The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

A Possible Alignment Between the Orbits of Planetary Systems and their Visual Binary Companions

Astronomers do not have a complete picture of the effects of wide-binary companions (semimajor axes greater than 100 au) on the formation and evolution of exoplanets. We investigate these effects using new data from Gaia Early Data Release 3 and the Transiting Exoplanet Survey Satellite mission to characterize wide-binary systems with transiting exoplanets. We identify a sample of 67 systems of transiting exoplanet candidates (with well-determined, edge-on orbital inclinations) that reside in wide visual binary systems. We derive limits on orbital parameters for the wide-binary systems and measure the minimum difference in orbital inclination between the binary and planet orbits. We determine that there is statistically significant difference in the inclination distribution of wide-binary systems with transiting planets compared to a control sample, with the probability that the two distributions are the same being 0.0037. This implies that there is an overabundance of planets in binary systems whose orbits are aligned with those of the binary. The overabundance of aligned systems appears to primarily have semimajor axes less than 700 au. We investigate some effects that could cause the alignment and conclude that a torque caused by a misaligned binary companion on the protoplanetary disk is the most promising explanation

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Chronic administration of amitriptyline differentially alters neuropathic pain-related behaviour in the presence and absence of a depressive-like phenotype

Chronic pain and depression share a complex, reciprocal relationship. Furthermore, in addition to treating depression, antidepressants such as amitriptyline are a first-line treatment for chronic pain conditions, indicating possible common neural substrates underlying both depression and pain. However, there is a paucity of studies examining the effect of antidepressant treatment on nociceptive and neuropathic pain responding in the presence of a depressive phenotype. The current study aimed to examine the effect of chronic amitriptyline administration on neuropathic pain-related behaviour and associated neuroinflammatory processes in the olfactory bulbectomised (OB) rat model of depression. Nociceptive responding to mechanical, innocuous cold or noxious heat stimuli in sham or OB rats was not altered by chronic amitriptyline administration. The induction of neuropathic pain following L5-L6 spinal nerve ligation (SNL) resulted in robust mechanical and cold allodynia and heat hyperalgesia in both sham and OB vehicle-treated animals. Chronic amitriptyline administration attenuated SNL-induced mechanical allodynia in both sham and OB rats at day 7 post-SNL, an effect which was enhanced and prolonged in OB rats. In comparison, chronic amitriptyline administration attenuated SNL-induced cold allodynia and heat hyperalgesia in sham, but not OB, rats. Evaluating the affective/motivational aspect of pain using the place escape avoidance paradigm revealed that OB-SNL rats exhibit reduced noxious avoidance behaviour when compared with sham counterparts, an effect not altered by chronic amitriptyline administration. Chronic amitriptyline administration prevented the increased expression of GFAP, IL-10 and CCL5, and enhanced the expression of TNF alpha, in the prefrontal cortex of OB-SNL rats. In conclusion, these data demonstrate that chronic amitriptyline differentially alters somatic nociceptive responding following peripheral nerve-injury, depending on stimulus modality and the presence or absence of a depressive-like phenotype, an effect which may involve modulation of neuroinflammatory processes. (C) 2014 Published by Elsevier B.V.Discipline of Physiology and the Millennium Fund, National University of Ireland Galway. N.B. received a College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Doctoral Fellowshippeer-reviewed2016-08-3

Psychological stress in early life as a predisposing factor for the development of chronic pain: Clinical and preclinical evidence and neurobiological mechanisms

A wealth of research over the past 2 decades has expanded our understanding of the impact of early-life adversity on physiological function and, consequently, health and wellbeing in later life. Early-life adversity increases the risk of developing a number of disorders, such as chronic pain, fibromyalgia, and irritable bowel syndrome. Although much of the research has examined the impact of physical maltreatment, an increasing number of studies have been published over the past few years examining the effect of childhood psychological stress and trauma on the development of various types of chronic pain conditions. We review the clinical and preclinical data examining the link among early-life psychological stress, altered nociceptive behavior, and chronic pain in later life. Evidence supporting a role for certain key neurobiological substrates, including the hypothalamic-pituitary-adrenal axis; monoaminergic, opioidergic, endocannabinoid and immune systems; and epigenetic mechanisms in the association between early-life psychological stress and chronic pain, is provided. Greater understanding of the impact of early-life stress may inform the development of personalized treatments for chronic pain in later life and strategies to prevent its onset in susceptible individuals. © 2016 Wiley Periodicals, Inc.peer-reviewe

Neuroinflammatory mechanisms linking pain and depression

Depression and chronic pain have been estimated to co-occur in up to 80% of patients suffering from these disorders, with this co-morbidity being more disabling and more expensive to both patients and society than either disorder alone. A number of neural substrates have been proposed to underlie this association; however, there has been increased interest and support for a role of neuroimmune and neuroinflammatory mechanisms as key players in this dyad. This chapter will provide an overview of the clinical and preclinical data supporting a role for neuroimmune alterations in depression-pain co-morbidity. We propose that such changes may impact on the functioning of key brain regions modulating emotional and nociceptive processing, thus resulting in the behavioural, psychological and physical symptoms observed in patients exhibiting depression and co-morbid pain.Science Foundation Ireland Research Frontiers Project (11/RFP/NES/3175), the Discipline of Physiology and a PhD Scholarship from the College of Medicine, National University of IrelandPeer reviewe

Altered neuropathic pain behaviour in a rat model of depression is associated with changes in inflammatory gene expression in the amygdala

The association between chronic pain and depression is widely recognized, the comorbidity of which leads to a heavier disease burden, increased disability and poor treatment response. This study examined nociceptive responding to mechanical and thermal stimuli prior to and following L5-L6 spinal nerve ligation (SNL), a model of neuropathic pain, in the olfactory bulbectomized (OB) rat model of depression. Associated changes in the expression of genes encoding for markers of glial activation and cytokines were subsequently examined in the amygdala, a key brain region for the modulation of emotion and pain. The OB rats exhibited mechanical and cold allodynia, but not heat hyperalgesia, when compared with sham-operated counterparts. Spinal nerve ligation induced characteristic mechanical and cold allodynia in the ipsilateral hindpaw of both sham and OB rats. The OB rats exhibited a reduced latency and number of responses to an innocuous cold stimulus following SNL, an effect positively correlated with interleukin (IL)-6 and IL-10 mRNA expression in the amygdala, respectively. Spinal nerve ligation reduced IL-6 and increased IL-10 expression in the amygdala of sham rats. The expression of CD11b (cluster of differentiation molecule 11b) and GFAP (glial fibrillary acidic protein), indicative of microglial and astrocyte activation, and IL-1 in the amygdala was enhanced in OB animals when compared with sham counterparts, an effect not observed following SNL. This study shows that neuropathic pain-related responding to an innocuous cold stimulus is altered in an animal model of depression, effects accompanied by changes in the expression of neuroinflammatory genes in the amygdala.The authors would like to gratefully acknowledge funding received from the Discipline of Physiology and the Millennium Fund, National University of Ireland Galway. N.B. is a recipient of College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Doctoral Fellowship.peer-reviewe

Sex differences and similarities in depressive-and anxiety-like behaviour in the Wistar-Kyoto rat

Depression is a debilitating psychiatric disorder that is highly comorbid with anxiety. Depression is twice as prevalent in women as in men, however, females remain underrepresented in preclinical research. The stress hyper-responsive Wistar-Kyoto (WKY) rat displays hypolocotnotion in a novel aversive environment and depressive and anxiety-like behaviours, which have been mostly characterised in males. The current study characterised behaviour in male and female rats in a battery of behavioural paradigms. Adult male and female WKY rats were tested in the open field and forced swim tests (tests with a locomotor component); and the marble burying, novelty induced hypophagia and sucrose preference tests (tests with a minimal locomotor component) and 24 h home-cage locomotor activity was also monitored. The tests were compared against the Sprague-Dawley (SD) strain, a commonly used "control" strain.SD, but not WKY, females exhibited higher home-cage locomotor activity-compared to males. In the open field, WKY rats of both sexes exhibited a significant reduction in locomotor activity and increased anxiety-like behaviour as demonstrated by reduced time in the aversive inner zone of the open field, compared to SD counterparts. In the marble burying test, WKY females, but not males, exhibited a trend towards increased burying, indicative of anxiety-like/neophobic behaviour. In comparison, WKY males, but not females, exhibited enhanced novelty induced hypophagia, indicative of increased anxiety-like behaviour compared to SD rats. In the forced swim test, WKY rats of both sexes spent more time immobile compared with SD counterparts, indicating depressive-like behaviour. However, in comparison to SD rats, WKY males, but not females, exhibited anhedonic-like behaviour. In conclusion, WKY rats exhibit depressive-and anxiety-like behaviours that are complex and nuanced depending on the sex of the rat and testing conditions. This study supports the use of a varied test battery to fully characterise depression/anxiety-like behaviour in male and female rats. (C) 2016 Elsevier Inc. All rights reserved.This study was supported by an Industry-Academia collaboration with funding provided by Alkermes (RIN997). Financial sponsors had no role in the study design, collection, analysis or interpretation of data.peer-reviewe

Locomotor and anti-immobility effects of buprenorphine in combination with the opioid receptor modulator samidorphan in rats

Modulation of the opioid system has re-emerged as a potential therapeutic avenue for treating depression, with efficacy of a fixed-dose combination of buprenorphine (BUP), a partial mu-opioid receptor (MOR) agonist and kappa-opioid receptor (KOR) antagonist, and samidorphan (SAM), a potent MOR antagonist, as an adjuvant treatment in patients with major depressive disorder (MDD). To advance understanding of the mechanism of action underlying this combination, we examined BUP, SAM and their combination in a series of rat behavioural assays. We examined effects on locomotor activity in Sprague Dawley (SD) rats over an extended period of time in a home-cage tracking system, and behavioural despair (immobility) in the forced swim test (FST), a commonly-used test to study antidepressants, in SD and Wistar-Kyoto (WKY) rats. Strain differences in opioid receptor and prepropeptide mRNA expression in the brain (prefrontal cortex, amygdala, hippocampus and striatum) were examined using qRT-PCR. BUP produced locomotor hyperactivity in SD rats from 2 to 6 h following administration, which was attenuated by SAM. In SD rats, a low, but not a high, dose of SAM in combination with BUP counteracted swim-stress induced immobility. This effect was not seen with BUP alone. In contrast, BUP alone reduced immobility in WKY rats, and this effect was enhanced by a low, but not high, dose of SAM. In WKY rats, MOR mRNA expression was higher in the hippocampus and lower in the striatum vs. SD rats. KOR mRNA expression was higher in the amygdala and nociceptin receptor (NOP) mRNA expression was lower in the hippocampus vs. SD rats. Differences in opioid receptor expression may account for the differential behavioural profile of WKY and SD rats. In summary, administration of BUP, a MOR receptor agonist together with a MOR opioid-receptor antagonist, SAM, reduces behavioural despair in animal models traditionally used to study effects of antidepressants.This study was supported by an Industry-Academia collaboration with funding and samidorphan provided by Alkermes Inc; and a Strategic Partnership Programme Grant from Science Foundation Ireland and Alkermes Inc (14/SPP/B3051).peer-reviewed2019-12-1