Eukaryotic translation elongation factor 1 alpha (eEF1A) inhibits Siniperca chuatsi rhabdovirus (SCRV) infection through two distinct mechanisms.

IMPORTANCE: Although a virus can regulate many cellular responses to facilitate its replication by interacting with host proteins, the host can also restrict virus infection through these interactions. In the present study, we showed that the host eukaryotic translation elongation factor 1 alpha (eEF1A), an essential protein in the translation machinery, interacted with two proteins of a fish rhabdovirus, Siniperca chuatsi rhabdovirus (SCRV), and inhibited virus infection via two different mechanisms: (i) inhibiting the formation of crucial viral protein complexes required for virus transcription and replication and (ii) promoting the ubiquitin-proteasome degradation of viral protein. We also revealed the functional regions of eEF1A that are involved in the two processes. Such a host protein inhibiting a rhabdovirus infection in two ways is rarely reported. These findings provided new information for the interactions between host and fish rhabdovirus.

Hepatic arterial infusion therapy for advanced hepatocellular carcinoma after systemic treatment failure: Multicenter, real-world study.

AIM: The study was conducted to evaluate the feasibility and safety profile of hepatic arterial infusion chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (HAIC-FOLFOX) as an alternative therapeutic choice for patients with advanced hepatocellular carcinoma (HCC) that is refractory to systemic treatment including immune checkpoint blockades or molecular targeting agents. METHODS: Two hundred and forty five consecutive patients with advanced HCC who received HAIC-FOLFOX treatment after systemic treatment failure were retrospectively reviewed in six institutions and their survival, tumor response, and tolerance were assessed. RESULTS: The median overall survival (OS) and progression-free survival of the 209 included participants were 10.5 months (95% confidence interval [CI], 8.1-12.9) and 6.0 months (95% CI, 5.1-6.9), respectively. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, the objective response rate was 21.1%, and the disease control rate was 64.6%. Multivariate analysis of risk factors of OS were albumin-bilirubin grade (2 and 3 vs. 1, hazard ratio [HR] 1.57; 95% CI, 1.05-2.34; p = 0.028), tumor number (>3 vs. 1-3, HR 2.18; 95% CI, 1.10-4.34; p = 0.026), extrahepatic spread (present vs. absent, HR 1.61, 95% CI, 1.06-2.45; p = 0.027), synchronous systemic treatment (present vs. absent, HR 0.55, 95% CI, 0.37-0.83; p = 0.004) and treatment response (responder vs. nonresponder, HR 0.30, 95% CI, 0.17-0.53; p < 0.001). Grade 3-4 adverse events (AEs) occurred in 59 (28.2%) HCC patients. All AEs were manageable, and deaths related to hepatic artery infusion chemotherapy treatment were not observed. CONCLUSIONS: Our findings support the effectiveness and safety of HAIC-FOLFOX treatment for patients with advanced HCC who have failed systemic treatment.

Advances on genomes studies of large DNA viruses in aquaculture: A minireview.

Genomic studies of viral diseases in aquaculture have received more and more attention with the growth of the aquaculture industry, especially the emerging and re-emerging viruses whose genome could contain recombination, mutation, insertion, and so on, and may lead to more severe diseases and more widespread infections in aquaculture animals. The present review is focused on aquaculture viruses, which is belonged to two clades, Varidnaviria and Duplodnaviria, and one class Naldaviricetes, and respectively three families: Iridoviridae (ranaviruses), Alloherpesviridae (fish herpesviruses), and Nimaviridae (whispoviruses). The viruses possessed DNA genomes nearly or larger than 100 kbp with gene numbers more than 100 and were considered large DNA viruses. Genome analysis and experimental investigation have identified several genes involved in genome replication, transcription, and virus-host interactions. In addition, some genes involved in virus genetic variation or specificity were also discussed. A summary of these advances would provide reference to future discovery and research on emerging or re-emerging aquaculture viruses.

Core-shell structured hollow copper sulfide@metal-organic framework for magnetic resonance imaging guided photothermal therapy in second near-infrared biological window.

Multifunctional core-shell hybrids formed by integration of metal-organic framework (MOF) and functional materials have attracted extensive attention as promising theranostic nanoplatforms due to their combined novel properties and enhanced therapeutic efficacy. Recently, the second near-infrared (NIR-II, 1000-1700 nm) laser-induced photothermal therapy (PTT) as compared to the NIR-I(700-950 nm) laser-induced PTT has displayed improved therapeutic effects owing to its merits that include deeper tissue penetration and increased maximum permissible exposure. Herein, a novel core-shell hollow copper sulfide@metal-organic framework (HCuS@MIL-100) has been successfully fabricated by a layer-by-layer technique for the first time and their collective theranostic effects are investigated in vitro and in vivo. In this platform, the inner HCuS was applied as the NIR-II photothermal agent with excellent NIR-II absorption feature, leading to impressive photothermal effects under irradiation by 1064 nm light. With MIL-100 as the shell, HCuS@MIL-100 not only displayed optimal biocompatibility but also presented superior T2 magnetic resonance imaging (MRI) ability. In the current study multifunctional hollow core-shell HCuS@MIL-100 are fabricated for the MRI-guided PTT. This study also offers a facile and effective strategy for the development of novel theranostic platforms with high efficiency through the integration of MOFs and functional materials.

See the Unseen: Red-Emissive Carbon Dots for Visualizing the Nucleolar Structures in Two Model Animals and In Vivo Drug Toxicity.

Nucleolus, which participates in many crucial cellular activities, is an ideal target for evaluating the state of a cell or an organism. Here, bright red-emissive carbon dots (termed CPCDs) with excitation-independent/polarity-dependent fluorescence emission are synthesized by a one-step hydrothermal reaction between congo red and p-phenylenediamine. The CPCDs can achieve wash-free, real-time, long-term, and high-quality nucleolus imaging in live cells, as well as in vivo imaging of two common model animals-zebrafish and Caenorhabditis elegans (C. elegans). Strikingly, CPCDs realize the nucleolus imaging of organs/flowing blood cells in zebrafish at a cellular level for the first time, and the superb nucleolus imaging of C. elegans suggests that the germ cells in the spermatheca probably have no intact nuclei. These previously unachieved imaging results of the cells/tissues/organs may guide the zebrafish-related studies and benefit the research of C. elegans development. More importantly, a novel strategy based on CPCDs for in vivo toxicity evaluation of materials/drugs (e.g., Ag+ ), which can visualize the otherwise unseen injuries in zebrafish, is developed. In conclusion, the CPCDs represent a robust tool for visualizing the structures and dynamic behaviors of live zebrafish and C. elegans, and may find important applications in cell biology and toxicology.

Fusing a TurboID tag with the Andrias davidianus ranavirus 2L reduced virus adsorption efficiency.

Andrias davidianus ranavirus (ADRV) is a member of the genus ranavirus (family Iridoviridae). ADRV 2L is an envelope protein that could be essential in viral infection. In the present study, the function of ADRV 2L was investigated by fusion with the biotin ligase TurboID tag. A recombinant ADRV with a V5-TurboID tag fused in the N-terminal of 2L (ADRVT-2L) and a recombinant ADRV expressing V5-TurboID (ADRVT) were constructed, respectively. Infection of the recombinant viruses and wild-type ADRV (ADRVWT) in the Chinese giant salamander thymus cell line (GSTC) showed that ADRVT-2L had reduced cytopathic effect and lower virus titers than the other two viruses, indicating the fusion of a big tag affected ADRV infection. Analysis of the temporal expression profile showed that the expression of V5-TurboID-2L was delayed than wild-type 2L. However, electron microscopy found that the virion morphogenesis was not affected in ADRVT-2L-infected cells. Furthermore, the virus binding assay revealed that the adsorption efficiency of ADRVT-2L was considerably decreased compared to the other two viruses. Therefore, these data showed that linking the TurboID tag to ADRV 2L affected virus adsorption to the cell membrane, which suggested an important role of 2L in virus entry into cells.

Impacts of Diabetes Mellitus on Cardiovascular Outcomes and Differential Effects of Direct Oral Anticoagulants in Patients with Left Ventricular Thrombus.

Background: The focus of this investigation into the impact of type 2 diabetes mellitus (T2DM) on left ventricular thrombus (LVT) is (a) the differences in LVT characteristics, (b) long-term clinical outcomes, and (c) differential effects of direct oral anticoagulants (DOAC) among patients with T2DM and without diabetes. Methods: Patients with confirmed LVT from 2009 to 2021 were included. The primary endpoints were major adverse cardiac and cerebrovascular events (MACCE), composite of cardiovascular death, ischemic stroke, and acute myocardial infarction (AMI). The secondary endpoints were all-cause death and cardiovascular death. Multivariable competing-risk regression and cumulative incidence functions (CIF) were used to evaluate the adverse consequences. Results: In total, 1675 patients were assessed initially. Follow-up data were available for 91.1% of the participants. Median follow-up was 3.8 years. This retrospective study ultimately comprised 1068 participants, of which 429 had T2DM. Significantly higher proportions of comorbidities were observed in the T2DM group. The location, morphology, and size of LVT were similar in the two groups. Multivariable analysis suggested a higher risk of MACCE among patients with T2DM. The difference in risk between the two groups after matching and weighting was not statistically significant. Among the whole sample (n = 638) or the just the non-diabetic patients with LVT and anticoagulation (n = 382), the incidence of MACCE did not differ between DOAC treatment and warfarin treatment. In the diabetic LVT population with anticoagulation (n = 256), DOAC treatment was associated with a significantly higher risk of MACCE than was warfarin treatment. Conclusions: The location and morphology of LVT are similar in T2DM and non-diabetic patients. A higher risk of MACCE was found among patients with diabetes.

Time Trends of Etiology, Treatment, and Long-Term Outcomes Among Patients with Left Ventricular Thrombus.

Background: Recommendations for drug treatment of left ventricular thrombus (LVT) are based on the ST-segment elevation myocardial infarction (STEMI) guidelines; however, the etiology of LVT has changed. Due to the lack of evidence regarding LVT treatment in the heart failure population, current heart failure guidelines do not cover LVT treatment. We sought to review the etiology of LVT and changes in antithrombotic therapy over the previous 12 years and explore the impact of anticoagulation treatment from a single center's experience. Methods: From January 2009 to June 2021, we studied 1675 patients with a discharge diagnosis of LVT at a single center to investigate the clinical characteristics, incidence of all-cause death, cardiovascular death, ischemic stroke, major adverse cardiac and cerebrovascular events (MACCE), systemic embolism (SE), and major bleeding events. Patients were divided into an anticoagulant group and a non-anticoagulant group according to whether they received oral anticoagulant therapy at discharge. Results: The study included 909 patients (anticoagulation, 510; no anticoagulation, 399). While overall antiplatelet therapy dramatically decreased, more patients with LVT received oral anticoagulation in 2021 (74.0%) than in 2009 (29.6%). In addition, more than half of the patients had heart failure with reduced ejection fraction (HFrEF) each year. The all-cause mortality was 17.3% during 3.8 years of follow-up. The incidences of cardiovascular death, stroke, MACCE, SE, and major bleeding were 16.0%, 3.3%, 19.8%, 5.1%, and 1.7%, respectively. The anticoagulation group had a significantly higher proportion of dilated cardiomyopathy than the non-anticoagulation group (24.7% vs. 5.5%, p < 0.001), and a lower LVEF (34.0 vs. 41.0, p < 0.001). The anticoagulation group also had a higher probability of adverse events on long-term follow-up (p > 0.05). A multivariable competing risk regression model found no significant difference in all six endpoints between the groups (all p > 0.05). Similar results were found by matched and weighted data analysis. Diabetes mellitus (hazard ratio (HR), 1.42; 95% confidence interval (CI), 1.04-1.93; p = 0.027), renal insufficiency (HR, 2.36; 95% CI, 1.60-3.50; p < 0.001), history of previous stroke (HR, 1.60; 95% CI, 1.13-2.29; p = 0.009), and HFrEF (HR, 2.54; 95% CI, 1.78-3.64; p < 0.001) were predictors of increased risk of MACCE. Conclusions: Heart failure, rather than acute myocardial infarction, is currently the primary cause of LVT. A trend towards better prognosis in the no anticoagulation group was noted. Multivariable, matching and weighting analysis showed no improvement in prognosis with anticoagulant therapy. Our study does not negate the efficacy of anticoagulation but suggests the need to strengthen the management of anticoagulation in order to achieve better efficacy.

Retrograde percutaneous coronary intervention of chronic total occlusion via discontinuous septal channels.

OBJECTIVES: The study aims to investigate the safety and feasibility of retrograde CTO intervention via collateral connection grade 0 (CC-0) septal channel and to identify predictors of collateral tracking failure. BACKGROUND: Guidewire crossing a collateral channel is a critical step for successful retrograde percutaneous coronary intervention (PCI) of chronic total occlusion (CTO). METHODS: Retrograde PCI was attempted in 122 cases of CTO with CC-0 septal collaterals from December 2018 to May 2021. A hydrophilic polymer coating guidewire was used for crossing all intended CC-0 collaterals. A multivariable logistic regression analysis was performed to identify the predictors of guidewire tracking failure via the CC-0 collaterals. RESULTS: Successful guidewire tracking via CC-0 septal channel was achieved in 98 (80.3%) of 122 cases. The independent predictors of CC-0 septal channel guidewire tracking failure included well-developed non-septal collateral (OR: 5.297, 95% CI: 1.107-25.353, p = 0.037) and the ratio length of posterior descending artery (PDA) versus the distance of PDA ostium to cardiac apex ≤2/3 (OR: 3.970, 95% CI: 1.454-10.835, p = 0.007). Collateral perforation, target vessel perforation, and cardiac tamponade occurred in 5 (4.1%), 3 (2.5%), and 6 (4.9%) cases, respectively. There were no complications requiring emergency cardiac surgery or revascularization of nontarget vessel. CONCLUSIONS: Retrograde PCI via CC-0 septal channels with a hydrophilic polymer-coated guidewire is feasible and safe in patients with CTO. Well-developed nonseptal collaterals and short PDA length influence the procedure success and the risk of guidewire tracking failure via CC-0 septal channels.

The Effects of Sacubitril/Valsartan Compared to Olmesartan on the Blood Pressure and Glucolipid Metabolism in DM Patients with Primary Hypertension.

PURPOSE: Given the beneficial effects of sacubitril/valsartan on blood pressure generally, this study investigates its antihypertension effects in diabetes mellitus (DM) patients with primary hypertension specifically, and the effect of sacubitril/valsartan on glycolipid metabolism. METHODS: We conducted a randomized, open-label, active-controlled study to compare the antihypertension effects of sacubitril/valsartan in DM individuals with primary hypertension. The primary end point was reduction in mean systolic blood pressure (SBP) from baseline with sacubitril/valsartan vs. olmesartan at week 8. The secondary endpoints included the changes in diastolic blood pressure (DBP), daytime SBP/DBP, nighttime SBP/DBP, BP achievement (office sitting BP < 130/80 mmHg), and lipid profile. The trial was registered with chictr.org.cn (ChiCTR2200066428) on Dec 22, 2022. RESULTS: A total of 124 patients were included in the final analysis. SBP decreased to a greater extent in the sacubitril/valsartan group from baseline to 8 weeks [between-treatment difference: 3.51 mm Hg, 95% confidence interval (95% CI) 0.41 to 6.62 mm Hg, P = 0.03]. Furthermore, more patients achieved the blood pressure goal with sacubitril/valasartan (74.60% vs. 54.70%, P = 0.03). Multiple logistical regression analysis showed that sacubitril/valsartan was associated with BP achievement [odds ratio (OR) 0.33, 95% CI 0.14-0.73, P = 0.007], but the difference in SBP, DBP, day time SBP/DBP, and night time SBP/DBP reduction did not approach statistical significance. HbA1C1, total cholesterol, and low-density lipoprotein-cholesterol were lower than baseline in both groups (P < 0.05); however, there was no difference in the effects on glucose and lipid metabolism from sacubitril/valsartan compared to olmesartan. CONCLUSIONS: Sacubitril/valsartan not only provided superior BP reduction compared to olmesartan, it did so without adverse effects on glycemic control and lipid parameters in DM patients with primary hypertension.

Application of metal stent implantation with endoscope and X-ray fluoroscopy combined laparoscopic surgery in the treatment of acute left hemicolon cancer obstruction.

BACKGROUND: This study aimed to conduct a case-control study of endoscopic and fluoroscopic metal stent placement combined with laparoscopic surgery versus conventional open Hartmann's procedure in treating acute left-sided colon cancer obstruction. Additionally, the study aims to discuss the application value of endoscopic and X-ray-guided metal stent placement combined with laparoscopic surgery in the treatment of acute left-sided colon cancer obstruction. METHODS: From June 2011 to December 2019, 23 patients with acute left-sided colon cancer obstruction who underwent metal stent implantation combined with laparoscopic surgery under endoscopy and X-ray fluoroscopy in Wenzhou Central Hospital were collected, and 20 patients with acute left-sided colon cancer obstruction who underwent traditional emergency open Hartmann's surgery during the same period were selected as a control group. All patients were diagnosed with left colon obstruction by plain abdominal film and/or CT before the operation and colon adenocarcinoma by colonoscopic biopsy and/or postoperative pathology. The operation time, intraoperative blood loss, postoperative anal exhaust time, the success rate of one-stage anastomosis, postoperative hospital stay, and postoperative complications were compared between the two groups. RESULTS: This study showed a significant difference in the therapeutic effect between the two groups. Compared with the traditional Hartmann's operation group, the success rate of one-stage anastomosis in endoscopic and X-ray-guided metal stent placement combined with the laparoscopic operation group was significantly higher than that in the Hartmann's operation group (P < 0.05). The overall incidence of postoperative complications and hospital stay were significantly lower in the observation group than in the Hartmann's group (P < 0.05). Further subgroup analysis of the overall postoperative complication rate of the two groups showed that the traditional Hartmann's operation group was more likely to have an incomplete intestinal obstruction (P < 0.05). This study also showed no significant differences between the two groups in operation time, intraoperative blood loss, number of harvested lymph nodes, and postoperative anal exhaust time (all P > 0.05). This study also found no significant differences between the two groups in overall survival rates or recurrence-free survival rates (all P > 0.05). CONCLUSIONS: The comparison of the therapeutic effects of the two groups verified the feasibility of endoscopy combined with X-ray fluoroscopy metal stent placement in combination with laparoscopic surgery in the treatment of acute left-sided colon cancer obstruction. Compared with the traditional emergency open Hartmann's procedure, metal stent implantation under endoscopy and X-ray fluoroscopy combined with laparoscopic surgery is more minimally invasive, safe, and effective. It avoids the traditional second or even third surgical trauma to effectively improve the quality of life of patients, so that patients can recover quickly after surgery.

WITHDRAWN: Novel subgroups of patients with left ventricular thrombus and their differential effects with anticoagulation: a data-driven cluster analysis.

UNSTRUCTURED: Ahead of Print article withdrawn by the publisher.

Recent Advances in Imaging Agents Anchored with pH (Low) Insertion Peptides for Cancer Theranostics.

The acidic extracellular microenvironment has become an effective target for diagnosing and treating tumors. A pH (low) insertion peptide (pHLIP) is a kind of peptide that can spontaneously fold into a transmembrane helix in an acidic microenvironment, and then insert into and cross the cell membrane for material transfer. The characteristics of the acidic tumor microenvironment provide a new method for pH-targeted molecular imaging and tumor-targeted therapy. As research has increased, the role of pHLIP as an imaging agent carrier in the field of tumor theranostics has become increasingly prominent. In this paper, we describe the current applications of pHLIP-anchored imaging agents for tumor diagnosis and treatment in terms of different molecular imaging methods, including magnetic resonance T1 imaging, magnetic resonance T2 imaging, SPECT/PET, fluorescence imaging, and photoacoustic imaging. Additionally, we discuss relevant challenges and future development prospects.

SNCA inhibits epithelial-mesenchymal transition and correlates to favorable prognosis of breast cancer.

Alpha-synuclein (SNCA) is a pathological hallmark of Parkinson's disease, known to be involved in cancer occurrence and development; however, its specific effects in breast cancer remain unknown. Data from 150 patients with breast cancer were retrieved from tissue microarray and analyzed for SNCA protein level using immunohistochemistry. Functional enrichment analysis was performed to investigate the potential role of SNCA in breast cancer. SNCA-mediated inhibition of epithelial-mesenchymal transition (EMT) was confirmed with western blotting. The effects of SNCA on invasion and migration were evaluated using transwell and wound-healing experiments. Furthermore, the potential influence of SNCA expression level on drug sensitivity and tumor infiltration by immune cells was analyzed using the public databases. SNCA is lowly expressed in breast cancer tissues. Besides, in vitro and in vivo experiments, SNCA overexpression blocked EMT and metastasis, and the knockdown of SNCA resulted in the opposite effect. A mouse model of metastasis verified the restriction of metastatic ability in vivo. Further analysis revealed that SNCA enhances sensitivity to commonly used anti-breast tumor drugs and immune cell infiltration. SNCA blocks EMT and metastasis in breast cancer and its expression levels could be useful in predicting the chemosensitivity and evaluating the immune microenvironment in breast cancer.

In Situ Hypoxia-Induced Supramolecular Perylene Diimide Radical Anions in Tumors for Photothermal Therapy with Improved Specificity.

Considering that hypoxia is closely associated with tumor proliferation, invasion, metastasis, and drug resistance, it is of great significance to overcome hypoxia in tumor treatment. Herein, we report a hypoxia-induced specific photothermal therapy (PTT) based on the photothermal agent of supramolecular perylene diimide radical anions. Hypoxic regions in various tumors display strong reductive ability, and in such environments the supramolecular complex of a perylene diimide derivative and cucurbit[7]uril could be reduced to supramolecular perylene diimide radical anions. Benefiting from the strong NIR absorption and good photothermal conversion performance of the in situ generated supramolecular perylene diimide radical anions, the hypoxia-induced PTT strategy exhibits excellent photothermal therapeutic efficiency as well as good specificity and biological safety. Moreover, hypoxia inducible factor expression of tumors decreases to the normal level after PTT treatment. It is anticipated that such a hypoxia-induced specific PTT strategy opens new horizons for photothermal therapy against hypoxic tumors with improved specificity and safety.

Distribution and density of tertiary lymphoid structures predict clinical outcome in intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: The prognostic value and clinical relevance of tertiary lymphoid structures (TLSs) in intrahepatic cholangiocarcinoma (iCCA) remain unclear. Thus, we aimed to investigate the prognostic value and functional involvement of TLSs in iCCA. METHODS: We retrospectively included 962 patients from 3 cancer centers across China. The TLSs at different anatomic subregions were quantified and correlated with overall survival (OS) by Cox regression and Kaplan-Meier analyses. Multiplex immunohistochemistry (mIHC) was applied to characterize the composition of TLSs in 39 iCCA samples. RESULTS: A quaternary TLS scoring system was established for the intra-tumor region (T score) and peri-tumor region (P score) respectively. T scores positively correlated with favorable prognosis (p <0.001), whereas a high P score signified worse survival (p <0.001). mIHC demonstrated that both T follicular helper and regulatory T cells were significantly increased in intra-tumoral TLSs compared to peri-tumoral counterparts (p <0.05), and regulatory T cell frequencies within intra-tumoral TLSs were positively associated with P score (p <0.05) rather than T score. Collectively, the combination of T and P scores stratified iCCAs into 4 immune classes with distinct prognoses (p <0.001) that differed in the abundance and distribution pattern of TLSs. Patients displaying an immune-active pattern had the lowest risk, with 5-year OS rates of 68.8%, whereas only 3.4% of patients with an immune-excluded pattern survived at 5 years (p <0.001). The C-index of the immune class was statistically higher than the TNM staging system (0.73 vs. 0.63, p <0.001). These results were validated in an internal and 2 external cohorts. CONCLUSIONS: The spatial distribution and abundance of TLSs significantly correlated with prognosis and provided a useful immune classification for iCCA. T follicular helper and regulatory T cells may play a critical role in determining the functional orientation of spatially different TLSs. LAY SUMMARY: Tertiary lymphoid structures (TLSs) are associated with favorable prognosis in a number of cancers. However, their role in intrahepatic cholangiocarcinoma (iCCA) remains unclear. Herein, we comprehensively evaluated the spatial distribution, abundance, and cellular composition of TLSs in iCCA, and revealed the opposite prognostic impacts of TLSs located within or outside the tumor. This difference could be mediated by the different immune cell subsets present within the spatially distinct TLSs. Based on our analysis, we were able to stratify iCCAs into 4 immune subclasses associated with varying prognoses.

Synergistic effect of the commonest residual risk factors, remnant cholesterol, lipoprotein(a), and inflammation, on prognosis of statin-treated patients with chronic coronary syndrome.

BACKGROUND: Currently, remnant cholesterol (RC), lipoprotein(a) [Lp(a)], and inflammation are considered the principal residual cardiovascular risk (RCVR) factors. This study sought to evaluate the combined impact of RC, Lp(a), and inflammation on prognosis of statin-treated patients with chronic coronary syndrome (CCS), which has not been investigated. METHODS: A total of 6839 patients with CCS were consecutively enrolled. Baseline RC, Lp(a), and high-sensitivity C-reactive protein (hsCRP) concentrations were measured and their medians were used for categorizations. All patients were followed for the major adverse cardiovascular events (MACEs), including cardiovascular death, non-fatal myocardial infarction, and stroke. The individual and combined effects of RC, Lp(a), and hsCRP on MACEs were examined and stratification analysis according to low-density lipoprotein cholesterol (LDL-C) was performed. RESULTS: Over an average of 54.93 ± 18.59 months follow-up, 462 MACEs were recorded. Multivariate Cox analysis showed that elevated RC and Lp(a) levels were significantly associated with an increased risk of MACEs, while high hsCRP levels were related to a slightly but non-significantly increased MACEs risk. Moreover, when participants were subgrouped according to RC, Lp(a), and hsCRP levels together, only High RC-High Lp(a)-High hsCRP group had significantly higher risk of MACEs [hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.15-3.47] compared with the reference group (Low RC-Low Lp(a)-Low hsCRP), especially in patients with LDL-C < 2.6 mmol/L. CONCLUSIONS: The combination of elevated levels of RC, Lp(a), and hsCRP potentiated the adverse effect on MACEs among statin-treated patients with CCS, suggesting that multiple RCVR factors assessment may be a better strategy to improve stratification in very-high risk population.

Effect of Thin-Walled Radial Sheath for Large-Bore Access On Reducing Periprocedural Radial Artery Occlusion Following Complex PCI: The REDUCE-RAO Randomized Trial.

Background: Transradial artery (TRA) access for percutaneous coronary intervention (PCI) was associated with lower risks of major bleeding and vascular complications compared to transfemoral artery access. Use of large-bore ( ≥ 7-Fr) guiding catheters through TRA approach increased the likelihood of radial artery occlusion (RAO). This study aimed to investigate whether use of the thin-walled 7-Fr Glidesheath Slender, allowing PCI with large-caliber guiding catheters, is superior to standard 7-Fr Cordis sheath with respect to periprocedural RAO within 24 hours after transradial coronary intervention (TRI) in complex lesions. Methods: A prospective randomized, controlled, single-blinded (patient-blinded) trial was conducted, randomizing 504 patients with TRI for complex lesions to either 7-Fr Glidesheath Slender or conventional 7-Fr Cordis sheath. The primary outcome was defined as the incidence of periprocedural RAO with Doppler ultrasound during the first 24 hours after TRI. Results: The incidence of early RAO was 10.3% for 7-Fr Glidesheath Slender and 13.5% for conventional 7-Fr sheath (p = 0.271). The procedural success rate for Glidesheath Slender was 92.9% and for Cordis sheath was 93.7% (p = 0.722). There was no signficiant difference between treatment arms in terms of local hematoma and radial spasm, whereas use of the Glidesheath Slender was associated with significantly less pain during the procedure (numeric rating scale [NRS], 2.27 ± 0.75 vs. 2.45 ± 0.95, p = 0.017). The assessment of radial artery in ultrasound parameters after complex TRI was improved with Glidesheath Slender. Conclusions: Among patients with complex coronary lesions undergoing TRI, 7-Fr Glidesheath Slender was not superior to conventional 7-Fr in the prevention of periprocedural RAO within 24 hours following complex PCI, without reducing RAO occurrence. Clinical Trial Registration: NCT04748068.

Establishing the optimal duration of DAPT following PCI in high-risk TWILIGHT-like patients with acute coronary syndrome.

OBJECTIVES: To determine the association of extended-term (>12-month) versus short-term dual antiplatelet therapy (DAPT) with ischemic and hemorrhagic events in high-risk "TWILIGHT-like" patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) in clinical practice. BACKGROUND: Recent emphasis on shorter DAPT regimen after PCI irrespective of indication for PCI may fail to account for the substantial residual risk of recurrent atherothrombotic events in ACS patients. METHODS: All consecutive patients fulfilling the "TWILIGHT-like" criteria undergoing PCI were identified from the prospective Fuwai PCI Registry. High-risk patients (n = 8,358) were defined by at least one clinical and one angiographic feature based on TWILIGHT trial selection criteria. The primary ischemic endpoint was major adverse cardiac and cerebrovascular events at 30 months, composed of all-cause mortality, myocardial infarction, or stroke while BARC type 2, 3, or 5 bleeding was key secondary outcome. RESULTS: Of 4,875 high-risk ACS patients who remained event-free at 12 months after PCI, DAPT>12-month compared with shorter DAPT reduced the primary ischemic endpoint by 63% (1.5 vs. 3.8%; HRadj: 0.374, 95% CI: 0.256-0.548; HRmatched: 0.361, 95% CI: 0.221-0.590). The HR for cardiovascular death was 0.049 (0.007-0.362) and that for MI 0.45 (0.153-1.320) and definite/probable stent thrombosis 0.296 (0.080-1.095) in propensity-matched analyses. Rates of BARC type 2, 3, or 5 bleeding (0.9 vs. 1.3%; HRadj: 0.668 [0.379-1.178]; HRmatched: 0.721 [0.369-1.410]) did not differ significantly between two groups. CONCLUSIONS: Among high-risk ACS patients undergoing PCI, long-term DAPT, compared with shorter DAPT, reduced ischemic events without a concomitant increase in clinically meaning bleeding events, suggesting that prolonged DAPT can be considered in ACS patients who present with a particularly higher risk for thrombotic complications without excessive risk of bleeding.

Thrombotic vs. Bleeding Events of Interruption of Dual Antiplatelet Therapy within 12 Months among Patients with Stent-Driven High Ischemic Risk Definition following PCI.

BACKGROUND: There is a paucity of real-world data regarding the clinical impact of dual antiplatelet therapy (DAPT) interruption (temporary or permanent) among patients at high ischemic risk. The aim of this study was to assess the risk of cardiovascular events after interruption of DAPT in high-risk PCI population. METHODS: This study used data from the Fuwai PCI registry, a large, prospective cohort of consecutive patients who underwent PCI. We assessed 3,931 patients with at least 1 high ischemic risk criteria of stent-related recurrent ischemic events proposed in the 2017 ESC guidelines for focused update on DAPT who were free of major cardiac events in the first 12 months. The primary ischemic endpoint was 30-month major adverse cardiac and cerebrovascular events, and the key safety endpoints were BARC class 2, 3, or 5 bleeding and net adverse clinical events. RESULTS: DAPT interruption within 12 months occurred in 1,122 patients (28.5%), most of which were due to bleeding events or patients' noncompliance to treatment. A multivariate Cox regression model, propensity score (PS) matching, and inverse probability of treatment weighting (IPTW) based on the propensity score demonstrated that DAPT interruption significantly increased the risk of primary ischemic endpoint compared with prolonged DAPT (3.9% vs. 2.2%; Cox-adjusted hazard ratio (HR): 1.840; 95% confidence interval (CI): 1.247 to 2.716; PS matching-HR: 2.049 [1.236-3.399]; IPTW-adjusted HR: 1.843 [1.250-2.717]). This difference was driven mainly by all-cause death (1.8% vs. 0.7%) and MI (1.3% vs. 0.5%). Furthermore, the rate of net adverse clinical events (4.9% vs. 3.2%; Cox-adjusted HR: 1.581 [1.128-2.216]; PS matching-HR: 1.639 [1.075-2.499]; IPTW-adjusted HR: 1.554 [1.110-2.177]) was also higher in patients with DAPT interruption (≤12 months), whereas no significant differences between groups were observed in terms of BARC 2, 3, or 5 bleeding. These findings were consistent across various stent-driven high-ischemic risk subsets with respect to the primary ischemic endpoints, with a greater magnitude of harm among patients with diffuse multivessel diabetic coronary artery disease. CONCLUSIONS: In patients undergoing high-risk PCI, interruption of DAPT in the first 12 months occurred infrequently and was associated with a significantly higher adjusted risk of major adverse cardiovascular events and net adverse clinical events. 2017 ESC stent-driven high ischemic risk criteria may help clinicians to discriminate patient selection in the use of long-term DAPT when the ischemic risk certainly overcomes the bleeding one.