Whole blood transcriptional profiles and the pathogenesis of tuberculous meningitis.

Mortality and morbidity from tuberculous meningitis (TBM) are common, primarily due to inflammatory response to infection, yet the underlying mechanisms remain poorly understood. We aimed to uncover genes and pathways associated with TBM pathogenesis and mortality, and determine the best predictors of death, utilizing whole-blood RNA sequencing from 281 Vietnamese adults with TBM, 295 pulmonary tuberculosis (PTB), and 30 healthy controls. Through weighted gene co-expression network analysis, we identified hub genes and pathways linked to TBM severity and mortality, with a consensus analysis revealing distinct patterns between HIV-positive and HIV-negative individuals.

A novel diagnostic model for tuberculous meningitis using Bayesian latent class analysis.

Background: Diagnosis of tuberculous meningitis (TBM) is hampered by the lack of a gold standard. Current microbiological tests lack sensitivity and clinical diagnostic approaches are subjective. We therefore built a diagnostic model that can be used before microbiological test results are known.

The Ability of a 3-Gene Host Signature in Blood to Distinguish Tuberculous Meningitis From Other Brain Infections.

Background: Tuberculous meningitis (TBM) is difficult to diagnose. We investigated whether a 3-gene host response signature in blood can distinguish TBM from other brain infections.

Methods: The expression of 3 genes (dual specificity phosphatase 3 [DUSP3], guanylate-binding protein [GBP5], krupple-like factor 2 [KLF2]) was analyzed by RNA sequencing of archived whole blood from 4 cohorts of Vietnamese adults: 281 with TBM, 279 with pulmonary tuberculosis, 50 with other brain infections, and 30 healthy controls.

Automated pupillometry and optic nerve sheath diameter ultrasound to define tuberculous meningitis disease severity and prognosis.

Background: Tuberculous meningitis (TBM) causes high mortality and morbidity, in part due to raised intracranial pressure (ICP). Automated pupillometry (NPi) and optic nerve sheath diameter (ONSD) are both low-cost, easy-to-use and non-invasive techniques that correlate with ICP and neurological status. However, it is uncertain how to apply these techniques in the management of TBM.

Urinary catecholamine excretion, cardiovascular variability, and outcomes in tetanus.

Severe tetanus is characterized by muscle spasm and cardiovascular system disturbance. The pathophysiology of muscle spasm is relatively well understood and involves inhibition of central inhibitory synapses by tetanus toxin. That of cardiovascular disturbance is less clear, but is believed to relate to disinhibition of the autonomic nervous system.

The prognostic and diagnostic value of intraleukocytic malaria pigment in patients with severe falciparum malaria.

Severe falciparum malaria is a major cause of death in tropical countries, particularly in African children. Rapid and accurate diagnosis and prognostic assessment are critical to clinical management. In 6027 prospectively studied patients diagnosed with severe malaria we assess the prognostic value of peripheral blood film counts of malaria pigment containing polymorphonuclear leukocytes (PMNs) and monocytes.

Tuberculous meningitis: progress and remaining questions.

Tuberculous meningitis is a devastating brain infection that is caused by Mycobacterium tuberculosis and is notoriously difficult to diagnose and treat. New technologies characterising the transcriptome, proteome, and metabolome have identified new molecules and pathways associated with tuberculous meningitis severity and poor outcomes that could offer novel diagnostic and therapeutic targets. The next-generation GeneXpert MTB/RIF Ultra assay, when used on CSF, offers diagnostic sensitivity for tuberculous meningitis of approximately 70%, although it is not widely available and a negative result cannot rule out tuberculous meningitis.

An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis.

Background: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro.

Evaluation of the molecular bacterial load assay for detecting viable Mycobacterium tuberculosis in cerebrospinal fluid before and during tuberculous meningitis treatment.

New tools to monitor treatment response and predict outcome from tuberculous meningitis (TBM) are urgently required. We retrospectively evaluated the 16S rRNA-based molecular bacterial load assay (MBLA) to quantify viable Mycobacterium tuberculosis in serial cerebrospinal fluid (CSF) from adults with TBM. 187 CSF samples were collected before and during the first two months of treatment from 99 adults TBM, comprising 56 definite, 43 probable or possible TBM, and 18 non-TBM and preserved at -80°C prior to MBLA.

Elevated cerebrospinal fluid cytokine levels in tuberculous meningitis predict survival in response to dexamethasone.

Adjunctive treatment with antiinflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in (), which regulates expression of the proinflammatory mediator leukotriene B (LTB). TT homozygotes, with increased expression of , have the highest survival when treated with dexamethasone and the lowest survival without.

Severe paradoxical reaction in tuberculous meningitis.

A 31-year-old female presented with a 3-week history of fever and headache. CSF Ziehl-Neelsen smear microscopy revealed acid-fast bacilli, and CSF GeneXpert MTB/RIF was positive for with no mutations of rifampicin resistance. Tuberculous meningitis (TBM) was diagnosed.

Optic Nerve Sheath Ultrasound for the Detection and Monitoring of Raised Intracranial Pressure in Tuberculous Meningitis.

Background: Neurological complications of tuberculous meningitis (TBM) often lead to raised intracranial pressure (ICP) resulting in high morbidity and mortality. Measurement of optic nerve sheath diameter (ONSD) by point-of-care ultrasound may aid in the identification of raised ICP in TBM.

Methods: From June 2017 to December 2019, 107 Vietnamese adults with TBM, enrolled in the ACT HIV or LAST ACT trials (NCT03092817, NCT03100786), underwent ONSD ultrasound at ≥1 of days 0, 3, 7, 14, 21, and day ±30 after enrollment.

Most-Probable-Number-Based Minimum Duration of Killing Assay for Determining the Spectrum of Rifampicin Susceptibility in Clinical Mycobacterium tuberculosis Isolates.

Accurate antibiotic susceptibility testing is essential for successful tuberculosis treatment. Recent studies have highlighted the limitations of MIC-based phenotypic susceptibility methods in detecting other aspects of antibiotic susceptibilities in bacteria. Duration and peak of antibiotic exposure, at or above the MIC required for killing the bacterial population, has emerged as another important factor for determining antibiotic susceptibility.

Influence of Strongyloides stercoralis Coinfection on the Presentation, Pathogenesis, and Outcome of Tuberculous Meningitis.

Background: Helminth infections may modulate the inflammatory response to Mycobacterium tuberculosis and influence disease presentation and outcome. Strongyloides stercoralis is common among populations with high tuberculosis prevalence. Our aim was to determine whether S.

Performance of Metagenomic Next-Generation Sequencing for the Diagnosis of Viral Meningoencephalitis in a Resource-Limited Setting.

Background: Meningoencephalitis is a devastating disease worldwide. Current diagnosis fails to establish the cause in ≥50% of patients. Metagenomic next-generation sequencing (mNGS) has emerged as pan-pathogen assays for infectious diseases diagnosis, but few studies have been conducted in resource-limited settings.

Concomitant Bacteremia in Adults With Severe Falciparum Malaria.

Background: Approximately 6% of children hospitalized with severe falciparum malaria in Africa are also bacteremic. It is therefore recommended that all children with severe malaria should receive broad-spectrum antibiotics in addition to parenteral artesunate. Empirical antibiotics are not recommended currently for adults with severe malaria.

Xpert MTB/RIF Ultra versus Xpert MTB/RIF for the diagnosis of tuberculous meningitis: a prospective, randomised, diagnostic accuracy study.

Background: Xpert MTB/RIF Ultra (Xpert Ultra) might have higher sensitivity than its predecessor, Xpert MTB/RIF (Xpert), but its role in tuberculous meningitis diagnosis is uncertain. We aimed to compare Xpert Ultra with Xpert for the diagnosis of tuberculous meningitis in HIV-uninfected and HIV-infected adults.

Methods: In this prospective, randomised, diagnostic accuracy study, adults (≥16 years) with suspected tuberculous meningitis from a single centre in Vietnam were randomly assigned to cerebrospinal fluid testing by either Xpert Ultra or Xpert at baseline and, if treated for tuberculous meningitis, after 3-4 weeks of treatment.

Proresolving mediator profiles in cerebrospinal fluid are linked with disease severity and outcome in adults with tuberculous meningitis.

Tuberculous meningitis (TBM) is the most lethal form of tuberculosis infection, characterized by a dysregulated immune response that frequently leads to neurologic injury and death despite the best available treatment. The mechanisms driving the inflammatory response in TBM are not well understood. To gain insights into these mechanisms, we used a lipid mediator-profiling approach to investigate the regulation of a novel group of host protective mediators, termed specialized proresolving mediators (SPMs), in the cerebrospinal fluid (CSF) of adults with TBM.

The neurocritical care of tuberculous meningitis.

Tuberculous meningitis is the most severe form of tuberculosis and often causes critical illness with high mortality. Two primary management objectives are reducing intracranial pressure, and optimising cerebral perfusion, while killing the bacteria and controlling intracerebral inflammation. However, the evidence base guiding the care of critically ill patients with tuberculous meningitis is poor and many patients do not have access to neurocritical care units.