On the interaction of observation and prior error correlations in data assimilation

The importance of prior error correlations in data assimilation has long been known, however, observation error correlations have typically been neglected. Recent progress has been made in estimating and accounting for observation error correlations, allowing for the optimal use of denser observations. Given this progress, it is now timely to ask how prior and observation error correlations interact and how this affects the value of the observations in the analysis. Addressing this question is essential to understanding the optimal design of future observation networks for high-resolution numerical weather prediction. This paper presents new results which unify and advance upon previous studies on this topic. The interaction of the prior and observation error correlations is illustrated with a series of 2-variable experiments in which the mapping between the state and observed variables (the observation operator) is allowed to vary. In an optimal system, the reduction in the analysis error variance and spread of information is shown to be greatest when the observation and prior errors have complementary statistics. For example, in the case of direct observations, when the correlations between the observation and prior errors have opposite signs. This can be explained in terms of the relative uncertainty of the observations and prior on different spatial scales. The results from these simple 2-variable experiments are used to inform the optimal observation density for observations of a circular domain (with 32 grid points). It is found that dense observations are most beneficial when they provide a more accurate estimate of the state at smaller scales than the prior estimate. In the case of second order auto-regressive correlation functions, this is achieved when the lengthscales of the observation error correlations are greater than those of the prior estimate and the observations are direct measurements of the state variables

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

LGBT ‘Communities’ and the (Self-)regulation and Shaping of Intimacy

This article draws on UK research with over 600 lesbian, gay, bisexual, and trans (LGBT+) people, funded by the Arts and Humanities Research Council (grant AH/J011894/1), which explored understandings and experiences of LGBT ‘community’. I examine the ways in which intimacy is regulated and shaped by and within social interaction, which was apparent in three main ways. First, the research identified how for some people the very concept of ‘LGBT community’ was linked to intimacy. Second, there was strong evidence to suggest that some LGBT+ people self-regulate their practices of intimacy (such as holding hands or kissing in public) so as not to be recognised as enacting a same-gender relationship. This was understood as a form of self-protection or hate crime prevention, though degrees of habit and professed concern for other people’s feelings were also contributing factors. Third, experiences of intimate relations were shaped by intersectional dynamics, particularly relating to various forms of discrimination, including ageism, biphobia, classism, (dis)ableism, racism, and transphobia from and among LGBT+ people. Whilst LGBT ‘communities’ were thought to enable opportunities to seek sexual and/or intimate encounters, this is not without its complexities. Although there have been improvements in relation to legislation and wider social attitudes, there is, for some, persistent apprehension and self-regulation which, whether necessary or not, are significant. LGBT+ people’s experiences thus suggest that intimacy can be shaped by multiple inequalities both within and without LGBT ‘communities’

Deletion of the Human Cytomegalovirus US17 Gene Increases the Ratio of Genomes per Infectious Unit and Alters Regulation of Immune and Endoplasmic Reticulum Stress Response Genes at Early and Late Times after Infection

Human cytomegalovirus (HCMV) employs numerous strategies to combat, subvert, or co-opt host immunity. One evolutionary strategy for this involves capture of a host gene and then its successive duplication and divergence, forming a family of genes, many of which have immunomodulatory activities. The HCMV US12 family consists of 10 tandemly arranged sequence-related genes in the unique short (US) region of the HCMV genome (US12 to US21). Each gene encodes a protein possessing seven predicted transmembrane domains, patches of sequence similarity with cellular G-protein-coupled receptors, and the Bax inhibitor 1 family of antiapoptotic proteins. We show that one member, US17, plays an important role during virion maturation. Microarray analysis of cells infected with a recombinant HCMV isolate with a US17 deletion (the ΔUS17 mutant virus) revealed blunted host innate and interferon responses at early times after infection (12 h postinfection [hpi]), a pattern opposite that previously seen in the absence of the immunomodulatory tegument protein pp65 (pUL83). Although the ΔUS17 mutant virus produced numbers of infectious particles in fibroblasts equal to the numbers produced by the parental virus, it produced \u3e3-fold more genome-containing noninfectious viral particles and delivered increased amounts of pp65 to newly infected cells. These results suggest that US17 has evolved to control virion composition, to elicit an appropriately balanced host immune response. At later time points (96 hpi), ΔUS17 mutant-infected cells displayed aberrant expression of several host endoplasmic reticulum stress response genes and chaperones, some of which are important for the final stages of virion assembly and egress. Our results suggest that US17 modulates host pathways to enable production of virions that elicit an appropriately balanced host immune response

Affects, Bodies and Desire: ‘Queering’ Methods and Methodologies to Research Queer Migration

© 2016 Royal Dutch Geographical Society KNAG In this paper we discuss the main methodological issues raised by a research project we carried out between 2012 and 2013 about Italian queer ‘creative’ migration in Berlin, focusing on the tensions among mobility/movement, desire, bodies, affects and fieldwork. Following an increasing international debate on the topic, the contribution discusses the (im)possibility to develop a queer method or methodology. We stress how ‘queering’ methodologies and methods is not an ontological position pre-assumed when conducting research with queer-identified subjects, but is a process of dismantling taken-for-granted, stable, monolithic categories and identities. In order to do so, the paper discusses positionalities, situated knowledge and the different interactions – with both human and non-human actors – shaping the field. Through analysing body performances in the terms introduced by Taylor, ‘a politics of becoming’ emerges as a way to consider the relation between sexualities and spaces. The ‘objects’ of our research, that is, queer migrants, can thus be reframed following Braidotti's conceptualisation of the ‘nomadic subject’ and Deleuze and Guattari's ‘desiring machines’. Since they are shaped by affects, personal trajectories are exceptional and unique, composing new territorial materialities

Writing in Britain and Ireland, c. 400 to c. 800

No abstract available

Aquatic therapy for children with Duchenne muscular dystrophy: a pilot feasibility randomised controlled trial and mixed-methods process evaluation.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare disease that causes the progressive loss of motor abilities such as walking. Standard treatment includes physiotherapy. No trial has evaluated whether or not adding aquatic therapy (AT) to land-based therapy (LBT) exercises helps to keep muscles strong and children independent. OBJECTIVES: To assess the feasibility of recruiting boys with DMD to a randomised trial evaluating AT (primary objective) and to collect data from them; to assess how, and how well, the intervention and trial procedures work. DESIGN: Parallel-group, single-blind, randomised pilot trial with nested qualitative research. SETTING: Six paediatric neuromuscular units. PARTICIPANTS: Children with DMD aged 7-16 years, established on corticosteroids, with a North Star Ambulatory Assessment (NSAA) score of 8-34 and able to complete a 10-m walk without aids/assistance. Exclusions: > 20% variation between baseline screens 4 weeks apart and contraindications. INTERVENTIONS: Participants were allocated on a 1 : 1 ratio to (1) optimised, manualised LBT (prescribed by specialist neuromuscular physiotherapists) or (2) the same plus manualised AT (30 minutes, twice weekly for 6 months: active assisted and/or passive stretching regime; simulated or real functional activities; submaximal exercise). Semistructured interviews with participants, parents (n = 8) and professionals (n = 8) were analysed using Framework analysis. An independent rater reviewed patient records to determine the extent to which treatment was optimised. A cost-impact analysis was performed. Quantitative and qualitative data were mixed using a triangulation exercise. MAIN OUTCOME MEASURES: Feasibility of recruiting 40 participants in 6 months, participant and therapist views on the acceptability of the intervention and research protocols, clinical outcomes including NSAA, independent assessment of treatment optimisation and intervention costs. RESULTS: Over 6 months, 348 children were screened - most lived too far from centres or were enrolled in other trials. Twelve (30% of target) were randomised to AT (n = 8) or control (n = 4). People in the AT (n = 8) and control (n = 2: attrition because of parental report) arms contributed outcome data. The mean change in NSAA score at 6 months was -5.5 [standard deviation (SD) 7.8] for LBT and -2.8 (SD 4.1) in the AT arm. One boy suffered pain and fatigue after AT, which resolved the same day. Physiotherapists and parents valued AT and believed that it should be delivered in community settings. The independent rater considered AT optimised for three out of eight children, with other children given programmes that were too extensive and insufficiently focused. The estimated NHS costs of 6-month service were between £1970 and £2734 per patient. LIMITATIONS: The focus on delivery in hospitals limits generalisability. CONCLUSIONS: Neither a full-scale frequentist randomised controlled trial (RCT) recruiting in the UK alone nor a twice-weekly open-ended AT course delivered at tertiary centres is feasible. Further intervention development research is needed to identify how community-based pools can be accessed, and how families can link with each other and community physiotherapists to access tailored AT programmes guided by highly specialised physiotherapists. Bayesian RCTs may be feasible; otherwise, time series designs are recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41002956. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 27. See the NIHR Journals Library website for further project information

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research