Mathematical and Experimental Analysis of Microbicide Vaginal Gels

HIV is a growing concern worldwide. With slow progress in the development of a vaccine, researchers have turned to alternate methods of preventing the spreading of HIV as a result of unprotected sexual intercourse. Developing a mechanism capable of protecting the vaginal or rectal epithelium from sexually transmitted pathogens can be an effective tool in the prevention of HIV infection. One such tool can come in the form of a microbicide gel, which provides a physical barrier and acts as a delivery vehicle for its active ingredient. In order for the microbicide to be an effective barrier and delivery vehicle, it must have the capability to coat the epithelium for a specific amount of time and sustain its structural integrity under the influence of gravity and other perturbation forces. In addition, to be used as a drug delivery vehicle the microbicide must serve the following functions: coat the surface completely without leaving any of the surface exposed, stay on the surface while influenced by external forces such as gravity and squeezing, and be able to contain potent concentrations of one or more active microbicidal ingredients. Many currently available vaginal spermicidal gels are applied using a syringe-like applicator. After vaginal application, several physical forces will perturb the gel: gravity, squeezing, surface tension and shearing. In this document I will outline the work that has been completed, for an original PhD dissertation, on the mathematical and experimental analysis of microbicide vaginal gels. This document contains an in-depth discussion of the methods taken to satisfy the following engineering goals: 1. An instrument/method for conducting gravity-induced flow experiments and obtaining spreading characteristics along with surface topography. 2. A numerical solution for a non-linear, second-order, partial differential equation that governs the evolution of the free surface of a spreading fluid. 3. A derivation and numerical solution for the 3-D power-law evolution equation. 4. A derivation and numerical solution for the 3-D Ellis evolution equation. All experimental and computational simulations presented in this study involve a finite bolus of fluid, with non-Newtonian viscous properties, spreading on an inclined plane under the influence of gravity. Using the two numerical models presented in this document, I conducted an in-depth parameter and parameter sensitivity analysis of the power-law model, and a parameter study of the Ellis model. Combining the experimental data with computational simulations allowed me to make the following conclusions: 1. Accounting for lateral slumping in the computational simulation will improve the theory's agreement with experiment. 2. Approximating the initial condition to disregard complex curvatures on the free surface, and only consider gross geometric parameters, will not compromise theoretical model's agreement with experiment. 3. The 3-D power-law model provides a sufficient approximation of Hydroxyethylcellulose (HEC) spreading under the influence of gravity, for gels at 2.4-3.0% HEC concentration. Furthermore, implementing a constitutive equation that accounts for the low-shear Newtonian plateau (Ellis constitutive eq.) does not improve the models agreement with experiment enough to justify its added complexity. In conclusion, the following work provides an original experiment and a computational simulation of non-Newtonian fluid spreading. It is my hope that this work can be used by researchers in the field of microbicide development and any other scenario where free surface flow of non-Newtonian fluids is applicable

Gravity-Driven Thin Film Flow of an Ellis Fluid

The thin film lubrication approximation has been studied extensively for moving contact lines of Newtonian fluids. However, many industrial and biological applications of the thin film equation involve shear-thinning fluids, which often also exhibit a Newtonian plateau at low shear. This study presents new numerical simulations of the three-dimensional (i.e. two-dimensional spreading), constant-volume, gravity-driven, free surface flow of an Ellis fluid. The numerical solution was validated with a new similarity solution, compared to previous experiments, and then used in a parametric study. The parametric study centered around rheological data for an example biological application of thin film flow: topical drug delivery of anti-HIV microbicide formulations, e.g. hydroxyethylcellulose (HEC) polymer solutions. The parametric study evaluated how spreading length and front velocity saturation depend on Ellis parameters. A lower concentration polymer solution with smaller zero shear viscosity (η0), τ1/2, and λ values spread further. However, when comparing any two fluids with any possible combinations of Ellis parameters, the impact of changing one parameter on spreading length depends on the direction and magnitude of changes in the other two parameters. In addition, the isolated effect of the shear-thinning parameter, λ, on the front velocity saturation depended on τ1/2. This study highlighted the relative effects of the individual Ellis parameters, and showed that the shear rates in this flow were in both the shear-thinning and plateau regions of rheological behavior, emphasizing the importance of characterizing the full range of shear-rates in rheological measurements. The validated numerical model and parametric study provides a useful tool for future steps to optimize flow of a fluid with rheological behavior well-described by the Ellis constitutive model, in a range of industrial and biological applications

Circulating miRNAs in Pediatric Pulmonary Hypertension Show Promise as Biomarkers of Vascular Function

Background/Objectives. The objective of this study was to evaluate the utility of circulating miRNAs as biomarkers of vascular function in pediatric pulmonary hypertension. Method. Fourteen pediatric pulmonary arterial hypertension patients underwent simultaneous right heart catheterization (RHC) and blood biochemical analysis. Univariate and stepwise multivariate linear regression was used to identify and correlate measures of reactive and resistive afterload with circulating miRNA levels. Furthermore, circulating miRNA candidates that classified patients according to a 20% decrease in resistive afterload in response to oxygen (O2) or inhaled nitric oxide (iNO) were identified using receiver-operating curves. Results. Thirty-two circulating miRNAs correlated with the pulmonary vascular resistance index (PVRi), pulmonary arterial distensibility, and PVRi decrease in response to O2 and/or iNO. Multivariate models, combining the predictive capability of multiple promising miRNA candidates, revealed a good correlation with resistive (r=0.97, P2−tailed<0.0001) and reactive (r=0.86, P2−tailed<0.005) afterloads. Bland-Altman plots showed that 95% of the differences between multivariate models and RHC would fall within 0.13 (mmHg−min/L)m2 and 0.0085/mmHg for resistive and reactive afterloads, respectively. Circulating miR-663 proved to be a good classifier for vascular responsiveness to acute O2 and iNO challenges. Conclusion. This study suggests that circulating miRNAs may be biomarkers to phenotype vascular function in pediatric PAH

The Rise and Fall of Slow Wave Tides: Vacillations in Coupled Slow Wave/Spindle Pairing Shift the Composition of Slow Wave Activity in Accordance With Depth of Sleep

Slow wave activity (SWA) during sleep is associated with synaptic regulation and memory processing functions. Each cycle of non-rapid-eye-movement (NREM) sleep demonstrates a waxing and waning amount of SWA during the transitions between stages N2 and N3 sleep, and the deeper N3 sleep is associated with an increased density of SWA. Further, SWA is an amalgam of different types of slow waves, each identifiable by their temporal coupling to spindle subtypes with distinct physiological features. The objectives of this study were to better understand the neurobiological properties that distinguish different slow wave and spindle subtypes, and to examine the composition of SWA across cycles of NREM sleep. We further sought to explore changes in the composition of NREM cycles that occur among aging adults. To address these goals, we analyzed subsets of data from two well-characterized cohorts of healthy adults: (1) The DREAMS Subjects Database ( n = 20), and (2) The Cleveland Family Study ( n = 60). Our analyses indicate that slow wave/spindle coupled events can be characterized as frontal vs. central in their relative distribution between electroencephalography (EEG) channels. The frontal predominant slow waves are identifiable by their coupling to late-fast spindles and occur more frequently during stage N3 sleep. Conversely, the central-associated slow waves are identified by coupling to early-fast spindles and favor occurrence during stage N2 sleep. Together, both types of slow wave/spindle coupled events form the composite of SWA, and their relative contribution to the SWA rises and falls across cycles of NREM sleep in accordance with depth of sleep. Exploratory analyses indicated that older adults produce a different composition of SWA, with a shift toward the N3, frontal subtype, which becomes increasingly predominant during cycles of NREM sleep. Overall, these data demonstrate that subtypes of slow wave/spindle events have distinct cortical propagation patterns and differ in their distribution across lighter vs. deeper NREM sleep. Future efforts to understand how slow wave sleep and slow wave/spindle coupling impact memory performance and neurological disease may benefit from examining the composition of SWA to avoid potential confounds that may occur when comparing dissimilar neurophysiological events

Novel left ventricular mechanical index in pulmonary arterial hypertension

Abstract Ventricular interdependence plays an important role in pulmonary arterial hypertension (PAH). It can decrease left ventricular (LV) longitudinal strain (LVLS) and lead to a leftward displacement (“transverse shortening”) of the interventricular septum (sTS). For this study, we hypothesized the ratio of LVLS/sTS would be a sensitive marker of systolic ventricular interactions in PAH. In a cross‐sectional cohort of patients with PAH (n = 57) and matched controls (n = 57), we quantified LVLS and septal TS in the amplitude and time domain. We then characterized LV phenotypes using upset plots, ventricular interactions using network analysis, and longitudinal analysis in a representative cohort of 45 patients. We also measured LV metrics in mice subjected to pulmonary arterial banding (PAB) using a 7 T magnetic resonance imaging at baseline, Week 1, and Week 7 post‐PAB (N = 9). Patients with PAH had significantly reduced absolute LVLS (15.4 ± 3.4 vs. 20.1 ± 2.3%, p < 0.0001), higher sTS (53.0 ± 12.2 vs. 28.0 ± 6.2%, p < 0.0001) and lower LVLS/sTS (0.30 ± 0.09 vs. 0.75 ± 0.16, p < 0.0001) compared to controls. Reduced LVLS/sTS was observed in 89.5% of patients, while diastolic dysfunction, impaired LVLS (<16%), and LV atrophy were observed in 73.7%, 52.6%, and 15.8%, respectively. In the longitudinal cohort, changes in LVLS/sTS were closely associated with changes in N‐terminal pro B‐type natriuretic peptide (r = 0.73, p < 0.0001) as well as survival. Mice subjected to PAB showed significant RV systolic dysfunction and decreased LVLS/sTS compared to sham animals. We conclude that in PAH, LVLV/sTS is a simple ratio that can reflect ventricular systolic interactions