Optimal Carotid Plaque Features on Computed Tomography Angiography Associated With Ischemic Stroke.

Background Stenosis has historically been the major factor used to determine carotid stroke sources. Recent evidence suggests that specific plaque features detected on imaging may be more highly associated with ischemic stroke than stenosis. We sought to determine computed tomography angiography (CTA) imaging features of carotid plaque that optimally discriminate ipsilateral stroke sources. Methods and Results In this institutional review board-approved retrospective cross-sectional study, 494 ipsilateral carotid CTA-brain magnetic resonance imaging pairs were available for analysis after excluding patients with alternative stroke sources. Carotid CTA and clinical markers were recorded, a multivariable Poisson regression model was fitted, and backward elimination was performed with a 2-sided threshold of P<0.10. Discriminatory value was determined using receiver operating characteristic analysis, area under the curve, and bootstrap validation. The final CTA carotid-source stroke prediction model included intraluminal thrombus (prevalence ratio, 2.8 [P<0.001]; 95% CI, 1.6-4.9), maximum soft plaque thickness (prevalence ratio, 1.2 [P<0.001]; 95% CI, 1.1-1.4), and the rim sign (prevalence ratio, 2.0 [P=0.007]; 95% CI, 1.2-3.3). The final discriminatory value (area under the curve=78.3%) was higher than intraluminal thrombus (56.4%, P<0.001), maximum soft plaque thickness (76.4%, P=0.007), or rim sign alone (69.9%, P=0.001). Furthermore, NASCET (North American Symptomatic Carotid Endarterectomy Trial) stenosis categories (cutoffs of 50% and 70%) had lower stroke discrimination (area under the curve=67.4%, P<0.001). Conclusions Optimal discrimination of ipsilateral carotid sources of stroke requires information on intraluminal thrombus, maximum soft plaque thickness, and the rim sign. These results argue against the sole use of carotid stenosis to determine stroke sources on CTA, and instead suggest these alternative markers may better diagnose vulnerable carotid plaque and guide treatment decisions.

Magnetic Resonance Imaging and Clinical Factors Associated With Ischemic Stroke in Patients Suspected of Cervical Artery Dissection.

Background and Purpose- Cervical artery dissection is a major cause of ischemic stroke in the young and presents with various imaging findings, including stenosis and intramural hematoma (IMH). Our goal was to determine the relative contribution of lumen findings and IMH to acute ischemic stroke and whether a heavily T1-weighted sequence could more reliably detect IMH. Methods- Institutional review board approval was obtained for this retrospective study of 254 patients undergoing magnetic resonance imaging/magnetic resonance angiography for suspected dissection. Imaging included standard turbo spin-echo (TSE) T1-fat saturation and heavily T1-weighted flow-suppressed magnetization-prepared rapid acquisition gradient-recalled echo sequences. Subjects with stents (1) or atherosclerotic disease (26) were excluded, leaving 227 subjects. Kappa analysis was used to determine IMH interrater reliability on magnetization-prepared rapid acquisition gradient-recalled echo and T1-fat saturation in 4 vessels per subject. Lumen findings, cardiovascular risk factors, medications, and nondissection stroke sources were recorded. Mixed-effects multivariate Poisson regression was used to determine the prevalence ratio of each factor with acute ischemic stroke, accounting for 4 vessels per patient with backward elimination to a threshold P value of 0.10. Results- Patients were 41.9% men, mean age of 47.3±16.6 years, with 114 dissections and 107 strokes. IMH interrater reliability was significantly higher for magnetization-prepared rapid acquisition gradient-recalled echo (κ=0.83; 95% CI, 0.78-0.86) versus T1-fat saturation (0.58; 95% CI, 0.57-0.68). The final acute stroke prediction model included magnetization-prepared rapid acquisition gradient-recalled echo-detected IMH (prevalence ratio, 2.0; 95% CI, 1.1-3.9; P=0.034), stenosis, pseudoaneurysm, male sex, current smoking, and nondissection stroke sources. The final model had high discrimination for acute stroke (area under the curve, 0.902; 95% CI, 0.872-0.932), compared with models without stenosis (0.861; 95% CI, 0.821-0.902), and without stenosis and IMH (0.831; 95% CI, 0.783-0.879). All 3 models were significantly different at P<0.05. Conclusions- Along with stenosis, IMH detection significantly contributed to acute ischemic stroke pathogenesis in patients with suspected cervical artery dissection. In addition, IMH detection can be made more reliable with heavily T1-weighted sequences.

Low b-value diffusion weighted imaging is promising in the diagnosis of brain death and hypoxic-ischemic injury secondary to cardiopulmonary arrest.

BACKGROUND: Cardiorespiratory arrest can result in a spectrum of hypoxic ischemic brain injury leading to global hypoperfusion and brain death (BD). Because up to 40% of patients with BD are viable organ donors, avoiding delayed diagnosis of this condition is critical. High b-value diffusion weighted imaging (DWI) measures primarily molecular self-diffusion; however, low b-values are sensitive to perfusion. We investigated the feasibility of low b-value DWI in discriminating the global hypoperfusion of BD and hypoxic ischemic encephalopathy (HIE). METHODS: We retrospectively reviewed cardiorespiratory arrest subjects with a diagnosis of HIE or BD. Inclusion criteria included brain DWI acquired at both low (50 s/mm2) and high (1000-2000 s/mm2) b-values. Automated segmentation was used to determine mean b50 apparent diffusion coefficient (ADC) values in gray and white matter regions. Normal subjects with DWI at both values were used as age- and sex-matched controls. RESULTS: We evaluated 64 patients (45 with cardiorespiratory arrest and 19 normal). Cardiorespiratory arrest patients with BD had markedly lower mean b50 ADC in gray matter regions compared with HIE (0.70 ± 0.18 vs. 1.95 ± 0.25 × 10-3 mm2/s, p < 0.001) and normal subjects (vs. 1.79 ± 0.12 × 10-3 mm2/s, p < 0.001). HIE had higher mean b50 ADC compared with normal (1.95 ± 0.25 vs. 1.79 ± 0.12 × 10-3 mm2/s, p = 0.016). There was wide separation of gray matter ADC values in BD subjects compared with age matched normal and HIE subjects. White matter values were also markedly decreased in the BD population, although they were less predictive than gray matter. CONCLUSION: Low b-value DWI is promising for the discrimination of HIE with maintained perfusion and brain death in cardiorespiratory arrest.

The criticality of high-resolution N-linked carbohydrate assays and detailed characterization of antibody effector function in the context of biosimilar development.

Accurate measurement and functional characterization of antibody Fc domain N-linked glycans is critical to successful biosimilar development. Here, we describe the application of methods to accurately quantify and characterize the N-linked glycans of 2 IgG1 biosimilars with effector function activity, and show the potential pitfalls of using assays with insufficient resolution. Accurate glycan assessment was combined with glycan enrichment using lectin chromatography or production with glycosylation inhibitors to produce enriched pools of key glycan species for subsequent assessment in cell-based antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity effector function assays. This work highlights the challenges of developing high-quality biosimilar candidates and the need for modern biotechnology capabilities. These results show that high-quality analytics, combined with sensitive cell-based assays to study in vivo mechanisms of action, is an essential part of biosimilar development.

Intraluminal thrombus, intraplaque hemorrhage, plaque thickness, and current smoking optimally predict carotid stroke.

BACKGROUND AND PURPOSE: Intraplaque hemorrhage (IPH) is associated with acute and future stroke. IPH is also associated with lumen markers of stroke risk including stenosis, plaque thickness, and ulceration. Whether IPH adds further predictive value to these other variables is unknown. The purpose of this study was to determine whether IPH improves carotid-source stroke prediction. METHODS: In this retrospective cross-sectional study, patients undergoing stroke workup were imaged with MRI and IPH detection. Seven hundred twenty-six carotid-brain image pairs were analyzed after excluding vessels with noncarotid plaque stroke sources (420) and occlusions (7) or near-occlusions (3). Carotid imaging characteristics were recorded, including percent diameter and mm stenosis, plaque thickness, ulceration, intraluminal thrombus, and IPH. Clinical confounders were recorded, and a multivariable logistic regression model was fitted. Backward elimination was used to determine essential carotid-source stroke predictors with a threshold 2-sided P<0.10. Receiver operating characteristic analysis was performed to determine discriminatory value. RESULTS: Significant predictors of carotid-source stroke included intraluminal thrombus (odds ratio=103.6; P<0.001), IPH (odds ratio=25.2; P<0.001), current smoking (odds ratio=2.78; P=0.004), and thickness (odds ratio=1.24; P=0.020). The final model discriminatory value was excellent (area under the curve=0.862). This was significantly higher than the final model without IPH (area under the curve=0.814), or models using only stenosis as a continuous variable (area under the curve=0.770) or cutoffs of 50% and 70% (area under the curve=0.669), P<0.001. CONCLUSIONS: After excluding patients with noncarotid plaque stroke sources, optimal discrimination of carotid-source stroke was obtained with intraluminal thrombus, IPH, plaque thickness, and smoking history but not ulceration and stenosis.