The severe acute respiratory syndrome (SARS) epidemic was caused by the spread of a previously unrecognized infectious agent, the SARS-associated coronavirus (SARS-CoV). Here we show that SARS-CoV could inhibit both virus-and interferon (IFN)-dependent signaling, two key steps of the antiviral response. We mapped a strong inhibitory activity to SARS-CoV nonstructural protein 1 (nsp1) and show that expression of nsp1 significantly inhibited the activation of all three virus-dependent signaling pathways. We show that expression of nsp1 significantly inhibited IFN-dependent signaling by decreasing the phosphorylation levels of STAT1 while having little effect on those of STAT2, JAK1, and TYK2. We engineered an attenuated mutant of nsp1 in SARS-CoV through reverse genetics, and the resulting mutant virus was viable and replicated as efficiently as wild-type virus in cells with a defective IFN response. However, mutant virus replication was strongly attenuated in cells with an intact IFN response. Thus, nsp1 is likely a virulence factor that contributes to pathogenicity by favoring SARS-CoV replication.Vertebrates have evolved sophisticated immunity mechanisms to manage infections by pathogens. The first line of defense is the innate immune response, which is initiated by the rapid recognition of pathogen-associated molecular patterns. In most cell types, viral RNA is sensed by RNA helicases (18) and triggers three signaling pathways, leading to the coordinated activation of the transcription factors ATF2/c-Jun, IRF3/IRF7, and NF-B (25). In addition, double-stranded RNA and other viral determinants are recognized by Toll-like receptors expressed by specialized cells involved in the immune response. Signaling downstream of the Toll-like receptors involves various adaptor molecules and ultimately results in the activation of the same or a closely related set of transcription factors to those activated in the generic response (reviewed in reference 18).Virus-activated transcription factors synergize to induce the production of a number of cytokines, including members of the type I interferon (IFN) family (which in humans comprises 14 IFN-␣ genes, 1 IFN-gene, and 1 IFN-␤ gene) and the type III IFN family (three human IFN-genes); inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, IL-12, tumor necrosis factor alpha (TNF-␣), and TNF-␤; and chemokines, such as RANTES and IL-8. Together, these cytokines signal the occurrence of the infection and orchestrate the innate immune response directed against the invading virus (2, 33, 37).Binding of type I or type III IFNs to their cognate receptors triggers a second wave of signaling, where phosphorylation and activation of the receptor-associated JAK1 and TYK2 kinases result in the phosphorylation and activation of the transcription factors STAT1 and STAT2. Activated STAT1/STAT2 forms a complex with IRF9, termed ISGF3, which activates the transcription of a set of IFN-inducible genes by binding to their IFN-stimulated response elements (ISREs) (1,33,37).The functional cons...

Virus infection results in the activation of a set of cellular genes involved in host antiviral defense. IRF-3 has been identified as a critical transcription factor in this process. The activation mechanism of IRF-3 is not fully elucidated, yet it involves a conformational change triggered by the virusdependent phosphorylation of its C-terminus. This conformational change leads to nuclear accumulation, DNA binding and transcriptional transactivation. Here we show that two distinct sets of Ser/Thr residues of IRF-3, on phosphorylation, synergize functionally to achieve maximal activation. Remarkably, we find that activated IRF-3 lacks transcriptional activity, but activates transcription entirely through the recruitment of the p300/CBP coactivators. Moreover, we show that two separate domains of IRF-3 interact with several distinct regions of p300/CBP. Interference with any of these interactions leads to a complete loss of transcriptional activity, suggesting that a bivalent interaction is essential for coactivator recruitment by IRF-3.

Patients undergoing total hip and knee arthroplasty are at high risk for venous thromboembolism (VTE) with an incidence of approximately 0.6–1.5%. Given the high volume of these operations, with approximately one million performed annually in the U.S., the rate of VTE represents a large absolute number of patients. The rate of VTE after total hip arthroplasty has been stable over the past decade, although there has been a slight reduction in the rate of deep venous thrombosis (DVT), but not pulmonary embolism (PE), after total knee arthroplasty. Over this time, there has been significant research into the optimal choice of pharmacologic VTE prophylaxis for individual patients, with the objective to reduce the rate of VTE while minimizing adverse side effects such as bleeding. Recently, aspirin has emerged as a promising prophylactic agent for patients undergoing arthroplasty due to its similar efficacy and good safety profile compared to other pharmacologic agents. However, there is no evidence to date that clearly demonstrates the superiority of any given prophylactic agent. Therefore, this review discusses (1) the current prevalence and trends in VTE after total hip and knee arthroplasty and (2) provides an update on pharmacologic VTE prophylaxis in regard to aspirin usage.

A shift toward a value-driven health-care model has made prospective collection of patient-reported outcome measures (PROMs) inextricably tied to measuring the success of orthopaedic surgery and patient satisfaction. While progress has been made in optimizing the utilization of PROM data, including establishing appropriate PROMs for a procedure and determining the clinical importance of unique tools, if these PROMs are not accurately analyzed and reported, a proportion of patients who do not reach the clinical thresholds may go unnoticed. Furthermore, parameters are unclear for setting a statistically and clinically important PROM threshold along with a minimum period for follow-up data collection.In this forum, we walk through simulated data sets modeling PROMs with the example of total joint arthroplasty. We discuss how the commonly used method of reporting PROMs by mean change can overestimate the treatment effects for the cohort as a whole and fail to capture distinct populations that are below a clinically relevant threshold. We demonstrate that when a study's outcome is PROMs, clinical importance should be reported using clinical thresholds such as the minimum clinically important difference (MCID), the smallest change in the treatment outcome that a patient perceives as beneficial, and the patient acceptable symptom state (PASS), the highest level of symptoms beyond which a patient considers himself or herself well. Finally, we propose a standardized reporting of PROMs that incorporates both the MCID and the PASS, and introduce a "clinical relevance ratio," which relies on a clinically relevant threshold to dichotomize outcomes and reports the number of patients achieving clinical importance at a given time point divided by the total number of patients included in the study. Unlike other common PROM-reporting approaches, the clinical relevance ratio is not skewed by patients who are lost to follow-up with increased time. Trends in health care demonstrate a rise in the dynamic of patients and clinicians sharing available evidence to support treatment decisions and improve care 1 . The 2016 Medicare Access and CHIP (Children's Health Insurance Program) Reau-thorization Act (MACRA) changed the way clinicians are rewarded, with reimbursement based on metrics of value rather than volume 2 . Importance has been placed on patient-reported outcome measures (PROMs), survey-based instruments that Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G532).