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

A Ceratopsian Dinosaur from the Lower Cretaceous of Western North America, and the Biogeography of Neoceratopsia

Competing interests: Andrew A. Farke has read the journal's policy and the authors of this manuscript have the following competing interests: Andrew A. Farke is a volunteer section editor and academic editor for PLOS ONE. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.Acknowledgments It is a pleasure to offer our most heartfelt thanks to Scott K. Madsen, who found OMNH 34557 and prepared it with consummate skill. We are grateful to James Taylor, Jack Owen, the Keebler family, and the Montana Bureau of Land Management for access to outcrops of the Cloverly Formation. We thank Xu Xing (IVPP) and Hai-Lu You (formerly CAGS-IG) for facilitating access to specimens, Mark Loewen, Joseph Frederickson, Darren Naish, and Leonardo Maiorino for productive discussion and comments, and Roger Burkhalter for assistance in photography. Gary Wisser, from the scientific visualization center at Western University of Health Sciences, is gratefully acknowledged for the high resolution scan of the cranium. Reviews by Peter Makovicky, Hai-Lu You, and editor Peter Wilf improved the manuscript.Author Contributions Conceived and designed the experiments: AAF WDM RLC. Performed the experiments: AAF WDM RLC. Analyzed the data: AAF WDM RLC MJW. Contributed reagents/materials/analysis tools: AAF WDM RLC MJW. Wrote the paper: AAF WDM RLC MJW.The fossil record for neoceratopsian (horned) dinosaurs in the Lower Cretaceous of North America primarily comprises isolated teeth and postcrania of limited taxonomic resolution, hampering previous efforts to reconstruct the early evolution of this group in North America. An associated cranium and lower jaw from the Cloverly Formation (?middle–late Albian, between 104 and 109 million years old) of southern Montana is designated as the holotype for Aquilops americanus gen. et sp. nov. Aquilops americanus is distinguished by several autapomorphies, including a strongly hooked rostral bone with a midline boss and an elongate and sharply pointed antorbital fossa. The skull in the only known specimen is comparatively small, measuring 84 mm between the tips of the rostral and jugal. The taxon is interpreted as a basal neoceratopsian closely related to Early Cretaceous Asian taxa, such as Liaoceratops and Auroraceratops. Biogeographically, A. americanus probably originated via a dispersal from Asia into North America; the exact route of this dispersal is ambiguous, although a Beringian rather than European route seems more likely in light of the absence of ceratopsians in the Early Cretaceous of Europe. Other amniote clades show similar biogeographic patterns, supporting an intercontinental migratory event between Asia and North America during the late Early Cretaceous. The temporal and geographic distribution of Upper Cretaceous neoceratopsians (leptoceratopsids and ceratopsoids) suggests at least intermittent connections between North America and Asia through the early Late Cretaceous, likely followed by an interval of isolation and finally reconnection during the latest Cretaceous.Funding was received from the National Science Foundation (DEB 9401094, 9870173, http://www.nsf.gov); National Geographic Society (5918-97, http://www.nationalgeographic.com/); and American Chemical Society (PRF #38572-AC8, http://www.acs.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Yeshttp://www.plosone.org/static/editorial#pee

Permian and Early Triassic extinction of non-marine tetrapods

Volume: 35Start Page: 571End Page: 58

Hypothesis of phylogeny and biogeography for Neoceratopsia.

<p>Some terminal taxa have been combined for space considerations, and the range bars for each taxon indicate uncertainty rather than known geological ranges. Continent icons indicate the ancestral areas reconstructed by DEC modeling. Silhouettes depict representative members of major clades and grades (<i>Psittacosaurus</i> by J. Headden, <i>Zuniceratops</i> by N. Tamura and modified by T. M. Keesey; <i>Triceratops</i> by R. Amos; all others by A. Farke; all images are CC-BY and provided via <a href="http://www.phylopic.org" target="_blank">www.phylopic.org</a>). Full results are presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0112055#pone.0112055.s001" target="_blank">File S1</a>.</p

Occlusal (lingual) surface of seventh right maxillary tooth in <i>Aquilops americanus</i>, OMNH 34557 (holotype).

<p>Note that enamel (highlighted by arrows in the inset) only occurs on the labial surface, and does not continue to the buccal extremity of the tooth at the bottom of the image. The discoloration adhering to the tooth at the top of the image (lingual side of the tooth) is sediment impregnated with consolidant resin, not enamel.</p

Lower jaw of <i>Aquilops americanus</i>, OMNH 34557 (holotype).

<p>Predentary and left dentary in A) medial; B) ventral; C) dorsal; and D) lateral views. The three fragments, although unattached, were placed into articulation for these photos. The rostral direction is to the right in A and to the left in B–D.</p

Skull of <i>Aquilops americanus</i>, OMNH 34557 (holotype).

<p>Partial cranium in A) dorsal and B) right lateral views. Partial lower jaw in C) right lateral and D) dorsal views. This interpretive figure is based on surface scans of the original specimen, with sutures highlighted. The lower jaw is reversed, to facilitate placement with the skull. Abbreviations: aof, antorbital fossa; d, dentary; ecp, ectopterygoid; fr, frontal; itf, infratemporal fenestra; j, jugal; la, lacrimal; m, maxilla; na, nasal; pal, palpebral; pd, predentary; pf, prefrontal; pm, premaxilla; po, postorbital; r, rostral; spl, sutural surface for splenial; sq, squamosal; stf, supratemporal fenestra.</p

Summary phylogeny of Ceratopsia with nomenclatural conventions used in this paper.

<p>Marginocephalia and Coronosauria are node-based clades, indicated by circles. The rest of the clades shown here are stem-based, indicated by half-brackets. See text for definitions and taxonomic authorities. Silhouettes are not to scale (<i>Acrotholus</i> by G. Monger, <i>Psittacosaurus</i> by J. Headden, <i>Triceratops</i> by R. Amos; all others by A. Farke; all images are CC-BY and provided via <a href="http://www.phylopic.org" target="_blank">www.phylopic.org</a>).</p

Cranial reconstruction and life restoration of <i>Aquilops americanus</i>.

<p>Cranium in A) right lateral and B) dorsal views; C) life restoration in right lateral view. The rendering is based on OMNH 34557 (holotype), with missing details patterned after <i>Liaoceratops yanzigouensis</i> and <i>Archaeoceratops oshimai</i>. Life restoration by Brian Engh.</p

Measurements of cranial bones for OMNH 34557, the holotype of <i>Aquilops americanus</i>.

<p>Measurements of cranial bones for OMNH 34557, the holotype of <i>Aquilops americanus</i>.</p