Evaluation of the impact of the GRACE risk score on the management and outcome of patients hospitalised with non-ST elevation acute coronary syndrome in the UK: protocol of the UKGRIS cluster-randomised registry-based trial

Introduction For non-ST-segment elevation acute coronary syndrome (NSTEACS) there is a gap between the use of class 1 guideline recommended therapies and clinical practice. The GRACE risk score is recommended in international guidelines for the risk stratification of NSTEACS, but its impact on adherence to guideline-indicated treatments and reducing adverse clinical outcomes is unknown. The objective of the UKGRIS trial is to assess the effectiveness of the GRACE risk score tool and associated treatment recommendations on the use of guideline-indicated care and clinical outcomes. Methods and Analysis The UK GRACE Risk Score Intervention Study (UKGRIS), a parallel-group cluster randomised registry-based controlled trial, will allocate hospitals in a 1:1 ratio to manage NSTEACS by standard care or according to the GRACE risk score and associated international guidelines. UKGRIS will recruit a minimum of 3000 patients from at least 30 English National Health Service hospitals and collect healthcare data from national electronic health records. The co-primary endpoints are the use of guideline-indicated therapies, and the composite of cardiovascular death, non-fatal myocardial infarction, new onset heart failure hospitalisation or cardiovascular readmission at 12 months. Secondary endpoints include duration of inpatient hospital stay over 12 months, EQ-5D-5L responses and utilities, unscheduled revascularisation and the components of the composite endpoint over 12 months follow-up. Ethics and Dissemination The study has ethical approval (North East - Tyne & Wear South Research Ethics Committee ref: 4/NE/1180). Findings will be announced at relevant conferences and published in peer-reviewed journals in line with the funder’s open access policy. Registration ISRCTN29731761, registered 12th January 2017

Ocean temperature and salinity components of the Madden-Julian oscillation observed by Argo floats

New diagnostics of the Madden-Julian Oscillation (MJO) cycle in ocean temperature and, for the first time, salinity are presented. The MJO composites are based on 4 years of gridded Argo float data from 2003 to 2006, and extend from the surface to 1,400 m depth in the tropical Indian and Pacific Oceans. The MJO surface salinity anomalies are consistent with precipitation minus evaporation fluxes in the Indian Ocean, and with anomalous zonal advection in the Pacific. The Argo sea surface temperature and thermocline depth anomalies are consistent with previous studies using other data sets. The near-surface density changes due to salinity are comparable to, and partially offset, those due to temperature, emphasising the importance of including salinity as well as temperature changes in mixed-layer modelling of tropical intraseasonal processes. The MJO-forced equatorial Kelvin wave that propagates along the thermocline in the Pacific extends down into the deep ocean, to at least 1,400 m. Coherent, statistically significant, MJO temperature and salinity anomalies are also present in the deep Indian Ocean

Isotope effect on the transition temperature TcT_c in Fe-based superconductors: the current status

The results of the Fe isotope effect (Fe-IE) on the transition temperature $T_c$ obtained up to date in various Fe-based high temperature superconductors are summarized and reanalyzed by following the approach developed in [Phys. Rev. B 82, 212505 (2010)]. It is demonstrated that the very controversial results for Fe-IE on $T_c$ are caused by small structural changes occurring simultaneously with the Fe isotope exchange. The Fe-IE exponent on $T_c$ [$\alpha_{\rm Fe}=-(\Delta T_c/T_c)/(\Delta M/M)$, $M$ is the isotope mass] needs to be decomposed into two components with the one related to the structural changes ($\alpha_{\rm Fe}^{\rm str}$) and the genuine (intrinsic) one ($\alpha_{\rm Fe}^{\rm int}$). The validity of such decomposition is further confirmed by the fact that $\alpha_{\rm Fe}^{\rm int}$ coincides with the Fe-IE exponent on the characteristic phonon frequencies $\alpha_{\rm Fe}^{\rm ph}$ as is reported in recent EXAFS and Raman experiments.Comment: 7 pages, 4 figures. The paper is partially based on the results published in [New J. Phys. 12, 073024 (2010) = arXiv:1002.2510] and [Phys. Rev. B 82, 212505 (2010) = arXiv:1008.4540

Structural Change and the Fall of Income Inequality in Latin America : Agricultural Development, Inter-sectoral Duality, and the Kuznets Curve

In this study we approach the recent decline in income inequality in Latin America from the perspective of structural change with a focus on the relative performance of the agricultural sector. Our focus is on the underlying forces implied by Kuznets (1965). We zoom in on the relative performance of agriculture in the development process and the rural-urban duality and pay particular attention to the last couple of decades in relation to the entire post-1950 period. We attempt to estimate empirically possible theoretical relations with regard to these patterns by posing the following basic questions: how does the resurgence of agriculture relate to the reduction of income inequality and to what extent is this an expression of Latin America moving downward on the Kuznets curve? The literature on agriculture’s relation to the recent changes of income distribution in Latin America is quite limited. For instance, in a recent ECLAC report titled “Structural change for equality” (2012), the role of agriculture is not even mentioned. By agriculture we mean both farming and agro-business that processes and transports that output. To our knowledge, this paper is the first attempt to investigate this relationship for the recent decades in the perspective of structural change in Latin America. There are strong theoretical reasons to connect agricultural development to income distribution. The closing of the rural-urban income gap reflects what Reynolds (1975) called a “dynamic” transformation of agriculture and relates to the contribution agriculture provides for overall growth of the economy. In addition, the elasticity of poverty reduction with respect to growth is estimated to be stronger when growth emanates in the agricultural sector (Ravallion and Chen 2007, de Janvry and Sadoulet 2009). Productivity growth in the lagging sector should also contribute to sectoral labor productivity to convergence and thus helps to reduce inequality (Timmer 1988). For these reasons, the resurgence of agriculture driven partly by improving commodity prices should be given due attention when assessing the decline in income inequality in Latin America. According to the logic of the Kuznets curve, the hypothesized “turning point” of the inverted U-curve is generated by a reduction of income inequality in one or both of the sectors and/or a reduction of the rural-urban income gap as the weight of the agricultural sector diminishes, and the income per capita gap between them declines. We find that the recent decline in income inequality is related to the recent resurgence of Latin American agriculture, and, by inference, its lack of decline across most of the 20th century must be related to a lack of productivity change in agriculture. We provide estimates showing that during the recent decades inter-sectoral duality has been reduced by agricultural productivity growth. The duality expressed as an inter-sectoral Gini shows the shape of an inverted U-curve and as such the closing of the rural-urban income gap corroborates with the theoretical expectations postulated by Kuznets. The wider implication of the study is, however, that with slower growth in agricultural labor productivity, continuing improvement in the income distribution becomes more difficult. In the absence of strong manufacturing growth, agriculture might be able to reduce income inequality further if agro-industries remain unskilled labor intensive, thus raising the opportunity cost of unskilled workers. On the other hand, the traditional service sector has perhaps become the “new agricultural sector” in terms of productivity and labor surplus. In other words, the source of the remaining dualism does not come only from rural areas, but also from urban areas

The Suppressor of AAC2 Lethality SAL1 Modulates Sensitivity of Heterologously Expressed Artemia ADP/ATP Carrier to Bongkrekate in Yeast

The ADP/ATP carrier protein (AAC) expressed in Artemia franciscana is refractory to bongkrekate. We generated two strains of Saccharomyces cerevisiae where AAC1 and AAC3 were inactivated and the AAC2 isoform was replaced with Artemia AAC containing a hemagglutinin tag (ArAAC-HA). In one of the strains the suppressor of ΔAAC2 lethality, SAL1, was also inactivated but a plasmid coding for yeast AAC2 was included, because the ArAACΔsal1Δ strain was lethal. In both strains ArAAC-HA was expressed and correctly localized to the mitochondria. Peptide sequencing of ArAAC expressed in Artemia and that expressed in the modified yeasts revealed identical amino acid sequences. The isolated mitochondria from both modified strains developed 85% of the membrane potential attained by mitochondria of control strains, and addition of ADP yielded bongkrekate-sensitive depolarizations implying acquired sensitivity of ArAAC-mediated adenine nucleotide exchange to this poison, independent from SAL1. However, growth of ArAAC-expressing yeasts in glycerol-containing media was arrested by bongkrekate only in the presence of SAL1. We conclude that the mitochondrial environment of yeasts relying on respiratory growth conferred sensitivity of ArAAC to bongkrekate in a SAL1-dependent manner. © 2013 Wysocka-Kapcinska et al

Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells

Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acitretin (50 μM) or R116010 (1 or 10 μM) in combination with either 10 μM ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma

Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe