Intravascular Ultrasound vs Angiography-Guided Drug-Coated Balloon Angioplasty: The ULTIMATE â ¢ Trial.

BACKGROUND: Drug-coated balloon (DCB) angioplasty seems a safe and effective option for specific de novo coronary lesions. However, the beneficial effect of intravascular ultrasound (IVUS)-guided DCB angioplasty in de novo lesions remains uncertain. OBJECTIVES: This study aimed to assess the benefits of IVUS guidance over angiography guidance during DCB angioplasty in de novo coronary lesions. METHODS: A total of 260 patients with high bleeding risk who had a de novo coronary lesion (reference vessel diameter 2.0-4.0 mm, and lesion length ≤15 mm) were randomly assigned to either an IVUS-guided or an angioplasty-guided DCB angioplasty group. The primary endpoint was in-segment late lumen loss (LLL) at 7 months after procedure. The secondary endpoint was target vessel failure at 6 months. RESULTS: A total of 2 patients in the angiography-guided group and 7 patients in the IVUS-guided group underwent bailout stent implantation (P = 0.172). The primary endpoint of 7-month LLL was 0.03 ± 0.52 mm with angiography guidance vs -0.10 ± 0.34 mm with IVUS guidance (mean difference 0.14 mm; 95% CI: 0.02-0.26; P = 0.025). IVUS guidance was also associated with a larger 7-month minimal lumen diameter (2.06 ± 0.62 mm vs 1.75 ± 0.63 mm; P < 0.001) and a smaller diameter stenosis (28.15% ± 13.88% vs 35.83% ± 17.69%; P = 0.001) compared with angiography guidance. Five target vessel failures occurred at 6 months, with 4 (3.1%) in the angiography-guided group and 1 (0.8%) in the IVUS-guided group (P = 0.370). CONCLUSIONS: This study demonstrated that IVUS-guided DCB angioplasty is associated with a lower LLL in patients with a de novo coronary lesion compared with angiography guidance. (Intravascular Ultrasound Versus Angiography Guided Drug-Coated Balloon [ULTIMATE-III]; NCT04255043).

Pathological Mechanism and Treatment of Calcified Aortic Stenosis.

Calcified aortic stenosis (AS) is one of the most common valvular heart diseases worldwide, characterized by progressive fibrocalcific remodeling and thickening of the leaflets, which ultimately leads to obstruction of blood flow. Its pathobiology is an active and complicated process, involving endothelial cell dysfunction, lipoprotein deposition and oxidation, chronic inflammation, phenotypic transformation of valve interstitial cells, neovascularization, and intravalvular hemorrhage. To date, no targeted drug has been proven to slow down or prevent disease progression. Aortic valve replacement is still the optimal treatment of AS. This article reviews the etiology, diagnosis, and management of calcified aortic stenosis and proposes novel potential therapeutic targets.

Transfemoral transcatheter aortic valve replacement with VitaFlowTM valve for pure native aortic regurgitation in patients with high surgical risk: Rationale and design of a prospective, multicenter, and randomized SEASON-AR trial.

BACKGROUND: Previous studies primarily demonstrated that transfemoral transcatheter aortic valve replacement (TAVR) with self-expanding valve appeared to be a safe and feasible treatment for patients with pure native aortic regurgitation (AR). However, the routine application of transfemoral TAVR for pure AR patients lacks support from randomized trials. TRIAL DESIGN: SEASON-AR trial is a prospective, multicenter, randomized, controlled, parallel-group, open-label trial, involving at least 20 sites in China, aiming to enroll 210 patients with pure native severe AR and high surgical risk. All enrolled patients are randomly assigned in a 1:1 fashion to undergo transfemoral TAVR with VitaFlowTM valve and receive guideline-directed medical therapy (GDMT) or to receive GDMT alone. The primary endpoint is the rate of major adverse cardiac events (MACE) at 12 months after the procedure, defined by the composite of all-cause mortality, disabling stroke, and rehospitalization for heart failure. The major secondary endpoints encompass various measures, including procedure-related complications, device success, 6-minute walk distance, and the occurrence of each individual component of the primary endpoint. After hospital discharge, follow-up was conducted through clinical visits or telephone contact at 1, 6, and 12 months. The follow-up will continue annually until 5 years after the index procedure to assess the long-term outcomes. CONCLUSION: SEASON-AR trial is the first study designed to investigate the clinical efficacy and safety of transfemoral TAVR with a self-expanding valve in patients with pure native severe AR with inoperable or high-risk, as compared to medical treatment only.

Mapping visual working memory models to a theoretical framework.

The body of research on visual working memory (VWM)-the system often described as a limited memory store of visual information in service of ongoing tasks-is growing rapidly. The discovery of numerous related phenomena, and the many subtly different definitions of working memory, signify a challenge to maintain a coherent theoretical framework to discuss concepts, compare models and design studies. A lack of robust theory development has been a noteworthy concern in the psychological sciences, thought to be a precursor to the reproducibility crisis (Oberauer & Lewandowsky, Psychonomic Bulletin & Review, 26, 1596-1618, 2019). I review the theoretical landscape of the VWM field by examining two prominent debates-whether VWM is object-based or feature-based, and whether discrete-slots or variable-precision best describe VWM limits. I share my concerns about the dualistic nature of these debates and the lack of clear model specification that prevents fully determined empirical tests. In hopes of promoting theory development, I provide a working theory map by using the broadly encompassing memory for latent representations model (Hedayati et al., Nature Human Behaviour, 6, 5, 2022) as a scaffold for relevant phenomena and current theories. I illustrate how opposing viewpoints can be brought into accordance, situating leading models of VWM to better identify their differences and improve their comparison. The hope is that the theory map will help VWM researchers get on the same page-clarifying hidden intuitions and aligning varying definitions-and become a useful device for meaningful discussions, development of models, and definitive empirical tests of theories.

Vascular Smooth Muscle Cells Phenotypic Switching in Cardiovascular Diseases.

Vascular smooth muscle cells (VSMCs), the major cell type in the arterial vessel wall, have a contractile phenotype that maintains the normal vessel structure and function under physiological conditions. In response to stress or vascular injury, contractile VSMCs can switch to a less differentiated state (synthetic phenotype) to acquire the proliferative, migratory, and synthetic capabilities for tissue reparation. Imbalances in VSMCs phenotypic switching can result in a variety of cardiovascular diseases, including atherosclerosis, in-stent restenosis, aortic aneurysms, and vascular calcification. It is very important to identify the molecular mechanisms regulating VSMCs phenotypic switching to prevent and treat cardiovascular diseases with high morbidity and mortality. However, the key molecular mechanisms and signaling pathways participating in VSMCs phenotypic switching have still not been fully elucidated despite long-term efforts by cardiovascular researchers. In this review, we provide an updated summary of the recent studies and systematic knowledge of VSMCs phenotypic switching in atherosclerosis, in-stent restenosis, aortic aneurysms, and vascular calcification, which may help guide future research and provide novel insights into the prevention and treatment of related diseases.

The interaction effect of grip strength and lung function (especially FVC) on cardiovascular diseases: a prospective cohort study in Jiangsu Province, China.

OBJECTIVE: Lung function and grip strength (GS) are associated with cardiovascular disease (CVD), but whether these risk factors interact to affect CVD is unknown. This study aimed to explore the interactions between lung function and GS with major CVD (defined as fatal/non-fatal myocardial infarction, stroke, and heart failure) incidence. METHODS: We conducted a prospective cohort study on the Chinese population in Jiangsu Province. Cox proportional hazards models were used to explore the associations between GS, lung function, and major CVD incidence. RESULTS: A total of 5967 participants were included in our study; among them, 182 participants developed major CVD. Participants with low forced vital capacity (FVC) had a higher risk of major CVD (hazard ratio (HR) = 1.45; 95% confidence interval (CI): 1.05-2.01; P < 0.05) compared with normal FVC. The risk of major CVD incidence (HR = 0.54; 95% CI: 0.35-0.83; P < 0.01) was significantly lower in participants with high GS than in individuals with low GS. The interaction between FVC and GS for major CVD incidence (P = 0.006) was statistically significant. Compared with normal FVC participants with high GS, low FVC participants with low GS had the highest risk of major CVD incidence (HR = 2.50; 95% CI: 1.43-4.36; P < 0.01). CONCLUSION: Among people with low FVC, the risk of major CVD is lower with high GS. Participants with low FVC and low GS have the highest risk of major CVD. Therefore, more attention should be paid to the incidence of major CVD in individuals with low FVC, especially those who have lower GS.

Alkali metal-modified crystalline carbon nitride for photocatalytic nitrogen fixation.

Alkali metal chlorides have been used as molten salts for further preparing crystalline carbon nitride, but the effect of alkali metal types on the properties of crystalline carbon nitride has not been systematically studied. Therefore, in this paper, a series of crystalline carbon nitride samples doped with different alkali metals were successfully prepared using LiCl-KCl, KCl-NaCl, LiCl-KCl-NaCl and LiCl-NaCl as molten salts: LK-HTCN (Li-K co-doping), KN-HCN (K-Na co-doping), LKN-HTCN (Li-K-Na co-doping) and LN-HTCN (Li-Na co-doping). The experimental results show that KN-HCN contains only the heptazine unit structure, while the other samples contain heptazine and triazine unit structures. Meanwhile, the concentration of the cyano group in the KN-HCN sample structure is significantly higher than that of other samples, which may be related to the fact that there is only a heptazine unit in the structure of the KN-HCN sample. In addition, the loading mode of K and Na ions in the KN-HCN structure is favorable for the migration and separation of photogenerated charges. Thanks to these characteristics, KN-HCN showed excellent photocatalytic ammonia production activity. This study can provide theoretical insight for the development of crystallized carbon nitride.

DPP4 as a Potential Candidate in Cardiovascular Disease.

The rising prevalence of cardiovascular disease has become a global health concern. The occurrence of cardiovascular disease is the result of long-term interaction of many risk factors, one of which is diabetes. As a novel anti-diabetic drug, DPP4 inhibitor has been proven to be cardiovascular safe in five recently completed cardiovascular outcome trials. Accumulating studies suggest that DPP4 inhibitor has potential benefits in a variety of cardiovascular diseases, including hypertension, calcified aortic valve disease, coronary atherosclerosis, and heart failure. On the one hand, in addition to improving blood glucose control, DPP4 inhibitor is involved in controlling cardiovascular risk factors. On the other hand, DPP4 inhibitor directly regulates the occurrence and progression of cardiovascular diseases through a variety of mechanisms. In this review, we summarize the recent advances of DPP4 in cardiovascular disease, aiming to discuss DPP4 inhibitor as a potential option for cardiovascular therapy.

Which evaluation criteria of the short-term efficacy can better reflect the long-term outcomes for patients with nasopharyngeal carcinoma?

PURPOSE: To compare the consistency of one-dimensional Response Evaluation Criteria in Solid Tumors (1D-RECIST), two-dimensional WHO criteria (2D-WHO), and three-dimensional (3D) measurement for therapeutic response assessment of nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Retrospective data of 288 newly diagnosed NPC patients were reviewed. Tumor size was assessed on magnetic resonance imaging (MRI) according to the 1D-RECIST, 2D-WHO, and 3D measurement criteria. Agreement between tumor responses was assessed using unweighted k statistics. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off point of the PTV. The Kaplan-Meier method and Cox regression were used for the survival analysis. RESULTS: The optimal cut-off point of the PTV for progression-free survival (PFS) was 29.6%. Agreement with PTV measurement was better for 1D measurement than for 2D and 3D measurements (kappa values of 0.646, 0.537, and 0.577 for 1D, 2D, and 3D measurements, respectively; P < 0.05). The area under the curve of the 1D measurement (AUC=0.596) was similar to that of the PTV measurement (AUC=0.621). Compared with 2D and 3D measurements, 1D measurement is superior for predicting prognosis in NPC (C-index of 0.672, 0.663, and 0.646 were for 1D, 2D, and 3D measurements, respectively; P < 0.005). Survival analysis showed that patients with non-responders had worse prognosis (P < 0.05). CONCLUSIONS: The 1D measurement more closely agreed with the PTV measurement than the 2D and 3D measurements for predicting therapeutic responses in NPC. Therefore, we recommend using the less time-consuming 1D-RECIST criteria in routine clinical practice.

Rationale and design for comparison of non-compliant balloon with drug-coating balloon angioplasty for side branch after provisional stenting for patients with true coronary bifurcation lesions: a prospective, multicentre and randomised DCB-BIF trial.

INTRODUCTION: Provisional stenting using drug-eluting stent is effective for simple coronary bifurcation lesions. Kissing balloon inflation using conventional non-compliant balloon is the primary treatment of side branch (SB) after main vessel (MV) stenting. Drug-coating balloon (DCB) is reported to be associated with less frequent clinical events in in-stent restenosis and small vessel disease. The importance of DCB in bifurcation treatment is understudied. Accordingly, this trial is designed to investigate the superiority of DCB to non-compliant balloon angioplasty for SB after provisional stenting in patients with true coronary bifurcation lesions. METHODS AND ANALYSIS: The DCB-BIF trial is a prospective, multicentre, randomised, superiority trial including 784 patients with true coronary bifurcation lesions. Patients will be randomised in a 1:1 fashion to receive either DCB or non-compliant balloon angioplasty if SB diameter stenosis >70% after MV stenting. The primary endpoint is the composite of major adverse cardiac event at the 1-year follow-up, including cardiac death, myocardial infarction (MI) or clinically driven target lesion revascularisation. The major secondary endpoints include all-cause death, periprocedural MI, spontaneous MI, clinically driven target vessel revascularisation, in-stent restenosis, stroke and individual component of the primary endpoint. The safety endpoint is the risk of stent thrombosis. ETHICS AND DISSEMINATION: The study protocol and informed consent have been reviewed and approved by the Institutional Review Board of all participating centres. The written informed consent for participation in the trial will be obtained from all participants. The results of this study will be published in a peer-reviewed journal and disseminated at conferences. TRIAL REGISTRATION NUMBER: NCT04242134.

Effect of microRNA-221 targeting tissue inhibitor of metalloproteinase-2 to mediate Akt / mTOR signaling pathway on non-small cell lung cancer transplanted tumor mouse model / 解剖学报

Objective To explore the effects of miR-221 on tumor cell proliferation, migration and invasion in nonsmall cell lung cancer (NSCLC) xenograft model mice, and to preliminarily analyze its possible mechanism of regulating Akt/ mammalian target of rapamycin(mTOR) signaling pathway by targeting tissue inhibitor of metalloproteinase-2 (TIMP-2) on tumor cells in non-small cell lung cancer (NSCLC) through tumor-bearing nude mice. Methods The A549 cells were divided into control group, mimic group, TIMP-2 group and mimic+TIMP-2 group. The mimic group and TIMP-2 group were transfected with miR-221 mimic and TIMP-2 overexpression plasmids, respectively. The mimic + TIMP-2 group was simultaneously transfected with miR-221 mimic and TIMP-2 overexpression plasmids. The control group was transfected with the same amount of negative control plasmid. After transfection, the cells of each group were injected subcutaneously into the left forelimb to construct the corresponding 4 groups of NSCLC mouse models. The proliferation-related protein (Ki67) was detected by immunohistochemical staining to detected the effect of cell proliferation ability. Matrix metalloproteinase-2 (MMP-2) and N-cadherin proteins in each group were tested by Western blotting to assess and compare the abilities of migration and invasion. The levels of miR-221, TIMP-2 and Akt/ mTOR pathways in bone marrow and tumor tissues were detected by Real-time PCR and Western blotting. Results When co-transfected with wild type(WT)-TIMP-2 and miR-221 mimic, the relative luciferase activity in the cells reduced significantly (P<0. 05). Compared with the control group, the tumor mass, volume, Ki67, MMP-2 and N-cadherin protein expression levels, miR-221 and Akt/ mTOR pathway levels were increased significantly, while the levels of TIMP-2 mRNA and protein were significantly reduced in the mimic group (P<0. 05). Compared with the control group, the levels of TIMP-2 mRNA and protein in the TIMP-2 group increased significantly, while the other indicators decreased significantly (P<0. 05). Tumor tissue mass, volume, Ki67, MMP-2, Ncadherin, miR-221 and Akt/ mTOR pathway levels in mimic+TIMP-2 group were significantly lower than those in the mimic group and significantly higher than those in the TIMP-2 group, while TIMP-2 mRNA and protein levels were significantly higher than those in the mimic group and significantly lower than those in the TIMP-2 group (P<0. 05). Conclusion In the NSCLC transplanted tumor mouse model, miR-221 may mediate the Akt/ mTOR pathway by targeting the expression of TIMP-2 protein to promote cell proliferation, migration and invasion.

Single-Cell RNA Sequencing of the Rat Carotid Arteries Uncovers Potential Cellular Targets of Neointimal Hyperplasia.

Aims: In-stent restenosis (ISR) remains an Achilles heel of drug-eluting stents despite technical advances in devices and procedural techniques. Neointimal hyperplasia (NIH) is the most important pathophysiological process of ISR. The present study mapped normal arteries and stenotic arteries to uncover potential cellular targets of neointimal hyperplasia. Methods and Results: By comparing the left (control) and right (balloon injury) carotid arteries of rats, we mapped 11 clusters in normal arteries and 11 mutual clusters in both the control and experimental groups. Different clusters were categorized into 6 cell types, including vascular smooth muscle cells (VSMCs), fibroblasts, endothelial cells (ECs), macrophages, unknown cells and others. An abnormal cell type expressing both VSMC and fibroblast markers at the same time was termed a transitional cell via pseudotime analysis. Due to the high proportion of VSMCs, we divided them into 6 clusters and analyzed their relationship with VSMC phenotype switching. Moreover, N-myristoyltransferase 1 (NMT1) was verified as a credible VSMC synthetic phenotype marker. Finally, we proposed several novel target genes by disease susceptibility gene analysis, such as Cyp7a1 and Cdk4, which should be validated in future studies. Conclusion: Maps of the heterogeneous cellular landscape in the carotid artery were defined by single-cell RNA sequencing and revealed several cell types with their internal relations in the ISR model. This study highlights the crucial role of VSMC phenotype switching in the progression of neointimal hyperplasia and provides clues regarding the underlying mechanism of NIH.

Xanthohumol Induces ROS through NADPH Oxidase, Causes Cell Cycle Arrest and Apoptosis.

Reactive oxygen species (ROS) are either toxic in excess or essential for redox signalling at the physiological level, which is closely related to the site of generation. Xanthohumol (XN) is an important natural product of hops (Humulus lupulus L.) and was reported to induce ROS in mitochondria. While in the present study, our data indicate that NADPH oxidase (NOX) is another site. In human acute myeloid leukemia HL-60 cells, we first identified that cell proliferation was inhibited by XN without affecting viability, and this could be alleviated by the antioxidant N-acetyl-L-cysteine (NAC); cell cycles were blocked at G1 phase, apoptosis was induced in a dose-dependent manner, and malondialdehyde (MDA) content was upregulated. XN-induced ROS generation was detected by flow cytometry, which can be inhibited by diphenyleneiodonium chloride (DPI, a NOX inhibitor), while not by NG-methyl-L-arginine acetate (L-NMMA, a nitric oxide synthase inhibitor). The involvement of NOX in XN-induced ROS generation was further evaluated: immunofluorescence assay indicated subunits assembled in the membrane, and gp91phox knockdown with siRNA decreased XN-induced ROS. Human red blood cells (with NOX, without mitochondria) were further selected as a cell model, and the XN-induced ROS and DPI inhibiting effects were found again. In conclusion, our results indicate that XN exhibits antiproliferation effects through ROS-related mechanisms, and NOX is a source of XN-induced ROS. As NOX-sourced ROS are critical for phagocytosis, our findings may contribute to the anti-infection and anti-inflammatory effect of XN.

Dog10K_Boxer_Tasha_1.0: A Long-Read Assembly of the Dog Reference Genome.

The domestic dog has evolved to be an important biomedical model for studies regarding the genetic basis of disease, morphology and behavior. Genetic studies in the dog have relied on a draft reference genome of a purebred female boxer dog named "Tasha" initially published in 2005. Derived from a Sanger whole genome shotgun sequencing approach coupled with limited clone-based sequencing, the initial assembly and subsequent updates have served as the predominant resource for canine genetics for 15 years. While the initial assembly produced a good-quality draft, as with all assemblies produced at the time, it contained gaps, assembly errors and missing sequences, particularly in GC-rich regions, which are found at many promoters and in the first exons of protein-coding genes. Here, we present Dog10K_Boxer_Tasha_1.0, an improved chromosome-level highly contiguous genome assembly of Tasha created with long-read technologies that increases sequence contiguity >100-fold, closes >23,000 gaps of the CanFam3.1 reference assembly and improves gene annotation by identifying >1200 new protein-coding transcripts. The assembly and annotation are available at NCBI under the accession GCF_000002285.5.

Plasma Small Extracellular Vesicle-Carried miRNA-501-5p Promotes Vascular Smooth Muscle Cell Phenotypic Modulation-Mediated In-Stent Restenosis.

Vascular smooth muscle cell (VSMC) phenotypic modulation plays an important role in the occurrence and development of in-stent restenosis (ISR), the underlying mechanism of which remains a key issue needing to be urgently addressed. This study is designed to investigate the role of plasma small extracellular vesicles (sEV) in VSMC phenotypic modulation. sEV were isolated from the plasma of patients with ISR (ISR-sEV) or not (Ctl-sEV) 1 year after coronary stent implantation using differential ultracentrifugation. Plasma sEV in ISR patients are elevated markedly and decrease the expression of VSMC contractile markers α-SMA and calponin and increase VSMC proliferation. miRNA sequencing and qRT-PCR validation identified that miRNA-501-5p was the highest expressed miRNA in the plasma ISR-sEV compared with Ctl-sEV. Then, we found that sEV-carried miRNA-501-5p level was significantly higher in ISR patients, and the level of plasma sEV-carried miRNA-501-5p linearly correlated with the degree of restenosis (R 2 = 0.62). Moreover, miRNA-501-5p inhibition significantly increased the expression of VSMC contractile markers α-SMA and calponin and suppressed VSMC proliferation and migration; in vivo inhibition of miRNA-501-5p could also blunt carotid artery balloon injury induced VSMC phenotypic modulation in rats. Mechanically, miRNA-501-5p promoted plasma sEV-induced VSMC proliferation by targeting Smad3. Notably, endothelial cells might be the major origins of miRNA-501-5p. Collectively, these findings showed that plasma sEV-carried miRNA-501-5p promotes VSMC phenotypic modulation-mediated ISR through targeting Smad3.

Assessment of the expression and response of PD-1, LAG-3, and TIM-3 after neoadjuvant radiotherapy in rectal cancer.

Many studies have verified the safety of combined radiotherapy and immune checkpoint blockades (ICBs) without the specific radiation dose or sequencing of combination. We aimed to evaluate the expression and response of PD-1, TIM-3, LAG-3 after neoadjuvant radiotherapy (NRT) and explore the possibility and optimal schedule of combining immunotherapy with radiotherapy in treating rectal cancer. Immunohistochemistry was performed to detect the expression of PD-1, TIM-3, LAG-3, CD8, and CD3. These molecules' expression was detected on the specimens of 76 rectal cancer patients following NRT and 13 of these patients before NRT. The expression of ICBs was assessed by the percentage of positive cells. The levels of PD-1 and immune cells (ICs) LAG-3 in rectal cancer increased after NRT (0% vs. 3%, p=0.043 and 5% vs. 45%, p=0.039, respectively). However, TIM-3 in ICs and tumor cells (TCs) were both decreased (80% vs. 50%, p=0.011, 90% vs. 0%, p=0.000, respectively). The LAG-3 expression was higher in patients treated with short-course RT than long-course RT (22.5% vs. 8.0%, p=0.0440 in ICs; 0% vs. 70%, p<0.001 in TCs). On the contrary, CD8 was higher after long-course RT (15% vs. 8%, p=0.0146). Interestingly, the level of ICs TIM-3 was low in > eight weeks after long-course RT (p=0.045). The expressions of PD-1, ICs TIM-3, ICs LAG-3, CD3, and CD8 were associated with the disease-free survival (DFS) in univariate analysis (p=0.036, 0.008, 0.018, 0.025, and 0.004, respectively). Adjusted by the relevant variables, PD-1 (HR 0.274; 95% CI 0.089-0.840; p=0.024) and ICs TIM-3 (HR 0.425; 95% CI 0.203-0.890; p=0.023) were independent prognostic factors of DFS in rectal cancer patients following NRT. In conclusion, we have identified that PD-1 and ICs LAG-3 presented a trend towards increased expression after NRT, supporting the ICBs and NRT combination as a potential treatment option for local advanced rectal cancer patients. The radiotherapeutic mode and timing of the treatment might significantly affect the expression of ICBs, which indicated that the sequencing and time window of ICBs immunotherapy utility might deserve a high value.

Effectiveness of cognitive behavior therapy for sleep disturbance and glycemic control in persons with type 2 diabetes mellitus: A community-based randomized controlled trial in China.

BACKGROUND: Poor sleep quality is a common clinical feature in patients with type 2 diabetes mellitus (T2DM), and often negatively related with glycemic control. Cognitive behavioral therapy (CBT) may improve sleep quality and reduce blood sugar levels in patients with T2DM. However, it is not entirely clear whether CBT delivered by general practitioners is effective for poor sleep quality in T2DM patients in community settings. AIM: To test the effect of CBT delivered by general practitioners in improving sleep quality and reducing glycemic levels in patients with T2DM in community. METHODS: A cluster randomized controlled trial was conducted from September 2018 to October 2019 in communities of China. Overall 1033 persons with T2DM and poor sleep quality received CBT plus usual care or usual care. Glycosylated hemoglobin A1c (HbAlc) and sleep quality [Pittsburgh Sleep Quality Index (PSQI)] were assessed. Repeated measures analysis of variance and generalized linear mixed effects models were used to estimate the intervention effects on hemoglobin A1c and sleep quality. RESULTS: The CBT group had 0.64, 0.50, and 0.9 lower PSQI scores than the control group at 2 mo, 6 mo, and 12 mo, respectively. The CBT group showed 0.17 and 0.43 lower HbAlc values than the control group at 6 mo and 12 mo. The intervention on mean ΔHbAlc values was significant at 12 mo (t = 3.68, P < 0.01) and that mean ΔPSQI scores were closely related to ΔHbAlc values (t = 7.02, P < 0.01). Intention-to-treat analysis for primary and secondary outcomes showed identical results with completed samples. No adverse events were reported. CONCLUSION: CBT delivered by general practitioners, as an effective and practical method, could reduce glycemic levels and improve sleep quality for patients with T2DM in community.

Gastrodin ameliorates learning and memory impairment in rats with vascular dementia by promoting autophagy flux via inhibition of the Ca2+/CaMKII signal pathway.

Vascular dementia (VD) is a common disease that occurs during human aging. Gastrodin (GAS) has potential benefits for the prevention and treatment of VD. In the present study, we investigated the effects of GAS on cognitive dysfunction in rats with VD induced by permanent middle cerebral artery occlusion (pMCAO) and explored the underlying mechanism. Immunohistochemical and western blot analyses revealed that GAS attenuated hippocampal levels of LC3 (microtubule-associated protein 1 light chain 3), p62, and phosphorylated CaMKII (Ca2+-calmodulin stimulated protein kinase II) in VD rats. Additionally, our results revealed that cobalt chloride blocked autophagic flux in HT22 cells, which was confirmed by increased levels of LC3 and p62 when combined with chloroquine. Notably, GAS ameliorated the impaired autophagic flux. Furthermore, we confirmed that GAS combined with KN93 (a CaMKII inhibitor) or CaMKII knockdown did not impact the reduced p62 levels when compared with GAS treatment alone. Furthermore, a co-immunoprecipitation assay demonstrated that endogenous p62 bound to CaMKII, as confirmed by mass spectrometric analysis after the immunoprecipitation of p62 from HT22 cells. These findings revealed that GAS attenuated autophagic flux dysfunction by inhibiting the Ca2+/CaMKII signaling pathway to ameliorate cognitive impairment in VD.

3-Year Outcomes of the ULTIMATE Trial Comparing Intravascular Ultrasound Versus Angiography-Guided Drug-Eluting Stent Implantation.

OBJECTIVES: The aim of this study was to explore the difference in target vessel failure (TVF) 3 years after intravascular ultrasound (IVUS) guidance versus angiographic guidance among all comers undergoing second-generation drug-eluting stent (DES) implantation. BACKGROUND: The multicenter randomized ULTIMATE (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions) trial showed a lower incidence of 1-year TVF after IVUS-guided DES implantation among all comers compared with angiographic guidance. However, the 3-year clinical outcomes of the ULTIMATE trial remain unknown. METHODS: A total of 1,448 all comers undergoing DES implantation who were randomly assigned to either IVUS guidance or angiographic guidance in the ULTIMATE trial were followed for 3 years. The primary endpoint was the risk for TVF at 3 years. The safety endpoint was definite or probable stent thrombosis (ST). RESULTS: At 3 years, TVF occurred in 47 patients (6.6%) in the IVUS-guided group and in 76 patients (10.7%) in the angiography-guided group (p = 0.01), driven mainly by the decrease in clinically driven target vessel revascularization (4.5% vs. 6.9%; p = 0.05). The rate of definite or probable ST was 0.1% in the IVUS-guided group and 1.1% in the angiography-guided group (p = 0.02). Notably, the IVUS-defined optimal procedure was associated with a significant reduction in 3-year TVF relative to that with the suboptimal procedure. CONCLUSIONS: IVUS-guided DES implantation was associated with significantly lower rates of TVF and ST during 3-year follow-up among all comers, particularly those who underwent the IVUS-defined optimal procedure compared with those with angiographic guidance. (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions; NCT02215915).

Comparison of one-month versus twelve-month dual antiplatelet therapy after implantation of drug-eluting stents guided by either intravascular ultrasound or angiography in patients with acute coronary syndrome: rationale and design of prospective, multicenter, randomized, controlled IVUS-ACS and ULTIMATE-DAPT trial.

BACKGROUND: Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor. METHODS: The IVUS-ACS and ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine (1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and (2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE 1-12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (first randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT)group or ticagrelor plus aspirin (DAPT)group for an additional 11 months (second randomization). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3, or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1-12 months in the second randomized population. CONCLUSION: The IVUS-ACS and ULTIMATE-DAPT trial is designed to test the efficacy and safety of 2 different antiplatelet strategies in ACS patients undergoing PCI with DES implantation guided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoing PCI and provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients.