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

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

Creating a common approach to safety management through structured training development

The successful management of workplace safety has many benefits for employees, employers and the community. Similar to other areas of job performance, safety performance can be enhanced through appropriate and well-designed training. The foundation of the development of effective training is a thorough training needs analysis (TNA). Currently, the application of psychometrically valid TNA practices for the management of workplace safety is an under-researched topic and limited guidance is available for implementing appropriate strategies. To address this gap in the literature, this chapter will provide an overview of TNA practices, including the purpose and benefits associated with implementing the systematic procedure. A case study will then be presented to illustrate how the TNA process was successfully applied to investigate the training needs of Australasian rail incident investigators to achieve an industry-approved national training package. Recommendations will be made to assist practitioners with implementing TNA practices with the goal of enhancing workplace safety management through targeted workforce development.

Common hazards and their mitigating measures in work zones : a qualitative study of worker perceptions

Road construction and maintenance activities present challenges for ensuring the safety of workers and the traveling public alike. Hazards in work zones are typically studied using historical crash records but the current study took a qualitative approach by interviewing 66 workers from various work zones in Queensland, Australia. This supplemented and enhanced the limited available data regarding the frequency and nature of work zone crashes in Australia, provided worker insights into contributing factors, and assessed their opinions on the likely effectiveness of current or future approaches to hazard mitigation. Workers may not be aware of objective data regarding effectiveness, but their attitudes and consequent levels of compliance can influence both the likelihood of implementation and the outcomes of safety measures. Despite the potential importance of worker perceptions, they have not been studied comprehensively to date, and thus this study fills a significant gap in the literature. Excessive vehicle speeds, driver distraction and aggression towards roadworkers, working in wet weather, at night and close to traffic stream were among the most common hazards noted by workers. The safety measures perceived to be most effective included police presence, active enforcement, and improving driver awareness and education about work zones. Worker perceptions differed according to their level of exposure to hazards.

In silico analyses reveal common cellular pathways affected by loss of heterozygosity (LOH) events in the lymphomagenesis of Non-Hodgkin’s lymphoma (NHL)

Background The analysis of cellular networks and pathways involved in oncogenesis has increased our knowledge about the pathogenic mechanisms that underlie tumour biology and has unmasked new molecular targets that may lead to the design of better anti-cancer therapies. Recently, using a high resolution loss of heterozygosity (LOH) analysis, we identified a number of potential tumour suppressor genes (TSGs) within common LOH regions across cases suffering from two of the most common forms of Non-Hodgkin’s lymphoma (NHL), Follicular Lymphoma (FL) and Diffuse Large B-cell Lymphoma (DLBCL). From these studies LOH of the protein tyrosine phosphatase receptor type J (PTPRJ) gene was identified as a common event in the lymphomagenesis of these B-cell lymphomas. The present study aimed to determine the cellular pathways affected by the inactivation of these TSGs including PTPRJ in FL and DLBCL tumourigenesis. Results Pathway analytical approaches identified that candidate TSGs located within common LOH regions participate within cellular pathways, which may play a crucial role in FL and DLBCL lymphomagenesis (i.e., metabolic pathways). These analyses also identified genes within the interactome of PTPRJ (i.e. PTPN11 and B2M) that when inactivated in NHL may play an important role in tumourigenesis. We also detected genes that are differentially expressed in cases with and without LOH of PTPRJ, such as NFATC3 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 3). Moreover, upregulation of the VEGF, MAPK and ERBB signalling pathways was also observed in NHL cases with LOH of PTPRJ, indicating that LOH-driving events causing inactivation of PTPRJ, apart from possibly inducing a constitutive activation of these pathways by reduction or abrogation of its dephosphorylation activity, may also induce upregulation of these pathways when inactivated. This finding implicates these pathways in the lymphomagenesis and progression of FL and DLBCL. Conclusions The evidence obtained in this research supports findings suggesting that FL and DLBCL share common pathogenic mechanisms. Also, it indicates that PTPRJ can play a crucial role in the pathogenesis of these B-cell tumours and suggests that activation of PTPRJ might be an interesting novel chemotherapeutic target for the treatment of these B-cell tumours.

Combustion analysis of microalgae methyl ester in a common rail direct injection diesel engine

In this study, the biodiesel properties and effects of blends of oil methyl ester petroleum diesel on a CI direct injection diesel engine is investigated. Blends were obtained from the marine dinoflagellate Crypthecodinium cohnii and waste cooking oil. The experiment was conducted using a four-cylinder, turbo-charged common rail direct injection diesel engine at four loads (25%, 50%, 75% and 100%). Three blends (10%, 20% and 50%) of microalgae oil methyl ester and a 20% blend of waste cooking oil methyl ester were compared to petroleum diesel. To establish suitability of the fuels for a CI engine, the effects of the three microalgae fuel blends at different engine loads were assessed by measuring engine performance, i.e. mean effective pressure (IMEP), brake mean effective pressure (BMEP), in cylinder pressure, maximum pressure rise rate, brake-specific fuel consumption (BSFC), brake thermal efficiency (BTE), heat release rate and gaseous emissions (NO, NOx,and unburned hydrocarbons (UHC)). Results were then compared to engine performance characteristics for operation with a 20% waste cooking oil/petroleum diesel blend and petroleum diesel. In addition, physical and chemical properties of the fuels were measured. Use of microalgae methyl ester reduced the instantaneous cylinder pressure and engine output torque, when compared to that of petroleum diesel, by a maximum of 4.5% at 50% blend at full throttle. The lower calorific value of the microalgae oil methyl ester blends increased the BSFC, which ultimately reduced the BTE by up to 4% at higher loads. Minor reductions of IMEP and BMEP were recorded for both the microalgae and the waste cooking oil methyl ester blends at low loads, with a maximum of 7% reduction at 75% load compared to petroleum diesel. Furthermore, compared to petroleum diesel, gaseous emissions of NO and NOx, increased for operations with biodiesel blends. At full load, NO and NOx emissions increased by 22% when 50% microalgae blends were used. Petroleum diesel and a 20% blend of waste cooking oil methyl ester had emissions of UHC that were similar, but those of microalgae oil methyl ester/petroleum diesel blends were reduced by at least 50% for all blends and engine conditions. The tested microalgae methyl esters contain some long-chain, polyunsaturated fatty acid methyl esters (FAMEs) (C22:5 and C22:6) not commonly found in terrestrial-crop-derived biodiesels yet all fuel properties were satisfied or were very close to the ASTM 6751-12 and EN14214 standards. Therefore, Crypthecodinium cohnii- derived microalgae biodiesel/petroleum blends of up to 50% are projected to meet all fuel property standards and, engine performance and emission results from this study clearly show its suitability for regular use in diesel engines.

Terrestrial locomotion of the New Zealand short-tailed bat Mystacina tuberculata and the common vampire bat Desmodus rotundus

Bats (Chiroptera) are generally awkward crawlers, but the common vampire bat (Desmodus rotundus) and the New Zealand short-tailed bat (Mystacina tuberculata) have independently evolved the ability to manoeuvre well on the ground. In this study we describe the kinematics of locomotion in both species, and the kinetics of locomotion in M. tuberculata. We sought to determine whether these bats move terrestrially the way other quadrupeds do, or whether they possess altogether different patterns of movement on the ground than are observed in quadrupeds that do not fly. Using high-speed video analyses of bats moving on a treadmill, we observed that both species possess symmetrical lateral-sequence gaits similar to the kinematically defined walks of a broad range of tetrapods. At high speeds, D. rotundus use an asymmetrical bounding gait that appears to converge on the bounding gaits of small terrestrial mammals, but with the roles of the forelimbs and hindlimbs reversed. This gait was not performed by M. tuberculata. Many animals that possess a single kinematic gait shift with increasing speed from a kinetic walk (where kinetic and potential energy of the centre of mass oscillate out of phase from each other) to a kinetic run (where they oscillate in phase). To determine whether the single kinematic gait of M. tuberculata meets the kinetic definition of a walk, a run, or a gait that functions as a walk at low speed and a run at high speed, we used force plates and high-speed video recordings to characterize the energetics of the centre of mass in that species. Although oscillations in kinetic and potential energy were of similar magnitudes, M. tuberculata did not use pendulum-like exchanges of energy between them to the extent that many other quadrupedal animals do, and did not transition from a kinetic walk to kinetic run with increasing speed. The gait of M. tuberculata is kinematically a walk, but kinetically run-like at all speeds.

Challenging the myth of an "epidemic" of common mental disorders : trends in the global prevalence of anxiety and depression between 1990 and 2010

Background Anxiety disorders and major depressive disorder (MDD) are common and disabling mental disorders. This paper aims to test the hypothesis that common mental disorders have become more prevalent over the past two decades. Methods We conducted a systematic review of prevalence, remission, duration, and excess mortality studies for anxiety disorders and MDD and then used a Bayesian meta-regression approach to estimate point prevalence for 1990, 2005, and 2010. We also conducted a post-hoc search for studies that used the General Health Questionnaire (GHQ) as a measure of psychological distress and tested for trends to present a qualitative comparison of study findings. Results This study found no evidence for an increased prevalence of anxiety disorders or MDD. While the crude number of cases increased by 36%, this was explained by population growth and changing age structures. Point prevalence of anxiety disorders was estimated at 3.8% (3.6-4.1%) in 1990 and 4.0% (3.7-4.2%) in 2010. The prevalence of MDD was unchanged at 4.4% in 1990 (4.2-4.7%) and 2010 (4.1-4.7%). However, 8 of the 11 GHQ studies found a significant increase in psychological distress over time. Conclusions The perceived "epidemic" of common mental disorders is most likely explained by the increasing numbers of affected patients driven by increasing population sizes. Additional factors that may explain this perception include the higher rates of psychological distress as measured using symptom checklists, greater public awareness, and the use of terms such as anxiety and depression in a context where they do not represent clinical disorders.

Common values in assessing health outcomes from disease and injury: Disability weights measurement study for the Global Burden of Disease Study 2010

BACKGROUND Measurement of the global burden of disease with disability-adjusted life-years (DALYs) requires disability weights that quantify health losses for all non-fatal consequences of disease and injury. There has been extensive debate about a range of conceptual and methodological issues concerning the definition and measurement of these weights. Our primary objective was a comprehensive re-estimation of disability weights for the Global Burden of Disease Study 2010 through a large-scale empirical investigation in which judgments about health losses associated with many causes of disease and injury were elicited from the general public in diverse communities through a new, standardised approach. METHODS We surveyed respondents in two ways: household surveys of adults aged 18 years or older (face-to-face interviews in Bangladesh, Indonesia, Peru, and Tanzania; telephone interviews in the USA) between Oct 28, 2009, and June 23, 2010; and an open-access web-based survey between July 26, 2010, and May 16, 2011. The surveys used paired comparison questions, in which respondents considered two hypothetical individuals with different, randomly selected health states and indicated which person they regarded as healthier. The web survey added questions about population health equivalence, which compared the overall health benefits of different life-saving or disease-prevention programmes. We analysed paired comparison responses with probit regression analysis on all 220 unique states in the study. We used results from the population health equivalence responses to anchor the results from the paired comparisons on the disability weight scale from 0 (implying no loss of health) to 1 (implying a health loss equivalent to death). Additionally, we compared new disability weights with those used in WHO's most recent update of the Global Burden of Disease Study for 2004. FINDINGS 13,902 individuals participated in household surveys and 16,328 in the web survey. Analysis of paired comparison responses indicated a high degree of consistency across surveys: correlations between individual survey results and results from analysis of the pooled dataset were 0·9 or higher in all surveys except in Bangladesh (r=0·75). Most of the 220 disability weights were located on the mild end of the severity scale, with 58 (26%) having weights below 0·05. Five (11%) states had weights below 0·01, such as mild anaemia, mild hearing or vision loss, and secondary infertility. The health states with the highest disability weights were acute schizophrenia (0·76) and severe multiple sclerosis (0·71). We identified a broad pattern of agreement between the old and new weights (r=0·70), particularly in the moderate-to-severe range. However, in the mild range below 0·2, many states had significantly lower weights in our study than previously. INTERPRETATION This study represents the most extensive empirical effort as yet to measure disability weights. By contrast with the popular hypothesis that disability assessments vary widely across samples with different cultural environments, we have reported strong evidence of highly consistent results.

The use of prescribed drugs for common chronic conditions in South Africa in 1998

Purpose To determine the prescribed drug-utilisation pattern for six common chronic conditions in adult South Africans in a cross-sectional survey. Methods 13 826 randomly selected participants, 15 years and older, were surveyed by trained fieldworkers at their homes in 1998. Questionnaires included socio-demographic, chronic-disease and drug-use data. The prescribed drugs were recorded from participants' medication containers. The Anatomical Therapeutic Classification (ATC) code of the drugs for tuberculosis (TB), diabetes, hypertension, hyperlipidaemia, other atherosclerosis-related conditions, such as heart conditions or cerebrovascular accidents (CVA), and asthma or chronic obstructive pulmonary disease (COPD), was recorded. The use of logistic regression analyses identified the determinants of those patients who used prescription medication for these six conditions. Results 18.4% of the women and 12.5% of the men used drugs for the six chronic conditions. Men used drugs most frequently for hypertension (50.9%) and asthma or chronic bronchitis (24.3%), while in women it was for hypertension (59.9%) and diabetes (17.5%). The logistic regression analyses showed that women, wealthier and older people, and those with medical insurance used these chronic-disease drugs more frequently compared to men, younger or poor people, or those without medical insurance. The African population group used these drugs less frequently than any other ethnic group. The inappropriate use of methyldopa was found for 14.8% of all antihypertensive drugs, while very few people used aspirin. Conclusions The methodology of this study provides a means of ascertaining the chronic-disease drug-utilisation pattern in national health surveys. The pattern described, suggests an inequitable use of chronic-disease drugs and inadequate use of some effective drugs to control the burden of chronic diseases in South Africa. Copyright © 2004 John Wiley & Sons, Ltd.

Mapping Hydrophobicity on the Protein Molecular Surface at Atom-Level Resolution

A precise representation of the spatial distribution of hydrophobicity, hydrophilicity and charges on the molecular surface of proteins is critical for the understanding of the interaction with small molecules and larger systems. The representation of hydrophobicity is rarely done at atom-level, as this property is generally assigned to residues. A new methodology for the derivation of atomic hydrophobicity from any amino acid-based hydrophobicity scale was used to derive 8 sets of atomic hydrophobicities, one of which was used to generate the molecular surfaces for 35 proteins with convex structures, 5 of which, i.e., lysozyme, ribonuclease, hemoglobin, albumin and IgG, have been analyzed in more detail. Sets of the molecular surfaces of the model proteins have been constructed using spherical probes with increasingly large radii, from 1.4 to 20 A˚, followed by the quantification of (i) the surface hydrophobicity; (ii) their respective molecular surface areas, i.e., total, hydrophilic and hydrophobic area; and (iii) their relative densities, i.e., divided by the total molecular area; or specific densities, i.e., divided by property-specific area. Compared with the amino acid-based formalism, the atom-level description reveals molecular surfaces which (i) present an approximately two times more hydrophilic areas; with (ii) less extended, but between 2 to 5 times more intense hydrophilic patches; and (iii) 3 to 20 times more extended hydrophobic areas. The hydrophobic areas are also approximately 2 times more hydrophobicity-intense. This, more pronounced "leopard skin"-like, design of the protein molecular surface has been confirmed by comparing the results for a restricted set of homologous proteins, i.e., hemoglobins diverging by only one residue (Trp37). These results suggest that the representation of hydrophobicity on the protein molecular surfaces at atom-level resolution, coupled with the probing of the molecular surface at different geometric resolutions, can capture processes that are otherwise obscured to the amino acid-based formalism.