Isolation and characterization of 21 polymorphic microsatellite loci in the iconic Australian lungfish, Neoceratodus forsteri, using the Ion Torrent next-generation sequencing platform

We isolated and characterized 21 microsatellite loci in the vulnerable and iconic Australian lungfish, Neoceratodus forsteri. Loci were screened across eight individuals from the Burnett River and 40 individuals from the Pine River. Genetic diversity was low with between one and six alleles per locus within populations and a maximum expected heterozygosity of 0.774. These loci will now be available to assess effective population sizes and genetic structure in N. forsteri across its natural range in South East Queensland, Australia.

First-cycle rash and survival in patients with advanced non-small-cell lung cancer receiving cetuximab in combination with first-line chemotherapy : a subgroup analysis of data from the FLEX phase 3 study

Background: The randomised phase 3 First-Line Erbitux in Lung Cancer (FLEX) study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival compared with chemotherapy alone in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). The main cetuximab-related side-effect was acne-like rash. Here, we assessed the association of this acne-like rash with clinical benefit. Methods: We did a subgroup analysis of patients in the FLEX study, which enrolled patients with advanced NSCLC whose tumours expressed epidermal growth factor receptor. Our landmark analysis assessed if the development of acne-like rash in the first 21 days of treatment (first-cycle rash) was associated with clinical outcome, on the basis of patients in the intention-to-treat population alive on day 21. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: 518 patients in the chemotherapy plus cetuximab group-290 of whom had first-cycle rash-and 540 patients in the chemotherapy alone group were alive on day 21. Patients in the chemotherapy plus cetuximab group with first-cycle rash had significantly prolonged overall survival compared with patients in the same treatment group without first-cycle rash (median 15·0 months [95% CI 12·8-16·4] vs 8·8 months [7·6-11·1]; hazard ratio [HR] 0·631 [0·515-0·774]; p<0·0001). Corresponding significant associations were also noted for progression-free survival (median 5·4 months [5·2-5·7] vs 4·3 months [4·1-5·3]; HR 0·741 [0·607-0·905]; p=0·0031) and response (rate 44·8% [39·0-50·8] vs 32·0% [26·0-38·5]; odds ratio 1·703 [1·186-2·448]; p=0·0039). Overall survival for patients without first-cycle rash was similar to that of patients that received chemotherapy alone (median 8·8 months [7·6-11·1] vs 10·3 months [9·6-11·3]; HR 1·085 [0·910-1·293]; p=0·36). The significant overall survival benefit for patients with first-cycle rash versus without was seen in all histology subgroups: adenocarcinoma (median 16·9 months, [14·1-20·6] vs 9·3 months [7·7-13·2]; HR 0·614 [0·453-0·832]; p=0·0015), squamous-cell carcinoma (median 13·2 months [10·6-16·0] vs 8·1 months [6·7-12·6]; HR 0·659 [0·472-0·921]; p=0·014), and carcinomas of other histology (median 12·6 months [9·2-16·4] vs 6·9 months [5·2-11·0]; HR 0·616 [0·392-0·966]; p=0·033). Interpretation: First-cycle rash was associated with a better outcome in patients with advanced NSCLC who received cisplatin and vinorelbine plus cetuximab as a first-line treatment. First-cycle rash might be a surrogate clinical marker that could be used to tailor cetuximab treatment for advanced NSCLC to those patients who would be most likely to derive a significant benefit. Funding: Merck KGaA. © 2011 Elsevier Ltd.

Taxation determinations as de facto regulation : private equity exits in Australia

The Australian Taxation Office (AT)) attempted to challenge both the private equity fund reliance on double tax agreements and the assertion that profits were capital in nature in its dispute with private equity group TPG. Failure to resolve the dispute resulted in the ATO issuing two taxation determinations: TD 2010/20 which states that the general anti-avoidance provisions can apply to arrangements designed to alter the intended effect of Australia's international tax agreements net; and TD 2010/21 which states that the profits on the sale of shares in a company group acquired in a leveraged buyout is assessable income. The purpose of this article is to determine the effectiveness of the administrative rulings regime as a regulatory strategy. This article, by using the TPG-Myer scenario and subsequent tax determinations as a case study, collects qualitative data which is then analysed (and triangulated) using tonal and thematic analysis. Contemporaneous commentary of private equity stakeholders, tax professionals, and media observations are analysed and evaluated within a framework of responsive regulation and utilising the current ATO compliance model. Contrary to the stated purpose of the ATO rulings regime to alleviate complexities in Australian taxation law and provide certainty to taxpayers, and despite the de facto law status afforded these rulings, this study found that the majority of private equity stakeholders and their advisors perceived that greater uncertainty was created by the two determinations. Thus, this study found that in the context of private equity fund investors, a responsive regulation measure in the form of taxation determinations was not effective.

Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010

BACKGROUND Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time. METHODS We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable definitions and methods. YLLs were calculated from age-sex-country-time-specific estimates of mortality by cause, with death by standardised lost life expectancy at each age. YLDs were calculated as prevalence of 1160 disabling sequelae, by age, sex, and cause, and weighted by new disability weights for each health state. Neither YLLs nor YLDs were age-weighted or discounted. Uncertainty around cause-specific DALYs was calculated incorporating uncertainty in levels of all-cause mortality, cause-specific mortality, prevalence, and disability weights. FINDINGS Global DALYs remained stable from 1990 (2·503 billion) to 2010 (2·490 billion). Crude DALYs per 1000 decreased by 23% (472 per 1000 to 361 per 1000). An important shift has occurred in DALY composition with the contribution of deaths and disability among children (younger than 5 years of age) declining from 41% of global DALYs in 1990 to 25% in 2010. YLLs typically account for about half of disease burden in more developed regions (high-income Asia Pacific, western Europe, high-income North America, and Australasia), rising to over 80% of DALYs in sub-Saharan Africa. In 1990, 47% of DALYs worldwide were from communicable, maternal, neonatal, and nutritional disorders, 43% from non-communicable diseases, and 10% from injuries. By 2010, this had shifted to 35%, 54%, and 11%, respectively. Ischaemic heart disease was the leading cause of DALYs worldwide in 2010 (up from fourth rank in 1990, increasing by 29%), followed by lower respiratory infections (top rank in 1990; 44% decline in DALYs), stroke (fifth in 1990; 19% increase), diarrhoeal diseases (second in 1990; 51% decrease), and HIV/AIDS (33rd in 1990; 351% increase). Major depressive disorder increased from 15th to 11th rank (37% increase) and road injury from 12th to 10th rank (34% increase). Substantial heterogeneity exists in rankings of leading causes of disease burden among regions. INTERPRETATION Global disease burden has continued to shift away from communicable to non-communicable diseases and from premature death to years lived with disability. In sub-Saharan Africa, however, many communicable, maternal, neonatal, and nutritional disorders remain the dominant causes of disease burden. The rising burden from mental and behavioural disorders, musculoskeletal disorders, and diabetes will impose new challenges on health systems. Regional heterogeneity highlights the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account. Because of improved definitions, methods, and data, these results for 1990 and 2010 supersede all previously published Global Burden of Disease results.

Telephone-delivered health coaching improves anxiety outcomes after myocardial infarction: The 'ProActive Heart' trial

Background: Recently, we found a telephone-delivered secondary prevention programme using health coaching (‘ProActive Heart’) to be effective in improving a range of key behavioural outcomes for myocardial infarction (MI) patients. What remains unclear, however, is the extent to which these treatment effects translate to important psychological outcomes such as depression and anxiety outcomes, an issue of clinical significance due to the substantial proportion of MI patients who experience depression and anxiety. The objective of the study was to investigate, as a secondary hypothesis of a larger trial, the effects of a telephone-delivered health coaching programme on depression and anxiety outcomes of MI patients. Design: Two-arm, parallel-group, randomized, controlled design with six-months outcomes. Methods: Patients admitted to one of two tertiary hospitals in Brisbane, Australia following MI were assessed for eligibility. Four hundred and thirty patients were recruited and randomly assigned to usual care or an intervention group comprising up to 10 telephone-delivered ‘health coaching’ sessions (ProActive Heart). Regression analysis compared Hospital Anxiety and Depression Scale scores of completing participants at six months (intervention: n = 141 versus usual care: n = 156). Results: The intervention yielded reductions in anxiety at follow-up (mean difference = −0.7, 95% confidence interval=−1.4,−0.02) compared with usual care. A similar pattern was observed in mean depression scores but was not statistically significant. Conclusions: The ProActive Heart programme effectively improves anxiety outcomes of patients following myocardial infarction. If combined with psychological-specific treatment, this programme could impact anxiety of greater intensity in a clinically meaningful way.

Marginal costs of hospital-acquired conditions : information for priority-setting for patient safety programmes and research

Objective: To estimate the relative inpatient costs of hospital-acquired conditions. Methods: Patient level costs were estimated using computerized costing systems that log individual utilization of inpatient services and apply sophisticated cost estimates from the hospital's general ledger. Occurrence of hospital-acquired conditions was identified using an Australian ‘condition-onset' flag for diagnoses not present on admission. These were grouped to yield a comprehensive set of 144 categories of hospital-acquired conditions to summarize data coded with ICD-10. Standard linear regression techniques were used to identify the independent contribution of hospital-acquired conditions to costs, taking into account the case-mix of a sample of acute inpatients (n = 1,699,997) treated in Australian public hospitals in Victoria (2005/06) and Queensland (2006/07). Results: The most costly types of complications were post-procedure endocrine/metabolic disorders, adding AU$21,827 to the cost of an episode, followed by MRSA (AU$19,881) and enterocolitis due to Clostridium difficile (AU$19,743). Aggregate costs to the system, however, were highest for septicaemia (AU$41.4 million), complications of cardiac and vascular implants other than septicaemia (AU$28.7 million), acute lower respiratory infections, including influenza and pneumonia (AU$27.8 million) and UTI (AU$24.7 million). Hospital-acquired complications are estimated to add 17.3% to treatment costs in this sample. Conclusions: Patient safety efforts frequently focus on dramatic but rare complications with very serious patient harm. Previous studies of the costs of adverse events have provided information on ‘indicators’ of safety problems rather than the full range of hospital-acquired conditions. Adding a cost dimension to priority-setting could result in changes to the focus of patient safety programmes and research. Financial information should be combined with information on patient outcomes to allow for cost-utility evaluation of future interventions.

Psychological health and the risk of diabetes mellitus in Australian women: A 21-year prospective study

Background Symptoms of depression can be recurrent or limited to one episode. This study discusses the prospective association between psychological health, measured as change in depression symptoms, and the risk of diabetes mellitus in Australian women. Methods Data obtained from the Mater-University of Queensland Study of Pregnancy. Depression was measured using the Delusions-Symptoms: States Inventory. To examine possible transitions over time, depression was grouped into four categories and assessed at different phases over the 21-year period. Multiple logistic regression models and sensitivity analysis to assess the robustness of our analytical strategy were performed. Results Three hundred and one women reported diabetes 21 years after the index pregnancy. Almost one-third of the women who reported depression symptoms continued to report these at a subsequent follow-up (FU) phase. About 1 in 20 women who had not reported depression symptoms at the 5-year FU did so at the subsequent 14-year FU. In prospective analyses, we did not find a significant association between diabetes and negative change (not depressed to depressed, at subsequent phase); however, for women with positive history of symptoms of depression and women with persistent symptoms, there was a 1.97-fold (95% confidence interval [CI]: 1.14–3.40) to 2.23-fold (95% CI: 1.09–4.57) greater risk of diabetes. Conclusions Our study suggests that an increased risk of diabetes is significantly associated with persistent depression symptoms. It highlights the importance of recognizing depression symptoms in terms of women's psychological wellbeing and thus provides a basis for targeting those most at risk.

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010

BACKGROUND Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. METHODS We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. FINDINGS In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. INTERPRETATION Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children.

Developing pictorial conceptual metaphors as a means of understanding and changing the Australian health system for Indigenous people

This paper describes the development of Pictorial Conceptual Metaphors, created out of a literature review on gendered Indigenous health and wellbeing that depicts the inherited effects of the ‘system’ past, present and future. The Pictorial Conceptual Metaphors are pictures that were created to tell the story of colonisation and its inherited and ongoing impacts on Indigenous people’s health and wellbeing. Aboriginal historical experiences, past, present and future are briefly overviewed in order to unpack and communicate to readers the significance and impact of these experiences on Aboriginal health, and ultimately, to bring about understanding to initiate change within the Australian health system. Systemic racism, embedded in the Australian health system, excludes and discriminates against Indigenous peoples through a lack of cultural consideration resulting in a cumulative and ongoing negative effect on Indigenous people’s health (Dudgeon et al. 2014; Fredericks 2008; Marmot 2011; Queensland Government 2012). Systemic action research identifies actions and processes in large systems such as health and education in order to bring about systemic change. Our intention to highlight the systemic changes needed in the Australian health system to improve Indigenous people’s health and wellbeing require us to understand the processes involved in bringing about systemic change. For this to occur, we needed to ‘see the system’ in order to identify the system dynamics in operation. The Pictorial Conceptual Metaphors are the first step in ‘seeing the system’; they illustrate the past and the present, and identify the preferred future for Indigenous health and wellbeing outcomes

Mimicry of 21. 5 KDa myelin basic protein peptide by a Maedi Visna virus polymerase peptide does not contribute to the pathogenesis of encephalitis in sheep

Epitope mimicry is the theory that an infectious agent such as a virus causes pathological effects via mimicry of host proteins and thus elicits a cross-reactive immune response to host tissues. Weise and Carnegie (1988) found a region of sequence similarity between the pol gene of the Maedi Visna virus (MVV), which induces demyelinating encephalitis in sheep, and myelin basic protein (MBP), which is known to induce experimental allergic encephalitis (EAE) in laboratory animals. In this study, cross-reactions between sera raised in sheep against synthetic peptides of MVV (TGKIPWILLPGR) and 21.5 kDa MBP (SGKVPWLKRPGR) were demonstrated using enzyme-linked immunosorbant assay (ELISA) and thin layer chromatography (TLC) immunoprobing. The antibody responses of MVV-infected sheep were investigated using ELISA against the peptides, and MBP protein, immunoprobing of the peptides on TPC plates and Western blotting against MBP. Slight significant reactions to the 21.5 kDa MBP peptide (P < 0.001) and to a lesser extent sheep MBP (P < 0.004) were detected in ELISA. The MBP peptide evoked stronger responses from more sera than the MVV peptide on immunoprobed TLC plates. On the Western blots, eight of the 23 sheep with Visna had serum reactivity to MBP. This slight reaction to MBP in MVV-infected sheep is of interest because of the immune responses to MBP evident in multiple sclerosis and EAE, but its relevance in Visna is limited since no correlation with disease severity was observed. The cell-mediated immune responses of MVV-infected sheep against similar peptides was assessed. The peptides did not stimulate proliferation of peripheral blood lymphocytes of MVV-infected sheep. Since the MVV peptide was not recognised by antibodies or T lymphocytes from MVV-infected and encephalic sheep, it was concluded that epitope mimicry of this 21.5 kDa MBP peptide by the similar MVV pol peptide was not contributing to the immunopathogenesis of Visna. The slight antibody response to MBP and the MBP peptide can be attributed to by-stander effects of the immunopathology of MVV-induced encephalitis.

Single 2×1 domain orientation on Si(001) surfaces using aperiodic Bi line arrays

Studies of Bi heteroepitaxy on Si(001) have shown that lines grow to lengths of up to 500nm if the substrate is heated to above the Bi desorption temperature (500°C) during or after Bi deposition. Unlike many other nanoline systems, the lines formed by this nonequilibrium growth process have no detectable width dispersion. Although much attention has been given to the atomic geometery of the line, in this paper, we focus on how the lines can be used to create a majority 2×1 domain orientation. It is demonstrated that the Bi lines can be used to produce a single-domain orientation on Si(001) if the lines are grown on Si(001) surfaces with a regular distribution of single height steps. This is a compelling example of how a nanoscale motif can be used to modify mesoscopic surface structure on Si(001).

Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations

Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.