The training process of many deep networks explores the same low-dimensional manifold.

We develop information-geometric techniques to analyze the trajectories of the predictions of deep networks during training. By examining the underlying high-dimensional probabilistic models, we reveal that the training process explores an effectively low-dimensional manifold. Networks with a wide range of architectures, sizes, trained using different optimization methods, regularization techniques, data augmentation techniques, and weight initializations lie on the same manifold in the prediction space. We study the details of this manifold to find that networks with different architectures follow distinguishable trajectories, but other factors have a minimal influence; larger networks train along a similar manifold as that of smaller networks, just faster; and networks initialized at very different parts of the prediction space converge to the solution along a similar manifold.

Infrapopliteal Endovascular Interventions for Claudication Are Associated with Poor Long-Term Outcomes in Medicare-Matched Registry Patients.

BACKGROUND: There are limited data supporting or opposing the use of infrapopliteal peripheral vascular interventions (PVI) for the treatment of claudication. OBJECTIVES: We aimed to evaluate the association of infrapopliteal PVI with long-term outcomes compared with isolated femoropopliteal PVI for the treatment of claudication. METHODS: We conducted a retrospective analysis of all patients in the Medicare-matched Vascular Quality Initiative database who underwent an index infrainguinal PVI for claudication from January 2004-December 2019 using Cox proportional hazards models. RESULTS: Of 14,261 patients (39.9% female; 85.6% age ≥65 years, 87.7% non-Hispanic white) who underwent an index infrainguinal PVI for claudication, 16.6% (N=2,369) received an infrapopliteal PVI. The median follow-up after index PVI was 3.7 years (IQR 2.1-6.1). Compared to patients who underwent isolated femoropopliteal PVI, patients receiving any infrapopliteal PVI had a higher 3-year cumulative incidence of conversion to CLTI (33.3% vs. 23.8%; P<0.001); repeat PVI (41.0% vs. 38.2%; P<0.01); and amputation (8.1% vs. 2.8%; P<0.001). After risk-adjustment, patients undergoing infrapopliteal PVI had a higher risk of conversion to CLTI (aHR 1.39, 95% CI, 1.25-1.53); repeat PVI (aHR 1.10, 95% CI, 1.01-1.19); and amputation (aHR 2.18, 95% CI, 1.77-2.67). Findings were consistent after adjusting for competing risk of death; in a 1:1 propensity-matched analysis; and in subgroup analyses stratified by TASC disease, diabetes, and end-stage kidney disease. CONCLUSIONS: Infrapopliteal PVI is associated with worse long-term outcomes than femoropopliteal PVI for claudication. These risks should be discussed with patients.

Robot-Assisted Surgery and Racial and Ethnic Disparities in Post-Prostatectomy Outcomes Among Prostate Cancer Patients.

BACKGROUND: We sought to determine whether the differences in short-term outcomes between patients undergoing robot-assisted radical prostatectomy (RARP) and those treated with open radical prostatectomy (ORP) differ by race and ethnicity. METHODS: This observational study used New York State Cancer Registry data linked to discharge records and included patients undergoing radical prostatectomy for localized prostate cancer during 2008-2018. We used logistic regression to examine the association between race and ethnicity (non-Hispanic White [NHW], non-Hispanic Black [NHB], Hispanic), surgical approach (RARP, ORP), and postoperative outcomes (major events, prolonged length of stay [pLOS], 30-day re-admission). We tested interaction between race and ethnicity and surgical approach on multiplicative and additive scales. RESULTS: The analytical cohort included 18,926 patients (NHW 14,215 [75.1%], NHB 3195 [16.9%], Hispanic 1516 [8.0%]). The average age was 60.4 years (standard deviation 7.1). NHB and Hispanic patients had lower utilization of RARP and higher risks of postoperative adverse events than NHW patients. NHW, NHB, and Hispanic patients all had reduced risks of adverse events when undergoing RARP versus ORP. The absolute reductions in the risks of major events and pLOS following RARP versus ORP were larger among NHB {relative excess risk due to interaction (RERI): major events -0.32 [95% confidence interval (CI) -0.71 to -0.03]; pLOS -0.63 [95% CI -0.98 to -0.35]) and Hispanic (RERI major events -0.27 [95% CI -0.77 to 0.09]; pLOS -0.93 [95% CI -1.46 to -0.51]) patients than among NHW patients. The interaction was absent on the multiplicative scale. CONCLUSIONS: RARP use has not penetrated and benefited all racial and ethnic groups equally. Increasing utilization of RARP among NHB and Hispanic patients may help reduce disparities in patient outcomes after radical prostatectomy.

Human Pharmacokinetic and CYP3A Drug-Drug Interaction Prediction of GDC-2394 Using Physiologically Based Pharmacokinetic Modeling and Biomarker Assessment.

Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and drug-drug interaction (DDI) of GDC-2394. PBPK models were developed using in vitro and in vivo data to reflect the oral and intravenous PK profiles of mouse, rat, dog, and monkey. The learnings from preclinical PBPK models were applied to a human PBPK model for prospective human PK predictions. The prospective human PK predictions were within 3-fold of the clinical data from the first-in-human study, which was used to optimize and validate the PBPK model and subsequently used for DDI prediction. Based on the majority of PBPK modeling scenarios using the in vitro CYP3A induction data (mRNA and activity), GDC-2394 was predicted to have no-to-weak induction potential at 900 mg twice daily (BID). Calibration of the induction mRNA and activity data allowed for the convergence of DDI predictions to a narrower range. The plasma concentrations of the 4ß-hydroxycholesterol (4ß-HC) were measured in the multiple ascending dose study to assess the hepatic CYP3A induction risk. There was no change in plasma 4ß-HC concentrations after 7 days of GDC-2394 at 900 mg BID. A dedicated DDI study found that GDC-2394 has no induction effect on midazolam in humans, which was reflected by the totality of predicted DDI scenarios. This work demonstrates the prospective utilization of PBPK for human PK and DDI prediction in early drug development of GDC-2394. PBPK modeling accompanied with CYP3A biomarkers can serve as a strategy to support clinical pharmacology development plans. SIGNIFICANCE STATEMENT: This work presents the application of physiologically based pharmacokinetic modeling for prospective human pharmacokinetic (PK) and drug-drug interaction (DDI) prediction in early drug development. The strategy taken in this report represents a framework to incorporate various approaches including calibration of in vitro induction data and consideration of CYP3A biomarkers to inform on the overall CYP3A-related DDI risk of GDC-2394.

Comparison of endovascular therapies for chronic limb-threatening ischemia and claudication.

OBJECTIVE: Analysis of regional data from the Vascular Quality Initiative (VQI) suggested improved survival for patients undergoing stent placement compared with balloon angioplasty and atherectomy. Using national data from the VQI linked to Medicare claims data through the Vascular Implant Surveillance and Interventional Outcomes Network program, this study aimed to compare the rates of mortality, reintervention, and amputation after endovascular interventions (atherectomy, stenting, and balloon angioplasty) for two separate cohorts: patients with chronic limb-threatening ischemia (CLTI) and patients with claudication. METHODS: This was a secondary data analysis of Society for Vascular Surgery National VQI data linked to Medicare claims, between October 2016 and December 2019. Patients aged ≥65 years with symptoms of claudication or CLTI and a diagnosis of occlusive disease were included. Urgent or emergent interventions or those with concurrent procedures (endarterectomy, bypass, or bilateral intervention) were excluded. Interventions were grouped into (1) balloon angioplasty only; (2) stent (with or without balloon angioplasty); or (3) atherectomy (alone, with or without stent, with or without balloon angioplasty). Propensity score-matched cohorts were constructed to conduct pairwise intervention comparisons of mortality, reintervention, and amputation rates. Multivariable logistic regression was used to derive propensity scores for each patient. Kaplan-Meier estimates and Cox proportional hazards ratios (HRs) (95% confidence interval [CI]) analyses were performed. RESULTS: A total of 9785 (2665 claudication, 7120 CLTI) eligible patients were identified. After propensity score matching for the CLTI group, 2826, 3608, and 2796 pairs of cases were used to compare balloon angioplasty vs atherectomy, balloon angioplasty vs stent, and stent vs atherectomy, respectively. No statistically significant difference in mortality was observed among all interventions. However, atherectomy was associated with a significant increase in reintervention rate compared with balloon angioplasty (HR, 1.22; 95% CI, 1.06-1.39; P = .01) and compared with stenting (HR, 1.27; 95% CI, 1.10-1.46; P < .01) within the first year after the index procedure. Of note, both atherectomy (HR, 0.82; 95% CI, 0.68-0.98; P < .05) and stenting (HR, 0.76; 95% CI, 0.64-0.90; P < .01) showed lower rates of major amputation when compared with balloon angioplasty within 1 year after the index procedure. In the claudication group, there were no significant differences observed among interventions for peripheral arterial disease for mortality, reintervention, or amputation rates. CONCLUSIONS: Further studies are needed to identify appropriate indications for atherectomy, because there may be a subset of patients with CLTI who benefit from this therapy with respect to amputation rates. Until then, caution should be exercised when using atherectomy because it is also associated with higher reintervention rates.

Long-Term Outcomes of Elective Endovascular versus Open Repair of Popliteal Artery Aneurysms in the VISION Database.

INTRODUCTION: The best modality for elective popliteal artery aneurysm repair (PAR) remains controversial. Most single center studies suggest open popliteal aneurysm repair (OPAR) is more durable than endovascular (EPAR), but large randomized multicenter studies are lacking. This study compares long-term outcomes of EPAR and OPAR in the VQI-VISION database. METHODS: Vascular Quality Initiative (VQI) Medicare-linked VISION database (2010-2019) for peripheral vascular interventions and infrainguinal bypass were reviewed for elective PAR. Patients undergoing OPAR and EPAR were propensity-matched to compare outcomes. RESULTS: There were 1,159 PAA repairs (65.1% open). EPAR patients were older (77 vs 73 years, p<0.001) and more likely to be on P2Y12 inhibitors (26.5% vs 17.0%, p<0.001). After matching, there were 396 patients in each group with similar baseline characteristics. EPAR patients were more likely to be discharged home (87.6% vs 48.5%, p<0.001) and have shorter hospital length-of-stay (1 vs 3 days, p<0.001). Kaplan-Meier curves showed no difference in mortality, reintervention, or major amputation at 1, 3, and 5 years. Cox proportional hazards regression showed no significant association between revascularization strategy and mortality, reintervention, or major amputation. Subgroup analysis of patients undergoing OPAR with great saphenous vein (GSV) bypass compared to EPAR showed that OPAR with GSV bypass was associated with lower mortality without difference in reintervention or major amputation. CONCLUSION: Elective EPAR is durable and comparable to OPAR in terms of limb outcomes, even when GSV is used as conduit. However, bypass with GSV was associated with increased survival after open popliteal aneurysm repair compared to endovascular therapy.

Factors associated with 90-day reintervention following lower extremity revascularization.

OBJECTIVE: Peripheral artery disease (PAD) represents a high-volume, high-cost burden on the health care system. The Centers for Medicare and Medicaid Services has developed the Bundled Payments for Care Improvement-Advanced program, in which a single payment is provided for all services administered in a postsurgical 90-day episode of care. Factors associated with 30- and 90-day reinterventions after PAD interventions would represent useful data for both payors and stake holders. METHODS: We conducted a national cohort study of adults 65 years and older in the Vascular Quality Initiative and Centers for Medicare and Medicaid Services-linked dataset who underwent an open, endovascular, or hybrid revascularization procedure for PAD between January 1, 2010, and December 31, 2018. Procedures for acute limb ischemia and aneurysms were excluded. The primary outcome was 90-day reintervention. Reintervention at 30 days was a secondary outcome. Covariates of interest included demographics, comorbidities, and patient- and facility-level characteristics. Multivariable Cox regression was used to determine the association between patient- and facility-level characteristics and the risk of 30- and 90-day reinterventions. RESULTS: Among 42,429 patients (71.3% endovascular, 23.3% open, and 5.4% hybrid), median age was 74 years (interquartile range, 69-80 years), 57.9% were male, and 84.3% were White. Chronic limb-threatening ischemia was the operative indication in 40.4% of the procedures. Overall, 42.8% were completed in the outpatient setting (40.3% outpatient, 2.5% office-based lab). Over 70% of procedures for chronic limb-threatening ischemia were completed as inpatient, whereas 60% of the claudication interventions were done as outpatient. The 90-day reintervention rate was 14.5%, and the 30-day reintervention rate was 5.5%. Compared with inpatient procedures, PAD interventions completed in the outpatient or office-based lab setting had significantly higher 90- and 30-day reintervention rates (reference, inpatient; outpatient 90-day reintervention: hazard ratio [HR], 1.41; 95% confidence interval [CI] 1.25-1.60; outpatient 30-day reintervention: HR, 1.90; 95% CI, 1.62-2.24; office-based lab 90-day reintervention: HR, 2.09; 95% CI, 1.82-2.41; office-based lab 30-day reintervention: HR, 3.54; 95% CI, 3.17-3.94). Open and hybrid approaches demonstrated lower risk of reintervention compared with endovascular procedures at 30 and 90 days and, compared with aortoiliac disease, all other anatomic segments of disease were associated with higher 90-day reintervention, but no difference was noted at 30 days. CONCLUSIONS: Although outpatient PAD interventions may be convenient for patients and providers, the outpatient setting is associated with a significant risk of subsequent reintervention. Additional work is needed to understand how to improve the longevity of outpatient PAD interventions.

The association of ruptured abdominal aortic aneurysm diameter with mortality in the International Consortium of Vascular Registries.

BACKGROUND: The mortality after ruptured abdominal aortic aneurysm (rAAA) repair is high, despite improvements in perioperative care, centralization of emergency vascular surgical services, and the introduction of endovascular aneurysm repair (EVAR). The diameter of intact AAA has been shown to be a predictor of short- and long-term survival. The aim of this study was to analyze the impact of AAA diameter on mortality for rAAA repair using contemporary data collected from the International Consortium of Vascular Registries and compare outcomes by sex and the type of repair patients received. METHODS: Prospective registry data on repair of rAAA from seven countries were collected from 2010 to 2016. The primary outcome was perioperative mortality after EVAR and open surgical repair (OSR). Data were stratified by type of repair and sex. Logistic regression models were used to estimate odds ratio (OR) for the association between AAA diameter and perioperative mortality and the association between type of repair and mortality. Multivariable logistic regression models were used to adjust for differences in patient characteristics. RESULTS: The study population consisted of 6428 patients with a mean age ranging from 70.2 to 75.4 years; the mean AAA diameter was 7.7 ± 1.8 cm. Females had a significantly smaller AAA diameter at presentation compared with males (6.9 ± 1.6 cm vs 7.9 ± 1.8 cm; P < .001). who underwent OSR had larger AAA diameters compared with those who underwent EVAR (P < .001). Females who underwent repair were significantly older (P < .001). Males were more likely to have cardiac disease, diabetes mellitus, and renal impairment. Overall, AAA diameter was a predictor of mortality in univariate and multivariate analysis. When analyzing EVAR and OSR separately, the impact of AAA diameter per cm increase on mortality was apparent in both males and females undergoing EVAR, but not OSR (EVAR: male OR, 1.09 [95% confidence interval, 1.03-1.16] and EVAR: female OR, 1.17 [95% confidence interval, 1.02-1.35]). The early mortality rate for males and females who underwent EVAR was 18.9% and 25.9% (P < .001), respectively. The corresponding mortality for males and females who underwent OSR was 30.2% and 38.6% (P < .001), respectively. CONCLUSIONS: In these real-world international data, there is a significant association between rAAA diameters and early mortality in males and females. This association was more evident in patients undergoing EVAR, but not shown in OSR. Despite improvements in overall AAA repair outcomes, the risk of mortality after rAAA repair is consistently higher for females.

Long-term outcomes of great saphenous vein harvest techniques for infrainguinal arterial bypass in a Medicare-matched registry database.

OBJECTIVE: Long-term outcomes for harvesting techniques for great saphenous vein (GSV) and its impact on the outcomes of infrainguinal arterial bypass remains largely unknown. Endoscopic GSV harvesting (EVH) has emerged as a less invasive alternative to conventional open techniques. Using the Vascular Quality initiative Vascular Implant Surveillance & Interventional Outcomes Network (VQI-VISION) database, we compared the long-term outcomes of infrainguinal arterial bypass using open and endoscopic GSV harvest techniques. METHODS: Patients who underwent infrainguinal GSV bypass between 2010 and 2019 were identified in the VQI-VISION Medicare linked database. Long-term outcomes of major/minor amputations, and reinterventions up to 5 years of follow-up were compared between continuous incisions, skip incision, and EVH, with continuous incisions being the reference group. Secondary outcomes included 30- and 90-day readmission, in addition to surgical site infections and patency rates at 6 months to 2 years postoperatively. Survival analysis using Kaplan-Meier curves and Cox regression hazard models were utilized to compare outcomes between groups. To adjust for multiple comparisons between the study groups, a P value of 2.5% was considered significant. RESULTS: Among the 8915 patients included in the study, continuous and skip vein harvest techniques were used in 44.4% and 43.4% of cases each, whereas 12.3% underwent EVH. The utilization of EVH remained relatively stable at around 12% throughout the study period. Compared with GSV harvest using continuous incisions, EVH was associated with higher rates of reintervention at 1 year (46.5% vs 41.3%; adjusted hazard ratio [aHR], 1.22; 95% confidence interval [CI], 1.06-1.41; P = .01]. However, no significant difference was observed between EVH and continuous incisions, and between skip and continuous incisions in terms of long-term reintervention or major and minor amputations on adjusted analysis. Compared with continuous incision vein harvest, both EVH and skip incisions were associated with lower surgical site infection rates within the first 6 months post-bypass (aHR, 0.53; 95% CI, 0.35-0.82 and aHR, 0.68; 95% CI, 0.53-0.87, respectively). Loss of primary, primary-assisted, and secondary patency was higher after EVH compared with continuous incision vein harvest. Among surgeons performing EVH, comparable long-term outcomes were observed regardless of low (<4 cases/year), medium (4-7 cases/year), or high procedural volumes (>7 cases/year). CONCLUSIONS: Despite higher 1-year reintervention rates, EVH for infrainguinal arterial bypass is not associated with a significant difference in long-term reintervention or amputation rates compared with other harvesting techniques. These outcomes are not influenced by procedural volumes for EVH technique.

Association between tissue loss type and amputation risk among Medicare patients with concomitant diabetes and peripheral arterial disease.

OBJECTIVE: Prior studies have described risk factors associated with amputation in patients with concomitant diabetes and peripheral arterial disease (DM/PAD). However, the association between the severity and extent of tissue loss type and amputation risk remains less well-described. We aimed to quantify the role of different tissue loss types in amputation risk among patients with DM/PAD, in the context of demographic, preventive, and socioeconomic factors. METHODS: Applying International Classification of Diseases (ICD)-9 and ICD-10 codes to Medicare claims data (2007-2019), we identified all patients with continuous fee-for-service Medicare coverage diagnosed with DM/PAD. Eight tissue loss categories were established using ICD-9 and ICD-10 diagnosis codes, ranging from lymphadenitis (least severe) to gangrene (most severe). We created a Cox proportional hazards model to quantify associations between tissue loss type and 1- and 5-year amputation risk, adjusting for age, race/ethnicity, sex, rurality, income, comorbidities, and preventive factors. Regional variation in DM/PAD rates and risk-adjusted amputation rates was examined at the hospital referral region level. RESULTS: We identified 12,257,174 patients with DM/PAD (48% male, 76% White, 10% prior myocardial infarction, 30% chronic kidney disease). Although 2.2 million patients (18%) had some form of tissue loss, 10.0 million patients (82%) did not. The 1-year crude amputation rate (major and minor) was 6.4% in patients with tissue loss, and 0.4% in patients without tissue loss. Among patients with tissue loss, the 1-year any amputation rate varied from 0.89% for patients with lymphadenitis to 26% for patients with gangrene. The 1-year amputation risk varied from two-fold for patients with lymphadenitis (adjusted hazard ratio, 1.96; 95% confidence interval, 1.43-2.69) to 29-fold for patients with gangrene (adjusted hazard ratio, 28.7; 95% confidence interval, 28.1-29.3), compared with patients without tissue loss. No other demographic variable including age, sex, race, or region incurred a hazard ratio for 1- or 5-year amputation risk higher than the least severe tissue loss category. Results were similar across minor and major amputation, and 1- and 5-year amputation outcomes. At a regional level, higher DM/PAD rates were inversely correlated with risk-adjusted 5-year amputation rates (R2 = 0.43). CONCLUSIONS: Among 12 million patients with DM/PAD, the most significant predictor of amputation was the presence and extent of tissue loss, with an association greater in effect size than any other factor studied. Tissue loss could be used in awareness campaigns as a simple marker of high-risk patients. Patients with any type of tissue loss require expedited wound care, revascularization as appropriate, and infection management to avoid amputation. Establishing systems of care to provide these interventions in regions with high amputation rates may prove beneficial for these populations.

Short-Term Out-of-Pocket and Total Costs of Care After Ablation, Resection, or Transplant for Early-Stage Hepatocellular Carcinoma: A National SEER-Medicare Cost Comparison.

BACKGROUND. Differences in survival and morbidity among treatment options (ablation, surgical resection, and transplant) for early-stage hepatocellular carcinoma (HCC) have been well studied. Additional understanding of the costs of such care would help to identify drivers of high costs and potential barriers to care delivery. OBJECTIVE. The purpose of this article was to quantify total and patient out-of-pocket costs for ablation, surgical resection, and transplant in the management of early-stage HCC and to identify factors predictive of these costs. METHODS. This retrospective U.S. population-based study used the SEER-Medicare linked dataset to identify a sample of 1067 Medicare beneficiaries (mean age, 73 years; 674 men, 393 women) diagnosed with early-stage HCC (size ≤ 5 cm) treated with ablation (n = 623), resection (n = 201), or transplant (n = 243) between January 2009 and December 2016. Total costs and patient out-of-pocket costs for the index procedure as well as for any care within 30 and 90 days after the procedure were identified and stratified by treatment modality. Additional comparisons were performed among propensity score-matched subgroups of patients treated by ablation or resection (each n = 172). Multivariable linear regression models were used to identify factors predictive of total costs and out-of-pocket costs for index procedures as well as for 30- and 90-day post-procedure periods. RESULTS. For ablation, resection, and transplant, median index-procedure total cost was US$6689, US$25,614, and US$66,034; index-procedure out-of-pocket cost was US$1235, US$1650, and US$1317; 30-day total cost was US$9456, US$29,754, and US$69,856; 30-day out-of-pocket cost was US$1646, US$2208, and US$3198; 90-day total cost was US$14,572, US$34,984, and US$88,103; and 90-day out-of-pocket cost was US$2138, US$2462, and US$3876, respectively (all p < .001). In propensity score-matched subgroups, ablation and resection had median index-procedure, 30-day, and 90-day total costs of US$6690 and US$25,716, US$9995 and US$30,365, and US$15,851 and US$34,455, respectively. In multivariable analysis adjusting for socioeconomic factors, comorbidities, and liver-disease prognostic indicators, surgical treatment (resection or transplant) was predictive of significantly greater costs compared with ablation at all time points. CONCLUSION. Total and out-of-pocket costs for index procedures as well as for 30-day and 90-day postprocedure periods were lowest for ablation, followed by resection and then transplant. CLINICAL IMPACT. This comprehensive cost analysis could help inform future cost-effectiveness analyses.

Duplex Ultrasound-Only Surveillance after Endovascular Abdominal Aortic Aneurysm Repair is Associated with Favorable Long-Term Outcomes.

BACKGROUND: Long-term data surrounding the impact of different endovascular abdominal aortic aneurysm repair (EVAR) surveillance strategies are limited. Therefore, the purpose of this study was to characterize postoperative imaging patterns, as well as to evaluate the association of duplex ultrasound surveillance after the first postoperative year with 5-year EVAR outcomes. METHODS: EVAR patients (2003-2016), who survived at least 1 year without aneurysm rupture, conversion to open repair, and reintervention in the Vascular Implant Surveillance and Interventional Outcomes Network were examined to provide all subjects ≥3 years of follow-up time. Patients were categorized into 6 cohorts after the first postoperative year: No imaging (N = 953); computed tomography (CT)/magnetic resonance imaging (MRI)-only (N = 2,976); duplex ultrasound-only (DUS; N = 1,808); combined CT/MRI + DUS with >50% being CT/MRI (N = 1,937); combined CT/MRI + DUS with >50% being DUS (N = 2,253); and mixed (CT + DUS + MRI N = 1,272). Abdominal aortic aneurysm (AAA)-related reintervention, rupture, conversion to open repair, and all-cause mortality were estimated using Kaplan-Meier analysis. Multivariable logistic regression models identified variables associated with using DUS-only imaging (versus CT/MRI only). Cox regression models compared 5-year outcomes between patients receiving DUS-only versus CT/MRI-only imaging. RESULTS: A total of 11,199 EVAR patients were examined (mean age 76 ± 7 years; female: 20%; nonelective: 10%). DUS-only imaging surveillance after the first postoperative year was more likely to occur after elective repairs, as well as among older, male patients. Smaller (<6 cm) preoperative AAA diameter and absence of documented concurrent iliac aneurysm was also associated with DUS-only follow-up. Additionally, no endoleak detection on index EVAR completion imaging, as well as a documented >5 mm decrease in AAA sac diameter at 1-year follow-up was more common with DUS-only surveillance protocols. Post-EVAR DUS-only imaging after the first postoperative year had the lowest incidence of reintervention, conversion to open repair, and rupture (as well as the composite reintervention/open conversion/rupture; log-rank P < 0.001 for all). Further, patients receiving exclusively DUS after their first postoperative year had better overall survival (log-rank P < 0.001). These outcome advantages that were associated with DUS-only surveillance compared with CT/MRI-only surveillance after EVAR persisted when controlling for baseline covariates, preoperative AAA diameter, prior aortic surgery history, sac growth, and presence of endoleak (all P < 0.01). CONCLUSIONS: EVAR patients selected for DUS-only surveillance after the first postoperative year have excellent freedom from AAA-related reintervention, conversion to open repair, rupture and all-cause mortality. These findings remained on multivariable analysis after adjusting for baseline characteristics, endoleak status and sac diameter changes within the first year. This is the first registry-based investigation to document long-term EVAR outcomes for patients entered into a DUS-only monitoring protocol which serves to corroborate the growing evidence base that DUS may be able to supplant CT surveillance in certain subgroups. A prospective randomized multicenter trial comparing DUS versus CT-based imaging after EVAR is needed to validate these findings which may serve to change current practice guidelines, as well as industry and regulatory stakeholder requirements.

Readmissions Following Endovascular Thoracic and Thoracoabdominal Aortic Repairs in the Vascular Implant Surveillance and Interventional Outcomes Network (VISION).

BACKGROUND: Investigate readmission rates, diagnoses associated with readmission, and associations with mortality through 90 days postoperatively after elective endovascular thoracic and thoracoabdominal aortic repair overall and by extent of coverage. METHODS: A cohort of index elective nontraumatic endovascular thoracic and thoracoabdominal aortic cases from 2010 to 2018 was derived from the Vascular Implant Surveillance and Interventional Outcomes Network. Cohort readmissions within 90 days postoperative were examined both overall and by Crawford extent (CE) of aortic coverage. Postoperative mortality was examined by reason for readmission and CE. RESULTS: The cohort consisted of 2,105 patients who underwent endovascular thoracic and thoracoabdominal aortic repair (1,550 CE 0A/0B; 242 CE 1-3; 313 CE 4-5). Cumulative risk for 90-day readmission was 34.3% in CE 0A/0B repairs, 33.4% in CE 4-5 repairs, and 47.4% in CE 1-3 repairs. Compared with CE 0A/B, patients with CE 1-3 repairs experienced an increased risk of readmission within 90 days postoperatively after adjusting for preoperative factors (adjusted hazard ratio [HR] 1.27 [1.00, 1.61]), while the readmission risk for CE 4-5 repairs did not differ significantly (adjusted HR 0.83 [0.64, 1.06]). Significant risk factors for 90-day readmission included chronic obstructive pulmonary disease, dialysis dependence, limited ambulation, visceral/spinal ischemia, and in-hospital stroke. Discharge to home was protective against readmission (HR 0.65, confidence interval 0.54-0.79). Patients with a readmission within 90 days had a 7.89-fold increase in 90-day mortality (HR 7.84; 5.17, 11.9) compared with those not readmitted. CONCLUSIONS: Increasing extent of endovascular thoracic and thoracoabdominal aortic repair was associated with higher 90-day readmission rates. Readmission for all CE was associated with near 8-fold increased risk of mortality. Risk factors associated with increased risk for readmission included pulmonary insufficiency, renal disease, and poor functional status. These findings can inform stakeholders about investment of resources to improve processes of care that both target prevention and mitigate risk of readmission after elective endovascular thoracic and thoracoabdominal aortic repair.

An Umbrella Insight into the Phytochemistry Features and Biological Activities of Corn Silk: A Narrative Review.

Corn silk (Zea mays L.) is the stigma of an annual gramineous plant named corn, which is distributed in many regions worldwide and has a long history of medicinal use. In recent years, with the sustainable development of traditional Chinese medicine, studies of corn silk based on modern technologies, such as GC-MS, LC-MS, and other analytical means, have offered more comprehensive analyses. Phytochemistry studies have shown that the main bioactive components in corn silk include flavonoids, polyphenols, phenolic acids, fatty acids, and terpenoids. Pharmacological studies have shown that corn silk extract has various pharmacological effects, such as reducing blood lipids, lowering blood pressure, regulating blood sugar levels, anti-inflammatory effects, and anti-oxidation effects. In this paper, the related research on corn silk from the past few years is summarized to provide a theoretical reference for the further development and utilization of corn silk.

Long-term Mortality and Reintervention After Repair of Ruptured Abdominal Aortic Aneurysms Using VQI-matched Medicare Claims.

OBJECTIVE: The objective of this study was to compare endovascular aortic aneurysm repair (EVAR) versus open aortic repair (OAR) on mortality and reintervention after ruptured infrarenal abdominal aortic aneurysm (rAAA) repair in the Vascular Quality Initiative (VQI). BACKGROUND: The optimal treatment modality for rAAA remains debated, with little data on long-term comparisons. METHODS: VQI rAAA repairs (2004-2018) were matched with Medicare claims (VQI-VISION). Primary outcomes were in-hospital and long-term mortality. Secondary outcome was reintervention. Inverse probability weighting was used to adjust for treatment selection, and Cox Proportional Hazards models and negative binomial regressions were used for analysis. Landmark analysis was performed among patients surviving hospital discharge. RESULTS: Among 1885 VQI/Medicare rAAA patients, 790 underwent OAR, and 1095 underwent EVAR. Median age was 76 years; 73% were male. Inverse probability weighting produced comparable groups. In-hospital mortality was lower after EVAR versus OAR (21% vs 37%, odds ratio: 0.52, 95% CI, 0.4-0.7). One-year mortality rates were lower for EVAR versus OAR [hazard ratio (HR) 0.74, 95% CI, 0.6-0.9], but not statistically different after 1 year (HR: 0.95, 95% CI, 0.8-1.2). This implies additional benefits to EVAR in the short term. Reintervention rates were higher after EVAR than OAR at 2 and 5 years (rate ratio: 1.79 95% CI, 1.2-2.7 and rate ratio:2.03 95% CI, 1.4-3.0), but not within the first year. Reintervention was associated with higher mortality risk for both OAR (HR: 1.66 95% CI, 1.1-2.5) and EVAR (HR: 2.14 95% CI, 1.6-2.9). Long-term mortality was similar between repair types (HR: 0.99, 95% CI, 0.8-1.2). CONCLUSIONS: Within VQI/Medicare patients undergoing rAAA repair, the perioperative mortality rate favors EVAR but equalizes after 1 year. Reinterventions were more common after EVAR and were associated with higher mortality regardless of treatment.

Long-term Mortality and Reintervention After Endovascular and Open Abdominal Aortic Aneurysm Repairs in Australia, Germany, and the United States.

OBJECTIVE: To examine long-term outcomes after endovascular (EVAR) and open repairs (OAR) for intact abdominal aortic aneurysms in Australia, Germany, and the United States, using a unified study design. BACKGROUND: Similarities and differences in long-term outcomes after EVAR versus OAR across countries remained unclear, given differences in designs across existing studies. METHODS: We identified patients aged >65 years undergoing intact abdominal aortic aneurysm repairs during 2010-2017/2018. We compared long-term patient mortality and reintervention after EVAR and OAR using Kaplan-Meier analyses and Cox regressions. Propensity score matching was performed within each country to adjust for differences in baseline patient characteristics between procedure groups. RESULTS: We included 3311, 4909, and 145363 patients from Australia, Germany, and the United States, respectively. The median patient age was 76 to 77 years, and most patients were males (77%-84%). Patient mortality was lower after EVAR than OAR within the first 60 days and became similar at 3-year follow-up (Australia 14.7% vs 16.5%, Germany 18.2% vs 19.7%, United States: 24.4% vs 24.4%). At the end of follow-up, patient mortality after EVAR was higher than OAR in Australia [ hazard ratio (HR) 95% CI: 1.21 (0.96-1.54)] but similar to OAR in Germany [HR 95% CI: 0.92 (0.80-1.07)] and the United States [HR 95% CI: 1.02 (0.99-1.05)]. The risk of reintervention after EVAR was more than twice that after OAR in Australia [HR 95% CI: 2.60 (1.09-6.15)], Germany [HR 95% CI: 4.79 (2.56-8.98)], and the United States [HR 95% CI: 2.67 (2.38-3.00)]. The difference in reintervention risk appeared early in German and United States patients. CONCLUSIONS: This multinational study demonstrated important similarities in long-term outcomes after EVAR versus OAR across 3 countries. Variation in long-term mortality and reintervention comparisons indicates possible differences in patient profiles, surveillance, and best medical therapy across countries.

Quantifying KRAS G12C Covalent Drug Inhibitor Activity in Mouse Tumors Using Mass Spectrometry.

The growing opportunities recognized for covalent drug inhibitors, like KRAS G12C inhibitors, are driving the need for mass spectrometry methods that can quickly and robustly measure therapeutic drug activity in vivo for drug discovery research and development. Effective front-end sample preparation is critical for proteins extracted from tumors but is generally labor intensive and impractical for large sample numbers typical in pharmacodynamic (PD) studies. Herein, we describe an automated and integrated sample preparation method for the measurement of activity levels of KRAS G12C drug inhibitor alkylation from complex tumor samples involving high throughput detergent removal and preconcentration followed by quantitation using mass spectrometry. We introduce a robust assay with an average intra-assay coefficient of variation (CV) of 4% and an interassay CV of 6% obtained from seven studies, enabling us to understand the relationship between KRAS G12C target occupancy and the therapeutic PD effect from mouse tumor samples. Further, the data demonstrated that the drug candidate GDC-6036, a KRAS G12C covalent inhibitor, shows dose-dependent target inhibition (KRAS G12C alkylation) and MAPK pathway inhibition, which correlate with high antitumor potency in the MIA PaCa-2 pancreatic xenograft model.

Association between readmission care fragmentation and outcomes after interventions for peripheral arterial disease.

OBJECTIVE: Lower extremity revascularization (LER) for peripheral artery disease is complicated by the frequent need for readmission. However, it is unclear if readmission to a nonindex LER facility (ie, a facility different from the one where the LER was performed) compared with the index LER facility is associated with worse outcomes. METHODS: This was a national cohort study of older adults who underwent open, endovascular, or hybrid LER for peripheral artery disease (January 1, 2010, to December 31, 2018) in the Vascular Quality Initiative who were readmitted within 90 days of their vascular procedure. This dataset was linked to Medicare claims and the American Hospital Association Annual Survey. The primary outcome was 90-day mortality and the secondary outcome was major amputation at 90 days after LER. The primary exposure was the location of the first readmission after LER (categorized as occurring at the index LER facility vs a nonindex LER facility). Generalized estimating equations logistic regression models were used to assess the association between readmission location and 90-day mortality and amputation. RESULTS: Among 42,429 patients who underwent LER, 33.0% were readmitted within 90 days. Of those who were readmitted, 27.3% were readmitted to a nonindex LER facility, and 42.2% of all readmissions were associated with procedure-related complications. Compared with patients readmitted to the index LER facility, those readmitted to a nonindex facility had a lower proportion of procedure-related reasons for readmission (21.5% vs 50.1%; P < .001). Most of the patients readmitted to a nonindex LER facility lived further than 31 miles from the index LER facility (39.2% vs 19.6%; P < .001) and were readmitted to a facility with a total bed size of <250 (60.1% vs 11.9%; P < .001). Readmission to a nonindex LER facility was not associated with 90-day mortality or 90-day amputation. However, readmission for a procedure-related complication was associated with major amputation (90-day amputation: adjusted odds ratio, 3.33; 95% confidence interval, 2.89-3.82). CONCLUSIONS: Readmission after LER for a procedure-related complication is associated with subsequent amputation. This finding suggests that quality improvement efforts should focus on understanding various types of procedure-related failure after LER and its role in limb salvage.

High incidence of type 2 endoleak and low associated adverse events in the Vascular Quality Initiative linked to Medicare claims.

INTRODUCTION: Type 2 endoleak (T2EL) is the most common adverse finding on postoperative surveillance after endovascular aortic aneurysm repair (EVAR). A low rate of aneurysm-related mortality with T2EL has been established. However, the optimal management strategy and the efficacy of reintervention remain controversial. This study used data from the Vascular Quality Initiative linked to Medicare claims (VQI-Medicare) to evaluate T2LE in a real-world cohort. METHODS: This retrospective review of EVAR procedures in VQI-Medicare included patients undergoing their first EVAR procedure between 2015 and 2017. Patients with an endoleak other than T2EL on completion angiogram and those without VQI imaging follow-up were excluded. Patients without Medicare part A or part B enrollment at the time of the procedure or without 1-year complete Medicare follow-up data were also excluded. The exposure variable was T2EL, defined as any branch vessel flow detected within the first postoperative year. Outcomes of interest were mortality, reintervention, T2EL-related reintervention, post-EVAR imaging, and T2EL behavior including spontaneous resolution, aneurysm sac regression, and resolution after reintervention. The association of prophylactic branch vessel embolization (PBE) with T2EL resolution and aneurysm sac regression was also evaluated. RESULTS: In a final cohort of 5534 patients, 1372 (24.7%) had an identified T2EL and 4162 (75.2%) did not. The median age of patients with and without T2EL was 77 and 75 years, respectively. There were no differences in mortality, imaging, reintervention, or T2EL-related reintervention at 3 years after the procedure for patients with T2EL. The aneurysm sac diameter decreased by 4 mm (range: 9-0 mm decrease) in the total cohort. Patients with inferior mesenteric artery-based T2EL had the smallest decrease in aneurysm diameter (median 1 mm decrease compared with 1.5 mm for accessory renal artery-based T2EL, 2 mm for multiple feeding vessel-based T2EL, and 4 mm for lumbar artery-based T2EL; P < .001). Spontaneous resolution occurred in 73.7% of patients (n = 809). T2ELs with evidence of multiple feeding vessels were associated with the lowest rate of spontaneous resolution (n = 51, 54.9%), compared with those with a single identified feeding vessel of inferior mesenteric artery (n = 99, 60.0%), lumbar artery (n = 655, 77.7%), or accessory renal artery (n = 31, 79.5%) (P < .001). PBE was performed in 84 patients. Patients who underwent PBE and were without detectable T2EL after EVAR had the greatest rate of sac regression at follow-up (7 mm decrease) compared with baseline. CONCLUSIONS: T2EL after EVAR is associated with high rates of spontaneous resolution, low rates of aneurysm sac growth, and no evidence of increased early mortality or reintervention. PBE in conjunction with EVAR may be indicated in some circumstances.

Longer patient travel distance is associated with increased non-index readmission after complex aortic surgery.

OBJECTIVE: Recently evolving practice patterns in complex aortic surgery have led to regionalization of care within fewer centers in the United States, and thus patients may have to travel farther for complex aortic care. Travel distance has been associated with inferior outcomes after non-vascular surgery, particularly non-index readmission. This study aims to assess the impact of patient travel distance on perioperative outcomes and readmissions after complex aortic surgery. METHODS: A retrospective review was conducted of all patients in the Vascular Quality Initiative and Vascular Implant Surveillance and Interventional Outcomes Network databases undergoing complex endovascular aortic repair (EVAR) including internal iliac or visceral vessel involvement, complex thoracic endovascular aortic repair (TEVAR) including zone 0 to 2 proximal extent or branched devices, and complex open abdominal aortic aneurysm (AAA) repair including suprarenal or higher clamp sites. Travel distance was stratified by rural/urban commuting area (RUCA) population-density category. Wilcoxon and χ2 tests were used to assess relationships between travel distance quintiles and baseline characteristics, mortality, and readmission. Travel distance and other factors were included in multivariable Cox models for survival and Fine-Gray competing risk models for freedom from readmission. RESULTS: Between 2011 and 2018, 8782 patients underwent complex aortic surgery in the Vascular Quality Initiative and Vascular Implant Surveillance and Interventional Outcomes Network databases, including 4822 complex EVARs, 2672 complex TEVARs, and 1288 complex open AAA repairs. Median travel distance was 22.8 miles (interquartile range [IQR], 8.6-54.8 miles). Median age was 75 years for all distance quintiles, but patients traveling longer distances were more likely female (26.8% in quintile 5 [Q5] vs 19.9% in Q1; P < .001), white (93.8% of Q5 vs 83.8% of Q1; P < .001), to have larger-diameter AAAs (median 59 mm for Q5 vs 55 mm for Q1; P < .001), and to have had prior aortic surgery (20.8% for Q5 vs 5.9% for Q1; P < .001). Overall 30-day readmission was more common at farther distances (18.1% for Q5 vs 14.8% for Q1; P = .003), with higher non-index readmission (11.2% for Q5 vs 2.7% for Q1; P < .001) and conversely lower index readmission (6.9% for Q5 vs 12.0% for Q1; P < .001). Multivariable-adjusted Fine-Gray models confirmed greater hazard of non-index readmission with farther distance, with a Q5 hazard ratio of 3.02 (95% confidence interval, 2.12-4.30; P < .001). Multivariable-adjusted Cox models demonstrated no association between travel distance and long-term survival but found that non-index readmission was associated with increased long-term mortality (hazard ratio, 1.46; 95% confidence interval, 1.20-1.78; P = .0001). CONCLUSIONS: Patients traveling farther for complex aortic surgery demonstrate higher non-index readmission, which, in turn, is associated with increased long-term mortality risk. Aortic centers of excellence should consider targeting these patients for more comprehensive follow-up and care coordination to improve outcomes.