A Biomechanical Analysis of One-Third Tubular Plates for the Treatment of Benign Lesions in the Distal Femur

The purpose of this study was to evaluate the use of one-third tubular plates for the treatment of benign defects in the medial distal metaphysis of the femur. Benign cysts are a common occurrence in long bones, and are of concern in load-bearing bones, such as the tibia and femur. These space-occupying growths are removed by curettage of the affected region. Numerous post-curettage management options have been described in the literature, which generally include filling the defect with either synthetic or biological materials. Unfortunately, complications, such as infectious disease transmission, thermal injury, and a robust inflammatory have all been reported in the literature. In response to these concerns, a number of studies reported successful healing of benign cortical defects in long bones with no augmentation after curettage, however, the lack of structural support results in an increased risk of fracture through the defect site. Therefore, it is advantageous to investigate a treatment option that adds structural support to the defect site and permits the use of osteoconductive and osteoinductive materials within the bone cavity. The purpose of this thesis was threefold: First, a quasi-static experimental comparison of intact and cortical defect specimens was conducted to determine the structural consequences incurred by the introduction of a 15 mm cortical defect under isolated axial and torsional loads. Second, an experimental combined axial/torsional fatigue analysis was employed to further analyze the behavior of the defect specimens, and to determine the structural stiffness regained by the addition of a one-third tubular plate. Third, a numerical approach was used to consider the structural consequences of varying sized defects under isolated and combined quasi-static axial and torsional loading, and to further analyze the results of adding the plate to the defect specimens. This study revealed that a one-third tubular plate might be a clinically viable option for structural support of small cortical defects in the distal femur. Furthermore, the loss in stiffness by the defect is exacerbated under combined axial/torsional loading. This is a more physiologically relevant loading mode and may provide more clinically useful results

HIV Protective Efficacy and Correlates of Tenofovir Blood Concentrations in a Clinical Trial of PrEP for HIV Prevention

Background: Antiretroviral pre-exposure prophylaxis (PrEP) is a novel HIV prevention strategy for which adherence is a known determinant of efficacy. Blood concentrations of PrEP medications are one objective marker of adherence. Methods: In a placebo-controlled PrEP efficacy trial of tenofovir disoproxil fumarate (TDF) and TDF with emtricitabine (FTC/TDF) among 4747 African women and men with an HIV-infected partner, we measured plasma tenofovir concentrations from participants in the active PrEP arms: 29 HIV seroconverters (cases) and 196 randomly selected controls who remained uninfected. Results: Among controls, 71% of visits had tenofovir concentrations >40 ng/mL, consistent with steady-state daily dosing, compared with 21% of cases at the visit HIV was first detected. Pill count data indicated that 96% of controls and 66% of cases had >80% adherence for these same visits. The estimated protective effect of PrEP against HIV, based on concentrations >40 ng/mL, was 88% (95% confidence interval: 60 to 96, P 40 ng/mL at month 1, 75% maintained this concentration at month 12. Only 5 of 29 seroconverters seemed to be consistently adherent to PrEP. Tenofovir concentrations >40 ng/mL were associated with older age and shorter time on study; concentrations ≤40 ng/mL occurred more commonly when participants reported no sex with their HIV-infected partner. Conclusions: Plasma concentrations of tenofovir consistent with daily dosing were highly predictive of protection from HIV acquisition. Most of those who took PrEP seemed to have high and consistent adherence

Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution

Breast cancers that occur in women 2–5 years postpartum are more frequently diagnosed at metastatic stages and correlate with poorer outcomes compared with breast cancers diagnosed in young, premenopausal women. The molecular mechanisms underlying the malignant severity associated with postpartum breast cancers (ppBCs) are unclear but relate to stromal wound-healing events during postpartum involution, a dynamic process characterized by widespread cell death in milk-producing mammary epithelial cells (MECs). Using both spontaneous and allografted mammary tumors in fully immune–competent mice, we discovered that postpartum involution increases mammary tumor metastasis. Cell death was widespread, not only occurring in MECs but also in tumor epithelium. Dying tumor cells were cleared through receptor tyrosine kinase MerTK–dependent efferocytosis, which robustly induced the transcription of genes encoding wound-healing cytokines, including IL-4, IL-10, IL-13, and TGF-β. Animals lacking MerTK and animals treated with a MerTK inhibitor exhibited impaired efferocytosis in postpartum tumors, a reduction of M2-like macrophages but no change in total macrophage levels, decreased TGF-β expression, and a reduction of postpartum tumor metastasis that was similar to the metastasis frequencies observed in nulliparous mice. Moreover, TGF-β blockade reduced postpartum tumor metastasis. These data suggest that widespread cell death during postpartum involution triggers efferocytosis-induced wound-healing cytokines in the tumor microenvironment that promote metastatic tumor progression

Comparison of adherence to pre-exposure prophylaxis during blinded and open-label phases of a randomized trial

Thesis (Master's)--University of Washington, 2014The Partners PrEP Study, a randomized trial of daily oral pre-exposure prophylaxis for HIV prevention, demonstrated efficacy at an interim analysis, prompting discontinuation of its placebo arm and early release of results. Active arm participants continued followup, and placebo arm participants optionally re-consented to additional followup on active drug. We compared PrEP adherence, by multiple measures, during the placebo-controlled and subsequent open-label phases of the study. Learning of PrEP efficacy led to a modest, although statistically significant, increase in adherence: the odds of refilling study medication at each monthly visit increased by 24% (p = 0.03), and the odds of detecting PrEP drug in plasma increased by 76% (p < 0.01), the latter returning to counterfactual levels within twelve months. Placebo arm participants who chose to continue followup on active drug were more likely to refill than those originally randomized to active drug (odds ratio, 1.32; p < 0.01). These results suggest that knowledge of PrEP efficacy had a small impact on PrEP adherence in a trial where adherence was already high

A Noninvasive Neural Interface for Control of a Powered Lower Limb Prosthesis

Limb amputation results in a physical disability that causes activities of daily living to become difficult or impossible for the amputee. Current lower-limb prostheses provide limited control and result in only modest improvements in mobility for the amputee. Recent advancements in powered lower limb prostheses allow for more intelligent control and better walking functions. The incorporation of neural signals, specifically muscle and brain, may offer a viable method for improved volitional control by directly interpreting signals from muscle and cortical brain activations. In this study, we employ a multimodal neuroimaging approach to determine if noninvasively recorded brain signals can be used within a lower limb prosthesis control scheme. First, we use a mobile brain/body imaging (MoBI) approach to identify the neural correlates of walking during terrain transitions between level ground and stair ascent. These data are then used to demonstrate the feasibility of predicting the two terrains directly from EEG signals, with cross-validation accuracies achieving greater than 80% in offline decoding. Second, we utilize functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to study the brain of amputees during isolated movements of the intact and phantom limb. These data are used to: (1) identify neural correlates of movement during isolated limb movements in the amputee population, and (2) demonstrate the feasibility of control of a powered lower limb prosthesis using neural signals from the brain and muscles. We observed that the representation of the phantom limb is preserved in the deprived cortex. Additionally, using a Kalman Filtering approach, we achieved moderate reconstruction accuracy for predicting movements of the phantom and intact limb directly from EEG. The work in this dissertation contributes to a greater understanding of the neural signals associated with phantom limb movements in lower limb amputees and presents a strategy for neural control of powered prostheses.Electrical and Computer Engineering, Department o

A Critical Analysis of Parental Alienation Syndrome and Its Admissibility in the Family Court

Over the past three decades, parental alienation syndrome (PAS) has been proposed to explain behaviors by a child who refuses to spend time with a parent and actually denigrates that parent within the context of a child custody dispute. Although some mental health professionals and child custody evaluators, attorneys, and judges have been quick to accept and admit PAS as evidence in these disputes, there has been no consistent empirical or clinical evidence that PAS exists or that the alienator\u27s behavior is the actual cause of the alienated child\u27s behavior towards the target parent. This article attempts to help those working with custody issues understand how the PAS construct fails to meet scientific standards and should not be admissible in courts