Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil

Aim To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between- and within-subject variability and to evaluate the influence of covariates on the pharmacokinetic variability. Methods Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration-time points were available. Data were analysed using the first-order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler. Results The best base model was a two-compartment model with a lag time (apparent oral clearance was 271 h(-1), and apparent volume of the central compartment 981). There was visual evidence of complex absorption and time-dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined. Conclusions The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between-subject and between-occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.

Quantitative justification for target concentration intervention - parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides

Aims [1] To quantify the random and predictable components of variability for aminoglycoside clearance and volume of distribution [2] To investigate models for predicting aminoglycoside clearance in patients with low serum creatinine concentrations [3] To evaluate the predictive performance of initial dosing strategies for achieving an aminoglycoside target concentration. Methods Aminoglycoside demographic, dosing and concentration data were collected from 697 adult patients (>=20 years old) as part of standard clinical care using a target concentration intervention approach for dose individualization. It was assumed that aminoglycoside clearance had a renal and a nonrenal component, with the renal component being linearly related to predicted creatinine clearance. Results A two compartment pharmacokinetic model best described the aminoglycoside data. The addition of weight, age, sex and serum creatinine as covariates reduced the random component of between subject variability (BSVR) in clearance (CL) from 94% to 36% of population parameter variability (PPV). The final pharmacokinetic parameter estimates for the model with the best predictive performance were: CL, 4.7 l h(-1) 70 kg(-1); intercompartmental clearance (CLic), 1 l h(-1) 70 kg(-1); volume of central compartment (V-1), 19.5 l 70 kg(-1); volume of peripheral compartment (V-2) 11.2 l 70 kg(-1). Conclusions Using a fixed dose of aminoglycoside will achieve 35% of typical patients within 80-125% of a required dose. Covariate guided predictions increase this up to 61%. However, because we have shown that random within subject variability (WSVR) in clearance is less than safe and effective variability (SEV), target concentration intervention can potentially achieve safe and effective doses in 90% of patients.

Effect of inspiratory flow on methacholine challenge in children

Regulation of inspiratory flow alters the outcomes of the methacholine (MHC) challenge in adults and cough receptor sensitivity in children. The effect of inspiratory flow on the reproducibility of the MHC challenge in children is unknown. The aim of this study was to evaluate the effect of inspiratory flow alteration on the repeatabilty of the MHC challenge in children with and without asthma. Twenty-five children undertook the MHC challenge on three different days by using a dosimeter connected to a setup that allowed regulation of inspiratory flow and pattern. Children were randomized to commence the challenges at 20 or 60 L/min, and the last challenge was performed at 20 L/min. The within-subject standard deviation, 95% range for change, and doubling dose for the differing inspiratory flow (20 vs. 60 L/min) was more than twice that of when inspiratory flow was maintained at 20 L/min for both occasions. The range of the limits of agreement of the Bland and Altman plot was smaller when inspiratory flow was constant. For short-term comparative individual studies in children, inspiratory flow should be regulated. Laboratories and research measuring change in airway hyperrepsonsiveness to MHC should determine and report reproducibility indices of the challenge so airway hyperresponsiveness changes can be interpreted meaningfully.

Anthropometry profiles of elite rugby players: quantifying changes in lean mass

Objective: To demonstrate the utility of a practical measure of lean mass for monitoring changes in the body composition of athletes. Methods: Between 1999 and 2003 body mass and sum of seven skinfolds were recorded for 40 forwards and 32 backs from one Super 12 rugby union franchise. Players were assessed on 13 (7) occasions ( mean (SD)) over 1.9 (1.3) years. Mixed modelling of log transformed variables provided a lean mass index (LMI) of the form mass/skinfolds(x), for monitoring changes in mass controlled for changes in skinfold thickness. Mean effects of phase of season and time in programme were modelled as percentage changes. Effects were standardised for interpretation of magnitudes. Results: The exponent x was 0.13 for forwards and 0.14 for backs ( 90% confidence limits +/- 0.03). The forwards had a small decrease in skinfolds ( 5.3%, 90% confidence limits +/- 2.2%) between preseason and competition phases, and a small increase ( 7.8%, 90% confidence limits +/- 3.1%) during the club season. A small decrease in LMI (similar to 1.5%) occurred after one year in the programme for forwards and backs, whereas increases in skinfolds for forwards became substantial (4.3%, 90% confidence limits +/- 2.2%) after three years. Individual variation in body composition was small within a season (within subject SD: body mass, 1.6%; skinfolds, 6.8%; LMI, 1.1%) and somewhat greater for body mass (2.1%) and LMI (1.7%) between seasons. Conclusions: Despite a lack of substantial mean changes, there was substantial individual variation in lean mass within and between seasons. An index of lean mass based

Modelling manufacturing planning and control systems:the application of object-oriented principles and discrete-event simulation

Manufacturing planning and control systems are fundamental to the successful operations of a manufacturing organisation. 10 order to improve their business performance, significant investment is made by companies into planning and control systems; however, not all companies realise the benefits sought Many companies continue to suffer from high levels of inventory, shortages, obsolete parts, poor resource utilisation and poor delivery performance. This thesis argues that the fit between the planning and control system and the manufacturing organisation is a crucial element of success. The design of appropriate control systems is, therefore, important. The different approaches to the design of manufacturing planning and control systems are investigated. It is concluded that there is no provision within these design methodologies to properly assess the impact of a proposed design on the manufacturing facility. Consequently, an understanding of how a new (or modified) planning and control system will perform in the context of the complete manufacturing system is unlikely to be gained until after the system has been implemented and is running. There are many modelling techniques available, however discrete-event simulation is unique in its ability to model the complex dynamics inherent in manufacturing systems, of which the planning and control system is an integral component. The existing application of simulation to manufacturing control system issues is limited: although operational issues are addressed, application to the more fundamental design of control systems is rarely, if at all, considered. The lack of a suitable simulation-based modelling tool does not help matters. The requirements of a simulation tool capable of modelling a host of different planning and control systems is presented. It is argued that only through the application of object-oriented principles can these extensive requirements be achieved. This thesis reports on the development of an extensible class library called WBS/Control, which is based on object-oriented principles and discrete-event simulation. The functionality, both current and future, offered by WBS/Control means that different planning and control systems can be modelled: not only the more standard implementations but also hybrid systems and new designs. The flexibility implicit in the development of WBS/Control supports its application to design and operational issues. WBS/Control wholly integrates with an existing manufacturing simulator to provide a more complete modelling environment.

EpiTOP—a proteochemometric tool for MHC class II binding prediction

Motivation: T-cell epitope identification is a critical immunoinformatic problem within vaccine design. To be an epitope, a peptide must bind an MHC protein. Results: Here, we present EpiTOP, the first server predicting MHC class II binding based on proteochemometrics, a QSAR approach for ligands binding to several related proteins. EpiTOP uses a quantitative matrix to predict binding to 12 HLA-DRB1 alleles. It identifies 89% of known epitopes within the top 20% of predicted binders, reducing laboratory labour, materials and time by 80%. EpiTOP is easy to use, gives comprehensive quantitative predictions and will be expanded and updated with new quantitative matrices over time.

Developing and evaluating a methodology for business process improvement

Purpose – There appears to be an ever-insatiable demand from markets for organisations to improve their products and services. To meet this, there is a need to provide business process improvement (BPI) methodologies that are holistic, structured and procedural. Therefore, this paper describes research that has formed and tested a generic and practical methodology termed model-based and integrated process improvement (MIPI) to support the implementation of BPI; and to validate its effectiveness in organisations. This methodology has been created as an aid for practitioners within organisations. Design/methodology/approach – The research objectives were achieved by: reviewing and analysing current methodologies, and selecting a few frameworks against key performance indicators. Using a refined Delphi approach and semi-structured interview with the “experts” in the field. Intervention, case study and process research approach to evaluating a methodology. Findings – The BPI methodology was successfully formed and applied by the researcher and directly by the companies involved against the criteria of feasibility, usability and usefulness. Research limitations/implications – The paper has demonstrated a new knowledge on how to systematically assess a BPI methodology in practice. Practical implications – Model-based and integrated process improvement methodology (MIPI) methodology offers the practitioner (experienced and novice) a set of step-by-step aids necessary to make informed, consistent and efficient changes to business processes. Originality/value – The novelty of this research work is the creation of a holistic workbook-based methodology with relevant tools and techniques. It extends the capabilities of existing methodologies.

Servitization of manufacture:exploring the deployment and skills of people critical to the delivery of advanced services

Purpose - This "research note" sets out to fuel the debate around the practices and technologies within operations that are critical to success with servitization. It presents a study of four companies which are delivering advanced services and reports on the organisation and skill-sets of people within these. Design/methodology/approach - This has been case-based research at four manufacturers leading in their delivery of services. Findings - It describes the desirable behaviour of people in the front-line of service delivery, identifies the supporting skill-sets, how these people are organised, and explains why all these factors are so important. Originality/value - This paper contributes to the understanding of the servitization process and, in particular, the implications to broader operations of the firm. © 2013 Emerald Group Publishing Limited. All rights reserved.

Placebo expectancy effects in the relationship between glucose and cognition

The present study investigated the extent of expectancy in the ability of glucose to affect cognitive performance. Using a within-subjects design, subjects (n 26) completed four experimental sessions (in counterbalanced order and after an initial practice session) during which they were given a 500 ml drink 30 min prior to completing a cognitive assessment battery. In addition, all subjects completed a baseline practice session during which they were given no drink. During two of the sessions, subjects were given a drink containing 50 g glucose and on the other two they were given a drink containing aspartame. A balanced placebo design was used, such that for half the sessions subjects were accurately informed as to the content of the drink (glucose or aspartame), whereas in the other two sessions they were misinformed as to the content of the drink. The task battery comprised a 6 min visual analogue of the Bakan vigilance task, an immediate verbal free-recall task, an immediate verbal recognition memory task and a measure of motor speed (two-finger tapping). Blood glucose and self-reported mood were also recorded at several time points during each session. Glucose administration was found to improve recognition memory times, in direct contrast to previous findings in the literature. Glucose administration also improved performance on the Bakan task (relative to the control drink), but only in sessions where subjects were informed that they would receive glucose and not when they were told that they would receive aspartame. There were no effects either of the nature of the drink or expectancy on the other measures. These results are interpreted in terms of there being some contribution of expectancy concerning the positive effects of glucose on cognition in studies which have not used an equi-sweet dose of aspartame as a control drink.

Truthiness and falsiness of trivia claims depend on judgmental contexts

When people rapidly judge the truth of claims presented with or without related but nonprobative photos, the photos tend to inflate the subjective truth of those claims-a "truthiness" effect (Newman et al., 2012). For example, people more often judged the claim "Macadamia nuts are in the same evolutionary family as peaches" to be true when the claim appeared with a photo of a bowl of macadamia nuts than when it appeared alone. We report several replications of that effect and 3 qualitatively new findings: (a) in a within-subjects design, when people judged claims paired with a mix of related, unrelated, or no photos, related photos produced truthiness but unrelated photos had no significant effect relative to no photos; (b) in a mixed design, when people judged claims paired with related (or unrelated) and no photos, related photos produced truthiness and unrelated photos produced "falseness;" and © in a fully between design, when people judged claims paired with either related, unrelated, or no photos, neither truthiness nor falsiness occurred. Our results suggest that photos influence people's judgments when a discrepancy arises in the expected ease of processing, and also support a mechanism in which-against a backdrop of an expected standard-related photos help people generate pseudoevidence to support claims. (PsycINFO Database Record)

A Method of Estimating Usability of a User Interface Based on its Model

The article presents a new method to estimating usability of a user interface based on its model. The principal features of the method are: creation of an expandable knowledge base of usability defects, detection defects based on the interface model, within the design phase, and information to the developer not only about existence of defects but also advice on their elimination.

Identifying (territorial) tensions in the servitization value chain

Purpose: To understand the tensions that servitization activities create between actors within networks. Design/methodology/approach: Interviews were conducted with manufacturers, intermediaries and customers across a range of industrial sectors. Findings: Tensions relating to two key sets of capabilities are identified: in developing or acquiring (i) operant technical expertise and (ii) operand service infrastructure. The former tension concerns whom knowledge is co-created with and where expertise resides. The latter involves a territorial investment component; firms developing strategies to acquire greater access to, or ownership of, infrastructures closer to customers. Developing and acquiring these capabilities is a strategic decision on the part of managers of servitizing firms, in order to gain recognized power and control in a particular territory. Originality/value: This paper explores how firms’ servitization activities involve value appropriation (from the rest of the network), contrasting with the narrative norm for servitization: that it creates additional value. There is a need to understand the tensions that servitization activities create within networks. Some firms may be able to improve servitization performance through co-operation rather than competition, generating co-opetitive relationships. Others may need to become much more aggressive, if they are to take a greater share of the ‘value’ from the value chain.

Pre-existent expectancy effects in the relationship between caffeine and performance

The present study investigated the impact of pre-existent expectancy regarding the effects of the caffeine load of a drink and the perception of the caffeine content on subjective mood and vigilance performance. Caffeine deprived participants (N=25) were tested in four conditions (within subjects design), using a 2 × 2 design, with caffeine load and information regarding the caffeine content of the drink. In two sessions, they were given caffeinated coffee and in two were given decaffeinated coffee. Within these two conditions, on one occasion they were given accurate information about the drink and on the other they were given inaccurate information about the drink. Mood and vigilance performance were assessed post ingestion. Caffeine was found to enhance performance, but only when participants were accurately told they were receiving it. When decaffeinated coffee was given, performance was poorer, irrespective of expectancy. However, when caffeine was given, but participants were told it was decaffeinated coffee, performance was as poor as when no caffeine had been administered. There were no easily interpretable effects on mood. The pharmacological effects of caffeine appear to act synergistically with expectancy. © 2010.

Determinants of confidence and their effect on epistemic judgments: Implications for auditor calibration bias

Auditor decisions regarding the causes of accounting misstatements can have an audit effectiveness and efficiency. Specifically, overconfidence in one's decision can lead to an ineffective audit, whereas underconfidence in one's decision can lead to an inefficient audit. This dissertation explored the implications of providing various types of information cues to decision-makers regarding an Analytical Procedure task and investigated the relationship between different types of evidence cues (confirming, disconfirming, redundant or non-redundant) and the reduction in calibration bias. Information was collected using a laboratory experiment, from 45 accounting students participants. Research questions were analyzed using a 2 x 2 x 2 between-subject and within-subject analysis of covariance (ANCOVA). ^ Results indicated that presenting subjects with information cues dissimilar to the choice they made is an effective intervention in reducing the common overconfidence found in decision-making. In addition, other information characteristics, specifically non-redundant information can help in reducing a decision-maker's overconfidence/calibration bias for difficulty (compared to easy) decision-tasks. ^

The Effectiveness of an Intervention Package on Math Computation

Abstract: Four second-grade students participated in a B-A-B withdrawal single-subject design experiment. The intervention package implemented consisted of three components: self-monitoring, performance feedback, and reinforcers. Participants completed math probes across phases. Accuracy and productivity was recorded and calculated. Results demonstrated the intervention package improved accuracy and productivity for all participants.