Integrated genomic characterization of endometrial carcinoma

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

Book review: "Qualitative Health Psychology. Theories and Methods" Michael Murray and Kerry Chamberlain (Eds.)

Qualitative Health Psychology aims to contribute to the debate about the nature of psychology and of science through ‘an examination of the role of qualitative research within health psychology’ (p. 3). The editors, in bringing together contributors from the UK, Ireland, Canada, Brazil, New Zealand and Australia, have compiled a text that reflects different uses of qualitative health research in diverse social and cultural contexts. Structured into three parts, the book encompasses key theoretical and methodological issues in qualitative research in its attempt to encourage broad epistemological debate within health psychology.

Analysing the Sri Lankan conflict using Michael Mann's four-dimensional model of social power

This thesis provides an overview of the Sri Lankan civil war with a view to identifying some of the factors that contributed to the dispute between the Sri Lankan government and the Liberation Tigers of Tamil Eelam. It adopts a multi-causal explanation of the conflict by reference to the theories of social power developed by Michael Mann. The conflict has been variously described as an ethnic or political conflict, or has been characterised as a determined by a number of interacting factors (including colonialism, ethnicity, religion, economy, politics and globalisation). Mann’s four-dimensional model of social power is deployed to analyse the causal relationships, together with their inter-connections, which clarify the origins of the dispute. It argues that Mann’s theoretical framework helps to highlight some of the interconnected elements that contributed to the conflict.

Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20

To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

Mutations in cardiac T-Box Factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy

The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.

A systematic review of mathematical models of mosquito-borne pathogen transmission: 1970-2010

Mathematical models of mosquito-borne pathogen transmission originated in the early twentieth century to provide insights into how to most effectively combat malaria. The foundations of the Ross–Macdonald theory were established by 1970. Since then, there has been a growing interest in reducing the public health burden of mosquito-borne pathogens and an expanding use of models to guide their control. To assess how theory has changed to confront evolving public health challenges, we compiled a bibliography of 325 publications from 1970 through 2010 that included at least one mathematical model of mosquito-borne pathogen transmission and then used a 79-part questionnaire to classify each of 388 associated models according to its biological assumptions. As a composite measure to interpret the multidimensional results of our survey, we assigned a numerical value to each model that measured its similarity to 15 core assumptions of the Ross–Macdonald model. Although the analysis illustrated a growing acknowledgement of geographical, ecological and epidemiological complexities in modelling transmission, most models during the past 40 years closely resemble the Ross–Macdonald model. Modern theory would benefit from an expansion around the concepts of heterogeneous mosquito biting, poorly mixed mosquito-host encounters, spatial heterogeneity and temporal variation in the transmission process.

Parallel ABM for electricity distribution grids : a case study

This paper introduces a parallel implementation of an agent-based model applied to electricity distribution grids. A fine-grained shared memory parallel implementation is presented, detailing the way the agents are grouped and executed on a multi-threaded machine, as well as the way the model is built (in a composable manner) which is an aid to the parallelisation. Current results show a medium level speedup of 2.6, but improvements are expected by incor-porating newer distributed or parallel ABM schedulers into this implementa-tion. While domain-specific, this parallel algorithm can be applied to similarly structured ABMs (directed acyclic graphs).

Choroidal thickness in childhood

Purpose To examine choroidal thickness (ChT) and its spatial distribution across the posterior pole in pediatric subjects with normal ocular health and minimal refractive error. Methods ChT was assessed using spectral domain optical coherence tomography (OCT) in 194 children aged between 4-12 years, with spherical equivalent refractive errors between +1.25 and -0.50 DS. A series of OCT scans were collected, imaging the choroid along 4 radial scan lines centered on the fovea (each separated by 45°). Frame averaging was used to reduce noise and enhance chorio-scleral junction visibility. The transverse scale of each scan was corrected to account for magnification effects associated with axial length. Two independent masked observers manually segmented the OCT images to determine ChT at foveal centre, and averaged across a series of perifoveal zones over the central 5 mm. Results The average subfoveal ChT was 330 ± 65 µm (range 189-538 µm), and was significantly influenced by age (p=0.04). The ChT of the 4 to 6 year old age group (312 ± 62 µm) was significantly thinner compared to the 7 to 9 year olds (337 ± 65 µm, p<0.05) and bordered on significance compared to the 10 to 12 year olds (341 ± 61 µm, p=0.08). ChT also exhibited significant variation across the posterior pole, being thicker in more central regions. The choroid was thinner nasally and inferiorly compared to temporally and superiorly. Multiple regression analysis revealed age, axial length and anterior chamber depth were significantly associated with subfoveal ChT (p<0.001). Conclusions ChT increases significantly from early childhood to adolescence. This appears to be a normal feature of childhood eye growth.

Hyperopic defocus and diurnal changes in human choroid and axial length

Purpose To investigate the influence of monocular hyperopic defocus on the normal diurnal rhythms in axial length and choroidal thickness of young adults. Methods A series of axial length and choroidal thickness measurements (collected at ~3 hourly intervals, with the first measurement at ~9 am and the final measurement at ~9 pm) were obtained for 15 emmetropic young adults over three consecutive days. The natural diurnal rhythms (Day 1, no defocus), diurnal rhythms with monocular hyperopic defocus (Day 2, – 2.00 DS spectacle lens over the right eye), and the recovery from any defocus induced changes (Day 3, no defocus) in diurnal rhythms were examined. Results Both axial length and choroidal thickness underwent significant diurnal changes on each of the three measurement days (p<0.0001). The introduction of monocular hyperopic defocus resulted in significant changes in the diurnal variations observed in both parameters (p<0.05). A significant (p<0.001) increase in the mean amplitude (peak to trough) of change in axial length (mean increase, 0.016 ± 0.005 mm) and choroidal thickness (mean increase, 0.011 ± 0.003 mm) was observed on day 2 with hyperopic defocus compared to the two ‘no defocus’ days (days 1 and 3). At the second measurement (mean time 12:10 pm) on the day with hyperopic defocus, the eye was significantly longer by 0.012 ± 0.002 mm compared to the other two days (p<0.05). No significant difference was observed in the average timing of the daily peaks in axial length (mean peak time 12:12 pm) and choroidal thickness (21:02 pm) over the three days. Conclusions The introduction of monocular hyperopic defocus resulted in a significant increase in the amplitude of the diurnal change in axial length and choroidal thickness that returned to normal the following day after removal of the blur stimulus.

Virtual worlds in Australian and New Zealand higher education : remembering the past, understanding the present and imagining the future

3D virtual reality, including the current generation of multi-user virtual worlds, has had a long history of use in education and training, and it experienced a surge of renewed interest with the advent of Second Life in 2003. What followed shortly after were several years marked by considerable hype around the use of virtual worlds for teaching, learning and research in higher education. For the moment, uptake of the technology seems to have plateaued, with academics either maintaining the status quo and continuing to use virtual worlds as they have previously done or choosing to opt out altogether. This paper presents a brief review of the use of virtual worlds in the Australian and New Zealand higher education sector in the past and reports on its use in the sector at the present time, based on input from members of the Australian and New Zealand Virtual Worlds Working Group. It then adopts a forward-looking perspective amid the current climate of uncertainty, musing on future directions and offering suggestions for potential new applications in light of recent technological developments and innovations in the area.

Automatic segmentation of choroidal thickness in optical coherence tomography

The assessment of choroidal thickness from optical coherence tomography (OCT) images of the human choroid is an important clinical and research task, since it provides valuable information regarding the eye’s normal anatomy and physiology, and changes associated with various eye diseases and the development of refractive error. Due to the time consuming and subjective nature of manual image analysis, there is a need for the development of reliable objective automated methods of image segmentation to derive choroidal thickness measures. However, the detection of the two boundaries which delineate the choroid is a complicated and challenging task, in particular the detection of the outer choroidal boundary, due to a number of issues including: (i) the vascular ocular tissue is non-uniform and rich in non-homogeneous features, and (ii) the boundary can have a low contrast. In this paper, an automatic segmentation technique based on graph-search theory is presented to segment the inner choroidal boundary (ICB) and the outer choroidal boundary (OCB) to obtain the choroid thickness profile from OCT images. Before the segmentation, the B-scan is pre-processed to enhance the two boundaries of interest and to minimize the artifacts produced by surrounding features. The algorithm to detect the ICB is based on a simple edge filter and a directional weighted map penalty, while the algorithm to detect the OCB is based on OCT image enhancement and a dual brightness probability gradient. The method was tested on a large data set of images from a pediatric (1083 B-scans) and an adult (90 B-scans) population, which were previously manually segmented by an experienced observer. The results demonstrate the proposed method provides robust detection of the boundaries of interest and is a useful tool to extract clinical data.

Application of texture analysis in tear film surface assessment based on videokeratoscopy

Purpose Videokeratoscopy images can be used for the non-invasive assessment of the tear film. In this work the applicability of an image processing technique, textural-analysis, for the assessment of the tear film in Placido disc images has been investigated. Methods In the presence of tear film thinning/break-up, the reflected pattern from the videokeratoscope is disturbed in the region of tear film disruption. Thus, the Placido pattern carries information about the stability of the underlying tear film. By characterizing the pattern regularity, the tear film quality can be inferred. In this paper, a textural features approach is used to process the Placido images. This method provides a set of texture features from which an estimate of the tear film quality can be obtained. The method is tested for the detection of dry eye in a retrospective dataset from 34 subjects (22-normal and 12-dry eye), with measurements taken under suppressed blinking conditions. Results To assess the capability of each texture-feature to discriminate dry eye from normal subjects, the receiver operating curve (ROC) was calculated and the area under the curve (AUC), specificity and sensitivity extracted. For the different features examined, the AUC value ranged from 0.77 to 0.82, while the sensitivity typically showed values above 0.9 and the specificity showed values around 0.6. Overall, the estimated ROCs indicate that the proposed technique provides good discrimination performance. Conclusions Texture analysis of videokeratoscopy images is applicable to study tear film anomalies in dry eye subjects. The proposed technique appears to have demonstrated its clinical relevance and utility.

Interocular corneal symmetry in refractive error groups

Purpose: To examine between eye differences in corneal higher order aberrations and topographical characteristics in a range of refractive error groups. Methods: One hundred and seventy subjects were recruited including; 50 emmetropic isometropes, 48 myopic isometropes (spherical equivalent anisometropia ≤ 0.75 D), 50 myopic anisometropes (spherical equivalent anisometropia ≥ 1.00 D) and 22 keratoconics. The corneal topography of each eye was captured using the E300 videokeratoscope (Medmont, Victoria, Australia) and analyzed using custom written software. All left eye data were rotated about the vertical midline to account for enantiomorphism. Corneal height data were used to calculate the corneal wavefront error using a ray tracing procedure and fit with Zernike polynomials (up to and including the eighth radial order). The wavefront was centred on the line of sight by using the pupil offset value from the pupil detection function in the videokeratoscope. Refractive power maps were analysed to assess corneal sphero-cylindrical power vectors. Differences between the more myopic (or more advanced eye for keratoconics) and the less myopic (advanced) eye were examined. Results: Over a 6 mm diameter, the cornea of the more myopic eye was significantly steeper (refractive power vector M) compared to the fellow eye in both anisometropes (0.10 ± 0.27 D steeper, p = 0.01) and keratoconics (2.54 ± 2.32 D steeper, p < 0.001) while no significant interocular difference was observed for isometropic emmetropes (-0.03 ± 0.32 D) or isometropic myopes (0.02 ± 0.30 D) (both p > 0.05). In keratoconic eyes, the between eye difference in corneal refractive power was greatest inferiorly (associated with cone location). Similarly, in myopic anisometropes, the more myopic eye displayed a central region of significant inferior corneal steepening (0.15 ± 0.42 D steeper) relative to the fellow eye (p = 0.01). Significant interocular differences in higher order aberrations were only observed in the keratoconic group for; vertical trefoil C(3,-3), horizontal coma C(3,1) secondary astigmatism along 45 C(4, -2) (p < 0.05) and vertical coma C(3,-1) (p < 0.001). The interocular difference in vertical pupil decentration (relative to the corneal vertex normal) increased with between eye asymmetry in refraction (isometropia 0.00 ± 0.09, anisometropia 0.03 ± 0.15 and keratoconus 0.08 ± 0.16 mm) as did the interocular difference in corneal vertical coma C (3,-1) (isometropia -0.006 ± 0.142, anisometropia -0.037 ± 0.195 and keratoconus -1.243 ± 0.936 μm) but only reached statistical significance for pair-wise comparisons between the isometropic and keratoconic groups. Conclusions: There is a high degree of corneal symmetry between the fellow eyes of myopic and emmetropic isometropes. Interocular differences in corneal topography and higher order aberrations are more apparent in myopic anisometropes and keratoconics due to regional (primarily inferior) differences in topography and between eye differences in vertical pupil decentration relative to the corneal vertex normal. Interocular asymmetries in corneal optics appear to be associated with anisometropic refractive development.

The Child Behavior Checklist and Youth Self-Report in adolescents with epilepsy : testing measurement invariance of the Attention and Thought Problems subscales

The objective of this study was to test for the measurement invariance of the Attention and Thought Problems subscales of the Child Behavior Checklist (CBCL) and Youth Self-Report (YSR) in a population-based sample of adolescents with and without epilepsy. Data were obtained from the 14-year follow-up of the Mater University Study of Pregnancy in which 33 adolescents with epilepsy and 1068 healthy controls were included for analysis. Confirmatory factor analysis was used to test for measurement invariance between adolescents with and without epilepsy. Structural equation modeling was used to test for group differences in attention and thought problems as measured with the CBCL and YSR. Measurement invariance was demonstrated for the original CBCL Attention Problems and YSR Thought Problems. After the removal of ambiguous items (“confused” and “daydreams”),measurement invariance was established for the YSR Attention Problems. The original and reduced CBCL Thought Problems were noninvariant. Adolescents with epilepsy had significantly more symptoms of behavioral problems on the CBCL Attention Problems, β = 0.51, p = 0.002, compared with healthy controls. In contrast, no significant differences were found for the YSR Attention and Thought Problems, β = −0.11, p = 0.417 and β = −0.20, p = 0.116, respectively. In this population-based sample of adolescents with epilepsy, the CBCL Attention Problems and YSR Thought Problems appear to be valid measures of behavioral problems, whereas the YSR Attention Problems was valid only after the removal of ambiguous items. Replication of these findings in clinical samples of adolescents with epilepsy that overcome the limitations of the current study is warranted.