Involvement of peptidylarginine deiminase 4 in eosinophil extracellular trap formation and contribution to citrullinated histone signal in thrombi

Background: Extracellular traps formed by neutrophils (NETs) and eosinophils (EETs) have been described in coronary thrombi, contributing to thrombus stability. A key mechanism during NET formation is histone modification by the enzyme PAD4. Citrullinated histones, the product of PAD4 activity, are often attributed to neutrophils. Eosinophils also express high levels of PAD4. Objectives: We aimed to explore the contribution of PAD4 to EET formation. Methods: We performed immunohistological analyses on thrombi, including a large, intact, and eosinophil-containing thrombus retrieved from the right coronary artery using an aspiration catheter and stroke thrombi from thrombectomy retrieval. We studied eosinophils for their capability to form PAD4-dependent EETs in response to strong ET-inducing agonists as well as activated platelets and bacteria. Results: Histopathology and immunofluorescence microscopy identified a coronary thrombus rich in platelets and neutrophils, with distinct areas containing von Willebrand factor and citrullinated histone H3 (H3Cit). Eosinophils were also identified in leukocyte-rich areas. The majority of the H3Cit+ signal colocalized with myeloperoxidase, but some colocalized with eosinophil peroxidase, indicating EETs. Eosinophils isolated from healthy volunteers produced H3Cit+ EETs, indicating an involvement of PAD4 activity. The selective PAD4 inhibitor GSK484 blocked this process, supporting PAD4 dependence of H3Cit+ EET release. Citrullinated histones were also present in EETs produced in response to live Staphylococci. However, limited evidence for EETs was found in mouse models of venous thrombosis or infective endocarditis. Conclusion: As in NETosis, PAD4 can catalyze the formation of EETs. Inhibition of PAD4 decreases EET formation, supporting the future utility of PAD4 inhibitors as possible antithrombotic agents

Outcomes after coverage of lenticulostriate vessels by flow diverters: a multicenter experience

OBJECTIVE: With the increasing use of flow diversion as treatment for intracranial aneurysms, there is a concomitant increased vigilance in monitoring complications. The low porosity of flow diverters is concerning when the origins of vessels are covered, whether large circle of Willis branches or critical perforators. In this study, the authors report their experience with flow diverter coverage of the lenticulostriate vessels and evaluate their safety and outcomes. METHODS: The authors retrospectively reviewed 5 institutional databases of all flow diversion cases from August 2012 to June 2018. Information regarding patient presentation, aneurysm location, treatment, and outcomes were recorded. Patients who were treated with flow diverters placed in the proximal middle cerebral artery (MCA), proximal anterior cerebral artery, or distal internal carotid artery leading to coverage of the medial and lateral lenticulostriate vessels were included. Clinical outcomes according to the modified Rankin Scale were reviewed. Univariate and multivariate analyses were performed to establish risk factors for lenticulostriate infarct. RESULTS: Fifty-two patients were included in the analysis. Postprocedure cross-sectional images were available in 30 patients. Two patients experienced transient occlusion of the MCA during the procedure; one was asymptomatic, and the other had a clinical and radiographic ipsilateral internal capsule stroke. Five patients had transient symptoms without radiographic infarct in the lenticulostriate territory. Two patients experienced in-stent thrombosis, leading to clinical MCA infarcts (one in the ipsilateral caudate) after discontinuing antiplatelet therapy. Discontinuation of dual antiplatelet therapy prior to 6 months was the only variable that was significantly correlated with stroke outcome (p \u3c 0.01, OR 0.3, 95% CI 0-0.43), and this significance persisted when controlled for other risk factors, including age, smoking status, and aneurysm location. CONCLUSIONS: The use and versatility of flow diversion is increasing, and safety data are continuing to accumulate. Here, the authors provide early data on the safety of covering lenticulostriate vessels with flow diverters. The authors concluded that the coverage of these perforators does not routinely lead to clinically significant ischemia when dual antiplatelet therapy is continued for 6 months. Further evaluation is needed in larger cohorts and with imaging follow-up as experience develops in using these devices in more distal circulation

Prior traumatic brain injury is a risk factor for in-hospital mortality in moderate to severe traumatic brain injury: a TRACK-TBI cohort study.

OBJECTIVES: An estimated 14-23% of patients with traumatic brain injury (TBI) incur multiple lifetime TBIs. The relationship between prior TBI and outcomes in patients with moderate to severe TBI (msTBI) is not well delineated. We examined the associations between prior TBI, in-hospital mortality, and outcomes up to 12 months after injury in a prospective US msTBI cohort. METHODS: Data from hospitalized subjects with Glasgow Coma Scale score of 3-12 were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (enrollment period: 2014-2019). Prior TBI with amnesia or alteration of consciousness was assessed using the Ohio State University TBI Identification Method. Competing risk regressions adjusting for age, sex, psychiatric history, cranial injury and extracranial injury severity examined the associations between prior TBI and in-hospital mortality, with hospital discharged alive as the competing risk. Adjusted HRs (aHR (95% CI)) were reported. Multivariable logistic regressions assessed the associations between prior TBI, mortality, and unfavorable outcome (Glasgow Outcome Scale-Extended score 1-3 (vs. 4-8)) at 3, 6, and 12 months after injury. RESULTS: Of 405 acute msTBI subjects, 21.5% had prior TBI, which was associated with male sex (87.4% vs. 77.0%, p=0.037) and psychiatric history (34.5% vs. 20.7%, p=0.010). In-hospital mortality was 10.1% (prior TBI: 17.2%, no prior TBI: 8.2%, p=0.025). Competing risk regressions indicated that prior TBI was associated with likelihood of in-hospital mortality (aHR=2.06 (1.01-4.22)), but not with hospital discharged alive. Prior TBI was not associated with mortality or unfavorable outcomes at 3, 6, and 12 months. CONCLUSIONS: After acute msTBI, prior TBI history is independently associated with in-hospital mortality but not with mortality or unfavorable outcomes within 12 months after injury. This selective association underscores the importance of collecting standardized prior TBI history data early after acute hospitalization to inform risk stratification. Prospective validation studies are needed. LEVEL OF EVIDENCE: IV. TRIAL REGISTRATION NUMBER: NCT02119182

Association of Noncontrast Computed Tomography and Perfusion Modalities With Outcomes in Patients Undergoing Late-Window Stroke Thrombectomy

Importance: There is substantial controversy with regards to the adequacy and use of noncontrast head computed tomography (NCCT) for late-window acute ischemic stroke in selecting candidates for mechanical thrombectomy. Objective: To assess clinical outcomes of patients with acute ischemic stroke presenting in the late window who underwent mechanical thrombectomy stratified by NCCT admission in comparison with selection by CT perfusion (CTP) and diffusion-weighted imaging (DWI). Design, setting, and participants: In this multicenter retrospective cohort study, prospectively maintained Stroke Thrombectomy and Aneurysm (STAR) database was used by selecting patients within the late window of acute ischemic stroke and emergent large vessel occlusion from 2013 to 2021. Patients were selected by NCCT, CTP, and DWI. Admission Alberta Stroke Program Early CT Score (ASPECTS) as well as confounding variables were adjusted. Follow-up duration was 90 days. Data were analyzed from November 2021 to March 2022. Exposures: Selection by NCCT, CTP, or DWI. Main outcomes and measures: Primary outcome was functional independence (modified Rankin scale 0-2) at 90 days. Results: Among 3356 patients, 733 underwent late-window mechanical thrombectomy. The median (IQR) age was 69 (58-80) years, 392 (53.5%) were female, and 449 (65.1%) were White. A total of 419 were selected with NCCT, 280 with CTP, and 34 with DWI. Mean (IQR) admission ASPECTS were comparable among groups (NCCT, 8 [7-9]; CTP, 8 [7-9]; DWI 8, [7-9]; P = .37). There was no difference in the 90-day rate of functional independence (aOR, 1.00; 95% CI, 0.59-1.71; P = .99) after adjusting for confounders. Symptomatic intracerebral hemorrhage (NCCT, 34 [8.6%]; CTP, 37 [13.5%]; DWI, 3 [9.1%]; P = .12) and mortality (NCCT, 78 [27.4%]; CTP, 38 [21.1%]; DWI, 7 [29.2%]; P = .29) were similar among groups. Conclusions and relevance: In this cohort study, comparable outcomes were observed in patients in the late window irrespective of neuroimaging selection criteria. Admission NCCT scan may triage emergent large vessel occlusion in the late window

Abstract Number ‐ 60: Influence of Primary Wind Diameter and Length on Coil Volume: Comparing Stryker and CEREPAK coils

Introduction Coiling procedures for intracranial aneurysms (IAs) performed in the US have steadily increaseda, and volumetric efficiency may become an important consideration for hospitals. Coil volume depends on length and primary wind diameter (PWD), and volumetric efficiency can be achieved by either inserting more coils or using coils with larger volumetric filling. This scenario analysis evaluates the influence of PWD and length on total coil volume by comparing four similar Stryker and CEREPAK coils. Methods In this analysis, we test the influence of PWD (D2) and length (L) on the Coil Volume Formula: [Π(D2/2)2(L)]c. In two hypothetical scenarios, relative percent difference in total coil volume was calculated and compared between four Stryker Target 360 coils and four similar CEREPAK coils that were matched based on closest PWD and L. In scenario I, L remained constant and D2 varied. In scenario II, D2 and L were inversely varied. In both scenarios, coil volume achieved by CEREPAK and Stryker coils was calculated and descriptively compared. Results Scenario I: (a) Stryker Target XL 360 10mm x 40cm (D2 = 0.014”, length = 40cm) with volume of 39.726mm3 was matched to the CEREPAK Heliform XL 10mm x 40cm (D2 = 0.015”, length = 40cm) with 15% greater volume of 45.604mm3. (b)Stryker Target 360 3mm x 6cm (D2 = 0.010”, length = 6cm) with volume 3.040mm3 was matched to the CEREPAK Freeform 3mm x 6cm (D2 = 0.012”, length = 6cm) with 44% greater volume of 4.378mm3. Scenario II: (a) Stryker Target XL 360 12mm x 45cm (D2 = 0.014”, length = 45cm) with volume 44.692mm3 was matched to the CEREPAK Heliform XL 12mm x 42cm (D2 = 0.015”, length = 42cm) with 7% greater volume of 47.884mm3. (b)Stryker Target 360 5mm x 20cm (D2 = 0.010”, length = 20cm) with volume 10.134mm3 was matched to the CEREPAK Freeform 5mm x 15cm (D2 = 0.012”, length = 15cm) with 8% greater volume of 10.945mm3. Conclusions The four selected CEREPAK coils compared to four equivalent Stryker coils achieved higher total coil volume in all scenarios. An increase in PWD by as little as 0.001”‐0.002”, improved relative coil volume by 15%‐44% (with equivalent coil length) and 7–8% (with varied coil length by 3–5cm). Clinicians evaluate many coil characteristics when treating an IA, however, PWD might be given consideration over length due to its impact on total coil volume

Magnetoencephalography in the Detection and Characterization of Brain Abnormalities Associated with Traumatic Brain Injury: A Comprehensive Review

Magnetoencephalography (MEG) is a functional brain imaging technique with high temporal resolution compared with techniques that rely on metabolic coupling. MEG has an important role in traumatic brain injury (TBI) research, especially in mild TBI, which may not have detectable features in conventional, anatomical imaging techniques. This review addresses the original research articles to date that have reported on the use of MEG in TBI. Specifically, the included studies have demonstrated the utility of MEG in the detection of TBI, characterization of brain connectivity abnormalities associated with TBI, correlation of brain signals with post-concussive symptoms, differentiation of TBI from post-traumatic stress disorder, and monitoring the response to TBI treatments. Although presently the utility of MEG is mostly limited to research in TBI, a clinical role for MEG in TBI may become evident with further investigation

Emerging Utility of Applied Magnetic Resonance Imaging in the Management of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a widespread and expensive problem globally. The standard diagnostic workup for new TBI includes obtaining a noncontrast computed tomography image of the head, which provides quick information on operative pathologies. However, given the limited sensitivity of computed tomography for identifying subtle but meaningful changes in the brain, magnetic resonance imaging (MRI) has shown better utility for ongoing management and prognostication after TBI. In recent years, advanced applications of MRI have been further studied and are being implemented as clinical tools to help guide care. These include functional MRI, diffusion tensor imaging, MR perfusion, and MR spectroscopy. In this review, we discuss the scientific basis of each of the above techniques, the literature supporting their use in TBI, and how they may be clinically implemented to improve the care of TBI patients