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Background Host blood transcriptomic signatures, such as RISK11, have potential as tests for diagnosing and predicting tuberculosis. This thesis aimed to review the literature, evaluate host and non-host factors associated with variability of the RISK11 signature and impact on discriminatory performance and evaluate RISK11 performance in combination with tests of Mycobacterium tuberculosis sensitization. Methods A systematic review of discriminatory performance of transcriptomic signatures for tuberculosis was conducted. RISK11, QuantiFERON-TB Gold-Plus and host factors were analysed in a prospective cohort, in which a cross-sectional study of upper respiratory organisms was nested. Effects on RISK11 were quantified using multivariable generalised regression. Discriminatory performance of RISK11, and RISK11/QuantiFERON combinations, were quantified by area under the curve and/or sensitivity and specificity. Results In the literature, one signature (90% sensitivity; 74% specificity) met the minimal criteria for a triage test; one signature (86% sensitivity; 84% specificity) met the minimal criteria for a predictive test. In the prospective cohort, RISK11 scores were higher among individuals with prevalent tuberculosis (+18.90%), night sweats (+14.65%) and incident tuberculosis (+7.29%). Cough was associated with 72.55% higher RISK11 score in prevalent tuberculosis cases. Stratification by cough improved diagnostic performance from area under curve of 0.74 overall, to 0.97 in cough-positive participants. Adjustment for host factors affecting controls did not change RISK11 discriminatory performance. In the cross-sectional study, RISK11 scores were higher by +16.7%, +67.8% and +13.5% in participants with coronavirus, influenza and rhinovirus, respectively, such that RISK11 could not differentiate prevalent tuberculosis from upper respiratory viruses. Compared to RISK11, the Either-Positive test combination decreased diagnostic negative likelihood ratio from 0.7 to 0.3, and prognostic negative likelihood ratio from 0.9 to 0.3, but did not improve upon QuantiFERON alone. Compared to QuantiFERON, the Both-Positive test combination increased diagnostic positive likelihood ratio from 1.3 to 4.7, and prognostic positive likelihood ratio from 1.4 to 2.8, but did not improve upon RISK11 alone. Conclusion RISK11 holds promise as a triage test for tuberculosis. Further optimisation, or development of new signatures is needed to improve discrimination of subclinical tuberculosis, without cough, and to mitigate the impact of viral co-infection. RISK11/QuantiFERON combination testing is not recommended.

Schistosomiasis is a devastating and neglected tropical disease caused by Schistosoma spp. parasites. The disease remains greatly neglected by global health control programmes thus classified as a top neglected tropical disease of humankind. One of the most common species of these parasites, Schistosoma mansoni, causes hepatosplenic schistosomiasis and distributes widely in sub-Saharan Africa. Schistosoma mansoni is physiologically debilitating and potentially deadly with a known potential as a master regulator of the host immune responses. However, the mechanistic bases and the scope of this immunoregulatory potential of S. mansoni still remain poorly understood. This study explored the influence of S. mansoni-driven schistosomiasis on vaccine-induced memory immunity in schoolchildren from a rural endemic area of Cameroon and in laboratory mice. As a proof of concept, a well-established anti-viral vaccination programme with wide global coverage, i.e., anti-polio vaccination, was evaluated for its sustainability in the face of schistosomiasis in human and mouse hosts. Our findings using the poliovirus specific enzyme-linked immunosorbent assay revealed a schistosomiasis-associated impairment of polio specific serologic antibody memory responses in previously vaccinated schoolchildren and mice, as judged by significantly reduced serum anti-polio IgG antibody levels. To explore our findings further, cellular evaluations were conducted using flow cytometry in mouse modes of vaccination and schistosomiasis. The reduction of anti-polio elicited antibody responses was paralleled by the general depletion, through reduced survival and increased cell death, of bone marrow plasma cells and plasma blasts in schistosomiasis-diseased mice. Notably, schistosomiasis reduced memory T cell responses as well in vaccinated hosts and considerably impaired the expression of survival markers on antibody-producing long term plasma cells in the bone marrow. When attempting to control the disease by administration of the sole commercially available drug for schistosomiasis control, praziquantel, the parasite-driven depletion of the plasma cell and memory T cell compartment was restored followed by a partial recovery of antibody-producing abilities in vaccinated hosts. Taken together, our findings unprecedentedly demonstrate how schistosomiasis might negatively influence the efficacy and potentially the effectiveness of anti-viral vaccine memory immunity. Additionally, we present findings on how strategic therapeutic interventions against schistosomiasis might positively influence vaccine-elicited anti-viral immunity in schistosomiasis-diseased hosts. Our results have robust implications for future more informed deployment of effective vaccination campaigns, beyond the sole consideration of coverage and encourage frequent mass drug administration of praziquantel in schistosomiasis-endemic areas to ensure the sustainability of vaccine elicited responses thus protection of the hosts against vaccine preventable diseases.

Inner ear development involves the assembly of cells from a variety of different embryological origins. There is an unmet need for developing a human inner ear model in vitro to mimic both the complex structure and the function of the inner ear outside of the body. Since the human inner ear is difficult to biopsy, a major challenge is to accurately recapitulate the embryonic development of the inner ear from hiPSCs. However, our limited understanding of the microenvironmental niche in which human otic progenitors emerge and develop is a key barrier to progress. This project builds on our previous discovery of a 3D culture system that uses hiPSCs to generate inner ear (otic) organoid containing sensory epithelium, neurons, and mesenchymal cells. We also combine novel platforms such as organoid-on-a-chip (triple-decker inserts) to enable high-resolution time-lapse imaging of the inner ear vesicles. This provides a useful tool to study inner ear diseases and aids in the discovery of safe and precise therapies. / 2026-03-06T00:00:00Z

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Prostate cancer is the second most frequent cancer diagnosis and one of the leading causes of cancer death for American men. In the US, Black men have higher rates of prostate cancer with worse outcomes. We seek to investigate known biomarkers of prostate cancer in the diverse population at our urban safety net hospital and to establish any link between location of cancer occurrence and the differential prognosis between two cohorts, Black men and non-Black men. A variety of archival specimens for the Black cohort were selected with varying Gleason scores and patient ages; specimens for the non-Black cohort specimens were then matched based on age. Clinical slides were reviewed by a pathologist and marked for cancerous and benign regions. Tissue microarrays (TMAs) were made from the corresponding formalin-fixed paraffin-embedded (FFPE) blocks. Each TMA included 30 cases, 15 from each cohort, from the same approximate time period, but varied in patient age and Gleason score of the subjects. The TMAs were sectioned and stained, both manually and with an auto-stainer, with H&E, PTEN and ERG. Pathologists reviewed the slides. We pulled demographic and prognostic data from a total of 607 and found that the Black cohort had a higher percentage of men under the age of 55. For the TMAs we reviewed a total of 302 specimens. No association was found between PTEN staining and cohort. Significant association (p= < 6.7e-5) was found between ERG staining and cohort. No association was found between age group and location of tumor. Significant association (p =0.005) was found between descent and location of the tumor. Of the 302 patients, 14 were positive for both PTEN and ERG staining. Our results demonstrate no correlation between PTEN staining and cohort or age group and location of tumor; however, there is significant association between ERG staining and cohort and cohort and location of the tumor. As seen in previous studies there were more younger men in the Black cohort. In the future we hope to further validate our results by using fresh tissue along with archival specimens from the last 6 years. Next steps are to investigate additional markers on the TMAs made and determine if there is correlation between the findings in metadata for known and developing biomarkers of prostate cancer. Should correlations occur between biomarkers, zone, and biochemical recurrence, this could be used to guide treatment options.