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Background. Severe H1N1 influenza can be lethal in otherwise healthy individuals and can have features of reactive hemophagocytic lymphohistiocytosis (HLH). HLH is associated with mutations in lymphocyte cytolytic pathway genes, which have not been previously explored in H1N1 influenza. Methods. Sixteen cases of fatal influenza A(H1N1) infection, 81% with histopathologic hemophagocytosis, were identified and analyzed for clinical and laboratory features of HLH, using modified HLH-2004 and macrophage activation syndrome (MAS) criteria. Fourteen specimens were subject to whole-exome sequencing. Sequence alignment and variant filtering detected HLH gene mutations and potential disease-causing variants. Cytolytic function of the PRF1 p.A91V mutation was tested in lentiviral-transduced NK-92 natural killer (NK) cells. Results. Despite several lacking variables, cases of influenza A(H1N1) infection met 44% and 81% of modified HLH-2004 and MAS criteria, respectively. Five subjects (36%) carried one of 3 heterozygous LYST mutations, 2 of whom also possessed the p.A91V PRF1 mutation, which was shown to decrease NK cell cytolytic function. Several patients also carried rare variants in other genes previously observed in MAS. Conclusions. This cohort of fatal influenza A(H1N1) infections confirms the presence of hemophagocytosis and HLH pathology. Moreover, the high percentage of HLH gene mutations suggests they are risk factors for mortality among individuals with influenza A(H1N1) infection.

Background Improved, noninvasive biomarkers are needed to accurately detect lupus nephritis (LN) activity. The purpose of this study was to evaluate five S100 proteins (S100A4, S100A6, S100A8/9, and S100A12) in both serum and urine as potential biomarkers of global and renal system-specific disease activity in childhood-onset systemic lupus erythematosus (cSLE). Methods In this multicenter study, S100 proteins were measured in the serum and urine of four cSLE cohorts and healthy control subjects using commercial enzyme-linked immunosorbent assays. Patients were divided into cohorts on the basis of biospecimen availability: (1) longitudinal serum, (2) longitudinal urine, (3) cross-sectional serum, and (4) cross-sectional urine. Global and renal disease activity were defined using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the SLEDAI-2K renal domain score. Nonparametric testing was used for statistical analysis, including the Wilcoxon signed-rank test, Kruskal-Wallis test, Mann-Whitney U test, and Spearman’s rank correlation coefficient. Results All urine S100 proteins were elevated in patients with active LN compared with patients with active extrarenal disease and healthy control subjects. All urine S100 protein levels decreased with LN improvement, with S100A4 demonstrating the most significant decrease. Urine S100A4 levels were also higher with proliferative LN than with membranous LN. S100A4 staining in the kidney localized to mononuclear cells, podocytes, and distal tubular epithelial cells. Regardless of the S100 protein tested, serum levels did not change with cSLE improvement. Conclusions Higher urine S100 levels are associated with increased LN activity in cSLE, whereas serum S100 levels do not correlate with disease activity. Urine S100A4 shows the most promise as an LN activity biomarker, given its pronounced decrease with LN improvement, isolated elevation in urine, and positive staining in resident renal cells.

Background Patient-reported outcomes (PROs) are critical assessment tools for clinical practice, observational studies, and interventional trials. While families of children with systemic juvenile idiopathic arthritis (SJIA) and SJIA-associated lung disease (SJIA-LD) report significant limitations in their quality of life, existing PROs for juvenile idiopathic arthritis may not properly measure the full impact of these disorders. Our objective was to utilize a newly developed lung symptom survey as well as existing, validated Patient-Reported Outcomes Measurement Information System (PROMIS) measures in children with SJIA with and without LD. Methods Participants were parents/guardians of SJIA patients ≤ 18 years and were invited to participate using the Cincinnati Children’s Hospital Medical Center (CCHMC) JIA Registry, and memberships in the Systemic JIA Foundation, and SJIA Facebook Group. Participants provided proxy-reports for their child using several PRO questionnaires [CCHMC Lung Symptom Survey; PROMIS Asthma Impact, Sleep Disturbance, Sleep Impairment Forms] and selected demographic and SJIA specific information. Results There were 139 responses, of which 40.3% ( n  = 57) reported some lung disease including 12.9% ( n  = 20) with interstitial lung disease (ILD), pulmonary alveolar proteinosis (PAP) and/or pulmonary artery hypertension (PAH). All SJIA patients with any lung disease and those with ILD/PAP/PAH had significantly higher total questionnaire scores than patients without lung disease on the CCHMC Lung Symptoms Survey. Both the full survey and individual questions showed good ability to distinguish patients with ILD/PAP/PAH from those without (area under the curve (AUC) > 0.7). The majority of patients reported some level of sleep disturbance ( n  = 71/139 = 51.1%) and sleep impairment 53.2% ( n  = 74) regardless of presence or absence of lung disease, including moderate to severe sleep impairment and/or disturbance in 48% of SJIA patients. Conclusions Children with SJIA and lung problems had higher scores on the CCHMC Lung Symptom Survey; however, these measures did not discriminate between SJIA-LD and other pulmonary conditions such as asthma. Based on PROMIS measures, a majority of children with SJIA had sleep disturbance and impairment, regardless of steroid use or presence of lung disease.

BackgroundBiomarkers in easily obtained specimens that accurately predict uveitis in children with juvenile idiopathic arthritis (JIA) are needed. Aqueous humor has been studied for biomarkers, but is not routinely available. We evaluated tears from children with chronic anterior uveitis (CAU) for biomarkers reported in aqueous humor.In this pilot study, we used Schirmer strips to collect tears from seven children (nine eyes); three children had JIA- associated uveitis (JIA-U) and four had idiopathic disease (I-CAU). Liquid chromatography-tandem mass spectrometry was used to identify and quantify tear proteins. The Mann-Whitney U test identified differential tear protein expression between children with JIA-U and those with I-CAU.ResultsS100A9, LAP3, TTR, MIF, sCD14, S100A8, and SAA1 were detected in tears of all children; the same cytokines have been reported in aqueous humor of children with JIA-U. Tears from children with JIA-U had higher expression of proteins associated with inflammatory arthritis (SEMA3G, TIMP1, HEXB, ERN1, and SAA1) than tears from those with I-CAU. In addition, we found higher expression of sCD14, S100A8, and SAA1, but lower expression of S100A9, LAP3, TTR, and MIF, in tears from children with JIA-U compared to tears from those with I-CAU.ConclusionsTears contain similar cytokine profiles to aqueous humor in children with CAU and may be a clinically useful source of disease biomarkers. Tears from children with JIA-U also contain cytokines associated with inflammatory arthritis; furthermore, differential expression of other tear proteins as well may provide clues to intrinsic differences between JIA-U and I-CAU, despite their similar clinical phenotypes.

IntroductionRheumatic heart disease (RHD) affects over 39 million people worldwide, the majority in low-income and middle-income countries. Secondary antibiotic prophylaxis (SAP), given every 3–4 weeks can improve outcomes, provided more than 80% of doses are received. Poor adherence is strongly correlated with the distance travelled to receive prophylaxis. Decentralising RHD care has the potential to bridge these gaps and at least maintain or potentially increase RHD prophylaxis uptake. A package of implementation strategies was developed with the aim of reducing barriers to optimum SAP uptake.Methods and analysisA hybrid implementation-effectiveness study type III was designed to evaluate the effectiveness of a package of implementation strategies including a digital, cloud-based application to support decentralised RHD care, integrated into the public healthcare system in Uganda. Our overarching hypothesis is that secondary prophylaxis adherence can be maintained or improved via a decentralisation strategy, compared with the centralised delivery strategy, by increasing retention in care. To evaluate this, eligible patients with RHD irrespective of their age enrolled at Lira and Gulu hospital registry sites will be consented for decentralised care at their nearest participating health centre. We estimated a sample size of 150–200 registrants. The primary outcome will be adherence to secondary prophylaxis while detailed implementation measures will be collected to understand barriers and facilitators to decentralisation, digital application tool adoption and ultimately its use and scale-up in the public healthcare system.Ethics and disseminationThis study was approved by the Institutional Review Board (IRB) at Cincinnati Children’s Hospital Medical Center (IRB 2021-0160) and Makerere University School of Medicine Research Ethics Committee (Mak-SOMREC-2021-61). Participation will be voluntary and informed consent or assent (>8 but <18) will be obtained prior to participation. At completion, study findings will be communicated to the public, key stakeholders and submitted for publication.

IntroductionOver 46 million people are living with rheumatic heart disease (RHD) globally, resulting in 380 000 premature deaths each year. Effective RHD prevention strategies are known but their implementation in low-resource settings has lagged. This study evaluated the feasibility and effectiveness of integrating secondary antibiotic prophylaxis into primary health centres to improve access and adherence to RHD care.MethodsWe conducted a hybrid type III study using a mixed-method, pre–post design to evaluate a package of implementation strategies centred on decentralised RHD care and use of an electronic medical record in Gulu and Lira, Uganda. We combined clinical and programmatic data with provider and patient interviews to assess effectiveness, adoption and acceptability. The mean difference in the annualised percentage of days adherent to benzathine penicillin G (BPG) monthly injections predecentralisation and postdecentralisation was calculated using linear mixed effect regression. Thematic analysis was used to analyse qualitative data.ResultsWe decentralised 151 patients (median age 17.9 years, 64% female) from district hospitals to eight primary health centres. The percentage of days adherent to BPG was 77.2% predecentralisation and 80.5% postdecentralisation (mean difference 3.25, (95% CI −0.72 to 6.86), p=0.081), which was statistically non-inferior at the −10% non-inferiority margin. Interview data identified knowledge, confidence and intrinsic motivation as major determinants of provider adoption. Patients expressed mixed feelings towards pain control and provider services, but convenience and financial savings resulted in a high level of acceptability. The electronic registry presented challenges in a naive environment but showed a strong potential as an oversight tool at the district level.DiscussionThis study is the first to demonstrate that decentralised RHD care is effective in sub-Saharan Africa. Lessons learnt provide a platform for future integration of RHD services countrywide, with implications for increasing access to and scale-up of secondary prevention measures for RHD care in Uganda.

BackgroundScreening programmes using echocardiography offer opportunity for intervention through identification and treatment of early (latent) rheumatic heart disease (RHD). We aimed to compare two methods for classifying progression or regression of latent RHD: serial review method and blinded, side-by-side review.MethodsA four-member expert panel reviewed 799 enrolment (in 2018) and completion (in 2020) echocardiograms from the GOAL Trial of latent RHD in Uganda to make consensus determination of normal, borderline RHD or definite RHD. Serial interpretations (enrolment and completion echocardiograms read at two different time points, 2 years apart, not beside one another) were compared with blinded side-by-side comparisons (enrolment and completion echocardiograms displayed beside one another in random order on same screen) to determine outcomes according to prespecified definitions of disease progression (worsening), regression (improving) or no change. We calculated inter-rater agreement using Cohen’s kappa.ResultsThere were 799 pairs of echocardiogram assessments included. A higher number, 54 vs 38 (6.8% vs 4.5%), were deemed as progression by serial interpretation compared with side-by-side comparison. There was good inter-rater agreement between the serial interpretation and side-by-side comparison methods (kappa 0.89). Disagreement was most often a result of the difference in classification between borderline RHD and mild definite RHD. Most discrepancies between interpretation methods (46 of 47, 98%) resulted from differences in valvular morphological evaluation, with valves judged to be morphologically similar between enrolment and final echocardiograms when compared side by side but classified differently on serial interpretation.ConclusionsThere was good agreement between the methods of serial and side-by-side interpretation of echocardiograms for change over time, using the World Heart Federation criteria. Side-by-side interpretation has higher specificity for change, with fewer differences in the interpretation of valvular morphology, as compared with serial interpretation.

Background: Systemic Juvenile Idiopathic Arthritis (SJIA) is a subset of JIA that affects up to 15% of this population. In the past decade, chronic lung disease has emerged as a life-threatening complication of SJIA (SJIA-LD). Due to the novelty of this disorder, patient-reported outcomes and Health-Related Quality of Life (HRQOL) research is limited.Purpose: The main goal of this two-phase dissertation was to gain a better understanding of the lived experience of families caring for a child with SJIA-LD and to evaluate a current clinical measure for its ability to adequately capture those experiences. The following research questions were addressed in this dissertation: (1) What is the impact of SJIA-LD on affected children and their families, (2) What experiences of HRQOL domains for SJIA-LD are accurately captured by the PROMIS measures, and (3) What experiences of HRQOL domains for SJIA-LD are missing from the PROMIS measures.Methods: Phase 1of this project was a qualitative descriptive study designed to gain an understanding of the impact of SJIA-LD on patients' and families' quality of life through a series of in-depth interviews and focus groups conducted with primary caregivers of children with SJIA-LD. During Phase 2 of the project, cognitive interviews were conducted with these same caregivers to assess the PROMIS measures for potential use as an HRQOL tool. Participants were recruited from the Cincinnati Children's Hospital Rheumatology clinic and the Systemic Juvenile Arthritis Foundation.Results: Using descriptive qualitative methodologies, we embarked on the journey of understanding the experience of parents caring for children with SJIA-LD. Several salient themes and sub-themes emerged from the data analysis. The first described theme \"Setting Course\" reflects caregiver's reaction to the lung disease diagnosis with a focus on finding the best care and helping the child cope with the disease. \"Uncharted Territory\" is a theme that centers around the uncertainties and challenges of navigating life with this diagnosis and include sub-themes such as COVID and fears. The last important theme that emerged from this diagnosis was \"Destination Unknown\" which details participants perceptions of the coming to terms with the diagnosis and what the changes for every family member. During the cognitive interview, caregivers provided valuable feedback on the relevance of the PROMIS domains and items to their child's experience. All the three PROMIS domains (physical, mental and social health) were deemed relevant by participants, however the physical domain items were prioritized over the other items.Conclusion: This study demonstrated that, like other childhood chronic disorders, SJIA-LD has a negative impact on HRQOL for the affected children and the entire family. One of the most striking findings from this study is the toll delayed diagnosis takes on the entire family, especially parents. This is compounded by the fact that SJIA-LD is a rare not yet well understood disorder and finding knowledgeable healthcare providers is a notable challenge. Work to further explore the impact of SJIA-LD is needed to ensure diverse voices including affected children, siblings and other care givers voices are incorporated in future instruments.

ObjectivesSystemic juvenile idiopathic arthritis (SJIA) confers high risk for macrophage activation syndrome (MAS), a life-threatening cytokine storm driven by interferon (IFN)-γ. SJIA monocytes display IFN-γ hyper-responsiveness, but the molecular basis of this remains unclear. The objective of this study is to identify circulating monocyte and bone marrow macrophage (BMM) polarisation phenotypes in SJIA including molecular features contributing to IFN response.MethodsBulk RNA-seq was performed on peripheral blood monocytes (n=26 SJIA patients) and single cell (sc) RNA-seq was performed on BMM (n=1). Cultured macrophages were used to define consequences of tripartite motif containing 8 (TRIM8) knockdown on IFN-γ signalling.ResultsBulk RNA-seq of SJIA monocytes revealed marked transcriptional changes in patients with elevated ferritin levels. We identified substantial overlap with multiple polarisation states but little evidence of IFN-induced signature. Interestingly, among the most highly upregulated genes was TRIM8, a positive regulator of IFN-γ signalling. In contrast to PBMC from SJIA patients without MAS, scRNA-seq of BMM from a patient with SJIA and MAS identified distinct subpopulations of BMM with altered transcriptomes, including upregulated IFN-γ response pathways. These BMM also showed significantly increased expression of TRIM8. In vitro knockdown of TRIM8 in macrophages significantly reduced IFN-γ responsiveness.ConclusionsMacrophages with an ‘IFN-γ response’ phenotype and TRIM8 overexpression were expanded in the bone marrow from an MAS patient. TRIM8 is also upregulated in SJIA monocytes, and augments macrophage IFN-γ response in vitro, providing both a candidate molecular mechanism and potential therapeutic target for monocyte hyper-responsiveness to IFNγ in cytokine storms including MAS.