Public responses to precautionary information from the department of health (UK) about possible health risks from mobile phones

Understanding public perceptions of health information is of increasing importance in the light of the growing imperatives upon regulators to communicate information about risk and uncertainty. Communicating the possible health risks from mobile telecommunications is a domain that allows consideration of both public perceptions of uncertain public health information and public responses to precautionary advice. This research reports the results of a nationally representative survey in the UK (n = 1742) that explored public responses to a leaflet issued by the Department of Health (DoH) in 2000 providing information about the possible health risks of mobile phones. The aims of the study were twofold: a) to assess awareness of the leaflet and the extent to which participants could identify the precautionary advice that the leaflet contained as coming from the Government; and b) to examine publics’ responses to the current Government precautionary advice about mobile phone health risks; was this associated with increased concern or reassurance? The results indicate the importance of policy makers developing a clear understanding of the possible effects of communicating precautionary advice.Mobile Telecommunications and Health Research Programm

Sidus Stem-Free Shoulder System for primary osteoarthritis: short-term results of a multicenter study

BACKGROUND: The aim of this prospective multicenter study was to evaluate clinical and radiologic results of a new metaphyseal anchored system. This system features a different anchor geometry that potentially leads to better bony integration and less loosening. METHODS: From November 2012 until December 2015, 148 patients (151 shoulders) were treated with the Sidus Stem-Free Shoulder System at 9 centers in Europe. The main indication was primary osteoarthritis (80.1%). This analysis only includes patients diagnosed with primary osteoarthritis (n = 121). A clinical evaluation was performed using the Constant-Murley score, Subjective Shoulder Value, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form, and range of motion. Radiologic assessment was based on the occurrence of radiolucent lines and signs of implant migration, osteolysis, loosening, and heterotopic ossification. RESULTS: We evaluated 105 patients after a follow-up period of 2 years. There were 53 women and 52 men. The average age was 64 years. Total shoulder arthroplasty was performed in 73 cases and hemiarthroplasty in 32. The Constant-Murley score improved from 26 points preoperatively to 70 points at 2 years' follow-up (P < .001). The Subjective Shoulder Value increased from 34% to 84% (P < .001), and the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form increased from 34 points to 86 points (P < .001). Radiologically, neither migration nor loosening was found. However, radiolucent lines of 2 mm or greater could be detected around the glenoid in 2 cases, but none of them have had clinical relevance yet. The overall complication rate was 6.7%, and the revision rate was 0%. CONCLUSION: Patients with the Sidus Stem-Free Shoulder System achieve good clinical and radiologic short-term results that are comparable with the results of other stem-free shoulder implants

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Mapping site and disease specific modulation of epithelial differentiation programs

Skin specializes in a regional-specific manner, including the formation of distinct types of epidermally-derived glands during development, such as sweat glands in palmoplantar skin, sebaceous glands in hair-bearing skin, and meibomian glands in the eyelid. Our goal is to understand this regional specification. Palmoplantar skin is structurally and functionally unique, but transcriptional programs driving this specialization are unclear. Here, we use bulk and single-cell RNA sequencing of human palm, sole, and hip skin to describe the distinguishing characteristics of palmoplantar skin while also uncovering differences between palmar and plantar sites. Our approach reveals an altered immune environment in palmoplantar skin, with downregulation of diverse immunological processes and decreased immune populations. Further, we identify specific fibroblast populations that appear to orchestrate key differences in cell-cell communication in palm, sole, and hip. Dedicated keratinocyte analysis highlights major differences in basal cell fraction across three sites and demonstrates the existence of two spinous keratinocyte populations constituting parallel, site-selective epidermal differentiation trajectories. In summary, this deep characterization of highly adapted palmoplantar skin contributes key insights into the fundamental biology of human skin and provides a valuable data resource.In the eyelid, meibomian glands have received interest based on the association of observable gland dysfunction with dry eye disease. In particular, gland atrophy and changes in lipid quality are recognized as causing abnormal tear film break-up, leading to hyperosmolarity of the ocular surface, corneal epithelial damage and ocular surface inflammation. Here, we use single-cell and spatial transcriptomic approaches to characterize and spatially map the murine eyelid, with a particular focus on the meibomian gland. We identify sequential activation of lipid synthesis factors in meibocyte differentiation at the single cell level which we then validate spatially. Next, using an Awat2 KO mouse model, we characterize transcriptomic alterations, including an increase in immune populations and activation of psoriasis-like inflammatory pathways during meibomian gland dysfunction. Within the meibomian gland, we find marked expansion of the ductal epithelia and a shift in the meibocyte differentiation program. Finally, we identify a heightened immune environment in the aging eyelid, which is consistent both in healthy and KO mice

Human γδ T lymphocytes strip and kill tumor cells simultaneously

International audienceWhen human gammadelta lymphocytes bind to tumor cells for killing, they also strip their membrane for unknown reasons. Here we investigated this topic using the model of human gammadelta lymphocytes co-incubated with anaplastic large cell lymphomas, a group of tumors with cytolytic T or null lineage. By using flow cytometry and live cell imaging, we show that as soon as both cells were in contact, the TCR-mediated activation of gammadelta lymphocytes simultaneously triggered their secretion of lytic granules and stripping of lymphoma cell membranes, and both activities continued even after their cell death. However reciprocally in such conjugates, resistant lymphoma failed to strip gammadelta cells and to kill them by untargeted secretion of their own lytic granules. This indicated that secretion of lytic granules and target membrane stripping are associated in lytic cell conjugates, and that gammadelta T lymphocytes strip and kill their targets simultaneously

Use of RNA interference in Drosophila S2 cells to identify host pathways controlling compartmentalization of an intracellular pathogen

International audienc

IRX5 promotes DNA damage repair and activation of hair follicle stem cells

The molecular mechanisms allowing hair follicles to periodically activate their stem cells (HFSCs) are incompletely characterized. Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice have delayed anagen onset, with increased DNA damage and diminished HFSC proliferation. Open chromatin regions form near cell cycle progression and DNA damage repair genes in Irx5-/- HFSCs. DNA damage repair factor BRCA1 is an IRX5 downstream target. Inhibition of FGF kinase signaling partially rescues the anagen delay in Irx5-/- mice, suggesting that the Irx5-/- HFSC quiescent phenotype is partly due to failure to suppress Fgf18 expression. Interfollicular epidermal stem cells also show decreased proliferation and increased DNA damage in Irx5-/-mice. Consistent with a role for IRX5 as a promoter of DNA damage repair, we find that IRX genes are upregulated in many cancer types and that there is a correlation between IRX5 and BRCA1 expression in breast cancer