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BackgroundSARS-CoV-2 Delta variant has caused a dramatic resurgence in infections in the United Sates, raising questions regarding potential transmissibility among vaccinated individuals.MethodsBetween October 2020 and July 2021, we sequenced 4,439 SARS-CoV-2 full genomes, 23% of all known infections in Alachua County, Florida, including 109 vaccine breakthrough cases. Univariate and multivariate regression analyses were conducted to evaluate associations between viral load (VL) level and patient characteristics. Contact tracing and phylogenetic analysis were used to investigate direct transmissions involving vaccinated individuals.ResultsThe majority of breakthrough sequences with lineage assignment were classified as Delta variants (74.6%) and occurred, on average, about three months (104 ± 57.5 days) after full vaccination, at the same time (June-July 2021) of Delta variant exponential spread within the county. Six Delta variant transmission pairs between fully vaccinated individuals were identified through contact tracing, three of which were confirmed by phylogenetic analysis. Delta breakthroughs exhibited broad VL values during acute infection (IQR 1.2 – 8.64 Log copies/ml), on average 38% lower than matched unvaccinated patients (3.29 – 10.81 Log copies/ml, pConclusionsDelta infection transmissibility and general VL patterns in vaccinated individuals suggest limited levels of sterilizing immunity that need to be considered by public health policies. In particular, ongoing evaluation of vaccine boosters should address whether extra vaccine doses might curb breakthrough contribution to epidemic spread.

PurposePrognostic metrics for the rapid and accurate prediction of sepsis severity that could elicit a meaningful change in clinical practice are currently lacking. Here, we evaluated a whole blood, multiplex host mRNA expression metric, Inflammatix-Severity-2 (IMX-SEV-2), for identifying septic, hospitalized patients for 30-day mortality, development of chronic critical illness (CCI), discharge disposition, and/or secondary infections.MethodsThis is a retrospective, validation cohort analysis of a prospectively enrolled 335 patient study with surgical sepsis treated in the surgical intensive care unit. Whole blood collected in PAXgene®Blood RNA collection tubes at 24 hours post sepsis diagnosis was analyzed using a custom 29-mRNA classifier (IMX-SEV-2) in a CLIA-CAP-accredited diagnostic laboratory using the NanoString FLEX®profiler.ResultsAmong patients meeting Sepsis-3 criteria, the IMX-SEV-2 severity score was significantly better (pConclusionsThe IMX-SEV-2 severity score was superior at predicting secondary infections and overall adverse clinical outcomes versus other common metrics. Importantly, combining a rapidly measured transcriptomic metric with clinical or physiologic indices has sufficient precision to optimize resource utilization and allow adjustments to patient management that may improve outcomes in surgical sepsis. Hospitalized patients who are septic and present with an elevated IMX-SEV2 severity score and pre-existing comorbidities would be strong candidates for clinical interventions aimed at reducing the risk of secondary infections and adverse clinical outcomes.

PURPOSEWhile patients with advanced-stage non-small cell lung cancers (NSCLCs) harboringMETexon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.METHODSTargeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stageMETex14-mutated NSCLC.RESULTSProminent co-occurring RAS-MAPK pathway gene alterations (e.g. inKRAS, NF1) were detected in NSCLCs withMETex14 skipping alterations as compared toEGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonicalMETex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib.CONCLUSIONOur study provides a genomic landscape of co-occurring alterations in advanced-stageMETex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.