Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay.
Objective-Proinflammatory mediators influence atherosclerosis by inducing adhesion molecules (eg, VCAM-1) on endothelial cells (ECs) via signaling intermediaries including p38 MAP kinase. Regions of arteries exposed to high shear stress are protected from inflammation and atherosclerosis, whereas low-shear regions are susceptible. Here we investigated whether the transcription factor Nrf2 regulates EC activation in arteries. Methods and Results-En face staining revealed that Nrf2 was activated in ECs at an atheroprotected region of the murine aorta where it negatively regulated p38 -VCAM-1 signaling, but was expressed in an inactive form in ECs at an atherosusceptible site. Treatment with sulforaphane, a dietary antioxidant, activated Nrf2 and suppressed p38 -VCAM-1 signaling at the susceptible site in wild-type but not Nrf2 Ϫ/Ϫ animals, indicating that it suppresses EC activation via Nrf2. Studies of cultured ECs revealed that Nrf2 inactivates p38 by suppressing an upstream activator MKK3/6 and by enhancing the activity of the negative regulator MKP-1. Key Words: Nrf2 Ⅲ arterial endothelium Ⅲ shear stress Ⅲ sulforaphane Ⅲ proinflammatory activation Ⅲ p38 Ⅲ MKK3/6 Ⅲ MKP-1 E arly atherosclerotic lesions contain monocytes and T-lymphocytes which are recruited from the circulation by adhesion to activated vascular endothelial cells (ECs). 1 This process is triggered by proinflammatory mediators (eg, TNF␣) which induce cellular adhesion molecules (eg, VCAM-1) via signaling intermediaries including p38 mitogen-activated protein (MAP) kinase, which is activated by phosphorylation by MAP kinase kinases 3 and 6 (MKK 3/6). 2,3 Vascular inflammation and atherosclerosis develop predominantly at distinct sites of the arterial tree located near branches and bends which are exposed to nonuniform blood flow, which exerts relatively low shear stress on vascular endothelium, whereas regions of arteries that are exposed to unidirectional high shear stress are protected. 4 -6 Proinflammatory activation of ECs is reduced at high-shear sites compared to low-shear regions, thus providing a potential explanation for the distinct spatial localization of vascular inflammation and lesion formation. 5,7-10 Similarly, the application of unidirectional high shear stress can suppress proinflammatory activation of cultured ECs, whereas low or oscillatory shear can act as a positive regulator of EC activation. 5,10 -15 The molecular mechanisms underlying the antiinflammatory effects of shear stress are uncertain, but previous studies of cultured cells have suggested a role for the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). 16 -20 In unstimulated cells, Nrf2 is suppressed by kelch-like ECH-associated protein 1 (Keap1) which targets it for ubiquitination and proteasomal processing. Nrf2 can be activated by shear stress, dietary antioxidants (eg, sulforaphane) and other physiological stimuli which disrupt Keap1-Nrf2 interactions leading to stabilization and nuclear translocation of Nrf2. 16 -22 A previous study...
Cardiovascular pathologies are still the primary cause of death worldwide. The molecular mechanisms behind these pathologies have not been fully elucidated. Unravelling them will bring us closer to therapeutic strategies to prevent or treat cardiovascular disease. One of the major transcription factors that has been linked to both cardiovascular health and disease is NF-kappaB (nuclear factor kappaB). The NF-kappaB family controls multiple processes, including immunity, inflammation, cell survival, differentiation and proliferation, and regulates cellular responses to stress, hypoxia, stretch and ischaemia. It is therefore not surprising that NF-kappaB has been shown to influence numerous cardiovascular diseases including atherosclerosis, myocardial ischaemia/reperfusion injury, ischaemic preconditioning, vein graft disease, cardiac hypertrophy and heart failure. The function of NF-kappaB is largely dictated by the genes that it targets for transcription and varies according to stimulus and cell type. Thus NF-kappaB has divergent functions and can protect cardiovascular tissues from injury or contribute to pathogenesis depending on the cellular and physiological context. The present review will focus on recent studies on the function of NF-kappaB in the cardiovascular system.
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