Browsing by Subject "Treatment"

Lipids represent an important source of nutrition for infecting mycobacteria, accumulating within the necrotic core of granulomas and present in foamy macrophages associated with mycobacterial infection. In order to better understand the timing, process and importance of lipid accumulation, we developed methods for direct in vivo visualization and quantification of lipid accumulation using the zebrafish-M. marinum model of infection. We find that neutral lipids accumulate cell autonomously in mycobacterium-infected macrophages in vivo during early infection, with detectable levels of accumulation by two days post-infection. Reducing available free cholesterol and neutral lipids during early infection via treatment with ezetimibe, an FDA-approved drug, resulted in a reduction of bacterial growth in vivo. The effect of ezetimibe in reducing bacterial growth was dependent on the mce4 operon, a key bacterial determinant of lipid utilization. Thus, in vivo, lipid accumulation can occur cell autonomously at early timepoints of mycobacterial infection, and this early lipid accumulation confers a growth advantage to infecting mycobacteria.

This accumulation represents a perturbation of the normal homeostatic mechanisms by which intracellular lipids are tightly controlled. Under homeostatic conditions macrophages are central to the function of returning excess lipids to the liver where they are processed for excretion via the digestive tract. This function of macrophages, termed reverse cholesterol transport, results from the uptake of excess extracellular lipids, followed by the coordinated efflux of these lipids through the transport proteins ABCA1 and ABCG1 and packaging into HDL particles containing ApoAI and ApoAII. This process is controlled via the action of nuclear receptors including PPARγ, PPAR-α, and LXRα.

We performed RNA-seq analysis of gene expression in macrophages both uninfected and infected with mycobacteria and observed a profound down-regulation of all the major lipoproteins. The HDL associated lipoproteins ApoAI and ApoAII were the most profoundly down regulated. Based on this observation we sought to investigate the role of nuclear receptors involved in intracellular lipid sensing and control of apolipoprotein expression. We determined that agonism and antagonism of LXRα signaling decrease and increase infection burden during in vivo studies respectively. We further found that the ApoAI agonizing fibrate drugs fenofibrate and gemfibrozil reduce mycobacterial infection in vivo. This work demonstrates that lipid lowering agents already approved for use in humans might function as relevant adjuvant therapies toward treatment of mycobacterial infections.

Introduction: Mortality among HIV-infected individuals in sub-Saharan Africa, the region most affected by the HIV epidemic, has declined remarkably since the rapid scale-up of antiretroviral therapy (ART). Despite encouraging trends, an unacceptably high number of people in this region continue to die from HIV disease, accounting for nearly 70% of all HIV deaths globally. Although a substantial number of these deaths could be averted by further expansion of ART coverage, high rates of morality for those initiated on treatment threaten the success of large-scale ART coverage. A knowledge of the predicators of death among individuals on ART could lead to targeted interventions, thus reducing excess mortality. In this study, we investigated a cohort of HIV-infected individuals on ART in the Coping with HIV/AIDS in Tanzania (CHAT) to describe which predictors are associated with the outcome of death.

Methods: The Coping with HIV/AIDS in Tanzania (CHAT) study was an observational cohort study conducted between 2008 and 2012. A cohort of HIV-infected individuals on ART are analyzed by Kaplan-Meier models to estimate mortality and Cox proportional hazards to identify predictors of mortality.

Results: There were 25 deaths in 1775 person-years of follow-up. This overall mortality rate provides an incidence density of 1.4 deaths per 100 person-years. In univariate analysis, the factors associated with the predictor of mortality were male gender, secondary or higher education, and pre-ART CD4 count below 100 cells per milliliter. No such associations were found for age, marital status, asset score, underweight status, SF-8 physical health functioning, depressive symptoms, and perceived stigma. In multivariable analysis, significant predictors of mortality were gender, secondary or higher education, and pre-ART CD4 below 100 cells per milliliter.

Conclusion: A lower rate of mortality was detected among this cohort of HIV-infected individuals on ART in Tanzania. Male gender and pre-ART CD4 cell count below 100 cells per milliliter significant predictors of mortality. Interventions that target earlier engagement in care and improved outcomes for high risk groups such as men will lead to further optimization of HIV care.

Abstract

Background: While highly preventable cervical cancer remains a leading cause of

cancer in women globally. Sub-Saharan Africa is disproportionately affected, and in

Kenya specifically, over 4,800 new cervical cancer cases are diagnosed and over 2,000

deaths occur each year. While screening for human papillomavirus (HPV) is a more

cost-effective screening strategy with the potential to increase screening uptake, there is

substantial lost to follow-up (LTFU) for treatment following a positive HPV screen. This

study aimed to identify the predictors of successful treatment acquisition and explore

the barriers and facilitators to seeking treatment among HPV positive women.

Methods: This mixed-methods study was integrated into an ongoing clusterrandomized

trial of implementation strategies in rural western Kenya. This study

randomly selected 100 HPV positive women from the original study database and

conducted a treatment acquisition behavior survey. The study sought a 50/50 ratio of

women who were treated and LTFU, but obtained data from 61 treated women and 39

LTFU women. A subset of 10 women in each group were then selected for in-depth

interviews. Analysis included descriptive statistics to compare treated and LTFU

women’s responses to the survey questionnaire. Interview transcripts were coded and

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analyzed through code-by-code comparisons of women who were treated and women

who were LTFU.

Results: Cost of transportation and distance to the health facility were the most

common challenges in seeking treatment among both treated and LTFU women. Among

women who sought treatment, 67% (n=41) reported that their peers knew their HPV test

result, whereas among LTFU women only 38% (n=15) reported that their peers knew

their HPV test result (p=0.007). There was a significant difference in knowing their peers’

HPV result between treated and LTFU women (p=0.03). Partner support was described

by treated and LTFU women similarly, in that most women reported that they relied on

their partners for transportation money, and that men not understanding the disease

may prevent them from supporting their wives in seeking treatment. Additional barriers

included fear of the treatment process, stigma within their community, logistical

barriers, and lack of information on the disease and treatment. Facilitators to treatment

seeking included peer encouragement, support and encouragement of their children,

involving men in educational sessions, bringing facilities closer and providing

transportation to the health facility.

Conclusions: Cost of transportation, distance to the treatment facility, support of

partners and children, feelings of fear and stress, stigma within the community and

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logistical barriers were reported similarly across treated and LTFU groups. The greatest

disparity between the two groups was a lack of social support among LTFU women.

Given the potential impact of involving men and women in the community in

educational sessions, and promoting treatment seeking in groups, interventions that use

these treatment facilitators are needed.

Extremal quantile index is a concept that the quantile index will drift to zero (or one)

as the sample size increases. The three chapters of my dissertation consists of three

applications of this concept in three distinct econometric problems. In Chapter 2, I

use the concept of extremal quantile index to derive new asymptotic properties and

inference method for quantile treatment effect estimators when the quantile index

of interest is close to zero. In Chapter 3, I rely on the concept of extremal quantile

index to achieve identification at infinity of the sample selection models and propose

a new inference method. Last, in Chapter 4, I use the concept of extremal quantile

index to define an asymptotic trimming scheme which can be used to control the

convergence rate of the estimator of the intercept of binary response models.

Abstract

Background

Significant delay occurs in initiating cancer treatment worldwide. In Uganda, there has been an increase in HIV/AIDS related malignancies due to the large number of people with HIV/AIDS. One particular cancer that has had a very large increase in prevalence is Kaposi Sarcoma. Despite the availability of chemotherapy for Kaposi Sarcoma at the Uganda Cancer Institute, many patients will present with advanced disease. Most studies on delay in cancer have been done in developed countries and very few have been done in Africa. Even fewer studies have been done in the context of HIV/AIDS and KS where patients are under continuous care. This study sought to establish the causes of treatment delay and describe the pathway to care in KS patients in Uganda.

Methods

The study was a cross sectional study carried out at the Uganda Cancer Institute. The study enrolled adult consenting patients that presented to the Uganda Cancer Institute with histologically diagnosed Kaposi Sarcoma. The study used an interviewer-administered survey that comprised questions on demography, socio-economic status as well as different aspects of HIV/AIDS and KS care. The study lasted from July to August 2011.

Findings

180 patients were enrolled in the study, and 27% experienced delays in treatment initiation lasting more than 3 months. 44% of the study participants used traditional healers and of these, 33% experienced delays greater than 3 months (P value=0.05) compared to 23% in those that did not use traditional healers. The odds of delay in those who visited traditional healers was 2 times the odds of delay in those who did not use traditional healers (P Value= 0.07). Other factors that were correlated with delay were education status, attendance of HIV care clinics, use of HAART and marriage.

Discussion

Treatment delay still remains a significant problem in cancer patients in Uganda despite the increasing knowledge about cancer, and in HIV/AIDS related malignancies, despite the availability of evaluation in HIV care clinics. Some of the factors responsible for treatment delay use of traditional healers, and knowledge of cancer and the potential care, which is available. It is important that we address the lack of knowledge about cancer symptoms in the patients if we are to address treatment delay sufficiently. It is also imperative that we address the challenges in the health care systems that contribute to delay in order to ensure access to diagnostic and treatment services.