Tissue factor expression in monocyte subsets during human immunothrombosis, endotoxemia and sepsis.

INTRODUCTION: Tissue factor expression on monocytes is implicated in the pathophysiology of sepsis-induced coagulopathy. How tissue factor is expressed by monocyte subsets (classical, intermediate and non-classical) is unknown. METHODS: Monocytic tissue factor surface expression was investigated during three conditions. Primary human monocytes and microvascular endothelial cell co-cultures were used for in vitro studies. Volunteers received a bolus of lipopolysaccharide (2 ng/kg) to induce endotoxemia. Patients with sepsis, or controls with critical illness unrelated to sepsis, were recruited from four intensive care units. RESULTS: Contact with endothelium and stimulation with lipopolysaccharide reduced the proportion of intermediate monocytes. Lipopolysaccharide increased tissue factor surface expression on classical and non-classical monocytes. Endotoxemia induced profound, transient monocytopenia, along with activation of coagulation pathways. In the remaining circulating monocytes, tissue factor was up-regulated in intermediate monocytes, though approximately 60 % of individuals (responders) up-regulated tissue factor across all monocyte subsets. In critically ill patients, tissue factor expression on intermediate and non-classical monocytes was significantly higher in patients with established sepsis than among non-septic patients. Upon recovery of sepsis, expression of tissue factor increased significantly in classical monocytes. CONCLUSION: Tissue factor expression in monocyte subsets varies significantly during health, endotoxemia and sepsis.

L1000 connectivity map interrogation identifies candidate drugs for repurposing as SARS-CoV-2 antiviral therapies.

Adaptive clinical trials are underway to determine the efficacy of potential therapies for COVID-19, with flexibility to include emerging therapies if there is sufficient preclinical evidence for their potential utility. In silico screening of connectivity maps, which link gene expression profiles to libraries of perturbagens, may facilitate the identification of such emerging therapies. The L1000 Connectivity Map is built from samples of transcripts taken from gene expression profiles of cells in various experimental conditions followed by computational inferences of the remainder of the transcriptome. Searching the L1000 Connectivity Map for modulators of a protease that facilitates coronavirus infection identifies plausible candidate drugs for repurposing as antiviral agents against SARS-CoV-2 following further investigation.

The effect of ageing on the resolution of inflammation.

Ageing is associated with the development of a low-level, systemic, chronic inflammation known as "inflammaging". This chronic inflammatory state can contribute to diseases of ageing such as sarcopenia and frailty. The presence of inflammaging suggests a failure of the cell clearance mechanisms that ordinarily aid in the resolution of inflammation after pathogen infiltration or tissue injury. This review aims to explore what is known of how the processes involved in the resolution of inflammation might become defective with age.

Decision-Making with D-Dimer in the Diagnosis of Pulmonary Embolism.

The measurement of D-dimer can provide useful information to aid in the diagnosis of patients with suspected venous thromboembolism. D-dimer measurement in conjunction with adequate estimation of pretest probability can facilitate the safe discharge of patients with suspected pulmonary embolism and limit unnecessary investigation or anticoagulation. We review clinical decision-making strategies in the diagnosis of pulmonary embolism and propose means to minimize diagnostic error that might arise from knowledge of the D-dimer result prior to clinical assessment.

Traumatic chylothorax: A case report and review.

Chylothorax is a rare entity characterised by leakage of lymphatic fluid into the pleural cavity from the thoracic duct. We present a case of traumatic chylothorax following a traumatic fracture of the L1 vertebra. An 84-year-old lady presented to the emergency department after being found collapsed at home. She gave a preceding history of one day of diarrhoea. Chest X-ray showed a rightsided effusion. Drainage of the effusion yielded a cloudy, off-white fluid that settled in layers in the drainage container. Pleural fluid examination revealed a lymphocyte-rich transudate with high levels of cholesterol and triglycerides. CT imaging of the chest, abdomen and pelvis revealed an acute left sided pulmonary embolus, and a multisegment burst fracture of the L1 vertebra. The patient was anticoagulated for the pulmonary embolus. Conservative fracture management was advised. Chylous drainage of 1l/24hr was observed. Due to ongoing chylous leak the patient was commenced on a medium-chain fatty acid diet and octreotide. Whilst chylous drainage ceased the patient died from infected pressure sores, malnutrition and acute kidney injury. Spinal trauma can rarely cause disruption of the thoracic duct and chylothorax. Diagnosis of chylothorax hinges on the typically high triglyceride content of chylous fluid and the detection of chylomicrons where the triglyceride concentration is equivocal. Management options for persistently draining chylothorax are varied and range from non-invasive medical measures to radiological and surgical interventions (although the patient in the case we present was an unsuitable candidate for surgery). We discuss pertinent diagnostic testing and put forward possible medical management strategies for chylothorax.