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Key Points: Question: In patients with acute ischemic stroke undergoing thrombectomy, does a potential benefit associated with intravenous thrombolysis vary according to treatment times? Findings: In this individual participant data meta-analysis (n = 2313) of 6 randomized clinical trials, intravenous thrombolysis plus thrombectomy was significantly associated with a favorable shift in functional outcome at 90 days vs thrombectomy alone if the time from symptom onset to expected administration of intravenous thrombolysis was within 2 hours 20 minutes. Thereafter, there was no statistically significant association. Meaning: The findings indicate that the benefit associated with intravenous thrombolysis prior to thrombectomy was time dependent and lessened with longer times between symptom onset and expected administration of intravenous thrombolysis. Importance: The benefit of intravenous thrombolysis (IVT) for acute ischemic stroke declines with longer time from symptom onset, but it is not known whether a similar time dependency exists for IVT followed by thrombectomy. Objective: To determine whether the benefit associated with IVT plus thrombectomy vs thrombectomy alone decreases with treatment time from symptom onset. Design, Setting, and Participants: Individual participant data meta-analysis from 6 randomized clinical trials comparing IVT plus thrombectomy vs thrombectomy alone. Enrollment was between January 2017 and July 2021 at 190 sites in 15 countries. All participants were eligible for IVT and thrombectomy and presented directly at thrombectomy-capable stroke centers (n = 2334). For this meta-analysis, only patients with an anterior circulation large-vessel occlusion were included (n = 2313). Exposure: Interval from stroke symptom onset to expected administration of IVT and treatment with IVT plus thrombectomy vs thrombectomy alone. Main Outcomes and Measures: The primary outcome analysis tested whether the association between the allocated treatment (IVT plus thrombectomy vs thrombectomy alone) and disability at 90 days (7-level modified Rankin Scale [mRS] score range, 0 [no symptoms] to 6 [death]; minimal clinically important difference for the rates of mRS scores of 0-2: 1.3%) varied with times from symptom onset to expected administration of IVT. Results: In 2313 participants (1160 in IVT plus thrombectomy group vs 1153 in thrombectomy alone group; median age, 71 [IQR, 62 to 78] years; 44.3% were female), the median time from symptom onset to expected administration of IVT was 2 hours 28 minutes (IQR, 1 hour 46 minutes to 3 hours 17 minutes). There was a statistically significant interaction between the time from symptom onset to expected administration of IVT and the association of allocated treatment with functional outcomes (ratio of adjusted common odds ratio [OR] per 1-hour delay, 0.84 [95% CI, 0.72 to 0.97], P =.02 for interaction). The benefit of IVT plus thrombectomy decreased with longer times from symptom onset to expected administration of IVT (adjusted common OR for a 1-step mRS score shift toward improvement, 1.49 [95% CI, 1.13 to 1.96] at 1 hour, 1.25 [95% CI, 1.04 to 1.49] at 2 hours, and 1.04 [95% CI, 0.88 to 1.23] at 3 hours). For a mRS score of 0, 1, or 2, the predicted absolute risk difference was 9% (95% CI, 3% to 16%) at 1 hour, 5% (95% CI, 1% to 9%) at 2 hours, and 1% (95% CI, −3% to 5%) at 3 hours. After 2 hours 20 minutes, the benefit associated with IVT plus thrombectomy was not statistically significant and the point estimate crossed the null association at 3 hours 14 minutes. Conclusions and Relevance: In patients presenting at thrombectomy-capable stroke centers, the benefit associated with IVT plus thrombectomy vs thrombectomy alone was time dependent and statistically significant only if the time from symptom onset to expected administration of IVT was short. This individual participant data meta-analysis assesses treatment time from stroke symptom onset and disability level after treatment with intravenous thrombolysis plus thrombectomy vs thrombectomy alone among patients who presented directly at thrombectomy-capable stroke centers. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to determine the safety and efficacy of intravenous (IV) alteplase at 0.6 mg/kg for patients with acute wake-up or unclear-onset strokes in clinical practice. Methods: This multicenter observational study enrolled acute ischemic stroke patients with last-known-well time >4.5 h who had mismatch between DWI and FLAIR and were treated with IV alteplase. The safety outcomes were symptomatic intracranial hemorrhage (sICH) after thrombolysis, all-cause deaths, and all adverse events. The efficacy outcomes were favorable outcome defined as an mRS score of 0–1 or recovery to the same mRS score as the premorbid score, complete independence defined as an mRS score of 0–1 at 90 days, and change in NIHSS at 24 h from baseline. Results: Sixty-six patients (35 females; mean age, 74 ± 11 years; premorbid complete independence, 54 [82%]; median NIHSS on admission, 11) were enrolled at 15 hospitals. Two patients (3%) had sICH. Median NIHSS changed from 11 (IQR, 6.75–16.25) at baseline to 5 (3–12.25) at 24 h after alteplase initiation (change, −4.8 ± 8.1). At discharge, 31 patients (47%) had favorable outcome and 29 (44%) had complete independence. None died within 90 days. Twenty-three (35%) also underwent mechanical thrombectomy (no sICH, NIHSS change of −8.5 ± 7.3), of whom 11 (48%) were completely independent at discharge. Conclusions: In real-world clinical practice, IV alteplase for unclear-onset stroke patients with DWI-FLAIR mismatch provided safe and efficacious outcomes comparable to those in previous trials. Additional mechanical thrombectomy was performed safely in them. [ABSTRACT FROM AUTHOR]

Malaria infection elicits both protective and pathogenic immune responses, and IL‐27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4+ T cell responses that is targeted by IL‐27. Neutralization of IL‐27 during acute infection with Plasmodium chabaudi expanded specific CD4+ T cells, which were maintained at high levels thereafter. In the chronic phase, Plasmodium‐specific CD4+ T cells in IL‐27‐neutralized mice consisted mainly of CD127+KLRG1− and CD127−KLRG1+ subpopulations that displayed distinct cytokine production, proliferative capacity, and are maintained in a manner independent of active infection. Single‐cell RNA‐seq analysis revealed that these CD4+ T cell subsets formed independent clusters that express unique Th1‐type genes. These IL‐27‐neutralized mice exhibited enhanced cellular and humoral immune responses and protection. These findings demonstrate that IL‐27, which is produced during the acute phase of malaria infection, inhibits the development of unique Th1 memory precursor CD4+ T cells, suggesting potential implications for the development of vaccines and other strategic interventions. Synopsis: IL‐27 inhibits the generation of parasite‐specific memory CD4+ T cells in a malaria infection model. Transient blockade of IL‐27 elicits high levels of unique CD127+ and KLRG1+ memory CD4+ T cells, elevates antibody production, and enhances protective immunity against secondary infection. IL‐27 produced during the acute phase of malaria infection is inhibitory for the generation of parasite‐specific memory CD4+ T cells.Two types of unique memory CD4+ T cells are generated in the absence of IL‐27: CD127+ and KLRG1+ cells expressing high levels of Ifng and Tbx21, respectively.Memory CD4+ T cells induced in the absence of IL‐27 can be maintained in the absence of persistent malaria infection.The absence of IL‐27 during the acute phase of malaria infection generates memory immune responses that are protective against challenge infection. [ABSTRACT FROM AUTHOR]

Introduction: Patients with stroke are at a high risk of recurrence, and although they receive antiplatelet therapies such as clopidogrel for secondary prevention of non-cardioembolic stroke, the recurrence rate remains high. Three phase 3 trials (PRASTRO-I/II/III) were conducted to determine the efficacy of prasugrel in preventing recurrent stroke. Here, we performed an integrated analysis of these studies to confirm the generalizability of the PRASTRO-III findings and to supplement the small sample size of the study. Methods: Patients from PRASTRO-I, PRASTRO-II, and PRASTRO-III with ischemic stroke (large-artery atherosclerosis or small-artery occlusion) and at least one of the following were included: hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease, or ischemic stroke history. The primary efficacy endpoint was the composite incidence of ischemic stroke, myocardial infarction (MI), and death from other vascular causes in the intention-to-treat population. Bleeding events (life-threatening bleeding, major bleeding, and clinically relevant bleeding) were evaluated as the primary safety endpoint. Cumulative incidences and 95% confidence intervals (CIs) were calculated for the study outcomes using the Kaplan-Meier method. Hazard ratios (HRs) and 95% CIs were calculated using the Cox regression model. Results: The data of 2,184, 274, and 230 patients from PRASTRO-I, PRASTRO-II, and PRASTRO-III, respectively, were analyzed (N = 2,688; prasugrel, N = 1,337; clopidogrel, N = 1,351). Stroke at enrollment was classified as large-artery atherosclerosis in 49.3% of patients and small-artery occlusion in 50.7% of patients. The primary efficacy endpoint composite incidence (prasugrel vs. clopidogrel) was 3.4% versus 4.3% (HR: 0.771, 95% CI: 0.522–1.138). The incidence of each component of the primary efficacy endpoint for prasugrel versus clopidogrel was 3.1% (n = 41) versus 4.1% (n = 55) for ischemic stroke, 0.3% (n = 4) versus 0.2% (n = 3) for MI, and no events of death from other vascular causes. For the primary safety endpoint, bleeding events were reported in 6.0% of patients in the prasugrel group versus 5.5% of patients in the clopidogrel group (HR: 1.074, 95% CI: 0.783–1.473). Conclusions: This integrated analysis supports the findings of PRASTRO-III. Prasugrel is a promising treatment that results in a numerical reduction in the composite incidence of ischemic stroke, MI, and death from other vascular causes in patients with ischemic stroke who are at a high risk of stroke recurrence. No major safety issues were observed for prasugrel. [ABSTRACT FROM AUTHOR]