Highlights d DN/IPN thalamocortical activity conveys a reliable feedforward motor timing signal d Silencing DN/IPN or recipient regions of thalamus blocks movement initiation d Photostimulation of the DN/IPN thalamocortical pathway triggers movement d Thalamocortical activation drives behavioral contextdependent movement initiation

Purpose The trajectory of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) is essential for clinical decisions, yet the focus so far has been on admission characteristics without consideration of the dynamic course of the disease in the context of applied therapeutic interventions. Methods We included adult patients undergoing invasive mechanical ventilation (IMV) within 48 h of intensive care unit (ICU) admission with complete clinical data until ICU death or discharge. We examined the importance of factors associated with disease progression over the first week, implementation and responsiveness to interventions used in acute respiratory distress syndrome (ARDS), and ICU outcome. We used machine learning (ML) and Explainable Artificial Intelligence (XAI) methods to characterise the evolution of clinical parameters and our ICU data visualisation tool is available as a web-based widget ( https://www.CovidUK.ICU ). Results Data for 633 adults with COVID-19 who underwent IMV between 01 March 2020 and 31 August 2020 were analysed. Overall mortality was 43.3% and highest with non-resolution of hypoxaemia [60.4% vs17.6%; P < 0.001; median PaO 2 /FiO 2 on the day of death was 12.3(8.9–18.4) kPa] and non-response to proning (69.5% vs.31.1%; P < 0.001). Two ML models using weeklong data demonstrated an increased predictive accuracy for mortality compared to admission data (74.5% and 76.3% vs 60%, respectively). XAI models highlighted the increasing importance, over the first week, of PaO 2 /FiO 2 in predicting mortality. Prone positioning improved oxygenation only in 45% of patients. A higher peak pressure (OR 1.42[1.06–1.91]; P < 0.05), raised respiratory component (OR 1.71[ 1.17–2.5]; P < 0.01) and cardiovascular component (OR 1.36 [1.04–1.75]; P < 0.05) of the sequential organ failure assessment (SOFA) score and raised lactate (OR 1.33 [0.99–1.79]; P = 0.057) immediately prior to application of prone positioning were associated with lack of oxygenation response. Prone positioning was not applied to 76% of patients with moderate hypoxemia and 45% of those with severe hypoxemia and patients who died without receiving proning interventions had more missed opportunities for prone intervention [7 (3–15.5) versus 2 (0–6); P < 0.001]. Despite the severity of gas exchange deficit, most patients received lung-protective ventilation with tidal volumes less than 8 mL/kg and plateau pressures less than 30cmH 2 O. This was despite systematic errors in measurement of height and derived ideal body weight. Conclusions Refractory hypoxaemia remains a major associ...

Background. To date the description of mechanically ventilated patients with Coronavirus Disease 2019 (COVID-19) has focussed on admission characteristics with no consideration of the dynamic course of the disease. Here, we present a data-driven analysis of granular, daily data from a representative proportion of patients undergoing invasive mechanical ventilation (IMV) within the United Kingdom (UK) to evaluate the complete natural history of COVID-19. Methods. We included adult patients undergoing IMV within 48 hours of ICU admission with complete clinical data until intensive care unit (ICU) death or discharge. We examined factors and trajectories that determined disease progression and responsiveness to interventions used in acute respiratory distress syndrome (ARDS). Our data visualisation tool is available as a web-based widget (https://www.CovidUK.ICU). Findings. Data for 633 adults with COVID-19 who were mechanically ventilated between 01 March 2020 and 31 August 2020 were analysed. Mortality, intensity of mechanical ventilation and severity of organ injury increased with severity of hypoxaemia. Median PaO2/FiO2 in non-survivors on the day of death was 12.3(8.9-18.4) kPa suggesting severe refractory hypoxaemia as a major contributor to mortality. Non-resolution of hypoxaemia over the first week of IMV was associated with higher ICU mortality (60.4% versus 17.6%; P<0.001). The reported ideal body weight overestimated our calculated ideal body weight derived from reported height, with three-quarters of all reported tidal volume values were above 6mL/kg of ideal body weight. Overall, 76% of patients with moderate hypoxaemia and 46% with severe did not undergo prone position at any stage of admission. Furthermore, only 45% showed a persistent oxygenation response on prone position. Non-responders to prone position show higher lactate, D-Dimers, troponin, cardiovascular component of the sequential organ failure assessment (SOFA) score, and higher ICU mortality (69.5% versus 31.1%; P<0.001). There was no difference in number of prone sessions between survivors and non-survivors, however, patients who died without receiving prone position had a greater number of missed opportunities for prone intervention (7(3-15.5) versus 2(0-6); P<0.001). Interpretation. A sizeable proportion of patients with progressive worsening of hypoxaemia had no application of and were refractory to evidence based ARDS strategies and showed a higher mortality. Strategies for early recognition and management of COVID-19 patients refractory to conventional management strategies will be critical to improving future outcomes.

Tel. +44 131 650 3113 53 Email: Ian.Duguid@ed.ac.uk 54 65 Stimulating the MThDN/IPN thalamocortical pathway in the absence of the cue recapitulated cue-66 evoked M1 membrane potential dynamics and forelimb behavior in the learned behavioral 67 context, but generated semi-random movements in an altered behavioral context. Thus, 68 cerebellar-recipient motor thalamocortical input to M1 is indispensable for the generation of 69 motor commands that initiate goal-directed movement, refining our understanding of how the 70 cerebellar-thalamocortical pathway contributes to movement timing. 71 72 129 ( Figure 1c and Video S1). Mice rapidly learned to execute the task (mean = 7.5 days, 95% CI 130 [6.3, 8.6], N = 16 mice, all data, unless otherwise stated, are presented as mean, 131 [bootstrapped 95% confidence interval]; last session task success, mean = 0.64 rewards per 132 cue presentation, 95% CI [0.56, 0.72]), displaying relatively fast reaction times (last session, 133 median = 0.32s [0.30, 0.34]) and reproducible forelimb kinematic trajectories (Figures 1d-1f, 134 Video S1).135 136