121 research outputs found
Determinants of innate immune responses to mycobacteria
No full textIncludes bibliographical references.Innate cells such as macrophages, monocytes, myeloid dendritic cells and granulocytes recognise mycobacteria and initiate immune responses such as phagocytosis, cytokine production and expression of maturation markers. The type and magnitude of innate responses to mycobacteria may determine the subsequent adaptive responses generated. Our aims were to determine maturational changes in innate immune responses to mycobacteria over the first 9 months of life, and to assess effects of genetic variations in toll-like receptors on host responses to mycobacteria. This knowledge is important for designing rational strategies for vaccination against tuberculosis
Comparing the test performance of dried-blood-spot and plasma HIV recent infection testing samples in a nationally scaled sex worker programme in Zimbabwe.
No full textRecency testing can provide strategic insights as to whether a person newly diagnosed with HIV recently acquired their infection or not. To understand potential biases associated with HIV recency testing, we explored the extent sample type influences whether a person is assigned as being recent. Implementing a laboratory-based Recent Infection Testing Algorithm (RITA) across the Centre for Sexual Health and HIV/AIDS Research (CeSHHAR) key populations programme in Zimbabwe between October 2021 and January 2023, we compared plasma-based and dried-bloodspot (DBS) HIV recency samples. Over the study period, 24,976 individual female sex workers HIV tested, of whom 9.5% (2,363/24,979) newly tested HIV positive. Of these 2,363 women, 55.5% (1311/2,363) were offered and gave consent for a sample to be taken for DBS recency and viral load testing, among whom 11.7% (153/1,311) were classified as having a recent infection. A subset of 464 women were offered and consented to paired sample collection, among whom 10.1% (47) and 12.3% (57) of plasma and DBS samples, respectively, were classified as recent. Overall, categorical determination was good, with 97% of results concordant. Of 58 women with paired sample collection who had a test result classified as recent, 46 (79.3%) were concordant recent on both DBS and plasma, with 12 (20.7%) being discordant. Of these 12 women's samples, 11 were deemed long-standing by the plasma assay but recent by the paired DBS, and one deemed long-standing by DBS but recent by the paired plasma sample. On average, plasma samples had a higher normalised optical density than DBS samples (mean difference of 0.53). Depending on use-case and setting, there are trade-offs when considering DBS or plasma-based samples between test performance and ease of implementation. Our data can help inform statistical adjustments to harmonise cut-offs on DBS and plasma assays, thereby improving the use and interpretation of recency assays in population-level HIV surveillance activities
Insights on the implementation strategies for a potential new tuberculosis vaccine in South Africa.
No full textSeveral tuberculosis (TB) vaccines intended for adults and adolescents are in late-stage clinical trials, but there is limited research into how a new TB vaccine would be introduced. South Africa is at the forefront of TB vaccine research, with involvement in the clinical trials of leading candidates. We sought to understand what the priorities and implementation approach of a potential new TB vaccine in South Africa would be. We conducted semi-structured interviews with 26 stakeholders with different expertise during April and May 2025. Deductive analysis was used to develop a coding framework for thematic content analysis of the data. Stakeholders supported introducing a new TB vaccine in South Africa due to the high disease burden, but feasibility of the roll out was said to depend on vaccine price, cost-effectiveness, efficacy, regulatory approval, and implementation logistics. Efficacy below 50% could raise concerns unless supported by robust modelling demonstrating significant public health impact and cost-effectiveness. Stakeholders preferred a cheaper vaccine course to enable a broad population-based introduction. Priority populations for vaccination included adolescents and adults for a broad population approach, and high-risk groups such as, people living with HIV, healthcare workers and TB household contacts. Whilst a national broad population-based approach was preferred, constraints may result in a phased introduction in high-burden areas and/or targeted vaccination to high-risk groups first. Strong advocacy, detailed cost effectiveness assessments, regulatory alignment, and integrated service delivery were seen as essential to successful implementation. With the introduction of a new TB vaccine potentially as early as 2030, this study provides valuable insights, particularly regarding target populations, that can be utilised for the implementation of a new TB vaccine in South Africa to ensure a successful introduction. Further research is required on vaccine acceptability, TB infection prevalence and modelling to estimate cost effectiveness and budget impact
The immunomodulatory role of prednisone in patients with HIV-associated tuberculosis and assessment of its impact on lung function outcome
No full textIn this thesis, I assess the effect of prednisone on immunopathology and pulmonary function in HIV-associated tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS). I do this using data collected during the PredART trial. This randomized, double-blind, placebo-controlled trial showed that a 28-day course of prophylactic prednisone in adult patients identified as being at high risk for paradoxical TB-IRIS reduced the incidence of paradoxical TB-IRIS by 30%, without an excess of adverse events
Activation of MAIT cells by antigen presenting cells: a comprehensive analysis and assessment of HIV and TB disease on these interactions
No full textMAIT cells are non-classical, innate-like T lymphocyte subsets, which recognize microbial vitamin B metabolites and rapidly respond by producing pro-inflammatory cytokines such as IFN-γ, TNF-α and cytotoxic molecules, which may result in the killing of bacteria-infected cells. Unlike conventional T cells, MAIT cells can be activated by either antigen presentation on MR1 or directly by cytokines. MAIT cells play a protective role against bacterial infections in mice but so far, no human studies have confirmed a direct role of MAIT cells in the control of bacterial infections or prevention of disease progression. Circulating MAIT cell numbers decrease in patients with active TB, but findings regarding functional changes have been conflicting. The aims of this study were to assess the cellular interactions between antigen presenting cells and MAIT cells, and determine the effect of TB, HIV and HIV-associated TB on MAIT cell numbers, activation, inhibitory and functional profile. We recruited 26 healthy controls (HC) without HIV or TB disease, 30 people with HIV only, 30 with active TB only, and 26 with HIV-associated TB. All TB patient samples were obtained before treatment. Blood was collected from all participants and peripheral blood mononuclear cells (PBMC) isolated from the blood and cryopreserved. Later, PBMC were thawed, rested and stimulated with BCG expressing GFP (BCG-GFP) and heat-killed (HK) M.tb. Media only, LPS and PHA were used as stimulation controls. The numbers, functional profile, inhibitory and activation status of MAIT cells were determined by flow cytometry. Soluble cytokines were measured by ELISA and multiplex Luminex assays. For HIV-infected participants with no TB and patients with HIV-associated TB, the median CD4 counts were 501 cells/µL and 228 cells/µL, and HIV viral loads were 1673 copies/mL and 66509 copies/mL, respectively. 63% and 69% of HIV infected patients were on ART in the HIV alone and HIV/TB groups, respectively. We observed lower frequencies of circulating MAIT cells in individuals with active TB only or HIV only compared to HC. HIV/TB resulted in lower but nonsignificant MAIT cell frequencies and numbers compared to HC. In response to stimulation with whole mycobacteria, MAIT cells were more highly activated (expressing high HLA-DR) in people with TB and HIV-associated TB compared to HC. Furthermore, MAIT cells from people with active TB only had significantly upregulated PD-1 expression compared to HC. MAIT cells from individuals with active TB and HIV-associated TB had a lower capacity to degranulate (express CD107a) and produce IFN-γ compared to HC. HIV-infection alone did not affect these functions. The levels of soluble IFN-α2 were reduced in the groups with HIV only and active TB only while IFN-γ was reduced in all patient groups. Blocking experiments revealed that MAIT cell activation in response to BCG was primarily through MR1 antigen presentation pathway. The level of monocyte and dendritic cell infection (expression of GFP) was similar in all groups. We observed a positive correlation between monocyte infection and the frequencies of MAIT cells producing IFN-γ in people with active TB only. We also observed a positive correlation between the amount of soluble IL-12 and the proportion of MAIT cells producing IFN-γ and CD107a in HC and in people with HIV infection, respectively. Our data show that HIV, TB and or HIV/TB result in a decrease in circulating MAIT cells, impaired functional profile, and a significant alteration in activation status and inhibitory potential. The MR1 antigen presentation was the predominant pathway for MAIT cell activation. There was also a relationship observed between MAIT cell activation and magnitude of innate response to mycobacterial antigens. These results provide further evidence of the potential role of MAIT cells in infectious disease pathogenesis and demonstrate how HIV and TB alter their function
Elevated plasma matrix metalloproteinases are associated with <i>Mycobacterium tuberculosis </i>bloodstream infection and mortality in human immunodeficiency virus-associated tuberculosis
No full textMortality from human immunodeficiency virus (HIV)-associated tuberculosis (TB) is high, particularly among hospitalized patients. In 433 people with HIV hospitalized with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality, and Mycobacterium tuberculosis (Mtb) bloodstream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb-BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP-3, -7, -8, -10, and PIIINP were associated with Mtb-BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV-TB.</p
Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis
No full textBackground: HIV-associated tuberculosis (HIV-TB) comprises 9% of global tuberculosis cases but contributes a disproportionate 17% of tuberculosis deaths. Tuberculosis is the leading cause of death, hospitalization and in-hospital death in HIV-positive patients world-wide with case fatality rates in hospitalized patients ranging between 13% and 32%. Underlying causes of mortality remain poorly characterized and better characterization of causes could inform development of novel management strategies to improve survival. This study aimed to assess determinants of mortality in hospitalized HIV-TB patients. I assessed the association of clinical, microbiologic and treatment factors, host soluble inflammatory mediators, markers of tuberculosis dissemination, antituberculosis drug concentrations and markers of microbial translocation with 12-week mortality in hospitalized HIV-TB patients. Methods: We conducted a prospective observational cohort study and enrolled adult HIV-positive patients hospitalized with a new diagnosis of HIV-TB in Khayelitsha Hospital in Cape Town between 2014-2016. Detailed tuberculosis diagnostic testing was performed (including urine Xpert testing) and we collected clinical samples for analysis at baseline. We performed intensive pharmacokinetic studies in a subset of patients on the third day of antituberculosis therapy. Patients were followed up for 12 weeks to ascertain vital status. Results: We enrolled 682 participants and included 576 patients with tuberculosis in the cohort analyses. Twelve-week mortality was 124/576 (21.5%) with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Determinants of mortality included tuberculosis dissemination, rifampicin resistance and having features of sepsis syndrome. Using principal components analysis, we characterised an innate immune profile which was associated with mortality and with biomarkers of disseminated tuberculosis. A large proportion of patients had sub-optimal concentrations of rifampicin and isoniazid. Patients who presented with elevated lactate concentrations had higher rifampicin concentration and exposure. Opportunistic infections other than tuberculosis and microbial translocation did not have a significant association with mortality. Conclusions: There was high early mortality in hospitalized HIV-TB patients. An innate immune profile was associated with tuberculosis dissemination and mortality. Rifampicin and isoniazid concentrations and exposure were sub-optimal. These findings provide novel pathophysiologic insight and provide rationale to test high dose rifampicin and immune modulatory therapy for safety and efficacy to improve survival in this patient population
New Contributions to the Palaeographic Description of the Kvarezimal and Tlmačenje od muki of scribe Šimun Greblo on the Basis of Selected Text Samples
No full textKvarezimal i Tlmačenje od muki Šimuna Grebla papirni je kodeks od 158 folija dimenzija 20,2 x 14,5 cm koji se sastoji od dviju zasebnih knjiga pisanih glagoljičnim knjiškim kurzivom. U postskriptu zapisanome ćirilicom na 132v piše da je Tlmačenje od muki napisao i završio klerik akolit nižega reda Šimun u Roču 5. ožujka 1493., a Kvarezimal pop Simun Greblić uz pomoć svojega klerika Mihovila iz Boljuna u mjesecu travnju 1498. godine. Uvriježeno je mišljenje da je riječ o istoj osobi, o čemu piše i Štefanić u svojemu kraćem paleografskom osvrtu. U kodeksu postoje pojedini dijelovi čiji duktus pisma ostavlja sporiji i istrzan dojam karakterističan za još neizvježbane pisare (početnike) ili autore koji su već ušli u pozne godine života (tzv. rukopis staroga čovjeka). Cilj je usporedbe takvih dijelova s reprezentativnim uzorkom grafije azbučnoga niza ustanoviti mogućnost postojanja razlika u autorstvu i kronologiji te njihov odnos. Ključne paleografske smjernice u istraživanju temelje se na grafolingvističkoj metodi, koja pismo promatra kao proces (pisanje), a ne kao završenu i petrificiranu strukturu kao u tradicionalnoj paleografiji.The Kvarezimal and Tlmačenje od muki, written by scribe Šimun Greblo, is a paper codex with 158 folios measuring 20.2 x 14.5 cm. This codex consists of two separate books written in Glagolitic cursive. The postscript on f 132v, written in Cyrillic script, mentions clerical acolyte of the lower order Šimun as the author of Tlmačenje od muki, which was completed in the town of Roč on 5 March 1493. The other work, Kvarezimal, was completed with the help of cleric Mihovil from Boljun in April 1498. The writing of some parts of the codex gives a slower, disorderly impression, which could be a characteristic of the untrained scribe or the author who was already in his later years (a so-called ‘old manuscript’) . The aim of comparing such parts with a representative sample of the engraving is to determine the possibility of differences in authorship and chronology and their mutual relationship . The main palaeographic guidelines of the research are based on the grapholinguistic method, which considers writing a process and not as a finished, petrified structure as in traditional paleography
Effects of fractional dose yellow fever vaccination: a systematic review and meta-analysis
No full textPersistent yellow fever endemicity and continued outbreaks have continued to increase vaccine demand, while straining global vaccine supply. Fractional dose vaccination is being considered as a dose-sparing strategy to mitigate current global vaccine shortages. This study therefore assessed the effects of fractional dose yellow fever vaccination, in comparison to those of the standard dose. We registered the review in the prospective register of systematic reviews; conducted a comprehensive search of published and grey literature; used standard Cochrane methods to collect and synthesise the evidence and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidance. We stratified analyses by the strength of the fractional dose. We retrieved 2495 records from the literature search, nine of them potentially eligible. We included six eligible studies (three randomised and three quasi-randomised trials), with 2371 participants. There was no statistically significant difference in immunogenicity between participants who received fractional doses containing one-third (two trials, 547 participants: RR 1.02, 95% CI 1.00 to 1.04; I2 = 0%), 1/5th (one trial, 155 participants: RR 1.00, 95% CI 0.98 to 1.03), 1/10th (four trials, 890 participants: RR 0.99, 95% CI 0.96 to 1.01, I 2 = 0%), and 1/50th (three trials, 661 participants: RR 0.97, 95% CI 0.92 to 1.02, I2 = 72%) of the standard dose and those who received the full standard dose. However, immunogenicity was significantly lower among participants who received fractional doses containing 1/100th (four trials, 868 participants: RR 0.92, 95% CI 0.87 to 0.97, I2 = 60%) and < 1/100th (five trials, 1053 participants; RR 0.53, 95% CI 0.44 to 0.64, I2= 98%) of the standard dose compared to participants who received the full standard dose. Minor adverse events following vaccination did not differ across doses, but no serious adverse events were reported in any study arm. The combined data provide moderate certainty evidence that there is little or no difference in immunogenicity between ≥1/50th fractional doses and the standard dose of yellow fever vaccines. However, these studies were of short duration ranging from four weeks to a year. These findings support the use of fractional dose vaccination as a dose-sparing strategy for yellow fever vaccination
Abstraction, cruelty and other aspects of animal play (exemplified by the playfulness of Muki and Maluca)
No full textPlay behaviour is notorious for constituting a much debated, yet little clarified field of research. In this article, attempts are made to reach conclusions on the relation between human play and the play of other animals (especially cat play), as well as on the very character of play. The concept of Umwelt is reviewed, as are definitions of animal play, categorization of animal play and the role of meta-communication in playful behaviour. For some, play is a symbol of everything that is good. The author of the current article does not deny that social morality may have originated from play behaviour, but stresses the existence of cruelty play, which leads to additional assumptions. Another notion that is treated in some detail is perceptual play, which proves to demonstrate complex semiotic play that is related first of all to signification. At the end of the article an alternative categorization of animal play is suggested, in which the fundamental role of mind games is emphasized. Throughout the text, examples of play behaviour are offered by the two domestic cats Muki and Maluca
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