MRI quantification of blood-brain barrier leakage in the ageing brain

Cerebral small vessel disease, or SVD, refers to processes that lead to dysfunction and damage in cerebral microvessels, and is implicated in ischaemic stroke and vascular dementia. Although the pathophysiology is poorly understood, a subtle breakdown in the blood-brain barrier (BBB) has been implicated as a potential underlying mechanism. BBB breakdown is difficult to measure in-vivo however - Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) is the dominant technique for assessing BBB integrity in clinical populations and is the focus of the work presented in this thesis. In this work, there are two main objectives: 1. Assess and optimise current DCE-MRI processing methods to provide accurate measurements of BBB breakdown. 2. Relate BBB breakdown to other features of SVD: clinical outcomes, imaging markers, and risk factors. To achieve the first objective, simulations were used to estimate the effects of various technical and modelling errors in measured BBB breakdown. By generating a realistic simulation of biological processes during a DCE-MRI sequence, sources of systematic error could be identified along with potential solutions. The implementation of MRI processing recommendations (a slow injection of contrast agent, exclusion of first-pass data from model fitting, and the use of a novel fitting method that better represents underlying biophysics) was found to reduce the sensitivity of calculated DCE-MRI parameters to the effects of variable blood plasma flow, variable water exchange rates, and injection delay by over 90%. Additionally, correction for field inhomogeneities was also found to reduce the error of calculated DCE-MRI parameters. Combining all the suggested processing methods was found to reduce the systematic error of calculated DCE-MRI parameters by up to 97%. These simulations form the basis of an open access framework and include an accessible GUI (1). For the second objective data was obtained from a prospective cohort study of mild stroke patients, and multiple linear regression was used to investigate how regional BBB breakdown is related to various patient factors. Regression models were controlled for several potential confounds and were implemented for both cross-sectional and longitudinal data. It was found that areas of hyperintensity on MRI images (which are indicative of vascular damage) presented lesser BBB breakdown when the severity of imaging markers was greater. Additionally, greater breakdown in the BBB of the basal ganglia is associated with greater disability scores, suggesting that vascular damage in this region may affect motor function and cognition. Risk factors associated with greater BBB breakdown include: age, a diagnosis of hypertension, and a diagnosis of diabetes, although the causality of these relationships is unclear. In summary, this thesis aims to improve the measurement of subtle BBB breakdown using DCE-MRI, and then use the optimised methods to investigate how BBB breakdown relates to clinical outcomes, imaging markers, and risk factors associated with SVD

Agricultural productivity in past societies: toward an empirically informed model for testing cultural evolutionary hypotheses

Agricultural productivity, and its variation in space and time, plays a fundamental role in many theories of human social evolution. However, we often lack systematic information about the productivity of past agricultural systems on a scale large enough to test these theories properly. The effect of climate on crop yields has received a great deal of attention resulting in a range of empirical and process-based models, yet the focus has primarily been on current or future conditions. In this paper, we argue for a “bottom-up” approach that estimates potential productivity based on information about the agricultural practices and technologies used in past societies. Of key theoretical interest is using this information to estimate the carrying high quality historical and archaeological information about past societies in order to infer the temporal and geographic patterns of change in agricultural productivity and potential. We discuss information we need to collect about past agricultural techniques and practices, and introduce a new databank initiative that we have developed for collating the best available historical and archaeological evidence. A key benefit of our approach lies in making explicit the steps in the estimation of past productivities and carrying capacities, and in being able to assess the effects of different modelling assumptions. This is undoubtedly an ambitious task, yet promises to provide important insights into fundamental aspects of past societies, enabling us to test more rigorously key hypotheses about human socio-cultural evolution

Continuous Infusions of Meropenem in Ambulatory Care: Clinical Efficacy, Safety and Stability

Objectives: Concerns regarding the clinical impact of meropenem instability in continuous infusion (CI) devices may contribute to inconsistent uptake of this method of administration across outpatient parenteral antimicrobial therapy (OPAT) services. Methods: We retrospectively reviewed the clinical efficacy and safety of CIs of meropenem in two Australian tertiary hospitals and assessed its stability under simulated OPAT conditions including in elastomeric infusion devices containing 1% (2.4 g) or 2% (4.8 g) concentrations at either ‘room temperature’ or ‘cooled’ conditions. Infusate aliquots were assayed at different time-points over 24 hours. Results: Forty-one (82%) of 50 patients had clinical improvement or were cured. Adverse patient outcomes including hemato-, hepato- and nephrotoxicity were infrequent. Cooled infusers with 1% meropenem had a mean 24-hour recovery of 90.3%. Recoveries of 1% and 2% meropenem at room temperature and 2% under cooled conditions were 88%, 83% and 87%, respectively. Patients receiving 1% meropenem are likely to receive >95% of the maximum deliverable dose (MDD) over a 24-hour period whilst patients receiving 2% meropenem should receive 93% and 87% of the MDD under cooled and room temperature conditions, respectively. Conclusions: Meropenem infusers are likely to deliver ~95% MDD and maintain effective plasma concentrations throughout the dosing period. These data reflect our local favourable clinical experience with eropenem CIs

Managing Big Sagebrush in a Changing Climate

This publication identifies areas where big sagebrush populations are most and least vulnerable to climate change and demonstrates where continued investment in sagebrush conservation and restoration could have the most impact

Is treatment "intensity" associated with healthier lifestyle choices?:An application of the dose response function

Healthy lifestyle choices and doctor consultations can be substitutes or complements in the health production function. In this paper we consider the relation between the number of doctor consultations and the frequency of patient physical activity. We use a novel application of the Dose-Response Function model proposed by Hirano and Imbens (2004) to deal with treatment endogeneity under the no unmeasured confounding assumption. Our application takes account of unobserved heterogeneity and uses dynamic non-linear models for the treatment and outcome variables of interest. Using seven waves of the British Household Panel Survey, we find that higher treatment intensity and frequency of physical activity are inversely related. We show that accounting for both treatment selection and unobserved heterogeneity halves the size of this relationship. An additional doctor consultation is associated with a 0.5 percentage point reduction in the probability of undertaking vigorous physical activity. Our results hold for a sub-sample visiting the doctor for health check-ups, and are shown to be robust using instrumental variables

Visual motion and decision-making in dyslexia: reduced accumulation of sensory evidence and related neural dynamics

Children with and without dyslexia differ in their behavioural responses to visual information, particularly when required to pool dynamic signals over space and time. Importantly, multiple processes contribute to behavioural responses. Here we investigated which processing stages are affected in children with dyslexia when performing visual motion processing tasks, by combining two methods that are sensitive to the dynamic processes leading to responses. We used a diffusion model which decomposes response time and accuracy into distinct cognitive constructs, and high-density EEG. 50 children with dyslexia (24 male) and 50 typically developing children (28 male) aged 6 to 14 years judged the direction of motion as quickly and accurately as possible in two global motion tasks (motion coherence and direction integration), which varied in their requirements for noise exclusion. Following our pre-registered analyses, we fitted hierarchical Bayesian diffusion models to the data, blinded to group membership. Unblinding revealed reduced evidence accumulation in children with dyslexia compared to typical children for both tasks. Additionally, we identified a response-locked EEG component which was maximal over centro-parietal electrodes which indicated a neural correlate of reduced drift-rate in dyslexia in the motion coherence task, thereby linking brain and behaviour. We suggest that children with dyslexia tend to be slower to extract sensory evidence from global motion displays, regardless of whether noise exclusion is required, thus furthering our understanding of atypical perceptual decision-making processes in dyslexia

Synchronizing chromosome segregation by flux-dependent force equalization at kinetochores

The synchronous movement of chromosomes during anaphase ensures their correct inheritance in every cell division. This reflects the uniformity of spindle forces acting on chromosomes and their simultaneous entry into anaphase. Although anaphase onset is controlled by the spindle assembly checkpoint, it remains unknown how spindle forces are uniformly distributed among different chromosomes. In this paper, we show that tension uniformity at metaphase kinetochores and subsequent anaphase synchrony in Drosophila S2 cells are promoted by spindle microtubule flux. These results can be explained by a mechanical model of the spindle where microtubule poleward translocation events associated with flux reflect relaxation of the kinetochore–microtubule interface, which accounts for the redistribution and convergence of kinetochore tensions in a timescale comparable to typical metaphase duration. As predicted by the model, experimental acceleration of mitosis precludes tension equalization and anaphase synchrony. We propose that flux-dependent equalization of kinetochore tensions ensures a timely and uniform maturation of kinetochore–microtubule interfaces necessary for error-free and coordinated segregation of chromosomes in anaphase