In Reply

We appreciate the opportunity to respond to Dr. Laudanski’s critical commentary. The key result of our study suggests that signaling activity of the Toll-like receptor 4 (TLR4) in a presurgical whole blood sample predicts the speed at which patients regain function of their operated hip.1 We agree with Dr. Laudanski that nuclear factor kappa-light-chain-enhancer of activated B cells is ubiquitous. However, our findings are related to specific signaling events downstream of TLR4, including mitogen activated protein kinase-activated protein kinase-2, cyclic adenosine monophophate response element-binding protein, and ribosomal protein S6, that occurred in a precisely phenotyped subset of monocytes.1,2 The detected signaling patterns were highly specific with respect to pathway and cell type, which diverges from Dr. Laudanski’s view that “activation of the immune system is often non-specific.” Our findings further highlight the sentinel role of TLR4 in detecting tissue damage and mediating sterile inflammation and extend previous work by linking TLR4 activation patterns to patients’ functional recovery.3,4 Functional recovery is at the very core of current enhanced recovery after surgery protocols, and delays of weeks, as reported by us and others, matter greatly to patients and healthcare providers.2,5,6 A blood test identifying patients at risk for delayed functional recovery is an important step toward providing individualized, effective, cost-conscious, and high-value care in the context of the perioperative surgical home.7 While we agree that the blood test used an external or “artificial” TLR4 ligand (lipopolysaccharide) that may not recapitulate biology as it unfolds during surgery, the use of lipopolysaccharide to activate a specific signaling pathway does not negate the predictive value of the test.The scientific endeavor never stops, and interesting results will always trigger the next set of important questions. While our strong correlative findings provide a link to relevant biology, we agree that they do not prove cause and effect—and we never in our report suggested such a relationship. This is the next obvious question that we need to address. The prospect of validating TLR4 as a therapeutic target is exciting in light of preclinical studies, suggesting that preemptive dampening of TLR4 with a nontoxic agonist attenuated proinflammatory events and enhanced host resistance to infection and survival in models of burn injury and systemic infection.8,9There is certainly important work ahead of us and room to improve on all fronts. However, our bets have been placed, and we see a clear light at the end of the tunnel.Mrs. Fragiadakis is supported by the Stanford Bio-X Graduate Research Fellowship, Stanford, California, and the U.S. National Institutes of Health (NIH), Bethesda, Maryland (grant no. T32GM007276). Dr. Gaudillière is supported by the U.S. NIH (grant nos. 1K23GM111657-01 and T32GM089626). Dr. Aghaeepour is supported by an Ann Schreiber Mentored Investigator Award from the Ovarian Cancer Research Fund, New York, New York (OCRF 292495), a Canadian Institute of Health Research Postdoctoral Fellowship, Ottawa, Ontario, Canada (CIHR 321510), and an International Society for Advancement of Cytometry Scholarship, Bethesda, Maryland. This work was supported by grants from the U.S. NIH (grant nos. U19 AI057229, U54CA149145, N01-HV-00242, 1U19AI100627, 5R01AI07372405, R01CA184968, 1 R33 CA183654, R33 CA183692, 1R01GM10983601, 201303028, and 1R01NS08953301), NIH-the Baylor Research Institute, Dallas, Texas (grant no. 41000411217), the NIH-Northrop Grumman Corp., Falls Church, Virginia (grant no. 7500108142), the California Institute for Regenerative Medicine, San Francisco, California (grant no. DR1-01477), the U.S. Department of Defense, Washington, D.C. (grant no. OC110674), the European Commission, Brussels, Belgium (grant no. Health.2010.1.2-1), the U.S. Food and Drug Administration, Silver Spring, Maryland (grant no. HHSF223201210194C), the Bill and Melinda Gates Foundation, Seattle, Washington (grant nos. OPP1017093 and OPP1113682), the Alliance for Lupus Research, New York, New York, the Lymphoma Research Foundation, New York, New York, the Entertainment Industry Foundation, Los Angeles, California (National Women’s Cancer Research Alliance grant), and the Stanford Department of Anesthesiology, Perioperative and Pain Medicine, Stanford, California.Dr. Nolan has a personal financial interest in Fluidigm (South San Francisco, California), the manufacturer of the mass cytometer used in this article. The other authors declare no competing interests.

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