Drug combinations rather than increasing doses of one drug can achieve greater efficacy and lower risks. Thus, as an alternative to high-intensity statin monotherapy, moderate-intensity statin with ...ezetimibe combination therapy can lower LDL cholesterol concentrations effectively while reducing adverse effects. However, evidence from randomised trials to compare long-term clinical outcomes is needed.
In this randomised, open-label, non-inferiority trial, patients with atherosclerotic cardiovascular disease (ASCVD) at 26 clinical centres in South Korea were randomly assigned (1:1) to receive either moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg with ezetimibe 10 mg) or high-intensity statin monotherapy (rosuvastatin 20 mg). The primary endpoint was the 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke, in the intention-to-treat population with a non-inferiority margin of 2·0%. This trial is registered with ClinicalTrials.gov, NCT03044665 and is complete.
Between Feb 14, 2017, and Dec 18, 2018, 3780 patients were enrolled: 1894 patients to the combination therapy group and 1886 to the high-intensity statin monotherapy group. The primary endpoint occurred in 172 patients (9·1%) in the combination therapy group and 186 patients (9·9%) in the high-intensity statin monotherapy group (absolute difference -0·78%; 90% CI -2·39 to 0·83). LDL cholesterol concentrations of less than 70 mg/dL at 1, 2, and 3 years were observed in 73%, 75%, and 72% of patients in the combination therapy group, and 55%, 60%, and 58% of patients in the high-intensity statin monotherapy group (all p<0·0001). Discontinuation or dose reduction of the study drug by intolerance was observed in 88 patients (4·8%) and 150 patients (8·2%), respectively (p<0·0001).
Among patients with ASCVD, moderate-intensity statin with ezetimibe combination therapy was non-inferior to high-intensity statin monotherapy for the 3-year composite outcomes with a higher proportion of patients with LDL cholesterol concentrations of less than 70 mg/dL and lower intolerance-related drug discontinuation or dose reduction.
Hanmi Pharmaceutical.
This paper addresses the inverter nonlinearity of a three-level T-type inverter. The main causes of the nonlinearity are pulse shaping, pulse skipping due to narrow pulses for the dead time, and ...voltage drop of the switching devices. Although the same causes have existed in two-level inverters, the pulse skipping phenomenon and results are quite different in the case of the three-level T-type inverter. The effects of pulse shaping and skipping have been investigated and discussed. In addition, the voltage drop of the switching devices has been considered in conjunction with the conduction path of the T-type inverter. Compensation methods based on the pulse width modulation (PWM) of T-type inverter to alleviate the inverter nonlinearity have been proposed from research results. The proposed methods could be easily implemented by adding appropriate offset voltages to the voltage references of the inverter in PWM. Furthermore, a neutral voltage balancing method of a three-level T-type inverter has been proposed in conjunction with the proposed PWM methods using offset voltage. Through extensive experimental tests, the fifth- and seventh-harmonic components of the current are conspicuously reduced along with the even harmonics. The neutral voltage of the inverter can be balanced effectively with the proposed offset voltage adjustments as well.
A high‐efficiency blue‐emitting organic light‐emitting diode (OLED) approaching theoretical efficiency using an exciplex‐forming co‐host composed of N,N′‐dicarbazolyl‐3,5‐benzene (mCP) and ...bis‐4,6‐(3,5‐di‐3‐pyridylphenyl)‐ 2‐methylpyrimidine (B3PYMPM) is fabricated. Iridium(III)bis(4,6‐difluorophenyl)‐ pyridinato‐N,C2′picolinate (FIrpic) is used as the emitter, which turns out to have a preferred horizontal dipole orientation in the emitting layer. The OLED shows a maximum external quantum efficiency of 29.5% (a maximum current efficiency of 62.2 cd A−1), which is in perfect agreement with the theoretical prediction.
Emerging evidence indicates that angiopoietin-2 (Angpt2), a well-recognized vascular destabilizing factor, is a biomarker of poor outcome in ischemic heart disease. However, its precise role in ...postischemic cardiovascular remodeling is poorly understood. Here, we show that Angpt2 plays multifaceted roles in the exacerbation of cardiac hypoxia and inflammation after myocardial ischemia. Angpt2 was highly expressed in endothelial cells at the infarct border zone after myocardial infarction (MI) or ischemia/reperfusion injury in mice. In the acute phase of MI, endothelial-derived Angpt2 antagonized Angpt1/Tie2 signaling, which was greatly involved in pericyte detachment, vascular leakage, increased adhesion molecular expression, degradation of the glycocalyx and extracellular matrix, and enhanced neutrophil infiltration and hypoxia in the infarct border area. In the chronic remodeling phase after MI, endothelial- and macrophage-derived Angpt2 continuously promoted abnormal vascular remodeling and proinflammatory macrophage polarization through integrin α5β1 signaling, worsening cardiac hypoxia and inflammation. Accordingly, inhibition of Angpt2 either by gene deletion or using an anti-Angpt2 blocking antibody substantially alleviated these pathological findings and ameliorated postischemic cardiovascular remodeling. Blockade of Angpt2 thus has potential as a therapeutic option for ischemic heart failure.
Proper storage of excessive dietary fat into subcutaneous adipose tissue (SAT) prevents ectopic lipid deposition-induced insulin resistance, yet the underlying mechanism remains unclear. Here, we ...identify angiopoietin-2 (Angpt2)-integrin α5β1 signaling as an inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of Angpt2 markedly reduced fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic insulin resistance. Mechanistically, Angpt2 activated integrin α5β1 signaling in the endothelium and triggered fatty acid transport via CD36 and FATP3 into SAT. Genetic or pharmacological inhibition of the endothelial integrin α5β1 recapitulated adipocyte-specific Angpt2 knockout phenotypes. Our findings demonstrate the critical roles of Angpt2-integrin α5β1 signaling in SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte-endothelial crosstalk as a potential target for prevention of ectopic lipid deposition-induced lipotoxicity and insulin resistance.
If a small dc-link capacitor is used in the dc link fed by a single-phase ac source, then the dc-link voltage severely fluctuates at twice of the source frequency. To handle this fluctuation, the ...concept of "average voltage constraint" is proposed in this study. On the basis of this concept, a flux-weakening scheme, generating the d-axis current reference (i ds r *) for the interior permanent-magnet synchronous machine, is devised. The q-axis current reference (i qs r *) is modified for the unity power factor operation in the viewpoint of an ac source without an additional sensor. The proposed scheme has been applied to the inverter-driven 1-kW compressor of an air conditioner. From the experimental results, it has been verified that the compressor operates well at the required operating condition, regardless of the severe fluctuation of dc-link voltage, because of the reduced dc-link capacitance. The frequency spectrum of the ac source current reveals that the harmonics of the source current meet the regulation of IEC 61000-3-2 Class A and that the overall power factor is above 96% without any additional circuit, such as an input filter and a power factor correction circuit.
The impact of protons on metallic nanoparticles (MNPs) produces the potent release of MNP-induced secondary electrons and characteristic x-rays. To determine the ability of secondary radiations to ...enhance proton treatment, the therapeutic irradiation of tumors was investigated in mice receiving 100-300 mg MNPs/kg intravenously prior to single dose, 10-41 Gy, proton irradiation. A proton beam was utilized to irradiate nanoparticles with a single Bragg peak set to occur inside a tumor volume (fully absorbed) or to occur after the beam had traversed the entire body. The dose-dependent increase in complete tumor regression (CTR) was 37-62% in the fully-absorbed irradiation group or 50-100% in the traversing irradiation group, respectively, compared with the proton-alone control mice (p < 0.01). One year survival was 58-100% versus 11-13% proton alone. The dose-dependent increase of intracellular reactive oxygen species level was 12-36% at 10 Gy compared with the proton-alone control cell. Therapeutic effective drug concentration that led to 100% CTR with a proton dose of 31 Gy was measured either 41 µg Au/g tissue or 59 µg Fe/g tissue. MNP-based proton treatment increased not only percent CTR and survival in vivo but also ROS generation in vitro, suggesting tumor dose enhancement from secondary radiation as one potent pathway of therapeutic enhancement.
This paper presents a carrier-based pulsewidth modulation (PWM) method that reduces the common-mode voltage (CMV) of a three-level four-leg converter. Based on an analysis of space vector PWM (SVPWM) ...and sinusoidal-PWM switching patterns, the fourth-leg pole voltage of a three-phase converter, known as the "f pole voltage," is manipulated to reduce the CMV. To synthesize the f pole voltage for the suppression of the CMV, positive and negative pole voltage references of the f leg are calculated. In addition, the offset voltage to prevent distortion of the a, b, and c phase voltages regarding the neutral point is deduced. The proposed PWM strategy can be easily implemented in the software of a DSP-based converter control. The three-level four-leg converter with the proposed PWM algorithm results in a remarkable reduction in the peak-to-peak value of the CMV. From the simulation and the experimental results, the peak-to-peak value of the CMV when using the proposed PWM method is 33% compared to that when using the SVPWM method, while the number of CMV transitions during the switching period in the proposed PWM method is only 25% of that when using the SVPWM method.
Aim
This study evaluated the safety and efficacy of a moderate‐intensity statin with ezetimibe combination therapy versus high‐intensity statin monotherapy in patients with metabolic syndrome (MetS) ...and atherosclerotic cardiovascular disease.
Materials and Methods
In this post‐hoc subgroup analysis of the RACING trial, patients were analysed based on the presence of MetS. MetS was defined as meeting at least three of the five following criteria: (a) elevated waist circumference; (b) elevated triglycerides; (c) reduced high‐density lipoprotein cholesterol; (d) elevated blood pressure; and (e) elevated fasting glucose. The primary outcome was a 3‐year composite of cardiovascular death, major cardiovascular events, or non‐fatal stroke.
Results
Of the 3780 patients enrolled in the RACING trial, 1703 (45.1%) had MetS at baseline. The primary outcome rate was 10.1% and 10.3% in patients with MetS receiving ezetimibe combination therapy versus high‐intensity statin monotherapy (hazard ratio = 0.97; 95% confidence interval = 0.72‐1.32; p = .868). Lower rates of intolerance‐related drug discontinuation or dose reduction (3.9% vs. 8.0%; p < .001) and lower low‐density lipoprotein cholesterol levels (57 vs. 65 mg/dl; p < .001) were observed with ezetimibe combination therapy versus high‐intensity statin monotherapy. Furthermore, the rate of new‐onset diabetes was 18.5% and 19.1% in each group (p = .822). There were no significant interactions between MetS and therapy regarding study outcomes in the total population.
Conclusions
In patients with MetS and atherosclerotic cardiovascular disease, a moderate‐intensity statin with ezetimibe combination therapy had comparable cardiovascular benefits with those of high‐intensity statin monotherapy. Meanwhile, ezetimibe combination therapy was associated with lower drug intolerance and low‐density lipoprotein cholesterol levels, but there was no apparent between‐group difference in new‐onset diabetes.
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