HIV-associated malignancies among children attending the Baylor Clinic in Kampala, Uganda

Introduction: HIV-associated malignancies such as Kaposi’s sarcoma and Non-Hodgkin’s lymphoma occur in children and usually lead to significant morbidity and mortality. No studies have been done to establish prevalence and outcome of these malignancies in children in a hospital setting in Uganda. ^ Research question: What proportion of children attending the Baylor-Uganda COE present with HIV-associated malignancies and what are the characteristics and outcome of these malignancies? The objective was to determine the prevalence, associated factors and outcome of HIV-associated malignancies among children attending the Baylor-Uganda Clinic in Kampala, Uganda. Study Design: This was a retrospective case series involving records review of patients who presented to the Baylor-Clinic between January 2004 and December 2008. Study Setting: The Baylor-Uganda Clinic, where I worked as a physician before coming to Houston, is a well funded, well staffed; Pediatric HIV clinic located in Mulago Hospital, Kampala, Uganda and is affiliated to Makerere University Medical School. Study Participants: Medical charts of patients aged 6 weeks to 18 years who enrolled for care at the clinic during the years 2004 to 2008 were retrieved for data abstraction. Selection Criteria: Study participants had to be patients of Baylor-Uganda seen during the study period; they had to be aged 6 weeks to 18 years; and had to be HIV positive. Patients with incomplete data or whose malignancies were not confirmed by histology were excluded. Study Variables: Data on patient’s age, sex, diagnosis, type of malignancy, anatomic location of the malignancy; pathology report, baseline laboratory results and outcome of treatment, were abstracted. Data Analysis: Cross tabulation to determine associations between variables using Pearson’s chi square at 95% level of significance was done. Proportions of malignancies among different groups were determined. In addition, Kaplan Meier survival analysis and comparison of survival distributions using the log-rank test was done. Change in CD4 percentages from baseline was assessed with the Wilcoxon signed rank test. Results: The proportion of children with malignancies during the study period was found to be 1.65%. Only 2 malignancies: Kaposi’s sarcoma and Non-Hodgkin’s lymphoma were found. 90% of the malignancies were Kaposi’s sarcoma. Lymph node involvement in children with Kaposi’s sarcoma was common, but the worst prognosis was seen with visceral involvement. Deaths during follow-up were seen in the first few weeks to months. Upon starting treatment the CD4 cell percentage increased significantly from a baseline median of 6% to 14% at 6 months and 15.8% at 12 months of follow-up.^

Trastuzumab use and risk of congestive heart failure in older breast cancer patients

Trastuzumab is a humanized-monoclonal antibody, developed specifically for HER2-neu over-expressed breast cancer patients. Although highly effective and well tolerated, it was reported associated with Congestive Heart Failure (CHF) in clinical trial settings (up to 27%). This leaves a gap where, Trastuzumab-related CHF rate in general population, especially older breast cancer patients with long term treatment of Trastuzumab remains unknown. This thesis examined the rates and risk factors associated with Trastuzumab-related CHF in a large population of older breast cancer patients. A retrospective cohort study using the existing Surveillance, Epidemiology and End Results (SEER) and Medicare linked de-identified database was performed. Breast cancer patients ≥ 66 years old, stage I-IV, diagnosed in 1998-2007, fully covered by Medicare but no HMO within 1-year before and after first diagnosis month, received 1st chemotherapy no earlier than 30 days prior to diagnosis were selected as study cohort. The primary outcome of this study is a diagnosis of CHF after starting chemotherapy but none CHF claims on or before cancer diagnosis date. ICD-9 and HCPCS codes were used to pool the claims for Trastuzumab use, chemotherapy, comorbidities and CHF claims. Statistical analysis including comparison of characteristics, Kaplan-Meier survival estimates of CHF rates for long term follow up, and Multivariable Cox regression model using Trastuzumab as a time-dependent variable were performed. Out of 17,684 selected cohort, 2,037 (12%) received Trastuzumab. Among them, 35% (714 out of 2037) were diagnosed with CHF, compared to 31% (4784 of 15647) of CHF rate in other chemotherapy recipients (p<.0001). After 10 years of follow-up, 65% of Trastuzumab users developed CHF, compared to 47% in their counterparts. After adjusting for patient demographic, tumor and clinical characteristics, older breast cancer patients who used Trastuzumab showed a significantly higher risk in developing CHF than other chemotherapy recipients (HR 1.69, 95% CI 1.54 - 1.85). And this risk is increased along with the increment of age (p-value < .0001). Among Trastuzumab users, these covariates also significantly increased the risk of CHF: older age, stage IV, Non-Hispanic black race, unmarried, comorbidities, Anthracyclin use, Taxane use, and lower educational level. It is concluded that, Trastuzumab users in older breast cancer patients had 69% higher risk in developing CHF than non-Trastuzumab users, much higher than the 27% increase reported in younger clinical trial patients. Older age, Non-Hispanic black race, unmarried, comorbidity, combined use with Anthracycline or Taxane also significantly increase the risk of CHF development in older patients treated with Trastuzumab. ^

Comparison of OG1RF and an isogenic fsrB deletion mutant by transcriptional analysis: the Fsr system of Enterococcus faecalis is more than the activator of gelatinase and serine protease.

The FsrABC system of Enterococcus faecalis controls the expression of gelatinase and a serine protease via a quorum-sensing mechanism, and recent studies suggest that the Fsr system may also regulate other genes important for virulence. To investigate the possibility that Fsr influences the expression of additional genes, we used transcriptional profiling, with microarrays based on the E. faecalis strain V583 sequence, to compare the E. faecalis strain OG1RF with its isogenic mutant, TX5266, an fsrB deletion mutant. We found that the presence of an intact fsrB influences expression of numerous genes throughout the growth phases tested, namely, late log to early stationary phase. In addition, the Fsr regulon is independent of the activity of the proteases, GelE and SprE, whose expression was confirmed to be activated at all three time points tested. While expression of some genes (i.e., ef1097 and ef0750 to -757, encoding hypothetical proteins) was activated in late log phase in OG1RF versus the fsrB deletion mutant, expression of ef1617 to -1634 (eut-pdu orthologues) was highly repressed by the presence of an intact Fsr at entry into stationary phase. This is the first time that Fsr has been characterized as a negative regulator. The newly recognized Fsr-regulated targets include other factors, besides gelatinase, described as important for biofilms (BopD), and genes predicted to encode the surface proteins EF0750 to -0757 and EF1097, along with proteins implicated in several metabolic pathways, indicating that the FsrABC system may be an important regulator in strain OG1RF, with both positive and negative effects.

INFLUENCE OF A CLINIC BASED IMMUNIZATION INFORMATION SYSTEM ON INFANT IMMUNIZATIONS

This study focuses on the impact of a clinic-based intervention program on the immunization status of limited-income urban children. The intervention program consisted of an information session for clinic health care providers and the placement of individualized immunization information labels on clinic notes at the time of each visit. The degree of impact of the intervention on immunization administration was ascertained through a comparison of two similar groups of infants born in the same months of the year immediately before (N = 201) and after (N = 203) the information session and initiation of the labeling system. The timeliness of administration of each diphtheria, pertussis, tetanus and trivalent oral polio vaccine (DPT/TOPV) in the first year series of three was compared pre- to postintervention. Significantly more third immunizations were given the postintervention subjects within ten days of the recommended time of application ( p = .0361). Life table analysis indicated that the probability of an infant's passing one year of age without the administration of the third immunization decreased for postintervention infants (p = .0515). The intervention was most successful in assuring administration of the series of immunizations in those infants who were seen by the health care provider for at least 50% of their first year visits. Results indicate that minor changes in the format of information given a relatively continuous provider can increase completion of immunization series in infants. ^

AN ANALYSIS OF THE RELATIVE INFLUENCE OF RACE, INCOME, EDUCATION, AND FOOD STAMP PROGRAM PARTICIPATION/NONPARTICIPATION ON THE FOOD AND NUTRIENT CONSUMPTION OF A NORTH FLORIDA URBAN CLINIC POPULATION IN CONJUNCTION WITH A SURVEY OF NUTRITION RELATED HABITS AND ATTITUDES

The relative influence of race, income, education, and Food Stamp Program participation/nonparticipation on the food and nutrient intake of 102 fecund women ages 18-45 years in a Florida urban clinic population was assessed using the technique of multiple regression analysis. Study subgroups were defined by race and Food Stamp Program participation status. Education was found to have the greatest influence on food and nutrient intake. Race was the next most influential factor followed in order by Food Stamp Program participation and income. The combined effect of the four independent variables explained no more than 19 percent of the variance for any of the food and nutrient intake variables. This would indicate that a more complex model of influences is needed if variations in food and nutrient intake are to be fully explained.^ A socioeconomic questionnaire was administered to investigate other factors of influence. The influence of the mother, frequency and type of restaurant dining, and perceptions of food intake and weight were found to be factors deserving further study.^ Dietary data were collected using the 24-hour recall and food frequency checklist. Descriptive dietary findings indicated that iron and calcium were nutrients where adequacy was of concern for all study subgroups. White Food Stamp Program participants had the greatest number of mean nutrient intake values falling below the 1980 Recommended Dietary Allowances (RDAs). When Food Stamp Program participants were contrasted to nonparticipants, mean intakes of six nutrients (kilocalories, calcium, iron, vitamin A, thiamin, and riboflavin) were below the 1980 RDA compared to five mean nutrient intakes (kilocalories, calcium, iron, thiamin and riboflavin) for the nonparticipants. Use of the Index of Nutritional Quality (INQ), however, revealed that the quality of the diet of Food Stamp Program participants per 1000 kilocalories was adequate with exception of calcium and iron. Intakes of these nutrients were also not adequate on a 1000 kilocalorie basis for the nonparticipant group. When mean nutrient intakes of the groups were compared using Student's t-test oleicacid intake was the only significant difference found. Being a nonparticipant in the Food Stamp Program was found to be associated with more frequent consumption of cookies, sweet rolls, doughnuts, and honey. The findings of this study contradict the negative image of the Food Stamp Program participant and emphasize the importance of education. ^

A comparison of two statistical methods for analysis of day of the week effect on births from 2005-2007 in Harris County of Texas

The pattern of the births during the week has been reported by many studies. The births occurred in weekends are found consistently less then births occurred in weekdays. This study employed two statistical methods, two-way ANOVA and two-way Friedman's test to analyse the daily variations in amount of births of 222,735 births from 2005-2007 in Harris County, Texas. The two methods were compared on their assumptions, procedures and results. Both of the tests showed a significant result which indicated that the births through the week are not uniformly distributed. The result of multiple comparison demonstrated the births occurring on weekends were significantly different than the births occurring on weekdays with least amount on Sundays.^

Comparison of two statistical methods for rare variant association analysis

Studies have shown that rare genetic variants have stronger effects in predisposing common diseases, and several statistical methods have been developed for association studies involving rare variants. In order to better understand how these statistical methods perform, we seek to compare two recently developed rare variant statistical methods (VT and C-alpha) on 10,000 simulated re-sequencing data sets with disease status and the corresponding 10,000 simulated null data sets. The SLC1A1 gene has been suggested to be associated with diastolic blood pressure (DBP) in previous studies. In the current study, we applied VT and C-alpha methods to the empirical re-sequencing data for the SLC1A1 gene from 300 whites and 200 blacks. We found that VT method obtains higher power and performs better than C-alpha method with the simulated data we used. The type I errors were well-controlled for both methods. In addition, both VT and C-alpha methods suggested no statistical evidence for the association between the SLC1A1 gene and DBP. Overall, our findings provided an important comparison of the two statistical methods for future reference and provided preliminary and pioneer findings on the association between the SLC1A1 gene and blood pressure.^

Comparison of two strategies for the treatment of acute myocardial infarction: In-hospital outcomes analysis

A strategy of pre-hospital reduced dose fibrinolytic administration coupled with urgent coronary intervention (PCI) for patients with STEMI (FAST-PCI) has been found to be superior to primary PCI (PPCI) alone. A coordinated STEMI system-of-care that includes FAST-PCI might offer better outcomes than pre-hospital diagnosis and STEMI team activation followed by PPCI alone. We compared the in-hospital outcomes for patients treated with the FAST-PCI approach with outcomes for patients treated with the PPCI approach during a pause in the FAST-PCI protocol. In-hospital data for 253 STEMI patients (03/2003–12/2009), treated with FAST-PCI protocol were compared to 124 patients (12/2009–08/2011), treated with PPCI strategy alone. In-hospital mortality was the primary endpoint. Stroke, major bleeding, and reinfarction during index hospitalization were secondary endpoints. Comparing the strategies used during the two time intervals, in-hospital mortality was significantly lower with FAST-PCI than with PPCI (2.77% vs. 10.48%, p = 0.0017). Rates of stroke, reinfarction and major bleeding were similar between the two groups. There was a lower frequency of pre- PCI TIMI 0 flow (no patency) seen in patients treated with FAST-PCI compared to the PPCI patients (26.7% vs. 62.7%, p<0.0001). Earlier infarct related artery patency in the FAST-PCI group had a favorable impact on the incidence of cardiogenic shock at hospital admission (FAST-PCI- 3.1% vs. PPCI- 20.9%, p<0.0001). The FAST-PCI strategy was associated with earlier infarct related artery patency and the lower incidence of cardiogenic shock on hospital arrival, as well as with reduced in-hospital mortality among STEMI patients.^

Comparison of Tumor Shrinkage and Cumulative Dose Distribution for Lung Cancers

Background: The physical characteristic of protons is that they deliver most of their radiation dose to the target volume and deliver no dose to the normal tissue distal to the tumor. Previously, numerous studies have shown unique advantages of proton therapy over intensity-modulated radiation therapy (IMRT) in conforming dose to the tumor and sparing dose to the surrounding normal tissues and the critical structures in many clinical sites. However, proton therapy is known to be more sensitive to treatment uncertainties such as inter- and intra-fractional variations in patient anatomy. To date, no study has clearly demonstrated the effectiveness of proton therapy compared with the conventional IMRT under the consideration of both respiratory motion and tumor shrinkage in non-small cell lung cancer (NSCLC) patients. Purpose: This thesis investigated two questions for establishing a clinically relevant comparison of the two different modalities (IMRT and proton therapy). The first question was whether or not there are any differences in tumor shrinkage between patients randomized to IMRT versus passively scattered proton therapy (PSPT). Tumor shrinkage is considered a standard measure of radiation therapy response that has been widely used to gauge a short-term progression of radiation therapy. The second question was whether or not there are any differences between the planned dose and 5D dose under the influence of inter- and intra-fractional variations in the patient anatomy for both modalities. Methods: A total of 45 patients (25 IMRT patients and 20 PSPT patients) were used to quantify the tumor shrinkage in terms of the change of the primary gross tumor volume (GTVp). All patients were randomized to receive either IMRT or PSPT for NSCLC. Treatment planning goals were identical for both groups. All patients received 5 to 8 weekly repeated 4-dimensional computed tomography (4DCT) scans during the course of radiation treatments. The original GTVp contours were propagated to T50 of weekly 4DCT images using deformable image registration and their absolute volumes were measured. Statistical analysis was performed to compare the distribution of tumor shrinkage between the two population groups. In order to investigate the difference between the planned dose and the 5D dose with consideration of both breathing motion and anatomical change, we re-calculated new dose distributions at every phase of the breathing cycle for all available weekly 4DCT data sets which resulted 50 to 80 individual dose calculations for each of the 7 patients presented in this thesis. The newly calculated dose distributions were then deformed and accumulated to T50 of the planning 4DCT for comparison with the planned dose distribution. Results: At the end of the treatment, both IMRT and PSPT groups showed mean tumor volume reductions of 23.6% ( 19.2%) and 20.9% ( 17.0 %) respectively. Moreover, the mean difference in tumor shrinkage between two groups is 3% along with the corresponding 95% confidence interval, [-8%, 14%]. The rate of tumor shrinkage was highly correlated with the initial tumor volume size. For the planning dose and 5D dose comparison study, all 7 patients showed a mean difference of 1 % in terms of target coverage for both IMRT and PSPT treatment plans. Conclusions: The results of the tumor shrinkage investigation showed no statistically significant difference in tumor shrinkage between the IMRT and PSPT patients, and the tumor shrinkage between the two modalities is similar based on the 95% confidence interval. From the pilot study of comparing the planned dose with the 5D dose, we found the difference to be only 1%. Overall impression of the two modalities in terms of treatment response as measured by the tumor shrinkage and 5D dose under the influence of anatomical change that were designed under the same protocol (i.e. randomized trial) showed similar result.