The Egyptian Cardiothoracic Surgeon (ECTS - E-Journal)
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Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma
No full textUNLABELLED: Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell-derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma.SIGNIFICANCE: Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments.</p
Plant community controls on short-term ecosystem nitrogen retention
No full textRetention of nitrogen (N) is a critical ecosystem function, especially in the face of widespread anthropogenic N enrichment; however, our understanding of the mechanisms involved is limited. Here, we tested under glasshouse conditions how plant community attributes, including variations in the dominance, diversity and range of plant functional traits, influence N uptake and retention in temperate grassland. We added a pulse of 15N to grassland plant communities assembled to represent a range of community-weighted mean plant traits, trait functional diversity and divergence, and species richness, and measured plant and microbial uptake of 15N, and leaching losses of 15N, as a short-term test of N retention in the plant–soil system. Root biomass, herb abundance and dominant plant traits were the main determinants of N retention in the plant–soil system: greater root biomass and herb abundance, and lower root tissue density, increased plant 15N uptake, while higher specific leaf area and root tissue density increased microbial 15N uptake. Our results provide novel, mechanistic insight into the short-term fate of N in the plant–soil system, and show that dominant plant traits, rather than trait functional diversity, control the fate of added N in the plant–soil system
Geological setting and timing of the world-class Sn, Nb–Ta and Li mineralization of Manono-Kitotolo (Katanga, Democratic Republic of Congo)
No full textProlonged PR interval, first-degree heart block and adverse cardiovascular outcomes: a systematic review and meta-analysis.
No full textOBJECTIVE: First-degree atrioventricular block is frequently encountered in clinical practice and is generally considered a benign process. However, there is emerging evidence that prolonged PR interval may be associated with adverse outcomes. This study aims to determine if prolonged PR interval is associated with adverse cardiovascular outcomes and mortality. METHODS: We searched MEDLINE and EMBASE for studies that evaluated clinical outcomes associated with prolonged and normal PR intervals. Relevant studies were pooled using random effects meta-analysis for risk of mortality, cardiovascular mortality, heart failure, coronary heart disease, atrial fibrillation and stroke or transient ischaemic attack (TIA). Sensitivity analyses were performed considering the population type and the use of adjustments. RESULTS: Our search yielded 14 studies that were undertaken between 1972 and 2011 with 400 750 participants. Among the studies that adjusted for potential confounders, the pooled results suggest an increased risk of mortality with prolonged PR interval risk ratio (RR) 1.24 95% CI 1.02 to 1.51, five studies. Prolonged PR interval was associated with significant risk of heart failure or left ventricular dysfunction (RR 1.39 95% CI 1.18 to 1.65, three studies) and atrial fibrillation (RR 1.45 95% CI 1.23 to 1.71, eight studies) but not cardiovascular mortality, coronary heart disease or myocardial infarction or stroke or TIA. Similar observations were recorded when limited to studies of first-degree heart block. CONCLUSIONS: Data from observational studies suggests a possible association between prolonged PR interval and significant increases in atrial fibrillation, heart failure and mortality. Future prospective studies are needed to confirm the relationships reported, consider possible mechanisms and define the optimal monitoring strategy for such patients
Shale gas: A review of the economic, environmental and social sustainability
No full textThe growth of the shale gas industry in the US has raised expectations that other nations could boost domestic gas production, leading to lower energy prices and improved energy security. However, the degree to which the US experience is transferable to other countries is uncertain. Furthermore, sustainability implications of shale gas development remain largely unknown. In an attempt to find out if and how shale gas could be exploited in a sustainable way, this paper reviews the economic, environmental, and social aspects of shale gas. These include costs, energy security, employment, water and land pollution, greenhouse gas emissions, earthquakes, and public perception. The literature suggests that it is possible to develop shale gas in a sustainable way, but its future will depend on the industry being able to address the environmental concerns, the political will to see the industry through to maturity, and public support, with the latter most likely being the biggest determinant
Examination of the synthetic control method for evaluating health policies with multiple treated units
No full textThis paper examines the synthetic control method in contrast to commonly used difference-in-differences (DiD) estimation, in the context of a re-evaluation of a pay-for-performance (P4P) initiative, the Advancing Quality scheme. The synthetic control method aims to estimate treatment effects by constructing a weighted combination of control units, which represents what the treated group would have experienced in the absence of receiving the treatment. While DiD estimation assumes that the effects of unobserved confounders are constant over time, the synthetic control method allows for these effects to change over time, by re-weighting the control group so that it has similar pre-intervention characteristics to the treated group.We extend the synthetic control approach to a setting of evaluation of a health policy where there are multiple treated units. We re-analyse a recent study evaluating the effects of a hospital P4P scheme on risk-adjusted hospital mortality. In contrast to the original DiD analysis, the synthetic control method reports that, for the incentivised conditions, the P4P scheme did not significantly reduce mortality and that there is a statistically significant increase in mortality for non-incentivised conditions. This result was robust to alternative specifications of the synthetic control method
An investigation into aripiprazole's partial D2 agonist effects within the dorsolateral prefrontal cortex during working memory in healthy volunteers.
No full textRATIONALE: Working memory impairments in schizophrenia have been attributed to dysfunction of the dorsolateral prefrontal cortex (DLPFC) which in turn may be due to low DLPFC dopamine innervation. Conventional antipsychotic drugs block DLPFC D2 receptors, and this may lead to further dysfunction and working memory impairments. Aripiprazole is a D2 receptor partial agonist hypothesised to enhance PFC dopamine functioning, possibly improving working memory. OBJECTIVES: We probed the implications of the partial D2 receptor agonist actions of aripiprazole within the DLPFC during working memory. Investigations were carried out in healthy volunteers to eliminate confounds of illness or medication status. Aripiprazole's prefrontal actions were compared with the D2/5-HT2A blocker risperidone to separate aripiprazole's unique prefrontal D2 agonist actions from its serotinergic and striatal D2 actions that it shares with risperidone. METHOD: A double-blind, placebo-controlled, parallel design was implemented. Participants received a single dose of either 5 mg aripiprazole, 1 mg risperidone or placebo before performing the n-back task whilst undergoing fMRI scanning. RESULTS: Compared with placebo, the aripiprazole group demonstrated enhanced DLPFC activation associated with a trend for improved discriminability (d') and speeded reaction times. In contrast to aripiprazole's neural effects, the risperidone group demonstrated a trend for reduced DLPFC recruitment. Unexpectedly, the risperidone group demonstrated similar effects to aripiprazole on d' and additionally had reduced errors of commission compared with placebo. CONCLUSION: Aripiprazole has unique DLPFC actions attributed to its prefrontal D2 agonist action. Risperidone's serotinergic action that results in prefrontal dopamine release may have protected against any impairing effects of its prefrontal D2 blockade
The Political Economy of Longevity: Developing New Forms of Solidarity for Later Life
No full textAging populations now exert influence on all aspects of social life. This article examines changes to major social and economic institutions linked with old age, taking the period from the mid-20 Century to the opening decades of the 21st century. These developments are set within the context of the influence of globalization as well as the impact of the 2008 financial crisis, these re-structuring debates around the longevity revolution. The paper examines how how the basis for a new framework for accommodating longevity can be built, outlining ways of securing new forms of solidarity in later life
Belfast Pathways: Space-Time Analysis of Every Day Activities in a Segregated Environment
No full textThe human geography of Belfast has inspired a long tradition of social science research, stretching from the classic work of Boal and others on sectarian divisions during ‘the troubles’ (e.g. Boal, 1996; Doherty & Poole, 1997; Shirlow, 2003) to more recent work mapping the changing face of the post-conflict city (e.g. Murtagh, 2012; Lysaght & Baston, 2003). Much of this work has focused on the nature and consequences of residential polarization. Our study extends this literature by exploring emerging patterns of activity space segregation and integration in north Belfast. Segregation in North Belfast assumes a distinctive ‘checkerboard’ pattern in which ‘loyalist’ and ‘nationalist’ neighbourhoods exist in close proximity yet remain divided by various territorial boundaries, including peace walls, interface barriers and institutional structures (Figure 1). Perhaps because the two communities live in such close proximity, we believe that the management of the daily activities and routines of movement is especially important to local residents. Indeed, who goes where, when, why and along what routes is an ingrained feature of the local ‘geographic imagination’, making North Belfast a particularly rich context in which to explore activity space segregation
Almost a spider: A 305-million-year-old fossil arachnid and spider origins
No full textSpiders are an important animal group, with a long history. Details of their origins remain limited, with little knowledge of their stem group, and no insights into the sequence of character acquisition during spider evolution. We describe a new fossil arachnid,Idmonarachne brasierigen. et sp. nov. from the Late Carboniferous (Stephanian,ca305-299 Ma) of Montceau-les-Mines, France. It is three-dimensionally preserved within a siderite concretion, allowing both laboratory- and synchrotron-based phase-contrast computed tomography reconstruction. The latter is a first for siderite-hosted fossils and has allowed us to investigate fine anatomical details. Although distinctly spider-like in habitus, this remarkable fossil lacks a key diagnostic character of Araneae: spinnerets on the underside of the opisthosoma. It also lacks a flagelliform telson found in the recently recognized, spider-related, Devonian-Permian Uraraneida. Cladistic analysis resolves our new fossil as sister group to the spiders: the spider stem-group comprises the uraraneids andI. brasieri While we are unable to demonstrate the presence of spigots in this fossil, the recovered phylogeny suggests the earliest character to evolve on the spider stem-group is the secretion of silk. This would have been followed by the loss of a flagelliform telson, and then the ability to spin silk using spinnerets. This last innovation defines the true spiders, significantly post-dates the origins of silk, and may be a key to the group's success. The Montceau-les-Mines locality has previously yielded a mesothele spider (with spinnerets). Evidently, Late Palaeozoic spiders lived alongside Palaeozoic arachnid grades which approached the spider condition, but did not express the full suite of crown-group autapomorphies