Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial : study protocol for a randomized controlled trial

Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI

Emerging Infectious Disease leads to Rapid Population Decline of Common British Birds

Emerging infectious diseases are increasingly cited as threats to wildlife, livestock and humans alike. They can threaten geographically isolated or critically endangered wildlife populations; however, relatively few studies have clearly demonstrated the extent to which emerging diseases can impact populations of common wildlife species. Here, we report the impact of an emerging protozoal disease on British populations of greenfinch Carduelis chloris and chaffinch Fringilla coelebs, two of the most common birds in Britain. Morphological and molecular analyses showed this to be due to Trichomonas gallinae. Trichomonosis emerged as a novel fatal disease of finches in Britain in 2005 and rapidly became epidemic within greenfinch, and to a lesser extent chaffinch, populations in 2006. By 2007, breeding populations of greenfinches and chaffinches in the geographic region of highest disease incidence had decreased by 35% and 21% respectively, representing mortality in excess of half a million birds. In contrast, declines were less pronounced or absent in these species in regions where the disease was found in intermediate or low incidence. Also, populations of dunnock Prunella modularis, which similarly feeds in gardens, but in which T. gallinae was rarely recorded, did not decline. This is the first trichomonosis epidemic reported in the scientific literature to negatively impact populations of free-ranging non-columbiform species, and such levels of mortality and decline due to an emerging infectious disease are unprecedented in British wild bird populations. This disease emergence event demonstrates the potential for a protozoan parasite to jump avian host taxonomic groups with dramatic effect over a short time period

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Keratinocyte growth factor in acute lung injury to reduce pulmonary dysfunction – a randomised placebo-controlled trial (KARE): study protocol

Abstract Background Acute lung injury is a common, devastating clinical syndrome associated with substantial mortality and morbidity with currently no proven therapeutic interventional strategy to improve patient outcomes. The objectives of this study are to test the potential therapeutic effects of keratinocyte growth factor for patients with acute lung injury on oxygenation and biological indicators of acute inflammation, lung epithelial and endothelial function, protease:antiprotease balance, and lung extracellular matrix degradation and turnover. Methods/design This will be a prospective, randomised, double-blind, allocation-concealed, placebo-controlled, phase 2, multicentre trial. Randomisation will be stratified by presence of severe sepsis requiring vasopressors. Patients in an ICU fulfilling the American–European Consensus Conference Definition of acute lung injury will be randomised in a 1:1 ratio to receive an intravenous bolus of either keratinocyte growth factor (palifermin, 60 μg/kg) or placebo (0.9% sodium chloride solution) daily for a maximum of 6 days. The primary endpoint of this clinical study is to evaluate the efficacy of palifermin to improve the oxygenation index at day 7 or the last available oxygenation index prior to patient discontinuation from the study.A formal statistical analysis plan has been constructed. Analyses will be carried out on an intention-to-treat basis. A single analysis is planned at the end of the trial. P = 0.05 will be considered statistically significant and all tests will be two-sided. For continuously distributed outcomes, differences between groups will be tested using independent-sample t tests, analysis of variance and analysis of covariance with transformation of variables to normality or nonparametric equivalents. The trial will be reported in line with the Consolidated Standards of Reporting Trials (Consort 2010 guidelines). Trial registration http://ISRCTN9569067

Lifestyle gambling, indebtedness and anxiety: A deviant leisure perspective

While once subject to wide-ranging state control, gambling has successfully culturally embedded itself within the normalised and legitimised forms of leisure such as the night-time economy, sports fandom and online forums of socialisation. Consequently, this article argues that existing research which conceptualises gambling as separate from everyday life is largely obsolete in the contemporary context. We argue here that gambling has become an integral feature of the wider masculine weekend leisure experience, intimately connected to an infantilised consumer identity that is peculiar to late-capitalism. This article, drawing upon ongoing ethnographic research among what we term ‘lifestyle gamblers’, utilises a deviant leisure perspective to problematise the myriad harms that emerge from this relationship, situated within a broader critique of consumerism and global capitalism. While social gambling is defended fiercely by the industry, this article argues that an identity-based culture of sports-betting that attaches fragile social and cultural capital to the allure of the gambling win encourages the chasing of losses and impulsive betting. Underscored by a culture of readily available and high-interest credit, we explore how gamblers in a technologically accelerated culture develop a pathological relationship to money as it becomes desublimated and loses its symbolic value. Such processes, exacerbated by the promise of consumer culture, have the potential to cast these young adults into a paralysing reality of indebtedness that is fraught with depression, stress, domestic instability and destructive behaviours of consumption

Historical perspectives on pastoralism and land tenure transformation in Ngamiland, Botswana: What are the policy and institutional lessons?

Pastoral societies in dryland Africa continue to face changes to their pastoral systems. These systems are influenced by a range of historical factors but little use is made of this information to design policies that suit pastoralists’ landscapes. This article provides a synthesis of historical perspectives on pastoral land use and tenure transformations in Ngamiland, south of the Okavango Delta, Botswana. Little documentation of herders’ historical perspectives exists and less is known about how past experiences can be applied to sustainable pastoralism policies. In this article, current land use pressing issues are examined and analysed within the context of past experiences. We use a series of oral histories with key informants, focus group discussions, expert interviews and rangelands field observations. Ngamiland historical perspectives depict a pastoral landscape that has been shaped by a variety of factors; livestock diseases, Human-wildlife-conflicts, droughts, land tenure transformations associated with rangeland policies and the pastoral identity of the Ovaherero/Ovambanderu ethnic groups. Pastoralists have followed unique trajectories, specific to their rangeland conditions and socio-cultural context. Resilience to climate shocks and diseases has been weakened by inequitable patterns of control over rangeland resources. We recommend institutional diversity such that from experiences of the past, lessons can be drawn of the sort of processes and institutions required for pastoralism policies including targeted pastoralists’ adaptations. Using pastoralists to provide information, especially in the area of indigenous knowledge, strategies can be developed to link conservation of wildlife and rangelands with pastoral production by developing ecologically-sensitive low-volume tourism that pastoral communities can tap in to diversify their livelihoods

Understanding the implementation of evidence-based care: A structural network approach

<p>Abstract</p> <p>Background</p> <p>Recent study of complex networks has yielded many new insights into phenomenon such as social networks, the internet, and sexually transmitted infections. The purpose of this analysis is to examine the properties of a network created by the 'co-care' of patients within one region of the Veterans Health Affairs.</p> <p>Methods</p> <p>Data were obtained for all outpatient visits from 1 October 2006 to 30 September 2008 within one large Veterans Integrated Service Network. Types of physician within each clinic were nodes connected by shared patients, with a weighted link representing the number of shared patients between each connected pair. Network metrics calculated included edge weights, node degree, node strength, node coreness, and node betweenness. Log-log plots were used to examine the distribution of these metrics. Sizes of k-core networks were also computed under multiple conditions of node removal.</p> <p>Results</p> <p>There were 4,310,465 encounters by 266,710 shared patients between 722 provider types (nodes) across 41 stations or clinics resulting in 34,390 edges. The number of other nodes to which primary care provider nodes have a connection (172.7) is 42% greater than that of general surgeons and two and one-half times as high as cardiology. The log-log plot of the edge weight distribution appears to be linear in nature, revealing a 'scale-free' characteristic of the network, while the distributions of node degree and node strength are less so. The analysis of the k-core network sizes under increasing removal of primary care nodes shows that about 10 most connected primary care nodes play a critical role in keeping the <it>k</it>-core networks connected, because their removal disintegrates the highest <it>k</it>-core network.</p> <p>Conclusions</p> <p>Delivery of healthcare in a large healthcare system such as that of the US Department of Veterans Affairs (VA) can be represented as a complex network. This network consists of highly connected provider nodes that serve as 'hubs' within the network, and demonstrates some 'scale-free' properties. By using currently available tools to explore its topology, we can explore how the underlying connectivity of such a system affects the behavior of providers, and perhaps leverage that understanding to improve quality and outcomes of care.</p

Azimuthal anisotropy and correlations at large transverse momenta in p+pp+p and Au+Au collisions at sNN\sqrt{s_{_{NN}}}= 200 GeV

Results on high transverse momentum charged particle emission with respect to the reaction plane are presented for Au+Au collisions at $\sqrt{s_{_{NN}}}$= 200 GeV. Two- and four-particle correlations results are presented as well as a comparison of azimuthal correlations in Au+Au collisions to those in $p+p$ at the same energy. Elliptic anisotropy, $v_2$, is found to reach its maximum at $p_t \sim 3$ GeV/c, then decrease slowly and remain significant up to $p_t\approx 7$ -- 10 GeV/c. Stronger suppression is found in the back-to-back high-$p_t$ particle correlations for particles emitted out-of-plane compared to those emitted in-plane. The centrality dependence of $v_2$ at intermediate $p_t$ is compared to simple models based on jet quenching.Comment: 4 figures. Published version as PRL 93, 252301 (2004