BACKGROUND: The FAVOR (Comparison of Quantitative Flow Ratio Guided and Angiography Guided Percutaneous Intervention in Patients with Coronary Artery Disease) III China trial demonstrated that percutaneous coronary intervention (PCI) lesion selection using quantitative flow ratio (QFR) measurement, a novel angiography-based approach for estimating fractional flow reserve, improved two-year clinical outcomes compared with standard angiography guidance. This study aimed to assess the cost-effectiveness of QFR-guided PCI from the perspective of the current Chinese healthcare system. METHODS: This study is a pre-specified analysis of the FAVOR III China trial, which included 3825 patients randomized between December 25, 2018, and January 19, 2020, from 26 centers in China. Patients with stable or unstable angina pectoris or those ≥72 hours post-myocardial infarction who had at least one lesion with a diameter stenosis between 50% and 90% in a coronary artery with a ≥2.5 mm reference vessel diameter by visual assessment were randomized to a QFR-guided strategy or an angiography-guided strategy with 1:1 ratio. During the two-year follow-up, data were collected on clinical outcomes, quality-adjusted life-years (QALYs), estimated costs of index procedure hospitalization, outpatient cardiovascular medication use, and rehospitalization due to major adverse cardiac and cerebrovascular events (MACCE). The primary analysis calculated the incremental cost-effectiveness ratio (ICER) as the cost per MACCE avoided. An ICER of ¥10,000/MACCE event avoided was considered economically attractive in China. RESULTS: At two years, the QFR-guided group demonstrated a reduced rate of MACCE compared to the angiography-guided group (10.8% vs . 14.7%, P <0.01). Total two-year costs were similar between the groups (¥50,803 ± 21,121 vs . ¥50,685 ± 23,495, P = 0.87). The ICER for the QFR-guided strategy was ¥3055 per MACCE avoided, and the probability of QFR being economically attractive was 64% at a willingness-to-pay threshold of ¥10,000/MACCE avoided. Sensitivity analysis showed that QFR-guided PCI would become cost-saving if the cost of QFR were below ¥3682 (current cost: ¥3800). Cost-utility analysis yielded an ICER of ¥56,163 per QALY gained, with a 53% probability of being cost-effective at a willingness-to-pay threshold of ¥85,000 per QALY gained. CONCLUSION: In patients undergoing PCI, a QFR-guided strategy appears economically attractive compared to angiographic guidance from the perspective of the Chinese healthcare system. TRIAL REGISTRATION ClinicalTrials.gov , NCT03656848.
Humans ; Cost-Benefit Analysis ; Percutaneous Coronary Intervention/methods* ; Male ; Female ; Coronary Angiography/methods* ; Middle Aged ; Aged ; Coronary Artery Disease/surgery* ; Quality-Adjusted Life Years ; Fractional Flow Reserve, Myocardial/physiology*

OBJECTIVE: To investigate whether auraptene (AUR) exerts a protective effect on acute diquat (DQ)-induced liver injury in mice and explore its underlying mechanisms. METHODS: Forty SPF-grade healthy male C57BL/6 mice were randomly divided into normal control group (Control group), DQ poisoning model group (DQ group), AUR treatment group (DQ+AUR group), and AUR control group (AUR group), with 10 mice in each group. The DQ poisoning model was established via a single intraperitoneal injection of 40 mg/kg DQ aqueous solution (0.5 mL); Control group and AUR group received an equal volume of pure water intraperitoneally. Four hours post-modeling, DQ+AUR group and AUR group were administered 0.5 mg/kg AUR aqueous solution (0.2 mL) by gavage once daily for 7 consecutive days, while Control group and DQ group received pure water. Blood and liver tissues were collected after anesthesia on day 7. Liver ultrastructure was observed by transmission electron microscopy. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured via enzyme-linked immunosorbent assay (ELISA). Hepatic glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were detected using WST-1, thiobarbituric acid (TBA), and enzymatic reaction methods, respectively. Protein expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Kelch-like ECH-associated protein 1 (Keap1), and activated caspase-9 in liver tissues was analyzed by Western blotting. RESULTS: Transmission electron microscopy revealed that mitochondria in the Control group exhibited mild swelling, uneven distribution of matrix, and a small number of cristae fractures. In the AUR group, mitochondria showed mild swelling, with no obvious disruption of cristae structure. In the DQ group, mitochondria demonstrated marked swelling and increased volume, matrix dissolution, loss and fragmentation of cristae, and extensive vacuolization. In contrast, the DQ+AUR group showed significantly reduced mitochondrial swelling, volume increase, matrix dissolution, cristae loss and fragmentation, and vacuolization compared to the DQ group. Compared with the DQ group, the DQ+AUR group exhibited significantly lower serum AST levels (U/L: 173.45±23.60 vs. 255.33±41.51), ALT levels (U/L: 51.77±21.63 vs. 100.70±32.35), and hepatic MDA levels (μmol/g: 12.40±2.76 vs. 19.74±4.10), along with higher hepatic GSH levels (mmol/g: 37.65±14.95 vs. 20.58±8.52) and SOD levels (kU/g: 124.10±33.77 vs. 82.81±22.00), the differences were statistically significant (all P < 0.05). Western blotting showed upregulated Nrf2 expression (Nrf2/β-actin: 0.87±0.37 vs. 0.53±0.22) and HO-1 expression (HO-1/β-actin: 1.06±0.22 vs. 0.49±0.08), and downregulated Keap1 expression (Keap1/β-actin: 0.82±0.12 vs. 1.52±0.76) and activated caspase-9 expression (activated caspase-9/β-actin: 1.16±0.28 vs. 1.71±0.30) in the DQ+AUR group compared to the DQ group (all P < 0.05). CONCLUSION AUR attenuates DQ-induced acute liver injury in mice by activating the Keap1/Nrf2 signaling pathway.
Animals ; Male ; Mice ; Mice, Inbred C57BL ; Liver/pathology* ; Chemical and Drug Induced Liver Injury/drug therapy* ; Diquat/poisoning* ; NF-E2-Related Factor 2/metabolism* ; Oxidative Stress ; Apoptosis ; Coumarins

Objective To investigate the effect of endothelial cells in the perivascular niche on the stem cell-like characteristics of osteosarcoma cells and primarily explore the possible molecular mechanism.Methods A co-culture model was established in vitro using SV40T-human umbilical vein endothelial cells(HUVEC-T1)and osteosarcoma stem cells(OSCs)derived from the human osteosarcoma cell line 143B.Thus,there were 2 groups of cells,OSCs and co-cultured OSCs.The self-renewal capacity of OSCs between the 2 groups was assessed using a limiting dilution forming sphere assay.Flow cytometry and Western blotting were used to detect the expression of stem cell marker CD133 and stemness transcription factors SOX2 and NANOG.Fourteen female nude mice(4～6 weeks old,weighing 18～20 g)were randomly and equally divided into 2 groups of subcutaneous xenograft models:the control group(OSCs suspension)and the experimental group(OSCs+HUVEC-T1 mixed suspension).The tumor volume and mass were compared between the 2 xenograft groups.Immunofluorescence(IF)staining was used to verify the spatial proximity between endothelial cells and OSCs in vivo,while immunohistochemistry was employed to compare microvessel density(MVD)and CD133 expression level between the 2 groups.RNA-seq was performed to identify potential signaling pathways of endothelial cells affecting the stemness of OSCs.PCR and Western blotting were applied to confirm the RNA-seq findings.Exogenous protein treatment,IF staining,Western blotting and sphere formation assay were utilized to preliminarily validate the role of the identified pathway in regulating the stemness phenotype of OSCs.Results The in vitro co-culture model of HUVEC-T1 and OSCs was successfully established.Compared with the control group,the co-culture group exhibited significantly enhanced self-renewal ability of OSCs,laeger proportion of the stemness marker CD133+[(8.20±1.64)％vs(4.32±1.34)％,P<0.05],enhanced expression of CD117,SOX2 and NANOG(P<0.05),along with more sphere formation(P<0.05)and elevated SOX2/NANOG protein levels.The xenograft mice from the experimental group showed larger tumor volume(643.10±413.50 vs 247.90±93.66 mm3,P<0.05)and heavier tumor weight(0.52±0.27 vs 0.24±0.10 g,P<0.05)when compared the control group,correspondingly showing increased MVD(22.57±11.84 vs 11.43±5.38,P<0.05)and elevated CD133 expression(P<0.05).IF staining confirmed the adjacency of CD31-labeled endothelial cells and CD133-labeled OSCs in vivo.RNA-seq and functional experiments demonstrated that CXCR4 was highly expressed in co-cultured OSCs,CXCL12 was highly expressed in co-cultured endothelial cells,and exogenous CXCL12 promoted the sphere formation and expression levels of SOX2 and NANOG of OSCs(P<0.05).Conclusion Endothelial cells within the perivascular niche may promote the stemness phenotype of osteosarcoma cells via the CXCL12/CXCR4 pathway.

Objective:To evaluate the long-term outcomes and predictors of coronary atherosclerotic lesions deemed functionally non-ischemic (quantitative flow ratio(QFR)>0.80) and deferred from intervention.Methods:This study is a post-hoc analysis of the FAVOR Ⅲ China trial, which enrolled 3 825 patients with stable or unstable angina pectoris or with myocardial infarction occurring at least 72 hours prior to screening, between December 5, 2018 and January 9, 2020 from 26 research centers in China. Coronary vessels with QFR>0.80 and without interventional treatment were analyzed in this study. The primary endpoint was 3-year target vessel revascularization. Vessels with revascularization (revascularized group) during follow-up were matched 1∶1 using propensity score matching to comparable vessels without revascularization (non-revascularized group). Multivariate Cox regression analysis was used to identify the risk factors for target vessel revascularization (TVR).Results:A total of 6 212 functionally negative vessels with deferred intervention were included in the final analysis, among which 153 vessels (2.5%) underwent TVR during a 3-year follow-up. Prior to propensity score matching, 6 059 vessels comprised the non-revascularized group. At the vessel level, compared to the non-revascularized group, the revascularized group exhibited a significantly higher proportion of males (79.1% (121/153) vs. 70.2% (4 253/6 059), P=0.018), higher body mass index ((25.6±4.0) kg/m2 vs. (24.3±5.2) kg/m2, P=0.003), and a higher prevalence of hypertension (73.9% (113/153) vs. 65.1% (3 944/6 059), P=0.025). And 152 pairs of vessels were successfully matched. Multivariate Cox regression analysis identified in-stent restenosis lesions ( HR=2.59, 95% CI 1.28-5.23, P=0.008) as an independent risk factor for target vessel revascularization. Conclusions:Coronary lesions classified as functionally non-ischemic at baseline are not entirely stable and may progress to lesions that requiring revascularization over time. In-stent restenosis emerges as a critical independent predictor of revascularization.

Objectives:To explore the predictive value of residual Murray's law-based quantitative flow ratio(μQFR)on long-term vessel-oriented composite endpoints(VoCE).Methods:This retrospective study included 3 510 patients from the FAVOR Ⅲ China trial.Offline residual μQFR analysis was performed on all vessels(diameter≥2.5 mm)with 50%-90%stenotic lesions.Patients were stratified into high-,intermediate-,and low-risk groups based on residual μQFR tertiles.The primary endpoint was 3-year VoCE,defined as a composite of cardiac death related to the target vessel,target vessel-related spontaneous myocardial infarction,and ischemia-driven target vessel revascularization.Results:Offline analysis was performed on 5 256 vessels from 3 510 patients.The mean residual μQFR was 0.92±0.75.The high-risk group(residual μQFR≤0.91)with 1 554 patients(1 958 vessels);the intermediate-risk group(residual μQFR 0.92-0.96)with 1 211 patients(1 906 vessels);and the low-risk group(residual μQFR>0.96)with 745 patients(1 392 vessels).Over 3-year follow-up,VoCE occurred in 227 vessels(4.3%).The 3-year VoCE incidence was significantly higher in the high-risk group compared to the intermediate-and low-risk groups(6.2%vs.4.1%vs.2.5%,log-rank P<0.001),primarily driven by ischemia-driven target vessel revascularization(5.0%vs.3.0%vs.1.6%,log-rank P<0.001).Hypertension(OR=0.83,95%CI:0.72-0.96),hypercholesterolemia(OR=0.84,95%CI:0.73-0.97),bifurcation lesions(OR=0.72,95%CI:0.63-0.83),moderate/severe calcification(OR=0.70,95%CI:0.57-0.84),and tandem lesions(OR=0.59,95%CI:0.47-0.75)were independent predictors of lower residual μQFR values.Conclusions:Lower residual μQFR is significantly associated with increased VoCE risk during the 3-year follow up period.

Objective:To evaluate the effectiveness of diaphragm ultrasound in predicting the success of extubation from tracheotomy in patients with acquired brain injury.Methods:A retrospective analysis was conducted on 51 brain-injured patients. They were divided into an extubation failure group and an extubation success group. The results of ultrasound examination of the diaphragm in the 2 groups were analyzed by univariate analysis, and the independent variables with significance were further subjected to multivariate logistic regression analysis. R software was applied to build the diaphragm indicators showing significant predictive power into a histogram model. The predictive value of this nomogram model was assessed using the receiver operating characteristics (ROC) curve.Results:The univariate analysis revealed significant differences between the two groups in terms of diaphragm excursion, diaphragm thickening fraction and diaphragm excursion-time index. The multivariate logistic regression analysis and the nomogram showed that those three variables are independent influencing factors predicting the success of decannulation. The areas under the ROC curves confirmed that finding.Conclusions:Diaphragm excursion, diaphragm thickening fraction and the diaphragm excursion-time index are useful independent predictors of the success of decannulation among brain injury patients.

Objective:To evaluate the effectiveness of diaphragm ultrasound in predicting the success of extubation from tracheotomy in patients with acquired brain injury.Methods:A retrospective analysis was conducted on 51 brain-injured patients. They were divided into an extubation failure group and an extubation success group. The results of ultrasound examination of the diaphragm in the 2 groups were analyzed by univariate analysis, and the independent variables with significance were further subjected to multivariate logistic regression analysis. R software was applied to build the diaphragm indicators showing significant predictive power into a histogram model. The predictive value of this nomogram model was assessed using the receiver operating characteristics (ROC) curve.Results:The univariate analysis revealed significant differences between the two groups in terms of diaphragm excursion, diaphragm thickening fraction and diaphragm excursion-time index. The multivariate logistic regression analysis and the nomogram showed that those three variables are independent influencing factors predicting the success of decannulation. The areas under the ROC curves confirmed that finding.Conclusions:Diaphragm excursion, diaphragm thickening fraction and the diaphragm excursion-time index are useful independent predictors of the success of decannulation among brain injury patients.

Objectives:To explore the predictive value of residual Murray's law-based quantitative flow ratio(μQFR)on long-term vessel-oriented composite endpoints(VoCE).Methods:This retrospective study included 3 510 patients from the FAVOR Ⅲ China trial.Offline residual μQFR analysis was performed on all vessels(diameter≥2.5 mm)with 50%-90%stenotic lesions.Patients were stratified into high-,intermediate-,and low-risk groups based on residual μQFR tertiles.The primary endpoint was 3-year VoCE,defined as a composite of cardiac death related to the target vessel,target vessel-related spontaneous myocardial infarction,and ischemia-driven target vessel revascularization.Results:Offline analysis was performed on 5 256 vessels from 3 510 patients.The mean residual μQFR was 0.92±0.75.The high-risk group(residual μQFR≤0.91)with 1 554 patients(1 958 vessels);the intermediate-risk group(residual μQFR 0.92-0.96)with 1 211 patients(1 906 vessels);and the low-risk group(residual μQFR>0.96)with 745 patients(1 392 vessels).Over 3-year follow-up,VoCE occurred in 227 vessels(4.3%).The 3-year VoCE incidence was significantly higher in the high-risk group compared to the intermediate-and low-risk groups(6.2%vs.4.1%vs.2.5%,log-rank P<0.001),primarily driven by ischemia-driven target vessel revascularization(5.0%vs.3.0%vs.1.6%,log-rank P<0.001).Hypertension(OR=0.83,95%CI:0.72-0.96),hypercholesterolemia(OR=0.84,95%CI:0.73-0.97),bifurcation lesions(OR=0.72,95%CI:0.63-0.83),moderate/severe calcification(OR=0.70,95%CI:0.57-0.84),and tandem lesions(OR=0.59,95%CI:0.47-0.75)were independent predictors of lower residual μQFR values.Conclusions:Lower residual μQFR is significantly associated with increased VoCE risk during the 3-year follow up period.

Objective:To evaluate the long-term outcomes and predictors of coronary atherosclerotic lesions deemed functionally non-ischemic (quantitative flow ratio(QFR)>0.80) and deferred from intervention.Methods:This study is a post-hoc analysis of the FAVOR Ⅲ China trial, which enrolled 3 825 patients with stable or unstable angina pectoris or with myocardial infarction occurring at least 72 hours prior to screening, between December 5, 2018 and January 9, 2020 from 26 research centers in China. Coronary vessels with QFR>0.80 and without interventional treatment were analyzed in this study. The primary endpoint was 3-year target vessel revascularization. Vessels with revascularization (revascularized group) during follow-up were matched 1∶1 using propensity score matching to comparable vessels without revascularization (non-revascularized group). Multivariate Cox regression analysis was used to identify the risk factors for target vessel revascularization (TVR).Results:A total of 6 212 functionally negative vessels with deferred intervention were included in the final analysis, among which 153 vessels (2.5%) underwent TVR during a 3-year follow-up. Prior to propensity score matching, 6 059 vessels comprised the non-revascularized group. At the vessel level, compared to the non-revascularized group, the revascularized group exhibited a significantly higher proportion of males (79.1% (121/153) vs. 70.2% (4 253/6 059), P=0.018), higher body mass index ((25.6±4.0) kg/m2 vs. (24.3±5.2) kg/m2, P=0.003), and a higher prevalence of hypertension (73.9% (113/153) vs. 65.1% (3 944/6 059), P=0.025). And 152 pairs of vessels were successfully matched. Multivariate Cox regression analysis identified in-stent restenosis lesions ( HR=2.59, 95% CI 1.28-5.23, P=0.008) as an independent risk factor for target vessel revascularization. Conclusions:Coronary lesions classified as functionally non-ischemic at baseline are not entirely stable and may progress to lesions that requiring revascularization over time. In-stent restenosis emerges as a critical independent predictor of revascularization.

OBJECTIVE: To investigate the protective effect and mechanism of tumor necrosis factor receptor-associated factor 6 (TRAF6) inhibitor C25-140 on acute kidney injury (AKI) induced by acute diquat (DQ) poisoning in mice. METHODS: A total of 80 SPF grade healthy male C57BL/6 mice were randomly divided into the normal control group, DQ model group, C25-140 intervention group, and C25-140 control group, with 20 mice in each group. The DQ poisoning mouse model was established by using one-time intraperitoneal injection of 1 mL of 40 mg/kg DQ solution. The normal control group and C25-140 control group were injected with an equal amount of pure water into the peritoneal cavity. After 4 hours of model establishment, the C25-140 intervention group and C25-140 control group were given intraperitoneal injection of C25-140 5 mg/kg. The normal control group and DQ model group were given equal amounts of pure water, once a day for 7 consecutive days. After 7 days, the mice were anesthetized, eye blood was collected, and renal tissue was collected after sacrifice. The pathological changes of renal tissue were observed under a light microscope and renal tissue structure and mitochondrial changes were observed under transmission electron microscopy. The levels of serum creatinine (SCr) and blood urea nitrogen (BUN) were measured. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of serum interleukins (IL-6, IL-1β) and tumor necrosis factor-α (TNF-α). Western blotting was used to detect the protein expression levels of TRAF6, myeloid differentiation factor 88 (MyD88), and nuclear factor-κB (NF-κB) in renal tissue. Chemical method was used to determine the content of serum malondialdehyde (MDA) and superoxide dismutase (SOD). RESULTS: During the observation period, there were no abnormal behaviors in the normal control group mice. The DQ model group mice gradually showed symptoms such as mental fatigue, fluffy fur, reduced activity, and low food intake after being exposed to the toxin, and severe cases resulted in death. The above symptoms were alleviated in the C25-140 intervention group compared to the DQ model group. Under light microscopy, HE staining showed infiltration of inflammatory cells, glomerulosclerosis, proximal tubular dilation, and vacuolization in the DQ model group, while the inflammatory response was reduced in the C25-140 intervention group compared to the DQ model group. Under transmission electron microscopy, the DQ model group showed relatively high levels of mitochondrial damage, severe swelling, increased volume, matrix dissolution, ridge fracture and loss. The degree of mitochondrial damage in the C25-140 intervention group was reduced compared to the DQ model group. Compared with the normal control group, the levels of serum SCr, BUN, IL-6, IL-1β, TNF-α, and MDA in the DQ model group were significantly increased, while the serum SOD level was significantly decreased. Compared with the DQ model group, the levels of serum SCr, BUN, IL-6, IL-1β, TNF-α, and MDA in the C25-140 intervention group were significantly reduced [SCr (μmol/L): 59.07±13.11 vs. 83.61±20.13, BUN (mmol/L): 25.83±9.95 vs. 40.78±11.53, IL-6 (ng/L): 40.76±7.03 vs. 83.33±21.83, IL-1β (ng/L): 53.87±7.82 vs. 91.74±12.53, TNF-α (ng/L): 102.52±32.13 vs. 150.92±31.75, MDA (μmol/L): 3.57±1.06 vs. 5.75±1.83], and the serum SOD level was significantly increased (kU/g: 162.52±36.13 vs. 122.72±22.13), and the differences were statistically significant (all P < 0.01). Western blotting results showed that the protein expression levels of TRAF6, NF-κB, and MyD88 in the renal tissue of DQ model group mice were significantly higher than those in the normal control group. The expression levels of the above-mentioned proteins in the C25-140 intervention group of mice were significantly lower than those in the DQ model group (TRAF6/β-actin: 1.05±0.36 vs. 1.74±0.80, NF-κB/β-actin: 0.57±0.07 vs. 1.03±0.75, MyD88/β-actin: 0.58±0.07 vs. 1.03±0.33, all P < 0.05). CONCLUSIONS TRAF6 inhibitor C25-140 can alleviate AKI induced by DQ poisoning in mice by regulating the Toll-like receptor 4 (TLR4)/TRAF6/NF-κB signaling pathway and downregulating the levels of inflammatory cytokines IL-1β, IL-6, and TNF-α.
Animals ; Male ; Acute Kidney Injury/prevention & control* ; Mice ; Mice, Inbred C57BL ; Diquat ; TNF Receptor-Associated Factor 6/metabolism* ; Interleukin-6/blood* ; Kidney/pathology* ; NF-kappa B/metabolism* ; Peptide Fragments