Soluble Receptor for Advanced Glycation End Products (sRAGE) is decreased in patients with Juvenile Idiopathic Arthritis (ERA category) and inversely correlates with disease activity and S100A12 levels

Objectives: Membrane bound receptor for advanced glycation end products (RAGE) is over-expressed in response to increasing concentrations of its ligand (eg S100A12) and triggers an inflammatory immune response. Its truncated form sRAGE acts as decoy receptor and competes for ligands thus down-modulating inflammation. Decreased sRAGE levels are associated with rheumatoid arthritis, Sjogren syndrome and Kawasaki disease, however limited data is available in JIA thus we studied its levels in JIA-ERA patients. Methods: sRAGE levels were estimated in serum of patients with ERA (n=101), SoJIA and polyJIA (n=10 each) and healthy controls (n=45). Synovial fluid (SF) sRAGE was measured in ERA, RA, ReA and OA patients (n=10). S100A12 levels were also measured. 24 ERA patients were followed up for 4 months. Disease activity was assessed by swollen joint count (SJC), tender joint count (TJC) and ESR. Results: Serum sRAGE (pg/ml) level was significantly lower in patients compared to healthy controls [515 (64-1887) vs 1542 (627-3159); p<0.0001]. In paired samples, SF had lower levels compared to corresponding plasma level [102 (51-799) vs 481 (134-1006); p<0.0001]. S100A12 (ng/ml) was higher in SF (1042; 573-1415) than sera (638; 208-779). Serum sRAGE negatively correlated with S100A12 levels (r= -0.474; p<0.01.), ESR (r= -0.306; p<0.01), SJC(r= -0.237; p<0.05) but not with TJC (r= -0.134; p=ns). The levels of sRAGE remained stable over time in patients with stable disease. Conclusion: sRAGE levels are reduced in patients with ERA and negatively correlate with disease activity and S100A12 levels. sRAGE may be a modulator of inflammation in these patients

Complications of nephrogenic systemic fibrosis following repeated exposure to gadolinium in a man with hypothyroidism: a case report

Introduction Nephrogenic systemic fibrosis is a condition that has recently been recognized in patients with chronic renal disease and is associated with use of gadolinium-based contrast agents of ubiquitous use in magnetic resonance imaging scans. The condition is believed to arise through inadequate renal clearance of the gadolinium-based contrast agents, resulting in bodily deposition of the gadolinium; this is most widely recognized in the skin, but also occurs in other tissues. Case presentation We report the case of a 52-year-old Caucasian man with hypothyroidism and chronic renal disease who developed nephrogenic systemic fibrosis upon repeated exposure to gadolinium, and who presented with a subsequent malabsorption of levothyroxine. This malabsorption resolved only partially upon amelioration of other conditions that might contribute to malabsorption, including edema and infectious diarrhea. The presence of gadolinium was quantified in specimens from his gastrointestinal tract. Our patient otherwise demonstrated adequate gastrointestinal nutritive absorption, objectively shown by normal albumin levels, resolution of diarrhea, and maintenance of his bodily weight. Conclusions Our observations suggest that nephrogenic systemic fibrosis can also affect tissue of the gastrointestinal tract, potentially contributing to partial malabsorption of levothyroxine in patients with hypothyroidism

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Expression of Toll-like receptors 2 and 4 is increased in peripheral blood and synovial fluid monocytes of patients with enthesitis-related arthritis subtype of juvenile idiopathic arthritis

Objective: Bacterial trigger possibly causes disease exacerbation in enthesitis-related arthritis (ERA) patients. Microbes initiate immune responses through Toll-like receptors (TLRs). We studied TLR expression on blood and SF monocytes and the effect of TLR ligands on peripheral blood (PB) mononuclear cells (PBMCs) in ERA patients. Methods: PB from 26 ERA patients and 19 healthy subjects and paired SF from 13 patients were collected. Dual-colour flow cytometry was done for TLR and CD14 expression. Results are expressed as median fluorescence intensity (MFI). Real-time PCR was done for TLRs. PBMCs were stimulated with lipopolysaccharide (LPS) or peptidoglycan and levels of IL-6 and MMP-3 measured in the culture supernatants. Results: PBMCs from ERA patients had higher expression of TLR-2 [MFI 295.5 (48.1-598) vs 179 (68.7-442); P<0.05] and TLR-4 [MFI 448 (178-2581) vs 402 (229-569); P<0.05] as compared with controls. TLR-9 expression showed no significant difference between the two groups. In paired samples, SF mononuclear cells (SFMCs) had higher expression of both TLR-2 [MFI 485 (141-1683) vs 353 (118-598); P<0.05] and TLR-4 [MFI 1016 (42.4-3159) vs 513 (193-2581); P<0.05] as compared with PBMCs. Difference in TLR-9 expression was not significant. TLR RNA expression data were similar. Patients' PBMCs produced more IL-6 (13.51 vs 6.54ng/ml) and MMP-3 (61 vs 32.9ng/ml) as compared with those of the controls, on stimulation by LPS. With peptidoglycan also, IL-6 (30.58 vs 10.84) and MMP-3 (102.54 vs 49.45) were higher than in controls. Conclusion: Increased TLR-2 and TLR-4 expression on PBMCs and SFMCs may recognize microbial/endogenous ligands and up-regulate IL-6 and MMP-3 leading to disease exacerbation

Lack of association of single nucleotide polymorphisms in toll-like receptors 2 and 4 with enthesitis-related arthritis category of juvenile idiopathic arthritis in Indian population

Toll-like receptors 2 and 4 are over expressed in patients with enthesitis-related arthritis and cause increased production of pro-inflammatory cytokines. This aberrant functioning could be due to polymorphisms in TLR2 and TLR4. Hence, we genotyped ERA patients for Arg753Gln and Arg677Trp polymorphism in TLR2 gene and Asp299Gly and Thr399Ile polymorphism in TLR4 gene. DNA was extracted from blood from ERA patients and healthy controls. All four polymorphisms were studied by PCR–RFLP method. 200 healthy controls and 97 ERA patients were enrolled. All healthy controls and patients had wild-type allele for Arg753Gln and Arg677Trp TLR2 polymorphism. Regarding TLR4, Asp299Gly polymorphism A allele frequency was 90 % in controls and 96 % in patients (OR 2.7, 95 % CI 0.81–8.8). GG homozygous genotype was detected in one healthy control and was absent from patients. The TLR4 Thr399Ileu variant was not detected in patients. Out of 200 healthy controls, 10 were heterozygous (5 %) and only one was homozygous for rare variant (0.5 %). Polymorphisms in TLR2 and TLR4 are not associated with ERA

Synovial fluid mononuclear cell gene expression profiling suggests dysregulation of innate immune genes in enthesitis-related arthritis patients

Objective. Microarray studies have provided insight into the pathogenesis of systemic JIA and have opened new avenues for therapy. Data on the pathogenesis of the enthesitis-related arthritis (ERA) category of JIA are limited, thus we studied the expression profile of ERA patients' peripheral blood and SF mononuclear cells (PBMCs and SFMCs, respectively). PBMCs from healthy subjects were used as controls. Methods. RNA from PBMCs of ERA patients (n = 17) and healthy controls (n = 8) and seven ERA SFMCs were converted to labelled cRNA and hybridized to Illumina Human WG-6_v3_BeadChip chips. Expression profiles were analysed using GeneSpring software. Selected genes of interest were validated by real-time PCR. Results. There was no significant difference in PBMC gene expression of ERA and control groups. However, there was a significant difference between expression profiles of SFMCs and PBMCs of patients with ERA, with 131 genes being overexpressed and 216 being underexpressed in SFMCs. Among genes involved with immune function, cluster of differentiation (CD)1b, CD1d, MHC class II alpha and beta chain, and soluble CD163 were overexpressed, whereas genes related to NK cell function, namely, Granzyme H, killer cell lectin-like receptor subfamily F member 1, killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail (KIR3DL3), natural killer group 7 (NKG7) and other genes like CD244, CD248 and Fas apoptotic inhibitory molecule 3 (FAIM3) were underexpressed. Conclusion. ERA SFMCs had a distinct gene expression profile from PBMCs and had higher expression of genes associated with antigen presentation, scavenger function, chemotaxis and proteases, whereas genes involved in NK cell function, cell adhesion and inhibitors of apoptosis were underexpressed

Learn to intervene: An adaptive learning policy for restless bandits in application to preventive healthcare

In many public health settings, it is important for patients to adhere to health programs, such as taking medications and periodic health checks. Unfortunately, beneficiaries may gradually disengage from such programs, which is detrimental to their health. A concrete example of gradual disengagement has been observed by an organization that carries out a free automated call-based program for spreading preventive care information among pregnant women. Many women stop picking up calls after being enrolled for a few months. To avoid such disengagements, it is important to provide timely interventions. Such interventions are often expensive and can be provided to only a small fraction of the beneficiaries. We model this scenario as a restless multi-armed bandit (RMAB) problem, where each beneficiary is assumed to transition from one state to another depending on the intervention. Moreover, since the transition probabilities are unknown a priori, we propose a Whittle index based Q-Learning mechanism and show that it converges to the optimal solution. Our method improves over existing learning-based methods for RMABs on multiple benchmarks from literature and also on the maternal healthcare dataset.Comment: To appear in the 30th International Joint Conference on Artificial Intelligence (IJCAI 2021

Prolonged adrenal insufficiency after unilateral adrenalectomy for Cushing′s Syndrome

The contralateral healthy adrenal in patients undergoing unilateral adrenalectomy for Cushing′s is known to be suppressed temporarily and forms the basis of peri and postoperative steroids. We present four cases of Cushing′s who had prolonged adrenal insufficiency with continued requirement for steroids for periods ranging 1-4 years after unilateral adrenalectomy for Cushing′s. We further review literature regarding the recovery of the hypothalamo pituitary adrenal axis postsurgery in patients with Cushing′s syndrome