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PubMed2005

An evaluation of an optimal sampling strategy for meropenem in febrile neutropenics.

Optimal sampling design with nonparametric population modeling offers the opportunity to determine pharmacokinetic parameters for patients in whom blood sampling is restricted. This approach was compared to a standard individualized modeling method for meropenem pharmacokinetics in febrile neutropenic patients. The population modeling program, nonparametric approach of expectation maximization (NPEM), with a full data set was compared to a sparse data set selected by D-optimal sampling design. The authors demonstrated that the D-optimal sampling strategy, when applied to this clinical population, provided good pharmacokinetic parameter estimates along with their variability. Four individualized and optimally selected sampling time points provided the same parameter estimates as more intensive sampling regimens using traditional and population modeling techniques. The different modeling methods were considerably consistent, except for the estimation of CL(d) with sparse sampling. The findings suggest that D-optimal sparse sampling is a reasonable approach to population pharmacokinetic/pharmacodynamic studies during drug development when limited sampling is necessary.

Anti-Bacterial Agents↗

PubMed2002

Positive parenting and child psychosocial adjustment in inner-city single-parent African American families. The role of maternal optimism.

The primary purposes of this study were to examine whether maternal optimism is related to positive parenting and child adjustment and whether it contributes beyond maternal depressive symptoms to our understanding. The participants were 141 African American single mothers and one of their children. Findings revealed that maternal optimism was associated with positive parenting and this association was only partially mediated by maternal depressive symptoms. Maternal optimism was not associated with child psychosocial adjustment, but positive parenting was associated with lower levels of both internalizing and externalizing difficulties. The utility of understanding the link between maternal optimism and parenting for prevention and intervention efforts aimed at enhancing quality of life and subsequent child adjustment is discussed, as well as directions for future research on maternal optimism.

Adaptation, Psychological↗

PubMed2005

Software for optimization of SNP and PCR-RFLP genotyping to discriminate many genomes with the fewest assays.

BACKGROUND: Microbial forensics is important in tracking the source of a pathogen, whether the disease is a naturally occurring outbreak or part of a criminal investigation. RESULTS: A method and SPR Opt (SNP and PCR-RFLP Optimization) software to perform a comprehensive, whole-genome analysis to forensically discriminate multiple sequences is presented. Tools for the optimization of forensic typing using Single Nucleotide Polymorphism (SNP) and PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) analyses across multiple isolate sequences of a species are described. The PCR-RFLP analysis includes prediction and selection of optimal primers and restriction enzymes to enable maximum isolate discrimination based on sequence information. SPR Opt calculates all SNP or PCR-RFLP variations present in the sequences, groups them into haplotypes according to their co-segregation across those sequences, and performs combinatoric analyses to determine which sets of haplotypes provide maximal discrimination among all the input sequences. Those set combinations requiring that membership in the fewest haplotypes be queried (i.e. the fewest assays be performed) are found. These analyses highlight variable regions based on existing sequence data. These markers may be heterogeneous among unsequenced isolates as well, and thus may be useful for characterizing the relationships among unsequenced as well as sequenced isolates. The predictions are multi-locus. Analyses of mumps and SARS viruses are summarized. Phylogenetic trees created based on SNPs, PCR-RFLPs, and full genomes are compared for SARS virus, illustrating that purported phylogenies based only on SNP or PCR-RFLP variations do not match those based on multiple sequence alignment of the full genomes. CONCLUSION: This is the first software to optimize the selection of forensic markers to maximize information gained from the fewest assays, accepting whole or partial genome sequence data as input. As more sequence data becomes available for multiple strains and isolates of a species, automated, computational approaches such as those described here will be essential to make sense of large amounts of information, and to guide and optimize efforts in the laboratory. The software and source code for SPR Opt is publicly available and free for non-profit use at http://www.llnl.gov/IPandC/technology/software/softwaretitles/spropt.php.

Cluster Analysis↗

PubMed2005

Optimization of the Lactococcus lactis nisin-controlled gene expression system NICE for industrial applications.

BACKGROUND: The nisin-controlled gene expression system NICE of Lactococcus lactis is one of the most widely used expression systems in Gram-positive bacteria. Despite its widespread use, no optimization of the culture conditions and nisin induction has been carried out to obtain maximum yields. As a model system induced production of lysostaphin, an antibacterial protein (mainly against Staphylococcus aureus) produced by S. simulans biovar. Staphylolyticus, was used. Three main areas need optimization for maximum yields: cell density, nisin-controlled induction and protein production, and parameters specific for the target-protein. RESULTS: In a series of pH-controlled fermentations the following parameters were optimized: pH of the culture, use of NaOH or NH4OH as neutralizing agent, the addition of zinc and phosphate, the fermentation temperature, the time point of induction (cell density of the culture), the amount of nisin added for induction and the amount of three basic medium components, i.e. yeast extract, peptone and lactose. For each culture growth and lysostaphin production was followed. Lysostaphin production yields depended on all parameters that were varied. In the course of the optimization a three-fold increase in lysostaphin yield was achieved from 100 mg/l to 300 mg/l. CONCLUSION: Protein production with the NICE gene expression system in L. lactis strongly depends on the medium composition, the fermentation parameters and the amount of nisin added for induction. Careful optimization of key parameters lead to a significant increase in the yield of the target protein.

Journal Article↗

PubMed2005

Meta-analysis of hemodynamic optimization: relationship to methodological quality.

INTRODUCTION: To review systematically the effect of interventions aimed at hemodynamic optimization and to relate this to the quality of individual published trials. METHODS: A systematic, computerized bibliographic search of published studies and citation reviews of relevant studies was performed. All randomized clinical trials in which adult patients were included in a trial deliberately aiming at an optimized or maximized hemodynamic condition of the patients (with oxygen delivery, cardiac index, oxygen consumption, mixed venous oxygen saturation and/or stroke volume as end-points) were selected. A total of 30 studies were selected for independent review. Two reviewers extracted data on population, intervention, outcome and methodological quality. Agreement between reviewers was high: differences were eventually resolved by third-party decision. The methodological quality of the studies was moderate (mean 9.0, SD 1.7), and the outcomes of the randomized clinical trials were not related to their quality. RESULTS: Efforts to achieve an optimized hemodynamic condition resulted in a decreased mortality rate (relative risk ratio (RR) 0.75 (95% confidence interval (CI) 0.62 to 0.90) in all studies combined. This was due to a significantly decreased mortality in peri-operative intervention studies (RR 0.66 (95% CI 0.54 to 0.81). Overall, patients with sepsis and overt organ failure do not benefit from this method (RR 0.92 (95% CI 0.75 to 1.11)). CONCLUSION: This systematic review showed that interventions aimed at hemodynamic optimization reduced mortality. In particular, trials including peri-operative interventions aimed at the hemodynamic optimization of high-risk surgical patients reduce mortality. Overall, this effect was not related to the trial quality.

Critical Care↗

PubMed2005

New trends in astrodynamics and applications: optimal trajectories for space guidance.

This paper represents recent results on the development of optimal analytic solutions to the variation problem of trajectory optimization and their application in the construction of on-board guidance laws. The importance of employing the analytically integrated trajectories in a mission design is discussed. It is assumed that the spacecraft is equipped with a power-limited propulsion and moving in a central Newtonian field. Satisfaction of the necessary and sufficient conditions for optimality of trajectories is analyzed. All possible thrust arcs and corresponding classes of the analytical solutions are classified based on the propulsion system parameters and performance index of the problem. The solutions are presented in a form convenient for applications in escape, capture, and interorbital transfer problems. Optimal guidance and neighboring optimal guidance problems are considered. It is shown that the analytic solutions can be used as reference trajectories in constructing the guidance algorithms for the maneuver problems mentioned above. An illustrative example of a spiral trajectory that terminates on a given elliptical parking orbit is discussed.

Journal Article↗

PubMed2006

Optimal strategy for cardiopulmonary resuscitation with continuous chest compression.

OBJECTIVES: To apply the mathematical techniques of optimal control theory (OCT) to a validated model of the human circulation during cardiopulmonary resuscitation (CPR), so as to discover improved waveforms for chest compression and decompression that maximize the coronary perfusion pressure (CPP). METHODS: The human circulatory system is represented by seven difference equations that describe the pressure changes in systemic vascular compartments that are caused by chest compression. The forcing term is the intrathoracic pressure that is generated by the external chest compression, which is taken as the control variable for the system. The optimum waveform of this forcing pressure as a function of time, determined from OCT, is that which maximizes the calculated CPP between the thoracic aorta and the superior vena cava over a period of 13.3 seconds of continuous chest compression. RESULTS: The optimal waveform included both compression and decompression of the chest to the maximum allowable extent. Compression-decompression waveforms were rectangular in shape. The frequency of optimal compression-decompression that was found by OCT was 90 per minute. The optimal duty cycle (compression duration per cycle time) was 40%. The CPP for the optimum control waveform was 36 mm Hg vs. 25 mm Hg for standard CPR. CONCLUSIONS: Optimal control theory suggests that both compression and decompression of the chest are needed for best hemodynamics during CPR.

Cardiopulmonary Resuscitation↗

PubMed1992

The optimal timing of autologous bone marrow transplantation in Hodgkin's disease patients after a chemotherapy relapse.

PURPOSE: The optimal sequence of salvage chemotherapy (SC) and autologous bone marrow transplantation (ABMT) for Hodgkin's disease (HD) patients who relapse after primary chemotherapy is unknown. We created a decision analysis model to determine the optimal treatment strategy and the most cost-effective approach. METHODS: The decision tree simulated a 25-year-old HD patient who relapsed less than 12 months after mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy. Four strategies used ABMT in some sequence with SC; the final strategy considered SC alone. Clinical data were derived from 17 published reports chosen by explicit criteria. Costs of care were estimated from the published literature and institutional experience. RESULTS: The optimal strategy was ABMT in second relapse, which was superior to the SC-only option by 1.9 years at an incremental cost of $26,200 per each year of life saved. When the probabilities of complete remission and disease-free survival were reduced for SC, similar to the clinical expectation of SC after a seven- or eight-drug regimen like MOPP/doxorubicin, bleomycin, and vinblastine with or without dacarbazine (MOPP/ABV[D]), ABMT in first relapse was the preferred strategy and provided 6 additional months. However, when the data from favorable (or unfavorable) SC and ABMT reports were compared head-to-head in this model, SC followed by ABMT in second relapse was always optimal. CONCLUSIONS: All relapsed HD patients should plan to use ABMT in some sequence with SC, if necessary. In most situations the optimal strategy is ABMT in second relapse. This analysis will assist clinicians in planning treatment for relapsed HD patients. It could be refined if historical series were updated to report the incidence and outcomes of SC relapse from seven- or eight-drug regimens.

Adult↗

PubMed2002

Breathing easy: a prospective study of optimism and pulmonary function in the normative aging study.

Although there is good evidence that emotions are associated with chronic airways obstruction, evidence for the influence of psychological factors on the level and decline of pulmonary function is sparse. Optimism has been linked to enhanced well-being, whereas pessimism has been identified as a risk factor for poor physical health. This investigation examines prospectively the effects of optimism versus pessimism on pulmonary function. Data are from the Veterans Administration Normative Aging Study, an ongoing cohort of older men. In 1986, 670 men completed the revised Minnesota Multiphasic Personality Inventory from which we derived the bipolar Revised Optimism-Pessimism Scale. During an average of 8 years of follow-up, an average of 3 pulmonary function exams were obtained. Men with a more optimistic explanatory style had significantly higher levels of forced expiratory volume in 1 sec (FEV1) and forced vital capacity (both p < .01). Interactions between time and optimism suggested that rate of decline in FEV1 over time was slower in men with a more optimistic explanatory style relative to men who were more pessimistic. These data are the first to link optimism with higher levels of pulmonary function and slower rate of pulmonary function decline in older men, a protective effect that is independent of smoking.

Adult↗

PubMed2005

A strategy for optimizing and evaluating behavioral interventions.

BACKGROUND: Although the optimization of behavioral interventions offers the potential of both public health and research benefits, currently there is no widely agreed-upon principled procedure for accomplishing this. PURPOSE: This article suggests a multiphase optimization strategy (MOST) for achieving the dual goals of program optimization and program evaluation in the behavioral intervention field. METHODS: MOST consists of the following three phases: (a) screening, in which randomized experimentation closely guided by theory is used to assess an array of program and/or delivery components and select the components that merit further investigation; (b) refining, in which interactions among the identified set of components and their interrelationships with covariates are investigated in detail, again via randomized experiments, and optimal dosage levels and combinations of components are identified; and (c) confirming, in which the resulting optimized intervention is evaluated by means of a standard randomized intervention trial. To make the best use of available resources, MOST relies on design and analysis tools that help maximize efficiency, such as fractional factorials. RESULTS: A slightly modified version of an actual application of MOST to develop a smoking cessation intervention is used to develop and present the ideas. CONCLUSIONS: MOST has the potential to husband program development resources while increasing our understanding of the individual program and delivery components that make up interventions. Considerations, challenges, open questions, and other potential benefits are discussed.

Behavior Therapy↗

PubMed1997

Stability of a Q-sort model of optimal mental health.

This study explores clinicians' conceptions of optimal mental health as a function of target age and asks whether contemporary conceptions of optimal mental health differ from Block's (1961) earlier Q-sort model. Ten experienced clinicians from Northwestern University described the personality characteristics of optimally adjusted 25- and 50-year-old targets using the California Q-set. Item scores from these Q-sorts were aggregated to form 25-year-old, 50-year-old, and composite templates of optimal mental health. Using the Spearman-Brown formula, the reliability of the 10-judge composite was .97. The 3 templates were very highly correlated with each other and with Block's original template. Q-sort descriptions of optimal mental health are remarkably stable over 2 generations of clinicians and between young adulthood and mid-life.

Adaptation, Psychological↗

PubMed2006

Dispositional optimism and coping: a meta-analytic review.

The relation between dispositional optimism and better adjustment to diverse stressors may be attributable to optimism's effects on coping strategies. A meta-analytic review (K = 50, N = 11,629) examined the impact of dispositional optimism on coping. Dispositional optimism was found to be positively associated with approach coping strategies aiming to eliminate, reduce, or manage stressors or emotions (r = .17), and negatively associated with avoidance coping strategies seeking to ignore, avoid, or withdraw from stressors or emotions (r = -.21). Effect sizes were larger for the distinction between approach and avoidance coping strategies than for that between problem and emotion-focused coping. Meta-analytic findings also indicate that optimists may adjust their coping strategies to meet the demands of the stressors at hand, and that the optimism-coping relationship is strongest in English-speaking samples.

Adaptation, Psychological↗

PubMed2002

A statistical technique for the development of an alternate list when using constrained optimization to make admission decisions.

BACKGROUND: In an earlier study it was demonstrated that constrained optimization could be used to accurately translate admission goals. Constrained optimization differs from weighting equations in that it does not assign a rank ordering. Although constrained optimization is conceptually superior, some procedures within the admissions process require a rank ordering of applicants. PURPOSE: The purpose of this study is to describes and evaluate the use of two discriminant analysis procedures to obtain a rank order list by generating weights that model constrained optimization procedures. This study also evaluates the usefulness of an additional method that does not require a rank ordering. METHODS: Premium Solver selected a class from the 1998/99 applicant pool. A discriminant analysis was used to generate a discriminant function for modeling the dichotomous group classification selection variable. These weights were then applied and the discriminant function values calculated. The success of the procedure was evaluated by examining rank orders and the magnitude of the correlation and R-square statistic. RESULTS: Discriminant analysis accounted for 70% of the decision variance generated by the constrained optimization procedure. Using real data allowed an estimate of the number of students impacted by inconsistent outcomes. CONCLUSION: Discriminant analysis could be used to manage an alternate list, however it will be based on somewhat different criteria than the initial selection procedure. Each method evaluated has advantages and disadvantages and the selection of one method over another depends on what outcomes are most valued by the college.

Discriminant Analysis↗

PubMed2001

Statistical optimization of gastric floating system for oral controlled delivery of calcium.

The development of an optimized gastric floating drug delivery system is described. Statistical experimental design and data analysis using response surface methodology is also illustrated. A central, composite Box-Wilson design for the controlled release of calcium was used with 3 formulation variables: X1 (hydroxypropyl methylcellulose [HPMC] loading), X2 (citric acid loading), and X3 (magnesium stearate loading). Twenty formulations were prepared, and dissolution studies and floating kinetics were performed on these formulations. The dissolution data obtained were then fitted to the Power Law, and floating profiles were analyzed. Diffusion exponents obtained by Power Law were used as targeted response variables, and the constraints were placed on other response variables. All 3 formulation variables were found to be significant for the release properties (P <.05), while only HPMC loading was found to be significant for floating properties. Optimization of the formulations was achieved by applying the constrained optimization. The optimized formulation delivered calcium at the release rate of 40 mg/hr, with predicted n and T50% values at 0.93 and 3.29 hours, respectively. Experimentally, calcium was observed to release from the optimized formulation with n and T50% values of 0.89 (+/- 0.10) and 3.20 (+/- 0.21) hours, which showed an excellent agreement. The quadratic mathematical model developed could be used to further predict formulations with desirable release and floating properties.

Administration, Oral↗

PubMed2002

Response surface methodology for the optimization of ubiquinone self-nanoemulsified drug delivery system.

The aim of the present study was to prepare and evaluate an optimized, self-nanoemulsified drug delivery system of ubiquinone. A 3-factor, 3-level Box-Behnken design was used for the optimization procedure with the amounts of Polyoxyl 35 castor oil (X1), medium-chain mono- and diglyceride (X2), and lemon oil (X3) as the independent variables. The response variable was the cumulative percentage of ubiquinone emulsified in 10 minutes. Different ubiquinone release rates were obtained. The amount released ranged from 11% to 102.3%. Turbidity profile revealed 3 regions that were used to describe the progress of emulsion formation: lag phase, pseudolinear phase, and plateau turbidity. An increase in the amount of surfactant decreased turbidity values and caused a delay in lag time. Addition of cosurfactant enhanced the release rates. Increasing the amount of the eutectic agent was necessary to overcome drug precipitation especially at higher loading of surfactants and cosurfactants. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the cumulative percentage emulsified in 10 minutes was Y1 = 90.9 - 22.1X1 + 5.03X2 + 13.95X3 + 12.13X1X2 + 15.13X1X3 - 14.40X1(2) - 6.25X3(2). The optimization model predicted a 93.4% release with X1, X2, and X3 levels of 35, 35, and 30 respectively. The observed responses were in close agreement with the predicted values of the optimized formulation. This demonstrated the reliability of the optimization procedure in predicting the dissolution behavior of a self-emulsified drug delivery system.

Castor Oil↗

PubMed2003

Artificial neural networks in the modeling and optimization of aspirin extended release tablets with Eudragit L 100 as matrix substance.

The purpose of the present study was to model the effects of the concentration of Eudragit L 100 and compression pressure as the most important process and formulation variables on the in vitro release profile of aspirin from matrix tablets formulated with Eudragit L 100 as matrix substance and to optimize the formulation by artificial neural network. As model formulations, 10 kinds of aspirin matrix tablets were prepared. The amount of Eudragit L 100 and the compression pressure were selected as causal factors. In vitro dissolution time profiles at 4 different sampling times were chosen as responses. A set of release parameters and causal factors were used as tutorial data for the generalized regression neural network (GRNN) and analyzed using a computer. Observed results of drug release studies indicate that drug release rates vary widely between investigated formulations, with a range of 5 hours to more than 10 hours to complete dissolution. The GRNN model was optimized. The root mean square value for the trained network was 1.12%, which indicated that the optimal GRNN model was reached. Applying the generalized distance function method, the optimal tablet formulation predicted by GRNN was with 5% of Eudragit L 100 and tablet hardness 60N. Calculated difference (f1 2.465) and similarity (f2 85.61) factors indicate that there is no difference between predicted and experimentally observed drug release profiles for the optimal formulation. This work illustrates the potential for an artificial neural network, GRNN, to assist in development of extended release dosage forms.

Aspirin↗

PubMed2004

Artificial neural network as an alternative to multiple regression analysis in optimizing formulation parameters of cytarabine liposomes.

The objective of the study was to optimize the formulation parameters of cytarabine liposomes by using artificial neural networks (ANN) and multiple regression analysis using 3(3) factorial design (FD). As model formulations, 27 formulations were prepared. The formulation variables, drug (cytarabine)/lipid (phosphatidyl choline [PC] and cholesterol [Chol]) molar ratio (X1), PC/Chol in percentage ratio of total lipids (X2), and the volume of hydration medium (X3) were selected as the independent variables; and the percentage drug entrapment (PDE) was selected as the dependent variable. A set of causal factors was used as tutorial data for ANN and fed into a computer. The optimization was performed by minimizing the generalized distance between the predicted values of each response and the optimized one that was obtained individually. In case of 3(3) factorial design, a second-order full-model polynomial equation and a reduced model were established by subjecting the transformed values of independent variables to multiple regression analysis, and contour plots were drawn using the equation. The optimization methods developed by both ANN and FD were validated by preparing another 5 liposomal formulations. The predetermined PDE and the experimental data were compared with predicted data by paired t test, no statistically significant difference was observed. ANN showed less error compared with multiple regression analysis. These findings demonstrate that ANN provides more accurate prediction and is quite useful in the optimization of pharmaceutical formulations when compared with the multiple regression analysis method.

Artificial Intelligence↗

PubMed2006

Constrained optimization in human running.

Walking humans spontaneously select different speed, frequency and step length combinations, depending on which of these three parameters is specified. This behavior can be explained by constrained optimization of cost of transport (metabolic cost/distance) where cost of transport is seen as the main component of an underlying objective function that is minimized within the limitations of specified constraints. It is then of interest to ask whether or not such results are specific to walking only, or indicate a more general feature of locomotion control. The current study examines running gait selection within the framework of constrained optimization by comparing self-selected running gaits to the gaits predicted by constrained optimization of a cost surface constructed from cost data available in the literature. Normalizing speed and frequency values in the behavioral data by preferred speed and frequency reduced inter-subject variability and made group behavioral trends more visible. Although actual behavior did not coincide exactly with running cost optimization, self-selected gait and predictions from the general human cost surface did agree to within the 95% confidence interval and the region of minimal cost+0.005 ml O2 kg(-1) m(-1). This was similar to the level of agreement between actual and predicted behavior observed in walking. Thus, there seems to be substantial evidence to suggest that (i) selection of gait parameters in running can largely be predicted using constrained optimization, and (ii) general cost surfaces can be constructed using metabolic data from one group that will largely predict the behavior of other groups.

Adult↗