The role of physics based models for simulating runoff responses to rural land management scenarios

Recent floods in the UK have focused attention on the effects of rural land use and land management change on flood risk. Over recent decades agricultural intensification has been widespread across the uplands of the UK, with increases in stocking density, ploughing, reseeding and drainage of fields, use of heavy machinery, and the removal of trees from the landscape. A key scientific question is whether or not these changes in land use and land management in the uplands are increasing flood frequency and magnitude. Although land use and land management changes have been observed to change local surface runoff, attempts to isolate these responses at the catchment scale have failed due to limitations of data sets and modelling capability. While hydrological modelling is a well advanced field of science, a key methodological challenge that remains is how to upscale information about local scale changes. This Thesis evaluates the role of physics based hydrological models for upscaling local scale hydrological process knowledge and data to catchment scale flood flow responses. A model upscaling procedure that aims to quantify the changes in peak flows at multiple scales related to localised land use management changes is presented. The procedure divides the catchment into a number of runoff generating elements, which are each classified based on soil types and land management. For each runoff generating element, a physics based model is developed, incorporating understanding of hydrological processes and properties. This permits the investigation of local scale impacts, but cannot be applied at the catchment scale due to excessive computational burden. Therefore, the outputs from these physics based models are used to train simpler “metamodels”, which are then incorporated into a semi-distributed catchment model. In this way, the understanding of local changes in physical properties can be incorporated into a more flexible and computationally efficient catchment scale conceptual model. This procedure has previously been tested to a limited extent on a 12km² experimental catchment in upland Wales, which provided multi-scale hydrological data sets. The applicability of the procedure is now examined for a 25km² upland subcatchment of the Hodder in north-west England for an extended range of land management questions. This catchment is currently undergoing a number of land management changes, including: the blocking of open drains in the peatlands that cover the upper extent of the subcatchment, changes to an existing coniferous plantation and extensive deciduous riparian planting. The catchment does not include supporting multi-scale monitoring; without local data, physics based models are developed a priori using information from the literature, qualitative field observations and a proxy catchment. The significance of the uncertainties due to this lack of data and also uncertainties related to the upscaling procedure itself are explored, particularly examining the identifiability of the predicted effects at multiple scales. Based on the findings, the strengths and limitations of physics based modelling and the upscaling procedure in terms of ability to predict catchment-scale impacts of local land management interventions are assessed. The outputs from the multi scale modelling are also used to increase conceptual understanding of the hydrological processes and their relative importance under different land use and land management scenarios at the local scale, and also to quantify the impacts of land management scenarios at the catchment scale, taking into account the limitations of the modelling procedure

Use of epiphyseal and total fusion scores as methods of age estimation and evaluation of morphological indices in the macropodidae

Includes bibliographical references (pages [120]-132).This dissertation developed and assessed postcranial age estimation methods in the Macropodidae. Data was collected from museum specimens of nine macropodid genera. Collected data included both postcranial measurements of size, shape, and epiphysial fusion and cheek tooth observations of morphology and eruption. The objectives of this study were: 1) to describe cheek tooth morphology for species absent in the literature, 2) develop a system for scoring molar eruption, 3) describe molar eruption patterns across the family, 4) develop a method for estimating age using degree of fusion at the epiphysis of the forelimb, 5) describe patterns of epiphyseal fusion in the forelimb across the family, 6) use epiphyseal fusion scores to assign specimens to age categories, 7) assess whether any specimens with partly unfused epiphyses can be placed in the same morphological group as those with totally fused epiphyses, and 8) to compare potential postcranial age estimation methods. The results of this study show that of the four postcranial age estimation methods (total fusion, humerus fusion, ulna fusion, and radius fusion), that of humerus epiphyseal fusion is the most significant when regressed on and correlated with molar eruption scores and as such is the best indicator of age. The other three postcranial fusion scores also are significant (though less so) when regressed on and correlated with molar eruption scores and can therefore also be used in age estimation. Results for age categories and assessing which specimens group together morphologically were less clear. Discriminant function analysis using the long bones did clearly show three age categories: adult (fusion scores of 5), subadult (fusion scores of 3 and 4), and juvenile (fusion scores of 1 and 2). However, these analyses also showed that on some of the functions generated by the analyses (especially those where measures of the trochlea and capitulum were influential) the highest three scores were indistinguishable, indicating that these specimens grouped together and could be included in the same morphological study. Discriminant function analysis using total fusion scores did not produce meaningful plots.Ph.D. (Doctor of Philosophy

Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia:Data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers

INTRODUCTION: People with type 2 diabetes have increased risk of dementia. Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs) are among the promising therapies for repurposing as a treatment for Alzheimer's disease; a key unanswered question is whether they reduce dementia incidence in people with type 2 diabetes. METHODS: We assessed exposure to GLP‐1 RAs in patients with type 2 diabetes and subsequent diagnosis of dementia in two large data sources with long‐term follow‐up: pooled data from three randomized double‐blind placebo‐controlled cardiovascular outcome trials (15,820 patients) and a nationwide Danish registry‐based cohort (120,054 patients). RESULTS: Dementia rate was lower both in patients randomized to GLP‐1 RAs versus placebo (hazard ratio [HR]: 0.47 (95% confidence interval [CI]: 0.25–0.86) and in the nationwide cohort (HR: 0.89; 95% CI: 0.86–0.93 with yearly increased exposure to GLP‐1 RAs). DISCUSSION: Treatment with GLP‐1 RAs may provide a new opportunity to reduce the incidence of dementia in patients with type 2 diabetes

RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia—an international Delphi consensus

Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson’s disease dementia) apart from cholinesterase inhibitors. We reviewed several promising compounds that might potentially be disease-modifying agents for Lewy body dementia and then undertook an International Delphi consensus study to prioritise compounds. We identified ambroxol as the top ranked agent for repurposing and identified a further six agents from the classes of tyrosine kinase inhibitors, GLP-1 receptor agonists, and angiotensin receptor blockers that were rated by the majority of our expert panel as justifying a clinical trial. It would now be timely to take forward all these compounds to Phase II or III clinical trials in Lewy body dementia

A Framework for Prioritizing the TESS Planetary Candidates Most Amenable to Atmospheric Characterization

A key legacy of the recently launched TESS mission will be to provide the astronomical community with many of the best transiting exoplanet targets for atmospheric characterization. However, time is of the essence to take full advantage of this opportunity. JWST, although delayed, will still complete its nominal five year mission on a timeline that motivates rapid identification, confirmation, and mass measurement of the top atmospheric characterization targets from TESS. Beyond JWST, future dedicated missions for atmospheric studies such as ARIEL require the discovery and confirmation of several hundred additional sub-Jovian size planets (R_p < 10 R_Earth) orbiting bright stars, beyond those known today, to ensure a successful statistical census of exoplanet atmospheres. Ground-based ELTs will also contribute to surveying the atmospheres of the transiting planets discovered by TESS. Here we present a set of two straightforward analytic metrics, quantifying the expected signal-to-noise in transmission and thermal emission spectroscopy for a given planet, that will allow the top atmospheric characterization targets to be readily identified among the TESS planet candidates. Targets that meet our proposed threshold values for these metrics would be encouraged for rapid follow-up and confirmation via radial velocity mass measurements. Based on the catalog of simulated TESS detections by Sullivan et al. (2015), we determine appropriate cutoff values of the metrics, such that the TESS mission will ultimately yield a sample of $\sim300$ high-quality atmospheric characterization targets across a range of planet size bins, extending down to Earth-size, potentially habitable worlds.Comment: accepted to PAS

DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT.

BACKGROUND: Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil. METHOD: DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization. DISCUSSION: There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point. TRIAL REGISTRATION: Current controlled trials ISRCTN49545035.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are