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Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

SARS-CoV-2 continues to pose a threat to public health. Current therapeutics remain limited to direct acting antivirals that lack distinct mechanisms of action and are already showing signs of viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) that plays an important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation of Mac1 abrogates viral replication in vivo by potentiating host innate immune responses. However, it is unknown whether this can be achieved by pharmacologic inhibition and can therefore be exploited therapeutically. Here we report a potent and selective lead small molecule, AVI-4206, that is effective in an in vivo model of SARS-CoV-2 infection. Cellular models indicate that AVI-4206 has high target engagement and can weakly inhibit viral replication in a gamma interferon- and Mac1 catalytic activity-dependent manner; a stronger antiviral effect for AVI-4206 is observed in human airway organoids. In an animal model of severe SARS-CoV-2 infection, AVI-4206 reduces viral replication, potentiates innate immune responses, and leads to a survival benefit. Our results provide pharmacological proof of concept that Mac1 is a valid therapeutic target via a novel immune-restoring mechanism that could potentially synergize with existing therapies targeting distinct, essential aspects of the coronaviral life cycle. This approach could be more widely used to target other viral macrodomains to develop antiviral therapeutics beyond COVID-19., Competing Interests: A.R.R, P.J., R.L.G., T.T., M.R., J.S.F., G.J.C., B.K.S., R.J.N, A.A., M.D., P.C.O., Y.D.P., N.K., M.O., T.Y.T., R.S., F.Z.B., and M.M. are listed as inventors on a patent application describing small molecule macrodomain inhibitors, which includes compounds described herein. T.Y.T and M.O. are listed as inventors on a patent application filed by the Gladstone Institutes that covers the use of pGLUE to generate SARS-CoV-2 infectious clones and replicons. The Krogan laboratory has received research support from Vir Biotechnology, F. Hoffmann-La Roche and Rezo Therapeutics. N.J.K. has financially compensated consulting agreements with Maze Therapeutics and Interline Therapeutics. He is on the Board of Directors and is President of Rezo Therapeutics and is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, GEn1E Lifesciences and Interline Therapeutics. B.K.S is co-founder of BlueDolphin LLC, Epiodyne Inc, and Deep Apple Therapeutics, Inc., and serves on the SRB of Genentech, the SAB of Schrodinger LLC, and the SAB of Vilya Therapeutics. M.O. is a cofounder of Directbio and board member of InVisishield. A.R.R. is a co-founder of TheRas, Elgia Therapeutics, and Tatara Therapeutics, and receives sponsored research support from Merck, Sharp and Dohme. A.A. is a co-founder of Tango Therapeutics, Azkarra Therapeutics and Kytarro; a member of the board of Cytomx, Ovibio Corporation, Cambridge Science Corporation; a member of the scientific advisory board of Genentech, GLAdiator, Circle, Bluestar/Clearnote Health, Earli, Ambagon, Phoenix Molecular Designs, Yingli/280Bio, Trial Library, ORIC and HAP10; a consultant for ProLynx, Next RNA and Novartis; receives research support from SPARC; and holds patents on the use of PARP inhibitors held jointly with AstraZeneca from which he has benefited financially (and may do so in the future). J.S.F. is a consultant to, shareholder of, and receives sponsored research support from Relay Therapeutics.

Objective: Workers' compensation guidelines may reinforce unhelpful thoughts regarding symptoms that are known to increase symptom intensity and magnitude of incapability., Methods: One guideline commonly used (the Official Disability Guidelines) was reviewed regarding carpal tunnel syndrome. For 15 statements, we created an alternative statement based on a set of consensus principles for health, value, and quality in care. One hundred eight upper extremity surgeons of the Science of Variation Group reviewed both versions of the statements to indicate their preference., Results: Surgeons preferred seven revised statements and five guideline statements and were neutral on three statements. Favored revisions related to more accurate discernment of symptoms that are clearly related to idiopathic median neuropathy and representative of severity of pathology., Conclusions: There may be important mental health considerations for care under a work claim, such as unhelpful thoughts or distress regarding symptoms, which are not adequately considered by the Official Disability Guidelines., Competing Interests: Disclosures: S.G., S.R., and T.J.C. certify that they have no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. One of the authors (J.M.M.) is an unpaid, voluntary reviewer for Official Disability Guidelines and the American College of Occupational and Environmental Medicine. One of the authors (D.R.) certifies that he, or a member of his immediate family, has or may receive payment or benefits from Skeletal Dynamics (less than US $100,000), Wright Medical for elbow implants (less than US $10,000), deputy editor for Clinical Orthopaedics and Related Research, Universities and Hospitals, and lawyers outside of the submitted work., (Copyright © 2022 American College of Occupational and Environmental Medicine.)

Bacterial cells and their associated plasmids and bacteriophages encode numerous small proteins of unknown function. One example, the 73-amino-acid protein TraR, is encoded by the transfer operon of the conjugative F plasmid of Escherichia coli. TraR is a distant homolog of DksA, a protein found in almost all proteobacterial species that is required for ppGpp to regulate transcription during the stringent response. TraR and DksA increase or decrease transcription initiation depending on the kinetic features of the promoter by binding directly to RNA polymerase without binding to DNA. Unlike DksA, whose full activity requires ppGpp as a cofactor, TraR is fully active by itself and unaffected by ppGpp. TraR belongs to a family of divergent proteins encoded by proteobacterial bacteriophages and other mobile elements. Here, we experimentally addressed whether other members of the TraR family function like the F element-encoded TraR. Purified TraR and all 5 homologs that were examined bound to RNA polymerase, functioned at lower concentrations than DksA, and complemented a dksA -null strain for growth on minimal medium. One of the homologs, λ Orf73, encoded by bacteriophage lambda, was examined in greater detail. λ Orf73 slowed host growth and increased phage burst size. Mutational analysis suggested that λ Orf73 and TraR have a similar mechanism for inhibiting rRNA and r-protein promoters. We suggest that TraR and its homologs regulate host transcription to divert cellular resources to phage propagation or conjugation without induction of ppGpp and a stringent response. IMPORTANCE TraR is a distant homolog of the transcription factor DksA and the founding member of a large family of small proteins encoded by proteobacterial phages and conjugative plasmids. Reprogramming transcription during the stringent response requires the interaction of DksA not only with RNA polymerase but also with the stress-induced regulatory nucleotide ppGpp. We show here that five phage TraR homologs by themselves, without ppGpp, regulate transcription of host promoters, mimicking the effects of DksA and ppGpp together. During a stringent response, ppGpp independently binds directly to, and inhibits the activities of, many proteins in addition to RNA polymerase, including translation factors, enzymes needed for ribonucleotide biosynthesis, and other metabolic enzymes. Here, we suggest a physiological role for TraR-like proteins: bacteriophages utilize TraR homologs to reprogram host transcription in the absence of ppGpp induction and thus without inhibiting host enzymes needed for phage development.