Consequences of incorrect sampling procedures in resonance-based radar target identification

Radar target identification based on complex natural resonances is sometimes achieved by convolving a linear time-domain filter with a received target signature. The filter is constructed from measured or pre-calculated target resonances. The performance of the target identification procedure is degraded if the difference between the sampling rates of the target signature and the filter is ignored. The problem is investigated for the natural extinction pulse technique (E-pulse) for the case of identifying stick models of aircraft.

Sensitivity of marine-reserve design to the spatial resolution of socioeconomic data

Socioeconomic considerations should have an important place in reserve design, Systematic reserve-selection tools allow simultaneous optimization for ecological objectives while minimizing costs but are seldom used to incorporate socioeconomic costs in the reserve-design process. The sensitivity of this process to biodiversity data resolution has been studied widely but the issue of socioeconomic data resolution has not previously been considered. We therefore designed marine reserves for biodiversity conservation with the constraint of minimizing commercial fishing revenue losses and investigated how economic data resolution affected the results. Incorporating coarse-resolution economic data from official statistics generated reserves that were only marginally less costly to the fishery than those designed with no attempt to minimize economic impacts. An intensive survey yielded fine-resolution data that, when incorporated in the design process, substantially reduced predicted fishery losses. Such an approach could help minimize fisher displacement because the least profitable grounds are selected for the reserve. Other work has shown that low-resolution biodiversity data can lead to underestimation of the conservation value of some sites, and a risk of overlooking the most valuable areas, and we have similarly shown that low-resolution economic data can cause underestimation of the profitability of some sites and a risk of inadvertently including these in the reserve. Detailed socioeconomic data are therefore an essential input for the design of cost-effective reserve networks.

Some considerations on the design of population pharmacokinetic studies

The goal of this manuscript is to introduce a framework for consideration of designs for population pharmacokinetic orpharmacokinetic-pharmacodynamic studies. A standard one compartment pharmacokinetic model with first-order input and elimination is considered. A series of theoretical designs are considered that explore the influence of optimizing the allocation of sampling times, allocating patients to elementary designs, consideration of sparse sampling and unbalanced designs and also the influence of single vs. multiple dose designs. It was found that what appears to be relatively sparse sampling (less blood samples per patient than the number of fixed effects parameters to estimate) can also be highly informative. Overall, it is evident that exploring the population design space can yield many parsimonious designs that are efficient for parameter estimation and that may not otherwise have been considered without the aid of optimal design theory.

Prospective evaluation of a D-optimal designed population pharmacokinetic study

Recently, methods for computing D-optimal designs for population pharmacokinetic studies have become available. However there are few publications that have prospectively evaluated the benefits of D-optimality in population or single-subject settings. This study compared a population optimal design with an empirical design for estimating the base pharmacokinetic model for enoxaparin in a stratified randomized setting. The population pharmacokinetic D-optimal design for enoxaparin was estimated using the PFIM function (MATLAB version 6.0.0.88). The optimal design was based on a one-compartment model with lognormal between subject variability and proportional residual variability and consisted of a single design with three sampling windows (0-30 min, 1.5-5 hr and 11 - 12 hr post-dose) for all patients. The empirical design consisted of three sample time windows per patient from a total of nine windows that collectively represented the entire dose interval. Each patient was assigned to have one blood sample taken from three different windows. Windows for blood sampling times were also provided for the optimal design. Ninety six patients were recruited into the study who were currently receiving enoxaparin therapy. Patients were randomly assigned to either the optimal or empirical sampling design, stratified for body mass index. The exact times of blood samples and doses were recorded. Analysis was undertaken using NONMEM (version 5). The empirical design supported a one compartment linear model with additive residual error, while the optimal design supported a two compartment linear model with additive residual error as did the model derived from the full data set. A posterior predictive check was performed where the models arising from the empirical and optimal designs were used to predict into the full data set. This revealed the optimal'' design derived model was superior to the empirical design model in terms of precision and was similar to the model developed from the full dataset. This study suggests optimal design techniques may be useful, even when the optimized design was based on a model that was misspecified in terms of the structural and statistical models and when the implementation of the optimal designed study deviated from the nominal design.

Teleonomic entropy: measuring the phase-space of end-directed systems

We introduce a novel way of measuring the entropy of a set of values undergoing changes. Such a measure becomes useful when analyzing the temporal development of an algorithm designed to numerically update a collection of values such as artificial neural network weights undergoing adjustments during learning. We measure the entropy as a function of the phase-space of the values, i.e. their magnitude and velocity of change, using a method based on the abstract measure of entropy introduced by the philosopher Rudolf Carnap. By constructing a time-dynamic two-dimensional Voronoi diagram using Voronoi cell generators with coordinates of value- and value-velocity (change of magnitude), the entropy becomes a function of the cell areas. We term this measure teleonomic entropy since it can be used to describe changes in any end-directed (teleonomic) system. The usefulness of the method is illustrated when comparing the different approaches of two search algorithms, a learning artificial neural network and a population of discovering agents. (C) 2004 Elsevier Inc. All rights reserved.

Recommendations and guidelines for the performance of accurate heat transfer measurements in rapid forming processes

The published requirements for accurate measurement of heat transfer at the interface between two bodies have been reviewed. A strategy for reliable measurement has been established, based on the depth of the temperature sensors in the medium, on the inverse method parameters and on the time response of the sensors. Sources of both deterministic and stochastic errors have been investigated and a method to evaluate them has been proposed, with the help of a normalisation technique. The key normalisation variables are the duration of the heat input and the maximum heat flux density. An example of application of this technique in the field of high pressure die casting is demonstrated. The normalisation study, coupled with previous determination of the heat input duration, makes it possible to determine the optimum location for the sensors, along with an acceptable sampling rate and the thermocouples critical response-time (as well as eventual filter characteristics). Results from the gauge are used to assess the suitability of the initial design choices. In particular the unavoidable response time of the thermocouples is estimated by comparison with the normalised simulation. (c) 2006 Elsevier Ltd. All rights reserved.

Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients

Objective: The objective of the study was to characterise the population pharmacokinetic properties of itraconazole and its active metabolite hydroxyitraconazole in a representative paediatric population of cystic fibrosis and bone marrow transplant (BMT) patients and to identify patient characteristics influencing the pharmacokinetics of itraconazole. The ultimate goals were to determine the relative bioavailability between the two oral formulations (capsules vs oral solution) and to optimise dosing regimens in these patients. Methods: All paediatric patients with cystic fibrosis or patients undergoing BMT at The Royal Children's Hospital, Brisbane, QLD, Australia, who were prescribed oral itraconazole for the treatment of allergic bronchopulmonary aspergillosis (cystic fibrosis patients) or for prophylaxis of any fungal infection (BMT patients) were eligible for the study. Blood samples were taken from the recruited patients as per an empirical sampling design either during hospitalisation or during outpatient clinic visits. ltraconazole and hydroxy-itraconazole plasma concentrations were determined by a validated high-performance liquid chromatography assay with fluorometric detection. A nonlinear mixed-effect modelling approach using the NONMEM software to simultaneously describe the pharmacokinetics of itraconazole and its metabolite. Results: A one-compartment model with first-order absorption described the itraconazole data, and the metabolism of the parent drug to hydroxy-itraconazole was described by a first-order rate constant. The metabolite data also showed one-compartment characteristics with linear elimination. For itraconazole the apparent clearance (CLitraconazole) was 35.5 L/hour, the apparent volume of distribution (V-d(itraconazole)) was 672L, the absorption rate constant for the capsule formulation was 0.0901 h(-1) and for the oral solution formulation was 0.96 h-1. The lag time was estimated to be 19.1 minutes and the relative bioavailability between capsules and oral solution (F-rel) was 0.55. For the metabolite, volume of distribution, V-m/(F (.) f(m)), and clearance, CL/(F (.) fm), were 10.6L and 5.28 L/h, respectively. The influence of total bodyweight was significant, added as a covariate on CLitraconazoie/F and V-d(itraconazole)/F (standardised to a 70kg person) using allometric three-quarter power scaling on CLitraconazole/F, which therefore reflected adult values. The unexplained between-subject variability (coefficient of variation %) was 68.7%, 75.8%, 73.4% and 61.1% for CLitraconazoie/F, Vd(itraconazole)/F, CLm/(F (.) fm) and F-rel, respectively. The correlation between random effects of CLitraconazole and Vd((itraconazole)) was 0.69. Conclusion: The developed population pharmacokinetic model adequately described the pharmacokinetics of itraconazole and its active metabolite, hydroxy-itraconazole, in paediatric patients with either cystic fibrosis or undergoing BMT. More appropriate dosing schedules have been developed for the oral solution and the capsules to secure a minimum therapeutic trough plasma concentration of 0.5 mg/L for these patients.

Sustainable design practitioners: Why they must be at the centre of discussions on sustainable design education

Sustainable design education is vital for engineering students. This is to allow them to meet the challenges both engineering and the wider community will face in the future. This need has not only been mandated by Engineers Australia’s graduate attributes from an Australian perspective, but more widely the issue of sustainability is one of the greatest challenges humanity has ever faced. Engineers need to be at the forefront of this challenge, because we can not only do the greatest good, but have the potential to cause the greatest harm. The biggest question with respect to the education of engineers about sustainable design is what do engineers need to know, and how best to enable this learning. This paper argues that since the entire phenomenon of sustainable design is constantly growing and changing, it is only by looking at practitioners currently trying design sustainably, and their ways of experiencing sustainable design, can we hope to articulate what it is, and therefore what and how we need to teach engineering students. It also argues that to accommodate sustainable design within engineering, we need to go further and transform the engineering profession to enable it to meet the challenges that sustainability presents. © 2005, Australasian Association for Engineering Education

A D-optimal designed population pharmacokinetic study of itraconazole capsules and solution in adults with cystic fibrosis

Background: Oral itraconazole (ITRA) is used for the treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis (CF) because of its antifungal activity against Aspergillus species. ITRA has an active hydroxy-metabolite (OH-ITRA) which has similar antifungal activity. ITRA is a highly lipophilic drug which is available in two different oral formulations, a capsule and an oral solution. It is reported that the oral solution has a 60% higher relative bioavailability. The influence of altered gastric physiology associated with CF on the pharmacokinetics (PK) of ITRA and its metabolite has not been previously evaluated. Objectives: 1) To estimate the population (pop) PK parameters for ITRA and its active metabolite OH-ITRA including relative bioavailability of the parent after administration of the parent by both capsule and solution and 2) to assess the performance of the optimal design. Methods: The study was a cross-over design in which 30 patients received the capsule on the first occasion and 3 days later the solution formulation. The design was constrained to have a maximum of 4 blood samples per occasion for estimation of the popPK of both ITRA and OH-ITRA. The sampling times for the population model were optimized previously using POPT v.2.0.[1] POPT is a series of applications that run under MATLAB and provide an evaluation of the information matrix for a nonlinear mixed effects model given a particular design. In addition it can be used to optimize the design based on evaluation of the determinant of the information matrix. The model details for the design were based on prior information obtained from the literature, which suggested that ITRA may have either linear or non-linear elimination. The optimal sampling times were evaluated to provide information for both competing models for the parent and metabolite and for both capsule and solution simultaneously. Blood samples were assayed by validated HPLC.[2] PopPK modelling was performed using FOCE with interaction under NONMEM, version 5 (level 1.1; GloboMax LLC, Hanover, MD, USA). The PK of ITRA and OH‑ITRA was modelled simultaneously using ADVAN 5. Subsequently three methods were assessed for modelling concentrations less than the LOD (limit of detection). These methods (corresponding to methods 5, 6 & 4 from Beal[3], respectively) were (a) where all values less than LOD were assigned to half of LOD, (b) where the closest missing value that is less than LOD was assigned to half the LOD and all previous (if during absorption) or subsequent (if during elimination) missing samples were deleted, and (c) where the contribution of the expectation of each missing concentration to the likelihood is estimated. The LOD was 0.04 mg/L. The final model evaluation was performed via bootstrap with re-sampling and a visual predictive check. The optimal design and the sampling windows of the study were evaluated for execution errors and for agreement between the observed and predicted standard errors. Dosing regimens were simulated for the capsules and the oral solution to assess their ability to achieve ITRA target trough concentration (Cmin,ss of 0.5-2 mg/L) or a combined Cmin,ss for ITRA and OH-ITRA above 1.5mg/L. Results and Discussion: A total of 241 blood samples were collected and analysed, 94% of them were taken within the defined optimal sampling windows, of which 31% where taken within 5 min of the exact optimal times. Forty six per cent of the ITRA values and 28% of the OH-ITRA values were below LOD. The entire profile after administration of the capsule for five patients was below LOD and therefore the data from this occasion was omitted from estimation. A 2-compartment model with 1st order absorption and elimination best described ITRA PK, with 1st order metabolism of the parent to OH-ITRA. For ITRA the clearance (ClItra/F) was 31.5 L/h; apparent volumes of central and peripheral compartments were 56.7 L and 2090 L, respectively. Absorption rate constants for capsule (kacap) and solution (kasol) were 0.0315 h-1 and 0.125 h-1, respectively. Comparative bioavailability of the capsule was 0.82. There was no evidence of nonlinearity in the popPK of ITRA. No screened covariate significantly improved the fit to the data. The results of the parameter estimates from the final model were comparable between the different methods for accounting for missing data, (M4,5,6)[3] and provided similar parameter estimates. The prospective application of an optimal design was found to be successful. Due to the sampling windows, most of the samples could be collected within the daily hospital routine, but still at times that were near optimal for estimating the popPK parameters. The final model was one of the potential competing models considered in the original design. The asymptotic standard errors provided by NONMEM for the final model and empirical values from bootstrap were similar in magnitude to those predicted from the Fisher Information matrix associated with the D-optimal design. Simulations from the final model showed that the current dosing regimen of 200 mg twice daily (bd) would provide a target Cmin,ss (0.5-2 mg/L) for only 35% of patients when administered as the solution and 31% when administered as capsules. The optimal dosing schedule was 500mg bd for both formulations. The target success for this dosing regimen was 87% for the solution with an NNT=4 compared to capsules. This means, for every 4 patients treated with the solution one additional patient will achieve a target success compared to capsule but at an additional cost of AUD $220 per day. The therapeutic target however is still doubtful and potential risks of these dosing schedules need to be assessed on an individual basis. Conclusion: A model was developed which described the popPK of ITRA and its main active metabolite OH-ITRA in adult CF after administration of both capsule and solution. The relative bioavailability of ITRA from the capsule was 82% that of the solution, but considerably more variable. To incorporate missing data, using the simple Beal method 5 (using half LOD for all samples below LOD) provided comparable results to the more complex but theoretically better Beal method 4 (integration method). The optimal sparse design performed well for estimation of model parameters and provided a good fit to the data.