OBJECTIVE To evaluate the cost-effectiveness of iruplinalkib for ALK-positive non-small cell lung cancer （NSCLC） patients who had not previously received ALK-tyrosine kinase inhibitors （TKIs） from the perspective of the Chinese healthcare system. METHODS Based on the INSPIRE clinical trial， a three-health state partitioned survival model was developed to simulate the progression of disease， with model cycle of 3 weeks and a life-year time range of 15 years； the discount rate was 5%. For the treatment of ALK-positive advanced NSCLC， total cost， quality-adjusted life year （QALY）， and incremental cost- effectiveness ratio （ICER） were compared between iruplinalkib and crizotinib； using 1-3 times China’s per capita gross domestic product （GDP） （89 358-268 074 yuan） in 2023 as the willingness-to-pay （WTP） threshold， the cost-effectiveness of two regimens were compared. The sensitivity analysis and scenario analysis （altering the distribution of survival curves， utility values） were conducted to assess model robustness. RESULTS Compared with the crizotinib regimen， the ICER for the iruplinalkib regimen was 194 412.74 yuan/QALY， which was below the WTP threshold of three times China’s per capita GDP in 2023 yuan）. The results under the scenario of altering the survival curve distribution were consistent with the base case analysis. However， after increasing the utility value of the disease progression state， the ICER exceeded the WTP threshold， and iruplinalkib no longer had a cost-effective advantage. The results of the one-way sensitivity analysis indicated that the cost of iruplinalkib and the utility values of disease progression states had a significant impact on the ICER. The probabilistic sensitivity analysis confirmed the robustness of the base case analysis results. CONCLUSIONS From the perspective of China’s healthcare system， compared with crizotinib regimen， the therapy with iruplinalkib is cost-effective for ALK-positive NSCLC patients who have not previously received ALK-TKIs.

Objective To investigate the mechanism behind the protective effects of gastrodin against microglia-mediated inflammatory responses following hypoxic-ischemic brain damage(HIBD)in neonatal mice.Methods Thirty-six 10-day-old C57BL/6J mice were randomized into sham-operated group,HIBD(induced by ligation of the left common carotid artery followed by hypoxia for 40 min)group,and HIBD with gastrodin treatment groups(n=12).In gastrodin treatment group,100 mg/kg gastrodin was injected intraperitoneally 1 h before and at 2 and 12 h after hypoxia.After the treatments,the expressions of CCR5,AKT,p-AKT,and TNF-α and the co-expression of IBA1 and CCR5 in the corpus callosum of the mice were detected with Western blotting and immunofluorescence double staining.In a BV2 microglial cell model of oxygen-glucose deprivation(OGD),the effects of pretreatment with gastrodin and Maraviroc(an CCR5 antagonist)on protein expressions of CCR5,AKT,p-AKT,TNF-α and IL-1β were evaluated using Western blotting and immunofluorescence double staining.Results The neonatal mice with HIBD showed significantly increased expressions of CCR5 and TNF-α with lowered p-AKT expression in the brain tissues,and GAS treatment obviously reversed these changes.HIBD also significantly increased the co-expression of IBA1 and CCR5 in the corpus callosum of the mice,which was obviously lowered by gastrodin treatment.In BV2 cells,OGD significantly increased the expressions of CCR5,TNF-α,and IL-1β and decreased the expression of p-AKT,and these changes were inhibited by treatment with gastrodin,Maraviroc or their combination;the inhibitory effect of the combined treatment did not differ significantly from that of gastrodin or Maraviroc alone.Conclusion Gastrodin can produce neuroprotective effects in neonatal mice with HIBD by inhibiting inflammatory cytokine production and activate AKT phosphorylation via inhibiting CCR5.

Objective To explore the guiding value of thromboelastography(TEG)in the formulation of personalized anticoagulation regimen after knee arthroscopy.Methods A total of 50 patients who underwent knee arthroscopy in our hos-pital from April to August 2023 were randomly divided into two groups.Twenty-seven patients with routine anticoagulation were selected as the control group,and 23 patients with personalized anticoagulation were selected as the experimental group.Conventional anticoagulation was a prophylactic dose of low molecular weight heparin calcium(LMWHC)selected according to body weight,once a day to 7 days after surgery.Personalized anticoagulation was performed according to the prophylactic dose of LMWHC until postoperative day 3.On postoperative day 3,LMWHC was changed to aspirin according to the TEG return index(MA>70 mm,α Angle>72°,K value<1 min),and the initial prophylactic dose was 100 mg/d.LMWHC was changed to rivaroxaban when R<5 min,and the prophylactic dose was 10 mg/d until postoperative day 7.Pa-tients with hypocoagulation or subcutaneous ecchymosis stopped the drug first,and if it was further aggravated,component blood transfusion was performed according to the TEG results.The difference of Caprini score in perioperative period,the correlation between TEG and CCT on postoperative day 1,and the accuracy of predicting thrombosis on postoperative day 7 were compared between the two groups using the receiver operating characteristic curve(ROC).Results There was a sig-nificant difference in Caprini score between the two groups at 7 days after operation(P<0.05),suggesting that the adjust-ment of anticoagulant drugs in the experimental group was effective at 3 days after operation.Pearson correlation evaluation showed that there was a strong positive correlation between maximum coagulation intensity(MA)in TEG and platelet(Plt)in CCT at day 1 after surgery(P<0.05).Thrombosis was found in the control group at 7 days after operation,all of which were CMVT and disappeared after therapeutic antithrombotic therapy.MA was included in the ROC curve for model analysis.The area under the ROC curve(AUC)of the control group was 0.819,and the AUC of the experimental group was 0.508.It was found that the control group model had higher accuracy in predicting the formation of CMVT.Conclusion Individu-alized anticoagulation under TEG monitoring can effectively reduce the occurrence of CMVT after knee arthroscopy,which has guiding value for anticoagulation and thrombosis prevention.

Objective To investigate the mechanism behind the protective effects of gastrodin against microglia-mediated inflammatory responses following hypoxic-ischemic brain damage(HIBD)in neonatal mice.Methods Thirty-six 10-day-old C57BL/6J mice were randomized into sham-operated group,HIBD(induced by ligation of the left common carotid artery followed by hypoxia for 40 min)group,and HIBD with gastrodin treatment groups(n=12).In gastrodin treatment group,100 mg/kg gastrodin was injected intraperitoneally 1 h before and at 2 and 12 h after hypoxia.After the treatments,the expressions of CCR5,AKT,p-AKT,and TNF-α and the co-expression of IBA1 and CCR5 in the corpus callosum of the mice were detected with Western blotting and immunofluorescence double staining.In a BV2 microglial cell model of oxygen-glucose deprivation(OGD),the effects of pretreatment with gastrodin and Maraviroc(an CCR5 antagonist)on protein expressions of CCR5,AKT,p-AKT,TNF-α and IL-1β were evaluated using Western blotting and immunofluorescence double staining.Results The neonatal mice with HIBD showed significantly increased expressions of CCR5 and TNF-α with lowered p-AKT expression in the brain tissues,and GAS treatment obviously reversed these changes.HIBD also significantly increased the co-expression of IBA1 and CCR5 in the corpus callosum of the mice,which was obviously lowered by gastrodin treatment.In BV2 cells,OGD significantly increased the expressions of CCR5,TNF-α,and IL-1β and decreased the expression of p-AKT,and these changes were inhibited by treatment with gastrodin,Maraviroc or their combination;the inhibitory effect of the combined treatment did not differ significantly from that of gastrodin or Maraviroc alone.Conclusion Gastrodin can produce neuroprotective effects in neonatal mice with HIBD by inhibiting inflammatory cytokine production and activate AKT phosphorylation via inhibiting CCR5.

Zearalenone(ZEN)is a mycotoxin that extensively contaminates food and feed,posing a significant threat to public health.However,the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear.In this study,Sprague-Dawley(SD)rats were exposed to ZEN at a dosage of 5 mg/kg/day b.w.for a duration of 14 days.The results demonstrated that ZEN exposure led to notable pathological alterations and immunosup-pression within the intestine.Furthermore,ZEN exposure caused a significant reduction in the levels of apolipoprotein E(ApoE)and liver X receptor(LXR)(P＜0.05).Conversely,it upregulated the levels of myeloid-derived suppressor cells(MDSCs)markers(P＜0.05)and decreased the presence of 27-hydroxycholesterol(27-HC)in the intestine(P＜0.05).It was observed that ApoE or LXR agonists were able to mitigate the immunosuppressive effects induced by ZEN.Additionally,a bioinformatics analysis highlighted that the downregulation of ApoE might elevate the susceptibility to colorectal,breast,and lung cancers.These find-ings underscore the crucial role of the 27-HC/LXR/ApoE axis disruption in ZEN-induced MDSCs proliferation and subsequent inhibition of T lymphocyte activation within the rat intestine.Notably,ApoE may emerge as a pivotal target linking ZEN exposure to cancer development.

Extracellular vesicles (EV) are highly heterogeneous nanoscale vesicles secreted by cells. They carry various bioactive molecules derived from the parent cells. EV are widely distributed in various body fluids, showing enormous potential in liquid biopsy and disease treatment. However, conventional flow cytometers face challenges in detecting single EV with a diameter smaller than 300 nm. The nano-flow cytometry (nFCM) developed based on Raleigh scattering and sheath-flow single-molecule fluorescence detection has successfully pushed the detection limit of EV to 40 nm. Through multi-parameter detection at the single-particle level, nFCM enables simultaneous analysis of particle size, particle concentration, and multiple biochemical properties of individual EV. nFCM can be applied to clinical diagnosis and therapeutics based on EV.

Humans ; Vaccines, Inactivated ; COVID-19/prevention & control* ; Vaccination ; Viral Vaccines ; Immunity ; Antibodies, Viral

Deacetylation of chitin is closely related to insect development and metamorphosis. Chitin deacetylase (CDA) is a key enzyme in the process. However, to date, the CDAs of Bombyx mori (BmCDAs), which is a model Lepidopteran insect, were not well studied. In order to better understand the role of BmCDAs in the metamorphosis and development of silkworm, the BmCDA2 which is highly expressed in epidermis was selected to study by bioinformatics methods, protein expression purification and immunofluorescence localization. The results showed that the two mRNA splicing forms of BmCDA2, namely BmCDA2a and BmCDA2b, were highly expressed in the larval and pupal epidermis, respectively. Both genes had chitin deacetylase catalytic domain, chitin binding domain and low density lipoprotein receptor domain. Western blot showed that the BmCDA2 protein was mainly expressed in the epidermis. Moreover, fluorescence immunolocalization showed that BmCDA2 protein gradually increased and accumulated with the formation of larval new epidermis, suggesting that BmCDA2 may be involved in the formation or assembly of larval new epidermis. The results increased our understandings to the biological functions of BmCDAs, and may facilitate the CDA study of other insects.
Animals ; Bombyx/metabolism* ; Metamorphosis, Biological/genetics* ; Larva/metabolism* ; Gene Expression ; Insect Proteins/metabolism* ; Chitin

Based on the national policies, regulations and documents on residency training, this paper sorts out the historical evolution of the standardized residency training system in China, and divides its development into four stages: preliminary exploration, local pilot, national trials, and implementation. It also puts forward some practical thoughts on its development law and future trend, such aspects as that the system reform follows the top-down administrative order and indicative plan, the system pays attention to the gradual implementation on the basis of summing up practical experience, and the system needs continuous implementation and improvement from the overall perspective.

Objective:To analyse the association between triglyceride glucose (TyG) index and the number of coronary artery lesions in patients with stable coronary artery disease.Methods:It was a cross-sectional study. Patients with stable coronary artery disease who were admitted to Zhongshan Hospital, Fudan University from 1st January 2019 to 30th April 2020 for percutaneous coronary intervention (PCI) were selected. We collected general clinical information and laboratory results from the enrolled patients, then calculated the TyG index. We evaluated coronary artery lesions by coronary angiography and analysed the factors associated with the number of coronary artery lesion branches by the logistic regression model.Results:A total of 832 patients were included in this study, 641 (77.0%) were male, the age was (64.6±11.5) years. The mean TyG index was 8.78. Patients with the TyG index≥8.78 were included in the high TyG index group (411 patients), and those with the TyG index<8.78 were included in the low TyG index group (421 patients). Compared with the low TyG index group, the high TyG index group had the higher body mass index and diastolic blood pressure, more smokers and diabetes mellitus, younger age of onset of coronary heart disease (all P<0.05), and a lower proportion of patients using statins ( P=0.027). Compared with the low TyG index group, the high TyG index group had the higher levels of erythrocyte count, hemoglobin, white blood cell count, albumin, urea nitrogen, uric acid, fasting blood glucose, HbA1c, triglyceride, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, apolipoprotein E, and C-reactive protein (all P<0.05). However, the levels of high density lipoprotein, apolipoprotein A1 and apolipoprotein A were lower in the high TyG index group than those in the low TyG index group (all P<0.05). The number of coronary artery lesions in patients in the high TyG index group was 2.35±0.91, more than the low TyG index group 2.10±0.95 ( P<0.001).After adjusting for the other factors, multivariate logistic regression analysis showed that male, smoking history (smoking cessation or smoking), TyG index and troponin T levels were independently positively associated with the number of coronary artery lesions (all OR>1, P<0.05), while ApoA1 was independently negatively associated with the number of coronary artery lesions ( OR=0.140, P=0.007). Conclusions:TyG index is positively associated with the number of coronary artery lesions in patients with stable coronary artery disease.