Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Risk analysis of prostate cancer in PRACTICAL, a multinational consortium, using 25 known prostate cancer susceptibility loci

Background Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS).We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived agespecific absolute risks of developing prostate cancer by PRS stratum and family history. Results The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact:We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.

"Get new lawyers!"

In James Rubin's account of the Kosovo war, he describes an exchange between Secretary Albright and Robin Cook (the British Foreign Secretary). Cook was explaining that it is difficult for Britain to commit to the war without UN Security Council approval because the legal advice he had received was that such action would be illegal under international law. Albright's response was, simply, "get new lawyers". Rubin "credits" Blair with a "push" that swung the British to "finally agree" that a UN Security Council resolution was "not legally required". Robin Cook later stated in Parliament and that the war was legal. Interestingly, Blair did not. This article does not look at whether or not such an exchange took place; rather look at the ethical issues that such a situation would generate. The article suggests what the ethical obligations of the key legal players in such institutional dramas should be—including governments seeking advice, the lawyers giving it, the ministers reporting it and the opposition in Parliament. The article sets out the particular responsibilities of the lawyers and officials of a Westminster system. It also sets out some of the institutional mechanisms for making it more likely that those obligations are fulfilled—as always through the interaction of obligations by different players that make it more risky for any player to breach his or her ethical obligations. Analogous duties would be faced by the relevant actors in other systems.

More and more lawyers but still no judges

This paper discusses some parallels and contrasts between the legal roads to war and suggest that the case is stronger than ever for adjudication of the matter before an independent tribunal where the competing views can be tested.

Educating the Other: Standpoint and Theory on the 'Internationalisation' of Higher Education

How adequate are current theoretical standpoints, tools and categories for explaining the flows of international students to Anglo/American/European universities? This essay takes a different analytic tact and historical standpoint to the study of them and us, insiders and outsiders (cf. Foley, Levinson & Hurtig, 2001), in the internationalisation of education.

Maternal reminiscing style during early childhood predicts the age of adolescents' earliest memories

Individual differences in parental reminiscing style are hypothesized to have long-lasting effects on children’s autobiographical memory development, including the age of their earliest memories. This study represents the first prospective test of this hypothesis. Conversations about past events between 17 mother–child dyads were recorded on multiple occasions between the children’s 2nd and 4th birthdays. When these children were aged 12–13 years, they were interviewed about their early memories. Adolescents whose mothers used a greater ratio of elaborations to repetitions during the early childhood conversations had earlier memories than adolescents whose mothers used a smaller ratio of elaborations to repetitions. This finding is consistent with the hypothesis that past-event conversations during early childhood have long-lasting effects on autobiographical memory.

Crime in Rural and Regional Areas

This Chapter provides an overview of available corrent data measuring crime in Australia's States and Territories broken down into regions and localities The data is limited, has reliability problems and lots of gaps. Nevertheless when the data are analysed according to offence type (in particulary violence versus property offences) an interesting but complicated empirical picture emerges that departs from what most scholars and policy makes have commonly assumed about crime and rural communities - that there is not much of it! The chapter begins with an assessment of the uses and limitations of different ways of measuring crime for those interested in a spatialised analysis of crome dispersion in rural communities.

The Development of a Critical Thinking Conceptual Model to Enhance Critical Thinking Skills in Middle-Eastern Nurses: A Middle-Eastern Experience

This paper aims to describe the development of a critical thinking conceptual model which was constructed to guide the teaching and evaluation of critical thinking skills to Middle-Eastern nurses.

A framework guiding critical thinking through reflective journal documentation: A Middle Eastern experience

The purpose of this paper is to present a framework to guide critical thinking through reflective journaling, and describe how a group of 20 Middle Eastern nurses used reflective journaling to enhance their practice. Journal documentation was used during clinical practicum to foster the development of critical thinking in order to assist nurses when analysing and evaluating their clinical experiences. The findings from this study demonstrated that nurses accepted the framework for journal documentation because it provided structure for reflection, speculation, synthesis and metacognition of events experienced during clinical practice. Journaling gave nurses the opportunity to transfer thoughts onto paper and write down subjective and objective data, and created dialogue between the nurse educators and nurses. They were engaged in productive and positive activity to enhance their nursing practice. Nurses also commented that writing helped to develop their confidence in writing English.

The coming

Through an exploration of representations of metamorphosis and the creation of a body of written work, this thesis uses a critical examination of theoretical approaches to metamorphosis in combination with textual analysis of representations of metamorphosis and creative practice as research to arrive at the beginnings of an ethic of writing. The creative work, The Coming, consists of a collection of short fiction, The Coming, and two collections of poetry, Orison and Milagros. The exegesis, Transhuman Change: towards an ethic of writing, explores theories about metamorphosis as a figure for writing, as a trope, and as a motif for exploring identity to contextualise the analysis of representations of metamorphosis from which the ethic is developed. With reference to the psychosexual development theory of Jacques Lacan and Elaine Scarry’s philosophy of the body, pain, language and creativity, the exegesis examines existing approaches to metamorphosis and uses supplementary textual analysis of influential representations of metamorphosis from Ovid to Pygmalion, X-Men and Extreme Makeover to explore assumptions about the body, language, the self, gender in western culture. The limitations of the performance of representations of metamorphosis as a figure for the self’s survival of death are considered in the light of voice as metonym for self to propose an ethic which valorises life. The experience of sex and the construction of gender in representations of metamorphosis are considered in the light of Lacan’s theory of desire and Scarry’s theory of the body and language to propose an ethic of representing gender ironically. The motif of the faithless lover and the Pygmalion myth are considered in the light of the (m)other’s role in language to propose an ethic in which indeterminacy constitutes the condition for being aware of oneself among selves. Each of the three proposals is discussed in relation to the short fiction, memoir and poems produced in the course of this research to test their limits and possibilities as the foundation of an emerging ethic of writing.