Efficacy and safety of baricitinib or ravulizumab in adult patients with severe COVID-19 (TACTIC-R): a randomised, parallel-arm, open-label, phase 4 trial

Background From early in the COVID-19 pandemic, evidence suggested a role for cytokine dysregulation and complement activation in severe disease. In the TACTIC-R trial, we evaluated the efficacy and safety of baricitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2, and ravulizumab, a monoclonal inhibitor of complement C5 activation, as an adjunct to standard of care for the treatment of adult patients hospitalised with COVID-19. Methods TACTIC-R was a phase 4, randomised, parallel-arm, open-label platform trial that was undertaken in the UK with urgent public health designation to assess the potential of repurposing immunosuppressants for the treatment of severe COVID-19, stratified by a risk score. Adult participants (aged ≥18 years) were enrolled from 22 hospitals across the UK. Patients with a risk score indicating a 40% risk of admission to an intensive care unit or death were randomly assigned 1:1:1 to standard of care alone, standard of care with baricitinib, or standard of care with ravulizumab. The composite primary outcome was the time from randomisation to incidence (up to and including day 14) of the first event of death, invasive mechanical ventilation, extracorporeal membrane oxygenation, cardiovascular organ support, or renal failure. The primary interim analysis was triggered when 125 patient datasets were available up to day 14 in each study group and we included in the analysis all participants who were randomly assigned. The trial was registered on ClinicalTrials.gov (NCT04390464). Findings Between May 8, 2020, and May 7, 2021, 417 participants were recruited and randomly assigned to standard of care alone (145 patients), baricitinib (137 patients), or ravulizumab (135 patients). Only 54 (39%) of 137 patients in the baricitinib group received the maximum 14-day course, whereas 132 (98%) of 135 patients in the ravulizumab group received the intended dose. The trial was stopped after the primary interim analysis on grounds of futility. The estimated hazard ratio (HR) for reaching the composite primary endpoint was 1·11 (95% CI 0·62–1·99) for patients on baricitinib compared with standard of care alone, and 1·53 (0·88–2·67) for ravulizumab compared with standard of care alone. 45 serious adverse events (21 deaths) were reported in the standard-of-care group, 57 (24 deaths) in the baricitinib group, and 60 (18 deaths) in the ravulizumab group. Interpretation Neither baricitinib nor ravulizumab, as administered in this study, was effective in reducing disease severity in patients selected for severe COVID-19. Safety was similar between treatments and standard of care. The short period of dosing with baricitinib might explain the discrepancy between our findings and those of other trials. The therapeutic potential of targeting complement C5 activation product C5a, rather than the cleavage of C5, warrants further evaluation

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

The role of instructions and demonstrations in learning a coordination skill

Four experiments were conducted to examine how pre-practice information affected the early stage of acquisition when the motor skill was not an existing part of the learner's movement repertoire. More specifically, the experiments examined why instruction concerning the correct way to perform a motor skill has a negative influence on acquisition and subsequently under what conditions it is useful. In all experiments participants practiced a difficult, bimanual coordination pattern, which resulted in circular shapes on a monitor. In Experiment 1 information prior to and during acquisition was manipulated to examine whether instructions benefited learning when feedback informed as to how they were implemented. No support was found for this prediction, somewhat due to the complexity of the feedback. When only circle feedback was provided pre-practice information hindered acquisition, which supported findings from an initial investigation. In the second experiment focus of attention was manipulated via the instructions to examine whether attention mediated the instructional effects. It was predicted that instructions directing attention onto the effects of the action would facilitate learning. This hypothesis was generally supported, however, non-instructed participants performed as well as an external focus group and all attention-directing instructions decreased the negative effects of feedback withdrawal. The final experiments were designed to examine whether instructions that built upon existing behaviours would facilitate acquisition when only a gradual replacement of an existing behaviour was required (Experiment 4) as compared to a qualitative change (Experiment 3). In Experiment 3, only participants biased to in- and anti-phase movements were studied (bi-stable). In Experiment 4 participants biased to patterns other than these (multi-stable) were examined. Instruction did not benefit learning, irrespective of initial bias. Instructions that built upon in-phase movements were detrimental to acquisition. More permanent changes to the underlying dynamics were manifest in post-practice scanning tasks for the non-instructed participants only. As a result of these studies it was concluded that movement demonstrations and instructions conveyed little useful information in the early stage of acquisition, if information regarding goal attainment was available. Instructions can hinder the break from prepractice patterns, but may possibly help refine the movement at a later stage.Education, Faculty ofKinesiology, School ofGraduat

Right and left-handed pitch-type recognition among hitters and pitchers in baseball: Testing the motor simulation hypothesis

Both visual and motor experiences impact action prediction, yet through potentially different mechanisms. Having physical experience with an action is thought to engage motor simulative processes, potentially activating the watcher’s motor system in an effector-specific manner, aiding prediction. Leveraging baseball’s unique specialization demands, we assessed pitch discrimination in athletes with predominantly visual experience seeing pitches (hitters, n = 41; 7 = left-handed hitters) and motor experience producing pitches (pitchers, n = 42; 9 = left-handed). Videos of right-handed (RH) pitches, with temporal occlusion applied at or after ball release, of three different pitches, were used to assess pitch prediction accuracy. Two versions of each video clip were shown; the original RH clips were “flipped” to make the pitcher appear to throw left-handed (LH). Pitchers and hitters had reliable responses and showed high accuracy (~70%) and discriminability. Pitchers were more discriminatory than hitters when contrasting two pitch types with the same initial trajectory and speed, but different postural cues (curveballs and changeups; d’ pitchers = 2.18, hitters = 1.88). Although there was the predicted interaction for the pitchers when comparing LH and RH pitchers watching LH and RH videos (p<.05), only LH pitchers showed a trend for a same-side, LH video advantage (p=.06). Because pitchers did not differ in accuracy from hitters, despite a lack of visual experience seeing and responding, this suggests that their motor experience aided predictions. However, there was only partial support for a simulation explanation based on effector specificity (due to absence of any differences in RH pitchers)

Assessing the validity and reliability of a baseball pitch discrimination online task

Baseball action prediction data and dynamic visual acuity data for an online tas

Instructions

Complete instruction

Effects of Target Size and Absolute Number of Successes on Motor Learning

This study examines whether the motor learning benefit of practicing with an easier goal (larger target) is moderated by the absolute number of successful trials experienced by learners practicing with a more difficult goal (smaller target)