Integrated genomic characterization of endometrial carcinoma

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Introduction

This book explores the impacts of global economic, political and cultural shifts on various international legal frameworks and legal norms. The economic growth of states throughout Asia, South and Central America and Africa is having a profound effect on the dynamics of international relations, with a resulting impact on the operation and development of international law. This book examines the influence of emerging economies on international legal rules, institutions and processes. It describes recent and predicted changes in economic, political and cultural powers, flowing from the growth of emerging economies such as China, India, Brazil, South Africa and Russia, and analyses the influence of these changes on various legal frameworks and norms. Expert contributors drawn from a variety of fields, including international law, politics, environmental law, human rights, economics and finance, provide a broad analysis of the nature of the shifting global dynamic in its historical and contemporary contexts, and a range of perspectives on the impact of these changes as they relate to specific regimes and issues, including climate change regulation, collective security, indigenous rights, the rights of women and girls, environmental protection and foreign aid and development. The book provides a fresh and comprehensive analysis of an issue with extensive implications for international law and politics.

The Rise of the BASIC Group Within the International Climate Regime : The Challenge of Ensuring Equitable Mitigation Obligations

The chapter examines the current emission reduction obligations within the climate regime. It looks at the formation and rise of the BASIC negotiation group within the international climate COP negotiations and examines the role that BASIC nations are now playing shaping international mitigation policy.

Dreams and nightmares of alternative powers' futures

This chapter argues the importance of the role and nature of other powers to world order. The author suggests that, if the US are not prepared to take a lead in creating a rules-based legal order, they should and can do so – and it is in their interests to do so. America should be a natural leader in this process, taking part in a global dialogue just as they did in the transatlantic dialogue during the late eighteenth century.

Consumer perceptions of medication warnings about driving : a comparison of French and Australian labels

OBJECTIVE Little research has examined user perceptions of medication warnings about driving. Consumer perceptions of the Australian national approach to medication warnings about driving are examined. The Australian approach to warning presentation is compared with an alternative approach used in France. Visual characteristics of the warnings and overall warning readability are investigated. Risk perceptions and behavioral intentions associated with the warnings are also examined. METHOD Surveys were conducted with 358 public hospital outpatients in Queensland, Australia. Extending this investigation is a supplementary comparison study of French hospital outpatients (n = 75). RESULTS The results suggest that the Australian warning approach of using a combination of visual characteristics is important for consumers but that the use of a pictogram could enhance effects. Significantly higher levels of risk perception were found among the sample for the French highest severity label compared to the analogous mandatory Australian warning, with a similar trend evident in the French study results. The results also indicated that the French label was associated with more cautious behavioral intentions. CONCLUSION The results are potentially important for the Australian approach to medication warnings about driving impairment. The research contributes practical findings that can be used to enhance the effectiveness of warnings and develop countermeasures in this area. Hospital pharmacy patients should include persons with the highest level of likelihood of knowledge and awareness of medication warning labeling. Even in this context it appears that a review of the Australian warning system would be useful particularly in the context of increasing evidence relating to associated driving risks. Reviewing text size and readability of messages including the addition of pictograms, as well as clarifying the importance of potential risk in a general community context, is recommended for consideration and further research.

The idea of women : representations of power in the work of Charles Bukowski

This thesis is a comparative textual analysis of Charles Bukowski's representations of power in relation to the idea of women. The exegesis explores Bukowski's idea of women and power as exemplified by the representational differences between his short stories for Hustler Magazine and his novel Women. The creative piece, a novel, "Many a Broken Hearted Woman" informed and was informed by this research.

Imaginative cinematic geographies of Australia : the mapped view in Charles Chauvel's Jedda and Baz Luhrmann's Australia

Cinema is central to the mediation of history and the construction of imaginative geographies that offer a politicized view of the land and its people. This article investigates cinematic representations of landscape and analyses the ways in which maps and journeys in Charles Chauvel’s film Jedda (1955) and Baz Luhrmann’s Australia (2008)—both set in the far North of Australia—articulate conceptions of “Australianness” in relationship to Indigeneity and the land. We argue the exotic tropics and arid outback regions of northern Australia function metonymically as representative of the nation in these films, working to naturalize ideological values and affirm dominant narratives of history, identity, and entitlement.

Strategic IMC : from abstract concept to marketing management tool

Although integrated marketing communication (IMC) has progressed towards midrange maturity level, its full-scale adoption has been impeded by a lack of consensus on its defining constructs. The purpose of this study is to move from abstraction to define the construct of strategic integration (SI) and develop this into a management tool, thus making an important contribution to both the theory and practice of IMC. Drawing from both IMC and strategic management literature, the construct of SI is operationalised into a number of key factors and a well-cited management model, Fuchs’ ‘integration valuator’ is explored as the starting point of a measurement tool for IMC. To do this, a Delphi study invites the scrutiny of an expert panel of world-leading IMC researchers and practitioners. The panel validated the model construction process,redefined overarching constructs and key factors with a high degree of consensus, supported a process measure, suggested a weighted evaluation measure and recognised the importance of developing such a measure. They delivered clear and consistent imperatives guiding model development. The result is a measure of SI that evaluates organisational proficiency and diagnoses the integration of IMC campaigns. It also advances theory by providing a better understanding of the construct of SI.

Saffman-Taylor fingers with kinetic undercooling

The mathematical model of a steadily propagating Saffman-Taylor finger in a Hele-Shaw channel has applications to two-dimensional interacting streamer discharges which are aligned in a periodic array. In the streamer context, the relevant regularisation on the interface is not provided by surface tension, but instead has been postulated to involve a mechanism equivalent to kinetic undercooling, which acts to penalise high velocities and prevent blow-up of the unregularised solution. Previous asymptotic results for the Hele-Shaw finger problem with kinetic undercooling suggest that for a given value of the kinetic undercooling parameter, there is a discrete set of possible finger shapes, each analytic at the nose and occupying a different fraction of the channel width. In the limit in which the kinetic undercooling parameter vanishes, the fraction for each family approaches 1/2, suggesting that this selection of 1/2 by kinetic undercooling is qualitatively similar to the well-known analogue with surface tension. We treat the numerical problem of computing these Saffman-Taylor fingers with kinetic undercooling, which turns out to be more subtle than the analogue with surface tension, since kinetic undercooling permits finger shapes which are corner-free but not analytic. We provide numerical evidence for the selection mechanism by setting up a problem with both kinetic undercooling and surface tension, and numerically taking the limit that the surface tension vanishes.

A Web-based system enabling the integration, analysis, and 3D sub-surface visualization of groundwater monitoring data and geological models

The 3D Water Chemistry Atlas is an intuitive, open source, Web-based system that enables the three-dimensional (3D) sub-surface visualization of ground water monitoring data, overlaid on the local geological model (formation and aquifer strata). This paper firstly describes the results of evaluating existing virtual globe technologies, which led to the decision to use the Cesium open source WebGL Virtual Globe and Map Engine as the underlying platform. Next it describes the backend database and search, filtering, browse and analysis tools that were developed to enable users to interactively explore the groundwater monitoring data and interpret it spatially and temporally relative to the local geological formations and aquifers via the Cesium interface. The result is an integrated 3D visualization system that enables environmental managers and regulators to assess groundwater conditions, identify inconsistencies in the data, manage impacts and risks and make more informed decisions about coal seam gas extraction, waste water extraction, and water reuse.

An exploration of The Virtues Project: Ontological, educational and cross-cultural inquiries into a moral education program within a Mongolian school setting

This thesis explores The Virtues Project's ontological, educational and cross-cultural dimensions taking Charles Taylor's philosophical perspective of an anthropological account of the self and a phenomenological account of moral life and engagement. The experience of Mongolian schoolteachers implementing this moral education program is analyzed using a narrative inquiry method. The globally attractive project appears in moral education and virtues ethics research and surveys, yet no critical evaluation has been undertaken. Its conceptual features are appraised from a Taylorean perspective. The Listening Guide analysis of teacher experiences is presented in two narratives. The first is about the teachers' implementation experiences of moral flourishing as selves, in relationships and in community. The second is about their experience of becoming Mongolian in their modern day context. In conclusion, the project is coherent, constructive and potentially suitable cross-culturally.

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4, 5, 6, 7, 8, 9, 10, 11. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression...

Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990–2013: Quantifying the epidemiological transition

Background The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age–sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development. Methods We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time. Findings Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6–6·6), from 65·3 years (65·0–65·6) in 1990 to 71·5 years (71·0–71·9) in 2013, HALE at birth rose by 5·4 years (4·9–5·8), from 56·9 years (54·5–59·1) to 62·3 years (59·7–64·8), total DALYs fell by 3·6% (0·3–7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6–29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non–communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries. Interpretation Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition—in which increasing sociodemographic status brings structured change in disease burden—is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions.

Directional dominance on stature and cognition in diverse human populations

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.