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New SARS-CoV-2 variants emerge as part of the virus' adaptation to the human host. The Health Organizations are monitoring newly emerging variants with suspected impact on disease or vaccination efficacy as Variants Being Monitored (VBM), like Delta and Omicron. Genetic changes (SNVs) compared to the Wuhan variant characterize VBMs with current emphasis on the spike protein and lineage markers. However, monitoring VBMs in such a way might miss SNVs with functional effect on disease. Here we introduce a lineage-agnostic genome-wide approach to identify SNVs associated with disease. We curated a case-control dataset of 10,520 samples and identified 117 SNVs significantly associated with adverse patient outcome. While 40% (47) SNV are already monitored and 36% (43) are in the spike protein, we also identified 70 new SNVs that are associated with disease outcome. 31 of these are disease-worsening and predominantly located in the 3'-5' exonuclease (NSP14) with structural modelling revealing a concise cluster in the Zn binding domain that has known host-immune modulating function. Furthermore, we generate clade-independent VBM groupings by identifying interacting SNVs (epistasis). We find 37 sets of higher-order epistatic interactions joining 5 genomic regions (nsp3, nsp14, Spike S1, ORF3a, N). Structural modelling of these regions provides insights into potential mechanistic pathways of increased virulence as well as orthogonal methods of validation. Clade-independent monitoring of functionally interacting (epistasis, co-evolution) SNVs detected emerging VBM a week before they were flagged by Health Organizations and in conjunction with structural modelling provides faster, mechanistic insight into emerging strains to guide public health interventions.

To systematically review the accuracy of early (≤7 days) predictors of poor outcome defined as death or vegetative state (Cerebral Performance Categories [CPC] 4-5) or death, vegetative state or severe disability (CPC 3-5) in comatose survivors from cardiac arrest not treated using therapeutic hypothermia (TH). PubMed, Scopus and the Cochrane Database of Systematic reviews were searched for eligible studies. Sensitivity, specificity, false positive rates (FPR) for each predictor were calculated and results of predictors with similar time points and outcome definitions were pooled. Quality of evidence (QOE) was evaluated according to the GRADE guidelines.50 studies (2828 patients) were included in final analysis. Presence of myoclonus at 24-48h, bilateral absence of short-latency somatosensory evoked potential (SSEP) N20 wave at 24-72h, absence of electroencephalographic activity20-21μV ≤72h and absence of pupillary reflex at 72h predicted CPC 4-5 with 0% FPR and narrow (10%) 95% confidence intervals. Absence of SSEP N20 wave at 24h predicted CPC 3-5 with 0% [0-8] FPR. Serum thresholds for 0% FPR of biomarkers neuron specific enolase (NSE) and S-100B were highly inconsistent among studies. Most of the studies had a low or very low QOE and did not report blinding of the treating team from the results of the investigated predictor.In comatose resuscitated patients not treated with TH presence of myoclonus, absence of pupillary reflex, bilateral absence of N20 SSEP wave and low EEG voltage each predicted poor outcome early and accurately, but with a relevant risk of bias.