ORCID Profile
0000-0002-5338-2538
Current Organisation
The University of Edinburgh
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 20-11-2021
DOI: 10.1186/S12879-021-06829-7
Abstract: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, 0.17605/OSF.IO/GEHFX ). In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92 1.02) with between-study heterogeneity not beyond chance (I 2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
Publisher: Springer Science and Business Media LLC
Date: 26-10-2020
Publisher: Cold Spring Harbor Laboratory
Date: 04-10-2022
DOI: 10.1101/2022.10.03.22280649
Abstract: This study aims to explore the impact of COVID-19 vaccination on critical care by examining associations between vaccination and admission to critical care with COVID-19 during England’s Delta wave, by age group, dose, and over time. We used linked routinely-collected data to conduct a population cohort study of patients admitted to adult critical care in England for management of COVID-19 between 1 May and 15 December 2021. Included participants were the whole population of England aged 18 years or over (44.7 million), including 10,141 patients admitted to critical care with COVID-19. The intervention was vaccination with one, two, or a booster/three doses of any COVID-19 vaccine. Compared with unvaccinated patients, vaccinated patients were older (median 64 years for patients receiving two or more doses versus 50 years for unvaccinated), with higher levels of severe comorbidity (20.3% versus 3.9%) and immunocompromise (15.0% versus 2.3%). Compared with patients who were unvaccinated, those vaccinated with two doses had a relative risk reduction (RRR) of between 90.1% (patients aged 18–29, 95% CI, 86.8% to 92.7%) and 95.9% (patients aged 60–69, 95% CI, 95.5% to 96.2%). Waning was only observed for those aged 70+, for whom the RRR reduced from 97.3% (91.0% to 99.2%) to 86.7% (85.3% to 90.1%) between May and December but increased again to 98.3% (97.6% to 98.8%) with a booster/third dose. Important demographic and clinical differences exist between vaccinated and unvaccinated patients admitted to critical care with COVID-19. While not a causal analysis, our findings are consistent with a substantial and sustained impact of vaccination on reducing admissions to critical care during England’s Delta wave, with evidence of waning predominantly restricted to those aged 70+.
Publisher: Springer Science and Business Media LLC
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 12-05-2017
DOI: 10.1007/S00134-017-4821-1
Abstract: Septic shock remains a global health challenge with millions of cases every year, high rates of mortality and morbidity, impaired quality of life among survivors and relatives, and high resource use both in developed and developing nations. Care and outcomes are improving through organisational initiatives and updated clinical practice guidelines based on clinical research mainly carried out by large collaborative networks. This progress is likely to continue through the collaborative work of the established and merging trials groups in many parts of the world and through refined trial methodology and translational work. In this review, international experts summarize the current position of clinical research in septic shock and propose a research agenda to advance this field.
Publisher: Springer Science and Business Media LLC
Date: 30-07-2010
Abstract: To the best of our knowledge, this is the first report in the literature of development of neurogenic diabetes insipidus in a patient with subacute liver failure. A 25-year-old man presented with subacute liver failure. While awaiting a liver transplant, the patient developed cerebral edema, which resulted in neurogenic diabetes insipidus secondary to cerebral edema. The patient died before the liver transplantation could be carried out. Neurogenic diabetes insipidus is well recognized in the neurosurgical population as a consequence of cerebral edema and increased intracranial pressure, both of which occur commonly in patients with subacute liver failure.
Publisher: American Society for Microbiology
Date: 20-04-2022
DOI: 10.1128/JCM.02283-21
Abstract: Tools to detect SARS-CoV-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing s les with low viral loads or low RNA quality.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2020
DOI: 10.1038/S41591-020-1038-6
Abstract: Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, in idual traits within this signature may collectively and in idually guide treatment options offer insights into COVID-19 pathogenesis and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.
Publisher: SAGE Publications
Date: 08-10-2020
Abstract: Early in a pandemic, outcomes are biased towards patients with shorter durations of critical illness. We describe 60-day outcomes for patients critically ill with confirmed COVID-19 and explore the potential bias in the weekly reported data by ICNARC. First 200 consecutive patients with confirmed COVID-19, admitted for critical care in England, Wales and Northern Ireland, followed-up for a minimum of 60 days from admission. Outcomes included survival and duration of critical care, receipt/duration of organ support in critical care and hospital survival . Mean age was 62.6 years, 70.5% were male, 52.0% were white, 39.2% obese and 9.0% had serious comorbidities. Median APACHE II score was 16 (IQR 12, 19). After 60 days, 83 (41.5%) patients had been discharged from hospital, 15 (7.5%) had been discharged from critical care but remained in hospital, 1 (0.5%) was still receiving critical care, 90 (45.0%) had died while receiving critical care and 11 (5.5%) had died in hospital after discharge from critical care. Median duration of critical care was 14.0 days (IQR 6.1, 23.0) for survivors and 10.0 days (IQR 5.0, 16.0) for non-survivors of critical care. Overall, 158 (79.0%) patients received advanced respiratory support for a median of 13 (IQR 8, 20) calendar days. Compared with weekly reports during the pandemic, critical care mortality started higher than but then decreased below that of the first 200 consecutive patients. Duration of critical care, for both survivors and non-survivors increased over time however, both were still lower than those for the first 200 consecutive patients. Receipt and duration of organ support increased to values similar to those for the first 200 consecutive patients. COVID-19 in critical care has high mortality and places a large burden on resources. Analysis of preliminary data with limited follow-up should be interpreted with caution, particularly for future planning in a pandemic.
Publisher: BMJ
Date: 26-08-2021
DOI: 10.1136/BMJ.N1931
Abstract: To assess the association between covid-19 vaccines and risk of thrombocytopenia and thromboembolic events in England among adults. Self-controlled case series study using national data on covid-19 vaccination and hospital admissions. Patient level data were obtained for approximately 30 million people vaccinated in England between 1 December 2020 and 24 April 2021. Electronic health records were linked with death data from the Office for National Statistics, SARS-CoV-2 positive test data, and hospital admission data from the United Kingdom’s health service (NHS). 29 121 633 people were vaccinated with first doses (19 608 008 with Oxford-AstraZeneca (ChAdOx1 nCoV-19) and 9 513 625 with Pfizer-BioNTech (BNT162b2 mRNA)) and 1 758 095 people had a positive SARS-CoV-2 test. People aged ≥16 years who had first doses of the ChAdOx1 nCoV-19 or BNT162b2 mRNA vaccines and any outcome of interest were included in the study. The primary outcomes were hospital admission or death associated with thrombocytopenia, venous thromboembolism, and arterial thromboembolism within 28 days of three exposures: first dose of the ChAdOx1 nCoV-19 vaccine first dose of the BNT162b2 mRNA vaccine and a SARS-CoV-2 positive test. Secondary outcomes were subsets of the primary outcomes: cerebral venous sinus thrombosis (CVST), ischaemic stroke, myocardial infarction, and other rare arterial thrombotic events. The study found increased risk of thrombocytopenia after ChAdOx1 nCoV-19 vaccination (incidence rate ratio 1.33, 95% confidence interval 1.19 to 1.47 at 8-14 days) and after a positive SARS-CoV-2 test (5.27, 4.34 to 6.40 at 8-14 days) increased risk of venous thromboembolism after ChAdOx1 nCoV-19 vaccination (1.10, 1.02 to 1.18 at 8-14 days) and after SARS-CoV-2 infection (13.86, 12.76 to 15.05 at 8-14 days) and increased risk of arterial thromboembolism after BNT162b2 mRNA vaccination (1.06, 1.01 to 1.10 at 15-21 days) and after SARS-CoV-2 infection (2.02, 1.82 to 2.24 at 15-21 days). Secondary analyses found increased risk of CVST after ChAdOx1 nCoV-19 vaccination (4.01, 2.08 to 7.71 at 8-14 days), after BNT162b2 mRNA vaccination (3.58, 1.39 to 9.27 at 15-21 days), and after a positive SARS-CoV-2 test increased risk of ischaemic stroke after BNT162b2 mRNA vaccination (1.12, 1.04 to 1.20 at 15-21 days) and after a positive SARS-CoV-2 test and increased risk of other rare arterial thrombotic events after ChAdOx1 nCoV-19 vaccination (1.21, 1.02 to 1.43 at 8-14 days) and after a positive SARS-CoV-2 test. Increased risks of haematological and vascular events that led to hospital admission or death were observed for short time intervals after first doses of the ChAdOx1 nCoV-19 and BNT162b2 mRNA vaccines. The risks of most of these events were substantially higher and more prolonged after SARS-CoV-2 infection than after vaccination in the same population.
Publisher: Springer Science and Business Media LLC
Date: 27-11-2020
Publisher: National Institute for Health and Care Research
Date: 12-2022
DOI: 10.3310/EQAB4594
Abstract: A previous National Institute for Health and Care Research study [Harrison DA, Ferrando-Vivas P, Shahin J, Rowan KM. Ensuring comparisons of health-care providers are fair: development and validation of risk prediction models for critically ill patients. Health Serv Deliv Res 2015 3 (41)] identified the need for more research to understand risk factors and consequences of critical care and subsequent outcomes. First, to improve risk models for adult general critical care by developing models for mortality at fixed time points and time-to-event outcomes, end-stage renal disease, type 2 diabetes, health-care utilisation and costs. Second, to improve risk models for cardiothoracic critical care by enhancing risk factor data and developing models for longer-term mortality. Third, to improve risk models for in-hospital cardiac arrest by enhancing risk factor data and developing models for longer-term mortality and critical care utilisation. Risk modelling study linking existing data. NHS adult critical care units and acute hospitals in England. Patients admitted to an adult critical care unit or experiencing an in-hospital cardiac arrest. None. Mortality at hospital discharge, 30 days, 90 days and 1 year following critical care unit admission mortality at 1 year following discharge from acute hospital new diagnosis of end-stage renal disease or type 2 diabetes hospital resource use and costs return of spontaneous circulation sustained for 20 minutes survival to hospital discharge and 1 year and length of stay in critical care following in-hospital cardiac arrest. Case Mix Programme, National Cardiac Arrest Audit, UK Renal Registry, National Diabetes Audit, National Adult Cardiac Surgery Audit, Hospital Episode Statistics and Office for National Statistics. Data were linked for 965,576 critical care admissions between 1 April 2009 and 31 March 2016, and 83,939 in-hospital cardiac arrests between 1 April 2011 and 31 March 2016. For admissions to adult critical care units, models for 30-day mortality had similar predictors and performance to those for hospital mortality and did not reduce heterogeneity. Models for longer-term outcomes reflected increasing importance of chronic over acute predictors. New models for end-stage renal disease and diabetes will allow benchmarking of critical care units against these important outcomes and identification of patients requiring enhanced follow-up. The strongest predictors of health-care costs were prior hospitalisation, prior dependency and chronic conditions. Adding pre- and intra-operative risk factors to models for cardiothoracic critical care gave little improvement in performance. Adding comorbidities to models for in-hospital cardiac arrest provided modest improvements but were of greater importance for longer-term outcomes. Delays in obtaining linked data resulted in the data used being 5 years old at the point of publication: models will already require recalibration. Data linkage provided enhancements to the risk models underpinning national clinical audits in the form of additional predictors and novel outcomes measures. The new models developed in this report may assist in providing objective estimates of potential outcomes to patients and their families. (1) Develop and test care pathways for recovery following critical illness targeted at those with the greatest need (2) explore other relevant data sources for longer-term outcomes (3) widen data linkage for resource use and costs to primary care, outpatient and emergency department data. This study is registered as NCT02454257. This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research Vol. 10, No. 39. See the NIHR Journals Library website for further project information.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-10-2020
DOI: 10.1097/CCM.0000000000004740
Abstract: To identify characteristics that predict 30-day mortality among patients critically ill with coronavirus disease 2019 in England, Wales, and Northern Ireland. Observational cohort study. A total of 258 adult critical care units. A total of 10,362 patients with confirmed coronavirus disease 2019 with a start of critical care between March 1, 2020, and June 22, 2020, of whom 9,990 were eligible (excluding patients with a duration of critical care less than 24 hr or missing core variables). The main outcome measure was time to death within 30 days of the start of critical care. Of 9,990 eligible patients (median age 60 yr, 70% male), 3,933 died within 30 days of the start of critical care. As of July 22, 2020, 189 patients were still receiving critical care and a further 446 were still in acute hospital. Data were missing for between 0.1% and 7.2% of patients across prognostic factors. We imputed missing data ten-fold, using fully conditional specification and continuous variables were modeled using restricted cubic splines. Associations between the candidate prognostic factors and time to death within 30 days of the start of critical care were determined after adjustment for multiple variables with Cox proportional hazards modeling. Significant associations were identified for age, ethnicity, deprivation, body mass index, prior dependency, immunocompromise, lowest systolic blood pressure, highest heart rate, highest respiratory rate, Pa o 2 /F io 2 ratio (and interaction with mechanical ventilation), highest blood lactate concentration, highest serum urea, and lowest platelet count over the first 24 hours of critical care. Nonsignificant associations were found for sex, sedation, highest temperature, and lowest hemoglobin concentration. We identified patient characteristics that predict an increased likelihood of death within 30 days of the start of critical care for patients with coronavirus disease 2019. These findings may support development of a prediction model for benchmarking critical care providers.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2020
Publisher: National Institute for Health and Care Research
Date: 07-2021
DOI: 10.3310/EME08100
Abstract: Sepsis and acute respiratory distress syndrome are two heterogeneous acute illnesses with high risk of death and for which there are many ‘statistically negative’ randomised controlled trials. We hypothesised that negative randomised controlled trials occur because of between-participant differences in response to treatment, illness manifestation (phenotype) and risk of outcomes (heterogeneity). To assess (1) heterogeneity of treatment effect, which tests whether or not treatment effect varies with a patient’s pre-randomisation risk of outcome and (2) whether or not subphenotypes explain the treatment response differences in sepsis and acute respiratory distress syndrome demonstrated in randomised controlled trials. We performed secondary analysis of two randomised controlled trials in patients with sepsis [i.e. the Vasopressin vs Noradrenaline as Initial Therapy in Septic Shock (VANISH) trial and the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial] and one acute respiratory distress syndrome multicentre randomised controlled trial [i.e. the Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial], conducted in the UK. The VANISH trial is a 2 × 2 factorial randomised controlled trial of vasopressin (Pressyn AR ® Ferring Pharmaceuticals, Saint-Prex, Switzerland) and hydrocortisone sodium phosphate (hereafter referred to as hydrocortisone) (Efcortesol TM Amdipharm plc, St Helier, Jersey) compared with placebo. The LeoPARDS trial is a two-arm-parallel-group randomised controlled trial of levosimendan (Simdax ® Orion Pharma, Espoo, Finland) compared with placebo. The HARP-2 trial is a parallel-group randomised controlled trial of simvastatin compared with placebo. To test for heterogeneity of the effect on 28-day mortality of vasopressin, hydrocortisone and levosimendan in patients with sepsis and of simvastatin in patients with acute respiratory distress syndrome. We used the total Acute Physiology And Chronic Health Evaluation II (APACHE II) score as the baseline risk measurement, comparing treatment effects in patients with baseline APACHE II scores above (high) and below (low) the median using regression models with an interaction between treatment and baseline risk. To identify subphenotypes, we performed latent class analysis using only baseline clinical and biomarker data, and compared clinical outcomes across subphenotypes and treatment groups. The odds of death in the highest APACHE II quartile compared with the lowest quartile ranged from 4.9 to 7.4, across the three trials. We did not observe heterogeneity of treatment effect for vasopressin, hydrocortisone and levosimendan. In the HARP-2 trial, simvastatin reduced mortality in the low-APACHE II group and increased mortality in the high-APACHE II group. In the VANISH trial, a two-subphenotype model provided the best fit for the data. Subphenotype 2 in iduals had more inflammation and shorter survival. There were no treatment effect differences between the two subphenotypes. In the LeoPARDS trial, a three-subphenotype model provided the best fit for the data. Subphenotype 3 in iduals had the greatest inflammation and lowest survival. There were no treatment effect differences between the three subphenotypes, although survival was lowest in the levosimendan group for all subphenotypes. In the HARP-2 trial, a two-subphenotype model provided the best fit for the data. The inflammatory subphenotype was associated with fewer ventilator-free days and higher 28-day mortality. The lack of heterogeneity of treatment effect and any treatment effect differences between sepsis subphenotypes may be secondary to the lack of statistical power to detect such effects, if they truly exist. We highlight lack of heterogeneity of treatment effect in all three trial populations. We report three subphenotypes in sepsis and two subphenotypes in acute respiratory distress syndrome, with an inflammatory phenotype with greater risk of death as a consistent finding in both sepsis and acute respiratory distress syndrome. Our analysis highlights the need to identify key discriminant markers to characterise subphenotypes in sepsis and acute respiratory distress syndrome with an observational cohort study. This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation Vol. 8, No. 10. See the NIHR Journals Library website for further project information.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2021
DOI: 10.1038/S41586-021-03767-X
Abstract: The genetic make-up of an in idual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Publisher: Cold Spring Harbor Laboratory
Date: 07-03-2022
DOI: 10.1101/2022.03.07.22271833
Abstract: Pulmonary inflammation drives critical illness in Covid-19, 1 creating a clinically homogeneous extreme phenotype, which we have previously shown to be highly efficient for discovery of genetic associations. 3 Despite the advanced stage of illness, we have found that immunomodulatory therapies have strong beneficial effects in this group. 1 Further genetic discoveries may identify additional therapeutic targets to modulate severe disease. 6 In this new data release from the GenOMICC (Genetics Of Mortality in Critical Care) study we include new microarray genotyping data from additional critically-ill cases in the UK and Brazil, together with cohorts of severe Covid-19 from the ISARIC4C 7 and SCOURGE 8 studies, and meta-analysis with previously-reported data. We find an additional 14 new genetic associations. Many are in potentially druggable targets, in inflammatory signalling (JAK1, PDE4A), monocyte-macrophage differentiation (CSF2), immunometabolism (SLC2A5, AK5), and host factors required for viral entry and replication (TMPRSS2, RAB2A). As with our previous work, these results provide tractable therapeutic targets for modulation of harmful host-mediated inflammation in Covid-19.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Elsevier BV
Date: 06-2021
Publisher: Springer Science and Business Media LLC
Date: 12-07-2021
Publisher: Springer Science and Business Media LLC
Date: 11-12-2021
DOI: 10.1038/S41586-020-03065-Y
Abstract: Host-mediated lung inflammation is present
Publisher: Springer Science and Business Media LLC
Date: 06-2022
DOI: 10.1038/S41591-022-01843-X
Abstract: Research and practice in critical care medicine have long been defined by syndromes, which, despite being clinically recognizable entities, are, in fact, loose amalgams of heterogeneous states that may respond differently to therapy. Mounting translational evidence-supported by research on respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-suggests that the current syndrome-based framework of critical illness should be reconsidered. Here we discuss recent findings from basic science and clinical research in critical care and explore how these might inform a new conceptual model of critical illness. De-emphasizing syndromes, we focus on the underlying biological changes that underpin critical illness states and that may be amenable to treatment. We hypothesize that such an approach will accelerate critical care research, leading to a richer understanding of the pathobiology of critical illness and of the key determinants of patient outcomes. This, in turn, will support the design of more effective clinical trials and inform a more precise and more effective practice at the bedside.
Publisher: Georg Thieme Verlag KG
Date: 05-06-2013
Abstract: The aim of this study was to develop a new international classification of acute pancreatitis severity on the basis of a sound conceptual framework, comprehensive review of published evidence, and worldwide consultation. The Atlanta definitions of acute pancreatitis severity are ingrained in the lexicon of pancreatologists but suboptimal because these definitions are based on empiric descriptions of occurrences that are merely associated with severity. A personal invitation to contribute to the development of a new international classification of acute pancreatitis severity was sent to all surgeons, gastroenterologists, internists, intensive medicine specialists, and radiologists who are currently active in clinical research on acute pancreatitis. The invitation was not limited to members of certain associations or residents of certain countries. A global Web-based survey was conducted and a dedicated international symposium was organised to bring contributors from different disciplines together and discuss the concept and definitions. The new international classification is based on the actual local and systemic determinants of severity, rather than descriptions of events that are correlated with severity. The local determinant relates to whether there is (peri)pancreatic necrosis or not, and if present, whether it is sterile or infected. The systemic determinant relates to whether there is organ failure or not, and if present, whether it is transient or persistent. The presence of one determinant can modify the effect of another such that the presence of both infected (peri)pancreatic necrosis and persistent organ failure have a greater effect on severity than either determinant alone. The derivation of a classification based on the above principles results in 4 categories of severity - mild, moderate, severe, and critical. This classification is the result of a consultative process amongst pancreatologists from 49 countries spanning North America, South America, Europe, Asia, Oceania, and Africa. It provides a set of concise up-to-date definitions of all the main entities pertinent to classifying the severity of acute pancreatitis in clinical practice and research. This ensures that the determinant-based classification can be used in a uniform manner throughout the world.
Publisher: Elsevier BV
Date: 10-2023
Publisher: Frontiers Media SA
Date: 08-01-2020
DOI: 10.3389/FIMMU.2020.600684
Abstract: A plethora of leukocyte modulations have been reported in critically ill patients. Critical illnesses such as acute respiratory distress syndrome and cardiogenic shock, which potentially require extracorporeal membrane oxygenation (ECMO) support, are associated with changes in leukocyte numbers, phenotype, and functions. The changes observed in these illnesses could be compounded by exposure of blood to the non-endothelialized surfaces and non-physiological conditions of ECMO. This can result in further leukocyte activation, increased platelet-leukocyte interplay, pro-inflammatory and pro-coagulant state, alongside features of immunosuppression. However, the effects of ECMO on leukocytes, in particular their phenotypic and functional signatures, remain largely overlooked, including whether these changes have attributable mortality and morbidity. The aim of our narrative review is to highlight the importance of studying leukocyte signatures to better understand the development of complications associated with ECMO. Increased knowledge and appreciation of their probable role in ECMO-related adverse events may assist in guiding the design and establishment of targeted preventative actions.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2020
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.MEDIN.2013.03.013
Abstract: To develop a new classification of acute pancreatitis severity on the basis of a sound conceptual framework, comprehensive review of the published evidence, and worldwide consultation. The Atlanta definitions of acute pancreatitis severity are ingrained in the lexicon of specialist in pancreatic diseases, but are suboptimal because these definitions are based on the empiric description of events not associated with severity. A personal invitation to contribute to the development of a new classification of acute pancreatitis severity was sent to all surgeons, gastroenterologists, internists, intensivists and radiologists currently active in the field of clinical acute pancreatitis. The invitation was not limited to members of certain associations or residents of certain countries. A global web-based survey was conducted, and a dedicated international symposium was organized to bring contributors from different disciplines together and discuss the concept and definitions. The new classification of severity is based on the actual local and systemic determinants of severity, rather than on the description of events that are non-causally associated with severity. The local determinant relates to whether there is (peri) pancreatic necrosis or not, and if present, whether it is sterile or infected. The systemic determinant relates to whether there is organ failure or not, and if present, whether it is transient or persistent. The presence of one determinant can modify the effect of another, whereby the presence of both infected (peri) pancreatic necrosis and persistent organ failure has a greater impact upon severity than either determinant alone. The derivation of a classification based on the above principles results in four categories of severity: mild, moderate, severe, and critical. This classification is the result of a consultative process among specialists in pancreatic diseases from 49 countries spanning North America, South America, Europe, Asia, Oceania and Africa. It provides a set of concise up to date definitions of all the main entities pertinent to classifying the severity of acute pancreatitis in clinical practice and research. This ensures that the determinant-based classification can be used in a uniform manner throughout the world.
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2021
DOI: 10.1101/2021.09.02.21262965
Abstract: Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care 1 or hospitalisation 2 4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling ( IL10RB, PLSCR1 ), leucocyte differentiation ( BCL11A ), and blood type antigen secretor status ( FUT2 ). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase ( ATP11A ), and increased mucin expression ( MUC1 ), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.
Publisher: Massachusetts Medical Society
Date: 26-08-2021
Publisher: Springer Science and Business Media LLC
Date: 05-01-2023
DOI: 10.1186/S13054-022-04289-2
Abstract: Hypotension following out-of-hospital cardiac arrest (OHCA) may cause secondary brain injury and increase mortality rates. Current guidelines recommend avoiding hypotension. However, the optimal blood pressure following OHCA is unknown. We hypothesised that exposure to hypotension and hypertension in the first 24 h in ICU would be associated with mortality following OHCA. We conducted a retrospective analysis of OHCA patients included in the Intensive Care National Audit and Research Centre Case Mix Programme from 1 January 2010 to 31 December 2019. Restricted cubic splines were created following adjustment for important prognostic variables. We report the adjusted odds ratio for associations between lowest and highest mean arterial pressure (MAP) and systolic blood pressure (SBP) in the first 24 h of ICU care and hospital mortality. A total of 32,349 patients were included in the analysis. Hospital mortality was 56.2%. The median lowest and highest MAP and SBP were similar in survivors and non-survivors. Both hypotension and hypertension were associated with increased mortality. Patients who had a lowest recorded MAP in the range 60–63 mmHg had the lowest associated mortality. Patients who had a highest recorded MAP in the range 95–104 mmHg had the lowest associated mortality. The association between SBP and mortality followed a similar pattern to MAP. We found an association between hypotension and hypertension in the first 24 h in ICU and mortality following OHCA. The inability to distinguish between the median blood pressure of survivors and non-survivors indicates the need for research into in idualised blood pressure targets for survivors following OHCA.
Publisher: American Medical Association (AMA)
Date: 05-04-2022
Publisher: American Thoracic Society
Date: 03-2021
Publisher: SAGE Publications
Date: 14-12-2020
Abstract: During the Coronavirus Disease 2019 (COVID-19) pandemic institutions have needed to develop pragmatic clinical pathways to balance the excess critical care demand and local resources. In this single-centre retrospective cohort study we describe the outcomes of COVID-19 patients admitted to Guy’s and St. Thomas’ NHS Foundation Trust (GSTT) critical care service. Patients were managed according to a local respiratory failure management pathway that was predicated on timely invasive ventilation when indicated and tailored ventilatory strategies according to pulmonary mechanics. Between 2 March and 25 May 2020 GSTT critical care service admitted 316 patients with confirmed COVID-19. Of the 201 patients admitted directly through the Emergency Department (ED) with a completed critical care outcome, 71.1% survived to critical care discharge. These favourable outcomes may serve to inform the wider debate on optimal organ support in COVID-19.
Publisher: Elsevier BV
Date: 09-2018
Publisher: Elsevier BV
Date: 04-2019
Publisher: Springer Science and Business Media LLC
Date: 07-03-2022
DOI: 10.1038/S41586-022-04576-6
Abstract: Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care 1 or hospitalization 2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from in iduals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill in iduals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling ( IL10RB and PLSCR1 ), leucocyte differentiation ( BCL11A ) and blood-type antigen secretor status ( FUT2 ). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase ( ATP11A ), and increased expression of a mucin ( MUC1 )—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules ( SELE , ICAM5 and CD209 ) and the coagulation factor F8 , all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
Publisher: Springer Science and Business Media LLC
Date: 09-09-2020
Publisher: Springer Science and Business Media LLC
Date: 19-02-2020
Publisher: Elsevier BV
Date: 02-2010
Publisher: Oxford University Press (OUP)
Date: 24-05-2021
Abstract: Convalescent plasma containing neutralizing antibody to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is under investigation for coronavirus disease 2019 (COVID-19) treatment. We report erse virological characteristics of UK intensive care patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomized controlled trial that potentially influence treatment outcomes. SARS-CoV-2 RNA in nasopharyngeal swabs collected pretreatment was quantified by PCR. Antibody status was determined by spike-protein ELISA. B.1.1.7 was differentiated from other SARS-CoV-2 strains using allele-specific probes or restriction site polymorphism (SfcI) targeting D1118H. Of 1274 subjects, 90% were PCR positive with viral loads 118–1.7 × 1011IU/mL. Median viral loads were 40-fold higher in those IgG seronegative (n = 354 28%) compared to seropositives (n = 939 72%). Frequencies of B.1.1.7 increased from & % in November 2020 to 82% of subjects in January 2021. Seronegative in iduals with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians 5.8 × 106 and 2.0 × 105 IU/mL, respectively P = 2 × 10−15). High viral loads in seropositive B.1.1.7-infected subjects and resistance to seroconversion indicate less effective clearance by innate and adaptive immune responses. SARS-CoV-2 strain, viral loads, and antibody status define subgroups for analysis of treatment efficacy.
Publisher: Massachusetts Medical Society
Date: 17-06-2021
Publisher: Springer Science and Business Media LLC
Date: 11-07-2023
Publisher: Springer Science and Business Media LLC
Date: 12-2015
DOI: 10.1186/S13054-015-1164-6
Abstract: Septic shock definitions are being revisited. We assess the feasibility , reliability , and validity characteristics of the current definitions and criteria of septic shock. Septic shock is conceptualised as cardiovascular dysfunction, tissue perfusion and cellular abnormalities caused by infection. Currently, for feasibility, septic shock is identified at the bedside by using either hypotension or a proxy for tissue perfusion/cellular abnormalities (e.g., hyperlactatemia). We propose that concurrent presence of cardiovascular dysfunction and perfusion/cellular abnormalities could improve validity of septic shock diagnosis, as we are more likely to identify a patient population with all elements of the illness concept. This epidemiological refinement should not affect clinical care and may aid study design to identify illness-specific biomarkers and interventions.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2012
Publisher: Massachusetts Medical Society
Date: 22-04-2021
Publisher: Cold Spring Harbor Laboratory
Date: 25-09-2020
DOI: 10.1101/2020.09.24.20200048
Abstract: The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs 1 and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases. 2 Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19. 3 GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org ) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing % of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study and results were confirmed in GWAS comparisons with two other population control groups: the 100,000 genomes project and Generation Scotland. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 × 10 −12 ), within the gene encoding dipeptidyl peptidase 9 ( DPP9 ), at chr12q24.13 (rs10735079, p =1.65 × 10 −8 ) in a gene cluster encoding antiviral restriction enzyme activators ( OAS1, OAS2, OAS3 ), and at chr21q22.1 (rs2236757, p = 4.99 × 10 −8 ) in the interferon receptor gene IFNAR2 . Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, p = 4.77 × 10 −30 ). We identify potential targets for repurposing of licensed medications. Using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2 , and high expression of TYK2 , to life-threatening disease. Transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.
Publisher: American Medical Association (AMA)
Date: 02-11-2021
Publisher: American Medical Association (AMA)
Date: 03-01-2023
Abstract: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm) futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Among 4869 randomized patients (mean age, 59.3 years 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR & .83) was high for therapeutic anticoagulation (99.9% HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2% HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6% HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9% HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8% HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2023
DOI: 10.1038/S41586-023-06034-3
Abstract: Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).
Publisher: American Thoracic Society
Date: 15-05-2023
Publisher: Cold Spring Harbor Laboratory
Date: 12-07-2022
DOI: 10.1101/2022.07.12.22277463
Abstract: Heterogeneity of sepsis limits discovery and targeting of treatments. Clustering approaches in critical illness have identified patient groups who may respond differently to therapies. These include in acute respiratory distress syndrome (ARDS) two inflammatory sub-phenotypes, using latent class analysis (LCA), and in sepsis two Sepsis Response Signatures (SRS), based on transcriptome profiling. It is unknown if inflammatory sub-phenotypes such as those identified in ARDS are present in sepsis and how sub-phenotypes defined with different techniques compare. To identify inflammatory sub-phenotypes in sepsis using LCA and assess if these show differential treatment responses. These sub-phenotypes were compared to hierarchical clusters based on inflammatory mediators and to SRS sub-phenotypes. LCA was applied to clinical and biomarker data from two septic shock randomized trials. VANISH compared norepinephrine to vasopressin and hydrocortisone to placebo and LeoPARDS compared levosimendan to placebo. Hierarchical cluster analysis (HCA) was applied to 65, 21 and 11 inflammatory mediators measured in patients from the GAinS (n=124), VANISH (n=155) and LeoPARDS (n=484) studies. LCA and HCA identified a sub-phenotype of patients with high cytokine levels and worse organ dysfunction and survival, with no interaction between LCA classes and trial treatment responses. Comparison of inflammatory and transcriptomic sub-phenotypes revealed some similarities but without sufficient overlap that they are interchangeable. A sub-phenotype with high levels of inflammation and increased disease severity is consistently identifiable in sepsis, with similarities to that described in ARDS. There was limited overlap with the transcriptomic sub-phenotypes.
Publisher: Springer Science and Business Media LLC
Date: 15-10-2021
DOI: 10.1038/S41564-021-00974-0
Abstract: COVID-19 vaccine design and vaccination rollout need to take into account a detailed understanding of antibody durability and cross-neutralizing potential against SARS-CoV-2 and emerging variants of concern (VOCs). Analyses of convalescent sera provide unique insights into antibody longevity and cross-neutralizing activity induced by variant spike proteins, which are putative vaccine candidates. Using sera from 38 in iduals infected in wave 1, we show that cross-neutralizing activity can be detected up to 305 days pos onset of symptoms, although sera were less potent against B.1.1.7 (Alpha) and B1.351 (Beta). Over time, despite a reduction in overall neutralization activity, differences in sera neutralization potency against SARS-CoV-2 and the Alpha and Beta variants decreased, which suggests that continued antibody maturation improves tolerance to spike mutations. We also compared the cross-neutralizing activity of wave 1 sera with sera from in iduals infected with the Alpha, the Beta or the B.1.617.2 (Delta) variants up to 79 days post onset of symptoms. While these sera neutralize the infecting VOC and parental virus to similar levels, cross-neutralization of different SARS-CoV-2 VOC lineages is reduced. These findings will inform the optimization of vaccines to protect against SARS-CoV-2 variants.
Publisher: Springer Science and Business Media LLC
Date: 10-04-2015
DOI: 10.1007/S00134-015-3725-1
Abstract: To describe the prevalence of, risk factors for, and prognostic importance of gastrointestinal (GI) bleeding and use of acid suppressants in acutely ill adult intensive care patients. We included adults without GI bleeding who were acutely admitted to the intensive care unit (ICU) during a 7-day period. The primary outcome was clinically important GI bleeding in ICU, and the analyses included estimations of baseline risk factors and potential associations with 90-day mortality. A total of 1,034 patients in 97 ICUs in 11 countries were included. Clinically important GI bleeding occurred in 2.6 % (95 % confidence interval 1.6-3.6 %) of patients. The following variables at ICU admission were independently associated with clinically important GI bleeding: three or more co-existing diseases (odds ratio 8.9, 2.7-28.8), co-existing liver disease (7.6, 3.3-17.6), use of renal replacement therapy (6.9, 2.7-17.5), co-existing coagulopathy (5.2, 2.3-11.8), acute coagulopathy (4.2, 1.7-10.2), use of acid suppressants (3.6, 1.3-10.2) and higher organ failure score (1.4, 1.2-1.5). In ICU, 73 % (71-76 %) of patients received acid suppressants most received proton pump inhibitors. In patients with clinically important GI bleeding, crude and adjusted odds for mortality were 3.7 (1.7-8.0) and 1.7 (0.7-4.3), respectively. In ICU patients clinically important GI bleeding is rare, and acid suppressants are frequently used. Co-existing diseases, liver failure, coagulopathy and organ failures are the main risk factors for GI bleeding. Clinically important GI bleeding was not associated with increased adjusted 90-day mortality, which largely can be explained by severity of comorbidity, other organ failures and age.
Publisher: Cold Spring Harbor Laboratory
Date: 09-06-2020
DOI: 10.1101/2020.06.08.20125112
Abstract: Person-to-person transmission of SARS-CoV-2 virus has triggered a global emergency because of its potential to cause life-threatening Covid-19 disease. By comparison to paucisymptomatic virus clearance by most in iduals, Covid-19 has been proposed to reflect insufficient and/or pathologically exaggerated immune responses. Here we identify a consensus peripheral blood immune signature across 63 hospital-treated Covid-19 patients who were otherwise highly heterogeneous. The core signature conspicuously blended adaptive B cell responses typical of virus infection or vaccination with discrete traits hitherto associated with sepsis, including monocyte and dendritic cell d ening, and hyperactivation and depletion of discrete T cell subsets. This blending of immuno-protective and immuno-pathogenic potentials was exemplified by near-universal CXCL10/IP10 upregulation, as occurred in SARS1 and MERS. Moreover, specific parameters including CXCL10/IP10 over-expression, T cell proliferation, and basophil and plasmacytoid dendritic cell depletion correlated, often prognostically, with Covid-19 progression, collectively composing a resource to inform SARS-CoV-2 pathobiology and risk-based patient stratification.
Publisher: Cold Spring Harbor Laboratory
Date: 05-03-2021
DOI: 10.1101/2021.02.24.21251989
Abstract: Treatment of COVID-19 patients with convalescent plasma containing neutralising antibody to SARS-CoV-2 is under investigation as a means of reducing viral loads, ameliorating disease outcomes, and reducing mortality. However, its efficacy might be reduced in those infected with the emerging B.1.1.7 SARS-CoV-2 variant. Here, we report the erse virological characteristics of UK patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomised controlled trial. SARS-CoV-2 viral RNA was detected and quantified by real-time PCR in nasopharyngeal swabs obtained from study subjects within 48 hours of admission to intensive care unit. Antibody status was determined by spike-protein ELISA. B.1.1.7 strain was differentiated from other SARS-CoV-2 strains by two novel typing methods detecting the B.1.1.7-associated D1118H mutation with allele-specific probes and by restriction site polymorphism (SfcI). Of 1260 subjects, 90% were PCR-positive with viral loads in nasopharyngeal swabs ranging from 72 international units [IUs]/ml to 1.7×10 11 IU/ml. Median viral loads were 45-fold higher in those who were seronegative for IgG antibodies (n=314 28%) compared to seropositives (n=804 72%), reflecting in part the latter group’s possible later disease stage on enrolment. Frequencies of B.1.1.7 infection increased from early November ( %) to December 2020 ( %). Anti-SARS-CoV-2 seronegative in iduals infected with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians of 1.2×10 6 and 3.4 ×10 4 IU/ml respectively p=2×10 −9 ). However, viral load distributions were elevated in both seropositive and seronegative subjects infected with B.1.1.7 (13.4×10 6 and 7.6×10 6 IU/ml p=0.18). High viral loads in seropositive B.1.1.7-infected subjects are consistent with increased replication capacity and/or less effective clearance by innate or adaptive immune response of B.1.1.7 strain than wild-type. As viral genotype was associated with erse virological and immunological phenotypes, metrics of viral load, antibody status and infecting strain should be used to define subgroups for analysis of treatment efficacy.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2022
DOI: 10.1007/S00134-022-06660-X
Abstract: The aim of this Intensive Care Medicine Rapid Practice Guideline (ICM‑RPG) was to formulate evidence‑based guidance for the use of dexmedetomidine for sedation in invasively mechanically ventilated adults in the intensive care unit (ICU). We adhered to the methodology for trustworthy clinical practice guidelines, including use of the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence, and the Evidence-to-Decision framework to generate recommendations. The guideline panel comprised 28 international panelists, including content experts, ICU clinicians, methodologists, and patient representatives. Through teleconferences and web‑based discussions, the panel provided input on the balance and magnitude of the desirable and undesirable effects, the certainty of evidence, patients' values and preferences, costs and resources, feasibility, acceptability, and research priorities. The ICM‑RPG panel issued one weak recommendation (suggestion) based on overall moderate certainty of evidence: "In invasively mechanically ventilated adult ICU patients, we suggest using dexmedetomidine over other sedative agents, if the desirable effects including a reduction in delirium are valued over the undesirable effects including an increase in hypotension and bradycardia". This ICM-RPG provides updated evidence-based guidance on the use of dexmedetomidine for sedation in mechanically ventilated adults, and outlines uncertainties and research priorities.
Publisher: American Medical Association (AMA)
Date: 10-08-2021
Publisher: Cold Spring Harbor Laboratory
Date: 02-11-2021
DOI: 10.1101/2021.11.01.21265384
Abstract: Tools to detect SARS-Coronavirus-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing s les with low viral loads or low RNA quality. An allele-specific probe polymerase chain reaction (ASP-PCR) targeting lineage-specific single nucleotide polymorphisms (SNPs) was developed and used to screen 1,082 s les from two clinical trials in the United Kingdom and Brazil. Probit regression models were developed to compare ASP-PCR performance against 1,771 NGS results for the same cohorts. In idual SNPs were shown to readily identify specific variants of concern. ASP-PCR was shown to discriminate SARS-CoV-2 lineages with a higher likelihood than NGS over a wide range of viral loads. Comparative advantage for ASP-PCR over NGS was most pronounced in s les with Ct values between 26-30 and in s les that showed evidence of degradation. Results for s les screened by ASP-PCR and NGS showed 99% concordant results. ASP-PCR is well-suited to augment but not replace NGS. The method can differentiate SARS-COV-2 lineages with high accuracy and would be best deployed to screen s les with lower viral loads or that may suffer from degradation. Future work should investigate further destabilization from primer:target base mismatch through altered oligonucleotide chemistry or chemical additives.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2021
End Date: 2025
Funder: NIHR Evaluation Trials and Studies Coordinating Centre
View Funded Activity