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The 100 000 Genomes Project (100KGP) is a UK-wide initiative that has a goal of using whole genome sequencing (WGS) to identify genetic causes of rare inherited diseases and embed the use of this technology within the NHS.1 Using data from this resource alongside international gene-matching efforts, four individuals from two independent families were identified harbouring homozygous frameshift or stop-gain variants in PRKG2 , a recently described skeletal dysplasia gene.2 Detailed clinical and radiological assessments helped extend the phenotypic range associated with this autosomal recessive condition while functional studies indicated that both variants had a similar impact on FGF-induced MAPK signalling. PRKG2 encodes the cyclic guanosine monophosphate dependent protein kinase II (cGKII), which acts downstream of the natriuretic peptide receptor-B/C- natriuretic peptide (NPR-B/CNP). NPR-B is encoded by NPR2, biallelic variants in which are responsible for acromesomelic dysplasia, Maroteaux type (AMDM; MIM 602875). Rodent models further implicate PRKG2 in skeletal development3 4 and cGKII deficiency was shown to be the cause of the dwarfism phenotype observed in Angus cattle.5 Building on support from pathway analysis and model organisms, a recent study showed that biallelic PRKG2 variants can result in acromesomelic dysplasia, PRKG2-type (AMDP) in humans,2 adding PRKG2 to a list of >400 genes associated with genetic skeletal disorders.6 As only two affected individuals were reported, it is important that the full clinical range of this condition is described. In this study, we searched for rare biallelic PRKG2 variants using data from the 100KGP via the LabKey application available within Genomic England’s research environment. Researchers can apply for access online (www.genomicsengland.co.uk/join-a-gecip-domain). Initial filtering employed a 1% population allele frequency threshold based on data from the 1000 Genomes Project as well as in-house frequency information. An additional family was identified via a network of collaborators and variants were …

Introduction Juvenile-onset systemic lupus erythematosus (JSLE) is a rare autoimmune/inflammatory disease with significant morbidity and mortality. Neuropsychiatric (NP) involvement is a severe complication, encompassing a heterogeneous range of neurological and psychiatric manifestations. Methods Demographic, clinical, and laboratory features of NP-SLE were assessed in participants of the UK JSLE Cohort Study, and compared to patients in the same cohort without NP manifestations. Results A total of 428 JSLE patients were included in this study, 25% of which exhibited NP features, half of them at first visit. Most common neurological symptoms among NP-JSLE patients included headaches (78.5%), mood disorders (48.6%), cognitive impairment (42%), anxiety (23.3%), seizures (19.6%), movement disorders (17.7%), and cerebrovascular disease (14.9%). Peripheral nervous system involvement was recorded in 7% of NP-SLE patients. NP-JSLE patients more frequently exhibited thrombocytopenia (9/L) ( p = 0.04), higher C-reactive protein levels ( p = 0.01), higher global pBILAG score at first visit ( p < 0.001), and higher SLICC damage index score at first ( p = 0.02) and last ( p < 0.001) visit when compared to JSLE patients without NP involvement. Conclusions A significant proportion of JSLE patients experience NP involvement (25%). Juvenile-onset NP-SLE most commonly affects the CNS and is associated with increased overall disease activity and damage.

Objectives Juvenile-onset systemic lupus erythematosus (jSLE) affects 15–20% of lupus patients. Clinical heterogeneity between racial groups, age groups and individual patients suggests variable pathophysiology. This study aimed to identify highly penetrant damaging mutations in genes associated with SLE/SLE-like disease in a large national cohort (UK JSLE Cohort Study) and compare demographic, clinical and laboratory features in patient sub-cohorts with ‘genetic’ SLE vs remaining SLE patients. Methods Based on a sequencing panel designed in 2018, target enrichment and next-generation sequencing were performed in 348 patients to identify damaging gene variants. Findings were integrated with demographic, clinical and treatment related datasets. Results Damaging gene variants were identified in ∼3.5% of jSLE patients. When compared with the remaining cohort, ‘genetic’ SLE affected younger children and more Black African/Caribbean patients. ‘Genetic’ SLE patients exhibited less organ involvement and damage, and neuropsychiatric involvement developed over time. Less aggressive first line treatment was chosen in ‘genetic’ SLE patients, but more second and third line agents were used. ‘Genetic’ SLE associated with anti-dsDNA antibody positivity at diagnosis and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit. Conclusion Approximately 3.5% of jSLE patients present damaging gene variants associated with younger age at onset, and distinct clinical features. As less commonly observed after treatment induction, in ‘genetic’ SLE, autoantibody positivity may be the result of tissue damage and explain reduced immune complex-mediated renal and haematological involvement. Routine sequencing could allow for patient stratification, risk assessment and target-directed treatment, thereby increasing efficacy and reducing toxicity.

Background: The association between diet, symptoms and health related quality of life in children and young people with Juvenile idiopathic arthritis (JIA) is not clearly understood. The objectives of this systematic review and meta-analysis were to explore the evidence for a relationship of dietary intakes and arthritis symptoms such as pain and inflammation, growth factors including weight and height and health related quality of life in children and young people with JIA.Method: The databases PubMed, CINAHL, PsycINFO, Web of Science and Cochrane were searched in October 2019, updated in September 2020 and October 2021. Searches were restricted to English language, human and age (2-18 years old). Studies were included if they measured the effect of dietary supplements, vitamins or minerals, or diet in general, on quality of life and/ or arthritis symptom management. Two researchers independently screened titles and abstracts. Full texts were sourced for relevant articles. PRISMA guidelines were used for extracting data. For variables (vitamin D and disease activity), a random-effects meta-analysis model was performed. Two authors using a standardized data extraction form extracted data independently.Results: 11793 papers were identified through database searching, 25 studies met our inclusion criteria with 1614 participants. There was a significant association between Ɯ-3 polyunsaturated fatty acids (PUFA) and Juvenile Arthritis Disease Activity Score (p

Introduction The CIMZIA® AutoClicks® pre-filled pen (CZP PFP) was developed to overcome barriers to self-injection, by improving self-injection confidence, reducing fear associated with needle use, and supporting patients with impaired dexterity. The purpose of this research was to gather feedback on injection experience and the usefulness of training materials. Methods Eligible patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA) were at least 18 years of age and initiated onto the CZP PFP. Routine self-injection training and support were provided by trained specialist nurses. Patient experience (pain and skin reactions, confidence, satisfaction, and ease of use) was evaluated at visits 1–3 using an amended version of the self-injection assessment questionnaire (SIAQ) v2.0. Nurse and patient feedback on the training materials, and nurse opinions on patient self-injection after self-injection at visit 1, were also collected. Results Of 355 patients invited to participate, 196 provided informed consent and 79 participated in all three visits. Patients generally found the CZP PFP easy to use, and self-confidence and satisfaction were high. From visit 1 to visit 3, there was a numerical trend towards improvement in all three aspects of patient experience, most notably in both confidence and satisfaction. After self-injection at visit 1, confidence around safe patient self-injection was higher among nurses than among patients. Meanwhile, “pain and skin reactions” remained low at all visits. Patients thought the training materials contained sufficient information and were easy to understand and useful. Conclusion After training, patients generally found the device easy to use and showed high confidence and satisfaction with self-injection. Some patients may have been competent (based on nurse opinion), but initially lacked self-confidence. Increasing self-injection experience, together with patient training and continued support, may have facilitated high patient confidence and satisfaction, thereby potentially overcoming some of the barriers to self-injection. Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01257-6) contains supplementary material, which is available to authorized users.

Objectives To assess the achievability and effect of attaining low disease activity (LDA) or remission in childhood-onset SLE (cSLE). Methods Attainment of three adult-SLE derived definitions of LDA (LLDAS, LA, Toronto-LDA), and four definitions of remission (clinical-SLEDAI-defined remission on/off treatment, pBILAG-defined remission on/off treatment) was assessed in UK JSLE Cohort Study patients longitudinally. Prentice–Williams–Petersen gap recurrent event models assessed the impact of LDA/remission attainment on severe flare/new damage. Results LLDAS, LA and Toronto-LDA targets were reached in 67%, 73% and 32% of patients, after a median of 18, 15 or 17 months, respectively. Cumulatively, LLDAS, LA and Toronto-LDA was attained for a median of 23%, 31% and 19% of total follow-up-time, respectively. Remission on-treatment was more common (61% cSLEDAI-defined, 42% pBILAG-defined) than remission off-treatment (31% cSLEDAI-defined, 21% pBILAG-defined). Attainment of all target states, and disease duration (>1 year), significantly reduced the hazard of severe flare (P 0.05). Attainment of all targets reduced the hazards of new damage (P Conclusions This is the first study demonstrating that adult-SLE-derived definitions of LDA/remission are achievable in cSLE, significantly reducing risk of severe flare/new damage. Of the LDA definitions, LLDAS performed best, leading to a statistically comparable reduction in the hazards of severe flare to attainment of clinical remission.

Objectives This study aimed to test the performance of the new ACR and EULAR criteria, that include ANA positivity as entry criterion, in JSLE. Methods Performance of the ACR/EULAR-2019 criteria were compared with Systemic Lupus International Collaborating Clinics (SLICC-2012), using data from children and young people (CYP) in the UK JSLE Cohort Study (n = 482), with the ACR-1997 criteria used as reference standard. An unselected cohort of CYP positive for ANA (n = 129) was used to calculate positive/negative predictive values of the criteria. Results At both first and last visits, the number of patients fulfilling the different classification criteria varied significantly (P < 0.001). The sensitivity of the SLICC-2012 criteria was higher when compared with that of the ACR/EULAR-2019 criteria at first and last visits (98% vs 94% for first visit, and 98% vs 96% for last visit; P < 0.001), when all available CYP were considered. The ACR/EULAR-2019 criteria were more specific when compared with the SLICC-2012 criteria (77% vs 67% for first visit, and 81% vs 71% for last visit; P < 0.001). Significant differences between the classification criteria were mainly caused by the variation in ANA positivity across ages. In the unselected cohort of ANA-positive CYP, the ACR/EULAR-2019 criteria produced the highest false-positive classification (6/129, 5%). Conclusion In CYP, the ACR/EULAR-2019 criteria are not superior to those of the SLICC-2012 or ACR-1997 criteria. If classification criteria are designed to include CYP and adult populations, paediatric rheumatologists should be included in the consensus and evaluation process, as seemingly minor changes can significantly affect outcomes.

Summary Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2. We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A, FZD2, and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins., Robinow syndrome (RS) is a genetically heterogeneous disorder caused by WNT/PCP-signaling dysfunction. We identified pathogenic variants in RS individuals (n = 22), including the first DVL2 variant. Quantitative HPO-term-based analyses unveiled gene/allele-specific correlations to disease traits, providing a model for delineating the phenotypic consequences of variants affecting paralogs in the same pathway.

The purpose of this study was to investigate our institution's experience with pediatric firearm events. We sought to determine the relationship between a community's level of socioeconomic distress and the incidence of youth gun violence.We performed a retrospective review of children18 years involved in firearm events. Using visual cluster analysis, we portrayed all firearm events and violent firearm events (assaults + homicides). Distressed community indices (DCIs) were obtained from an interface that uses US Census Bureau data. Incident rate ratios (IRRs) were calculated for firearm circumstances (i.e. assault, homicide, suicide) using a DCI. Significant IRRs were analyzed to discern which DCI metrics contributed most to gun violence.There were 114 children involved in firearm events; 66 were county residents. The DCI of injury location significantly predicted total firearm events (IRR 1.02, 95% CI 1.01-1.03), assaults (IRR 1.02, 95% CI 1.01-1.05), and violent firearm events (IRR 1.03, 95% CI 1.01-1.05). The proportion of adults without a high school diploma, poverty rate, median income ratio, and housing vacancy rate were highly predictive of gun violence (VIP1).Community distress significantly predicts pediatric firearm violence. Local interventions should target neighborhoods with high levels of distress to prevent further youth gun violence.Retrospective study, IV.

Objectives Data collected during routine clinic visits are key to driving successful quality improvement in clinical services and enabling integration of research into routine care. The purpose of this study was to develop a standardized core dataset for juvenile idiopathic arthritis (JIA) (termed CAPTURE-JIA), enabling routine clinical collection of research-quality patient data useful to all relevant stakeholder groups (clinicians, service-providers, researchers, health service planners and patients/families) and including outcomes of relevance to patients/families. Methods Collaborative consensus-based approaches (including Delphi and World Café methodologies) were employed. The study was divided into discrete phases, including collaborative working with other groups developing relevant core datasets and a two-stage Delphi process, with the aim of rationalizing the initially long data item list to a clinically feasible size. Results The initial stage of the process identified collection of 297 discrete data items by one or more of fifteen NHS paediatric rheumatology centres. Following the two-stage Delphi process, culminating in a consensus workshop (May 2015), the final approved CAPTURE-JIA dataset consists of 62 discrete and defined clinical data items including novel JIA-specific patient-reported outcome and experience measures. Conclusions CAPTURE-JIA is the first ‘JIA core dataset’ to include data items considered essential by key stakeholder groups engaged with leading and improving the clinical care of children and young people with JIA. Collecting essential patient information in a standard way is a major step towards improving the quality and consistency of clinical services, facilitating collaborative and effective working, benchmarking clinical services against quality indicators and aligning treatment strategies and clinical research opportunities.

Funder: LUPUS UK, Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease. Patients diagnosed with juvenile-onset SLE (jSLE), when compared to individuals with adult-onset SLE, develop more severe organ involvement, increased disease activity and greater tissue and organ damage. In adult-onset SLE, clinical characteristics, pathomechanisms, disease progression and outcomes do not only vary between individuals and age groups, but also ethnicities. However, in children and young people, the influence of ethnicity on disease onset, phenotype and outcome has not been investigated in detail. In this study, we investigated clinical and laboratory characteristics in pediatric SLE patients from different ethnic backgrounds (White Caucasian, Asian, Black African/Caribbean) accessing data from a national cohort of jSLE patients (the UK JSLE Cohort Study). Among jSLE patients in the UK, ethnicity affects both the disease's clinical course and outcomes. At diagnosis, Black African/Caribbean jSLE patients show more "classical" laboratory and clinical features when compared to White Caucasian or Asian patients. Black African/Caribbean jSLE patients exhibit more renal involvement and more frequently receive cyclophosphamide and rituximab. Studies targeting ethnicity-specific contributors to disease expression and phenotypes are necessary to improve our pathophysiological understanding, diagnosis and treatment of jSLE.

Juvenile idiopathic arthritis (JIA) of the temporomandibular joint (TMJ) is common in children, with an increasing awareness of the condition in all healthcare professionals. TMJ involvement presents a challenge in both diagnosis and treatment, as late presentation can still occur as the disease often develops asymptomatically. This can result in facial deformity and/or functional difficulties including obstructive sleep apnoea. Early diagnosis is therefore essential, requiring a high index of clinical suspicion coupled with the judicious use of gadolinium contrast magnetic resonance imaging (MRI). Long-term management is best provided by a multidisciplinary team as patients often need a combination of pharmacological management, surgical interventions, orthodontics, and psychological support. End stage deformity can be treated by different surgical options, each with their own risks and benefits, however recently there is increasing recognition for the role of total alloplastic TMJ replacement. This review focuses on the diagnosis and management of TMJ arthritis and aims to highlight the important role of maxillofacial surgeons in JIA treatment.

Rheumatology teams care for patients with diverse, systemic autoimmune diseases who are often immunosuppressed and at high risk of infections. The current COVID-19 pandemic has presented particular challenges in caring for and managing this patient group. The office of the chief medical officer (CMO) for England contacted the rheumatology community to provide expert advice on the identification of extremely vulnerable patients at very high risk during the COVID-19 pandemic who should be 'shielded'. This involves the patients being asked to strictly self-isolate for at least 12 weeks with additional funded support provided for them to remain at home. A group of rheumatologists (the authors) have devised a pragmatic guide to identifying the very highest risk group using a rapidly developed scoring system which went live simultaneous with the Government announcement on shielding and was cascaded to all rheumatologists working in England.

Summary Background Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are considered important in its causation. Monogenic lupus has been associated with around 30 genotypes in humans and 60 in mice, while genome-wide association studies have identified more than 90 risk loci. We aimed to analyse the contribution of rare and predicted pathogenic gene variants in a population of unselected cases of childhood-onset SLE. Methods For this genetic panel analysis we designed a next-generation sequencing panel comprising 147 genes, including all known lupus-causing genes in humans, and potentially lupus-causing genes identified through GWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteria for SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these data with those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREX Consortium. Findings After filtering, mendelian genotypes were confirmed in eight probands, involving variants in C1QA, C1QC, C2, DNASE1L3, and IKZF1. Seven additional patients carried heterozygous variants in complement or type I interferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9 recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in the childhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified to harbour at least one rare, predicted damaging variant (p=2·98 × 10−11). Inborn errors of immunity were estimated to account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the main monogenic contribution. Interpretation An accumulation of rare variants that are predicted to be damaging in SLE-associated genes might contribute to disease expression and clinical heterogeneity. Funding European Research Council.

Incorporation of barite-fluorspar mine waste (BFMW) as a fine aggregate additive has been investigated for its effect on the mechanical and shielding properties of cement mortar. Several mortar mixtures were prepared with different proportions of BFMW ranging from 0% to 30% as fine aggregate replacement. Cement mortar mixtures were evaluated for density, compressive and tensile strengths, and gamma ray radiation shielding. The results revealed that the mortar mixes containing 25% BFMW reaches the highest compressive strength values, which exceeded 50 MPa. Evaluation of gamma-ray attenuation was both measured by experimental tests and computationally calculated using MicroShield software package, and results have shown that using BFMW aggregates increases attenuation coefficient by about 20%. These findings have demonstrated that the mine waste can be suitably used as partial replacement aggregate to improve radiation shielding as well as to reduce the mortar and concrete costs.

Background There is a challenging lack of evidence to inform best practice in the routine clinical care of juvenile idiopathic arthritis (JIA). Wide inter-centre variation in the definition and documentation of clinical data items is a major barrier to improvement. In response, we have developed a consensus agreed standardised core dataset called CAPTURE-JIA (n = 62 data items and a ‘data dictionary’ including agreed definitions of terms) designed to support routine collection of high-quality clinical data. The feasibility and acceptability of CAPTURE-JIA in clinical practice is not yet known and was the focus of this pilot study. Methods A purposeful sample of six paediatric rheumatology centres across England was invited to collect the CAPTURE-JIA dataset using paper collection forms (n = 20 patients/centre). The dataset was analysed for missing data. Six focus groups (n = 3-10) explored clinicians’ views on acceptability and feasibility. Results One hundred and twenty-one patients were recruited over three months. The completeness of the dataset was similar across centres, with minor variations. The majority of data items (eg demographics, dates, ILAR type and examination) were >80% completed. However, 14/62 data items received >40% missing data. (Table 1) Further descriptive analyses highlighted incorrect completion of paper forms. Three themes emerged from the focus groups: problematic data items (missing from >10% forms at > 1 centre), format of clinician data forms and the role of digital data collection. Suggested solutions included minor changes to data item definitions and formatting. There were no refinements to the data items. Development of a digital data collection system was identified by all as essential. Due to a lack of clear consensus, the original CAPTURE forms included a number of ways to record joint count data. This proved confusing and a unanimous decision was taken to collect joint count data on all 83 joints in a tabular format. P10 Table 1: CAPTURE JIA data items with >40% missing data Data item % forms with data item missing (if item required) Relevant co-morbidities? 60 Macrophage activation syndrome? 100 Has the ILAR subtype changed? 50 Morning stiffness lasting >15 minutes? 42 History of any form of uveitis? 52 Date started uveitis mediation? 50 Strength of uveitis medication? 83 Counselled prior to new DMARD / biologic? 56 Enrolled in BECS/BCRD if new DMARD / biologic? 48 Joint count (homunculus or table format) 48 Physician assessment of systemic disease activity (VAS) 75 ESR 74 CRP 92 Plasma viscosity 100 Conclusion Paper collection of the CAPTURE-JIA data items is feasible and acceptable in the routine clinical setting, but unlikely to be sustainable in the longer term if collected in duplicate with medical notes. A digital tool in the clinical domain, ideally interlocking with local systems, would offer many advantages, including more complete and time-efficient data collection. Conflicts of Interest The authors declare no conflicts of interest.

Background Juvenile-onset systemic lupus erythematosus (JSLE) is more severe than adult-onset disease, including more lupus nephritis (LN). Despite differences in phenotype/pathogenesis, treatment is based upon adult trials. This study aimed to compare treatment response, damage accrual, time to inactive LN and subsequent flare, in JSLE LN patients treated with mycophenolate mofetil (MMF) versus intravenous cyclophosphamide (IVCYC). Methods UK JSLE Cohort Study participants, ≤16 years at diagnosis, with ≥4 American College of Rheumatology criteria for SLE, with class III or IV LN, were eligible. Mann–Whitney U tests, Fisher's exact test and Chi-squared tests were utilized for statistical analysis. Results Of the patients, 34/51 (67%) received MMF, and 17/51 (33%) received IVCYC. No significant differences were identified at 4–8 and 10–14 months post-renal biopsy and last follow-up, in terms of renal British Isles Lupus Assessment Grade scores, urine albumin/creatinine ratio, serum creatinine, ESR, anti-dsDNA antibody, C3 levels and patient/physician global scores. Standardized Damage Index scores did not differ between groups at 13 months or at last follow-up. Inactive LN was attained 262 (141–390) days after MMF treatment, and 151 (117–305) days following IVCYC ( p = 0.17). Time to renal flare was 451 (157–1266) days for MMF, and 343 (198–635) days for IVCYC ( p = 0.47). Conclusion This is the largest study to date investigating induction treatments for proliferative LN in children, demonstrating comparability of MMF and IVCYC.

In January 2017, the Emergency Trauma Advocate (ETA) program was piloted at our Level 1 trauma center to promote patient advocacy, particularly in pediatric patients. The goal was to empower emergency department nurses by improving their knowledge base through interactive didactic sessions. This study reviews the preliminary findings of the program. Surveys were administered after each teaching session to participating ETA nurses to determine their personal academic interests and how to improve the program. We then performed a retrospective review of pediatric trauma admissions from January 2017 through April 2017 to delineate the most common injury patterns. Survey responses demonstrated the greatest nursing interest in learning critical care (n = 11), orthopedic management (n = 11), and neurosurgical trauma education (n = 9). During this study period, 113 pediatric patients arrived and had a mean age of 7.8 ± 5.2 years. The most common injury patterns were orthopedic (n = 38) and neurosurgical (n = 28), and 35 patients required critical care management. Bivariate analysis revealed a significant and positive relationship between injury frequency and educational interests (R = 98.8%, p = .0057). A nurse's interest in educational topics directly correlates with recent pediatric trauma injury patterns. Future work should focus on determining what impact the ETA program has had on pediatric outcomes.

Objective Timely access to holistic multidisciplinary care is the core principle underpinning management of juvenile idiopathic arthritis (JIA). Data collected in national clinical audit programmes fundamentally aim to improve health outcomes of disease, ensuring clinical care is equitable, safe and patient-centred. The aim of this study was to develop a tool for national audit of JIA in the UK. Methods A staged and consultative methodology was used across a broad group of relevant stakeholders to develop a national audit tool, with reference to pre-existing standards of care for JIA. The tool comprises key service delivery quality measures assessed against two aspects of impact, namely disease-related outcome measures and patient/carer reported outcome and experience measures. Results Eleven service-related quality measures were identified, including those that map to current standards for commissioning of JIA clinical services in the UK. The three-variable Juvenile Arthritis Disease Activity Score and presence/absence of sacro-iliitis in patients with enthesitis-related arthritis were identified as the primary disease-related outcome measures, with presence/absence of uveitis a secondary outcome. Novel patient/carer reported outcomes and patient/carer reported experience measures were developed and face validity confirmed by relevant patient/carer groups. Conclusion A tool for national audit of JIA has been developed with the aim of benchmarking current clinical practice and setting future standards and targets for improvement. Staged implementation of this national audit tool should facilitate investigation of variability in levels of care and drive quality improvement. This will require engagement from patients and carers, clinical teams and commissioners of JIA services.

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.

Aicardi-Goutieres syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutieres syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials. (c) 2015 Wiley Periodicals, Inc

Arnold Schoenberg, of course, did not write a piano sonata. At any rate, none of his works for piano bears this title. As I have suggested elsewhere, however, sonata form was much in his thoughts as he wrote the piano pieces of opus 23, and one of his last two pieces for solo piano, written five years later, is a sonata movement which should stand as a model of the integration of twelve-note technique and classical form. When Pierre Boulez, in 1952, famously condemned Schoenberg for using the old forms instead of inventing new ones that were derived entirely from serialism, he might have taken just a moment to consider the ways in which the old form is articulated in opus 33a and been ever so slightly more charitable, for in this sonata movement, as in certain pieces of op. 23, themes and sections are defined and distinguished from each other in ways that have meaning only in relation to the twelve-note technique: though the form is an old one, the several parts are defined by reference to possibilities offered by the new method.

This paper considers the experience of mainstream students who have succeeded in school ‘against the odds’. The paper is Phase Three of a longitudinal study into the affective characteristics and performance of mainstream students.Phase One data (n = 327) revealed very strong relationships between students’ affective characteristics and their previously identified psycho-educational needs. Phase Two involved the tracking of the whole cohort over a four-year period in relation to key performance indicators. The data revealed strong relationships between the students’ affective profiles and their educational performance over time. (For an in-depth overview of Phases One and Two, see Rees & Rees, 2001.)This paper, Phase Three, is focused on 10 case studies of students from the cohort who, on the basis of their affective profiles, were identified as ‘at risk of school failure’, but went on to succeed. ‘Success’ was measured by the students’ academic (SATs) performance, behavioural record, level of attendance and need for additional support. Following their success, these students were interviewed using a semi-structured schedule and assessed using measures of self-esteem, academic self-concept and locus of control. The students’ parents were also interviewed using a semi-structured interview schedule. Teachers completed a questionnaire on each student.The case studies elicited within student, home, school, and community factors that may have contributed to the impressive success of these individuals. The paper discusses these factors and emerging themes.

OBJECTIVE: To determine whether mucocutaneous manifestations are associated with major organ involvement in a UK national cohort of juvenile-onset SLE (JSLE) patients. METHODS: JSLE patients (n = 241) from 15 different centres whose diagnosis fulfilled four or more of the ACR criteria were divided into two groups: those with at least one ACR mucocutaneous criterion (ACR skin feature positive) and those without (ACR skin feature negative) at diagnosis. The relative frequency of skin involvement was described by the paediatric adaptation of the 2004 British Isles Lupus Assessment Group (pBILAG-2004) index. RESULTS: One hundred and seventy-nine patients (74%) had ACR-defined skin involvement with no significant demographic differences compared with those without. ACR skin feature negative patients showed greater haematological (84% vs 67%), renal (43% vs 26%) (P < 0.05) and neurological (16% vs 4%) involvement (P = 0.001). Forty-two per cent of ACR skin feature negative patients had skin involvement using pBILAG-2004, which included maculopapular rash (17%), non-scaring alopecia (15%), cutaneous vasculitis (12%) and RP (12%). ACR skin feature negative patients with moderate to severe skin involvement by pBILAG-2004 showed greater renal and haematological involvement at diagnosis and over the follow-up period (P < 0.05). Higher immunosuppressive drug use in the skin feature negative group was demonstrated. CONCLUSION: Patients who fulfil the ACR criteria but without any of the mucocutaneous criteria at diagnosis have an increased risk of major organ involvement. The pBILAG-2004 index has shown that other skin lesions may go undetected using the ACR criteria alone, and these lesions show a strong correlation with disease severity and major organ involvement.

OBJECTIVE: The objective of this study was to investigate factors that may influence the interval between symptom onset and JSLE diagnosis. METHODS: Data from all patients recruited to the UK JSLE Cohort Study between 2006 and 2011 and meeting ACR criteria for lupus were analysed. Variables associated with time between symptom onset and diagnosis were identified using correlation tests. Linear regression was used to identify independent predictors of access to care. RESULTS: Two hundred and fifty-seven children with JSLE were included in the analysis (216 females, 41 males, ratio 5.3:1). The median time from symptom onset to diagnosis was 0.4 years (range 0.0-14.1 years, interquartile range 0.2-1.4). A linear regression model identified being of African or Caribbean origin (P = 0.006), Asian (P = 0.045), referred by a paediatrician (P = 0.047) or having nephritis (P = 0.045) at presentation as independent predictors of shorter time to diagnosis. Being of Caribbean or Asian origin, compared with white, was associated with a 56% and 37% reduction in geometric mean time to diagnosis, respectively. Similarly, being referred to paediatric rheumatology by a paediatrician or having nephritis at presentation was also associated with a 32% and 36% reduction in geometric mean time to diagnosis, respectively. CONCLUSION: Within this national UK cohort, ethnic origin, initial source of referral and having lupus nephritis at presentation were strong predictors of the interval to establishing a diagnosis of JSLE.

Background Some reports indicate financial concerns as a factor affecting ED patients leaving the acute care setting against medical advice (AMA). In India, no person is supposed to be denied urgent care because of inability to pay. Since a large proportion of the Indian health care system is financed by out-of-pocket expenses, we investigate the role of financial constraints for ED patients at a private hospital in India in leaving AMA. Methods A prospective ED-based cross-sectional survey of patients leaving AMA was conducted at a private hospital in India from 1 October 2010 to 31 December 2010. Descriptive statistics and the chi-square test were used to identify associations between financial factors and the decision to leave the hospital AMA. Results Overall, 55 (3.84%) ED patients left AMA, of which 46 (84%) reported leaving because of financial restrictions. Thirty-nine (71%) respondents indicated the medical bill would represent more that 25% of their annual income. Females (19/19) were more likely to leave AMA for financial reasons compared to males (27/36, p = 0.017). Among females who signed out AMA, the decision was never made by the female herself. Conclusion The number of people leaving the ED AMA in a private Indian hospital is relatively high, with most leaving for financial reasons. In most cases, women did not decide to leave the ED AMA for themselves, whereas males did. This survey suggests that steps are needed to ensure that the inability to pay does not prevent emergent care from being provided.

Less than 10 years ago, Army unit commanders planned battles using topographic paper maps overlaid with information written onto clear plastic acetate. This process was bulky, slow to update and every command post s picture was slightly different. In response to these limitations, the military developed new technologies that provide shared data on digital maps, displayed on several screens in the commander s tactical operations center. First introduced in Operation Iraqi Freedom as stand-alone systems, today s digitized maps use web-based, three-dimensional geospatial technology that pulls in data from various systems onto a single map. This comprehensive, common picture of the battlefield enables collaboration between the commander, Soldiers in the field and higher headquarters for optimal operational planning.

It is almost self-evident that the relationship between rhythm and metre must vary from one composer to another. Generalization in such matters is difficult and probably ill-advised. But it seems clear that for German/Austrian composers in the first half of this century, who customarily used divisive rhythms set within traditional metres, the interdependence of rhythm and metre was not as critical as it was in the music of composers such as Stravinsky and Bartók, whose typically additive rhythms were notated in those metres – often asymmetrical or constantly changing – that most clearly expressed their natural accents. In most cases the rhythms of a Schoenberg or a Webern, as well as-the choice of metre in which to express them, would seem not to have been intrinsic to the original musical idea in the same way that they were to a Stravinsky or a Bartók (even when folk music was not directly involved). This is not to say that rhythm and metre were not important to the two Viennese composers, but only that their conception seems initially to have been more concerned with pitch sequences and contours than with rhythm and metre, these being things that could be worked out later, as composition progressed. The surviving sketches of Webern, at least, appear to bear out such an assertion.

Periplasmic Cu,Zn-superoxide dismutases (Cu,Zn-SODs) are implicated in bacterial virulence. It has been proposed that some bacterial P(1B)-type ATPases supply copper to periplasmic cupro-proteins and such transporters have also been implicated in virulence. Here we show that either of two P(1B)-type ATPases, CopA or GolT, is needed to activate a periplasmic Cu,Zn-SOD (SodCII) in Salmonella enterica serovar Typhimurium. A ΔcopA/ΔgolT mutant accumulates inactive Zn-SodCII which can be activated by copper-supplementation in vitro. In contrast, either single ATPase mutant accumulates fully active Cu,Zn-SodCII. A contribution of GolT to copper handling is consistent with its copper-responsive transcription mediated by DNA-binding metal-responsive activator GolS. The requirement for duplicate transcriptional activators CueR and GolS remains unclear since both have similar tight K(Cu). Mutants lacking periplasmic cupro-protein CueP also accumulate inactive Zn-SodCII and while CopA and GolT show functional redundancy, both require CueP to activate SodCII in vivo. Zn-SodCII is also activated in vitro by incubation with Cu-CueP and this coincides with copper transfer as monitored by electron paramagnetic resonance spectroscopy. These experiments establish a role for CueP within the copper supply pathway for Salmonella Cu,Zn-SodCII. Copper binding by CueP in this pathogen may confer protection of the periplasm from copper-mediated damage while sustaining vital cupro-enzyme activity.

The skin is an organ that is highly sensitive to chronic arsenic (As) exposure. Skin lesions such as hyperkeratoses (HKs) are common early manifestations of arsenicosis in humans. HKs can be precursor lesions of nonmelanoma skin cancers (NMSCs), but the driving forces behind their formation and how they may ultimately progress to NMSCs are unknown. The goal of this study was to examine the global gene expression profiles of As-related HKs in an effort to better understand gene expression changes that are potentially associated with early stages of As carcinogenesis. HK biopsies were removed from individuals living in an arsenicosis-endemic region in Inner Mongolia who had been exposed to high As levels in their drinking water for >20 years. Gene expression profiling was performed on RNA isolated from 7 individuals in this group and from 4 lesion-free skin samples from healthy individuals. Consistent with the pathological characteristics of the HK lesions, major functional categories and known canonical pathways represented by altered transcripts include those involved in development, differentiation, apoptosis, proliferation, and stress response. The results of this study may help define a signature profile of gene expression changes associated with long-term As exposure in the skin.

Lung is a major target for arsenic carcinogenesis in humans by both oral and inhalation routes. However, the carcinogenic mode of action of arsenicals is unknown. We investigated the effects of inorganic arsenic (iAsIII), monomethylarsonous acid (MMAIII), dimethylarsinous acid (DMAIII) and dimethylthioarsinic acid (DMTA), a sulfur containing dimethyl arsenic metabolite, in human bronchial epithelial (BEAS-2B) cells. Cells were exposed to 3, 15 microM-iAsIII; 0.3, 1 microM-MMAIII; 0.2, 1 microM-DMAIII; 0.2, 0.9 microM-DMTA as non-cytotoxic and minimally cytotoxic ( approximately 20%) concentrations based on Neutral Red uptake assays after 24h of culture. Total RNA was isolated and gene expression analysis conducted using Affymetrix Human Genome 133 Plus 2.0 arrays. Differentially expressed genes (DEGs) were determined using a one-way ANOVA (por =0.05) by Rosetta Resolver, a Benjamini-Hochberg FDR (false discovery rate) multiple testing correction (0.05) followed by a Scheffe's post hoc test. For all compounds except DMTA,90% of DEG altered in the low concentration were also changed at the high concentration. There was a clear dose-response seen in the number of DEGs for all four compounds. iAsIII showed the highest number of DEG at both concentrations (2708 and 123, high and low, respectively). 1749, 420 and 120 DEGs were unique to the high concentrations of iAsIII, MMAIII and DMAIII, respectively. Transferrin receptor is a common DEG in low concentration arsenical treated cells. Ingenuity Pathway Analysis revealed p53 signaling (E2F1 and 2, SERPIN), and cell cycle related genes (cyclin D1) were altered by the high concentrations of DMTA, MMAIII and iAsIII. Oxidative stress (DUSP1, GPX2, NQO1, GCLC) and NF-kappaB signaling (TLR4, NF-kappaB) pathways were changed by the high concentrations of MMAIII and iAsIII. The genes identified in this study can be a valuable tool to determine the mechanism of arsenic toxicity and cancer formation. A number of similarities were observed in the gene expression profiles of DMAIII and DMTA and also iAsIII and MMAIII. These findings reveal some biological effects of arsenicals that will aid in creating a better risk assessment model for arsenical-induced lung cancer.