Amino Acid Requirements in Critically Ill Patients with Acute Kidney Injury Treated with Continuous Renal Replacement Therapy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90284/1/phco.28.5.600.pd

Reproductive Behaviour Evolves Rapidly When Intralocus Sexual Conflict Is Removed

Background Intralocus sexual conflict can inhibit the evolution of each sex towards its own fitness optimum. In a previous study, we confirmed this prediction through the experimental removal of female selection pressures in Drosophila melanogaster, achieved by limiting the expression of all major chromosomes to males. Compared to the control populations (C1-4) where the genomes are exposed to selection in both sexes, the populations with male-limited genomes (ML1-4) showed rapid increases in male fitness, whereas the fitness of females expressing ML-evolved chromosomes decreased [1]. Methodology/Principal Findings Here we examine the behavioural phenotype underlying this sexual antagonism. We show that males expressing the ML genomes have a reduced courtship level but acquire the same number of matings. On the other hand, our data suggest that females expressing the ML genomes had reduced attractiveness, stimulating a lower rate of courtship from males. Moreover, females expressing ML genomes tend to display reduced yeast-feeding behaviour, which is probably linked to the reduction of their fecundity. Conclusion/Significance These results suggest that reproductive behaviour is shaped by opposing selection on males and females, and that loci influencing attractiveness and foraging were polymorphic for alleles with sexually antagonistic expression patterns prior to ML selection. Hence, intralocus sexual conflict appears to play a role in the evolution of a wide range of fitness-related traits and may be a powerful mechanism for the maintenance of genetic variation in fitness

A cautionary note regarding count models of alcohol consumption in randomized controlled trials

BACKGROUND: Alcohol consumption is commonly used as a primary outcome in randomized alcohol treatment studies. The distribution of alcohol consumption is highly skewed, particularly in subjects with alcohol dependence. METHODS: In this paper, we will consider the use of count models for outcomes in a randomized clinical trial setting. These include the Poisson, over-dispersed Poisson, negative binomial, zero-inflated Poisson and zero-inflated negative binomial. We compare the Type-I error rate of these methods in a series of simulation studies of a randomized clinical trial, and apply the methods to the ASAP (Addressing the Spectrum of Alcohol Problems) trial. RESULTS: Standard Poisson models provide a poor fit for alcohol consumption data from our motivating example, and did not preserve Type-I error rates for the randomized group comparison when the true distribution was over-dispersed Poisson. For the ASAP trial, where the distribution of alcohol consumption featured extensive over-dispersion, there was little indication of significant randomization group differences, except when the standard Poisson model was fit. CONCLUSION: As with any analysis, it is important to choose appropriate statistical models. In simulation studies and in the motivating example, the standard Poisson was not robust when fit to over-dispersed count data, and did not maintain the appropriate Type-I error rate. To appropriately model alcohol consumption, more flexible count models should be routinely employed

The First Episode Rapid Early Intervention for Eating Disorders - Upscaled study: Clinical outcomes

BACKGROUND: First Episode Rapid Early Intervention for Eating Disorders (FREED) is a service model and care pathway for emerging adults aged 16 to 25‐years with a recent onset eating disorder (ED) of <3 years. A previous single‐site study suggests that FREED significantly improves clinical outcomes compared to treatment‐as‐usual (TAU). The present study (FREED‐Up) assessed the scalability of FREED. A multi‐centre quasi‐experimental pre‐post design was used, comparing patient outcomes before and after implementation of FREED in participating services. METHODS: FREED patients (n = 278) were consecutive, prospectively ascertained referrals to four specialist ED services in England, assessed at four time points over 12 months on ED symptoms, mood, service utilization and cost. FREED patients were compared to a TAU cohort (n = 224) of similar patients, identified retrospectively from electronic patient records in participating services. All were emerging adults aged 16–25 experiencing a first episode ED of <3 years duration. RESULTS: Overall, FREED patients made significant and rapid clinical improvements over time. 53.2% of FREED patients with anorexia nervosa reached a healthy weight at the 12‐month timepoint, compared to only 17.9% of TAU patients (X2 [1, N = 107] = 10.46, p < .001). Significantly fewer FREED patients required intensive (i.e., in‐patient or day‐patient) treatment (6.6%) compared to TAU patients (12.4%) across the follow‐up period (X2 [1, N = 40] = 4.36, p = .037). This contributed to a trend in cost savings in FREED compared to TAU (−£4472, p = .06, CI −£9168, £233). DISCUSSION: FREED is robust and scalable and is associated with substantial improvements in clinical outcomes, reduction in inpatient or day‐patient admissions, and cost‐savin

Male × Female Interaction for a Pre-Copulatory Trait, but Not a Post-Copulatory Trait, among Cosmopolitan Populations of Drosophila melanogaster

Sexual coevolution occurs when changes in the phenotype of one sex select for changes in the other sex. We can identify the “footprint” of this coevolution by mating males and females from different populations and testing for a male-female genotype interaction for a trait associated with male (or female) performance. Here we mated male Drosophila melanogaster from five different continents with females from their own and different continents to test for a male-female interaction for mating speed, a pre-copulatory trait, and female reproductive investment, a post-copulatory trait. We found a strong male-female interaction for mating speed, consistent with previous studies using different populations, suggesting that the potential for sexual coevolution for this trait is present in this species. In contrast, we did not detect a male-female interaction for female reproductive investment. Although a male-female interaction for mating speed is compatible with the hypothesis of ongoing sexual coevolution, the nature of our experimental design is unable to exclude alternate explanations. Thus, the evolutionary mechanisms promoting male-female genotype interactions for pre-copulatory mating traits in D. melanogaster warrant further investigation

Sexual selection protects against extinction

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring. It has been theorised that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load. Under sexual selection, competition between (usually) males, and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which depends on mutation load, then sexually selected filtering through ‘genic capture’ could offset the costs of sex because it provides genetic benefits to populations. Here, we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for ~7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress

Mechanisms of Risk and Resilience in Military Families: Theoretical and Empirical Basis of a Family-Focused Resilience Enhancement Program

Recent studies have confirmed that repeated wartime deployment of a parent exacts a toll on military children and families and that the quality and functionality of familial relations is linked to force preservation and readiness. As a result, family-centered care has increasingly become a priority across the military health system. FOCUS (Families OverComing Under Stress), a family-centered, resilience-enhancing program developed by a team at UCLA and Harvard Schools of Medicine, is a primary initiative in this movement. In a large-scale implementation project initiated by the Bureau of Navy Medicine, FOCUS has been delivered to thousands of Navy, Marine, Navy Special Warfare, Army, and Air Force families since 2008. This article describes the theoretical and empirical foundation and rationale for FOCUS, which is rooted in a broad conception of family resilience. We review the literature on family resilience, noting that an important next step in building a clinically useful theory of family resilience is to move beyond developing broad “shopping lists” of risk indicators by proposing specific mechanisms of risk and resilience. Based on the literature, we propose five primary risk mechanisms for military families and common negative “chain reaction” pathways through which they undermine the resilience of families contending with wartime deployments and parental injury. In addition, we propose specific mechanisms that mobilize and enhance resilience in military families and that comprise central features of the FOCUS Program. We describe these resilience-enhancing mechanisms in detail, followed by a discussion of the ways in which evaluation data from the program’s first 2 years of operation supports the proposed model and the specified mechanisms of action

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible

MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors

BACKGROUND MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. METHODS Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. RESULTS Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. CONCLUSIONS Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers

Xenohormone transactivities are inversely associated to serum POPs in Inuit

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