Effect of Silicon Content on Carbide Precipitation and Low-Temperature Toughness of Pressure Vessel Steels

Cr – Mn – Mo – Ni pressure vessel steels containing 0.54 and 1.55% Si are studied. Metallographic and fractographic analyses of the steels after tempering at 650 and 700°C are performed. The impact toughness at – 30°C and the hardness of the steels are determined. The mass fraction of the carbide phase in the steels is computed with the help of the J-MatPro 4.0 software

4-dimensional functional profiling in the convulsant-treated larval zebrafish brain

This is the final version of the article. Available from Springer Nature via the DOI in this record.Functional neuroimaging, using genetically-encoded Ca(2+) sensors in larval zebrafish, offers a powerful combination of high spatiotemporal resolution and higher vertebrate relevance for quantitative neuropharmacological profiling. Here we use zebrafish larvae with pan-neuronal expression of GCaMP6s, combined with light sheet microscopy and a novel image processing pipeline, for the 4D profiling of chemoconvulsant action in multiple brain regions. In untreated larvae, regions associated with autonomic functionality, sensory processing and stress-responsiveness, consistently exhibited elevated spontaneous activity. The application of drugs targeting different convulsant mechanisms (4-Aminopyridine, Pentylenetetrazole, Pilocarpine and Strychnine) resulted in distinct spatiotemporal patterns of activity. These activity patterns showed some interesting parallels with what is known of the distribution of their respective molecular targets, but crucially also revealed system-wide neural circuit responses to stimulation or suppression. Drug concentration-response curves of neural activity were identified in a number of anatomically-defined zebrafish brain regions, and in vivo larval electrophysiology, also conducted in 4dpf larvae, provided additional measures of neural activity. Our quantification of network-wide chemoconvulsant drug activity in the whole zebrafish brain illustrates the power of this approach for neuropharmacological profiling in applications ranging from accelerating studies of drug safety and efficacy, to identifying pharmacologically-altered networks in zebrafish models of human neurological disorders.This work was funded by the Biological and Biotechnology Research Council (CASE studentship BB/L502510/1, with AstraZeneca Safety Health and Environment), and by the University of Exeter and AstraZeneca

Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (NR5A1) in children and adults with primary adrenal failure: Ten years' experience

Context: Primary adrenal failure is a life-threatening condition that can be caused by a range of etiologies, including autoimmune, metabolic, and developmental disorders. The nuclear receptors DAX1 (NR0B1) and steroidogenic factor-1 (SF1/Ad4BP, NR5A1) play an important role in adrenal development and function, and mutations in these transcription factors have been found in patients with adrenal hypoplasia.Objective: Our objective was to investigate the prevalence of DAX1 and SF1 mutations in children and adults with primary adrenal failure of unknown etiology (i.e. not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease).Patients: One hundred seventeen patients were included. Eighty-eight individuals presented in infancy or childhood with adrenal hypoplasia or primary adrenal failure of unknown etiology (n = 64 46, XY phenotypic males; n = 17 46, XY gonadal dysgenesis/ impaired androgenization; n = 7 46, XX females). Twenty-nine individuals presented in adulthood with Addison's disease of unknown etiology.Methods: Mutational analysis of DAX1 ( NR0B1) ( including exon 2 alpha/1A) and SF1 ( NR5A1) was done by direct sequencing.Results: DAX1 mutations were found in 58% ( 37 of 64) of 46, XY phenotypic boys referred with adrenal hypoplasia and in all boys ( eight of eight) with hypogonadotropic hypogonadism and a family history suggestive of adrenal failure in males. SF1 mutations causing adrenal failure were found in only two patients with 46, XY gonadal dysgenesis. No DAX1 or SF1 mutations were identified in the adult-onset group.Conclusions: DAX1 mutations are a relatively frequent cause of adrenal failure in this group of boys. SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46, XY individuals

Health Impacts of Estrogens in the Environment, Considering Complex Mixture Effects

PublishedResearch Support, Non-U.S. Gov'tBACKGROUND: Environmental estrogens in wastewater treatment work (WwTW) effluents are well established as the principal cause of reproductive disruption in wild fish populations, but their possible role in the wider health effects of effluents has not been established. OBJECTIVES: We assessed the contribution of estrogens to adverse health effects induced in a model fish species by exposure to WwTW effluents and compared effects of an estrogen alone and as part of a complex mixture (i.e., spiked into effluent). METHODS: Growth, genotoxic, immunotoxic, metabolic, and endocrine (feminized) responses were compared in fathead minnows (Pimephales promelas) exposed for 21 days to a potent estrogenic effluent, a weakly estrogenic effluent before and after spiking with a steroidal estrogen [17 alpha-ethinyl-estradiol (EE2)], and to EE2 alone. RESULTS: In addition to endocrine disruption, effluent exposure induced genotoxic damage, modulated immune function, and altered metabolism; many of these effects were elicited in a sex-specific manner and were proportional to the estrogenic potencies of the effluents. A key finding was that some of the responses to EE2 were modified when it was present in a complex mixture (i.e., spiked into effluent), suggesting that mixture effects may not be easily modeled for effluent discharges or when the chemicals impact on a diverse array of biological axes. CONCLUSION: These data reveal a clear link between estrogens present in effluents and diverse, adverse, and sex-related health impacts. Our findings also highlight the need for an improved understanding of interactive effects of chemical toxicants on biological systems for understanding health effects of environmental mixtures.This work was funded by the Environment Agency to C.R.T. (project no. SC040078). T.N. was supported by a Fundação para a Ciência ea Tecnologia (FCT) fellowship (BPD/18192/04)

Cost-effectiveness analysis of 3-D computerized tomography colonography versus optical colonoscopy for imaging symptomatic gastroenterology patients.

BACKGROUND: When symptomatic gastroenterology patients have an indication for colonic imaging, clinicians have a choice between optical colonoscopy (OC) and computerized tomography colonography with three-dimensional reconstruction (3-D CTC). 3-D CTC provides a minimally invasive and rapid evaluation of the entire colon, and it can be an efficient modality for diagnosing symptoms. It allows for a more targeted use of OC, which is associated with a higher risk of major adverse events and higher procedural costs. A case can be made for 3-D CTC as a primary test for colonic imaging followed if necessary by targeted therapeutic OC; however, the relative long-term costs and benefits of introducing 3-D CTC as a first-line investigation are unknown. AIM: The aim of this study was to assess the cost effectiveness of 3-D CTC versus OC for colonic imaging of symptomatic gastroenterology patients in the UK NHS. METHODS: We used a Markov model to follow a cohort of 100,000 symptomatic gastroenterology patients, aged 50 years or older, and estimate the expected lifetime outcomes, life years (LYs) and quality-adjusted life years (QALYs), and costs (£, 2010-2011) associated with 3-D CTC and OC. Sensitivity analyses were performed to assess the robustness of the base-case cost-effectiveness results to variation in input parameters and methodological assumptions. RESULTS: 3D-CTC provided a similar number of LYs (7.737 vs 7.739) and QALYs (7.013 vs 7.018) per individual compared with OC, and it was associated with substantially lower mean costs per patient (£467 vs £583), leading to a positive incremental net benefit. After accounting for the overall uncertainty, the probability of 3-D CTC being cost effective was around 60 %, at typical willingness-to-pay values of £20,000-£30,000 per QALY gained. CONCLUSION: 3-D CTC is a cost-saving and cost-effective option for colonic imaging of symptomatic gastroenterology patients compared with OC

Physiological-social score (PMEWS) vs. CURB-65 to triage pandemic influenza: a comparative validation study using community-acquired pneumonia as a proxy

BACKGROUND: An influenza pandemic may increase Emergency Department attendance 7-fold. In the absence of a validated "flu score" to assess severity and assist triage decisions from primary into secondary care, current UK draft management recommendations have suggested the use of CURB-65 and chest X-ray as a proxy. We developed the Pandemic Medical Early Warning Score (PMEWS) to track and triage flu patients, taking into account physiological and social factors and without requiring laboratory or radiology services. METHODS: Validation of the PMEWS score against an unselected group of patients presenting and admitted to an urban UK teaching hospital with community acquired pneumonia. Comparison of PMEWS performance against CURB-65 for three outcome measures: need for admission, admission to high dependency or intensive care, and inpatient mortality using area under ROC curve (AUROC) and the Hanley-McNeil method of comparison. RESULTS: PMEWS was a better predictor of need for admission (AUROC 0.944) and need of higher level of care (AUROC 0.83) compared with CURB-65 (AUROCs 0.881 and 0.640 respectively) but was not as good a predictor of subsequent inpatient mortality (AUROC 0.663). CONCLUSION: Although further validation against other disease datasets as a proxy for pandemic flu is required, we show that PMEWS is rapidly applicable for triage of large numbers of flu patients to self-care, hospital admission or HDU/ICU care. It is scalable to reflect changing admission thresholds that will occur during a pandemic

A meta-review of literature reviews assessing the capacity of patients with severe mental disorders to make decisions about their healthcare.

Background: Determining the mental capacity of psychiatric patients for making healthcare related decisions is crucial in clinical practice. This meta-review of review articles comprehensively examines the current evidence on the capacity of patients with a mental illness to make medical care decisions. Methods: Systematic review of review articles following PRISMA recommendations. PubMed, Scopus, CINAHL and PsycInfo were electronically searched up to 31 January 2020. Free text searches and medical subject headings were combined to identify literature reviews and meta-analyses published in English, and summarising studies on the capacity of patients with serious mental illnesses to make healthcare and treatment related decisions, conducted in any clinical setting and with a quantitative synthesis of results. Publications were selected as per inclusion and exclusion criteria. The AMSTAR II tool was used to assess the quality of reviews. Results: Eleven publications were reviewed. Variability on methods across studies makes it difficult to precisely estimate the prevalence of decision-making capacity in patients with mental disorders. Nonetheless, up to three-quarters of psychiatric patients, including individuals with serious illnesses such as schizophrenia or bipolar disorder may have capacity to make medical decisions in the context of their illness. Most evidence comes from studies conducted in the hospital setting; much less information exists on the healthcare decision making capacity of mental disorder patients while in the community. Stable psychiatric and non-psychiatric patients may have a similar capacity to make healthcare related decisions. Patients with a mental illness have capacity to judge risk-reward situations and to adequately decide about the important treatment outcomes. Different symptoms may impair different domains of the decisional capacity of psychotic patients. Decisional capacity impairments in psychotic patients are temporal, identifiable, and responsive to interventions directed towards simplifying information, encouraging training and shared decision making. The publications complied satisfactorily with the AMSTAR II critical domains. Conclusions: Whilst impairments in decision-making capacity may exist, most patients with a severe mental disorder, such as schizophrenia or bipolar disorder are able to make rational decisions about their healthcare. Best practice strategies should incorporate interventions to help mentally ill patients grow into the voluntary and safe use of medications

Selection at the Y Chromosome of the African Buffalo Driven by Rainfall

Selection coefficients at the mammalian Y chromosome typically do not deviate strongly from neutrality. Here we show that strong balancing selection, maintaining intermediate frequencies of DNA sequence variants, acts on the Y chromosome in two populations of African buffalo (Syncerus caffer). Significant correlations exist between sequence variant frequencies and annual rainfall in the years before conception, with five- to eightfold frequency changes over short time periods. Annual rainfall variation drives the balancing of sequence variant frequencies, probably by affecting parental condition. We conclude that sequence variants confer improved male reproductive success after either dry or wet years, making the population composition and dynamics very sensitive to climate change. The mammalian Y chromosome, interacting with ecological processes, may affect male reproductive success much more strongly than previously thought

Lack of association between genetic polymorphisms within DUSP12 - ATF6 locus and glucose metabolism related traits in a Chinese population

<p>Abstract</p> <p>Background</p> <p>Genome-wide linkage studies in multiple ethnic populations found chromosome 1q21-q25 was the strongest and most replicable linkage signal in the human chromosome. Studies in Pima Indian, Caucasians and African Americans identified several SNPs in <it>DUSP12 </it>and <it>ATF6</it>, located in chromosome 1q21-q23, were associated with type 2 diabetes.</p> <p>Methods</p> <p>We selected 19 single nucleotide polymorphisms (SNPs) that could tag 98% of the SNPs with minor allele frequencies over 0.1 within <it>DUSP12-ATF6 </it>region. These SNPs were genotyped in a total of 3,700 Chinese Han subjects comprising 1,892 type 2 diabetes patients and 1,808 controls with normal glucose regulation.</p> <p>Results</p> <p>None of the SNPs and haplotypes showed significant association to type 2 diabetes in our samples. No association between the SNPs and quantitative traits was observed either.</p> <p>Conclusions</p> <p>Our data suggests common SNPs within <it>DUSP12</it>-<it>ATF6 </it>locus may not play a major role in glucose metabolism in the Chinese.</p