A randomised controlled trial of an exercise intervention promoting activity, independence and stability in older adults with mild cognitive impairment and early dementia (PrAISED) – A Protocol

© 2019 The Author(s). Background: People with dementia progressively lose cognitive and functional abilities. Interventions promoting exercise and activity may slow decline. We developed a novel intervention to promote activity and independence and prevent falls in people with mild cognitive impairment (MCI) or early dementia. We successfully undertook a feasibility randomised controlled trial (RCT) to refine the intervention and research delivery. We are now delivering a multi-centred RCT to evaluate its clinical and cost-effectiveness. Methods: We will recruit 368 people with MCI or early dementia (Montreal Cognitive Assessment score 13-25) and a family member or carer from memory assessment clinics, other community health or social care venues or an online register (the National Institute for Health Research Join Dementia Research). Participants will be randomised to an individually tailored activity and exercise programme delivered using motivational theory to promote adherence and continued engagement, with up to 50 supervised sessions over one year, or a brief falls prevention assessment (control). The intervention will be delivered in participants' homes by trained physiotherapists, occupational therapists and therapy assistants. We will measure disabilities in activities of daily living, physical activity, balance, cognition, mood, quality of life, falls, carer strain and healthcare and social care use. We will use a mixed methods approach to conduct a process evaluation to assess staff training and delivery of the intervention, and to identify individual- and context-level mechanisms affecting intervention engagement and activity maintenance. We will undertake a health economic evaluation to determine if the intervention is cost-effective. Discussion: We describe the protocol for a multi-centre RCT that will evaluate the clinical and cost-effectiveness of a therapy programme designed to promote activity and independence amongst people living with dementia. Trial registration: ISRCTN, ISRCTN15320670. Registered on 4 September 2018

Mapping post-glacial expansions: The peopling of Southwest Asia

Archaeological, palaeontological and geological evidence shows that post-glacial warming released human populations from their various climate-bound refugia. Yet specific connections between these refugia and the timing and routes of post-glacial migrations that ultimately established modern patterns of genetic variation remain elusive. Here, we use Y-chromosome markers combined with autosomal data to reconstruct population expansions from regional refugia in Southwest Asia. Populations from three regions in particular possess distinctive autosomal genetic signatures indicative of likely refugia: one, in the north, centered around the eastern coast of the Black Sea, the second, with a more Levantine focus, and the third in the southern Arabian Peninsula. Modern populations from these three regions carry the widest diversity and may indeed represent the most likely descendants of the populations responsible for the Neolithic cultures of Southwest Asia. We reveal the distinct and datable expansion routes of populations from these three refugia throughout Southwest Asia and into Europe and North Africa and discuss the possible correlations of these migrations to various cultural and climatic events evident in the archaeological record of the past 15,000 years

Searches for Cosmic-Ray Electron Anisotropies with the Fermi Large Area Telescope

The Large Area Telescope on board the \textit{Fermi} satellite (\textit{Fermi}-LAT) detected more than 1.6 million cosmic-ray electrons/positrons with energies above 60 GeV during its first year of operation. The arrival directions of these events were searched for anisotropies of angular scale extending from $\sim$ 10 $^\circ$ up to 90$^\circ$, and of minimum energy extending from 60 GeV up to 480 GeV. Two independent techniques were used to search for anisotropies, both resulting in null results. Upper limits on the degree of the anisotropy were set that depended on the analyzed energy range and on the anisotropy's angular scale. The upper limits for a dipole anisotropy ranged from $\sim0.5$ to $\sim10$.Comment: 16 pages, 10 figures, accepted for publication in Physical Review D - contact authors: M.N. Mazziotta and V. Vasileio

Fermi observations of TeV-selected AGN

We report on observations of TeV-selected AGN made during the first 5.5 months of observations with the Large Area Telescope (LAT) on-board the Fermi Gamma-ray Space Telescope (Fermi). In total, 96 AGN were selected for study, each being either (i) a source detected at TeV energies (28 sources) or (ii) an object that has been studied with TeV instruments and for which an upper-limit has been reported (68 objects). The Fermi observations show clear detections of 38 of these TeV-selected objects, of which 21 are joint GeV-TeV sources and 29 were not in the third EGRET catalog. For each of the 38 Fermi-detected sources, spectra and light curves are presented. Most can be described with a power law of spectral index harder than 2.0, with a spectral break generally required to accommodate the TeV measurements. Based on an extrapolation of the Fermi spectrum, we identify sources, not previously detected at TeV energies, which are promising targets for TeV instruments. Evidence for systematic evolution of the $\gamma$-ray spectrum with redshift is presented and discussed in the context of interaction with the EBL.Comment: 51 pages, 6 figures, accepted for The Astronomical Journa

Fermi Large Area Telescope Measurements of the Diffuse Gamma-Ray Emission at Intermediate Galactic Latitudes

The diffuse Galactic gamma-ray emission is produced by cosmic rays (CRs) interacting with the interstellar gas and radiation field. Measurements by the Energetic Gamma-Ray Experiment Telescope (EGRET) instrument on the Compton Gamma-Ray Observatory indicated excess gamma-ray emission > 1 GeV relative to diffuse Galactic gamma-ray emission models consistent with directly measured CR spectra (the so-called ``EGRET GeV excess''). The excess emission was observed in all directions on the sky, and a variety of explanations have been proposed, including beyond-the-Standard-Model scenarios like annihilating or decaying dark matter. The Large Area Telescope (LAT) instrument on the Fermi Gamma-ray Space Telescope has measured the diffuse gamma-ray emission with improved sensitivity and resolution compared to EGRET. We report on LAT measurements of the diffuse gamma-ray emission for energies 100 MeV to 10 GeV and Galactic latitudes 10 deg. <= |b| <= 20 deg. The LAT spectrum for this region of the sky is well reproduced by a diffuse Galactic gamma-ray emission model that is consistent with local CR spectra and inconsistent with the EGRET GeV excess.Comment: 2 figures, 1 table, accepted by Physical Review Letters, available online Dec. 18th, 200

Fermi Large Area Telescope Gamma-Ray Detection of the Radio Galaxy M87

We report the Fermi-LAT discovery of high-energy (MeV/GeV) gamma-ray emission positionally consistent with the center of the radio galaxy M87, at a source significance of over 10 sigma in ten-months of all-sky survey data. Following the detections of Cen A and Per A, this makes M87 the third radio galaxy seen with the LAT. The faint point-like gamma-ray source has a >100 MeV flux of 2.45 (+/- 0.63) x 10^-8 ph cm^-2 s^-1 (photon index = 2.26 +/- 0.13) with no significant variability detected within the LAT observation. This flux is comparable with the previous EGRET upper limit (< 2.18 x 10^-8 ph cm^-2 s^-1, 2 sigma), thus there is no evidence for a significant MeV/GeV flare on decade timescales. Contemporaneous Chandra and VLBA data indicate low activity in the unresolved X-ray and radio core relative to previous observations, suggesting M87 is in a quiescent overall level over the first year of Fermi-LAT observations. The LAT gamma-ray spectrum is modeled as synchrotron self-Compton (SSC) emission from the electron population producing the radio-to-X-ray emission in the core. The resultant SSC spectrum extrapolates smoothly from the LAT band to the historical-minimum TeV emission. Alternative models for the core and possible contributions from the kiloparsec-scale jet in M87 are considered, and can not be excluded.Comment: ApJ, accepted, 6 pages, 4 figures. Corresponding authors: C.C. Cheung, W. McConvill

Novel optics-based approaches for cardiac electrophysiology: a review

Optical techniques for recording and manipulating cellular electrophysiology have advanced rapidly in just a few decades. These developments allow for the analysis of cardiac cellular dynamics at multiple scales while largely overcoming the drawbacks associated with the use of electrodes. The recent advent of optogenetics opens up new possibilities for regional and tissue-level electrophysiological control and hold promise for future novel clinical applications. This article, which emerged from the international NOTICE workshop in 20181, reviews the state-of-the-art optical techniques used for cardiac electrophysiological research and the underlying biophysics. The design and performance of optical reporters and optogenetic actuators are reviewed along with limitations of current probes. The physics of light interaction with cardiac tissue is detailed and associated challenges with the use of optical sensors and actuators are presented. Case studies include the use of fluorescence recovery after photobleaching and super-resolution microscopy to explore the micro-structure of cardiac cells and a review of two photon and light sheet technologies applied to cardiac tissue. The emergence of cardiac optogenetics is reviewed and the current work exploring the potential clinical use of optogenetics is also described. Approaches which combine optogenetic manipulation and optical voltage measurement are discussed, in terms of platforms that allow real-time manipulation of whole heart electrophysiology in open and closed-loop systems to study optimal ways to terminate spiral arrhythmias. The design and operation of optics-based approaches that allow high-throughput cardiac electrophysiological assays is presented. Finally, emerging techniques of photo-acoustic imaging and stress sensors are described along with strategies for future development and establishment of these techniques in mainstream electrophysiological research

Logical Development of the Cell Ontology

<p>Abstract</p> <p>Background</p> <p>The Cell Ontology (CL) is an ontology for the representation of <it>in vivo </it>cell types. As biological ontologies such as the CL grow in complexity, they become increasingly difficult to use and maintain. By making the information in the ontology computable, we can use automated reasoners to detect errors and assist with classification. Here we report on the generation of computable definitions for the hematopoietic cell types in the CL.</p> <p>Results</p> <p>Computable definitions for over 340 CL classes have been created using a genus-differentia approach. These define cell types according to multiple axes of classification such as the protein complexes found on the surface of a cell type, the biological processes participated in by a cell type, or the phenotypic characteristics associated with a cell type. We employed automated reasoners to verify the ontology and to reveal mistakes in manual curation. The implementation of this process exposed areas in the ontology where new cell type classes were needed to accommodate species-specific expression of cellular markers. Our use of reasoners also inferred new relationships within the CL, and between the CL and the contributing ontologies. This restructured ontology can be used to identify immune cells by flow cytometry, supports sophisticated biological queries involving cells, and helps generate new hypotheses about cell function based on similarities to other cell types.</p> <p>Conclusion</p> <p>Use of computable definitions enhances the development of the CL and supports the interoperability of OBO ontologies.</p