Concordance of genetic risk across migraine subgroups: Impact on current and future genetic association studies

BACKGROUND There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) should be considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migraine cases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differ from male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, we examined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 population-matched controls. METHODS Detailed heterogeneity analysis of single-nucleotide polymorphism (SNP) effects (odds ratios) between migraine subgroups was performed for the 12 independent SNP loci significantly associated (p < 5 x 10(-8); thus surpassing the threshold for genome-wide significance) with migraine susceptibility. Overall genetic overlap was assessed using SNP effect concordance analysis (SECA) at over 23,000 independent SNPs. RESULTS: Significant heterogeneity of SNP effects (p het < 1.4 x 10(-3)) was observed between the MA and MO subgroups (for SNP rs9349379), and between the clinic- and population-based subgroups (for SNPs rs10915437, rs6790925 and rs6478241). However, for all 12 SNPs the risk-increasing allele was the same, and SECA found the majority of genome-wide SNP effects to be in the same direction across the subgroups. CONCLUSIONS Any differences in common genetic risk across these subgroups are outweighed by the similarities. Meta-analysis of additional migraine GWA datasets, regardless of their major subgroup composition, will identify new susceptibility loci for migraine.

Advanced practice: A survey of current perspectives of Australian pharmacists

Background An Advanced Pharmacy Practice Framework for Australia (the ‘APPF’) was published in October 2012. Further to the release of the APPF, the Advanced Pharmacy Practice Framework Steering Committee planned to develop an advanced practice recognition model for Australian pharmacists. Aim To gauge the perspectives of the pharmacy profession relating to advanced practice, via an online survey, in order to inform the design of the model. Method A survey was developed and administered to Australian pharmacists through SurveyMonkey . The survey content was based on findings from a review of national and international initiatives for recognition of advanced practice in pharmacy and other health disciplines, including medicine and nursing. Results The results of the survey showed that a high proportion of respondents considered they were already working at, or working towards achieving, an advanced level of practice. The responses relating to the assessment methods showed a clear preference for ‘submission of a professional portfolio’. A ‘written examination’ had a low level of support and in relation to an ‘oral examination by a panel’ there was a marked preference for a panel of multidisciplinary health professionals over a panel of pharmacists. Conclusion The survey outcomes will inform the development of an advanced pharmacy practice recognition model for Australian pharmacists, particularly in relation to the assessment methods. Survey outcomes also demonstrated that there is scope to further enhance the application of the APPF in the development and recognition of advanced practitioners, and to build greater awareness of the breadth of competencies encompassed by ‘advanced practice’.

Fair value accounting for non-current assets and audit fees: Evidence from Australian companies

We investigate the association between asset revaluations of non-current assets and audit fees, using a sample of ASX 300 companies from the years 2003–2007.We report that there is a significant increase in the audit fees paid when non-financial assets (PPEs, investment properties and intangible assets) are measured at fair values. Moreover, we provide evidence that an independent valuer or appraiser significantly weakens the positive association between asset revaluations and audit fees. Furthermore, companies whose noncurrent assets are revalued upwards and those that revalue their non-current assets upwards every year have significantly higher audit fees. Additional tests provide empirical evidence that the strength of corporate governance has a moderating effect on the level of audit fees. This study contributes to the ongoing debate on the role of fair value accounting. The findings suggest agency costs associated with fair value estimates may offset the benefits from the use of fair value accounting.

Susceptibility locus on chromosome 1q23-25 for a schizophrenia subtype resembling deficit schizophrenia identified by latent class analysis

Context: Identifying susceptibility genes for schizophrenia may be complicated by phenotypic heterogeneity, with some evidence suggesting that phenotypic heterogeneity reflects genetic heterogeneity. Objective: To evaluate the heritability and conduct genetic linkage analyses of empirically derived, clinically homogeneous schizophrenia subtypes. Design: Latent class and linkage analysis. Setting: Taiwanese field research centers. Participants: The latent class analysis included 1236 Han Chinese individuals with DSM-IV schizophrenia. These individuals were members of a large affected-sibling-pair sample of schizophrenia (606 ascertained families), original linkage analyses of which detected a maximum logarithm of odds (LOD) of 1.8 (z = 2.88) on chromosome 10q22.3. Main Outcome Measures: Multipoint exponential LOD scores by latent class assignment and parametric heterogeneity LOD scores. Results: Latent class analyses identified 4 classes, with 2 demonstrating familial aggregation. The first (LC2) described a group with severe negative symptoms, disorganization, and pronounced functional impairment, resembling “deficit schizophrenia.” The second (LC3) described a group with minimal functional impairment, mild or absent negative symptoms, and low disorganization. Using the negative/deficit subtype, we detected genome-wide significant linkage to 1q23-25 (LOD = 3.78, empiric genome-wide P = .01). This region was not detected using the DSM-IV schizophrenia diagnosis, but has been strongly implicated in schizophrenia pathogenesis by previous linkage and association studies.Variants in the 1q region may specifically increase risk for a negative/deficit schizophrenia subtype. Alternatively, these results may reflect increased familiality/heritability of the negative class, the presence of multiple 1q schizophrenia risk genes, or a pleiotropic 1q risk locus or loci, with stronger genotype-phenotype correlation with negative/deficit symptoms. Using the second familial latent class, we identified nominally significant linkage to the original 10q peak region. Conclusion: Genetic analyses of heritable, homogeneous phenotypes may improve the power of linkage and association studies of schizophrenia and thus have relevance to the design and analysis of genome-wide association studies.

Rolling out the future: The current status of the Australian NBN and its impact for property

The future functioning of the digital economy is inextricably linked to the use of high-speed broadband networks. As evidenced by recent Australian federal election campaigns, a focus has been on the rollout of the physical networks. The research seeks to determine the effectiveness of the current NBN rollout as a measure of Australia’s progression towards a fully functioning digital economy. The author examines submissions to the recent RTIRC Telecommunications Review 2015 in order to ascertain the NBN’s current impact upon Australia’s digital economy.

Mechanical testing of internal fixation devices: A theoretical and practical examination of current methods

Successful healing of long bone fractures is dependent on the mechanical environment created within the fracture, which in turn is dependent on the fixation strategy. Recent literature reports have suggested that locked plating devices are too stiff to reliably promote healing. However, in vitro testing of these devices has been inconsistent in both method of constraint and reported outcomes, making comparisons between studies and the assessment of construct stiffness problematic. Each of the methods previously used in the literature were assessed for their effect on the bending of the sample and concordant stiffness. The choice of outcome measures used in in vitro fracture studies was also assessed. Mechanical testing was conducted on seven hole locked plated constructs in each method for comparison. Based on the assessment of each method the use of spherical bearings, ball joints or similar is suggested at both ends of the sample. The use of near and far cortex movement was found to be more comprehensive and more accurate than traditional centrally calculated inter fragmentary movement values; stiffness was found to be highly susceptible to the accuracy of deformation measurements and constraint method, and should only be used as a within study comparison method. The reported stiffness values of locked plate constructs from in vitro mechanical testing is highly susceptible to testing constraints and output measures, with many standard techniques overestimating the stiffness of the construct. This raises the need for further investigation into the actual mechanical behaviour within the fracture gap of these devices.

The current status of heart failure diagnostic biomarkers

Heart failure (HF) affects approximately 23 million individuals worldwide and this number is increasing, due to an aging and growing population. Early detection of HF is crucial in the management of this debilitating disease. Current diagnostic methods for HF rely heavily on clinical imaging techniques and blood analysis, which makes them less than ideal for population-based screening purposes. Studies focusing on developing novel biomarkers for HF have utilized various techniques and biological fluids, including urine and saliva. Promising results from these studies imply that these body fluids can be used in evaluating the clinical manifestation of HF and will one day be integrated into a clinical workflow and facilitate HF management.

Current understanding of streptococcal urinary tract infection

Group B streptococcus (GBS), also known as Streptococcus agalactiae is a Gram-positive, β-hemolytic, chain-forming bacterium and a commensal within the genital tract flora in approximately 25% of healthy adult women (Campbell et al., 2000). The organism is a leading cause of serious infection in newborns, pregnant women, and older persons with chronic medical illness (Baker et al., Edwards&Baker, 2005). In neonates GBS infection most commonly causes pneumonia, meningitis, and sepsis. In addition to maternal cervicovaginal colonization and neonatal infection that can result from vertical transmission of GBS from mothers to their infants, the bacterium can also cause urinary tract infection (UTI). The spectrum of GBS UTI includes asymptomatic bacteriuria (ABU), cystitis, pyelonephritis, urethritis, and urosepsis (Bronsema et al., 1993, Edwards&Baker, 2005, Farley et al., 1993, Lefevre et al., 1991, McKenna et al., 2003, Munoz et al., 1992, Ulett et al., 2009). GBS ABU is particularly common among pregnant women, although those most at risk for cystitis due to GBS appear to be elderly individuals (Edwards&Baker, 2005, Falagas et al., 2006, Muller et al., 2006). In addition to acute and asymptomatic UTI other invasive diseases caused by GBS infection include skin infections, bacteraemia, pneumonia, arthritis, and endocarditis (Liston et al., 1979, Patil & Martin, 2010, Tissi et al., 1997, Trivalle et al., 1998). Thus, GBS is considered unique in terms of its ability to cause a spectrum of diseases in newborns and adult humans and its ability to colonize the genital tract of healthy women in a commensal-type manner...

Dasatinib, nilotinib and standard-dose imatinib for the first line treatment of chronic myeloid leukaemia: Systematic reviews and economic analyses

- Background Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). - Objective This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. - Data sources Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. - Review methods A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. - Results Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. - Limitations Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. - Conclusions From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. - Funding The Health Technology Assessment Programme of the National Institute for Health Research.

The context of enterprise education: Insights into current practices

This paper presents the results of an investigation into contextual differences in the development and delivery of enterprise education in higher education globally. Using information gathered from an online survey distributed to enterprise educators, distinct differences in the provision of enterprise education are identified, as are differences of opinion among enterprise educators. The findings demonstrate that although enterprise education is highly diversified in terms of presentation, content and style, there are clear commonalities with regard to expected student outcomes. The respondents reported low levels of business start-up activity among students during enterprise education and/or within one year of graduation. Over 75% of the educators surveyed had personal start-up experience, and there was limited reliance on academic literature, with a preference for referencing broader stakeholder perspectives. With regard to the practical implications of this research, the international metric of enterprise education appears to be a broad set of enterprising skills that equip and enable students to recognize and exploit opportunities in order to navigate future unknowns. The commonly employed metric of business start-up appears less valid in light of this investigation.

An alternative view of small firm adaptation

Increasingly, small firms with a history tied to a specific geographic location are having their survival threatened by new and innovative web-based entrants. This paper considers the plight of such firms and proposes an alternative means to reflect on how they may or may not learn about such threats. Adopting an evolutionary perspective, the construct absorptive capacity is used to highlight the deficiencies of current market orientation theory to explain the process of firm learning. The conceptual model of evolutionary potential provides a framework through which both the firm and its owner/s' abilities to learn can be taken into account.

New lads or ladettes? A critique of current theoretical explanations for young women’s violence proliferated over social media

Current theoretical explanations for young women’s violence examine physical violence as a masculine behaviour. This means that young women are constructed as rejecting elements of their femininity in favour of masculine behaviours in order to perform violence in an acceptable way, which results in them being constructed as violent femmes, new lads or ladettes. Alternatively, theoretical explanations construct young women as adhering to a feminine gender performance when avoiding physical violence, or engaging what are traditionally considered to be feminine characteristics of aggression. This paper critiques existing theoretical approaches applied to young women’s violence, by drawing on empirical research that examined young women’s physical altercations proliferated through social media. Preliminary research findings illustrate how continuing to construct young women’s violence through a gendered paradigm offers inadequate explanations for what young women’s violence actually entails. It concludes by suggesting how young women’s violence may be more adequately explained using a theoretical framework of embodying gender that moves away from gender dichotomies and constructs violence as a series of bodily practices.

Developing standardized methods to assess cost of healthy and unhealthy (current) diets in Australia

Unhealthy diets contribute at least 14% to Australia's disease burden and are driven by ‘obesogenic’ food environments. Compliance with dietary recommendations is particularly poor amongst disadvantaged populations including low socioeconomic groups, those living in rural/remote areas and Aboriginal and Torres Strait Islanders. The perception that healthy foods are expensive is a key barrier to healthy choices and a major determinant of diet-related health inequities. Available state/regional/local data (limited and non-comparable) suggests that, despite basic healthy foods not incurring GST, the cost of healthy food is higher and has increased more rapidly than unhealthy food over the last 15 years in Australia. However, there were no nationally standardised tools or protocols to benchmark, compare or monitor food prices and affordability in Australia. Globally, we are leading work to develop and test approaches to assess the price differential of healthy and less-healthy (current) diets under the food price module of the International Network for Food and Obesity/non-communicable diseases (NCDs) Research, Monitoring and Action Support (INFORMAS). This presentation describes contextualization of the INFORMAS approach to develop standardised Australian tools, survey protocols and data collection and analysis systems. The ‘healthy diet basket’ was based on the Australian Foundation Diet, 1 The ‘current diet basket’ and specific items included in each basket, were based on recent national dietary survey data.2 Data collection methods were piloted. The final tools and protocols were then applied to measure the price and affordability of healthy and less healthy (current) diets of different household groups in diverse communities across the nation. We have compared results for different geographical locations/population subgroups in Australia and assessed these against international INFORMAS benchmarks. The results inform the development of policy and practice, including those relevant to mooted changes to the GST base, to promote nutrition and healthy weight and prevent chronic disease in Australia.

A model for determining the optimal project life span and concession period of BOT projects

The concession agreement is the core feature of BOT projects, with the concession period being the most essential feature in determining the time span of the various rights, obligations and responsibilities of the government and concessionaire. Concession period design is therefore crucial for financial viability and determining the benefit/cost allocation between the host government and the concessionaire. However, while the concession period and project life span are essentially interdependent, most methods to date consider their determination as contiguous events that are determined exogenously. Moreover, these methods seldom consider the, often uncertain, social benefits and costs involved that are critical in defining, pricing and distributing benefits and costs between the various parties and evaluating potentially distributable cash flows. In this paper, we present the results of the first stage of a research project aimed at determining the optimal build-operate-transfer (BOT) project life span and concession period endogenously and interdependently by maximizing the combined benefits of stakeholders. Based on the estimation of the economic and social development involved, a negotiation space of the concession period interval is obtained, with its lower boundary creating the desired financial return for the private investors and its upper boundary ensuring the economic feasibility of the host government as well as the maximized welfare within the project life. The outcome of the new quantitative model is considered as a suitable basis for future field trials prior to implementation. The structure and details of the model are provided in the paper with Hong Kong tunnel project as a case study to demonstrate its detailed application. The basic contributions of the paper to the theory of construction procurement are that the project life span and concession period are determined jointly and the social benefits taken into account in the examination of project financial benefits. In practical terms, the model goes beyond the current practice of linear-process thinking and should enable engineering consultants to provide project information more rationally and accurately to BOT project bidders and increase the government's prospects of successfully entering into a contract with a concessionaire. This is expected to generate more negotiation space for the government and concessionaire in determining the major socioeconomic features of individual BOT contracts when negotiating the concession period. As a result, the use of the model should increase the total benefit to both parties.