Browsing by Author "Naluyima, Prossy"
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Item Assessment of tuberculosis disease activity in people infected with Mycobacterium tuberculosis and living with HIV: A longitudinal cohort study(EClinicalMedicine, 2022) Kroidl, Inge; Ahmed, Mohamed I.M.; Horn, Sacha; Kibuuka, Hannah; Semwogerere, Michael; Mwesigwa, Betty; Naluyima, Prossy; Kasumba, Joy Mary; Maswai, Jonah; Geldmacher, ChristofEarly detection of asymptomatic incipient tuberculosis (TB) could improve clinical outcomes and reduce the spread of Mycobacterium tuberculosis (MTB) infection, particularly in HIV endemic settings. This study assessed TB disease activity over 5 years in people living with HIV co-infected with MTB using a surrogate biomarker. Methods Between Jan 1, 2013 and Aug 31, 2018, 2014 people living with HIV were screened annually for active TB using the Xpert MTB/RIF diagnostic assay in 11 clinics in Kenya, Tanzania, Uganda, and Nigeria. Longitudinal blood mononuclear cell samples from 46 selected patients with active and recurrent tuberculosis, latent infection, or incipient TB were further analysed for MTB-specific T-cell activation (defined by CD38 expression) as a well-defined surrogate marker for TB disease covering a total of 1758 person-months. Findings MTB-specific CD4 T-cell activation differentiated active, Xpert MTB/RIF positive TB from latent TB with a sensitivity and specificity of 86% and was reduced upon TB treatment initiation. Activated MTB-specific T cells were present in 63% and 23% of incipient TB cases 6 and 12 months before diagnosis of active disease, respectively. Transient increases of MTB-specific T cell activation were also observed in individuals with latent infection, while persistent activation was a hallmark of recurrent TB after the end of treatment. Interpretation In most cases, progression to active TB disease started 6−12 months before diagnosis by clinical symptoms and sputum occurrence of bacilli. Blood biomarkers could facilitate early detection of incipient TB, improve clinical outcomes, and reduce the transmission of MTB. Funding This work was supported by the President’s Emergency Plan for AIDS Relief via a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense [W81XWH-11-2-0174, W81XWH-18-2-0040] and by the Bundesministerium f€ur Bildung und Forschung (BmBF) through funding of the Deutsches Zentrum f€ur Infektionsforschung (DZIF, TTU-TB personalized medicine TTU 02_813).Item In-vitro Immunomodulatory activity of Azadirachta indica A.Juss. Ethanol: water mixture against HIV associated chronic CD4+ T-cell activation/ exhaustion(BMC Complementary Medicine and Therapies, 2021) Olwenyi, Omalla A.; Asingura, Bannet; Naluyima, Prossy; Anywar, Godwin Upoki; Nalunga, Justine; Nakabuye, MariamIn Sub-Saharan Africa, herbal therapy continues to be utilized for HIV-1 disease management. However, the therapeutic benefits of these substances remain ambiguous. To date, little is known about the effects of these plant extracts on chronic CD4 + T-cell activation and exhaustion which is partly driven by HIV-1 associated microbial translocation. Effects of Azadirachta indica, Momordica foetida and Moringa oleifera ethanol: water mixtures on cell viability were evaluated using the Guava PCA system. Then, an in-vitro cell culture model was developed to mimic CD4+ T cell exposures to antigens following HIV-1 microbial translocation. In this, peripheral blood mononuclear cells (PBMCs) isolated from HIV negative (n = 13), viral load < 1000 copies per mL (n = 10) and viral load > 1000 copies per mL (n = 6) study participants from rural Uganda were treated with Staphylococcus enterotoxin B (SEB). Then, the candidate plant extract (A. indica) was added to test the potential to inhibit corresponding CD4+ T cell activation. Following BD Facs Canto II event acquisition, variations in %CD38, %CD69, Human Leukocyte Antigen -DR (HLA-DR), Programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), interferon gamma (IFN γ) and interleukin 2 (IL-2) CD4 + T cell expression were evaluated. Following exposure to SEB, only A. indica demonstrated a concentration-dependent ability to downregulate the levels of CD4 + T cell activation. At the final concentration of 0.500 μg/mL of A. indica, a significant downregulation of CD4 + CD38 + HLA-DR+ expression was observed in HIV negative (p < 0.0001) and both HIV infected groups (P = 0.0313). This plant extract also significantly lowered SEB induced % CD4+ T cell HLADR, PD-1 and Tim-3 levels. PD-1 and CD69 markers were only significantly downmodulated in only the HIV negative ((p = 0.0001 and p = 0.0078 respectively) and viral load< 1000 copies per ml (p = 0.0078) groups. A. indica exhibited the in-vitro immunomodulatory potential to inhibit the continuum of SEB induced CD4+ T-cell activation/ exhaustion without impacting general T-cell specific functions such as cytokine secretion. Additional studies are needed to confirm A. indica as a source of natural products for targeting persistent immune activation and inflammation during ART.Item The Joint Mobile Emerging Disease Clinical Capability (JMEDICC) laboratory approach: Capabilities for high-consequence pathogen clinical research(PLoS Neglected Tropical Diseases, 2019) Naluyima, Prossy; Kayondo, Willy; Wandege, Joseph; Kagabane, Sharon; Tumubeere, Lydia; Kusiima, Brenda; Kibombo, Daniel; Atukunda, Sharon; Nanteza, Christine; Zaman, SaimaFollowing the 2013–2016 Ebola virus outbreak in West Africa, numerous groups advocated for the importance of executing clinical trials in outbreak settings. The difficulties associated with obtaining reliable data to support regulatory approval of investigational vaccines and therapeutics during that outbreak were a disappointment on a research and product development level, as well as on a humanitarian level. In response to lessons learned from the outbreak, the United States Department of Defense established a multi-institute project called the Joint Mobile Emerging Disease Intervention Clinical Capability (JMEDICC). JMEDICC’s primary objective is to establish the technical capability in western Uganda to execute clinical trials during outbreaks of high-consequence pathogens such as the Ebola virus. A critical component of clinical trial execution is the establishment of laboratory operations. Technical, logistical, and political challenges complicate laboratory operations, and these challenges have been mitigated by JMEDICC to enable readiness for laboratory outbreak response operations.Item Pre-positioned Outbreak Research: The Joint Medical Emerging Diseases Intervention Clinical Capability Experience in Uganda(Health security, 2020) Martins, Karen A.; Ayebare, Rodgers R.; Bhadelia, Nahid; Kiweewa, Francis; Waitt, Peter; Mimbe, Derrick; Okello, Stephen; Naluyima, Prossy; Brett-Major, David M.; Lawler, James V.; Millard, Monica; Walwema, Richard; Cardile, Anthony P.; Ritchie, Chi; Kwiecien, Antonia; Badu, Helen; Espinosa, Benjamin J.; Beckett, Charmagne; Bavari, Sina; Zaman, Saima; Christopher, George; Clark, Danielle V.; Lamorde, Mohammed; Kibuuka, HannahThe West Africa Ebola virus disease outbreak of 2014-2016 demonstrated that responses to viral hemorrhagic fever epidemics must go beyond emergency stopgap measures and should incorporate high-quality medical care and clinical research. Optimal patient management is essential to improving outcomes, and it must be implemented regardless of geographical location or patient socioeconomic status. Coupling clinical research with improved care has a significant added benefit: Improved data quality and management can guide the development of more effective supportive care algorithms and can support regulatory approvals of investigational medical countermeasures (MCMs), which can alter the cycle of emergency response to reemerging pathogens. However, executing clinical research during outbreaks of high-consequence pathogens is complicated and comes with ethical and research regulatory challenges. Aggressive care and excellent quality control must be balanced by the requirements of an appropriate infection prevention and control posture for healthcare workers and by overcoming the resource limitations inherent in many outbreak settings. The Joint Mobile Emerging Disease Intervention Clinical Capability was established in 2015 to develop a high-quality clinical trial capability in Uganda to support rigorous evaluation of MCMs targeting high-consequence pathogens like Ebola virus. This capability assembles clinicians, laboratorians, clinical researchers, logisticians, and regulatory professionals trained in infection prevention and control and in good clinical and good clinical laboratory practices. The resulting team is prepared to provide high-quality medical care and clinical research during high-consequence outbreaks.Item Training Needs for Emerging Infectious Diseases Research, Surveillance and Control in High-Risk and Resource-Constrained Settings: Findings and Recommendations for Uganda(ResearchSquare, 2022) Asingura, Bannet; Kiweewa, Francis; Kaawa-Mafigiri, David; Achabo, Sheila; Mimbe, Derrick; Okullo, Allen Eva; Eyu, Patricia; Nanyondo, Jauhara; Naluyima, Prossy; Kandole, Martha; Tindikahwa, Allan; Nalunga, Justine; Ssekitoleko, Mathias; Nakakeeto, Josephine; Nawatti, Jesca; Kibirige, Daniel; Nansalire, WinfredUganda is prone to Emerging Infectious Diseases (EIDs) which can cause serious epidemics and pandemics. Uganda’s capacity for EID research, surveillance and control is improving but still low partly due to inadequate highly knowledgeable and skilled human and animal health workers. To inform the design of training programs that can address Uganda’s health workforce capacity gaps, we conducted a training needs assessment.A qualitative study involving a desk review, 25 key informant interviews and a 1-day consultative workshop to review study findings.The majority of infectious disease research, surveillance and control in Uganda focuses on HIV/AIDS, Tuberculosis, Malaria and viral hemorrhagic fevers e.g., Ebola and Marburg. Health workforce capacity for surveillance and control is robust compared to many other resource-constrained settings but research capacity and output are relatively low, especially for EIDs. Public and private tertiary institutions in Uganda predominantly offer training in primary health care and population studies through problem-based learning, community-based education and services, and Blended Learning (BL). There are several training programs in advanced clinical and epidemiological sciences, but few opportunities in biomedical sciences (e.g. virology, immunology, bioinformatics and predictive modeling), social sciences, One Health and leadership. To address the gaps, the following interventions were recommended: 1) advanced graduate and/or post-graduate training in basic biomedical sciences; 2) short-term training for continuous knowledge and skills development in multidisciplinary/One Health approaches; and 3) pedagogy and mentorship through BL, networking and experiential training programs that effectively leverage North-South collaborations. Training and mentorship should be achieved by (a) conducting most of the in-person didactic and experiential training at Southern tertiary and research institutions, (b) utilizing electronic-learning for didactic training and mentor-mentee interactions with subject-matter experts at Northern institutions, and (c) well-orchestrated placements at Northern institutions for hands-on experience using the latest advances in science and technology.Inadequate health workforce capacity for EID research was identified as a priority gap that requires long and short-term multidisciplinary training interventions. Efficiently leveraging North-South collaborations for e-learning, short-term placements and mentorship will enable Uganda to remain abreast with latest advances in science and technology for EID research, surveillance and control.