ABSTRACT
Type I interferons (IFN-I) are cytokines with potent antiviral and inflammatory capacities. IFN-I signaling drives the expression of hundreds of IFN-I stimulated genes (ISGs), whose aggregate function results in the control of viral infection. A few of these ISGs are tasked with negatively regulating the IFN-I response to prevent overt inflammation. ISG15 is a negative regulator whose absence leads to persistent, low-grade elevation of ISG expression and concurrent, self-resolving mild autoinflammation. The limited breadth and low-grade persistence of ISGs expressed in ISG15 deficiency are sufficient to confer broad-spectrum antiviral resistance. Inspired by ISG15 deficiency, we have identified a nominal collection of 10 ISGs that recapitulate the broad antiviral potential of the IFN-I system. The expression of the 10 ISG collection in an IFN-I non-responsive cell line increased cellular resistance to Zika, Vesicular Stomatitis, Influenza A (IAV), and SARS-CoV-2 viruses. A deliverable prophylactic formulation of this syndicate of 10 ISGs significantly inhibited IAV PR8 replication in vivo in mice and protected hamsters against a lethal SARS-CoV-2 challenge, suggesting its potential as a broad-spectrum antiviral against many current and future emerging viral pathogens. One-Sentence Summary: Human inborn error of immunity-guided discovery and development of a broad-spectrum RNA antiviral therapy.
ABSTRACT
Background: There are known classifications that describe thoracolumbar (TL) burst type injury but it is unclear which have the most influence on management. Our objective is to investigate the association of classification publications with the quantity and type of the most influential articles on TL burst fractures. Methods: Web of Science was searched, and exclusion and inclusion criteria were used to extract the top 100 cited articles on TL burst fractures. The effects on type, number, and other variables were separated into four eras as defined by four major classification publications. Results: 30 out of the top 100 articles represent level 1 or 2 evidence. The most influential journal was Spine, accounting for 35 articles and 4,537 citations. The highest number of articles (53) was published between the years 1995-2005, culminating with the Thoracolumbar Injury Severity Classification Score (TLICS) paper. After 2005, there was an increase in average citations per year. Following 2013, the number of highly influential articles decreased, and systematic reviews (SRs) became a larger proportion of the literature. There was a statistically significant increase in the level of 1 and 2 evidence articles with time until the publication of TLICS. The predictive value of time for higher levels of evidence was only seen in the pre-2005 years (AUC: 0.717, 95% CI 0.579-0.855, p = 0.002). Conclusions: In 1994, two articles marked the beginning of an era of highly influential TL burst fracture literature. The 2005 TLICS score was associated with a preceding increase in LOE and productivity. Following 2005, the literature saw a decrease in productivity and an increase in systematic review/meta-analysis (SR-MAs). These trends represent an increase in scholarly discussion that led to a systematic synthesis of the existing literature after publication of the 2005 TLICS article.
