Initial combination of linagliptin and metformin compared with linagliptin monotherapy in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia: a randomized, double-blind, active-controlled, parallel group, multinational clinical trial.

Aims To evaluate glucose-lowering treatment strategies with linagliptin and metformin in people with newly diagnosed type 2 diabetes and marked hyperglycaemia, a prevalent population for which few dedicated studies of oral antidiabetes drugs have been conducted. Methods A total of 316 patients, with type 2 diabetes diagnosed for ≤12 months and with glycated haemoglobin (HbA1c) concentration in the range 8.5–12.0%, were randomized 1:1 to double-blind, free-combination treatment with linagliptin 5 mg once daily and metformin twice daily (uptitrated to 2000 mg/day maximum) or to linagliptin monotherapy. The primary endpoint was change in HbA1c concentration from baseline at week 24 (per-protocol completers' cohort: n = 245). Results The mean (standard deviation) age and HbA1c at baseline were 48.8 (11.0) years and 9.8 (1.1)%, respectively. At week 24, the mean ± standard error (s.e.) HbA1c decreased from baseline by –2.8 ± 0.1% with linagliptin/metformin and –2.0 ± 0.1% with linagliptin; a treatment difference of –0.8% (95% confidence interval –1.1 to –0.5; p <0.0001). Similar results were observed in a sensitivity analysis based on intent-to-treat principles: adjusted mean ± s.e. changes in HbA1c of –2.7 ± 0.1% and –1.8 ± 0.1%, respectively; treatment difference of –0.9% (95% CI –1.3 to –0.6; p <0.0001). A treatment response of HbA1c <7.0% was achieved by 61 and 40% of patients in the linagliptin/metformin and linagliptin groups, respectively. Few patients experienced drug-related adverse events (8.8 and 5.7% of patients in the linagliptin/metformin and linagliptin groups, respectively). Hypoglycaemia occurred in 1.9 and 3.2% of patients in the linagliptin/metformin and linagliptin groups, respectively (no severe episodes). Body weight decreased significantly with the combination therapy (–1.3 kg between-group difference; p =0.0033). Conclusions Linagliptin in initial combination with metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia, an understudied group, elicited significant improvements in glycaemic control with a low incidence of hypoglycaemia, weight gain or other adverse effects. These results support early combination treatment strategies and suggest that newly diagnosed patients with marked hyperglycaemia may be effectively managed with oral, non-insulin therapy

Alternate SlyA and H-NS nucleoprotein complexes control hlyE expression in Escherichia coli K-12

Haemolysin E is a cytolytic pore-forming toxin found in several Escherichia coli and Salmonella enterica strains. Expression of hlyE is repressed by the global regulator H-NS (histone-like nucleoid structuring protein), but can be activated by the regulator SlyA. Expression of a chromosomal hlyE–lacZ fusion in an E. coli slyA mutant was reduced to 60% of the wild-type level confirming a positive role for SlyA. DNase I footprint analysis revealed the presence of two separate SlyA binding sites, one located upstream, the other downstream of the hlyE transcriptional start site. These sites overlap AT-rich H-NS binding sites. Footprint and gel shift data showed that whereas H-NS prevented binding of RNA polymerase (RNAP) at the hlyE promoter (PhlyE), SlyA allowed binding of RNAP, but inhibited binding of H-NS. Accordingly, in vitro transcription analyses showed that addition of SlyA protein relieved H-NS-mediated repression of hlyE. Based on these observations a model for SlyA/H-NS regulation of hlyE expression is proposed in which the relative concentrations of SlyA and H-NS govern the nature of the nucleoprotein complexes formed at PhlyE. When H-NS is dominant RNAP binding is inhibited and hlyE expression is silenced; when SlyA is dominant H-NS binding is inhibited allowing RNAP access to the promoter facilitating hlyE transcription

Determination of the Fermi Velocity by Angle-dependent Periodic Orbit Resonance Measurements in the Organic Conductor alpha-(BEDT-TTF)2KHg(SCN)4

We report detailed angle-dependent studies of the microwave (f=50 to 90 GHz) interlayer magneto-electrodynamics of a single crystal sample of the organic charge-density-wave (CDW) conductor alpha-(BEDT-TTF)2KHg(SCN)4. Recently developed instrumentation enables both magnetic field (B) sweeps for a fixed sample orientation and, for the first time, angle sweeps at fixed f/B. We observe series' of resonant absorptions which we attribute to periodic orbit resonances (POR) - a phenomenon closely related to cyclotron resonance. The angle dependence of the POR indicate that they are associated with the low temperature quasi-one-dimensional (Q1D) Fermi surface (FS) of the title compound; indeed, all of the resonance peaks collapse beautifully onto a single set of f/B versus angle curves, generated using a semiclassical magneto-transport theory for a single Q1D FS. We show that Q1D POR measurements provide one of the most direct methods for determining the Fermi velocity, without any detailed assumptions concerning the bandstructure; our analysis yields an average value of v_F=6.5x10^4 m/s. Quantitative analysis of the POR harmonic content indicates that the Q1D FS is strongly corrugated. This is consistent with the assumption that the low-temperature FS derives from a reconstruction of the high temperature quasi-two-dimensional FS, caused by the CDW instability. Detailed analysis of the angle dependence of the POR yields parameters associated with the CDW superstructure which are consistent with published results. Finally, we address the issue as to whether or not the interlayer electrodynamics are coherent in the title compound.Comment: 28 pages, including 6 figures. Submitted to PR

The role of groups as local context in large Enterprise Social Networks: A Case Study of Yammer at Deloitte Australia

Enterprise Social Networking, the application of popular social networking techniques to the workplaces of organisations, is an increasingly common phenomenon. But its nature, benefits and proliferation are not yet fully understood. In this study we investigate ESN communication at the micro-level. We focus on the role of the group feature in structuring and providing context for communication in large ESNs. Our case study is Yammer at Deloitte. In contrast to previous studies we carry out an analysis of communication at the thread (conversation) level, rather than at the level of single messages. This allows us to provide a more contextual understanding of the group aspects of communication. We find that information sharing underpins the majority of communication threads, which speaks to the usefulness of ESN, in particular in the context of knowledge-intensive work. We further uncover differences between network-wide and group-centred communication and derive a framework of four group archetypes, based on different group communication patterns. Our findings are useful for decision-makers in providing a better understanding of the role of groups in providing local contexts for users in large ESNs

Risk factors for delirium and cognitive decline following coronary artery bypass grafting surgery: a systematic review and meta-analysis

Background: Coronary artery bypass grafting (CABG) is known to improve heart function and quality of life, while rates of surgery-related mortality are low. However, delirium and cognitive decline are common complications. We sought to identify preoperative, intraoperative, and postoperative risk or protective factors associated with delirium and cognitive decline (across time) in patients undergoing CABG. Methods and Results: We conducted a systematic search of Medline, PsycINFO, EMBASE, and Cochrane (March 26, 2019) for peer-reviewed, English publications reporting post-CABG delirium or cognitive decline data, for at least one risk factor. Random-effects meta-analyses estimated pooled odds ratio for categorical data and mean difference or standardized mean difference for continuous data. Ninety-seven studies, comprising data from 60 479 patients who underwent CABG, were included. Moderate to large and statistically significant risk factors for delirium were as follows: (1) preoperative cognitive impairment, depression, stroke history, and higher European System for Cardiac Operative Risk Evaluation (EuroSCORE) score, (2) intraoperative increase in intubation time, and (3) postoperative presence of arrythmia and increased days in the intensive care unit; higher preoperative cognitive performance was protective for delirium. Moderate to large and statistically significant risk factors for acute cognitive decline were as follows: (1) preoperative depression and older age, (2) intraoperative increase in intubation time, and (3) postoperative presence of delirium and increased days in the intensive care unit. Presence of depression preoperatively was a moderate risk factor for midterm (1–6 months) post-CABG cognitive decline. Conclusions: This meta-analysis identified several key risk factors for delirium and cognitive decline following CABG, most of which are nonmodifiable. Future research should target preoperative risk factors, such as depression or cognitive impairment, which are potentially modifiable.Danielle Greaves, Peter J. Psaltis, Daniel H.J. Davis, Tyler J. Ross, Erica S. Ghezzi, Amit Lampit, Ashleigh E. Smith, Hannah A.D. Keag

Somatotypes trajectories during adulthood and their association with COPD phenotypes

Rationale: Chronic obstructive pulmonary disease (COPD) comprises distinct phenotypes, all characterised by airflow limitation. Objectives: We hypothesised that somatotype changes - as a surrogate of adiposity - from early adulthood follow different trajectories to reach distinct phenotypes. Methods: Using the validated Stunkard''s Pictogram, 356 COPD patients chose the somatotype that best reflects their current body build and those at ages 18, 30, 40 and 50 years. An unbiased group-based trajectory modelling was used to determine somatotype trajectories. We then compared the current COPD-related clinical and phenotypic characteristics of subjects belonging to each trajectory. Measurements and main results: At 18 years of age, 88% of the participants described having a lean or medium somatotype (estimated body mass index (BMI) between 19 and 23 kg.m(-2)) while the other 12% a heavier somatotype (estimated BMI between 25 and 27 kg.m(-2)). From age 18 onwards, five distinct trajectories were observed. Four of them demonstrating a continuous increase in adiposity throughout adulthood with the exception of one, where the initial increase was followed by loss of adiposity after age 40. Patients with this trajectory were primarily females with low BMI and D-LCO (diffusing capacity of the lung for carbon monoxide). A persistently lean trajectory was seen in 14% of the cohort. This group had significantly lower forced expiratory volume in 1 s (FEV1), D-LCO, more emphysema and a worse BODE (BMI, airflow obstruction, dyspnoea and exercise capacity) score thus resembling the multiple organ loss of tissue (MOLT) phenotype. Conclusions: COPD patients have distinct somatotype trajectories throughout adulthood. Those with the MOLT phenotype maintain a lean trajectory throughout life. Smoking subjects with this lean phenotype in early adulthood deserve particular attention as they seem to develop more severe COPD

Alternative Systems of Crime Control. National, Transnational, and International Dimensions

The typical trial-oriented systems of criminal justice that are primarily based on the strict application of substantive criminal law have reached their functional and logistical limits in most parts of the modern legal world. As a result, new sanction models, less formal, administrative, and discretionary case disposals, plea bargaining arrangements, and other alternative procedural and transitional justice mechanisms have emerged at unprecedented levels in national and international legal orders affiliated both with the civil law and the common law tradition. These normative constructs and practices aim at abbreviating, simplifying, or circumventing the conventional criminal investigation and prosecution. They seek to enhance the effectiveness of conflict resolution proceedings and to shift the focus of crime control from repression to prevention. The present volume explores these alternative, informal, preventive, and transitional types of criminal justice and the legitimacy of new sanction models in the global risk society from the perspective of national and international justice and by focusing on the special regimes of anti-terrorism measures and security law. The authors of the papers are experts and internationally acclaimed scholars in this field. Their research results were presented and discussed at an inter-national conference held on 26-27 January 2018 at Middle Temple in London, UK, which was organized by the School of Law of the Queen Mary University of London, the Max Planck Institute for Foreign and International Criminal Law (Freiburg), and the European & International Criminal Law Institute (Athens)

Low PCA3 expression is a marker of poor differentiation in localized prostate tumors: exploratory analysis from 12,076 patients

Contains fulltext : 177804.pdf (publisher's version ) (Open Access)BACKGROUND: Prostate cancer antigen 3 (PCA3) is a prostate cancer diagnostic biomarker that has been clinically validated. The limitations of the diagnostic role of PCA3 in initial biopsy and the prognostic role are not well established. Here, we elucidate the limitations of tissue PCA3 to predict high grade tumors in initial biopsy. RESULTS: PCA3 has a bimodal distribution in both biopsy and radical prostatectomy (RP) tissues, where low PCA3 expression was significantly associated with high grade disease (p/=8) with 55% sensitivity and high false negative rates; 42% of high Gleason (>/=8) samples had low PCA3. In RP, low PCA3 is associated with adverse pathological features, clinical recurrence outcome and greater probability of metastatic progression (p<0.001). MATERIALS AND METHODS: A total of 1,694 expression profiles from biopsy and 10,382 from RP patients with high risk tumors were obtained from the Decipher Genomic Resource Information Database (GRIDTM)prostate cancer database. The primary clinical endpoint was distant metastasis-free survival for RP and high Gleason grade for biopsy. Logistic regression analyses and Cox proportional hazards models were used to evaluate the association of PCA3 with clinical variables and risk of metastasis. CONCLUSIONS: There is high prevalence of high grade tumors with low PCA3 expression in the biopsy setting. Therefore, urologists should be warned that using PCA3 as stand-alone test may lead to high rate of under-diagnosis of high grade disease in initial biopsy setting

Marine pelagic ecosystems: the West Antarctic Peninsula

The marine ecosystem of the West Antarctic Peninsula (WAP) extends from the Bellingshausen Sea to the northern tip of the peninsula and from the mostly glaciated coast across the continental shelf to the shelf break in the west. The glacially sculpted coastline along the peninsula is highly convoluted and characterized by deep embayments that are often interconnected by channels that facilitate transport of heat and nutrients into the shelf domain. The ecosystem is divided into three subregions, the continental slope, shelf and coastal regions, each with unique ocean dynamics, water mass and biological distributions. The WAP shelf lies within the Antarctic Sea Ice Zone (SIZ) and like other SIZs, the WAP system is very productive, supporting large stocks of marine mammals, birds and the Antarctic krill, Euphausia superba. Ecosystem dynamics is dominated by the seasonal and interannual variation in sea ice extent and retreat. The Antarctic Peninsula is one among the most rapidly warming regions on Earth, having experienced a 28C increase in the annual mean temperature and a 68C rise in the mean winter temperature since 1950. Delivery of heat from the Antarctic Circumpolar Current has increased significantly in the past decade, sufficient to drive to a 0.68C warming of the upper 300 m of shelf water. In the past 50 years and continuing in the twenty-first century, the warm, moist maritime climate of the northern WAP has been migrating south, displacing the once dominant cold, dry continental Antarctic climate and causing multi-level responses in the marine ecosystem. Ecosystem responses to the regional warming include increased heat transport, decreased sea ice extent and duration, local declines in icedependent Ade´lie penguins, increase in ice-tolerant gentoo and chinstrap penguins, alterations in phytoplankton and zooplankton community composition and changes in krill recruitment, abundance and availability to predators. The climate/ecological gradients extending along theWAPand the presence of monitoring systems, field stations and long-term research programmes make the region an invaluable observatory of climate change and marine ecosystem response