Brainstem Circuitry Regulating Phasic Activation of Trigeminal Motoneurons during REM Sleep

Rapid eye movement sleep (REMS) is characterized by activation of the cortical and hippocampal electroencephalogram (EEG) and atonia of non-respiratory muscles with superimposed phasic activity or twitching, particularly of cranial muscles such as those of the eye, tongue, face and jaw. While phasic activity is a characteristic feature of REMS, the neural substrates driving this activity remain unresolved. Here we investigated the neural circuits underlying masseter (jaw) phasic activity during REMS. The trigeminal motor nucleus (Mo5), which controls masseter motor function, receives glutamatergic inputs mainly from the parvocellular reticular formation (PCRt), but also from the adjacent paramedian reticular area (PMnR). On the other hand, the Mo5 and PCRt do not receive direct input from the sublaterodorsal (SLD) nucleus, a brainstem region critical for REMS atonia of postural muscles. We hypothesized that the PCRt-PMnR, but not the SLD, regulates masseter phasic activity during REMS.To test our hypothesis, we measured masseter electromyogram (EMG), neck muscle EMG, electrooculogram (EOG) and EEG in rats with cell-body specific lesions of the SLD, PMnR, and PCRt. Bilateral lesions of the PMnR and rostral PCRt (rPCRt), but not the caudal PCRt or SLD, reduced and eliminated REMS phasic activity of the masseter, respectively. Lesions of the PMnR and rPCRt did not, however, alter the neck EMG or EOG. To determine if rPCRt neurons use glutamate to control masseter phasic movements, we selectively blocked glutamate release by rPCRt neurons using a Cre-lox mouse system. Genetic disruption of glutamate neurotransmission by rPCRt neurons blocked masseter phasic activity during REMS.These results indicate that (1) premotor glutamatergic neurons in the medullary rPCRt and PMnR are involved in generating phasic activity in the masseter muscles, but not phasic eye movements, during REMS; and (2) separate brainstem neural circuits control postural and cranial muscle phasic activity during REMS

Causes of death among homeless people: a population-based cross-sectional study of linked hospitalisation and mortality data in England. [version 1; peer review: 2 approved]

Background: Homelessness has increased by 165% since 2010 in England, with evidence from many settings that those affected experience high levels of mortality. In this paper we examine the contribution of different causes of death to overall mortality in homeless people recently admitted to hospitals in England with specialist integrated homeless health and care (SIHHC) schemes.  Methods: We undertook an analysis of linked hospital admission records and mortality data for people attending any one of 17 SIHHC schemes between 1st November 2013 and 30th November 2016. Our primary outcome was death, which we analysed in subgroups of 10th version international classification of disease (ICD-10) specific deaths; and deaths from amenable causes. We compared our results to a sample of people living in areas of high social deprivation (IMD5 group). Results: We collected data on 3,882 individual homeless hospital admissions that were linked to 600 deaths. The median age of death was 51.6 years (interquartile range 42.7-60.2) for SIHHC and 71.5 for the IMD5 (60.67-79.0).  The top three underlying causes of death by ICD-10 chapter in the SIHHC group were external causes of death (21.7%; 130/600), cancer (19.0%; 114/600) and digestive disease (19.0%; 114/600).  The percentage of deaths due to an amenable cause after age and sex weighting was 30.2% in the homeless SIHHC group (181/600) compared to 23.0% in the IMD5 group (578/2,512). Conclusion: Nearly one in three homeless deaths were due to causes amenable to timely and effective health care. The high burden of amenable deaths highlights the extreme health harms of homelessness and the need for greater emphasis on prevention of homelessness and early healthcare interventions

Outcomes of specialist discharge coordination and intermediate care schemes for patients who are homeless: analysis protocol for a population-based historical cohort

Introduction People who are homeless often experience poor hospital discharge arrangements, reflecting ongoing care and housing needs. Specialist integrated homeless health and care provision (SIHHC) schemes have been developed and implemented to facilitate the safe and timely discharge of homeless patients from hospital. Our study aims to investigate the health outcomes of patients who were homeless and seen by a selection of SIHHC services. Methods and analysis Our study will employ a historical population-based cohort in England. We will examine health outcomes among three groups of adults: (1) homeless patients seen by specialist discharge schemes during their hospital admission; (2) homeless patients not seen by a specialist scheme and (3)admitted patients who live in deprived neighbourhoods and were not recorded as being homeless. Primary outcomes will be: time from discharge to next hospital inpatient admission; time from discharge to next accident and emergency attendance and 28-day emergency readmission. Outcome data will be generated through linkage to hospital admissions data (Hospital Episode Statistics) and mortality data for November 2013 to November 2016. Multivariable regression will be used to model the relationship between the study comparison groups and each of the outcomes. Ethics and dissemination Approval has been obtained from the National Health Service (NHS) Confidentiality Advisory Group (reference 16/CAG/0021) to undertake this work using unconsented identifiable data. Health Research Authority Research Ethics approval (REC 16/EE/0018) has been obtained in addition to local research and development approvals for data collection at NHS sites. We will feedback the results of our study to our advisory group of people who have lived experience of homelessness and seek their suggestions on ways to improve or take this work further for their benefit. We will disseminate our findings to SIHHC schemes through a series of regional workshops

The first ever anti-football painting: A consideration of the soccer match in John Singer Sargent’s "Gassed"

The paper presents a discussion of Gassed, a large oil painting by John Singer Sargent displayed at the Imperial War Museum in London. Completed in 1919, Gassed is the major achievement from Sargent’s commission as an official war artist at the appointment of the British War Memorials Committee during the latter period of World War I. Prominent in the painting is a group of soldiers, blinded by a mustard gas attack, being lead to a casualty clearing station tent. In the distant background of the painting, another group of soldiers can be seen kitted out in football attire playing a match. The significance of this football imagery is our point of enquiry. As our title suggests, some recent interpretations regard the painting as offering critical reflection, from the time, about the symbolic links between sport and war. However, while the painting may certainly be left open to this type of viewer interpretation, archival and secondary resource material research does not support such a critical intention by the artist. Yet, nor is there evidence that Sargent’s intention was the projection of war-heroism. Rather, Sargent’s endeavour to faithfully represent what he observed allows Gassed to be regarded as a visual record of routine activity behind the lines and of football as an aspect of the daily life of British soldiers during the Great War

Perspective: The Role of Cryopreservation Techniques in Manufacturing, Transport, and Storage of Car-T Therapy Products

Several clinical trials have proved the efficacy and safety of T-cells chimeric antigen receptor (CAR-T cells) in treatment of malignant lymphoma and the first products were registered in the European Union in 2018. The shelf-life of CAR-T cell products in the liquid state is short, so cryopreservation offers a significant benefit for logistics in manufacturing and patient management. Direct shipment of the cryopreserved CAR-T cell therapy products to the clinical department is feasible, nevertheless, intermediate storage in the hospital cryostorage facility gives significant advantage in planning of their administration to patients. Moreover, some manufacturers prefer transport of the starting material cryopreserved at the collection site. The cryopreservation protocol used for starting material by the authors is based on combining dimethyl sulphoxide (DMSO) with hydroxyethyl starch (HES) and slow controlled cooling in cryobags housed in metal cassettes. This achieves the mononuclear cell post-thaw viability of 98.8 ± 0.5 % and recovery of 72.8, ± 10.2 %. Transport of the starting material to the manufactures and return transport of the CAR-T therapy product is performed by authorized courier companies. Intermediate cryostorage of the final CAR-T cell therapy product is performed in a separate dry-storage liquid nitrogen container. On the day of infusion, the cryopreserved products are transported to the clinical department in a dry shipper. On the wards the product is removed from the cassette, inserted into a sterile plastic bag, thawed in a 37 °C water bath followed by immediate intravenous administration. The authors discuss the adherence of the used technology to good manufacturing practice (GMP) principles and genetic safety assurance rules

Homelessness and integrated care: an application of integrated care knowledge to understanding services for wicked issues

Purpose: People experiencing homelessness often have complex needs requiring a range of support. These may include health problems (physical illness, mental health and/or substance misuse) as well as social, financial and housing needs. Addressing these issues requires a high degree of coordination amongst services. It is, thus, an example of a wicked policy issue. The purpose of this paper is to examine the challenge of integrating care in this context using evidence from an evaluation of English hospital discharge services for people experiencing homelessness. Design/methodology/approach: The paper undertakes secondary analysis of qualitative data from a mixed methods evaluation of hospital discharge schemes and uses an established framework for understanding integrated care, the Rainbow Model of Integrated Care (RMIC), to help examine the complexities of integration in this area. Findings: Supporting people experiencing homelessness to have a good discharge from hospital was confirmed as a wicked policy issue. The RMIC provided a strong framework for exploring the concept of integration, demonstrating how intertwined the elements of the framework are and, hence, that solutions need to be holistically organised across the RMIC. Limitations to integration were also highlighted, such as shortages of suitable accommodation and the impacts of policies in aligned areas of the welfare state. Research limitations/implications: The data for this secondary analysis were not specifically focussed on integration which meant the themes in the RMIC could not be explored directly nor in as much depth. However, important issues raised in the data directly related to integration of support, and the RMIC emerged as a helpful organising framework for understanding integration in this wicked policy context. Practical implications: Integration is happening in services directly concerned with the discharge from hospital of people experiencing homelessness. Key challenges to this integration are reported in terms of the RMIC, which would be a helpful framework for planning better integrated care for this area of practice. Social implications: Addressing homelessness not only requires careful planning of integration of services at specific pathway points, such as hospital discharge, but also integration across wider systems. A complex set of challenges are discussed to help with planning the better integration desired, and the RMIC was seen as a helpful framework for thinking about key issues and their interactions. Originality/value: This paper examines an application of integrated care knowledge to a key complex, or wicked policy issue

Improving hospital discharge arrangements for people who are homeless: a realist synthesis of the intermediate care literature

This review presents a realist synthesis of “what works and why” in intermediate care for people who are homeless. The overall aim was to update an earlier synthesis of intermediate care by capturing new evidence from a recent UK government funding initiative (the “Homeless Hospital Discharge Fund”). The initiative made resources available to the charitable sector to enable partnership working with the National Health Service (NHS) in order to improve hospital discharge arrangements for people who are homeless. The synthesis adopted the RAMESES guidelines and reporting standards. Electronic searches were carried out for peer-reviewed articles published in English from 2000 to 2016. Local evaluations and the grey literature were also included. The inclusion criteria was that articles and reports should describe “interventions” that encompassed most of the key characteristics of intermediate care as previously defined in the academic literature. Searches yielded 47 articles and reports. Most of these originated in the UK or the USA and fell within the realist quality rating of “thick description”. The synthesis involved using this new evidence to interrogate the utility of earlier programme theories. Overall, the results confirmed the importance of (i) collaborative care planning, (ii) reablement and (iii) integrated working as key to effective intermediate care delivery. However, the additional evidence drawn from the field of homelessness highlighted the potential for some theory refinements. First, that “psychologically informed” approaches to relationship building may be necessary to ensure that service users are meaningfully engaged in collaborative care planning and second, that integrated working could be managed differently so that people are not “handed over” at the point at which the intermediate care episode ends. This was theorised as key to ensuring that ongoing care arrangements do not break down and that gains are not lost to the person or the system vis-à-vis the prevention of readmission to hospital

Supramammillary glutamate neurons are a key node of the arousal system

Basic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report that glutamate-releasing neurons of the supramammillary region (SuMvglut2) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuMvglut2 neurons. Inhibition of SuMvglut2 neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuMvglut2 neurons include a subpopulation containing both glutamate and GABA (SuMvgat/vglut2) and another also expressing nitric oxide synthase (SuMNos1/Vglut2). Activation of SuMvgat/vglut2 neurons produces minimal wake and optogenetic stimulation of SuMvgat/vglut2 terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuMNos1/Vglut2 neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuMvglut2 neurons as a key node of the wake−sleep regulatory system

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Lanthanoid “Bottlebrush” Clusters: Remarkably Elongated Metal-Oxo Core Structures with Controllable Lengths

Large metal-oxo clusters consistently assume spherical or regular polyhedral morphologies rather than high-aspect-ratio structures. Access to elongated core structures has now been achieved by the reaction of lanthanoid salts with a tetrazole-functionalized calixarene in the presence of a simple carboxylate coligand.The resulting Ln19 and Ln12 clusters are constructed from apex-fused Ln5O6 trigonal bipyramids and are formed consistently under a range of reaction conditions and reagent ratios. Altering the carboxylate coligandstructure reliably controls the cluster length, giving access to a new class of rod-like clusters of variable length