ABSTRACT
INTRODUCTION: Prior publications about the association between participation in the American College of Surgeons National Surgical Quality Improvement Program and improved postoperative outcomes have reported mixed results. We aimed to perform a comprehensive analysis of preoperative characteristics and unadjusted and risk-adjusted postoperative complication rates over time in the American College of Surgeons National Surgical Quality Improvement Program dataset. METHODS: We used the American College of Surgeons National Surgical Quality Improvement Program database, 2005 to 2018, to analyze preoperative patient characteristics and unadjusted and risk-adjusted rates of adverse postoperative outcomes by year. Expected events were calculated using multiple logistic regression, with each complication as the dependent variable and the 28 non-laboratory preoperative American College of Surgeons National Surgical Quality Improvement Program variables as the independent variables. Annual observed-to-expected ratios for each outcome were used to risk-adjust outcomes over time. RESULTS: The analytic cohort included 7,474,298 operations across 9 surgical specialties. Both the preoperative patient risk and the unadjusted rate of postoperative complications decreased over time. While the observed-to-expected ratio for mortality remained around 1, the observed-to-expected ratios for the other outcomes decreased over time from 2005 to 2018, except for the following cardiac complications: overall morbidity 1.11 (95% confidence interval: 1.10-1.13) to 0.97 (0.96-0.98); pulmonary 1.18 (1.15-1.21) to 0.91 (0.89-0.92); infection 1.19 (1.16-1.21) to 1.01 (1.00-1.01); urinary tract infection 1.29 (1.23-1.34) to 0.87 (0.86-0.89); venous thromboembolism 1.10 (1.03-1.16) to 0.92 (0.90-0.94) ; cardiac 0.76 (0.70-0.81) to 1.04 (1.01-1.07); renal 1.14 (1.08-1.21) to 0.96 (0.93-0.99); stroke 1.12 (1.00-1.25) to 0.98 (0.94-1.03); and bleeding 1.35 (1.33-1.36) to 0.80 (0.79-0.81). CONCLUSION: Hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program have experienced a decrease in risk-adjusted postoperative surgical complications over time in all areas except for mortality and cardiac complications.
ABSTRACT
We previously showed that long-range stapling of two Asn-linked O-allyl PEG oligomers via olefin metathesis substantially increases the conformational stability of the WW domain through an entropic effect. The impact of stapling was more favorable when the staple connected positions that were far apart in primary sequence but close in the folded tertiary structure. Here we validate these criteria for identifying new stabilizing PEG-stapling sites within the WW domain and the SH3 domain, both ß-sheet proteins. We find that stapling via olefin metathesis vs. the copper(I)-catalyzed azide/alkyne cycloaddition (CuAAC) results in similar energetic benefits, suggesting that olefin and triazole staples can be used interchangeably. Proteolysis assays of selected WW variants reveal that the observed staple-based increases in conformational stability lead to enhanced proteolytic resistance. Finally, we find that an intermolecular staple dramatically increases the quaternary structural stability of an α-helical GCN4 coiled-coil heterodimer.
ABSTRACT
Hydrocarbon stapling and PEGylation are distinct strategies for enhancing the conformational stability and/or pharmacokinetic properties of peptide and protein drugs. Here we combine these approaches by incorporating asparagine-linked O-allyl PEG oligomers at two positions within the ß-sheet protein WW, followed by stapling of the PEGs via olefin metathesis. The impact of stapling two sites that are close in primary sequence is small relative to the impact of PEGylation alone and depends strongly on PEG length. In contrast, stapling of two PEGs that are far apart in primary sequence but close in tertiary structure provides substantially more stabilization, derived mostly from an entropic effect. Comparison of PEGylation + stapling vs. alkylation + stapling at the same positions in WW reveals that both approaches provide similar overall levels of conformational stability.
