A direct method for measuring discounting and QALYs more easily and reliably

Time discounting and quality of life are two important factors in evaluations of medical interventions. The measurement of these two factors is complicated because they interact. Existing methods either simply assume one factor given, based on heuristic assumptions, or invoke complicating extraneous factors, such as risk, that generate extra biases. The authors introduce a method for measuring discounting (and then quality of life) that involves no extraneous factors and that avoids distorting interactions. Their method is considerably simpler and more realistic for subjec

A Shift Symmetry in the Higgs Sector: Experimental Hints and Stringy Realizations

We interpret reported hints of a Standard Model Higgs boson at ~ 125 GeV in terms of high-scale supersymmetry breaking with a shift symmetry in the Higgs sector. More specifically, the Higgs mass range suggested by recent LHC data extrapolates, within the (non-supersymmetric) Standard Model, to a vanishing quartic Higgs coupling at a UV scale between 10^6 and 10^18 GeV. Such a small value of lambda can be understood in terms of models with high-scale SUSY breaking if the Kahler potential possesses a shift symmetry, i.e., if it depends on H_u and H_d only in the combination (H_u+\bar{H}_d). This symmetry is known to arise rather naturally in certain heterotic compactifications. We suggest that such a structure of the Higgs Kahler potential is common in a wider class of string constructions, including intersecting D7- and D6-brane models and their extensions to F-theory or M-theory. The latest LHC data may thus be interpreted as hinting to a particular class of compactifications which possess this shift symmetry.Comment: v2: References added. v3: References added, published versio

Precision Gauge Unification from Extra Yukawa Couplings

We investigate the impact of extra vector-like GUT multiplets on the predicted value of the strong coupling. We find in particular that Yukawa couplings between such extra multiplets and the MSSM Higgs doublets can resolve the familiar two-loop discrepancy between the SUSY GUT prediction and the measured value of alpha_3. Our analysis highlights the advantages of the holomorphic scheme, where the perturbative running of gauge couplings is saturated at one loop and further corrections are conveniently described in terms of wavefunction renormalization factors. If the gauge couplings as well as the extra Yukawas are of O(1) at the unification scale, the relevant two-loop correction can be obtained analytically. However, the effect persists also in the weakly-coupled domain, where possible non-perturbative corrections at the GUT scale are under better control.Comment: 26 pages, LaTeX. v6: Important early reference adde

Global Development and Climate Change: A Game Theory Approach

The increasing concern with climate change is one of the main issues of our time, and thus we aim to theoretically and mathematically analyse its causes. However our approach follows a different stream of thought, presenting the reasoning and decision-making processes between technical and moral solutions. We have resorted to game theory models in order to demonstrate cooperative and non-cooperative scenarios, ranging from the traditional to the evolutionary within game theory. In doing so we are able to glimpse the development of modern society and a paradigm shift regarding human control over nature and to what extent it is harmful to the sustainability of our environment and the survival of future generations. Merging different fields of knowledge, we present a theoretical-philosophical approach, combined with empirical-mathematical solutions taking into account the agent-based behaviour guided blindly by instrumental rationality

How many crowdsourced workers should a requester hire?

Recent years have seen an increased interest in crowdsourcing as a way of obtaining information from a potentially large group of workers at a reduced cost. The crowdsourcing process, as we consider in this paper, is as follows: a requester hires a number of workers to work on a set of similar tasks. After completing the tasks, each worker reports back outputs. The requester then aggregates the reported outputs to obtain aggregate outputs. A crucial question that arises during this process is: how many crowd workers should a requester hire? In this paper, we investigate from an empirical perspective the optimal number of workers a requester should hire when crowdsourcing tasks, with a particular focus on the crowdsourcing platform Amazon Mechanical Turk. Specifically, we report the results of three studies involving different tasks and payment schemes. We find that both the expected error in the aggregate outputs as well as the risk of a poor combination of workers decrease as the number of workers increases. Surprisingly, we find that the optimal number of workers a requester should hire for each task is around 10 to 11, no matter the underlying task and payment scheme. To derive such a result, we employ a principled analysis based on bootstrapping and segmented linear regression. Besides the above result, we also find that overall top-performing workers are more consistent across multiple tasks than other workers. Our results thus contribute to a better understanding of, and provide new insights into, how to design more effective crowdsourcing processes

Extensive telomere erosion is consistent with localised clonal expansions in Barrett’s metaplasia

Barrett’s oesophagus is a premalignant metaplastic condition that predisposes patients to the development of oesophageal adenocarcinoma. However, only a minor fraction of Barrett’s oesophagus patients progress to adenocarcinoma and it is thus essential to determine bio-molecular markers that can predict the progression of this condition. Telomere dysfunction is considered to drive clonal evolution in several tumour types and telomere length analysis provides clinically relevant prognostic and predictive information. The aim of this work was to use high-resolution telomere analysis to examine telomere dynamics in Barrett’s oesophagus. Telomere length analysis of XpYp, 17p, 11q and 9p, chromosome arms that contain key cancer related genes that are known to be subjected to copy number changes in Barrett’s metaplasia, revealed similar profiles at each chromosome end, indicating that no one specific telomere is likely to suffer preferential telomere erosion. Analysis of patient matched tissues (233 samples from 32 patients) sampled from normal squamous oesophagus, Z-line, and 2 cm intervals within Barrett’s metaplasia, plus oesophago-gastric junction, gastric body and antrum, revealed extensive telomere erosion in Barrett’s metaplasia to within the length ranges at which telomere fusion is detected in other tumour types. Telomere erosion was not uniform, with distinct zones displaying more extensive erosion and more homogenous telomere length profiles. These data are consistent with an extensive proliferative history of cells within Barrett’s metaplasia and are indicative of localised clonal growth. The extent of telomere erosion highlights the potential of telomere dysfunction to drive genome instability and clonal evolution in Barrett’s metaplasia

A Social Identity Approach to Sport Psychology: Principles, Practice, and Prospects.

Drawing on social identity theory and self-categorization theory, we outline an approach to sport psychology that understands groups not simply as features of sporting contexts but rather as elements that can be, and often are, incorporated into a person's sense of self and, through this, become powerful determinants of their sport-related behavior. The underpinnings of this social identity approach are outlined, and four key lessons for sport that are indicative of the analytical and practical power of the approach are presented. These suggest that social identity is the basis for sports group (1) behavior, (2) formation and development, (3) support and stress appraisal, and (4) leadership. Building on recent developments within sport science, we outline an agenda for future research by identifying a range of topics to which the social identity approach could fruitfully contribute

SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras

SHANK3, a synaptic scaffold protein and actin regulator, is widely expressed outside of the central nervous system with predominantly unknown function. Solving the structure of the SHANK3 N-terminal region revealed that the SPN domain is an unexpected Ras-association domain with high affinity for GTP-bound Ras and Rap G-proteins. The role of Rap1 in integrin activation is well established but the mechanisms to antagonize it remain largely unknown. Here, we show that SHANK1 and SHANK3 act as integrin activation inhibitors by sequestering active Rap1 and R-Ras via the SPN domain and thus limiting their bioavailability at the plasma membrane. Consistently, SHANK3 silencing triggers increased plasma membrane Rap1 activity, cell spreading, migration and invasion. Autism-related mutations within the SHANK3 SPN domain (R12C and L68P) disrupt G-protein interaction and fail to counteract integrin activation along the Rap1-RIAM-talin axis in cancer cells and neurons. Altogether, we establish SHANKs as critical regulators of G-protein signalling and integrin-dependent processes

Ergocalciferol and Microcirculatory Function in Chronic Kidney Disease and Concomitant Vitamin D Deficiency: An Exploratory, Double Blind, Randomised Controlled Trial

Vitamin D deficiency and endothelial dysfunction are non-traditional risk factors for cardiovascular events in chronic kidney disease. Previous studies in chronic kidney disease have failed to demonstrate a beneficial effect of vitamin D on arterial stiffness, left ventricular mass and inflammation but none have assessed the effect of vitamin D on microcirculatory endothelial function.We conducted a randomised controlled trial of 38 patients with non diabetic chronic kidney disease stage 3-4 and concomitant vitamin D deficiency (<16 ng/dl) who received oral ergocalciferol (50,000 IU weekly for one month followed by 50,000 IU monthly) or placebo over 6 months. The primary outcome was change in microcirculatory function measured by laser Doppler flowmetry after iontophoresis of acetylcholine. Secondary endpoints were tissue advanced glycation end products, sublingual functional capillary density and flow index as well as macrovascular parameters. Parallel in vitro experiments were conducted to determine the effect of ergocalciferol on cultured human endothelial cells.Twenty patients received ergocalciferol and 18 patients received placebo. After 6 months, there was a significant improvement in the ergocalciferol group in both endothelium dependent microcirculatory vasodilatation after iontophoresis of acetylcholine (p = 0.03) and a reduction in tissue advanced glycation end products (p = 0.03). There were no changes in sublingual microcirculatory parameters. Pulse pressure (p = 0.01) but not aortic pulse wave velocity was reduced. There were no significant changes in bone mineral parameters, blood pressure or left ventricular mass index suggesting that ergocalciferol improved endothelial function independently of these parameters. In parallel experiments, expression of endothelial nitric oxide synthase and activity were increased in human endothelial cells in a dose dependent manner.Ergocalciferol improved microcirculatory endothelial function in patients with chronic kidney disease and concomitant vitamin D deficiency. This process may be mediated through enhanced expression and activity of endothelial nitric oxide synthase.Clinical trials.gov NCT00882401