Coronavirus disease 2019 (COVID-19) has caused significant devastation globally. Despite the development of several vaccines, with uncertainty around global uptake and vaccine efficacy, the need for effective therapeutic agents remains. Increased levels of cytokines including tumour necrosis factor are significant in the pathogenesis of COVID-19 and associated with poor outcomes including ventilator requirement and mortality. Repurposing tumour necrosis factor blocker therapy used in conditions such as rheumatoid arthritis and inflammatory bowel disease seems promising, with early feasibility data showing a reduction in circulation of pro-inflammatory cytokines and encouraging the evaluation of such interventions in preventing disease progression and clinical deterioration in patients with COVID-19. Here, we examine the biological activities of tumour necrosis factor inhibitors indicative of their potential in COVID-19 and briefly outline the randomised control trials assessing their benefit-risk profile in COVID-19 therapy.
COVID-19 Drug Treatment , Inflammation/drug therapy , SARS-CoV-2/drug effects , Tumor Necrosis Factor Inhibitors/pharmacology , Animals , COVID-19/metabolism , Cytokines/metabolism , Humans , Inflammation/metabolism
BACKGROUND: Vasoplegia has been associated with inferior outcomes following heart transplantation (HTx). This observational study was designed to investigate outcomes in recipients with vasoplegia following left ventricular assist device (LVAD) explant HTx. METHODS: Patients undergoing LVAD explant followed by HTx from 01/2013-12/2018 at our centre were included. Vasoplegia was defined as the requirement for high dose vasopressor [noradrenaline (>0.5 µg/kg/min) and vasopressin (>1 U/h)] over the first 24 hours following HTx. Demographic and outcome data were retrieved from the transplant unit database. RESULTS: During the study period 24 patients underwent LVAD explant HTx. Of these, 13 (54.2%) developed vasoplegia. Both groups had similar duration of LVAD support (median 684 vs. 620 days P=0.62). There was a higher incidence of driveline infection in patients developing vasoplegia (69.2% vs. 18.2% P=0.02). HTx following donation after circulatory death (DCD) occurred in 9 (37.5%) patients and was not associated with a higher incidence of vasoplegia (P=0.21). Vasoplegia developed early following reperfusion and intensive care unit admission vasopressor-inotrope scores were significantly higher in patients with vasoplegia (P=0.002). Patients developing vasoplegia had similar ICU (P=0.79) and hospital (P=0.93) lengths of stay. Survival was equivalent both at 30-day (92.3% vs. 100% P=0.99) and 1-year (67.7% vs. 74.7% P=0.70). Our overall HTx 1-year survival was 89.3% over this period. CONCLUSIONS: Vasoplegia is seen with a high incidence in HTx recipients bridged with an LVAD. This appears to be associated with the presence of driveline infections. Early aggressive management is advocated, resulting in equivalent 1-year survival to those patients not developing vasoplegia.
Contact repulsion of growing axons is an essential mechanism for spinal nerve patterning. In birds and mammals the embryonic somites generate a linear series of impenetrable barriers, forcing axon growth cones to traverse one half of each somite as they extend towards their body targets. This study shows that protein disulphide isomerase provides a key component of these barriers, mediating contact repulsion at the cell surface in chick half-somites. Repulsion is reduced both in vivo and in vitro by a range of methods that inhibit enzyme activity. The activity is critical in initiating a nitric oxide/S-nitrosylation-dependent signal transduction pathway that regulates the growth cone cytoskeleton. Rat forebrain grey matter extracts contain a similar activity, and the enzyme is expressed at the surface of cultured human astrocytic cells and rat cortical astrocytes. We suggest this system is co-opted in the brain to counteract and regulate aberrant nerve terminal growth.
Axon Guidance/physiology , Membrane Proteins/metabolism , Nitric Oxide/metabolism , Protein Disulfide-Isomerases/metabolism , Signal Transduction , Animals , Astrocytes/physiology , Cell Line , Chick Embryo , Chickens , Developmental Biology , Gene Knockdown Techniques , Growth Cones/physiology , Humans , Membrane Proteins/genetics , Neurosciences , Procollagen-Proline Dioxygenase/genetics , Procollagen-Proline Dioxygenase/metabolism , Protein Disulfide-Isomerases/genetics , Rats , Somites/embryology , Somites/physiology , Spinal Nerves/embryology , Spinal Nerves/physiology
Continuity of Patient Care/organization & administration , Critical Care/psychology , Family/psychology , General Practitioners , Professional-Family Relations/ethics , Stress Disorders, Post-Traumatic , Survivors/psychology , General Practitioners/ethics , General Practitioners/psychology , General Practitioners/standards , Humans , Intensive Care Units , Patient Discharge , Physician's Role , Psychosocial Support Systems , Stress Disorders, Post-Traumatic/diagnosis , Stress Disorders, Post-Traumatic/etiology , Stress Disorders, Post-Traumatic/psychology , Stress Disorders, Post-Traumatic/rehabilitation
Drug-induced liver injury (DILI) has not been previously reported as a complication of treatment with everolimus. A 56-year-old Caucasian male liver transplant recipient developed DILI after receiving everolimus. Elevations in transaminase levels occurred within a week of starting everolimus and an upward trend in the transaminase levels continued with supporting histopathologic changes confirmed by liver biopsy. Within one week of drug discontinuation, his liver enzymes normalized to baseline. This report includes a brief review of the pharmacokinetic properties of everolimus, a review of the relevant literature, and an analysis using the RUCAM and Naranjo algorithms.
