Anaesthetist-controlled versus patient-maintained effect-site targeted propofol sedation during elective primary lower-limb arthroplasty performed under spinal anaesthesia (ACCEPTS): study protocol for a parallel-group randomised comparison trial

Background: The clinical efficacy of effect-site targeted patient-maintained propofol sedation (PMPS) compared to anaesthetist-controlled propofol sedation (ACPS) for patients undergoing awake joint replacement surgery is currently unknown. There is no commercially available medical device capable of delivering PMPS so we have designed and built such a device. We plan a clinical trial to compare PMPS to ACPS and to collect data relating to the safety of our prototype device in delivering sedation. Methods: The trial is an open-label, randomised, controlled superiority trial recruiting adults who are undergoing elective primary lower-limb arthroplasty with sedation by propofol infusion by effect-site targeting into two equal-sized parallel arms: PMPS and ACPS. The primary research objective is to compare the body-weight-normalised rate of propofol consumption when sedation for surgery on adults undergoing elective primary lower-limb arthroplasty under spinal anaesthesia is patient-maintained versus when it is anaesthetist-controlled. The study primary null hypothesis is that there is no difference in the rate of propofol consumption when sedation is patient-maintained versus anaesthetist-controlled. Discussion: This is the first trial to test the superiority of effect-site-targeted patient-maintained propofol sedation versus anaesthetist-controlled propofol sedation in terms of total propofol consumption during the sedation period. The results of this trial will help inform clinicians and device manufacturers of the clinical efficacy and safety of patient-maintained propofol sedation applied to a common operative setting. Trial registration: International Standard Randomised Controlled Trial Number Registry, ISRCTN29129799. Prospectively registered on 12 June 2018

Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57

Endoplasmic reticulum (ER) malfunction, leading to ER stress, can be a consequence of genome instability and hypoxic tissue environments. Cancer cells survive by acquiring or enhancing survival mechanisms to counter the effects of ER stress and these homeostatic responses may be new therapeutic targets. Understanding the links between ER stress and apoptosis may be approached using drugs specifically to target ER stress responses in cancer cells. The retinoid analogue fenretinide [N-(4-hydroxyphenyl) retinamide] is a new cancer preventive and chemotherapeutic drug, that induces apoptosis of some cancer cell types via oxidative stress, accompanied by induction of an ER stress-related transcription factor, GADD153. The aim of this study was to test the hypothesis that fenretinide induces ER stress in neuroectodermal tumour cells, and to elucidate the role of ER stress responses in fenretinide-induced apoptosis. The ER stress genes ERdj5, ERp57, GRP78, calreticulin and calnexin were induced in neuroectodermal tumour cells by fenretinide. In contrast to the apoptosis-inducing chemotherapeutic drugs vincristine and temozolomide, fenretinide induced the phosphorylation of eIF2α, expression of ATF4 and splicing of XBP-1 mRNA, events that define ER stress. In these respects, fenretinide displayed properties similar to the ER stress inducer thapsigargin. ER stress responses were inhibited by antioxidant treatment. Knockdown of ERp57 or ERdj5 by RNA interference in these cells increased the apoptotic response to fenretinide. These data suggest that downregulating homeostatic ER stress responses may enhance apoptosis induced by oxidative stress-inducing drugs acting through the ER stress pathway. Therefore, ER-resident proteins such as ERdj5 and ERp57 may represent novel chemotherapeutic targets

Statistical Mechanics and the Physics of the Many-Particle Model Systems

The development of methods of quantum statistical mechanics is considered in light of their applications to quantum solid-state theory. We discuss fundamental problems of the physics of magnetic materials and the methods of the quantum theory of magnetism, including the method of two-time temperature Green's functions, which is widely used in various physical problems of many-particle systems with interaction. Quantum cooperative effects and quasiparticle dynamics in the basic microscopic models of quantum theory of magnetism: the Heisenberg model, the Hubbard model, the Anderson Model, and the spin-fermion model are considered in the framework of novel self-consistent-field approximation. We present a comparative analysis of these models; in particular, we compare their applicability for description of complex magnetic materials. The concepts of broken symmetry, quantum protectorate, and quasiaverages are analyzed in the context of quantum theory of magnetism and theory of superconductivity. The notion of broken symmetry is presented within the nonequilibrium statistical operator approach developed by D.N. Zubarev. In the framework of the latter approach we discuss the derivation of kinetic equations for a system in a thermal bath. Finally, the results of investigation of the dynamic behavior of a particle in an environment, taking into account dissipative effects, are presented.Comment: 77 pages, 1 figure, Refs.37

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Breaking barriers: using the behavior change wheel to develop a tailored intervention to overcome workplace inhibitors to breaking up sitting time

© The Author(s). 2019. Background: The workplace is a prominent domain for excessive sitting. The consequences of increased sitting time include adverse health outcomes such as cardiovascular disease and poor mental wellbeing. There is evidence that breaking up sitting could improve health, however, any such intervention in the workplace would need to be informed by a theoretical evidence-based framework. The aim of this study was to use the Behaviour Change Wheel (BCW) to develop a tailored intervention to break up and reduce workplace sitting in desk-based workers. Methods: The BCW guide was followed for this qualitative, pre-intervention development study. Semi-structured interviews were conducted with 25 office workers (26–59years, mean age 40.9 [SD=10.8] years; 68% female) who were purposively recruited from local council offices and a university in the East of England region. The interview questions were developed using the Theoretical Domains Framework (TDF). Transcripts were deductively analysed using the COM-B (Capability, Opportunity, Motivation – Behaviour) model of behaviour. The Behaviour Change Technique Taxonomy Version 1 (BCTv1) was thereafter used to identify possible strategies that could be used to facilitate change in sitting behaviour of office workers in a future intervention. Results: Qualitative analysis using COM-B identified that participants felt that they had the physical Capability to break up their sitting time, however, some lacked the psychological Capability in relation to the knowledge of both guidelines for sitting time and the consequences of excess sitting. Social and physical Opportunity was identified as important, such as a supportive organisational culture (social) and the need for environmental resources (physical). Motivation was highlighted as a core target for intervention, both reflective Motivation, such as beliefs about capability and intention and automatic in terms of overcoming habit through reinforcement. Seven intervention functions and three policy categories from the BCW were identified as relevant. Finally, 39 behaviour change techniques (BCTs) were identified as potential active components for an intervention to break up sitting time in the workplace. Conclusions: The TDF, COM-B model and BCW can be successfully applied through a systematic process to understand the drivers of behaviour of office workers to develop a co-created intervention that can be used to break up and decrease sitting in the workplace. Intervention designers should consider the identified BCW factors and BCTs when developing interventions to reduce and break up workplace sitting

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research