Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial): A Multicenter, Randomized, Controlled Clinical Trial.

Rationale: Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in coronavirus disease (COVID-19)-related acute respiratory distress syndrome (ARDS). Objectives: We investigated the safety and efficacy of ORBCEL-C (CD362 [cluster of differentiation 362]-enriched, umbilical cord-derived MSCs) in COVID-19-related ARDS. Methods: In this multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial (NCT03042143), patients with moderate to severe COVID-19-related ARDS were randomized to receive ORBCEL-C (400 million cells) or placebo (Plasma-Lyte 148). The primary safety and efficacy outcomes were the incidence of serious adverse events and oxygenation index at Day 7, respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2:FiO2 ratio, and Sequential Organ Failure Assessment score. Clinical outcomes relating to duration of ventilation, lengths of ICU and hospital stays, and mortality were collected. Long-term follow-up included diagnosis of interstitial lung disease at 1 year and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at Days 0, 4, and 7. Measurements and Main Results: Sixty participants were recruited (final analysis: n = 30 received ORBCEL-C, n = 29 received placebo; 1 participant in the placebo group withdrew consent). Six serious adverse events occurred in the ORBCEL-C group and three in the placebo group (risk ratio, 2.9 [95% confidence interval, 0.6-13.2]; P = 0.25). Day 7 mean (SD) oxygenation index did not differ (ORBCEL-C, 98.3 [57.2] cm H2O/kPa; placebo, 96.6 [67.3] cm H2O/kPa). There were no differences in secondary surrogate outcomes or in mortality at Day 28, Day 90, 1 year, or 2 years. There was no difference in the prevalence of interstitial lung disease at 1 year or significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome. Conclusion: ORBCEL-C MSCs were safe in subjects with moderate to severe COVID-19-related ARDS but did not improve surrogates of pulmonary organ dysfunction.

COSCA (Core Outcome Set for Cardiac Arrest) in Adults: An Advisory Statement From the International Liaison Committee on Resuscitation.

Cardiac arrest effectiveness trials have traditionally reported outcomes that focus on survival. A lack of consistency in outcome reporting between trials limits the opportunities to pool results for meta-analysis. The COSCA initiative (Core Outcome Set for Cardiac Arrest), a partnership between patients, their partners, clinicians, research scientists, and the International Liaison Committee on Resuscitation, sought to develop a consensus core outcome set for cardiac arrest for effectiveness trials. Core outcome sets are primarily intended for large, randomized clinical effectiveness trials (sometimes referred to as pragmatic trials or phase III/IV trials) rather than for pilot or efficacy studies. A systematic review of the literature combined with qualitative interviews among cardiac arrest survivors was used to generate a list of potential outcome domains. This list was prioritized through a Delphi process, which involved clinicians, patients, and their relatives/partners. An international advisory panel narrowed these down to 3 core domains by debate that led to consensus. The writing group refined recommendations for when these outcomes should be measured and further characterized relevant measurement tools. Consensus emerged that a core outcome set for reporting on effectiveness studies of cardiac arrest (COSCA) in adults should include survival, neurological function, and health-related quality of life. This should be reported as survival status and modified Rankin scale score at hospital discharge, at 30 days, or both. Health-related quality of life should be measured with ≥1 tools from Health Utilities Index version 3, Short-Form 36-Item Health Survey, and EuroQol 5D-5L at 90 days and at periodic intervals up to 1 year after cardiac arrest, if resources allow.

An Energy-Independent Pro-longevity Function of Triacylglycerol in Yeast.

Intracellular triacylglycerol (TAG) is a ubiquitous energy storage lipid also involved in lipid homeostasis and signaling. Comparatively, little is known about TAG's role in other cellular functions. Here we show a pro-longevity function of TAG in the budding yeast Saccharomyces cerevisiae. In yeast strains derived from natural and laboratory environments a correlation between high levels of TAG and longer chronological lifespan was observed. Increased TAG abundance through the deletion of TAG lipases prolonged chronological lifespan of laboratory strains, while diminishing TAG biosynthesis shortened lifespan without apparently affecting vegetative growth. TAG-mediated lifespan extension was independent of several other known stress response factors involved in chronological aging. Because both lifespan regulation and TAG metabolism are conserved, this cellular pro-longevity function of TAG may extend to other organisms.

Portable standoff spectrometer for hazard identification using integrated quantum cascade laser arrays from 6.5 to 11 µm.

This article presents new spectroscopic results in standoff chemical detection that are enabled by monolithic arrays of Distributed Feedback (DFB) Quantum Cascade Lasers (QCLs), with each array element at a slightly different wavelength than its neighbor. The standoff analysis of analyte/substrate pairs requires a laser source with characteristics offered uniquely by a QCL Array. This is particularly true for time-evolving liquid chemical warfare agent (CWA) analysis. In addition to describing the QCL array source developed for long wave infrared coverage, a description of an integrated prototype standoff detection system is provided. Experimental standoff detection results using the man-portable system for droplet examination from 1.3 meters are presented using the CWAs VX and T-mustard as test cases. Finally, we consider three significant challenges to working with droplets and liquid films in standoff spectroscopy: substrate uptake of the analyte, time-dependent droplet spread of the analyte, and variable substrate contributions to retrieved signals.

Dynamic evolution of the GnRH receptor gene family in vertebrates.

BACKGROUND: Elucidating the mechanisms underlying coevolution of ligands and receptors is an important challenge in molecular evolutionary biology. Peptide hormones and their receptors are excellent models for such efforts, given the relative ease of examining evolutionary changes in genes encoding for both molecules. Most vertebrates possess multiple genes for both the decapeptide gonadotropin releasing hormone (GnRH) and for the GnRH receptor. The evolutionary history of the receptor family, including ancestral copy number and timing of duplications and deletions, has been the subject of controversy. RESULTS: We report here for the first time sequences of three distinct GnRH receptor genes in salamanders (axolotls, Ambystoma mexicanum), which are orthologous to three GnRH receptors from ranid frogs. To understand the origin of these genes within the larger evolutionary context of the gene family, we performed phylogenetic analyses and probabilistic protein homology searches of GnRH receptor genes in vertebrates and their near relatives. Our analyses revealed four points that alter previous views about the evolution of the GnRH receptor gene family. First, the "mammalian" pituitary type GnRH receptor, which is the sole GnRH receptor in humans and previously presumed to be highly derived because it lacks the cytoplasmic C-terminal domain typical of most G-protein coupled receptors, is actually an ancient gene that originated in the common ancestor of jawed vertebrates (Gnathostomata). Second, unlike previous studies, we classify vertebrate GnRH receptors into five subfamilies. Third, the order of subfamily origins is the inverse of previous proposed models. Fourth, the number of GnRH receptor genes has been dynamic in vertebrates and their ancestors, with multiple duplications and losses. CONCLUSION: Our results provide a novel evolutionary framework for generating hypotheses concerning the functional importance of structural characteristics of vertebrate GnRH receptors. We show that five subfamilies of vertebrate GnRH receptors evolved early in the vertebrate phylogeny, followed by several independent instances of gene loss. Chief among cases of gene loss are humans, best described as degenerate with respect to GnRH receptors because we retain only a single, ancient gene.

Conservation genetics and the implication for recovery of the endangered Mitchell's satyr Butterfly, Neonympha mitchellii mitchellii.

The modern delineation of taxonomic groups is often aided by analyses of molecular data, which can also help inform conservation biology. Two subspecies of the butterfly Neonympha mitchellii are classified as federally endangered in the United States: Neonympha mitchellii mitchellii, the Mitchell's satyr, and Neonympha mitchellii francisi, the Saint Francis's satyr. The recent discovery of additional disjunct populations of N. mitchellii in the southeastern US could have important implications for both legal protection and management decisions. We elucidated the relationships among 48 individuals representing 5 N. mitchellii populations using 6 molecular markers (5 nuclear and 1 mitochondrial) under a variety of analytical frameworks. Phylogenetic analysis resulted in moderately supported clades that corresponded with the geographic region where samples originated. Clustering analyses identified 3 groups, wherein the 2 named subspecies formed separate clusters. Coalescent analyses indicated evolutionary divergence between N. m. mitchellii and all other populations but weakly supported divergence among N. m. francisi and the recently discovered populations. Hence, the 2 currently accepted subspecies were clearly different from one another, but the recently discovered populations could not be completely distinguished from N. m. francisi or each other. We propose that N. m. mitchellii and N. m. francisi continue to be managed as separate endangered species.

"I'd rather wait and see what's around the corner": A multi-perspective qualitative study of treatment escalation planning in frailty.

INTRODUCTION: People living with frailty risk adverse outcomes following even minor illnesses. Admission to hospital or the intensive care unit is associated with potentially burdensome interventions and poor outcomes. Decision-making during an emergency is fraught with complexity and potential for conflict between patients, carers and clinicians. Advance care planning is a process of shared decision-making which aims to ensure patients are treated in line with their wishes. However, planning for future care is challenging and those living with frailty are rarely given the opportunity to discuss their preferences. The aim of the ProsPECT (Prospective Planning for Escalation of Care and Treatment) study was to explore perspectives on planning for treatment escalation in the context of frailty. We spoke to people living with frailty, their carers and clinicians across primary and secondary care. METHODS: In-depth online or telephone interviews and online focus groups. The topic guide explored frailty, acute decision-making and planning for the future. Data were thematically analysed using the Framework Method. Preliminary findings were presented to a sample of study participants for feedback in two online workshops. RESULTS: We spoke to 44 participants (9 patients, 11 carers and 24 clinicians). Four main themes were identified: frailty is absent from treatment escalation discussions, planning for an uncertain future, escalation in an acute crisis is 'the path of least resistance', and approaches to facilitating treatment escalation planning in frailty. CONCLUSION: Barriers to treatment escalation planning include a lack of shared understanding of frailty and uncertainty about the future. Emergency decision-making is focussed on survival or risk aversion and patient preferences are rarely considered. To improve planning discussions, we recommend frailty training for non-specialist clinicians, multi-disciplinary support, collaborative working between patients, carers and clinicians as well as broader public engagement.

Ancient gene duplication provided a key molecular step for anaerobic growth of Baker's yeast.

Mitochondria are essential organelles required for a number of key cellular processes. As most mitochondrial proteins are nuclear encoded, their efficient translocation into the organelle is critical. Transport of proteins across the inner membrane is driven by a multicomponent, matrix-localized "import motor," which is based on the activity of the molecular chaperone Hsp70 and a J-protein cochaperone. In Saccharomyces cerevisiae, two paralogous J-proteins, Pam18 and Mdj2, can form the import motor. Both contain transmembrane and matrix domains, with Pam18 having an additional intermembrane space (IMS) domain. Evolutionary analyses revealed that the origin of the IMS domain of S. cerevisiae Pam18 coincides with a gene duplication event that generated the PAM18/MDJ2 gene pair. The duplication event and origin of the Pam18 IMS domain occurred at the relatively ancient divergence of the fungal subphylum Saccharomycotina. The timing of the duplication event also corresponds with a number of additional functional changes related to mitochondrial function and respiration. Physiological and genetic studies revealed that the IMS domain of Pam18 is required for efficient growth under anaerobic conditions, even though it is dispensable when oxygen is present. Thus, the gene duplication was beneficial for growth capacity under particular environmental conditions as well as diversification of the import motor components.

Co-evolution-driven switch of J-protein specificity towards an Hsp70 partner.

Molecular mechanisms by which protein-protein interactions are preserved or lost after gene duplication are not understood. Taking advantage of the well-studied yeast mtHsp70:J-protein molecular chaperone system, we considered whether changes in partner proteins accompanied specialization of gene duplicates. Here, we report that existence of the Hsp70 Ssq1, which arose by duplication of the gene encoding multifunction mtHsp70 and specializes in iron-sulphur cluster biogenesis, correlates with functional and structural changes in the J domain of its J-protein partner Jac1. All species encoding this shorter alternative version of the J domain share a common ancestry, suggesting that all short JAC1 proteins arose from a single deletion event. Construction of a variant that extended the length of the J domain of a 'short' Jac1 enhanced its ability to partner with multifunctional Hsp70. Our data provide a causal link between changes in the J protein partner and specialization of duplicate Hsp70.

Repair of acute respiratory distress syndrome by stromal cell administration (REALIST): a structured study protocol for an open-label dose-escalation phase 1 trial followed by a randomised, triple-blind, allocation concealed, placebo-controlled phase 2 trial.

BACKGROUND: Mesenchymal stromal cells (MSCs) may be of benefit in ARDS due to immunomodulatory and reparative properties. This trial investigates a novel CD362 enriched umbilical cord derived MSC product (REALIST ORBCEL-C), produced to Good Manufacturing Practice standards, in patients with moderate to severe ARDS due to COVID-19 and ARDS due to other causes. METHODS: Phase 1 is a multicentre open-label dose-escalation pilot trial. Patients will receive a single infusion of REALIST ORBCEL-C (100 × 106 cells, 200 × 106 cells or 400 × 106 cells) in a 3 + 3 design. Phase 2 is a multicentre randomised, triple blind, allocation concealed placebo-controlled trial. Two cohorts of patients, with ARDS due to COVID-19 or ARDS due to other causes, will be recruited and randomised 1:1 to receive either a single infusion of REALIST ORBCEL-C (400 × 106 cells or maximal tolerated dose in phase 1) or placebo. Planned recruitment to each cohort is 60 patients. The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is oxygenation index at day 7. The trial will be reported according to the Consolidated Standards for Reporting Trials (CONSORT 2010) statement. DISCUSSION: The development and manufacture of an advanced therapy medicinal product to Good Manufacturing Practice standards within NHS infrastructure are discussed, including challenges encountered during the early stages of trial set up. The rationale to include a separate cohort of patients with ARDS due to COVID-19 in phase 2 of the trial is outlined. TRIAL REGISTRATION: ClinicalTrials.gov NCT03042143. Registered on 3 February 2017. EudraCT Number 2017-000584-33.

Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial.

BACKGROUND: Mesenchymal stromal cells (MSCs) may be of benefit in acute respiratory distress syndrome (ARDS) due to immunomodulatory, reparative, and antimicrobial actions. ORBCEL-C is a population of CD362 enriched umbilical cord-derived MSCs. The REALIST phase 1 trial investigated the safety and feasibility of ORBCEL-C in patients with moderate to severe ARDS. METHODS: REALIST phase 1 was an open label, dose escalation trial in which cohorts of mechanically ventilated patients with moderate to severe ARDS received increasing doses (100, 200 or 400 × 106 cells) of a single intravenous infusion of ORBCEL-C in a 3 + 3 design. The primary safety outcome was the incidence of serious adverse events. Dose limiting toxicity was defined as a serious adverse reaction within seven days. Trial registration clinicaltrials.gov NCT03042143. FINDINGS: Nine patients were recruited between the 7th January 2019 and 14th January 2020. Study drug administration was well tolerated and no dose limiting toxicity was reported in any of the three cohorts. Eight adverse events were reported for four patients. Pyrexia within 24 h of study drug administration was reported in two patients as pre-specified adverse events. A further two adverse events (non-sustained ventricular tachycardia and deranged liver enzymes), were reported as adverse reactions. Four serious adverse events were reported (colonic perforation, gastric perforation, bradycardia and myocarditis) but none were deemed related to administration of ORBCEL-C. At day 28 no patients had died in cohort one (100 × 106), three patients had died in cohort two (200 × 106) and one patient had died in cohort three (400 × 106). Overall day 28 mortality was 44% (n = 4/9). INTERPRETATION: A single intravenous infusion of ORBCEL-C was well tolerated in patients with moderate to severe ARDS. No dose limiting toxicity was reported up to 400 × 106 cells.

Genome-scale approaches to resolving incongruence in molecular phylogenies.

One of the most pervasive challenges in molecular phylogenetics is the incongruence between phylogenies obtained using different data sets, such as individual genes. To systematically investigate the degree of incongruence, and potential methods for resolving it, we screened the genome sequences of eight yeast species and selected 106 widely distributed orthologous genes for phylogenetic analyses, singly and by concatenation. Our results suggest that data sets consisting of single or a small number of concatenated genes have a significant probability of supporting conflicting topologies. By contrast, analyses of the entire data set of concatenated genes yielded a single, fully resolved species tree with maximum support. Comparable results were obtained with a concatenation of a minimum of 20 genes; substantially more genes than commonly used but a small fraction of any genome. These results have important implications for resolving branches of the tree of life.

Detection of Chemical Warfare Agents by Colorimetric Sensor Arrays.

We report the successful use of colorimetric arrays to identify chemical warfare agents (CWAs). Methods were developed to interpret and analyze a 73-indicator array with an entirely automated workflow. Using a cross-validated first-nearest-neighbor algorithm for assessing detection and identification performances on 632 exposures, at 30 min postexposure we report, on average, 78% correct chemical identification, 86% correct class-level identification, and 96% correct red light/green light (agent versus non-agent) detection. Of 174 total independent agent test exposures, 164 were correctly identified from a 30 min exposure in the red light/green light context, yielding a 94% correct identification of CWAs. Of 149 independent non-agent exposures, 139 were correctly identified at 30 min in the red light/green light context, yielding a 7% false alarm rate. We find that this is a promising approach for the development of a miniaturized, field-portable analytical equipment suitable for soldiers and first responders.

Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration in COVID-19 (REALIST-COVID-19): A structured summary of a study protocol for a randomised, controlled trial.

OBJECTIVES: The primary objective of the study is to assess the safety of a single intravenous infusion of Mesenchymal Stromal Cells (MSCs) in patients with Acute Respiratory Distress Syndrome (ARDS) due to COVID-19. Secondary objectives are to determine the effects of MSCs on important clinical outcomes, as described below. TRIAL DESIGN: REALIST COVID 19 is a randomised, placebo-controlled, triple blinded trial. PARTICIPANTS: The study will be conducted in Intensive Care Units in hospitals across the United Kingdom. Patients with moderate to severe ARDS as defined by the Berlin definition, receiving invasive mechanical ventilation and with a diagnosis of COVID-19 based on clinical diagnosis or PCR test will be eligible. Patients will be excluded for the following reasons: more than 72 hours from the onset of ARDS; age < 16 years; patient known to be pregnant; major trauma in previous 5 days; presence of any active malignancy (other than non-melanoma skin cancer); WHO Class III or IV pulmonary hypertension; venous thromboembolism currently receiving anti-coagulation or within the past 3 months; patient receiving extracorporeal life support; severe chronic liver disease (Child-Pugh > 12); Do Not Attempt Resuscitation order in place; treatment withdrawal imminent within 24 hours; prisoners; declined consent; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; previously enrolled in the REALIST trial. INTERVENTION AND COMPARATOR: Intervention: Allogeneic donor CD362 enriched human umbilical cord derived mesenchymal stromal cells (REALIST ORBCEL-C) supplied as sterile, single-use cryopreserved cell suspension of a fixed dose of 400 x106 cells in 40ml volume, to be diluted in Plasma-Lyte 148 to a total volume of 200mls for administration. Comparator (placebo): Plasma-Lyte 148 Solution for Infusion (200mls). The cellular product (REALIST ORBCEL-C) was developed and patented by Orbsen Therapeutics. MAIN OUTCOMES: The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is Oxygenation Index (OI) at day 7. Secondary outcomes include: OI at days 4 and 14; respiratory compliance, driving pressure and PaO2/FiO2 ratio (PF ratio) at days 4, 7 and 14; Sequential Organ Failure Assessment (SOFA) score at days 4, 7 and 14; extubation and reintubation; ventilation free days at day 28; duration of mechanical ventilation; length of ICU and hospital stay; 28-day and 90-day mortality. RANDOMISATION: After obtaining informed consent, patients will be randomised via a centralised automated 24-hour telephone or web-based randomisation system (CHaRT, Centre for Healthcare Randomised Trials, University of Aberdeen). Randomisation will be stratified by recruitment centre and by vasopressor use and patients will be allocated to REALIST ORBCEL-C or placebo control in a 1:1 ratio. BLINDING (MASKING): The investigator, treating physician, other members of the site research team and participants will be blinded. The cell therapy facility and clinical trials pharmacist will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A sample size of 60 patients with 30 patients randomised to the intervention and 30 to the control group. If possible, recruitment will continue beyond 60 patients to provide more accurate and definitive trial results. The total number of patients recruited will depend on the pandemic and be guided by the data monitoring and ethics committee (DMEC). TRIAL STATUS: REALIST Phase 1 completed in January 2020 prior to the COVID-19 pandemic. This was an open label dose escalation study of REALIST ORBCEL-C in patients with ARDS. The COVID-19 pandemic emerged as REALIST Phase 2 was planned to commence and the investigator team decided to repurpose the Phase 2 trial as a COVID-19 specific trial. This decision was discussed and approved by the Trial Steering Committee (TSC) and DMEC. Submissions were made to the Research Ethics Committee (REC) and MHRA to amend the protocol to a COVID-19 specific patient population and the protocol amendment was accepted by the REC on 27th March 2020 and MHRA on 30th March 2020 respectively. Other protocol changes in this amendment included an increase in the time of onset of ARDS from 48 to 72 hours, inclusion of clinical outcomes as secondary outcomes, the provision of an option for telephone consent, an indicative sample size and provision to continue recruitment beyond this indicative sample size. The current protocol in use is version 4.0 23.03.2020 (Additional file 1). Urgent Public Health status was awarded by the NIHR on 2 April 2020 and the trial opened to recruitment and recruited the first participant the same day. At the time of publication the trial was open to recruitment at 5 sites across the UK (Belfast Health and Social Care Trust, King's College London, Guys and St Thomas' Hospital London, Birmingham Heartlands Hospital and the Queen Elizabeth Hospital Birmingham) and 12 patients have been recruited across these sites. Additional sites are planned to open and appropriate approvals for these are being obtained. It is estimated recruitment will continue for 6 months. TRIAL REGISTRATION: ClinicalTrials.gov NCT03042143 (Registered 3 Feb 2017). EudraCT 2017-000585-33 (Registered 28 Nov 2017). FULL PROTOCOL: The full protocol (version 4.0 23.03.2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Evolution of mitochondrial chaperones utilized in Fe-S cluster biogenesis.

Biogenesis of Fe-S clusters is an essential process [1]. In both Escherichia coli and Saccharomyces cerevisiae, insertion of clusters into an apoprotein requires interaction between a scaffold protein on which clusters are assembled and a molecular chaperone system--an unusually specialized mitochondrial Hsp70 (mtHsp70) and its J protein cochaperone [2]. It is generally assumed that mitochondria inherited their Fe-S cluster assembly machinery from prokaryotes via the endosymbiosis of a bacterium that led to formation of mitochondria. Indeed, phylogenetic analyses demonstrated that the S. cerevisiae J protein, Jac1, and the scaffold, Isu, are orthologous to their bacterial counterparts [3, 4]. However, our analyses indicate that the specialized mtHsp70, Ssq1, is only present in a subset of fungi; most eukaryotes have a single mtHsp70, Ssc1. We propose that an Hsp70 having a role limited to Fe-S cluster biogenesis arose twice during evolution. In the fungal lineage, the gene encoding multifunctional mtHsp70, Ssc1, was duplicated, giving rise to specialized Ssq1. Therefore, Ssq1 is not orthologous to the specialized Hsp70 from E. coli (HscA), but shares a striking level of convergence at the biochemical level. Thus, in the vast majority of eukaryotes, Jac1 and Isu function with the single, multifunctional mtHsp70 in Fe-S cluster biogenesis.

COSCA (Core Outcome Set for Cardiac Arrest) in Adults: An Advisory Statement From the International Liaison Committee on Resuscitation.

Cardiac arrest effectiveness trials have traditionally reported outcomes that focus on survival. A lack of consistency in outcome reporting between trials limits the opportunities to pool results for meta-analysis. The COSCA initiative (Core Outcome Set for Cardiac Arrest), a partnership between patients, their partners, clinicians, research scientists, and the International Liaison Committee on Resuscitation, sought to develop a consensus core outcome set for cardiac arrest for effectiveness trials. Core outcome sets are primarily intended for large, randomised clinical effectiveness trials (sometimes referred to as pragmatic trials or phase III/IV trials) rather than for pilot or efficacy studies. A systematic review of the literature combined with qualitative interviews among cardiac arrest survivors was used to generate a list of potential outcome domains. This list was prioritised through a Delphi process, which involved clinicians, patients, and their relatives/partners. An international advisory panel narrowed these down to 3 core domains by debate that led to consensus. The writing group refined recommendations for when these outcomes should be measured and further characterised relevant measurement tools. Consensus emerged that a core outcome set for reporting on effectiveness studies of cardiac arrest (COSCA) in adults should include survival, neurological function, and health-related quality of life. This should be reported as survival status and modified Rankin scale score at hospital discharge, at 30 days, or both. Health-related quality of life should be measured with ≥1 tools from Health Utilities Index version 3, Short-Form 36-Item Health Survey, and EuroQol 5D-5L at 90 days and at periodic intervals up to 1 year after cardiac arrest, if resources allow. © 2018 European Resuscitation Council and American Heart Association, Inc. Published by Elsevier B.V. All rights reserved.