Modelling and simulating unplanned and urgent healthcare: the contribution of scenarios of future healthcare systems.

The current financial challenges being faced by the UK economy have meant that the NHS will have to make £20 billion of savings between 2010 and 2014 requiring it to be innovative about how it delivers healthcare. This paper presents the methodology of a research project that is simulating the whole healthcare system with the aim of reducing waste within urgent unscheduled care streams whilst understanding the impact of such changes on the whole system. The research is aimed at care commissioners who could use such simulation in their decision-making practice, and the paper presents the findings from early stakeholder discussions about the scope and focus of the research and the relevance of stakeholder consultation and scenarios in the development of a valid decision-support tool that is fit for purpose

A multi-faceted approach to optimising a complex unplanned healthcare system

Unscheduled and urgent health care represents the largest area of activity and cost for the UK’s National Health Service (NHS). Like typical complex systems unplanned care has the features of interdependence and having structures at different scales which requires modelling at different levels. The aim of this paper is to discuss the development of a multifaceted approach to study and optimise this complex system. We aim to integrate four different methodologies to gain better understanding of the nature of the system and to develop ways to enhance its performance. These methodologies are: (a) Lean/ Flow theory to look at the process and patients and other flows; (b) Simulation/ System Dynamics to undertake analytical analysis and multi-level modelling; (c) stakeholder consultation and use of system thinking to analyse the system and identify options, barriers and good practice; and (d) visual analytic modelling to facilitate effective decision making in this complex environment. Of particular concern are the boundary issues i.e. how changes in unplanned care will impact on the adjacent facilities and ultimately on the whole Healthcare system

Narcissism and Neo-Liberalism : Work, Leisure, and alienation in an era of consumption

The purpose of this paper is to trace some of the links between neo-liberalism, narcissism and the influence of work, leisure and consumer culture on self-identity. By examining narcissism as an instrument of personality and social psychological analysis, we investigate the ways in which self-identity in neo-liberal societies is constructed and fulfilled through interactions with the marketplace, promoting self-interest and success in the form of wealth, admiration and bodily perfection. It is our contention that this process creates narcissistic identities, which attempt to defend the self against the degradation of work in neo-liberal societies, and where anxiety, emptiness and isolation are converted into pleasure and healing through leisure consumerism. In the final analysis we explore some of the links between narcissistic work and leisure, and psychological distress and disorders. © 2008 Presses de l’Université du Québec

Diverse Spatial, Temporal, and Sexual Expression of Recently Duplicated Androgen-Binding Protein Genes in \u3ci\u3eMus musculus\u3c/i\u3e

Background The genes for salivary androgen-binding protein (ABP) subunits have been evolving rapidly in ancestors of the house mouse Mus musculus, as evidenced both by recent and extensive gene duplication and by high ratios of nonsynonymous to synonymous nucleotide substitution rates. This makes ABP an appropriate model system with which to investigate how recent adaptive evolution of paralogous genes results in functional innovation (neofunctionalization). Results It was our goal to find evidence for the expression of as many of the Abp paralogues in the mouse genome as possible. We observed expression of six Abpa paralogues and five Abpbg paralogues in ten glands and other organs located predominantly in the head and neck (olfactory lobe of the brain, three salivary glands, lacrimal gland, Harderian gland, vomeronasal organ, and major olfactory epithelium). These Abp paralogues differed dramatically in their specific expression in these different glands and in their sexual dimorphism of expression. We also studied the appearance of expression in both late-stage embryos and postnatal animals prior to puberty and found significantly different timing of the onset of expression among the various paralogues. Conclusion The multiple changes in the spatial expression profile of these genes resulting in various combinations of expression in glands and other organs in the head and face of the mouse strongly suggest that neofunctionalization of these genes, driven by adaptive evolution, has occurred following duplication. The extensive diversification in expression of this family of proteins provides two lines of evidence for a pheromonal role for ABP: 1) different patterns of Abpa/Abpbg expression in different glands; and 2) sexual dimorphism in the expression of the paralogues in a subset of those glands. These expression patterns differ dramatically among various glands that are located almost exclusively in the head and neck, where the sensory organs are located. Since mice are nocturnal, it is expected that they will make extensive use of olfactory as opposed to visual cues. The glands expressing Abp paralogues produce secretions (lacrimal and salivary) or detect odors (MOE and VNO) and thus it appears highly likely that ABP proteins play a role in olfactory communication

Rapid Bursts of \u3ci\u3eAndrogen-Binding Protein (Abp)\u3c/i\u3e Gene Duplication Occurred Independently in Diverse Mammals

Background The draft mouse (Mus musculus) genome sequence revealed an unexpected proliferation of gene duplicates encoding a family of secretoglobin proteins including the androgen-binding protein (ABP) α, β and γ subunits. Further investigation of 14 α-like (Abpa) and 13 β- or γ-like (Abpbg) undisrupted gene sequences revealed a rich diversity of developmental stage-, sex- and tissue-specific expression. Despite these studies, our understanding of the evolution of this gene family remains incomplete. Questions arise from imperfections in the initial mouse genome assembly and a dearth of information about the gene family structure in other rodents and mammals. Results Here, we interrogate the latest \u27finished\u27 mouse (Mus musculus) genome sequence assembly to show that the Abp gene repertoire is, in fact, twice as large as reported previously, with 30 Abpa and 34 Abpbg genes and pseudogenes. All of these have arisen since the last common ancestor with rat (Rattus norvegicus). We then demonstrate, by sequencing homologs from species within the Mus genus, that this burst of gene duplication occurred very recently, within the past seven million years. Finally, we survey Abp orthologs in genomes from across the mammalian clade and show that bursts of Abp gene duplications are not specific to the murid rodents; they also occurred recently in the lagomorph (rabbit, Oryctolagus cuniculus) and ruminant (cattle, Bos taurus) lineages, although not in other mammalian taxa. Conclusion We conclude that Abp genes have undergone repeated bursts of gene duplication and adaptive sequence diversification driven by these genes\u27 participation in chemosensation and/or sexual identification

Next-generation sequencing of advanced prostate cancer treated with androgen-deprivation therapy

<b>Background:</b> Androgen-deprivation therapy (ADT) is standard treatment for locally advanced or metastatic prostate cancer (PCa). Many patients develop castration resistance (castration-resistant PCa [CRPC]) after approximately 2–3 yr, with a poor prognosis. The molecular mechanisms underlying CRPC progression are unclear.<p></p> <b>Objective:</b> To undertake quantitative tumour transcriptome profiling prior to and following ADT to identify functionally important androgen-regulated pathways or genes that may be reactivated in CRPC.<p></p> <b>Design, setting, and participants:</b> RNA sequencing (RNA-seq) was performed on tumour-rich, targeted prostatic biopsies from seven patients with locally advanced or metastatic PCa before and approximately 22 wk after ADT initiation. Differentially regulated genes were identified in treatment pairs and further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on cell lines and immunohistochemistry on a separate CRPC patient cohort. Functional assays were used to determine the effect of pathway modulation on cell phenotypes.<p></p> <b>Outcome measurements and statistical analysis:</b> We searched for gene expression changes affecting key cell signalling pathways that may be targeted as proof of principle in a CRPC in vitro cell line model.<p></p> <b>Results and limitations:</b> We identified ADT-regulated signalling pathways, including the Wnt/β-catenin signalling pathway, and observed overexpression of β-catenin in a subset of CRPC by immunohistochemistry. We validated 6 of 12 (50%) pathway members by qRT-PCR on LNCaP/LNCaP-AI cell RNAs, of which 4 (67%) demonstrated expression changes consistent with RNA-seq data. We show that the tankyrase inhibitor XAV939 (which promotes β-catenin degradation) reduced androgen-independent LNCaP-AI cell line growth compared with androgen-responsive LNCaP cells via an accumulation of cell proportions in the G0/G1 phase and reduction in the S and G2/M phases. Our biopsy protocol did not account for tumour heterogeneity, and pathway inhibition was limited to pharmacologic approaches.<p></p> <b>Conclusions:</b> RNA-seq of paired PCa samples revealed ADT-regulated signalling pathways. Proof-of-principle inhibition of the Wnt/β-catenin signalling pathway specifically delays androgen-independent PCa cell cycle progression and proliferation and warrants further investigation as a potential target for therapy for CRPC.<p></p&gt

Mathematical Model of Easter Island Society Collapse

In this paper we consider a mathematical model for the evolution and collapse of the Easter Island society, starting from the fifth century until the last period of the society collapse (fifteen century). Based on historical reports, the available primary sources consisted almost exclusively on the trees. We describe the inhabitants and the resources as an isolated system and both considered as dynamic variables. A mathematical analysis about why the structure of the Easter Island community collapse is performed. In particular, we analyze the critical values of the fundamental parameters driving the interaction humans-environment and consequently leading to the collapse. The technological parameter, quantifying the exploitation of the resources, is calculated and applied to the case of other extinguished civilization (Cop\'an Maya) confirming, with a sufficiently precise estimation, the consistency of the adopted model.Comment: 9 pages, 1 figure, final version published on EuroPhysics Letter

The PDZ domain of the SpoIVB serine peptidase facilitates multiple functions

During spore formation in Bacillus subtilis, the SpoIVB protein is a critical component of the sigma (K) regulatory checkpoint. SpoIVB has been shown to be a serine peptidase that is synthesized in the spore chamber and which self-cleaves, releasing active forms. These forms can signal proteolytic processing of the transcription factor sigma (K) in the outer mother cell chamber of the sporulating cell. This forms the basis of the sigma (K) checkpoint and ensures accurate sigma (K)-controlled gene expression. SpoIVB has also been shown to activate a second distinct process, termed the second function, which is essential for the formation of heat-resistant spores. In addition to the serine peptidase domain, SpoIVB contains a PDZ domain. We have altered a number of conserved residues in the PDZ domain by site-directed mutagenesis and assayed the sporulation phenotype and signaling properties of mutant SpoIVB proteins. Our work has revealed that the SpoIVB PDZ domain could be used for up to four distinct processes, (i) targeting of itself for trans proteolysis, (11) binding to the protease inhibitor BofC, (iii) signaling of pro-sigma (K) processing, and (iv) signaling of the second function of SpoIVB