Response to pulmonary arterial hypertension drug therapies in patients with pulmonary arterial hypertension and cardiovascular risk factors.

The age at diagnosis of pulmonary arterial hypertension (PAH) and the prevalence of cardiovascular (CV) risk factors are increasing. We sought to determine whether the response to drug therapy was influenced by CV risk factors in PAH patients. We studied consecutive incident PAH patients (n = 146) between January 1, 2008, and July 15, 2011. Patients were divided into two groups: the PAH-No CV group included patients with no CV risk factors (obesity, systemic hypertension, type 2 diabetes mellitus, permanent atrial fibrillation, mitral and/or aortic valve disease, and coronary artery disease), and the PAH-CV group included patients with at least one. The response to PAH treatment was analyzed in all the patients who received PAH drug therapy. The PAH-No CV group included 43 patients, and the PAH-CV group included 69 patients. Patients in the PAH-No CV group were younger than those in the PAH-CV group (P < 0.0001). In the PAH-No CV group, 16 patients (37%) improved on treatment and 27 (63%) did not improve, compared with 11 (16%) and 58 (84%) in the PAH-CV group, respectively (P = 0.027 after adjustment for age). There was no difference in survival at 30 months (P = 0.218). In conclusion, in addition to older age, CV risk factors may predict a reduced response to PAH drug therapy in patients with PAH

Magnetic-field-induced charge redistribution in disordered graphene double quantum dots

We have studied the transport properties of a large graphene double quantum dot under the influence of a background disorder potential and a magnetic field. At low temperatures, the evolution of the charge-stability diagram as a function of the B field is investigated up to 10 T. Our results indicate that the charging energy of the quantum dot is reduced, and hence the effective size of the dot increases at a high magnetic field. We provide an explanation of our results using a tight-binding model, which describes the charge redistribution in a disordered graphene quantum dot via the formation of Landau levels and edge states. Our model suggests that the tunnel barriers separating different electron/hole puddles in a dot become transparent at high B fields, resulting in the charge delocalization and reduced charging energy observed experimentally.This work was financially supported by the European GRAND project (ICT/FET, Contract No. 215752) and EPSRC

Vortex detection and quantum transport in mesoscopic graphene Josephson-junction arrays

We investigate mesoscopic Josephson junction arrays created by patterning superconducting disks on monolayer graphene, concentrating on the high-$T/T_c$ regime of these devices and the phenomena which contribute to the superconducting glass state in diffusive arrays. We observe features in the magnetoconductance at rational fractions of flux quanta per array unit cell, which we attribute to the formation of flux-quantized vortices. The applied fields at which the features occur are well described by Ginzburg-Landau simulations that take into account the number of unit cells in the array. We find that the mean conductance and universal conductance fluctuations are both enhanced below the critical temperature and field of the superconductor, with greater enhancement away from the graphene Dirac point.This work was financially supported by the Engineering and Physical Sciences Research Council, and an NPL/EPSRC Joint Postdoctoral Partnership (RG61493).This is the accepted manuscript. The final version is available at http://journals.aps.org/prb/abstract/10.1103/PhysRevB.91.245418

Edoxaban: an update on the new oral direct factor Xa inhibitor.

Edoxaban is a once-daily oral anticoagulant that rapidly and selectively inhibits factor Xa in a concentration-dependent manner. This review describes the extensive clinical development program of edoxaban, including phase III studies in patients with non-valvular atrial fibrillation (NVAF) and symptomatic venous thromboembolism (VTE). The ENGAGE AF-TIMI 48 study (N = 21,105; mean CHADS2 score 2.8) compared edoxaban 60 mg once daily (high-dose regimen) and edoxaban 30 mg once daily (low-dose regimen) with dose-adjusted warfarin [international normalized ratio (INR) 2.0-3.0] and found that both regimens were non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with NVAF. Both edoxaban regimens also provided significant reductions in the risk of hemorrhagic stroke, cardiovascular mortality, major bleeding and intracranial bleeding. The Hokusai-VTE study (N = 8,292) in patients with symptomatic VTE had a flexible treatment duration of 3-12 months and found that following initial heparin, edoxaban 60 mg once daily was non-inferior to dose-adjusted warfarin (INR 2.0-3.0) for the prevention of recurrent VTE, and also had a significantly lower risk of bleeding events. Both studies randomized patients at moderate-to-high risk of thromboembolic events and were further designed to simulate routine clinical practice as much as possible, with edoxaban dose reduction (halving dose) at randomisation or during the study if required, a frequently monitored and well-controlled warfarin group, a well-monitored transition period at study end and a flexible treatment duration in Hokusai-VTE. Given the phase III results obtained, once-daily edoxaban may soon be a key addition to the range of antithrombotic treatment options

Imaging ballistic carrier trajectories in graphene using scanning gate microscopy

We use scanning gate microscopy to map out the trajectories of ballistic carriers in high-mobility graphene encapsulated by hexagonal boron nitride and subject to a weak magnetic field. We employ a magnetic focusing geometry to image carriers that emerge ballistically from an injector, follow a cyclotron path due to the Lorentz force from an applied magnetic field, and land on an adjacent collector probe. The local electric field generated by the scanning tip in the vicinity of the carriers deflects their trajectories, modifying the proportion of carriers focused into the collector. By measuring the voltage at the collector while scanning the tip, we are able to obtain images with arcs that are consistent with the expected cyclotron motion. We also demonstrate that the tip can be used to redirect misaligned carriers back to the collector.This work was partly supported by the EPSRC; a Grant-in-Aid for Scientific Research on Innovative Areas “Science of Atomic Layers” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT); the Project for Developing Innovation Systems of MEXT; the Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS); and the CREST, Japan Science and Technology Agency.This is the author accepted manuscript. The final version is available from AIP via http://dx.doi.org/10.1063/1.493747

Encapsulation of graphene transistors and vertical device integration by interface engineering with atomic layer deposited oxide

We demonstrate a simple, scalable approach to achieve encapsulated graphene transistors with negligible gate hysteresis, low doping levels and enhanced mobility compared to as-fabricated devices. We engineer the interface between graphene and atomic layer deposited (ALD) Al$_{2}$O$_{3}$ by tailoring the growth parameters to achieve effective device encapsulation whilst enabling the passivation of charge traps in the underlying gate dielectric. We relate the passivation of charge trap states in the vicinity of the graphene to conformal growth of ALD oxide governed by $\textit{in situ}$ gaseous H$_{2}$O pretreatments. We demonstrate the long term stability of such encapsulation techniques and the resulting insensitivity towards additional lithography steps to enable vertical device integration of graphene for multi-stacked electronics fabrication.This work was supported by the EPSRC (Grant Nos. EP/K016636/1, GRAPHTED and EP/L020963/1) and the ERC (Grant No. 279342, InsituNANO). JAA-W acknowledges a Research Fellowship from Churchill College, Cambridge. JS acknowledges support from NUDT. ZAVV acknowledges funding from ESPRC grant EP/L016087/1. ACV acknowledges the Conacyt Cambridge Scholarship and the Roberto Rocca Fellowship. RW acknowledges EPSRC Doctoral Training Award (EP/M506485/1)

Children and older adults exhibit distinct sub-optimal cost-benefit functions when preparing to move their eyes and hands

"© 2015 Gonzalez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited"Numerous activities require an individual to respond quickly to the correct stimulus. The provision of advance information allows response priming but heightened responses can cause errors (responding too early or reacting to the wrong stimulus). Thus, a balance is required between the online cognitive mechanisms (inhibitory and anticipatory) used to prepare and execute a motor response at the appropriate time. We investigated the use of advance information in 71 participants across four different age groups: (i) children, (ii) young adults, (iii) middle-aged adults, and (iv) older adults. We implemented 'cued' and 'non-cued' conditions to assess age-related changes in saccadic and touch responses to targets in three movement conditions: (a) Eyes only; (b) Hands only; (c) Eyes and Hand. Children made less saccade errors compared to young adults, but they also exhibited longer response times in cued versus non-cued conditions. In contrast, older adults showed faster responses in cued conditions but exhibited more errors. The results indicate that young adults (18 -25 years) achieve an optimal balance between anticipation and execution. In contrast, children show benefits (few errors) and costs (slow responses) of good inhibition when preparing a motor response based on advance information; whilst older adults show the benefits and costs associated with a prospective response strategy (i.e., good anticipation)

Numerical analysis of the resistance behavior of an electrostatically-induced graphene double junction

We present a numerical approach that we have developed in order to reproduce and explain the resistance behavior recently observed, as a function of the backgate voltage and of the position of a biased scanning probe, in a graphene flake in which a double p-n junction has been electrostatically induced. A simplified electrostatic model has been adopted to simulate the effect of gate voltages on the potential landscape, assuming for it a slow variation in space and using a simple capacitive model for the coupling between the electrodes and the graphene sheet. The transport analysis has then been performed with a solution of the Dirac equation in the reciprocal space coupled with a recursive scattering matrix approach. The efficiency of the adopted numerical procedure has allowed us to explore a wide range of possible potential landscapes and bias points, with the result of achieving a good agreement with available experimental data

Evidence of altered fatty acid metabolism in dogs with naturally occurring valvular heart disease and congestive heart failure

Introduction Myxomatous mitral valve disease (MMVD) is the most common cardiac condition in adult dogs. The disease progresses over several years and affected dogs may develop congestive heart failure (HF). Research has shown that myocardial metabolism is altered in cardiac disease, leading to a reduction in β-oxidation of fatty acids and an increased dependence upon glycolysis. Objectives This study aimed to evaluate whether a shift in substrate use occurs in canine patients with MMVD; a naturally occurring model of human disease. Methods Client-owned dogs were longitudinally evaluated at a research clinic in London, UK and paired serum samples were selected from visits when patients were in ACVIM stage B1: asymptomatic disease without cardiomegaly, and stage C: HF. Samples were processed using ultra-performance liquid chromatography mass spectrometry and lipid profiles were compared using mixed effects models with false discovery rate adjustment. The effect of disease stage was evaluated with patient breed entered as a confounder. Features that significantly differed were screened for selection for annotation efforts using reference databases. Results Dogs in HF had altered concentrations of lipid species belonging to several classes previously associated with cardiovascular disease. Concentrations of certain acylcarnitines, phospholipids and sphingomyelins were increased after individuals had developed HF, whilst some ceramides and lysophosphatidylcholines decreased. Conclusions The canine metabolome appears to change as MMVD progresses. Findings from this study suggest that in HF myocardial metabolism may be characterised by reduced β-oxidation. This proposed explanation warrants further research

High-dose intravenous iron reduces myocardial infarction in patients on haemodialysis

AIMS: To investigate the effect of high-dose iron vs. low-dose intravenous (IV) iron on myocardial infarction (MI) in patients on maintenance haemodialysis. METHODS AND RESULTS: This was a pre-specified analysis of secondary endpoints of the Proactive IV Iron Therapy in Hemodialysis Patients trial (PIVOTAL) randomized, controlled clinical trial. Adults who had started haemodialysis within the previous year, who had a ferritin concentration <400 μg per litre and a transferrin saturation <30% were randomized to high-dose or low-dose IV iron. The main outcome measure for this analysis was fatal or non-fatal MI. Over a median of 2.1 years of follow-up, 8.4% experienced a MI. Rates of type 1 MIs (3.2/100 patient-years) were 2.5 times higher than type 2 MIs (1.3/100 patient-years). Non-ST-elevation MIs (3.3/100 patient-years) were 6 times more common than ST-elevation MIs (0.5/100 patient-years). Mortality was high after non-fatal MI (1- and 2-year mortality of 40% and 60%, respectively). In time-to-first event analyses, proactive high-dose IV iron reduced the composite endpoint of non-fatal and fatal MI [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.52-0.93, P = 0.01] and non-fatal MI (HR 0.69, 95% CI 0.51-0.93; P = 0.01) when compared with reactive low-dose IV iron. There was less effect of high-dose IV iron on recurrent MI events than on the time-to-first event analysis. CONCLUSION: In total, 8.4% of patients on maintenance haemodialysis had an MI over 2 years. High-dose compared to low-dose IV iron reduced MI in patients receiving haemodialysis. EUDRACT REGISTRATION NUMBER: 2013-002267-25