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Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19
COVID-19 is associated with diverse neurological abnormalities, but the underlying mechanisms are unclear. We hypothesized that microglia, the resident immune cells of the brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy, protein and mRNA datasets in postmortem mirror blocks of brain and peripheral organ samples from cases of COVID-19. We observed focal loss of microglial P2Y12R, CX3CR1–CX3CL1 axis deficits and metabolic failure at sites of virus-associated vascular inflammation in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction is linked to mitochondrial injury at sites of excessive synapse and myelin phagocytosis and loss of glutamatergic terminals, in line with proteomic changes of synapse assembly, metabolism and neuronal injury. Furthermore, regionally heterogeneous microglial changes are associated with viral load and central and systemic inflammation related to interleukin (IL)-1 or IL-6 via virus-sensing pattern recognition receptors and inflammasomes. Thus, SARS-CoV-2-induced inflammation might lead to a primarily gliovascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.
COVID-19 health data prediction: a critical evaluation of CNN-based approaches
The COVID-19 pandemic has significantly accelerated the demand for accurate and efficient prediction models to support effective disease management, containment strategies, and informed decision-making. Predictive models capable of analyzing complex health data are essential for monitoring disease trends, evaluating risk factors, and optimizing resource allocation during the pandemic. Among various machine learning approaches, convolutional neural networks (CNNs) have emerged as powerful tools due to their ability to process large volumes of high-dimensional health data, such as medical images, time-series data, and patient demographics, with impressive precision. This research seeks to systematically examine the challenges and limitations inherent in utilizing CNNs for COVID-19 health data prediction, offering a comprehensive perspective grounded in data science research. Key areas of investigation include issues related to data quality and availability, such as incomplete, noisy, and imbalanced datasets, which often hinder the training of robust models. Additionally, architectural constraints of CNNs, including their sensitivity to hyperparameter tuning and reliance on substantial computational resources, are explored as critical bottlenecks that impact scalability and efficiency. A significant focus is placed on generalization challenges, where models trained on specific datasets struggle to adapt to unseen data from diverse populations or clinical settings, limiting their applicability in real-world scenarios. The study further highlights a reported accuracy of 63%, underscoring the need for improved methodologies to enhance model performance and reliability. By addressing these challenges, this research aims to provide actionable insights and practical recommendations to optimize the use of CNNs for COVID-19 health data prediction. In particular, the study emphasizes the importance of incorporating advanced strategies such as transfer learning, data augmentation, and regularization techniques to overcome dataset limitations and enhance model robustness. The integration of multimodal approaches combining medical images with auxiliary data, such as patient demographics and laboratory results, is proposed to improve contextual understanding and diagnostic precision. Finally, the research underscores the necessity of interdisciplinary collaboration, leveraging domain expertise from data scientists, healthcare professionals, and epidemiologists to develop holistic solutions for tackling the complexities of COVID-19 prediction. By shedding light on the limitations and potential of CNNs in this domain, this study aims to guide researchers and practitioners in making informed decisions about model design, implementation, and optimization. Ultimately, it contributes to advancing AI-driven diagnostics and predictive modeling for COVID-19 and other public health crises, fostering the development of scalable and reliable tools for better healthcare outcomes.
The cellular and molecular cardiac tissue responses in human inflammatory cardiomyopathies after SARS-CoV-2 infection and COVID-19 vaccination
Myocarditis, characterized by inflammatory cell infiltration, can have multiple etiologies, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or, rarely, mRNA-based coronavirus disease 2019 (COVID-19) vaccination. The underlying cellular and molecular mechanisms remain poorly understood. In this study, we performed single-nucleus RNA sequencing on left ventricular endomyocardial biopsies from patients with myocarditis unrelated to COVID-19 (Non-COVID-19), after SARS-CoV-2 infection (Post-COVID-19) and after COVID-19 vaccination (Post-Vaccination). We identified distinct cytokine expression patterns, with interferon-γ playing a key role in Post-COVID-19, and upregulated IL16 and IL18 expression serving as a hallmark of Post-Vaccination myocarditis. Although myeloid responses were similar across all groups, the Post-Vaccination group showed a higher proportion of CD4+ T cells, and the Post-COVID-19 group exhibited an expansion of cytotoxic CD8+ T and natural killer cells. Endothelial cells showed gene expression changes indicative of vascular barrier dysfunction in the Post-COVID-19 group and ongoing angiogenesis across all groups. These findings highlight shared and distinct mechanisms driving myocarditis in patients with and without a history of SARS-CoV-2 infection or vaccination.
Clinical characteristics and outcomes of BCMA-targeted CAR-T cell recipients with COVID-19 during the Omicron wave: a retrospective study
Patients with relapsed or refractory multiple myeloma (R/R-MM) are more susceptible to develop severe coronavirus disease 2019 (COVID-19) for their immunocompromised states. Despite good responses to B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cell therapy, deficiencies in humoral immunity following CAR-T cell infusions can still cause life-threatening complications in these patients. We conducted a comparative study to delineate the clinical characteristics and outcomes between recipients of BCMA-targeted CAR-T cell therapy who contracted COVID-19 vs. unaffected counterparts. Advanced age (odds ratio [OR] = 1.367, 95% confidence interval [CI] = 1.017–1.838, P = 0.038) was a risk factor for developing severe COVID-19, while complete remission (CR) achieved by CAR-T cell therapy (OR = 0.012, 95% CI = 0.000–0.674, P = 0.032) was protective. Male sex (hazard ratio [HR] = 5.274, 95% CI = 1.584–17.562, P = 0.007) and CR achieved by CAR-T cell therapy (HR = 3.107, 95% CI = 1.025–9.418, P = 0.045) were protective factors associated with COVID-19 duration. CR achieved by CAR-T cell therapy (HR = 0.064, 95% CI = 0.007–0.589, P = 0.015) was also a protective factor for OS, while progression disease at the time of COVID-19 diagnosis (HR = 14.206, 95% CI = 1.555–129.819, P = 0.019) was regarded as a risk factor. Thus, older patients with R/R-MM and those who do not achieve CR after CAR-T cell therapy should be most protected from COVID-19 infection by the Omicron variant.
Dysregulated autoantibodies targeting AGTR1 are associated with the accumulation of COVID-19 symptoms
Coronavirus disease 2019 (COVID-19) presents a wide spectrum of symptoms, the causes of which remain poorly understood. This study explored the associations between autoantibodies (AABs), particularly those targeting G protein-coupled receptors (GPCRs) and renin‒angiotensin system (RAS) molecules, and the clinical manifestations of COVID-19. Using a cross-sectional analysis of 244 individuals, we applied multivariate analysis of variance, principal component analysis, and multinomial regression to examine the relationships between AAB levels and key symptoms. Significant correlations were identified between specific AABs and symptoms such as fever, muscle aches, anosmia, and dysgeusia. Notably, anti-AGTR1 antibodies, which contribute to endothelial glycocalyx (eGC) degradation, a process reversed by losartan, have emerged as strong predictors of core symptoms. AAB levels increased with symptom accumulation, peaking in patients exhibiting all four key symptoms. These findings highlight the role of AABs, particularly anti-AGTR1 antibodies, in determining symptom severity and suggest their involvement in the pathophysiology of COVID-19, including vascular complications.
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