Efficacy and safety of evogliptin treatment in patients with type 2 diabetes: A multicentre, active-controlled, randomized, double-blind study with open-label extension (the EVERGREEN study).

AIM: To investigate the efficacy and safety of evogliptin compared with linagliptin in patients with type 2 diabetes. MATERIALS AND METHODS: In this 12-week, multicentre, randomized, double-blind, active-controlled, and 12-week open-label extension study, a total of 207 patients with type 2 diabetes who had HbA1c levels of 7.0%-10.0% were randomized 1:1 to receive evogliptin 5 mg (n = 102) or linagliptin 5 mg (n = 105) daily for 12 weeks. The primary efficacy endpoint was the change from baseline HbA1c at week 12. The secondary endpoint was the change in the mean amplitude of glycaemic excursion (MAGE) assessed by continuous glucose monitoring. In the extension study conducted during the following 12 weeks, evogliptin 5 mg daily was administered to both groups: evogliptin/evogliptin group (n = 95) and linagliptin/evogliptin group (n = 92). RESULTS: After 12 weeks of treatment, the mean change in HbA1c in the evogliptin group and in the linagliptin group was -0.85% and -0.75%, respectively. The between-group difference was -0.10% (95% CI: -0.32 to 0.11), showing non-inferiority based on a non-inferiority margin of 0.4%. The change in MAGE was -24.6 mg/dL in the evogliptin group and -16.7 mg/dL in the linagliptin group. These values were significantly lower than the baseline values in both groups. However, they did not differ significantly between the two groups. In the evogliptin/evogliptin group at week 24, HbA1c decreased by -0.94%, with HbA1c values of <7.0% in 80.2% of the patients. The incidence and types of adverse events were comparable between the two groups for 24 weeks. CONCLUSION: In this study, the glucose-lowering efficacy of evogliptin was non-inferior to linagliptin. It was maintained at week 24 with a 0.94% reduction in HbA1c. Evogliptin therapy improved glycaemic variability without causing any serious adverse events in patients with type 2 diabetes.

A feasibility study of OCT for anatomical and vascular phenotyping of mouse embryo.

The embryo phenotyping of genetic murine model is invaluable when investigating functions of genes underlying embryonic development and birth defect. Although traditional imaging technologies such as ultrasound are very useful for evaluating phenotype of murine embryos, the use of advanced techniques for phenotyping is desirable to obtain more information from genetic research. This letter tests the feasibility of optical coherence tomography (OCT) as a high-throughput phenotyping tool for murine embryos. Three-dimensional OCT imaging is performed for live and cleared mouse embryos in the late developmental stage (embryonic day 17.5). By using a dynamic focusing method and OCT angiography (OCTA) approach, our OCT imaging of the embryo exhibits rapid and clean visualization of organ structures deeper than 5 mm and complex microvasculature of perfused blood vessels in the murine embryonic body. This demonstration suggests that OCT imaging can be useful for comprehensively assessing embryo anatomy and angiography of genetically engineered mice.

Prognosis of patients with gastric variceal bleeding after endoscopic variceal obturation according to the type of varices.

BACKGROUND AND AIMS: This study was performed to evaluate the treatment efficacy of endoscopic variceal obturation (EVO) in patients with gastric variceal bleeding (GVB) according to the type of varices. PATIENTS AND METHODS: All patients who were treated with EVO for bleeding from gastric varices (GVs) were included. Patients with a previous history of endoscopic treatment for GVB and those with accompanying portal vein invasion by hepatocellular carcinoma or other malignancy were excluded. RESULTS: Ninety-one patients with GVB were included. Mean age was 59.4±12.4 years and 72 (79.1%) patients were men. The types of varices were gastroesophageal varices (GOV) type 1 (GOV1), GOV2, and isolated gastric varices type 1 (IGV1) in 30 (33.3%), 35 (38.5%), and 26 (28.6%) patients, respectively. Hemostasis and GV obliteration were achieved in 88 (96.7%) and 81 (89.0%) patients, respectively. Among 81 patients with GV obliteration, GV recurred in 26 (32.1%) patients. The GV recurrence rate was significantly lower in patients with GOV1 than in those with GOV2 (P=0.007), while it was comparable between patients with GOV1 and IGV1 (P=0.111) and between patients with GOV2 and IGV1 (P=0.278). Variceal rebleeding occurred in 11 (13.6%) patients. GVB recurrence rate was significantly higher in patients with GOV2 than in those with GOV1 (P=0.034) and IGV1 (P=0.018), while it was comparable between patients with GOV1 and IGV1 (P=0.623). Mortality rate was comparable among the three groups. CONCLUSIONS: EVO was very effective in patients with GVB. GV recurrence and GV rebleeding were significantly lower in patients with GOV1 than in those with GOV2.

The one-hundred most-cited articles focused on thyroid research: a bibliometric analysis.

INTRODUCTION: The number of citations that an article has received reflects its impact on a particular research area. EVIDENCE ACQUISITION: We determined the one-hundred most-cited articles in thyroid research via the Institute for Scientific Information Web of Knowledge database, using the search term. The following parameters were used to analyze the characteristics of the 100 most-cited articles: publication year, journal (including subject category and impact factor), number of citations and annual citations, authors, department, institution, country, type of study, and topic. EVIDENCE SYNTHESIS: The number of citations for the 100 most-cited articles ranged from 2521 to 412 (mean, 643.4) and the number of annual citations ranged from 392.9 to 7.1 (mean, 38.0). The majority of articles were published in 2000-2009 (32%), published in endocrinology journals (29%), originated in the USA (70%), were clinical observation study (31%), and dealt with nodular thyroid disease (32%). Department of Internal Medicine, Johns Hopkins University School of Medicine and Department of Internal Medicine, Ohio State University College of Medicine (N.=6 each) were the leading institutions and Mazzaferri EL (N.=7) was the most prolific author. CONCLUSIONS: Our study presents a detailed list and analysis of the 100 most-cited thyroid research articles, which provides a unique insight into the historical development in this field.

Impact of Not Addressing Partially Cross-Classified Multilevel Structure in Testing Measurement Invariance: A Monte Carlo Study.

In educational settings, researchers are likely to encounter multilevel data with cross-classified structure. However, due to the lack of familiarity and limitations of statistical software for cross-classified modeling, most researchers adopt less optimal approaches to analyze cross-classified multilevel data in testing measurement invariance. We conducted two Monte Carlo studies to investigate the performances of testing measurement invariance with cross-classified multilevel data when the noninvarinace is at the between-level: (a) the impact of ignoring crossed factor using conventional multilevel confirmatory factor analysis (MCFA) which assumes hierarchical multilevel data in testing measurement invariance and (b) the adequacy of the cross-classified multiple indicators multiple causes (MIMIC) models with cross-classified data. We considered two design factors, intraclass correlation (ICC) and magnitude of non-invariance. Generally, MCFA demonstrated very low statistical power to detect non-invariance. The low power was plausibly related to the underestimated factor loading differences and the underestimated ICC due to the redistribution of the variance component from the ignored crossed factor. The results demonstrated possible incorrect statistical inferences with conventional MCFA analyses that assume multilevel data as hierarchical structure for testing measurement invariance with cross-classified data (non-hierarchical structure). On the contrary, the cross-classified MIMIC model demonstrated acceptable performance with cross-classified data.

Elevated electrochemical impedance in the endoluminal regions with high shear stress: implication for assessing lipid-rich atherosclerotic lesions.

BACKGROUND: Identifying metabolically active atherosclerotic lesions remains an unmet clinical challenge during coronary intervention. Electrochemical impedance (EIS) increased in response to oxidized low density lipoprotein (oxLDL)-laden lesions. We hereby assessed whether integrating EIS with intravascular ultrasound (IVUS) and shear stress (ISS) provided a new strategy to assess oxLDL-laden lesions in the fat-fed New Zealand White (NZW) rabbits. METHODS AND RESULTS: A micro-heat transfer sensor was deployed to acquire the ISS profiles at baseline and post high-fat diet (HD) in the NZW rabbits (n=8). After 9 weeks of HD, serum oxLDL levels (mg/dL) increased by 140 fold, accompanied by a 1.5-fold increase in kinematic viscosity (cP) in the HD group. Time-averaged ISS (ISSave) in the thoracic aorta also increased in the HD group (baseline: 17.61±0.24 vs. 9 weeks: 25.22±0.95dyne/cm(2), n=4), but remained unchanged in the normal diet group (baseline: 22.85±0.53dyn/cm(2) vs. 9 weeks: 22.37±0.57dyne/cm(2), n=4). High-frequency intravascular ultrasound (IVUS) revealed atherosclerotic lesions in the regions with augmented ISSave, and concentric bipolar microelectrodes demonstrated elevated EIS signals, which were correlated with prominent anti-oxLDL immuno-staining (oxLDL-free regions: 497±55Ω, n=8 vs. oxLDL-rich lesions: 679±125Ω, n=12, P<0.05). The equivalent circuit model for tissue resistance between the lesion-free and ox-LDL-rich lesions further validated the experimental EIS signals. CONCLUSIONS: By applying electrochemical impedance in conjunction with shear stress and high-frequency ultrasound sensors, we provided a new strategy to identify oxLDL-laden lesions. The study demonstrated the feasibility of integrating EIS, ISS, and IVUS for a catheter-based approach to assess mechanically unstable plaque.

Predictive factors of impaired quality of life in Korean patients with inactive inflammatory bowel disease: association with functional gastrointestinal disorders and mood disorders.

BACKGROUND AND AIM: Inflammatory bowel disease is a chronic and relapsing inflammatory disorder of the intestine and has a great effect on patients' health-related quality of life (HRQOL). Some patients in remission are known to show functional gastrointestinal disorders (FGIDs) and mood disorders (MDs), which may also negatively impact HRQOL. The aim of this study was to evaluate predictors of impaired HRQOL in inactive inflammatory bowel disease (IBD) patients. METHODS: Patients presenting a long-standing remission during the previous year completed questionnaires of EuroQol, Rome III criteria for FGID, and Hospital Anxiety and Depression Survey. Demographic data including age, sex, employment status, education, smoking, and location of residence were also collected. RESULTS: Among the 513 patients with IBD, 226 (Crohn's disease 107 and ulcerative colitis 119, age 39.01±15.63, male 141) defined in remission were enrolled. Overall, 147 (65.0%) had at least 1 FGID with irritable bowel syndrome being the most common disorder (36.3%). Anxiety and depression were identified in 27.4% and 33.6%, respectively. Participants with FGID or MD had a significantly lower HRQOL status than those without disorders (P<0.01). Among various demographic and clinical variables, aged 40 or older [odds ratio (OR), 2.342; 95% confidence interval (CI), 1.195-4.590; P=0.01], irritable bowel syndrome (OR, 3.932; 95% CI, 1.937-7.982; P<0.01), and anxiety (OR, 2.423; 95% CI, 1.067-5.502; P=0.03) were significant independent predictors of impaired HRQOL in inactive IBD patients. CONCLUSIONS: FGID and MD are common in Korean quiescent IBD patients. Appropriate management should be administered according to age of patients and presence of concomitant FGID and MD to improve patients' HRQOL.

Relationship between adipokines and manifestations of childhood asthma.

Although the prevalences of asthma and obesity are increasing substantially in recent decades, very little is known about the possible association between them. We evaluated the roles of leptin, adiponectin, and resistin, which are adipokines produced by adipose tissue, on childhood asthma, and their association with pulmonary function and bronchial hyperresponsiveness. We studied 149 atopic asthmatic children, 37 non-atopic asthmatic children, and 54 healthy children. Body mass index was calculated using height and weight, which were measured on the same day that pulmonary function tests and methacholine challenge tests were performed. Skin prick tests were performed, and total eosinophil count, total serum immunoglobulin E (IgE), serum eosinophil cationic protein, leptin, adiponectin, and resistin were measured in all subjects. Atopic asthmatics had lower resistin levels compared with non-atopic asthma and control groups, but leptin and adiponectin did not show any difference among these three groups. Resistin demonstrated positive correlation with methacholine PC(20) and negative correlations with eosinophil count and serum total IgE. Leptin and adiponectin showed associations with forced expiratory volume in 1 s or forced expiratory flow between 25-75%. Multiple regression analysis revealed that resistin was a significant predictive factor for asthma. There was no direct association between asthma and leptin or adiponectin. Our findings suggest that resistin may play a negative predictive role in asthma. Adiponectin and leptin showed close associations with pulmonary function and may have disease-modifying effects in children with asthma.

The suppressive effects of oxcarbazepine on mechanical and cold allodynia in a rat model of neuropathic pain.

Oxcarbazepine (OCBZ) is a keto analog of carbamazepine (CBZ) and may have similar analgesic properties to CBZ, but studies on its effects in neuropathic pain conditions are rare. In this study, we evaluated the analgesic effects of OCBZ in a rat neuropathic pain model. Male Sprague-Dawley rats were prepared by tightly ligating the left L5 and L6 spinal nerves to produce neuropathic pain. Sixty neuropathic rats were randomly assigned into six groups, and normal saline, a vehicle (polyethylene glycol 400), and OCBZ (10 mg/kg, 20 mg/kg, 30 mg/kg, and 50 mg/kg) were intraperitoneally administered to these individual groups. Mechanical and cold allodynia were observed at preadministration and 15, 30, 60, 90, 120, 150, and 180 min after drug administration and were quantified by measuring withdrawal frequencies to stimuli with von Frey filaments and 100% acetone, respectively. Rotarod performance was measured to detect drug-induced adverse motor effects. In the OCBZ-treated groups, withdrawal frequencies to mechanical and cold stimuli were significantly reduced in a dose-dependent manner (P < 0.05). Only at the largest dose did OCBZ reduce rotarod performance time. These results suggest that OCBZ may be a possible therapeutic consideration in neuropathic pain conditions associated with allodynia and hyperalgesia.

The Callander laryngoscope blade modification is associated with a decreased risk of dental contact.

PURPOSE: Dental damage may occur with laryngoscopy. The purpose of this study was twofold: to determine whether preoperative examination could predict the risk of contacting the teeth with the laryngoscope and to evaluate the effectiveness of a modified Macintosh blade on reducing dental contact. METHODS: Four hundred and eighty-three patients scheduled for elective surgery requiring general anesthesia with endotracheal tube placement were studied prospectively. Features that might predict difficult intubation were assessed preoperatively. Laryngoscopy was performed twice on each patient, once with a regular Macintosh 3 blade and once with a blade in which the flange was partially removed (Callander modification). The distance between the flange of the blade and the upper incisors at glottic exposure was measured. We calculated correlations between individual airway characteristics and the chance of hitting the upper teeth with the regular Macintosh 3 blade and compared the frequencies of contacting the teeth between the two blades. RESULTS: The chance of hitting the upper teeth when using the regular Macintosh 3 blade increased significantly with non-parametric scores for Mallampati classification, mandibular subluxation, head and neck movement, interincisor gap, and condition of the upper teeth. (P < 0.01) The frequency of direct contact varied significantly between the two blades: 20.3% vs 4.1% for Macintosh 3 and modified blades, respectively (P < 0.05). Laryngeal views were improved with the modified blade. CONCLUSION: Airway characteristics correlate with the risk of hitting the upper teeth during laryngoscopy. The modified Macintosh blade reduces the risk of contacting the teeth.

Monensin-mediated growth inhibition in acute myelogenous leukemia cells via cell cycle arrest and apoptosis.

Monensin, an Na(+) ionophore, regulates many cellular functions including apoptosis. However, there has been no report about the antitumoral effect of monensin on acute myelogenous leukemia (AML). Here, we investigated the antiproliferative effect of monensin on AML cells in vitro and in vivo. Monensin efficiently inhibited the proliferation of all of 10 AML cell lines, with IC(50) of about 0.5 microM. DNA flow cytometric analysis indicated that monensin induced a G(1) and/or a G(2)-M phase arrest in these cell lines. To address the mechanism of the antiproliferative effect of monensin, we examined the effect of monensin on cell cycle-related proteins in HL-60 cells. The levels of CDK6, cyclin D1 and cyclin A were decreased. In addition, monensin not only increased the p27 level but also enhanced its binding with CDK2. Furthermore, the activities of CDK2- and CDK6-associated kinases reduced by monensin were associated with hypophosphorylation of Rb protein. Monensin also induced apoptosis in AML cells including HL-60 cells. The apoptotic process of HL-60 cells was associated with changes in Bax, caspase-3, caspase-8 and mitochondria transmembrane potential (Deltapsi(m)). In particular, monensin (i.p. at a dose of 8 mg/kg thrice weekly) significantly reduced the tumor size of BALB/c mice that were inoculated s.c. with its derived cell line, WEHI-3BD cells (69% growth inhibition relative to control group; p < 0.05). Tumors from monensin-treated mice exhibited increased apoptosis, and these tumor were immunohistochemically more stained with Bax, Fas and p53 antibodies than control tumors. In conclusion, this is the first report that monensin potently inhibits the proliferation of AML cells.