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Transcriptomic signatures of recurrent tuberculosis disease and treatment response in HIV-infected individuals
Get PDFHIV-infected persons are at particularly high risk of tuberculosis (TB) disease, especially in TB endemic countries where M. tuberculosis transmission is common. Although antiretroviral therapy (ART) reduces risk of TB, it does not return to that of HIV-uninfected persons. In addition, a previous history of TB disease significantly increases the risk of recurrent TB disease. Identification of HIV-infected individuals at greatest risk of recurrent TB for highly targeted therapy before disease manifestation would be a major advance in the fight against TB. This would also allow the provision of TB treatment in persons with subclinical TB. Diagnosis of TB in HIV-infected persons is markedly undermined by the paucibacillary nature of HIV-associated disease. A non-sputum based diagnostic test that is highly sensitive and specific, such as a blood-based RNA signature, would be an important new tool. Such a test may also facilitate monitoring of TB treatment, opening the possibility for customizing the duration of TB treatment to that necessary for cure. We previously discovered and validated a 16-gene transcriptomic signature with promising prognostic and diagnostic utility for TB in HIV-uninfected persons. The transcriptomic signature could predict progression to active TB disease up to a year before diagnosis and was shown to be a useful tool for TB treatment response monitoring in a treatment cohort of HIV-uninfected persons. The signature was reduced to an 11-gene signature to improve throughput with equivalent prognostic and diagnostic performance. In addition, we developed a smaller, 6-gene signature in preparation for translation to point-of-care testing. In this thesis, we aimed to determine (1) the diagnostic performance of these two transcriptomic signatures in HIV-infected persons, (2) whether they could predict recurrent TB disease in HIV infected persons, and (3) their utility to monitor TB treatment response in HIV infected persons. To assess aim 1, we designed a cross-sectional study of HIV-infected (n=40) and uninfected persons (n=60), each comprising equal numbers of active TB cases and QuantiFERON-positive controls. To assess aims 2 and 3, we designed retrospective substudies among participants enrolled into two clinical studies previously completed by our collaborators at CAPRISA, namely the TRuTH and IMPRESS studies. In the TRuTH cohort participants who developed recurrent TB diagnosis, diagnosed by microbiological testing of induced sputum, were assigned as progressors (n=43), while those who remained asymptomatic were assigned as non-progressors (n=86). In the IMPRESS cohort, participants with a new diagnosis of recurrent TB who initiated TB treatment were stratified into early (n=44) and late (n=19) converters based on time to sputum culture conversion from diagnosis. RNA was isolated from cryopreserved PBMC or PAXgene whole blood and gene expression measured by microfluidic qRT-PCR. Signature scores were generated using in-house customised scripts in R and performance of the signatures was measured using receiver operating characteristic area under the curve (ROC AUC), calculated using the pROC and verification packages in R. The 11-gene and 6-gene signatures could diagnose active TB disease in HIV infected persons with good accuracy (AUC = 0.83 and 0.92, respectively), although performances were lower than those observed in HIV-uninfected persons (AUC = 0.97 and 0.96). Signature performance was decreased in HIV-infected persons due to higher signature scores, reflecting high expression of IFN-stimulated genes, especially in HIV-infected controls. In the TRuTH cohort, these signatures could identify those with recurrent TB within 3 months of diagnosis (AUC = 0.77, p = 0.003), suggesting detection of subclinical disease. Scores of both signatures decreased during TB treatment in the IMPRESS cohort, in participants with early or late sputum conversion. Importantly, two months after initiating TB treatment, the ACS 11-gene signature could differentiate early from late converters. Detectable plasma viral load was associated with higher signature scores in both cohorts, leading to a decrease in signature specificities. We show that the 11-gene and 6-gene signatures performed well as blood-based diagnostic tests for active TB disease in HIV-infected persons. The signatures could detect recurrent TB disease during the subclinical phase of disease progression and demonstrated promise as treatment response markers in HIV-infected persons. The signatures performed best in persons with effectively suppressed HIV load, highlighting the importance of ART adherence and integration of HIV and TB care for effective clinical management of TB
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Delayed BCG Vaccination: Effect on the Infant Immune Response, Unrelated Pathogens and Other EPI Vaccines
Get PDFTuberculosis (TB) is one of the leading causes of mortality in developing countries and infants are at particular risk. Currently, the only licensed vaccine is Bacillus Calmette-Guerin (BCG), which has variable efficacy. BCG has been shown to provide heterologous protection against unrelated pathogens and enhance immunity to other Expanded Programme on Immunization (EPI) vaccines when given at birth. However, only one recently published study has shown an enhanced pro-inflammatory effect of BCG among vaccinated neonates and the immunological mechanisms of this effect in infants are not known. Further studies are required if this BCG effect is to be understood.
This thesis describes the differences in soluble and cellular responses to vaccine specific and non-specific heterologous antigens and EPI antibody levels between infants vaccinated with BCG at 6 weeks and those delayed until 18 weeks of age using flow cytometry, multiplex cytokine arrays and vaccine antibody assays.
We found low plasma cytokine levels and little cytokine production to PPD (the BCG-recall antigen) regardless of vaccination status. However, the BCG vaccinated group had lower production of IL-10 with both Toll like receptor (TLR) agonists and unrelated pathogen stimulation when compared to their unvaccinated counterparts, and this was more prominent in females than males. This contrasts with previous studies showing enhanced pro-inflammatory responses to TLR agonists and killed pathogens following BCG vaccination. The infants received BCG Denmark in these latter studies, whereas BCG Russia was used in our study, therefore strain differences in heterologous effects of BCG may be one explanation for the discrepancy.
When cellular responses were analyzed by flow cytometry low cellular responses were observed in both groups. However, we observed a significantly higher proportion of IFNγ+ CD8+ cells 1 week after vaccination compared to the unvaccinated group in response to PPD and Candida albicans stimulation.
Despite their different vaccine schedules, protective antibody levels to polio, tetanus and hepatitis B vaccines were obtained by all subjects; although no boosting effect of BCG was seen in contrast to previous studies when BCG was given at birth. A tuberculin skin test (TST) was performed at 18 weeks of age as a functional measure of delayed type hypersensitivity to Mtb. Due to the influence of BCG vaccination on TST induration, the vaccinated infants had significantly higher indurations than the unvaccinated infants and this was more pronounced in males.
Our findings are in contrast to a study in South Africa, but support findings from a study in Uganda, where delayed BCG vaccination significantly reduced responses to BCG compared to infants vaccinated at birth, suggesting an impact of environment (including exposure to non-tuberculous mycobacteria) in masking the immune response to BCG, differences in vaccine strains might be a major reason for differences observed in our study and the other South African studies However, two major limitations of our study are the lack of a vaccine group at birth as per the current vaccine schedule, and a postvaccination follow up for the infants vaccinated at 18 weeks to determine differences in immunity to BCG with a further delay in vaccination.
In conclusion, BCG vaccination given at 6 weeks of age showed no difference in Th1 responses, but decreased IL-10 responses after TLR agonist and unrelated pathogen stimulation compared to unvaccinated infants. These effects, together with TST induration, were influenced by sex. Importantly, however, delaying vaccination did not have an effect on other EPI vaccine antibody levels, with all infants reaching protective levels by 18 weeks of age. This study provides further insight into BCG effects in infants in a West African setting
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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