PURPOSE: Assessing fluid responsiveness relying on central venous oxygen saturation (ScvO₂) yields varied outcomes across several studies. This study aimed to determine the ability of the change in ScvO₂ (ΔScvO₂) to detect fluid responsiveness in ventilated septic shock patients and potential influencing factors. METHODS: In this prospective, single-center study, all patients conducted from February 2023 to January 2024 received fluid challenge. Oxygen consumption was measured by indirect calorimetry, and fluid responsiveness was defined as an increase in cardiac index (CI) ≥ 10% measured by transthoracic echocardiography. Multivariate linear regression analysis was conducted to evaluate the impact of oxygen consumption, arterial oxygen saturation, CI, and hemoglobin on ScvO₂ and its change before and after fluid challenge. The Shapiro-Wilk test was used for the normality of continuous data. Data comparison between fluid responders and non-responders was conducted using a two-tailed Student t-test, Mann Whitney U test, and Chi-square test. Paired t-tests were used for normally distributed data, while the Wilcoxon signed-rank test was used for skewed data, to compare data before and after fluid challenge. RESULTS: Among 49 patients (31 men, aged (59 ± 18) years), 27 were responders. The patients had an acute physiology and chronic health evaluation II score of 24 ± 8, a sequential organ failure assessment score of 11 ± 4, and a blood lactate level of (3.2 ± 3.1) mmol/L at enrollment. After the fluid challenge, the ΔScvO₂ (mmHg) in the responders was greater than that in the non-responders (4 ± 6 vs. 1 ± 3, p = 0.019). Multivariate linear regression analysis suggested that CI was the only independent influencing factor of ScvO₂, with R² = 0.063, p = 0.008. After the fluid challenge, the change in CI became the only contributing factor to ΔScvO₂ (R² = 0.245, p < 0.001). ΔScvO₂ had a good discriminatory ability for the responders and non-responders with a threshold of 4.4% (area under the curve = 0.732, p = 0.006). CONCLUSION ΔScvO₂ served as a reliable surrogate marker for ΔCI and could be utilized to assess fluid responsiveness, given that the change in CI was the sole contributing factor to the ΔScvO₂. In stable hemoglobin conditions, the absolute value of ScvO₂ could serve as a monitoring indicator for adequate oxygen delivery independent of oxygen consumption.
Humans ; Shock, Septic/blood* ; Male ; Female ; Middle Aged ; Prospective Studies ; Oxygen Saturation ; Aged ; Fluid Therapy ; Oxygen/blood* ; Oxygen Consumption ; Adult

OBJECTIVES: To evaluate the causal association between circulating levels of zinc, magnesium, and other minerals and autism spectrum disorder (ASD). METHODS: A two-sample Mendelian randomization (MR) analysis was performed using summary statistics from large-scale genome-wide association studies of European populations, including 18 382 ASD cases and 27 969 controls. Genetic data for iron, calcium, and magnesium were obtained from the UK Biobank, and data for zinc and selenium were sourced from an Australian-British cohort. A total of 351 genetic instrumental variables were selected. Causal inference was performed using inverse-variance weighting as the primary analysis method. Sensitivity analyses were performed by Cochran's Q test and MR-PRESSO global test to assess the robustness of the findings. RESULTS: No statistically significant causal effect was observed for circulating zinc, magnesium, calcium, selenium, or iron levels on ASD risk (all P>0.05). The odds ratios and 95% confidence intervals from the inverse-variance weighting analysis were 0.934 (0.869-1.003) for zinc, 1.315 (0.971-1.850) for magnesium, 1.055 (0.960-1.159) for calcium, 1.015 (0.953-1.080) for selenium, and 0.946 (0.687-1.303) for iron. Sensitivity analysis revealed significant heterogeneity in the causal association between circulating calcium and ASD (P=0.006), while the effect estimate remained stable after MR-PRESSO correction (P=0.487). The causal effect estimates for the remaining minerals demonstrated good robustness. CONCLUSIONS This study did not find significant evidence supporting a causal association between circulating zinc, magnesium, calcium, selenium, or iron levels and ASD risk, providing important clues for the etiology of ASD and precision nutritional interventions.
Humans ; Mendelian Randomization Analysis ; Autism Spectrum Disorder/genetics* ; Magnesium/blood* ; Zinc/blood* ; Minerals/blood* ; Genome-Wide Association Study ; Selenium/blood*

Pancreatic cancer is one of the most prevalent malignant tumors of the digestive system， and its incidence and mortality rates are increasing year by year. Most patients with pancreatic cancer are unable to receive surgery due to the advanced stage. Although chemotherapy regimens based on gemcitabine and fluorouracil have prolonged the survival time of patients to some extent， some patients cannot tolerate chemotherapy and hence lose the opportunity for treatment. With the advent of the era of precision medicine， molecular-targeted therapy has exhibited an excellent therapeutic efficacy and has thus become one of the most important treatment techniques for tumors； however， due to the high heterogeneity of pancreatic cancer and its complicated tumor microenvironment， molecular-targeted therapy for pancreatic cancer has not achieved notable results. Therefore， it is imperative to seek new therapeutic targets and medications to overcome this issue. This article reviews the latest advances in the research on molecular-targeted therapy for unresectable pancreatic cancer based on common molecular targets and tumor immunity-related therapeutic targets， in order to provide new treatment strategies for patients with pancreatic cancer.

Objective:Given the high incidence and mortality rate of sepsis,early identification of high-risk patients and timely intervention are crucial.However,existing mortality risk prediction models still have shortcomings in terms of operation,applicability,and evaluation on long-term prognosis.This study aims to investigate the risk factors for death in patients with sepsis,and to construct the prediction model of short-term and long-term mortality risk. Methods:Patients meeting sepsis 3.0 diagnostic criteria were selected from the Medical Information Mart for Intensive Care-IV(MIMIC-IV)database and randomly divided into a modeling group and a validation group at a ratio of 7?3.Baseline data of patients were analyzed.Univariate Cox regression analysis and full subset regression were used to determine the risk factors of death in patients with sepsis and to screen out the variables to construct the prediction model.The time-dependent area under the curve(AUC),calibration curve,and decision curve were used to evaluate the differentiation,calibration,and clinical practicability of the model. Results:A total of 14 240 patients with sepsis were included in our study.The 28-day and 1-year mortality were 21.45%(3 054 cases)and 36.50%(5 198 cases),respectively.Advanced age,female,high sepsis-related organ failure assessment(SOFA)score,high simplified acute physiology score II(SAPS II),rapid heart rate,rapid respiratory rate,septic shock,congestive heart failure,chronic obstructive pulmonary disease,liver disease,kidney disease,diabetes,malignant tumor,high white blood cell count(WBC),long prothrombin time(PT),and high serum creatinine(SCr)levels were all risk factors for sepsis death(all P<0.05).Eight variables,including PT,respiratory rate,body temperature,malignant tumor,liver disease,septic shock,SAPS II,and age were used to construct the model.The AUCs for 28-day and 1-year survival were 0.717(95%CI 0.710 to 0.724)and 0.716(95%CI 0.707 to 0.725),respectively.The calibration curve and decision curve showed that the model had good calibration degree and clinical application value. Conclusion:The short-term and long-term mortality risk prediction models of patients with sepsis based on the MIMIC-IV database have good recognition ability and certain clinical reference significance for prognostic risk assessment and intervention treatment of patients.

Objective To compare the fidelity of chronic obstructive pulmonary disease(COPD)models established using two methods:exposure to cigarette smoke(CS)and exposure to motor vehicle exhaust(MVE)in rats.Methods Twenty-four male SD rats were randomly divided into control,CS-exposed(CS),and MVE-exposed(MVE)groups,with 8 rats per group.Rats in CS and MVE groups were exposed to CS or MVE,respectively,to induce COPD models.After COPD model established,lung function of each group was assessed.Bronchoalveolar lavage fluid(BALF)was collected to measure inflammatory cell counts,levels of inflammatory cytokines interleukin-6(IL-6)and tumor necrosis factor(TNF)-α,and expression levels of mucin 5AC(MUC5AC).Lung tissue sections were stained with hematoxylin and eosin(HE)to observe pulmonary tissue and airway pathological changes.Periodic acid-Schiff(PAS)staining was used to detect goblet cell hyperplasia in airways.Results Compared with control group,rats in CS and MVE groups showed significantly increased inspiratory resistance(RI),total lung capacity(TLC),and lung static compliance(Cchord)(P<0.05),while expiratory flow parameters FEV50/FVC were significantly decreased(P<0.05).Compared with MVE group,rats in CS group had significantly higher RI,TLC,and Cchord(P<0.05),and lower FEV50/FVC(P<0.05).HE staining of lung tissues showed that mean linear intercept(MLI)was significantly higher in both CS and MVE groups compared with control group(P<0.05),with CS group having higher MLI than MVE group(P<0.05).BALF analysis revealed that white blood cells,neutrophils,macrophages,lymphocytes,IL-6,and TNF-α levels were significantly higher in both CS and MVE groups compared with control group(P<0.05),and inflammatory cell counts,IL-6,and TNF-α levels were higher in CS group compared with MVE group(P<0.05).PAS staining of lung tissues indicated that goblet cells in large airways were significantly increased in both CS and MVE groups compared with control group(P<0.05),with CS group showing higher goblet cell counts than MVE group(P<0.05).Expression levels of MUC5AC in BALF were significantly higher in both CS and MVE groups compared with control group(P<0.05),with CS group having significantly higher MUC5AC levels than MVE group(P<0.05).Conclusions Exposure to CS or MVE can establish a rat model of COPD,with CS exposure better mimicking characteristics of acute exacerbation of COPD compared to MVE exposure.

Aim To investigate the mechanism of treatment of hepatolenticular degeneration with Garde-nia and Rhubarb decoction based on network pharma-cology and animal experiments.Methods The chemi-cal components and target sites of Gardenia and Rhu-barb decoction were retrieved using the Traditional Chi-nese Medicine System Pharmacology Analysis Platform(TCMSP).The disease targets were obtained by searching the databases of DisGeNET,GeneCards.The PPI network of active compound target sites was constructed using the STRING database.GO function and KEGG pathway enrichment analysis were per-formed using the DAVID database to predict the action pathway.A copper-loaded WD rat model was estab-lished by intragastric administration of copper sulfate pentahydrate.A total of 36 rats were randomly divided into the normal group,model group,penicillamine group and the low,medium and high dose groups of gardenia rhubarb.The relevant indicators and patho-logical changes of liver tissue were detected in WD rats.Results Network pharmacology screening identi-fied 68 potential active components of Gardenia and Rhubarb Decoction,30 intersection targets of diseases and drugs,involving key targets such as TNF,IL10,IGF1,IL1B,TP53,CASP3,PPARG,IL6,CXCL8,IL1A,TGFB1,mainly related to signal pathways such as MAPK,AGE-RAGE signaling pathway in diabetic complications.In the animal experiments,compared with the normal group,the urine copper,liver copper,blood copper,liver coefficient,serum and liver ALT,AST,TNF-α,CASP3,P53 levels in the model group rats significantly increased(P＜0.05);hepatocyte swelling,cytoplasm loose reticular appearance,feath-er-like degeneration and reticular necrosis were ob-served in liver tissue pathology;compared with the model group,the urine copper,liver copper,blood copper,liver coefficient,serum and liver ALT,AST,TNF-α,CASP3,P53 levels in the penicillamine group and Gardenia and Rhubarb decoction groups were sig-nificantly reduced(P＜0.05),and the degree of re-ticular necrosis in the rat liver cells in the penicilla-mine group and the Gardenia and Rhubarb decoction group was significantly reduced.Conclusions Garde-nia and Rhubarb decoction has the effect of regulating copper metabolism and reducing liver injury.The mechanism of action may be related to reversing apop-tosis and downregulating protein expression of TNF-α,CASP3,P53 in MAPK signaling pathway.

Osteoarthritis (OA) is a type of highly prevalent heterogeneous degenerative disease that leads to joint pain, deformity, the destruction of articular cartilage, and eventual disability. The current treatment strategies for OA often suffer from systemic side effects, poor anti-inflammatory efficacy, and persistent pain. To address these issues, we develop light-inducible nanomedicine that enables the co-delivery of anti-inflammatory drug (diacerein, DIA) and small interfering RNA (siRNA) targeting nerve growth factor (NGF) for pain relief to enhance the therapeutic efficacy of OA. The nanomedicine is based on poly(β-amino-ester)-coated gold nanocages (AuNCs), which is further incorporated with the phase-change material (lauric acid/stearic acid, LA/SA). Following intra-articular (IA) injection in vivo, the nanomedicine displays high degree of drug accumulation and retention in the joint lesion of OA mouse models. The photothermal effect, induced by AuNCs, not only promotes DIA and siRNA release, but also upregulates the expression of heat shock protein 70 (HSP-70) to resist the apoptosis of chondrocytes in the inflammatory condition. The internalization of both DIA and siRNA results in strong anti-inflammatory and pain-relieving effects, which greatly contribute to the joint repair of OA mice. This study offers a promising combination strategy for OA treatment.

Humans ; Anemia, Aplastic ; Hemoglobinuria, Paroxysmal/complications* ; Syndrome

Objective: To investigate how plasma exchange (PE) and double plasma molecular adsorption combined with half-volume plasma exchange (DPMAS + half-volume PE) affect the curative effect and short-term survival rate in liver failure. Methods: Data from 181 cases of liver failure caused by different etiologies from January 1, 2017 to September 31, 2020, were selected. Patients were divided into a PE treatment alone group and a DPMAS + half-dose PE treatment group. The laboratory indicators with different models of artificial liver before and after treatment and the survival rates of 7, 14, 28, and 90 days after discharge were observed in the two groups. Measurement data were analyzed by t-tests and rank sum tests. Categorical data were analyzed by χ (2) test. Results: Non-biological artificial liver therapy with different models improved the liver and coagulation function in the two groups of patients with liver failure (P < 0.05 in PTA% intra-group). The coagulation function was significantly improved in the PE treatment alone group compared with that in the DPMAS + half-dose PE group [PT after treatment: (20.15 ± 0.88) s in the PE treatment alone group, (23.43 ± 1.02) s, t = -2.44, P = 0.016 in the DPMAS+half-dose PE group; PTA: 44.72% ± 1.75% in the PE treatment alone group, 35.62% ± 2.25%, t = 3.215 P = 0.002 in the DPMAS + half-dose PE group]. Bilirubin levels were significantly decreased in the DPMAS+half-dose PE group compared to the PE treatment alone group [total bilirubin after treatment: (255.30 ± 15.64) μmol/L in the PE treatment alone group, (205.46 ± 9.03) μmol/L, t = 2.74, P = 0.07 in the DPMAS + half-dose PE group; direct bilirubin after treatment: (114.74 ± 7.11) μmol/L in the PE treatment alone group, (55.33 ± 3.18) μmol/L, t = 7.54, P < 0.001) in the DPMAS + half-dose PE group]. However, there was no significant effect on leukocytes and neutrophils after treatment with different models of artificial liver (P > 0.05) in the two groups, and platelets decreased after treatment, with no statistically significant difference between the groups (t = -0.15, P = 0.882). The inflammatory indexes of the two groups improved after treatment with different models of artificial liver (P < 0.05], and the 28 and 90 d survival rates were higher in the DPMAS+half-dose PE group than those of the PE treatment alone group (28 d: 60.3% vs. 75.0%, χ (2) = 4.315, P = 0.038; 90 d: 56.2% vs. 72.5%. χ (2) = 10.355 P < 0.001). DPMAS + half-dose PE group plasma saving was 1385 ml compared with PE treatment alone group (Z = -7.608, P < 0.05). Conclusion: Both DPMAS+half-dose PE and PE treatment alone have a certain curative effect on patients with liver failure. In DPMAS+half-dose PE, the 28-day survival rate is superior to PE treatment alone, and it saves plasma consumption and minimizes blood use in clinic.

OBJECTIVE: To investigate the optimal duration of dual antiplatelet therapy (DAPT) in patients with diabetes mellitus (DM) requiring complex percutaneous coronary intervention (PCI). METHODS: A total of 2403 patients with DM who underwent complex PCI from January to December 2013 were consecutively enrolled in this observational cohort study and divided according to DAPT duration into a standard group (11-13 months, n = 689) and two prolonged groups (13-24 months, n = 1133; > 24 months, n = 581). RESULTS: Baseline characteristics, angiographic findings, and complexity of PCI were comparable regardless of DAPT duration. The incidence of major adverse cardiac and cerebrovascular event was lower when DAPT was 13-24 months than when it was 11-13 months or > 24 months (4.6% vs. 8.1% vs. 6.0%, P = 0.008), as was the incidence of all-cause death (1.9% vs. 4.6% vs. 2.2%, P = 0.002) and cardiac death (1.0% vs. 3.0% vs. 1.2%, P = 0.002). After adjustment for confounders, DAPT for 13-24 months was associated with a lower risk of major adverse cardiac and cerebrovascular event [hazard ratio (HR) = 0.544, 95% CI: 0.373-0.795] and all-cause death (HR = 0.605, 95% CI: 0.387-0.944). DAPT for > 24 months was associated with a lower risk of all-cause death (HR = 0.681, 95% CI: 0.493-0.942) and cardiac death (HR = 0.620, 95% CI: 0.403-0.952). The risk of major bleeding was not increased by prolonging DAPT to 13-24 months (HR = 1.356, 95% CI: 0.766-2.401) or > 24 months (HR = 0.967, 95% CI: 0.682-1.371). CONCLUSIONS For patients with DM undergoing complex PCI, prolonging DAPT might improve the long-term prognosis by reducing the risk of adverse ischemic events without increasing the bleeding risk.