The Impact of the Covid-19 Pandemic on Recovery from Cardiac Surgery Over Time: Results of the Cardiaccovid Study from three Uk National Lockdowns.

This prospective study (clinicaltrials.gov NCT04366167) explores health-related quality of life (EQ-5D-5L), event-related distress (IES-R) and depression (CES-D) after cardiac surgery during the three UK national COVID-19 lockdowns. Overall, 253 patients participated (lockdown one n = 196; two n = 45; three n = 12) completing the above-mentioned questionnaires at baseline, one week after discharge and six weeks, six and 12 months after surgery. While EQ-5D-5L values were similar across all cohorts, those having surgery in lockdowns two and three had higher IES-R scores at 1-year and higher IES-R and CES-D baseline scores, respectively. Generally, increased distress, worse depression and poorer HRQoL were observed in women.

The impact of the COVID-19 pandemic on recovery from cardiac surgery: 1-year outcomes.

AIMS: The outbreak of COVID-19 was potentially stressful for everyone and possibly heightened in those having surgery. We sought to explore the impact of the pandemic on recovery from cardiac surgery. METHODS AND RESULTS: A prospective observational study of 196 patients who were ≥18years old undergoing cardiac surgery between March 23 and July 4, 2020 (UK lockdown) was conducted. Those too unwell or unable to give consent/complete the questionnaires were excluded. Participants completed (on paper or electronically) the impact of event [Impact of Events Scale-revised (IES-R)] (distress related to COVID-19), depression [Centre for Epidemiological Studies Depression Scale (CES-D)], and EQ-5D-5L [(quality of life, health-related quality of life (HRQoL)] questionnaires at baseline, 1 week after hospital discharge, and 6 weeks, 6 months and 1 year post-surgery. Questionnaire completion was >75.0% at all timepoints, except at 1 week (67.3%). Most participants were male [147 (75.0%)], white British [156 (79.6%)] with an average age 63.4years. No patients had COVID-19. IES-R sand CES-D were above average at baseline (indicating higher levels of anxiety and depression) decreasing over time. HRQoL pre-surgery was high, reducing at 1 week but increasing to almost pre-operative levels at 6 weeks and exceeding pre-operative levels at 6 months and 1 year. IES-R and CES-D scores were consistently higher in women and younger patients with women also having poorer HRQoL up to 1-year after surgery. CONCLUSIONS: High levels of distress were observed in patients undergoing cardiac surgery during the COVID-19 pandemic with women and younger participants particularly affected. Psychological support pre- and post-operatively in further crises or traumatic times should be considered to aid recovery. REGISTRATION: Clinicaltrials.gov ID:NCT04366167.

Discovery of brain-penetrant, orally bioavailable aminothienopyridazine inhibitors of tau aggregation.

Agents capable of preventing the misfolding and sequestration of the microtubule-stabilizing protein tau into insoluble fibrillar aggregates hold considerable promise for the prevention and/or treatment of neurodegenerative tauopathies such as Alzheimer's disease. Because tauopathies are characterized by amyloidosis that is restricted to the central nervous system (CNS), plausible candidate compounds for in vivo evaluation must both prevent tau fibrillization and achieve significant brain levels. Recently, we reported the discovery of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors and now describe a series of new analogues that are both effective inhibitors of tau fibrillization and display significant brain-to-plasma exposure ratios after administration to mice. Further, two of the most promising examples, 15 and 16, were found to reach significant brain exposure levels following oral administration. Taken together, these results suggest that examples from the ATPZ class hold promise as candidates for in vivo efficacy studies in animal models of neurodegenerative tauopathies.

Calcium-sensing soluble adenylyl cyclase mediates TNF signal transduction in human neutrophils.

Through chemical screening, we identified a pyrazolone that reversibly blocked the activation of phagocyte oxidase (phox) in human neutrophils in response to tumor necrosis factor (TNF) or formylated peptide. The pyrazolone spared activation of phox by phorbol ester or bacteria, bacterial killing, TNF-induced granule exocytosis and phox assembly, and endothelial transmigration. We traced the pyrazolone's mechanism of action to inhibition of TNF-induced intracellular Ca2+ elevations, and identified a nontransmembrane ("soluble") adenylyl cyclase (sAC) in neutrophils as a Ca2+-sensing source of cAMP. A sAC inhibitor mimicked the pyrazolone's effect on phox. Both compounds blocked TNF-induced activation of Rap1A, a phox-associated guanosine triphosphatase that is regulated by cAMP. Thus, TNF turns on phox through a Ca2+-triggered, sAC-dependent process that may involve activation of Rap1A. This pathway may offer opportunities to suppress oxidative damage during inflammation without blocking antimicrobial function.