Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

<i>C</i>. <i>albicans</i> suppresses pyochelin and pyoverdine biosynthetic pathways in <i>P</i>. <i>aeruginosa</i>.

<p><b>A</b>) Experimental schema of <i>in vivo P</i>. <i>aeruginosa</i> transcriptome analysis experiments. PA, <i>P</i>. <i>aeruginosa</i>. CA, <i>C</i>. <i>albicans</i>. <b>B</b>) Heatmap of RNA-Seq analysis of <i>P</i>. <i>aeruginosa</i> strain PAO1 transcripts recovered from cecums of neutropenic mice co-colonized with <i>P</i>. <i>aeruginosa</i> and <i>C</i>. <i>albicans</i> compared to mice mono-colonized with <i>P</i>. <i>aeruginosa</i>. Prokaryotic mRNA from 8 mice pooled for each biological replicate; 2 biological replicates performed. RNA-Seq analysis performed with DESeq. <b>C</b>, <b>D</b>) Summary tables of <i>P</i>. <i>aeruginosa</i> pyochelin (<b>C</b>) and pyoverdine (<b>D</b>) gene expression (data from RNA-Seq analysis). <b>E</b>) RT qPCR of <i>P</i>. <i>aeruginosa</i> pyochelin and pyoverdine biosynthetic genes (performed on the same RNA samples used for RNA-Seq analysis). All data shown are means ± SEM. Assays were performed in triplicate. Statistical analysis was performed by unpaired Student’s <i>t-test</i>. * p< 0.05; ** p<0.01; ns, not significant.</p

Survival of C3H/HeN Mice GI Colonized with <i>P</i>. <i>aeruginosa</i> ± <i>C</i>. <i>albicans</i> after Induction of Neutropenia.

<p>^a p-value by Fisher’s exact test compared to respective <i>P</i>. <i>aeruginosa</i> mono-colonized group.</p><p>Survival of C3H/HeN Mice GI Colonized with <i>P</i>. <i>aeruginosa</i> ± <i>C</i>. <i>albicans</i> after Induction of Neutropenia.</p

<i>C</i>. <i>albicans</i> inhibits <i>P</i>. <i>aeruginosa</i> virulence in mice.

<p><b>A</b>, <b>E</b>) <i>C</i>. <i>albicans</i> SC5314 (red triangles) and <i>P</i>. <i>aeruginosa</i> PAO1 (black circles) GI colonization levels in (<b>A</b>) adult antibiotic-treated mice (C3H/HeN) and (<b>E</b>) germ-free adult mice (C57BL/6). n = 8 per group for antibiotic-treated mice. n = 4 per group for germ-free mice. Points represent results from individual animals. Horizontal lines with bars represent the median with interquartile range. Statistical analysis performed by Mann-Whitney test. <b>B</b>, <b>F</b>) Survival curves of neutropenic antibiotic-treated (<b>B</b>) and germ-free (<b>F</b>) mice colonized with <i>P</i>. <i>aeruginosa</i> ± <i>C</i>. <i>albicans</i>. Mice were made neutropenic with intraperitoneal injection of 0.200 mg RB6-8C5 rat anti-mouse Ly-6G, Ly-6C monoclonal antibody. n = 8 for antibiotic-treated mice. n = 4 for germ-free mice. Statistical analysis performed by log-rank test. <b>C, D, G, H</b>) <i>P</i>. <i>aeruginosa</i> and <i>C</i>. <i>albicans</i> levels in spleens (<b>C</b>, <b>G</b>) and livers (<b>D</b>, <b>H</b>) of deceased neutropenic antibiotic-treated and germ-free mice colonized with <i>P</i>. <i>aeruginosa</i> ± <i>C</i>. <i>albicans</i>. Organ homogenates were plated on cetrimide, MacConkey (aerobic), TSA (aerobic,), BHI/Blood (anaerobic), and YVG (YPD agar with vancomycin and gentamicin) plates. The presence of a homogeneous population of green, oxidase-positive colonies on cetrimide agar and an absence of other bacterial growth on the MacConkey, TSA and BHI/Blood plates was used for confirmation of <i>P</i>. <i>aeruginosa</i> dissemination. The presence of a homogeneous population of creamy white colonies on YVG agar was used for confirmation of <i>C</i>. <i>albicans</i> dissemination. Points represent results from individual animals. Horizontal lines with bars represent the median with interquartile range. * p< 0.05; ** p<0.01; ns, not significant. CA, <i>C</i>. <i>albicans</i>. PA, <i>P</i>. <i>aeruginosa</i>. RB6, RB6-8C5 monoclonal antibody.</p

Deletion of <i>P</i>. <i>aeruginosa</i> pyochelin and pyoverdine genes attenuates <i>P</i>. <i>aeruginosa</i> virulence.

<p><b>A</b>) GI colonization levels of wild type <i>P</i>. <i>aeruginosa</i> PAO1(circles); pyochelin deletional mutants (squares; Δ<i>fptA</i>, Δ<i>pchE</i>, Δ<i>pchBA</i>); pyoverdine deletional mutants (triangles; Δ<i>pvdF</i>, Δ<i>pvdH</i>, Δ<i>pvdS</i>); and pyochelin/pyoverdine deletional mutants (diamonds; Δ<i>pchBA</i>Δ<i>pvdF</i>, Δ<i>pchBA</i>Δ<i>pvdS</i>, Δ<i>pchBA</i>Δ<i>pvdH</i>) in C3H/HeN mice. n = 8 mice per group. Points represent results from individual animals. Horizontal lines with bars represent the median with interquartile range. Statistical analysis performed by Mann-Whitney test. * p< 0.05; ** p<0.01; ns, not significant. <b>B, C, D</b>) Survival curves of antibiotic-treated neutropenic C3H/HeN mice GI colonized with <b>B</b>) PAO1 pyochelin deletional mutants, <b>C</b>) PAO1 pyoverdine deletional mutants, and <b>D</b>) PAO1 pyochelin/pyoverdine deletional mutants. n = 8 mice per group. Statistical analysis performed by log-rank test. * p< 0.05; ** p<0.01; ns, not significant.</p