Bayesian meta-analytical methods to incorporate multiple surrogate endpoints in drug development process.

A number of meta-analytical methods have been proposed that aim to evaluate surrogate endpoints. Bivariate meta-analytical methods can be used to predict the treatment effect for the final outcome from the treatment effect estimate measured on the surrogate endpoint while taking into account the uncertainty around the effect estimate for the surrogate endpoint. In this paper, extensions to multivariate models are developed aiming to include multiple surrogate endpoints with the potential benefit of reducing the uncertainty when making predictions. In this Bayesian multivariate meta-analytic framework, the between-study variability is modelled in a formulation of a product of normal univariate distributions. This formulation is particularly convenient for including multiple surrogate endpoints and flexible for modelling the outcomes which can be surrogate endpoints to the final outcome and potentially to one another. Two models are proposed, first, using an unstructured between-study covariance matrix by assuming the treatment effects on all outcomes are correlated and second, using a structured between-study covariance matrix by assuming treatment effects on some of the outcomes are conditionally independent. While the two models are developed for the summary data on a study level, the individual-level association is taken into account by the use of the Prentice's criteria (obtained from individual patient data) to inform the within study correlations in the models. The modelling techniques are investigated using an example in relapsing remitting multiple sclerosis where the disability worsening is the final outcome, while relapse rate and MRI lesions are potential surrogates to the disability progression

Ultrasonic Evaluation of Titanium Alloy Diffusion Bonding

During the diffusion bond process, parts are heated to about one half the absolute melting point, pressed together at a stress below the macroscopic yield stress, and conditions maintained for a specified time. Bonding proceeds through three steps: local yielding of contact points upon initial application of stress; creep deformation on the bonding plane to yield discontinuous voids; and closure of voids by vacancy diffusion. Presently, nondestructive evaluation emphasizes detection of residual unbonds and voids, from incomplete void isolation or closure

High Energy Gamma-Ray Emission From Blazars: EGRET Observations

We will present a summary of the observations of blazars by the Energetic Gamma Ray Experiment Telescope (EGRET) on the Compton Gamma Ray Observatory (CGRO). EGRET has detected high energy gamma-ray emission at energies greater than 100 MeV from more that 50 blazars. These sources show inferred isotropic luminosities as large as $3\times 10^{49}$ ergs s$^{-1}$. One of the most remarkable characteristics of the EGRET observations is that the gamma-ray luminosity often dominates the bolometric power of the blazar. A few of the blazars are seen to exhibit variability on very short time-scales of one day or less. The combination of high luminosities and time variations seen in the gamma-ray data indicate that gamma-rays are an important component of the relativistic jet thought to characterize blazars. Currently most models for blazars involve a beaming scenario. In leptonic models, where electrons are the primary accelerated particles, gamma-ray emission is believed to be due to inverse Compton scattering of low energy photons, although opinions differ as to the source of the soft photons. Hardronic models involve secondary production or photomeson production followed by pair cascades, and predict associated neutrino production.Comment: 16 pages, 7 figures, style files included. Invited review paper in "Observational Evidence for Black Holes in the Universe," 1999, ed. S. K. Chakrabarti (Dordrecht: Kluwer), 215-23

ClustalXeed: a GUI-based grid computation version for high performance and terabyte size multiple sequence alignment

Abstract Background There is an increasing demand to assemble and align large-scale biological sequence data sets. The commonly used multiple sequence alignment programs are still limited in their ability to handle very large amounts of sequences because the system lacks a scalable high-performance computing (HPC) environment with a greatly extended data storage capacity. Results We designed ClustalXeed, a software system for multiple sequence alignment with incremental improvements over previous versions of the ClustalX and ClustalW-MPI software. The primary advantage of ClustalXeed over other multiple sequence alignment software is its ability to align a large family of protein or nucleic acid sequences. To solve the conventional memory-dependency problem, ClustalXeed uses both physical random access memory (RAM) and a distributed file-allocation system for distance matrix construction and pair-align computation. The computation efficiency of disk-storage system was markedly improved by implementing an efficient load-balancing algorithm, called "idle node-seeking task algorithm" (INSTA). The new editing option and the graphical user interface (GUI) provide ready access to a parallel-computing environment for users who seek fast and easy alignment of large DNA and protein sequence sets. Conclusions ClustalXeed can now compute a large volume of biological sequence data sets, which were not tractable in any other parallel or single MSA program. The main developments include: 1) the ability to tackle larger sequence alignment problems than possible with previous systems through markedly improved storage-handling capabilities. 2) Implementing an efficient task load-balancing algorithm, INSTA, which improves overall processing times for multiple sequence alignment with input sequences of non-uniform length. 3) Support for both single PC and distributed cluster systems.</p

Change in non-alcoholic beverage sales following a 10-pence levy on sugar-sweetened beverages within a national chain of restaurants in the UK: interrupted time series analysis of a natural experiment

This is the final published version. Available from BMJ Publishing Group via the DOI in this record.The dataset used within this study is commercially sensitive and is owned by a third-party. The data provider (Jamie’s Italian) will accept requests to access to sales data used in the analyses presented here. These requests should be made in writing to the Jamie Oliver Food Foundation (http://www. jamieoliverfoodfoundation.org.uk).Background This study evaluates changes in sales of non-alcoholic beverages in Jamie’s Italian, a national chain of commercial restaurants in the UK, following the introduction of a £0.10 per-beverage levy on sugarsweetened beverages (SSBs) and supporting activity including beverage menu redesign, new products and establishment of a children’s health fund from levy proceeds. Methods We used an interrupted time series design to quantify changes in sales of non-alcoholic beverages 12 weeks and 6 months after implementation of the levy, using itemised electronic point of sale data. Main outcomes were number of SSBs and other nonalcoholic beverages sold per customer. Linear regression and multilevel random effects models, adjusting for seasonality and clustering, were used to investigate changes in SSB sales across all restaurants (n=37) and by tertiles of baseline restaurant SSB sales per customer. Results Compared with the prelevy period, the number of SSBs sold per customer declined by 11.0% (−17.3% to −4.3%) at 12 weeks and 9.3% (−15.2% to −3.2%) at 6months. For non-levied beverages, sales per customer of children’s fruit juice declined by 34.7% (−55.3% to −4.3%) at 12 weeks and 9.9% (−16.8% to −2.4%) at 6months. At 6months, sales per customer of fruit juice increased by 21.8% (14.0% to 30.2%) but sales of diet cola (−7.3%; −11.7% to −2.8%) and bottled waters (−6.5%; −11.0% to −1.7%) declined. Changes in sales were only observed in restaurants in the medium and high tertiles of baseline SSB sales per customer. Conclusions Introduction of a £0.10 levy on SSBs alongside complementary activities is associated with declines in SSB sales per customer in the short and medium term, particularly in restaurants with higher baseline sales of SSBsNational Institute for Health Research (NIHR)Medical Research Council (MRC)Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of ExcellenceUK Clinical Research CollaborationBritish Heart FoundationCancer Research UKEconomic and Social Research Council (ESRC)Wellcome Trus

Stable ultrahigh-density magneto-optical recordings using introduced linear defects

The stability of data bits in magnetic recording media at ultrahigh densities is compromised by thermal `flips' -- magnetic spin reversals -- of nano-sized spin domains, which erase the stored information. Media that are magnetized perpendicular to the plane of the film, such as ultrathin cobalt films or multilayered structures, are more stable against thermal self-erasure than conventional memory devices. In this context, magneto-optical memories seem particularly promising for ultrahigh-density recording on portable disks, and bit densities of $\sim$100 Gbit inch$^{-2}$ have been demonstrated using recent advances in the bit writing and reading techniques. But the roughness and mobility of the magnetic domain walls prevents closer packing of the magnetic bits, and therefore presents a challenge to reaching even higher bit densities. Here we report that the strain imposed by a linear defect in a magnetic thin film can smooth rough domain walls over regions hundreds of micrometers in size, and halt their motion. A scaling analysis of this process, based on the generic physics of disorder-controlled elastic lines, points to a simple way by which magnetic media might be prepared that can store data at densities in excess of 1 Tbit inch$^{-2}$.Comment: 5 pages, 4 figures, see also an article in TRN News at http://www.trnmag.com/Stories/041801/Defects_boost_disc_capacity_041801.htm

Efimov physics beyond three particles

Efimov physics originally refers to a system of three particles. Here we review recent theoretical progress seeking for manifestations of Efimov physics in systems composed of more than three particles. Clusters of more than three bosons are tied to each Efimov trimer, but no independent Efimov physics exists there beyond three bosons. The case of a few heavy fermions interacting with a lighter atom is also considered, where the mass ratio of the constituent particles plays a significant role. Following Efimov's study of the (2+1) system, the (3+1) system was shown to have its own critical mass ratio to become Efimovian. We show that the (4+1) system becomes Efimovian at a mass ratio which is smaller than its sub-systems thresholds, giving a pure five-body Efimov effect. The (5+1) and (6+1) systems are also discussed, and we show the absence of 6- and 7-body Efimov physics there

Links between traumatic brain injury and ballistic pressure waves originating in the thoracic cavity and extremities

Identifying patients at risk of traumatic brain injury (TBI) is important because research suggests prophylactic treatments to reduce risk of long-term sequelae. Blast pressure waves can cause TBI without penetrating wounds or blunt force trauma. Similarly, bullet impacts distant from the brain can produce pressure waves sufficient to cause mild to moderate TBI. The fluid percussion model of TBI shows that pressure impulses of 15-30 psi cause mild to moderate TBI in laboratory animals. In pigs and dogs, bullet impacts to the thigh produce pressure waves in the brain of 18-45 psi and measurable injury to neurons and neuroglia. Analyses of research in goats and epidemiological data from shooting events involving humans show high correlations (r > 0.9) between rapid incapacitation and pressure wave magnitude in the thoracic cavity. A case study has documented epilepsy resulting from a pressure wave without the bullet directly hitting the brain. Taken together, these results support the hypothesis that bullet impacts distant from the brain produce pressure waves that travel to the brain and can retain sufficient magnitude to induce brain injury. The link to long-term sequelae could be investigated via epidemiological studies of patients who were gunshot in the chest to determine whether they experience elevated rates of epilepsy and other neurological sequelae

Symptoms and signs of lung cancer prior to diagnosis: case-control study using electronic health records from ambulatory care within a large US-based tertiary care centre.

OBJECTIVE: Lung cancer is the most common cause of cancer-related death in the USA. While most patients are diagnosed following symptomatic presentation, no studies have compared symptoms and physical examination signs at or prior to diagnosis from electronic health records (EHRs) in the USA. We aimed to identify symptoms and signs in patients prior to diagnosis in EHR data. DESIGN: Case-control study. SETTING: Ambulatory care clinics at a large tertiary care academic health centre in the USA. PARTICIPANTS, OUTCOMES: We studied 698 primary lung cancer cases in adults diagnosed between 1 January 2012 and 31 December 2019, and 6841 controls matched by age, sex, smoking status and type of clinic. Coded and free-text data from the EHR were extracted from 2 years prior to diagnosis date for cases and index date for controls. Univariate and multivariable conditional logistic regression were used to identify symptoms and signs associated with lung cancer at time of diagnosis, and 1, 3, 6 and 12 months before the diagnosis/index dates. RESULTS: Eleven symptoms and signs recorded during the study period were associated with a significantly higher chance of being a lung cancer case in multivariable analyses. Of these, seven were significantly associated with lung cancer 6 months prior to diagnosis: haemoptysis (OR 3.2, 95% CI 1.9 to 5.3), cough (OR 3.1, 95% CI 2.4 to 4.0), chest crackles or wheeze (OR 3.1, 95% CI 2.3 to 4.1), bone pain (OR 2.7, 95% CI 2.1 to 3.6), back pain (OR 2.5, 95% CI 1.9 to 3.2), weight loss (OR 2.1, 95% CI 1.5 to 2.8) and fatigue (OR 1.6, 95% CI 1.3 to 2.1). CONCLUSIONS: Patients diagnosed with lung cancer appear to have symptoms and signs recorded in the EHR that distinguish them from similar matched patients in ambulatory care, often 6 months or more before diagnosis. These findings suggest opportunities to improve the diagnostic process for lung cancer

Randomised trial of glutamine and selenium supplemented parenteral nutrition for critically ill patients

Background: Mortality rates in the Intensive Care Unit and subsequent hospital mortality rates in the UK remain high. Infections in Intensive Care are associated with a 2–3 times increased risk of death. It is thought that under conditions of severe metabolic stress glutamine becomes "conditionally essential". Selenium is an essential trace element that has antioxidant and anti-inflammatory properties. Approximately 23% of patients in Intensive Care require parenteral nutrition and glutamine and selenium are either absent or present in low amounts. Both glutamine and selenium have the potential to influence the immune system through independent biochemical pathways. Systematic reviews suggest that supplementing parenteral nutrition in critical illness with glutamine or selenium may reduce infections and mortality. Pilot data has shown that more than 50% of participants developed infections, typically resistant organisms. We are powered to show definitively whether supplementation of PN with either glutamine or selenium is effective at reducing new infections in critically ill patients. Methods/design: 2 × 2 factorial, pragmatic, multicentre, double-blind, randomised controlled trial. The trial has an enrolment target of 500 patients. Inclusion criteria include: expected to be in critical care for at least 48 hours, aged 16 years or over, patients who require parenteral nutrition and are expected to have at least half their daily nutritional requirements given by that route. Allocation is to one of four iso-caloric, iso-nitrogenous groups: glutamine, selenium, both glutamine & selenium or no additional glutamine or selenium. Trial supplementation is given for up to seven days on the Intensive Care Unit and subsequent wards if practicable. The primary outcomes are episodes of infection in the 14 days after starting trial nutrition and mortality. Secondary outcomes include antibiotic usage, length of hospital stay, quality of life and cost-effectiveness. Discussion: To date more than 285 patients have been recruited to the trial from 10 sites in Scotland. Recruitment is due to finish in August 2008 with a further six months follow up. We expect to report the results of the trial in summer 2009. Trial registration: This trial is registered with the International Standard Randomised Controlled Trial Number system. ISRCTN87144826Not peer reviewedPublisher PD