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Tumor Necrosis Factor (TNF) is a trimeric cytokine induces innate inflammatory responses or cell death through TNFR1. Extracellular mutations in TNFR1 are associated with Receptor-Associated Periodic Syndrome (TRAPS), an autosomal dominant autoinflammatory disorder characterized by recurring fevers, dermal and synovial inflammation and elevated risk of amyloidosis. Previous work by our group has demonstrated that a TRAPS-like mutation in TNFR1 leads to accumulation of the receptor in the ER, leading to abnormal MAPK activation and correlated with reduced glucose metabolism. To better understand how the mutant TNFR1 signals to induce these abnormal cellular phenotypes, we immunoprecipitated the wild-type and TRAPS-associated mutant receptors and performed mass spectroscopy to identify associated proteins. Both WT and Mutant were able to bind the known adapter protein TRADD, but not the death domain (DD) deleted mutant. In addition, we also identified a novel association of WT and mutant TNFR1 with pyruvate kinase M2 (PKM2). Pyruvate kinase is the rate limiting enzyme in glycolysis and PKM2, and has been shown to be more activated in cancer cells, leading to abnormal metabolism known as the Warburg effect where cells undergo aerobic glycolysis. In addition, other studies suggest a link between activated PKM2 and induction of inflammatory responses, increasing TNF and IL1-b production. To confirm this interaction, we utilized colocalization microscopy techniques and IP/Western blot analysis which inferred a link between PKM2 and mutant TNFR1 more than the wild-type. Association between PKM2 TNFR1 may be a novel link between TNFR1 signaling and metabolism and explain some of the metabolic abnormalities in TRAPS cells.

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Background: Patients hospitalized with COVID-19 who develop cardiopulmonary arrest often have poor prognosis, prompting discussions with families about goals of care. The relationship between clinical and social determinants of code status change is poorly understood. Methods: This retrospective study included adult COVID-19 positive patients admitted to the intensive care unit with cardiac arrest in a multihospital center over the first 9 months of the pandemic (3/1/2020 - 12/1/2020). Data on medical and social factors was collected and adjudicated. Results: We identified 208 patients over the study timeline. The mean age was 63.7 ± 14.5 years and 54.3% (n=113) were male. The majority of patients with cardiopulmonary arrest had pulseless electrical activity (PEA) as their initial rhythm (91.3%, n=190). Code status was changed in 56.3% (n=117) of patients. The majority of COVID-19 patients with cardiac arrest were Hispanic (53.4%, n=111), followed by African American (27.9%, n=58), and White patients (13.5%, n=28). Race/ethnicity did not affect the rate of code status change. COVID-19 patients who had a code status change were statistically more likely to have a lower salary ($54,838 vs $62,374), have a history of stroke/transient ischemic attack (15.4 vs 4.4%, 18:4), or heart failure (28.2 vs 15.6%, 33:14), all with P<0.05. Patients with code status change had shorter courses of cardiopulmonary resuscitation (11.9 vs 16.9 minutes, P<0.05). Both groups had similar levels of aggressive care received including continuous renal replacement therapy, vasopressor and broad-spectrum antibiotics requirements. Insurance status, ethnicity, religion, and education did not lead to statistically significant changes in code status in COVID patients. Conclusion: Patients hospitalized with cardiopulmonary arrest and positive for COVID-19 are more likely to have a change in code status. This code status change is affected by cardiovascular comorbidities such as stroke and heart failure, along with lower income but not by insurance status, ethnicity, religion, and educational level.

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