Encephalomyocarditis virus may use different pathways to initiateinfection of primary human cardiomyocytes

Encephalomyocarditis virus (EMCV) caninfect a wide range of vertebrate species including swineand non-human primates, but few data are available forhumans. We therefore wanted to gain further insight intothe mechanisms involved in EMCV infection of humancells. For this purpose, we analyzed the permissiveness ofprimary human cardiomyocytes towards two strains ofEMCV; a pig myocardial strain (B279/95) and a rat strain(1086C). In this study, we show that both strains productivelyinfect primary human cardiomyocytes and inducecomplete cytolysis. Binding and infection inhibitionexperiments indicated that attachment and infection areindependent of sialic acid and heparan sulfate for B279/95and dependent for 1086C. Sequence comparison betweenthe two strains and three-dimensional analysis of the capsidrevealed that six of the seven variable residues are surfaceexposed,suggesting a role for these amino acids in binding.Moreover, analysis of variants isolated from the 1086Cstrain revealed the importance of lysine 231 of VP1 in theattachment of EMCV to cell-surface sialic acid residues.Together, these results show a potential for EMCV strainsto use at least two different binding possibilities to initiateinfection and provide new insights into the mechanismsinvolved in primary human cell recognition by EMCV

A copula model for marked point processes

The final publication (Diao, Liqun, Richard J. Cook, and Ker-Ai Lee. (2013) A copula model for marked point processes. Lifetime Data Analysis, 19(4): 463-489) is available at Springer via http://dx.doi.org/10.1007/s10985-013-9259-3Many chronic diseases feature recurring clinically important events. In addition, however, there often exists a random variable which is realized upon the occurrence of each event reflecting the severity of the event, a cost associated with it, or possibly a short term response indicating the effect of a therapeutic intervention. We describe a novel model for a marked point process which incorporates a dependence between continuous marks and the event process through the use of a copula function. The copula formulation ensures that event times can be modeled by any intensity function for point processes, and any multivariate model can be specified for the continuous marks. The relative efficiency of joint versus separate analyses of the event times and the marks is examined through simulation under random censoring. An application to data from a recent trial in transfusion medicine is given for illustration.Natural Sciences and Engineering Research Council of Canada (RGPIN 155849); Canadian Institutes for Health Research (FRN 13887); Canada Research Chair (Tier 1) – CIHR funded (950-226626

TYRANNOSAUR CANNIBALISM: A CASE OF A TOOTH-TRACED TYRANNOSAURID BONE IN THE LANCE FORMATION (MAASTRICHTIAN), WYOMING

A recently discovered tyrannosaurid metatarsal IV (SWAU HRS13997) from the uppermost Cretaceous (Maastrichtian) Lance Formation is heavily marked with several long grooves on its cortical surface, concentrated on the bone\u27s distal end. At least 10 separate grooves of varying width are present, which we interpret to be scores made by theropod teeth. In addition, the tooth ichnospecies Knethichnus parallelum is present at the end of the distal-most groove. Knethichnus parallelum is caused by denticles of a serrated tooth dragging along the surface of the bone. Through comparing the groove widths in the Knethichnus parallelum to denticle widths on Lance Formation theropod teeth, we conclude that the bite was from a Tyrannosaurus rex. The shape, location, and orientation of the scores suggest that they are feeding traces. The osteohistology of SWAU HRS13997 suggests that it came from a young animal, based on evidence that it was still rapidly growing at time of death. The tooth traces on SWAU HRS13997 are strong evidence for tyrannosaurid cannibalism—a large Tyrannosaurus feeding on a young Tyrannosaurus

On estimands arising from misspecified semiparametric rate‐based analysis of recurrent episodic conditions

This is the peer reviewed version of the following article: Jooyoung Lee and Richard J. Cook. On estimands arising from misspecified semiparametric rate-based analysis of recurrent episodic conditions. Statistics in Medicine (2019), 38 (25): 4977–4998 which has been published in final form at https://doi.org/10.1002/sim.8345.This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Marginal rate-based analyses are widely used for the analysis of recurrent events in clinical trials. In many areas of application, the events are not instantaneous but rather signal the onset of a symptomatic episode representing a recurrent infection, respiratory exacerbation, or bout of acute depression. In rate-based analyses, it is unclear how to best handle the time during which individuals are experiencing symptoms and hence are not at risk. We derive the limiting value of theNelson-Aalen estimator and estimators of the regression coefficients under a semiparametric rate-based model in terms of an underlying two-state process. We investigate the impact of the distribution of the episode durations, heterogeneity, and dependence on the asymptotic and finite sample properties of standard estimators. We also consider the impact of these features on power in trials designed to test intervention effects on rate functions. An application to a trial of individuals with herpes simplex virus is given for illustration.This research was supported by grants from the Natural Sciences and Engineering Research Council of Canada (RGPIN 155849) and the Canadian Institutes for Health Research (FRN 13887). Richard Cook is a Canada Research Chair in Statistical Methods for Health Research