Intravenous Midazolam-Droperidol (combination), Droperidol (only) or Olanzapine (only) for the acutely agitated patient: A multi-centred, randomised, double-blind, triple-dummy, clinical trial

AIM: To determine the most efficacious of three currently used drug regimens for the sedation of acutely agitated patients in the emergency department ...postprin

Midazolam-droperidol, droperidol or olanzapine for acute agitation: a randomised clinical trial

STUDY OBJECTIVE: We aim to determine the most efficacious of 3 common medication regimens for the sedation of acutely agitated emergency department (ED) patients. METHODS: We undertook a randomized, controlled, double-blind, triple-dummy, clinical trial in 2 metropolitan EDs between October 2014 and August 2015. Patients aged 18 to 65 years and requiring intravenous medication sedation for acute agitation were enrolled and randomized to an intravenous bolus of midazolam 5 mg-droperidol 5 mg, droperidol 10 mg, or olanzapine 10 mg. Two additional doses were administered, if required: midazolam 5 mg, droperidol 5 mg, or olanzapine 5 mg. The primary outcome was the proportion of patients adequately sedated at 10 minutes. RESULTS: Three hundred forty-nine patients were randomized to the 3 groups. Baseline characteristics were similar across the groups. Ten minutes after the first dose, significantly more patients in the midazolam-droperidol group were adequately sedated compared with the droperidol and olanzapine groups: differences in proportions 25.0% (95% confidence interval [CI] 12.0% to 38.1%) and 25.4% (95% CI 12.7% to 38.3%), respectively. For times to sedation, the differences in medians between the midazolam-droperidol group and the droperidol and olanzapine groups were 6 (95% CI 3 to 8) and 6 (95% CI 3 to 7) minutes, respectively. Patients in the midazolam-droperidol group required fewer additional doses or alternative drugs to achieve adequate sedation. The 3 groups' adverse event rates and lengths of stay did not differ. CONCLUSION: Midazolam-droperidol combination therapy is superior, in the doses studied, to either droperidol or olanzapine monotherapy for intravenous sedation of the acutely agitated ED patient. Copyright © 2016 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.postprin

PEACE: Parallel Environment for Assembly and Clustering of Gene Expression

We present PEACE, a stand-alone tool for high-throughput ab initio clustering of transcript fragment sequences produced by Next Generation or Sanger Sequencing technologies. It is freely available from www.peace-tools.org. Installed and managed through a downloadable user-friendly graphical user interface (GUI), PEACE can process large data sets of transcript fragments of length 50 bases or greater, grouping the fragments by gene associations with a sensitivity comparable to leading clustering tools. Once clustered, the user can employ the GUI's analysis functions, facilitating the easy collection of statistics and allowing them to single out specific clusters for more comprehensive study or assembly. Using a novel minimum spanning tree-based clustering method, PEACE is the equal of leading tools in the literature, with an interface making it accessible to any user. It produces results of quality virtually identical to those of the WCD tool when applied to Sanger sequences, significantly improved results over WCD and TGICL when applied to the products of Next Generation Sequencing Technology and significantly improved results over Cap3 in both cases. In short, PEACE provides an intuitive GUI and a feature-rich, parallel clustering engine that proves to be a valuable addition to the leading cDNA clustering tools

Sedating the agitated patient: a moving target? – In reply

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Genome-Wide Survey for Biologically Functional Pseudogenes

According to current estimates there exist about 20,000 pseudogenes in a mammalian genome. The vast majority of these are disabled and nonfunctional copies of protein-coding genes which, therefore, evolve neutrally. Recent findings that a Makorin1 pseudogene, residing on mouse Chromosome 5, is, indeed, in vivo vital and also evolutionarily preserved, encouraged us to conduct a genome-wide survey for other functional pseudogenes in human, mouse, and chimpanzee. We identify to our knowledge the first examples of conserved pseudogenes common to human and mouse, originating from one duplication predating the human–mouse species split and having evolved as pseudogenes since the species split. Functionality is one possible way to explain the apparently contradictory properties of such pseudogene pairs, i.e., high conservation and ancient origin. The hypothesis of functionality is tested by comparing expression evidence and synteny of the candidates with proper test sets. The tests suggest potential biological function. Our candidate set includes a small set of long-lived pseudogenes whose unknown potential function is retained since before the human–mouse species split, and also a larger group of primate-specific ones found from human–chimpanzee searches. Two processed sequences are notable, their conservation since the human–mouse split being as high as most protein-coding genes; one is derived from the protein Ataxin 7-like 3 (ATX7NL3), and one from the Spinocerebellar ataxia type 1 protein (ATX1). Our approach is comparative and can be applied to any pair of species. It is implemented by a semi-automated pipeline based on cross-species BLAST comparisons and maximum-likelihood phylogeny estimations. To separate pseudogenes from protein-coding genes, we use standard methods, utilizing in-frame disablements, as well as a probabilistic filter based on Ka/Ks ratios

The effects of postmenopausal hormone therapy on social activity, partner relationship, and sexual life – experience from the EPHT trial

<p>Abstract</p> <p>Background</p> <p>With the exception of sexual functioning and weight, social and behavioural effects of postmenopausal hormone therapy (HT) have not been reported from trials. This paper reports such results from the EPHT-trial in Estonia.</p> <p>Methods</p> <p>A randomized trial, with a blind and non-blind sub-trial in Estonia. From 1999–2001, 1778 women were recruited. The mean follow-up was 3.6 years. Women's experiences were asked in the first and final study year by mailed questionnaires (74 and 81% response rates). Comparisons of the groups were made by cross-tabulation and logistic regression, adjusting for age.</p> <p>Results</p> <p>There were no differences between the HT and non-HT groups in regard to being employed, the extent of social involvement or marital status or opinions on aging. There was no difference in the frequency of free-time exercise, or overweight. Some of the indicators suggested less sexual inactivity, but the differences were small.</p> <p>Conclusion</p> <p>In a trial setting, postmenopausal hormone therapy did not influence work or social involvement or health behaviour.</p> <p>Trial registration</p> <p>ISRCTN35338757</p

On the quest for selective constraints shaping the expressivity of the genes casting retropseudogenes in human

<p>Abstract</p> <p>Background</p> <p>Pseudogenes, the nonfunctional homologues of functional genes are now coming to light as important resources regarding the study of human protein evolution. Processed pseudogenes arising by reverse transcription and reinsertion can provide molecular record on the dynamics and evolution of genomes. Researches on the progenitors of human processed pseudogenes delved out their highly expressed and evolutionarily conserved characters. They are reported to be short and GC-poor indicating their high efficiency for retrotransposition. In this article we focused on their high expressivity and explored the factors contributing for that and their relevance in the milieu of protein sequence evolution.</p> <p>Results</p> <p>We here, analyzed the high expressivity of these genes configuring processed or retropseudogenes by their immense connectivity in protein-protein interaction network, an inclination towards alternative splicing mechanism, a lower rate of mRNA disintegration and a slower evolutionary rate. While the unusual trend of the upraised disorder in contrast with the high expressivity of the proteins encoded by processed pseudogene ancestors is accredited by a predominance of hub-protein encoding genes, a high propensity of repeat sequence containing genes, elevated protein stability and the functional constraint to perform the transcription regulatory jobs. Linear regression analysis demonstrates mRNA decay rate and protein intrinsic disorder as the influential factors controlling the expressivity of these retropseudogene ancestors while the latter one is found to have the most significant regulatory power.</p> <p>Conclusions</p> <p>Our findings imply that, the affluence of disordered regions elevating the network attachment to be involved in important cellular assignments and the stability in transcriptional level are acting as the prevailing forces behind the high expressivity of the human genes configuring processed pseudogenes.</p

Relaxed Purifying Selection and Possibly High Rate of Adaptation in Primate Lineage-Specific Genes

Genes in the same organism vary in the time since their evolutionary origin. Without horizontal gene transfer, young genes are necessarily restricted to a few closely related species, whereas old genes can be broadly distributed across the phylogeny. It has been shown that young genes evolve faster than old genes; however, the evolutionary forces responsible for this pattern remain obscure. Here, we classify human–chimp protein-coding genes into different age classes, according to the breath of their phylogenetic distribution. We estimate the strength of purifying selection and the rate of adaptive selection for genes in different age classes. We find that older genes carry fewer and less frequent nonsynonymous single-nucleotide polymorphisms than younger genes suggesting that older genes experience a stronger purifying selection at the protein-coding level. We infer the distribution of fitness effects of new deleterious mutations and find that older genes have proportionally more slightly deleterious mutations and fewer nearly neutral mutations than younger genes. To investigate the role of adaptive selection of genes in different age classes, we determine the selection coefficient (γ = 2Nes) of genes using the MKPRF approach and estimate the ratio of the rate of adaptive nonsynonymous substitution to synonymous substitution (ωA) using the DoFE method. Although the proportion of positively selected genes (γ > 0) is significantly higher in younger genes, we find no correlation between ωA and gene age. Collectively, these results provide strong evidence that younger genes are subject to weaker purifying selection and more tenuous evidence that they also undergo adaptive evolution more frequently

Similarly Strong Purifying Selection Acts on Human Disease Genes of All Evolutionary Ages

A number of studies have showed that recently created genes differ from the genes created in deep evolutionary past in many aspects. Here, we determined the age of emergence and propensity for gene loss (PGL) of all human protein–coding genes and compared disease genes with non-disease genes in terms of their evolutionary rate, strength of purifying selection, mRNA expression, and genetic redundancy. The older and the less prone to loss, non-disease genes have been evolving 1.5- to 3-fold slower between humans and chimps than young non-disease genes, whereas Mendelian disease genes have been evolving very slowly regardless of their ages and PGL. Complex disease genes showed an intermediate pattern. Disease genes also have higher mRNA expression heterogeneity across multiple tissues than non-disease genes regardless of age and PGL. Young and middle-aged disease genes have fewer similar paralogs as non-disease genes of the same age. We reasoned that genes were more likely to be involved in human disease if they were under a strong functional constraint, expressed heterogeneously across tissues, and lacked genetic redundancy. Young human genes that have been evolving under strong constraint between humans and chimps might also be enriched for genes that encode important primate or even human-specific functions