Ticagrelor, a platelet aggregation inhibitor for the potential prevention and treatment of arterial thrombosis and acute coronary syndromes

Ticagrelor is an orally active ADP P2Y12 receptor antagonist in development by AstraZeneca plc for the reduction of recurrent ischemic events in patients with acute coronary syndromes (ACS). Prior to the development of ticagrelor, thienopyridine compounds, such as clopidogrel, were the focus of research into therapies for ACS. Although the thienopyridines are effective platelet aggregation inhibitors, they are prodrugs and, consequently, exert a slow onset of action. In addition, the variability in inter-individual metabolism of thienopyridine prodrugs has been associated with reduced efficacy in some patients. Ticagrelor is not a prodrug and exhibits a more rapid onset of action than the thienopyridine prodrugs. In clinical trials conducted to date, ticagrelor was a potent inhibitor of ADP-induced platelet aggregation and demonstrated effects that were comparable to clopidogrel. In a phase II, short-term trial, the bleeding profile of participants treated with ticagrelor was similar to that obtained with clopidogrel; however, an increased incidence of dyspnea was observed - an effect that has not been reported with the thienopyridines. Considering the occurrence of dyspnea, and the apparent non-superiority of ticagrelor to clopidogrel, it is difficult to justify a clear benefit to the continued development of ticagrelor. Outcomes from an ongoing phase III trial comparing ticagrelor with clopidogrel in 18,000 patients with ACS are likely to impact on the future development of ticagrelor.

Different cognitive profiles for single compared with recurrent fallers without Dementia

Relationships between self-reported retrospective falls and cognitive measures (executive function, reaction time, processing speed, working memory, visual attention) were examined in a population based sample of older adults (n = 658). Two of the choice reaction time tests involved inhibiting responses to either targets of a specific color or location with hand and foot responses. Potentially confounding demographic variables, medical conditions and postural sway were controlled for in logistic regression models, excluding participants with possible cognitive impairment. A factor analysis of cognitive measures extracted factors measuring reaction time, accuracy and inhibition, and visual search. Single fallers did not differ from non-fallers in terms of health, sway or cognitive function, except that they performed worse on accuracy and inhibition. In contrast, recurrent fallers performed worse than non-fallers on all measures. Results suggest that occasional falls in late life may be associated with subtle age-related changes in the pre-frontal cortex leading to failures of executive control, whereas recurrent falling may result from more advanced brain ageing that is associated with generalized cognitive decline.

Age-related maculopathy : linking aetiology and pathophysiological changes to the ischaemia hypothesis

Age-related maculopathy (ARM) has remained a challenging topic with respect to its aetiology, pathomechanisms, early detection and treatment since the late 19th century when it was first described as its own entity. ARM was previously considered an inflammatory disease, a degenerative disease, a tumor and as the result of choroidal hemodynamic disturbances and ischaemia. The latter processes have been repeatedly suggested to have a key role in its development and progression. In vivo experiments under hypoxic conditions could be models for the ischaemic deficits in ARM. Recent research has also linked ARM with gene polymorphisms. It is however unclear what triggers a person's gene susceptibility. In this manuscript, a linking hypothesis between aetiological factors including ischaemia and genetics and the development of early clinicopathological changes in ARM is proposed. New clinical psychophysical and electrophysiological tests are introduced that can detect ARM at an early stage. Models of early ARM based upon hemodynamic, photoreceptor and post-receptoral deficits are described and the mechanisms by which ischaemia may be involved as a final common pathway are considered. In neovascular age-related macular degeneration (neovascular AMD), ischaemia is thought to promote release of vascular endothelial growth factor (VEGF) which induces chorioretinal neovascularisation. VEGF is critical in the maintenance of the healthy choriocapillaris. In the final section of the manuscript the documentation of the effect of new anti-VEGF treatments on retinal function in neovascular AMD is critically viewed.

The effect of Amblyopia on motor and psychosocial skills in children

Background/Aims: In an investigation of the functional impact of amblyopia on children, the fine motor skills, perceived self-esteem and eye movements of amblyopic children were compared with that of age-matched controls. The influence of amblyogenic condition or treatment factors that might predict any decrement in outcome measures was investigated. The relationship between indirect measures of eye movements that are used clinically and eye movement characteristics recorded during reading was examined and the relevance of proficiency in fine motor skills to performance on standardised educational tests was explored in a sub-group of the control children. Methods: Children with amblyopia (n=82; age 8.2 ± 1.3 years) from differing causes (infantile esotropia n=17, acquired strabismus n=28, anisometropia n=15, mixed n=13 and deprivation n=9), and a control group of children (n=106; age 9.5 ± 1.2 years) participated in this study. Measures of visual function included monocular logMAR visual acuity (VA) and stereopsis assessed with the Randot Preschool Stereoacuity test, while fine motor skills were measured using the Visual-Motor Control (VMC) and Upper Limb Speed and Dexterity (ULSD) subtests of the Brunicks-Oseretsky Test of Motor Proficiency. Perceived self esteem was assessed for those children from grade 3 school level with the Harter Self Perception Profile for Children and for those in younger grades (preschool to grade 2) with the Pictorial Scale of Perceived Competence and Acceptance for Young Children. A clinical measure of eye movements was made with the Developmental Eye Movement (DEM) test for those children aged eight years and above. For appropriate case-control comparison of data, the results from amblyopic children were compared with age-matched sub-samples drawn from the group of children with normal vision who completed the tests. Eye movements during reading for comprehension were recorded by the Visagraph infra-red recording system and results of standardised tests of educational performance were also obtained for a sub-set of the control group. Results Amblyopic children (n=82; age 8.2 ± 1.7 years) performed significantly poorer than age-matched control children (n=37; age 8.3 ± 1.3 years) on 9 of 16 fine motor skills sub-items and for the overall age-standardised scores for both VMC and ULSD items (p<0.05); differences were most evident on timed manual dexterity tasks. The underlying aetiology of amblyopia and level of stereoacuity significantly affected fine motor skill performance on both items. However, when examined in a multiple regression model that took into account the inter-correlation between visual characteristics, poorer fine motor skills performance was only associated with strabismus (F1,75 = 5.428; p =0. 022), and not with the level of stereoacuity, refractive error or visual acuity in either eye. Amblyopic children from grade 3 school level and above (n=47; age 9.2 ± 1.3 years), particularly those with acquired strabismus, had significantly lower social acceptance scores than age-matched control children (n=52; age 9.4 ± 0.5 years) (F(5,93) = 3.14; p = 0.012). However, the scores of the amblyopic children were not significantly different to controls for other areas related to self-esteem, including scholastic competence, physical appearance, athletic competence, behavioural conduct and global self worth. A lower social acceptance score was independently associated with a history of treatment with patching but not with a history of strabismus or wearing glasses. Amblyopic children from pre-school to grade 2 school level (n=29; age = 6.6 ± 0.6 years) had similar self-perception scores to their age-matched peers (n=20; age = 6.4 ± 0.5 years). There were no significant differences between the amblyopic (n=39; age 9.1 ± 0.9 years) and age-matched control (n = 42; age = 9.3 ± 0.38 years) groups for any of the DEM outcome measures (Vertical Time, Horizontal Time, Number of Errors and Ratio (Horizontal time/Vertical time)). Performance on the DEM did not significantly relate to measures of VA in either eye, level of binocular function, history of strabismus or refractive error. Developmental Eye Movement test outcome measures Horizontal Time and Vertical Time were significantly correlated with reading rates measured by the Visagraph for both reading for comprehension and naming numbers (r>0.5). Some moderate correlations were also seen between the DEM Ratio and word reading rates as recorded by Visagraph (r=0.37). In children with normal vision, academic scores in mathematics, spelling and reading were associated with measures of fine motor skills. Strongest effect sizes were seen with the timed manual dexterity domain, Upper Limb Speed and Dexterity. Conclusions Amblyopia may have a negative impact on a child’s fine motor skills and an older child’s sense of acceptance by their peers may be influenced by treatment that includes eye patching. Clinical measures of eye movements were not affected in amblyopic children. A number of the outcome measures of the DEM are associated with objective recordings of reading rates, supporting its clinical use for identification of children with slower reading rates. In children with normal vision, proficiency on clinical measures of fine motor skill are associated with outcomes on standardised measures of educational performance. Scores on timed manual dexterity tasks had the strongest association with educational performance. Collectively, the results of this study indicate that, in addition to the reduction in visual acuity and binocular function that define the condition, amblyopes have functional impairment in childhood development skills that underlie proficiency in everyday activities. The study provides support for strategies aimed at early identification and remediation of amblyopia and the co-morbidities that arise from abnormal visual neurodevelopment.

Distortional buckling tests of cold-formed steel compression members at elevated temperatures

In recent times, light gauge cold-formed steel sections have been used extensively since they have a very high strength to weight ratio compared with thicker hot-rolled steel sections. However, they are susceptible to various buckling modes including a distortional mode and hence show complex behaviour under fire conditions. Therefore a research project based on detailed experimental studies was undertaken to investigate the distortional buckling behaviour of light gauge cold-formed steel compression members under simulated fire conditions. More than 150 axial compression tests were undertaken at uniform ambient and elevated temperatures. Two types of cross sections were selected with nominal thicknesses of 0.60, 0.80, and 0.95 mm. Both low (G250) and high (G550) strength steels were used. Distortional buckling tests were conducted at six different temperatures in the range of 20 to 800°C. The ultimate loads of compression members subject to distortional buckling were then used to review the adequacy of the current design rules at ambient and elevated temperatures. This paper presents the details of this experimental study and the results.

Evaluating Specification Tests for Markov-Switching Time-Series Models

We evaluate the performance of several specification tests for Markov regime-switching time-series models. We consider the Lagrange multiplier (LM) and dynamic specification tests of Hamilton (1996) and Ljung–Box tests based on both the generalized residual and a standard-normal residual constructed using the Rosenblatt transformation. The size and power of the tests are studied using Monte Carlo experiments. We find that the LM tests have the best size and power properties. The Ljung–Box tests exhibit slight size distortions, though tests based on the Rosenblatt transformation perform better than the generalized residual-based tests. The tests exhibit impressive power to detect both autocorrelation and autoregressive conditional heteroscedasticity (ARCH). The tests are illustrated with a Markov-switching generalized ARCH (GARCH) model fitted to the US dollar–British pound exchange rate, with the finding that both autocorrelation and GARCH effects are needed to adequately fit the data.

Mathematical modelling of muscle recruitment and function in the lumbar spine

Low back pain is an increasing problem in industrialised countries and although it is a major socio-economic problem in terms of medical costs and lost productivity, relatively little is known about the processes underlying the development of the condition. This is in part due to the complex interactions between bone, muscle, nerves and other soft tissues of the spine, and the fact that direct observation and/or measurement of the human spine is not possible using non-invasive techniques. Biomechanical models have been used extensively to estimate the forces and moments experienced by the spine. These models provide a means of estimating the internal parameters which can not be measured directly. However, application of most of the models currently available is restricted to tasks resembling those for which the model was designed due to the simplified representation of the anatomy. The aim of this research was to develop a biomechanical model to investigate the changes in forces and moments which are induced by muscle injury. In order to accurately simulate muscle injuries a detailed quasi-static three dimensional model representing the anatomy of the lumbar spine was developed. This model includes the nine major force generating muscles of the region (erector spinae, comprising the longissimus thoracis and iliocostalis lumborum; multifidus; quadratus lumborum; latissimus dorsi; transverse abdominis; internal oblique and external oblique), as well as the thoracolumbar fascia through which the transverse abdominis and parts of the internal oblique and latissimus dorsi muscles attach to the spine. The muscles included in the model have been represented using 170 muscle fascicles each having their own force generating characteristics and lines of action. Particular attention has been paid to ensuring the muscle lines of action are anatomically realistic, particularly for muscles which have broad attachments (e.g. internal and external obliques), muscles which attach to the spine via the thoracolumbar fascia (e.g. transverse abdominis), and muscles whose paths are altered by bony constraints such as the rib cage (e.g. iliocostalis lumborum pars thoracis and parts of the longissimus thoracis pars thoracis). In this endeavour, a separate sub-model which accounts for the shape of the torso by modelling it as a series of ellipses has been developed to model the lines of action of the oblique muscles. Likewise, a separate sub-model of the thoracolumbar fascia has also been developed which accounts for the middle and posterior layers of the fascia, and ensures that the line of action of the posterior layer is related to the size and shape of the erector spinae muscle. Published muscle activation data are used to enable the model to predict the maximum forces and moments that may be generated by the muscles. These predictions are validated against published experimental studies reporting maximum isometric moments for a variety of exertions. The model performs well for fiexion, extension and lateral bend exertions, but underpredicts the axial twist moments that may be developed. This discrepancy is most likely the result of differences between the experimental methodology and the modelled task. The application of the model is illustrated using examples of muscle injuries created by surgical procedures. The three examples used represent a posterior surgical approach to the spine, an anterior approach to the spine and uni-lateral total hip replacement surgery. Although the three examples simulate different muscle injuries, all demonstrate the production of significant asymmetrical moments and/or reduced joint compression following surgical intervention. This result has implications for patient rehabilitation and the potential for further injury to the spine. The development and application of the model has highlighted a number of areas where current knowledge is deficient. These include muscle activation levels for tasks in postures other than upright standing, changes in spinal kinematics following surgical procedures such as spinal fusion or fixation, and a general lack of understanding of how the body adjusts to muscle injuries with respect to muscle activation patterns and levels, rate of recovery from temporary injuries and compensatory actions by other muscles. Thus the comprehensive and innovative anatomical model which has been developed not only provides a tool to predict the forces and moments experienced by the intervertebral joints of the spine, but also highlights areas where further clinical research is required.

Public health and clinical dilemmas resulting from imprecise vitamin D tests

Objective: To determine whether there are clinical and public health dilemmas resulting from the reproducibility of routine vitamin D assays. Methods: Blinded agreement studies were conducted in eight clinical laboratories using two commonly used assays to measure serum 25-hydroxyvitamin D (25(OH)D) levels in Australasia and Canada (DiaSorin Radioimmunoassay (RIA) and DiaSorin LIAISON® one). Results: Only one laboratory measured 25(OH)D with excellent precision. Replicate 25(OH)D measurements varied by up to 97% and 15% of paired results differed by more than 50%. Thirteen percent of subjects received one result indicating insufficiency [25-50 nmol/l] and another suggesting adequacy [>50 nmol/l]). Agreement ranged from poor to excellent for laboratories using the manual RIA, while the precision of the semi-automated Liaison® system was consistently poor. Conclusions: Recent interest in the relevance of vitamin D to human health has increased demand for 25(OH)D testing and associated costs. Our results suggest clinicians and public health authorities are making decisions about treatment or changes to public health policy based on imprecise data. Clinicians, researchers and policy makers should be made aware of the imprecision of current 25(OH)D testing so that they exercise caution when using these assays for clinical practice, and when interpreting the findings of epidemiological studies based on vitamin D levels measured using these assays. Development of a rapid, reproducible, accurate and robust assay should be a priority due to interest in populationbased screening programs and research to inform public health policy about the amount of sun exposure required for human health. In the interim, 25(OH)D results should routinely include a statement of measurement uncertainty.

Driving performance in persons with hemianopia and quadrantanopia assessed under in-traffic conditions

Purpose: To evaluate the on-road driving performance of persons with homonymous hemianopia or quadrantanopia in comparison to age-matched controls with normal visual fields. Methods: Participants were 22 hemianopes and eight quadrantanopes (mean age 53 years) and 30 persons with normal visual fields (mean age 52 years) and were either current drivers or aiming to resume driving. All participants completed a battery of tests of vision (ETDRS visual acuity, Pelli-Robson letter contrast sensitivity, Humphrey visual fields), cognitive tests (trials A and B, Mini Mental State Examination, Digit Symbol Substitution) and an on-road driving assessment. Driving performance was assessed in a dual-brake vehicle with safety monitored by a certified driving rehabilitation specialist. Backseat evaluators masked to the clinical characteristics of participants independently rated driving performance along a 22.7 kilometre route involving urban and interstate driving. Results: Seventy-three per cent of the hemianopes, 88 per cent of quadrantanopes and all of the drivers with normal fields received safe driving ratings. Those hemianopic and quadrantanopic drivers rated as unsafe tended to have problems with maintaining appropriate lane position, steering steadiness and gap judgment compared to controls. Unsafe driving was associated with slower visual processing speed and impairments in contrast sensitivity, visual field sensitivity and executive function. Conclusions: Our findings suggest that some drivers with hemianopia or quadrantanopia are capable of safe driving performance, when compared to those of the same age with normal visual fields. This finding has important implications for the assessment of fitness to drive in this population.

A comparison of executive function in very preterm and term infants at 8 months corrected age

Executive function (EF) emerges in infancy and continues to develop throughout childhood. Executive dysfunction is believed to contribute to learning and attention problems in children at school age. Children born very preterm are more prone to these problems than their full-term peers.

Experimental tests on structural members fabricated from high strength steel materials

Typical high strength steels (HSS) have exceptional high strengths with improved weldability making the material attractive in modern steel constructions. However, due to lack of understanding, most of the current steel design standards are limited to conventional low strength steels (LSS, i.e. fy ≤ 450 MPa). This paper presents the details of full-scale experimental tests on short beams fabricated from BISPLATE80 HSS materials (nominal fy = 690 MPa). The various slenderness ratios of the plate elements in the test specimens were chosen in the range near the current yield limit (AS4100-1998, etc.). The experimental studies presented in this paper have produced a better understanding of the structural behaviour of HSS members subjected to local instabilities. Comparisons have also presented in the paper regarding to the design predictions from the current steel standards (AS4100-1998). This study has enabled to provide a series of proposals for proper assessment of plate slenderness limits for structural members made of representative HSS materials. This research work also enables the inclusion of further versions in the steel design specifications for typical HSS materials to be used in buildings and bridges. This paper also presents a distribution model of residual stresses in the longitudinal direction for typical HSS I-sections.

Investigation of MEMS inertial sensors and aircraft dynamic models in global positioning system integrity monitoring for approaches with vertical guidance

An Approach with Vertical Guidance (APV) is an instrument approach procedure which provides horizontal and vertical guidance to a pilot on approach to landing in reduced visibility conditions. APV approaches can greatly reduce the safety risk to general aviation by improving the pilot’s situational awareness. In particular the incidence of Controlled Flight Into Terrain (CFIT) which has occurred in a number of fatal air crashes in general aviation over the past decade in Australia, can be reduced. APV approaches can also improve general aviation operations. If implemented at Australian airports, APV approach procedures are expected to bring a cost saving of millions of dollars to the economy due to fewer missed approaches, diversions and an increased safety benefit. The provision of accurate horizontal and vertical guidance is achievable using the Global Positioning System (GPS). Because aviation is a safety of life application, an aviation-certified GPS receiver must have integrity monitoring or augmentation to ensure that its navigation solution can be trusted. However, the difficulty with the current GPS satellite constellation alone meeting APV integrity requirements, the susceptibility of GPS to jamming or interference and the potential shortcomings of proposed augmentation solutions for Australia such as the Ground-based Regional Augmentation System (GRAS) justifies the investigation of Aircraft Based Augmentation Systems (ABAS) as an alternative integrity solution for general aviation. ABAS augments GPS with other sensors at the aircraft to help it meet the integrity requirements. Typical ABAS designs assume high quality inertial sensors to provide an accurate reference trajectory for Kalman filters. Unfortunately high-quality inertial sensors are too expensive for general aviation. In contrast to these approaches the purpose of this research is to investigate fusing GPS with lower-cost Micro-Electro-Mechanical System (MEMS) Inertial Measurement Units (IMU) and a mathematical model of aircraft dynamics, referred to as an Aircraft Dynamic Model (ADM) in this thesis. Using a model of aircraft dynamics in navigation systems has been studied before in the available literature and shown to be useful particularly for aiding inertial coasting or attitude determination. In contrast to these applications, this thesis investigates its use in ABAS. This thesis presents an ABAS architecture concept which makes use of a MEMS IMU and ADM, named the General Aviation GPS Integrity System (GAGIS) for convenience. GAGIS includes a GPS, MEMS IMU, ADM, a bank of Extended Kalman Filters (EKF) and uses the Normalized Solution Separation (NSS) method for fault detection. The GPS, IMU and ADM information is fused together in a tightly-coupled configuration, with frequent GPS updates applied to correct the IMU and ADM. The use of both IMU and ADM allows for a number of different possible configurations. Three are investigated in this thesis; a GPS-IMU EKF, a GPS-ADM EKF and a GPS-IMU-ADM EKF. The integrity monitoring performance of the GPS-IMU EKF, GPS-ADM EKF and GPS-IMU-ADM EKF architectures are compared against each other and against a stand-alone GPS architecture in a series of computer simulation tests of an APV approach. Typical GPS, IMU, ADM and environmental errors are simulated. The simulation results show the GPS integrity monitoring performance achievable by augmenting GPS with an ADM and low-cost IMU for a general aviation aircraft on an APV approach. A contribution to research is made in determining whether a low-cost IMU or ADM can provide improved integrity monitoring performance over stand-alone GPS. It is found that a reduction of approximately 50% in protection levels is possible using the GPS-IMU EKF or GPS-ADM EKF as well as faster detection of a slowly growing ramp fault on a GPS pseudorange measurement. A second contribution is made in determining how augmenting GPS with an ADM compares to using a low-cost IMU. By comparing the results for the GPS-ADM EKF against the GPS-IMU EKF it is found that protection levels for the GPS-ADM EKF were only approximately 2% higher. This indicates that the GPS-ADM EKF may potentially replace the GPS-IMU EKF for integrity monitoring should the IMU ever fail. In this way the ADM may contribute to the navigation system robustness and redundancy. To investigate this further, a third contribution is made in determining whether or not the ADM can function as an IMU replacement to improve navigation system redundancy by investigating the case of three IMU accelerometers failing. It is found that the failed IMU measurements may be supplemented by the ADM and adequate integrity monitoring performance achieved. Besides treating the IMU and ADM separately as in the GPS-IMU EKF and GPS-ADM EKF, a fourth contribution is made in investigating the possibility of fusing the IMU and ADM information together to achieve greater performance than either alone. This is investigated using the GPS-IMU-ADM EKF. It is found that the GPS-IMU-ADM EKF can achieve protection levels approximately 3% lower in the horizontal and 6% lower in the vertical than a GPS-IMU EKF. However this small improvement may not justify the complexity of fusing the IMU with an ADM in practical systems. Affordable ABAS in general aviation may enhance existing GPS-only fault detection solutions or help overcome any outages in augmentation systems such as the Ground-based Regional Augmentation System (GRAS). Countries such as Australia which currently do not have an augmentation solution for general aviation could especially benefit from the economic savings and safety benefits of satellite navigation-based APV approaches.

Full scale fire tests of a new light gauge steel floor-ceiling system

Cold-formed steel members can be assembled in various combinations to provide cost-efficient and safe light gauge floor systems for buildings. Such Light gauge Steel Framing (LSF) systems are widely accepted in industrial and commercial building construction. An example application is in floor-ceiling systems. Light gauge steel floor-ceiling systems must be designed to serve as fire compartment boundaries and provide adequate fire resistance. Fire-rated floor-ceiling assemblies formed with new materials and construction methodologies have been increasingly used in buildings. However, limited research has been undertaken in the past and hence a thorough understanding of their fire resistance behaviour is not available. Recently a new composite floor-ceiling system has been developed to provide higher fire rating under standard fire conditions. But its increased fire rating could not be determined using the currently available design methods. Therefore a research project was carried out to investigate its structural and fire resistance behaviour under standard fire conditions. In this research project full scale experimental tests of the new LSF floor system based on a composite ceiling unit were undertaken using a gas furnace at the Queensland University of Technology. Both the conventional and the new steel floor-ceiling systems were tested under structural and fire loads. Full scale fire tests provided a good understanding of the fire behaviour of the LSF floor-ceiling systems and confirmed the superior performance of the new composite system. This paper presents the details of this research into the structural and fire behaviour of light gauge steel floor systems protected by the new composite panel, and the results.