Assessment of smoking care by stroke specialists in patients with recent TIA and minor stroke: an international prospective registry-based cohort study.

OBJECTIVES: The objectives are to assess smoking abstinence and its effects on vascular risk and to report tobacco-cessation counselling and pharmacotherapy use in patients who had a recent minor stroke or transient ischaemic attack (TIA). DESIGN AND SETTING: The TIA registry.org project is a prospective, observational registry of patients with TIA and minor stroke that occurred in the previous 7 days with a 5-year follow-up, involving 61 sites with stroke specialists in 21 countries (Europe, Asia, Latin America and Middle East). Of those, 42 sites had 5-year follow-up data on more than 50% of their patients and were included in the present study. PARTICIPANTS: From June 2009 through December 2011, 3847 patients were eligible for the study (80% of the initial cohort). OUTCOMES: Tobacco counselling and smoking-cessation pharmacotherapy use in smoking patients were reported at discharge. Association between 3-month smoking status and risk of a major cardiovascular event (MACE) was analysed with multivariable Cox regression model. RESULTS: Among 3801 patients included, 835 (22%) were smokers. At discharge, only 35.2% have been advised to quit and 12.5% had smoking-cessation pharmacotherapy prescription. At 3 months, 383/835 (46.9%) baseline smokers were continuers. Living alone and alcohol abuse were associated with persistent smoking; high level of education, aphasia and dyslipidaemia with quitting. The adjusted HRs for MACE at 5 years were 1.13 (95% CI 0.90 to 1.43) in former smokers, 1.31 (95% CI 0.93 to 1.84) in quitters and 1.31 (95% CI 0.94 to 1.83) in continuers. Using time-varying analysis, current smoking at the time of MACE non-significantly increased the risk of MACE (HR 1.31 (95% CI 0.97 to 1.78); p=0.080). CONCLUSION: In the TIAregistry.org, smoking-cessation intervention was used in a minority of patients. Surprisingly, in this population in which, at 5 years, other vascular risk factors were well controlled and antithrombotic treatment maintained, smoking cessation non-significantly decreased the risk of MACE.

Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.

Stent Retriever AssIsted Lysis Technique with Tirofiban: A Potential Bailout Alternative to Angioplasty and Stenting.

BACKGROUND AND PURPOSE: Angioplasty and stent placement have been described as a bailout technique in individuals with failed thrombectomy. We aimed to investigate Stent retriever AssIsted Lysis (SAIL) with tirofiban before angioplasty and stent placement. MATERIALS AND METHODS: Patients from 2 comprehensive stroke centers were reviewed (2020-2023). We included patients with failed thrombectomy and/or underlying intracranial stenosis who received SAIL with tirofiban before the intended angioplasty and stent placement. SAIL consisted of deploying a stent retriever through the occluding lesion to create a bypass channel and infuse 10 mL of tirofiban for 10 minutes either intra-arterially or IV. The stent retriever was re-sheathed before retrieval. The primary end points were successful reperfusion (expanded TICI 2b-3) and symptomatic intracerebral hemorrhage. Additional end points included 90-day mRS 0-2 and mortality. RESULTS: After a median of 3 (interquartile range, 2-4) passes, 44 patients received the SAIL bridging protocol with tirofiban, and later they were considered potential candidates for angioplasty and stent placement bailout (43.2%, intra-arterial SAIL). Post-SAIL successful reperfusion was obtained in 79.5%. A notable residual stenosis (>50%) after successful SAIL was observed in 45.7%. No significant differences were detected according to post-SAIL: successful reperfusion (intra-arterial SAIL, 80.0% versus IV-SAIL, 78.9%; P = .932), significant stenosis (33.3% versus 55.0%; P = .203), early symptomatic re-occlusion (0% versus 8.0%; P = .207), or symptomatic intracerebral hemorrhage (5.3% versus 8.0%; P = .721). Rescue angioplasty and stent placement were finally performed in 15 (34.1%) patients (intra-arterial SAIL 21.0% versus IV-SAIL 44%; P = .112). At 90 days, mRS 0-2 (intra-arterial SAIL 50.0% versus IV-SAIL 43.5%; P = .086) and mortality (26.3% versus 12.0%; P = .223) were also similar. CONCLUSIONS: In patients with stroke in which angioplasty and stent placement are considered, SAIL with tirofiban, either intra-arterial or IV, seems to safely induce sustained recanalization, offering a potential alternative to definitive angioplasty and stent placement.

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.).

Intracranial thrombus composition is associated with occlusion location and endovascular treatment outcomes: results from ITACAT multicenter study.

BACKGROUND: The impact of thrombolytics directed towards different thrombus components regarding site of occlusion in combination with mechanical thrombectomy (MT) to achieve endovascular complete recanalization is unclear. METHODS: Retrospective analysis of a prospective database in two stroke centers. Intracranial thrombi retrieved by MT were analyzed using hematoxylin-eosin staining for fibrin and red blood cell proportions, and CD61 immunostaining for platelets proportion in thrombus (PLTPT) assessment. Thrombi composition, baseline variables, etiology, treatment features and occlusion location were analyzed. RESULTS: Overall, 221 patients completed the per protocol analysis and 110 cases achieved a final expanded Thrombolysis in Cerebral Infarction (eTICI) 3 (49%) of which 70 were MT (32%) by first pass effect (FPE). Thrombi from medium distal vessel occlusions had higher PLTPT compared with thrombi from proximal large vessel occlusions (68% vs 61%, P=0.026). In particular, middle cerebral artery M2-M3 segment thrombi had the highest PLTPT (70%), and basilar artery thrombi the lowest PLTPT (41%). After logistic regression analysis adjusted for occlusion location and intravenous fibrinolysis, lower baseline National Institutes of Health Stroke Scale score (adjusted OR (aOR) 0.95, 95% CI 0.913 to 0.998) and PLTPT (aOR 0.97, 95% CI 0.963 to 0.993) were independently associated with FPE. Fewer MT passes (aOR 0.67, 95% CI 0.538 to 0.842) and platelet poor thrombus (<62% PLTPT; aOR 2.39, 95% CI 1.288 to 4.440) were independently associated with final eTICI 3. CONCLUSIONS: Occlusion location might be a surrogate parameter for thrombus composition. Platelet poor clots and fewer MT passes were independently associated with complete endovascular recanalization. Clinical trials testing the benefits of combining selective intra-arterial platelet antagonists with MT to improve endovascular outcomes are warranted.

Effects of Achieving Rapid, Intensive, and Sustained Blood Pressure Reduction in Intracerebral Hemorrhage Expansion and Functional Outcome.

BACKGROUND AND OBJECTIVES: The time taken to achieve blood pressure (BP) control could be pivotal in the benefits of reducing BP in acute intracerebral hemorrhage (ICH). We aimed to assess the relationship between the rapid achievement and sustained maintenance of an intensive systolic BP (SBP) target with radiologic, clinical, and functional outcomes. METHODS: Rapid, Intensive, and Sustained BP lowering in Acute ICH (RAINS) was a multicenter, prospective, observational cohort study of adult patients with ICH <6 hours and SBP ≥150 mm Hg at 4 Comprehensive Stroke Centers during a 4.5-year period. Patients underwent baseline and 24-hour CT scans and 24-hour noninvasive BP monitoring. BP was managed under a rapid (target achievement ≤60 minutes), intensive (target SBP <140 mm Hg), and sustained (target stability for 24 hours) BP protocol. SBP target achievement ≤60 minutes and 24-hour SBP variability were recorded. Outcomes included hematoma expansion (>6 mL or >33%) at 24 hours (primary outcome), early neurologic deterioration (END, 24-hour increase in NIH Stroke Scale score ≥4), and 90-day ordinal modified Rankin scale (mRS) score. Analyses were adjusted by age, sex, anticoagulation, onset-to-imaging time, ICH volume, and intraventricular extension. RESULTS: We included 312 patients (mean age 70.2 ± 13.3 years, 202 [64.7%] male). Hematoma expansion occurred in 70/274 (25.6%) patients, END in 58/291 (19.9%), and the median 90-day mRS score was 4 (interquartile range, 2-5). SBP target achievement ≤60 minutes (178/312 [57.1%]) associated with a lower risk of hematoma expansion (adjusted odds ratio [aOR] 0.43, 95% confidence interval [CI] 0.23-0.77), lower END rate (aOR 0.43, 95% CI 0.23-0.80), and lower 90-day mRS scores (aOR 0.48, 95% CI 0.32-0.74). The mean 24-hour SBP variability was 21.0 ± 7.6 mm Hg. Higher 24-hour SBP variability was not related to expansion (aOR 0.99, 95% CI 0.95-1.04) but associated with higher END rate (aOR 1.15, 95% CI 1.09-1.21) and 90-day mRS scores (aOR 1.06, 95% CI 1.04-1.10). DISCUSSION: Among patients with acute ICH, achieving an intensive SBP target within 60 minutes was associated with lower hematoma expansion risk. Rapid SBP reduction and stable sustention within 24 hours were related to improved clinical and functional outcomes. These findings warrant the design of randomized clinical trials examining the impact of effectively achieving rapid, intensive, and sustained BP control on hematoma expansion. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in adults with spontaneous ICH and initial SBP ≥150 mm Hg, lowering SBP to <140 mm Hg within the first hour and maintaining this for 24 hours is associated with decreased hematoma expansion.

A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke with Proven Occlusion (TEMPO-2): Rational and design of a multicenter, randomized open-label clinical trial.

BACKGROUND: Almost half of acute ischemic stroke patients present with mild symptoms and there are large practice variations in their treatment globally. Individuals with an intracranial occlusion who present with minor stroke are at an increased risk of early neurological deterioration and poor outcomes. Individual patient data meta-analysis in the subgroup of patients with minor deficits showed benefit of alteplase in improving outcomes; however, this benefit has not been seen with intravenous alteplase in published randomized trials. DESIGN: TEMPO-2 (A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion) is a prospective, open label with blinded outcome assessment, randomized controlled trial, designed to test the superiority of intravenous tenecteplase (0.25 mg/kg) over nonthrombolytic standard of care, with an estimated sample size of 1274 patients. Adult patients presenting with acute ischemic stroke with the National Institutes of Health Stroke Scale (NIHSS) ⩽ 5 and visible arterial occlusion or perfusion deficit within 12 h of onset are randomized to receive either tenecteplase (0.25 mg/kg) or standard of care. The primary outcome is return to baseline neurological functioning, measured by the modified Rankin scale (mRS) at 90 days. Safety outcomes include death and symptomatic hemorrhage (intra or extra-cranial). Other secondary outcomes include mRS 0-1, mRS 0-2, ordinal shift analysis of the mRS, partial, and full recanalization on follow-up computed tomography angiogram. CONCLUSION: Results of this trial will aid in determining whether there is benefit of using tenecteplase (0.25 mg/kg) in treating patients presenting with minor stroke who are at high risk of developing poor outcomes due to presence of an intracranial occlusion. DATA ACCESS STATEMENT: Data will be available upon reasonable request.

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.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.

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.

Clinico-radiological features of intracranial atherosclerosis-related large vessel occlusion prior to endovascular treatment.

The identification of large vessel occlusion with underlying intracranial atherosclerotic disease (ICAS-LVO) before endovascular treatment (EVT) continues to be a challenge. We aimed to analyze baseline clinical-radiological features associated with ICAS-LVO that could lead to a prompt identification. We performed a retrospective cross-sectional study of consecutive patients with stroke treated with EVT from January 2020 to April 2022. We included anterior LVO involving intracranial internal carotid artery and middle cerebral artery. We analyzed baseline clinical and radiological variables associated with ICAS-LVO and evaluated the diagnostic value of a multivariate logistic regression model to identify ICAS-LVO before EVT. ICAS-LVO was defined as presence of angiographic residual stenosis or a trend to re-occlusion during EVT procedure. A total of 338 patients were included in the study. Of them, 28 patients (8.3%) presented with ICAS-LVO. After adjusting for confounders, absence of atrial fibrillation (OR 9.33, 95% CI 1.11-78.42; p = 0.040), lower hypoperfusion intensity ratio (HIR [Tmax > 10 s/Tmax > 6 s ratio], (OR 0.69, 95% CI 0.50-0.95; p = 0.025), symptomatic intracranial artery calcification (IAC, OR .15, 95% CI 1.64-26.42, p = 0.006), a more proximal occlusion (ICA, MCA-M1: OR 4.00, 95% CI 1.23-13.03; p = 0.021), and smoking (OR 2.91, 95% CI 1.08-7.90; p = 0.035) were associated with ICAS-LVO. The clinico-radiological model showed an overall well capability to identify ICAS-LVO (AUC = 0.88, 95% CI 0.83-0.94; p < 0.001). In conclusion, a combination of clinical and radiological features available before EVT can help to identify an ICAS-LVO. This approach could be useful to perform a rapid assessment of underlying etiology and suggest specific pathophysiology-based measures. Prospective studies are needed to validate these findings in other populations.

Safety and efficacy of platelet glycoprotein VI inhibition in acute ischaemic stroke (ACTIMIS): a randomised, double-blind, placebo-controlled, phase 1b/2a trial.

BACKGROUND: Antagonists of glycoprotein VI-triggered platelet activation used in combination with recanalisation therapies are a promising therapeutic approach in acute ischaemic stroke. Glenzocimab is an antibody fragment that inhibits the action of platelet glycoprotein VI. We aimed to determine and assess the safety and efficacy of the optimal dose of glenzocimab in patients with acute ischaemic stroke eligible to receive alteplase with or without mechanical thrombectomy. METHODS: This randomised, double-blind, placebo-controlled study with dose-escalation (1b) and dose-confirmation (2a) phases (ACTIMIS) was done in 26 stroke centres in six European countries. Participants were adults (≥18 years) with disabling acute ischaemic stroke with a National Institutes of Health Stroke Scale score of 6 or higher before alteplase administration. Patients were randomly assigned treatment using a central electronic procedure. Total administered dose at the end of the intravenous administration was 125 mg, 250 mg, 500 mg, and 1000 mg of glenzocimab or placebo in phase 1b and 1000 mg of glenzocimab or placebo in phase 2a. Treatment was initiated 4·5 h or earlier from stroke symptom onset in patients treated with alteplase with or without mechanical thrombectomy. The sponsor, study investigator and study staff, patients, and central laboratories were all masked to study treatment until database lock. Primary endpoints across both phases were safety, mortality, and intracranial haemorrhage (symptomatic, total, and fatal), assessed in all patients who received at least a partial dose of study medication (safety set). The trial is registered on ClinicalTrials.gov, NCT03803007, and is complete. FINDINGS: Between March 6, 2019, and June 27, 2021, 60 recruited patients were randomly assigned to 125 mg, 250 mg, 500 mg, or 1000 mg glenzocimab, or to placebo in phase 1b (n=12 per group) and were included in the safety analysis. Glenzocimab 1000 mg was well tolerated and selected as the phase 2a recommended dose; from Oct 2, 2020, to June 27, 2021, 106 patients were randomly assigned to glenzocimab 1000 mg (n=53) or placebo (n=53). One patient in the placebo group received glenzocimab in error and therefore 54 and 52, respectively, were included in the safety set. In phase 2a, the most frequent treatment-emergent adverse event was non-symptomatic haemorrhagic transformation, which occurred in 17 (31%) of 54 patients treated with glenzocimab and 26 (50%) of 52 patients treated with placebo. Symptomatic intracranial haemorrhage occurred in no patients treated with glenzocimab compared with five (10%) patients in the placebo group. All-cause deaths were lower with glenzocimab 1000 mg (four [7%] patients) than with placebo (11 [21%] patients). INTERPRETATION: Glenzocimab 1000 mg in addition to alteplase, with or without mechanical thrombectomy, was well tolerated, and might reduce serious adverse events, intracranial haemorrhage, and mortality. These findings support the need for future research into the potential therapeutic inhibition of glycoprotein VI with glenzocimab plus alteplase in patients with acute ischaemic stroke. FUNDING: Acticor Biotech.

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

Histogram analysis in the differentiation between adrenal adenomas and pheochromocytomas: the value of a single measurement / Análise por histograma para diferenciação entre adenomas da adrenal e feocromocitomas: o valor de uma medida única

Abstract Objective: To assess the diagnostic accuracy of histogram analysis on unenhanced computed tomography (CT) for differentiating between adrenal adenomas and pheochromocytomas (PCCs). Materials and Methods: We retrospectively identified patients with proven PCCs who had undergone CT examinations between January 2009 and July 2019 at one of two institutions. For each PCC, we selected one or two adenomas diagnosed within two weeks of the date of diagnosis of the PCC. For each lesion, two readers scored the size, determined the mean attenuation, and generated a voxel histogram. The 10th percentile (P10) was obtained from the conventional histogram analysis, as well as being calculated with the following formula: P10 = mean attenuation - (1.282 × standard deviation). The mean attenuation threshold, histogram analysis (observed) P10, and calculated P10 (calcP10) were compared in terms of their diagnostic accuracy. Results: We included 52 adenomas and 29 PCCs. The sensitivity, specificity, and accuracy of the mean attenuation threshold were 75.0%, 100.0%, and 82.5%, respectively, for reader 1, whereas they were 71.5%, 100.0%, and 81.5%, respectively, for reader 2. The sensitivity, specificity, and accuracy of the observed P10 and calcP10 were equal for both readers: 90.4%, 96.5%, and 92.6%, respectively, for reader 1; and 92.3%, 93.1%, and 92.6%, respectively, for reader 2. The increase in sensitivity was significant for both readers (p = 0.009 and p = 0.005, respectively). Conclusion: For differentiating between adenomas and PCCs, the histogram analysis (observed P10 and calcP10) appears to outperform the mean attenuation threshold as a diagnostic criterion.

Resumo Objetivo: Avaliar a acurácia diagnóstica da análise por histograma na tomografia computadorizada (TC) sem contraste para a diferenciação entre adenomas adrenais e feocromocitomas (FCCs). Materiais e Métodos: Identificamos, retrospectivamente, pacientes com diagnóstico de FCC confirmado que foram submetidos a exames de TC entre janeiro de 2009 e julho de 2019 em duas instituições distintas. Para cada FCC, selecionamos um ou dois adenomas diagnosticados em até duas semanas da data do diagnóstico do FCC. Para cada lesão, dois leitores pontuaram o tamanho, determinaram a atenuação média e geraram um histograma com os voxels das imagens. O percentil 10 (P10) foi obtido a partir da análise convencional do histograma, além de ser calculado com a seguinte fórmula: P10 = atenuação média - (1,282 × desvio-padrão). O limiar de atenuação média, o P10 da análise por histograma (P10 observado) e o P10 calculado (P10calc) foram comparados em termos de acurácia diagnóstica. Resultados: Foram incluídos 52 adenomas e 29 FCCs. A sensibilidade, especificidade e acurácia do limiar de atenuação média foram de 75,0%, 100,0% e 82,5% para o leitor 1, respectivamente, e de 71,5%, 100,0% e 81,5% para o leitor 2, respectivamente. A sensibilidade, especificidade e acurácia do P10 observado e do P10calc foram idênticas para os dois leitores: 90,4%, 96,5% e 92,6%, respectivamente, para o leitor 1; e 92,3%, 93,1% e 92,6%, respectivamente, para o leitor 2. O aumento da sensibilidade foi significativo para ambos os leitores (p = 0,009 e p = 0,005, respectivamente). Conclusão: Para a diferenciação entre adenomas e FCCs, a análise por histograma (P10 observado ou P10calc) parece superar o limiar de atenuação média como critério diagnóstico.

Efecto de la resonancia magnética sobre la agudeza visual cercana / Effect of magnetic resonance imaging on near visual acuity

Objetivos: determinar la variación de la agudeza visual cercana en pacientes expuestos a campos magnéticos intensos por períodos cortos en estudios de resonancia magnética.Métodos: estudio descriptivo de una serie de casos, que incluyó 9 hombres y 31 mujeres alfabetas mayores de 40 años; debían tener una agudeza visual mejor de 20/200 y no estar bajo los efectos de medicamentos ansiolíticos. Estas personas fueron sometidas a procedimientos diagnósticos de resonancia magnética de cabeza y cuello; antes del procedimiento e inmediatamente después de terminarlo se les midió la agudeza visual (AV) con la carta de visión cercana de Jaeger. Las mediciones fueron llevadas a cabo por dos observadores diferentes, cada uno de los cuales desconocía los resultados obtenidos por el otro.Resultados: las medias de la agudeza visual cercana antes y después de la resonancia magnética fueron, respectivamente, 1.4324 ± 0.4766 m y 1.4375 ± 0.5024 m (p = 0.505).Conclusiones: en el grupo evaluado no se evidenciaron cambios estadísticamente significativos de la agudeza visual cercana después de un estudio de resonancia magnética de cabeza y cuello.

Purpose: To determine the variation of near visual acuity, in patients exposed during short periods to intense magnetic fields in studies of magnetic resonance imaging. Methods: Descriptive study of a case series that included 40 healthy and literate individuals older than 40 years, nine of them men, submitted to a procedure of head and neck magnetic resonance imaging; all of them had near visual acuity better than 20/200 without glasses, and were not underthe effects of ansiolytic medications.Near vision was measured with the Jaeger chart before and immediately after the RM imaging procedure. Measurements were carried out by twodifferent observers; every one of them did not know the results obtained by the other.Results: Means for near vision acuity before and after the magnetic resonance imaging procedure were, respectively, 1.4324 ± 0.4766 m and 1.4375 ± 0.5024 m (p = 0.505).Conclusions: In the evaluated group, no statistically significant change was observed in near vision acuity after head and neck magnetic resonance imaging procedures.

Inmunoterapia en el tratamiento de la conjuntivitis alérgica crónica / Inmunotherapy in the treatment of chronic allergic conjuntivitis

Con el objeto de evaluar la respuesta a dos esquemas de Inmunoterapia alergénica para el tratamiento de la conjuntivitis alérgica crónica (CAC) en Individuos sensibles a Dermatophagoides farinae (ácaro del polvo) y refractarios a los tratamientos convencionales, se realizó un ensayo clínico controlado y ciego en el Hospital Universitario San Vicente de Paúl de Medellín, Colombia, entre agosto de 1990 y junio de 1993. Se estudiaron 18 hombres (82 por ciento) y 4 (18 por ciento) mujeres con edades entre los 5 y 25 anos pero en su mayoría menores de 11 años (63.6 por ciento); la evolución de su enfermedad era mayor de 5 meses. Se excluyeron los pacientes que habían recibido previamente algún esquema de Inmunoterapia o que eran sensibles a otros aeroalergenos. En 14 pacientes (63.6 por ciento) se administró el esquema agrupado (tipo cluster) y en ocho (36.4 por ciento) el convencional. No se encontraron diferencias estadísticamente significativas entre las dos modalidades; en 16 pacientes (72.7 por ciento) hubo mejoría subjetiva parcial, demostrada por el interrogatorio, y en 15 (68.2 por ciento) mejoría objetiva parcial evidenciada por el examen oftalmológico. En tres pacientes de tratamiento agrupado no se obtuvo mejoría. Los síntomas que más disminuyeron al finalizar el seguimiento fueron el prurito en 16 casos (72.7 por ciento) y el lagrimeo (15 casos; 68.2 por ciento); sólo en 4 de los 11 pacientes (36.4 por ciento) que al Inicio del estudio tenían papilas se observó la desaparición de éstas, a pesar de una buena respuesta clínica. Se concluyó que la inmunoterapia es útil en el manejo de la CAC refractaria a tratamientos convencionales y no se encontraron diferencias significativas entre los dos esquemas utilizados

Between August 1990 and June 1993, a blind clinic assay was carried out at Hospital Universitario San Vicente de Paúl, in Mede1lín, Colombia, with the purpose of evaluating the response to two Immunotherapy schemes (cluster and conventional), for treatment of Chronic Allergic Conjunctivitis (CAC) refractory to conventional pharmacological treatments. In patients sensitized to Dermatophagoides farinae. The study was performed on 22 patients aged 5-25 years. The evolution of the disease had been 6 months or longer. Patients who had previously received an Im. munotherapy scheme or showed sensitivity to other aeroallergens were excluded. Fourteen patients (63.6%) received the cluster scheme and eight (36.4%) the conventional one. No statistically significant differences were found between the two groups. In 16 patientes (72.7%) partial subjective Improvement and in 15 (68.2%) partial objective improvement were observed. Most notoriously Improved were scratching (16 cases; 72.7%) and tearing (15 cases 68.2%). Papillary hyper. trophy persisted In 7 (63.6%) of the 11 patients that presented it at the begining of the study, regardless of good clinical response. It is concluded that immunotherapy is useful for the treatment of refractory CAC and that there are no significant differences between cluster and conventional schemes

Medellín: mortalidad por causas en la década de los ochenta. Una interpretación socio-demográfica / Medellin. Caused mortality in the 80’s decade. A socio-demographic interpretation

Los resultados que aquí se presentan son parciales y hacen parte de una investigación que busca aportar al conocimiento del proceso salud-enfermedad-muerte en la ciudad de Medellín. La información utilizada está contenida en datos anuales sobre defunciones, entre 1982 y 1992, generadas por el Departamento de Sistematización del Municipio de Medellín. Las causas básicas de defunción fueron clasificadas según la IX Clasificación Internacional de Enfermedades (CIE) y reagrupadas según definiciones de evitabilidad. Entre los hallazgos se destacan: permanencia de una alta contribución a la mortalidad por defunciones que pudieron haber sido evitadas (más del 50 por ciento). La sobremortalidad masculina sigue siendo explicada por este tipo de causas, en donde los accidentes y violencias aportan altos porcentajes. Más de 60 de cada 100 muertes masculinas son clasificadas como accidentes, traumatismos o violencias. Los datos sugieren que estamos ante un perfil de mortalidad de una población en guerra, donde los que no son víctimas de la violencia, en forma directa son personas adultas que no disponen de los servicios de salud necesarios para convivir con enfermedades crónico-degenerativas propias de su edad. El perfil de mortalidad encontrado no se corresponde con el de sociedades modernas, caracterizado por enfermedades propias del desarrollo como las cardiovasculares y los tumores, sino que se asemeja a estructuras arcaicas en correspondencia con el capitalismo salvaje en que vivimos.