Cortical thickness mapping to identify focal osteoporosis in patients with hip fracture.

BACKGROUND: Individuals with osteoporosis are predisposed to hip fracture during trips, stumbles or falls, but half of all hip fractures occur in those without generalised osteoporosis. By analysing ordinary clinical CT scans using a novel cortical thickness mapping technique, we discovered patches of markedly thinner bone at fracture-prone regions in the femurs of women with acute hip fracture compared with controls. METHODS: We analysed CT scans from 75 female volunteers with acute fracture and 75 age- and sex-matched controls. We classified the fracture location as femoral neck or trochanteric before creating bone thickness maps of the outer 'cortical' shell of the intact contra-lateral hip. After registration of each bone to an average femur shape and statistical parametric mapping, we were able to visualise and quantify statistically significant foci of thinner cortical bone associated with each fracture type, assuming good symmetry of bone structure between the intact and fractured hip. The technique allowed us to pinpoint systematic differences and display the results on a 3D average femur shape model. FINDINGS: The cortex was generally thinner in femoral neck fracture cases than controls. More striking were several discrete patches of statistically significant thinner bone of up to 30%, which coincided with common sites of fracture initiation (femoral neck or trochanteric). INTERPRETATION: Femoral neck fracture patients had a thumbnail-sized patch of focal osteoporosis at the upper head-neck junction. This region coincided with a weak part of the femur, prone to both spontaneous 'tensile' fractures of the femoral neck, and as a site of crack initiation when falling sideways. Current hip fracture prevention strategies are based on case finding: they involve clinical risk factor estimation to determine the need for single-plane bone density measurement within a standard region of interest (ROI) of the femoral neck. The precise sites of focal osteoporosis that we have identified are overlooked by current 2D bone densitometry methods.

Systematic misregistration and the statistical analysis of surface data.

Spatial normalisation is a key element of statistical parametric mapping and related techniques for analysing cohort statistics on voxel arrays and surfaces. The normalisation process involves aligning each individual specimen to a template using some sort of registration algorithm. Any misregistration will result in data being mapped onto the template at the wrong location. At best, this will introduce spatial imprecision into the subsequent statistical analysis. At worst, when the misregistration varies systematically with a covariate of interest, it may lead to false statistical inference. Since misregistration generally depends on the specimen's shape, we investigate here the effect of allowing for shape as a confound in the statistical analysis, with shape represented by the dominant modes of variation observed in the cohort. In a series of experiments on synthetic surface data, we demonstrate how allowing for shape can reveal true effects that were previously masked by systematic misregistration, and also guard against misinterpreting systematic misregistration as a true effect. We introduce some heuristics for disentangling misregistration effects from true effects, and demonstrate the approach's practical utility in a case study of the cortical bone distribution in 268 human femurs.

Systematic delay-driven power optimisation and power-driven delay optimisation of combinational circuits

With the proliferation of mobile wireless communication and embedded systems, the energy efficiency becomes a major design constraint. The dissipated energy is often referred as the product of power dissipation and the input-output delay. Most of electronic design automation techniques focus on optimising only one of these parameters either power or delay. Industry standard design flows integrate systematic methods of optimising either area or timing while for power consumption optimisation one often employs heuristics which are characteristic to a specific design. In this work we answer three questions in our quest to provide a systematic approach to joint power and delay Optimisation. The first question of our research is: How to build a design flow which incorporates academic and industry standard design flows for power optimisation? To address this question, we use a reference design flow provided by Synopsys and integrate in this flow academic tools and methodologies. The proposed design flow is used as a platform for analysing some novel algorithms and methodologies for optimisation in the context of digital circuits. The second question we answer is: Is possible to apply a systematic approach for power optimisation in the context of combinational digital circuits? The starting point is a selection of a suitable data structure which can easily incorporate information about delay, power, area and which then allows optimisation algorithms to be applied. In particular we address the implications of a systematic power optimisation methodologies and the potential degradation of other (often conflicting) parameters such as area or the delay of implementation. Finally, the third question which this thesis attempts to answer is: Is there a systematic approach for multi-objective optimisation of delay and power? A delay-driven power and power-driven delay optimisation is proposed in order to have balanced delay and power values. This implies that each power optimisation step is not only constrained by the decrease in power but also the increase in delay. Similarly, each delay optimisation step is not only governed with the decrease in delay but also the increase in power. The goal is to obtain multi-objective optimisation of digital circuits where the two conflicting objectives are power and delay. The logic synthesis and optimisation methodology is based on AND-Inverter Graphs (AIGs) which represent the functionality of the circuit. The switching activities and arrival times of circuit nodes are annotated onto an AND-Inverter Graph under the zero and a non-zero-delay model. We introduce then several reordering rules which are applied on the AIG nodes to minimise switching power or longest path delay of the circuit at the pre-technology mapping level. The academic Electronic Design Automation (EDA) tool ABC is used for the manipulation of AND-Inverter Graphs. We have implemented various combinatorial optimisation algorithms often used in Electronic Design Automation such as Simulated Annealing and Uniform Cost Search Algorithm. Simulated Annealing (SMA) is a probabilistic meta heuristic for the global optimization problem of locating a good approximation to the global optimum of a given function in a large search space. We used SMA to probabilistically decide between moving from one optimised solution to another such that the dynamic power is optimised under given delay constraints and the delay is optimised under given power constraints. A good approximation to the global optimum solution of energy constraint is obtained. Uniform Cost Search (UCS) is a tree search algorithm used for traversing or searching a weighted tree, tree structure, or graph. We have used Uniform Cost Search Algorithm to search within the AIG network, a specific AIG node order for the reordering rules application. After the reordering rules application, the AIG network is mapped to an AIG netlist using specific library cells. Our approach combines network re-structuring, AIG nodes reordering, dynamic power and longest path delay estimation and optimisation and finally technology mapping to an AIG netlist. A set of MCNC Benchmark circuits and large combinational circuits up to 100,000 gates have been used to validate our methodology. Comparisons for power and delay optimisation are made with the best synthesis scripts used in ABC. Reduction of 23% in power and 15% in delay with minimal overhead is achieved, compared to the best known ABC results. Also, our approach is also implemented on a number of processors with combinational and sequential components and significant savings are achieved.

Mapping the semantic structure of cognitive neuroscience.

Cognitive neuroscience, as a discipline, links the biological systems studied by neuroscience to the processing constructs studied by psychology. By mapping these relations throughout the literature of cognitive neuroscience, we visualize the semantic structure of the discipline and point to directions for future research that will advance its integrative goal. For this purpose, network text analyses were applied to an exhaustive corpus of abstracts collected from five major journals over a 30-month period, including every study that used fMRI to investigate psychological processes. From this, we generate network maps that illustrate the relationships among psychological and anatomical terms, along with centrality statistics that guide inferences about network structure. Three terms--prefrontal cortex, amygdala, and anterior cingulate cortex--dominate the network structure with their high frequency in the literature and the density of their connections with other neuroanatomical terms. From network statistics, we identify terms that are understudied compared with their importance in the network (e.g., insula and thalamus), are underspecified in the language of the discipline (e.g., terms associated with executive function), or are imperfectly integrated with other concepts (e.g., subdisciplines like decision neuroscience that are disconnected from the main network). Taking these results as the basis for prescriptive recommendations, we conclude that semantic analyses provide useful guidance for cognitive neuroscience as a discipline, both by illustrating systematic biases in the conduct and presentation of research and by identifying directions that may be most productive for future research.

Application of the Intervention Mapping protocol to develop Keys, a family child care home intervention to prevent early childhood obesity.

BACKGROUND: Many families rely on child care outside the home, making these settings important influences on child development. Nearly 1.5 million children in the U.S. spend time in family child care homes (FCCHs), where providers care for children in their own residences. There is some evidence that children in FCCHs are heavier than those cared for in centers. However, few interventions have targeted FCCHs for obesity prevention. This paper will describe the application of the Intervention Mapping (IM) framework to the development of a childhood obesity prevention intervention for FCCHs METHODS: Following the IM protocol, six steps were completed in the planning and development of an intervention targeting FCCHs: needs assessment, formulation of change objectives matrices, selection of theory-based methods and strategies, creation of intervention components and materials, adoption and implementation planning, and evaluation planning RESULTS: Application of the IM process resulted in the creation of the Keys to Healthy Family Child Care Homes program (Keys), which includes three modules: Healthy You, Healthy Home, and Healthy Business. Delivery of each module includes a workshop, educational binder and tool-kit resources, and four coaching contacts. Social Cognitive Theory and Self-Determination Theory helped guide development of change objective matrices, selection of behavior change strategies, and identification of outcome measures. The Keys program is currently being evaluated through a cluster-randomized controlled trial CONCLUSIONS: The IM process, while time-consuming, enabled rigorous and systematic development of intervention components that are directly tied to behavior change theory and may increase the potential for behavior change within the FCCHs.

Cartographic veracity in medieval mapping: analyzing geographical variation in the Gough Map of Great Britain

This article explores statistical approaches for assessing the relative accuracy of medieval mapping. It focuses on one particular map, the Gough Map of Great Britain. This is an early and remarkable example of a medieval “national” map covering Plantagenet Britain. Conventionally dated to c. 1360, the map shows the position of places in and coastal outline of Great Britain to a considerable degree of spatial accuracy. In this article, aspects of the map's content are subjected to a systematic analysis to identify geographical variations in the map's veracity, or truthfulness. It thus contributes to debates among historical geographers and cartographic historians on the nature of medieval maps and mapping and, in particular, questions of their distortion of geographic space. Based on a newly developed digital version of the Gough Map, several regression-based approaches are used here to explore the degree and nature of spatial distortion in the Gough Map. This demonstrates that not only are there marked variations in the positional accuracy of places shown on the map between regions (i.e., England, Scotland, and Wales), but there are also fine-scale geographical variations in the spatial accuracy of the map within these regions. The article concludes by suggesting that the map was constructed using a range of sources, and that the Gough Map is a composite of multiscale representations of places in Great Britain. The article details a set of approaches that could be transferred to other contexts and add value to historic maps by enhancing understanding of their contents.

Identification of candidate small-molecule therapeutics to cancer by gene-signature perturbation in connectivity mapping.

Connectivity mapping is a recently developed technique for discovering the underlying connections between different biological states based on gene-expression similarities. The sscMap method has been shown to provide enhanced sensitivity in mapping meaningful connections leading to testable biological hypotheses and in identifying drug candidates with particular pharmacological and/or toxicological properties. Challenges remain, however, as to how to prioritise the large number of discovered connections in an unbiased manner such that the success rate of any following-up investigation can be maximised. We introduce a new concept, gene-signature perturbation, which aims to test whether an identified connection is stable enough against systematic minor changes (perturbation) to the gene-signature. We applied the perturbation method to three independent datasets obtained from the GEO database: acute myeloid leukemia (AML), cervical cancer, and breast cancer treated with letrozole. We demonstrate that the perturbation approach helps to identify meaningful biological connections which suggest the most relevant candidate drugs. In the case of AML, we found that the prevalent compounds were retinoic acids and PPAR activators. For cervical cancer, our results suggested that potential drugs are likely to involve the EGFR pathway; and with the breast cancer dataset, we identified candidates that are involved in prostaglandin inhibition. Thus the gene-signature perturbation approach added real values to the whole connectivity mapping process, allowing for increased specificity in the identification of possible therapeutic candidates.

Novel breast cancer biomarkers identified by integrative proteomic and gene expression mapping

Proteomic and transcriptomic platforms both play important roles in cancer research, with differing strengths and limitations. Here, we describe a proteo-transcriptomic integrative strategy for discovering novel cancer biomarkers, combining the direct visualization of differentially expressed proteins with the high-throughput scale of gene expression profiling. Using breast cancer as a case example, we generated comprehensive two-dimensional electrophoresis (2DE)/mass spectrometry (MS) proteomic maps of cancer (MCF-7 and HCC-38) and control (CCD-1059Sk) cell lines, identifying 1724 expressed protein spots representing 484 different protein species. The differentially expressed cell-line proteins were then mapped to mRNA transcript databases of cancer cell lines and primary breast tumors to identify candidate biomarkers that were concordantly expressed at the gene expression level. Of the top nine selected biomarker candidates, we reidentified ANX1, a protein previously reported to be differentially expressed in breast cancers and normal tissues, and validated three other novel candidates, CRAB, 6PGL, and CAZ2, as differentially expressed proteins by immunohistochemistry on breast tissue microarrays. In total, close to half (4/9) of our protein biomarker candidates were successfully validated. Our study thus illustrates how the systematic integration of proteomic and transcriptomic data from both cell line and primary tissue samples can prove advantageous for accelerating cancer biomarker discovery.

Nanometer-scale mapping of irreversible electrochemical nucleation processes on solid Li-ion electrolytes

Electrochemical processes associated with changes in structure, connectivity or composition typically proceed via new phase nucleation with subsequent growth of nuclei. Understanding and controlling reactions requires the elucidation and control of nucleation mechanisms. However, factors controlling nucleation kinetics, including the interplay between local mechanical conditions, microstructure and local ionic profile remain inaccessible. Furthermore, the tendency of current probing techniques to interfere with the original microstructure prevents a systematic evaluation of the correlation between the microstructure and local electrochemical reactivity. In this work, the spatial variability of irreversible nucleation processes of Li on a Li-ion conductive glass-ceramics surface is studied with ~30 nm resolution. An increased nucleation rate at the boundaries between the crystalline AlPO4 phase and amorphous matrix is observed and attributed to Li segregation. This study opens a pathway for probing mechanisms at the level of single structural defects and elucidation of electrochemical activities in nanoscale volumes.

Mapping multi-species habitat use for marine conservation planning

Tese de Doutoramento, Ciências do Mar (Biologia Marinha)

Mapping the cytoskeletal prestress

Park CY, Tambe D, Alencar AM, Trepat X, Zhou EH, Millet E, Butler JP, Fredberg JJ. Mapping the cytoskeletal prestress. Am J Physiol Cell Physiol 298: C1245-C1252, 2010. First published February 17, 2010; doi: 10.1152/ajpcell.00417.2009.-Cell mechanical properties on a whole cell basis have been widely studied, whereas local intracellular variations have been less well characterized and are poorly understood. To fill this gap, here we provide detailed intracellular maps of regional cytoskeleton (CSK) stiffness, loss tangent, and rate of structural rearrangements, as well as their relationships to the underlying regional F-actin density and the local cytoskeletal prestress. In the human airway smooth muscle cell, we used micropatterning to minimize geometric variation. We measured the local cell stiffness and loss tangent with optical magnetic twisting cytometry and the local rate of CSK remodeling with spontaneous displacements of a CSK-bound bead. We also measured traction distributions with traction microscopy and cell geometry with atomic force microscopy. On the basis of these experimental observations, we used finite element methods to map for the first time the regional distribution of intracellular prestress. Compared with the cell center or edges, cell corners were systematically stiffer and more fluidlike and supported higher traction forces, and at the same time had slower remodeling dynamics. Local remodeling dynamics had a close inverse relationship with local cell stiffness. The principal finding, however, is that systematic regional variations of CSK stiffness correlated only poorly with regional F-actin density but strongly and linearly with the regional prestress. Taken together, these findings in the intact cell comprise the most comprehensive characterization to date of regional variations of cytoskeletal mechanical properties and their determinants.

A systematic grounded approach to the development of complex interventions : The Australian WorkHealth Program – Arthritis as a case study

Despite demands for evidence-based research and practice, little attention has been given to systematic approaches to the development of complex interventions to tackle workplace health problems. This paper outlines an approach to the initial stages of a workplace program development which integrates health promotion and disease management. The approach commences with systematic and genuine processes of obtaining information from key stakeholders with broad experience of these interventions. This information is constructed into a program framework in which practice-based and research-informed elements are both valued. We used this approach to develop a workplace education program to reduce the onset and impact of a common chronic disease – osteoarthritis.

To gain information systematically at a national level, a structured concept mapping workshop with 47 participants from across Australia was undertaken. Participants were selected to maximise the whole-of-workplace perspective and included health education providers, academics, clinicians and policymakers. Participants generated statements in response to a seeding statement: Thinking as broadly as possible, what changes in education and support should occur in the workplace to help in the prevention and management of arthritis? Participants grouped the resulting statements into conceptually coherent groups and a computer program was used to generate a ‘cluster map’ along with a list of statements sorted according to cluster membership.

In combination with research-based evidence, the concept map informed the development of a program logic model incorporating the program's guiding principles, possible service providers, services, training modes, program elements and the causal processes by which participants might benefit. The program logic model components were further validated through research findings from diverse fields, including health education, coaching, organisational learning, workplace interventions, workforce development and osteoarthritis disability prevention.

In summary, wide and genuine consultation, concept mapping, and evidence-based program logic development were integrated to develop a whole-of-system complex intervention in which potential effectiveness and assimilation into the workplace for which optimised.

Dealing with alcohol-related problems in the night-time economy: a study protocol for mapping trends in harm and stakeholder views surrounding local community level interventions

This project will provide a comprehensive investigation into the prevalence of alcohol-related harms and community attitudes in the context of community-based interventions being implemented to reduce harm in two regional centres of Australia. While considerable experimentation and innovation to address these harms has occurred in both Geelong and Newcastle, only limited ad-hoc documentation and analysis has been conducted on changes in the prevalence of harm as a consequence, leaving a considerable gap in terms of a systematic, evidence-based analysis of changes in harm over time and the need for further intervention. Similarly, little evidence has been reported regarding the views of key stakeholder groups, industry, government agencies, patrons or community regarding the need for, and the acceptability of, interventions to reduce harms. This project will aim to provide evidence regarding the impact and acceptability of local initiatives aimed at reducing alcohol-related harms.

Women’s reproductive choices in Australia: mapping federal and state/territory policy instruments governing choice

The reproductive choices available to women, and the consequences of those choices, exist within the broader policy context whereby policy is influenced by pervasive ideologies of women’s roles in society and the family. Women’s reproductive rights and their resulting consequences are governed by policy at the federal and state/territory levels within Australia yet little is known about the number or scope of these policies. This study aimed to systematically search and map Australian policy to identify the number and scope of policies governing women’s reproductive choices and their consequences, including how policy interprets the role of women in society through their reproductive choices. The systematic search identified 147 Australian policies in 2013. The mapping of the policies identified common themes that drive policy agenda impacting women’s reproductive choices, including those where the focus is promoting motherhood and/or children, providing economic incentives, regulating reproduction, or a broader health focus. These policy agendas simultaneously construct and are shaped by the context in which women’s reproductive choices and impacts occur. Women’s reproductive choices are highly politicised and regulated, impacting women’s position within society.

Microsatellite Organization in the Grasshopper Abracris flavolineata (Orthoptera: Acrididae) Revealed by FISH Mapping: Remarkable Spreading in the A and B Chromosomes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)