Proposed HAM disease mechanism(s) of spinal cord infiltration and inflammation triggered by combined effects of AIM2 inflammasome activation, monocyte/microglial activation, pro-inflammatory cytokines (IL1β, IL-6, TNF, IFN-γ), decreased antioxidant capacity, and reprogramming of lipid #metabolism.

Using proviral load as phenotype, small molecule/lipid metabolism and oxidation-reduction GO terms were enriched for AFR, AMR, ASN, EUR datasets. So we performed 1H-NMR #metabolomics: lower major lipid metabolites in HAM patients, including ApoA1, ApoB, total and HDL-cholesterol!

Exploring publicly available single-cell RNAseq data: broad HAM gene module (95 genes shared Brazil/Japan GWAS, overexpressed in HAM) shows widespread expression across all cell types in the spinal cord: oligodendrocyte precursor cells >astrocytes >oligodendrocytes >microglia >glutamergic neurons

We validated genetically predicted higher HAM blood monocyte levels in two independent cohorts (Brazil/Peru). Monocyte counts also predicted long-term outcome: higher monocyte baseline predicts worse disease progression (Osame Motor Disability Scale) and lower activities of daily living (Lawton)

Enriched neuronal pathways included axon guidance, cholinergic/dopaminergic/serotonergic synapse, and long-term #depression. Phenome-wide screening in UK Biobank identified monocyte count, broad neurological phenotypes (anhedonia, depression) and neurocognitive skills

Brazilian GWAS showed a strong enrichment for #mitochondria, neuron/synapse and cell membrane, hinting at energy #metabolism and cellular signaling in the CNS, which was confirmed when examining only the 435 genes overlapping Japanese GWAS. Overlapping pathways: signaling, metabolic and neuronal

Polygenic risk scores (PRS) based on Japanese GWAS summary statistics were validated in Brazil cohort. Multivariable logistic regression corrected for age/sex: PRS and proviral load are independent predictors of HAM disease. PRS asymptomatics < intermediate (IS), incident HAM (iHAM) and HAM

African-specific genome-wide significant association at AIM2 (=cytosolic DNA sensor and inflammasome activator) locus. The lead SNP is rare in ASN populations (1000 Genomes), hence absent in Japanese GWAS, but with frequencies of 0.50, 0.07, and 0.05 in AFR, AMR, and EUR populations (see map below)

The #Brazil cohort displayed mainly European and African admixture, with smaller contributions from Amerindian (AMR) and Asian (ASN) ancestries, as shown by PCA and ADMIXTURE plots (left and right panel below)

Making of...

In difficult times, flowers bring me comfort... I hope they help you get through your day, too 🙏

We found NFL neurodamage marker went up over time with anticoagulant treatment in most patients, while both GFAP and NFL went down very quickly after 15 days of Paxlovid: is there a direct link between a viral reservoir and CNS damage?

Tldr: Yes! Antiviral treatment (Paxlovid) is the only significant independent predictor of broadly and strictly defined clinical improvement. Also, severe patients did significantly better with antiviral treatment👇

First, clinical recovery was measured by both patients and the clinician (Dr. Marc Jamoulle) using validated scales. Patients used COOP charts that require only 2-3 min, as we know filing out long questionnaires is exhausting. It rapidly scores 6 aspects of daily life
#QoL

#LongCovid is complex to diagnose and treat, so we need #biomarkers!
Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition - The Lancet Microbe
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