Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Kiran L. Kadam

This report was prepared as an account of work sponsored by an agency of the United States government. Neither the United States government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recommendation, or favoring by the United States government or any agency thereof. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States government or any agency thereof. Available electronically at http://www.doe.gov/bridge Available for a processing fee to U.S. Department of Energy and its contractors, in paper, from: U.S. Department of Energy Office of Scientific and Technical Information P.O. Box 62 Oak Ridge, TN 37831-0062 phone: 865.576.8401 fax: 865.576.5728 email: [email protected] Available for sale to the public, in paper, from: U.S. Department of Commerce National Technical Information Service 5285 Port Royal Road Springfield, VA 22161 phone: 800.553.6847 fax: 703.605.6900 email: [email protected] online ordering: http://www.ntis.gov/ordering.htm Printed on paper containing at least 50% wastepaper, including 20% postconsumer waste ii TABLE OF CONTENTS Acknowledgments____________________________________________________________ vii Executive Summary _________________________________________________..

DOEGO85004_1: Final Non-proprietary Technical Report, Generating Process and Economic Data for Preliminary Design of PureVision Biorefineries DOEGO85004_2: One Original Final Proprietary Technical Report to be mailed to DOE Golden.

The overall objective of the project was to define a two-stage reactive fractionation process for converting corn stover into a solid cellulose stream and two liquid streams containing mostly hemicellulosic sugars and lignin, respectively. Toward this goal, biomass fractionation was conducted using a small continuous pilot unit with a nominal capacity of 100 pounds per day of dry biomass to generate performance data using primarily corn stover as feedstock. In the course of the program, the PureVision process was optimized for efficient hemicellulose hydrolysis in the first stage employing autohydrolysis and delignification in the second stage using sodium hydroxide as a catalyst. The remaining cellulose was deemed to be an excellent substrate for producing fermentation sugars, requiring 40% less enzymes for hydrolysis than conventional pretreatment systems using dilute acid. The fractionated cellulose was also determined to have potential higher-value applications as a pulp product. The lignin coproduct was determined to be substantially lower in molecular weight (MW) compared to lignins produced in the kraft or sulfite pulping processes. This low-MW lignin can be used as a feed and concrete binder and as an intermediate for producing a range of high-value products including phenolic resins. This research adds to the understanding of the biomass conversion area in that a new process was developed in the true spirit of biorefineries. The work completed successfully demonstrated the technical effectiveness of the process at the pilot level indicating the technology is ready to advance to a 2–3 ton per day scale. No technical showstoppers are anticipated in scaling up the PureVision fractionation process to commercial scale. Also, economic feasibility of using the PureVision process in a commercial-scale biorefinery was investigated and the minimum ethanol selling price for the PureVision process was calculated to be $0.94/gal ethanol vs.$1.07/gal ethanol for the NREL process. Thus, the PureVision process is economically attractive. Given its technical and economic feasibility, the project is of benefit to the public in the following ways: 1) it demonstrated a novel biomass fractionation process that can provide domestic supply of renewable transportation fuel from all three biomass components (cellulose, hemicellulose and lignin), 2) the lignin stream from the process has many higher-value applications beyond simply burning the lignin for energy as proposed by competing technologies, 3) it can be deployed in rural areas and create jobs in these areas, and 3) it can add to the nation’s economy and security

Copyright 2001 by Humana Press Inc.

Hydrolysates were obtained from dilute sulfuric acid pretreatment of whole-tree softwood forest thinnings and softwood sawdust. Mid-infrared (IR) spectra were obtained on sample sets of wet washed hydrolysates, and 45C vacuum-dried washed hydrolysates, using a Fourier transform infrared (FTIR) spectrophotometer equipped with a diamond-composite attenuated total reflectance (ATR) cell. Partial least squares(PLS)analysisofspectra from each sample set was performed. Regression analyses for sugar components and lignin were generated using results obtained from standard wet chemicalandhigh-performance liquid chromatographymethods.The correlation coefficients of the predicted and measured values were >0.9. The root mean square standard error of the estimate for each component in the residues was generally within 2 wt% of the measured value except where reported in the tables. The PLS regression analysis of the wet washed solids was similar to the PLS regression analysis on the 45C vacuum-dried sample set. The FTIR-ATR technique allows mid-IR spectra to be obtained in a few minutes from wet washed or dried washed pretreated biomass solids. The prediction of the solids composition of anunknownwashed pretreated solid is very rapid once the PLS method has been calibrated with known standard solid residues