Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes

Background Despite the number of medications for type 2 diabetes, many people with the condition do not achieve good glycaemic control. Some existing glucose-lowering agents have adverse effects such as weight gain or hypoglycaemia. Type 2 diabetes tends to be a progressive disease, and most patients require treatment with combinations of glucose-lowering agents. The sodium glucose co-transporter 2 (SGLT2) receptor inhibitors are a new class of glucose-lowering agents. Objective To assess the clinical effectiveness and safety of the SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. Data sources MEDLINE, Embase, Cochrane Library (all sections); Science Citation Index; trial registries; conference abstracts; drug regulatory authorities; bibliographies of retrieved papers. Inclusion criteria Randomised controlled trials of SGLT2 receptor inhibitors compared with placebo or active comparator in type 2 diabetes in dual or combination therapy. Methods Systematic review. Quality assessment used the Cochrane risk of bias score. Results Seven trials, published in full, assessed dapagliflozin and one assessed canagliflozin. Trial quality appeared good. Dapagliflozin 10 mg reduced HbA1c by −0.54% (weighted mean differences (WMD), 95% CI −0.67 to −0.40) compared to placebo, but there was no difference compared to glipizide. Canagliflozin reduced HbA1c slightly more than sitagliptin (up to −0.21% vs sitagliptin). Both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD −1.81 kg (95% CI −2.04 to −1.57), canagliflozin up to −2.3 kg compared to placebo). Limitations Long-term trial extensions suggested that effects were maintained over time. Data on canagliflozin are currently available from only one paper. Costs of the drugs are not known so cost-effectiveness cannot be assessed. More data on safety are needed, with the Food and Drug Administration having concerns about breast and bladder cancers. Conclusions Dapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed

Recurrent Instability in LMXB Accretion Disks: How Strange is GRS 1915+105?

Low Mass X-Ray Binaries (LMXBs) are systems in which a compact object accretes from a binary companion star via an accretion disk. The X-ray properties of LMXBs show strong variability over timescales ranging from milliseconds to decades, much of which is tied to the extreme environment of the inner accretion disk, hence an understanding of this behaviour is key to understanding how matter behaves in such an environment. GRS 1915+105 and MXB 1730-335 are two LMXBs which show particularly unusual variability. GRS 1915+105 shows a large number of distinct classes of second-to-minute scale variability, consisting of repeated patterns of dips and flares. MXB 1730 shows Type II X-ray Bursts; minute-scale increases in X-ray intensity with a sudden onset and a slow decay. More recently two new objects, IGR J17091-3624 and GRO J1744-28 have been shown to display similar behaviours. In this thesis I present a new framework with which to classify variability in IGR J17091. I perform a comparison study between this source and GRS 1915. In GRS 1915, hard X-rays lag soft X-rays in all variability classes; in IGR J17091, I find that the sign of this lag varies between variability classes. Additionally, while GRS 1915+105 accretes at close to its Eddington Limit, I find that IGR J17091-3624 accretes at only ~5-33% of its Eddington Limit. I also perform a study of variability in GRO J1744 and find that it is more complex than in MXB 1730, consisting of at least 4 separate phenomena which may have separate physical origins. One of these phenomena, `Structured Bursting', consists of patterns of flares and dips similar to those seen in GRS 1915 and IGR J17091. I compare these types of variability and discuss the possibility of a physical link. I also present the alternative hypothesis that Structured Bursting is caused my 'hiccup accretion' similar to that seen in systems approaching the propeller regime.Comment: Thesis submitted to University of Southampton. 274 page

The Facilitation of the Brady Plan: Emerging Markets Debt Trading From 1989 to 1993

This Article completes the analysis of the first decade of the modern emerging market\u27s operation by considering two further periods: (iv) Adolescence: March 1989 to October 1991; and (v) Young Adulthood: October 1991 to December 1993. The primary importance of the market in these periods, as will be discovered, lies in its promotion and facilitation of the Brady Plan

An Atlas of Exotic Variability in IGR J17091-3624: A Comparison with GRS 1915+105

We performed an analysis of all RXTE observations of the Low Mass X-ray Binary and Black Hole Candidate IGR J17091-3624 during the 2011-2013 outburst of the source. By creating lightcurves, hardness-intensity diagrams and power density spectra of each observation, we have created a set of 9 variability `classes' that phenomenologically describe the range of types of variability seen in this object. We compare our set of variability classes to those established by Belloni et al. (2000) to describe the similar behaviour of the LMXB GRS 1915+105, finding that some types of variability seen in IGR J17091-3624 are not represented in data of GRS 1915+105. We also use all available X-ray data of the 2011-2013 outburst of IGR J17091-3624 to analyse its long-term evolution, presenting the first detection of IGR J17091-3624 above 150 keV as well as noting the presence of `re-flares' during the latter stages of the outburst. Using our results we place new constraints on the mass and distance of the object, and find that it accretes at <33% of its Eddington limit. As such, we conclude that Eddington-limited accretion can no longer be considered a sufficient or necessary criterion for GRS 1915+105-like variability to occur in Low Mass X-Ray Binaries.Comment: 26 Pages, 31 Figures, 8 Tables. Accepted to MNRA

Higher-order QED effects in hadronic processes

In this presentation, we describe the computation of higher-order QED effects relevant in hadronic collisions. In particular, we discuss the calculation of mixed QCD-QED one-loop contributions to the Altarelli-Parisi splittings functions, as well as the pure two-loop QED corrections. We explain how to extend the DGLAP equations to deal with new parton distributions, emphasizing the consequences of the novel corrections in the determination (and evolution) of the photon distributions.Comment: 7 pages, 2 figures. Contribution to the Proceedings of the EPS-HEP 2017 Conferenc

Physics of biological evolution

Part I: A remarkable feature of life on Earth is that despite the apparent observed diversity, the underlying chemistry that powers it is highly conserved. From the level of the nucleobases, through the amino acids and proteins they encode, to the metabolic pathways of chemical reactions catalyzed by these proteins, biology often utilizes identical solutions in vastly disparate organisms. This universality is intriguing as it raises the question of whether these recurring features exist because they represent some truly optimal solution to a given problem in biology, or whether they simply exist by chance, having arisen very early in life's history. In this project we consider the universality of metabolism { the set of chemical reactions providing the energy and building blocks for cells to grow and divide. We develop an algorithm to construct the complete network of all possible biochemically feasible compounds and reactions, including many that could have been utilized by life but never were. Using this network we investigate the most highly conserved piece of metabolism in all of biology, the trunk pathway of glycolysis. We design a method which allows a comparison between the large number of alternatives to this pathway and which takes into account both thermodynamic and biophysical constraints, finding evidence that the existing version of this pathway produces optimal metabolic fluxes under physiologically relevant intracellular conditions. We then extend our method to include an evolutionary simulation so as to more fully explore the biochemical space. Part II: Studies of population dynamics have a long history and have been used to understand the properties of complex networks of ecological interactions, extinction events, biological diversity and the transmission of infectious disease. One aspect of these models that is known to be of great importance, but one which nonetheless is often neglected, is spatial structure. Various classes of models have been proposed with each allowing different insights into the role space plays. Here we use a lattice-based approach. Motivated by gene transfer and parasite dynamics, we extend the well-studied contact process of statistical physics to include multiple levels. Doing so generates a simple model which captures in a general way the most important features of such biological systems: spatial structure and the inclusion of both vertical as well as horizontal transmission. We show that spatial structure can produce a qualitatively new effect: a coupling between the dynamics of the infection and of the underlying host population, even when the infection does not affect the fitness of the host. Extending the model to an arbitrary number of levels, we find a transition between regimes where both a finite and infinite number of parasite levels are sustainable, and conjecture that this transition is related to the roughening transition of related surface growth models

Best practice restoration: building the evidence-base for restoring eucalypt woodlands of Southern Australia

Approximately a third of the Earth’s surface is degraded. The enormous scale of degradation has stimulated multilateral agreements with ambitious restoration targets (e.g. The Bonn Challenge aspires to restore 350 million ha by 2030). Humankind has greater awareness than ever before of the factors contributing to landscape degradation, and has developed sophisticated practices to assist in its repair. The principal management intervention used to combat the biodiversity declines associated with land degradation is restoration. However, unprecedented environmental challenges from climate change, rapid biodiversity loss, and human population pressures add to the complexity of achieving sustainable restoration outcomes. There are valid concerns that sub-optimal restoration interventions are jeopardizing outcomes, which brings into question our capacity to reach global targets. To establish a strategic approach for improving restoration practice and to promote resilient outcomes, I reviewed current restoration practices and found that the management of plant genetic resources and inconsistent monitoring of projects are key impediments to optimal restoration outcomes. I found a suitable mechanism for investigating these knowledge gaps, through embedded experiments, and subsequently established them in restoration projects. I addressed the plant genetic resource knowledge gaps by testing in situ the relationship between plant fitness and seed origin for six Myrtaceae species. I investigated plant fitness in three empirical studies that included five common garden experiments, from provenances spanning 2.5 degrees of latitude (ca. 460 km) in southern Australian eucalypt woodlands, and found sub-optimal plant performance was common. Furthermore, signals of maladaptation occurred in two of my three empirical studies. I determined that the Myrtaceae species I studied persisted in a range of climatic conditions by combining specific adaptations to aridity and acclimating to new environmental conditions via phenotypic plasticity. I confirmed that this response was strongly directional (e.g. arid to mesic), and the genetic diversity harboured in non-local provenances could be harnessed to counteract plant fitness concerns (e.g. adaptation lags due to climate or lack of connectivity due habitat fragmentation), and ultimately help to achieve more sustainable outcomes. I then explored the utility of high throughput 16S amplicon sequencing (e.g. metabarcoding soil eDNA) as an assessment tool to assist in monitoring restoration performance. I used metabarcoding of soil eDNA to assess a chronosequence of restoration and found that the process of restoration (i.e. revegetation of the native plant community) strongly impacted soil bacteria, an important functional component of the ecosystem. I observed dramatic changes of the bacterial community after eight years of revegetation, where the bacterial communities in younger sites were more similar to cleared degraded land and older restoration sites were more similar to remnant native stands. This work has identified evidence of community flux and functional recovery following restoration that would remain unrecognised through orthodox monitoring. The synthesis of this work supports the use of evidence-based approaches to iteratively improve restoration practices. Science-practice synergies will come from harvesting the knowledge of these approaches and networking the results more broadly is the most efficient mechanism to achieve best-practice restoration and resilient project outcomes.Thesis (Ph.D.) -- University of Adelaide, School of Biololgical Sciences, 201

Developmental organization of central neurons in the adult Drosophila ventral nervous system

We have used MARCM to reveal the adult morphology of the post embryonically produced neurons in the thoracic neuromeres of the Drosophila VNS. The work builds on previous studies of the origins of the adult VNS neurons to describe the clonal organization of the adult VNS. We present data for 58 of 66 postembryonic thoracic lineages, excluding the motor neuron producing lineages (15 and 24) which have been described elsewhere. MARCM labels entire lineages but where both A and B hemilineages survive (e.g., lineages 19, 12, 13, 6, 1, 3, 8, and 11), the two hemilineages can be discriminated and we have described each hemilineage separately. Hemilineage morphology is described in relation to the known functional domains of the VNS neuropil and based on the anatomy we are able to assign broad functional roles for each hemilineage. The data show that in a thoracic hemineuromere, 16 hemilineages are primarily involved in controlling leg movements and walking, 9 are involved in the control of wing movements, and 10 interface between both leg and wing control. The data provide a baseline of understanding of the functional organization of the adult Drosophila VNS. By understanding the morphological organization of these neurons, we can begin to define and test the rules by which neuronal circuits are assembled during development and understand the functional logic and evolution of neuronal networks.</p

Monitoring of zincate pre-treatment of aluminium prior to electroless nickel plating

<p>Zincating is used as a pre-treatment for aluminium prior to electroless nickel deposition during preparation of magnetic computer memory discs. Four immersion zincating solutions were evaluated at 22°C using single step or double zincating followed by electroless nickel deposition from a high phosphorus hypophosphite bath at 90°C. The coating process was monitored by potential <i>vs.</i> time curves obtained under open-circuit conditions during zincating then electroless nickel plating. The surface morphology of the aluminium, at various stages, was imaged by scanning electron microscopy and atomic force microscopy. Zero resistance ammetry was used to record galvanic currents between the aluminium and an inert platinum counter electrode during zincating. This, together with potential-time measurements, provided simple and valuable methods for following the zincating process and subsequent electroless Ni plating. Double zincating enabled a shorter induction time for electroless Ni deposition and resulted in a more complete coverage of the surface by Zn.</p