Masseygilliam1708

Acute stress transiently increases vigilance, enhancing the detection of salient stimuli in one's environment. This increased perceptual sensitivity is thought to promote associating rewarding outcomes with relevant cues. The mesolimbic dopamine system is critical for learning cue-reward associations. Dopamine levels in the ventral striatum are elevated following exposure to stress. Together, this suggests the mesolimbic dopamine system could mediate the influence of acute stress on cue-reward learning. To address this possibility, we examined how a single stressful experience influenced learning in an appetitive Pavlovian conditioning task. Male rats underwent an episode of restraint prior to the first conditioning session. This acute stress treatment augmented conditioned responding in subsequent sessions. Voltammetry recordings of mesolimbic dopamine levels demonstrated that acute stress selectively increased reward-evoked dopamine release in the ventral lateral striatum (VLS), but not in the ventral medial striatum (VMS). Antagonizing dopamine receptors in the VLS blocked the stress-induced enhancement of conditioned responding. Collectively, these findings illustrate that stress engages dopamine signaling in the VLS to facilitate appetitive learning.SignificanceAcute stress influences learning about aversive and rewarding outcomes. Dopamine neurons are sensitive to stress and critical for reward learning. However, it is unclear if stress regulates reward learning via dopamine signaling. Using fast-scan cyclic voltammetry as rats underwent Pavlovian conditioning, we demonstrate that a single stressful experience increases reward-evoked dopamine release in the ventral lateral striatum. This enhanced dopamine signal accompanies a long-lasting increase in conditioned behavioral responding. These findings highlight that the ventral lateral striatum is a node for mediating the effect of stress on reward processing. Copyright © 2020 Stelly et al.Rodents can successfully learn multiple, novel stimulus-response associations after only a few repetitions when the contingencies predict reward. The circuits modified during such reinforcement learning to support decision making are not known, but the olfactory tubercle (OT) and posterior piriform cortex (pPC) are candidates for decoding reward category from olfactory sensory input and relaying this information to cognitive and motor areas. Through single-cell recordings in behaving male and female C57BL/6 mice, we show here that an explicit representation for reward category emerges in the OT within minutes of learning a novel odor-reward association, whereas the pPC lacks an explicit representation even after weeks of overtraining. The explicit reward category representation in OT is visible in the first sniff (50-100ms) of an odor on each trial, and precedes the motor action. Together, these results suggest that coding of stimulus information required for reward prediction does not occur within olfactory cortex, but rather in circuits involving the olfactory striatum.Significance StatementRodents are olfactory specialists and can use odors to learn contingencies quickly and well. We have found that mice can readily learn to place multiple odors into rewarded and unrewarded categories. Once they have learned the rule, they can do such categorization in a matter of minutes (less than 10 trials). We found that neural activity in olfactory cortex largely reflects sensory coding, with very little explicit information about categories. By contrast, neural activity in a brain region in the ventral striatum is rapidly modified in a matter of minutes to reflect reward category. Our experiments set up a paradigm for studying rapid sensorimotor reinforcement in a circuit that is right at the interface of sensory input and reward areas. Copyright © 2020 Millman and Murthy.The gabapentinoid drugs gabapentin and pregabalin (Neurontin® and Lyrica®) are mainstay treatments for neuropathic pain and for preventing focal seizures. Both drugs have similar effects to each other in animal models and clinically. Studies have shown that a protein first identified as an auxiliary subunit of voltage-gated calcium channels (the alpha2-delta subunit, α2δ-1 or Cava2d1) is the high-affinity binding site for gabapentin and pregabalin, and is required for the efficacy of these drugs. The α2δ-1 protein is required for the ability of gabapentin and pregabalin to reduce neurotransmitter release in neuronal tissue, consistent with a therapeutic mechanism of action via voltage-gated calcium channels. However, recent studies have revealed that α2δ-1 interacts with several proteins in addition to voltage-gated calcium channels, and these additional proteins could be involved in gabapentinoid pharmacology. Furthermore, gabapentin and pregabalin have been shown to modify the action of a subset of NMDA-sensitive glutamate receptors, neurexin-1, and thrombospondin proteins by binding to α2δ-1. Thus, these effects may contribute substantially to gabapentinoid therapeutic mechanism of action. SIGNIFICANCE STATEMENT It is widely believed that gabapentin and pregabalin act by modestly reducing the membrane localization and activation of voltage-gated calcium channels at synaptic endings in spinal cord and neocortex via binding to the α2δ-1 protein. However, recent findings show that the α2δ-1 protein also interacts with NMDA-sensitive glutamate receptors, neurexin-1α, thrombospondins (adhesion molecules), and other presynaptic proteins. These newly discovered interactions, in addition to actions at calcium channels, may be important mediators of gabapentin and pregabalin therapeutic effects. The American Society for Pharmacology and Experimental Therapeutics.BACKGROUND Valuable information for planning future end-of-life care (EOLC) services and care facilities can be gained by studying trends in place of death (POD). Scarce data exist on the POD in small developing countries. This study aims to examine shifts in the POD of all persons dying between 1999 and 2010 in Trinidad and Tobago, to draw conclusions about changes in the distribution of POD over time and the possible implications for EOLC practice and policy. METHODS A population-level analysis of routinely collected death certificate data of the most recent available fully coded years at the time of the study-1999 to 2010. Observed proportions for the POD of all deaths were standardised according to the age, sex and cause of death distribution in 1999. Trends for a subgroup of persons who died from causes indicative of a palliative care (PC) need were also examined. RESULTS The proportion of deaths in government hospitals increased from 48.9% to 55.4% and decreased from 38.7% to 29.7% at private homes. There was little variation between observed and standardised rates. The decrease in home deaths was stronger when the PC subcategory was considered, most notably from cancer. CONCLUSION Internationally, the proportion of deaths at institutions is increasing. A national strategy on palliative and EOLC is needed to facilitate the increasing number of people who seek EOLC at government hospitals in Trinidad and Tobago, including an investigation into the reasons for the trend. Alternatives to accommodate out-of-hospital deaths can be considered. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Label-Free Quantitative mass spectrometry based workflows for differential expression (DE) analysis of proteins impose important challenges on the data analysis due to peptide-specific effects and context dependent missingness of peptide intensities. Peptide-based workflows, like MSqRob, test for DE directly from peptide intensities and outperform summarization methods which first aggregate MS1 peptide intensities to protein intensities before DE analysis. However, these methods are computationally expensive, often hard to understand for the non-specialised end-user, and do not provide protein summaries, which are important for visualisation or downstream processing. In this work, we therefore evaluate state-of-the-art summarization strategies using a benchmark spike-in dataset and discuss why and when these fail compared to the state-of-the-art peptide based model, MSqRob. Based on this evaluation, we propose a novel summarization strategy, MSqRobSum, which estimates MSqRob's model parameters in a two-stage procedure circumventing the drawbacks of peptide-based workflows. MSqRobSum maintains MSqRob's superior performance, while providing useful protein expression summaries for plotting and downstream analysis. Summarising peptide to protein intensities considerably reduces the computational complexity, the memory footprint and the model complexity, and makes it easier to disseminate DE inferred on protein summaries. Moreover, MSqRobSum provides a highly modular analysis framework, which provides researchers with full flexibility to develop data analysis workflows tailored towards their specific applications. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.BACKGROUND Multimodal analgesia (MMA) may reduce opioid use after surgery for Chiari malformation type I. An MMA protocol was implemented after both posterior fossa decompression without dural opening (PFD) and posterior fossa decompression with duraplasty (PFDD). METHODS Scheduled nonsteroidal antiinflammatory drugs (ketorolac or ibuprofen) and diazepam were alternated with acetaminophen, and as-needed oxycodone or intravenous morphine. The primary outcome was total opioid requirement over postoperative days 0 to 2. RESULTS From 2012 to 2017, 49 PFD and 29 PFDD procedures were performed, and 46 of 78 patients used the protocol. Patients with PFD required less opioids than patients with PFDD. Among patients with PFDD, patients with MMA protocol usage had a lower mean opioid requirement than patients with no MMA protocol usage (0.53 ± 0.49 mgEq/kg versus 1.4 ± 1.0 mgEq/kg, P = .0142). In multivariable analysis, MMA protocol usage status independently predicted a mean decrease in opioid requirement of 0.146 mg equivalents/kg (P = .0497) after adjustment for procedure and surgeon. Statistically significant differences were not demonstrated in antiemetic requirements, discharge opioid prescriptions, total direct cost, and length of stay. CONCLUSIONS A protocol of scheduled nonsteroidal antiinflammatory drugs alternating with scheduled acetaminophen and diazepam was associated with opioid use reductions. Copyright © 2020 by the American Academy of Pediatrics.OBJECTIVES With soaring US health care costs, identifying areas for reducing cost is prudent. Our objective was to identify the burden of potentially unnecessary pediatric emergency department (ED) transfers and factors associated with these transfers. METHODS We performed a retrospective analysis of Pediatric Hospital Information Systems data. We performed a secondary analysis of all patients ≤19 years transferred to 46 Pediatric Hospital Information Systems-participating hospital EDs (January 1, 2013, to December 31, 2014). mTOR inhibitor The primary outcome was the proportion of potentially unnecessary transfers from any ED to a participating ED. Necessary ED-to-ED transfers were defined a priori as transfers with the disposition of death or admission >24 hours or for patients who received sedation, advanced imaging, operating room, or critical care charges. RESULTS Of 1 819 804 encounters, 1 698 882 were included. A total of 1 490 213 (87.7%) encounters met our definition for potentially unnecessary transfer. In multivariate analysis, age 1 to 4 years (odds ratio [OR], 1.