Joyce Davidson

Embodying emotion sensing space: introducing emotional geographies

Recent years have witnessed a welling‐up of emotion within geography, a surge of interest reminiscent of the fascination and exploration of embodiment that characterized much social and cultural ge...

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

Autoantibodies to a 140‐kd protein in juvenile dermatomyositis are associated with calcinosis

Objective The identification of novel autoantibodies in juvenile dermatomyositis (DM) may have etiologic and clinical implications. The aim of this study was to describe autoantibodies to a 140-kd protein in children recruited to the Juvenile DM National Registry and Repository for UK and Ireland. Methods Clinical data and sera were collected from children with juvenile myositis. Sera that recognized a 140-kd protein by immunoprecipitation were identified. The identity of the p140 autoantigen was investigated by immunoprecipitation/immunodepletion, using commercial monoclonal antibodies to NXP-2, reference anti-p140, and anti-p155/140, the other autoantibody recently described in juvenile DM. DNA samples from 100 Caucasian children with myositis were genotyped for HLA class II haplotype associations and compared with those from 864 randomly selected UK Caucasian control subjects. Results Sera from 37 (23%) of 162 patients with juvenile myositis were positive for anti-p140 autoantibodies, which were detected exclusively in patients with juvenile DM and not in patients with juvenile DM–overlap syndrome or control subjects. No anti-p140 antibody–positive patients were positive for other recognized autoantibodies. Immunodepletion suggested that the identity of p140 was consistent with NXP-2 (the previously identified MJ autoantigen). In children with anti-p140 antibodies, the association with calcinosis was significant compared with the rest of the cohort (corrected P < 0.005, odds ratio 7.0, 95% confidence interval 3.0–16.1). The clinical features of patients with anti-p140 autoantibodies were different from those of children with anti-p155/140 autoantibodies. The presence of HLA–DRB1*08 was a possible risk factor for anti-p140 autoantibody positivity. Conclusion This study has established that anti-p140 autoantibodies represent a major autoantibody subset in juvenile DM. This specificity may identify a further immunogenetic and clinical phenotype within the juvenile myositis spectrum that includes an association with calcinosis.

Long-Term Efficacy and Safety of Infliximab plus Methotrexate for The Treatment of Polyarticular Course Juvenile Rheumatoid Arthritis: Findings from an Open-Label Treatment Extension

Objective To assess the long-term efficacy and safety of infliximab plus methotrexate in juvenile rheumatoid arthritis (JRA). Methods Patients eligible for the open-label extension (OLE, weeks 52–204) received infliximab 3–6 mg/kg every 8 weeks plus methotrexate. Results Of the 78/122 (64%) children entering the OLE, 42 discontinued infliximab, most commonly due to consent withdrawal (11 patients), lack of efficacy (eight patients) or patient/physician/sponsor requirement (eight patients). Infliximab (mean dose 4.4 mg/kg per infusion) was generally well tolerated. Infusion reactions occurred in 32% (25/78) of patients, with a higher incidence in patients positive for antibodies to infliximab (58%, 15/26). At week 204, the proportions of patients achieving ACR-Pedi-30/50/70/90 response criteria and inactive disease status were 44%, 40%, 33%, 24% and 13%, respectively. Conclusions In the limited population of JRA patients remaining in the study at 4 years, infliximab was safe and effective but associated with a high patient discontinuation rate. Clinical trials registration number NCT00036374.

Disease activity, severity, and damage in the UK juvenile-onset systemic lupus erythematosus cohort

OBJECTIVE The UK Juvenile-Onset Systemic Lupus Erythematosus (JSLE) Cohort Study is a multicenter collaborative network established with the aim of improving the understanding of juvenile SLE. The present study was undertaken to describe the clinical manifestations and disease course in patients with juvenile SLE from this large, national inception cohort. METHODS Detailed data on clinical phenotype were collected at baseline and at regular clinic reviews and annual followup assessments in 232 patients from 14 centers across the UK over 4.5 years. Patients with SLE were identified according to the American College of Rheumatology (ACR) SLE classification criteria. The present cohort comprised children with juvenile SLE (n=198) whose diagnosis fulfilled ≥4 of the ACR criteria for SLE. RESULTS Among patients with juvenile SLE, the female:male sex distribution was 5.6:1 and the median age at diagnosis was 12.6 years (interquartile range 10.4-14.5 years). Male patients were younger than female patients (P<0.01). Standardized ethnicity data demonstrated a greater risk of juvenile SLE in non-Caucasian UK patients (P<0.05). Scores on the pediatric adaptation of the 2004 British Isles Lupus Assessment Group disease activity index demonstrated significantly increased frequencies of musculoskeletal (82%), renal (80%), hematologic (91%), immunologic (54%), and neurologic (26%) involvement among the patients over time. A large proportion of the patients (93%) were taking steroids and 24% of the patients required treatment with cyclophosphamide. Disease damage was common, with 28% of the patients having a Systemic Lupus International Collaborating Clinics/ACR damage score of ≥1. CONCLUSION The data on these patients from the UK JSLE Cohort Study, comprising one of the largest national inception cohorts of patients with juvenile SLE to date, indicate that severe organ involvement and significant disease activity are primary characteristics in children with juvenile SLE. In addition, accumulation of disease-associated damage could be seen.

Autistic culture online: virtual communication and cultural expression on the spectrum

Drawing on first-hand accounts of the Autism Spectrum (AS), this paper argues that that there are distinctive autistic styles of communication. It suggests that these differences can usefully be conceptualized in Wittgensteinian terms as ‘language games’, and further, that these are associated with an autistic culture emerging alongside their practice, particularly online. The Internet is shown to be an appropriate, accommodating medium for those on the spectrum, given characteristic preferences for communication at a socio-spatial distance. The Internet has potential implications for AS social exclusion/inclusion, and hopes expressed in AS writings are high; one author claims that ‘[t]he impact of the Internet on autistics may one day be compared to the spread of sign language among the deaf’ (Singer 1999: 67). This paper investigates such claims, and the extent to which those with autism describe using the Internet to connect with similar Others, not just for social support, but to organize and advocate for recognition of autistic cultural difference.

Duration of etanercept treatment and reasons for discontinuation in a cohort of juvenile idiopathic arthritis patients

OBJECTIVE Since 2004, juvenile idiopathic arthritis (JIA) patients treated with etanercept and/or MTX have been monitored in the British Society for Paediatric and Adolescent Rheumatology Biologics and New Drug Register. Here, we report the duration of etanercept use for the first 5 years of the register and reasons for discontinuation. METHODS Disease subtype and activity, comorbidity, treatment efficacy and safety data were recorded. Etanercept discontinuation was defined as stopping the drug because of disease remission or treatment failure. Time to discontinuation was explored using Kaplan-Meier survival analysis with remaining patients censored at 5-year follow-up. RESULTS A total of 483 etanercept-treated JIA patients were enrolled from 30 UK centres, representing 941 patient-years of follow-up. A total of 100 (20.7%) patients discontinued etanercept; 9 due to disease control, 88 because of treatment failure, 2 for unknown reasons and 1 because of a change in diagnosis. Of the 53 patients in whom etanercept was perceived to be ineffective at controlling the inflammation, 48 were prescribed other biologic drugs [26/48 (54%) infliximab]. In 21 patients with intolerance, infections, CNS events and a few isolated events were associated with discontinuation. Using Kaplan-Meier analysis, at 5 years 69% (95% CI 61, 77%) had not experienced treatment failure. Discontinuation of etanercept for inefficacy was associated with systemic arthritis subtype [odds ratio (OR) 2.55, 95% CI 1.27, 5.14], chronic anterior uveitis (OR 2.39, 95% CI 1.06, 5.35) and inefficacy of MTX before starting etanercept (OR 8.3, 95% CI 1.14, 60.58). CONCLUSIONS In a cohort of JIA patients treated with etanercept and followed for a median of 2 years (maximum 5 years), the majority (69%) remain on the drug.

Disease activity and disability in children with juvenile idiopathic arthritis one year following presentation to paediatric rheumatology. Results from the Childhood Arthritis Prospective Study.

Objective. Inflammatory arthritis in childhood is variable in terms of both presentation and outcome. This analysis describes disease activity in children with juvenile idiopathic arthritis (JIA) during the first year following presentation to a paediatric rheumatologist and identifies predictors of moderate to severe disability [defined using a Childhood HAQ (CHAQ) score ⩾0.75] at 1 year. Methods. The Childhood Arthritis Prospective Study recruits children <16 years with new inflammatory arthritis persisting for ⩾2 weeks from five UK tertiary referral centres. Demographics, disease features, joint count, CHAQ, physicians global assessment, parents general evaluation of well-being (PGE), ESR and treatment, are collected at first presentation, 6 months and then yearly. Independent predictors of CHAQ ⩾0.75 at 1 year in children diagnosed with JIA were identified using multivariable logistic regression models. Results. Seven hundred and forty children with JIA were included; median age at presentation 7.6 years, 64% girls. During the first year, 85% received NSAIDs, 70% IA corticosteroids, 47% MTX and 27% systemic steroids (oral or i.v.). Median presenting CHAQ score was 0.63 and decreased to 0.25 at 1 year; 32% had CHAQ ⩾0.75 at 1 year. The strongest predictor of CHAQ ⩾0.75 at 1 year was CHAQ ⩾0.75 at presentation (odds ratio 3.92; 95% CI 2.17, 7.09). Additional predictors included female gender and higher PGE Conclusion. Although CHAQ score improved in most children, the strongest predictor of persistent disability at 1 year was moderate to severe disability at first presentation. Follow-up beyond 1 year will assess whether CHAQ at presentation will continue to be a predictor of future poor outcome.

A phenomenology of fear: Merleau-Ponty and agoraphobic life-worlds

This paper explores the nature of agoraphobic sufferers’ fears of social spaces drawing on Merleau-Ponty’s dual conceptions of ‘lived’ and ‘objective’ space. Merleau-Ponty’s phenomenological approach highlights both the mediating role of sensations in acquiring a sense of identity and the importance of recognising the social (as opposed to the merely individual) construction of lived space. I argue that an approach capable of theorising agoraphobic ‘being-in-the-world’ requires just such recognition of the effect that other people have on the space that they occupy. The potential relevance of this approach for sufferers from agoraphobia is explored through a case study.

‘Coming out’ on the spectrum: autism, identity and disclosure

Much has been written by queer theorists about the personal and political ramifications of being out of the closet, and connections with experiences of disclosure for those with ‘hidden’ health conditions have been made by researchers studying critical geographies of disabilities and chronic illness. To date, however, the impact of such issues for those on the autism spectrum (AS) has received comparatively little attention. Popular re-presentations of AS suggest disclosure is irrelevant for those assumed so obviously different and unlikely to pass as ‘normal.’ However, AS authors reveal a broad spectrum of experience indicating that concealment and disclosure are complex and selective strategies of information and identity management. Applying discourse analysis to AS autobiographies and personal narratives, this paper explores four sense-making discourse clusters, or repertoires, that emerge from the texts under study: a ‘keeping safe’ repertoire, which addresses protective strategies in disclosure and coming out; a ‘qualified deception’ repertoire, which relates to the complexities of non-disclosure; a ‘like/as resistance’ repertoire, which captures the tendency of AS authors to position their individual and collective experiences of coming out on the spectrum as analogous to the process of coming out for other marginalized groups, most notably gay and Deaf communities; and an ‘education’ repertoire, which contributes to the project of building a community to come out to. Each of these repertoires is situated within the broader literature in social and cultural geography and critical disability studies.