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Tanya Miladinovic,1,2 Manu Sharma,1,2 Andy Phan,1,2 Hana Geres,1,2 Robert G Ungard,1,2 Katja Linher-Melville,1,2 Gurmit Singh1,2 1Michael G. DeGroote Institute for Pain Research and Care, Medicine, McMaster University, Hamilton, ON L8S 4M1, Canada; 2Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4M1, Canada Introduction: Pain is a common and debilitating comorbidity of metastatic breast cancer. The hippocampus has been implicated in nociceptive processing, particularly relating to the subjective aspect of pain. Here, a syngeneic mouse model was used to characterize the effects of peripheral tumors on hippocampal microglial activation in relation to cancer-induced pain (CIP). Materials and methods: Mice were systemically treated with the colony-stimulating factor 1 receptor inhibitor Pexidartinib prior to intrafemoral (IF) or subcutaneous 4T1 carcinoma cell inoculation. Spontaneous and evoked nociceptive responses were quantitated throughout tumor development, and contralateral hippocampi were collected via endpoint microdissection for RNA analysis. Additionally, IF tumor-bearing animals were sacrificed on days 5, 10, 15, and 20 post 4T1 cell inoculation, and brain sections were immunofluorescently stained for Iba1, a marker of activated microglia. Results: Ablation of these neuroimmune cells with the CSF1R inhibitor Pexidartinib delayed the onset and severity of cancer-induced nociceptive behaviors in IF tumor-bearing animals, adding to the body of literature that demonstrates microglial contribution to the development and maintenance of CIP. Furthermore, in untreated IF tumor-bearing mice, nociceptive behaviors appeared to progress in parallel with microglial activation in hippocampal regions. Immunofluorescent Iba1+ microglia increased in the dentate gyrus and cornu ammonis 1 hippocampal regions in IF tumor-bearing animals over time, which was confirmed at the mRNA level using relevant microglial markers. Conclusion: This is the first experimental evidence to demonstrate the effects of peripheral tumor-induced nociception on hippocampal microglial activation. The increase in hippocampal microglia observed in the present study may reflect the emotional and cognitive deficits reported by patients with CIP. Keywords: nociception, hippocampus, cancer-induced bone pain, breast cancer, Iba1

Background: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are frequently caused by multidrug-resistant organisms. Patient-centered endpoints in clinical trials are needed to develop new antibiotics for HABP/VABP. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials based on a patient-centered, benefit-risk evaluation., Methods: A multidisciplinary committee created an infectious diseases DOOR endpoint customized for HABP/VABP, incorporating infectious complications, serious adverse events, and mortality. We applied this to 2 previously completed, large randomized controlled trials for HABP/VABP. ZEPHyR compared vancomycin to linezolid and VITAL compared linezolid to tedizolid. For each trial, we evaluated the DOOR distribution and probability, including DOOR component and partial credit analyses. We also applied DOOR in subgroup analyses., Results: In both trials, the HABP/VABP DOOR demonstrated similar overall clinical outcomes between treatment groups. In ZEPHyR, the probability that a participant treated with linezolid would have a more desirable outcome than a participant treated with vancomycin was 50.2% (95% confidence interval [CI], 45.1%--55.3%). In VITAL, the probability that a participant treated with tedizolid would have a more desirable outcome than a participant treated with linezolid was 48.7% (95% CI, 44.8%-52.6%). The DOOR component analysis revealed that participants treated with tedizolid had a less desirable outcome than those treated with linezolid when considering clinical response alone. However, participants with decreased renal function had improved overall outcomes with tedizolid., Conclusions: The HABP/VABP DOOR provided more granular information about clinical outcomes than is typically presented in clinical trials. HABP/VABP trials would benefit from prospectively using DOOR., Competing Interests: Potential conflicts of interest. H. W. B. declares consulting fees from Antimicrobial Agents and Chemotherapy/American Society for Microbiology (ASM), Sanford Guide, and ID Clinics of North America/Elsevier; royalties from Sanford Guide; payment or honoraria from Grand Rounds at Temple; Finland Award for IDWeek Lecture travel; and role with travel reimbursed as Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (PACCARB) Voting Member and Board of Trustees, College of the Holy Cross. D. C. reports honoraria from ARLG, SimBioSys, AstraZeneca, Apellis Pharmaceutical, Kinnate Biopharma, MaxisIT Clinical Sciences, Pfizer, Parexel, Health Literacy Media, Incyte, American Society of Clinical Oncology, and Aster Insights, all unrelated to this work; and consulting fees from AstraZeneca, Incyte, Apellis Pharmaceuticals, Kinnate Biopharma, Maxis Health, Parexel, Health Literacy Media (nonprofit), and SimBioSys; reimbursement for personal expenses for attending meetings and/or travel from Aster Insights and the American Society of Clinical Oncology (ASCO); participation with honorarium to author on a data and safety monitoring board (DSMB) or advisory board for ASCO; a role as unpaid volunteer for the Metastatic Breast Cancer Alliance; and a role with honorarium to author from ORIEN Patient Advisory Council. H. F. C. reports grant funding from NIH; royalties from Sanford Guide to Antimicrobial Therapy; payment from The George Washington University for ID board review course lectures; participation in a DSMB for Merck; and stock in Merck and Moderna. S. B. D. reports research funding for clinical research studies from Gilead, Regeneron, Pfizer, F2G, Chan Zuckerberg Initiative Biohub, and NIH/NIAID; payments for clinical event adjudication committees from Basilea, Duke Clinical Research Institute, and Shionogi; a patent pending for Mif agonists (patent US20100143379A1); money for travel to conference from the Infectious Diseases Society of America (IDSA); and consulting fees from Genentech and Janssen/Johnson & Johnson (J&J); and leadership or fiduciary roles with IDSA Antibacterial Resistance Committee, California Department of Public Health Healthcare Associated Infections Advisory Committee, and the ARLG Innovations Group, Laboratory Center, Mentorship Committee, Gram Positive Committee, and Immunosuppressed Host Group. S. R. E. reports grant funding from NIH (NIAID, National Cancer Institute, National Heart, Lung, and Blood Institute), Centers for Disease Control and Prevention (CDC), and De Gruyter (Editor-in-Chief of Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genetech, AstraZeneca, Takeda, Microbiotix, J&J, Endologix, ChemoCentryx, Becton Dickenson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute (IDDI), SVB Leerink, Medtronic, Regeneron, Wake Forest University, Recor, Janssen, and IDDI; payments from lectures from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); support for attending meetings from FDA; and participation on DSMBs for NIH, Breast International Group, University of Pennsylvania, Washington University, Duke University, Roche, Pfizer, Takeda, Akouous, Appelis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Candel, Novartis, and Advantagene; and being an unpaid board member for the American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. V. G. F. reports personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, The Medicines Co, MedImmune, Bayer, Basilea, Affinergy, Janssen, ContraFect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, ContraFect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from IDSA for his service as Associate Editor of Clinical Infectious Diseases; and a patent pending in sepsis diagnostics. H. L.-T. is an employee of Pfizer and holds stock in Pfizer. C. H. receives stock dividends from GlaxoSmithKline. T. L. H. declares grant funding from NIH and Karius; royalties from UpToDate; consulting fees from Basilea Pharmaceutica, Affinivax, Lysovant, Aridis, and Pfizer; and participation on DSMB for platform trial for SNAP Trial and advisory board for Basilea. J. H.-A. reports grant funding from NIH and CDC; and payment from IDSA (reviewing IDSA/Clinical Infectious Diseases supplement), ARLG (for speaking at IDWeek dinner and Texas Medical Center Antimicrobial Resistance and Stewardship Conference conference), and Society for Healthcare Epidemiology of America (SHEA) (for speaking at SHEA Spring Conference). S. N. is an employee of J&J and holds stock in J&J; received support for travel to meetings paid by employer; and participated as unpaid member of a scientific advisory committee of Global Antibiotic Research and Development Partnership. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)