Four-day antithrombin therapy does not seem to attenuate hypercoagulability in patients suffering from sepsis

INTRODUCTION: Sepsis activates the coagulation system and frequently causes hypercoagulability, which is not detected by routine coagulation tests. A reliable method to evaluate hypercoagulability is thromboelastography (TEG), but this has not so far been used to investigate sepsis-induced hypercoagulability. Antithrombin (AT) in plasma of septic patients is decreased, and administration of AT may therefore reduce the acquired hypercoagulability. Not clear, however, is to what extent supraphysiologic plasma levels of AT decrease the acute hypercoagulability in septic patients. The present study investigates the coagulation profile of septic patients before and during four day high-dose AT therapy. METHODS: Patients with severe sepsis were randomly assigned to receive either 6,000 IU AT as a bolus infusion followed by a maintenance dose of 250 IU/hour over four days (n = 17) or placebo (n = 16). TEG, platelet count, plasma fibrinogen levels, prothrombin time and activated partial thromboplastin time were assessed at baseline and daily during AT therapy. RESULTS: TEG showed a hypercoagulability in both groups at baseline, which was neither reversed by bolus or by maintenance doses of AT. The hypercoagulability was mainly caused by increased plasma fibrinogen, and to a lesser extent by platelets. Plasmatic coagulation as assessed by the prothrombin time and activated partial thromboplastin time was similar in both groups, and did not change during the study period. CONCLUSION: The current study shows a distinct hypercoagulability in patients suffering from severe sepsis, which was not reversed by high-dose AT treatment over four days. This finding supports recent data showing that modulation of coagulatory activation in septic patients by AT does not occur before one week of therapy. Trial registration: Current Control Trials ISRCTN2293102

Endobronchial intubation detected by insertion depth of endotracheal tube, bilateral auscultation, or observation of chest movements: randomised trial

Objective To determine which bedside method of detecting inadvertent endobronchial intubation in adults has the highest sensitivity and specificity

Drugit: Crowd-sourcing molecular design of non-peptidic VHL binders

Given the role of human intuition in current drug design efforts, crowd-sourced \u27citizen scientist\u27 games have the potential to greatly expand the pool of potential drug designers. Here, we introduce ‘Drugit\u27, the small molecule design mode of the online ‘citizen science’ game Foldit. We demonstrate its utility for design with a use case to identify novel binders to the von Hippel Lindau E3 ligase. Several thousand molecule suggestions were obtained from players in a series of 10 puzzle rounds. The proposed molecules were then evaluated by in silico methods and by an expert panel and selected candidates were synthesized and tested. One of these molecules, designed by a player, showed dose-dependent shift perturbations in protein-observed NMR experiments. The co-crystal structure in complex with the E3 ligase revealed that the observed binding mode matched in major parts the player’s original idea. The completion of one full design cycle is a proof of concept for the Drugit approach and highlights the potential of involving citizen scientists in early drug discovery