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Background Perioperative fluid strategies influence clinical outcomes following major surgery. Many intravenous fluid preparations are based on simple solutions, such as normal saline, that feature an electrolyte composition that differs from that of physiological plasma. Buffered fluids have a theoretical advantage of containing a substrate that acts to maintain the body’s acid-base status - typically a bicarbonate or a bicarbonate precursor such as maleate, gluconate, lactate, or acetate. Buffered fluids also provide additional electrolytes, including potassium, magnesium, and calcium, more closely matching the electrolyte balance of plasma. The putative benefits of buffered fluids have been compared with those of non-buffered fluids in the context of clinical studies conducted during the perioperative period. This review was published in 2012, and was updated in 2017. Objectives To review effects of perioperative intravenous administration of buffered versus non-buffered fluids for plasma volume expansion or maintenance, or both, on clinical outcomes in adults undergoing all types of surgery. Search methods We electronically searched the Clinicaltrials.gov major trials registry, the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 6) in the Cochrane Library, MEDLINE (1966 to June 2016), Embase (1980 to June 2016), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to June 2016). We handsearched conference abstracts and, when possible, contacted leaders in the field. We reran the search in May 2017. We added one potential new study of interest to the list of ‘Studies awaiting classification' and will incorporate this trial into formal review findings when we prepare the review update. Selection criteria Only randomized controlled trials that compared buffered versus non-buffered intravenous fluids for surgical patients were eligible for inclusion. We excluded other forms of comparison such as crystalloids versus colloids and colloids versus different colloids. Data collection and analysis Two review authors screened references for eligibility, extracted data, and assessed risks of bias. We resolved disagreements by discussion and consensus, in collaboration with a third review author. We contacted trial authors to request additional information when appropriate. We presented pooled estimates for dichotomous outcomes as odds ratios (ORs) and for continuous outcomes as mean differences (MDs), with 95% confidence intervals (CIs). We analysed data via Review Manager 5.3 using fixed-effect models, and when heterogeneity was high (I² > 40%), we used random-effects models. Main results This review includes, in total, 19 publications of 18 randomized controlled trials with a total of 1096 participants. We incorporated five of those 19 studies (330 participants) after the June 2016 update. Outcome measures in the included studies were thematically similar, covering perioperative electrolyte status, renal function, and acid-base status; however, we found significant clinical and statistical heterogeneity among the included studies. We identified variable protocols for fluid administration and total volumes of fluid administered to patients intraoperatively. Trial authors variably reported outcome data at disparate time points and with heterogeneous patient groups. Consequently, many outcome measures are reported in small group sizes, reducing overall confidence in effect size, despite relatively low inherent bias in the included studies. Several studies reported orphan outcome measures. We did not include in the results of this review one large, ongoing study of saline versus Ringer's solution. We found insufficient evidence on effects of fluid therapies on mortality and postoperative organ dysfunction (defined as renal insufficiency leading to renal replacement therapy); confidence intervals were wide and included both clinically relevant benefit and harm: mortality (Peto OR 1.85, 95% CI 0.37 to 9.33; I² = 0%; 3 trials, 6 deaths, 276 participants; low-quality evidence); renal insufficiency (OR 0.82, 95% CI 0.34 to 1.98; I² = 0%; 4 trials, 22 events, 276 participants; low-quality evidence). We noted several metabolic differences, including a difference in postoperative pH measured at end of surgery of 0.05 units - lower in the non-buffered fluid group (12 studies with a total of 720 participants; 95% CI 0.04 to 0.07; I² = 61%). However, this difference was not maintained on postoperative day one. We rated the quality of evidence for this outcome as moderate. We observed a higher postoperative serum chloride level immediately after operation, with use of non-buffered fluids reported in 10 studies with a total of 530 participants (MD 6.77 mmol/L, 95% CI 3.38 to 10.17), and this difference persisted until day one postoperatively (five studies with a total of 258 participants; MD 8.48 mmol/L, 95% CI 1.08 to 15.88). We rated the quality of evidence for this outcome as moderate. Authors' conclusions Current evidence is insufficient to show effects of perioperative administration of buffered versus non-buffered crystalloid fluids on mortality and organ system function in adult patients following surgery. Benefits of buffered fluid were measurable in biochemical terms, particularly a significant reduction in postoperative hyperchloraemia and metabolic acidosis. Small effect sizes for biochemical outcomes and lack of correlated clinical follow-up data mean that robust conclusions on major morbidity and mortality associated with buffered versus non-buffered perioperative fluid choices are still lacking. Larger studies are needed to assess these relevant clinical outcomes

Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial

<p>(<b>A</b>) Immunofluorescence signal for dystrophin is significantly reduced in the SSI heart (bottom left panel) compared with the immunofluorescent signal in the SHAM heart (upper left panel), and the SHAM+ALLN (upper right panel) and SSI+ALLN (bottom right panel) myocardium. (<b>B</b>) Protein levels of dystrophin in the SHAM, SSI, SHAM+ALLN and SSI+ALLN hearts were measured 24 h after the CLP procedure and were expressed in arbitrary units (AUs). α-Tubulin was used to determine equivalent loading conditions. The results (n = 6 per group) are representative of three different experiments. Scale bars indicate 50 μm.</p

Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19

Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients

Perioperative administration of buffered versus non-buffered crystalloid intravenous fluid to improve outcomes following adult surgical procedures: a Cochrane systematic review

Background: Buffered intravenous fluid preparations contain substrates to maintain acid-base status. The objective of this systematic review was to compare the effects of buffered and non-buffered fluids administered during the perioperative period on clinical and biochemical outcomes. Methods: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library until May 2017 and included all randomised controlled trials that evaluated buffered versus non-buffered fluids, whether crystalloid or colloid, administered to surgical patients. We assessed the selected studies for risk of bias and graded the level of evidence in accordance with Cochrane recommendations. Results: We identified 19 publications of 18 randomised controlled trials, totalling 1096 participants. Mean difference (MD) in postoperative pH was 0.05 units lower immediately following surgery in the non-buffered group (12 studies of 720 participants; 95% confidence interval (CI) 0.04 to 0.07; I2 = 61%). This difference did not persist on postoperative day 1. Serum chloride concentration was higher in the non-buffered group at the end of surgery (10 trials of 530 participants; MD 6.77 mmol/L, 95% CI 3.38 to 10.17). This effect persisted until postoperative day 1 (5 trials of 258 participants; MD 8.48 mmol/L, 95% CI 1.08 to 15.88). Quality of this evidence was moderate. We identified variable protocols for fluid administration and total volumes of fluid administered to patients intraoperatively. Outcome data was variably reported at disparate time points and with heterogeneous patient groups. Consequently, the effect size and overall confidence interval was reduced, despite the relatively low inherent risk of bias. There was insufficient evidence on the effect of fluid composition on mortality and organ dysfunction. Confidence intervals of this outcome were wide and the quality of evidence was low (3 trials of 276 participants for mortality; odds ratio (OR) 1.85, 95% CI 0.37 to 9.33; I2 = 0%). Conclusions: Small effect sizes for biochemical outcomes and lack of correlated clinical follow-up data mean that robust conclusions on major morbidity and mortality associated with buffered versus non-buffered perioperative fluid choices are still lacking. Buffered fluid may have biochemical benefits, including a significant reduction in postoperative hyperchloraemia and metabolic acidosis

Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial):A Multicentre, Randomised, Controlled Trial

RationaleMesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in COVID-19-related Acute Respiratory Distress Syndrome (ARDS).ObjectivesWe investigated safety and efficacy of ORBCEL-C (CD362-enriched, umbilical cord-derived MSCs) in COVID-related ARDS.MethodsThis multicentre, randomised, double-blind, allocation concealed, placebo-controlled trial (NCT03042143) randomised patients with moderate-to-severe COVID-related ARDS to receive ORBCEL-C (400million cells) or placebo (Plasma-Lyte148).MeasurementsThe primary safety and efficacy outcomes were incidence of serious adverse events and oxygenation index at day 7 respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2/FiO2 ratio and SOFA score. Clinical outcomes relating to duration of ventilation, length of intensive care unit and hospital stays, and mortality were collected. Long-term follow up included diagnosis of interstitial lung disease at 1 year, and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at day 0, 4 and 7.Main results60 participants were recruited (final analysis n=30 ORBCEL-C, n=29 placebo: 1 in placebo group withdrew consent). 6 serious adverse events occurred in the ORBCEL-C and 3 in the placebo group, RR 2.9(0.6-13.2)p=0.25. Day 7 mean[SD] oxygenation index did not differ (ORBCEL-C 98.357.2], placebo 96.667.3). There were no differences in secondary surrogate outcomes, nor mortality at day 28, day 90, 1 or 2 years. There was no difference in prevalence of interstitial lung disease at 1year nor significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome.ConclusionORBCEL-C MSCs were safe in moderate-to-severe COVID-related ARDS, but did not improve surrogates of pulmonary organ dysfunction. Clinical trial registration available at www.Clinicaltrialsgov, ID: NCT03042143. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/)

Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19:a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK

Background Studies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use. Methods We analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age (<16 years, 16–49 years, and ≥50 years). In-hospital mortality was measured by use of multilevel Cox proportional hazards, adjusting for demographics, comorbidities, and medications (inhaled corticosteroids, short-acting β-agonists [SABAs], and long-acting β-agonists [LABAs]). Patients with asthma who were taking an inhaled corticosteroid plus LABA plus another maintenance asthma medication were considered to have severe asthma. Findings 75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 [8·6%] with asthma), 8950 patients aged 16–49 years (1867 [20·9%] with asthma), and 65 653 patients aged 50 years and older (5918 [9·0%] with asthma, 10 266 [15·6%] with chronic pulmonary disease, and 2071 [3·2%] with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16–49 years: adjusted odds ratio [OR] 1·20 [95% CI 1·05–1·37]; p=0·0080; patients aged ≥50 years: adjusted OR 1·17 [1·08–1·27]; p<0·0001), and patients aged 50 years and older with chronic pulmonary disease (with or without asthma) were significantly less likely than those without a respiratory condition to receive critical care (adjusted OR 0·66 [0·60–0·72] for those without asthma and 0·74 [0·62–0·87] for those with asthma; p<0·0001 for both). In patients aged 16–49 years, only those with severe asthma had a significant increase in mortality compared to those with no asthma (adjusted hazard ratio [HR] 1·17 [95% CI 0·73–1·86] for those on no asthma therapy, 0·99 [0·61–1·58] for those on SABAs only, 0·94 [0·62–1·43] for those on inhaled corticosteroids only, 1·02 [0·67–1·54] for those on inhaled corticosteroids plus LABAs, and 1·96 [1·25–3·08] for those with severe asthma). Among patients aged 50 years and older, those with chronic pulmonary disease had a significantly increased mortality risk, regardless of inhaled corticosteroid use, compared to patients without an underlying respiratory condition (adjusted HR 1·16 [95% CI 1·12–1·22] for those not on inhaled corticosteroids, and 1·10 [1·04–1·16] for those on inhaled corticosteroids; p<0·0001). Patients aged 50 years and older with severe asthma also had an increased mortality risk compared to those not on asthma therapy (adjusted HR 1·24 [95% CI 1·04–1·49]). In patients aged 50 years and older, inhaled corticosteroid use within 2 weeks of hospital admission was associated with decreased mortality in those with asthma, compared to those without an underlying respiratory condition (adjusted HR 0·86 [95% CI 0·80−0·92]). Interpretation Underlying respiratory conditions are common in patients admitted to hospital with COVID-19. Regardless of the severity of symptoms at admission and comorbidities, patients with asthma were more likely, and those with chronic pulmonary disease less likely, to receive critical care than patients without an underlying respiratory condition. In patients aged 16 years and older, severe asthma was associated with increased mortality compared to non-severe asthma. In patients aged 50 years and older, inhaled corticosteroid use in those with asthma was associated with lower mortality than in patients without an underlying respiratory condition; patients with chronic pulmonary disease had significantly increased mortality compared to those with no underlying respiratory condition, regardless of inhaled corticosteroid use. Our results suggest that the use of inhaled corticosteroids, within 2 weeks of admission, improves survival for patients aged 50 years and older with asthma, but not for those with chronic pulmonary disease

Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study.

BACKGROUND: Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions. METHODS: We developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal-external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London). FINDINGS: 74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal-external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [-0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model. INTERPRETATION: The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19. FUNDING: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London

Importance of patient bed pathways and length of stay differences in predicting COVID-19 hospital bed occupancy in England.

Background: Predicting bed occupancy for hospitalised patients with COVID-19 requires understanding of length of stay (LoS) in particular bed types. LoS can vary depending on the patient’s “bed pathway” - the sequence of transfers of individual patients between bed types during a hospital stay. In this study, we characterise these pathways, and their impact on predicted hospital bed occupancy. Methods: We obtained data from University College Hospital (UCH) and the ISARIC4C COVID-19 Clinical Information Network (CO-CIN) on hospitalised patients with COVID-19 who required care in general ward or critical care (CC) beds to determine possible bed pathways and LoS. We developed a discrete-time model to examine the implications of using either bed pathways or only average LoS by bed type to forecast bed occupancy. We compared model-predicted bed occupancy to publicly available bed occupancy data on COVID-19 in England between March and August 2020. Results: In both the UCH and CO-CIN datasets, 82% of hospitalised patients with COVID-19 only received care in general ward beds. We identified four other bed pathways, present in both datasets: “Ward, CC, Ward”, “Ward, CC”, “CC” and “CC, Ward”. Mean LoS varied by bed type, pathway, and dataset, between 1.78 and 13.53 days. For UCH, we found that using bed pathways improved the accuracy of bed occupancy predictions, while only using an average LoS for each bed type underestimated true bed occupancy. However, using the CO-CIN LoS dataset we were not able to replicate past data on bed occupancy in England, suggesting regional LoS heterogeneities. Conclusions: We identified five bed pathways, with substantial variation in LoS by bed type, pathway, and geography. This might be caused by local differences in patient characteristics, clinical care strategies, or resource availability, and suggests that national LoS averages may not be appropriate for local forecasts of bed occupancy for COVID-19. Trial registration: The ISARIC WHO CCP-UK study ISRCTN66726260 was retrospectively registered on 21/04/2020 and designated an Urgent Public Health Research Study by NIHR.</p

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC