European society of intensive care medicine study of therapeutic hypothermia (32-35 °C) for intracranial pressure reduction after traumatic brain injury (the Eurotherm3235Trial).

BACKGROUND: Traumatic brain injury is a major cause of death and severe disability worldwide with 1,000,000 hospital admissions per annum throughout the European Union.Therapeutic hypothermia to reduce intracranial hypertension may improve patient outcome but key issues are length of hypothermia treatment and speed of re-warming. A recent meta-analysis showed improved outcome when hypothermia was continued for between 48 hours and 5 days and patients were re-warmed slowly (1 °C/4 hours). Previous experience with cooling also appears to be important if complications, which may outweigh the benefits of hypothermia, are to be avoided. METHODS/DESIGN: This is a pragmatic, multi-centre randomised controlled trial examining the effects of hypothermia 32-35 °C, titrated to reduce intracranial pressure 20 mmHg in accordance with the Brain Trauma Foundation Guidelines, 2007. DISCUSSION: The Eurotherm3235Trial is the most important clinical trial in critical care ever conceived by European intensive care medicine, because it was launched and funded by the European Society of Intensive Care Medicine and will be the largest non-commercial randomised controlled trial due to the substantial number of centres required to deliver the target number of patients. It represents a new and fundamental step for intensive care medicine in Europe. Recruitment will continue until January 2013 and interested clinicians from intensive care units worldwide can still join this important collaboration by contacting the Trial Coordinating Team via the trial website http://www.eurotherm3235trial.eu. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34555414

Polarized point sources in the LOFAR Two-meter Sky Survey: A preliminary catalog

The polarization properties of radio sources at very low frequencies (h45m–15h30m right ascension, 45°–57° declination, 570 square degrees). We have produced a catalog of 92 polarized radio sources at 150 MHz at 4.′3 resolution and 1 mJy rms sensitivity, which is the largest catalog of polarized sources at such low frequencies. We estimate a lower limit to the polarized source surface density at 150 MHz, with our resolution and sensitivity, of 1 source per 6.2 square degrees. We find that our Faraday depth measurements are in agreement with previous measurements and have significantly smaller errors. Most of our sources show significant depolarization compared to 1.4 GHz, but there is a small population of sources with low depolarization indicating that their polarized emission is highly localized in Faraday depth. We predict that an extension of this work to the full LOTSS data would detect at least 3400 polarized sources using the same methods, and probably considerably more with improved data processing

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

A functional polymorphism under positive evolutionary selection in ADRB2 is associated with human intelligence with opposite effects in the young and the elderly

Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior. © 2008 Springer Science+Business Media, LLC

Do MZ twins have discordant experiences of friendship? : A qualitative hypothesis-generating MZ twin differences study

[This corrects the article DOI: 10.1371/journal.pone.0180521.]

Individual differences in puberty onset in girls: Bayesian estimation of heritabilities and genetic correlations

We report heritabilities for individual differences in female pubertal development at the age of 12. Tanner data on breast and pubic hair development in girls and data on menarche were obtained from a total of 184 pairs of monozygotic and dizygotic twins. Genetic correlations were estimated to determine to what extent the same genes are involved in different aspects of physical development in puberty. A Bayesian estimation approach was taken, using Markovchain Monte Carlo simulation to estimate model parameters. All three phenotypes were to a significant extent heritable and showed high genetic correlations, suggesting that a common set of genes is involved in the timing of puberty in general. However, gonadarche (menarche and breast development) and adrenarche (pubic hair) are affected by different environmental factors, which does not support the three phenotypes to be regarded as indicators of a unitary physiological factor. © 2006 Springer Science+Business Media, Inc

Phenotypic Complexity, Measurement Bias, and Poor Phenotypic Resolution Contribute to the Missing Heritability Problem in Genetic Association Studies

Background The variance explained by genetic variants as identified in (genome-wide) genetic association studies is typically small compared to family-based heritability estimates. Explanations of this ‘missing heritability’ have been mainly genetic, such as genetic heterogeneity and complex (epi-)genetic mechanisms. Methodology We used comprehensive simulation studies to show that three phenotypic measurement issues also provide viable explanations of the missing heritability: phenotypic complexity, measurement bias, and phenotypic resolution. We identify the circumstances in which the use of phenotypic sum-scores and the presence of measurement bias lower the power to detect genetic variants. In addition, we show how the differential resolution of psychometric instruments (i.e., whether the instrument includes items that resolve individual differences in the normal range or in the clinical range of a phenotype) affects the power to detect genetic variants. Conclusion We conclude that careful phenotypic data modelling can improve the genetic signal, and thus the statistical power to identify genetic variants by 20-99

Simulation of propofol anaesthesia for intracranial decompression using brain hypothermia treatment

<p>Abstract</p> <p>Background</p> <p>Although propofol is commonly used for general anaesthesia of normothermic patients in clinical practice, little information is available in the literature regarding the use of propofol anaesthesia for intracranial decompression using brain hypothermia treatment. A novel propofol anaesthesia scheme is proposed that should promote such clinical application and improve understanding of the principles of using propofol anaesthesia for hypothermic intracranial decompression.</p> <p>Methods</p> <p>Theoretical analysis was carried out using a previously-developed integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems. Propofol kinetics is described using a framework similar to that of this model and combined with the thermoregulation subsystem through the pharmacodynamic relationship between the blood propofol concentration and the thermoregulatory threshold. A propofol anaesthesia scheme for hypothermic intracranial decompression was simulated using the integrative model.</p> <p>Results</p> <p>Compared to the empirical anaesthesia scheme, the proposed anaesthesia scheme can reduce the required propofol dosage by more than 18%.</p> <p>Conclusion</p> <p>The integrative model of the thermoregulatory, hemodynamic and pharmacokinetic subsystems is effective in analyzing the use of propofol anaesthesia for hypothermic intracranial decompression. This propofol infusion scheme appears to be more appropriate for clinical application than the empirical one.</p