Hosptial Preparedness for an Internal Mass Casualty Event

The purpose of this study was to determine hospital preparedness for an internal mass casualty/active shooter event at Tennessee hospitals. Data were collected during May of 2019 by surveying the CEOs of the 86 acute care hospitals in Tennessee. The survey solicited responses about training, preparedness, and internal evaluation of procedures. CEOs of 28 (32.5%) of Tennessee’s acute care hospitals responded to the survey. Just over half (53.6%) of those responding indicated that they believed their facility was prepared or well prepared for an active shooter event. The mean responses of CEOs who had experienced an active shooter event were significantly lower than those CEOs who had not. Seventy-two percent of CEOs indicated that policies and procedures for active shooter/mass casualty events were updated at least every other year

Developmental regulation of Foxp3 expression during ontogeny

Thymectomy of neonatal mice can result in the development of autoimmune pathology. It has been proposed that thymic output of regulatory T (T reg) cells is delayed during ontogeny and that the development of autoimmune disease in neonatally thymectomized mice is caused by the escape of self-reactive T cells before thymectomy without accompanying T reg cells. However, the kinetics of T reg cell production within the thymus during ontogeny has not been assessed. We demonstrate that the development of Foxp3-expressing T reg cells is substantially delayed relative to nonregulatory thymocytes during ontogeny. Based on our data, we speculate that induction of Foxp3 in developing thymocytes and, thus, commitment to the T reg cell lineage is facilitated by a signal largely associated with the thymic medulla

Histone Modifications within the Human X Centromere Region

Human centromeres are multi-megabase regions of highly ordered arrays of alpha satellite DNA that are separated from chromosome arms by unordered alpha satellite monomers and other repetitive elements. Complexities in assembling such large repetitive regions have limited detailed studies of centromeric chromatin organization. However, a genomic map of the human X centromere has provided new opportunities to explore genomic architecture of a complex locus. We used ChIP to examine the distribution of modified histones within centromere regions of multiple X chromosomes. Methylation of H3 at lysine 4 coincided with DXZ1 higher order alpha satellite, the site of CENP-A localization. Heterochromatic histone modifications were distributed across the 400–500 kb pericentromeric regions. The large arrays of alpha satellite and gamma satellite DNA were enriched for both euchromatic and heterochromatic modifications, implying that some pericentromeric repeats have multiple chromatin characteristics. Partial truncation of the X centromere resulted in reduction in the size of the CENP-A/Cenp-A domain and increased heterochromatic modifications in the flanking pericentromere. Although the deletion removed ∼1/3 of centromeric DNA, the ratio of CENP-A to alpha satellite array size was maintained in the same proportion, suggesting that a limited, but defined linear region of the centromeric DNA is necessary for kinetochore assembly. Our results indicate that the human X centromere contains multiple types of chromatin, is organized similarly to smaller eukaryotic centromeres, and responds to structural changes by expanding or contracting domains

Interactions between metabolic, reward and cognitive processes in appetite control:Implications for novel weight management therapies

Traditional models of appetite control have emphasised the role of parallel homeostatic and hedonic systems, but more recently the distinction between independent homeostatic and hedonic systems has been abandoned in favour of a framework that emphasises the cross talk between the neurochemical substrates of the two systems. In addition, evidence has emerged more recently, that higher level cognitive functions such as learning, memory and attention play an important role in everyday appetite control and that homeostatic signals also play a role in cognition. Here, we review this evidence and present a comprehensive model of the control of appetite that integrates cognitive, homeostatic and reward mechanisms. We discuss the implications of this model for understanding the factors that may contribute to disordered patterns of eating and suggest opportunities for developing more effective treatment approaches for eating disorders and weight management

OpenMM 8: Molecular Dynamics Simulation with Machine Learning Potentials

Machine learning plays an important and growing role in molecular simulation. The newest version of the OpenMM molecular dynamics toolkit introduces new features to support the use of machine learning potentials. Arbitrary PyTorch models can be added to a simulation and used to compute forces and energy. A higher-level interface allows users to easily model their molecules of interest with general purpose, pretrained potential functions. A collection of optimized CUDA kernels and custom PyTorch operations greatly improves the speed of simulations. We demonstrate these features on simulations of cyclin-dependent kinase 8 (CDK8) and the green fluorescent protein (GFP) chromophore in water. Taken together, these features make it practical to use machine learning to improve the accuracy of simulations at only a modest increase in cost.Comment: 16 pages, 5 figure

OpenMM 8:Molecular Dynamics Simulation with Machine Learning Potentials

Machine learning plays an important and growing role in molecular simulation. The newest version of the OpenMM molecular dynamics toolkit introduces new features to support the use of machine learning potentials. Arbitrary PyTorch models can be added to a simulation and used to compute forces and energy. A higher-level interface allows users to easily model their molecules of interest with general purpose, pretrained potential functions. A collection of optimized CUDA kernels and custom PyTorch operations greatly improves the speed of simulations. We demonstrate these features in simulations of cyclin-dependent kinase 8 (CDK8) and the green fluorescent protein chromophore in water. Taken together, these features make it practical to use machine learning to improve the accuracy of simulations with only a modest increase in cost.</p

Experiences and views of people who frequently call emergency ambulance services: a qualitative study of UK service users

Introduction: People who call emergency ambulances frequently are often vulnerable because of health and social circumstances, have unresolved problems or cannot access appropriate care. They have higher mortality rates. Case management by interdisciplinary teams can help reduce demand for emergency services and is available in some UK regions. We report results of interviews with people who use emergency ambulance services frequently to understand their experiences of calling and receiving treatment. Methods: We used a two‐stage recruitment process. A UK ambulance service identified six people who were known to them as frequently calling emergency services. Through third‐sector organisations, we also recruited nine individuals with healthcare experiences reflecting the characteristics of people who call frequently. We gained informed consent to record and transcribe all telephone interviews. We used thematic analysis to explore the results. Results: People said they make frequent calls to emergency ambulance services as a last resort when they perceive their care needs are urgent and other routes to help have failed. Those with the most complex health needs generally felt their immediate requirements were not resolved and underlying mental and physical problems led them to call again. A third of respondents were also attended to by police and were arrested for behaviour associated with their health needs. Those callers receiving case management did not know they were selected for this. Some respondents were concerned that case management could label frequent callers as troublemakers. Conclusion: People who make frequent calls to emergency ambulance services feel their health and care needs are urgent and ongoing. They cannot see alternative ways to receive help and resolve problems. Communication between health professionals and service users appears inadequate. More research is needed to understand service users' motivations and requirements to inform design and delivery of accessible and effective services. Patient or Public Contribution: People with relevant experience were involved in developing, undertaking and disseminating this research. Two public contributors helped design and deliver the study, including developing and analysing service user interviews and drafting this paper. Eight public members of a Lived Experience Advisory Panel contributed at key stages of study design, interpretation and dissemination. Two more public contributors were members of an independent Study Steering Committee

Tailoring pharmacotherapy to specific eating behaviours in obesity: Can recommendations for personalised therapy be made from the current data?

Pharmacotherapy provides an adjunct to behaviour modification in the management of obesity. There are a number of new drug therapies purportedly targeting appetite; liraglutide, and bupropion/naltrexone, which are European Medicines Agency and US Food and Drug Administration (FDA) approved, and lorcaserin and phentermine/topiramate, which have FDA approval only. Each of the six drugs, used singly or in combination, has distinct pharmacological, and presumably distinct behavioural, mechanisms of action, thus the potential to provide defined therapeutic options to personalise the management of obesity. Yet, with regard to pharmacotherapy for obesity, we are far from true personalised medicine. We review the limited mechanistic data with four mono and combination pharmacotherapies, to assess the potential for tailoring their use to target specific obesogenic behaviours. Potential treatment options are considered, but in the absence of adequate research in respect to effects of these drugs on eating behaviour, neural activity and psychological substrates that underlie poorly controlled eating, we are far from definitive therapeutic recommendations. Specific mechanistic studies and broader behavioural phenotyping, possibly in conjunction with pharmacogenetic research, are required to characterise responders for distinct pharmacotherapeutic options

Association of T-Zone Reticular Networks and Conduits with Ectopic Lymphoid Tissues in Mice and Humans

Ectopic or tertiary lymphoid tissues (TLTs) are often induced at sites of chronic inflammation. They typically contain various hematopoietic cell types, high endothelial venules, and follicular dendritic cells; and are organized in lymph node–like structures. Although fibroblastic stromal cells may play a role in TLT induction and persistence, they have remained poorly defined. Herein, we report that TLTs arising during inflammation in mice and humans in a variety of tissues (eg, pancreas, kidney, liver, and salivary gland) contain stromal cell networks consisting of podoplanin+ T-zone fibroblastic reticular cells (TRCs), distinct from follicular dendritic cells. Similar to lymph nodes, TRCs were present throughout T-cell–rich areas and had dendritic cells associated with them. They expressed lymphotoxin (LT) β receptor (LTβR), produced CCL21, and formed a functional conduit system. In rat insulin promoter–CXCL13–transgenic pancreas, the maintenance of TRC networks and conduits was partially dependent on LTβR and on lymphoid tissue inducer cells expressing LTβR ligands. In conclusion, TRCs and conduits are hallmarks of secondary lymphoid organs and of well-developed TLTs, in both mice and humans, and are likely to act as important scaffold and organizer cells of the T-cell–rich zone

The 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) reduces palatable food consumption and BOLD fMRI responses to food images in healthy female volunteers

RATIONALE: Brain 5-HT2C receptors form part of a neural network that controls eating behaviour. 5-HT2C receptor agonists decrease food intake by activating proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus, but recent research in rodents has suggested that 5-HT2C receptor agonists may also act via dopaminergic circuitry to reduce the rewarding value of food and other reinforcers. No mechanistic studies on the effects of 5-HT2C agonists on food intake in humans have been conducted to date. OBJECTIVES: The present study examined the effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) on food consumption, eating microstructure and blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) responses to food pictures in healthy female volunteers. METHODS: In a double-blind, placebo-controlled, crossover design, participants were randomized immediately after screening to receive oral mCPP (30mg) in a single morning dose, or placebo, in a counterbalanced order. Test foods were served from a Universal Eating Monitor (UEM) that measured eating rate and fMRI BOLD signals to the sight of food and non-food images were recorded. RESULTS: mCPP decreased rated appetite and intake of a palatable snack eaten in the absence of hunger but had no significant effect on the consumption of a pasta lunch (although pasta eating rate was reduced). mCPP also decreased BOLD fMRI responses to the sight of food pictures in areas of reward-associated circuitry. A post hoc analysis identified individual variability in the response to mCPP (exploratory responder-non-responder analysis). Some participants did not reduce their cookie intake after treatment with mCPP and this lack of response was associated with enhanced ratings of cookie pleasantness and enhanced baseline BOLD responses to food images in key reward and appetite circuitry. CONCLUSIONS: These results suggest that 5-HT2C receptor activation in humans inhibits food reward-related responding and that further investigation of stratification of responding to mCPP and other 5-HT2C receptor agonists is warranted