ORCID Profile
0000-0002-4853-9377
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: Cold Spring Harbor Laboratory
Date: 14-09-2021
DOI: 10.1101/2021.09.03.21262611
Abstract: The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole exome sequencing data of about 4,000 SARS-CoV-2-positive in iduals were used to define an interpretable machine learning model for predicting COVID-19 severity. Firstly, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthly, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.
Publisher: Cold Spring Harbor Laboratory
Date: 02-06-2020
DOI: 10.1101/2020.05.29.20115253
Abstract: There is a paucity of data that can be used to guide the management of critically ill patients with coronavirus disease 2019 (COVID-19). Global collaboration offers the best chance of obtaining these data, at scale and in time. In the absence of effective therapies, insights derived from real-time observational data will be a crucial means of improving outcomes. In response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a research and data-sharing collaborative has been assembled to harness the cumulative experience of intensive care units (ICUs) worldwide. The resulting observational study provides a platform to rapidly disseminate detailed data and insights. The COVID-19 Critical Care Consortium observational study is an international, multicenter, prospective, observational study of patients with confirmed or suspected SARSCoV-2 infection admitted to ICUs. This is an evolving, open-ended study that commenced on January 1 st , 2020 and currently includes more than 350 sites in over 48 countries. The study enrolls patients at the time of ICU admission and follows them to the time of death, hospital discharge, or 28 days post-ICU admission, whichever occurs last. All subjects, without age limit, requiring admission to an ICU for SARS-CoV-2 infection, confirmed by real-time polymerase chain reaction (PCR) and/or next-generation sequencing or with high clinical suspicion of the infection. Patients admitted to an ICU for any other reason are excluded. Key data, collected via an electronic case report form devised in collaboration with the ISARIC/SPRINT-SARI networks, include: patient demographic data and risk factors, clinical features, severity of illness and respiratory failure, need for non-invasive and/or mechanical ventilation and/or extracorporeal membrane COVID–19 CCC observational study protocol oxygenation (ECMO), and associated complications, as well as data on adjunctive therapies. Final outcomes of in-hospital death, discharge or continuing admissions at 28 days. This large-scale, observational study of COVID-19 in the critically ill will provide rapid international characterization. Open-ended accrual will increase the power to answer hypothesis-led questions over time. Several sub-studies have already been initiated, examining hemostasis, neurological, cardiac, and long-term outcomes.
Publisher: Elsevier BV
Date: 2019
Publisher: Frontiers Media SA
Date: 05-07-2022
Abstract: The discovery of biological subphenotypes in acute respiratory distress syndrome (ARDS) might offer a new approach to ARDS in general and possibly targeted treatment, but little is known about the underlying biology yet. To validate our recently described ovine ARDS phenotypes model, we compared a subset of messenger ribonucleic acid (mRNA) markers in leukocytes as reported before to display differential expression between human ARDS subphenotypes to the expression in lung tissue in our ovine ARDS phenotypes model (phenotype 1 (Ph1): hypoinflammatory phenotype 2 (Ph2): hyperinflammatory). We studied 23 anesthetized sheep on mechanical ventilation with observation times between 6 and 24 h. They were randomly allocated to the two phenotypes ( n = 14 to Ph1 and n = 9 to Ph2). At study end, lung tissue was harvested and preserved in RNAlater. After tissue homogenization in TRIzol, total RNA was extracted and custom capture and reporter probes designed by NanoString Technologies were used to measure the expression of 14 genes of interest and the 6 housekeeping genes on a nCounter SPRINT profiler. Among the 14 mRNA markers, in all animals over all time points, 13 markers showed the same trend in ovine Ph2/Ph1 as previously reported in the MARS cohort: matrix metalloproteinase 8, olfactomedin 4, resistin, G protein-coupled receptor 84, lipocalin 2, ankyrin repeat domain 22, CD177 molecule, and transcobalamin 1 expression was higher in Ph2 and membrane metalloendopeptidase, adhesion G protein-coupled receptor E3, transforming growth factor beta induced, histidine ammonia-lyase, and sulfatase 2 expression was higher in Ph1. These expression patterns could be found when different sources of mRNA – such as blood leukocytes and lung tissue – were compared. In human and ovine ARDS subgroups, similar activated pathways might be involved (e.g., oxidative phosphorylation, NF-κB pathway) that result in specific phenotypes.
Publisher: European Respiratory Society (ERS)
Date: 10-12-2021
DOI: 10.1183/23120541.00552-2021
Abstract: Due to the large number of patients with severe coronavirus disease 2019 (COVID-19), many were treated outside the traditional walls of the intensive care unit (ICU), and in many cases, by personnel who were not trained in critical care. The clinical characteristics and the relative impact of caring for severe COVID-19 patients outside the ICU is unknown. This was a multinational, multicentre, prospective cohort study embedded in the International Severe Acute Respiratory and Emerging Infection Consortium World Health Organization COVID-19 platform. Severe COVID-19 patients were identified as those admitted to an ICU and/or those treated with one of the following treatments: invasive or noninvasive mechanical ventilation, high-flow nasal cannula, inotropes or vasopressors. A logistic generalised additive model was used to compare clinical outcomes among patients admitted or not to the ICU. A total of 40 440 patients from 43 countries and six continents were included in this analysis. Severe COVID-19 patients were frequently male (62.9%), older adults (median (interquartile range (IQR), 67 (55–78) years), and with at least one comorbidity (63.2%). The overall median (IQR) length of hospital stay was 10 (5–19) days and was longer in patients admitted to an ICU than in those who were cared for outside the ICU (12 (6–23) days versus 8 (4–15) days, p .0001). The 28-day fatality ratio was lower in ICU-admitted patients (30.7% (5797 out of 18 831) versus 39.0% (7532 out of 19 295), p .0001). Patients admitted to an ICU had a significantly lower probability of death than those who were not (adjusted OR 0.70, 95% CI 0.65–0.75 p .0001). Patients with severe COVID-19 admitted to an ICU had significantly lower 28-day fatality ratio than those cared for outside an ICU.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2016
Publisher: Springer Science and Business Media LLC
Date: 27-04-2022
DOI: 10.1038/S41598-022-08032-3
Abstract: COVID-19 is clinically characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. However, it is the clinical associations of different patterns of symptoms which influence diagnostic and therapeutic decision-making. In this study, we applied clustering techniques to a large prospective cohort of hospitalised patients with COVID-19 to identify clinically meaningful sub-phenotypes. We obtained structured clinical data on 59,011 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 25,477 cases according to symptoms reported at recruitment. We validated our findings in a second group of 33,534 cases recruited to ISARIC-4C, and in 4,445 cases recruited to a separate study of community cases. Unsupervised clustering identified distinct sub-phenotypes. First, a core symptom set of fever, cough, and dyspnoea, which co-occurred with additional symptoms in three further patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were also identified, alongside a sub-phenotype of patients reporting few or no symptoms. Patients presenting with gastrointestinal symptoms were more commonly female, had a longer duration of symptoms before presentation, and had lower 30-day mortality. Patients presenting with confusion, with or without core symptoms, were older and had a higher unadjusted mortality. Symptom sub-phenotypes were highly consistent in replication analysis within the ISARIC-4C study. Similar patterns were externally verified in patients from a study of self-reported symptoms of mild disease. The large scale of the ISARIC-4C study enabled robust, granular discovery and replication. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four sub-phenotypes are usefully distinct from the core symptom group: gastro-intestinal disease, productive cough, confusion, and pauci-symptomatic presentations. Importantly, each is associated with an in-hospital mortality which differs from that of patients with core symptoms.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Cold Spring Harbor Laboratory
Date: 27-09-2022
DOI: 10.1101/2022.09.25.22280081
Abstract: Optimising statistical power in early-stage trials and observational studies accelerates discovery and improves the reliability of results. Ideally, intermediate outcomes should be continuously distributed and lie on the causal pathway between an intervention and a definitive outcome such as mortality. In order to optimise power for an intermediate outcome in the RECOVERY trial, we devised and evaluated a modification to a simple, pragmatic measure of oxygenation function - the S a O 2 / F I O 2 (S/F) ratio. We demonstrate that, because of the ceiling effect in oxyhaemoglobin saturation, S/F ceases to reflect pulmonary oxygenation function at high values of S a O 2 . Using synthetic and real data, we found that the correlation of S/F with a gold standard ( P a O 2 / F I O 2 , P/F ratio) improved substantially when measurements with S a O 2 ≥ 0.94 are excluded (Spearman r , synthetic data: S/F : 0.31 S/F 94 : 0.85). We refer to this measure as S/F 94 . In order to test the underlying assumptions and validity of S/F 94 as a predictor of a definitive outcome (mortality), we collected an observational dataset including over 39,000 hospitalised patients with COVID-19 in the ISARIC4C study. We first demonstrated that S/F 94 is predictive of mortality in COVID-19. We then compared the s le sizes required for trials using different outcome measures ( S/F 94 , the WHO ordinal scale, sustained improvement at day 28 and mortality at day 28) ensuring comparable effect sizes. The smallest s le size was needed when S/F 94 on day 5 was used as an outcome measure. To facilitate future study design, we provide an online user interface to quantify real-world power for a range of outcomes and inclusion criteria, using a synthetic dataset retaining the population-level clinical associations in real data accrued in ISARIC4C ndpoints . We demonstrated that S/F 94 is superior to S/F as a measure of pulmonary oxygenation function and is an effective intermediate outcome measure in COVID-19. It is a simple and non-invasive measurement, representative of disease severity and provides greater statistical power to detect treatment differences than other intermediate endpoints.
Publisher: Institute of Advanced Engineering and Science
Date: 05-2018
DOI: 10.11591/IJEECS.V10.I2.PP741-747
Abstract: span lang="EN-US" This article presents the investigation of specific absorption rate (SAR) of a rectangular-shaped planar inverted-F antenna (PIFA) at frequency of 2.6 GHz. Initially, the design antenna is presented with parametric study concerning the dimensions of antenna patch length, shorting plate, ground plane and substrate. The proposed PIFA antenna has -20.46 dB reflection coefficient and 2.383 dB gain. The PIFA’s SAR is correlated with the antenna gain and excitation power. The analysis shows that higher gain contributes to a lower SAR value. While, the higher excitation power causes a higher SAR value. All the design and analysis are performed using the CST Microwave Studio /span
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-06-2023
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: BMJ
Date: 12-2020
DOI: 10.1136/BMJOPEN-2020-041417
Abstract: There is a paucity of data that can be used to guide the management of critically ill patients with COVID-19. In response, a research and data-sharing collaborative—The COVID-19 Critical Care Consortium—has been assembled to harness the cumulative experience of intensive care units (ICUs) worldwide. The resulting observational study provides a platform to rapidly disseminate detailed data and insights crucial to improving outcomes. This is an international, multicentre, observational study of patients with confirmed or suspected SARS-CoV-2 infection admitted to ICUs. This is an evolving, open-ended study that commenced on 1 January 2020 and currently includes sites in over 48 countries. The study enrols patients at the time of ICU admission and follows them to the time of death, hospital discharge or 28 days post-ICU admission, whichever occurs last. Key data, collected via an electronic case report form devised in collaboration with the International Severe Acute Respiratory and Emerging Infection Consortium/Short Period Incidence Study of Severe Acute Respiratory Illness networks, include: patient demographic data and risk factors, clinical features, severity of illness and respiratory failure, need for non-invasive and/or mechanical ventilation and/or extracorporeal membrane oxygenation and associated complications, as well as data on adjunctive therapies. Local principal investigators will ensure that the study adheres to all relevant national regulations, and that the necessary approvals are in place before a site may contribute data. In jurisdictions where a waiver of consent is deemed insufficient, prospective, representative or retrospective consent will be obtained, as appropriate. A web-based dashboard has been developed to provide relevant data and descriptive statistics to international collaborators in real-time. It is anticipated that, following study completion, all de-identified data will be made open access. ACTRN12620000421932 ( anzctr.org.au/ACTRN12620000421932.aspx ).
Publisher: Oxford University Press (OUP)
Date: 28-12-2020
DOI: 10.1093/OFID/OFAA640
Abstract: Pulmonary microthrombosis and vasculitis occur in fatal coronavirus disease 2019. To determine whether these processes occur in other life-threatening respiratory virus infections, we identified autopsy studies of fatal influenza (n = 455 patients), severe acute respiratory syndrome ([SARS] n = 37), Middle East respiratory syndrome (n = 2), adenovirus (n = 34), and respiratory syncytial virus (n = 30). Histological evidence of thrombosis was frequently present in adults with fatal influenza and SARS, with vasculitis also reported.
Publisher: Cold Spring Harbor Laboratory
Date: 05-07-2021
DOI: 10.1101/2021.07.04.21259945
Abstract: Continuous positive airways pressure (CPAP) and high-flow nasal oxygen (HFNO) are considered ‘aerosol-generating procedures’ (AGPs) in the treatment of COVID-19. We aimed to measure air and surface environmental contamination of SARS-CoV-2 virus when CPAP and HFNO were used, compared with supplemental oxygen, to investigate the potential risks of viral transmission to healthcare workers and patients. 30 hospitalised patients with COVID-19 requiring supplemental oxygen, with a fraction of inspired oxygen ≥0.4 to maintain oxygen saturations ≥94%, were prospectively enrolled into an observational environmental s ling study. Participants received either supplemental oxygen, CPAP or HFNO (n=10 in each group). A nasopharyngeal swab, three air and three surface s les were collected from each participant and the clinical environment. RT qPCR analyses were performed for viral and human RNA, and positive/suspected-positive s les were cultured for the presence of biologically viable virus. Overall 21/30 (70%) of participants tested positive for SARS-CoV-2 RNA in the nasopharynx. In contrast, only 4/90 (4%) and 6/90 (7%) of all air and surface s les tested positive (positive for E and ORF1a) for viral RNA respectively, although there were an additional 10 suspected-positive s les in both air and surfaces s les (positive for E or ORF1a). CPAP/HFNO use or coughing was not associated with significantly more environmental contamination. Only one nasopharyngeal s le was culture positive. The use of CPAP and HFNO to treat moderate/severe COVID-19 was not associated with significantly higher levels of air or surface viral contamination in the immediate care environment.
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: Springer Science and Business Media LLC
Date: 20-08-2019
Publisher: SAGE Publications
Date: 04-2019
Abstract: There is a significant long-term burden on survivors after acute respiratory distress syndrome, even 5 years after discharge. This is not well investigated in patients treated with extracorporeal membrane oxygenation. The objective of this study was to describe very-long-term (⩾3 years) disability in lung function and morphology, quality of life, mood disorders, walking capacity, and return to work status in extracorporeal membrane oxygenation survivors. Single-center retrospective cohort study on long-term survivors treated with extracorporeal membrane oxygenation for respiratory failure between 1995 and 2010 at a tertiary referral center in Sweden. Eligible patients were approached, and those who consented were interviewed and investigated during a day at the hospital. A total of 38 patients were investigated with a median follow-up time of 9.0 years. Quality of life was reduced in several Short form 36 (SF-36) subscales and all domains of the St George’s Respiratory Questionnaire, similar to previous studies in conventionally managed acute respiratory distress syndrome survivors. A reduced diffusion capacity of carbon monoxide was seen in 47% of patients, and some degree of residual lung parenchymal pathology was seen in 82%. Parenchymal pathology correlated with reductions in quality of life and diffusion capacity. Symptoms of anxiety and depression were seen in 22% and 14%, respectively. A significant long-term burden remains even 3–17 years after extracorporeal membrane oxygenation treatment, similar to conventionally managed acute respiratory distress syndrome survivors. Future prospective studies are needed to elucidate risk factors for these sequelae.
Publisher: Springer Science and Business Media LLC
Date: 25-05-2020
DOI: 10.1186/S40635-020-00303-5
Abstract: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly being used to treat patients with refractory severe heart failure. Large animal models are developed to help understand physiology and build translational research projects. In order to better understand those experimental models, we conducted a systematic literature review of animal models combining heart failure and VA-ECMO. A systematic review was performed using Medline via PubMed, EMBASE, and Web of Science, from January 1996 to January 2019. Animal models combining experimental acute heart failure and ECMO were included. Clinical studies, abstracts, and studies not employing VA-ECMO were excluded. Following variables were extracted, relating to four key features: (1) study design, (2) animals and their peri-experimental care, (3) heart failure models and characteristics, and (4) ECMO characteristics and management. Nineteen models of heart failure and VA-ECMO were included in this review. All were performed in large animals, the majority ( n = 13) in pigs. Acute myocardial infarction ( n = 11) with left anterior descending coronary ligation ( n = 9) was the commonest mean of inducing heart failure. Most models employed peripheral VA-ECMO ( n = 14) with limited reporting. Among models that combined severe heart failure and VA-ECMO, there is a large heterogeneity in both design and reporting, as well as methods employed for heart failure. There is a need for standardization of reporting and minimum dataset to ensure translational research achieve high-quality standards.
Publisher: BMJ
Date: 19-05-2015
Publisher: BMJ
Date: 04-11-2021
DOI: 10.1136/THORAXJNL-2021-218035
Abstract: Continuous positive airways pressure (CPAP) and high-flow nasal oxygen (HFNO) are considered ‘aerosol-generating procedures’ in the treatment of COVID-19. To measure air and surface environmental contamination with SARS-CoV-2 virus when CPAP and HFNO are used, compared with supplemental oxygen, to investigate the potential risks of viral transmission to healthcare workers and patients. 30 hospitalised patients with COVID-19 requiring supplemental oxygen, with a fraction of inspired oxygen ≥0.4 to maintain oxygen saturation ≥94%, were prospectively enrolled into an observational environmental s ling study. Participants received either supplemental oxygen, CPAP or HFNO (n=10 in each group). A nasopharyngeal swab, three air and three surface s les were collected from each participant and the clinical environment. Real-time quantitative polymerase chain reaction analyses were performed for viral and human RNA, and positive/suspected-positive s les were cultured for the presence of biologically viable virus. Overall 21/30 (70%) participants tested positive for SARS-CoV-2 RNA in the nasopharynx. In contrast, only 4/90 (4%) and 6/90 (7%) of all air and surface s les tested positive (positive for E and ORF1a) for viral RNA respectively, although there were an additional 10 suspected-positive s les in both air and surfaces s les (positive for E or ORF1a). CPAP/HFNO use or coughing was not associated with significantly more environmental contamination than supplemental oxygen use. Only one nasopharyngeal s le was culture positive. The use of CPAP and HFNO to treat moderate/severe COVID-19 did not appear to be associated with substantially higher levels of air or surface viral contamination in the immediate care environment, compared with the use of supplemental oxygen.
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: Wiley
Date: 05-07-2016
Publisher: Wiley
Date: 19-07-2023
DOI: 10.1111/AOR.14608
Abstract: Extracorporeal life support (ECLS) has extensive applications in managing patients with acute cardiac and pulmonary failure. Two primary modalities of ECLS, cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO), include several similarities in their composition, complications, and patient outcomes. Both CPB and ECMO pose a high risk of thrombus formation and platelet activation due to the large surface area of the devices and bleeding due to system anticoagulation. Therefore, novel methods of anticoagulation are needed to reduce the morbidity and mortality associated with extracorporeal support. Nitric oxide (NO) has potent antiplatelet properties and presents a promising alternative or addition to anticoagulation with heparin during extracorporeal support. We developed two ex vivo models of CPB and ECMO to investigate NO effects on anticoagulation and inflammation in these systems. Sole addition of NO as an anticoagulant was not successful in preventing thrombus formation in the ex vivo setups, therefore a combination of low‐level heparin with NO was used. Antiplatelet effects were observed in the ex vivo ECMO model when NO was delivered at 80 ppm. Platelet count was preserved after 480 min when NO was delivered at 30 ppm. Combined delivery of NO and heparin did not improve haemocompatibility in either ex vivo model of CPB and ECMO. Anti‐inflammatory effects of NO in ECMO systems have to be evaluated further.
Publisher: Elsevier BV
Date: 02-2022
Publisher: American Thoracic Society
Date: 12-2020
Publisher: SAGE Publications
Date: 2018
Publisher: Elsevier BV
Date: 02-2021
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: Elsevier
Date: 2018
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: Ovid Technologies (Wolters Kluwer Health)
Date: 03-05-2020
Publisher: Wiley
Date: 10-2021
DOI: 10.14814/PHY2.15048
Abstract: The acute respiratory distress syndrome (ARDS) describes a heterogenous population of patients with acute severe respiratory failure. However, contemporary advances have begun to identify distinct sub‐phenotypes that exist within its broader envelope. These sub‐phenotypes have varied outcomes and respond differently to several previously studied interventions. A more precise understanding of their pathobiology and an ability to prospectively identify them, may allow for the development of precision therapies in ARDS. Historically, animal models have played a key role in translational research, although few studies have so far assessed either the ability of animal models to replicate these sub‐phenotypes or investigated the presence of sub‐phenotypes within animal models. Here, in three ovine models of ARDS, using combinations of oleic acid and intravenous, or intratracheal lipopolysaccharide, we investigated the presence of sub‐phenotypes which qualitatively resemble those found in clinical cohorts. Principal Component Analysis and partitional clustering identified two clusters, differentiated by markers of shock, inflammation, and lung injury. This study provides a first exploration of ARDS phenotypes in preclinical models and suggests a methodology for investigating this phenomenon in future studies.
Publisher: SAGE Publications
Date: 26-03-2014
Abstract: Hypercarbic respiratory failure, occurring secondary to chronic lung disease, is a frequently encountered problem. These patients present a significant challenge to respiratory and critical care services, as many are unsuitable for mechanical ventilation and most have multiple comorbidities. Recently, noninvasive ventilation (NIV) has become established as the primary modality for respiratory support in this group of patients. Several factors limit patient compliance with NIV, not least comfort and tolerability. A recent innovation in adult critical care is the use of high-flow nasal oxygen (HFNO) devices. These systems are capable of delivering high gas flows via nasal cannulae, with the ability to blend air and oxygen to give a controlled FiO 2 . Few clinical studies have been conducted in adults, although several are planned. To date the majority of available evidence addresses the use of HFNO in hypoxemic respiratory failure. Here we present a case in which a HFNO system was used to successfully manage hypercarbic respiratory failure in a patient unable to tolerate conventional NIV.
Publisher: Elsevier BV
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 13-08-2021
Publisher: University of Queensland Library
Date: 2021
DOI: 10.14264/EC27A42
Publisher: European Respiratory Society (ERS)
Date: 15-11-2022
DOI: 10.1183/16000617.0030-2022
Abstract: To assess the safety and efficacy of extracorporeal carbon dioxide removal (ECCO 2 R) versus standard care in patients with acute hypoxaemic respiratory failure (AHRF). MEDLINE, Embase and clinical trial registries were searched from 1994 to 31 December 2021. We included randomised controlled trials (RCTs) and observational studies. Pairs of reviewers independently extracted data and assessed the risk of bias. The primary outcome was mortality. Secondary outcomes included ventilator-free days, length of stay, safety and adverse events and physiological changes. As a primary analysis, we performed a meta-analysis of mortality until day 30 using a Bayesian random effects model. We then performed a trial sequential analysis of RCTs. 21 studies met inclusion criteria: three RCTs, enrolling 531 patients, and 18 observational studies. In a pooled analysis of RCTs, the posterior probability of increased mortality with the use of ECCO 2 R was 73% (relative risk 1.19, 95% credible interval 0.70–2.29). There was substantial heterogeneity in the reporting of safety and adverse events. However, the incidence of extra and intracranial haemorrhage was higher (relative risk 3.00, 95% credible interval 0.41–20.51) among those randomised to ECCO 2 R. Current trials have accumulated 80.8% of the ersity-adjusted required information size and the lack of effect reaches futility for a 10% absolute risk reduction in mortality. The use of ECCO 2 R in patients with AHRF is not associated with improvements in clinical outcomes. Furthermore, it is likely that further trials of ECCO 2 R aiming to achieve an absolute risk reduction in mortality of ≥10% are futile.
Publisher: SAGE Publications
Date: 05-2020
Abstract: Cerebral complications in veno-arterial extracorporeal membrane oxygenation are known to have a strong impact on mortality and morbidity. Aim of this study is to investigate the early incidence, risk factors and in-hospital mortality of intra-cranial ischaemia and haemorrhage in adults undergoing veno-arterial extracorporeal membrane oxygenation treatment. This study is a single-centre retrospective analysis on adult patients undergoing veno-arterial extracorporeal membrane oxygenation for different indications. The inclusion criterion included patients with early routine cerebral computed tomography imaging during extracorporeal membrane oxygenation, with no clinical evidence of cerebral pathology prior to cannulation. Cerebral complications were grouped by aetiology and the territories of the brain’s supplying arteries. One hundred eighty-seven adult patients with a total of 190 veno-arterial extracorporeal membrane oxygenation treatments were included. A total of 16.3% (n = 31) had evidence of either cerebral ischaemia (11.1%) or haemorrhage (5.8%) one patient suffered from both. Cerebral computed tomography scans were performed early in median on the first day after extracorporeal membrane oxygenation cannulation in-hospital mortality of intra-cranial ischaemia and haemorrhage was 71.4% and 45.5%, respectively. Associated with an increased risk for ischaemic lesions were cannulation of the ascending aorta, higher age, presence of an autoimmune disease and cardiac surgery prior to veno-arterial extracorporeal membrane oxygenation. An association with haemorrhagic lesions was found for a lower blood PaCO 2 at 2 hours, lower blood flow through the extracorporeal membrane oxygenation device at 2 hours, higher international normalized ratio and constantly higher activated partial thromboplastin time values as well as higher mean arterial pressures until haemorrhagic lesions were evident. Cerebral complications are frequent in patients on veno-arterial extracorporeal membrane oxygenation and may be clinically silent events. Careful monitoring with routine neuroimaging seems to be the most appropriate diagnostic approach at present. Intra-cranial ischaemia occurs more frequent than haemorrhage and is associated with cannulation of the aorta ascendens.
Publisher: SAGE Publications
Date: 05-2020
Abstract: With ongoing progress of components of extracorporeal membrane oxygenation including improvements of oxygenators, pumps, and coating materials, extracorporeal membrane oxygenation became increasingly accepted in the clinical practice. A suitable testing in an adequate setup is essential for the development of new technical aspects. Relevant tests can be conducted in ex vivo models specifically designed to test certain aspects. Different setups have been used in the past for specific research questions. We conducted a systematic literature review of ex vivo models of extracorporeal membrane oxygenation components. MEDLINE and Embase were searched between January 1996 and October 2017. The inclusion criteria were ex vivo models including features of extracorporeal membrane oxygenation technology. The exclusion criteria were clinical studies, abstracts, studies in which the model of extracorporeal membrane oxygenation has been reported previously, and studies not reporting on extracorporeal membrane oxygenation components. A total of 50 studies reporting on different ex vivo extracorporeal membrane oxygenation models have been identified from the literature search. Models have been grouped according to the specific research question they were designed to test for. The groups are focused on oxygenator performance, pump performance, hemostasis, and pharmacokinetics. Pre-clinical testing including use of ex vivo models is an important step in the development and improvement of extracorporeal membrane oxygenation components and materials. Furthermore, ex vivo models offer valuable insights for clinicians to better understand the consequences of choice of components, setup, and management of an extracorporeal membrane oxygenation circuit in any given condition. There is a need to standardize the reporting of pre-clinical studies in this area and to develop best practice in their design.
Publisher: Springer Science and Business Media LLC
Date: 18-02-2019
Publisher: Research Square Platform LLC
Date: 14-12-2020
DOI: 10.21203/RS.3.RS-125428/V1
Abstract: Background Heterogeneous respiratory system static compliance (C RS ) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level. Methods We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe the impact of C RS on the ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide. Results We enrolled 318 COVID-19 patients enrolled into the study from January 14th through September 31th, 2020 in 19 countries and stratified into two C RS groups. C RS was calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)] and available within 48 h from commencement of MV in 318 patients. Patients were mean ± SD of 58.0 ± 12.2, predominantly from Europe (54%) and males (68%). Median C RS (IQR) was 34.1 mL/cmH 2 O (26.5–45.5) and PaO 2 /FiO 2 was 119 mmHg (87.1–164) and was not correlated with C RS . Female sex presented lower C RS than in males (95% CI: -13.8 to -8.5 P 0.001) and higher body mass index (34.7 ± 10.9 vs 29.1 ± 6.0, p 0.001). Median (IQR) PEEP was 12 cmH 2 O (10–15), throughout the range of C RS , while median (IQR) driving pressure was 12.3 (10–15) cmH 2 O and significantly decreased as C RS improved (p 0.001). No differences were found in comorbidities and clinical management between C RS strata. In addition, 28-day ICU mortality and hospital mortality did not differ between C RS groups. Conclusions This multicentre report provides a comprehensive account of C RS in COVID-19 patients on MV – predominantly males or overweight females, in their late 50 s – admitted to ICU during the first international outbreaks. Phenotypes associated with different C RS upon commencement of MV could not be identified. Trial documentation: Available at tudy. Trial registration ACTRN12620000421932.
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: Elsevier BV
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 17-05-2022
DOI: 10.1186/S13054-022-03983-5
Abstract: The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis. We analyzed a convenience s le of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2 days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48 h from commencement of IMV were compared with subjects who did not receive NMBAs or only upon commencement of IMV (control). The primary objective in the PS-matched cohort was comparison between groups in 90-day in-hospital mortality, assessed through Cox proportional hazard modeling. Secondary objectives were comparisons in the numbers of ventilator-free days (VFD) between day 1 and day 28 and between day 1 and 90 through competing risk regression. Data from 1953 patients were included. After propensity score matching, 210 cases from each group were well matched. In the PS-matched cohort, mean (± SD) age was 60.3 ± 13.2 years and 296 (70.5%) were male and the most common comorbidities were hypertension (56.9%), obesity (41.1%), and diabetes (30.0%). The unadjusted hazard ratio (HR) for death at 90 days in the NMBA treatment vs control group was 1.12 (95% CI 0.79, 1.59, p = 0.534). After adjustment for smoking habit and critical therapeutic covariates, the HR was 1.07 (95% CI 0.72, 1.61, p = 0.729). At 28 days, VFD were 16 (IQR 0–25) and 25 (IQR 7–26) in the NMBA treatment and control groups, respectively (sub-hazard ratio 0.82, 95% CI 0.67, 1.00, p = 0.055). At 90 days, VFD were 77 (IQR 0–87) and 87 (IQR 0–88) (sub-hazard ratio 0.86 (95% CI 0.69, 1.07 p = 0.177). In patients with COVID-19 and moderate-to-severe ARDS, short course of NMBA treatment, applied early, did not significantly improve 90-day mortality and VFD. In the absence of definitive data from clinical trials, NMBAs should be indicated cautiously in this setting.
Publisher: Cold Spring Harbor Laboratory
Date: 05-02-2021
DOI: 10.1101/2021.02.03.21251097
Abstract: Obesity has become a global pandemic, as a result surgical intervention for weight loss has increased in popularity. Obese patients undergoing operative intervention pose several challenges in respect of their peri-operative care. A prominent feature is the alteration in respiratory mechanics and physiology evident in the obese. These combine to predispose in iduals to a reduction in end expiratory lung volume (EELV) and atelectasis after anaesthesia. Consequently, the incidence of post-operative pulmonary complications (PPC) in this cohort has been reported to be in excess of 35%. High flow nasal oxygen (HFNO) has been suggested as a means of increasing EELV in post-operative patients, reducing the likelihood of PPC. We conducted a single centre, pilot, randomised controlled trial (RCT) of conventional oxygen therapy versus HFNO in patients after bariatric surgery. The aim of the study was to investigate the feasibility of using Electrical Impedance Tomography (EIT) as a means of assessing respiratory mechanics and to inform the design of larger, definitive RCT. Fifty patients were randomised during a 10-month period (conventional O 2 n=25 vs. HFNO n = 25). One patient crossed over from conventional O 2 to HFNO. There was no loss to follow-up. and analyses were performed on an intention-to-treat basis. Delta EELI was higher at 1 hour in patients receiving HFNO (mean difference = 831 Au (95% CI -1636 – 3298), p = 0.5). Continuous EIT beyond 1 hour was poorly tolerated. At 6 hours, there were no differences in PaO 2 /FiO 2 ratio or PaCO 2 . ICU and hospital LOS were comparable. Only one patient developed a PPC (in the HFNO group). In a secondary analysis, delta EELI was positively correlated with increasing BMI. These data suggest that a large-scale randomised controlled trial of HFNO after bariatric surgery in an ‘all-comers’ population is likely infeasible. Furthermore, while EIT is a useful tool for assessing respiratory mechanics in this group it could not be considered a patient-centred outcome in a larger study. Similarly, the infrequency of PPC precludes its use as a primary outcome in a definitive trial. Future studies should focus on identifying patients most at risk for post-operative pulmonary complications and those in whom HFNO is likely to confer greatest benefit.
Publisher: Springer Science and Business Media LLC
Date: 2014
DOI: 10.1186/CC13875
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-12-2019
Publisher: SAGE Publications
Date: 14-12-2020
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 27-07-2018
Publisher: Springer Science and Business Media LLC
Date: 26-05-2023
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1186/S40635-021-00425-4
Abstract: Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for severe/end-stage cardiac disease, but is limited by a global donor heart shortage. Consequently, innovative solutions to increase donor heart availability and utilisation are rapidly expanding. Clinically relevant preclinical models are essential for evaluating interventions for human translation, yet few exist that accurately mimic all key HTx components, incorporating injuries beginning in the donor, through to the recipient. To enable future assessment of novel perfusion technologies in our research program, we thus aimed to develop a clinically relevant sheep model of HTx following 24 h of donor BSD. BSD donors (vs. sham neurological injury, 4/group) were hemodynamically supported and monitored for 24 h, followed by heart preservation with cold static storage. Bicaval orthotopic HTx was performed in matched recipients, who were weaned from cardiopulmonary bypass (CPB), and monitored for 6 h. Donor and recipient blood were assayed for inflammatory and cardiac injury markers, and cardiac function was assessed using echocardiography. Repeated measurements between the two different groups during the study observation period were assessed by mixed ANOVA for repeated measures. Brainstem death caused an immediate catecholaminergic hemodynamic response (mean arterial pressure, p = 0.09), systemic inflammation (IL-6 - p = 0.025, IL-8 - p = 0.002) and cardiac injury (cardiac troponin I, p = 0.048), requiring vasopressor support (vasopressor dependency index, VDI, p = 0.023), with normalisation of biomarkers and physiology over 24 h. All hearts were weaned from CPB and monitored for 6 h post-HTx, except one (sham) recipient that died 2 h post-HTx. Hemodynamic (VDI - p = 0.592, heart rate - p = 0.747) and metabolic (blood lactate, p = 0.546) parameters post-HTx were comparable between groups, despite the observed physiological perturbations that occurred during donor BSD. All p values denote interaction among groups and time in the ANOVA for repeated measures. We have successfully developed an ovine HTx model following 24 h of donor BSD. After 6 h of critical care management post-HTx, there were no differences between groups, despite evident hemodynamic perturbations, systemic inflammation, and cardiac injury observed during donor BSD. This preclinical model provides a platform for critical assessment of injury development pre- and post-HTx, and novel therapeutic evaluation.
Publisher: Springer Science and Business Media LLC
Date: 11-07-2023
Publisher: Elsevier BV
Date: 05-2021
Publisher: Cold Spring Harbor Laboratory
Date: 09-2020
DOI: 10.1101/2020.08.27.20182238
Abstract: The increasing body of literature describing the role of host factors in COVID-19 pathogenesis demonstrates the need to combine erse, multi-omic data to evaluate and substantiate the most robust evidence and inform development of therapies. Here we present a dynamic ranking of host genes implicated in human betacoronavirus infection (SARS-CoV-2, SARS-CoV, MERS-CoV, seasonal coronaviruses). Researchers can search and review the ranked genes and the contribution of different experimental methods to gene rank at aic/covid19 . We conducted an extensive systematic review of experiments identifying potential host factors. Gene lists from erse sources were integrated using Meta-Analysis by Information Content (MAIC). This previously described algorithm uses data-driven gene list weightings to produce a comprehensive ranked list of implicated host genes. From 32 datasets, the top ranked gene was PPIA, encoding cyclophilin A, a drug-gable target using cyclosporine.Other highly-ranked genes included proposed prognostic factors ( CXCL10, CD4, CD3E ) and investigational therapeutic targets ( IL1A ) for COVID-19. Gene rankings also inform the interpretation of COVID-19 GWAS results, implicating FYCO1 over other nearby genes in a disease-associated locus on chromosome 3. As new data are published we will regularly update list of genes as a resource to inform and prioritise future studies.
Publisher: BMJ
Date: 14-03-2016
Publisher: American Thoracic Society
Date: 08-2020
Publisher: BMJ
Date: 09-12-2020
DOI: 10.1136/EMERMED-2020-209686
Abstract: Procedural sedation is a core skill of the emergency physician. Bolus administration of propofol is widely used in UK EDs. Titrated to an end point of sedation, it has a rapid effect but has been associated with adverse incidents. The use of a target-controlled infusion (TCI) of propofol is not routine but may reduce the incidence of adverse incidents. The primary aims of this single-arm feasibility study were patient satisfaction and to establish recruitment rates for a randomised controlled trial comparing propofol TCI to bolus administration. Four EDs in Scotland, UK, participated. Patients aged 18-65 years, with anterior shoulder dislocation, weight ≥ 50kg, fasted ≥ 90 min were screened. Patients underwent reduction of their dislocated shoulder using TCI propofol. The primary end point was patient satisfaction recorded on a Visual Analogue Scale. Between 3 April 2017 and 31 December 2018, 25 patients were recruited with a recruitment rate of 20% for the 16-month recruitment window, with a temporary pause to allow amendment of drug dosage. Two patients were excluded. Twenty achieved adequate sedation, defined as a Modified Observer’s Assessment of Alertness/Sedation Scale (OAA/S) 3. Successful reduction was achieved in all adequately sedated. Patient satisfaction was documented in 14 patients, mean±SD of 97±9 and time to sedation was 25±8 min. No adverse events were recorded using the Society of Intravenous Anaesthesia adverse event reporting tool. Propofol TCI was acceptable as a method of procedural sedation for patients. The lower than expected recruitment rates highlight the need for dedicated research support. NCT03442803 .
Publisher: Cold Spring Harbor Laboratory
Date: 03-12-2020
DOI: 10.1101/2020.12.02.408682
Abstract: The Acute Respiratory Distress Syndrome (ARDS) describes a heterogenous population of patients with acute severe respiratory failure. However, contemporary advances have begun to identify distinct sub-phenotypes that exist within its broader envelope. These sub-phenotypes have varied outcomes and respond differently to several previously studied interventions. A more precise understanding of their pathobiology and an ability to prospectively identify them, may allow for the development of precision therapies in ARDS. Historically, animal models have played a key role in translational research, although few studies have so far assessed either the ability of animal models to replicate these sub-phenotypes or investigated the presence of sub-phenotypes within animal models. Here, in three ovine models of ARDS, using combinations of oleic acid and intravenous, or intratracheal lipopolysaccharide, we demonstrate the presence of sub-phenotypes which qualitatively resemble those found in clinical cohorts. Principal Components Analysis and partitional clustering reveal two clusters, differentiated by markers of shock, inflammation, and lung injury. This study provides the first preliminary evidence of ARDS phenotypes in pre-clinical models and develops a methodology for investigating this phenomenon in future studies.
Publisher: Springer Science and Business Media LLC
Date: 25-03-2019
Publisher: Elsevier BV
Date: 07-2022
Publisher: Springer Science and Business Media LLC
Date: 18-12-2020
DOI: 10.1038/S41598-020-79033-3
Abstract: The increasing body of literature describing the role of host factors in COVID-19 pathogenesis demonstrates the need to combine erse, multi-omic data to evaluate and substantiate the most robust evidence and inform development of therapies. Here we present a dynamic ranking of host genes implicated in human betacoronavirus infection (SARS-CoV-2, SARS-CoV, MERS-CoV, seasonal coronaviruses). We conducted an extensive systematic review of experiments identifying potential host factors. Gene lists from erse sources were integrated using Meta-Analysis by Information Content (MAIC). This previously described algorithm uses data-driven gene list weightings to produce a comprehensive ranked list of implicated host genes. From 32 datasets, the top ranked gene was PPIA, encoding cyclophilin A, a druggable target using cyclosporine. Other highly-ranked genes included proposed prognostic factors ( CXCL10 , CD4 , CD3E ) and investigational therapeutic targets ( IL1A ) for COVID-19. Gene rankings also inform the interpretation of COVID-19 GWAS results, implicating FYCO1 over other nearby genes in a disease-associated locus on chromosome 3. Researchers can search and review the gene rankings and the contribution of different experimental methods to gene rank at aic/covid19 . As new data are published we will regularly update the list of genes as a resource to inform and prioritise future studies.
Publisher: BMJ
Date: 07-09-2013
Publisher: BMJ
Date: 12-04-2016
DOI: 10.1136/BMJ.I2025
Publisher: Informa UK Limited
Date: 26-11-2020
Publisher: Massachusetts Medical Society
Date: 19-07-2100
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: Elsevier BV
Date: 08-2023
Publisher: Cold Spring Harbor Laboratory
Date: 16-08-2020
DOI: 10.1101/2020.08.14.20168088
Abstract: Severe COVID-19 is characterised by fever, cough, and dyspnoea. Symptoms affecting other organ systems have been reported. However, it is the clinical associations of different patterns of symptoms which influence diagnostic and therapeutic decision-making. In this study, we applied simple machine learning techniques to a large prospective cohort of hospitalised patients with COVID-19 identify clinically meaningful sub-groups. We obtained structured clinical data on 59 011 patients in the UK (the ISARIC Coronavirus Clinical Characterisation Consortium, 4C) and used a principled, unsupervised clustering approach to partition the first 25 477 cases according to symptoms reported at recruitment. We validated our findings in a second group of 33 534 cases recruited to ISARIC-4C, and in 4 445 cases recruited to a separate study of community cases. Unsupervised clustering identified distinct sub-groups. First, a core symptom set of fever, cough, and dyspnoea, which co-occurred with additional symptoms in three further patterns: fatigue and confusion, diarrhoea and vomiting, or productive cough. Presentations with a single reported symptom of dyspnoea or confusion were common, and a subgroup of patients reported few or no symptoms. Patients presenting with gastrointestinal symptoms were more commonly female, had a longer duration of symptoms before presentation, and had lower 30-day mortality. Patients presenting with confusion, with or without core symptoms, were older and had a higher unadjusted mortality. Symptom clusters were highly consistent in replication analysis using a further 35446 in iduals subsequently recruited to ISARIC-4C. Similar patterns were externally verified in 4445 patients from a study of self-reported symptoms of mild disease. The large scale of the ISARIC-4C study enabled robust, granular discovery and replication of patient clusters. Clinical interpretation is necessary to determine which of these observations have practical utility. We propose that four patterns are usefully distinct from the core symptom groups: gastro-intestinal disease, productive cough, confusion, and pauci-symptomatic presentations. Importantly, each is associated with an in-hospital mortality which differs from that of patients with core symptoms. These observations deepen our understanding of COVID-19 and will influence clinical diagnosis, risk prediction, and future mechanistic and clinical studies. Medical Research Council National Institute Health Research Well-come Trust Department for International Development Bill and Melinda Gates Foundation Liverpool Experimental Cancer Medicine Centre.
Publisher: Springer Science and Business Media LLC
Date: 09-06-2021
DOI: 10.1186/S13054-021-03518-4
Abstract: Heterogeneous respiratory system static compliance ( C RS ) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level. We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe C RS —calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)]—and its association with ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide. We studied 745 patients from 22 countries, who required admission to the ICU and MV from January 14 to December 31, 2020, and presented at least one value of C RS within the first seven days of MV. Median (IQR) age was 62 (52–71), patients were predominantly males (68%) and from Europe/North and South America (88%). C RS , within 48 h from endotracheal intubation, was available in 649 patients and was neither associated with the duration from onset of symptoms to commencement of MV ( p = 0.417) nor with PaO 2 /FiO 2 ( p = 0.100). Females presented lower C RS than males (95% CI of C RS difference between females-males: − 11.8 to − 7.4 mL/cmH 2 O p 0.001), and although females presented higher body mass index (BMI), association of BMI with C RS was marginal ( p = 0.139). Ventilatory management varied across C RS range, resulting in a significant association between C RS and driving pressure (estimated decrease − 0.31 cmH 2 O/L per mL/cmH 2 0 of C RS , 95% CI − 0.48 to − 0.14, p 0.001). Overall, 28-day ICU mortality, accounting for the competing risk of being discharged within the period, was 35.6% (SE 1.7). Cox proportional hazard analysis demonstrated that C RS (+ 10 mL/cm H 2 O) was only associated with being discharge from the ICU within 28 days (HR 1.14, 95% CI 1.02–1.28, p = 0.018). This multicentre report provides a comprehensive account of C RS in COVID-19 patients on MV. C RS measured within 48 h from commencement of MV has marginal predictive value for 28-day mortality, but was associated with being discharged from ICU within the same period. Trial documentation: Available at tudy . Trial registration : ACTRN12620000421932.
Publisher: Massachusetts Medical Society
Date: 25-02-2021
Publisher: Elsevier BV
Date: 02-2020
Publisher: SAGE Publications
Date: 04-2019
Abstract: Mesenchymal stem cells exhibit immunomodulatory properties which are currently being investigated as a novel treatment option for Acute Respiratory Distress Syndrome. However, the feasibility and efficacy of mesenchymal stem cell therapy in the setting of extracorporeal membrane oxygenation is poorly understood. This study aimed to characterise markers of innate immune activation in response to mesenchymal stem cells during an ex vivo simulation of extracorporeal membrane oxygenation. Ex vivo extracorporeal membrane oxygenation simulations (n = 10) were conducted using a commercial extracorporeal circuit with a CO 2 -enhanced fresh gas supply and donor human whole blood. Heparinised circuits (n = 4) were injected with 40 × 10 6 -induced pluripotent stem cell–derived human mesenchymal stem cells, while the remainder (n = 6) acted as controls. Simulations were maintained, under physiological conditions, for 240 minutes. Circuits were s led at 15, 30, 60, 120 and 240 minutes and assessed for levels of interleukin-1β, interleukin-6, interleukin-8, interleukin-10, tumour necrosis factor-α, transforming growth factor-β1, myeloperoxidase and α-Defensin-1. In addition, haemoglobin, platelet and leukocyte counts were performed. There was a trend towards reduced levels of pro-inflammatory cytokines in mesenchymal stem cell–treated circuits and a significant increase in transforming growth factor-β1. Blood cells and markers of neutrophil activation were reduced in mesenchymal stem cell circuits during the length of the simulation. As previously reported, the addition of mesenchymal stem cells resulted in a reduction of flow and increased trans-oxygenator pressures in comparison to controls. The addition of mesenchymal stem cells during extracorporeal membrane oxygenation may cause an increase in transforming growth factor-β1. This is despite their ability to adhere to the membrane oxygenator. Further studies are required to confirm these findings.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.AMJCARD.2018.10.022
Abstract: Magnetic resonance imaging (MRI) studies have consistently identified a high incidence of silent brain infarction (SBI) after cardiac intervention. The frequent occurrence, objective measurement and clinical sequelae of SBI have seen interest in their detection for both research and clinical purposes. However, MRI is expensive, time-consuming, unsafe in acutely-ill patients, and not always available, limiting its use as a routine screening tool. For this purpose, a blood biomarker of SBI would be the "Holy Grail." By performing targeted profiling of serologic biomarkers this study aimed to assess their potential as screening tools for perioperative SBI. This is a nested case-control study of 20 prospectively recruited patients undergoing transcatheter aortic valve implantation under general anesthesia. Clinical and diffusion-weighted MRI assessments were performed at baseline and on day 3 postprocedure to identify the presence (cases) or absence (controls) of new SBI. Blood was collected at baseline and 24, 48, and 72 hours postprocedure and analyzed for S100 calcium-binding protein B, neuron specific enolase (NSE), matrix metalloproteinase 9 (MMP 9), and glial fibrillary acidic protein. Best-fit polynomial curves using a smoothing model were generated for each biomarker and inferential testing at a predefined 24-hour postprocedure timepoint detected a significant difference for MMP 9 (72,435 SEM: 25,030 p = 0.027). Longitudinal regression revealed a statistically significant case-control difference for both NSE (mean: 10,747 SEM: 3,114) and MMP 9 (63,842 SEM: 16,173). In conclusion, NSE and MMP 9 are present in higher levels following SBI and warrant further investigation for their utility as screening tools.
Publisher: BMJ
Date: 05-04-2018
DOI: 10.1136/THORAXJNL-2017-211439
Abstract: Mesenchymal stem cells (MSCs) have attracted attention as a potential therapy for Acute Respiratory Distress Syndrome (ARDS). At the same time, the use of extracorporeal membrane oxygenation (ECMO) has increased among patients with severe ARDS. To date, early clinical trials of MSCs in ARDS have excluded patients supported by ECMO. Here we provide evidence from an ex-vivo model of ECMO to suggest that the intravascular administration of MSCs during ECMO may adversely impact the function of a membrane oxygenator. The addition of clinical grade MSCs resulted in a reduction of flow through the circuit in comparison to controls (0.6 ±0.35 L min -1 vs 4.12 ± 0.03 L min -1 , at 240 minutes) and an increase in the transoygenator pressure gradient (101±9 mmHg vs 21±4 mmHg, at 240 minutes). Subsequent immunohistochemistry analysis demonstrated quantities of MSCs highly adherent to membrane oxygenator fibres. This study highlights the potential harm associated with MSC therapy during ECMO and suggests further areas of research required to advance the translation of cell therapy in this population.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Jonathan E Millar.