OBJECTIVE To investigate the effects and mechanism of Wenpi tongluo kaiqiao formula （WPTL） against neuronal necroptosis in Alzheimer’s disease （AD） mice based on the Z-DNA binding protein 1 （ZBP1）/mixed lineage kinase domain-like protein （MLKL） signaling pathway. METHODS Forty APP/PS1 transgenic AD mice were randomly divided into model group， WPTL low-dose （WPTL-L） group （10.4 g/kg， calculated by the raw medicine）， WPTL high-dose （WPTL-H） group （20.8 g/kg， calculated by the raw medicine） and donepezil hydrochloride group （3 mg/kg）， with 10 mice in each group； another 10 C57BL/6J mice were selected as normal control group. Intragastric administration， once a day， for 30 consecutive days. Twenty-four hours after the last administration， Morris water maze test was performed to evaluate learning and memory abilities； the pathological morphology of hippocampal tissues was observed； the serum levels of tumor necrosis factor-α （TNF-α） and interleukin-4 （IL-4） were determined； the expressions of amyloid precursor protein （APP）， Tau protein， and ZBP1/MLKL signaling pathway-related proteins in hippocampal tissues were detected； the positive expression of phosphorylated receptor-interacting protein kinase 3 （p-RIPK3） in the neurons of hippocampal tissues and mRNA expression of ZBP1 were measured in hippocampal tissues. RESULTS Compared with normal control group， the escape latency of mice in model group was prolonged significantly on day 3 to 5 （P＜0.05）， the times of crossing platform reduced significantly （P＜0.05）， and obvious pathological changes were observed in the hippocampal tissue. The level of TNF- α， the expressions of APP， p-Tau and ZBP1， the phosphorylation levels of RIPK1， RIPK3 and MLKL， the fluorescence intensity of p-RIPK3 as well as the mRNA expression of ZBP1 were significantly increased （P＜0.05）， while the serum level of IL-4 was decreased significantly （P＜0.05）. Compared with model group， above indexes were reversed significantly in administration groups （P＜0.05）， and pathological damage of hippocampal tissue was alleviated. CONCLUSIONS WPTL can inhibit the ZBP1/MLKL signaling pathway， reduce neuronal necroptosis in AD mice， and inhibit inflammatory responses， thereby improving learning and spatial memory abilities in AD mice.

Conducting drug clinical trials can enhance hospitals' clinical research capabilities and influence,making it particularly important to improve the management efficiency of trial projects through multiple approaches.Remote monitoring sys-tems enable clinical researchers to remotely access hospital diagnosis and treatment-related systems online,allowing timely,se-cure,and standardized review of subjects' source data and key data traceability.These systems monitor the progress of drug clini-cal trial projects,control project risks to ensure compliance with laws,regulations,trial protocols,and standard operating proce-dures,and safeguard the rights of subjects.In the internet era,remote monitoring systems complement on-site monitoring,enhan-cing hospitals' risk resilience in drug clinical trials while improving efficiency and reducing costs.This paper analyzes recent do-mestic and international laws,regulations,policy directions,and research progress in remote monitoring for clinical trials,dis-cusses current challenges and shortcomings,and provides recommendations and insights for the future informatization development of remote monitoring systems in hospital drug clinical trials.

Conducting drug clinical trials can enhance hospitals' clinical research capabilities and influence,making it particularly important to improve the management efficiency of trial projects through multiple approaches.Remote monitoring sys-tems enable clinical researchers to remotely access hospital diagnosis and treatment-related systems online,allowing timely,se-cure,and standardized review of subjects' source data and key data traceability.These systems monitor the progress of drug clini-cal trial projects,control project risks to ensure compliance with laws,regulations,trial protocols,and standard operating proce-dures,and safeguard the rights of subjects.In the internet era,remote monitoring systems complement on-site monitoring,enhan-cing hospitals' risk resilience in drug clinical trials while improving efficiency and reducing costs.This paper analyzes recent do-mestic and international laws,regulations,policy directions,and research progress in remote monitoring for clinical trials,dis-cusses current challenges and shortcomings,and provides recommendations and insights for the future informatization development of remote monitoring systems in hospital drug clinical trials.

AIM:To investigate the mechanism by which the Z-DNA-binding protein 1(ZBP1)/receptor-in-teracting protein kinase 1(RIPK1)/mixed lineage kinase domain-like protein(MLKL)pathway modulates the necroptosis of neurons in a mouse model of Alzheimer disease(AD).METHODS:Thirty mice were randomly divided into three groups:normal control(NC)group,APP/PS1 model(MOD)group,and necroptosis inhibitor necrostatin-1(Nec-1)group,each with 10 mice.The learning and memory capacities of mice were assessed using the Morris water maze assays.The pathological morphology of hippocampal tissue was examined based on the HE staining assay.The expression levels of tumor necrosis factor-α(TNF-α)and interleukin-10(IL-10)in serum samples were measured by ELISA.The phosphory-lation of amyloid precursor protein(APP),Tau protein and the expression levels of proteins related to the ZBP1/RIPK1/MLKL pathway in hippocampal tissue were measured by Western blot.Immunofluorescence analysis was performed to de-tect the positive expression of p-RIPK1,while the mRNA level of ZBP1 was measured by RT-qPCR.RESULTS:Com-pared with NC group,the escape latency of mice in the MOD group was significantly longer(P<0.05),the number of crossing platforms was reduced(P<0.05),and the arrangement of hippocampal neurons was disordered accompanied with nuclear condensation.The concentration of TNF-α in serum was increased,whereas the concentration level of IL-10 was decreased(P<0.05).The expression levels of APP,p-Ttau and ZBP1 proteins in the hippocampal tissue and the ratios of p-RIPK1/RIPK1,p-RIPK3/RIPK3 and p-MLKL/MLKL were significantly upregulated(P<0.05).Similarly,the positive expression level of p-RIPK1 and the mRNA level of ZBP1 in hippocampal tissue were significantly upregulated(P<0.05).Compared with the MOD group,the cognitive function of AD mice,pathological damage of hippocampal tissue,and the levels of TNF-α and IL-10 in serum were reversed in the Nec-1 group(P<0.05).Moreover,the Nec-1 treatment signifi-cantly downregulated the expression levels of the above proteins(P<0.05),and the positive expression of p-RIPK1 and the mRNA level of ZBP1 were significantly decreased(P<0.05).CONCLUSION:The ZBP1/RIPK1/MLKL pathway is involved in the occurrence of neuronal necroptosis and the pathological process of AD mice.Inhibition of this pathway sig-nificantly ameliorates cognitive dysfunction and neuroinflammatory responses in AD mice.

OBJECTIVE To investigate the intervention effect and its potential mechanism of Yifei xuanfei jiangzhuo formula by inhibiting mitochondrial fission in a vascular dementia(VaD)model rats.METHODS VaD rat model was established by bilateral common carotid artery ligation.The experimental animals were randomly divided into sham operation group(SHAM),model group(MOD),Yifei xuanfei jiangzhuo formula low-dose group(YFXF-L),Yifei xuanfei jiangzhuo formula high-dose group(YFXF-H),and Donepezil hydrochloride group(positive control),with 9 animals in each group.After 30 days of intervention,the spatial learning memory ability was assessed by Morris water maze experiment;HE staining was used to observe histopathological changes in CA1 area of hippocampus;ELISA was used to detect the levels of serum inflammatory factors[interleukin-1β(IL-1β)and IL-4];Western blot was used to detect the expressions of heat shock protein 90(HSP90)/mixed lineage kinase domain-like protein(MLKL)/dynamin-related protein 1(Drp1)pathway-related proteins,mitochondrial fusion proteins(MFN1,MFN2),and adenosine triphosphate synthase 5A(ATP5A)in hippocampal tissues.The immunohistochemistry was used to detect the level of phosphorylated MLKL(p-MLKL);real-time fluorescence quantitative PCR was adopted to detect mRNA expressions of HSP90,MFN1,MFN2 and ATP5A.RESULTS Compared with SHAM group,the escape latency of rats in the MOD group was significantly prolonged,the number of crossing the platform was significantly reduced,and the hippocampal tissues showed typical neuronal damage characteristics,the positive expression level of p-MLKL and the serum level of IL-1β significantly increased,while the serum level of IL-4 significantly decreased,the protein and mRNA expression of HSP90,as well as the protein expressions of p-MLKL/MLKL and p-Drp1(Ser616)/Drp1 were all significantly increased in hippocampal tissue,the protein and mRNA expressions of MFN1,MFN2 and ATP5A,and protein expression of p-Drp1(Ser637)/Drp1 were all significantly decreased(P＜0.05).After the intervention of Yifei xuanfei jiangzhuo formula,above indicators in each treatment group were all significantly reversed(P＜0.05).CONCLUSIONS Yifei xuanfei jiangzhuo formula may alleviate neuronal damage and neuroinflammatory responses in VaD rats by regulating the HSP90/MLKL/Drp1 signaling pathway,inhibiting mitochondrial fission,thereby maintaining mitochondrial dynamic balance and improving mitochondrial function.

AIM:To investigate the mechanism by which the Z-DNA-binding protein 1(ZBP1)/receptor-in-teracting protein kinase 1(RIPK1)/mixed lineage kinase domain-like protein(MLKL)pathway modulates the necroptosis of neurons in a mouse model of Alzheimer disease(AD).METHODS:Thirty mice were randomly divided into three groups:normal control(NC)group,APP/PS1 model(MOD)group,and necroptosis inhibitor necrostatin-1(Nec-1)group,each with 10 mice.The learning and memory capacities of mice were assessed using the Morris water maze assays.The pathological morphology of hippocampal tissue was examined based on the HE staining assay.The expression levels of tumor necrosis factor-α(TNF-α)and interleukin-10(IL-10)in serum samples were measured by ELISA.The phosphory-lation of amyloid precursor protein(APP),Tau protein and the expression levels of proteins related to the ZBP1/RIPK1/MLKL pathway in hippocampal tissue were measured by Western blot.Immunofluorescence analysis was performed to de-tect the positive expression of p-RIPK1,while the mRNA level of ZBP1 was measured by RT-qPCR.RESULTS:Com-pared with NC group,the escape latency of mice in the MOD group was significantly longer(P<0.05),the number of crossing platforms was reduced(P<0.05),and the arrangement of hippocampal neurons was disordered accompanied with nuclear condensation.The concentration of TNF-α in serum was increased,whereas the concentration level of IL-10 was decreased(P<0.05).The expression levels of APP,p-Ttau and ZBP1 proteins in the hippocampal tissue and the ratios of p-RIPK1/RIPK1,p-RIPK3/RIPK3 and p-MLKL/MLKL were significantly upregulated(P<0.05).Similarly,the positive expression level of p-RIPK1 and the mRNA level of ZBP1 in hippocampal tissue were significantly upregulated(P<0.05).Compared with the MOD group,the cognitive function of AD mice,pathological damage of hippocampal tissue,and the levels of TNF-α and IL-10 in serum were reversed in the Nec-1 group(P<0.05).Moreover,the Nec-1 treatment signifi-cantly downregulated the expression levels of the above proteins(P<0.05),and the positive expression of p-RIPK1 and the mRNA level of ZBP1 were significantly decreased(P<0.05).CONCLUSION:The ZBP1/RIPK1/MLKL pathway is involved in the occurrence of neuronal necroptosis and the pathological process of AD mice.Inhibition of this pathway sig-nificantly ameliorates cognitive dysfunction and neuroinflammatory responses in AD mice.

Shared decision-making is a medical model developed in the 1970s where physicians and patients jointly participate in making healthcare decisions. It has been widely adopted in developed countries in Europe and the United States. In recent years, more and more studies have explored the localization of shared decision-making in China, but the clinical application model in Chinese context has not yet been established. This article reviews the basic concept, clinical application, advantages and disadvantages, and future development of the shared decision-making between doctor and patient, in hope of providing ideas for the construction of a shared decision-making model in China.

Objective:To investigate the current status and quality and safety of radiation therapy resources in medical institutions in Hunan province.Methods:The basic situation questionnaire, quality and safety self-assessment form were designed according to the content of the survey, distributed and recovered through the network, and the survey was conducted on all medical institutions (excluding military hospitals) conducting radiotherapy in Hunan province in 2022, and the quality and safety evaluation was checked by the Hunan Radiotherapy Quality Control Center using stratified sampling field inspection. The differences between the self-evaluation scores of radiotherapy quality and safety and the on-site inspection scores of each unit was compared using Wilcoxon test.Results:By the end of 2022, there were 76 medical institutions (excluding military hospitals) conducting radiotherapy in Hunan province, including 62 tertiary hospitals and 14 secondary hospitals, with a total of 44 253 radiotherapy patients admitted annually. The total number of personnel engaged in radiotherapy was 1 381, including 746 physicians, 205 physicists, 397 technicians and 33 maintenance engineers. There were a total of 88 accelerators (including 3 tomotherapy units), 10 gamma knives, and 28 rear-loading machines, with 1.33 gas pedals per million population. There were 36 units that were carrying out three-dimensional conformal technology, 60 static intensity modulation technology, 20 volumetric rotational intensity modulation, 27 stereotactic radiotherapy, 44 image-guided radiotherapy, 33 respiratory motion management, and 27 rear-loading radiotherapy. In the quality and safety evaluation situation, the basic requirements of radiotherapy specialty scored high, with 2 units achieving full marks and no failing units. Radiotherapy personnel and organization, radiotherapy process, documentation record score and other aspects of no full-score units, the score was concentrated in 60~＜80 points, and all have part of the unit failed.Conclusions:The radiotherapy industry in Hunan province has been developed steadily in recent years in general, and the structure of radiotherapy personnel tends to be reasonable, but there still exists uneven distribution of radiotherapy resources, poor utilization of equipment in some areas, and inadequate development of technology. The overall quality and safety evaluation are good, but there are still many deficiencies in the organizational requirements of radiotherapy personnel, process requirements and documentation, which need to be continuously optimized and improved in the future, and at the same time, field inspections will be intensified to ensure the quality and safety of radiotherapy.

Objective This study aims to analyze the relationship between reproductive tract microecological changes,metabolic differences,and pregnancy outcomes at different time points in the frozen-thawed embryo transfer cycle while patients are undergoing hormone replacement therapy,which will be a breakthrough point for improving outcomes.Methods A total of 20 women undergoing frozen-thawed single blastocyst transfer for the first time at the Reproductive Medicine Center of Fujian Maternal and Child Health Hospital between July 2022 and January 2023 were recruited for this study.Their vaginal and cervical secretions were collected for 16S rRNA sequencing and non-targeted metabolomics analysis on days 2-5 of menstruation,day 7 after estrogen replacement therapy started,the day when progesterone was added,and the day of transplantation.The subjects were divided into different groups according to their clinical pregnancy status and the sequencing results were analyzed using bioinformatics methods.Results 1)The alpha-diversity index of the vaginal and cervical microbiota was higher on days 2-5 of menstruation(P<0.01),but did not differ significantly on day 7 after oral estrogen replacement therapy started,the day of progesterone administration,and the day of transplantation(P≥0.1).2)Both the pregnant group and the non-pregnant group showed a variety of microorganisms and metabolites with significant differences in the lower reproductive tract at different time points.3)Microbial analysis at different time points showed that there were significant differences in vaginal flora,including Peptoniphilus,Enterocloster,Finegoldia,Klebsiella,Anaerobutyricum,Agathobaculum,Sporanaerobacter,Bilophila,Prevotella,and Anaerococcus in the pregnant group(P<0.05).4)Metabolite analysis at different time points showed that there were significant differences in 3-hydroxybenzoic acid,linatine,(R)-amphetamine,hydroxychloroquine,and L-altarate in the vaginal secretions of the pregnant group(P<0.05),and that there were significant differences in isocitric acid,quassin,citrinin,and 12(R)-HETE in the cervical secretions(P<0.05).5)Metabolite analysis at different time points showed that,in the non-pregnant group,there were significant differences in linatine,decanoyl-L-carnitine,aspartame,sphingosine,and hydroxychloroquine in the vaginal secretions(P<0.05),and the isocitric acid,quassin,ctrinin,and 12(R)-HETE in the cervical secretions(P<0.05).6)Combined microbiome and metabolomics analysis showed that certain metabolites were significantly associated with microbial communities,especially Klebsiella.Conclusions Significant differences in the microbiota genera and metabolites at different time points were found during the frozen-embryo transfer cycle of hormone replacement therapy,which may be used as potential biomarkers to predict pregnancy outcomes of embryo transfer.

Although the development of COVID-19 vaccines has been a remarkable success, the heterogeneous individual antibody generation and decline over time are unknown and still hard to predict. In this study, blood samples were collected from 163 participants who next received two doses of an inactivated COVID-19 vaccine (CoronaVac®) at a 28-day interval. Using TMT-based proteomics, we identified 1,715 serum and 7,342 peripheral blood mononuclear cells (PBMCs) proteins. We proposed two sets of potential biomarkers (seven from serum, five from PBMCs) at baseline using machine learning, and predicted the individual seropositivity 57 days after vaccination (AUC = 0.87). Based on the four PBMC's potential biomarkers, we predicted the antibody persistence until 180 days after vaccination (AUC = 0.79). Our data highlighted characteristic hematological host responses, including altered lymphocyte migration regulation, neutrophil degranulation, and humoral immune response. This study proposed potential blood-derived protein biomarkers before vaccination for predicting heterogeneous antibody generation and decline after COVID-19 vaccination, shedding light on immunization mechanisms and individual booster shot planning.
Humans ; COVID-19 Vaccines ; Leukocytes, Mononuclear ; Proteomics ; COVID-19/prevention & control* ; Vaccination ; Antibodies ; Antibodies, Viral ; Antibodies, Neutralizing