Novel Simulation Model of Non-Muscle Invasive Bladder Cancer: A Platform for a Virtual Randomized Trial of Conservative Therapy vs. Cystectomy in BCG Refractory Patients.

Introduction: There have been no randomized controlled trials (RCTs) evaluating the clinical or economic benefit of mitomycin C intravesical therapy vs. radical cystectomy in patients with high-risk non-muscle invasive bladder cancer (NMIBC). We used the Archimedes computational model to simulate RCT comparing radical cystectomy versus intravesical mitomycin C (MMC) therapy to evaluate the clinical and economic outcomes for BCG-refractory NMIBC as well demonstrate the utility of computer based models to simulate a clinical trial. Methods: The Archimedes model was developed to generate a virtual population using the Surveillance Epidemiology and End Results database, other clinical trials, and expert opinions. Patients selected were diagnosed with NMIBC (

Cost-effectiveness of chemoprevention of breast cancer using tamoxifen in a postmenopausal US population.

BACKGROUND: Previous cost-effectiveness analyses of tamoxifen therapy account for breast cancer risk reduction during active treatment but not for its persistent protective effect after active treatment. METHODS: A detailed, continuous time, mathematical model of breast cancer and healthcare processes was used to simulate a postmenopausal population aged <55 years in a virtual trial comparing tamoxifen treatment with no treatment for lifetime follow-up. Unlike previous work, the current model of tamoxifen therapy is based on a meta-analysis of 4 randomized, placebo-controlled chemoprevention trials with breast cancer risk reduction continuing for 10 years after treatment termination. Cancer incidence and survival data were derived from Surveillance, Epidemiology and End Results statistics. Noncancer disease incidences, quality-adjusted life year (QALY) utility weights, and costs were derived from the literature. RESULTS: Tamoxifen treatment (vs no treatment) saved 29 QALYs in a population of 1000 postmenopausal women aged <55 years with an additional cost of $333,000 over the population's lifetime (average cost-effectiveness ratio, $11,530 per QALY). Tamoxifen therapy, compared with no treatment, was cost saving when higher risk populations were targeted (5-year risk ≥1.66%). The cost-effectiveness results were sensitive to parameters that characterized menopausal symptoms and adverse side effects of tamoxifen. CONCLUSIONS: The current results indicated that tamoxifen chemoprophylaxis for postmenopausal women aged <55 years is a cost-effective health policy that reduces breast cancer incidence and improves life expectancy. Focusing on a postmenopausal population aged <55 years minimized the threat of adverse events associated with tamoxifen.

On the fluctuations that drive small ions toward, and away from, interfaces between polar liquids and their vapors.

Contrary to the expectations from classic theories of ion solvation, spectroscopy and computer simulations of the liquid-vapor interface of aqueous electrolyte solutions suggest that ions little larger than a water molecule can prefer to reside near the liquid's surface. Here we advance the view that such affinity originates in a competition between strong opposing forces, primarily due to volume exclusion and dielectric polarization, that are common to all dense polar liquids. We present evidence for this generic mechanism from computer simulations of (i) water and (ii) a Stockmayer fluid near its triple point. In both cases, we show that strong surface enhancement of small ions, obtained by tuning solutes' size and charge, can be accentuated or suppressed by modest changes in either of those parameters. Statistics of solvent polarization, when the ion is held at and above the Gibbs dividing surface, highlight a basic deficiency in conventional models of dielectric response, namely, the neglect of interfacial flexibility. By distorting the solution's boundary, an ion experiences fluctuations in electrostatic potential and in electric field whose magnitudes attenuate much more gradually (as the ion is removed from the liquid phase) than for a quiescent planar interface. As one consequence, the collective responses that determine free energies of solvation can resolve very differently in nonuniform environments than in bulk. We show that this persistence of electric-field fluctuations additionally shapes the sensitivity of solute distributions to ion polarizability.

Toward a simple molecular understanding of sum frequency generation at air-water interfaces.

Second-order vibrational spectroscopies successfully isolate signals from interfaces, but they report on intermolecular structure in a complicated and indirect way. Here, we adapt a perspective on vibrational response developed for bulk spectroscopies to explore the microscopic fluctuations to which sum frequency generation (SFG), a popular surface-specific measurement, is most sensitive. We focus exclusively on inhomogeneous broadening of spectral susceptibilities for OH stretching of HOD as a dilute solute in D(2)O. Exploiting a simple connection between vibrational frequency shifts and an electric field variable, we identify several functions of molecular orientation whose averages govern SFG. The frequency dependence of these quantities is well captured by a pair of averages, involving alignment of OH and OD bonds with the surface normal at corresponding values of the electric field. The approximate form we obtain for SFG susceptibility highlights a dramatic sensitivity to the way a simulated liquid slab is partitioned for calculating second-order response.

A diagrammatic formulation of the kinetic theory of fluctuations in equilibrium classical fluids. VI. Binary collision approximations for the memory function for self-correlation functions.

We use computer simulation results for a dense Lennard-Jones fluid for a range of temperatures to test the accuracy of various binary collision approximations for the memory function for density fluctuations in liquids. The approximations tested include the moderate density approximation of the generalized Boltzmann-Enskog memory function (MGBE) of Mazenko and Yip [Statistical Mechanics. Part B. Time-Dependent Processes, edited by B. J. Berne (Plenum, New York, 1977)], the binary collision approximation (BCA) and the short time approximation (STA) of Ranganathan and Andersen [J. Chem. Phys. 121, 1243 (2004); J. Phys. Chem. 109, 21437 (2005)] and various other approximations we derived by using diagrammatic methods. The tests are of two types. The first is a comparison of the correlation functions predicted by each approximate memory function with the simulation results, especially for the self-longitudinal current correlation (SLCC) function. The second is a direct comparison of each approximate memory function with a memory function numerically extracted from the correlation function data. The MGBE memory function is accurate at short times but decays to zero too slowly and gives a poor description of the correlation function at intermediate times. The BCA is exact at zero time, but it predicts a correlation function that diverges at long times. The STA gives a reasonable description of the SLCC but does not predict the correct temperature dependence of the negative dip in the function that is associated with caging at low temperatures. None of the other binary collision approximations is a systematic improvement on the STA. The extracted memory functions have a rapidly decaying short time part, much like the STA, and a much smaller, more slowly decaying part of the type predicted by a mode coupling theory. Theories that use mode coupling commonly include a binary collision term in the memory function but do not discuss in detail the nature of that term. It is clear from the present work that the short time part of the memory function has a behavior associated with brief binary repulsive collisions, such as those described by the STA. Collisions that include attractive as well as repulsive interactions, such as those of the MGBE, have a much longer duration, and theories that include them have memory functions that decay to zero much too slowly to provide a good first approximation of the correlation function. This leads us to speculate that the memory function for density fluctuations can be usefully regarded as a sum of at least three parts: a contribution from repulsive binary collisions (the STA or something similar to it), another short time part that is related to all the other interactions (but whose nature is not understood), and a longer time slowly decaying part that describes caging (of the type predicted by the mode coupling theory).