结论：相较于TT疗法，PD-1Ab的加入可显著延长aHCC患者OS和PFS，并提高其整体ORR与DCR；TT PD-1Ab治疗组患者发生全级别及≥ 3级AE的整体发生率没有显著增加，整体耐受性良好，但在高血压、皮肤与黏膜及甲状腺AE上有较高的发生率，应予以重视。

Objective:To explore potential biomarkers that can predict the clinical efficacy of PD-1/PD-L1 inhibitors in malig-nancies.Methods:The PubMed,Web of Science,CNKI,Wanfang and VIP databases were searched from the establishment of the database to September 20,2022.After literature screening,data extraction and the risk of bias were evaluated independently by two evaluators,the Meta-analysis was performed using RevMan5.4 and STATA16.0 software.Results:This paper included 18 studies with a total of 4 018 patients.Tumor patients with a high tumor mutational burden(TMB)were found to have higher overall survival(OS)(P=0.003,P=0.01)and progression-free survival(PFS)(P=0.000 2,P=0.04)with PD-1/PD-L1 inhibitors within 1 year and 2 years of follow-up.At different follow-up times,with 1%as the critical value,there was no statistical significance in the level of PD-L1 ex-pression as a biomarker for predicting OS and PFS of PD-1/PD-L1 inhibitors(P>0.05).Conclusion:TMB can be used as a biological indicator to predict the clinical efficacy of PD-1/PD-L1 inhibitors in patients with malignant tumors within 2 years after treatment,but whether its efficacy can last longer remains to be further studied.PD-L1 single test is not currently a biomarker for predicting the bene-fit of PD-1/PD-L1 inhibitors.

Objective:To construct an evaluation index system for clinical practice effectiveness of undergraduate nursing students, so as to provide a basis for the evaluation of clinical practice effectiveness of undergraduate nursing students.Methods:Based on the improved Miller's pyramid theory, a preliminary evaluation index system for clinical practice effectiveness of nursing undergraduate students was formed by literature analysis and semi-structured interview method. From April to July 2023, purposive sampling was used to select 20 experts in nursing education, clinical nursing teaching, and other fields. After two rounds of Delphi expert consultation, a final evaluation index system for clinical practice effectiveness of undergraduate nursing students was formed, and the weights of each index were determined.Results:After two rounds of consultation, the effective response rates of the questionnaire were 95.00% (19/20) and 100.00% (19/19), respectively. The expert authority coefficients were 0.86 and 0.88, and the Kendall harmony coefficients were 0.226 and 0.183 ( P<0.01). The final established evaluation index system for clinical practice effectiveness of undergraduate nursing students included five primary indicators, 13 secondary indicators, and 56 tertiary indicators. Conclusions:Based on the improved Miller's pyramid theory, the evaluation index system for clinical practice effectiveness of undergraduate nursing students constructed is scientific, reliable, and practical, which can provide reference for the evaluation of clinical practice for undergraduate nursing students.

Chemical cleaning and disinfection are crucial steps for eliminating infection in root canal treatment.However,irrigant selection or irrigation procedures are far from clear.The vapor lock effect in the apical region has yet to be solved,impeding irrigation efficacy and resulting in residual infections and compromised treatment outcomes.Additionally,ambiguous clinical indications for root canal medication and non-standardized dressing protocols must be clarified.Inappropriate intracanal medication may present side effects and jeopardize the therapeutic outcomes.Indeed,clinicians have been aware of these concerns for years.Based on the current evidence of studies,this article reviews the properties of various irrigants and intracanal medicaments and elucidates their effectiveness and interactions.The evolution of different kinetic irrigation methods,their effects,limitations,the paradigm shift,current indications,and effective operational procedures regarding intracanal medication are also discussed.This expert consensus aims to establish the clinical operation guidelines for root canal irrigation and a position statement on intracanal medication,thus facilitating a better understanding of infection control,standardizing clinical practice,and ultimately improving the success of endodontic therapy.