A comparative analysis of three knee arthrodesis techniques to manage failed total knee arthroplasty due to infection: intramedullary nailing, LRS external fixator, and compression plating.

Tuberculous meningitis (TBM) is the most severe extrapulmonary form of tuberculosis (TB) and is a central nervous system (CNS) disease caused by () (Organization, ). Accurately diagnosing TBM remains a major challenge because it presents with clinical symptoms similar to other meningeal diseases, and the pathogen’s microbial load in the cerebrospinal fluid (CSF), which is considered the gold standard sample matrix for diagnosis, is usually very low and requires highly sensitive detection tools (Donovan et al., ). Furthermore, many patients still suffer permanent neurological disabilities or die, despite the best treatment efforts. The severity of the disease, inadequate diagnostics, and poor treatment outcomes warrant further exploratory research using alternative research strategies, such as “omics” technologies, across a variety of available sample matrices, to understand the disease’s pathophysiology and pathogenesis. A breakthrough in this area could lead to significant clinical improvements, as early detection of TBM in patients with early onsets would allow treatment to commence early enough to improve clinical outcomes. The patient sample matrices previously analyzed in modern analytical research include urine, CSF, plasma, serum, and brain tissue (Isaiah et al., ; Kumar et al., ). The latter poses a major limitation, since the acquisition of human brain tissue is only possible after the patient’s demise, and because of the cost of storage (if employing cold storage), cumbersome ethical clearance requirements, and challenges in post-acquisition analyses with formalin-fixed, paraffin-embedded (FFPE) tissue. Limited omics research has been conducted on FFPE tissue, and only recently has a standardized protocol been published for such (Isaiah et al., ). Despite the advancements made in research over time, there are to date still no specific validated biomarkers which can be applied towards the early detection or diagnosis of TBM in adults (although there are some in early diagnosis of the disease in children) (Manyelo et al., ). There is also a paucity of understanding of the disease pathophysiology (Davis et al., , Jain et al., ), and the formation of organized immune clusters known as granulomas in the brainstem and subarachnoid space, which primarily distinguishes TBM from other forms of meningitis histologically (Davis et al., , El-Kebir et al., ), has recently sparked curiosity about granuloma composition and formation (Sholeye et al., ). Untargeted metabolomics is a useful tool for generating hypotheses and has been applied across a range of fields to elucidate disease mechanisms. When conducting an untargeted metabolomics study, it is important to consider the instrument’s sensitivity and specificity. Existing metabolomics studies have identified metabolites associated with TBM infection, such as myo-inositol, leucine, and lysine; however, these metabolites have yet to be validated (Isaiah et al., ). Commonly used equipment for untargeted metabolomics studies includes two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS) and proton nuclear magnetic resonance spectroscopy (H-NMR). The former is more sensitive and better suited for analyzing small sample quantities. In this study, we performed an untargeted metabolomics analysis using GCxGC-TOFMS on post-mortem FFPE human brain tissue to metabolically characterize TBM granulomatous brain tissue relative to non-TBM controls.