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Background and Aim: Inadequately designed equipment has been implicated in poor efficiency and critical incidents associated with resuscitation. A novel resuscitation trolley (Resus:Station) was designed and evaluated for impact on team efficiency, user opinion, and teamwork, compared with the standard trolley, in simulated cardiac arrest scenarios.Methods: Fifteen experienced cardiac arrest teams were recruited (45 participants). Teams performed recorded resuscitation simulations using new and conventional trolleys, with order of use randomised. After each simulation, efficiency ("time to drugs", un-locatable equipment, unnecessary drawer opening) and team performance (OSCAR) were assessed from the video recordings and participants were asked to complete questionnaires scoring various aspects of the trolley on a Likert scale.Results: Time to locate the drugs was significantly faster (p=0.001) when using the Resus:Station (mean 5.19s (SD 3.34)) than when using the standard trolley (26.81s (SD16.05)). There were no reports of missing equipment when using the Resus:Station. However, during four of the fifteen study sessions using the standard trolley participants were unable to find equipment, with an average of 6.75 unnecessary drawer openings per simulation. User feedback results clearly indicated a highly significant preference for the newly designed Resus:Station for all aspects. Teams performed equally well for all dimensions of team performance using both trolleys, despite it being their first exposure to the Resus:Station.Conclusion: We conclude that in this simulated environment, the new design of trolley is safe to use, and has the potential to improve efficiency at a resuscitation attempt. [ABSTRACT FROM AUTHOR]

Background: Although generally mild, the 2009-2010 influenza A/H1N1 pandemic caused two major surges in hospital admissions in the UK. The characteristics of patients admitted during successive waves are described.Methods: Data were systematically obtained on 1520 patients admitted to 75 UK hospitals between May 2009 and January 2010. Multivariable analyses identified factors predictive of severe outcome.Results: Patients aged 5-54 years were over-represented compared with winter seasonal admissions for acute respiratory infection, as were non-white ethnic groups (first wave only). In the second wave patients were less likely to be school age than in the first wave, but their condition was more likely to be severe on presentation to hospital and they were more likely to have delayed admission. Overall, 45% had comorbid conditions, 16.5% required high dependency (level 2) or critical (level 3) care and 5.3% died. As in 1918-1919, the likelihood of severe outcome by age followed a W-shaped distribution. Pre-admission antiviral drug use decreased from 13.3% to 10% between the first and second waves (p=0.048), while antibiotic prescribing increased from 13.6% to 21.6% (p<0.001). Independent predictors of severe outcome were age 55-64 years, chronic lung disease (non-asthma, non-chronic obstructive pulmonary disease), neurological disease, recorded obesity, delayed admission (≥5 days after illness onset), pneumonia, C-reactive protein ≥100 mg/litre, and the need for supplemental oxygen or intravenous fluid replacement on admission.Conclusions: There were demographic, ethnic and clinical differences between patients admitted with pandemic H1N1 infection and those hospitalised during seasonal influenza activity. Despite national policies favouring use of antiviral drugs, few patients received these before admission and many were given antibiotics. [ABSTRACT FROM AUTHOR]

Background: Shared decision-making (SDM) is increasingly expected in healthcare systems prioritising patient autonomy. Treatment escalation plans (TEPs) outline contingency for medical intervention in the event of patient deterioration. This study aimed to understand clinicians' perspectives on SDM in TEP for older patients in the acute medical setting., Methods: This was a qualitative study following a constructivist approach. Semistructured interviews with vignettes were conducted with 26 consultant and registrar doctors working in emergency medicine, general internal medicine, intensive care medicine and palliative care medicine. Reflexive thematic analysis was performed., Results: There were three themes: 'An unequal partnership', 'Options without equipoise' and 'Decisions with shared understanding'. Clinicians' expertise in synthesising complex, uncertain clinical information was contrasted with perceived patient unfamiliarity with future health planning and medical intervention. There was a strong sense of morality underpinning decision-making and little equipoise about appropriate TEP decisions. Communication around the TEP was important, and clinicians sought control over the high-stakes decision whilst avoiding conflict and achieving shared understanding., Conclusions: Clinicians take responsibility for securing a 'good' TEP decision for older patients in the acute medical setting. They synthesise clinical data with implicit ethical reasoning according to their professional predictions of qualitative and quantitative success following medical intervention. SDM is seldom considered a priority for this context. Nonetheless, avoidance of conflict, preserving the clinical relationship and shared understanding with the patient and family are important., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Importance: Whether β-lactam antibiotics administered by continuous compared with intermittent infusion reduces the risk of death in patients with sepsis is uncertain., Objective: To evaluate whether continuous vs intermittent infusion of a β-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all-cause mortality at 90 days in critically ill patients with sepsis., Design, Setting, and Participants: An international, open-label, randomized clinical trial conducted in 104 intensive care units (ICUs) in Australia, Belgium, France, Malaysia, New Zealand, Sweden, and the United Kingdom. Recruitment occurred from March 26, 2018, to January 11, 2023, with follow-up completed on April 12, 2023. Participants were critically ill adults (≥18 years) treated with piperacillin-tazobactam or meropenem for sepsis., Intervention: Eligible patients were randomized to receive an equivalent 24-hour dose of a β-lactam antibiotic by either continuous (n = 3498) or intermittent (n = 3533) infusion for a clinician-determined duration of treatment or until ICU discharge, whichever occurred first., Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days after randomization. Secondary outcomes were clinical cure up to 14 days after randomization; new acquisition, colonization, or infection with a multiresistant organism or Clostridioides difficile infection up to 14 days after randomization; ICU mortality; and in-hospital mortality., Results: Among 7202 randomized participants, 7031 (mean [SD] age, 59 [16] years; 2423 women [35%]) met consent requirements for inclusion in the primary analysis (97.6%). Within 90 days, 864 of 3474 patients (24.9%) assigned to receive continuous infusion had died compared with 939 of 3507 (26.8%) assigned intermittent infusion (absolute difference, -1.9% [95% CI, -4.9% to 1.1%]; odds ratio, 0.91 [95% CI, 0.81 to 1.01]; P = .08). Clinical cure was higher in the continuous vs intermittent infusion group (1930/3467 [55.7%] and 1744/3491 [50.0%], respectively; absolute difference, 5.7% [95% CI, 2.4% to 9.1%]). Other secondary outcomes were not statistically different., Conclusions and Relevance: The observed difference in 90-day mortality between continuous vs intermittent infusions of β-lactam antibiotics did not meet statistical significance in the primary analysis. However, the confidence interval around the effect estimate includes the possibility of both no important effect and a clinically important benefit in the use of continuous infusions in this group of patients., Trial Registration: ClinicalTrials.gov Identifier: NCT03213990.

Importance: There is uncertainty about whether prolonged infusions of β-lactam antibiotics improve clinically important outcomes in critically ill adults with sepsis or septic shock., Objective: To determine whether prolonged β-lactam antibiotic infusions are associated with a reduced risk of death in critically ill adults with sepsis or septic shock compared with intermittent infusions., Data Sources: The primary search was conducted with MEDLINE (via PubMed), CINAHL, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to May 2, 2024., Study Selection: Randomized clinical trials comparing prolonged (continuous or extended) and intermittent infusions of β-lactam antibiotics in critically ill adults with sepsis or septic shock., Data Extraction and Synthesis: Data extraction and risk of bias were assessed independently by 2 reviewers. Certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation approach. A bayesian framework was used as the primary analysis approach and a frequentist framework as the secondary approach., Main Outcomes and Measures: The primary outcome was all-cause 90-day mortality. Secondary outcomes included intensive care unit (ICU) mortality and clinical cure., Results: From 18 eligible randomized clinical trials that included 9108 critically ill adults with sepsis or septic shock (median age, 54 years; IQR, 48-57; 5961 men [65%]), 17 trials (9014 participants) contributed data to the primary outcome. The pooled estimated risk ratio for all-cause 90-day mortality for prolonged infusions of β-lactam antibiotics compared with intermittent infusions was 0.86 (95% credible interval, 0.72-0.98; I2 = 21.5%; high certainty), with a 99.1% posterior probability that prolonged infusions were associated with lower 90-day mortality. Prolonged infusion of β-lactam antibiotics was associated with a reduced risk of intensive care unit mortality (risk ratio, 0.84; 95% credible interval, 0.70-0.97; high certainty) and an increase in clinical cure (risk ratio, 1.16; 95% credible interval, 1.07-1.31; moderate certainty)., Conclusions and Relevance: Among adults in the intensive care unit who had sepsis or septic shock, the use of prolonged β-lactam antibiotic infusions was associated with a reduced risk of 90-day mortality compared with intermittent infusions. The current evidence presents a high degree of certainty for clinicians to consider prolonged infusions as a standard of care in the management of sepsis and septic shock., Trial Registration: PROSPERO Identifier: CRD42023399434.

Objective: To describe characteristics and acute clinical outcomes for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated patients at highest risk per National Health Service (NHS) criteria., Methods: Retrospective study of non-hospitalized patients between 1 December 2021 and 31 May 2022, using data from the Discover-NOW dataset (North-West London). Included patients were aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated but expected to be eligible for early treatment per NHS highest-risk criteria. COVID-19-related and all-cause hospitalizations were reported for 28 days from COVID-19 diagnosis (index). Subgroup analyses were conducted in patients with advanced renal disease, those aged 18-64 and ≥65 years, and by period of Omicron BA.1, BA.2 and BA.5 (post-hoc exploratory) predominance., Results: Overall, 1503 treated and 4044 eligible high-risk untreated patients were included. A high proportion of patients on sotrovimab had advanced renal disease (29.3%), ≥3 high-risk comorbidities (47.6%) and were aged ≥65 years (36.9%). Five of 696 (0.7%) patients on sotrovimab, <5/337 (0.3-1.2%) on nirmatrelvir/ritonavir, 10/470 (2.1%) on molnupiravir and 114/4044 (2.8%) untreated patients were hospitalized with COVID-19. Similar results were observed across all subgroups. The proportion of patients dying within 28 days of the index period was similarly low across all cohorts (<2%)., Conclusion: Patients receiving sotrovimab appeared to show evidence of multiple high-risk comorbidities. Low hospitalization rates were observed for all treated cohorts across subgroups and periods of predominant variants of concern. These results require confirmation with comparative effectiveness analyses adjusting for differences in underlying patient characteristics.

Background: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer., Methods: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed., Results: Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion., Conclusions: These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes., Competing Interests: Competing interests: MSC is a retained consultant for BioInvent International and has performed educational and advisory roles for Baxalta and Boehringer Ingelheim. He has consulted for GSK, Radiant, iTeos Therapeutics, Surrozen, Hanall and Mestag and received research funding from BioInvent, Surrozen, GSK, UCB and iTeos. SB, HJ, LS-W, DK, HS, PB, JJ, HN, AJS, LH, SH, SJB, RS, JS, AH, EP, SLM, PJM and NY are (or were at the time the work was conducted) employees of GSK., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite the existence of evidence-based guidelines for the assessment and management of pain in the critical care setting, the prevalence of acute pain remains high. Inadequate pain management is associated with longer duration of mechanical ventilation, reduced capacity for rehabilitation and long-term psychological sequelae. This study aimed to describe the experiences of pain management from healthcare professionals working in intensive care units. Healthcare professionals were recruited from intensive care units in London, UK using a purposive sampling technique. Semi-structured interviews were transcribed verbatim. Transcripts were analysed using an inductive thematic analysis technique. Thirty participants were recruited from eight diverse intensive care units. Five themes were identified. First, there was a lack of consensus in pain assessment in the ICU where nursing staff described more knowledge and confidence of validated pain measures than physicians, and concerns over validity and usability were raised. Second, there was a universal perception of resource availability impacting the quality of pain management including high clinical workload, staff turnover and availability of certain pain management techniques. Third, acknowledgement of the importance of pain management was highest in those with experience of interacting with critical care survivors. Fourth, participants described their own emotional reaction to managing those in pain which influenced their learning. Finally, there was a perception that, due to the complexity of the intensive care unit population, pain was de-prioritised and there were conflicting views as to whether standardised analgosedation algorithms were useful. This study provides evidence to suggest interdisciplinary training, collaboratively designed decision-making tools, prioritisation initiatives and research priorities are areas that could be targeted to improve pain management in critical care., (© 2023 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Background: We assessed the effectiveness of sotrovimab vs no early COVID-19 treatment in highest-risk COVID-19 patients during Omicron predominance., Methods: Retrospective cohort study using the Discover dataset in North West London. Included patients were non-hospitalised, aged ≥12 years and met ≥1 National Health Service highest-risk criterion for sotrovimab treatment. We used Cox proportional hazards models to compare HRs of 28-day COVID-19-related hospitalisation/death between highest-risk sotrovimab-treated and untreated patients. Age, renal disease and Omicron subvariant subgroup analyses were performed., Results: We included 599 sotrovimab-treated patients and 5191 untreated patients. Compared with untreated patients, the risk of COVID-19 hospitalisation/death (HR 0.50, 95% CI 0.24, 1.06; p=0.07) and the risk of COVID-19 hospitalisation (HR 0.43, 95% CI 0.18, 1.00; p=0.051) were both lower in the sotrovimab-treated group; however, statistical significance was not reached. In the ≥65 years and renal disease subgroups, sotrovimab was associated with a significantly reduced risk of COVID-19 hospitalisation, by 89% (HR 0.11, 95% CI 0.02, 0.82; p=0.03) and 82% (HR 0.18, 95% CI 0.05, 0.62; p=0.007), respectively., Conclusions: Risk of COVID-19 hospitalisation in sotrovimab-treated patients aged ≥65 years and with renal disease was significantly lower compared with untreated patients. Overall, risk of hospitalisation was also lower for sotrovimab-treated patients, but statistical significance was not reached., Competing Interests: Competing interests: MD, DCG, EJL, WK and HJB are employees of, and/or shareholders in, GSK. VP was an employee of GSK at the time of the study and is now an employee of KVM Analytics. ERG, MJY, JDW, SY, BFP and TK are (or were at time of study) employees of Imperial College Health Partners, which received funding from GSK and Vir Biotechnology to conduct the study. BL is an employee of OPEN Health, which received funding from GSK and Vir Biotechnology, Inc, to conduct the study. A consultancy fee was paid to SJB’s institutional account., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Molecular diagnostic tests may improve antibiotic prescribing by enabling earlier tailoring of antimicrobial therapy. However, clinicians' trust and acceptance of these tests will determine their application in practice., Objectives: To examine ICU prescribers' views on the application of molecular diagnostics in patients with suspected hospital-acquired and ventilator-associated pneumonia (HAP/VAP)., Methods: Sixty-three ICU clinicians from five UK hospitals completed a cross-sectional questionnaire between May 2020 and July 2020 assessing attitudes towards using molecular diagnostics to inform initial agent choice and to help stop broad-spectrum antibiotics early., Results: Attitudes towards using molecular diagnostics to inform initial treatment choices and to stop broad-spectrum antibiotics early were nuanced. Most (83%) were positive about molecular diagnostics, agreeing that using results to inform broad-spectrum antibiotic prescribing is good practice. However, many (58%) believed sick patients are often too unstable to risk stopping broad-spectrum antibiotics based on a negative result., Conclusions: Positive attitudes towards the application of molecular diagnostics to improve antibiotic stewardship were juxtapositioned against the perceived need to initiate and maintain broad-spectrum antibiotics to protect unstable patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objectives: The objective of this study is to explore patient, relative/carer and clinician perceptions of barriers to early physical rehabilitation in intensive care units (ICUs) within an associated group of hospitals in the UK and how they can be overcome., Design: Qualitative study using semi-structured interviews and thematic framework analysis., Setting: Four ICUs over three hospital sites in London, UK., Participants: Former ICU patients or their relatives/carers with personal experience of ICU rehabilitation. ICU clinicians, including doctors, nurses, physiotherapists and occupational therapists, involved in the delivery of physical rehabilitation or decisions over its initiation., Primary and Secondary Outcomes Measures: Views and experiences on the barriers and facilitators to ICU physical rehabilitation., Results: Interviews were carried out with 11 former patients, 3 family members and 16 clinicians. The themes generated related to: safety and physiological concerns, patient participation and engagement, clinician experience and knowledge, teamwork, equipment and environment and risks and benefits of rehabilitation in intensive care. The overarching theme for overcoming barriers was a change in working model from ICU clinicians having separate responsibilities (a multidisciplinary approach) to one where all parties have a shared aim of providing patient-centred ICU physical rehabilitation (an interdisciplinary approach)., Conclusions: The results have revealed barriers that can be modified to improve rehabilitation delivery in an ICU. Interdisciplinary working could overcome many of these barriers to optimise recovery from critical illness., Competing Interests: Competing interests: HRW reports personal lecture fees from Brunel University and the University of East London. CN reports personal lecture fees from Janssen Pharmaceuticals and Web MD. CMA is a National Institute of Health Research PhD fellowship committee member, although not at the time that funding was awarded for this study. ACG reports salary support from an NIHR Research Professorship (RP-2015-06-018) and research support from the NIHR Imperial BRC., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)