OCT2013, an ischaemia-activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine

Background and Purpose Sudden cardiac death (SCD) caused by acute myocardial ischaemia and ventricular fibrillation (VF) is an unmet therapeutic need. Lidocaine suppresses ischaemia-induced VF, but its utility is limited by side effects and a narrow therapeutic index. Here, we characterise OCT2013, a putative ischaemia-activated prodrug of lidocaine. Experimental Approach The rat Langendorff-perfused isolated heart, anaesthetised rat and rat ventricular myocyte preparations were utilised in a series of blinded and randomised studies to investigate the antiarrhythmic effectiveness, adverse effects and mechanism of action of OCT2013, compared with lidocaine. Key Results In isolated hearts, OCT2013 and lidocaine prevented ischaemia-induced VF equi-effectively, but OCT2013 did not share lidocaine's adverse effects (PR widening, bradycardia and negative inotropy). In anaesthetised rats, i.v. OCT2013 and lidocaine suppressed VF and increased survival equi-effectively; OCT2013 had no effect on cardiac output even at 64 mg·kg⁻¹ i.v., whereas lidocaine reduced it even at 1 mg·kg⁻¹. In adult rat ventricular myocytes, OCT2013 had no effect on Ca²⁺ handling, whereas lidocaine impaired it. In paced isolated hearts, lidocaine caused rate-dependent conduction slowing and block, whereas OCT2013 was inactive. However, during regional ischaemia, OCT2013 and lidocaine equi-effectively hastened conduction block. Chromatography and MS analysis revealed that OCT2013, detectable in normoxic OCT2013-perfused hearts, became undetectable during global ischaemia, with lidocaine becoming detectable. Conclusions and Implications OCT2013 is inactive but is bio-reduced locally in ischaemic myocardium to lidocaine, acting as an ischaemia-activated and ischaemia-selective antiarrhythmic prodrug with a large therapeutic index, mimicking lidocaine's benefit without adversity

UK national clinical audit: Management of pregnancies in women with HIV

BACKGROUND: The potential for HIV transmission between a pregnant woman and her unborn child was first recognized in 1982. Since then a complex package of measures to reduce risk has been developed. This project aims to review UK management of HIV in pregnancy as part of the British HIV Association (BHIVA) audit programme. METHODS: The National Study of HIV in Pregnancy and Childhood (NSHPC), a population-based surveillance study, provided data for pregnancies with an expected delivery date from 1/1/13 - 30/6/14. Services also completed a survey on local management policies. Data were audited against the 2012 BHIVA pregnancy guidelines. RESULTS: During the audit period 1483 pregnancies were reported and 112 services completed the survey. Use of dedicated multidisciplinary teams was reported by 99% although 26% included neither a specialist midwife nor nurse. 17% of services reported delays >1 week for HIV specialist review of women diagnosed antenatally. Problematic urgent HIV testing had been experienced by 9% of services although in a further 49% the need for urgent testing had not arisen. Delays of >2 h in obtaining urgent results were common. Antiretroviral therapy (ART) was started during pregnancy in 37% women with >94% regimens in accordance with guidelines. Late ART initiation was common, particularly in those with a low CD4 count or high viral load. Eleven percent of services reported local policy contrary to guidelines regarding delivery mode for women with a VL <50 copies/mL at ≥36 weeks. According to NSHPC reports 27% of women virologically eligible for vaginal delivery planned to deliver by CS. CONCLUSIONS: Pregnant women in the UK are managed largely in accordance with BHIVA guidelines. Improvements are needed to ensure timely referral and ART initiation to ensure the best possible outcomes

Hypersensitivity reactions, hepatotoxicity, and other discontinuations in persons receiving integrase strand transfer inhibitors: results from the EuroSIDA study

Background: Hypersensitivity reaction (HSR) and hepatotoxicity are rare, but potentially serious side-effects of antiretroviral use. / Objective: To investigate discontinuations due to HSR, hepatotoxicity or other reasons among users of dolutegravir (DTG) vs. raltegravir (RAL) or elvitegravir (EVG) in the EuroSIDA cohort. / Methods: We compared individuals ≥18 years and starting combination antiretroviral therapy (ART, ≥3 drugs) with DTG vs. RAL or EVG, with or without abacavir (ABC), between January 16, 2014 and January 23, 2019. Discontinuations due to serious adverse events (SAEs) were independently reviewed. / Results: Altogether 4366 individuals started 5116 ART regimens including DTG, RAL, or EVG, contributing 9180 person-years of follow-up (PYFU), with median follow-up 1.6 (interquartile range 0.7-2.8) years per treatment episode. Of these, 3074 (60.1%) used DTG (1738 with ABC, 1336 without) and 2042 (39.9%) RAL or EVG (286 with ABC, 1756 without). 1261 (24.6%) INSTI episodes were discontinued, 649 of the DTG-containing regimens (discontinuation rate 115, 95% CI 106-124/1000 PYFU) and 612 RAL or EVG-containing regimens (173, CI 160-188/1000 PYFU). After independent review, there were five HSR discontinuations, two for DTG (one with and one without ABC, discontinuation rate 0.35, CI 0.04-1.28/1000 PYFU), and three for RAL or EVG without ABC (0.85, CI 0.18-2.48/1000 PYFU). There was one hepatotoxicity discontinuation on DTG with ABC (discontinuation rate 0.18, CI 0.00-0.99/1000 PYFU). / Conclusion: During 5 years of observations in the EuroSIDA cohort independently reviewed discontinuations due to HSR or hepatotoxicity were very rare, indicating a low rate of SAEs

Impact of high water pressure on oil generation and maturation in Kimmeridge Clay and Monterey source rocks: implications for petroleum retention and gas generation in shale gas systems

This study presents results for pyrolysis experiments conducted on immature Type II and IIs source rocks (Kimmeridge Clay, Dorset UK, and Monterey shale, California, USA respectively) to investigate the impact of high water pressure on source rock maturation and petroleum (oil and gas) generation. Using a 25 ml Hastalloy vessel, the source rocks were pyrolysed at low (180 and 245 bar) and high (500, 700 and 900 bar) water pressure hydrous conditions at 350 °C and 380 °C for between 6 and 24 h. For the Kimmeridge Clay (KCF) at 350 °C, Rock Eval HI of the pyrolysed rock residues were 30–44 mg/g higher between 6 h and 12 h at 900 bar than at 180 bar. Also at 350 °C for 24 h the gas, expelled oil, and vitrinite reflectance (VR) were all reduced by 46%, 61%, and 0.25% Ro respectively at 900 bar compared with 180 bar. At 380 °C the retardation effect of pressure on the KCF was less significant for gas generation. However, oil yield and VR were reduced by 47% and 0.3% Ro respectively, and Rock Eval HI was also higher by 28 mg/g at 900 bar compared with 245 bar at 12 h. The huge decrease in gas and oil yields and the VR observed with an increase in water pressure at 350 °C for 24 h and 380 °C for 12 h (maximum oil generation) were also observed for all other times and temperatures investigated for the KCF and the Monterey shale. This shows that high water pressure significantly retards petroleum generation and source rock maturation. The retardation of oil generation and expulsion resulted in significant amounts of bitumen and oil being retained in the rocks pyrolysed at high pressures, suggesting that pressure is a possible mechanism for retaining petroleum (bitumen and oil) in source rocks. This retention of petroleum within the rock provides a mechanism for oil-prone source rocks to become potential shale gas reservoirs. The implications from this study are that in geological basins, pressure, temperature and time will all exert significant control on the extent of petroleum generation and source rock maturation for Type II source rocks, and that the petroleum retained in the rocks at high pressures may explain in part why oil-prone source rocks contain the most prolific shale gas resources

Operational aspects of an externally driven neutron multiplier assembly concept using a Z-pinch 14-MeV Neutron Source (ZEDNA).

This report documents the key safety and operational aspects of a Z-pinch Externally Driven Nuclear Assembly (ZEDNA) reactor concept which is envisioned to be built and operated at the Z-machine facility in Technical Area IV. Operating parameters and reactor neutronic conditions are established that would meet the design requirements of the system. Accident and off-normal conditions are analyzed using a point-kinetics, one-dimensional thermo-mechanical code developed specifically for ZEDNA applications. Downwind dose calculations are presented to determine the potential dose to the collocated worker and public in the event of a hypothetical catastrophic accident. Current and magnetic impulse modeling and the debris shield design are examined for the interface between the Z machine and the ZEDNA. This work was performed as part of the Advanced Fusion Grand Challenge Laboratory Directed Research and Development Program. The conclusion of this work is that the ZEDNA concept is feasible and could be operated at the Z-machine facility without undue risk to collocated workers and the public

Magmatic gas percolation through the old lava dome of El Misti volcano

The proximity of the major city of Arequipa to El Misti has focused attention on the hazards posed by the active volcano. Since its last major eruption in the fifteenth century, El Misti has experienced a series of modest phreatic eruptions and fluctuating fumarolic activity. Here, we present the first measurements of the compositions of gas emitted from the lava dome in the summit crater. The gas composition is found to be fairly dry with a H2O/SO2 molar ratio of 32 ± 3, a CO2/SO2 molar ratio of 2.7 ± 0.2, a H2S/SO2 molar ratio of 0.23 ± 0.02 and a H2/SO2 molar ratio of 0.012 ± 0.002. This magmatic gas signature with minimal evidence of hydrothermal or wall rock interaction points to a shallow magma source that is efficiently outgassing through a permeable conduit and lava dome. Field and satellite observations show no evolution of the lava dome over the last decade, indicating sustained outgassing through an established fracture network. This stability could be disrupted if dome permeability were to be reduced by annealing or occlusion of outgassing pathways. Continued monitoring of gas composition and flux at El Misti will be essential to determine the evolution of hazard potential at this dangerous volcano.This research was conducted as part of the ‘Trail By Fire’ expedition (PI: Y. Moussallam). The project was supported by the Royal Geographical Society (with the Institute of British Geographers) with the Land Rover Bursary; the Deep Carbon Observatory DECADE Initiative; Santander, Ocean Optics; Crowcon; Air Liquide; Thermo Fisher Scientific; Cactus Outdoor; Turbo Ace and Team Black Sheep. We thank Jean-loup Guyot, Sebastien Carretier, Rose-Marie Ojeda, Pablo Samaniego and Jean-Luc Lepennec together with IRD South-America personnel for all their logistical help. We are extremely grateful to Marco Rivera and all OVI personnel for their help and support. YM acknowledges support from the Scripps Institution of Oceanography Postdoctoral Fellowship program. A.A and G.T acknowledge the ERC grant no. 305377 (BRIDGE). CIS acknowledges a research start-up grant from Victoria University of Wellington. C.O. is supported by the NERC Centre for the Observation and Modelling of Earthquakes, Volcanoes and Tectonics. The Earth Observing-1 (EO-1) spacecraft is managed by NASA’s Goddard Space Flight Center, Greenbelt, Maryland, USA

Global nuclear energy partnership fuels transient testing at the Sandia National Laboratories nuclear facilities : planning and facility infrastructure options.

The Global Nuclear Energy Partnership fuels development program is currently developing metallic, oxide, and nitride fuel forms as candidate fuels for an Advanced Burner Reactor. The Advance Burner Reactor is being designed to fission actinides efficiently, thereby reducing the long-term storage requirements for spent fuel repositories. Small fuel samples are being fabricated and evaluated with different transuranic loadings and with extensive burnup using the Advanced Test Reactor. During the next several years, numerous fuel samples will be fabricated, evaluated, and tested, with the eventual goal of developing a transmuter fuel database that supports the down selection to the most suitable fuel type. To provide a comparative database of safety margins for the range of potential transmuter fuels, this report describes a plan to conduct a set of early transient tests in the Annular Core Research Reactor at Sandia National Laboratories. The Annular Core Research Reactor is uniquely qualified to perform these types of tests because of its wide range of operating capabilities and large dry central cavity which extents through the center of the core. The goal of the fuels testing program is to demonstrate that the design and fabrication processes are of sufficient quality that the fuel will not fail at its design limit--up to a specified burnup, power density, and operating temperature. Transient testing is required to determine the fuel pin failure thresholds and to demonstrate that adequate fuel failure margins exist during the postulated design basis accidents

Drug coverage in treatment of malaria and the consequences for resistance evolution - evidence from the use of sulphadoxine/pyrimethamine

BACKGROUND\ud \ud It is argued that, the efficacy of anti-malarials could be prolonged through policy-mediated reductions in drug pressure, but gathering evidence of the relationship between policy, treatment practice, drug pressure and the evolution of resistance in the field is challenging. Mathematical models indicate that drug coverage is the primary determinant of drug pressure and the driving force behind the evolution of drug resistance. These models show that where the basis of resistance is multigenic, the effects of selection can be moderated by high recombination rates, which disrupt the associations between co-selected resistance genes.\ud \ud METHODS\ud \ud To test these predictions, dhfr and dhps frequency changes were measured during 2000-2001 while SP was the second-line treatment and contrasted these with changes during 2001-2002 when SP was used for first-line therapy. Annual cross sectional community surveys carried out before, during and after the policy switch in 2001 were used to collect samples. Genetic analysis of SP resistance genes was carried out on 4,950 Plasmodium falciparum infections and the selection pressure under the two policies compared.\ud \ud RESULTS\ud \ud The influence of policy on the parasite reservoir was profound. The frequency of dhfr and dhps resistance alleles did not change significantly while SP was the recommended second-line treatment, but highly significant changes occurred during the subsequent year after the switch to first line SP. The frequency of the triple mutant dhfr (N51I,C59R,S108N) allele (conferring pyrimethamine resistance) increased by 37% - 63% and the frequency of the double A437G, K540E mutant dhps allele (conferring sulphadoxine resistance) increased 200%-300%. A strong association between these unlinked alleles also emerged, confirming that they are co-selected by SP.\ud \ud CONCLUSION\ud \ud The national policy change brought about a shift in treatment practice and the resulting increase in coverage had a substantial impact on drug pressure. The selection applied by first-line use is strong enough to overcome recombination pressure and create significant linkage disequilibrium between the unlinked genetic determinants of pyrimethamine and sulphadoxine resistance, showing that recombination is no barrier to the emergence of resistance to combination treatments when they are used as the first-line malaria therapy

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal