Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

The effect of intermittent alcohol vapor or pulsatile heroin on somatic and negative affective indices during spontaneous withdrawal in Wistar rats

RATIONALE: Once dependent on alcohol or opioids, negative affect may accompany withdrawal. Dependent individuals are hypothesized to “self-medicate” in order to cope with withdrawal, which promotes escalated drug or alcohol use. OBJECTIVES: The current study aimed to develop a reliable animal model to assess symptoms that occur during spontaneous alcohol and opioid withdrawal. METHODS: Dependence was induced using intermittent alcohol exposure or pulsatile heroin delivery and assessed for the presence of withdrawal symptoms during acute withdrawal by measuring somatic signs, behavior in the forced swim test (FST) and air-puff induced 22-kHz ultrasonic vocalizations (USVs). Additional animals subjected to eight weeks of alcohol vapor exposure were evaluated for altered somatic signs, operant alcohol self-administration and 22-kHz USV production, as well as performance in the elevated plus-maze (EPM). RESULTS: During spontaneous withdrawal from pulsatile heroin or intermittent alcohol vapor, animals displayed increased somatic withdrawal signs, FST immobility and 22-kHz USV production, but did not show any behavioral change in the EPM unless the duration of exposure was extended to four weeks. Following eight weeks of alcohol vapor exposure, animals displayed somatic withdrawal signs, escalated alcohol self-administration and increased 22-kHz USVs. CONCLUSIONS: These paradigms provide consistent methods to evaluate the behavioral ramifications, and neurobiological substrates, of alcohol and opioid dependence during spontaneous withdrawal. As immobility in the FST and percent open-arm time in the EPM were dissociable, with 22-kHz USVs paralleling immobility in the FST, assessment of air-puff induced 22-kHz USVs could provide an ethologically-valid alternative to the FST

Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes.

Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-β peptide (Aβ42) are key pathogenic agents in Alzheimer's disease (AD). To investigate the relationship between Aβ42 aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly reduces the toxicity of the resulting oligomers to neuroblastoma cells by inhibiting their binding to the cellular membranes. When administered to a C. elegans model of AD, we again observe an increase in aggregate formation alongside the suppression of Aβ42-induced toxicity. In addition to oligomer displacement, the reduced toxicity could also point towards an increased rate of conversion of oligomers to less toxic fibrils. The ability of a small molecule to reduce the toxicity of oligomeric species represents a potential therapeutic strategy against AD.This work was supported by the Cambridge Centre for Misfolding Diseases (R.L., S.C., F.S.R., M.P., G.T.H., G.M., B.M., J.H., T.C.T.M, P.K.C., M.A., S.T.C., N.F., C.K.X., N.D.K., J.R.K., T.P.J.K., M.V. and C.M.D.), the UK Biotechnology and Biochemical Sciences Research Council (M.V. and C.M.D.), the Wellcome Trust (T.P.J.K, M.V. and C.M.D.), the Frances and Augustus Newman Foundation (T.P.J.K.), the Regione Toscana – FAS Salute (R.C., C.C. and F.C.), Darwin College Cambridge (F.S.R.), Sidney Sussex College Cambridge (G.M.), Peterhouse College Cambridge (T.C.T.M), the Swiss National Science Foundation (T.C.T.M.), a Gates Cambridge Scholarship (R.L. and G.T.H.) and a St. John’s College Benefactors’ Scholarship (R.L.). The NMR facility (Department of Chemistry, University of Cambridge) is supported, in part, by an EPSRC Core Capability grant (EP/K039520/1)

The effect of intermittent alcohol vapor or pulsatile heroin on somatic and negative affective indices during spontaneous withdrawal in Wistar rats

RATIONALE: Once dependent on alcohol or opioids, negative affect may accompany withdrawal. Dependent individuals are hypothesized to “self-medicate” in order to cope with withdrawal, which promotes escalated drug or alcohol use. OBJECTIVES: The current study aimed to develop a reliable animal model to assess symptoms that occur during spontaneous alcohol and opioid withdrawal. METHODS: Dependence was induced using intermittent alcohol exposure or pulsatile heroin delivery and assessed for the presence of withdrawal symptoms during acute withdrawal by measuring somatic signs, behavior in the forced swim test (FST) and air-puff induced 22-kHz ultrasonic vocalizations (USVs). Additional animals subjected to eight weeks of alcohol vapor exposure were evaluated for altered somatic signs, operant alcohol self-administration and 22-kHz USV production, as well as performance in the elevated plus-maze (EPM). RESULTS: During spontaneous withdrawal from pulsatile heroin or intermittent alcohol vapor, animals displayed increased somatic withdrawal signs, FST immobility and 22-kHz USV production, but did not show any behavioral change in the EPM unless the duration of exposure was extended to four weeks. Following eight weeks of alcohol vapor exposure, animals displayed somatic withdrawal signs, escalated alcohol self-administration and increased 22-kHz USVs. CONCLUSIONS: These paradigms provide consistent methods to evaluate the behavioral ramifications, and neurobiological substrates, of alcohol and opioid dependence during spontaneous withdrawal. As immobility in the FST and percent open-arm time in the EPM were dissociable, with 22-kHz USVs paralleling immobility in the FST, assessment of air-puff induced 22-kHz USVs could provide an ethologically-valid alternative to the FST