Trends in paediatric rheumatology referral times and disease activity indices over a ten-year period among children and young people with Juvenile Idiopathic Arthritis: results from the childhood arthritis prospective Study

OBJECTIVES: The medical management of JIA has advanced significantly over the past 10 years. It is not known whether these changes have impacted on outcomes. The aim of this analysis was to identify and describe trends in referral times, treatment times and 1-year outcomes over a 10-year period among children with JIA enrolled in the Childhood Arthritis Prospective Study. METHODS: The Childhood Arthritis Prospective Study is a prospective inception cohort of children with new-onset inflammatory arthritis. Analysis included all children recruited in 2001–11 with at least 1 year of follow-up, divided into four groups by year of diagnosis. Median referral time, baseline disease pattern (oligoarticular, polyarticular or systemic onset) and time to first definitive treatment were compared between groups. Where possible, clinical juvenile arthritis disease activity score (cJADAS) cut-offs were applied at 1 year. RESULTS: One thousand and sixty-six children were included in the analysis. The median time from symptom onset and referral to first paediatric rheumatology appointment (22.7–24.7 and 3.4–4.7 weeks, respectively) did not vary significantly (∼20% seen within 10 weeks of onset and ∼50% within 4 weeks of referral). For oligoarticular and polyarticular disease, 33.8–47 and 25.4–34.9%, respectively, achieved inactive disease by 1 year, with ∼30% in high disease activity at 1 year. A positive trend towards earlier definitive treatment reached significance in oligoarticular and polyarticular pattern disease. CONCLUSION: Children with new-onset JIA have a persistent delay in access to paediatric rheumatology care, with one-third in high disease activity at 1 year and no significant improvement over the past 10 years. Contributing factors may include service pressures and poor awareness. Further research is necessary to gain a better understanding and improve important clinical outcomes

Treatment prescribing patterns in patients with juvenile idiopathic arthritis (JIA): Analysis from the UK Childhood Arthritis Prospective Study (CAPS)

OBJECTIVE: Initial treatment of juvenile idiopathic arthritis (JIA) is largely based on the extent of joint involvement, disease severity and ILAR category. The licensing of biologic therapies for JIA has expanded treatment options. The aims of the study are (1) to describe treatment prescribing patterns in JIA over the first 3 years following first presentation to paediatric rheumatology and (2) to determine whether patterns of treatment have changed as biologics have become more widely available. METHODS: Children with at least 3 years of follow-up within the Childhood Arthritis Prospective Study (CAPS) were included. For analysis, children were placed into one of five groups according to their initial presentation to paediatric rheumatology: oligoarthritis (oJIA), polyarthritis (pJIA), systemic (sJIA), enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). Treatment patterns over 3 years were described. RESULTS: Of 1051 children, 58% received synthetic disease-modifying anti-rheumatic drugs (sDMARD) and 20% received biologics over the 3 years. Use of sDMARDs and biologics was higher in more severe disease presentations (sJIA and pJIA); however, 35% and 10% who presented with oJIA were also treated with sDMARDs and biologics, respectively. The number of children receiving sDMARD after 2006 was higher (p = 0.02); however, there was no difference in biologic prescribing before and after 2006 (p = 0.4). CONCLUSIONS: A high proportion of children presenting with JIA received sDMARDs plus/minus biologics during 3 years of follow-up. This was most common for patients with severe JIA but was also prescribed for patients with oligoarticular disease, despite the lack of evidence for effectiveness in this category

Symbolic Partial-Order Execution for Testing Multi-Threaded Programs

We describe a technique for systematic testing of multi-threaded programs. We combine Quasi-Optimal Partial-Order Reduction, a state-of-the-art technique that tackles path explosion due to interleaving non-determinism, with symbolic execution to handle data non-determinism. Our technique iteratively and exhaustively finds all executions of the program. It represents program executions using partial orders and finds the next execution using an underlying unfolding semantics. We avoid the exploration of redundant program traces using cutoff events. We implemented our technique as an extension of KLEE and evaluated it on a set of large multi-threaded C programs. Our experiments found several previously undiscovered bugs and undefined behaviors in memcached and GNU sort, showing that the new method is capable of finding bugs in industrial-size benchmarks.Comment: Extended version of a paper presented at CAV'2

Functionalized α-Helical Peptide Hydrogels for Neural Tissue Engineering.

This is the final version of the article. Available from the American Chemical Society via the DOI in this record.Trauma to the central and peripheral nervous systems often lead to serious morbidity. Current surgical methods for repairing or replacing such damage have limitations. Tissue engineering offers a potential alternative. Here we show that functionalized α-helical-peptide hydrogels can be used to induce attachment, migration, proliferation and differentiation of murine embryonic neural stem cells (NSCs). Specifically, compared with undecorated gels, those functionalized with Arg-Gly-Asp-Ser (RGDS) peptides increase the proliferative activity of NSCs; promote their directional migration; induce differentiation, with increased expression of microtubule-associated protein-2, and a low expression of glial fibrillary acidic protein; and lead to the formation of larger neurospheres. Electrophysiological measurements from NSCs grown in RGDS-decorated gels indicate developmental progress toward mature neuron-like behavior. Our data indicate that these functional peptide hydrogels may go some way toward overcoming the limitations of current approaches to nerve-tissue repair.This work was supported by the Biotechnology and Biological Sciences Research Council (H01716X, D.N.W. and M.A.B.); the European Research Council (StG243261, BS; and ADG340764, D.N.W.); the Royal Society (UF051616, B.S.); the Medical Research Council (G1100623, A.D.R.); and the Engineering and Physical Sciences Research Council (Bristol Chemical Synthesis Centre for Doctoral Training, EP/G036764/1, K.L.H.). D.N.W. holds a Royal Society Wolfson Research Merit Award

Retinal Biomarker Discovery for Dementia in an Elderly Diabetic Population

Dementia is a devastating disease, and has severe implications on affected individuals, their family and wider society. A growing body of literature is studying the association of retinal microvasculature measurement with dementia. We present a pilot study testing the strength of groups of conventional (semantic) and texture-based (non-semantic) measurements extracted from retinal fundus camera images to classify patients with and without dementia. We performed a 500-trial bootstrap analysis with regularized logistic regression on a cohort of 1,742 elderly diabetic individuals (median age 72.2). Age was the strongest predictor for this elderly cohort. Semantic retinal measurements featured in up to 81% of the bootstrap trials, with arterial caliber and optic disk size chosen most often, suggesting that they do complement age when selected together in a classifier. Textural features were able to train classifiers that match the performance of age, suggesting they are potentially a rich source of information for dementia outcome classification

Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis

OBJECTIVE: To determine whether rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, or carriage of shared epitope (SE) and PTPN22 genetic susceptibility variants predict response to therapy in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor (TNF) agents. METHODS: UK-wide multicentre collaborations were established to recruit a large cohort of patients treated with anti-TNF drugs for RA. Serum RF, anti-CCP antibody and SE status were determined using commercially available kits. PTPN22 R620W genotyping was performed by Sequenom MassArray. Linear regression analyses were performed to investigate the role of these four factors in predicting response to treatment by 6 months, defined as the absolute change in 28-joint Disease Activity Score (DAS28). RESULTS: Of the 642 patients analysed, 46% received infliximab, 43% etanercept and 11% adalimumab. In all, 89% and 82% of patients were RF and anti-CCP positive, respectively. Patients that were RF negative had a 0.48 (95% CI 0.08 to 0.87) greater mean improvement in DAS28 compared to patients that were RF positive. A better response was also seen among patients that were anti-CCP negative. No association was demonstrated between drug response and SE or PTPN22 620W carriage. CONCLUSION: The presence of RF or anti-CCP antibodies was associated with a reduced response to anti-TNF drugs. However, these antibodies only account for a small proportion of the variance in treatment response. It is likely that genetic factors will contribute to treatment response, but these do not include the well established RA susceptibility loci, SE and PTPN22

Parametric study of EEG sensitivity to phase noise during face processing

<b>Background: </b> The present paper examines the visual processing speed of complex objects, here faces, by mapping the relationship between object physical properties and single-trial brain responses. Measuring visual processing speed is challenging because uncontrolled physical differences that co-vary with object categories might affect brain measurements, thus biasing our speed estimates. Recently, we demonstrated that early event-related potential (ERP) differences between faces and objects are preserved even when images differ only in phase information, and amplitude spectra are equated across image categories. Here, we use a parametric design to study how early ERP to faces are shaped by phase information. Subjects performed a two-alternative force choice discrimination between two faces (Experiment 1) or textures (two control experiments). All stimuli had the same amplitude spectrum and were presented at 11 phase noise levels, varying from 0% to 100% in 10% increments, using a linear phase interpolation technique. Single-trial ERP data from each subject were analysed using a multiple linear regression model. <b>Results: </b> Our results show that sensitivity to phase noise in faces emerges progressively in a short time window between the P1 and the N170 ERP visual components. The sensitivity to phase noise starts at about 120–130 ms after stimulus onset and continues for another 25–40 ms. This result was robust both within and across subjects. A control experiment using pink noise textures, which had the same second-order statistics as the faces used in Experiment 1, demonstrated that the sensitivity to phase noise observed for faces cannot be explained by the presence of global image structure alone. A second control experiment used wavelet textures that were matched to the face stimuli in terms of second- and higher-order image statistics. Results from this experiment suggest that higher-order statistics of faces are necessary but not sufficient to obtain the sensitivity to phase noise function observed in response to faces. <b>Conclusion: </b> Our results constitute the first quantitative assessment of the time course of phase information processing by the human visual brain. We interpret our results in a framework that focuses on image statistics and single-trial analyses