Tuberculosis (TB) remains the single biggest infectious cause of death globally, claiming almost two million lives and causing disease in over 10 million individuals annually. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes with various physiological roles implicated as key factors contributing to the spread of TB. They are involved in the breakdown of lung extracellular matrix and the consequent release of Mycobacterium tuberculosis bacilli into the airways. Evidence demonstrates that MMPs also play a role in central nervous system (CNS) tuberculosis, as they contribute to the breakdown of the blood brain barrier and are associated with poor outcome in adults with tuberculous meningitis (TBM). However, in pediatric TBM, data indicate that MMPs may play a role in both pathology and recovery of the developing brain. MMPs also have a significant role in HIV-TB-associated immune reconstitution inflammatory syndrome in the lungs and the brain, and their modulation offers potential novel therapeutic avenues. This is a review of recent research on MMPs in pulmonary and CNS TB in adults and children and in the context of co-infection with HIV. We summarize different methods of MMP investigation and discuss the translational implications of MMP inhibition to reduce immunopathology.

Hepatocellular carcinoma (HCC) is a leading cause of mortality in sub-Saharan Africa (SSA). This systematic review aimed to appraise all population-based studies describing the management and outcomes of HCC in SSA. A systematic review based on a search in PubMed, PubMed Central, Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), AfricaWide and Cochrane up to June 2023 was performed. PRISMA guidelines for systematic reviews were followed. The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (registration no: CRD42022363955). Thirty-nine publications from 15 of 48 SSA countries were identified; 3989 patients were studied. The majority (74%) were male, with median ages ranging from 28 to 54 years. Chronic Hepatitis B infection was a leading aetiology and non-cirrhotic HCC was frequently reported. Curative treatment (liver resection, transplantation and ablation) was offered to 6% of the cohort. Most patients (84%) received only best supportive care (BSC), with few survivors at one year. The majority of SSA countries do not have data reporting outcomes for HCC. Most patients receive only BSC, and curative treatment is seldom available in the region. Outcomes are poor compared to high-income countries.

We collected lumbar and ventricular cerebrospinal fluid and serum from 40 children treated for tuberculous meningitis and measured the concentrations of gelatinases and their inhibitors. The concentrations of matrix metalloproteinase 9 (MMP-9), MMP-2, tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2 were significantly elevated in the lumbar CSF samples, and we found interesting dynamics for MMP-9 that offer novel insight into its role in pediatric patients with tuberculous meningitis.

Paediatric penetrating cardiac injury is extremely rare, precluding published management guidelines, therefore warranting a case-by-case approach with learning points gleaned from each case. A 7-year-old boy presented to a rural hospital with a stab wound to the chest by a Withaak (Vachellia tortilis) thorn. The patient was haemodynamically stable on presentation, but a 2 cm subcutaneous, pulsatile mass was present at the cardiac apex. Echocardiography revealed a foreign body penetrating from the apex into the heart, with evidence for a fistula between a cardiac chamber and the pulsatile mass. Angiography confirmed the existence of the fistula between the right ventricle (RV) and the pulsatile mass. A controlled extraction under general anaesthaesia via median sternotomy was performed in-theatre, with blood products and cardiac bypass on standby. The patient recovered without complications and was discharged after 4 days. Our case illustrates the limitations of echocardiography in identifying the precise anatomical definition of penetrating cardiac injuries. Angiography is therefore indicated in such cases. The injury to the RV and the haemostatic effects of the in situ thorn were favourable prognostic factors. We believe that the mortality risk reduction of extraction under full control warrants the minor morbidity of a median sternotomy.

Background: Rare heterozygous loss-of-function (LoF) variants in SVIL , encoding the Z-disk and costameric protein supervillin, have recently been identified as a cause of hypertrophic cardiomyopathy (HCM). Although supervillin is implicated in actin-dependent mechanotransduction, the mechanisms linking SVIL deficiency to cardiomyopathy remain poorly understood. Homozygous LoF cause a novel skeletal Myofibrillar Myopathy-10 (MFM-10) while heterozygous LoF cause HCM without skeletal myopathy. In this study we use a human model system to disentangle the LoF pathomechanism of the scaffolding protein supervillin in cardiomyocytes and its clinical implications. Methods: Using CRISPR/Cas-9 we engineered a representative pathogenic LoF variant Q255X into an isogenic induced pluripotent stem cell (iPSC) line creating the heterozygous SVIL ^Q255X/+ and homozygous SVIL ^Q255X/Q255X cell lines. These lines were differentiated into iPSC-derived cardiomyocytes (iPSC-CMs) and cellular phenotypes were assessed using bulk RNA-sequencing, LC-MS proteomics, electrophysiological and calcium handling analyses, contractility measurements, sarcomere organization analysis, Seahorse metabolic flux assay, and pharmacological intervention with mavacamten. Results: The Q255X variant resulted in SVIL haploinsufficiency at both RNA and protein levels with no evidence of a truncated protein. Compared with isogenic controls, SVIL ^Q255X/+ iPSC-CMs demonstrated action potential shortening, calcium transient elongation, sarcomeric disorganization and hypertrophy, and impaired mitochondrial respiration. Multi-omic analyses of SVIL ^Q255X/+ iPSC-CMs showed a profile of cellular stress and inflammation, hypertrophic and pro-fibrotic signalling, and a pseudohypoxic state driven by decreased respiration and a HIF-induced glycolytic shift. These abnormalities were not present in SVIL ^Q255X/Q255X cardiomyocytes, consistent with a relatively limited cardiac phenotype reported in homozygous variant carriers. Mavacamten improved sarcomeric disorganization and hypertrophy in SVIL ^Q255X/+ cells but did not rescue energetic compromise. Conclusions: Pathogenic heterozygous SVIL LoF produces a distinct cellular phenotype characterized by impaired mechanotransduction, mitochondrial dysfunction, and maladaptive metabolic remodelling that promotes hypertrophic and pro-fibrotic signalling. These findings define a mechanistic basis for SVIL -associated cardiomyopathy and identify metabolic dysfunction as a potential therapeutic target beyond sarcomere-directed therapy. Clinical Perspective: What Is New?: SVIL haploinsufficiency causes HCM through a mechanism distinct from canonical sarcomeric disease, characterized by impaired mechanotransduction, mitochondrial dysfunction, and pseudohypoxia-driven metabolic remodeling. Heterozygous SVIL loss of function produces a substantially more severe cardiomyocyte phenotype than homozygous loss of function, providing a mechanistic explanation for the predominance of cardiac disease in heterozygous variant carriers. Mavacamten improves sarcomeric organization but does not restore impaired mitochondrial respiration, demonstrating that energetic dysfunction persists despite sarcomere-directed therapy. What Are the Clinical Implications?: Our findings give functional evidence to support SVIL as a clinically relevant HCM disease gene and its inclusion in clinical genetic testing panels. These findings establish SVIL -associated cardiomyopathy as a mechanistically distinct form of HCM and offer insight into the pathomechanism of Z-disk and costameric HCM The persistence of mitochondrial dysfunction despite myosin inhibition suggests that drugs targeting mitochondrial bioenergetics may be a therapeutic strategy in patients with SVIL -associated cardiomyopathy.