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

Changes to the Fossil Record of Insects through Fifteen Years of Discovery

The first and last occurrences of hexapod families in the fossil record are compiled from publications up to end-2009. The major features of these data are compared with those of previous datasets (1993 and 1994). About a third of families (>400) are new to the fossil record since 1994, over half of the earlier, existing families have experienced changes in their known stratigraphic range and only about ten percent have unchanged ranges. Despite these significant additions to knowledge, the broad pattern of described richness through time remains similar, with described richness increasing steadily through geological history and a shift in dominant taxa, from Palaeoptera and Polyneoptera to Paraneoptera and Holometabola, after the Palaeozoic. However, after detrending, described richness is not well correlated with the earlier datasets, indicating significant changes in shorter-term patterns. There is reduced Palaeozoic richness, peaking at a different time, and a less pronounced Permian decline. A pronounced Triassic peak and decline is shown, and the plateau from the mid Early Cretaceous to the end of the period remains, albeit at substantially higher richness compared to earlier datasets. Origination and extinction rates are broadly similar to before, with a broad decline in both through time but episodic peaks, including end-Permian turnover. Origination more consistently exceeds extinction compared to previous datasets and exceptions are mainly in the Palaeozoic. These changes suggest that some inferences about causal mechanisms in insect macroevolution are likely to differ as well

ORDER-DISORDER TRANSITION PRODUCED BY DISLOCATIONS IN AN FCC LENNARD-JONES SOLID

On a étudié les changements structuraux et thermodynamiques accompagnant une transition ordre-désordre donnée grâce à un modèle pseudostatique calculé par ordinateur. Les déplacements atomiques entraînés par l'insertion de dislocations parfaites réparties et orientées au hasard ont été répétés jusqu'à saturation. Chaque dislocation résultait de la solution élastique du champ de déformation et on procédait ensuite à une relaxation du système par une technique modifiée de dynamique moléculaire. La configuration atomique désordonnée obtenue s'apparente à celle d'un liquide. Une simulation complètement dynamique de la fusion a été ensuite menée à bien au cours de laquelle on a observé la formation de petites boucles partielles de dislocation de type Schockley. La concentration des dislocations va en augmentant lorsque le processus de fusion progresse. Ces 2 modèles de simulation pseudostatique et totalement dynamique présentent chacun des caractéristiques favorables à une théorie de la fusion faisant appel aux dislocations.A pseudostatic computational model has been used to study the structural and thermodynamic changes associated with an imposed order-disorder transition. Atomic displacement operations corresponding to the insertion of randomly situated and oriented perfect dislocations were repeatedly performed until saturation was observed. Each dislocation was generated according to the elastic solution for the displacement field and subsequently the system was permitted to relax using a modified molecular dynamics technique. The resulting disordered atomic configuration was found to display a liquid-like structure. In a fully dynamical simulation of the melting process the formation of small partial dislocation loops of the Shockly type was observed. The concentration of dislocations was found to increase as the melting process progressed. Both the pseudostatic and the fully dynamical simulation thus exhibit features which support the dislocation theory of melting

MOLECULAR DYNAMICS CALCULATIONS OF MICROCLUSTER PROPERTES

Les propriétés structurales et thermodynamiques des microclusters à 2 et 3 dimensions ont été étudiées par la technique de la dynamique moléculaire. Cette technique donne en principe pour chaque taille de cluster la configuration atomique de plus basse énergie libre. La fonction d'état des différents microclusters a été calculée en se servant d'une fonction de potentiel de paire de type Lennard-Jones tronquée. On a étudié le processus de fusion ainsi que certaines propriétés telles que la température de fusion, la chaleur latente de fusion et les phénomènes de préfusion qui se sont révélés être dépendants de la taille du cluster aussi bien que de la structure de la phase solide.The structural and thermodynamic properties of microclusters in two and three dimensions have been investigated by means of the molecular dynamics technique. This technique in principle produces the atomic configuration of lowest free energy for any given cluster size. The caloric equation of state for the different microclusters were calculated using a truncated Lennard-Jones pair potential. The nature of the melting transition was investigated and a number of properties, such as melting temperature, latent heat of melting, and premelting phenomena, were found to vary with cluster size, as well as with the structure of the solid phase

A Unified Theory of Melting, Crystallization and Glass Formation

Ces dernières années des théories faisant appel aux dislocations ont été proposées pour expliquer la fusion, comme modèles de l'état liquide et pour calculer la viscosité des verres. Le modèle de Mott-Guerney est particulièrement digne d'intérêt à cet égard qui décrit un liquide comme étant constitué par un polycristal dont la taille de grain (donc la taille du réseau de dislocation) est de l'ordre des dimensions atomiques ainsi que la démonstration par Kotze et Kulhmann-Wilsdorf suivant laquelle l'énergie interfaciale est proportionnelle à l'énergie de joint de grain pour de multiples éléments. A la suite de ces travaux, on peut envisager l'existence d'un modèle relativement simple pour expliquer la cristallisation et la solidification vitreuse. Pour une densité à saturation, les dislocations sont, dans un liquide, en mouvement constant et la structure microscopique de joint de grain qu'elle forme est en perpétuelle évolution par interaction dislocation-dislocation. Lorsque le liquide est refroidi au-dessous du point de fusion, le minimum d'énergie libre est en faveur de la cristallisation et les grains ayant une taille supérieure à la taille critique de germination vont grossir aux dépens des grains environnants. Si le processus ne se produit pas, les dislocations subsistent et un verre va se former. Expérimentalement, le choix entre ces deux alternatives dépendra, pour un matériau donné, de l'intensité des mouvements de dislocations pendant la période critique où la nucléation et la croissance deviennent thermodynamiquement favorables. Donc l'état vitreux aura des chances de se former si le liquide est particulièrement visqueux ou si la vitesse de refroidissement est particulièrement grande.In recent years, dislocations have been involved in theories of melting, in models of the liquid state, and in calculations of the viscosity of glasses. Particularly noteworthy are the Mott-Gurney model of a liquid as a polycrystal with a grain size (i. e. a dislocation network size) of near-atomic dimensions, and the demonstration by Kotze and Kuhlmann-Wilsdorf that the solid-liquid interfacial energy is proportional to the grain boundary energy for a number of elements. These developments suggest the possibility of a relatively simple picture of crystallization and glass formation. In the liquid state dislocations, at the saturation density, are in constant motion and the microscopic grain boundary structure that they form is constantly changing due to dislocation-dislocation interaction. As the liquid is cooled below the melting point the free energy favors the crystalline form and grains larger than the critical nucleation size at any given temperature will grow at the expense of the surrounding grains. If this process does not occur the dislocations will remain and a glass will be formed. Just which of these alternatives will actually be observed for a given material will depend especially on the amount of dislocation motion that can take place during the critical period when nucleation and growth becomes favored thermodynamically. Thus the glassy form will have a better chance of being formed if either the liquid is particularly viscous or if the cooling rate is particularly rapid