Imbalance properties of centre-stratified permuted-block and complete randomisation for several treatments in a clinical trial

Randomisation schemes are rules that assign patients to treatments in a clinical trial. Many of these schemes have the common aim of maintaining balance in the numbers of patients across treatment groups. The properties of imbalance that have been investigated in the literature are based on two treatment groups. In this paper, their properties for K > 2 treatments are studied for two randomisation schemes: centre-stratified permuted-block and complete randomisation. For both randomisation schemes, analytical approaches are investigated assuming that the patient recruitment process follows a Poisson–gamma model. When the number of centres involved in a trial is large, the imbalance for both schemes is approximated by a multivariate normal distribution. The accuracy of the approximations is assessed by simulation. A test for treatment differences is also considered for normal responses, and numerical values for its power are presented for centre-stratified permuted-block randomisation. To speed up the calculations, a combined analytical/approximate approach is used

A systematic review of models to predict recruitment to multicentre clinical trials

<p>Abstract</p> <p>Background</p> <p>Less than one third of publicly funded trials managed to recruit according to their original plan often resulting in request for additional funding and/or time extensions. The aim was to identify models which might be useful to a major public funder of randomised controlled trials when estimating likely time requirements for recruiting trial participants. The requirements of a useful model were identified as usability, based on experience, able to reflect time trends, accounting for centre recruitment and contribution to a commissioning decision.</p> <p>Methods</p> <p>A systematic review of English language articles using MEDLINE and EMBASE. Search terms included: randomised controlled trial, patient, accrual, predict, enrol, models, statistical; Bayes Theorem; Decision Theory; Monte Carlo Method and Poisson. Only studies discussing prediction of recruitment to trials using a modelling approach were included. Information was extracted from articles by one author, and checked by a second, using a pre-defined form.</p> <p>Results</p> <p>Out of 326 identified abstracts, only 8 met all the inclusion criteria. Of these 8 studies examined, there are five major classes of model discussed: the unconditional model, the conditional model, the Poisson model, Bayesian models and Monte Carlo simulation of Markov models. None of these meet all the pre-identified needs of the funder.</p> <p>Conclusions</p> <p>To meet the needs of a number of research programmes, a new model is required as a matter of importance. Any model chosen should be validated against both retrospective and prospective data, to ensure the predictions it gives are superior to those currently used.</p

Thawing of permafrost may disturb historic cattle burial grounds in East Siberia

Climate warming in the Arctic may increase the risk of zoonoses due to expansion of vector habitats, improved chances of vector survival during winter, and permafrost degradation. Monitoring of soil temperatures at Siberian cryology control stations since 1970 showed correlations between air temperatures and the depth of permafrost layer that thawed during summer season. Between 1900s and 1980s, the temperature of surface layer of permafrost increased by 2–4°C; and a further increase of 3°C is expected. Frequent outbreaks of anthrax caused death of 1.5 million deer in Russian North between 1897 and 1925. Anthrax among people or cattle has been reported in 29,000 settlements of the Russian North, including more than 200 Yakutia settlements, which are located near the burial grounds of cattle that died from anthrax. Statistically significant positive trends in annual average temperatures were established in 8 out of 17 administrative districts of Yakutia for which sufficient meteorological data were available. At present, it is not known whether further warming of the permafrost will lead to the release of viable anthrax organisms. Nevertheless, we suggest that it would be prudent to undertake careful monitoring of permafrost conditions in all areas where an anthrax outbreak had occurred in the past

First-principles design and subsequent synthesis of a material to search for the permanent electric dipole moment of the electron

We describe the first-principles design and subsequent synthesis of a new material with the specific functionalities required for a solid-state-based search for the permanent electric dipole moment of the electron. We show computationally that perovskite-structure europium barium titanate should exhibit the required large and pressure-dependent ferroelectric polarization, local magnetic moments, and absence of magnetic ordering even at liquid helium temperature. Subsequent synthesis and characterization of Eu$_{0.5}$Ba$_{0.5}$TiO$_3$ ceramics confirm the predicted desirable properties.Comment: Nature Materials, in pres

Promoting Recruitment using Information Management Efficiently (PRIME): statistical analysis plan for a stepped wedge cluster randomised trial within the REstart or STop Antithrombotics Randomised Trial (RESTART)

BACKGROUND: Promoting Recruitment using Information Management Efficiently (PRIME) is a stepped wedge, cluster randomised trial-within-a-trial of a complex intervention to help sites in the United Kingdom to attain their own target number of participants to recruit to the REstart or STop Antithrombotics Randomised Trial (RESTART, ISRCTN71907627). METHODS: Seventy-two hospital sites had opted into PRIME and were randomly allocated (using a computer-generated block randomisation algorithm, stratified by hospital location) to one of 12 months in which a complex intervention would be delivered. All sites began in the control state. The primary outcome is the total number of patients randomised into RESTART per month per site, which will be analysed in a negative binomial generalised linear mixed model. Secondary outcomes include the proportion of sites using stroke databases to identify potentially eligible patients before PRIME, frequency of using bespoke stroke audit data exports during PRIME, barriers to recruitment in PRIME, barriers to using the bespoke stroke audit data exports, and disadvantages of the bespoke stroke audit exports identified by PRIME sites. PRIME began in September 2015. The last intervention will be delivered in August 2016. Six-month follow-up will be complete in February 2017. This statistical analysis plan was written and submitted for publication before all sites received the PRIME intervention and before outcome data were known. DISCUSSION: Final results of PRIME will be analysed and disseminated in 2017. TRIAL REGISTRATION: Northern Ireland Hub for Trials Methodology Research SWAT repository (SWAT22)

Thermopower of the Correlated Narrow Gap Semiconductor FeSi and Comparison to RuSi

Iron based narrow gap semiconductors such as FeSi, FeSb2, or FeGa3 have received a lot of attention because they exhibit a large thermopower, as well as striking similarities to heavy fermion Kondo insulators. Many proposals have been advanced, however, lacking quantitative methodologies applied to this problem, a consensus remained elusive to date. Here, we employ realistic many-body calculations to elucidate the impact of electronic correlation effects on FeSi. Our methodology accounts for all substantial anomalies observed in FeSi: the metallization, the lack of conservation of spectral weight in optical spectroscopy, and the Curie susceptibility. In particular we find a very good agreement for the anomalous thermoelectric power. Validated by this congruence with experiment, we further discuss a new physical picture of the microscopic nature of the insulator-to-metal crossover. Indeed, we find the suppression of the Seebeck coefficient to be driven by correlation induced incoherence. Finally, we compare FeSi to its iso-structural and iso-electronic homologue RuSi, and predict that partially substituted Fe(1-x)Ru(x)Si will exhibit an increased thermopower at intermediate temperatures.Comment: 14 pages. Proceedings of the Hvar 2011 Workshop on 'New materials for thermoelectric applications: theory and experiment

Overshoot mechanism in transient excitation of THz and Gunn oscillations in wide-bandgap semiconductors

A detailed study of high-field transient and direct-current (DC) transport in GaN-based Gunn diode oscillators is carried out using the commercial simulator Sentaurus Device. Applicability of drift-diffusion (DD) and hydrodynamic (HD) models to high-speed, highfrequency devices is discussed in depth, and the results of the simulations from these models are compared. It is shown, for a highly homogeneous device based on a short (2 μm) supercritically doped (1017 cm-3) GaN specimen, that the DD model is unable to correctly take into account some essential physical effects which determine the operation mode of the device. At the same time, the HD model is ideally suited to solve such problems due to its ability to incorporate non-local effects. We show that the velocity overshoot near the device contacts and space charge injection and extraction play a crucial role in defining the operation mode of highly homogeneous short diodes in both the transient regime and the voltagecontrolled oscillation regime. The transient conduction current responses are fundamentally different in the DD and HD models. The DD current simply repeats the velocity-field (v-F) characteristics, and the sample remains in a completely homogeneous state. In the HD model, the transient current pulse with a full width at half maximum of approximately 0.2 ps is increased about twofold due to the carrier injection (extraction) into (from) the active region and the velocity overshoot. The electron gas is characterized by highly inhomogeneous distributions of the carrier density, the electric field and the electron temperature. The simulation of the DC steady states of the diodes also shows very different results for the two models. The HD model shows the trapped stable anodic domain in the device, while the DD model completely retains all features of the v-F characteristics in a homogeneous gas. Simulation of the voltage-controlled oscillator shows that it operates in the accumulation layer mode generating microwave signals at 0.3 to 0.7 THz. In spite of the fact that the known criterion of a Gunn domain mode n0L > (n0L)0 was satisfied, no Gunn domains were observed. The explanation of this phenomenon is given. © 2012 Momox et al

Crystallization of Ti33Cu67 metallic glass under high-current density electrical pulses

We have studied the phase and structure evolution of the Ti33Cu67 amorphous alloy subjected to electrical pulses of high current density. By varying the pulse parameters, different stages of crystallization could be observed in the samples. Partial polymorphic nanocrystallization resulting in the formation of 5- to 8-nm crystallites of the TiCu2 intermetallic in the residual amorphous matrix occurred when the maximum current density reached 9.7·108 A m-2 and the pulse duration was 140 μs, though the calculated temperature increase due to Joule heating was not enough to reach the crystallization temperature of the alloy. Samples subjected to higher current densities and higher values of the evolved Joule heat per unit mass fully crystallized and contained the Ti2Cu3 and TiCu3 phases. A common feature of the crystallized ribbons was their non-uniform microstructure with regions that experienced local melting and rapid solidification

Bacteriophage-Resistant Mutants in Yersinia pestis: Identification of Phage Receptors and Attenuation for Mice

Background: Bacteriophages specific for Yersinia pestis are routinely used for plague diagnostics and could be an alternative to antibiotics in case of drug-resistant plague. A major concern of bacteriophage therapy is the emergence of phageresistant mutants. The use of phage cocktails can overcome this problem but only if the phages exploit different receptors. Some phage-resistant mutants lose virulence and therefore should not complicate bacteriophage therapy. Methodology/Principal Findings: The purpose of this work was to identify Y. pestis phage receptors using site-directed mutagenesis and trans-complementation and to determine potential attenuation of phage-resistant mutants for mice. Six receptors for eight phages were found in different parts of the lipopolysaccharide (LPS) inner and outer core. The receptor for R phage was localized beyond the LPS core. Most spontaneous and defined phage-resistant mutants of Y. pestis were attenuated, showing increase in LD 50 and time to death. The loss of different LPS core biosynthesis enzymes resulted in the reduction of Y. pestis virulence and there was a correlation between the degree of core truncation and the impact on virulence. The yrbH and waaA mutants completely lost their virulence. Conclusions/Significance: We identified Y. pestis receptors for eight bacteriophages. Nine phages together use at least seven different Y. pestis receptors that makes some of them promising for formulation of plague therapeutic cocktails. Most phage-resistant Y. pestis mutants become attenuated and thus should not pose a serious problem for bacteriophag