Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

PRERISK: A Personalized, Artificial Intelligence-Based and Statistically-Based Stroke Recurrence Predictor for Recurrent Stroke.

BACKGROUND: Predicting stroke recurrence for individual patients is difficult, but individualized prediction may improve stroke survivors' engagement in self-care. We developed PRERISK: a statistical and machine learning classifier to predict individual risk of stroke recurrence. METHODS: We analyzed clinical and socioeconomic data from a prospectively collected public health care-based data set of 41 975 patients admitted with stroke diagnosis in 88 public health centers over 6 years (2014-2020) in Catalonia-Spain. A new stroke diagnosis at least 24 hours after the index event was considered as a recurrent stroke, which was considered as our outcome of interest. We trained several supervised machine learning models to provide individualized risk over time and compared them with a Cox regression model. Models were trained to predict early, late, and long-term recurrence risk, within 90, 91 to 365, and >365 days, respectively. C statistics and area under the receiver operating characteristic curve were used to assess the accuracy of the models. RESULTS: Overall, 16.21% (5932 of 36 114) of patients had stroke recurrence during a median follow-up of 2.69 years. The most powerful predictors of stroke recurrence were time from previous stroke, Barthel Index, atrial fibrillation, dyslipidemia, age, diabetes, and sex, which were used to create a simplified model with similar performance, together with modifiable vascular risk factors (glycemia, body mass index, high blood pressure, cholesterol, tobacco dependence, and alcohol abuse). The areas under the receiver operating characteristic curve were 0.76 (95% CI, 0.74-0.77), 0.60 (95% CI, 0.58-0.61), and 0.71 (95% CI, 0.69-0.72) for early, late, and long-term recurrence risk, respectively. The areas under the receiver operating characteristic curve of the Cox risk class probability were 0.73 (95% CI, 0.72-0.75), 0.59 (95% CI, 0.57-0.61), and 0.67 (95% CI, 0.66-0.70); machine learning approaches (random forest and AdaBoost) showed statistically significant improvement (P<0.05) over the Cox model for the 3 recurrence time periods. Stroke recurrence curves can be simulated for each patient under different degrees of control of modifiable factors. CONCLUSIONS: PRERISK is a novel approach that provides a personalized and fairly accurate risk prediction of stroke recurrence over time. The model has the potential to incorporate dynamic control of risk factors.

Enhancing blood pressure management protocol implementation in patients with acute intracerebral haemorrhage through a nursing-led approach: A retrospective cohort study.

AIM: To evaluate the impact of nurse care changes in implementing a blood pressure management protocol on achieving rapid, intensive and sustained blood pressure reduction in acute intracerebral haemorrhage patients. DESIGN: Retrospective cohort study of prospectively collected data over 6 years. METHODS: Intracerebral haemorrhage patients within 6 h and systolic blood pressure ≥ 150 mmHg followed a rapid (starting treatment at computed tomography suite with a target achievement goal of ≤60 min), intensive (target systolic blood pressure < 140 mmHg) and sustained (maintaining target stability for 24 h) blood pressure management plan. We differentiated six periods: P1, stroke nurse at computed tomography suite (baseline period); P2, antihypertensive titration by stroke nurse; P3, retraining by neurologists; P4, integration of a stroke advanced practice nurse; P5, after COVID-19 impact; and P6, retraining by stroke advanced practice nurse. Outcomes included first-hour target achievement (primary outcome), tomography-to-treatment and treatment-to-target times, first-hour maximum dose of antihypertensive treatment and 6-h and 24-h systolic blood pressure variability. RESULTS: Compared to P1, antihypertensive titration by stroke nurses (P2) reduced treatment-to-target time and increased the rate of first-hour target achievement, retraining of stroke nurses by neurologists (P3) maintained a higher rate of first-hour target achievement and the integration of a stroke advanced practice nurse (P4) reduced both 6-h and 24-h systolic blood pressure variability. However, 6-h systolic blood pressure variability increased from P4 to P5 following the impact of the COVID-19 pandemic. Finally, compared to P1, retraining of stroke nurses by stroke advanced practice nurse (P6) reduced tomography-to-treatment time and increased the first-hour maximum dose of antihypertensive treatment. CONCLUSION: Changes in nursing care and continuous education can significantly enhance the time metrics and blood pressure outcomes in acute intracerebral haemorrhage patients. REPORTING METHOD: STROBE guidelines. PATIENT AND PUBLIC CONTRIBUTION: No Patient or Public Contribution.

Redefining Disability: Patient-Reported Outcome Measures After Minor Stroke and Transient Ischemic Attack.

BACKGROUND: Long-term outcome assessment patients with stroke is not fully captured by usual clinical scales such as the modified Rankin Scale (mRS). Patient-reported outcome measures (PROMs) are standardized and validated assessments that consider clinical outcomes from the patient perspective. We aim to analyze the added value of PROMs in patients with transient ischemic attack and minor stroke. METHODS: We included consecutive patients with minor stroke or transient ischemic attack (National Institutes of Health Stroke Scale score 0-5) from April 2020 to October 2021 that participated in the PROMs-through-App program (NORA, NoraHealth Barcelona Spain). Clinician and self-evaluated outcomes were assessed at 90 days: clinician-evaluated mRS, self-reported mRS, the 10-item patient-reported outcome measures questionnaire global health survey (v1.2), Hospital Anxiety and Depression Scale, and the Fatigue Assessment Scale. We evaluated the acceptability (response rate), reliability (internal consistency), and construct validity (correlation with mRS and between scales) of each questionnaire. RESULTS: We included 355 patients in the analysis, response rate was patient-reported outcome measures questionnaire 71.3% (253), Hospital Anxiety and Depression Scale 70.7% (251), Fatigue Assessment Scale 71.8% (255), and self-assessed mRS 66.8% (237). PROMS internal consistency was good or excellent, while agreement between clinician and self-reported mRS was fair (k=0.34). Rate of abnormal PROMS scores were as follows (all responders versus clinician-reported mRS score 0-2): patient-reported outcome measures questionnaire mental health (43.1% versus 36.3%), physical health (48.6% versus 43.6%); Hospital Anxiety and Depression Scale-anxiety (21.9% versus 17.7%) and depression (17.1% versus 13.3%); and Fatigue Assessment Scale (40.8% versus 36.4%). PROMs scores correlated with clinician and self-reported mRS at 90 days. CONCLUSIONS: Evaluation of PROMs using a mobile-app-based communication system is a reliable and valid strategy to assess the outcome of patients from their perspective after a mild stroke or transient ischemic attack.

Intracranial Artery Calcifications Profile as a Predictor of Recanalization Failure in Endovascular Stroke Treatment.

BACKGROUND: Acute ischemic stroke with large or medium-vessel occlusion associated with intracranial artery calcification (IAC) is an infrequent phenomenon presumably associated with intracranial atherosclerotic disease. We aimed to characterize IAC and its impact on endovascular treatment outcomes. METHODS: We performed a retrospective cross-sectional study of consecutive patients with stroke treated with thrombectomy from January 2020 to July 2021 in our institution. We described IAC findings (length, density, and location pattern) on baseline noncontrast computed tomography. Patients were divided into 3 groups: IAC related to the occlusion location (symptomatic-IAC group), unrelated to the occlusion (asymptomatic-IAC group), and absence of any IAC (non-IAC group). We analyzed the association between the IAC profile and outcomes using logistic regression models. Intracranial angioplasty and stenting were considered rescue treatments. RESULTS: Of the 393 patients included, 26 (6.6%) patients presented a symptomatic-IAC, 77 (19.6%) patients an asymptomatic-IAC, and in 290 (73.8%) patients no IAC was observed. The rate of failed recanalization (expanded Thrombolysis in Cerebral Infarction 0-2a) before rescue treatment was higher in symptomatic-IAC (65.4%) than in asymptomatic-IAC (15.6%; P<0.001) or non-IAC (13.4%; P<0.001). Rescue procedures were more frequently performed in symptomatic-IAC (26.9%) than in asymptomatic-IAC (1.3%; P<0.001) and non-IAC (4.1%; P<0.001). After adjusting for identifiable clinical and radiological confounders, symptomatic-IAC emerged as an independent predictor of failed recanalization (odds ratio, 11.89 [95% CI, 3.94-35.91]; P<0.001), adoption of rescue procedures (odds ratio, 12.38 [95% CI, 2.22-69.09]; P=0.004), and poor functional outcome (90-day modified Rankin Scale score ≥3; odds ratio, 3.51 [95% CI, 1.02-12.00]; P=0.046). CONCLUSIONS: The presence of IAC related to the occlusion location is associated with worse angiographic and functional outcomes. Therefore, identification of symptomatic-IAC on baseline imaging may guide optimal endovascular treatment strategy, predicting the need for intracranial stenting and angioplasty.

Association of Time of Day With Outcomes Among Patients Triaged for a Suspected Severe Stroke in Nonurban Catalonia.

BACKGROUND: We aim to assess whether time of day modified the treatment effect in the RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion Trial), a cluster-randomized trial that did not demonstrate the benefit of direct transportation to a thrombectomy-capable center versus nearest local stroke center for patients with a suspected large vessel stroke triaged in nonurban Catalonia between March 2017 and June 2020. METHODS: We performed a post hoc analysis of RACECAT to evaluate if the association between initial transport routing and functional outcome differed according to trial enrollment time: daytime (8:00 am-8:59 pm) and nighttime (9:00 pm-7:59 am). Primary outcome was disability at 90 days, as assessed by the shift analysis on the modified Rankin Scale score, in patients with ischemic stroke. Subgroup analyses according to stroke subtype were evaluated. RESULTS: We included 949 patients with an ischemic stroke, of whom 258 patients(27%) were enrolled during nighttime. Among patients enrolled during nighttime, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days (adjusted common odds ratio [acOR], 1.620 [95% CI, 1.020-2.551]); no significant difference between trial groups was present during daytime (acOR, 0.890 [95% CI, 0.680-1.163]; P interaction=0.014). Influence of nighttime on the treatment effect was only evident in patients with large vessel occlusion(daytime, acOR 0.766 [95% CI, 0.548-1.072]; nighttime, acOR, 1.785 [95% CI, 1.024-3.112] ; P interaction<0.01); no heterogeneity was observed for other stroke subtypes (P interaction>0.1 for all comparisons). We observed longer delays in alteplase administration, interhospital transfers, and mechanical thrombectomy initiation during nighttime in patients allocated to local stroke centers. CONCLUSIONS: Among patients evaluated during nighttime for a suspected acute severe stroke in non-urban areas of Catalonia, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days. This association was only evident in patients with confirmed large vessel occlusion on vascular imaging. Time delays in alteplase administration and interhospital transfers might mediate the observed differences in clinical outcome. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02795962.

Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA.

BACKGROUND: Trials have evaluated the use of clopidogrel and aspirin to prevent stroke after an ischemic stroke or transient ischemic attack (TIA). In a previous trial, ticagrelor was not better than aspirin in preventing vascular events or death after stroke or TIA. The effect of the combination of ticagrelor and aspirin on prevention of stroke has not been well studied. METHODS: We conducted a randomized, placebo-controlled, double-blind trial involving patients who had had a mild-to-moderate acute noncardioembolic ischemic stroke, with a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less (range, 0 to 42, with higher scores indicating more severe stroke), or TIA and who were not undergoing thrombolysis or thrombectomy. The patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive a 30-day regimen of either ticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily) or matching placebo plus aspirin. The primary outcome was a composite of stroke or death within 30 days. Secondary outcomes were first subsequent ischemic stroke and the incidence of disability within 30 days. The primary safety outcome was severe bleeding. RESULTS: A total of 11,016 patients underwent randomization (5523 in the ticagrelor-aspirin group and 5493 in the aspirin group). A primary-outcome event occurred in 303 patients (5.5%) in the ticagrelor-aspirin group and in 362 patients (6.6%) in the aspirin group (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P = 0.02). Ischemic stroke occurred in 276 patients (5.0%) in the ticagrelor-aspirin group and in 345 patients (6.3%) in the aspirin group (hazard ratio, 0.79; 95% CI, 0.68 to 0.93; P = 0.004). The incidence of disability did not differ significantly between the two groups. Severe bleeding occurred in 28 patients (0.5%) in the ticagrelor-aspirin group and in 7 patients (0.1%) in the aspirin group (P = 0.001). CONCLUSIONS: Among patients with a mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5) or TIA who were not undergoing intravenous or endovascular thrombolysis, the risk of the composite of stroke or death within 30 days was lower with ticagrelor-aspirin than with aspirin alone, but the incidence of disability did not differ significantly between the two groups. Severe bleeding was more frequent with ticagrelor. (Funded by AstraZeneca; THALES ClinicalTrial.gov number, NCT03354429.).

Thrombectomy for Stroke in the Public Health Care System of Brazil.

BACKGROUND: Randomized trials involving patients with stroke have established that outcomes are improved with the use of thrombectomy for large-vessel occlusion. These trials were performed in high-resource countries and have had limited effects on medical practice in low- and middle-income countries. METHODS: We studied the safety and efficacy of thrombectomy in the public health system of Brazil. In 12 public hospitals, patients with a proximal intracranial occlusion in the anterior circulation that could be treated within 8 hours after the onset of stroke symptoms were randomly assigned in a 1:1 ratio to receive standard care plus mechanical thrombectomy (thrombectomy group) or standard care alone (control group). The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. RESULTS: A total of 300 patients were enrolled, including 79 who had undergone thrombectomy during an open-label roll-in period. Approximately 70% in the two groups received intravenous alteplase. The trial was stopped early because of efficacy when 221 of a planned 690 patients had undergone randomization (111 to the thrombectomy group and 110 to the control group). The common odds ratio for a better distribution of scores on the modified Rankin scale at 90 days was 2.28 (95% confidence interval [CI], 1.41 to 3.69; P = 0.001), favoring thrombectomy. The percentage of patients with a score on the modified Rankin scale of 0 to 2, signifying an absence of or minor neurologic deficit, was 35.1% in the thrombectomy group and 20.0% in the control group (difference, 15.1 percentage points; 95% CI, 2.6 to 27.6). Asymptomatic intracranial hemorrhage occurred in 51.4% of the patients in the thrombectomy group and 24.5% of those in the control group; symptomatic intracranial hemorrhage occurred in 4.5% of the patients in each group. CONCLUSIONS: In this randomized trial conducted in the public health care system of Brazil, endovascular treatment within 8 hours after the onset of stroke symptoms in conjunction with standard care resulted in better functional outcomes at 90 days than standard care alone. (Funded by the Brazilian Ministry of Health; RESILIENT ClinicalTrials.gov number, NCT02216643.).

Workflow Times and Outcomes in Patients Triaged for a Suspected Severe Stroke.

INTRODUCTION: Current recommendations for regional stroke destination suggest that patients with severe acute stroke in non-urban areas should be triaged based on the estimated transport time to a referral thrombectomy-capable center. METHODS: We performed a post hoc analysis to evaluate the association of pre-hospital workflow times with neurological outcomes in patients included in the RACECAT trial. Workflow times evaluated were known or could be estimated before transport allocation. Primary outcome was the shift analysis on the modified Rankin score at 90 days. RESULTS: Among the 1,369 patients included, the median time from onset to emergency medical service (EMS) evaluation, the estimated transport time to a thrombectomy-capable center and local stroke center, and the estimated transfer time between centers were 65 minutes (interquartile ratio [IQR] = 43-138), 61 minutes (IQR = 36-80), 17 minutes (IQR = 9-27), and 62 minutes (IQR = 36-73), respectively. Longer time intervals from stroke onset to EMS evaluation were associated with higher odds of disability at 90 days in the local stroke center group (adjusted common odds ratio (acOR) for each 30-minute increment = 1.03, 95% confidence interval [CI] = 1.01-1.06), with no association in the thrombectomy-capable center group (acOR for each 30-minute increment = 1.01, 95% CI = 0.98-1.01, pinteraction  = 0.021). No significant interaction was found for other pre-hospital workflow times. In patients evaluated by EMS later than 120 minutes after stroke onset, direct transport to a thrombectomy-capable center was associated with better disability outcomes (acOR = 1.49, 95% CI = 1.03-2.17). CONCLUSION: We found a significant heterogeneity in the association between initial transport destination and neurological outcomes according to the elapse of time between the stroke onset and the EMS evaluation (ClinicalTrials.gov: NCT02795962). ANN NEUROL 2022;92:931-942.

Derivation and validation of three intracerebral hemorrhage expansion scores using different CT modalities.

OBJECTIVES: To derivate and validate three scores for the prediction of intracerebral hemorrhage (ICH) expansion depending on the use of non-contrast CT (NCCT), single-phase CTA, or multiphase CTA markers of hematoma expansion, and to evaluate the added value of single-phase and multiphase CTA over NCCT. METHODS: After prospectively deriving NCCT, single-phase CTA, and multiphase CTA hematoma expansion scores in 156 patients with ICH < 6 h, we validated them in 120 different patients. Discrimination and calibration of the three scores was assessed. Primary outcome was substantial hematoma expansion > 6 mL or > 33% at 24 h. RESULTS: The evaluation of single-phase and multiphase CTA markers gave a steadily increase in discrimination for substantial hematoma expansion over NCCT markers. The C-index (95% confidence interval) in derivation and validation cohorts was 0.69 (0.58-0.80) and 0.59 (0.46-0.72) for NCCT score, significantly lower than 0.75 ([0.64-0.87], p = 0.038) and 0.72 ([0.59-0.84], p = 0.016) for single-phase CTA score, and than 0.79 ([0.68-0.89], p = 0.033) and 0.73 ([0.62-0.85], p = 0.031) for multiphase CTA score, respectively. The three scores showed good calibration in both derivation and validation cohorts: NCCT (χ2 statistic 0.389, p = 0.533; and χ2 statistic 0.352, p = 0.553), single-phase CTA (χ2 statistic 2.052, p = 0.359; and χ2 statistic 2.230, p = 0.328), and multiphase CTA (χ2 statistic 0.559, p = 0.455; and χ2 statistic 0.020, p = 0.887) scores, respectively. CONCLUSION: This study shows the added prognostic value of more advanced CT modalities in acute ICH evaluation. NCCT, single-phase CTA, and multiphase CTA scores may help to refine the selection of patients at risk of expansion in different decision-making scenarios. KEY POINTS: • This study shows the added prognostic value of more advanced CT modalities in acute intracerebral hemorrhage evaluation. • The evaluation of single-phase and multiphase CTA markers provides a steadily increase in discrimination for intracerebral hemorrhage expansion over non-contrast CT markers. • Non-contrast CT, single-phase CTA, and multiphase CTA scores may help clinicians and researchers to refine the selection of patients at risk of intracerebral hemorrhage expansion in different decision-making scenarios.

Multiparametric Neuroimaging and Its Association with Non-Contrast Computed Tomography in Late-Window Large Vessel Occlusion Acute Stroke.

INTRODUCTION: Endovascular treatment (EVT) for acute ischemic stroke (AIS) between 6 and 24 h is established as a standard of care among patients selected by multiparametric neuroimaging. We aimed to explore neuroimaging parameters in late-window large vessel occlusion (LVO) patients and its association with non-contrast computed tomography (NCCT) findings. METHODS: We included consecutive AIS patients within 6-24 h from the symptoms onset with LVO. We described multiparametric imaging findings, the rate of patients who fulfilled imaging perfusion criteria according to the DAWN and DEFUSE-3 trials that define the computed tomography perfusion mismatch (CTP-MM) group and its association with NCCT focused on Alberta Stroke Program Early CT Score (ASPECTS). We also analyzed the association between neuroimaging parameters and the clinical outcome determined by the 90-day modified Rankin scale (mRS). RESULTS: We included 206 patients, of them, 176 (85.4%) presented CTP-MM and 184 (89.3%) presented an ASPECTS ≥6 on admission. The rate of CTP-MM was 90.8% in patients with ASPECTS ≥6, compared with 40.9% in those with low ASPECTS. ASPECTS was moderately correlated with ischemic core determined by cerebral blood flow <30% volume (rS = -0.557, p < 0.001). In EVT-treated patients (185, 89.8%), after adjusting for identifiable confounders, the presence of CTP-MM was a predictor of 90-day functional independence (OR: 3.38; 95% CI: 1.01-11.29; p = 0.048). We did not find an association between CTP-MM and 90-day functional disability (ordinal mRS shift, aOR: 1.39; 95% CI: 0.58-3.34; p = 0.459). CONCLUSIONS: A great majority of patients who presented a LVO in the late window fulfilled guidelines imaging criteria to undergo EVT, especially those with high ASPECTS (≥6). Our data suggest that NCCT with CT angiography could be a reasonable approach for AIS treatment selection also in the late window.

Evidence that the transcriptional repressor ICER is regulated via the N-end rule for ubiquitination.

ICER is a transcriptional repressor that is mono- or poly-ubiquitinated. This either causes ICER to be translocated from the nucleus, or degraded via the proteasome, respectively. In order to further studies the proteins involved in ICER regulation mass spectrometry analysis was performed to identify potential candidates. We identified twenty eight ICER-interacting proteins in human melanoma cells, Sk-Mel-24. In this study we focus on two proteins with potential roles in ICER proteasomal degradation in response to the N-end rule for ubiquitination: the N-alpha-acetyltransferase 15 (NAA15) and the E3 ubiquitin-protein ligase UBR4. Using an HA-tag on the N- or C-terminus of ICER (NHAICER or ICERCHA) it was found that the N-terminus of ICER is important for its interaction to UBR4, whereas NARG1 interaction is independent of HA-tag position. Silencing RNA experiments show that both NAA15 and UBR4 up-regulates ICER levels and that ICER's N-terminus is important for this regulation. The N-terminus of ICER was found to have dire consequences on its regulation by ubiquitination and cellular functions. The half-life of NHAICER was found to be about twice as long as ICERCHA. Polyubiquitination of ICER was found to be dependent on its N-terminus and mediated by UBR4. This data strongly suggests that ICER is ubiquitinated as a response to the N-end rule that governs protein degradation rate through recognition of the N-terminal residue of proteins. Furthermore, we found that NHAICER inhibits transcription two times more efficiently than ICERCHA, and causes apoptosis 5 times more efficiently than ICERCHA. As forced expression of ICER has been shown before to block cells in mitosis, our data represent a potentially novel mechanism for apoptosis of cells in mitotic arrest.

Intensive 90-day textile wearable Holter monitoring: an alternative to detect paroxysmal atrial fibrillation in selected patients with cryptogenic stroke.

We aimed to demonstrate the feasibility of 90-day cardiac monitoring with an external Holter device and to find a target population able to benefit from such a technique. Cryptogenic stroke patients were continuously monitored for 90 days with a textile wearable Holter (TWH). Compliance and quality of the monitoring were assessed by the number of hours of ECG stored per month. Mean predictors of pAF, including age, gender, stroke severity, and atrial size (LAVI), were evaluated. One-year follow-up assessed pAF detection outside per protocol monitoring. Out of 224 patients included in 5 stroke centers, 163 patients (72.76%) fulfilled the criteria for the protocol. Median monitoring time was similar among the three months. Per protocol pAF detection reached 35.37% at 90 days. The age (OR 1.095; 95% CI 1.03-1.14) and the LAVI (OR 1.055; 95% CI 1.01-1.09) independently predicted pAF. The cut-off point of 70 years (AUC 0.68) (95% CI 0.60-0.76) predicted pAF with a sensitivity of 75.8% and specificity of 50.5%. The LAVI cut-off point of 28.5 (AUC 0.67) (95% CI 0.56-0.77) had a sensitivity of 63.6% and a specificity of 61.8% to detect pAF. The combination of both markers enhanced the validity of pAF detection sensitivity to 89.6%, with a specificity of 27.59%. These patients had increased risk of pAF during the 90-day monitoring HR 3.23 (χ2 7.15) and beyond 90 days (χ2 5.37). Intensive 90-days TWH monitoring detected a high percentage of pAF. However, a significant number of patients did not complete the monitoring. Patients older than 70 years and with enlarged left atria benefitted more from the protocol.

Early Renin Recovery After Adrenalectomy in Aldosterone-Producing Adenomas: A Prospective Study.

The aim of the study was to clarify the relationship and the time of aldosterone and renin recoveries at immediate and long-term follow-up in aldosterone-producing adenoma (APA) patients who underwent adrenalectomy. Prospective and longitudinal protocol in a cohort of APA patients was followed in a single center. Among 43 patients with primary aldosteronism (PA), thirteen APA patients were enrolled in this study. Blood was collected for aldosterone, renin, potassium, creatinine, cortisol, and ACTH before and 1, 3, 5, 7, 15, 30, 60, 90, 120, 180, 270, 360 days after adrenalectomy. At diagnosis, most patients (84%) had hypokalemia and high median aldosterone levels (54.8; 24.0-103 ng/dl) that decreased to undetectable (<2.2) or very low (<3.0) levels between fifth to seventh days after surgery; then, between 3-12 months, its levels gradually increased to the lower normal range. The suppressed renin (2.3; 2.3-2.3 mU/l) became detectable between the fifteen and thirty days after surgery, remaining normal throughout the study. The aldosterone took longer than renin to recover (60 vs.15 days; p<0.002) and patients with higher aldosterone had later recovery (p=0.03). The cortisol/ACTH levels remained normal despite the presence of a post-operative hypoaldosteronism. Blood pressure and antihypertensive requirement decreased after adrenalectomy. In conclusion, our prospective study shows the borderline persistent post-operative hypoaldosteronism in the presence of early renin recovery indicating incapability of the zona glomerulosa of the remaining adrenal gland to produce aldosterone. These findings contribute to the comprehension of differences in renin and aldosterone regulation in APA patients, although both are part of the same interconnected system.

Effect of Direct Transportation to Thrombectomy-Capable Center vs Local Stroke Center on Neurological Outcomes in Patients With Suspected Large-Vessel Occlusion Stroke in Nonurban Areas: The RACECAT Randomized Clinical Trial.

Importance: In nonurban areas with limited access to thrombectomy-capable centers, optimal prehospital transport strategies in patients with suspected large-vessel occlusion stroke are unknown. Objective: To determine whether, in nonurban areas, direct transport to a thrombectomy-capable center is beneficial compared with transport to the closest local stroke center. Design, Setting, and Participants: Multicenter, population-based, cluster-randomized trial including 1401 patients with suspected acute large-vessel occlusion stroke attended by emergency medical services in areas where the closest local stroke center was not capable of performing thrombectomy in Catalonia, Spain, between March 2017 and June 2020. The date of final follow-up was September 2020. Interventions: Transportation to a thrombectomy-capable center (n = 688) or the closest local stroke center (n = 713). Main Outcomes and Measures: The primary outcome was disability at 90 days based on the modified Rankin Scale (mRS; scores range from 0 [no symptoms] to 6 [death]) in the target population of patients with ischemic stroke. There were 11 secondary outcomes, including rate of intravenous tissue plasminogen activator administration and thrombectomy in the target population and 90-day mortality in the safety population of all randomized patients. Results: Enrollment was halted for futility following a second interim analysis. The 1401 enrolled patients were included in the safety analysis, of whom 1369 (98%) consented to participate and were included in the as-randomized analysis (56% men; median age, 75 [IQR, 65-83] years; median National Institutes of Health Stroke Scale score, 17 [IQR, 11-21]); 949 (69%) comprised the target ischemic stroke population included in the primary analysis. For the primary outcome in the target population, median mRS score was 3 (IQR, 2-5) vs 3 (IQR, 2-5) (adjusted common odds ratio [OR], 1.03; 95% CI, 0.82-1.29). Of 11 reported secondary outcomes, 8 showed no significant difference. Compared with patients first transported to local stroke centers, patients directly transported to thrombectomy-capable centers had significantly lower odds of receiving intravenous tissue plasminogen activator (in the target population, 229/482 [47.5%] vs 282/467 [60.4%]; OR, 0.59; 95% CI, 0.45-0.76) and significantly higher odds of receiving thrombectomy (in the target population, 235/482 [48.8%] vs 184/467 [39.4%]; OR, 1.46; 95% CI, 1.13-1.89). Mortality at 90 days in the safety population was not significantly different between groups (188/688 [27.3%] vs 194/713 [27.2%]; adjusted hazard ratio, 0.97; 95% CI, 0.79-1.18). Conclusions and Relevance: In nonurban areas in Catalonia, Spain, there was no significant difference in 90-day neurological outcomes between transportation to a local stroke center vs a thrombectomy-capable referral center in patients with suspected large-vessel occlusion stroke. These findings require replication in other settings. Trial Registration: ClinicalTrials.gov Identifier: NCT02795962.

Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention.

BACKGROUND: Individuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding. Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets. METHODS: We began a phase II, double-blinded, randomized, placebo-controlled trial at 367 sites in 2019. Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD2 score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint. Participant follow-up will end in 2022. CONCLUSION: The AXIOMATIC-SSP trial will evaluate the dose-response of milvexian for ischemic stroke occurrence in participants with ischemic stroke or TIA.

The Role of Vascular Imaging atReferral Centers in the Drip and Ship Paradigm.

BACKGROUND: In drip-and-ship protocols, non-invasive vascular imaging (NIVI) at Referral Centers (RC), although recommended, is not consistently performed and its value is uncertain. We evaluated the role of NIVI at RC, comparing patients with (VI+) and without (VI-) vascular imaging in several outcomes. METHODS: Observational, multicenter study from a prospective government-mandated population-based registry of code stroke patients. We selected acute ischemic stroke patients, initially assessed at RC from January-2016 to June-2020. We compared and analyzed the rates of patients transferred to a Comprehensive Stroke Center (CSC) for Endovascular Treatment (EVT), rates of EVT and workflow times between VI+ and VI- patients. RESULTS: From 5128 ischemic code stroke patients admitted at RC; 3067 (59.8%) were VI+, 1822 (35.5%) were secondarily transferred to a CSC and 600 (11.7%) received EVT. Among all patients with severe stroke (NIHSS ≥16) at RC, a multivariate analysis showed that lower age, thrombolytic treatment, and VI+ (OR:1.479, CI95%: 1.117-1.960, p=0.006) were independent factors associated to EVT. The rate of secondary transfer to a CSC was lower in VI+ group (24.6% vs. 51.6%, p<0.001). Among transferred patients, EVT was more frequent in VI+ than VI- (48.6% vs. 21.7%, p<0.001). Interval times as door-in door-out (median-minutes 83.5 vs. 82, p= 0.13) and RC-Door to puncture (median-minutes 189 vs. 178, p= 0.47) did not show differences between both groups. CONCLUSION: In the present study, NIVI at RC improves selection for EVT, and is associated with receiving EVT in severe stroke patients. Time-metrics related to drip-and-ship model were not affected by NIVI.

Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack.

Background and Purpose: In patients with acute mild-moderate ischemic stroke or high-risk transient ischemic attack, the THALES trial (Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death) demonstrated that when added to aspirin, ticagrelor reduced stroke or death but increased risk of severe hemorrhage compared with placebo. The primary efficacy outcome of THALES included hemorrhagic stroke and death, events also counted in the primary safety outcome. We sought to disentangle risk and benefit, assess their relative impact, and attempt to identify subgroups with disproportionate risk or benefit. Methods: In a randomized, placebo-controlled, double-blind trial of patients with mild-to-moderate acute noncardioembolic ischemic stroke or high-risk transient ischemic attack, patients were randomized within 24 hours after symptom onset to a 30-day regimen of either ticagrelor plus aspirin or matching placebo plus aspirin. For the present analyses, we defined the efficacy outcome, major ischemic events, as the composite of ischemic stroke or nonhemorrhagic death, and defined the safety outcome, major hemorrhage, as intracranial hemorrhage or hemorrhagic death. Net clinical impact was defined as the combination of these 2 end points. Results: In 11 016 patients (5523 ticagrelor-aspirin and 5493 aspirin), a major ischemic event occurred in 294 patients (5.3%) in the ticagrelor-aspirin group and in 359 patients (6.5%) in the aspirin group (absolute risk reduction 1.19% [95% CI, 0.31%­2.07%]). Major hemorrhage occurred in 22 patients (0.4%) in the ticagrelor-aspirin group and 6 patients (0.1%) in the aspirin group (absolute risk increase 0.29% [95% CI, 0.10%­0.48%]). Net clinical impact favored ticagrelor-aspirin (absolute risk reduction 0.97% [95% CI, 0.08%­1.87%]). Findings were similar when different thresholds for disability were applied and over a range of predefined subgroups. Conclusions: In patients with mild-moderate ischemic stroke or high-risk transient ischemic attack, ischemic benefits of 30-day treatment with ticagrelor-aspirin outweigh risks of hemorrhage. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354429.

Defining a Target Population to Effectively Test a Neuroprotective Drug.

BACKGROUND AND PURPOSE: We aim to identify the subgroup of acute ischemic stroke patients with higher probabilities of benefiting from a potential neuroprotective drug using baseline outcome predictors and test whether different selection criteria strategies can improve detected treatment effect. METHODS: We analyzed the association between final infarct volume (FIV), measured on 24- to 72-hour computed tomography, and National Institutes of Health Stroke Scale at discharge/day 5 of acute stroke patients who underwent endovascular treatment. Models were adjusted for age, sex, and affected hemisphere. We analyzed the impact of absolute (5-15 mL) and relative (33%) FIV reductions in the National Institutes of Health Stroke Scale in the whole population and in different subsets of patients selected according to baseline imaging criteria using computed tomography perfusion. RESULTS: We analyzed 627 patients; association between FIV and 5-day National Institutes of Health Stroke Scale was best described with a quadratic function, with a regression coefficient ß=1.56 ([95% CI, 1.45-1.67] P<0.001) in the adjusted analysis. In the models considering a fixed absolute (5/15 mL) FIV reduction, treatment effect was highest when patients with predicted larger FIV were excluded, whereas in a 33% FIV reduction model, treatment effect increased with the exclusion of patients with expected excellent outcomes. CONCLUSIONS: Patients either with excellent outcomes after endovascular thrombectomy or with large infarcts may dilute the treatment effect in stroke neuroprotective drug trials. Computed tomography perfusion on admission may help selecting adequate patients according to expected drug effect profile.

Ischemic Core Overestimation on Computed Tomography Perfusion.

Background and Purpose: Different studies have pointed that CT perfusion (CTP) could overestimate ischemic core in early time window. We aim to evaluate the influence of time and collateral status on ischemic core overestimation. Methods: Retrospective single-center study including patients with anterior circulation large-vessel stroke that achieved reperfusion after endovascular treatment. Ischemic core and collateral status were automatically estimated on baseline CTP using commercially available software. CTP-derived core was considered as tissue with a relative reduction of cerebral blood flow <30%, as compared with contralateral hemisphere. Collateral status was assessed using the hypoperfusion intensity ratio (defined by the proportion of the time to maximum of tissue residue function >6 seconds with time to maximum of tissue residue function >10 seconds). Final infarct volume was measured on 24 to 48 hours noncontrast CT. Ischemic core overestimation was considered when CTP-derived core was larger than final infarct. Results: Four hundred and seven patients were included in the analysis. Median CTP-derived core and final infarct volume were 7 mL (interquartile range, 0­27) and 20 mL (interquartile range, 5­55), respectively. Median hypoperfusion intensity ratio was 0.46 (interquartile range, 0.23­0.59). Eighty-three patients (20%) presented ischemic core overestimation (median overestimation, 12 mL [interquartile range, 41­5]). Multivariable logistic regression analysis adjusted by CTP-derived core and confounding variables showed that poor collateral status (per 0.1 hypoperfusion intensity ratio increase; adjusted odds ratio, 1.41 [95% CI, 1.20­1.65]) and earlier onset to imaging time (per 60 minutes earlier; adjusted odds ratio, 1.14 [CI, 1.04­1.25]) were independently associated with core overestimation. No significant association was found with imaging to reperfusion time (per 30 minutes earlier; adjusted odds ratio, 1.17 [CI, 0.96­1.44]). Poor collateral status influence on core overestimation differed according to onset to imaging time, with a stronger size of effect on early imaging patients(Pinteraction <0.01). Conclusions: In patients with large-vessel stroke that achieve reperfusion after endovascular therapy, poor collateral status might induce higher rates of ischemic core overestimation on CTP, especially in patients in earlier window time. CTP reflects a hemodynamic state rather than tissue fate; collateral status and onset to imaging time are important factors to consider when estimating core on CTP.