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Purpose Cellular immune dysfunctions, which are common in intensive care patients, predict a number of significant complications. In order to effectively target treatments, clinically applicable measures need to be developed to detect dysfunction. The objective was to confirm the ability of cellular markers associated with immune dysfunction to stratify risk of secondary infection in critically ill patients. Methods Multi-centre, prospective observational cohort study of critically ill patients in four UK intensive care units. Serial blood samples were taken, and three cell surface markers associated with immune cell dysfunction [neutrophil CD88, monocyte human leucocyte antigen-DR (HLA-DR) and percentage of regulatory T cells (T.sub.regs)] were assayed on-site using standardized flow cytometric measures. Patients were followed up for the development of secondary infections. Results A total of 148 patients were recruited, with data available from 138. Reduced neutrophil CD88, reduced monocyte HLA-DR and elevated proportions of T.sub.regs were all associated with subsequent development of infection with odds ratios (95% CI) of 2.18 (1.00-4.74), 3.44 (1.58-7.47) and 2.41 (1.14-5.11), respectively. Burden of immune dysfunction predicted a progressive increase in risk of infection, from 14% for patients with no dysfunction to 59% for patients with dysfunction of all three markers. The tests failed to risk stratify patients shortly after ICU admission but were effective between days 3 and 9. Conclusions This study confirms our previous findings that three cell surface markers can predict risk of subsequent secondary infection, demonstrates the feasibility of standardized multisite flow cytometry and presents a tool which can be used to target future immunomodulatory therapies. Trial registration The study was registered with clinicaltrials.gov (NCT02186522)., Author(s): Andrew Conway Morris [sup.1] [sup.2], Deepankar Datta [sup.2] [sup.3], Manu Shankar-Hari [sup.4], Jacqueline Stephen [sup.5], Christopher J. Weir [sup.5], Jillian Rennie [sup.2], Jean Antonelli [sup.5], Anthony Bateman [sup.6], Noel [...]

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Measurements and Main Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatmentrelated serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB01391SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2-7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. Conclusions: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. [ABSTRACT FROM AUTHOR]

Clinical trials are considered the gold-standard method for the evaluation of healthcare interventions. However, randomised control trials are complex to perform and many researchers, especially those in the early stages of their career, can find it challenging to know where to start set up, contribute to or lead a trial. This guide provides an introduction to trials and also practical advice to help potential investigators complete their clinical trial to time and to budget by signposting the pathway through the complex regulatory landscape. The authors draw on their own recent experiences of running clinical trials and provide tips and tricks for troubleshooting common problems encountered including trial design and documentation. [ABSTRACT FROM AUTHOR]

Objectives: Various strategies to promote light sedation are highly recommended in recent guidelines, as deep sedation is associated with suboptimum patient outcomes. Yet, the challenges met by clinicians in delivering highquality analgosedation is rarely addressed. As part of the evaluation of a cluster-randomised quality improvement trial in eight Scottish intensive care units (ICUs), we aimed to understand the challenges to optimising sedation in the Scottish ICU settings prior to the trial. This article reports on the findings. Design: A qualitative exploratory design: We conducted focus groups (FG) with clinicians during the preintervention period. Setting and participants: Eight Scottish ICUs. Nurses, physiotherapists and doctors working in each ICU volunteered to participate. FG were recorded and verbatim transcribed and inserted in NVivo V.10 for analysis. Qualitative thematic analysis was undertaken to develop emergent themes from the patterns identified in relation to sedation practice. Ethical approval was secured by Scotland A Research ethics committee. Results: Three themes emerged from the inductive analysis: (a) a recent shift in sedation practice, (b) uncertainty in decision-making and (c) system-level factors including the ICU environment, organisational factors and educational gaps. Clinicians were challenged daily to manage agitated or difficult-to-sedate patients in the era of a progressive mantra of 'just sedate less' imposed by the pain-agitation-delirium guidelines. Conclusions: The current implementation of guidelines does not support behaviour change strategies to allow a patient-focused approach to sedation management, which obstructs optimum sedation-analgesia management. Recognition of the various challenges when mandating less sedation needs to be considered and novel sedation-analgesia strategies should allow a system-level approach to improve sedation-analgesia quality. [ABSTRACT FROM AUTHOR]

Introduction: Sepsis is an acute illness resulting from infection and the host immune response. Early identification of individuals at risk of developing lifethreatening severe sepsis could enable early triage and treatment, and improve outcomes. Currently available biomarkers have poor predictive value for predicting subsequent clinical course in patients with suspected infection. Circulating leucocytes provide readily accessible tissues that reflect many aspects of the complex immune responses described in sepsis. We hypothesise that measuring cellular markers of immune responses by flow cytometry will enable early identification of infected patients at risk of adverse outcomes. We aim to characterise leucocyte surface markers (biomarkers) and their abnormalities in a population of patients presenting to the hospital emergency department with suspected sepsis, and explore their ability to predict subsequent clinical course. Methods and analysis: We will conduct a prospective, multicentre, clinical, exploratory, cohort observational study. To answer our study question, 3 patient populations will be studied. First, patients with suspected sepsis from the emergency department (n=300). To assess performance characteristics of potential tests, critically ill patients with established sepsis, and age and gender matched patients without suspicion of infection requiring hospital admission (both n=100) will be recruited as comparator populations. In all 3 groups, we plan to assess circulating biomarker profiles using flow cytometry. We will select candidate biomarkers by cross-cohort comparison, and then explore their predictive value for clinical outcomes within the cohort with suspected sepsis. Ethics and dissemination: The study will be carried out based on the principles in the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice. Ethics approval has been granted from the Scotland A Research Ethics Committee (REC) and Oxford C REC. On conclusion of this study, the results will be disseminated via peer-reviewed journals. [ABSTRACT FROM AUTHOR]

Introduction: Critically ill patients are at high risk of nosocomial infections, with between 20% and 40% of patients admitted to the intensive care unit (ICU) acquiring infections. These infections result in increased antibiotic use, and are associated with morbidity and mortality. Although critical illness is classically associated with hyperinflammation, the high rates of nosocomial infection argue for an importance of effect of impaired immunity. Our group recently demonstrated that a combination of 3 measures of immune cell function (namely neutrophil CD88, monocyte HLA-DR and % regulatory T cells) identified a patient population with a 2.4-5-fold greater risk for susceptibility to nosocomial infections. Methods and analysis: This is a prospective, observational study to determine whether previously identified markers of susceptibility to nosocomial infection can be validated in a multicentre population, as well as testing several novel markers which may improve the risk of nosocomial infection prediction. Blood samples from critically ill patients (those admitted to the ICU for at least 48 hours and requiring mechanical ventilation alone or support of 2 or more organ systems) are taken and undergo whole blood staining for a range of immune cell surface markers. These samples undergo analysis on a standardised flow cytometry platform. Patients are followed up to determine whether they develop nosocomial infection. Infections need to meet strict prespecified criteria based on international guidelines; where these criteria are not met, an adjudication panel of experienced intensivists is asked to rule on the presence of infection. Secondary outcomes will be death from severe infection (sepsis) and change in organ failure. Ethics and dissemination: Ethical approval including the involvement of adults lacking capacity has been obtained from respective English and Scottish Ethics Committees. Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals. [ABSTRACT FROM AUTHOR]

Objectives: To describe the rationale, design and methodology for a trial of three novel interventions developed to improve sedation-analgesia quality in adult intensive care units (ICUs). Participants and Setting: 8 clusters, each a Scottish ICU. All mechanically ventilated sedated patients were potentially eligible for inclusion in data analysis. Design: Cluster randomised design in 8 ICUs, with ICUs randomised after 45 weeks baseline data collection to implement one of four intervention combinations: a web-based educational programme (2 ICUs); education plus regular sedation quality feedback using process control charts (2 ICUs); education plus a novel sedation monitoring technology (2 ICUs); or all three interventions. ICUs measured sedation-analgesia quality, relevant drug use and clinical outcomes, during a 45-week preintervention and 45-week postintervention period separated by an 8-week implementation period. The intended sample size was >100 patients per site per study period. Main Outcome measures: The primary outcome was the proportion of 12 h care periods with optimum sedation-analgesia, defined as the absence of agitation, unnecessary deep sedation, poor relaxation and poor ventilator synchronisation. Secondary outcomes were proportions of care periods with each of these four components of optimum sedation and rates of sedation-related adverse events. Sedative and analgesic drug use, and ICU and hospital outcomes were also measured. Analytic approach: Multilevel generalised linear regression mixed models will explore the effects of each intervention taking clustering into account, and adjusting for age, gender and APACHE II score. Sedation-analgesia quality outcomes will be explored at ICU level and individual patient level. A process evaluation using mixed methods including quantitative description of intervention implementation, focus groups and direct observation will provide explanatory information regarding any effects observed. Conclusions: The DESIST study uses a novel design to provide system-level evaluation of three contrasting complex interventions on sedation-analgesia quality. Recruitment is complete and analysis ongoing. [ABSTRACT FROM AUTHOR]