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COVID-19: famotidine, histamine, mast cells, and mechanisms [eprint]

Summary

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.
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Summary

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain...

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Kawasaki disease, multisystem inflammatory syndrome in children: antibody-induced mast cell activation hypothesis

Published in:
J Pediatrics & Pediatr Med. 2020; 4(2): 1-7

Summary

Multisystem Inflammatory Syndrome in Children (MIS-C) is appearing in infants, children, and young adults in association with COVID-19 (coronavirus disease 2019) infections of SARS-CoV-2. Kawasaki Disease (KD) is one of the most common vasculitides of childhood. KD presents with similar symptoms to MIS-C especially in severe forms such as Kawasaki Disease Shock Syndrome (KDSS). The observed symptoms for MIS-C and KD are consistent with Mast Cell Activation Syndrome (MCAS) characterized by inflammatory molecules released from activated mast cells. Based on the associations of KD with multiple viral and bacterial pathogens, we put forward the hypothesis that KD and MIS-C result from antibody activation of mast cells by Fc receptor-bound pathogen antibodies causing a hyperinflammatory response upon second pathogen exposure. Within this hypothesis, MIS-C may be atypical KD or a KD-like disease associated with SARS-CoV-2. We extend the mast cell hypothesis that increased histamine levels are inducing contraction of effector cells with impeded blood flow through cardiac capillaries. In some patients, pressure from impeded blood flow, within cardiac capillaries, may result in increased coronary artery blood pressure leading to aneurysms, a well-known complication in KD.
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Summary

Multisystem Inflammatory Syndrome in Children (MIS-C) is appearing in infants, children, and young adults in association with COVID-19 (coronavirus disease 2019) infections of SARS-CoV-2. Kawasaki Disease (KD) is one of the most common vasculitides of childhood. KD presents with similar symptoms to MIS-C especially in severe forms such as Kawasaki...

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Large-scale Bayesian kinship analysis

Summary

Kinship prediction in forensics is limited to first degree relatives due to the small number of short tandem repeat loci characterized. The Genetic Chain Rule for Probabilistic Kinship Estimation can leverage large panels of single nucleotide polymorphisms (SNPs) or sets of sequence linked SNPs, called haploblocks, to estimate more distant relationships between individuals. This method uses allele frequencies and Markov Chain Monte Carlo methods to determine kinship probabilities. Allele frequencies are a crucial input to this method. Since these frequencies are estimated from finite populations and many alleles are rare, a Bayesian extension to the algorithm has been developed to determine credible intervals for kinship estimates as a function of the certainty in allele frequency estimates. Generation of sufficiently large samples to accurately estimate credible intervals can take significant computational resources. In this paper, we leverage hundreds of compute cores to generate large numbers of Dirichlet random samples for Bayesian kinship prediction. We show that it is possible to generate 2,097,152 random samples on 32,768 cores at a rate of 29.68 samples per second. The ability to generate extremely large number of samples enables the computation of more statistically significant results from a Bayesian approach to kinship analysis.
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Summary

Kinship prediction in forensics is limited to first degree relatives due to the small number of short tandem repeat loci characterized. The Genetic Chain Rule for Probabilistic Kinship Estimation can leverage large panels of single nucleotide polymorphisms (SNPs) or sets of sequence linked SNPs, called haploblocks, to estimate more distant...

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