Cell-type dependence of necroptosis pathways triggered by viral infection.

Necroptosis, a potent host defense mechanism, limits viral replication and pathogenesis through three distinct initiation pathways. Toll-like receptor 3 (TLR3) via TIR-domain-containing adapter-inducing interferon-ß (TRIF), Z-DNA-binding protein 1 (ZBP1) and tumor necrosis factor (TNF)α mediate necroptosis, with ZBP1 and TNF playing pivotal roles in controlling viral infections, with the role of TLR3-TRIF being less clear. ZBP1-mediated necroptosis is initiated when host ZBP1 senses viral Z-form double stranded RNA and recruits receptor-interacting serine/threonine-protein kinase 3 (RIPK3), driving a mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis pathway, whereas TNF-mediated necroptosis is initiated by TNF signaling, which drives a RIPK1-RIPK3-MLKL pathway, resulting in necroptosis. Certain viruses (cytomegalovirus, herpes simplex virus and vaccinia) have evolved to produce proteins that compete with host defense systems, preventing programmed cell death pathways from being initiated. Two engineered viruses deficient of active forms of these proteins, murine cytomegalovirus M45mutRHIM and vaccinia virus E3∆Zα, trigger ZBP1-dependent necroptosis in mouse embryonic fibroblasts. By contrast, when bone-marrow-derived macrophages are infected with the viruses, necroptosis is initiated predominantly through the TNF-mediated pathway. However, when the TNF pathway is blocked by RIPK1 inhibitors or a TNF blockade, ZBP1-mediated necroptosis becomes the prominent pathway in bone-marrow-derived macrophages. Overall, these data implicate a cell-type preference for either TNF-mediated or ZBP1-mediated necroptosis pathways in host responses to viral infections. These preferences are important to consider when evaluating disease models that incorporate necroptosis because they may contribute to tissue-specific reactions that could alter the balance of inflammation versus control of virus, impacting the organism as a whole.

Approaches to Evaluating Necroptosis in Virus-Infected Cells.

The immune system functions to protect the host from pathogens. To counter host defense mechanisms, pathogens have developed unique strategies to evade detection or restrict host immune responses. Programmed cell death is a major contributor to the multiple host responses that help to eliminate infected cells for obligate intracellular pathogens like viruses. Initiation of programmed cell death pathways during the early stages of viral infections is critical for organismal survival as it restricts the virus from replicating and serves to drive antiviral inflammation immune recruitment through the release of damage-associated molecular patterns (DAMPs) from the dying cell. Necroptosis has been implicated as a critical programmed cell death pathway in a diverse set of diseases and pathological conditions including acute viral infections. This cell death pathway occurs when certain host sensors are triggered leading to the downstream induction of mixed-lineage kinase domain-like protein (MLKL). MLKL induction leads to cytoplasmic membrane disruption and subsequent cellular destruction with the release of DAMPs. As the role of this cell death pathway in human disease becomes apparent, methods identifying necroptosis patterns and outcomes will need to be further developed. Here, we discuss advances in our understanding of how viruses counteract necroptosis, methods to quantify the pathway, its effects on viral pathogenesis, and its impact on cellular signaling.

Electrocardiographic Features and Outcome: Correlations in 124 Hospitalized Patients With COVID-19 and Cardiovascular Events.

OBJECTIVES: Electrocardiographic (ECG) changes have been associated with coronavirus disease 2019 (COVID-19) severity. However, the progression of ECG findings in patients with COVID-19 has not been studied. The purpose of this study was to describe ECG features at different stages of COVID-19 cardiovascular (CV) events and to examine the effects of specific ECG parameters and cardiac-related biomarkers on clinical outcomes in COVID-19. DESIGN: Retrospective, cohort study. SETTING: Major tertiary-care medical centers and community hospitals in Louisville, KY. PARTICIPANTS: A total of 124 patients with COVID-19 and CV events during hospitalization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twelve-lead ECG parameters, biomarkers of cardiac injuries, and clinical outcomes were analyzed with Spearman correlation coefficients and Kruskal-Wallis 1-way analysis of variance. Atrial fibrillation/atrial flutter was more frequent on the ECG obtained at the time of the CV event when compared with admission ECG (9.5% v 26.9%; p = 0.007). Sinus tachycardia was higher in the last available hospital ECG than the CV event ECG (37.5% v 20.4%; p = 0.031). Admission ECG-corrected QT interval was significantly associated with admission troponin levels (R = 0.52; p < 0.001). The last available hospital ECG showed nonsurvivors had longer QRS duration than survivors (114.6 v 91.2 ms; p = 0.026), and higher heart rate was associated with longer intensive care unit length of stay (Spearman ρ = 0.339; p = 0.032). CONCLUSIONS: In hospitalized patients with COVID-19 and CV events, ECGs at various stages of COVID-19 hospitalization showed significantly different features with dissimilar clinical outcome correlations.

Use of a pacemaker magnet to remove a broken suture needle during a laparoscopic cholecystectomy.

Prompt removal of unintended surgical foreign bodies is essential for prevention of adverse consequences of retained surgical foreign bodies postop. Current practices utilizing radiographic images in combination with visual inspection and palpation to remove foreign bodies can lead to increased surgical times and tissue damage. A suture needle fragment broke off during a laparoscopic cholecystectomy performed on a morbidly obese adult female. After being unable to retrieve the fragment by increasing the midline incision by ~7 cm and undergoing an additional ~1 of intraoperative time, a pacemaker magnet wrapped in sterilized plastic was able to instantaneously remove the shard. Techniques utilizing magnetism could be researched and developed for the removal of surgical foreign bodies both intraoperatively and postop.