Publications
111 results found
Wu Z, Spencer LG, Banya W, et al., 2024, Morphine for treatment of cough in idiopathic pulmonary fibrosis (PACIFY COUGH): a prospective, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial, The Lancet Respiratory Medicine, Vol: 12, Pages: 273-280, ISSN: 2213-2600
BackgroundIdiopathic pulmonary fibrosis is a progressive fibrotic lung disease, with most patients reporting cough. Currently, there are no proven treatments. We examined the use of low dose controlled-release morphine compared with placebo as an antitussive therapy in individuals with idiopathic pulmonary fibrosis.MethodsThe PACIFY COUGH study is a phase 2, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial done in three specialist centres in the UK. Eligible patients aged 40–90 years had a diagnosis of idiopathic pulmonary fibrosis within 5 years, self-reported cough (lasting >8 weeks), and a cough visual analogue scale (VAS) score of 30 mm or higher. Patients were randomly assigned (1:1) to placebo twice daily or controlled-release morphine 5 mg orally twice daily for 14 days followed by crossover after a 7-day washout period. Patients were randomised sequentially to a sequence group defining the order in which morphine and placebo were to be given, according to a computer-generated schedule. Patients, investigators, study nurses, and pharmacy personnel were masked to treatment allocation. The primary endpoint was percentage change in objective awake cough frequency (coughs per h) from baseline as assessed by objective digital cough monitoring at day 14 of treatment in the intention-to-treat population, which included all randomised participants. Safety data were summarised for all patients who took at least one study drug and did not withdraw consent. This study was registered at ClinicalTrials.gov, NCT04429516, and has been completed.FindingsBetween Dec 17, 2020, and March 21, 2023, 47 participants were assessed for eligibility and 44 were enrolled and randomly allocated to treatment. Mean age was 71 (SD 7·4) years, and 31 (70%) of 44 participants were male and 13 (30%) were female. Lung function was moderately impaired; mean forced vital capacity (FVC) was 2·7 L (SD 0·76), mean predicted FVC was 82%
Brightling CE, Evans RA, Singapuri A, et al., 2023, Long COVID research: an update from the PHOSP-COVID Scientific Summit., Lancet Respir Med, Vol: 11, Pages: e93-e94
Toal CM, Fowler AJ, Patel BV, et al., 2023, Hypoxemia trajectory of non-COVID-19 acute respiratory distress syndrome patients. An observational study focusing on hypoxemia resolver status, Critical Care Explorations, Vol: 5, ISSN: 2639-8028
IMPORTANCE: Most studies on acute respiratory distress syndrome (ARDS) group patients by severity based on their initial degree of hypoxemia. However, this grouping has limitations, including inconsistent hypoxemia trajectories and outcomes.OBJECTIVES: This study explores the benefits of grouping patients by resolver status based on their hypoxemia progression over the first 7 days.DESIGN, SETTING, AND PARTICIPANTS: This is an observational study from a large single-center database. Medical Information Mart for Intensive Care (MIMIC)-IV and MIMIC Chest X-ray JPEG databases were used. Mechanically ventilated patients that met the Berlin ARDS criteria were included.MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of hypoxemia resolvers vs. nonresolvers in non-COVID-19 ARDS patients. Nonresolvers were defined as those whose hypoxemia worsened or remained moderate or severe over the first 7 days. Secondary outcomes included baseline admission characteristics, initial blood gases and ventilation settings, length of invasive mechanical ventilation, length of ICU stay, and ICU survival rates across resolver groups.RESULTS: A total of 894 ICU admissions were included in the study. Of these, 33.9% were hypoxemia nonresolvers. The resolver groups showed no significant difference in age, body mass index, comorbidities, or Charlson score. There was no significant difference in the percentage of those with initial severe hypoxemia between the two groups (8.1% vs. 9.2%; p = 0.126). The initial Pao2/Fio2 ratio did not significantly increase the odds ratio (OR) of being a nonresolver (OR, 0.84; 95% CI, 0.65–1.10). Nonresolver mortality was 61.4%, comparable to the survival rates seen in nonresolvers in a previous large COVID-19 ARDS study.CONCLUSIONS AND RELEVANCE: Our study shows that resolver status is a valuable grouping in ARDS. It has significant advantages over grouping by initial degree of hypoxemia, including better mapping of trajectory and comparab
Paul N, Grunow JJ, Rosenthal M, et al., 2023, Enhancing European Management of Analgesia, Sedation, and Delirium: A Multinational, Prospective, Interventional Before-After Trial, NEUROCRITICAL CARE, ISSN: 1541-6933
Kanai M, Andrews SJ, Cordioli M, et al., 2023, A second update on mapping the human genetic architecture of COVID-19, Nature, Vol: 621, Pages: E7-E26, ISSN: 0028-0836
Jackson C, Stewart ID, Plekhanova T, et al., 2023, Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study, The Lancet Respiratory Medicine, Vol: 11, Pages: 673-684, ISSN: 2213-2600
BACKGROUND: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. METHODS: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2-7 months after hospital discharge and a later time point 10-14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). FINDINGS: 2320 of 2468 participants in the PHOSP-COVID study attended
Pairo-Castineira E, Rawlik K, Bretherick AD, et al., 2023, Author Correction: GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19, Nature, Vol: 619, Pages: E61-E61, ISSN: 0028-0836
Patel BV, Lee T, O'Dea K, 2023, CLUSTERINg circulating histones in sepsis, American Journal of Respiratory and Critical Care Medicine, Vol: 208, Pages: 125-127, ISSN: 1073-449X
Jenkins TO, MacBean V, Poulsen MK, et al., 2023, The metabolic cost of inspiratory muscle training in mechanically ventilated patients in critical care., Intensive Care Medicine Experimental, Vol: 11, Pages: 1-14, ISSN: 2197-425X
BACKGROUND: Diaphragmatic dysfunction is well documented in patients receiving mechanical ventilation. Inspiratory muscle training (IMT) has been used to facilitate weaning by strengthening the inspiratory muscles, yet the optimal approach remains uncertain. Whilst some data on the metabolic response to whole body exercise in critical care exist, the metabolic response to IMT in critical care is yet to be investigated. This study aimed to quantify the metabolic response to IMT in critical care and its relationship to physiological variables. METHODS: We conducted a prospective observational study on mechanically ventilated patients ventilated for ≥ 72 h and able to participate in IMT in a medical, surgical, and cardiothoracic intensive care unit. 76 measurements were taken on 26 patients performing IMT using an inspiratory threshold loading device at 4 cmH2O, and at 30, 50 and 80% of their negative inspiratory force (NIF). Oxygen consumption (VO2) was measured continuously using indirect calorimetry. RESULTS: First session mean (SD) VO2 was 276 (86) ml/min at baseline, significantly increasing to 321 (93) ml/min, 333 (92) ml/min, 351(101) ml/min and 388 (98) ml/min after IMT at 4 cmH2O and 30, 50 and 80% NIF, respectively (p = 0.003). Post hoc comparisons revealed significant differences in VO2 between baseline and 50% NIF and baseline and 80% NIF (p = 0.048 and p = 0.001, respectively). VO2 increased by 9.3 ml/min for every 1 cmH2O increase in inspiratory load from IMT. Every increase in P/F ratio of 1 decreased the intercept VO2 by 0.41 ml/min (CI - 0.58 to - 0.24 p < 0.001). NIF had a significant effect on the intercept and slope, with every 1 cmH2O increase in NIF increasing intercept VO2 by 3.28 ml/min (CI 1.98-4.59 p < 0.001) and decreasing the dose-response slope by 0.15 ml/min/cmH2O (CI - 0.24 to - 0.05 p&th
Patel S, Francis T, Rajaram R, et al., 2023, Programmed myofibre necrosis in critical illness acquired muscle wasting, JCSM Rapid Communications, Vol: 6, Pages: 111-121, ISSN: 2617-1619
BackgroundAcute skeletal muscle wasting during critical illness is common and causes significant morbidity and functional limitation. Myofibre necrosis is a major histological finding but is often considered an unprogrammed by-product of muscle inflammation. This study sought to evaluate if a form of programmed necrosis, necroptosis, is activated in skeletal muscle during critical illness.MethodsA cohort of 28 patients from the MUSCLE-UK study (ClinicalTrials.gov: NCT01106300) with serum and skeletal muscle biopsy samples were identified. Samples were available from ICU admission (T1) and between day 7–10 post admission (T2). Skeletal muscle was stratified by a histopathologist in the original study as necrotic (NEC, N = 14) or non-necrotic (NONEC, N = 14) using haematoxylin and eosin staining. We used phosphorylated mixed-lineage kinase domain-like (pMLKL) protein (a key terminal effector protein) and receptor-interacting protein kinase 3 (RIPK3) as markers of necroptosis activation using Western blotting and immunohistochemistry.ResultsWe show that pMLKL expression is significantly higher in the NEC group [NEC: T2:T1 expression; 9.1 (IQR 3.9–22.3) vs. NONEC: T2:T1 expression; 0.9 (IQR 0.6–1.1), P = 0.003]. We then confirm this upregulation and describe co-localization with receptor interacting protein kinase 3 (RIPK3) in skeletal muscle using immunohistochemistry. We show that both RIPK3 and pMLKL are present within intact myofibres at the intermediate timepoint day 3 without cellular infiltrate. At T2, pMLKL is also present in the interstitial space where there is infiltrate of CD68 positive immune cells. The observed necroptosis may originate from both internal and infiltrating sources. These findings were absent in samples from patients who did not exhibit histopathological features of necrosis.ConclusionsWe show that necroptosis machinery, RIPK3 and pMLKL, are associated with conventional histopathological features of myonecrosis in a critica
Pairo-Castineira E, Rawlik K, Bretherick AD, et al., 2023, GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19, Nature, Vol: 617, Pages: 764-768, ISSN: 0028-0836
Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. 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 group3. 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).
Baldi RF, Chen J, Thomas C, et al., 2023, Microvesicles Induce Alveolar Epithelial Cell Death Via TNF-Caspase Signalling During Ventilator-induced Lung Injury, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Garfield BE, Bianchi P, Arachchillage DJ, et al., 2023, A comparison of long-term outcomes in patients managed with venovenous extracorporeal membrane oxygenation in the first and second waves of the COVID-19 pandemic in the United Kingdom.., Critical Care Medicine, Vol: 51, Pages: 1064-1073, ISSN: 0090-3493
OBJECTIVES: Early studies of venovenous extracorporeal membrane oxygenation (ECMO) in COVID-19 have revealed similar outcomes to historical cohorts. Changes in the disease and treatments have led to differences in the patients supported on venovenous ECMO in the first and second waves. We aimed to compare these two groups in both the acute and follow-up phase. DESIGN: Retrospective single-center cohort study comparing mortality at censoring date (November 30, 2021) and decannulation, patient characteristics, complications and lung function and quality of life (QOL-by European Quality of Life 5 Dimensions 3 Level Version) at first follow-up in patients supported on venovenous ECMO between wave 1 and wave 2 of the COVID-19 pandemic. SETTING: Critical care department of a severe acute respiratory failure service. PATIENTS: Patients supported on ECMO for COVID-19 between wave 1 (March 17, 2020, to August 31, 2020) and wave 2 (January 9, 2020, to May 25, 2021). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-three patients were included in our analysis. Survival at censoring date (χ2, 6.35; p = 0.012) and decannulation (90.4% vs 70.0%; p < 0.001) was significantly lower in the second wave, while duration of ECMO run was longer (12.0 d [18.0-30.0 d] vs 29.5 d [15.5-58.3 d]; p = 0.005). Wave 2 patients had longer application of noninvasive ventilation (NIV) prior to ECMO and a higher frequency of barotrauma. Patient age and NIV use were independently associated with increased mortality (odds ratio 1.07 [1.01-1.14]; p = 0.025 and 3.37 [1.12-12.60]; p = 0.043, respectively). QOL and lung function apart from transfer coefficient of carbon monoxide corrected for hemoglobin was similar at follow-up across the waves. CONCLUSIONS: Most patients with COVID-19 supported on ECMO in both waves survived in the short and longer term. At follow-up patients had similar lung function and QOL across the two waves. This suggests that ECMO has an ongoing role in
Nuh A, Ramadan N, Nwankwo L, et al., 2023, COVID-19 associated pulmonary aspergillosis in patients on extracorporeal membrane oxygenation treatment-a retrospective study, Journal of Fungi, Vol: 9, ISSN: 2309-608X
BACKGROUND: The incidence and outcome of pulmonary aspergillosis in coronavirus disease (COVID-19) patients on extracorporeal membrane oxygenation (ECMO) are unknown and have not been fully addressed. We investigated the incidence, risk factors and outcome of pulmonary aspergillosis in COVID-19 ECMO patients. In addition, the diagnostic utility of bronchoalveolar lavage fluid and CT scans in this setting were assessed. METHODS: We conducted a retrospective study on incidence and outcome of pulmonary aspergillosis in COVID-19 ECMO patients by reviewing clinical, radiological, and mycological evidence. These patients were admitted to a tertiary cardiothoracic centre during the early COVID-19 surge between March 2020 and January 2021. Results and measurements: The study included 88 predominantly male COVID-19 ECMO patients with a median age and a BMI of 48 years and 32 kg/m2, respectively. Pulmonary aspergillosis incidence was 10% and was associated with very high mortality. Patients with an Aspergillus infection were almost eight times more likely to die compared with those without infection in multivariate analysis (OR 7.81, 95% CI: 1.20-50.68). BALF GM correlated well with culture results, with a Kappa value of 0.8 (95% CI: 0.6, 1.0). However, serum galactomannan (GM) and serum (1-3)-β-D-glucan (BDG) lacked sensitivity. Thoracic computed tomography (CT) diagnostic utility was also inconclusive, showing nonspecific ground glass opacities in almost all patients. CONCLUSIONS: In COVID-19 ECMO patients, pulmonary aspergillosis incidence was 10% and associated with very high mortality. Our results support the role of BALF in the diagnosis of pulmonary aspergillosis in COVID-19 ECMO patients. However, the diagnostic utility of BDG, serum GM, and CT scans is unclear.
Price LC, Garfield B, Bloom C, et al., 2022, Persistent isolated impairment of gas transfer following COVID-19 pneumonitis relates to perfusion defects on dual-energy computed tomography, ERJ Open Research, Vol: 8, Pages: 1-5, ISSN: 2312-0541
Verdonk F, Feyaerts D, Badenes R, et al., 2022, Upcoming and urgent challenges in critical care research based on COVID-19 pandemic experience, Anaesthesia, Critical Care and Pain Medicine, Vol: 41, ISSN: 2352-5568
While the coronavirus disease 2019 (COVID-19) pandemic placed a heavy burden on healthcare systems worldwide, it also induced urgent mobilisation of research teams to develop treatments preventing or curing the disease and its consequences. It has, therefore, challenged critical care research to rapidly focus on specific fields while forcing critical care physicians to make difficult ethical decisions. This narrative review aims to summarise critical care research -from organisation to research fields- in this pandemic setting and to highlight opportunities to improve research efficiency in the future, based on what is learned from COVID-19. This pressure on research revealed, i.e., (i) the need to harmonise regulatory processes between countries, allowing simplified organisation of international research networks to improve their efficiency in answering large-scale questions; (ii) the importance of developing translational research from which therapeutic innovations can emerge; (iii) the need for improved triage and predictive scores to rationalise admission to the intensive care unit. In this context, key areas for future critical care research and better pandemic preparedness are artificial intelligence applied to healthcare, characterisation of long-term symptoms, and ethical considerations. Such collaborative research efforts should involve groups from both high and low-to-middle income countries to propose worldwide solutions. As a conclusion, stress tests on healthcare organisations should be viewed as opportunities to design new research frameworks and strategies. Worldwide availability of research networks ready to operate is essential to be prepared for next pandemics. Importantly, researchers and physicians should prioritise realistic and ethical goals for both clinical care and research.
Leahy TA, Chauhan A, Nicholas V, et al., 2022, Responder status and long term outcomes of critically ill patients with ARDS receiving high dose steroids as rescue therapy in a specialist acute respiratory failure centre, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Francis T, Patel S, Rajaram R, et al., 2022, Programmed Myofibre Necrosis in Critical Illness Acquired Muscle Wasting, Publisher: WILEY, Pages: 132-133, ISSN: 1748-1708
McFadyen C, Garfield B, Mancio J, et al., 2022, Use of sildenafil in patients with severe COVID-19 pneumonitis, British Journal of Anaesthesia, Vol: 129, Pages: E18-E21, ISSN: 0007-0912
Wilson J, Fisher R, Caetano F, et al., 2022, Managing Harlequin Syndrome in VA-ECMO - do not forget the right ventricle, PERFUSION-UK, Vol: 37, Pages: 526-529, ISSN: 0267-6591
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Baldi RF, Soni S, Patel BV, et al., 2022, Macrophage-Derived Microvesicles Induce Alveolar Epithelial Cell Death in an In Vitro Stretch Model, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Bos LDJ, Laffey JG, Ware LB, et al., 2022, Towards a biological definition of ARDS: are treatable traits the solution?, Intensive Care Medicine Experimental, Vol: 10, Pages: 1-14, ISSN: 2197-425X
The pathophysiology of acute respiratory distress syndrome (ARDS) includes the accumulation of protein-rich pulmonary edema in the air spaces and interstitial areas of the lung, variable degrees of epithelial injury, variable degrees of endothelial barrier disruption, transmigration of leukocytes, alongside impaired fluid and ion clearance. These pathophysiological features are different between patients contributing to substantial biological heterogeneity. In this context, it is perhaps unsurprising that a wide range of pharmacological interventions targeting these pathophysiological processes have failed to improve patient outcomes. In this manuscript, our goal is to provide a narrative summary of the potential methods to capture the underlying biological heterogeneity of ARDS and discuss how this information could inform future ARDS redefinitions. We discuss what biological tests are available to identify patients with any of the following predominant biological patterns: (1) epithelial and/or endothelial injury, (2) protein rich pulmonary edema and (3) systemic or within lung inflammatory responses.
Kousathanas A, Pairo-Castineira E, Rawlik K, et al., 2022, Whole genome sequencing reveals host factors underlying critical Covid-19, Nature, Vol: 607, Pages: 97-103, ISSN: 0028-0836
Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalisation2-4 following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing in 7,491 critically-ill cases 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 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 multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. Mendelian randomisation provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5, CD209) and 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 critically-ill cases and population controls is highly efficient for detection of therapeutically-relevant mechanisms of disease.
Wu Z, Banya W, Chaudhuri N, et al., 2022, PAciFy Cough-a multicentre, double-blind, placebo-controlled, crossover trial of morphine sulphate for the treatment of pulmonary Fibrosis Cough, Trials, Vol: 23, ISSN: 1745-6215
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease that leads to lung scarring. Cough is reported by 85% of patients with IPF and can be a distressing symptom with a significant impact on patients' quality of life. There are no proven effective therapies for IPF-related cough. Whilst morphine is frequently used as a palliative agent for breathlessness in IPF, its effects on cough have never been tested. PAciFy Cough is a multicenter, double-blind, placebo-controlled, crossover trial of morphine sulphate for the treatment of cough in IPF. METHODS: We will recruit 44 subjects with IPF prospectively from three interstitial lung disease units in the UK, namely the Royal Brompton Hospital, Manchester University NHS Foundation Trust (MFT) and Aintree University Hospital NHS Foundation Trust. Patients will be randomised (1:1) to either placebo twice daily or morphine sulphate 5 mg twice daily for 14 days. They will then crossover after a 7-day washout period. The primary endpoint is the percent change in daytime cough frequency (coughs per hour) from baseline as assessed by objective cough monitoring at day 14 of treatment. DISCUSSION: This multicentre, randomised trial will assess the effect of opioids on cough counts and cough associated quality of life in IPF subjects. If proven to be an effective intervention, it represents a readily available treatment for patients. TRIAL REGISTRATION: The study was approved by the UK Medicines and Healthcare Regulatory Agency (Ref: CTA 21268/0224/001-0001 - EUDRACT 2019-003571-19 - Protocol Number RBH2019/001) on 08 April 2020, in compliance with the European Clinical Trials Directive and the Medicines for Human Use (Clinical Trials) Regulations 2004 and its subsequent amendments. The study was provided with ethical approval by the London Brent Research Ethics Committee (Ref: 20/LO/0368) on 21 May 2020 and is registered with clinicaltrials.gov (NCT04429516) on 12 June 2020, available at https://cli
Tan YY, O'Dea KP, Patel BV, et al., 2022, Investigation of microvesicle uptake by mouse lung-marginated monocytes in vitro., Bio-protocol, Vol: 12, Pages: 1-1, ISSN: 2331-8325
Extracellular microvesicles (MVs) are released into the circulation in large numbers during acute systemic inflammation, yet little is known of their intravascular cell/tissue-specific interactions under these conditions. We recently described a dramatic increase in the uptake of intravenously injected MVs by monocytes marginated within the pulmonary vasculature, in a mouse model of low-dose lipopolysaccharide-induced systemic inflammation. To investigate the mechanisms of enhanced MV uptake by monocytes, we developed an in vitro model using in vivo derived monocytes. Although mouse blood is a convenient source, monocyte numbers are too low for in vitro experimentation. In contrast, differentiated bone marrow monocytes are abundant, but they are rapidly mobilized during systemic inflammation, and thus no longer available. Instead, we developed a protocol using marginated monocytes from the pulmonary vasculature as an anatomically relevant and abundant source. Mice are sacrificed by terminal anesthesia, the lungs inflated and perfused via the pulmonary artery. Perfusate cell populations are evaluated by flow cytometry, combined with in vitro generated fluorescently labelled MVs, and incubated in suspension for up to one hour. Washed cells are analyzed by flow cytometry to quantify MV uptake and confocal microscopy to localize MVs within cells (O'Dea et al., 2020). Using this perfusion-based method, substantial numbers of marginated pulmonary vascular monocytes are recovered, allowing multiple in vitro tests to be performed from a single mouse donor. As MV uptake profiles were comparable to those observed in vivo, this method is suitable for physiologically relevant high throughput mechanistic studies on mouse monocytes under in vitro conditions. Graphic abstract: Figure 1. Schematic of lung perfusate cell harvest and co-incubation with in vitro generated MVs. Created with BioRender.com.
Patel B, Mumby S, Johnson N, et al., 2022, Decision support system to evaluate ventilation in the acute respiratory distress syndrome (DeVENT study)-trial protocol, Trials, Vol: 23, Pages: 1-18, ISSN: 1745-6215
BackgroundThe acute respiratory distress syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator-induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS.MethodsWe will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS.DiscussionDespite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator-induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. Hence, personalised management demands the application of mechanical ventilation according to the physiological state of the diseased lung at that time. Hence, there is significant rationale for the development of point-of-care clinical decision support systems which help personalise ventilatory strateg
Griffiths M, Meade S, Summers C, et al., 2022, RAND appropriateness panel to determine the applicability of international guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic, Thorax, Vol: 77, Pages: 129-135, ISSN: 0040-6376
Background: COVID-19 has become the commonest cause of ARDS world-wide. Features of the pathophysiology and clinical presentation partially distinguish it from “classical” ARDS. A RAND analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template. Methods: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where, 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into: investigations 16, non-invasive respiratory support 18, basic ICU management of ARDS 20, management of refractory hypoxaemia 8, pharmacotherapy 7, and anticoagulation 7, was completed again. Results: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For ARDS patients with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous-thrombo-embolic disease.Conclusion: The expert panel found no reason to deviate from the evidence based supportive strategies for managing ARDS outlined in recent guidelines.
Fallerini C, Picchiotti N, Baldassarri M, et al., 2022, Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity, Human Genetics, Vol: 141, Pages: 147-173, ISSN: 0340-6717
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 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, 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. Noteworthily, 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.
Patel B, Mumby S, Johnson N, et al., 2021, Decision support system to evaluate VENTilation in the Acute Respiratory Distress Syndrome (DeVENT study) – Trial Protocol, Trials, ISSN: 1745-6215
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The Acute Respiratory Distress Syndrome (ARDS) occurs in response to a variety of insults, and mechanical ventilation is life-saving in this setting, but ventilator induced lung injury can also contribute to the morbidity and mortality in the condition. The Beacon Caresystem is a model-based bedside decision support system using mathematical models tuned to the individual patient’s physiology to advise on appropriate ventilator settings. Personalised approaches using individual patient description may be particularly advantageous in complex patients, including those who are difficult to mechanically ventilate and wean, in particular ARDS.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We will conduct a multi-centre international randomised, controlled, allocation concealed, open, pragmatic clinical trial to compare mechanical ventilation in ARDS patients following application of the Beacon Caresystem to that of standard routine care to investigate whether use of the system results in a reduction in driving pressure across all severities and phases of ARDS.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>Despite 20 years of clinical trial data showing significant improvements in ARDS mortality through mitigation of ventilator induced lung injury, there remains a gap in its personalised application at the bedside. Importantly, the protective effects of higher positive end-expiratory pressure (PEEP) were noted only when there were associated decreases in driving pressure. Hence, the pressures set on the ventilator should be determined by the diseased lungs’ pressure-volume relationship which is often unknown or difficult to determine. Knowledge of extent of recruitable lung could improve the ventilator driving pressure. H
Garfield B, Handslip R, Patel B, 2021, Ventilator-Associated Lung Injury, Encyclopedia of Respiratory Medicine, Publisher: Academic Press, Pages: 406-417, ISBN: 9780081027233
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