Carotid endarterectomy and transcarotid artery revascularization can be performed with acceptable morbidity and mortality in patients with chronic kidney disease.

OBJECTIVE: Patients with chronic kidney disease (CKD) are considered a high-risk population, and the optimal approach to the treatment of carotid disease remains unclear. Thus, we compared outcomes following carotid revascularization for patients with CKD by operative approach of carotid endarterectomy (CEA), transfemoral carotid artery stenting (TFCAS), and transcarotid arterial revascularization (TCAR). METHODS: The Vascular Quality Initiative was analyzed for patients undergoing carotid revascularizations (CEA, TFCAS, and TCAR) from 2016 to 2021. Patients with normal renal function (estimated glomular filtration rate >90 mL/min/1.72 m2) were excluded. Asymptomatic and symptomatic carotid stenosis were assessed separately. Preoperative demographics, operative details, and outcomes of 30-day mortality, stroke, myocardial infarction (MI), and composite variable of stroke/death were compared. Multivariable analysis adjusted for differences in groups, including CKD stage. RESULTS: A total of 90,343 patients with CKD underwent revascularization (CEA, n = 66,870; TCAR, n = 13,459; and TFCAS, n = 10,014; asymptomatic, 63%; symptomatic, 37%). Composite 30-day mortality/stroke rates were: asymptomatic: CEA, 1.4%; TCAR, 1.2%; TFCAS, 1.8%; and symptomatic: CEA, 2.7%; TCAR, 2.3%; TFCAS, 3.7%. In adjusted analysis, TCAR had lower 30-day mortality compared with CEA (asymptomatic: adjusted odds ratio [aOR], 0.4; 95% confidence interval [CI], 0.3-0.7; symptomatic: aOR, 0.5; 95% CI, 0.3-0.7), and no difference in stroke, MI, or the composite outcome of stroke/death in both symptom cohorts. TCAR had lower risk of other cardiac complications compared with CEA in asymptomatic patients (aOR, 0.7; 95% CI, 0.6-0.9) and had similar risk in symptomatic patients. Compared with TFCAS, TCAR patients had lower 30-day mortality (asymptomatic: aOR, 0.5; 95% CI, 0.2-0.95; symptomatic: aOR, 0.3; 95% CI, 0.2-0.4), stroke (symptomatic: aOR, 0.7; 95% CI, 0.5-0.97), and stroke/death (asymptomatic: aOR, 0.7; 95% CI, 0.5-0.97; symptomatic: aOR, 0.6; 95% CI, 0.4-0.7), but no differences in MI or other cardiac complications. Patients treated with TFCAS had higher 30-day mortality (aOR, 1.8; 95% CI, 1.2-2.5) and stroke risk (aOR, 1.3; 95% CI, 1.02-1.7) in symptomatic patients compared with CEA. There were no differences in MI or other cardiac complications. CONCLUSIONS: Among patients with CKD, TCAR and CEA showed rates of stroke/death less than 2% for asymptomatic patients and less than 3% for symptomatic patients. Given the increased risk of major morbidity and mortality, TFCAS should not be performed in patients with CKD who are otherwise anatomic candidates for TCAR or CEA.

Design and Characterization of 1,3-Dihydro-2H-benzo[d]azepin-2-ones as Rule-of-5 Compliant Bivalent BET Inhibitors.

The 1,3-dihydro-2H-benzo[d]azepin-2-ones are potent and ligand-efficient pan-BET bromodomain inhibitors. Here we describe the extension of this template to exploit a bivalent mode of action, binding simultaneously to both bromodomains. Initially the linker length and attachment vectors compatible with bivalent binding were explored, leading to the discovery of exceptionally potent bivalent BET inhibitors within druglike rule-of-5 space.

Distal embolic protection use during transfemoral carotid artery stenting is associated with improved in-hospital outcomes.

OBJECTIVE: Despite current guidelines recommending the use of distal embolic protection during transfemoral carotid artery stenting (tfCAS) to prevent periprocedural stroke, there remains significant variation in the routine use of distal filters. We sought to assess in-hospital outcomes in patients undergoing tfCAS with and without embolic protection using a distal filter. METHODS: We identified all patients undergoing tfCAS in the Vascular Quality Initiative from March 2005 to December 2021 and excluded those who received proximal embolic balloon protection. We created propensity score-matched cohorts of patients who underwent tfCAS with and without attempted placement of a distal filter. Subgroup analyses of patients with failed vs successful filter placement and failed vs no attempt at filter placement were performed. In-hospital outcomes were assessed using log binomial regression, adjusted for protamine use. Outcomes of interest were composite stroke/death, stroke, death, myocardial infarction (MI), transient ischemic attack (TIA), and hyperperfusion syndrome. RESULTS: Among 29,853 patients who underwent tfCAS, 28,213 (95%) had a filter attempted for distal embolic protection and 1640 (5%) did not. After matching, 6859 patients were identified. No attempted filter was associated with significantly higher risk of in-hospital stroke/death (6.4% vs 3.8%; adjusted relative risk [aRR], 1.72; 95% confidence interval [CI], 1.32-2.23; P < .001), stroke (3.7% vs 2.5%; aRR, 1.49; 95% CI, 1.06-2.08; P = .022), and mortality (3.5% vs 1.7%; aRR, 2.07; 95% CI, 1.42-3.020; P < .001). In a secondary analysis of patients who had failed attempt at filter placement vs successful filter placement, failed filter placement was associated with worse outcomes (stroke/death: 5.8% vs 2.7%; aRR, 2.10; 95% CI, 1.38-3.21; P = .001 and stroke: 5.3% vs 1.8%; aRR, 2.87; 95% CI, 1.78-4.61; P < .001). However, there were no differences in outcomes in patients with failed vs no attempted filter placement (stroke/death: 5.4% vs 6.2%; aRR, 0.99; 95% CI, 0.61-1.63; P = .99; stroke: 4.7% vs 3.7%; aRR, 1.40; 95% CI, 0.79-2.48; P = .20; death: 0.9% vs 3.4%; aRR, 0.35; 95% CI, 0.12-1.01; P = .052). CONCLUSIONS: tfCAS performed without attempted distal embolic protection was associated with a significantly higher risk of in-hospital stroke and death. Patients undergoing tfCAS after failed attempt at filter placement have equivalent stroke/death to patients in whom no filter was attempted, but more than a two-fold higher risk of stroke/death compared with those with successfully placed filters. These findings support current Society for Vascular Surgery guidelines recommending routine use of distal embolic protection during tfCAS. If a filter cannot be placed safely, an alternative approach to carotid revascularization should be considered.

Statin therapy is associated with improved perioperative outcomes and long-term mortality following carotid revascularization in the Vascular Quality Initiative.

OBJECTIVE: Statin therapy is the standard of care for patients with carotid artery stenosis given its proven cardiovascular benefits. However, the impact of statin therapy on outcomes in patients undergoing carotid revascularization in the Vascular Quality Initiative has not yet been evaluated. Therefore, our aim was to investigate the association of statin therapy with outcomes following carotid endarterectomy (CEA), transfemoral carotid artery stenting (tfCAS), and transcarotid artery revascularization (TCAR). METHODS: We identified all patients who underwent CEA, tfCAS, or TCAR in the Vascular Quality Initiative registry from January 2016 to September 2021. To compare outcomes, we stratified patients by procedure type and created 1:1 propensity score-matched cohorts of patients who received no preoperative statin therapy (within 36 hours of procedure) versus those who received preoperative statin therapy. Propensity scores incorporated demographic characteristics, comorbidities, carotid symptom status, preoperative medications, and physician and hospital procedural experience. The primary outcome was a composite end point of in-hospital stroke and/or death. As a secondary analysis, we performed repeat propensity score-matching by postoperative statin use (prescribed at discharge) and assessed 5-year mortality. Relative risks (RR) and hazard ratios (HR) were calculated using log binomial regression and Cox regression, respectively. RESULTS: Among 97,835 CEA, 20,303 tfCAS, and 22,371 TCAR patients, 15%, 17%, and 10% of patients did not receive preoperative statin therapy, respectively. Compared with statin use, no statin use was associated with a higher risk of in-hospital stroke or death among 13,434 matched CEA patients (no statin, 1.7% vs statin, 1.4%; RR, 1.2; 95% confidence interval [CI], 1.02-1.5) and among 2707 matched tfCAS patients (4.8% vs 2.8%; RR, 1.7; 95% CI, 1.3-2.3). However, there was no difference for this outcome by statin use among 2089 matched TCAR patients (1.8% vs 1.6%; RR, 1.1; 95% CI, 0.7-1.8). At 5 years, no statin therapy at discharge was associated with higher 5-year mortality after CEA (15% vs 10%; HR, 1.8; 95% CI, 1.6-2) and tfCAS (18% vs 14%; HR, 1.5; 95% CI, 1.2-1.8), but there was no difference after TCAR (14% vs 11%; HR, 1.3; 95% CI, 0.9-1.8). CONCLUSIONS: Compared with statin use, no statin use was associated with a higher risk of in-hospital stroke or death and 5-year mortality among CEA and tfCAS patients. Although there was no significant difference in outcomes among TCAR patients, this may in part be due to lower statistical power in this cohort. Overall, statin therapy is essential in the short- and long-term management of patients undergoing carotid revascularization. Our findings not only support current Society for Vascular Surgery recommendations for statin therapy in patients undergoing carotid revascularization, but they also highlight an important opportunity for quality improvement.

Racial disparities in treatment of ruptured abdominal aortic aneurysms.

OBJECTIVE: The Society for Vascular Surgery has recommended immediate transfer of patients with ruptured abdominal aortic aneurysms (rAAAs) to a regional center when feasible. However, Black patients might be less likely to be transferred and more likely to be turned down for repair. We, therefore, examined the transfer rates, turndown rates, and outcomes for Black vs White patients presenting with rAAAs in two large databases. METHODS: We examined all rAAA repairs in the Vascular Quality Initiative from 2003 to 2020 to evaluate the transfer rates and outcomes for Black vs White patients. We used the National Inpatient Sample from 2004 to 2015 to examine the turndown rates. Mixed effects logistic regression, Cox regression, and marginal effects modeling were used to study the interaction between race, insurance status, surgery type (open repair vs endovascular aortic aneurysm repair), and hospital volume. RESULTS: We identified 4935 patients with rAAAs in the Vascular Quality Initiative (6.2% Black) and 48,489 in the National Inpatient Sample (6.0% Black). The rates of transfer were high; however, Black patients were significantly less likely to undergo transfer before repair compared with White patients (49% Black vs 62% White; P = .002). The result was consistent in both crude and adjusted analyses when considering only stable patients and was not modified by insurance status, surgery type, or hospital volume. No significant differences were found in perioperative mortality (22% vs 26%; P = .098) or complications (52% vs 52%; P = .64). However, Black patients were significantly more likely to be turned down for repair (37% vs 28%; odds ratio, 1.5; 95% confidence interval, 1.2-1.9; P < .001). A significant interaction was found between race and insurance status with respect to turndown. Patients with private insurance had undergone surgery at a similar rate, regardless of race. However, among patients with Medicare or Medicaid/self-pay, Black patients were less likely than were White patients to undergo repair (Medicare, 64% vs 72%; P = .001; Medicaid/self-pay, 43% vs 61%; P = .031). Patients with Medicaid/self-pay were also less likely to undergo repair than were patients of the same race with either Medicare or private insurance (P < .05). CONCLUSIONS: We found that Black patients with rAAAs are poorly served by the current systems of interhospital transfer in the United States, because they less often undergo transfer before repair. Although the postoperative outcomes appeared similar, this finding could be falsely optimistic, because Black patients, especially the underinsured, were turned down for repair more often even after adjustment. Significant work is needed to better understand the reasons underlying these disparities and identify the targets to improve the care of Black patients with rAAAs.

The impact of neighborhood social disadvantage on abdominal aortic aneurysm severity and management.

OBJECTIVE: Recent studies have highlighted socioeconomic disparities in the severity and management of abdominal aortic aneurysm (AAA) disease. However, these studies focus on individual measures of social disadvantage such as income and insurance status. The area deprivation index (ADI), a validated measure of neighborhood deprivation, provides a more comprehensive assessment of social disadvantage. Therefore, we examined the impact of ADI on AAA severity and its management. METHODS: We identified all patients who underwent endovascular or open repair of an AAA in the Vascular Quality Initiative registry between 2003 and 2020. An ADI score of 1 to 100 was assigned to each patient based on their residential zip code, with higher ADI scores corresponding with increasing deprivation. Patients were categorized by ADI quintiles. Outcomes of interest included rates of ruptured AAA (rAAA) repair versus an intact AAA repair and rates of endovascular repair (EVAR) versus the open approach. Logistic regression was used to evaluate for an independent association between ADI quintile and these outcomes. RESULTS: Among 55,931 patients who underwent AAA repair, 6649 (12%) were in the lowest ADI quintile, 11,692 (21%) in the second, 15,958 (29%) in the third, 15,035 (27%) in the fourth, and 6597 (12%) in the highest ADI quintile. Patients in the two highest ADI quintiles had a higher proportion of rAAA repair (vs intact repair) compared with those in the lowest ADI quintile (8.8% and 9.1% vs 6.2%; P < .001). They were also less likely to undergo EVAR (vs open approach) when compared with the lowest ADI quintile (81% and 81% vs 88%; P < .001). There was an overall trend toward increasing rAAA and decreasing EVAR rates with increasing ADI quintiles (P < .001). In adjusted analyses, when compared with patients in the lowest ADI quintile, patients in the highest ADI quintile had higher odds of rAAA repair (odds ratio, 1.4; 95% confidence interval, 1.2-1.8; P < .001) and lower odds of undergoing EVAR (odds ratio, 0.54; 95% confidence interval, 0.45-0.65; P < .001). CONCLUSIONS: Among patients who underwent AAA repair in the Vascular Quality Initiative, those with higher neighborhood deprivation had significantly higher rates of rAAA repair (vs intact repair) and lower rates of EVAR (vs open approach). Further work is needed to better understand neighborhood factors that are contributing to these disparities to identify community-level targets for improvement.

Disparities in 5-year outcomes and imaging surveillance following elective endovascular repair of abdominal aortic aneurysm by sex, race, and ethnicity.

OBJECTIVES: Sex, racial, and ethnic disparities in postoperative outcomes following abdominal aortic aneurysm repair have been described, but differences in long-term outcomes are poorly understood. Our aim was to identify differences in 5-year outcomes and imaging surveillance after elective endovascular aortic aneurysm repair (EVAR) by sex, race, and ethnicity and to explore potential mechanisms underlying these differences. METHODS: We identified patients undergoing elective EVAR in the Vascular Quality Initiative from 2003 to 2017 with linkage to Medicare claims through 2018 for long-term outcomes. Our primary outcome was 5-year aneurysm rupture. Secondary outcomes were 5-year reintervention and mortality and 2-year loss-to-imaging follow-up (defined as no aortic imaging from 6 to 24 months after EVAR). We used Kaplan-Meier and Cox regression analyses to evaluate these outcomes by sex/race/ethnicity and constructed multivariable models to explore potential contributing factors. RESULTS: Among 16,040 patients, 11,764 (73%) were White males, 2891 (18%) were White females, 417 (2.6%) were Black males, 175 (1.1%) were Black females, 141 (0.9%) were Asian males, 34 (0.2%) were Asian females, 277 (1.7%) were Hispanic males, and 60 (0.4%) were Hispanic females. At 5 years, rupture rates were highest in Black females at 6.4% and lowest in white males at 2.3%. Compared with White males, rupture rates were higher in White females (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.1-2.0), Black females (HR, 2.5; 95% CI, 1.0-6.0), and Asian females (HR, 5.2; 95% CI, 1.3-21). White females also had higher mortality (HR, 1.2; 95% CI, 1.2-1.3) and loss-to-imaging-follow-up (HR, 1.2; 95% CI, 1.1-1.3), whereas Black females had higher mortality (HR, 1.4; 95% CI, 1.1-1.8) and reintervention (HR, 2.0; 95% CI, 1.4-2.8). Among other groups, Black males had higher reintervention (HR, 1.4; 95% CI, 1.0-1.8), and both Black and Hispanic males had higher loss-to-imaging-follow-up (Black: HR, 1.4; 95% CI, 1.1-1.7; Hispanic: HR, 1.3; 95% CI, 1.0-1.8). In adjusted analyses, White, Black, and Asian females remained at significantly higher risk for 5-year rupture after accounting for procedure year, clinical and anatomic characteristics, surgeon and hospital volume, and loss-to-imaging follow-up. CONCLUSIONS: Compared with White male patients, Black females had higher 5-year aneurysm rupture, reintervention, and mortality after elective EVAR, whereas White females had higher rupture, mortality and loss-to-imaging-follow-up. Asian females also had higher rupture, and Black males had higher reintervention and loss-to-imaging-follow-up. These populations may benefit from improved preoperative counseling and clinical outreach after EVAR. A larger-scale investigation of current practice patterns and their impact on sex, racial, and ethnic disparities in late outcomes after EVAR is needed to identify tangible targets for improvement.

A retroperitoneal operative approach is associated with improved perioperative outcomes compared with a transperitoneal approach in open repair of complex abdominal aortic aneurysms.

OBJECTIVE: Several studies have demonstrated the advantages of a retroperitoneal (RP) vs a transperitoneal (TP) approach during open repair of infrarenal abdominal aortic aneurysms (AAAs). We compared the outcomes after open repair of complex AAAs (cAAAs) using an RP vs a TP approach and evaluated the relative use of these approaches over time. METHODS: We identified all patients who had undergone open intact cAAA repair in the Vascular Quality Initiative from 2003 to -2019 and created 1:1-propensity score-matched cohorts stratified by the operative approach (RP vs TP). The primary outcome was perioperative mortality. The secondary outcomes included perioperative complications and approach usage over time. To create 1:1 propensity score-matched cohorts, the patients were matched for demographics, comorbidities, and anatomic and/or intraoperative characteristics, including proximal clamp site and renal revascularization. The approach usage over time was determined by plotting the proportion of RP usage over time for the overall open cAAA cohort and subgroups of repairs using a supraceliac cross clamp, repair with concomitant renal revascularization, and repairs performed at high-volume centers (highest quintile, >11 cases annually). RESULTS: Of a total of 4613 patients, 2843 (62%) had undergone open cAAA repair using the TP approach and 1770 (38%) using the RP approach. Of the 1256 matched pairs, the RP approach was associated with lower risk of perioperative mortality compared with the TP approach (3.9% vs 6.8%; relative risk [RR], 0.57; 95% confidence interval [CI], 0.41-0.80; P = .001). Furthermore, the RP approach was associated with a lower risk of cardiac complications (7.2% vs 9.6%; RR, 0.75; 95% CI, 0.58-0.98), bowel ischemia (3.1% vs 5.4%; RR, 0.56; 95% CI, 0.39-0.84), and postoperative dialysis (3.3% vs 5.5%; RR, 0.59; 95% CI, 0.41-0.87). Overall, the proportion of patients who had undergone repair via an RP approach became lower over time (-1.0%/y; 95% CI, -1.5 to -0.5; P < .001). A similar trend in the decrease was found for the patients who had undergone repair with a supraceliac clamp (-2.3%/y; 95% CI, -3.6 to -1.0; P < .001) and in the high-volume hospitals (-2.1%/y; 95% CI, -3.4 to -0.8; P = .001), although no statistically significant decrease in RP usage was found for the patients who had undergone concomitant renal revascularization (-0.9%/y; 95% CI, -2.6 to 0.8; P = .28). CONCLUSIONS: For open cAAA repair, an RP approach was associated with lower perioperative mortality and complications compared with a TP approach. However, the relative usage of the RP approach has been decreasing over time. An increased adoption of the RP approach, when appropriate, might lead to improved outcomes with open cAAA repair.

Overview of screening eligibility in patients undergoing ruptured AAA repair from 2003 to 2019 in the Vascular Quality Initiative.

OBJECTIVE: Although efforts such as the Screening Abdominal Aortic Aneurysms Very Efficiently (SAAAVE) Act have improved access to abdominal aortic aneurysm (AAA) screening, certain high-risk populations are currently excluded from the guidelines yet may benefit from screening. We therefore examined all patients who underwent repair of ruptured AAA (rAAA) to characterize those who are ineligible for screening under current guidelines and evaluate the potential impact of these restrictions on their disease. METHODS: We identified patients undergoing rAAA repair in the Vascular Quality Initiative (VQI) database between 2003 and 2019. These patients were stratified by AAA screening eligibility according to the Centers for Medicare and Medicaid reimbursement guidelines. We then described baseline characteristics to identify high-risk features of these cohorts. Groups with disproportionate representation in the screening-ineligible cohort were identified as potential targets of screening expansion. Trends over time in screening eligibility and the proportion of AAA repairs performed for rAAA were also analyzed. RESULTS: A total of 5340 patients underwent rAAA repair. The majority (66%) were screening-ineligible. When characterizing the screening-ineligible group by sex and risk factors (smoking history or family history of AAA), the largest contributors to screening ineligibility were males less than 65 years of age with a smoking history or family history of AAA (25%), males greater than 75 years of age with a smoking history (25%), and females older than 65 years of age with a smoking history (19%). In comparison with rAAAs prior to implementation of the SAAAVE act, the proportion of AAA repair performed for rupture among males undergoing AAA repair in the VQI decreased from 12% to 8% (P < .001), whereas in females, there was no change (P = .990). There was no statically significant difference in screening eligibility for either males (P = .762) or females (P = .335). CONCLUSIONS: Most patients who underwent rAAA repair were ineligible for initial AAA screening or aged out of the screening window. Furthermore, rAAA rates and screening ineligibility have not improved as much as expected since the passage of the SAAAVE Act. Our data suggest that three high-risk populations may benefit from expansion of AAA screening guidelines: males with a smoking history or family history of AAA between ages 55 and 64 years, female smokers older than 65 years, and male smokers older than 75 years who are otherwise in good health. Increased efforts to screen these high-risk populations may increase elective AAA repair and minimize the morbidity and mortality associated with rAAAs.

A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid-targeted bromodomain and extra-terminal domain inhibitor.

AIMS: GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995). METHODS: Part A (N = 23) included three dose-escalating periods of 1-40 mg of GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts. RESULTS: In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization. CONCLUSIONS: Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.

Discovery of a Novel Bromodomain and Extra Terminal Domain (BET) Protein Inhibitor, I-BET282E, Suitable for Clinical Progression.

The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.

Protocolized Based Management of Cerebrospinal Fluid Drains in Thoracic Endovascular Aortic Aneurysm Repair Procedures.

BACKGROUND: Spinal cord ischemia (SCI) resulting in paraplegia is a devastating complication associated with thoracic endovascular aortic aneurysm repair (TEVAR) whose incidence has significantly declined over time. In this review, we present our experience with a multidisciplinary clinical protocol for cerebrospinal fluid (CSF) drain management in patients undergoing TEVAR. Furthermore, we aimed to characterize complications of CSF drain placement in a large, single center experience of patients who underwent TEVAR. METHODS: This retrospective review is of patients undergoing TEVAR with and without CSF drain placement between January 2014 and December 2019 at a single institution. Patient demographics, hospital course, and drain-related complications were analyzed to assess the incidence of CSF drain-related complications. RESULTS: A total of 235 patients were included in this study, of which 85 received CSF drains. Eighty patients (94.1%) were placed by anesthesiologists, while 5 (5.9%) were placed under fluoroscopic guidance by interventional neurosurgery. The most common level of placement was L3-L4 in 38 (44.7%) cases followed by L4-L5 in 36 (42.4%) cases. The mean duration of CSF drain was 1.9 ± 1.4 days. Complications due to CSF drainage occurred in 5 (5.9%) patients and included partial retainment of catheter, subdural edema, epidural hematoma, headache, and bleeding near the drain site. The overall 30-day mortality rate was 5.5% and did not differ between those who received a CSF drain and those who did not (P = 0.856). The overall incidence of SCI resulting in paraplegia was 1.7% in the studied patients. CONCLUSIONS: A protocol-based CSF drainage program for spinal cord protection involves a multifaceted approach in identification and selection of patients meeting criteria for prophylactic drain placement, direct closed loop communication, and perioperative management by an experienced team. Despite the inherent advantages of CSF drain placement, it is not without complications, thus risk and benefit need to be weighed in context of the procedure and the patient with close communication and team approach.

Structure-Based Design of a Bromodomain and Extraterminal Domain (BET) Inhibitor Selective for the N-Terminal Bromodomains That Retains an Anti-inflammatory and Antiproliferative Phenotype.

The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects.

GSK789: A Selective Inhibitor of the First Bromodomains (BD1) of the Bromo and Extra Terminal Domain (BET) Proteins.

Pan-bromodomain and extra terminal (BET) inhibitors interact equipotently with all eight bromodomains of the BET family of proteins. They have shown profound efficacy in vitro and in vivo in oncology and immunomodulatory models, and a number of them are currently in clinical trials where significant safety signals have been reported. It is therefore important to understand the functional contribution of each bromodomain to assess the opportunity to tease apart efficacy and toxicity. This article discloses the in vitro and cellular activity profiles of GSK789, a potent, cell-permeable, and highly selective inhibitor of the first bromodomains of the BET family.

Application of Atypical Acetyl-lysine Methyl Mimetics in the Development of Selective Inhibitors of the Bromodomain-Containing Protein 7 (BRD7)/Bromodomain-Containing Protein 9 (BRD9) Bromodomains.

Non-BET bromodomain-containing proteins have become attractive targets for the development of novel therapeutics targeting epigenetic pathways. To help facilitate the target validation of this class of proteins, structurally diverse small-molecule ligands and methodologies to produce selective inhibitors in a predictable fashion are in high demand. Herein, we report the development and application of atypical acetyl-lysine (KAc) methyl mimetics to take advantage of the differential stability of conserved water molecules in the bromodomain binding site. Discovery of the n-butyl group as an atypical KAc methyl mimetic allowed generation of 31 (GSK6776) as a soluble, permeable, and selective BRD7/9 inhibitor from a pyridazinone template. The n-butyl group was then used to enhance the bromodomain selectivity of an existing BRD9 inhibitor and to transform pan-bromodomain inhibitors into BRD7/9 selective compounds. Finally, a solvent-exposed vector was defined from the pyridazinone template to enable bifunctional molecule synthesis, and affinity enrichment chemoproteomic experiments were used to confirm several of the endogenous protein partners of BRD7 and BRD9, which form part of the chromatin remodeling PBAF and BAF complexes, respectively.

The role of transfemoral carotid artery stenting with proximal balloon occlusion embolic protection in the contemporary endovascular management of carotid artery stenosis.

OBJECTIVE: Recent data have shown that transcarotid artery revascularization (TCAR) with flow reversal provides a superior method of embolic protection compared with transfemoral carotid artery stenting (tfCAS) with distal embolic protection. Flow reversal or flow arrest systems with proximal endovascular balloon occlusion can also be used through the transfemoral approach; however, their outcomes compared with TCAR with flow reversal and tfCAS with distal embolic protection are poorly described. METHODS: We performed a retrospective review of all patients undergoing tfCAS with proximal balloon occlusion, tfCAS with distal embolic protection, and TCAR with flow reversal in the Society for Vascular Surgery Vascular Quality Initiative from March 2005 to May 2019. We assessed in-hospital outcomes in propensity score-matched cohorts of patients using tfCAS with proximal balloon occlusion as the comparison cohort. The primary outcome was stroke or death. Secondary end points included the individual outcomes of stroke, death, transient ischemic attack (TIA), and myocardial infarction. RESULTS: Of the 24,232 patients undergoing carotid artery stenting, 561 (2.3%) procedures were performed through tfCAS with proximal balloon occlusion, 18,126 (74%) through tfCAS with distal embolic protection, and 5545 (22.9%) through TCAR with flow reversal. After matching, 463 pairs of patients undergoing tfCAS with proximal balloon occlusion and tfCAS with distal embolic protection were identified. There were no differences in stroke or death (proximal balloon, 3.2%; distal embolic protection, 3.7%; relative risk [RR], 0.88; 95% confidence interval [CI], 0.45-1.73; P = .73), stroke (2.4% vs 2.6%; RR, 0.92; 95% CI, 0.42-2.00; P = .83), death (1.1% vs 1.5%; RR, 0.71; 95% CI, 0.41-3.15; P = .80), TIA (1.7% vs 1.5%; RR, 1.14; 95% CI, 0.41-3.15; P = .80), or myocardial infarction (0.4% vs 0.6%; RR, 0.67; 95% CI, 0.11-3.99; P = .65). However, after matching 357 pairs of patients undergoing tfCAS with proximal balloon occlusion and TCAR with flow reversal, tfCAS with proximal balloon occlusion was associated with higher rates of stroke or death (3.1% vs 0.8%; RR, 3.67; 95% CI, 1.02-13.14; P = .03) and a trend toward higher rates of stroke (2.5% vs 0.8%; RR, 3.00; 95% CI, 0.81-11.08; P = .08) and death (0.8% vs 0.0%; P = .08), but no statistically significant differences in TIA (0.8% vs 0.8%; P > .99) or myocardial infarction (0.6% vs 0.3%; RR, 2.00; 95% CI, 0.18-22.06; P = .56). CONCLUSIONS: Compared with tfCAS with distal embolic protection, tfCAS with proximal balloon occlusion has similar major outcomes. However, tfCAS with proximal balloon occlusion does not offer the same degree of embolic protection compared with TCAR with flow reversal, given the significantly higher risk of perioperative stroke or death.

Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation.

The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.

Aspartate transaminase to platelet ratio index and Model for End-Stage Liver Disease scores are associated with morbidity and mortality after endovascular aneurysm repair among patients with liver dysfunction.

BACKGROUND: Liver cirrhosis dramatically increases morbidity and mortality after open surgical procedures and is often a contraindication to open repair of abdominal aortic aneurysms. However, limited data have evaluated the effect of liver disease on outcomes after endovascular repair of aortic aneurysms. METHODS: The National Surgical Quality Improvement Program was used to evaluate all nonemergent endovascular aneurysm repairs (EVARs) from 2005 to 2016. The aspartate transaminase to platelet ratio index is a sensitive, noninvasive screening tool used to screen for liver disease and was calculated for all patients. A value >0.5 was used to identify those with significant liver fibrosis. Demographics, comorbidities, and 30-day outcomes were then compared between patients with and patients without fibrosis. Additional analysis was then completed to assess the effect of increasing Model for End-Stage Liver Disease (MELD) score on 30-day outcomes. Multivariable regression was used to account for differences in baseline factors. RESULTS: EVAR was performed on 18,484 patients including 2286 with liver fibrosis and 16,198 without. Patients with liver fibrosis had an increased 30-day mortality (1.5% vs 2.4%; P < .01) and significantly higher rates of major morbidities including return to the operating room, pulmonary complications, transfusion, and discharge other than home. After multivariable analysis, patients with liver fibrosis had a significant increase in 30-day mortality (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.1-2.1), return to the operating room (OR, 1.5; 95% CI, 1.2-1.8), pulmonary complications (OR, 1.6; 95% CI, 1.2-2.0), transfusion (OR, 1.7; 95% CI, 1.5-2.0), and discharge other than home (OR, 1.5; 95% CI, 1.3-1.8). In further analysis, mortality also increased in a stepwise fashion with increasing MELD score (MELD <10, 1.3%; MELD 10-15, 2.3%; MELD >15, 4.7%; P < .01), as did major complications (MELD <10, 7%; MELD 10-15, 11%; MELD >15, 15%; P < .01). These increases persisted in adjusted analysis. CONCLUSIONS: Liver fibrosis significantly increases mortality and major morbidity after EVAR. The aspartate transaminase to platelet ratio index and MELD score should be used for preoperative risk stratification. Moreover, current 30-day morbidity and mortality rates among patients with MELD scores >10 exceed 5%, which is higher than the annual rupture risk for aneurysms <6 cm. Therefore, an increased size threshold of >6 cm may be warranted before EVAR in patients with liver fibrosis.

Thirty-Day Outcomes After Open Revascularization for Acute Mesenteric Ischemia From the American College of Surgeons National Surgical Quality Improvement Program.

BACKGROUND: Open revascularization for acute mesenteric ischemia (AMI) is associated with high perioperative morbidity and mortality; however, results from contemporary studies are varied. Therefore, we evaluated 30-day mortality after open revascularization for AMI and identified preoperative factors associated with mortality. METHODS: We performed a retrospective cohort study of patients in the American College of Surgeons National Surgical Quality Improvement Program database undergoing open mesenteric revascularization for AMI from 2005 to 2017. The primary outcome was 30-day mortality. We used multivariable logistic regression to identify preoperative factors independently associated with 30-day mortality. RESULTS: The study cohort included 918 patients; their median age was 70 years (interquartile range: 59-80 years), 62% were female, and 90% were white. Thirty-day mortality after open revascularization for AMI was 32%, specifically 35% after embolectomy, 31% after thromboendarterectomy, and 28% after mesenteric bypass. Mortality was higher in patients requiring concomitant bowel resection (38% vs. 29%, respectively, P < 0.01). The preoperative factor most strongly associated with 30-day mortality was disseminated cancer (odds ratio = 8.8, 95% confidence interval = 2.4-32, P = 0.001). Other factors independently associated with mortality were renal dysfunction, preoperative intubation, preoperative blood transfusion, diabetes, elevated preoperative international normalized ratio, elevated preoperative white blood cell count, and increasing age. CONCLUSIONS: In this retrospective cohort study using a real-world, nationwide cohort, open revascularization for AMI was associated with high mortality, with nearly one-third of patients dying within 30 days of their operation. The factors identified to be independently associated with 30-day mortality, particularly disseminated cancer, preoperative renal dysfunction, and elevated preoperative WBC count, are an important tool for preoperative risk stratification.