Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial: study protocol for a multicentre international trial of cardiac output-guided fluid therapy with low-dose inotrope infusion compared with usual care in patients undergoing major elective gastrointestinal surgery.

INTRODUCTION: Postoperative morbidity and mortality in older patients with comorbidities undergoing gastrointestinal surgery are a major burden on healthcare systems. Infections after surgery are common in such patients, prolonging hospitalisation and reducing postoperative short-term and long-term survival. Optimal management of perioperative intravenous fluids and inotropic drugs may reduce infection rates and improve outcomes from surgery. Previous small trials of cardiac-output-guided haemodynamic therapy algorithms suggested a modest reduction in postoperative morbidity. A large definitive trial is needed to confirm or refute this and inform widespread clinical practice. METHODS: The Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial is a multicentre, international, parallel group, open, randomised controlled trial. 2502 high-risk patients undergoing major elective gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intravenous fluid combined with low-dose inotrope infusion, or usual care. The trial intervention will be carried out during and for 4 hours after surgery. The primary outcome is postoperative infection of Clavien-Dindo grade II or higher within 30 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation; however, outcome assessors will be blinded when feasible. Participant recruitment started in January 2017 and is scheduled to last 3 years, within 50 hospitals worldwide. ETHICS/DISSEMINATION: The OPTIMISE II trial has been approved by the UK National Research Ethics Service and has been approved by responsible ethics committees in all participating countries. The findings will be disseminated through publication in a widely accessible peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: ISRCTN39653756.The OPTIMISE II trial is supported by Edwards Lifesciences (Irvine, CA) and the UK National Institute for Health Research through RMP’s NIHR Professorship

Graphene Conductance Uniformity Mapping

We demonstrate a combination of micro four-point probe (M4PP) and non-contact terahertz time-domain spectroscopy (THz-TDS) measurements for centimeter scale quantitative mapping of the sheet conductance of large area chemical vapor deposited graphene films. Dual configuration M4PP measurements, demonstrated on graphene for the first time, provide valuable statistical insight into the influence of microscale defects on the conductance, while THz-TDS has potential as a fast, non-contact metrology method for mapping of the spatially averaged nanoscopic conductance on wafer-scale graphene with scan times of less than a minute for a 4-in. wafer. The combination of M4PP and THz-TDS conductance measurements, supported by micro Raman spectroscopy and optical imaging, reveals that the film is electrically continuous on the nanoscopic scale with microscopic defects likely originating from the transfer process, dominating the microscale conductance of the investigated graphene film

Risk of incident atrial fibrillation in patients presenting with retinal artery or vein occlusion: a nationwide cohort study

Abstract Background The inter-relationships of atrial fibrillation (AF) to retinal vascular occlusions (whether retinal artery occlusion (RAO) or retinal venous occlusion (RVO)) remain unclear. It is unknown if a presentation of retinal artery or venous occlusions may indicate a new onset cardiac arrhythmia. To shed light on this association, we investigated the risk of new onset AF in patients with known RAO and RVO. Methods Patients with retinal occlusions from 1997 to 2011 were identified through Danish nationwide registries and matched 1:5 according to sex and age. Cumulative incidence and unadjusted rates of AF according to retinal vascular occlusions (i.e. RAO or RVO) were determined. Hazard ratios (HR) of AF according to retinal vascular occlusion were adjusted for hypertension, diabetes, vascular disease and prior stroke/systemic thromboembolism/transient ischemic attack. Results One thousand three hundred sixty-eight cases with retinal vascular occlusions were identified (median age 71.4 (inter quartile range (IQR); 61.2–79.8), 47.3% male). RAO constituted 706 cases (51.6%) and RVO 529 (38.7%). The rate of incident AF amongst all cases with retinal vascular occlusion was 1.74 per 100 person-years (95% confidence interval (CI), 1.47–2.06) compared to 1.22 (95% CI, 1.12–1.33) in the matched control group. The rate of AF in RAO was 2.01 (95% CI, 1.6–2.52) and 1.52 (1.15–2.01) in RVO. HRs of incident AF adjusted for cardiovascular comorbidities were 1.26 (95% CI; 1.04–1.53, p = 0.019) for any retinal vascular occlusion, 1.45 (95% CI; 1.10–1.89, p = 0.015) for RAO, and 1.02 (95% CI; 0.74–1.39, p = 0.920) for RVO. Conclusions A new diagnosis of retinal vascular occlusion in patients without prior AF was associated with increased risk of incident AF, particularly amongst patients with RAO. Awareness of AF in patients with retinal vascular occlusions is advised

Inhibition of Bcl-xL prevents pro-death actions of ΔN-Bcl-xL at the mitochondrial inner membrane during glutamate excitotoxicity.

ABT-737 is a pharmacological inhibitor of the anti-apoptotic activity of B-cell lymphoma-extra large (Bcl-xL) protein; it promotes apoptosis of cancer cells by occupying the BH3-binding pocket. We have shown previously that ABT-737 lowers cell metabolic efficiency by inhibiting ATP synthase activity. However, we also found that ABT-737 protects rodent brain from ischemic injury in vivo by inhibiting formation of the pro-apoptotic, cleaved form of Bcl-xL, ΔN-Bcl-xL. We now report that a high concentration of ABT-737 (1 μM), or a more selective Bcl-xL inhibitor WEHI-539 (5 μM) enhances glutamate-induced neurotoxicity while a low concentration of ABT-737 (10 nM) or WEHI-539 (10 nM) is neuroprotective. High ABT-737 markedly increased ΔN-Bcl-xL formation, aggravated glutamate-induced death and resulted in the loss of mitochondrial membrane potential and decline in ATP production. Although the usual cause of death by ABT-737 is thought to be related to activation of Bax at the outer mitochondrial membrane due to sequestration of Bcl-xL, we now find that low ABT-737 not only prevents Bax activation, but it also inhibits the decline in mitochondrial potential produced by glutamate toxicity or by direct application of ΔN-Bcl-xL to mitochondria. Loss of mitochondrial inner membrane potential is also prevented by cyclosporine A, implicating the mitochondrial permeability transition pore in death aggravated by ΔN-Bcl-xL. In keeping with this, we find that glutamate/ΔN-Bcl-xL-induced neuronal death is attenuated by depletion of the ATP synthase c-subunit. C-subunit depletion prevented depolarization of mitochondrial membranes in ΔN-Bcl-xL expressing cells and substantially prevented the morphological change in neurites associated with glutamate/ΔN-Bcl-xL insult. Our findings suggest that low ABT-737 or WEHI-539 promotes survival during glutamate toxicity by preventing the effect of ΔN-Bcl-xL on mitochondrial inner membrane depolarization, highlighting ΔN-Bcl-xL as an important therapeutic target in injured brain