Safer sex choices among African-American college women

The purpose of this dissertation was to explore and describe the factors that influence the safer sex choices of African-American college women. The pandemic of HIV and the prevalence of other sexually transmitted diseases has disproportionately affected African-American females. As young women enter college they are faced with a myriad of choices. Unprotected sexual exploration is one choice that can lead to deadly consequences. This dissertation explores, through in-depth interviews, the factors associated with the decision to practice or not practice safe sex. ^ The first study describes the factors associated with increased sexual risk taking among African-American college women. Sexual risk taking or sex without a condom was found to be more likely when issues of self or partner pleasure were raised. Participants were also likely to have sexual intercourse without a condom if they desired a long term relationship with their partner. ^ The second study examined safe sex decision making processes among a group of African-American college women. Women were found to employ both emotional and philosophical strategies to determine their safe sex behavior. These strategies range from assessing a partner's physical capabilities and appearance to length of the dating relationship. ^ The third study explores the association between knowledge and risk perception as predictors for safer sex behaviors. Knowledge of HIV/AIDS and other STDs was not found to be a determinant of safer sex behavior. Perception of personal risk was also not highly correlated with consistent safer sex behavior. ^ These studies demonstrate the need for risk-based safer sex education and intervention programs. The current climate of knowledge-based program development insures that women will continue to predicate their decision to practice safer sex on their limited perception and understanding of the risks associated with unprotected sexual behavior. Further study into the emotional and philosophical determinants of sexual behavior is necessary for the realistic design of applicable and meaningful interventions. ^

An Innovative Phase I Trial Design Allowing for the Identification of Multiple Potential Maximum Tolerated Doses with Combination Therapy of Targeted Agents

Treatment for cancer often involves combination therapies used both in medical practice and clinical trials. Korn and Simon listed three reasons for the utility of combinations: 1) biochemical synergism, 2) differential susceptibility of tumor cells to different agents, and 3) higher achievable dose intensity by exploiting non-overlapping toxicities to the host. Even if the toxicity profile of each agent of a given combination is known, the toxicity profile of the agents used in combination must be established. Thus, caution is required when designing and evaluating trials with combination therapies. Traditional clinical design is based on the consideration of a single drug. However, a trial of drugs in combination requires a dose-selection procedure that is vastly different than that needed for a single-drug trial. When two drugs are combined in a phase I trial, an important trial objective is to determine the maximum tolerated dose (MTD). The MTD is defined as the dose level below the dose at which two of six patients experience drug-related dose-limiting toxicity (DLT). In phase I trials that combine two agents, more than one MTD generally exists, although all are rarely determined. For example, there may be an MTD that includes high doses of drug A with lower doses of drug B, another one for high doses of drug B with lower doses of drug A, and yet another for intermediate doses of both drugs administered together. With classic phase I trial designs, only one MTD is identified. Our new trial design allows identification of more than one MTD efficiently, within the context of a single protocol. The two drugs combined in our phase I trial are temsirolimus and bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) pathway which is fundamental for tumor growth and metastasis. One mechanism of tumor resistance to antiangiogenic therapy is upregulation of hypoxia inducible factor 1α (HIF-1α) which mediates responses to hypoxic conditions. Temsirolimus has resulted in reduced levels of HIF-1α making this an ideal combination therapy. Dr. Donald Berry developed a trial design schema for evaluating low, intermediate and high dose levels of two drugs given in combination as illustrated in a recently published paper in Biometrics entitled “A Parallel Phase I/II Clinical Trial Design for Combination Therapies.” His trial design utilized cytotoxic chemotherapy. We adapted this design schema by incorporating greater numbers of dose levels for each drug. Additional dose levels are being examined because it has been the experience of phase I trials that targeted agents, when given in combination, are often effective at dosing levels lower than the FDA-approved dose of said drugs. A total of thirteen dose levels including representative high, intermediate and low dose levels of temsirolimus with representative high, intermediate, and low dose levels of bevacizumab will be evaluated. We hypothesize that our new trial design will facilitate identification of more than one MTD, if they exist, efficiently and within the context of a single protocol. Doses gleaned from this approach could potentially allow for a more personalized approach in dose selection from among the MTDs obtained that can be based upon a patient’s specific co-morbid conditions or anticipated toxicities.

Design and Optimization of Four-dimensional Cone-beam Computed Tomography in Image-guided Radiation Therapy

The influence of respiratory motion on patient anatomy poses a challenge to accurate radiation therapy, especially in lung cancer treatment. Modern radiation therapy planning uses models of tumor respiratory motion to account for target motion in targeting. The tumor motion model can be verified on a per-treatment session basis with four-dimensional cone-beam computed tomography (4D-CBCT), which acquires an image set of the dynamic target throughout the respiratory cycle during the therapy session. 4D-CBCT is undersampled if the scan time is too short. However, short scan time is desirable in clinical practice to reduce patient setup time. This dissertation presents the design and optimization of 4D-CBCT to reduce the impact of undersampling artifacts with short scan times. This work measures the impact of undersampling artifacts on the accuracy of target motion measurement under different sampling conditions and for various object sizes and motions. The results provide a minimum scan time such that the target tracking error is less than a specified tolerance. This work also presents new image reconstruction algorithms for reducing undersampling artifacts in undersampled datasets by taking advantage of the assumption that the relevant motion of interest is contained within a volume-of-interest (VOI). It is shown that the VOI-based reconstruction provides more accurate image intensity than standard reconstruction. The VOI-based reconstruction produced 43% fewer least-squares error inside the VOI and 84% fewer error throughout the image in a study designed to simulate target motion. The VOI-based reconstruction approach can reduce acquisition time and improve image quality in 4D-CBCT.

Design, synthesis and cellular and molecular pharmacology of 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401): A novel non-cross-resistant anthracycline antibiotic with the intrinsic ability to circumvent P -glycoprotein-mediated drug resistance

We designed and synthesized a novel daunorubicin (DNR) analogue that effectively circumvents P-glycoprotein (P-gp)-mediated drug resistance. The fully protected carbohydrate intermediate 1,2-dibromoacosamine was prepared from acosamine and effectively coupled to daunomycinone in high yield. Deprotection under alkaline conditions yielded 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401). The in vitro cytotoxicity and cellular and molecular pharmacology of WP401 were compared with those of DNR in a panel of wild-type cell lines (KB-3-1, P388S, and HL60S) and their multidrug-resistant (MDR) counterparts (KB-V1, P388/DOX, and HL60/DOX). Fluorescent spectrophotometry, flow cytometry, and confocal laser scanning microscopy were used to measure intracellular accumulation, retention, and subcellular distribution of these agents. All MDR cell lines exhibited reduced DNR uptake that was restored, upon incubation with either verapamil (VER) or cyclosporin A (CSA), to the level found in sensitive cell lines. In contrast, the uptake of WP401 was essentially the same in the absence or presence of VER or CSA in all tested cell lines. The in vitro cytotoxicity of WP401 was similar to that of DNR in the sensitive cell lines but significantly higher in resistant cell lines (resistance index (RI) of 2-6 for WP401 vs 75-85 for DNR). To ascertain whether drug-mediated cytotoxicity and retention were accompanied by DNA strand breaks, DNA single- and double-strand breaks were assessed by alkaline elution. High levels of such breaks were obtained using 0.1-2 $\mu$g/mL of WP401 in both sensitive and resistant cells. In contrast, DNR caused strand breaks only in sensitive cells and not much in resistant cells. We also compared drug-induced DNA fragmentation similar to that induced by DNR. However, in P-gp-positive cells, WP401 induced 2- to 5-fold more DNA fragmentation than DNR. This increased DNA strand breakage by WP401 was correlated with its increased uptake and cytotoxicity in these cell lines. Overall these results indicate that WP401 is more cytotoxic than DNR in MDR cells and that this phenomenon might be related to the reduced basicity of the amino group and increased lipophilicity of WP401. ^

Use of universal precautions in the workplace: A comparison of two fire /EMS services

The Health Belief Model (HBM) provided the theoretical framework for examining Universal Precautions (UP) compliance factors by Firefighter, EMTs and Paramedics (prehospital care providers). A convenient sample of prehospital care providers (n = 4000) from two cities (Houston and Washington DC), were surveyed to explore the factors related to their decision to comply with Universal Precautions. Eight hundred and sixty-five useable questionnaires were analyzed. The responders were primarily male (95.7%) eight hundred and twenty-eight and thirty-seven were female, prehospital based (100%), EMTs (60.0%) and paramedics (12.8%) who had a mean 13 years of prehospital care experience. ^ Linear regression was used to evaluate the four hypotheses. The first hypothesis evaluating perceived susceptibility and seriousness with reported UP use was statistically significant (p = < .05). Perceived susceptibility, when considered independently, did not make a significant contribution (t = −4.2852; p = 0.0000) to the stated use of Universal precautions. The hypothesis is not supported as stated. The data indicates the opposite effect. Supported is the premise that as perceived susceptibility and perceived seriousness increase the use of Universal Precautions decreases. Hypothesis two tested perceived benefits with internal and external barriers. Both perceived benefits and internal and external barriers as well as the overall regression were significant (F = 112.6, p = 0.0000). The contribution of internal and external barriers was statistically significant (t = 0.0175; p = 0.0000) and (t = 0.0128; p = 0.0000). Hypothesis three which tested modifying factors, cues to action, select demographic variables, and the main effects of the HBM with self reported UP compliance overall was significant. The variables gender, birth, education, job type, EMS certification, years of service, years of experience providing patient care, Universal Precautions training hours, type of apparatus assigned to and the number of EMS related incidents responded to in a month were found to have a significant contribution to the stated use of Universal Precautions. ^ The additive effects were tested by use of a stepwise regression that assessed the contribution of each of the significant variables. Three variables in the equation were statistically significant. Internal barriers (t = −8.5507; p = 0.0000), external barriers (t = −6.2862; p = 0.000) and job type 2 & 3. Job type two (t = −2.8464; p = 0.0045 is titled Engineer/Operator. Job type three (t = −2.5730; p = 0.0103) is titled captain. The overall regression was significant (F = 24.06; p = 0.000). The Hypothesis is supported in the certain demographic variables do influence the stated use of Universal precautions and that as internal and external barriers are decreased, there is an increase in the stated use of Universal Precautions. ^ In summary, this study demonstrated that internal and external barriers have a significant impact on the stated use of Universal Precautions. Internal barriers are those factors within the individual that require an internal change (i.e., forgetfulness, freedom, perception of the urgency of the patient's needs etc.) and external barriers are things in the environment that can be altered (i.e., equipment design, availability of equipment, ease of use). These two model variables explained 23%–30% of the variance. ^