Iets over Socrates en het geheugen

OPENBARE LES uitgesproken bij de aanvaarding van het ambt van gewoon lector in de neurologie aan de Medische Faculteit Rotterdam op donderdag 11 december 196

The C-Type Lectin Receptor CLECSF8/CLEC4D Is a Key Component of Anti-Mycobacterial Immunity

Open Access funded by Wellcome Trust: Under a Creative Commons license Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. Acknowledgments We would like to thank S. Hardison, P. Redelinghuys, J. Taylor, C. Wallace, A. Richmond, S. Hadebe, A. Plato, F. Abbass, L. Fick, N. Allie, R. Wilkinson, K. Wilkinson, S. Cooper, D. Lang, and V. Kumar for reagents and assistance, and the animal facility staff for the care of our animals. This work was supported by the MRC (UK) and Wellcome Trust (G.D.B.); MRC (South Africa) and Sydney Brenner Fellowship (M.J.M.); Vici (M.G.N.), Vidi (R.v.C.), and Veni grants (T.S.P.) from the Netherlands Organization for Scientific Research; the Royal Netherlands Academy of Arts and Sciences (T.H.M.O.); EC FP7 projects (NEWTBVAC, ADITEC; T.H.M.O.); Carnegie Corporation and CIDRI (J.C.H.); and the University of Aberdeen (B.K.).Peer reviewedPublisher PD

A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis.

Tuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in the leukotriene A4 hydrolase (LTA4H) gene encoding an enzyme that regulates inflammatory eicosanoids. LTA4H TT patients with increased expression had increased survival, consistent with corticosteroids benefiting individuals with hyper-inflammatory responses. However, an Indonesia study did not find an LTA4H TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that LTA4H TT genotype confers survival benefit that begins early and continues long-term in both populations. This benefit is nullified in the most severe cases with high early mortality. LTA4H genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it

A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis.

Tuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in the leukotriene A4 hydrolase (LTA4H) gene encoding an enzyme that regulates inflammatory eicosanoids. LTA4H TT patients with increased expression had increased survival, consistent with corticosteroids benefiting individuals with hyper-inflammatory responses. However, an Indonesia study did not find an LTA4H TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that LTA4H TT genotype confers survival benefit that begins early and continues long-term in both populations. This benefit is nullified in the most severe cases with high early mortality. LTA4H genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it

Timing and sequence of vaccination against COVID-19 and influenza (TACTIC):a single-blind, placebo-controlled randomized clinical trial

Background: Novel mRNA-based vaccines have been used to protect against SARS-CoV-2, especially in vulnerable populations who also receive an annual influenza vaccination. The TACTIC study investigated potential immune interference between the mRNA COVID-19 booster vaccine and the quadrivalent influenza vaccine, and determined if concurrent administration would have effects on safety or immunogenicity. Methods: TACTIC was a single-blind, placebo-controlled randomized clinical trial conducted at the Radboud University Medical Centre, the Netherlands. Individuals ≥60 years, fully vaccinated against COVID-19 were eligible for participation and randomized into one of four study groups: 1) 0.5 ml influenza vaccination Vaxigrip Tetra followed by 0.3 ml BNT162b2 COVID-19 booster vaccination 21 days later, (2) COVID-19 booster vaccination followed by influenza vaccination, (3) influenza vaccination concurrent with the COVID-19 booster vaccination, and (4) COVID-19 booster vaccination only (reference group). Primary outcome was the geometric mean concentration (GMC) of IgG against the spike (S)-protein of the SARS-CoV-2 virus, 21 days after booster vaccination. We performed a non-inferiority analysis of concurrent administration compared to booster vaccines alone with a predefined non-inferiority margin of −0.3 on the log10-scale. Findings: 154 individuals participated from October, 4, 2021, until November, 5, 2021. Anti-S IgG GMCs for the co-administration and reference group were 1684 BAU/ml and 2435 BAU/ml, respectively. Concurrent vaccination did not meet the criteria for non-inferiority (estimate −0.1791, 95% CI −0.3680 to −0.009831) and antibodies showed significantly lower neutralization capacity compared to the reference group. Reported side-effects were mild and did not differ between study groups. Interpretation: Concurrent administration of both vaccines is safe, but the quantitative and functional antibody responses were marginally lower compared to booster vaccination alone. Lower protection against COVID-19 with concurrent administration of COVID-19 and influenza vaccination cannot be excluded, although additional larger studies would be required to confirm this. Trial registration number: EudraCT: 2021-002186-17 Funding: The study was supported by the ZonMw COVID-19 Programme.</p

Standardized methods for enhanced quality and comparability of tuberculous meningitis studies

Tuberculous meningitis remains a major cause of death and disability in tuberculosis endemic areas, especially in young children and immunocompromised adults. Research aimed at improving outcomes is hampered by poor standardization, which limits study comparison and the generalizability of results. We propose standardized methods for the conduct of tuberculous meningitis clinical research that were drafted at an international tuberculous meningitis research meeting organized by the Oxford University Clinical Research Unit in Vietnam. We propose a core dataset including demographic and clinical information to be collected at study enrolment, important aspects related to patient management and monitoring, and standardized reporting of patient outcomes. The criteria proposed for the conduct of observational and intervention tuberculous meningitis studies should improve the quality of future research outputs, facilitate multi-centre studies and meta-analyses of pooled data, and could provide the foundation for a global tuberculous meningitis data repository

Impact of the COVID-19 pandemic on tuberculosis control in Indonesia:a nationwide longitudinal analysis of programme data

BACKGROUND: The impact of the COVID-19 pandemic on tuberculosis control in high-burden countries has not been adequately assessed. We aimed to estimate the impact of the COVID-19 pandemic on the national tuberculosis programme in Indonesia, in association with indicators of human development and health-system capacity across all 514 districts in 34 provinces. METHODS: We did a nationwide longitudinal analysis to compare tuberculosis case notification, treatment coverage, and mortality rates in Indonesia before (2016-19) and during (2020-21) the COVID-19 pandemic. The following outcomes were assessed: the district-level quarterly reported tuberculosis case notification rate (number of all reported tuberculosis cases per 100 000 population), treatment coverage (proportion of tuberculosis patients who started treatment), and all-cause mortality rate in patients with tuberculosis (number of reported deaths per 100 000 population). District-level data on COVID-19 incidence and deaths, health-system capacity, and human development and sociodemographics were also analysed. Multilevel linear spline regression was done to assess quarterly time trends for the three outcomes. FINDINGS: During the COVID-19 pandemic, the tuberculosis case notification rate declined by 26% (case notification rate ratio 0·74, 95% CI 0·72-0·77) and treatment coverage declined by 11% (treatment coverage ratio 0·89, 95% CI 0·88-0·90), but there was no significant increase in all-cause mortality (all-cause mortality rate ratio 0·97, 95% CI 0·91-1·04) compared with the pre-pandemic period. In the second year of the pandemic, we observed a partial recovery of the case notification rate from Q1 to Q4 of 2021, a persistent decrease in treatment coverage, and a decrease in the all-cause mortality rate from Q2 of 2020 to Q4 of 2021. The multivariable analysis showed that the reduction in the tuberculosis case notification rate was associated with a higher COVID-19 incidence rate (adjusted odds ratio 3·1, 95% CI 1·1-8·6, for the highest compared with the lowest group) and fewer GeneXpert machines for tuberculosis diagnosis (3·1, 1·0-9·4, for the lowest compared with the highest group) per 100 000 population. The reduction in tuberculosis treatment coverage was associated with higher COVID-19 incidence (adjusted odds ratio 11·7, 95% CI 1·5-93·4, for the highest compared with the lowest group), fewer primary health centres (10·6, 4·1-28·0, for the lowest compared with the middle-high group), and a very low number of doctors (0·3, 0·1-0·9, for the low-middle compared with the lowest group) per 100 000 population. No factors were shown to be significantly associated with all-cause mortality. INTERPRETATION: The COVID-19 pandemic adversely and unevenly affected the national tuberculosis programme across Indonesia, with the greatest impacts observed in districts with the lowest health-system capacity. These disruptions could lead to an escalation in tuberculosis transmission in the coming years, warranting the need for intensified efforts to control tuberculosis and strengthen local health systems. FUNDING: Wellcome Africa Asia Programme Vietnam. TRANSLATION: For the Bahasa translation of the abstract see Supplementary Materials section.</p

Treatment of knee prosthesis infections: evaluation of 15 patients over a 5-year period

Our objective was to evaluate different treatment alternatives for total knee arthroplasty (TKA) infection and to compare outcomes depending on adherence to a current treatment algorithm. All patients treated for a first episode of TKA infection between January 2000 and July 2005 were included. Patient records were reviewed and data were extracted retrospectively. Fifteen patients were followed up for a median of 25 months. The cure rate in patients with two-stage exchange of knee prosthesis was higher than in patients who had débridement without implant removal (100 vs 37%, p = 0.03). Cure rates were not different between these two surgical approaches in ten patients who were treated according to a current treatment algorithm. Success rates for treatment of TKA infections varied considerably with the treatment strategy chosen. Our results support the use of existing algorithms to select patients who are eligible for débridement with retention of the prosthesis or need two-stage exchange of knee implants

Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells

Contains fulltext : 171426.pdf (publisher's version ) (Open Access)Cells in homeostasis metabolize glucose mainly through the tricarboxylic acid cycle and oxidative phosphorylation, while activated cells switch their basal metabolism to aerobic glycolysis. In this study, we examined whether metabolic reprogramming toward aerobic glycolysis is important for the host response to Mycobacterium tuberculosis (Mtb). Through transcriptional and metabolite analysis we show that Mtb induces a switch in host cellular metabolism toward aerobic glycolysis in human peripheral blood mononuclear cells (PBMCs). The metabolic switch is TLR2 dependent but NOD2 independent, and is mediated in part through activation of the AKT-mTOR (mammalian target of rapamycin) pathway. We show that pharmacological inhibition of the AKT/mTOR pathway inhibits cellular responses to Mtb both in vitro in human PBMCs, and in vivo in a model of murine tuberculosis. Our findings reveal a novel regulatory layer of host responses to Mtb that will aid understanding of host susceptibility to Mtb, and which may be exploited for host-directed therapy