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.
Although transcatheter aortic-valve replacement (TAVR) is an accepted alternative to surgery in patients with severe aortic stenosis who are at high surgical risk, less is known about comparative ...outcomes among patients with aortic stenosis who are at intermediate surgical risk.
We evaluated the clinical outcomes in intermediate-risk patients with severe, symptomatic aortic stenosis in a randomized trial comparing TAVR (performed with the use of a self-expanding prosthesis) with surgical aortic-valve replacement. The primary end point was a composite of death from any cause or disabling stroke at 24 months in patients undergoing attempted aortic-valve replacement. We used Bayesian analytical methods (with a margin of 0.07) to evaluate the noninferiority of TAVR as compared with surgical valve replacement.
A total of 1746 patients underwent randomization at 87 centers. Of these patients, 1660 underwent an attempted TAVR or surgical procedure. The mean (±SD) age of the patients was 79.8±6.2 years, and all were at intermediate risk for surgery (Society of Thoracic Surgeons Predicted Risk of Mortality, 4.5±1.6%). At 24 months, the estimated incidence of the primary end point was 12.6% in the TAVR group and 14.0% in the surgery group (95% credible interval Bayesian analysis for difference, -5.2 to 2.3%; posterior probability of noninferiority, >0.999). Surgery was associated with higher rates of acute kidney injury, atrial fibrillation, and transfusion requirements, whereas TAVR had higher rates of residual aortic regurgitation and need for pacemaker implantation. TAVR resulted in lower mean gradients and larger aortic-valve areas than surgery. Structural valve deterioration at 24 months did not occur in either group.
TAVR was a noninferior alternative to surgery in patients with severe aortic stenosis at intermediate surgical risk, with a different pattern of adverse events associated with each procedure. (Funded by Medtronic; SURTAVI ClinicalTrials.gov number, NCT01586910 .).
Objectives
We aimed to evaluate structural and functional connectivity of patients with newly diagnosed juvenile myoclonic epilepsy (JME) compared to healthy subjects.
Methods
We enrolled 36 patients ...with a diagnosis of JME, who were newly diagnosed and drug‐naïve. They underwent T1‐weighted imaging, and structural volumes were calculated using FreeSurfer software. In addition, EEG data were obtained from all of them. Structural and functional connectivity matrices were estimated by calculating the structural volumes and EEG amplitude correlation, respectively. Then, the connectivity measures were calculated using the BRAPH program. We also enrolled healthy subjects to compare its structural and functional connectivity with the patients with JME.
Results
We observed that patients with JME exhibited significantly different functional and structural connectivity compared to healthy control subjects. In the global structural connectivity, global efficiency, and local efficiency, and small‐worldness index were decreased, whereas characteristic path length was increased in patients with JME. Betweenness centrality of cingulate, precentral, superior parietal, and superior frontal cortex was increased in patients with JME whereas that of hippocampus was decreased. In the functional connectivity, the betweenness centrality of the fronto‐central electrodes was significantly increased.
Conclusions
This study reports that the structural connectivity and functional connectivity in patients with JME are significantly different from those in healthy control subjects, even those with newly diagnosed drug‐naive state. The patients with JME exhibited disrupted topological disorganization of the global brain network and hub reorganization in structural and functional connectivity. These alterations are implicated in the pathogenesis of JME and suggestive of network disease.
Background Recent studies have reported improved diastolic function in patients administered sodium-glucose cotransporter 2 inhibitors (SGLT2i). We aimed to investigate the effect of dapagliflozin on ...left ventricular (LV) diastolic function in a diabetic animal model and to determine the molecular and cellular mechanisms underlying its function. Methods A total of 30 male New Zealand white rabbits were randomized into control, diabetes, or diabetes+dapagliflozin groups (n = 10/per each group). Diabetes was induced by intravenous alloxan. Cardiac function was evaluated using echocardiography. Myocardial samples were obtained for histologic and molecular evaluation. For cellular evaluation, fibrosis-induced cardiomyoblast (H9C2) cells were obtained, and transfection was performed for mechanism analysis (serum and glucocorticoid-regulated kinase 1 (SGK1) signaling analysis). Results The diabetes+dapagliflozin group showed attenuation of diastolic dysfunction compared with the diabetes group. Dapagliflozin inhibited myocardial fibrosis via inhibition of SGK1 and epithelial sodium channel (ENaC) protein, which was observed both in myocardial tissue and H9C2 cells. In addition, dapagliflozin showed an anti-inflammatory effect and ameliorated mitochondrial disruption. Inhibition of SGK1 expression by siRNA decreased and ENaC and Na+/H+ exchanger isoform 1 (NHE1) expression was confirmed as significantly reduced as siSGK1 in the diabetes+dapagliflozin group. Conclusions Dapagliflozin attenuated left ventricular diastolic dysfunction and cardiac fibrosis via regulation of SGK1 signaling. Dapagliflozin also reduced macrophages and inflammatory proteins and ameliorated mitochondrial disruption. Keywords: Heart failure, Diabetes mellitus, Sodium-glucose cotransporter 2 inhibitor, Left ventricular diastolic function
Adoptive immunotherapy utilizing natural killer (NK) cells has demonstrated remarkable efficacy in treating hematologic malignancies. However, its clinical intervention for solid tumors is hindered ...by the limited expression of tumor‐specific antigens. Herein, lipid‐PEG conjugated hyaluronic acid (HA) materials (HA‐PEG‐Lipid) for the simple ex‐vivo surface coating of NK cells is developed for 1) lipid‐mediated cellular membrane anchoring via hydrophobic interaction and thereby 2) sufficient presentation of the CD44 ligand (i.e., HA) onto NK cells for cancer targeting, without the need for genetic manipulation. Membrane‐engineered NK cells can selectively recognize CD44‐overexpressing cancer cells through HA‐CD44 affinity and subsequently induce in situ activation of NK cells for cancer elimination. Therefore, the surface‐engineered NK cells using HA‐PEG‐Lipid (HANK cells) establish an immune synapse with CD44‐overexpressing MIA PaCa‐2 pancreatic cancer cells, triggering the “recognition‐activation” mechanism, and ultimately eliminating cancer cells. Moreover, in mouse xenograft tumor models, administrated HANK cells demonstrate significant infiltration into solid tumors, resulting in tumor apoptosis/necrosis and effective suppression of tumor progression and metastasis, as compared to NK cells and gemcitabine. Taken together, the HA‐PEG‐Lipid biomaterials expedite the treatment of solid tumors by facilitating a sequential recognition‐activation mechanism of surface‐engineered HANK cells, suggesting a promising approach for NK cell‐mediated immunotherapy.
Lipidated hyaluronic acid biomaterials are anchored to the surfaces of natural killer (NK) cells to enhance tumor recognition ability. Engineered NK cells effectively recognize CD44‐positive pancreatic cancer cells, triggering activation for cancer elimination, resulting in potent inhibition of tumor growth and metastasis. Therefore, this biomaterial‐mediated NK cell therapy can have a major impact in the development of novel cancer immunotherapy.
Purpose To determine the effects of forward head posture on static and dynamic balance control. Subjects and Methods This study included 30 participants who were included into a forward head posture ...group (n = 14) and a control group (n = 16) according to their craniovertebral angles. Static balance control was assessed according to center of gravity sway velocity and total sway distance using an automatic balance calibration system. Dynamic balance control was assessed using the diagnosis mode of a body-tilt training and measurement system. Results Sway velocities on a hard surface with eyes open and closed and those on an unstable sponge surface with eyes closed were significantly higher in the forward head posture group than in the control group. Furthermore, on both the hard and sponge surfaces in the eyes open and closed conditions, total sway distances were significantly higher in the forward head posture group than in the control group. Results of dynamic balance control were not significantly different between groups. Conclusion Forward head posture has a greater effect on static balance control than on dynamic balance control.
We propose a novel and unified solution for user-guided video object segmentation tasks. In this work, we consider two scenarios of user-guided segmentation: semi-supervised and interactive ...segmentation. Due to the nature of the problem, available cues - video frame(s) with object masks (or scribbles) - become richer with the intermediate predictions (or additional user inputs). However, the existing methods make it impossible to fully exploit this rich source of information. We resolve the issue by leveraging memory networks and learning to read relevant information from all available sources. In the semi-supervised scenario, the previous frames with object masks form an external memory, and the current frame as the query is segmented using the information in the memory. Similarly, to work with user interactions, the frames that are given user inputs form the memory that guides segmentation. Internally, the query and the memory are densely matched in the feature space, covering all the space-time pixel locations in a feed-forward fashion. The abundant use of the guidance information allows us to better handle challenges such as appearance changes and occlusions. We validate our method on the latest benchmark sets and achieve state-of-the-art performance along with a fast runtime.
It is unclear whether laparoscopic distal gastrectomy for locally advanced gastric cancer is oncologically equivalent to open distal gastrectomy. The noninferiority of laparoscopic subtotal ...gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer compared with open surgery in terms of 3-year relapse-free survival rate was evaluated.
A phase III, open-label, randomized controlled trial was conducted for patients with histologically proven locally advanced gastric adenocarcinoma suitable for distal subtotal gastrectomy. The primary end point was the 3-year relapse-free survival rate; the upper limit of the hazard ratio (HR) for noninferiority was 1.43 between the laparoscopic and open distal gastrectomy groups.
From November 2011 to April 2015, 1,050 patients were randomly assigned to laparoscopy (n = 524) or open surgery (n = 526). After exclusions, 492 patients underwent laparoscopic surgery and 482 underwent open surgery and were included in the analysis. The laparoscopy group, compared with the open surgery group, suffered fewer early complications (15.7%
23.4%, respectively;
= .0027) and late complications (4.7%
9.5%, respectively;
= .0038), particularly intestinal obstruction (2.0%
4.4%, respectively;
= .0447). The 3-year relapse-free survival rate was 80.3% (95% CI, 76.0% to 85.0%) for the laparoscopy group and 81.3% (95% CI, 77.0% to 85.0%; log-rank
= .726) for the open group. Cox regression analysis after stratification by the surgeon revealed an HR of 1.035 (95% CI, 0.762 to 1.406; log-rank
= .827;
for noninferiority = .039). When stratified by pathologic stage, the HR was 1.020 (95% CI, 0.751 to 1.385; log-rank
= .900;
for noninferiority = .030).
Laparoscopic distal gastrectomy with D2 lymphadenectomy was comparable to open surgery in terms of relapse-free survival for patients with locally advanced gastric cancer. Laparoscopic distal gastrectomy with D2 lymphadenectomy could be a potential standard treatment option for locally advanced gastric cancer.
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•The sensitivity of DA detection can be varied by controlling the conditions of PTH polymerization.•PTH is polymerized with/without activation (PTH-S and PTH-D, respectively) onto ...GCE.•PTH-S suppresses the oxidation signals of AA and UA from that of DA with low sensitivity.•PTH-D separates the oxidation signals of AA, DA, and UA with high sensitivity.•Sensitivity increase is mainly due to the increase in the surface charge upon polymerization.
We investigated conducting poly(thionine) (PTH) films prepared by single-step and double-step electrochemical methods (PTH-S and PTH-D, respectively) on the surface of a glassy carbon electrode (GCE) for the detection of dopamine (DA) with varying sensitivity. Electrochemical and spectroscopic analysis revealed that both PTH films have identical chemical structures, but the sensitivity of DA detection was significantly dependent on the polymerization conditions. A simple variation of the electropolymerization conditions dramatically changed the catalytic activity of the PTH films towards the oxidation of DA in the presence of ascorbic acid (AA) and uric acid (UA) as well as the PTH formation mechanism. PTH-D was found to have a higher surface charge than PTH-S, and also showed a sensitivity enhancement for DA detection of up to one order of magnitude compared to PTH-S.
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