Two-transcript gene expression classifiers in the diagnosis and prognosis of human diseases.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: Identification of molecular classifiers from genome-wide gene expression analysis is an important practice for the investigation of biological systems in the post-genomic era--and one with great potential for near-term clinical impact. The 'Top-Scoring Pair' (TSP) classification method identifies pairs of genes whose relative expression correlates strongly with phenotype. In this study, we sought to assess the effectiveness of the TSP approach in the identification of diagnostic classifiers for a number of human diseases including bacterial and viral infection, cardiomyopathy, diabetes, Crohn's disease, and transformed ulcerative colitis. We examined transcriptional profiles from both solid tissues and blood-borne leukocytes. RESULTS: The algorithm identified multiple predictive gene pairs for each phenotype, with cross-validation accuracy ranging from 70 to nearly 100 percent, and high sensitivity and specificity observed in most classification tasks. Performance compared favourably with that of pre-existing transcription-based classifiers, and in some cases was comparable to the accuracy of current clinical diagnostic procedures. Several diseases of solid tissues could be reliably diagnosed through classifiers based on the blood-borne leukocyte transcriptome. The TSP classifier thus represents a simple yet robust method to differentiate between diverse phenotypic states based on gene expression profiles. CONCLUSION: Two-transcript classifiers have the potential to reliably classify diverse human diseases, through analysis of both local diseased tissue and the immunological response assayed through blood-borne leukocytes. The experimental simplicity of this method results in measurements that can be easily translated to clinical practice

Epinephrine Impairs Lipid Resuscitation from Bupivacaine Overdose

Background Lipid emulsion infusion reverses local anesthetic-induced cardiac toxicity, but the effect of adding epinephrine has not been studied. We compared escalating doses of epinephrine on recovery with lipid infusion in a rat model of bupivacaine overdose. Methods Rats anesthetized with isoflurane received an IV bolus of 20 mg/kg bupivacaine, producing asystole (zero time) in all animals. Ventilation (100% oxygen) and chest compressions were started immediately, and at 3 min the rats received one of six IV treatments (n = 5 for all groups): 5 ml/kg saline followed by infusion for 2 min at 1.0 ml x kg x min, and a second 5 ml/kg bolus at 5 min; or the same bolus and infusion treatment using 30% lipid emulsion plus a single injection of epinephrine at one of five doses: 0 (lipid control), 1, 2.5, 10, or 25 mcg/kg. An electrocardiogram and arterial pressure were monitored continuously, and arterial blood gas was measured at 7.5 and 15 min. Results Epinephrine improved initial return of spontaneous circulation (rate-pressure product > 30% baseline) but only 3 of 5 rats at 10 mcg/kg and 1 of 5 rats at 25 mcg/kg sustained return of spontaneous circulation by 15 min. Lipid alone resulted in slower but more sustained recovery. Epinephrine doses above a threshold near 10 mcg/kg increased lactate, worsened acidosis, and resulted in poor recovery at 15 min, as compared with lipid controls. There was tight correlation of epinephrine dose to serum lactate at 15 min. Conclusions Epinephrine over a threshold dose near 10 mcg/kg impairs lipid resuscitation from bupivacaine overdose, possibly by inducing hyperlactatemia

Epistemic Beliefs: Relationship to Future Expectancies and Quality of Life in Cancer Patients.

CONTEXT: Expectations about the future (future expectancies) are important determinants of psychological well-being among cancer patients, but the strategies patients use to maintain positive and cope with negative expectancies are incompletely understood. OBJECTIVES: To obtain preliminary evidence on the potential role of one strategy for managing future expectancies: the adoption of epistemic beliefs in fundamental limits to medical knowledge. METHODS: A sample of 1307 primarily advanced-stage cancer patients participating in a genomic tumor testing study in community oncology practices completed measures of epistemic beliefs, positive future expectancies, and mental and physical health-related quality of life (HRQOL). Descriptive and linear regression analyses were conducted to assess the relationships between these factors and test two hypotheses: 1) epistemic beliefs affirming fundamental limits to medical knowledge ( fallibilistic epistemic beliefs ) are associated with positive future expectancies and mental HRQOL, and 2) positive future expectancies mediate this association. RESULTS: Participants reported relatively high beliefs in limits to medical knowledge (M = 2.94, s.d.=.67) and positive future expectancies (M = 3.01, s.d.=.62) (range 0-4), and relatively low mental and physical HRQOL. Consistent with hypotheses, fallibilistic epistemic beliefs were associated with positive future expectancies (b = 0.11, SE=.03, P\u3c 0.001) and greater mental HRQOL (b = 0.99, SE=.34, P = 0.004); positive expectancies also mediated the association between epistemic beliefs and mental HRQOL (Sobel Z=4.27, P\u3c0.001). CONCLUSIONS: Epistemic beliefs in limits to medical knowledge are associated with positive future expectancies and greater mental HRQOL; positive expectancies mediate the association between epistemic beliefs and HRQOL. More research is needed to confirm these relationships and elucidate their causal mechanisms

Adding Bupivacaine to High-potassium Cardioplegia Improves Function and Reduces Cellular Damage of Rat Isolated Hearts after Prolonged, Cold Storage

Background Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone. Methods After measuring cardiac function on a Langendorff apparatus, hearts were perfused with cardioplegia alone (controls), cardioplegia containing 500 microm bupivacaine, or cardioplegia containing 2 mm lidocaine; were stored at 4 degrees C for 12 h; and were then reperfused. Heart rate and left ventricular developed pressures were measured for 60 min. Maximum positive rate of change in ventricular pressure, oxygen consumption, and lactate dehydrogenase release were also measured. Results All bupivacaine-treated, four of five lidocaine-treated, and no control hearts beat throughout the 60-min recovery period. Mean values of heart rate, left ventricular developed pressure, maximum positive rate of change in ventricular pressure, rate-pressure product, and efficiency in bupivacaine-treated hearts exceeded those of the control group (P < 0.001 at 60 min for all). Mean values of the lidocaine group were intermediate. Oxygen consumption of the control group exceeded the other groups early in recovery, but not at later times. Lactate dehydrogenase release from the bupivacaine group was less than that from the control group (P < 0.001) but did not differ from baseline. Conclusions Adding bupivacaine to a depolarizing cardioplegia solution reduces cell damage and improves cardiac function after prolonged storage. Metabolic inhibition may contribute to this phenomenon, which is not entirely explained by sodium channel blockade

Nature doesn't judge you – how urban nature supports young people's mental health and wellbeing in a diverse UK city

Reviewed research reveals a lack of young people's voices articulating if and how urban nature supports their mental health and wellbeing. This paper presents qualitative research with young multi-ethnic urban residents living in a northern UK city and offers an important counter-narrative to the pervasive notion of childhood nature-deficit disorder. Using interviews and creative arts workshops, we explored the value of urban nature for the mental health and wellbeing of 24 young people aged 17–27 years, 9 of whom had lived experience of mental health difficulties. Trees, water, open spaces and views were frequently experienced nature typologies offering benefits. Deteriorating landscapes, young people's shifting identities and perceived time pressures disrupted support. Young people expressed how urban nature encounters were experienced as accepting and relational, offering a: stronger sense of self; feelings of escape; connection and care with the human and non-human world

Open Data from the Third Observing Run of LIGO, Virgo, KAGRA, and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in 2019 April and lasting six months, O3b starting in 2019 November and lasting five months, and O3GK starting in 2020 April and lasting two weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main data set, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages

Search for Eccentric Black Hole Coalescences during the Third Observing Run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass $M>70$ $M_\odot$) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities $0 < e \leq 0.3$ at $0.33$ Gpc$^{-3}$ yr$^{-1}$ at 90\% confidence level.Comment: 24 pages, 5 figure

Open data from the third observing run of LIGO, Virgo, KAGRA and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in April of 2019 and lasting six months, O3b starting in November of 2019 and lasting five months, and O3GK starting in April of 2020 and lasting 2 weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main dataset, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages.Comment: 27 pages, 3 figure

Making Different Differences: Representation and Rights in Sexuality Activism

This paper argues that current iterations of lesbian, gay, bisexual, transgender and intersex (LGBTI) rights are limited by an overreliance on particular representations of sexuality, in which homosexuality is defined negatively through a binary of homosexual/heterosexual. The limits of these representations are explored in order to unpick the possibility of engaging in a form of sexuality politics that is grounded in difference rather than in sameness or opposition. The paper seeks to respond to Braidotti’s call for an “affirmative politics” that is open to forms of creative, future-oriented action and that might serve to answer some of the more common criticisms of current LGBTI rights activism