Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28

The Vehicle, 1964, Vol. 6

Vol. 6 Table of Contents Milepostspage 2 John Fitzgerald Kennedy Memorial Pagepage 4 Sadness No. 4 (Sorgen)Sherry S. Frypage 5 Christian BurialRoger J. Barrypage 7 The World of BeautyDavid Helmpage 9 The Song of the LarksDon Kapraunpage 10 ContrastKeith Haierpage 13 PanoramaDaun Alan Leggpage 13 A Child\u27s View of DeathCherie Brondellpage 14 RegretLiz Puckettpage 16 Brutal WarMary H. Soukuppage 17 aloneLiz Puckettpage 18 MadgeLinda Galeypage 19 Moon WatchingJoel E. Hendrickspage 20 AnalysisLiz Puckettpage 21 UniverseRick Talleypage 21 Anyone Can Be A LuniticRick Towsonpage 22 I, Too, Have A Rendezvous with DeathElaine Lancepage 23 The ReturnRobert D. Thomaspage 24 NamesLarry Gatespage 25 Eternal MomentsDavid Helmpage 25 The Last DaysPauline B. Smithpage 26 BeliefRichard J. Wiesepage 27 StormPauline B. Smithpage 28 ExplosionLiz Puckettpage 29 Autumn EveJoel E. Hendrickspage 29 The Girl On the White PonyLarry Gatespage 31 HoffnungTerry Michael Salempage 33 Stone WallsDaun Alan Leggpage 34 AdorationGail M. Barenfangerpage 37 MirageRoy L. Carlsonpage 38 Nature and NonsenseRick Talleypage 39 A Step Through A Looking GlassMarilyn Henrypage 40 Thoughts of a Summer PastPauline B Smithpage 42 Indiana GrassLarry Gatespage 43 RedondillaRoberta Matthewspage 44 Summer LoveDaun Alan Leggpage 45 To Youth Reaching For MaturityDavid Helmpage 45 Thanksgiving DayJoel E. Hendrickspage 46 Sadness No. 6 (Schatten)Sherry S. Frypage 48https://thekeep.eiu.edu/vehicle/1012/thumbnail.jp

Tocilizumab in patients hospitalised with COVID-19 pneumonia: efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)

Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference –0·5% [95% CI –9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase–quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti–SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C

Carnitine Palmitoyltransferase 1A Has a Lysine Succinyltransferase Activity

Summary: Lysine succinylation was recently identified as a post-translational modification in cells. However, the molecular mechanism underlying lysine succinylation remains unclear. Here, we show that carnitine palmitoyltransferase 1A (CPT1A) has lysine succinyltransferase (LSTase) activity in vivo and in vitro. Using a stable isotope labeling by amino acid in cell culture (SILAC)-based proteomics approach, we found that 101 proteins were more succinylated in cells expressing wild-type (WT) CPT1A compared with vector control cells. One of the most heavily succinylated proteins in this analysis was enolase 1. We found that CPT1A WT succinylated enolase 1 and reduced enolase enzymatic activity in cells and in vitro. Importantly, mutation of CPT1A Gly710 (G710E) selectively inactivated carnitine palmitoyltransferase (CPTase) activity but not the LSTase activity that decreased enolase activity in cells and promoted cell proliferation under glutamine depletion. These findings suggest that CPT1A acts as an LSTase that can regulate enzymatic activity of a substrate protein and metabolism independent of its classical CPTase activity

The ethics of problem representation: Widening the scope of ethical debate

Copyright © 2007 Policy & Society Associates (APSS) Published by Elsevier Ltd.This paper makes a case for extending the scope of ethical reflection and debate in public policy beyond the current tendency to confine ethical scrutiny to the behaviours of individual politicians or public servants, and/or to a restricted set of issues characterized as “moral” issues, decided by “conscience” (eg abortion, euthanasia, etc.). It argues that reflecting on the ways in which public policies construct or represent social “problems” provides a rationale for broadening ethical scrutiny to the basic purposes of government. This is because the ways in which policy “problems” are represented (problem representations) have a range of ethical implications for targeted groups and individuals and for the general population, in terms of people’s sense of self-worth, their participation in democratic decision-making, and their ability to live full and meaningful lives.Carol Bacchihttp://www.elsevier.com/wps/find/journaldescription.cws_home/714836/description#descriptio

Establishment of Regional Phytoremediation Buffer Systems for Ecological Restoration in the Great Lakes Basin, USA. I. Genotype × Environment Interactions

Poplar remediation systems are ideal for reducing runoff, cleaning groundwater, and delivering ecosystem services to the North American Great Lakes and globally. We used phyto-recurrent selection (PRS) to establish sixteen phytoremediation buffer systems (phyto buffers) (buffer groups: 2017 × 6; 2018 × 5; 2019 × 5) throughout the Lake Superior and Lake Michigan watersheds comprised of twelve PRS-selected clones each year. We tested for differences in genotypes, environments, and their interactions for health, height, diameter, and volume from ages one to four years. All trees had optimal health. Mean first-, second-, and third-year volume ranged from 71 ± 26 to 132 ± 39 cm3; 1440 ± 575 to 5765 ± 1132 cm3; and 8826 ± 2646 to 10,530 ± 2110 cm3, respectively. Fourth-year mean annual increment of 2017 buffer group trees ranged from 1.1 ± 0.7 to 7.8 ± 0.5 Mg ha−1 yr−1. We identified generalist varieties with superior establishment across a broad range of buffers (‘DM114’, ‘NC14106’, ‘99038022’, ‘99059016’) and specialist clones uniquely adapted to local soil and climate conditions (‘7300502’, ‘DN5’, ‘DN34’, ‘DN177’, ‘NM2’, ‘NM5’, ‘NM6’). Using generalists and specialists enhances the potential for phytoremediation best management practices that are geographically robust, being regionally designed yet globally relevant