Organotypic culture of human brain explants as a preclinical model for AI-driven antiviral studies.

Viral neuroinfections represent a major health burden for which the development of antivirals is needed. Antiviral compounds that target the consequences of a brain infection (symptomatic treatment) rather than the cause (direct-acting antivirals) constitute a promising mitigation strategy that requires to be investigated in relevant models. However, physiological surrogates mimicking an adult human cortex are lacking, limiting our understanding of the mechanisms associated with viro-induced neurological disorders. Here, we optimized the Organotypic culture of Post-mortem Adult human cortical Brain explants (OPAB) as a preclinical platform for Artificial Intelligence (AI)-driven antiviral studies. OPAB shows robust viability over weeks, well-preserved 3D cytoarchitecture, viral permissiveness, and spontaneous local field potential (LFP). Using LFP as a surrogate for neurohealth, we developed a machine learning framework to predict with high confidence the infection status of OPAB. As a proof-of-concept, we showed that antiviral-treated OPAB could partially restore LFP-based electrical activity of infected OPAB in a donor-dependent manner. Together, we propose OPAB as a physiologically relevant and versatile model to study neuroinfections and beyond, providing a platform for preclinical drug discovery.

Brain exposure to SARS-CoV-2 virions perturbs synaptic homeostasis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with short- and long-term neurological complications. The variety of symptoms makes it difficult to unravel molecular mechanisms underlying neurological sequalae after coronavirus disease 2019 (COVID-19). Here we show that SARS-CoV-2 triggers the up-regulation of synaptic components and perturbs local electrical field potential. Using cerebral organoids, organotypic culture of human brain explants from individuals without COVID-19 and post-mortem brain samples from individuals with COVID-19, we find that neural cells are permissive to SARS-CoV-2 to a low extent. SARS-CoV-2 induces aberrant presynaptic morphology and increases expression of the synaptic components Bassoon, latrophilin-3 (LPHN3) and fibronectin leucine-rich transmembrane protein-3 (FLRT3). Furthermore, we find that LPHN3-agonist treatment with Stachel partially restored organoid electrical activity and reverted SARS-CoV-2-induced aberrant presynaptic morphology. Finally, we observe accumulation of relatively static virions at LPHN3-FLRT3 synapses, suggesting that local hindrance can contribute to synaptic perturbations. Together, our study provides molecular insights into SARS-CoV-2-brain interactions, which may contribute to COVID-19-related neurological disorders.

Haemophilic knee arthropathy: long-term outcome after total knee replacement.

PURPOSE: The objective of this study was to evaluate the long-term outcome and prosthetic survival of primary total knee arthroplasty in haemophilic patients. It was hypothesized that the infection and revision rate are higher and the outcome inferior when compared with patients without haemophilia. METHODS: Between 1985 and 2004, forty-three consecutive primary total knee replacements were performed in thirty haemophilic patients. These patients' charts were reviewed retrospectively. Twenty-five patients (34 knees) were available for clinical and radiological follow-up. The outcome was assessed using the Knee Society score, WOMAC and Kaplan-Meier survivorship analysis. RESULTS: An haematogenous infection occurred in two patients. In three patients, component revision was needed: two because of an infection and one because of a mechanical failure. After a mean follow-up of 9.6 years (2-20), 94% of the patients rated their result as either excellent or good. At time of follow-up, the Knee Society Score averaged 73.3 points (range, 29-100) and showed a significant gain (p < 0.001) compared to preoperative. Flexion contracture could be reduced significantly (p < 0.001) from 18.1° preoperatively to 8.4° at follow-up, whereas flexion remained unchanged. When infection or any component replacement was set as endpoints, the 10 years prosthetic survival was 90 and 86%, respectively. CONCLUSION: Total knee arthroplasty in haemophilic patients is a reliable treatment that results in pain relief and functional improvement with a low risk of postoperative infection. However, neither the postoperative infection rate nor the functional result does reach the same level as in a population not affected by haemophilia. LEVEL OF EVIDENCE: IV.