Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes : the randomised, head-to-head CONCLUDE trial

Aims/hypothesis A head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin. Methods This randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0–5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period. Results Of the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300. Conclusions/interpretation There was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300

Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial.

OBJECTIVE: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) study demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status. RESEARCH DESIGN AND METHODS: We enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2, and urinary albumin-to-creatinine ratio 200-5,000 mg/g. The primary composite end point was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death. RESULTS: Of 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent (P for interaction = 0.19) in normoglycemia (hazard ratio [HR] 0.62 [95% CI 0.39, 1.01]), prediabetes (HR 0.37 [0.21, 0.66]), and type 2 diabetes (HR 0.64 [0.52, 0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes. CONCLUSIONS: Dapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status

An exceptional horizontal gene transfer in plastids: gene replacement by a distant bacterial paralog and evidence that haptophyte and cryptophyte plastids are sisters

BACKGROUND: Horizontal gene transfer (HGT) to the plant mitochondrial genome has recently been shown to occur at a surprisingly high rate; however, little evidence has been found for HGT to the plastid genome, despite extensive sequencing. In this study, we analyzed all genes from sequenced plastid genomes to unearth any neglected cases of HGT and to obtain a measure of the overall extent of HGT to the plastid. RESULTS: Although several genes gave strongly supported conflicting trees under certain conditions, we are confident of HGT in only a single case beyond the rubisco HGT already reported. Most of the conflicts involved near neighbors connected by long branches (e.g. red algae and their secondary hosts), where phylogenetic methods are prone to mislead. However, three genes – clpP, ycf2, and rpl36 – provided strong support for taxa moving far from their organismal position. Further taxon sampling of clpP and ycf2 resulted in rejection of HGT due to long-branch attraction and a serious error in the published plastid genome sequence of Oenothera elata, respectively. A single new case, a bacterial rpl36 gene transferred into the ancestor of the cryptophyte and haptophyte plastids, appears to be a true HGT event. Interestingly, this rpl36 gene is a distantly related paralog of the rpl36 type found in other plastids and most eubacteria. Moreover, the transferred gene has physically replaced the native rpl36 gene, yet flanking genes and intergenic regions show no sign of HGT. This suggests that gene replacement somehow occurred by recombination at the very ends of rpl36, without the level and length of similarity normally expected to support recombination. CONCLUSION: The rpl36 HGT discovered in this study is of considerable interest in terms of both molecular mechanism and phylogeny. The plastid acquisition of a bacterial rpl36 gene via HGT provides the first strong evidence for a sister-group relationship between haptophyte and cryptophyte plastids to the exclusion of heterokont and alveolate plastids. Moreover, the bacterial gene has replaced the native plastid rpl36 gene by an uncertain mechanism that appears inconsistent with existing models for the recombinational basis of gene conversion

Activation of Peroxisome Proliferator-Activated Receptor Gamma by Rosiglitazone Increases Sirt6 Expression and Ameliorates Hepatic Steatosis in Rats

Sirt6 has been implicated in the regulation of hepatic lipid metabolism and the development of hepatic steatosis. The aim of this study was to address the potential role of Sirt6 in the protective effects of rosiglitazone (RGZ) on hepatic steatosis.) by stomach gavage for 6 weeks. The involvement of Sirt6 in the RGZ's regulation was evaluated by Sirt6 knockdown in AML12 mouse hepatocytes.RGZ treatment ameliorated hepatic lipid accumulation and increased expression of Sirt6, peroxisome proliferator-activated receptor gamma coactivtor-1-α (Ppargc1a/PGC1-α) and Forkhead box O1 (Foxo1) in rat livers. AMP-activated protein kinase (AMPK) phosphorylation was also increased by RGZ, accompanied by alterations in phosphorylation of LKB1. Interestingly, in free fatty acid-treated cells, Sirt6 knockdown increased hepatocyte lipid accumulation measured as increased triglyceride contents (p = 0.035), suggesting that Sirt6 may be beneficial in reducing hepatic fat accumulation. In addition, Sirt6 knockdown abolished the effects of RGZ on hepatocyte fat accumulation, mRNA and protein expression of Ppargc1a/PGC1-α and Foxo1, and phosphorylation levels of LKB1 and AMPK, suggesting that Sirt6 is involved in RGZ-mediated metabolic effects.Our results demonstrate that RGZ significantly decreased hepatic lipid accumulation, and that this process appeared to be mediated by the activation of the Sirt6-AMPK pathway. We propose Sirt6 as a possible therapeutic target for hepatic steatosis

Angiogenesis inhibitors in the treatment of prostate cancer

Prostate cancer remains a significant public health problem, with limited therapeutic options in the setting of castrate-resistant metastatic disease. Angiogenesis inhibition is a relatively novel antineoplastic approach, which targets the reliance of tumor growth on the formation of new blood vessels. This strategy has been used successfully in other solid tumor types, with the FDA approval of anti-angiogenic agents in breast, lung, colon, brain, and kidney cancer. The application of anti-angiogenic therapy to prostate cancer is reviewed in this article, with attention to efficacy and toxicity results from several classes of anti-angiogenic agents. Ultimately, the fate of anti-angiogenic agents in prostate cancer rests on the eagerly anticipated results of several key phase III studies

Re-examining the Unified Theory of Acceptance and Use of Technology (UTAUT): Towards a Revised Theoretical Model

YesBased on a critical review of the Unified Theory of Acceptance and Use of Technology (UTAUT), this study first formalized an alternative theoretical model for explaining the acceptance and use of information system (IS) and information technology (IT) innovations. The revised theoretical model was then empirically examined using a combination of meta-analysis and structural equation modelling (MASEM) techniques. The meta-analysis was based on 1600 observations on 21 relationships coded from 162 prior studies on IS/IT acceptance and use. The SEM analysis showed that attitude: was central to behavioural intentions and usage behaviours, partially mediated the effects of exogenous constructs on behavioural intentions, and had a direct influence on usage behaviours. A number of implications for theory and practice are derived based on the findings

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

EEG artifacts reduction by multivariate empirical mode decomposition and multiscale entropy for monitoring depth of anaesthesia during surgery

Electroencephalography (EEG) has been widely utilized to measure the depth of anaesthesia (DOA) during operation. However, the EEG signals are usually contaminated by artifacts which have a consequence on the measured DOA accuracy. In this study, an effective and useful filtering algorithm based on multivariate empirical mode decomposition and multiscale entropy (MSE) is proposed to measure DOA. Mean entropy of MSE is used as an index to find artifacts-free intrinsic mode functions. The effect of different levels of artifacts on the performances of the proposed filtering is analysed using simulated data. Furthermore, 21 patients' EEG signals are collected and analysed using sample entropy to calculate the complexity for monitoring DOA. The correlation coefficients of entropy and bispectral index (BIS) results show 0.14 ± 0.30 and 0.63 ± 0.09 before and after filtering, respectively. Artificial neural network (ANN) model is used for range mapping in order to correlate the measurements with BIS. The ANN method results show strong correlation coefficient (0.75 ± 0.08). The results in this paper verify that entropy values and BIS have a strong correlation for the purpose of DOA monitoring and the proposed filtering method can effectively filter artifacts from EEG signals. The proposed method performs better than the commonly used wavelet denoising method. This study provides a fully adaptive and automated filter for EEG to measure DOA more accuracy and thus reduce risk related to maintenance of anaesthetic agents.This research was financially supported by the Center for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan, which is sponsored by Ministry of Science and Technology (Grant Number: NSC102-2911-I-008-001). Also, it was supported by Chung-Shan Institute of Science and Technology in Taiwan (Grant Numbers: CSIST-095-V301 and CSIST-095-V302) and National Natural Science Foundation of China (Grant Number: 51475342)

Particulate Fillers in Thermoplastics

The characteristics of particulate filled thermoplastics are determined by four factors: component properties, composition, structure and interfacial interactions. The most important filler characteristics are particle size, size distribution, specific surface area and particle shape, while the main matrix property is stiffness. Segregation, aggregation and the orientation of anisotropic particles determine structure. Interfacial interactions lead to the formation of a stiff interphase considerably influencing properties. Interactions are changed by surface modification, which must be always system specific and selected according to its goal. Under the effect of external load inhomogeneous stress distribution develops around heterogeneities, which initiate local micromechanical deformation processes determining the macroscopic properties of the composites