Of all tuberculosis (TB) cases, 1% affects the central nervous system (CNS), with a mortality rate of up to 60%. Our aim is to fill the 'key gap' in TBM research by analyzing brain specimens in a unique historical cohort of 84 patients, focusing on granuloma formation. We describe three different types: non-necrotizing, necrotizing gummatous, and necrotizing abscess type granuloma. Our hypothesis is that these different types of granuloma are developmental stages of the same pathological process. All types were present in each patient and were mainly localized in the leptomeninges. Intra-parenchymal granulomas were less abundant than the leptomeningeal ones and mainly located close to the cerebrospinal fluid (subpial and subependymal). We found that most of the intraparenchymal granulomas are an extension of leptomeningeal lesions which is the opposite of the classical Rich focus theory. We present a 3D-model to facilitate further understanding of the topographic relation of granulomas with leptomeninges, brain parenchyma and blood vessels. We describe innate and adaptive immune responses during granuloma formation including the cytokine profiles. We emphasize the presence of leptomeningeal B-cell aggregates as tertiary lymphoid structures. Our study forms a basis for further research in neuroinflammation and infectious diseases of the CNS, especially TB.

Background: Bacterial meningitis (BM) is a serious, life-threatening infectious disease of the central nervous system that often occurs in young children. The most common severe to moderate sequelae following BM are sensorineural hearing loss, neuromotor disabilities and mental retardation, while subtle sequelae include academic and behavioral disabilities. It is largely unknown whether these more subtle sequelae persist into adolescence and adulthood. Therefore, this study will investigate the very long-term effects of childhood BM in later life. Better understanding of long-term effects and early identification of adverse outcomes after BM are essential for more timely interventions. Additionally, certain single nucleotide polymorphisms (SNPs) are associated with disease severity and might predict adverse sequelae. These include SNPs in genes encoding for pathogen recognition and immune response upon infection. Accordingly, a secondary objective of this study is to investigate the role of genetic variation in BM and use any insights to predict short- and long-term outcomes.Methods: In the Dutch 20|30 Postmeningitis study, adolescents and young adults (n = 947) from two historical cohorts with a prior episode of BM during childhood will be enrolled into a cross-sectional follow-up investigation using mainly questionnaires that examine executive and behavioral functioning, health-related quality of life, subjective hearing, mood and sleeping disorders, academic performance, and economic self-sufficiency. The results will be compared to normative data by one-sample t-tests. Multivariable regression analysis will be used to assess for any associations with causative pathogens and severity of BM. Participants that complete the questionnaires will be approached to provide a swab for buccal DNA and subsequent sequencing analyses. Logistic regression models will be used to predict sequelae.Discussion: The unique follow-up duration of this cohort will enable us to gain insights into the possible very long-term adverse effects of childhood BM and how these might impact on quality of life. The investigation of host genetic factors will contribute to the development of prediction models which will serve as prognostic tools to identify children who are at high risk of adverse outcome after BM.Trial Registration: Dutch Trial RegisterNTR-6891. Retrospectively registered 28 December 2017.

HIV and HIV stigma remain a burden to healthcare in South Africa. One way to alleviate the load on the health system is through collaboration between healthcare workers and faith leaders. Faith communities in South Africa are perfectly positioned to support healthcare. They are integrated into the communities and have an authoritative voice. Also, healthcare workers are often religious and therefore are also part of faith communities which can be beneficial for collaborations and education on HIV topics. This research aimed to investigate the facilitators and barriers of collaborations between faith communities and healthcare centres when addressing HIV and HIV stigma. With a qualitative interpretive descriptive approach, in-depth interviews with 10 faith leaders and 8 healthcare workers were conducted in two townships of Cape Town, South Africa. The interviews were conducted in 2018, and thematically analysed. The study found facilitators and barriers of each of the six main themes namely, faith leaders are significant in medication adherence; health education about HIV is necessary but complex; faith and healthcare collaboration acknowledged but challenged; HIV stigma is prominent in communities; comprehensive role of the faith leader; and faith healing creates a complex challenge. There is a spirit of collaboration between faith leaders and healthcare workers, although the participants did not seem to know how to go about this engagement. Further research could design an intervention to facilitate such collaboration. Highlights A collaborative spirit exists between faith leaders and healthcare workers. Faith leaders play a role when healthcare workers cannot reach the community. Demands faced by faith leaders and healthcare workers cause difficulties.

Background: In May 2020, many European countries have begun to introduce an exit strategy for the coronavirus disease 2019 (COVID-19) pandemic which involves relaxing social distancing measures. Predictive epidemiological modeling indicates that chances for resurgence are high. However, parametrization of the epidemiological nature of COVID-19 and the effect of relaxing social distancing is not well constrained, resulting in highly uncertain outcomes in view of managing future intensive care unit (ICU) needs. Methods and findings: For performance analysis of exit strategies we developed an open-source ensemble-based Susceptible-Exposed-Infectious-Removed (SEIR) model. It takes into account uncertainties for the COVID-19 parametrization and social distancing measures. The model is calibrated to data of the outbreak and lockdown phase. For the exit phase, the model includes the capability to activate an emergency brake, reinstating lockdown conditions. Alternatively, the model uses an adaptive COVID-19 cruise control (ACCC) capable to retain a targeted ICU level. The model is demonstrated for the Netherlands and we analyzed progressive and adaptive exit strategies through a stress test of managing ICU rates. The progressive strategy reflects the outcome of social and economic pressure to use one-way steering toward progressively relaxing measures at an early stage. It is marked by a high probability for the activation of the emergency brake due to an unsolicited growth of ICU needs in the following months. Alternatively, the two-way steering ACCC can flatten ICU needs in a more gradual way and avoids activation of the emergency brake. It also performs well for seasonal variation in the reproduction number of severe acute respiratory syndrome-coronavirus. Conclusions: The adaptive strategy (ACCC) is favored, as it avoids the use of the emergency brake at the expense of small steps of restrictive measures and allows the exploration of riskier and potentially rewarding measures in the future pathways of the exit strategy.

Background: Tuberculous meningitis (TBM), caused by Mycobacterium tuberculosis, is the most severe form of extrapulmonary tuberculosis and isassociated with high morbidity and mortality, particularly when diagnosis is delayed. Improved understanding of the metabolic alterations associated withTBM may support the development of novel diagnostic biomarkers and provide insights into disease pathophysiology. Method: In this study, we applied anuntargeted two-dimensional gas chromatography–time-of-flight mass spectrometry (GC×GC-TOFMS) metabolomics approach to formalin-fixed, paraffin-embedded (FFPE) postmortem human brain tissue from 41 TBM cases and 36 tissue sections from 6 non-TBM control cases. Metabolomics data wereprocessed, normalized, and analyzed using multivariate and univariate statistical approaches, including principal component analysis (PCA) and partialleast squares–discriminant analysis (PLS-DA), with variable importance in projection (VIP) scores. These results were further correlated with patient clinical data. Results: Distinct metabolic profiles were observed between TBM and control tissues. Several metabolites were significantly reduced in TBM samples, particularly within the alkane and alkene classes, with additional decreases observed in metabolites associated with alcohols, fatty acids, lipids, carbohydrates, and amino acids. These metabolic alterations suggest substantial perturbations, primarily in the host lysine degradation pathway (linked to the kynurenine pathway), in TBM-affected brain tissue. Conclusion: Collectively, these findings provide insight into the metabolic landscape of terminalTBM and suggest potential metabolic pathways that may contribute to disease pathophysiology. Further investigation of these metabolic signatures in accessible patient tissue and biofluids may support the development of biomarkers and inform future therapeutic strategies for TBM.