Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07). This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National Health and Medical Research Council of Australia and others; ENCHANTED ClinicalTrials.gov number, NCT01422616.)

Background: Coronavirus disease 2019 (COVID‐19) is an emerging infectious disease of pandemic proportions. Healthcare workers in Singapore working in high‐risk areas were mandated to wear personal protective equipment (PPE) such as N95 face mask and protective eyewear while attending to patients. Objectives: We sought to determine the risk factors associated with the development of de novo PPE‐associated headaches as well as the perceived impact of these headaches on their personal health and work performance. The impact of COVID‐19 on pre‐existing headache disorders was also investigated. Methods: This is a cross‐sectional study among healthcare workers at our tertiary institution who were working in high‐risk hospital areas during COVID‐19. All respondents completed a self‐administered questionnaire. Results: A total of 158 healthcare workers participated in the study. Majority [126/158 (77.8%)] were aged 21‐35 years. Participants included nurses [102/158 (64.6%)], doctors [51/158 (32.3%)], and paramedical staff [5/158 (3.2%)]. Pre‐existing primary headache diagnosis was present in about a third [46/158 (29.1%)] of respondents. Those based at the emergency department had higher average daily duration of combined PPE exposure compared to those working in isolation wards [7.0 (SD 2.2) vs 5.2 (SD 2.4) hours, P < .0001] or medical ICU [7.0 (SD 2.2) vs 2.2 (SD 0.41) hours, P < .0001]. Out of 158 respondents, 128 (81.0%) respondents developed de novo PPE‐associated headaches. A pre‐existing primary headache diagnosis (OR = 4.20, 95% CI 1.48‐15.40; P = .030) and combined PPE usage for >4 hours per day (OR 3.91, 95% CI 1.35‐11.31; P = .012) were independently associated with de novo PPE‐associated headaches. Since COVID‐19 outbreak, 42/46 (91.3%) of respondents with pre‐existing headache diagnosis either “agreed” or “strongly agreed” that the increased PPE usage had affected the control of their background headaches, which affected their level of work performance. Conclusion: Most healthcare workers develop de novo PPE‐associated headaches or exacerbation of their pre‐existing headache disorders.