Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

The Physics of the B Factories

This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C

The making of modern scientific personae: the scientist as a moral person? Emil Du Bois-Reymond and his friends

This article examines the notion of the \u27scientist as a moral person\u27 in the light of the early stages of the commodification of science and the transformation of research into a big enterprise, operating on the principle of the division of labour. These processes were set in train at the end of the 19th century. The article focuses on the concomitant changes in the public persona and the habitus of scientific entrepreneurs. I begin by showing the significance of the professional networks that were built up and maintained to further a group\u27s research ideas and the careers of its members, thus demonstrating one condition on which depended their practice of science and their ability to earn a living. This leads to a characterization of the changing styles of work, thought and life, and to a consideration of public perceptions and of the ways in which a new self-image of scholarship and science was fashioned. A critical discussion of the public role of these mandarin scientists follows in order to highlight the strains created by the commodification of science at a time of international tensions and conflicts, when shared beliefs in scholarly cosmopolitanism were subverted by appeals to science and scholarship to work in the service of one\u27s own nation as its \u27courtiers\u27. Various considerations of peculiar analogies between national styles of research and the style of social organization are then noted. In the final section, the article queries the long-term impact of these developments on the ideal of the scientist as a \u27moral person\u27. Taking a cue from Max Weber and pursuing reflections by Zygmunt Bauman on \u27science moralized\u27, I argue that the emergence of a type of \u27specialists without spirit\u27 was an unintended but fatal consequence of the changes in research practices promoted by scientific entrepreneurs such as Du Bois-Reymond. I conclude that the temptation to sever the ties to a general ethos of civil virtues lay in the rationalization, specialization and potential de-humanization of the objectifying scientific outlook once advocated for its efficiency.<br /