Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene

Aims/hypothesis Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study. Methods Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot. Results The top ranked variant was rs3805931 with p = 2.66 × 10−7, but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10−5) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10−8). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina. Conclusions/interpretation Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.

Dark city

A synopsis and critique of an Australian/American film, Dark City, directed by Alex Proyas in the science fiction genre.

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.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5–89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.

Global Nursing Issues and Development: Analysis of World Health Organization Documents

Purpose To analyze World Health Organization (WHO) documents to identify global nursing issues and development. Design Qualitative content analysis. Methods Documents published by the six WHO regions between 2007 and 2012 and with key words related to nurse/midwife or nursing/midwifery were included. Themes, categories, and subcategories were derived. The final coding reached 80% agreement among three independent coders, and the final coding for the discrepant coding was reached by consensus. Findings Thirty-two documents from the regions of Europe (n = 19), the Americas (n = 6), the Western Pacific (n = 4), Africa (n = 1), the Eastern Mediterranean (n = 1), and Southeast Asia (n = 1) were examined. A total of 385 units of analysis dispersed in 31 subcategories under four themes were derived. The four themes derived (number of unit of analysis, %) were Management & Leadership (206, 53.5), Practice (75, 19.5), Education (70, 18.2), and Research (34, 8.8). Conclusions The key nursing issues of concern at the global level are workforce, the impacts of nursing in health care, professional status, and education of nurses. International alliances can help advance nursing, but the visibility of nursing in the WHO needs to be strengthened. Clinical Relevance Organizational leadership is important in order to optimize the use of nursing competence in practice and inform policy makers regarding the value of nursing to promote people's health.

Introducing a new limit states design concept to railway concrete sleepers: An Australian experience

Over 50 years, a large number of research and development projects with respect to the use of cementitious and concrete materials for manufacturing railway sleepers have been significantly progressed in Australia, Europe, and Japan (Wang, 1996; Murray and Cai, 1998; Wakui and Okuda, 1999; Esveld, 2001; Freudenstein and Haban, 2006; Remennikov and Kaewunruen, 2008). Traditional sleeper materials are timber, steel, and concrete. Cost-efficiency, superior durability, and improved track stability are the main factors toward significant adoption of concrete materials for railway sleepers. The sleepers in a track system, as shown in Figure 1, are subjected to harsh and aggressive external forces and natural environments across a distance. Many systemic problems and technical issues associated with concrete sleepers have been tackled over decades. These include pre-mature failures of sleepers, concrete cancer or ettringite, abrasion of railseats and soffits, impact damages by rail machinery, bond-slip damage, longitudinal and lateral instability of track system, dimensional instability of sleepers, nuisance noise and vibration, and so on (Pfeil, 1997; Gustavson, 2002; Kaewunruen and Remennikov, 2008a,b, 2013). These issues are, however, becoming an emerging risk for many countries (in North and South Americas, Asia, and the Middle East) that have recently installed large volumes of concrete sleepers in their railway networks (Federal Railroad Administration, 2013). As a result, it is vital to researchers and practitioners to critically review and learn from previous experience and lessons around the world.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10−8). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Feasibility of a stepped wedge cluster RCT and concurrent observational sub-study to evaluate the effects of modified ward night lighting on inpatient fall rates and sleep quality: A protocol for a pilot trial

Background: Falls among hospitalised patients impose a considerable burden on health systems globally and prevention is a priority. Some patient-level interventions have been effective in reducing falls, but others have not. An alternative and promising approach to reducing inpatient falls is through the modification of the hospital physical environment and the night lighting of hospital wards is a leading candidate for investigation. In this pilot trial, we will determine the feasibility of conducting a main trial to evaluate the effects of modified night lighting on inpatient ward level fall rates. We will test also the feasibility of collecting novel forms of patient level data through a concurrent observational sub-study. Methods/design: A stepped wedge, cluster randomised controlled trial will be conducted in six inpatient wards over 14 months in a metropolitan teaching hospital in Brisbane (Australia). The intervention will consist of supplementary night lighting installed across all patient rooms within study wards. The planned placement of luminaires, configurations and spectral characteristics are based on prior published research and pre-trial testing and modification. We will collect data on rates of falls on study wards (falls per 1000 patient days), the proportion of patients who fall once or more, and average length of stay. We will recruit two patients per ward per month to a concurrent observational sub-study aimed at understanding potential impacts on a range of patient sleep and mobility behaviour. The effect on the environment will be monitored with sensors to detect variation in light levels and night-time room activity. We will also collect data on possible patient-level confounders including demographics, pre-admission sleep quality, reported vision, hearing impairment and functional status. Discussion: This pragmatic pilot trial will assess the feasibility of conducting a main trial to investigate the effects of modified night lighting on inpatient fall rates using several new methods previously untested in the context of environmental modifications and patient safety. Pilot data collected through both parts of the trial will be utilised to inform sample size calculations, trial design and final data collection methods for a subsequent main trial.

Quality of life after early enteral feeding versus standard care for proven or suspected advanced epithelial ovarian cancer: Results from a randomised trial

Background Malnutrition is common in patients with advanced epithelial ovarian cancer (EOC), and is associated with impaired quality of life (QoL), longer hospital stay and higher risk of treatment-related adverse events. This phase III multi-centre randomised clinical trial tested early enteral feeding versus standard care on postoperative QoL. Methods From 2009 to 2013, 109 patients requiring surgery for suspected advanced EOC, moderately to severely malnourished were enrolled at five sites across Queensland and randomised to intervention (n = 53) or control (n = 56) groups. Intervention involved intraoperative nasojejunal tube placement and enteral feeding until adequate oral intake could be maintained. Despite being randomised to intervention, 20 patients did not receive feeds (13 did not receive the feeding tube; 7 had it removed early). Control involved postoperative diet as tolerated. QoL was measured at baseline, 6 weeks postoperatively and 30 days after the third cycle of chemotherapy. The primary outcome measure was the difference in QoL between the intervention and the control group. Secondary endpoints included treatment-related adverse event occurrence, length of stay, postoperative services use, and nutritional status. Results Baseline characteristics were comparable between treatment groups. No significant difference in QoL was found between the groups at any time point. There was a trend towards better nutritional status in patients who received the intervention but the differences did not reach statistical significance except for the intention-to-treat analysis at 7 days postoperatively (11.8 intervention vs. 13.8 control, p 0.04). Conclusion Early enteral feeding did not significantly improve patients' QoL compared to standard of care but may improve nutritional status.

The status of entrepreneurship education in Australian universities

Purpose The purpose of this paper is to provide an analytical overview of the current state of entrepreneurship education (EE) in Australia; placing emphasis on programs, curricula and entrepreneurship ecosystems. Design/methodology/approach The authors performed a contextual review of the literature by delineating entrepreneurship education programs, the entrepreneurial ecosystem and EE learning and teaching. The review was enhanced by a systematic collection of data from higher education institutions web sites, depicting the prevailing situation of entrepreneurship programs, courses, subjects and their ecosystems. Findings A number of interesting findings emerged from this study. From a curricular perspective, Australian universities offer 584 subjects related to entrepreneurship. This includes dominance at undergraduate level, representing 24 minors/majors and specializations in entrepreneurship. In total, 135 entrepreneurship ecosystems were identified. Research limitations/implications This paper presents findings from university web sites and as such requires introspection to validate individual university offerings. Practical implications The study provides the status of EE in Australia, and may guide academic and policy decision makers to further develop entrepreneurship initiatives. Originality/value This paper provides the first analytical overview of EE in Australia and paves the way for further evaluation.

Enterprise education: For all, or just some?

Purpose The purpose of this paper is to provocatively enter four imagined worlds of enterprise education with the express aim of contemplating an emerging future. The authors do so not to expressly determine what positioning is most appropriate for enterprise/entrepreneurship education, but rather to consider the issues associated with each of the four imagined worlds. Design/methodology/approach The authors’ approach is built around a combination of cycles of reflective practice and the use of scenario development processes. The authors seek to suspend their collective judgement whilst entering the four imagined worlds, but ultimately do not claim to have hidden their personal biases. Findings It is concluded that enterprise/entrepreneurship education should be shared across the university and not owned by any school or faculty. While the authors find it difficult to dismiss the underlying purpose of each scenario, they sense an opportunity to unite their common focus on the development of a transformative student experience. Practical implications This process has provided unexpected insights into the potential of scenario planning as a tool that could conceivably be employed more often to tackle complex issues, such as the positioning of enterprise/entrepreneurship education in Higher Education. Originality/value This paper, despite its inherent biases, offers the reader an opportunity to gain a sense of the various roles forced upon enterprise/entrepreneurship education by its various key stakeholders. In doing so, the shortcomings of the current situation are highlighted.

Constituting religion after Williams: The false dichotomy of theocracy and secularism

The Williams case is a relevant segue to consider the broader issue of constitutional relations between church and state in Australia. This paper argues that the dichotomous approach of theocracy as opposed to secularism is false and actually undermines the proper operation of s 116. A theocracy would contravene s 116 as an establishment of religion, but secularism also amounts to a conflict with s 116 as prohibiting the free exercise of religion. The necessary alternative is to find a middle ground compatible with s 116, one which will not establish any single state religion but will allow the contribution of different religious perspectives in the process of policy-making. This paper briefly considers how such an approach may be implemented.

Popper or Kuhn: Truth and the progress of science

The questions of whether science pursues truth as correspondence to reality and whether science in fact progresses towards attaining a truthful understanding of physical reality are fundamental and contested in the philosophy of science. On one side of the debate stands Popper, who argues that science is objective, necessarily assumes a correspondence theory of truth, and inevitably progresses toward truth as physical theories develop, gaining a more truthful understanding of reality through progressively more sophisticated empirical analysis. Conversely Kuhn, influenced by postmodern philosophy, argues that ultimate truth cannot be attained since no objective metaphysical reality exists and it cannot be known, and consequently the notion of scientific objectivity and "progress" is a myth, marred by philosophical and ideological value judgments. Ultimately, Kuhn reduces so-called scientific progress through the adoption of successive paradigms to leaps of "faith". This paper seeks a reconciliation of the two extremes, arguing that Popper is correct in the sense that science assumes a correspondence theory of truth and may progress toward truth as physical theories develop, while simultaneously acknowledging with Kuhn that science is not purely objective and free of value judgments. The notion of faith is also critical, for it was the acknowledgement of God's existence as the creator and instituter of observable natural laws which allowed the development of science and the scientific method in the first place. Therefore, accepting and synthesising the contentions that science is to some extent founded on faith, assumes and progresses toward truth, and is subject to value judgments is necessary for the progress of science.