An evaluation of a Bayesian method of dose escalation based on bivariate binary responses

Recently, various approaches have been suggested for dose escalation studies based on observations of both undesirable events and evidence of therapeutic benefit. This article concerns a Bayesian approach to dose escalation that requires the user to make numerous design decisions relating to the number of doses to make available, the choice of the prior distribution, the imposition of safety constraints and stopping rules, and the criteria by which the design is to be optimized. Results are presented of a substantial simulation study conducted to investigate the influence of some of these factors on the safety and the accuracy of the procedure with a view toward providing general guidance for investigators conducting such studies. The Bayesian procedures evaluated use logistic regression to model the two responses, which are both assumed to be binary. The simulation study is based on features of a recently completed study of a compound with potential benefit to patients suffering from inflammatory diseases of the lung.

The potential for the use of agent-based models in ecotoxicology

This chapter introduces ABMs, their construction, and the pros and cons of their use. Although relatively new, agent-basedmodels (ABMs) have great potential for use in ecotoxicological research – their primary advantage being the realistic simulations that can be constructed and particularly their explicit handling of space and time in simulations. Examples are provided of their use in ecotoxicology primarily exemplified by different implementations of the ALMaSS system. These examples presented demonstrate how multiple stressors, landscape structure, details regarding toxicology, animal behavior, and socioeconomic effects can and should be taken into account when constructing simulations for risk assessment. Like ecological systems, in ABMs the behavior at the system level is not simply the mean of the component responses, but the sum of the often nonlinear interactions between components in the system; hence this modeling approach opens the door to implementing and testing much more realistic and holistic ecotoxicological models than are currently used.

Attenuating mutations in the influenza virus genome which may increase the safety of vaccine production

Influenza virus epidemics occur on an annual basis and cause severe disease in the very young and old. The vaccine administered to high-risk groups is generated by amplifying reassortant viruses, with chronologically relevant viral surface antigens, in eggs. Every 20 years or so, influenza pandemics occur causing widespread fatality in all age groups. These viruses display novel viral surface antigens acquired from a zoonotic source, and vaccination against them poses new issues since production of large amounts of a respiratory virus containing novel surface antigens could be dangerous for those involved in manufacture. To minimise risks, it is advisable to use a virus whose genetic backbone is highly attenuated in man. Traditionally, the A/PR/8/34 strain of virus is used, however, the genetic basis of its attenuation is unclear. Cold-adapted (CA) strains of the influenza virus are all based on the H2N2 subtype, itself a virus with pandemic potential, and again the genetic basis of temperature sensitivity is not yet established. Reverse genetics technology allows us to engineer designer influenza viruses to order. Using this technology, we have been investigating mutations in several different gene segments to effectively attenuate potential vaccine strains allowing the safe production of vaccine to protect against the next pandemic. (C) 2003 Elsevier B.V. All rights reserved.

Solvent-induced dynamic single-crystal-to-single-crystal transformation of a synthetic peptide-based cyclic compound

Solvent induced single-crystal-to-single-crystal transformation has been demonstrated indicating the dynamic behavior of one dimensional arrays obtained from a self-assembled new synthetic cyclic peptide.

Predictions of some product parameters based on the processing conditions of ultra-high-temperature milk plants

The temperature-time profiles of 22 Australian industrial ultra-high-temperature (UHT) plants and 3 pilot plants, using both indirect and direct heating, were surveyed. From these data, the operating parameters of each plant, the chemical index C*, the bacteriological index B* and the predicted changes in the levels of beta-lactoglobulin, alpha-lactalbumin, lactulose, furosine and browning were determined using a simulation program based on published formulae and reaction kinetics data. There was a wide spread of heating conditions used, some of which resulted in a large margin of bacteriological safety and high chemical indices. However, no conditions were severe enough to cause browning during processing. The data showed a clear distinction between the indirect and direct heating plants. They also indicated that degree of denaturation of alpha-lactalbumin varied over a wide range and may be a useful discriminatory index of heat treatment. Application of the program to pilot plants illustrated its value in determining processing conditions in these plants to simulate the conditions in industrial UHT plants. (C) 2008 Elsevier Ltd. All rights reserved.

Consistently inconsistent: commercially available starch-based Dysphagia products

Individuals with dysphagia may be prescribed thickened fluids to promote a safer and more successful swallow. Starch-based thickening agents are often employed; however, these exhibit great variation in consistency. The aim of this study was to compare viscosity and the rheological profile parameters complex (G*), viscous (G″), and elastic modulus (G′) over a range of physiological shear rates. UK commercially available dysphagia products at “custard” consistency were examined. Commercially available starch-based dysphagia products were prepared according to manufacturers’ instructions; the viscosity and rheological parameters were tested on a CVOR Rheometer. At a measured shear rate of 50 s−1, all products fell within the viscosity limits defined according to the National Dysphagia Diet Task Force guidelines. However, at lower shear rates, large variations in viscosity were observed. Rheological parameters G*, G′, and G″ also demonstrated considerable differences in both overall strength and rheological behavior between different batches of the same product and different product types. The large range in consistency and changes in the overall structure of the starch-based products over a range of physiological shear rates show that patients could be receiving fluids with very different characteristics from that advised. This could have detrimental effects on their ability to swallow.

A bridge-ship collision avoidance system based on FLIR image sequences

In this paper, a forward-looking infrared (FLIR) video surveillance system is presented for collision avoidance of moving ships to bridge piers. An image preprocessing algorithm is proposed to reduce clutter background by multi-scale fractal analysis, in which the blanket method is used for fractal feature computation. Then, the moving ship detection algorithm is developed from image differentials of the fractal feature in the region of surveillance between regularly interval frames. When the moving ships are detected in region of surveillance, the device for safety alert is triggered. Experimental results have shown that the approach is feasible and effective. It has achieved real-time and reliable alert to avoid collisions of moving ships to bridge piers.

The significance of insecure attachment and disorganization in the development of children's externalizing behavior: A meta-analytic study

This study addresses the extent to which insecure and disorganized attachments increase risk for externalizing problems using meta-analysis. From 69 samples (N = 5,947), the association between insecurity and externalizing problems was significant, d = 0.31 (95% CI: 0.23, 0.40). Larger effects were found for boys (d = 0.35), clinical samples (d = 0.49), and from observation-based outcome assessments (d = 0.58). Larger effects were found for attachment assessments other than the Strange Situation. Overall, disorganized children appeared at elevated risk (d = 0.34, 95% CI: 0.18, 0.50), with weaker effects for avoidance (d = 0.12, 95% CI: 0.03, 0.21) and resistance (d = 0.11, 95% CI: −0.04, 0.26). The results are discussed in terms of the potential significance of attachment for mental health.

Spatiotemporal behavior of the TIGGE medium-range ensemble forecasts

Using the recently-developed mean–variance of logarithms (MVL) diagram, together with the TIGGE archive of medium-range ensemble forecasts from nine different centres, an analysis is presented of the spatiotemporal dynamics of their perturbations, showing how the differences between models and perturbation techniques can explain the shape of their characteristic MVL curves. In particular, a divide is seen between ensembles based on singular vectors or empirical orthogonal functions, and those based on bred vector, Ensemble Transform with Rescaling or Ensemble Kalman Filter techniques. Consideration is also given to the use of the MVL diagram to compare the growth of perturbations within the ensemble with the growth of the forecast error, showing that there is a much closer correspondence for some models than others. Finally, the use of the MVL technique to assist in selecting models for inclusion in a multi-model ensemble is discussed, and an experiment suggested to test its potential in this context.

Do in vivo terahertz imaging systems comply with safety guidelines?

Techniques for the coherent generation and detection of electromagnetic radiation in the far infrared, or terahertz, region of the electromagnetic spectrum have recently developed rapidly and may soon be applied for in vivo medical imaging. Both continuous wave and pulsed imaging systems are under development, with terahertz pulsed imaging being the more common method. Typically a pump and probe technique is used, with picosecond pulses of terahertz radiation generated from femtosecond infrared laser pulses, using an antenna or nonlinear crystal. After interaction with the subject either by transmission or reflection, coherent detection is achieved when the terahertz beam is combined with the probe laser beam. Raster scanning of the subject leads to an image data set comprising a time series representing the pulse at each pixel. A set of parametric images may be calculated, mapping the values of various parameters calculated from the shape of the pulses. A safety analysis has been performed, based on current guidelines for skin exposure to radiation of wavelengths 2.6 µm–20 mm (15 GHz–115 THz), to determine the maximum permissible exposure (MPE) for such a terahertz imaging system. The international guidelines for this range of wavelengths are drawn from two U.S. standards documents. The method for this analysis was taken from the American National Standard for the Safe Use of Lasers (ANSI Z136.1), and to ensure a conservative analysis, parameters were drawn from both this standard and from the IEEE Standard for Safety Levels with Respect to Human Exposure to Radio Frequency Electromagnetic Fields (C95.1). The calculated maximum permissible average beam power was 3 mW, indicating that typical terahertz imaging systems are safe according to the current guidelines. Further developments may however result in systems that will exceed the calculated limit. Furthermore, the published MPEs for pulsed exposures are based on measurements at shorter wavelengths and with pulses of longer duration than those used in terahertz pulsed imaging systems, so the results should be treated with caution.

Reducing contamination by exposure plus safety behaviour

Background and objectives: It has been proposed that the judicious use of safety behaviour can facilitate improvements in the acceptability of cognitive behaviour therapy (CBT). It was decided to explore the possibility of facilitating CBT by introducing a form of safety behaviour.We sought to assess the degree to which Exposure plus Safety Behaviour (E þ SB) is an effective intervention for contamination fears. Methods: A comparison was made between the effects of a control condition (Exposure and Response Prevention; ERP) and an experimental condition (Exposure plus Safety Behaviour; E þ SB) in which each exposure to a contaminant was followed by the use of a hygienic wipe in a sample of (n ¼ 80) undergraduate students. In session one, each participant touched a confirmed contaminant 20 times. After each exposure participants were asked to report their feelings of contamination, fear, disgust, and danger. In the second session, two weeks later, the same procedure was carried out for a further 16 trials. Results: The ERP and the E þ SB conditions both produced large, significant and stable reductions in contamination. Significant reductions in fear, danger and disgust were also reported in both conditions. Limitations: The treatment was provided to an analogue sample and over two sessions. Conclusions: The use of hygienic wipes, the safety behaviour used in this experiment, did not preclude significant reductions in contamination, disgust, fear and danger. If it is replicated and extended over a longer time-frame, this finding may enable practitioners to enhance the acceptability of cognitive behavioural treatments and boost their effectiveness.

PINCER trial: a cluster randomised trial comparing the effectiveness and cost-effectiveness of a pharmacist-led IT-based intervention with simple feedback in reducing rates of clinically important errors in medicines management in general practices

Background: Medication errors in general practice are an important source of potentially preventable morbidity and mortality. Building on previous descriptive, qualitative and pilot work, we sought to investigate the effectiveness, cost-effectiveness and likely generalisability of a complex pharm acist-led IT-based intervention aiming to improve prescribing safety in general practice. Objectives: We sought to: • Test the hypothesis that a pharmacist-led IT-based complex intervention using educational outreach and practical support is more effective than simple feedback in reducing the proportion of patients at risk from errors in prescribing and medicines management in general practice. • Conduct an economic evaluation of the cost per error avoided, from the perspective of the National Health Service (NHS). • Analyse data recorded by pharmacists, summarising the proportions of patients judged to be at clinical risk, the actions recommended by pharmacists, and actions completed in the practices. • Explore the views and experiences of healthcare professionals and NHS managers concerning the intervention; investigate potential explanations for the observed effects, and inform decisions on the future roll-out of the pharmacist-led intervention • Examine secular trends in the outcome measures of interest allowing for informal comparison between trial practices and practices that did not participate in the trial contributing to the QRESEARCH database. Methods Two-arm cluster randomised controlled trial of 72 English general practices with embedded economic analysis and longitudinal descriptive and qualitative analysis. Informal comparison of the trial findings with a national descriptive study investigating secular trends undertaken using data from practices contributing to the QRESEARCH database. The main outcomes of interest were prescribing errors and medication monitoring errors at six- and 12-months following the intervention. Results: Participants in the pharmacist intervention arm practices were significantly less likely to have been prescribed a non-selective NSAID without a proton pump inhibitor (PPI) if they had a history of peptic ulcer (OR 0.58, 95%CI 0.38, 0.89), to have been prescribed a beta-blocker if they had asthma (OR 0.73, 95% CI 0.58, 0.91) or (in those aged 75 years and older) to have been prescribed an ACE inhibitor or diuretic without a measurement of urea and electrolytes in the last 15 months (OR 0.51, 95% CI 0.34, 0.78). The economic analysis suggests that the PINCER pharmacist intervention has 95% probability of being cost effective if the decision-maker’s ceiling willingness to pay reaches £75 (6 months) or £85 (12 months) per error avoided. The intervention addressed an issue that was important to professionals and their teams and was delivered in a way that was acceptable to practices with minimum disruption of normal work processes. Comparison of the trial findings with changes seen in QRESEARCH practices indicated that any reductions achieved in the simple feedback arm were likely, in the main, to have been related to secular trends rather than the intervention. Conclusions Compared with simple feedback, the pharmacist-led intervention resulted in reductions in proportions of patients at risk of prescribing and monitoring errors for the primary outcome measures and the composite secondary outcome measures at six-months and (with the exception of the NSAID/peptic ulcer outcome measure) 12-months post-intervention. The intervention is acceptable to pharmacists and practices, and is likely to be seen as costeffective by decision makers.

Designing persuasive third party applications for social networking services based on the 3D-RAB model

The use of social networks services for promoting business, teaching, learning, persuasion and spread of information continues to attract attention as most social networking services (SNSs) now allow third party applications to operate on their sites. In the field of persuasive technology, the ability of SNSs to build relationships among their users and create momentum and enthusiasm through rapid cycles also give it a greater advantage over other persuasive technology approaches. In this paper we discuss the 3-dimensional relationship between attitude and behavior (3D-RAB) model, and demonstrate how it can be used in designing third-party persuasive applications in SNSs by considering external factors which affects persuasive strategies.