In situ study of Polymorphism and Melting of Metals and Compounds under Extreme Conditions of High Pressure and High Temperature

This thesis presents the experimental investigation of structure and melting of three important materials under extreme conditions of high pressure and high temperature. The melting points of elements and compounds are of fundamental importance for the study of planetary interiors and for fundamental and applied physics. The high pressure apparatus used in this thesis is the diamond anvil cell, which has been used to reach pressures of up to 137 GPa and temperatures up to 6000-7000 K via laser-heating techniques. The melting point has been determined at high pressure by the first onset of liquid scattering in X-ray diffraction patterns that are collected in situ. At temperatures towards the melting point, important information on the crystalline state of these materials has been extracted. The polymorphism of Sn has been studied into the megabar range (P > 100 GPa) at room temperature. The equation of state of Sn has been determined up to 137 GPa. A previously unreported structural transformation occurs at 32 GPa into a body centered orthorhombic structure (spacegroup Immm). Coexistence of this polymorph with a body centered cubic structure (spacegroup: Im-3m) is observed over a wide pressure range. These new findings for this important element are reported within. The melting relations of Sn have been determined to beyond 1 megabar in pressure and reveal a dip in the melt slope followed by a sudden sharp rise between 40 and 70 GPa. High temperature experiments using resistive-heating and laser-heating in the diamond anvil cell reveal the observation of multiple X-ray diffraction signatures at high temperatures. The results are discussed and overlap with the discoveries from the room temperature investigation of Sn. TaC and MgO are two important refractory materials and have also been investigated using laser-heated diamond anvil cell techniques combined with in situ synchrotron X-ray diffraction. TaC has the highest ambient melting temperature of any binary compound. MgO constitutes approximately 37 % of the Earth’s lower mantle and the melting temperature as a function of pressure can provide us with information on the melting behaviour, phase relations and rheology of the Earth’s lower mantle. The results and their impact on current high pressure research are discussed

Cost-effectiveness of the SEN-concept: Specialized Emergency Nurses (SEN) treating ankle/foot injuries

<p>Abstract</p> <p>Background</p> <p>Emergency Departments (EDs) are confronted with progressive overcrowding. As a consequence, the workload for ED physicians increases and waiting times go up with the risk of unnecessary complications and patient dissatisfaction. To cope with these problems, Specialized Emergency Nurses (SENs), regular ED-nurses receiving a short, injury-specific course, were trained to assess and treat minor injuries according to a specific protocol.</p> <p>Methods</p> <p>An economic evaluation was conducted alongside a randomized controlled trial comparing House Officers (HOs) and SENs in their assessment of ankle and foot injuries. Cost prices were established for all parts of healthcare utilization involved. Total costs of health care utilization were computed per patient in both groups. Cost-effectiveness was investigated by comparing the difference in total cost between groups with the difference in sensitivity and specificity between groups in diagnosing fractures and severe sprains. Finally, cost-effectiveness ratios were calculated and presented on a cost-effectiveness plane.</p> <p>Results</p> <p>No significant differences were seen between treatment groups for any of the health care resources assessed. However, the waiting times for both first assessment by a treatment officer and time spent waiting between hearing the diagnosis and final treatment were significantly longer in the HO group. There was no statistically significant difference in costs between groups. The total costs were € 186 (SD € 623) for patients in the SEN group and € 153 (SD € 529) for patients in the HO group. The difference in total costs was € 33 (95% CI: – € 84 to € 155). The incremental cost-effectiveness ratio was € 27 for a reduction of one missed diagnosis and € 18 for a reduction of one false negative.</p> <p>Conclusion</p> <p>Considering the benefits of the SEN-concept in terms of decreased workload for the ED physicians, increased patient satisfaction and decreased waiting times, SENs appear to be a useful solution to the problem of ED crowding.</p

Protocol for an observational cohort study investigating personalised medicine for intensification of treatment in people with type 2 diabetes mellitus: the PERMIT study

INTRODUCTION: For people with type 2 diabetes mellitus (T2DM) who require an antidiabetic drug as an add-on to metformin, there is controversy about whether newer drug classes such as dipeptidyl peptidase-4 inhibitors (DPP4i) or sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce the risk of long-term complications compared with sulfonylureas (SU). There is widespread variation across National Health Service Clinical Commissioning Groups (CCGs) in drug choice for second-line treatment in part because National Institute for Health and Care Excellence guidelines do not specify a single preferred drug class, either overall or within specific patient subgroups. This study will evaluate the relative effectiveness of the three most common second-line treatments in the UK (SU, DPP4i and SGLT2i as add-ons to metformin) and help target treatments according to individual risk profiles. METHODS AND ANALYSIS: The study includes people with T2DM prescribed one of the second-line treatments-of-interest between 2014 and 2020 within the UK Clinical Practice Research Datalink linked with Hospital Episode Statistics and Office of National Statistics. We will use an instrumental variable (IV) method to estimate short-term and long-term relative effectiveness of second-line treatments according to individuals' risk profiles. This method minimises bias from unmeasured confounders by exploiting the natural variation in second-line prescribing across CCGs as an IV for the choice of prescribed treatment. The primary outcome to assess short-term effectiveness will be change in haemoglobin A1c (%) 12 months after treatment initiation. Outcome measures to assess longer-term effectiveness (maximum ~6 years) will include microvascular and macrovascular complications, all-cause mortality and hospital admissions during follow-up. ETHICS AND DISSEMINATION: This study was approved by the Independent Scientific Advisory Committee (20-064) and the London School of Hygiene & Tropical Medicine Research Ethics Committee (21395). Results, codelists and other analysis code will be made available to patients, clinicians, policy-makers and researchers

“Cycles upon cycles, stories upon stories” : contemporary audio media and podcast horror’s new frights

During the last ten years the ever-fertile horror and Gothic genres have birthed a new type of fright-fiction: podcast horror. Podcast horror is a narrative horror form based in audio media and the properties of sound. Despite association with oral ghost tales, radio drama, and movie and TV soundscapes, podcast horror remains academically overlooked. Podcasts offer fertile ground for the revitalization and evolution of such extant audio-horror traditions, yet they offer innovation too. Characterized by their pre-recorded nature, individualized listening times and formats, often “amateur” or non-corporate production, and isolation from an ongoing media stream more typical of radio or TV, podcasts potentialize the instigation of newer audio-horror methods and traits. Podcast horror shows vary greatly in form and content, from almost campfire-style oral tales, comprising listener-produced and performed content (Drabblecast; Tales to Terrify; NoSleep); to audio dramas reminiscent of radio’s Golden Era (Tales from Beyond the Pale; 19 Nocturne Boulevard); to dramas delivered in radio-broadcast style (Welcome to Night Vale; Ice Box Theatre); to, most recently, dramas, which are themselves acknowledging and exploratory of the podcast form (TANIS; The Black Tapes Podcast; Lime Town). Yet within this broad spectrum, sympathies and conventions arise which often not only explore and expand notions of Gothic sound, but which challenge broader existing horror and Gothic genre norms. This article thus demonstrates the extent to which podcast horror uses its audio form, technology and mediation to disrupt and evolve Gothic/horror fiction, not through a cumulative chronological formulation of podcast horror but through a maintained and alternately synthesized panorama of forms. Herein new aspects of generic narration, audience, narrative and aesthetic emerge. Exploring a broad spectrum of American and British horror podcasts, this article shows horror podcasting to utilize podcasting’s novel means of horror and Gothic distribution/consumption to create fresh, unique and potent horror forms. This article reveals plot details about some of the podcasts examined

A randomized controlled trial of mycophenolate mofetil in patients with IgA nephropathy [ISRCTN62574616]

BACKGROUND: IgAN is the most common type of glomerulonephritis in the world. Between 15 and 40 percent of adults and children diagnosed with IgAN eventually progress to ESRD. Despite the need for effective treatment strategies, very few RCTs for IgAN have been performed. The most effective therapies for IgAN appear to be corticosteroids, ACEi, and FOS that contain a high concentration of omega 3 fatty acids. While ACEi and FOS are generally well tolerated with minimal side effects, the use of high dose steroids over a long course of therapy is often associated with significant morbidity. OBJECTIVE OF THE STUDY: The objective of the study is to test the hypothesis that treatment with the immunosuppressive agent, MMF, will lead to significant and sustained improvement in urinary protein excretion in patients with IgAN who have been pre-treated (and continue to be treated) with ACE(i )and FOS compared to a placebo control group of patients receiving comparable doses of ACEi and FOS without MMF. DESIGN: After a three month treatment period with the ACEi, lisinopril and the FOS, Omacor(®), 100 (2 × 50) patients with IgAN and a urinary P/C ratio ≥ 0.6 (males) and ≥ 0.8 (females) and an estGFR ≥ 40 ml/min/1.73 m2 will be randomized to treatment with either MMF or placebo for one year. All patients will be followed off study drug for a second year, but will continue treatment with lisinopril and Omacor(® )for the two year duration of the study. The primary outcome measure of change in urine P/C ratio will be assessed at the end of years one and two

Differential sensitivity of Src-family kinases to activation by SH3 domain displacement

Src-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12) to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo. © 2014 Moroco et al

A Pycellerator Tutorial.

We present a tutorial on using Pycellerator for biomolecular simulations. Models are described in human readable (and editable) text files (UTF8 or ASCII) containing collections of reactions, assignments, initial conditions, function definitions, and rate constants. These models are then converted into a Python program that can optionally solve the system, e.g., as a system of differential equations using ODEINT, or be run by another program. The input language implements an extended version of the Cellerator arrow notation, including mass action, Hill functions, S-Systems, MWC, and reactions with user-defined kinetic laws. Simple flux balance analysis is also implemented. We will demonstrate the implementation and analysis of progressively more complex models, starting from simple mass action through indexed cascades. Pycellerator can be used as a library that is integrated into other programs, run as a command line program, or in iPython notebooks. It is implemented in Python 2.7 and available under an open source GPL license

Sea-level constraints on the amplitude and source distribution of Meltwater Pulse 1A.

During the last deglaciation, sea levels rose as ice sheets retreated. This climate transition was punctuated by periods of more intense melting; the largest and most rapid of these—Meltwater Pulse 1A—occurred about 14,500 years ago, with rates of sea-level rise reaching approximately 4 m per century1, 2, 3. Such rates of rise suggest ice-sheet instability, but the meltwater sources are poorly constrained, thus limiting our understanding of the causes and impacts of the event4, 5, 6, 7. In particular, geophysical modelling studies constrained by tropical sea-level records1, 8, 9 suggest an Antarctic contribution of more than seven metres, whereas most reconstructions10 from Antarctica indicate no substantial change in ice-sheet volume around the time of Meltwater Pulse 1A. Here we use a glacial isostatic adjustment model to reinterpret tropical sea-level reconstructions from Barbados2, the Sunda Shelf3 and Tahiti1. According to our results, global mean sea-level rise during Meltwater Pulse 1A was between 8.6 and 14.6 m (95% probability). As for the melt partitioning, we find an allowable contribution from Antarctica of either 4.1 to 10.0 m or 0 to 6.9 m (95% probability), using two recent estimates11, 12 of the contribution from the North American ice sheets. We conclude that with current geologic constraints, the method applied here is unable to support or refute the possibility of a significant Antarctic contribution to Meltwater Pulse 1A

Improved curve fits to summary survival data: application to economic evaluation of health technologies

addresses: Peninsula College of Medicine and Dentistry, Veysey Building, Salmon Pool Lane, Exeter, EX2 4SG, UK. [email protected]: PMCID: PMC3198983types: Journal Article; Research Support, Non-U.S. Gov't© 2011 Hoyle and Henley; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Mean costs and quality-adjusted-life-years are central to the cost-effectiveness of health technologies. They are often calculated from time to event curves such as for overall survival and progression-free survival. Ideally, estimates should be obtained from fitting an appropriate parametric model to individual patient data. However, such data are usually not available to independent researchers. Instead, it is common to fit curves to summary Kaplan-Meier graphs, either by regression or by least squares. Here, a more accurate method of fitting survival curves to summary survival data is described