This study assessed implementation status of collaborative TB/HIV services in Addis Ababa City Administration aiming to promote better implementation strategies. The study employed mixed research methods and was descriptive. The study design used both quantitative and qualitative data using structured questionnaires and semi-structured interview guides, respectively. The study population for the quantitative design included 1,683 TB/HIV patients from 10 conveniently selected health facilities: Zewditu and Menelik Hospitals, health centres of Lideta, Yeka, Kazanchis, NifaSilk-Lafto-No1, Woreda-7, Kality, Bole and Gulele. All the patients who were on their follow-up cares during the data collection period were interviewed. Participants for qualitative design were 1,650 TB/HIV patients for short answered questions; 8 FGDs among patients; interview of 10 TB/HIV care facility coordinators/health workers and one regional TB/HIV care coordinator, all purposively selected. Quantitative data was analysed using SPSS 15.0, while qualitative data were thematically analysed manually. Majority of HIV patients (92.8%) self-reported that they had been screened for TB; of which, 11.2% were diagnosed for active TB during their follow-up cares. Whereas, 87.1% of TB patients had been offered for HIV test; 79.8% tested; 20.2% tested positive. Knowledge on TB and HIV diseases, transmission and prevention was found to be low. However, participants appreciated the support of the healthcare delivery system in improving their health. Collaborative TB/HIV activities brought additional on-the-job training for healthcare workers; improved flow of logistics and re-arrangement of infrastructures of facilities. The study revealed that, implementation of collaborative TB/HIV activities in Addis Ababa need boosting. The study recommends the need for coordinated efforts of all stakeholders for improving implementation of collaborative TB/HIV care services, as identified by this study. The contribution of this study developed pocket-guide for healthcare workers on collaborative TB/HIV care services, which provides guidance in promoting better TB/HIV care / Health Studies / D. Litt. et Phil. (Health Studies)

Tuberculosis remains a major public health problem and one of the leading causes of death worldwide. Human genetic factors determine susceptibility to M. tuberculosis (M. tb) infection and predispose to clinical TB. Genome-wide association studies (GWAS) aim to discover human genes associated with susceptibility to TB. Recently, a GWAS conducted by our lab identified a new TB-associated gene ASAP1 that encodes an Arf GTPase-activating protein (GAP). ASAP1 is known to be involved in regulation of actin and membrane remodeling. My Ph.D. included three projects. In my first project, I used RNAi and CRISPR-Cas9 technologies to study the role of ASAP1 in dendritic cells and macrophages, cells that play critical roles during mycobacterial infection. I demonstrated that in these cells ASAP1 is essential for migration and phagocytosis of mycobacteria. I characterized proteins that ASAP1 interacts with during mycobacterial infection. Finally, I found that the ASAP1-mediated pathway regulates expression of a large number of the immune response genes. These findings emphasize the important role of ASAP1 in mycobacterial infection and explain its involvement in TB pathogenesis. In my second project, I was involved in a large study conducted by our laboratory that characterized transcriptional responses to M. tb infection in macrophages from a cohort of 144 healthy subjects. We used RNA-Seq to study transcriptomes of the infected and non-infected macrophages and identified differentially expressed genes. We also genotyped DNA polymorphisms of these subjects and studied the association between genetic variants and levels of gene expression, which allows us to identify expression quantitative trait loci (eQTLs), i.e., DNA polymorphism that affect gene expression. In particular, we identified an eQTL located in the TLR10-TLR1-TLR6 gene cluster. In non-infected macrophages, a group of polymorphisms in this region was associated in cis with the level of expression of TLR1, but not of the other two TLR genes. In M. tb-infected macrophages the same polymorphisms were associated in trans with levels of expression of 37 genes. This network includes essential immune response proteins, including multiple cytokines and chemokines. The discovery of this TLR1-driven network will help to better understand mechanisms of macrophage responses to mycobacterial infection. Our study also identified a DNA polymorphism located upstream of the ARHGAP27 gene, regulating its expression in infected and non-infected macrophages. In our GWAS this polymorphism was associated with TB risk, which implicated ARHGAP27 in TB pathogenesis. The ARHGAP27 protein is a Rho-GAP involved in the endocytic pathway. In my third project, I used CRISPR technology to establish the ARHGAP27-knockout macrophage cell model and characterized the function of ARHGAP27, showing that it is involved in cell migration and phagocytosis of mycobacteria. Taken together, my studies highlighted functional mechanisms implicating TB-associated GAP proteins ASAP1 and ARHGAP27 in mycobacterial infection and TB pathogenesis.

Foram medidos os momentos magnéticos dos estados da banda rotacional do estado fundamental do ANTPOT 159 Tb, através da técnica da distribuição angular perturbada, utilizando-se o campo magnético transiente. Os estados do ANTPOT. 159 Tb foram populados via excitação coulombiana com feixe de ANTPOT. 35 Cl a 88 Me V, sendo os raios -y, emitidos na desexcitação dos estados, observados em coincidência com as partículas retroespalhadas do feixe. Os momentos magnéticos medidos neste trabalho, foram comparados com as previsões de modelos híbridos (rotor+partícula e rotor triaxial+quase-partícula), nos quais a hamiltoniana do núcleo é separada em uma parte fenomenológica que descreve o caroço e uma parte microscópica que leva em conta o movimento da partícula desemparelhada. Os resultados experimentais também foram interpretados com um cálculo puramente microscópico, baseado no modelo de camadas com projeção de momento angular. Os níveis de energia da banda do estado fundamental são bem descritos pelos modelos, embora o staggering em energia previsto pelo modelo rotor triaxial+quase-partícula apresente uma fase de oscilação oposta à observada. Os momentos magnéticos experimentais são bem reproduzidos pelos modelos, nos quais a inclusão de outras configurações sugere uma pequena oscilação, observada nos resultados experimentais. As probabilidades de transição magnéticas B(M1) não são bem descritas por nenhum dos modelos, nos quais a inclusão de várias configurações atenua os valores calculados. / Magnetic moments of the levels in the ground state rotational band of 159Tb were measured using the transient magnetic field perturbed angular distribution technique. The levels in 159Tb were populated by Coulomb excitation with an 88 MeV beam and the deexciting rays were observed in coincidence with backscattered projectiles. The magnetic moments measured in this work were compared with hybrid models (rotor+particle and triaxial rotor+quasiparticle) in which the Hamiltonian of the nucleus is separated in a phenomenological part describing the core and a rnicroscopic part which takes into acconnt the movement of the unpaired particle. The experimental results were also interpreted with a purely microscopic calculation based on the angular momentum projection shell model. The energy levels in the ground state band are well described by the models, although the energy staggering predicted in the triaxial rotor+quasi-particle calculation has a phase opposite to the observed one. The experimental magnetic moments are well reproduced by the models, with the band miring suggesting a slight oscillation as observed in the experimental data. The magnetic transition probabilities B(M1) are not well described by the models, in which the band mixing attenuates the calculated values.

Made available in DSpace on 2014-07-29T15:26:20Z (GMT). No. of bitstreams: 1 TeseLorenaCristina2010.pdf: 1826396 bytes, checksum: fc176dacea640559fe92237b2a050e60 (MD5) Previous issue date: 2010-12-07 / Tuberculosis (TB) is a serious global public health. In Brazil for the confirmed TB cases is recommended a multi-drug therapy regimen which combines different drugs during at least 6 month. However, because of treatment inconsistency, the emergency and spread of drug resistant M. tuberculosis become a serious threat. Actually, strains resistant to at least one drug used in the TB treatment have been one of the main factor that avoid the effective TB control. According to WHO M. tuberculosis strains that are resistant to at least INH and RMP, the key drugs used in the TB treatment, are considered multidrug resistant (MDRTB). The main mutations responsible for INH and RMP resistance occur at some specific regions in the katG, inhA and rpoB genes. We analyzed by phenotypic and genotypic methods the susceptibility profile of M. tuberculosis isolated from 132 patients treated at a reference hospital in Goiânia-Goiás, between January of 2006 and July of 2007 and then performed the resistant strains genotypic identifications by RFLP-IS6110. Additionally, clinical and epidemiological informations from the patients was collected. A high frequency of drug resistance was observed in previously untreated patients (13.6% to at least one antibiotic and 6.1% MDR-TB), and a high DNA polymorphism was observed among these strains. Our results suggest that the prevalence of resistant TB in Goiás is underestimated and that resistance in new TB cases was not associated with an outbreak in this region. / A tuberculose (TB) é um problema de saúde pública em todo o mundo. Nos casos confirmados de tuberculose (TB) no Brasil, preconiza-se o esquema multidroga terapêutico que combina diferentes drogas por um período mínimo de 6 meses de tratamento. Devido, principalmente, ao tratamento inadequado, a emergência e disseminação de linhagens de M. tuberculosis multi resistentes a drogas se tornou uma séria ameaça. Atualmente, linhagens resistentes a pelo menos uma droga utilizada no tratamento da TB têm sido um dos principais fatores que impedem o controle efetivo da doença. De acordo com a OMS, linhagens multi-droga resistentes (MDR-TB) são aquelas resistentes a no mínimo isoniazida (H) e rifampicina (R), as principais drogas utilizadas no tratamento da TB. As principais mutações responsáveis por desenvolvimento de resistência à H e R acontecem principalmente em algumas regiões dos genes katG, inhA e rpoB, respectivamente. No presente estudo foi analisado o perfil de suscetibilidade de M. tuberculosis isolados de 132 pacientes atendidos em um hospital de referência em doenças infecciosas em Goiânia-Goiás, no período de janeiro de 2006 a julho de 2007. Foram coletados dados clínicos, epidemiológicos e utilizados testes de susceptibilidade à drogas, sequenciamento parcial dos genes katG e rpoB, análise de mutação por PCR do gene inhA e genotipagem por RFLP-IS6110. Foi observada uma alta frequência de resistência à drogas em pacientes virgens de tratamento (13,6% de resistência a no mínimo uma das droga testada e 6,1% de MDR-TB), e um alto grau de polimorfismo de DNA entre as linhagens resistentes. Estes resultados sugerem que a prevalência de linhagens resistentes na região está subestimada e que resistência aos antimicrobianos não está associada a um surto específico na região.

In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models. Comparative numerical results are also provided for each model.

<p>Background: Although clinicians encounter antimycobacterial treatment in Human mmunodeficiency (HIV)-infected children as one of the most common treatments coadministered with antiretroviral treatment (ART), quantitative data on the extent of antimycobacterial treatment among HIV-infected children at the time of commencement of ART and at different times during ART is scarce. The baseline risk factors associated with being on both ART and antimycobacterial treatments are not known and it remains to be elucidated how the different exposure factors impact on the antimycobacterial treatment-free survival of children who begin ART without antimycobacterial treatment.Objectives: To describe the prevalence of antimycobacterial treatment among children at the time of starting ART and the antimycobacterial treatment-free survival after starting ART. Design: A retrospective cohort study based on record reviews at the Harriet Shezi children&lsquo / s clinic (HSCC).Population: HIV-infected children less than fifteen years of age presumed ART na&iuml / ve started on ART at HSCC.Analysis: A descriptive analysis of the prevalence of antimycobacterial treatment at time of start of ART was done. Kaplan Meier (KM) survival curves were used to determine the antimycobacterial treatment-free survival and logistic regression was used to analyze the association between baseline factors and future antimycobacterial treatment among children who had no antimycobacterial treatment at time of start of ART. Results: The prevalence of antimycobacterial treatment at the time of starting ART was 518/1941 (26.7%, 95% confidence interval (CI): 24.7-28.7). Among children who started ART without antimycobacterial treatment, the KM cumulative probability of antiretroviral and antimycobacterial (ART/antimycobacterial) co-treatment in the first 3 months of starting ART was 4.6% (95% CI: 4.1- 5.2), in the first 12 months it was 18.1% (95% CI: 17.0-19.2) and in the first 24 months of starting ART it was 24% (95% CI: 21.9-25.1). Survival analysis suggested that children with high baseline viral load, advanced World Health Organization (WHO) stage of disease, very low normalized weight for age (waz) and very young age (less than one year) at start of ART had significantly reduced antimycobacterial treatment-free survival (log rank p &lt / 0.05) in the first two years of starting ART. In the logistic regression model, age less than one year {Odds ratio (OR): 3.7 (95% CI: 2.2-6.0 / p &lt / 0.0001)} and very low weight for age Z-score (waz &lt / -3) {OR / 2.2 (95% CI: 1.4-3.6 / p = 0.0015)} were the two critical risk factors independently associated with future antimycobacterial treatment. Conclusions: Antimycobacterial treatment is extremely common among HIV-infected children at the time of starting ART and early after starting ART and the incremental risk of being on ART/antimycobacterial co-treatment decreases with time on ART. The results emphasize the need for a heightened and careful alertness for mycobacterial events especially among children starting ART with severe malnutrition and those who start ART at age less than one year. The results further suggest that it is probably optimal to start ART in children before their nutritional status has deteriorated severely in the course of the HIV disease so that they get protection against mycobacterial events by early ART.</p>

<p>The global impact of the converging dual epidemics of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major public health challenges of our time, because in many countries, human immunodeficiency virus (HIV) and mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. It is found that infection with HIV increases the risk of reactivating latent TB infection, and HIV-infected individuals who acquire new TB infections have high rates of disease progression. Research has shown that these two diseases are enormous public health burden, and unfortunately, not much has been done in terms of modeling the dynamics of HIV-TB co-infection at a population level. In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models.&nbsp / Comparative numerical results are also provided for each model.</p>

<p>The global impact of the converging dual epidemics of tuberculosis (TB) and human immunodeficiency virus (HIV) is one of the major public health challenges of our time, because in many countries, human immunodeficiency virus (HIV) and mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. It is found that infection with HIV increases the risk of reactivating latent TB infection, and HIV-infected individuals who acquire new TB infections have high rates of disease progression. Research has shown that these two diseases are enormous public health burden, and unfortunately, not much has been done in terms of modeling the dynamics of HIV-TB co-infection at a population level. In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models.&nbsp / Comparative numerical results are also provided for each model.</p>

In this thesis, we study these models and design and analyze robust numerical methods to solve them. To proceed in this direction, first we study the sub-models and then the full model. The first sub-model describes the transmission dynamics of HIV that accounts for behavior change. The impact of HIV educational campaigns is also studied. Further, we explore the effects of behavior change and different responses of individuals to educational campaigns in a situation where individuals may not react immediately to these campaigns. This is done by considering a distributed time delay in the HIV sub-model. This leads to Hopf bifurcations around the endemic equilibria of the model. These bifurcations correspond to the existence of periodic solutions that oscillate around the equilibria at given thresholds. Further, we show how the delay can result in more HIV infections causing more increase in the HIV prevalence. Part of this study is then extended to study a co-infection model of HIV-TB. A thorough bifurcation analysis is carried out for this model. Robust numerical methods are then designed and analyzed for these models. Comparative numerical results are also provided for each model.

<p>Background: Although clinicians encounter antimycobacterial treatment in Human mmunodeficiency (HIV)-infected children as one of the most common treatments coadministered with antiretroviral treatment (ART), quantitative data on the extent of antimycobacterial treatment among HIV-infected children at the time of commencement of ART and at different times during ART is scarce. The baseline risk factors associated with being on both ART and antimycobacterial treatments are not known and it remains to be elucidated how the different exposure factors impact on the antimycobacterial treatment-free survival of children who begin ART without antimycobacterial treatment.Objectives: To describe the prevalence of antimycobacterial treatment among children at the time of starting ART and the antimycobacterial treatment-free survival after starting ART. Design: A retrospective cohort study based on record reviews at the Harriet Shezi children&lsquo / s clinic (HSCC).Population: HIV-infected children less than fifteen years of age presumed ART na&iuml / ve started on ART at HSCC.Analysis: A descriptive analysis of the prevalence of antimycobacterial treatment at time of start of ART was done. Kaplan Meier (KM) survival curves were used to determine the antimycobacterial treatment-free survival and logistic regression was used to analyze the association between baseline factors and future antimycobacterial treatment among children who had no antimycobacterial treatment at time of start of ART. Results: The prevalence of antimycobacterial treatment at the time of starting ART was 518/1941 (26.7%, 95% confidence interval (CI): 24.7-28.7). Among children who started ART without antimycobacterial treatment, the KM cumulative probability of antiretroviral and antimycobacterial (ART/antimycobacterial) co-treatment in the first 3 months of starting ART was 4.6% (95% CI: 4.1- 5.2), in the first 12 months it was 18.1% (95% CI: 17.0-19.2) and in the first 24 months of starting ART it was 24% (95% CI: 21.9-25.1). Survival analysis suggested that children with high baseline viral load, advanced World Health Organization (WHO) stage of disease, very low normalized weight for age (waz) and very young age (less than one year) at start of ART had significantly reduced antimycobacterial treatment-free survival (log rank p &lt / 0.05) in the first two years of starting ART. In the logistic regression model, age less than one year {Odds ratio (OR): 3.7 (95% CI: 2.2-6.0 / p &lt / 0.0001)} and very low weight for age Z-score (waz &lt / -3) {OR / 2.2 (95% CI: 1.4-3.6 / p = 0.0015)} were the two critical risk factors independently associated with future antimycobacterial treatment. Conclusions: Antimycobacterial treatment is extremely common among HIV-infected children at the time of starting ART and early after starting ART and the incremental risk of being on ART/antimycobacterial co-treatment decreases with time on ART. The results emphasize the need for a heightened and careful alertness for mycobacterial events especially among children starting ART with severe malnutrition and those who start ART at age less than one year. The results further suggest that it is probably optimal to start ART in children before their nutritional status has deteriorated severely in the course of the HIV disease so that they get protection against mycobacterial events by early ART.</p>