L-DOPA increases slow-wave sleep duration and selectively modulates memory persistence in older adults

INTRODUCTION: Millions of people worldwide take medications such as L-DOPA that increase dopamine to treat Parkinson's disease. Yet, we do not fully understand how L-DOPA affects sleep and memory. Our earlier research in Parkinson's disease revealed that the timing of L-DOPA relative to sleep affects dopamine's impact on long-term memory. Dopamine projections between the midbrain and hippocampus potentially support memory processes during slow wave sleep. In this study, we aimed to test the hypothesis that L-DOPA enhances memory consolidation by modulating NREM sleep. METHODS: We conducted a double-blind, randomised, placebo-controlled crossover trial with healthy older adults (65-79 years, n = 35). Participants first learned a word list and were then administered long-acting L-DOPA (or placebo) before a full night of sleep. Before sleeping, a proportion of the words were re-exposed using a recognition test to strengthen memory. L-DOPA was active during sleep and the practice-recognition test, but not during initial learning. RESULTS: The single dose of L-DOPA increased total slow-wave sleep duration by approximately 11% compared to placebo, while also increasing spindle amplitudes around slow oscillation peaks and around 1-4 Hz NREM spectral power. However, behaviourally, L-DOPA worsened memory of words presented only once compared to re-exposed words. The coupling of spindles to slow oscillation peaks correlated with these differential effects on weaker and stronger memories. To gauge whether L-DOPA affects encoding or retrieval of information in addition to consolidation, we conducted a second experiment targeting L-DOPA only to initial encoding or retrieval and found no behavioural effects. DISCUSSION: Our results demonstrate that L-DOPA augments slow wave sleep in elderly, perhaps tuning coordinated network activity and impacting the selection of information for long-term storage. The pharmaceutical modification of slow-wave sleep and long-term memory may have clinical implications. CLINICAL TRIAL REGISTRATION: Eudract number: 2015-002027-26; https://doi.org/10.1186/ISRCTN90897064, ISRCTN90897064

Clinical and laboratory characteristics in juvenile-onset systemic lupus erythematosus across age groups

BACKGROUND Systemic lupus erythematous (SLE) is a systemic autoimmune/inflammatory condition. Approximately 15–20% of patients develop symptoms before their 18th birthday and are diagnosed with juvenile-onset SLE (JSLE). Gender distribution, clinical presentation, disease courses and outcomes vary significantly between JSLE patients and individuals with adult-onset SLE. This study aimed to identify age-specific clinical and/or serological patterns in JSLE patients enrolled to the UK JSLE Cohort Study. METHODS Patient records were accessed and grouped based on age at disease-onset: pre-pubertal (≤7 years), peri-pubertal (8–13 years) and adolescent (14–18 years). The presence of American College of Rheumatology (ACR) classification criteria, laboratory results, disease activity [British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) scores] and damage [Systemic Lupus International Collaborating Clinics (SLICC) damage index] were evaluated at diagnosis and last follow up. RESULTS A total of 418 JSLE patients were included in this study: 43 (10.3%) with pre-pubertal disease onset; 240 (57.4%) with peri-pubertal onset and 135 (32.3%) were diagnosed during adolescence. At diagnosis, adolescent JSLE patients presented with a higher number of ACR criteria when compared with pre-pubertal and peri-pubertal patients [pBILAG2004 scores: 9(4–20] vs. 7(3–13] vs. 7(3–14], respectively, p = 0.015] with increased activity in the following BILAG domains: mucocutaneous (p = 0.025), musculoskeletal (p = 0.029), renal (p = 0.027) and cardiorespiratory (p = 0.001). Furthermore, adolescent JSLE patients were more frequently ANA-positive (p = 0.034) and exhibited higher anti-dsDNA titres (p = 0.001). Pre-pubertal individuals less frequently presented with leukopenia (p = 0.002), thrombocytopenia (p = 0.004) or low complement (p = 0.002) when compared with other age groups. No differences were identified in disease activity (pBILAG2004 score), damage (SLICC damage index) and the number of ACR criteria fulfilled at last follow up. CONCLUSIONS Disease presentations and laboratory findings vary significantly between age groups within a national cohort of JSLE patients. Patients diagnosed during adolescence exhibit greater disease activity and “classic” autoantibody, immune cell and complement patterns when compared with younger patients. This supports the hypothesis that pathomechanisms may vary between patient age groups

Long‐Term Outcomes Following Achievement of Clinically Inactive Disease in Juvenile Idiopathic Arthritis

OBJECTIVE: Potential targets for treat‐to‐target strategies in juvenile idiopathic arthritis are minimal disease activity (MDA) and clinically inactive disease (CID). We undertook this study to compare short‐ and long‐term outcomes following achievement of MDA and CID on the 10‐joint clinical Juvenile Arthritis Disease Activity Score (cJADAS10) and following achievement of CID on Wallace et al's preliminary criteria. METHODS: Children recruited to the Childhood Arthritis Prospective Study, a UK multicenter inception cohort, were selected if they were recruited prior to January 2011 and diagnosed as having oligoarthritis or rheumatoid factor–negative or –positive polyarthritis. One year following diagnosis, children were assessed for MDA on the cJADAS10 and for CID on both Wallace et al's preliminary criteria and the cJADAS10. Associations were tested between those disease states and functional ability, absence of joints with limited range of motion, psychosocial health, and pain at 1 year and annually to 5 years. RESULTS: Of 832 children, 70% were female and the majority had oligoarthritis (68%). At 1 year, 21% had achieved CID according to both definitions, 7% according to Wallace et al's preliminary criteria alone, and 16% according to the cJADAS10 alone; 56% had not achieved CID. Only 10% of children in the entire cohort achieved MDA without also achieving CID. Achieving either early CID state was associated with a greater absence of joints with limited range of motion. However, only CID according to the cJADAS10 was associated with improved functional ability and psychosocial health. Achieving CID was superior to achieving MDA in terms of short‐ and long‐term pain and the absence of joints with limited range of motion

Разработка бизнес-плана как основа подготовки конкурентоспособного специалиста

Objective: The aim was to investigate the time course of lower limb disease activity and walking disability in children with JIA over a 5-year course. Methods: The Childhood Arthritis Prospective Study is a longitudinal study of children with a new JIA diagnosis. Childhood Arthritis Prospective Study data include demographics and core outcome variables at baseline, 6 months and yearly thereafter. Prevalence and transition rates from baseline to 5 years were obtained for active and limited joint counts at the hip, knee, ankle and foot joints; and walking disability, measured using the Childhood Health Assessment Questionnaire walking subscale. Missing data were accounted for using multiple imputation. Results: A total of 1041 children (64% female), with a median age of 7.7 years at first visit, were included. Baseline knee and ankle synovitis prevalence was 71 and 34%, respectively, decreasing to 8-20 and 6-12%, respectively, after 1 year. Baseline hip and foot synovitis prevalence was <11%, decreasing to <5% after 6 months. At least mild walking disability was present in 52% at baseline, stabilizing at 25-30% after 1 year. Conclusion: Lower limb synovitis and walking disability are relatively common around the time of initial presentation in children and young people with JIA. Mild to moderate walking disability persisted in ∼25% of patients for the duration of the study, despite a significant reduction in the frequency of lower limb synovitis. This suggests that there is an unmet need for non-medical strategies designed to prevent and/or resolve persistent walking disability in JIA

Patient-reported wellbeing and clinical disease measures over time captured by multivariate trajectories of disease activity in individuals with juvenile idiopathic arthritis in the UK: a multicentre prospective longitudinal study

Background: Juvenile idiopathic arthritis (JIA) is a heterogeneous disease, the signs and symptoms of which can be summarised with use of composite disease activity measures, including the clinical Juvenile Arthritis Disease Activity Score (cJADAS). However, clusters of children and young people might experience different global patterns in their signs and symptoms of disease, which might run in parallel or diverge over time. We aimed to identify such clusters in the 3 years after a diagnosis of JIA. The identification of these clusters would allow for a greater understanding of disease progression in JIA, including how physician-reported and patient-reported outcomes relate to each other over the JIA disease course. / Methods: In this multicentre prospective longitudinal study, we included children and young people recruited before Jan 1, 2015, to the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort. Participants without a cJADAS score were excluded. To assess groups of children and young people with similar disease patterns in active joint count, physician’s global assessment, and patient or parental global evaluation, we used latent profile analysis at initial presentation to paediatric rheumatology and multivariate group-based trajectory models for the following 3 years. Optimal models were selected on the basis of a combination of model fit, clinical plausibility, and model parsimony. / Finding: Between Jan 1, 2001, and Dec 31, 2014, 1423 children and young people with JIA were recruited to CAPS, 239 of whom were excluded, resulting in a final study population of 1184 children and young people. We identified five clusters at baseline and six trajectory groups using longitudinal follow-up data. Disease course was not well predicted from clusters at baseline; however, in both cross-sectional and longitudinal analyses, substantial proportions of children and young people had high patient or parent global scores despite low or improving joint counts and physician global scores. Participants in these groups were older, and a higher proportion of them had enthesitisrelated JIA and lower socioeconomic status, compared with those in other groups. / Interpretation: Almost one in four children and young people with JIA in our study reported persistent, high patient or parent global scores despite having low or improving active joint counts and physician’s global scores. Distinct patient subgroups defined by disease manifestation or trajectories of progression could help to better personalise health-care services and treatment plans for individuals with JIA. / Funding: Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children’s Charity, Olivia’s Vision, and National Institute for Health Researc

UNICORNS: Uveitis in childhood prospective national cohort study protocol [version 1; peer review: 1 approved, 1 approved with reservations]

Background: Childhood uveitis is a rare inflammatory eye disease which is typically chronic, relapsing-remitting in nature, with an uncertain aetiology (idiopathic). Visual loss occurs due to structural damage caused by uncontrolled inflammation. Understanding of the determinants of long term outcome is lacking, including the predictors of therapeutic response or how to define disease control. Aims: To describe disease natural history and outcomes amongst a nationally representative group of children with non-infectious uveitis, describe the impact of disease course on quality of life for both child and family, and identify determinants of adverse visual, structural and developmental outcomes. Methods: UNICORNS is a prospective longitudinal multicentre cohort study of children newly diagnosed with uveitis about whom a core minimum clinical dataset will be collected systematically. Participants and their families will also complete patient-reported outcome measures annually from recruitment. The association of patient (child- and treatment- dependent) characteristics with outcome will be investigated using logistic and ordinal regression models which incorporate adjustment for within-child correspondence between eyes for those with bilateral disease and repeated outcomes measurement. Discussion: Through this population based, prospective longitudinal study of childhood uveitis, we will describe the characteristics of childhood onset disease. Early (1-2 years following diagnosis) outcomes will be described in the first instance, and through the creation of a national inception cohort, longer term studies will be enabled of outcome for affected children and families

Multi-centre national audit of juvenile localised scleroderma: describing current UK practice in disease assessment and management

OBJECTIVE: To describe current United Kingdom practice in assessment and management of patients with juvenile localised scleroderma (JLS) compared to Paediatric Rheumatology European Society (PRES) scleroderma working party recommendations. METHODS: Patients were included if they were diagnosed with JLS and were under the care of paediatric rheumatology between 04/2015-04/2016. Retrospective data was collected in eleven UK centres using a standardised proforma and collated centrally. RESULTS: 149 patients were included with a median age of 12.5 years. The outcome measures recommended by the PRES scleroderma working party were not utilised widely. The localised scleroderma cutaneous assessment tool was only used in 37.6% of patients. Screening for extracutaneous manifestations did not meet recommendations that patients with head involvement have regular screening for uveitis and baseline magnetic resonance imaging (MRI) brain: only 38.5% of these patients were ever screened for uveitis; 71.2% had a MRI brain. Systemic treatment with disease-modifying anti-rheumatic drugs (DMARDs) or biologics was widely used (96.0%). In keeping with the recommendations, 95.5% of patients were treated with methotrexate as first-line therapy. 82.6% received systemic corticosteroids and 34.2% of patients required two or more DMARDs/biologics, highlighting the significant treatment burden. Second-line treatment was mycophenolate mofetil in 89.5%. CONCLUSION: There is wide variation in assessment and screening of patients with JLS but a consistent approach to systemic treatment within UK paediatric rheumatology. Improved awareness of PRES recommendations is required to ensure standardised care. As recommendations are based on low level evidence and consensus opinion, further studies are needed to better define outcome measures and treatment regimens for JLS

Oral abstracts 3: RA Treatment and outcomesO13. Validation of jadas in all subtypes of juvenile idiopathic arthritis in a clinical setting

Background: Juvenile Arthritis Disease Activity Score (JADAS) is a 4 variable composite disease activity (DA) score for JIA (including active 10, 27 or 71 joint count (AJC), physician global (PGA), parent/child global (PGE) and ESR). The validity of JADAS for all ILAR subtypes in the routine clinical setting is unknown. We investigated the construct validity of JADAS in the clinical setting in all subtypes of JIA through application to a prospective inception cohort of UK children presenting with new onset inflammatory arthritis. Methods: JADAS 10, 27 and 71 were determined for all children in the Childhood Arthritis Prospective Study (CAPS) with complete data available at baseline. Correlation of JADAS 10, 27 and 71 with single DA markers was determined for all subtypes. All correlations were calculated using Spearman's rank statistic. Results: 262/1238 visits had sufficient data for calculation of JADAS (1028 (83%) AJC, 744 (60%) PGA, 843 (68%) PGE and 459 (37%) ESR). Median age at disease onset was 6.0 years (IQR 2.6-10.4) and 64% were female. Correlation between JADAS 10, 27 and 71 approached 1 for all subtypes. Median JADAS 71 was 5.3 (IQR 2.2-10.1) with a significant difference between median JADAS scores between subtypes (p < 0.01). Correlation of JADAS 71 with each single marker of DA was moderate to high in the total cohort (see Table 1). Overall, correlation with AJC, PGA and PGE was moderate to high and correlation with ESR, limited JC, parental pain and CHAQ was low to moderate in the individual subtypes. Correlation coefficients in the extended oligoarticular, rheumatoid factor negative and enthesitis related subtypes were interpreted with caution in view of low numbers. Conclusions: This study adds to the body of evidence supporting the construct validity of JADAS. JADAS correlates with other measures of DA in all ILAR subtypes in the routine clinical setting. Given the high frequency of missing ESR data, it would be useful to assess the validity of JADAS without inclusion of the ESR. Disclosure statement: All authors have declared no conflicts of interest. Table 1Spearman's correlation between JADAS 71 and single markers DA by ILAR subtype ILAR Subtype Systemic onset JIA Persistent oligo JIA Extended oligo JIA Rheumatoid factor neg JIA Rheumatoid factor pos JIA Enthesitis related JIA Psoriatic JIA Undifferentiated JIA Unknown subtype Total cohort Number of children 23 111 12 57 7 9 19 7 17 262 AJC 0.54 0.67 0.53 0.75 0.53 0.34 0.59 0.81 0.37 0.59 PGA 0.63 0.69 0.25 0.73 0.14 0.05 0.50 0.83 0.56 0.64 PGE 0.51 0.68 0.83 0.61 0.41 0.69 0.71 0.9 0.48 0.61 ESR 0.28 0.31 0.35 0.4 0.6 0.85 0.43 0.7 0.5 0.53 Limited 71 JC 0.29 0.51 0.23 0.37 0.14 -0.12 0.4 0.81 0.45 0.41 Parental pain 0.23 0.62 0.03 0.57 0.41 0.69 0.7 0.79 0.42 0.53 Childhood health assessment questionnaire 0.25 0.57 -0.07 0.36 -0.47 0.84 0.37 0.8 0.66 0.4