Simultaneous Biofilm Disruption, Bacterial Killing, and Inflammation Elimination for Wound Treatment Using Silver Embellished Polydopamine Nanoplatform.

Due to the presence of spatial barriers, persistent bacteria, and excessive inflammation in bacteria biofilm-infected wounds, current nanoplatforms cannot effectively address these issues simultaneously during the therapeutic process. Herein, a novel biomimetic photothermal nanoplatform integrating silver and polydopamine nanoparticles (Ag/PDAs) that can damage biofilms, kill bacterial persisters, and reduce inflammation for wound treatment is presented. These findings reveal that Ag/PDAs exhibit a broad-spectrum antimicrobial activity through direct damage to the bacterial membrane structure. Additionally, Ag/PDAs demonstrate a potent photothermal conversion efficiency. When combined with near-infrared (NIR) irradiation, Ag/PDAs effectively disrupt the spatial structure of biofilms and synergistically eradicate the resident bacteria. Furthermore, Ag/PDAs show remarkable anti-inflammatory properties in counteracting bacterium-induced macrophage polarization. The in vivo results confirm that the topical application of Ag/PDAs significantly suppress Staphylococcus aureus biofilm-infected wounds in murine models, concurrently facilitating wound healing. This research provides a promising avenue for the eradication of bacterial biofilms and the treatment of biofilm-infected wounds.

Clinical Effectiveness and Safety Comparison between Reduced Rivaroxaban Dose and Dual Antiplatelet Therapy for Nonvalvular Atrial Fibrillation Patients Following Percutaneous Left Atrial Appendage Closure: A Prospective Observational Study.

Background: Device-related thrombosis (DRT) after successful closure implantation on left atrial appendage (LAA) was considered as a major challenge and optimal strategy on antithrombotic therapy remains to be solved. This study was performed to compare the clinical effectiveness and safety of reduced rivaroxaban dose (RRD) and dual antiplatelet therapy (DAPT) after left atrial appendage closure (LAAC) implantation with the Watchman device. Methods: After successful LAAC, consecutive participants were medicated with a standard DAPT or RRD. The primary endpoints included DRT, thrombosis events (TE), and bleeding events that were documented during a 12-month follow-up period. Results: 767 patients (DAPT: n = 140; RRD: n = 627) were initially included. After propensity score matching (PSM), 140 patients treated with DAPT and 280 patients with RRD were included in each group with similar baseline information, thromboembolic and bleeding risk factors, cardiovascular risk factors and concomitant medication. In the RRD group, 193 patients were on rivaroxaban 15 mg ( R 15 ) and 47 received rivaroxaban 10 mg ( R 10 ). The incidence of DRT was documented in 12 (9.3%) patients in the DAPT group and 3 (6.3%) in R 10 and 7 (3.0%) in R 15 (log-rank p = 0.050). DAPT subgroups were more likely to experience shorter time to DRT as compared to R 15 ( R 15 vs. DAPT hazard ratio (HR) = 0.334, p = 0.015, 95% CI: 0.131-0.850). The median length of DRT in the R 15 group was significantly lower than that of the DAPT group (1.721 [1.610-1.818] mm vs. 1.820 [1.725-1.925] mm, p = 0.029). Compared with the unadjusted estimated rates of ischemic events for patients with similar congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex category ( CHA 2 DS 2 - VAS c ) scores, a significant decrease of 68.6% in ischemic stroke rates was noted in the R 15 group, which contributed to a 54.9% reduction of overall thromboembolic events. The overall minor bleeding was not significantly different amongst the three groups (p = 0.944). Procedural bleeding was more common in the DAPT group, as compared with the R 10 and R 15 groups. Conclusions: After successful closure implantation, long-term RRD significantly reduced the DRT and TE occurrence compared with DAPT.

Combination of Rivaroxaban and Amiodarone Increases Bleeding in Patients With Atrial Fibrillation.

BACKGROUND: Rivaroxaban and amiodarone are commonly used for treating patients with atrial fibrillation. Drug-drug interactions between rivaroxaban and amiodarone may increase exposure to rivaroxaban. However, the clinical relevance of this drug-drug interaction is still not clear. OBJECTIVE: The aim was to investigate the risk of bleeding in patients receiving a combination of rivaroxaban and amiodarone. METHODS: This was a prospective observational study in which we included atrial fibrillation patients treated with rivaroxaban. The patients were divided into the rivaroxaban group and the combination of rivaroxaban and amiodarone group (the combination group). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to adjust between-group differences. The primary endpoint was defined as the time to the first occurrence of a composite of major, clinically relevant nonmajor, and minor bleeding. RESULTS: In total, 481 atrial fibrillation patients were included in the analysis. After PSM, 154 patients in the rivaroxaban group were matched with 154 patients in the combination group. The bleeding events mainly consisted of clinically relevant nonmajor and minor bleeding. Only one patient experienced major bleeding. The primary outcome was recorded in 26.0% of patients in the combination group and 10.4% of patients in the rivaroxaban group (hazard ratio = 2.76, 95% CI = 1.55-4.93, P < 0.001). The bleeding risk was significantly higher in the combination group compared with that in the rivaroxaban group in the IPTW and stabilized IPTW analyses (hazard ratio = 2.17, 95% CI = 1.32-3.56, P = 0.002). CONCLUSION AND RELEVANCE: The combination of rivaroxaban and amiodarone increased the risk of bleeding in patients with atrial fibrillation, especially clinically relevant nonmajor and minor bleeding. Physicians prescribing rivaroxaban and amiodarone together should be concerned about an increase in the risk of nonmajor bleeding.

Mutant CYP3A4/5 Correlated with Clinical Outcomes by Affecting Rivaroxaban Pharmacokinetics and Pharmacodynamics in Patients with Atrial Fibrillation.

PURPOSE: This study was designed to investigate the impact of single-nucleotide polymorphism-encoded cytochrome P450 enzymes (CYP3A4/5) on clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) based on pharmacokinetics and pharmacodynamics (PK/PD) aspects. METHOD: A prospective study enrolling 165 rivaroxaban-treated patients with NVAF was conducted. Genotyping of CYP3A4 (rs2242480, rs2246709, rs3735451, and rs4646440) and CYP3A5 (rs776746) was performed to explore their impact on the trough plasma concentrations (Ctrough) of rivaroxaban, coagulation indicators at the Ctrough including activated partial thromboplastin time (APTT) and prothrombin time (PT), and clinical outcomes. RESULTS: Patients with mutant genotype CYP3A4 (rs2242480, rs2246709, and rs3735451) and CYP3A5 (rs776746) had higher levels of rivaroxaban Ctrough, PT values than that of wild-type. Furthermore, a positive relationship was revealed between Ctrough and PT (r = 0.212, p = 0.007), while no significant correlation was found between Ctrough and APTT. Regarding the clinical outcomes, the minor allele carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were associated with higher incidence of minor bleeding (p = 0.028 and p = 0.038, respectively) and were identified as the independent risk factors of minor bleeding treated with rivaroxaban (p = 0.024 and p = 0.036, respectively), with the receiver operating characteristic (ROC) curve validated (AUC = 0.8956, 95% CI: 0.829-0.962). CONCLUSION: The CYP3A4 polymorphisms (rs2242480, rs2246709, and rs3735451) and CYP3A5 rs776746 were associated with variations in rivaroxaban PK/PD. The minor allele (C) carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were correlated with clinical outcomes.

Nanovaccine-based strategies for lymph node targeted delivery and imaging in tumor immunotherapy.

Therapeutic tumor vaccines have attracted considerable attention in the past decade; they can induce tumor regression, eradicate minimal residual disease, establish lasting immune memory and avoid non-specific and adverse side effects. However, the challenge in the field of therapeutic tumor vaccines is ensuring the delivery of immune components to the lymph nodes (LNs) to activate immune cells. The clinical response rate of traditional therapeutic tumor vaccines falls short of expectations due to inadequate lymph node delivery. With the rapid development of nanotechnology, a large number of nanoplatform-based LN-targeting nanovaccines have been exploited for optimizing tumor immunotherapies. In addition, some nanovaccines possess non-invasive visualization performance, which is benefit for understanding the kinetics of nanovaccine exposure in LNs. Herein, we present the parameters of nanoplatforms, such as size, surface modification, shape, and deformability, which affect the LN-targeting functions of nanovaccines. The recent advances in nanoplatforms with different components promoting LN-targeting are also summarized. Furthermore, emerging LNs-targeting nanoplatform-mediated imaging strategies to both improve targeting performance and enhance the quality of LN imaging are discussed. Finally, we summarize the prospects and challenges of nanoplatform-based LN-targeting and /or imaging strategies, which optimize the clinical efficacy of nanovaccines in tumor immunotherapies.

Bavachinin selectively modulates PPAR γ and maintains bone homeostasis in Type 2 Diabetes.

Full peroxisome proliferator-activated receptor (PPAR) γ agonists, Thiazolidinediones (TZDs), effectively prevent the process of Type 2 Diabetes Mellitus (T2DM), but their side effects have curtailed use in the clinic, including weight gain and bone loss. Here, we identified that a selective PPAR γ modulator, Bavachinin (BVC), isolated from the seeds of Psoralea Corylifolia L., could potently regulate bone homeostasis. MC3T3-E1 pre-osteoblast cells and C3H10T1/2 mesenchymal stem cells were assessed for osteogenic differentiation activities, and receptor activator of NF-κB ligand (RANKL)-induced RAW 264.7 cells were assessed osteoclasts formation. Leptin receptor-deficient mice and diet-induced obesity mice were applied to evaluate the effect of BVC on bone homeostasis in vivo. Compared to full PPAR γ agonist rosiglitazone, BVC significantly increased the osteogenesis differentiation activities under normal and high glucose conditions in MC3T3-E1 cells. Moreover, BVC could alleviate osteoclast differentiation in RANKL-induced RAW 264.7 cells. In vivo, synthesized BVC prodrug (BN) has been applied to improve water solubility, increase the extent of oral absorption of BVC and prolong its residence time in blood circulation. BN could prevent weight gain, ameliorate lipid metabolism disorders, improve insulin sensitivity, and maintain bone mass and bone biomechanical properties. BVC, a unique PPAR γ selective modulator, could maintain bone homeostasis, and its prodrug (BN) exhibits insulin sensitizer activity while circumventing the side effects of the TZDs, including bone loss and undesirable weight gain.

Risk Factors and Outcomes of AKI after LAAC Operation: A Single-Center Observational Study from Mainland China.

Background: This study aimed to investigate the predictors and prognosis of acute kidney injury (AKI) occurrence among Chinese patients following left atrial appendage closure (LAAC). Methods: We retrospectively enrolled 512 consecutive patients who underwent LAAC between January 2014 and December 2019. AKI was clinically defined according to the Kidney Disease Improving Global Outcomes serum creatinine criteria. Major adverse cardiovascular events were defined as the composite of all-cause mortality, readmission due to heart failure, cardiac surgery, systemic embolism, or bleeding events. Results: The incidence of AKI was 5.3% and was highest in patients with chronic kidney disease (CKD) stages 4-5 (25.0%), followed by those with CKD stages 3a-3b (9.1%), and those with CKD stages 1-2 or without CKD (3.9% only). Multivariate logistic regression showed that lower body mass index (odds ratio [OR] = 0.889; 95% confidence interval [CI], 0.803-0.986; p = 0.017), hypertension (OR = 5.577; 95% CI, 1.267-24.558; p = 0.023), and CKD stages 4-5 (OR = 6.729; 95% CI, 1.566-28.923; p = 0.010) were independent risk factors for AKI development after LAAC. AKI after LAAC was associated with 3-year major adverse cardiovascular events (33.3% vs. 7.5%, p < 0.001) and all-cause mortality (11.1% vs. 0.9%, p < 0.001) compared to that in the non-AKI group. Conclusions: AKI is relatively common after LAAC in patients with a baseline impaired glomerular filtration rate. Moreover, AKI after LAAC is mainly related to increased midterm mortality and morbidity, which require more strategies for prevention and treatment.

Outcomes of Total Endovascular Aortic Arch Repair with Surgeon-Modified Fenestrated Stent-Grafts on Zone 0 Landing for Aortic Arch Pathologies.

OBJECTIVES: This study evaluated the feasibility and safety of total endovascular aortic arch repair with surgeon-modified fenestrated stent-graft on zone 0 landing for aortic arch pathologies. METHODS: Between June 2016 and October 2019, 37 consecutive patients underwent total endovascular arch repair with surgeon-modified fenestrated stent-grafts on zone 0 landing. Outcomes included technical success, perioperative and follow-up morbidity and mortality, and branch artery patency. RESULTS: During the study period, 37 patients were treated with total endovascular aortic arch repair with surgeon-modified fenestrated stent-graft. Twenty-one (56.8%) patients were diagnosed with aortic dissections, 15 (40.5%) patients with aneurysms, and 1 (2.7%) patient required reintervention due to endoleak and sac expansion from previous thoracic endovascular aortic repair for thoracoabdominal aneurysm. The proximal landing zone for all patients were in zone 0, and all branch arteries of aortic arch were reconstructed. Technical success was achieved in 34 cases (91.9%). Three (8.1%) patients had fenestrations misaligned with target arteries, and the chimney technique was applied as a complementary measure. Thirty-day mortality rate was 5.4% (n=2). Thirty-day stroke rate was 5.4% (n=2). Thirty-day reintervention rate was 2.7% (n=1). At a median follow-up of 20 months (range, 3-49 months), 5 (13.5%) patients died, including 2 aortic-related deaths, 1 nonaortic-related death, and 2 deaths of unknown reason. One (2.7%) patient had stroke. Four patients (10.8%) had reintervention during the follow-up, including 2 cases of left subclavian artery occlusion and 2 cases of type II endoleak. The estimated survival (±SE) at 2 years was 72.4%±9.7% (95% CI 53.4%-91.4%). The estimated freedom from reintervention (±SE) at 2 years was 87.4%±5.9% (95% CI 75.84%-98.96%). CONCLUSIONS: Total endovascular aortic arch repair with surgeon-modified fenestrated stent-grafts on zone 0 landing is an alternate option for the treatment of aortic arch pathologies in experienced centers.

Outcomes of Zone 1 Thoracic Endovascular Aortic Repair With Fenestrated Surgeon-Modified Stent-Graft for Aortic Arch Pathologies.

OBJECTIVES: This study evaluated the feasibility and safety of zone 1 thoracic endovascular aortic repair (TEVAR) with fenestrated surgeon-modified stent-graft (SMSG) for aortic arch pathologies. METHODS: Between March 2016 and November 2020, 34 consecutive patients underwent zone 1 TEVAR with fenestrated SMSG for aortic arch pathologies. Outcomes included technical success, perioperative, and follow-up morbidity and mortality. RESULTS: During the study period, 34 patients were treated with zone 1 TEVAR with fenestrated SMSG. Twenty-four (70.6%) patients presented with type B aortic dissections, 9 (26.5%) patients presented with aneurysms (7 located on the lesser curvature side of aortic arch), 1 (2.9%) patient presented with type Ia endoleak after previous TEVAR owing to traumatic aortic dissection. The proximal landing zone for all patients were in zone 1, and all supra-aortic trunks were reconstructed, except for one left subclavian artery. Technical success was achieved in all cases. The 30-day estimated survival (±SE) was 90.9% ± 5.0% [95% confidence interval (CI): 77.0%-97.0%]. The 30-day estimated freedom from reintervention (±SE) was 87.9% ± 5.7% (95% CI: 73.4%-95.3%). At a median follow-up of 48 months (range, 12-68 months), 2 patients died, including 1 aortic-related death and 1 non-aortic-related death. One patient had reintervention 13 months after the operation owing to type Ia endoleak. All supra-aortic trunks were patent. The estimated survival (±SE) during follow-up was 85.1% ± 6.2% (95% CI: 69.9%-93.6%). One (2.7%) patient had stroke. The estimated freedom from reintervention (±SE) during follow-up was 84.2% ± 6.5% (95% CI: 69.9%-93.5%). CONCLUSIONS: Zone 1 TEVAR with fenestrated SMSG is an alternate option for treatment of aortic arch pathologies in experienced centers.

Advances and perspectives of proteolysis targeting chimeras (PROTACs) in drug discovery.

Proteolysis-targeting chimeras (PROTACs), bifunctional molecules consisting of a ligand of protein of interest (POI), an E3 ligase ligand and a linker, have been developed to hijack the ubiquitin-proteasome system (UPS) to induce different POIs degradation. Currently, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging efficacy in clinical trials of prostate and breast cancer treatment, which turns a new avenue for the development of PROTAC research. In this review, we focus on a detailed summary of the latest progress of PROTACs and elucidate the advantages of PROTACs technology. In addition, potential challenges and perspectives of PRTOACs are discussed.

Effectiveness and safety of sacubitril/valsartan for patients with hypertension and heart failure in the real-world setting: A retrospective study in China.

WHAT IS KNOWN AND OBJECTIVE: Hypertension (HP) is associated with heart failure (HF). Sacubitril/valsartan (sac/val) has been approved for primary HP by China Food and Drug Administration (CFDA) in June 2021. The present study aimed to provide evidence on the effectiveness and safety of sac/val in Chinese patients complicated with HP and HF. METHODS: This retrospective study was conducted on adult patients diagnosed with HP and HF and treated with sac/val between July 2020 and December 2020. The potential risk factors for the discontinuation events caused by sac/val-related adverse events (AEs) were explored. The data, including blood pressure (BP), cardiac indicators, corresponding values on echocardiographic parameters, unplanned visits, and AEs throughout 3-12 months, were collected. RESULTS AND DISCUSSION: A total of 446 eligible patients were included in this study. The discontinuation events of sac/val were mainly attributed to its AEs (hypotension, hyperkalemia, and deterioration in kidney function). Univariate analysis revealed that history of chronic kidney disease, atrial fibrillation, higher values of serum creatinine, serum uric acid, serum N-terminal pro B-type natriuretic peptide, and lower estimated glomerular filtration rate were potential risk factors for discontinuation. Patients who maintained sac/val therapy throughout 3-12 months showed significantly improved values of clinical BP, cardiac indicators, and echocardiographic parameters compared to those at baseline (p < 0.0001). WHAT IS NEW AND CONCLUSION: Sac/val was effective on BP and improved cardiac function in patients complicated with HP and HF. The physicians should focus on patients with renal dysfunction to take timely precautions to improve tolerability for sac/val.

The impact of ABCB1 and CES1 polymorphisms on dabigatran pharmacokinetics and pharmacodynamics in patients with atrial fibrillation.

AIMS: Our study aimed to determine the impact of genetic polymorphisms of ABCB1 and CES1 on the pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran in patients with nonvalvular atrial fibrillation (NVAF). METHODS: We conducted a prospective study and enrolled NVAF patients treated with dabigatran. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration (PDC) and coagulation parameters including activated partial thromboplastin time (APTT) and thrombin time. Patients' demographics and clinical outcomes from scheduled follow-up visits were all recorded. Statistical analysis was performed to identify the impact of genetic polymorphisms on the PK/PD and bleeding risk of dabigatran. RESULTS: A total of 198 patients were included in analysis. For the ABCB1 polymorphisms rs4148738 and rs1045642, no significant association was found with dabigatran PK/PD. For the CES1 polymorphism rs8192935, the minor allele(C) was associated with increased trough PDCs (ANOVA: P < .001; CC vs. TT genotype, P < .001; CT vs. TT genotype, P = .014) and with APTT values at trough level (P = .015). For the CES1 polymorphism rs2244613, the minor allele(A) carriers had higher levels of trough PDC than noncarriers (ANOVA: P < .001; AA vs. CC genotype, P < .001; CA vs. CC genotype, P = .004) and increased risk for minor bleeding (P = .034; odds ratio = 2.71, 95% confidence interval 1.05-7.00). CONCLUSION: Our study indicated that the minor allele(C) on the CES1 SNP rs8192935 was associated with PDCs and APTT values at trough level. The minor allele(A) on the CES1 SNP rs2244613 was associated with increased trough PDCs and higher risk for minor bleeding in NVAF patients treated with dabigatran.

Thoracic Endovascular Repair for Aortic Arch Pathologies with Surgeon Modified Fenestrated Stent Grafts: A Multicentre Retrospective Study.

OBJECTIVE: To evaluate the outcome of thoracic endovascular repair (TEVAR) for aortic arch pathologies with surgeon modified fenestrated stent grafts. METHODS: A multicentre, retrospective study consisting of consecutive patients from seven centres treated with surgeon modified fenestrated stent grafts for aortic arch pathologies was conducted. A technique to align fenestrations and supra-aortic vessels was applied. Rates of technical success, mortality, complications, and re-interventions were evaluated. RESULTS: Between February 2016 and January 2020, 513 consecutive patients with aortic arch pathologies received TEVAR with surgeon modified fenestrated stent grafts. The technical success rate was 98.6% (n = 506). In total, 626 fenestrations were created to revascularise 684 branch arteries of the aortic arch. There were 13 deaths and 15 re-interventions within 30 days of the operation. The estimated clinical success rate at 30 days was 94.4% (95% confidence interval [CI] 92.4 - 96.4), the estimated survival at 30 days was 97.5% (95% CI 96.1 - 98.9), and the estimated freedom from re-intervention at 30 days was 97.1% (95% CI 95.7 - 98.5). The median follow up was 27 (interquartile range 13 - 31) months. During follow up, there were five aortic related deaths, three non-aortic related deaths, and four deaths of unknown cause. Eighteen patients underwent re-intervention. The estimated clinical success rate at 24 months was 88.2% (95% CI 85.5 - 91.0), the estimated survival at 24 months was 94.9% (95% CI 92.7 - 97.1), and the estimated freedom from re-intervention at 24 months was 93.1% (95% CI 91.0 - 95.3). In total, 18 cases of stroke were recorded, including 12 within 30 days and six during follow up; six cases of retrograde type A aortic dissection were recorded, including five within 30 days and one during the follow up. CONCLUSION: TEVAR with surgeon modified fenestrated stent grafts for the treatment of aortic arch pathologies provides acceptable outcomes. Further follow up is required to confirm the benefits of this approach.

Safety of hydroxychloroquine in COVID-19 and other diseases: a systematic review and meta-analysis of 53 randomized trials.

INTRODUCTION: Many concerns still exist regarding the safety of hydroxychloroquine (HCQ) in the treatment of Coronavirus Disease 2019 (COVID-19). OBJECTIVES: The purpose of this study was to evaluate the safety of HCQ in the treatment of COVID-19 and other diseases by performing a systematic review and meta-analysis. METHODS: Randomized controlled trials (RCTs) reporting the safety of HCQ in PubMed, Embase, and Cochrane Library were retrieved starting from the establishment of the database till June 5, 2020. Literature screening, data extraction, and assessment of risk bias were performed independently by two reviewers. RESULTS: We identified 53 eligible studies involving 5496 patients. The meta-analysis indicated that the risk of adverse effects (AEs) in the HCQ group was significantly increased compared with that in the control group (RD 0.05, 95%CI, 0.02 to 0.07, P = 0.0002), and the difference was also statistically significant in the COVID-19 subgroup (RD 0.15, 95%CI, 0.07 to 0.23, P = 0.0002) as well as in the subgroup for other diseases (RD 0.03, 95%CI, 0.01 to 0.04, P = 0.003). CONCLUSIONS: HCQ is associated with a high total risk of AEs compared with the placebo or no intervention in the overall population. Given the small number of COVID-19 participants included, we should be cautious regarding the conclusion stating that HCQ is linked with an increase incidence of AEs in patients with COVID-19, which we hope to confirm in the future through well-designed and larger sample size studies.

Cilostazol increases adenosine plasma concentration in patients with acute coronary syndrome.

WHAT IS KNOWN AND OBJECTIVE: Cilostazol is a specific and strong inhibitor of phosphodiesterase (PDE) type III which can suppress the platelet aggregation by increasing cyclic adenosine monophosphate (cAMP) levels. The clinical benefit of cilostazol in ACS patients suggested that the drug may have non-platelet-directed properties. Some in vitro and animal studies also indicated that the 'pleiotropic' properties of cilostazol might be related to the interaction with adenosine metabolism. Adenosine is an important regulatory metabolite and an inhibitor of platelet activation. However, no human study has been conducted to determine whether cilostazol could increase the adenosine plasma concentration in vivo. As a result, this study aimed to investigate the impact of cilostazol on adenosine plasma concentration (APC) in acute coronary syndrome (ACS) patients. METHODS: We prospectively analysed 149 ACS patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents. The included patients were divided into two groups according to the presence (cilostazol group, n = 64) or absence (aspirin group, n = 85) of aspirin intolerance. The inhibition of platelet aggregation (IPA), APC and cAMP concentration was measured. Patient characteristics, medications and 30-day clinical outcomes were examined. RESULTS: Patients receiving cilostazol had a significantly higher adenosine and cAMP plasma concentration than patients receiving aspirin (3.00 ± 0.67 vs 2.56 ± 0.74 mol/L, P < .001; 28.10 ± 14.74 vs 20.48 ± 11.35 pmol/mL, P = .0014). Cilostazol was associated with a higher inhibition rate of ADP induced platelet aggregation than aspirin (63.35 ± 26.71 vs 52.2 ± 28.35, P = .036). The plasma levels of adenosine and cAMP showed a positive correlation with ADP induced platelet aggregation. WHAT IS NEW AND CONCLUSION: Cilostazol increases adenosine concentration compared with aspirin. Its potent antiplatelet effect in ACS patients may be partly mediated by adenosine.

Preparing sparse solvers for exascale computing.

Sparse solvers provide essential functionality for a wide variety of scientific applications. Highly parallel sparse solvers are essential for continuing advances in high-fidelity, multi-physics and multi-scale simulations, especially as we target exascale platforms. This paper describes the challenges, strategies and progress of the US Department of Energy Exascale Computing project towards providing sparse solvers for exascale computing platforms. We address the demands of systems with thousands of high-performance node devices where exposing concurrency, hiding latency and creating alternative algorithms become essential. The efforts described here are works in progress, highlighting current success and upcoming challenges. This article is part of a discussion meeting issue 'Numerical algorithms for high-performance computational science'.

Efficacy assessment of ticagrelor versus clopidogrel in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention by data mining and machine-learning decision tree approaches.

WHAT IS KNOWN AND OBJECTIVE: Although ticagrelor has been well-known to improve clinical outcomes in patients undergoing percutaneous coronary intervention (PCI), and its effectiveness and safety have not been well evaluated in Chinese patients. This study aimed to evaluate the effectiveness and safety of ticagrelor in Chinese patients. In order to find potential effect modifiers on the drug effects, a decision tree method was performed to detect interactions between treatment and patient characteristics in an automatic and systematic manner. METHODS: This retrospective study included acute coronary syndrome (ACS) patients who underwent PCI and received either ticagrelor (N = 250) or clopidogrel (N = 291) while hospitalized between August 2014 and August 2015. After propensity score matching, Kaplan-Meier analysis was used to study the event-free survival against major adverse cardiovascular events (MACE, primary efficacy outcome, defined as the composite of cardiac death, non-fatal myocardial infarction [MI], stroke, restenosis and target vessel revascularization [TVR]), re-hospitalization, the need for urgent re-PCI (secondary efficacy outcome) and bleeding events (safety outcome) within 12 months of the PCI date. To search for effect modifiers of the two antiplatelet therapies, a machine-learning decision tree algorithm was conducted to predict re-hospitalization status. RESULTS: After propensity score matching (N = 442), ticagrelor and clopidogrel had no significant difference in MACE, re-hospitalization and bleeding. The decision tree analysis showed that the number of diseased vessels modulated the effect of ticagrelor and clopidogrel on re-hospitalization rates. In single-vessel disease (SVD) patients, ticagrelor was associated with lower hazards than clopidogrel for all efficacy outcomes: MACE (HR = 0.190, 95% CI: 0.042-0.866), re-hospitalization (HR = 0.296, 95% CI: 0.108-0.808), urgent re-PCI (HR = 0.249, 95% CI: 0.069-0.895), bleeding (HR = 1.006, 95% CI: 0.063-16.129). However, in multi-vessel disease (MVD) patients, the two treatments did not show significant difference. WHAT IS NEW AND CONCLUSION: In the general patient population, there was no significant difference between ticagrelor and clopidogrel on the hazard of MACE. However, ticagrelor achieved a better effectiveness than clopidogrel in patients with SVD. This pilot study provides scientific basis to call for a large-scale prospective study in this population.

miR-101-3p induces vascular endothelial cell dysfunction by targeting tet methylcytosine dioxygenase 2.

Endothelial cell (EC) dysfunction represents an early key event in atherosclerosis. Recently, MicroRNAs have been demonstrated to regulate EC function. miR-101-3p has been discovered to regulate cell apoptosis and proliferation in cardiovascular diseases. Therefore, the aim of the current study was to clarify whether miR-101-3p regulates the dysfunction of vascular endothelial cells. In this study, the transfection of human umbilical vein endothelial cells (HUVECs) with miR-101-3p mimic induced reactive oxygen species (ROS) production, EC dysfunction, and activated nuclear factor-κB (NF-κB), whereas transfection with miR-101-3p inhibitor alleviated these events. The antioxidant N-acetylcysteine alleviated miR-101-3p-induced EC dysfunction. Moreover, we observed that miR-101-3p inhibited the expression of tet methylcytosine dioxygenase 2 (TET2) at the posttranscriptional level, resulting in increased ROS production and activated NF-κB. TET2 overexpression inhibited ROS production, EC dysfunction, and NF-κB activation in miR-101-3p-transfected HUVECs. These results indicate that miR-101-3p induces EC dysfunction by targeting TET2, which regulates ROS production, EC dysfunction, and NF-κB activation. Taken together, our current study reveals a novel pathway associated with EC dysfunction. The modulation of miR-101-3p and TET2 expression levels may serve as a potential target for therapeutic strategies for atherosclerosis.

Classical swine fever virus C-strain with eight mutation sites shows enhanced cell adaptation and protects pigs from lethal challenge.

Control of classical swine fever (CSF) in developing countries is achieved by immunization with attenuated vaccines, such as the lapinized C-strain vaccine that has been widely used in China. However, C-strain has relatively low growth rate in cell cultures, thus affecting productivity of the vaccine for the industry. In this study, eight amino acid residues were mutated on the C-strain backbone, resulting in a cell-adapted strain Cmut8. The mutant strain exhibited rapid growth with titer of about 100 fold higher than its parental C-strain. The mutation sites located at structural proteins Erns and E2 contributed more to cell adaptation than those located in non-structural proteins. Sera collected from pigs inoculated with Cmut8 and C-strain at the same dose showed similar antibody levels and neutralization titers. Pigs inoculated with different doses of Cmut8 (low, medium and high) and with C-strain offered full protection against challenge with a virulent strain, shown as absence of fever and other symptoms, marginal low levels of viral load, and no obvious gross pathological changes in major organs. Unvaccinated control pigs challenged with the virulent strain showed high fever from day 2 post-challenge and apparent clinical symptoms with two deaths. Viral load were markedly elevated in these control pigs after challenge. The pigs inoculated with high dose of Cmut8 did not show fever or other typical CSF symptoms, and no apparent pathological changes were observed in major organs. Besides, the Cmut8 strain did not induce typical fever response in rabbits. These results demonstrate that the cell-adapted Cmut8 strain remains non-pathogenic to the weaned pigs, provides full protection and could be a good candidate vaccine strain for improved yield at lower cost.

E2 and Erns of classical swine fever virus C-strain play central roles in its adaptation to rabbits.

The classical swine fever virus (CSFV) C-strain has been used as a vaccine strain for over 60 years in China. A recent study has demonstrated that the E2 protein of C-strain plays a major role in its adaptation to rabbits. E2 protein in combination with either Erns or E1 confers rabbit adaptation for the C-strain, and the residues P108 and T109 in domain I of E2 are critical for rabbit adaptation. To further identify the contributions of the glycoproteins to rabbit adaptation, a series of C-strain-based chimeric viruses containing single or double glycoprotein substitutions of the Shimen strain were generated and inoculated into rabbits. Profiles of rectal temperature, viral RNA, E2 protein expression, and antibody responses were compared among the chimeric viruses. Replacement of Erns, E2, Erns-E2, or E1-E2 of the C-strain with the counterpart(s) of the Shimen strain led to decreased fever response, reduction of viral RNA and antibody responses in rabbits, as compared with their parental C-strain. The C-strain-based chimeric virus expressing the Shimen strain E1 exhibited typical fever response and viral RNA level similar to the C-strain. However, substitution of both Erns and E2 in the C-strain backbone abolished fever response, and the chimeric virus did not show adaptation in rabbits as demonstrated by lack of viral RNA and E2 protein expression in the spleen and weak antibody responses. These results indicate that Erns has partial contribution to adaptation of the C-strain in rabbits, and combination of E2 and Erns is essential for the C-strain to have adaptive replication in rabbits.