AIM2 Inflammasome Activation Contributes to Aortic Dissection in a Sporadic Aortic Disease Mouse Model.

BACKGROUND: The absent in melanoma 2 (AIM2) inflammasome induces pyroptosis, tissue inflammation, and extracellular matrix destruction. We tested the hypothesis that the AIM2 inflammasome contributes to aortic aneurysm and dissection (AAD) development by promoting pyroptosis in smooth muscle cells (SMCs). METHODS: We examined AIM2 expression in aortic tissues from patients with ascending thoracic aortic aneurysm (ATAA) and aortic dissection (ATAD) and from organ donor controls. AIM2's role in AAD development was evaluated in AIM2-deficient mice in a sporadic AAD model induced by challenging mice with a high-fat diet and angiotensin II infusion. The direct effects of dsDNA on SMC death in vitro were studied. RESULTS: Western blot analyses showed that AIM2 was increased in ATAD compared to ATAA and control tissue. Immunofluorescence demonstrated increased AIM2 in SMCs and macrophages in the aortic media and adventitia of dissected tissue. Increased AIM2 abundance was associated with increased cleavage of caspase-1 and cleavage of gasdermin-D, indicating activation of pyroptosis. In a mouse model of sporadic AAD induced by high-fat diet and angiotensin II infusion, AIM2-deficient mice showed significant reduction in aortic dissection, but not aneurysm formation in all aortic segments, versus wild-type mice. Finally, treating cultured human aortic SMCs with double-stranded DNA induced AIM2 expression, caspase-1 cleavage, and gasdermin-D cleavage; these effects were reduced by silencing AIM2 and caspase-1 genes, suggesting involvement of the AIM2 inflammasome in cytosolic DNA-induced activation of SMC pyroptosis. CONCLUSIONS: Activation of the AIM2 inflammasome cascade contributes to aortic degeneration and dissection, in part, by activating pyroptosis.

Fixed and Variable Relationship Models to Define the Volume-Value Relationship in Spinal Fusion Surgery: A Macroeconomic Analysis Using Evidence-Based Thresholds.

OBJECTIVE: Increased surgical volume has been associated with improved patient outcomes at the surgeon and hospital level. To date, clinically meaningful stratified volume benchmarks have yet to be defined for surgeons or hospitals in the context of spinal fusion surgery. The objective of this study was to establish evidence-based thresholds using outcomes and cost to stratify surgeons and hospitals performing spinal fusion surgery by volume. METHODS: Using 155,788 patients undergoing spinal fusion surgery, we created and applied 4 models using stratum-specific likelihood ratio (SSLR) analysis of a receiver operating characteristic (ROC) curve. This statistical approach was used to generate 4 sets of volume thresholds predictive of increased length of stay (LOS) and increased cost for surgeons and hospitals. RESULTS: SSLR analysis of the 2 ROC curves by annual surgical volume produced 3 or 4 distinct volume categories. Analysis of LOS by annual surgeon spinal fusion volume produced 4 strata: low, medium, high, and very high. Analysis of LOS by annual hospital spinal fusion volume produced 3 strata: low, medium, and high. No relationship between volume and cost could be clearly defined based on the generation of ROC curves for surgeons or hospitals offering spinal fusion. CONCLUSION: This study used evidence-based thresholds to identify a direct, variable relationship model between volume and outcomes of spinal fusion surgery, using LOS as a surrogate, for both surgeons and hospitals. A fixed relationship model was identified between surgeon and hospital volume and cost, as no statistically meaningful relationship could be established.