Interleukin-1 mediated hyperinflammation in XIAP-deficiency is associated with defective autophagy.

Deficiency of X-linked Inhibitor of Apoptosis Protein (XIAP) is a rare genetic condition that can present with recurrent episodes of hemophagocytic lymphohistiocytosis (HLH), though the exact mechanisms leading to this hyperinflammatory disorder are unclear. Understanding its biology is critical to developing targeted therapies for this potentially fatal disease. Here we report on a novel multi-exonic intragenic duplication leading to XIAP deficiency with recurrent HLH that demonstrated complete response to interleukin (IL)-1b blockade. We further demonstrate using both primary patient cells and genetically modified THP-1 monocyte cell lines that, contrary to what has previously been shown in mouse cells, XIAP-deficient human macrophages do not produce excess IL-1b when stimulated under standard conditions. Instead, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated hyperproduction of IL-1b is observed only when the XIAP-deficient cells are stimulated under autophagy-promoting conditions and this correlates with defective autophagic flux as measured by decreased accumulation of the early autophagy marker LC3-II. This work therefore highlights IL-1b blockade as a therapeutic option for patients with XIAP deficiency experiencing recurrent HLH and identifies a critical role for XIAP in promoting autophagy as a means of limiting IL-1b-mediated hyperinflammation during periods of cellular stress.

Effect of Endovascular Thrombectomy for Acute Ischemic Stroke on Cognitive Outcomes: A Secondary Analysis of the ESCAPE Trial.

BACKGROUND AND OBJECTIVES: The effect of endovascular therapy (EVT) for large vessel occlusion stroke on cognitive outcomes is not well understood. We evaluated the effect of EVT on cognitive function in the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial. METHODS: Patient data from the ESCAPE randomized trial were analyzed. Cognitive assessments completed at 90 days after stroke were the Montreal Cognitive Assessment (MoCA), the Sunnybrook Neglect Assessment Procedure (SNAP), the Boston Naming Test (BNT), Trail-making test A (Trails A), and Trail-making test B (Trails B). We used logistic regression to evaluate the association between EVT and favorable cognitive outcome on the 5 separate tests, adjusting for demographic and clinical factors. We used generalized estimating equations and ordinal regression to determine the odds of favorable outcome with EVT on global cognition incorporating the 5 tests. We added final infarct volume (FIV) to the models to assess the relationship of FIV with cognitive outcome. RESULTS: The ESCAPE trial included 315 patients, 165 randomized to EVT and 150 randomized to control. There was higher odds of favorable outcome with EVT for MoCA (adjusted odds ratio [aOR] 2.32, 95% CI 1.30-4.16), SNAP (aOR 3.85, 95% CI 2.00-7.45), BNT (aOR 2.33, 95% CI 1.30-4.17), trails A (aOR 3.50, 95% CI 1.93-6.36), and trails B (aOR 2.56, 95% CI 1.46-4.48). There was higher odds of favorable outcome with EVT on global binary (aOR 2.57, 95% CI 1.67-3.94) and ordinal analyses (aOR 2.83, 95% CI 1.68-4.76) of cognitive function. After adding FIV to the models, both FIV and EVT were significantly associated with cognitive outcome. There was a significant correlation between global cognitive performance and mRS at day 90 (r = -0.78, p < 0.001), with the largest reductions in favorable cognitive outcome from mRS score 4 to 5 and from mRS 2 to 3. DISCUSSION: In this secondary analysis of the ESCAPE trial, EVT was associated with favorable outcome on 5 separate cognitive tests and in global analyses of cognitive benefit. These results provide novel evidence for the effect of EVT on cognition and support the global benefit of treatment with EVT. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with acute ischemic stroke due to intracranial internal carotid artery (ICA) or M1 segment MCA occlusion, including tandem extracranial ICA occlusions, EVT compared with best medical therapy increased odds of favorable cognitive outcome.

Rescue Therapy for Failed Mechanical Thrombectomy in Acute Ischemic Stroke: A Pooled Analysis of the Society of Vascular and Interventional Neurology Registry.

OBJECTIVE: We aimed to evaluate the association between rescue therapy (RT) and functional outcomes compared to medical management (MM) in patients presenting after failed mechanical thrombectomy (MT). METHODS: This cross-sectional study utilized prospectively collected and maintained data from the Society of Vascular and Interventional Neurology Registry, spanning from 2011 to 2021. The cohort comprised patients with large vessel occlusions (LVOs) with failed MT. The primary outcome was the shift in the degree of disability, as gauged by the modified Rankin Scale (mRS) at 90 days. Additional outcomes included functional independence (90-day mRS score of 0-2), symptomatic intracranial hemorrhage (sICH), and 90-day mortality. RESULTS: Of a total of 7,018 patients, 958 presented failed MT and were included in the analysis. The RT group comprised 407 (42.4%) patients, and the MM group consisted of 551 (57.5%) patients. After adjusting for confounders, the RT group showed a favorable shift in the overall 90-day mRS distribution (adjusted common odds ratio = 1.79, 95% confidence interval [CI] = 1.32-2.45, p < 0.001) and higher rates of functional independence (RT: 28.8% vs MM: 15.7%, adjusted odds ratio [aOR] = 1.93, 95% CI = 1.21-3.07, p = 0.005) compared to the MM group. RT also showed lower rates of sICH (RT: 3.8% vs MM: 9.1%, aOR = 0.52, 95% CI = 0.28-0.97, p = 0.039) and 90-day mortality (RT: 33.4% vs MM: 45.5%, aOR = 0.61, 95% CI = 0.42-0.89, p = 0.009). INTERPRETATION: Our findings advocate for the utilization of RT as a potential treatment strategy for cases of LVO resistant to first-line MT techniques. Prospective studies are warranted to validate these observations and optimize the endovascular approach for failed MT patients. ANN NEUROL 2024.

Anesthetic management for large vessel occlusion acute ischemic stroke with tandem lesions.

BACKGROUND: Endovascular therapy (EVT) stands as an established and effective intervention for acute ischemic stroke in patients harboring tandem lesions (TLs). However, the optimal anesthetic strategy for EVT in TL patients remains unclear. This study aims to evaluate the impact of distinct anesthetic techniques on outcomes in acute ischemic stroke patients presenting with TLs. METHODS: Patient-level data, encompassing cases from 16 diverse centers, were aggregated for individuals with anterior circulation TLs treated between January 2015 and December 2020. A stratification based on anesthetic technique was conducted to distinguish between general anesthesia (GA) and procedural sedation (PS). Multivariable logistic regression models were built to discern the association between anesthetic approach and outcomes, including the favorable functional outcome defined as 90-day modified Rankin Score (mRS) of 0-2, ordinal shift in mRS, symptomatic intracranial hemorrhage (sICH), any hemorrhage, successful recanalization (modified Thrombolysis In Cerebral Infarction (mTICI) score ≥2b), excellent recanalization (mTICI 3), first pass effect (FPE), early neurological improvement (ENI), door-to-groin and recanalization times, intrahospital mortality, and 90-day mortality. RESULTS: Among 691 patients from 16 centers, 595 patients (GA 38.7%, PS 61.3%) were included in the final analysis. There were no significant differences noted in the door-to-groin time (80 (46-117.5) mins vs 54 (21-100), P=0.607) and groin to recanalization time (59 (39.5-85.5) mins vs 54 (38-81), P=0.836) among the groups. The odds of a favorable functional outcome (36.6% vs 52.6%; adjusted OR (aOR) 0.56, 95% CI 0.38 to 0.84, P=0.005) and a favorable shift in the 90-day mRS (aOR 0.71, 95% CI 0.51 to 0.99, P=0.041) were lower in the GA group. No differences were noted for sICH (3.9% vs 4.7%, P=0.38), successful recanalization (89.1% vs 86.5%, P=0.13), excellent recanalization (48.5% vs 50.3%, P=0.462), FPE (53.6% vs 63.4%, P=0.05), ENI (38.9% vs 38.8%, P=0.138), and 90-day mortality (20.3% vs 16.3%, P=0.525). An interaction was noted for favorable functional outcome between the type of anesthesia and the baseline Alberta Stroke Program Early CT Score (ASPECTS) (P=0.033), degree of internal carotid artery (ICA) stenosis (P<0.001), and ICA stenting (P<0.001), and intraparenchymal hematoma between the type of anesthesia and intravenous thrombolysis (P=0.019). In a subgroup analysis, PS showed better functional outcomes in patients with age ≤70 years, National Institutes of Health Stroke Scale (NIHSS) score <15, and acute ICA stenting. CONCLUSIONS: Our findings suggest that the preference for PS not only aligns with comparable procedural safety but is also associated with superior functional outcomes. These results prompt a re-evaluation of current anesthesia practices in EVT, urging clinicians to consider patient-specific characteristics when determining the optimal anesthetic strategy for this patient population.

Endovascular treatment of acute ischemic stroke patients with tandem lesions: antegrade versus retrograde approach.

OBJECTIVE: The optimal technique for treating tandem lesions (TLs) with endovascular therapy is debatable. The authors evaluated the functional, safety, and procedural outcomes of different approaches in a multicenter study. METHODS: Anterior circulation TL patients treated from January 2015 to December 2020 were divided on the basis of antegrade versus retrograde approach and included. The evaluated outcomes were favorable modified Rankin Scale (mRS) score (mRS score 0-2) at 3 months, ordinal shift in mRS score, successful recanalization, excellent recanalization, first-pass effect (FPE), time from groin puncture to successful recanalization, symptomatic intracranial hemorrhage (sICH), and 90-day mortality. RESULTS: Among 691 patients treated at 16 centers, 286 patients (174 antegrade and 112 retrograde approach patients) with acute stenting were included in the final analysis. There were no significant differences in mRS score 0-2 at 90 days (52.2% vs 50.0%, adjusted odds ratio [aOR] 0.83, 95% CI 0.42-1.56, p = 0.54), favorable shift in 90-day mRS score (aOR 1.03, 95% CI 0.66-1.29, p = 0.11), sICH (4.0% vs 4.5%, aOR 0.64, 95% CI 0.24-1.51, p = 0.45), successful recanalization (89.4% vs 93%, aOR 0.49, 95% CI 0.19-1.28, p = 0.19), excellent recanalization (51.4% vs 58.9%, aOR 0.59, 95% CI 0.40-1.07, p = 0.09), FPE (58.3% vs 69.7%, aOR 0.62, 95% CI 0.44-1.15, p = 0.21), and mortality at 90 days (16.6% vs 14.0%, aOR 0.94, 95% CI 0.35-2.44, p = 0.81) between the groups. The median (interquartile range) groin puncture to recanalization time was significantly longer in the antegrade group (59 [43-90] minutes vs 49 [35-73] minutes, p = 0.036). CONCLUSIONS: The retrograde approach was associated with faster recanalization times with a similar functional and safety profile when compared with the antegrade approach in patients with acute ischemic stroke with TL.

Safety Outcomes of Antiplatelet Therapy During Endovascular Treatment of Tandem Lesions in Acute Ischemic Stroke Patients.

Risk of hemorrhage remains with antiplatelet medications required with carotid stenting during endovascular therapy (EVT) for tandem lesion (TLs). We evaluated the safety of antiplatelet regimens in EVT of TLs. This multicenter study included anterior circulation TL patients from 2015 to 2020, stratified by periprocedural EVT antiplatelet strategy: (1) no antiplatelets, (2) single oral, (3) dual oral, and (4) intravenous IV (in combination with single or dual oral). Primary outcome was symptomatic intracranial hemorrhage (sICH). Secondary outcomes were any hemorrhage, favorable functional status (mRS 0-2) at 90 days, successful reperfusion (mTICI score ≥ 2b), in-stent thrombosis, and mortality at 90 days. Of the total 691 patients, 595 were included in the final analysis. One hundred and nineteen (20%) received no antiplatelets, 134 (22.5%) received single oral, 152 (25.5%) dual oral, and 196 (31.9%) IV combination. No significant association was found for sICH (ref: no antiplatelet: 5.7%; single:4.2%; aOR 0.64, CI 0.20-2.06, p = 0.45, dual:1.9%; aOR 0.35, CI 0.09-1.43, p = 0.15, IV combination: 6.1%; aOR 1.05, CI 0.39-2.85, p = 0.92). No association was found for parenchymal or petechial hemorrhage. Odds of successful reperfusion were significantly higher with dual oral (aOR 5.85, CI 2.12-16.14, p = 0.001) and IV combination (aOR 2.35, CI 1.07-5.18, p = 0.035) compared with no antiplatelets. Odds of excellent reperfusion (mTICI 2c/3) were significantly higher for cangrelor (aOR 4.41; CI 1.2-16.28; p = 0.026). No differences were noted for mRS 0-2 at 90 days, in-stent thrombosis, and mortality rates. Administration of dual oral and IV (in combination with single or dual oral) antiplatelets during EVT was associated with significantly increased odds of successful reperfusion without an increased rate of symptomatic hemorrhage or mortality in patients with anterior circulation TLs.

Low dose intravenous cangrelor versus glycoprotein IIb/IIIa inhibitors in endovascular treatment of tandem lesions.

OBJECTIVES: Intravenous (IV) periprocedural antiplatelet therapy (APT) for patients undergoing acute carotid stenting during mechanical thrombectomy (MT) is not fully investigated. We aimed to compare the safety profile of IV low dose cangrelor versus IV glycoprotein IIb/IIIa (GP-IIb/IIIa) inhibitors in patients with acute tandem lesions (TLs). MATERIALS AND METHODS: We retrospectively identified all cases of periprocedural administration of IV cangrelor or GP-IIb/IIIa inhibitors during acute TLs intervention from a multicenter collaboration. Patients were divided in two groups according to the IV APT regimen at the time of MT procedure: 1) cangrelor and 2) GP-IIb/IIIa inhibitors (tirofiban and eptifibatide). Safety outcomes included rates of symptomatic intracranial hemorrhage (sICH), parenchymal hematoma type 1 and 2 (PH1-PH2), and hemorrhagic infarction type 1 and 2 (HI1-HI2). RESULTS: Sixty-three patients received IV APT during MT, 30 were in the cangrelor group, and 33 were in the GP-IIb/IIIa inhibitors group. There were no significant differences in the rates of sICH (3.3% vs. 12.1%, aOR=0.21, 95%CI 0.02-2.18, p=0.229), HI1-HI2 (21.4% vs 42.4%, aOR=0.21, 95%CI 0.02-2.18, p=0.229), and PH1-PH2 (17.9% vs. 12.1%, aOR=1.63, 95%CI 0.29-9.83, p=0.577) between both treatment groups. However, there was a trend toward reduced hemorrhage rates with cangrelor. Cangrelor was associated with increased odds of complete reperfusion (aOR=5.86; 95%CI 1.57-26.62;p=0.013). CONCLUSIONS: In this retrospective non-randomized cohort study, our findings suggest that low dose cangrelor has similar safety and increased rate of complete reperfusion compared to IV GP-IIb/IIIa inhibitors. Further prospective studies are warranted to confirm this association.

Safety Outcomes of Mechanical Thrombectomy Versus Combined Thrombectomy and Intravenous Thrombolysis in Tandem Lesions.

BACKGROUND: We aimed to describe the safety and efficacy of mechanical thrombectomy (MT) with or without intravenous thrombolysis (IVT) for patients with tandem lesions and whether using intraprocedural antiplatelet therapy influences MT's safety with IVT treatment. METHODS: This is a subanalysis of a pooled, multicenter cohort of patients with acute anterior circulation tandem lesions treated with MT from 16 stroke centers between January 2015 and December 2020. Primary outcomes included symptomatic intracranial hemorrhage (sICH) and parenchymal hematoma type 2. Additional outcomes included hemorrhagic transformation, successful reperfusion (modified Thrombolysis in Cerebral Infarction score 2b-3), complete reperfusion (modified Thrombolysis in Cerebral Infarction score 3), favorable functional outcome (90-day modified Rankin Scale score 0-2), excellent functional outcome (90-day modified Rankin Scale score 0-1), in-hospital mortality, and 90-day mortality. RESULTS: Of 691 patients, 512 were included (218 underwent IVT+MT and 294 MT alone). There was no difference in the risk of sICH (adjusted odds ratio [aOR], 1.22 [95% CI, 0.60-2.51]; P=0.583), parenchymal hematoma type 2 (aOR, 0.99 [95% CI, 0.47-2.08]; P=0.985), and hemorrhagic transformation (aOR, 0.95 [95% CI, 0.62-1.46]; P=0.817) between the IVT+MT and MT alone groups after adjusting for confounders. Administration of IVT was associated with an increased risk of sICH in patients who received intravenous antiplatelet therapy (aOR, 3.04 [95% CI, 0.99-9.37]; P=0.05). The IVT+MT group had higher odds of a 90-day modified Rankin Scale score 0 to 2 (aOR, 1.72 [95% CI, 1.01-2.91]; P=0.04). The odds of successful reperfusion, complete reperfusion, 90-day modified Rankin Scale score 0 to 1, in-hospital mortality, or 90-day mortality did not differ between the IVT+MT versus MT alone groups. CONCLUSIONS: Our study showed that the combination of IVT with MT for tandem lesions did not increase the overall risk of sICH, parenchymal hematoma type 2, or overall hemorrhagic transformation independently of the cervical revascularization technique used. However, intraprocedural intravenous antiplatelet therapy during acute stent implantation might be associated with an increased risk of sICH in patients who received IVT before MT. Importantly, IVT+MT treatment was associated with a higher rate of favorable functional outcomes at 90 days.

Mechanical thrombectomy beyond 24 hours from last known well in tandem lesions: A multicenter cohort study.

BACKGROUND: While recent studies suggest a benefit of mechanical thrombectomy (MT) for the treatment of patients with isolated large vessel occlusions presenting after 24 hours from the last known well (LKW), the effect of MT for acute cervical tandem lesions (TLs) beyond 24 hours remains unknown. We aimed to evaluate the safety and effectiveness of MT beyond 24 hours of LKW in patients with TLs. METHODS: We conducted a subanalysis study of patients with anterior circulation TL enrolled in a large, multicenter registry between January 2015 and December 2020. Patients were divided into 2 groups: MT beyond 24 hours versus MT 0-24-hour window. Outcomes of interest were functional independence (90-day modified Rankin scale 0-2), complete reperfusion (modified thrombolysis in cerebral infarction 3), delta NIH Stroke Scale (NIHSS), symptomatic intracranial hemorrhage (sICH), parenchymal hematoma 2 (PH2), in-hospital mortality, and 90-day mortality. Inverse probability of treatment weighting (IPTW) was used to balance the groups. RESULTS: Overall, 589 participants were included, with 33 treated beyond 24 hours and 556 treated in the 0-24-hour window. After IPTW, we found no significant difference in the rates of achieving functional independence (odds ratio (OR) = 0.51; 95% confidence interval (CI) 0.22-1.16; p = 0.108), complete reperfusion (OR = 1.35; 95% CI 0.60-3.05; p = 0.464), sICH (OR = 1.96; 95% CI 0.37-10.5; p = 0.429), delta NIHSS (ß = -3.61; 95% CI -8.11 to 0.87; p = 0.114), PH2 (OR = 1.46; 95% CI 0.29-7.27; p = 0.642), in-hospital mortality (OR = 1.74; 95% CI 0.52-5.86; p = 0.370), or 90-day mortality (OR = 1.37; 95% CI 0.49-3.83; p = 0.544) across both time windows. CONCLUSIONS: Our results suggest that MT appears to benefit patients with TLs beyond 24 hours from LKW. Future prospective studies are warranted.

Clinical and Safety Outcomes of Endovascular Therapy 6 to 24 Hours After Large Vessel Occlusion Ischemic Stroke With Tandem Lesions.

BACKGROUND AND PURPOSE: Effect of endovascular therapy (EVT) in acute large vessel occlusion (LVO) patients with tandem lesions (TLs) within 6-24 hours after last known well (LKW) remains unclear. We evaluated the clinical and safety outcomes among TL-LVO patients treated within 6-24 hours. METHODS: This multicenter cohort was divided into two groups, based on LKW to puncture time: early window (<6 hours), and late window (6-24 hours). Primary clinical and safety outcomes were 90-day functional independence measured by the modified Rankin Scale (mRS: 0-2) and symptomatic intracranial hemorrhage (sICH). Secondary outcomes were successful reperfusion (modified Thrombolysis in Cerebral Infarction score ≥2b), first-pass effect, early neurological improvement, ordinal mRS, and in-hospital and 90-day mortality. RESULTS: Of 579 patients (median age 68, 32.1% females), 268 (46.3%) were treated in the late window and 311 (53.7%) in the early window. Late window group had lower median National Institutes of Health Stroke Scale score at admission, Alberta Stroke Program Early Computed Tomography Score, rates of intravenous thrombolysis, and higher rates for perfusion imaging. After adjusting for confounders, the odds of 90-day mRS 0-2 (47.7% vs. 45.0%, adjusted odds ratio [aOR] 0.71, 95% confidence interval [CI] 0.49-1.02), favorable shift in mRS (aOR 0.88, 95% CI 0.44-1.76), and sICH (3.7% vs. 5.2%, aOR 0.56, 95% CI 0.20-1.56) were similar in both groups. There was no difference in secondary outcomes. Increased time from LKW to puncture did not predicted the probability of 90-day mRS 0-2 (aOR 0.99, 95% CI 0.96-1.01, for each hour delay) among patients presenting <24 hours. CONCLUSION: EVT for acute TL-LVO treated within 6-24 hours after LKW was associated with similar rates of clinical and safety outcomes, compared to patients treated within 6 hours.

Using Ion Substitution and Fluid Indicators to Monitor Macropinosome Dynamics in Live Cells.

All forms of endocytosis involve the incidental uptake of fluid (pinocytosis). Macropinocytosis is a specialized type of endocytosis that results in the bulk ingestion of extracellular fluid via large (>0.2 µm) vacuoles called macropinosomes. The process is a means of immune surveillance, a point of entry for intracellular pathogens, and a source of nutrients for proliferating cancer cells. Macropinocytosis has also recently emerged as a tractable system that can be experimentally exploited to understand fluid handling in the endocytic pathway. In this chapter, we describe how stimulating macropinocytosis in the presence of extracellular fluids of a defined ionic composition can be combined with high-resolution microscopy to understand the role of ion transport in controlling membrane traffic.

Stroke-related risk factors during pregnancy in women who underwent metabolic and bariatric surgery compared with women who have not undergone metabolic and bariatric surgery.

BACKGROUND: Stroke during pregnancy is rare, occurring in 30 of 100,000 pregnancies and accounting for 7% of maternal deaths in the United States from 2016 to 2018. Metabolic and bariatric surgery (MBS) has been shown to reduce symptoms of chronic conditions that are risk factors for stroke, including hypertension, hypercholesterolemia, and diabetes in women. However, little is known about the impact of MBS on stroke risk during pregnancy. OBJECTIVES: To examine stroke and stroke risk factors including preeclampsia, eclampsia, gestational hypertension, and embolism/thrombosis in women of reproductive age who have had MBS. SETTING: We used the National Inpatient Sample, a publicly available data set from the Healthcare Cost and Utilization Project that samples 20% of hospital discharges in the United States. METHODS: This cross-sectional study included women between the ages of 20 and 44 years who had a maternal admission code. Weighted logistic regression was conducted to assess the odds of stroke and stroke risk factors in women with a history of MBS compared with other women of reproductive age. RESULTS: Women with a history of MBS have 12% lower adjusted odds of developing preeclampsia/eclampsia and 10% lower adjusted odds of gestational hypertension than women who did not undergo MBS. When stratified by race, the difference was significant in White women (preeclampsia/eclampsia: adjusted odds ratio [aOR] = .89; 95% confidence interval [CI], .81-.98; gestational hypertension: aOR = .91; 95% CI, .83-1.00). Latinas with MBS had significantly lower odds of preeclampsia/eclampsia (aOR = .75; 95% CI, .64-.90). CONCLUSIONS: MBS helps women lose weight and decrease the incidence of some pregnancy-related risk factors for stroke. However, there is a notable racial health disparity.

Functional and Safety Outcomes of Carotid Artery Stenting and Mechanical Thrombectomy for Large Vessel Occlusion Ischemic Stroke With Tandem Lesions.

Importance: Approximately 10% to 20% of large vessel occlusion (LVO) strokes involve tandem lesions (TLs), defined as concomitant intracranial LVO and stenosis or occlusion of the cervical internal carotid artery. Mechanical thrombectomy (MT) may benefit patients with TLs; however, optimal management and procedural strategy of the cervical lesion remain unclear. Objective: To evaluate the association of carotid artery stenting (CAS) vs no stenting and medical management with functional and safety outcomes among patients with TL-LVOs. Design, Setting, and Participants: This cross-sectional study included consecutive patients with acute anterior circulation TLs admitted across 17 stroke centers in the US and Spain between January 1, 2015, and December 31, 2020. Data analysis was performed from August 2021 to February 2022. Inclusion criteria were age of 18 years or older, endovascular therapy for intracranial occlusion, and presence of extracranial internal carotid artery stenosis (>50%) demonstrated on pre-MT computed tomography angiography, magnetic resonance angiography, or digital subtraction angiography. Exposures: Patients with TLs were divided into CAS vs nonstenting groups. Main Outcomes and Measures: Primary clinical and safety outcomes were 90-day functional independence measured by a modified Rankin Scale (mRS) score of 0 to 2 and symptomatic intracranial hemorrhage (sICH), respectively. Secondary outcomes were successful reperfusion (modified Thrombolysis in Cerebral Infarction score ≥2b), discharge mRS score, ordinal mRS score, and mortality at 90 days. Results: Of 685 patients, 623 (mean [SD] age, 67 [12.2] years; 406 [65.2%] male) were included in the analysis, of whom 363 (58.4%) were in the CAS group and 260 (41.6%) were in the nonstenting group. The CAS group had a lower proportion of patients with atrial fibrillation (38 [10.6%] vs 49 [19.2%], P = .002), a higher proportion of preprocedural degree of cervical stenosis on digital subtraction angiography (90%-99%: 107 [32.2%] vs 42 [20.5%], P < .001) and atherosclerotic disease (296 [82.0%] vs 194 [74.6%], P = .003), a lower median (IQR) National Institutes of Health Stroke Scale score (15 [10-19] vs 17 [13-21], P < .001), and similar rates of intravenous thrombolysis and stroke time metrics when compared with the nonstenting group. After adjustment for confounders, the odds of favorable functional outcome (adjusted odds ratio [aOR], 1.67; 95% CI, 1.20-2.40; P = .007), favorable shift in mRS scores (aOR, 1.46; 95% CI, 1.02-2.10; P = .04), and successful reperfusion (aOR, 1.70; 95% CI, 1.02-3.60; P = .002) were significantly higher for the CAS group compared with the nonstenting group. Both groups had similar odds of sICH (aOR, 0.90; 95% CI, 0.46-2.40; P = .87) and 90-day mortality (aOR, 0.78; 95% CI, 0.50-1.20; P = .27). No heterogeneity was noted for 90-day functional outcome and sICH in prespecified subgroups. Conclusions and Relevance: In this multicenter, international cross-sectional study, CAS of the cervical lesion during MT was associated with improvement in functional outcomes and reperfusion rates without an increased risk of sICH and mortality in patients with TLs.

Stroke and stroke risk factors in women of reproductive age with a history of metabolic or bariatric surgery.

OBJECTIVE: To determine the odds of stroke in women of reproductive age who have had metabolic or bariatric surgery (MBS). METHODS: We used the National Inpatient Sample (NIS), a publicly available dataset that samples 20% of hospital discharges. The study population includes women between the ages of 20 and 44 without a maternal admission code. Weighted logistic regression analyses were conducted to assess the odds of stroke in women with history of MBS compared to other women of reproductive age. Adjustment of odds was done for the following covariates: age, race, primary payer, severity of illness, depression, and obesity. RESULTS: Women with a history of MBS had 52% lower adjusted odds of having a stroke than women who did not have MBS (OR = 0.48, 95%CI = 0.42-0.55). Additionally, women who had MBS had lower odds of risk factors for stroke, including diabetes (OR = 0.61, 95%CI = 0.59-0.63), hypertension (OR = 0.82, 95%CI = 0.81-0.84), hypercholesterolemia (OR=0.72, 95%CI =0.68-0.77), and migraine with aura (OR = 0.86, 95%CI = 0.74-0.99). CONCLUSIONS: Among women of reproductive age with a history of MBS, there were lower odds of having a stroke and stroke risk factors when compared to women who did not have MBS. Additionally, this study showed a modest decrease in the odds of stroke among women with obesity when adjusted for other risk factors. Future research should focus on examining this finding further, with a focus on the moderation of the impact of having obesity on stroke risk independent of other stroke risk factors.

Ultrasound-Assisted Extraction of Natural Pigments From Food Processing By-Products: A Review.

Ultrasound is an emerging technology, which has been highly explored in the food area to improve processes and products. When ultrasound is applied to a product with solid or fluid characteristics, the passage of acoustic waves and acoustic cavitation generates different mechanisms responsible for modifications in the original matrix of the sample. These effects of ultrasound can also be used to take advantage of by-products, for example by extracting compounds of interest, including natural pigments. Natural pigments or colorants are being highly demanded by different industries not only for color purposes but also due to their healthy properties, the greater demands in regulations and new consumer preferences. This review presents an updated critical analysis of the application of ultrasound-assisted extraction (UAE) to obtain natural pigments from food processing by-products. Initially, the ultrasound effects and mechanisms that improve the extraction of natural pigments in a fluid medium, as well as the factors that influence the extraction and the energy consumption of UAE are analyzed and described. Subsequently, the UAE application to obtain pigments belonging to the groups of carotenoids, chlorophyll, anthocyanins and betalains is evaluated. These sections detail the processing conditions, positive and negative effects, as well as possible applications of the extracted pigments. This review presents relevant information that may be useful to expand and explore new applications of ultrasound technology as well as promote the revaluation of by-products to obtain pigments that can be used in food, pharmaceutical or cosmetic industries.

Validation of field assessment stroke triage for emergency destination for prehospital use in a rural EMS system.

BACKGROUND: Field Assessment Stroke Triage for Emergency Destination (FAST-ED) is a simple and accurate prehospital stroke severity scale that has been shown to have comparable accuracy to the gold standard National Institutes of Health Stroke Scale (NIHSS) but requires further field validation for use by emergency medical services (EMS), particularly in rural systems. FAST-ED scores ≥4 are considered high probability for large vessel occlusion (LVO) strokes, while scores <4 are low to moderate probability for LVO. The objective of this study was to assess inter-rater reliability of the EMS FAST-ED (EMS) score to the emergency department FAST-ED (ED-MD) scores. METHODS: EMS calculated FAST-ED scores prior to transport to the emergency department (ED) on patients with a positive prehospital stroke screen. EDMD calculated FAST-ED scores for the same patients upon arrival to the ED. Interrater reliability and test characteristics were calculated. RESULTS: A total of 95 patients were included in this study and 14 were subsequently diagnosed with an LVO. EMS assigned 34 patients (35.8%) a FAST-ED score of ≥4. EDMD assigned 25 patients (26.3%) a FAST-ED score of ≥4. Using the clinical cut-points of FAST-ED scores <4 and ≥ 4, a linearly weighted Cohen's kappa coefficient showed moderate interrater reliability when comparing EMS and EDMD scores (kw 0.44, 95% CI 0.25-0.63). At ≥4, EMS FAST-ED scores had a sensitivity 0.48, specificity 0.75, PPV 0.62, NPV 0.62 for predicting an LVO, while EDMD FAST-ED scores had a sensitivity 0.36, specificity 0.82, PPV 0.64, NPV 0.60. Comparable receiver operator curve area under the curve values were obtained. CONCLUSIONS: EMS and EDMD FAST-ED scores were moderately comparable in a rural EMS system. Similar NPVs compared to EDMD suggest the use of FAST-ED as an appropriate screening tool for EMS to predict the probability of LVO in the prehospital setting and make destination determinations regarding primary transport to a thrombectomy-capable stroke center.

Prostaglandin E2 Receptor 4 (EP4) as a Therapeutic Target to Impede Breast Cancer-Associated Angiogenesis and Lymphangiogenesis.

The formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Angiogenesis is essential for cancer cell survival. Lymphangiogenesis is critical in maintaining tumoral interstitial fluid balance and importing tumor-facilitatory immune cells. Both vascular routes also serve as conduits for cancer metastasis. Intratumoral hypoxia promotes both events by stimulating multiple angiogenic/lymphangiogenic growth factors. Studies on tumor-associated lymphangiogenesis and its exploitation for therapy have received less attention from the research community than those on angiogenesis. Inflammation is a key mediator of both processes, hijacked by many cancers by the aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and showed that COX-2 is a major promoter of both events, primarily resulting from the activation of prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and the induction of oncogenic microRNAs. The COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and the stimulation of stem-like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors.

Neurothrombectomy for Acute Ischemic Stroke Across Clinical Trial Design and Technique: A Single Center Pooled Analysis.

Introduction: The practice of endovascular therapy has evolved dramatically over the last 10 years with randomized clinical trials investigating the benefit of thrombectomy in select patient populations based on time of presentation, imaging criteria, and procedural technique. We sought to understand the benefit of thrombectomy in patients treated within the context of a clinical trial at a single academic center. Methods: Patient-level data recorded in case forms and core-lab adjudicated data were analyzed from patients enrolled in RCTs investigating the benefit of endovascular thrombectomy over medical management (IMSIII, MR RESCUE, ESCAPE, SWIFT PRIME, and DAWN) between 2007 and 2017 at a single academic referral center. Results: A total of 134 patients (intervention group, n = 81; medical group, n = 53) were identified across five clinical trials (IMSIII, n = 46; MR RESCUE, n = 4; ESCAPE, n = 24; SWIFT PRIME, n = 14; DAWN, n = 46). There were no significant differences between the treatment arm and control arm in terms of age, gender, baseline NIHSS, ASPECTS, and site of occlusion. Rates of good outcome were superior in the intervention group with early neurological recovery (NIHSS of 0-1 or increase NIHSS of 8 points at 24 h) at a higher rate of 49% vs. 17% (p = <0.001) and higher rates of functional independence (90 day mRS 0-2 of 53% vs. 26%, p = 0.002). In multivariate logistic regression analysis, lower NIHSS and younger age were predictors of good outcome. There were comparable rates of good outcome irrespective of clinical trial, imaging selection criteria (CTP vs. MRI), early vs. late time window (0-6 h vs. 6-24 h) and procedural technique (Merci vs. Solitaire/Trevo device). There were no differences in rates of sICH, PH-2 or mortality in the intervention group vs. medical group. Conclusions: At a large academic center, the benefit of endovascular therapy over medical therapy is observed irrespective of clinical trial design, patient selection or procedural technique.