The MRI colonic function test: Reproducibility of the Macrogol stimulus challenge

Background Magnetic resonance imaging (MRI) of the colonic response to a macrogol challenge drink can be used to assess the mechanisms underlying severe constipation. We measured the intra-subject reproducibility of MRI measures of colonic function to aid their implementation as a possible clinical test. Methods Healthy participants attended for MRI on two occasions (identical protocols, minimum 1 week apart). They underwent a fasted scan then consumed the macrogol drink. Subjects were scanned at 60 and 120 minutes, with maximum value reached used for comparison. The colonic volume, water content, mixing of colonic content and the movement of the colon walls were measured. Coefficients of variation and intraclass correlation coefficients (ICC) were calculated. Results 12 participants completed the study: 9 female, mean age 26 years (SD 5) and body mass index 24.8kg/m2 (SD 3.2). All measures consistently increased above baseline following provocation with macrogol. The volume, water content and content mixing had good intra-subject reproducibility (ICC volume=0.84, water content=0.93, mixing=0.79,

Whole-Retina Reduced Electrophysiological Activity in Mice Bearing Retina-Specific Deletion of Vesicular Acetylcholine Transporter

Background: Despite rigorous characterization of the role of acetylcholine in retinal development, long-term effects of its absence as a neurotransmitter are unknown. One of the unanswered questions is how acetylcholine contributes to the functional capacity of mature retinal circuits. The current study investigates the effects of disrupting cholinergic signalling in mice, through deletion of vesicular acetylcholine transporter (VAChT) in the developing retina, pigmented epithelium, optic nerve and optic stalk, on electrophysiology and structure of the mature retina. Methods & Results A combination of electroretinography, optical coherence tomography imaging and histological evaluation assessed retinal integrity in mice bearing retina-targeted (embryonic day 12.5) deletion of VAChT (VAChT(Six3-Cre-flox/flox)) and littermate controls at 5 and 12 months of age. VAChT(Six3-Cre-flox/flox) mice did not show any gross changes in nuclear layer cellularity or synaptic layer thickness. However, VAChT(Six3-Cre-flox/flox) mice showed reduced electrophysiological response of the retina to light stimulus under scotopic conditions at 5 and 12 months of age, including reduced a-wave, b-wave, and oscillatory potential (OP) amplitudes and decreased OP peak power and total energy. Reduced a-wave amplitude was proportional to the reduction in b-wave amplitude and not associated with altered a-wave 10%-90% rise time or inner and outer segment thicknesses. Significance This study used a novel genetic model in the first examination of function and structure of the mature mouse retina with disruption of cholinergic signalling. Reduced amplitude across the electroretinogram wave form does not suggest dysfunction in specific retinal cell types and could reflect underlying changes in the retinal and/or extraretinal microenvironment. Our findings suggest that release of acetylcholine by VAChT is essential for the normal electrophysiological response of the mature mouse retina

Tourists’ Attitudes towards Linguistic Variation in Scotland

This paper joins studies of linguistic variation (e.g. Labov 1972; Dubois & Horvath 2000) and discourse (e.g. Jaworski & Lawson 2005; Jaworski & Pritchard 2005; Thurlow & Jaworski 2010) that consider the intersection between language and tourism. By examining the language attitudes that tourists hold toward linguistic variability in their host community, we find that attitudes differ by context and with respect to tourists’ travel motivations. We suggest that these results are particularly likely in a context like Edinburgh, Scotland, where linguistic variation has an iconic link to place authenticity. We propose that the joint commodification of ‘intelligibility’ and ‘authenticity’ explains this variability. The results raise questions about how the commodity value of travel motivation and the associated context of language use influence language attitudes

Heme oxygenase-1 deficiency alters erythroblastic Island formation, steady-state erythropoiesis and red blood cell lifespan in mice

Heme oxygenase-1 is critical for iron recycling during red blood cell turnover, whereas its impact on steady-state erythropoiesis and red blood cell lifespan is not known. We show here that in 8- to 14-week old mice, heme oxygenase- 1 deficiency adversely affects steady-state erythropoiesis in the bone marrow. This is manifested by a decrease in Ter-119+-erythroid cells, abnormal adhesion molecule expression on macrophages and erythroid cells, and a greatly diminished ability to form erythroblastic islands. Compared with wild-type animals, red blood cell size and hemoglobin content are decreased, while the number of circulating red blood cells is increased in heme oxygenase-1 deficient mice, overall leading to microcytic anemia. Heme oxygenase-1 deficiency increases oxidative stress in circulating red blood cells and greatly decreases the frequency of macrophages expressing the phosphatidylserine receptor Tim4 in bone marrow, spleen and liver. Heme oxygenase-1 deficiency increases spleen weight and Ter119+-erythroid cells in the spleen, although α4β1-integrin expression by these cells and splenic macrophages positive for vascular cell adhesion molecule 1 are both decreased. Red blood cell lifespan is prolonged in heme oxygenase-1 deficient mice compared with wild-type mice. Our findings suggest that while macrophages and relevant receptors required for red blood cell formation and removal are substantially depleted in heme oxygenase- 1 deficient mice, the extent of anemia in these mice may be ameliorated by the prolonged lifespan of their oxidatively stressed erythrocytes

Sociolinguistics of Style and Social Class in Contemporary Athens

This ethnographic study deals with the ways people in Athens, Greece, use style to construct their social class identities. Including a rich dataset comprising ethnographic interviews with actual people who live in the stereotypically seen as leafy and posh northern suburbs and in the stereotypically treated as working class western suburbs of Athens coupled with data from popular literary novels, TV series and Greek hip hop music, it argues that the relationship between style and social class identity is mediated by complex social meanings encompassing features from and discourses relevant to both areas, which are structured across different orders of indexicality depending on the genre of speech in which they are created. As such, it will be of interest to scholars in sociolinguistics, discourse analysis, anthropology, sociology, Modern Greek studies, and to everyone who is interested in how social class is constructed via language.Greek State Scholarships Foundation, Onassis Public Benefit Fund, Foundation for Education and European Cultur

The Photopic Negative Response: An Objective Measure of Retinal Ganglion Cell Function in Patients With Leber's Hereditary Optic Neuropathy

Purpose: The photopic negative response (PhNR) is a slow negative component of a flash photopic full-field ERG that has been shown to be specific for retinal ganglion cell (RGC) activity. Direct evaluation of RGC function is desirable in patients with Leber's hereditary optic neuropathy (LHON) in which the loss of central acuity can make it difficult to monitor patients with standard metrics. The purpose of this study was to evaluate the use of PhNR as an objective noninvasive clinical metric in LHON.Methods: Full-field photopic ERG recordings were collected in subjects with the mt.11778G>A/ND4 LHON mutation using a red on blue stimulus. The PhNR was identified using a computer-based automated detection system, and data were manually examined to remove movement artifacts.Results: The PhNR amplitude was compared between controls (n = 13), carriers (n = 17), and affected (n = 6). Mean PhNR amplitude decreased significantly across groups (P < 0.0001). Post hoc Tukey's test revealed a significant decrease in PhNR amplitude between carriers and controls (P < 0.05) and between carriers and affected (P < 0.01).Conclusions: We are able to demonstrate that the PhNR amplitude is significantly decreased in patients affected by LHON compared to carriers in a well-described pedigree. Surprisingly, there was also a decrease in PhNR in carriers, suggesting potential subclinical RGC dysfunction in some carriers. This is important in patients affected with LHON who typically have a dense central scotoma. The PhNR may be a useful objective outcome measure for future clinical trials

Underrepresentation of Elderly People in Randomised Controlled Trials. The Example of Trials of 4 Widely Prescribed Drugs

BACKGROUND: We aimed to determine the representation of elderly people in published reports of randomized controlled trials (RCTs). We focused on trials of 4 medications--pioglitazone, rosuvastatin, risedronate, and valsartan-frequently used by elderly patients with chronic medical conditions. METHODS AND FINDINGS: We selected all reports of RCTs indexed in PubMed from 1966 to April 2008 evaluating one of the 4 medications of interest. Estimates of the community-based "on-treatment" population were from a national health insurance database (SNIIR-AM) covering approximately 86% of the population in France. From this database, we evaluated data claims from January 2006 to December 2007 for 1,958,716 patients who received one of the medications of interest for more than 6 months. Of the 155 RCT reports selected, only 3 studies were exclusively of elderly patients (2 assessing valsartan; 1 risedronate). In only 4 of 37 reports (10.8%) for pioglitazone, 4 of 22 (18.2%) for risedronate, 3 of 29 (10.3%) for rosuvastatine and 9 of 67 (13.4%) for valsartan, the proportion of patients aged 65 or older was within or above that treated in clinical practice. In 62.2% of the reports for pioglitazone, 40.9% for risedronate, 37.9% for rosuvastatine, and 70.2% for valsartan, the proportion of patients aged 65 or older was lower than half that in the treated population. The representation of elderly people did not differ by publication date or sample size. CONCLUSIONS: Elderly patients are poorly represented in RCTs of drugs they are likely to receive

Marine robots for coastal ocean research in the Western Indian Ocean

Marine robots have the potential to enhance WIO marine research to improve regional adaptation to the challenges presented by climate change by providing enhanced research capacity that bypasses the requirement for expensive infrastructure, such as large research vessels. This paper tests this potential and assesses the readiness of WIO communities to adopt autonomous technologies to meet its marine research priorities. We apply a range of analyses to a marine robots case study undertaken in waters around the island of Pemba, part of the Zanzibar archipelago, in Tanzania in 2019. The campaign formed part of a multinational project focused on increasing WIO capacity to meet food security and ocean sustainability challenges. A community engagement programme with six Tanzanian coastal communities resulted in positive changes in attitudes towards marine robots with reported increases in understanding and acceptance of such technologies. Suspicion of the robots was reduced and a lower risk of removing operational equipment was recorded following the provision of educational material. Cost, risk and benefit analysis shows that marine robots are perceived to provide high level benefits, but come at a high cost that is difficult to achieve using national or regional funding. An assessment of the capacity of WIO marine institutes to adopt such technologies shows that prior to this work, few skills or infrastructure related to marine robots were available to researchers and further confirmed that funding opportunities were perceived to be largely unavailable at institutional, national, regional or international levels. Responses from regional partners following completion of the case study however, revealed an uplift in perceived capacity, particularly related to access to infrastructure and expertise as well as support and opportunities for funding at each level. The presented case study is shown to have been a valuable demonstrator of the benefits of using marine robots to meet WIO coastal ocean research requirements and regional capacity was shown to be substantially increased within the broad range of marine institutes surveyed throughout the case study period. This study demonstrates that taking early steps towards adopting marine autonomous robots has increased WIO regional marine research capacity and increased the confidence and willingness of local researchers to seek alternative solutions to ongoing marine research challenges. Recommendations for future action that will continue to increase the capacity and readiness for regional adoption of marine robots include investment at local, national and regional levels to provide accessible training opportunities and to facilitate regional and international collaborations; investment in a regional hub, or centre of excellence for marine robotic technology; early adoption of newly emerging smaller, cheaper autonomous technologies; investment in local skills and support facilities to aid local buy-in and acceptance while supporting regional capacity

Large-scale sequencing of SARS-CoV-2 genomes from one region allows detailed epidemiology and enables local outbreak management.

The COVID-19 pandemic has spread rapidly throughout the world. In the UK, the initial peak was in April 2020; in the county of Norfolk (UK) and surrounding areas, which has a stable, low-density population, over 3200 cases were reported between March and August 2020. As part of the activities of the national COVID-19 Genomics Consortium (COG-UK) we undertook whole genome sequencing of the SARS-CoV-2 genomes present in positive clinical samples from the Norfolk region. These samples were collected by four major hospitals, multiple minor hospitals, care facilities and community organizations within Norfolk and surrounding areas. We combined clinical metadata with the sequencing data from regional SARS-CoV-2 genomes to understand the origins, genetic variation, transmission and expansion (spread) of the virus within the region and provide context nationally. Data were fed back into the national effort for pandemic management, whilst simultaneously being used to assist local outbreak analyses. Overall, 1565 positive samples (172 per 100 000 population) from 1376 cases were evaluated; for 140 cases between two and six samples were available providing longitudinal data. This represented 42.6 % of all positive samples identified by hospital testing in the region and encompassed those with clinical need, and health and care workers and their families. In total, 1035 cases had genome sequences of sufficient quality to provide phylogenetic lineages. These genomes belonged to 26 distinct global lineages, indicating that there were multiple separate introductions into the region. Furthermore, 100 genetically distinct UK lineages were detected demonstrating local evolution, at a rate of ~2 SNPs per month, and multiple co-occurring lineages as the pandemic progressed. Our analysis: identified a discrete sublineage associated with six care facilities; found no evidence of reinfection in longitudinal samples; ruled out a nosocomial outbreak; identified 16 lineages in key workers which were not in patients, indicating infection control measures were effective; and found the D614G spike protein mutation which is linked to increased transmissibility dominates the samples and rapidly confirmed relatedness of cases in an outbreak at a food processing facility. The large-scale genome sequencing of SARS-CoV-2-positive samples has provided valuable additional data for public health epidemiology in the Norfolk region, and will continue to help identify and untangle hidden transmission chains as the pandemic evolves.The sequencing costs were funded by the COVID-19 Genomics UK (COG-UK) Consortium which is supported by funding from the Medical Research Council (MRC) part of UK Research and Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute