Orthotropic active strain models for the numerical simulation of cardiac biomechanics

An active strain formulation for orthotropic constitutive laws arising in cardiac mechanics modeling is introduced and studied. The passive mechanical properties of the tissue are described by the Holzapfel-Ogden relation. In the active strain formulation, the Euler-Lagrange equations for minimizing the total energy are written in terms of active and passive deformation factors, where the active part is assumed to depend, at the cell level, on the electrodynamics and on the specific orientation of the cardiac cells. The well-posedness of the linear system derived from a generic Newton iteration of the original problem is analyzed and different mechanical activation functions are considered. In addition, the active strain formulation is compared with the classical active stress formulation from both numerical and modeling perspectives. Taylor-Hood and MINI finite elements are employed to discretize the mechanical problem. The results of several numerical experiments show that the proposed formulation is mathematically consistent and is able to represent the main key features of the phenomenon, while allowing savings in computational costs.

Simulation methods with extended stability for stiff biochemical kinetics

Background: With increasing computer power, simulating the dynamics of complex systems in chemistry and biology is becoming increasingly routine. The modelling of individual reactions in (bio)chemical systems involves a large number of random events that can be simulated by the stochastic simulation algorithm (SSA). The key quantity is the step size, or waiting time, τ, whose value inversely depends on the size of the propensities of the different channel reactions and which needs to be re-evaluated after every firing event. Such a discrete event simulation may be extremely expensive, in particular for stiff systems where τ can be very short due to the fast kinetics of some of the channel reactions. Several alternative methods have been put forward to increase the integration step size. The so-called τ-leap approach takes a larger step size by allowing all the reactions to fire, from a Poisson or Binomial distribution, within that step. Although the expected value for the different species in the reactive system is maintained with respect to more precise methods, the variance at steady state can suffer from large errors as τ grows. Results: In this paper we extend Poisson τ-leap methods to a general class of Runge-Kutta (RK) τ-leap methods. We show that with the proper selection of the coefficients, the variance of the extended τ-leap can be well-behaved, leading to significantly larger step sizes.Conclusions: The benefit of adapting the extended method to the use of RK frameworks is clear in terms of speed of calculation, as the number of evaluations of the Poisson distribution is still one set per time step, as in the original τ-leap method. The approach paves the way to explore new multiscale methods to simulate (bio)chemical systems.

Population PK-guided simulation study in children exposed to drugs in human milk

Risks of significant infant drug exposure through human milk arepoorly defined due to lack of large-scale PK data. We propose to useBayesian approach based on population PK (popPK)-guided modelingand simulation for risk prediction. As a proof-of-principle study, weexploited fluoxetine milk concentration data from 25 women. popPKparameters including milk-to-plasma ratio (MP ratio) were estimatedfrom the best model. The dose of fluoxetine the breastfed infant wouldreceive through mother's milk, and infant plasma concentrations wereestimated from 1000 simulated mother-infant pairs, using randomassignment of feeding times and milk volume. A conservative estimateof CYP2D6 activity of 20% of the allometrically-adjusted adult valuewas assumed. Derived model parameters, including MP ratio were consistentwith those reported in the literature. Visual predictive check andother model diagnostics showed no signs of model misspecifications.The model simulation predicted that infant exposure levels to fluoxetinevia mother's milk were below 10% of weight-adjusted maternal therapeuticdoses in >99% of simulated infants. Predicted median ratio ofinfant-mother serum levels at steady state was 0.093 (range 0.033-0.31),consistent with literature reported values (mean=0.07; range 0-0.59).Predicted incidence of relatively high infant-mother ratio (>0.2) ofsteady-state serum fluoxetine concentrations was <1.3%. Overall, ourpredictions are consistent with clinical observations. Our approach maybe valid for other drugs, allowing in silico prediction of infant drugexposure risks through human milk. We will discuss application of thisapproach to another drug used in lactating women.

Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine

BACKGROUND: Risks of significant infant drug exposurethrough breastmilk are poorly defined for many drugs, and largescalepopulation data are lacking. We used population pharmacokinetics(PK) modeling to predict fluoxetine exposure levels ofinfants via mother's milk in a simulated population of 1000 motherinfantpairs.METHODS: Using our original data on fluoxetine PK of 25breastfeeding women, a population PK model was developed withNONMEM and parameters, including milk concentrations, wereestimated. An exponential distribution model was used to account forindividual variation. Simulation random and distribution-constrainedassignment of doses, dosing time, feeding intervals and milk volumewas conducted to generate 1000 mother-infant pairs with characteristicssuch as the steady-state serum concentrations (Css) and infantdose relative to the maternal weight-adjusted dose (relative infantdose: RID). Full bioavailability and a conservative point estimate of1-month-old infant CYP2D6 activity to be 20% of the adult value(adjusted by weigth) according to a recent study, were assumed forinfant Css calculations.RESULTS: A linear 2-compartment model was selected as thebest model. Derived parameters, including milk-to-plasma ratios(mean: 0.66; SD: 0.34; range, 0 - 1.1) were consistent with the valuesreported in the literature. The estimated RID was below 10% in >95%of infants. The model predicted median infant-mother Css ratio was0.096 (range 0.035 - 0.25); literature reported mean was 0.07 (range0-0.59). Moreover, the predicted incidence of infant-mother Css ratioof >0.2 was less than 1%.CONCLUSION: Our in silico model prediction is consistent withclinical observations, suggesting that substantial systemic fluoxetineexposure in infants through human milk is rare, but further analysisshould include active metabolites. Our approach may be valid forother drugs. [supported by CIHR and Swiss National Science Foundation(SNSF)]

Iowa's Adult Basic Education Program Annual Benchmark Report Executive Summary, 2002

The purpose of this publication is to present the Executive Summary for the Program Year 2002 report on Iowa’s adult basic education program benchmarks. The passage of the Workforce Investment Act (WIA) of 1998 [Public Law 105-220] by the 105th Congress has ushered in a new era of collaboration, coordination, cooperation and accountability. The overall goal of the Act is “to increase the employment, retention, and earnings of participants, and increase occupational skill attainment by participants, and, as a result improve the quality of the workforce, reduce welfare dependency, and enhance the productivity and competitiveness of the Nation.”

Iowa's Adult Basic Education Program Annual Benchmark Report, 2002

One of the major intents of AEFLA was to establish performance measures and benchmarks to demonstrate increased accountability in line with the major goals and objectives of WIA. Section 212(2)(A) of the Act specifies that each eligible agency (e.g. The Iowa Department of Education) is subject to certain core indicators of performance and has the authority to specify additional indicators.

Iowa's Adult Basic Education Program Annual Benchmark Report Executive Summary, 2001

The purpose of this publication is to present the Executive Summary of the first annual report on the results of Iowa’s adult basic education program benchmarks. The passage of the Workforce Investment Act (WIA) of 1998 [Public Law 105-220] by the 105th Congress has ushered in a new era of collaboration, coordination, cooperation and accountability. The overall goal of the Act is “to increase the employment, retention, and earnings of participants, and increase occupational skill attainment by participants, and, as a result improve the quality of the workforce, reduce welfare dependency, and enhance the productivity and competitiveness of the Nation.”

Iowa's Adult Basic Education Program Annual Benchmark Report, 2001

The purpose of Title II, The Adult Education and Family Literacy Act (AEFLA) of the Workforce Investment Act of 1998, is to create a partnership among the federal government, states, and localities to provide, on a voluntary basis, adult basic education and literacy services.

Iowa Adult Literacy Program Annual Benchmark Report, 2003

The purpose of Title II, The Adult Education and Family Literacy Act (AEFLA) of the Workforce Investment Act of 1998, is to create a partnership among the federal government, states, and localities to provide, on a voluntary basis, adult basic education and literacy services.

Iowa's Adult Literacy Program Benchmark Analysis Report, 2002

The purpose of this document is to present Iowa’s Adult Literacy Benchmark Analysis Report: Program Year 2002. The report is designed to provide a supplemental analysis of the information presented in Tables 5-19 (pp. 16-37) referenced in the publication titled Iowa's Adult Basic Education Program Annual Benchmark Report: Program Year 2002. The original data source for Tables 1-7 is from Iowa’s National Reporting System (NRS) report Tables 4B and 5 and the publication titled Iowa’s Community College Basic Literacy Skills Credential Program: Program Year 2002. (See Appendix B of Iowa’s Adult Basic Education Program Annual Benchmark Report: Program Year 2002, [pp. 54-55] and Iowa’s Community College Basic Literacy Skills Credential Program Annual Report: Program Year 2002 Tables 1-2 [pp. 6-7]).

Iowa Adult Basic Education Program Benchmark Objective for Program Year, 2002

The benchmark objectives for Program Year 2002 are designed to improve Iowa's basic skills literacy program in those instructional programs, educational functioning levels, and follow-up categories which did not achieve the negotiated benchmark levels for Program Year 2001. The instructional programs, educational functioning levels and follow-up categories in which the attained benchmarks met or exceeded the negotiated benchmarks for Program Year 2001 should not be allowed to fall below the Program Year 2001 levels for Program Year 2002.

Iowa’s Adult Literacy Program Annual Benchmark Report Executive Summary, 2004

This report was produced by the Iowa Department of Education about Adult Literacy.

Iowa’s Adult Literacy Program Benchmark Projection Report, 2004

This report was produced by the Iowa Department of Education about Adult Literacy.

Iowa Adult Literacy Program Annual Benchmark Report, 2005

The purpose of this publication is to present the Program Year 2005 report on Iowa’s adult literacy program benchmarks. The passage of the Workforce Investment Act (WIA) of 1998 [Public Law 105-220] by the 105th Congress ushered in a new era of collaboration, coordination, cooperation and accountability. The overall goal of the Act is “to increase the employment, retention, and earnings of participants, and increase occupational skill attainment by participants, and, as a result improve the quality of the workforce, reduce welfare dependency, and enhance the productivity and competitiveness of the Nation.”