Supervised exercise delivered via telehealth in real time to manage chronic conditions in adults: a protocol for a scoping review to inform future research in stroke survivors

Introduction: Increasing physical activity reduces secondary stroke risk factors, but many stroke survivors have low levels of physical activity. Supervised exercise delivered via telehealth has the potential to overcome barriers to increased physical activity in stroke survivors. Our scoping review will examine the emerging field of supervised exercise delivered via telehealth to map the available evidence in relation to its efficacy, acceptability, safety and feasibility in chronic conditions to inform future research into its ability to increase physical activity. Methods and Analysis: The methodological framework of Arksey and O'Malley will be applied to our scoping review. A systematic search of Medline, CINAHL, Scopus, Cochrane, Pedro and Embase; hand searching of pertinent studies' reference lists; and consultation with experts in the field will identify relevant papers. Studies involving participants with a chronic condition who undertake supervised exercise delivered by a health professional via telehealth targeted at improving secondary stroke risk factors or involving lower limb weight-bearing exercise will be included. Study selection and critical appraisal of individual studies will be carried out independently by two authors with discrepancies resolved by a third author. Quantitative and qualitative data will be charted using a standardised form. Results will be tabulated and narratively summarised to highlight findings relevant to the review's research questions and to inform recommendations for future research. Ethics and Dissemination: Our review will significantly contribute to the knowledge base of exercise and rehabilitation delivered via telehealth and its application in chronic conditions, including stroke. Findings will be relevant to researchers, healthcare workers and policy-makers and will be disseminated through publication and presentations. Only secondary deidentified data will be included, therefore ethics approval will not be sought. This protocol is not registered as PROSPERO currently excludes scoping reviews.Emily R Ramage, Natalie A Fini, Elizabeth A Lynch, Amanda Patterson, Catherine M Said, Coralie Englis

Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway

During early brain development, N-methyl-d-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog

Novel Druggable Hot Spots in Avian Influenza Neuraminidase H5N1 Revealed by Computational Solvent Mapping of a Reduced and Representative Receptor Ensemble

The influenza virus subtype H5N1 has raised concerns of a possible human pandemic threat because of its high virulence and mutation rate. Although several approved anti-influenza drugs effectively target the neuraminidase, some strains have already acquired resistance to the currently available anti-influenza drugs. In this study, we present the synergistic application of extended explicit solvent molecular dynamics (MD) and computational solvent mapping (CS-Map) to identify putative ‘hot spots’ within flexible binding regions of N1 neuraminidase. Using representative conformations of the N1 binding region extracted from a clustering analysis of four concatenated 40-ns MD simulations, CS-Map was utilized to assess the ability of small, solvent-sized molecules to bind within close proximity to the sialic acid binding region. Mapping analyses of the dominant MD conformations reveal the presence of additional hot spot regions in the 150- and 430-loop regions. Our hot spot analysis provides further support for the feasibility of developing high-affinity inhibitors capable of binding these regions, which appear to be unique to the N1 strain

Cold War : a Transnational Approach to a Global Heritage

Although within living memory, many countries now consider their surviving Cold War architecture as part of their heritage. It can even be a priority for heritage managers given that significant buildings are often suitable for reuse while extensive ‘brownfield’ sites such as airfields can be used for large-scale redevelopment. In a number of countries whose work we refer to here (notably the United Kingdom and elsewhere in Europe), agencies responsible for managing their country’s heritage have approached this priority by creating national inventories of sites and buildings with a view to taking informed decisions on their future. This paper presents the argument that the wider international context of the Cold War provides a more appropriate (or additional, higher-level) framework for such decision making. Such a ‘transnational’ approach would allow the comparison of similar (e.g. European) sites not merely within national borders but across the full extent of their western NATO1 deployment in Europe and North America. Taking this approach would also allow comparison with related sites in countries that formed part of the eastern-bloc Warsaw Pact.2 After outlining some examples of how national agencies have approached their Cold War heritage, this paper presents the four stages of this transnational approach making provision for an improved understanding and management of Cold War heritage sites wherever they occur. With a specific focus on the direct comparison between England and Russia, and also referring to sites surviving elsewhere within the former NATO and Warsaw Pact regions, as well as the United States, we argue that this four-stage approach: provides new understandings of a complex archaeological and architectural record; gives fresh perspectives on significance; and (importantly in a time of geopolitical instability) does so in a spirit of cooperation and friendship

Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Objectives: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. Methods: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105–377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. Results: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). Conclusion: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease