Population pharmacokinetics: model-free approach and nonlinear mixed-effects modelling

The work is devoted to the application and further development of modern statistical methods to study pharmacokinetics of drugs. Specifically, it deals with applications and development of repeated measures analysis, so called 'population approach' methods, in the field of pharmacokinetics. hi the first part of the thesis, a new, model-free approach is developed and tested. It introduces a model-free measure of patient's exposure to drugs, and then investigates the relationships between the exposure level and covariates using various statistical techniques. Classification tree models (CART) and regression analysis are used to study various subpopulations of interest. It is shown, via simulations, that the model-free method is capable to identify predictors of exposure in a wide range of variability in the data. The non-linear mixed effect modelling is used to confirm the results of the model-free investigation. Model-free approach is successfully applied to several drugs. Non-linear Mixed Effects population models developed for the same data agree with its results. Limits of the new method are also identified. Specifically, it does not allow the estimation of the variability: either the within-subject (intra-individual) variability in response, or between-subject (inter-individual) variability of the pharmacokinetic parameters in the population. The second part of the thesis is devoted to applications of the Non-linear Mixed Effect methodology to population pharmacokinetics and dose-response analysis. Population pharmacokinetic and dose-response models of several drugs are developed. Pharmacokinetic models allow for complete characterisation of the drug's pharmacokinetics and its relationships to safety and efficacy. The developed models are used to explore the relationships between the exposure (individual Bayes estimates) and demographic predictors of exposure, and safety and efficacy of the drug. Finally, the developed models are used in simulations to guide the design of new studies

Bacteria Use Type IV Pili to Walk Upright and Detach from Surfaces

1. Department of Bioengineering, California Nano Systems Institute,University of California, Los Angeles, CA 90024, USA. 2. Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA. 3. Department of Materials Science and Engineering, University of Illinois, Urbana-Champaign, IL 61801, USA. 4. Department of Civil Engineering and Geological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA.Bacterial biofilms are structured multicellular communities involved in a broad range of infections. Knowing how free-swimming bacteria adapt their motility mechanisms near surfaces is crucial for understanding the transition between planktonic and biofilm phenotypes. By translating microscopy movies into searchable databases of bacterial behavior, we identified fundamental type IV pili–driven mechanisms for Pseudomonas aeruginosa surface motility involved in distinct foraging strategies. Bacteria stood upright and “walked” with trajectories optimized for two-dimensional surface exploration. Vertical orientation facilitated surface detachment and could influence biofilm morphology.Center for Nonlinear Dynamic

Cool Companions to White Dwarf Stars from the Two Micron All Sky Survey All Sky Data Release

We present the culmination of our near-infrared survey of the optically spectroscopically identified white dwarf stars from the McCook and Sion catalog, conducted using photometric data from the Two Micron All Sky Survey final All Sky Data Release. The color selection technique, which identifies candidate binaries containing a white dwarf and a low-mass stellar (or substellar) companion via their distinctive locus in the near-infrared color-color diagram, is demonstrated to be simple to apply and to yield candidates with a high rate of subsequent confirmation. We recover 105 confirmed binaries, and identify 27 firm candidates (19 of which are new to this work) and 21 tentative candidates (17 of which are new to this work) from the 2MASS data. Only a small number of candidates from our survey have likely companion spectral types later than M5, none of which is an obvious L-type (i.e., potential brown dwarf) companion. Only one previously known white dwarf + brown dwarf binary is detected. This result is discussed in the context of the 2MASS detection limits, as well as other recent observational surveys that suggest a very low rate of formation (or survival) for binary stars with extreme mass ratios

Convolutional Recurrent Neural Networks for Small-Footprint Keyword Spotting

Keyword spotting (KWS) constitutes a major component of human-technology interfaces. Maximizing the detection accuracy at a low false alarm (FA) rate, while minimizing the footprint size, latency and complexity are the goals for KWS. Towards achieving them, we study Convolutional Recurrent Neural Networks (CRNNs). Inspired by large-scale state-of-the-art speech recognition systems, we combine the strengths of convolutional layers and recurrent layers to exploit local structure and long-range context. We analyze the effect of architecture parameters, and propose training strategies to improve performance. With only ~230k parameters, our CRNN model yields acceptably low latency, and achieves 97.71% accuracy at 0.5 FA/hour for 5 dB signal-to-noise ratio.Comment: Accepted to Interspeech 201

Design of three dimensional isotropic microstructures for maximized stiffness and conductivity

The level-set method of topology optimization is used to design isotropic two-phase periodic multifunctional composites in three dimensions. One phase is stiff and insulating whereas the other is conductive and mechanically compliant. The optimization objective is to maximize a linear combination of the effective bulk modulus and conductivity of the composite. Composites with the Schwartz primitive and diamond minimal surfaces as the phase interface have been shown to have maximal bulk modulus and conductivity. Since these composites are not elastically isotropic their stiffness under uniaxial loading varies with the direction of the load. An isotropic composite is presented with similar conductivity which is at least 23% stiffer under uniaxial loading than the Schwartz structures when loaded uniaxially along their weakest direction. Other new near-optimal isotropic composites are presented, proving the capablities of the level-set method for microstructure design.Comment: 25 pages, 11 figures, to be submitted to International Journal of Solids and Structure