Bayesian data assimilation to support informed decision-making in individualized chemotherapy

An essential component of therapeutic drug/biomarker monitoring (TDM) is to combine patient data with prior knowledge for model-based predictions of therapy outcomes. Current Bayesian forecasting tools typically rely only on the most probable model parameters (maximum a-posteriori (MAP) estimate). This MAP-based approach, however, does neither necessarily predict the most probable outcome nor does it quantify the risks of treatment inefficacy or toxicity. Bayesian data assimilation (DA) methods overcome these limitations by providing a comprehensive uncertainty quantification. We compare DA methods with MAP-based approaches and show how probabilistic statements about key markers related to chemotherapy-induced neutropenia can be leveraged for more informative decision support in individualized chemotherapy. Sequential Bayesian DA proved to be most computational efficient for handling interoccasion variability and integrating TDM data. For new digital monitoring devices enabling more frequent data collection, these features will be of critical importance to improve patient care decisions in various therapeutic areas

On the distribution function of the information speed in computer network

We review a study of the Internet traffic properties. We analyze under what conditions the reported results could be reproduced. Relations of results of passive measurements and those of modelling are also discussed. An example of the first-order phase transitions in the Internet traffic is presented.Comment: cpcauth.cls included, 6 pages, 3 eps figures, Proceeding CCP 2001 Aachen, to appear in Comp. Phys. Com

Translational Pharmacometric Evaluation of Typical Antibiotic Broad-Spectrum Combination Therapies Against Staphylococcus Aureus Exploiting In Vitro Information

Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK-PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK-PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN-MER might be favorable over LZD-MER due to an unfavorable antagonistic interaction between LZD and MER

A Microscopic Model for Packet Transport in the Internet

A microscopic description of packet transport in the Internet by using a simple cellular automaton model is presented. A generalised exclusion process is introduced which allows to study travel times of the particles ('data packets') along a fixed path in the network. Computer simulations reveal the appearance of a free flow and a jammed phase separated by a (critical) transition regime. The power spectra are compared to empirical data for the RTT (Round Trip Time) obtained from measurements in the Internet. We find that the model is able to reproduce the characteristic statistical behaviour in agreement with the empirical data for both phases (free flow and congested). The phases are therefore jamming properties and not related to the structure of the network. Moreover the model shows, as observed in reality, critical behaviour (1/f-noise) for paths with critical load.Comment: 9 pages, 7 figure

Quantitative analysis of chromatin compaction in living cells using FLIM-FRET

FRET analysis of cell lines expressing fluorescently tagged histones on separate nucleosomes demonstrates that variations in chromosome compaction occur during mitosis

The Essential Spectral Radius and Asymptotic Properties of Transfer Operators

Abs t r ac t The statistical behavior of deterministic and stochastic dynamical sys-tems may be described using transfer operators, which generalize the no-tion of Frobenius-Perron and Koopman operators. Since numerical tech-niques to analyse dynamical systems based on eigenvalues problems for the corresponding transfer operator have emerged, bounds on its essential spectral radius became of interest. This article shows that they are also of great theoretical interest. We give an analytical representation of the essential spectral radius in L\fj,), which then is exploited to analyse the asymptotical properties of transfer operators by combining results from functional analysis, Markov operators and Markov chain theory. In par ticular, it is shown that an essential spectral radius less than 1, uniform constrictiveness and some "weak form " of the so-called Doeblin condition are equivalent. Finally, we apply the results to study three main prob-lem classes: deterministic systems stochastically perturbed deterministic systems and stochastic systems K e y w o r d s, uniformly constrictive, asymptotically stable, exact, asymptotically pe

Self-monitoring : an efficient and effective intervention for academic and behavioral targets in the school

This research paper will review current research concerning the use of self-monitoring as an intervention technique for academic and behavioral targets in the school. The history and theory will be described, as well as the elements and implementation of self-monitoring as an intervention technique. Classroom applications with academic and behavioral targets are reviewed, as well as caveats on the use of self-monitoring as a classroom intervention technique. Recommendations concerning the need for additional research on the applicability of self-monitoring as an intervention technique are also described

A prospective observational study

Background: Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application. Methods: A prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100%T>MIC, 50%T>4×MIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non- attainment. Results: Large inter- and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100%T>MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50%T>4×MIC. A hyperbolic relationship between CLCRCG (25–255 ml/ minute) and meropenem serum concentrations at the end of the dosing interval (C8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non- attainment (for MIC 8 mg/L, additionally, moderate renal impairment). Conclusions: The investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy- and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed

Investigation of the Interactions of Cationic Polyelectrolytes with Anionic Surfactants: Effects of Polymer, Surfactant and Solution Properties

The intent of this research is to explore and understand the effects that a range of polymer, surfactant and solution parameters have on the interaction of oppositely-charged polymers and surfactants. Cationic polysaccharides were chosen for this research because they are known to interact with anionic surfactants, and they offer a wide range of adjustable polymer properties, including molecular weight, charge substitution, and backbone structure. Cationic poly(vinylpyridinium hydrochloride) polymers were chosen for these studies because they provide the opportunity to explore the effects of charge position on the interaction of cationic polymers with anionic surfactants and how this influences the mechanism of interaction. The overall goal of this research is to define the effects of polymer and surfactant structural properties, and solution properties, on the interaction between cationic polymers and anionic surfactants, and the subsequent formation of coacervate in these systems. The interaction of cationic polymers with varying properties with anionic surfactant was studied using conventional microscopic and macroscopic methodologies to probe the mechanism of interaction in these systems. Polyquaternium-10 systems interacted with anionic surfactant in accordance with the cooperative mechanism of interaction and coacervate formation as described by Goddard. The mechanism of interaction between poly(vinylpyridinium hydrochloride) polymers and anionic surfactant was found to be dependent on the position of the cationic charge relative to the hydrophobic polymer backbone. Polymer-surfactant interaction with poly(4- vinylpyridinium hydrochloride) and anionic surfactant occurred via the site-specific cooperative mechanism of interaction. However, the interaction of poly(2- vinylpyridinium hydrochloride) with anionic surfactant exhibited characteristics of the site-specific cooperative interaction mechanism as well as the macroion-macroion interaction mechanism. A high-throughput screening method was developed to facilitate systematic studies of the effects of polymer, surfactant and solution properties on the macroscopic property of coacervate formation. This method allowed rapid and reproducible preparation and analysis of multi-component systems and representation of the amount of coacervate and compositional range of coacervate formation in these systems in easily understood contour phase diagrams. In the cationic polysaccharide systems, the amount of coacervate and the compositional range of coacervate formation displayed a dependence on both the polymer charge density and molecular weight. Also, the polymer critical overlap concentration was observed to affect coacervate amount with higher coacervate formation observed above c*. Coacervate formation with the poly(vinylpyridinium hydrochloride) polymers was found to be dependent not only on the position of the cationic charge on the polymer, but also on the structure of the surfactant tail group. Coacervate formed initially with P4VP and P2 VP and sodium capryl sulfonate and sodium xylene sulfonate was not stable over 24 hours, however coacervate formed between these polymers and sodium dodecylbenzene sulfonate was stable over 24 hours. This indicates that a hydrophobic chain with sufficient length and/or an aromatic group is necessary to form thermodynamically stable coacervate. The effect of salt in solution on polymer-surfactant interaction was studied with both classes of polymer. A dependence of coacervate amount and compositional range of coacervate formation on salt concentration was observed. The effect of salt was dependent on the degree of polymer charge substitution. The order of addition of polymer, surfactant, and salt also affected coacervate formation. This was consistent for both low and high molecular weight polymers, as well as low and high charge substituted polymers. Although an effect of addition order was observed in all systems, the specific effects differed depending on the polymer properties

Augmented reality reading support in higher education: Exploring effects on perceived motivation and confidence in comprehension for struggling readers in higher education

Technology has shown promise to aid struggling readers in higher education, particularly through new and emerging technologies. Augmented reality (AR) has been used successfully in the classroom to motivate and engage struggling learners, yet little research exists on how augmented print might help struggling readers. This study explores this gap, specifically art/design students in higher education and their perceived motivation to read, as well as their engagement with, and comprehension of an augmented design theory text. This study employed an exploratory, mixed methods design. Analysis of the findings indicates most students, including self-identified struggling and typical readers, would use AR support for other text if provided. Results highlight the potential for using AR on text to provide reading support and the need for additional research on its implementation and impact