Browsing by Author "Thwaites, Guy E."

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    Host directed therapies for tuberculous meningitis
    (Wellcome Trust, 2020-07-01) Davis, Angharad G.; Donovan, Joseph; Bremer, Marise; Van Toorn, Ronald; Schoeman, Johan; Dadabhoy, Ariba; Lai, Rachel P. J.; Cresswell, Fiona V.; Boulware, David R.; Wilkinson, Robert J.; Thuong, Nguyen Thuy Thuong; Thwaites, Guy E.; Bahr, Nathan C.; Tuberculous Meningitis International Research Consortium
    ENGLISH ABSTRACT: A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM). Effective host directed therapies (HDTs) are critical to improve survival and clinical outcomes. Currently only one HDT, dexamethasone, is proven to improve mortality. However, there is no evidence dexamethasone reduces morbidity, how it reduces mortality is uncertain, and it has no proven benefit in HIV co-infected individuals. Further research on these aspects of its use, as well as alternative HDTs such as aspirin, thalidomide and other immunomodulatory drugs is needed. Based on new knowledge from pathogenesis studies, repurposed therapeutics which act upon small molecule drug targets may also have a role in TBM. Here we review existing literature investigating HDTs in TBM, and propose new rationale for the use of novel and repurposed drugs. We also discuss host variable responses and evidence to support a personalised approach to HDTs in TBM.
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    Knowledge gaps and research priorities in tuberculous meningitis
    (Wellcome Open Research, 2019-11-28) Seddon, James A.; Wilkinson, Robert; Van Crevel, Reinout; Figaji, Anthony; Thwaites, Guy E.; Tuberculous Meningitis International Research Consortium
    ENGLISH ABSTRACT: Tuberculous meningitis (TBM) is the most severe and disabling form of tuberculosis (TB), accounting for around 1-5% of the global TB caseload, with mortality of approximately 20% in children and up to 60% in persons co-infected with human immunodeficiency virus even in those treated. Relatively few centres of excellence in TBM research exist and the field would therefore benefit from greater co-ordination, advocacy, collaboration and early data sharing. To this end, in 2009, 2015 and 2019 we convened the TBM International Research Consortium, bringing together approximately 50 researchers from five continents. The most recent meeting took place on 1 st and 2 nd March 2019 in Lucknow, India. During the meeting, researchers and clinicians presented updates in their areas of expertise, and additionally presented on the knowledge gaps and research priorities in that field. Discussion during the meeting was followed by the development, by a core writing group, of a synthesis of knowledge gaps and research priorities within seven domains, namely epidemiology, pathogenesis, diagnosis, antimicrobial therapy, host-directed therapy, critical care and implementation science. These were circulated to the whole consortium for written input and feedback. Further cycles of discussion between the writing group took place to arrive at a consensus series of priorities. This article summarises the consensus reached by the consortium concerning the unmet needs and priorities for future research for this neglected and often fatal disease.
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    Tuberculous meningitis : new tools and new approaches required [version 1; peer review: not peer reviewed]
    (F1000Research, 2019) Seddon, James A.; Thwaites, Guy E.; Tuberculous Meningitis International Research Consortium
    ENGLISH ABSTRACT: Tuberculous meningitis is the most severe form of tuberculosis and causes widespread mortality and morbidity. Understanding of the epidemiology and pathogenesis is incomplete, and the optimal diagnosis and treatment are poorly defined. To generate research collaboration and coordination, as well as to promote sharing of ideas and advocacy efforts, the International Tuberculous Meningitis Research Consortium was formed in 2009. During the most recent meeting of this group in Lucknow, India, in March 2019, the Consortium decided to bring together key articles on tuberculous meningitis in one supplement. The supplement covers recent scientific updates, expert perspectives on specific clinical challenges, consensus statements on how to conduct research, and a set of priorities for future investigation.