Listensgaard5200

Our study shows the utility of leveraging genetic variation in expression to elucidate how essential cellular processes impact human aging. The findings extend the evolutionary conservation of protein synthesis as a critical process that drives animal aging to include humans.The dorsal raphe nucleus (DRN) contains the largest population of serotonin (5-HT) neurons in the central nervous system. 5-HT, synthesized via tryptophan hydroxylase 2 (Tph2), is a widely functioning neuromodulator implicated in fear learning. Here, we sought to investigate whether DRN 5-HT is necessary to reduce fear via negative prediction error (-PE). Using male and female TPH2-cre rats, DRNtph2+ cells were selectively deleted via cre-caspase (rAAV5-Flex-taCasp3-TEVp) in experiment 1. Rats then underwent fear discrimination during which three cues were associated with unique foot shock probabilities safety p = 0.00, uncertainty p = 0.375, and danger p = 1.00. ITF3756 price Rats then received selective extinction to the uncertainty cue, a behavioral manipulation designed to probe -PE. Deleting DRNtph2+ cells had no impact on initial discrimination but slowed selective extinction. In experiment 2, we used a within-subjects optogenetic inhibition design to causally implicate DRNtph2+ cells in prediction error signaling. Male and female TPH2-cre rats received intra-DRN infusions of cre-dependent halorhodopsin (rAAV5-Ef1a-DIO-eNpHR3.0-eYFP) or cre-YFP. DRNtph2+ cells were inhibited specifically during the time of prediction error or a control period. Illumination during either positive prediction error (+PE) or control periods had no impact on fear to the uncertainty cue. Inhibition of DRNtph2+ cells at the time of -PE did not impact immediate fear, but facilitated selective extinction in postillumination sessions. Together, these results demonstrate a role for DRNtph2+ cells in using, but not generating, -PE to weaken cue-shock associations.Nuclear receptors (NRs), a superfamily of ligand-activated transcription factors, are critical in cell growth, proliferation, differentiation, metabolism, and numerous biologic events. NRs have been reported to play important roles in hepatomegaly (liver enlargement) and liver regeneration by regulating target genes or interacting with other signals. In this review, the roles and involved molecular mechanisms of NRs in hepatomegaly and liver regeneration are summarized and the future perspectives of NRs in the treatment of liver diseases are discussed. SIGNIFICANCE STATEMENT NRs play critical roles in hepatomegaly and liver regeneration, indicating the potential of NRs as targets to promote liver repair after liver injury. This paper reviews the characteristics and molecular mechanisms of NRs in regulating hepatomegaly and liver regeneration, providing more evidence for NRs in the treatment of related liver diseases.Furan-containing compounds are abundant in nature, and many, but not all, have been found to be hepatotoxic and carcinogenic. The furan ring present in the chemical structures may be one of the domineering factors to bring about the toxic response resulting from the generation of reactive epoxide or cis-enedial intermediates, which have the potential to react with biomacromolecules. This review sets out to explore the relationship between the metabolic activation and hepatotoxicity of furan-containing compounds on the strength of scientific reports on several typical alkylated furans, synthetic pharmaceuticals, and components extracted from herbal medicines. The pharmacological activities as well as concrete evidence of their liver injuries are described, and the potential toxic mechanisms were discussed partly based on our previous work. Efforts were made to understand the development of liver injury and seek solutions to prevent adverse effects. SIGNIFICANCE STATEMENT This review mainly elucidates the vital role of metabolic activation in the hepatotoxicity of furan-containing compounds through several typical chemicals studied. The possible mechanisms involved in the toxicities are discussed based on collective literatures as well as our work. Additionally, the structural features responsible for toxicities are elaborated to predict toxicity potentials of furan-containing compounds. This article may assist to seek solutions for the occurring problems and prevent the toxic effects of compounds with furan(s) in clinical practice.We present a case of a non-diabetic 84-year-old woman who presented with recurrent falls and hypoglycaemic episodes and was subsequently diagnosed to have a solitary insulinoma. Her multiple fall episodes may have been precipitated by her low blood glucose levels. We discuss the clinical and radiological findings of insulinoma.Cardiac troponin I and T are particularly sensitive and specific markers for cardiomyocyte damage. Myocardial injury can occur due to a discrepancy between oxygen supply and demand (eg coronary artery occlusion and arrhythmias), other cardiac causes (eg pericarditis, myocarditis, cardiac surgery, cardioversion etc) or systemic conditions (eg sepsis, stroke and chronic renal disease). The latest European Society of Cardiology guidelines help to guide clinicians through these different causes. Occasionally troponin concentrations may not fit the clinical presentation and, therefore, other aetiologies should be considered. An under-appreciated basis of a high troponin concentration is a false positive result, which can be attributable to analytical interference from components in the patient's blood. Uncovering this interference can be pivotal to avoid unnecessary and potentially harmful investigations or treatment for patients. We present two cases of false positive troponin results caused by analytical interference. The normal reference range for the assay (Access; Beckman Coulter, High Wycombe, UK) used at our organisation is 0-18 ng/L.Hyperosmolar hyperglycaemic state (HHS) is a life-threatening metabolic complication of type 2 diabetes (T2DM) that often presents with neurological symptoms. A 74-year-old man with known T2DM presented to the emergency department with collapse, left-sided weakness and slurred speech (National Institutes of Health Stroke Scale (NIHSS) 3) and a biochemical profile consistent with HHS. When he further deteriorated (NIHSS 20), he was managed for concurrent ischaemic stroke. All his symptoms fully resolved after 24 hours, which coincided with establishment of normoglycaemia. Subsequent magnetic resonance imaging (MRI) of the head revealed a tiny parietal lobe infarct. Two further cases of HHS mimicking ischaemic stroke have been reported with symptoms and imaging findings resolving with treatment of HHS. Our case demonstrates how HHS can also accentuate symptoms of a minor stroke, highlighting the importance of excluding ischaemic stroke in HHS patients with neurological dysfunction. We recommend consideration of early MRI and/or computed tomography angiography in this cohort, especially in those appropriate for intervention.Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a growing public health epidemic. In the UK, over 1.3 million people have a diagnosis of AF and an estimated 400,000 remain undiagnosed. AF-related strokes account for a quarter of all strokes and, as AF episodes are often asymptomatic, are still often the first manifestation of AF. Early diagnosis and initiation of oral anticoagulation, where appropriate, may prevent some of these thromboembolic strokes. Public Health England is committed to decrease the incidence of AF-related strokes and has sponsored initiatives aimed at improving AF detection by promoting the uptake of wearable technologies. However, the National Institute for Health and Care Excellence (NICE) has not recommended wearable technology in their recent AF diagnosis and management guidelines (NG196). Diagnostic accuracy of single-lead electrocardiography (ECG) generated by the latest iteration of wearable devices is excellent and, in many cases, superior to general practitioner interpretation of the 12-lead ECG. High-quality ECG from wearable devices that unequivocally shows AF can expedite AF detection. Otherwise, there is a real risk of delaying AF diagnosis with the potential of devastating consequences for patients and their families.

Severity scores in pneumonia and sepsis are being applied to SARS-CoV-2 infection. We aimed to assess whether these severity scores are accurate predictors of early adverse outcomes in COVID-19.

We conducted a multicentre observational study of hospitalised SARS-CoV-2 infection. We assessed risk scores (CURB65, qSOFA, Lac-CURB65, MuLBSTA and NEWS2) in relation to admission to intensive care or death within 7 days of admission, defined as early severe adverse events (ESAE). The 4C Mortality Score was also assessed in a sub-cohort of patients.

In 2,387 participants, the overall mortality was 18%. In all scores examined, increasing score was associated with increased risk of ESAE. Area under the curve (AUC) to predict ESAE for CURB65, qSOFA, Lac-CURB65, MuLBSTA and NEWS2 were 0.61, 0.62, 0.59, 0.59 and 0.68, respectively. AUC to predict ESAE was 0.60 with ISARIC 4C Mortality Score.

None of the scores examined accurately predicted ESAE in SARS-CoV-2 infection. Non-validated scores should not be used to inform clinical decision making in COVID-19.

None of the scores examined accurately predicted ESAE in SARS-CoV-2 infection. Non-validated scores should not be used to inform clinical decision making in COVID-19.Clinicians are responsible for both commencing and stopping medications. This study evaluates the attitudes of older acute medical inpatients about deprescribing. Overall, patients are positive toward stopping medications, want to be involved and do not feel a clinician is giving up on them if a medication is stopped. Patients on fewer medications counterintuitively feel a greater medication burden, are more interested in being involved in decision making and consider deprescribing appropriate to a greater degree than patients who are taking more medications. Conversely, they also reported greater concerns about stopping medications. We discuss these findings in the context of the positive and negative effects of deprescribing, in the context of patient engagement and shared decision making, and how clinicians can work with inpatients to reduce potentially inappropriate medications.

In the context of an ageing population, many healthcare professionals have limited experience and confidence in having necessary advance care planning (ACP) conversations.

We conducted nine half-day simulation sessions, using professional actors. One-hundred and thirty-two participants attended from multidisciplinary backgrounds across primary and secondary care.

Following the course, 90.2% felt confident or very confident initiating conversations, compared with 14.4% beforehand. Understanding of when ACP is appropriate also increased from 70% to 100%. Post-course, 98% of participants stated that they would be more likely to initiate an ACP. Three months later, 86% had a sustained change in practice. All participants said they would recommend this simulation course and multidisciplinary approach.

Multidisciplinary simulation training is an effective way to teach ACP to doctors, nurses and allied healthcare professionals. The simulation was shown to improve participant understanding, confidence and reduce barriers to discussions, both immediately and 3 months later.