Abstract Case report - Introduction Juvenile Idiopathic Arthritis (JIA) is a lifelong condition in over 50% but there is limited knowledge of JIA in adulthood. We discuss C, who presented in childhood with polyarticular JIA which evolved into systemic lupus erythematosus (SLE). After careful transition she defaulted on care and had a life-threatening SLE flare. In adult services axial symptoms became dominant. Adult rheumatologists queried a third diagnosis of axial spondyloarthropathy, not recognising axial disease as a feature of JIA. This case highlights that knowledge sharing is needed to improve care of adults with JIA and reminds us that transfer can be a risky time. Case report - Case description C presented age 11 with pain and swelling in the small joints of her hands and feet. She was treated for polyarticular JIA with methotrexate and etanercept. At the point of transfer and having had early, detailed transition planning, C developed mouth ulcers, and Raynaud’s with lymphopenia, positive ANA, DsDNA, Ro, Sm, and RNP antibodies, low C4 and an elevated ESR, resulting in a diagnosis of evolving SLE/JIA. Treatment with methotrexate and etanercept continued but C’s adherence became poor. She stopped taking methotrexate due to nausea and ceased etanercept some months previously. C had extra transition support to enhance adherence and transferred into the young adult clinic (YAC) re-established on treatment. After transfer, her SLE became more complex so there was further transition into the adult connective tissue disease (CTD) service. Azathioprine was prescribed but failed to control symptoms and was stopped, although adherence was a significant issue again. C was admitted to hospital with an SLE flare causing rash, inflammatory arthritis, and nephritis with strongly positive DsDNA and low C3 and C4. She also had hyperferritinaemia, anaemia, leucopoenia, neutropenia, a raised CRP, and haemophagocytosis on bone marrow trephine due to haemophagocytic lymphohistiocytosis (HLH). This flare was a life-threatening culmination of poor adherence. C commenced mycophenolate and rituximab during this admission. Engagement improved significantly but C developed back pain associated with a raised CRP. An MRI scan revealed evidence of bilateral sacroiliitis, interpreted by the adult SLE team as possible axial spondyloarthropathy, as she has a history of psoriasis. Referral back to the adolescent team highlighted that axial disease is a feature of polyarticular JIA. Close liaison between the two led to a revision of her diagnosis away from SLE to polyarticular JIA/SLE crossover syndrome with axial disease. C is currently managed with tocilizumab and mycophenolate. Case report - Discussion Paediatric and adolescent rheumatologists recognise that inflammatory disease in young people may evolve: C went from a diagnosis of polyarticular JIA to SLE to possible axial spondyloarthropathy to polyarticular JIA/SLE crossover. C transitioned into the YAC and then into the adult CTD service. There may have been a conflict here between focusing on generic young adult care, as opposed to specialist disease-related care. Defaulting on medical care is a normal phenomenon in adolescent development. For C this resulted in a life-threatening SLE flare. In adolescents, it is crucial to recognise transfer as a high-risk time, to remain alert to potential non-adherence and to chase up non-attendance especially immediately after seemingly successful transfer. Therefore, extra appointments and support may be needed in adult services. JIA is a small yet significant part of general adult rheumatology workload. In Sheffield, JIA comprises 4% of the adult inflammatory arthritis service (compared with 39% for rheumatoid arthritis (RA), the commonest adult inflammatory arthritis). There is little in the literature about the phenotype or treatment of JIA in adults leading to the relative invisibility of JIA in adult rheumatology and relabelling of JIA as RA. Management of adolescent and adult JIA is further complicated by the differing definition and distributions of active joints between JIA and adult inflammatory arthritis. Both recognise tender and swollen joints as active, but in paediatrics, restricted joints are also ‘active’. Paediatric joint counts include all joints, not just selected joints as in, for example, DAS28 in RA. The burden of adolescent and adult JIA may be under-recognised and under-treated. For C this led to delayed recognition of axial disease in adult services, but early and close working of adolescent and adult specialists led to the correct diagnosis and reinforces the importance of taking a life course approach to JIA. Case report - Key learning points C was managed in a seamless service where child-to-adult pathways are well developed. Despite this, she had significant non-adherence to medication, causing a life-threatening disease flare. The period immediately after transfer may be one of particular vulnerability and should be a target for extra support in adult services. Adult rheumatology is often super-specialised and just as transition from child to adult services may risk information being lost and a failure of developmentally appropriate care, transition within adult services (here from the YAC to the specialist CTD clinic) may also be challenging for patients and professionals alike. What worked well here was referral back to the YAC when axial disease was recognised and the shared approach to diagnosis and appropriate management. The optimum way to assess JIA activity in adults is not established. There is evidence that using scores for rheumatoid arthritis such as DAS28 risks underestimating JIA activity and denying young people access to treatment but there are no validated scores for adult JIA. This is a key area for future research. JIA persists into adult life in at least half of those with childhood onset disease. It is important that all rheumatologists appreciate the course, impact, and phenotypes of JIA in adults, to ensure the best outcomes and treatment. Young adult clinics are an ideal way to ensure developmentally appropriate care, but may not be feasible in all services, making education about JIA for adult rheumatologists (which paediatric and adolescent rheumatologists are ideally placed to deliver) all the more necessary. Young people with JIA need to be continually educated about their disease especially at transfer to adult services so they can remind adult rheumatologists that they have JIA. Good collaboration across all areas of rheumatology improves care for children, adolescents, and adults with rheumatic disease
Abstract BACKGROUND Ependymomas are heterogenous group of tumours with variable clinical course and diverse molecular features. RELA fusion status has been reported to have prognostic impact in ST-EPEN. Our retrospective study analysed the prevalence and clinical impact of RELA fusion in childhood ST-EPEN at our centre. STUDY METHODS FFPE tissues of all childhood ST-EPEN diagnosed during 2011–2017 were evaluated for RELA fusion 1/2 by RT-PCR. Children were treated as per guidelines by the Neuro-oncology multidisciplinary team. Outcomes were correlated with RELA fusion, histological features and immunohistochemical parameters(L1CAM expression and Mib-1 index). Only patients with therapy details were included. RESULTS A total of 37 patients(0–50 years) with ST-EPEN were included(median age-10.2 years; boy:girl ratio-1.4:1)for analysis. Histological grade II, II/III and III was seen in 4(11%),2(5%) and 31(84%) patients respectively. Mib-1 index was assessable in 33 patients of which, 9 patients (24%) had a Mib-1 index >20%. RELA fusion was detected in 13(35%)tumors. The 3-year and 5-year EFS/OS of the overall cohort was 64.2%/83.6% and 60.1%/73.1% respectively. The 3-year/5-year EFS of RELA-positive tumors was inferior compared to RELA-negative tumours (53.8%/36% v/s 62.6%/53.6%; p=0.391). The 3-year/5-year EFS of tumors expressing L1CAM versus negative-expression was comparable (61.1%/55%v/s59.8%/47.9%;p=0.44). Presence of Mib-1>20% correlated with inferior survival (5-year EFS:81.1%vs22.2%; p<0.01). CONCLUSIONS ST-EPEN with RELA fusion had trend towards increased relapse/progression. High Mib-1 correlated with poor survival. RELA fusion status needs to be studied in a larger cohort prospectively to confirm its clinical impact.
Abstract Background Individuals at clinical high risk (CHR) of psychosis have an approximately 20% probability of developing psychosis within 2 years, as well as an associated risk of non-psychotic disorders and functional impairment. People with subclinical psychotic experiences (PEs) are also at risk of future psychotic and non-psychotic disorders and decreased functioning. It is difficult to accurately predict outcomes in individuals at risk of psychosis on the basis of symptoms alone. Biomarkers for accurate prediction of outcomes could inform the clinical management of this group. Methods We conducted two nested case-control studies. Study 1, a clinical high-risk (CHR) sample, was nested within the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) cohort study. The sample comprised 133 CHR participants who were followed clinically for up to 6 years, of whom 49 transitioned to psychosis and 84 did not. Study 2, a general population sample, was nested within the Avon Longitudinal Study of Parents and Children (ALSPAC). The sample comprised 121 participants who did not report psychotic experiences (PEs) at age 12, of whom 55 later reported PEs at age 18 and 66 did not. We employed discovery-based proteomic methods to analyse protein expression in baseline plasma samples in EU-GEI and age 12 plasma samples in ALSPAC using liquid chromatography mass spectrometry. Differential expression of quantified proteomic markers was determined by analyses of covariance (with false discovery rate of 5%) comparing expression levels for each marker between those who did not and did not develop psychosis in Study 1 (adjusting for age, gender, body mass index and years in education), and between those who did and did not develop PEs in Study 2 (adjusting for gender, body mass index and maternal social class). Support vector machine algorithms were used to develop models for prediction of transition vs. non-transition (as determined by the Comprehensive Assessment of At Risk Mental States) and poor vs. good functional outcome at 2 years in Study 1 (General Assessment of Functioning: Disability subscale score 60). Similar algorithms were used to develop a model for prediction of PEs vs. no PEs at age 18 in Study 2 (as determined by the Psychosis Like Symptoms Interview). Results In Study 1, 35 of 166 quantified proteins were significantly differentially expressed between CHR participants who did and did not develop psychosis. Functional enrichment analysis provided evidence for particular implication of the complement and coagulation cascade (false discovery rate-adjusted Fisher’s exact test p=2.23E-21). Using 65 clinical and 166 proteomic features a model demonstrated excellent performance for prediction of transition status (area under the receiver-operating curve [AUC] 0.96, positive predictive value [PPV] 83.0%, negative predictive value [NPV] 93.8%). A model based on the ten most predictive proteins accurately predicted transition status in training (AUC 0.96, PPV 87.5%, NPV 95.8%) and withheld data (AUC 0.92, PPV 88.9%, NPV 91.4%). A model using the same 65 clinical and 166 proteomic features predicted 2-year functional outcome with AUC 0.72 (PPV 67.6%, NPV 47.6%). In Study 2, 5 of 265 quantified proteins were significantly differentially expressed between participants who did and did not report PEs at age 18. A model using 265 proteomic features predicted PEs at age 18 with AUC 0.76 (PPV 69.1%, NPV 74.2%). Discussion With external validation, models incorporating proteomic data may contribute to improved prediction of clinical outcomes in individuals at risk of psychosis.
Abstract Background In an effort to support stewardship endeavors, the MITIGATE (a Multifaceted Intervention to Improve Prescribing for Acute Respiratory Infection for Adult and Children in Emergency Department and Urgent Care Settings) Toolkit was published in 2018, aiming to reduce unnecessary antibiotics for viral respiratory tract infections (RTIs). At the University of Washington, we have incorporated strategies from this toolkit at our urgent care clinics. This study aims to address solutions to some of the challenges we experienced. Challenges and Solutions Methods This was a retrospective observational study conducted at Valley Medical Center (Sept 2019-Mar 2020) and the University of Washington (Jan 2019-Feb 2020) urgent care clinics. Patients were identified through ICD-10 diagnosis codes included in the MITIGATE toolkit. The primary outcome was identifying challenges and solutions developed during this process. Results We encountered five challenges during our roll-out of MITIGATE. First, using both ICD-9 and ICD-10 codes can lead to inaccurate data collection. Second, technical support for coding a complex data set is essential and should be accounted for prior to beginning stewardship interventions of this scale. Third, unintentional incorrect diagnosis selection was common and may require reeducation of prescribers on proper selection. Fourth, focusing on singular issues rather than multiple outcomes is more feasible and can offer several opportunities for stewardship interventions. Lastly, changing prescribing behavior can cause unintended tension during implementation. Modifying benchmarks measured, allowing for bi-directional feedback, and identifying provider champions can help maintain open communication. Conclusion Resources such as the MITIGATE toolkit are helpful to implement standardized data driven stewardship interventions. We have experienced some challenges including a complex data build, errors with diagnostic coding, providing constructive feedback while maintaining positive stewardship relationships, and choosing feasible outcomes to measure. We present solutions to these challenges with the aim to provide guidance to those who are considering using this toolkit for outpatient stewardship interventions. Disclosures All Authors: No reported disclosures
Abstract Eight to ten percent of children have a developmental disability (DD). Caring for a child with DD can be rewarding. It can also be difficult, particularly for older parents or other caregivers (hereafter parents). Few studies have examined their experiences. We followed parents for 18 years using the nationally representative Panel Study of Income Dynamics (PSID). We defined DD with criteria used in research and education law, as: (1) autism, intellectual disability, learning disorder, epilepsy with seizures, attention deficit disorder/attention deficit hyperactivity disorder, cerebral palsy, or traumatic brain injury; and (2) qualification for professional services. We used three waves of the PSID’s Childhood Development Study, 1997-2007, linking children’s and parents’ PSID data (n=4,070) to study three outcomes: parents “not very” or “not at all” satisfied with “life as a whole”; nonspecific psychological distress; and reports that depressive feelings interfered with life or activities “a lot.” Discrete-time hazard models controlled for: child disability; children’s and parents’ age, sex, and education; survey design; and repeated measures. Among parents ages 47-61 at baseline (65-79 in 2015), those who cared for a child with DD were significantly more likely to report low satisfaction with life (hazard ratio, HR 4.6, 95% confidence interval, CI 1.6-13.2), distress (HR 2.8, CI 1.1-6.9) and, among women, depressive feelings (HR 1.3 CI 1.0-1.8). We found no such differences for parents less than age 65 in 2015. Results highlight the need to provide emotional support, respite, or other services for older adults caring for children with disabilities.
Abstract Background Little is known about the epidemiology of Cytomegalovirus (CMV) infection in low resource countries. We evaluated the frequency and effects of post-natal CMV infection in infants from a prospective cohort study designed to assess the effects of post-natal Zika on neurodevelopment (ND) in rural Guatemala. Infants with CMV infection (blue bars) were older compared CMV-negative (red bars) infants. Methods Infants were evaluated for CMV infection by PCR using urine samples collected at 0-3 months of age. ND testing was conducted by local psychologists using a culturally adapted Mullen Scales of Early Learning (MSEL). We explored associations between CMV infection and microcephaly, neurological, visual and hearing deficits, malnutrition and ND outcomes at 1 year of age. Results The infant cohort (N = 469) had a mean age at enrollment of 1.5 (SD 0.75) months; 47% were female and 71% were breastfeeding at 1 year. A total of 103 (22%) were CMV positive and the majority of these (97%) were > 4 weeks of age at testing. Infants > 4 weeks of age were more likely to be CMV positive (P < 0.0001) (Figure). Gender was not correlated with CMV positivity. Among children with head circumference (HC) measurements, microcephaly (HC < 2 SD) was present in 9/87 (10.3%) CMV positive and 35/338 (10.4%) CMV negative infants at 0-3 months of age (p =0.99). Among 438 infants who underwent screening for hearing deficits and a complete ophthalmologic evaluation, none of the CMV positive children had abnormal vision or hearing. Abnormal neurological exams in the first year of life occurred in 50/100 (50%) CMV positive and 166/365 (45.5%) CMV negative infants (p =0.56). There was no association between CMV infection at 0-3 months and MSEL overall or subdomain scores at 1 year (overall Relative risk (RR) 1.02, 95% CI 0.99-1.05, p=0.16). Malnutrition at 0-3 months (RR: 1.53, 95% CI 0.89-2.66, p = 0.13) and 1 year (RR: 1.10, 95% CI 0.77-1.58, p=0.59) was not associated with CMV infection at 0-3 months. Conclusion In a cohort of Guatemalan infants, postnatal CMV infection was common (22%) and more likely to occur after the neonatal period. There was no correlation between CMV infection and microcephaly at 0-3 months or at 1 year of age, nor with abnormal nutritional, neurologic, ophthalmologic, hearing or ND deficits at 1 year of age. This is the first epidemiologic report on CMV infection in early life in rural Guatemala. Disclosures Molly Lamb, PhD, BioFire (Grant/Research Support)
ABSTRACT IMPACT: This study evaluates the long term effects of pharmacologic weaning therapy for opiate exposed infants. OBJECTIVES/GOALS: Infants born to chronic opioid users often suffer from neonatal abstinence syndrome (NAS), a condition characterized by tremors, diarrhea, hyperirritability and an inconsolable high-pitched cry. Symptoms are treated with pharmacologic weaning therapy, but long-term effects of this treatment have not been established. METHODS/STUDY POPULATION: A sample of infants born between 2011-2017 was obtained from a large metropolitan hospital system. All infants who were exposed to opioids and received a Finnegan score were included in the sample (N=1,807). The analysis utilizes three dependent variables to measure developmental delay: motor delay, language delay or any delay, which includes general/non-specific delay in addition to motor and language delay. The treatment is defined as receipt of pharmacologic therapy with methadone or morphine. Maximum Finnegan score was also included as a continuous measure of the extent of the infant’s withdrawal symptoms. Linear models were utilized to determine a relationship between pharmacologic therapy and developmental delay with Maximum Finnegan score as an interaction term. RESULTS/ANTICIPATED RESULTS: In the linear models examining the main effects of weaning therapy on developmental delay, there was no relationship between pharmacologic therapy and motor delay (p=.260), language delay (p=.542) or any developmental delay (p=.176). When maximum Finnegan score was entered into the model as an interaction term the relationships were not significant. DISCUSSION/SIGNIFICANCE OF FINDINGS: These results suggest that while pharmacologic weaning is an appropriate treatment for withdrawal symptoms in infants, it is not a deterrent against developmental delays associated with NAS. This provides support suggest an increased focus on non-pharmacologic interventions such as breastfeeding as the first line of treatment for NAS infants.
Abstract BACKGROUND Apparent diffusion coefficient (ADC) is a quantitative measure reflecting observed net movement of water calculated from a diffusion-weighted image (DWI), correlating with tumor cellularity. The higher cellularity of high-grade gliomas results in diffusion restriction and reduced ADC values, whereas the lower cellularity of low-grade gliomas (LGGs) gives higher ADC values. Here we examine changes in ADC values in patients with LGGs treated with the type 2 RAF inhibitor DAY101 (formerly TAK580). METHODS Historical, baseline, and on-treatment brain MRIs for 9 patients enrolled on a phase 1 study of DAY101 in children and young adults with radiographically recurrent or progressive LGG harboring MAPK pathway alterations were obtained, de-identified and independently evaluated for ADC changes. Time points included baseline, first follow-up, and best response. Data processing of ADC estimates was performed using pmod molecular image software package. ADC changes were displayed as a histogram with mean values. Results were based upon a single read paradigm. RESULTS There was a clear shift to lower ADC values for the solid component of tumors, reflecting changes in cellularity and tissue organization, while necrosis correlated with a shift toward higher ADC values. DWI reveals reduced ADCs in responding tumors, with the percent change in ADC from baseline correlating with deeper RANO responses. CONCLUSION DWI analysis reveals reductions in ADC values that correlates with treatment response and a shift toward more normal cellularity in tumors treated with DAY101. Changes in ADC may represent a novel imaging biomarker, reflecting biological response to DAY101 treatment.
Abstract BACKGROUND Medulloblastoma (MB), the most malignant brain tumor of childhood has survival outcomes exceeding 80% for standard risk and 60% for high risk patients in high-income countries (HIC). These results have not been replicated in low-to-middle income countries (LMIC), where 80% of children with cancer live. Brazil is an upper-middle income country according to World Bank, with features of LMIC and HIC. METHODS We conducted a retrospective review of 126 children (0–18 years) diagnosed with MB from 1997 to 2016 at INCA. Data on patients, disease characteristics and treatment information were retrieved from the charts and summarized descriptively; overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier Method. RESULTS The male/female ratio was 1.42 and the median age at diagnosis was 7.9 years. Headache (79%) and nausea/vomiting (75%) were the most common presenting symptoms. The median time from onset of symptoms to surgery was 50 days. The OS for standard-risk patients was 69% and 53% for high-risk patients. Patients initiating radiation therapy within 42 days after surgery (70.6% versus 59.6% p=0.016) experienced better OS. Forty-five patients (35%) had metastatic disease at admission. Lower maternal education correlated with lower OS (71.3% versus 49% p=0.025). Patients who lived >40km from INCA fared better (OS= 68.2% versus 51.1% p=0.032). Almost 20% of families lived below the Brazilian minimum wage. CONCLUSIONS These findings suggest that socioeconomic factors, education, early diagnosis and continuous data collection, besides oncological treatment must be adressed to improve the survival of children with MB.
Abstract Background: Healthy Ageing is the process of the development and maintenance of functional capacity which allows well-being at an older age. This understanding is comprehensive and relevant for all older persons. Despite the global attention being given to healthy ageing, there is limited information on the perceptions of this concept among older persons in low resource settings like Nigeria, hence the need for this study. Methods: In depth interviews were conducted among older persons aged 60 years and above residing in Idikan Community, an urban slum area in Ibadan, Nigeria. Using an interview guide, perceptions of older persons on meanings of healthy ageing, factors related to healthy ageing and experience of ageing were explored. Results: A total number of 24 interviews were conducted. Slightly more than half of the respondents were females. The majority of the respondents were of the opinion that healthy ageing is about being “ strong” and able to move around, without being dependent on anyone for mobility and activities of daily living. In their opinion, healthy ageing is related to different health dimensions: biological (adoption of healthy habits and behaviors with self-responsibility, psychological (feelings of optimism and happiness), spiritual (faith and religiosity) and family and social support (healthy and well children, friends and family). Conclusion: Urban Community dwelling older persons’ perception of healthy ageing was positive and incorporating their opinions on healthy aging from the perspective of the older persons can support the activities of professionals who work with this population group.
