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The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint 1 , 2 . It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity 3 – 5 ; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1 ). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients—emanating from vascular endothelial cells outwards—in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis. NOTCH3 signalling is shown to be the underlying driver of the differentiation and expansion of a subset of synovial fibroblasts implicated in the pathogenesis of rheumatoid arthritis.

Abstract Context Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. Objective The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. Methods In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. Results DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] −5.94 [0.879] vs −4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] −9.67 [1.429] vs −4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). Conclusion DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.

The relationship between maternal mental health and infant development has been established in the literature. The Neonatal Intensive Care Unit (NICU) is a particularly challenging environment for new mothers as several natural processes are disrupted. The objective of this study is to elucidate protective factors and environmental deficits associated with the NICU. The experiences of forty-six (n = 46) mothers of infants admitted to a Level III NICU in the Midwestern United States, who responded to a related open-ended question, were analyzed thematically. Five themes related to the NICU environment emerged as being either stressful or helpful: (1) amount and quality of communication with medical staff, (2) bedside manner of medical staff, (3) feeling alienated from infant’s care, (4) support from other NICU mothers and families, and (5) NICU Physical Environment and Regulations. There is a need for medical staff training on awareness, communication, empathy, and other behaviors that might improve maternal (and parental) experiences in the NICU. The physical environment, including rules and regulations of the NICU, should be reexamined with family comfort in mind in addition to the clinical care of the infant.

In 2006, the United States had the largest mumps outbreak in two decades. A total of 6584 cases were reported, with an estimated incidence of 2.2 cases per 100,000 persons. In patients for whom vaccination status was known, 63% had received two doses of the mumps vaccine. The same mumps strain that caused a recent outbreak in the United Kingdom caused the 2006 outbreak. In 2006, the United States had the largest mumps outbreak in two decades. A total of 6584 cases were reported. In patients for whom vaccination status was known, 63% had received two doses of the mumps vaccine. Mumps is an acute viral infection characterized by fever and inflammation of the salivary glands. 1 The spectrum of illness ranges from subclinical infection to meningoencephalitis, deafness, and orchitis, and severity increases with age. 2 In the prevaccine era, the highest attack rate was among children in primary school, and most adolescents showed evidence of previous infection. 2 After the implementation of a policy for the administration of a one-dose mumps vaccine (Jeryl Lynn strain) for children in 1977, 3 reports of mumps cases fell dramatically. However, in the late 1980s, outbreaks occurred in both unvaccinated and vaccinated adolescents and young adults. 4 Widespread use . . .

ObjectiveThe aim of this study was to characterize continuous renal replacement therapy (CRRT) utilization on extracorporeal membrane oxygenation (ECMO) and to determine the association of both fluid overload (FO) at CRRT initiation and fluid removal during CRRT with mortality in a large multicenter cohort.MethodsRetrospective chart review of all children < 18 years of age concurrently treated with ECMO and CRRT from January 1, 2007, to December 31, 2011, at six tertiary care children’s hospital. Children treated with hemodialysis or peritoneal dialysis were excluded from the FO analysis.Measurements and main resultsA total of 756 of the 1009 children supported with ECMO during the study period had complete FO data. Of these, 357 (47.2%) received either CRRT or were treated with an in-line filter and thus entered into the final analysis. Survival to ECMO decannulation was 66.4% and survival to hospital discharge was 44.3%. CRRT initiation occurred at median of 1 day (IQR 0, 2) after ECMO initiation. Median FO at CRRT initiation was 20.1% (IQR 5, 40) and was significantly lower in ECMO survivors vs. non-survivors (15.3% vs. 30.5% p = 0.005) and in hospital survivors vs. non-survivors (13.5% vs. 25.9%, p = 0.004). Median FO at CRRT discontinuation was significantly lower in ECMO survivors (23% vs. 37.6% p = 0.002) and hospital survivors vs. non-survivors (22.6% vs. 36.1%, p = 0.002). In ECMO survivors, after adjusting for pH at CRRT initiation, non-renal complications, ECMO mode, support type, center, patient age and AKI, FO at CRRT initiation (p = 0.01), and FO at CRRT discontinuation (p = 0.0002) were independently associated with duration of ECMO. In a similar multivariable analysis, FO at CRRT initiation (adjusted adds ratio [aOR] 1.09, 95% CI 1.00–1.18, p = 0.045) and at CRRT discontinuation (aOR 1.11, 95% CI 1.03–1.19, p = 0.01) were independently associated with hospital mortality.ConclusionsIn a multicenter pediatric ECMO cohort, this study demonstrates that severe FO was very common at CRRT initiation. We found an independent association between the degree of FO at CRRT initiation with adverse outcomes including mortality and increased duration of ECMO support. The results suggest that intervening prior to the development of significant FO may be a clinical therapeutic target and warrants further evaluation.

Background Leveraging the Accelerating Medicines Partnership (AMP) Lupus Nephritis (LN) dataset, we evaluated longitudinal patterns, rates, and predictors of response to standard-of-care therapy in patients with lupus nephritis. Methods Patients from US academic medical centers with class III, IV, and/or V LN and a baseline urine protein/creatinine (UPCR) ratio ≥ 1.0 ( n  = 180) were eligible for this analysis. Complete response (CR) required the following: (1) UPCR < 0.5; (2) normal serum creatinine (≤ 1.3 mg/dL) or, if abnormal, ≤ 125% of baseline; and (3) prednisone ≤ 10 mg/day. Partial response (PR) required the following: (1) > 50% reduction in UPCR; (2) normal serum creatinine or, if abnormal, ≤ 125% of baseline; and (3) prednisone dose ≤ 15 mg/day. Results Response rates to the standard of care at week 52 were CR = 22.2%; PR = 21.7%; non-responder (NR) = 41.7%, and not determined (ND) = 14.4%. Only 8/180 (4.4%) patients had a week 12 CR sustained through week 52. Eighteen (10%) patients attained a week 12 PR or CR and sustained their responses through week 52 and 47 (26.1%) patients achieved sustained PR or CR at weeks 26 and 52. Week 52 CR or PR attainment was associated with baseline UPCR > 3 (OR adj  = 3.71 [95%CI = 1.34–10.24]; p  = 0.012), > 25% decrease in UPCR from baseline to week 12 (OR adj  = 2.61 [95%CI = 1.07–6.41]; p  = 0.036), lower chronicity index (OR adj = 1.33 per unit decrease [95%CI = 1.10–1.62]; p  = 0.003), and positive anti-dsDNA antibody (OR adj  = 2.61 [95%CI = 0.93–7.33]; p  = 0.069). Conclusions CR and PR rates at week 52 were consistent with the standard-of-care response rates observed in prospective registrational LN trials. Low sustained response rates underscore the need for more efficacious therapies and highlight how critically important it is to understand the molecular pathways associated with response and non-response.

BackgroundCurrent melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.MethodsRabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. Patients: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.ResultsIntravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%–79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged.ConclusionsTaken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

BackgroundTwo doses of trivalent inactivated influenza vaccine (TIV) are recommended for children <9 years old receiving vaccine for the first time, but compliance is suboptimal. This study assessed the need for a second dose of TIV in this age group MethodsIn this prospective, open-label study, 232 influenza vaccine–naive 5–8-year-olds enrolled in a health maintenance organization received 2 doses of TIV in fall 2004. Serum for antibody titer measurement was obtained at 3 time points (n=222). Parents completed diaries for 5 days ResultsBoth doses of vaccine were well tolerated. The strongest predictor of a protective antibody response (⩾1:40) after 1 dose of TIV was baseline seropositive status. In multivariate analysis adjusting for age, sex, and baseline serostatus, the proportion of children with protective antibody responses was significantly higher after 2 doses than after 1 dose of TIV for each antigen (P<.001, for A/H1N1; P=.01, for A/H3N2; P<.001, for B). Age and sex were not independently predictive of a protective antibody response. Over one-third of children had antibody responses <1:40 for the type B vaccine component, even after 2 doses ConclusionsThe present study supports the need for 2 doses of TIV in 5–8-year-olds receiving TIV for the first time. Efforts to increase compliance with the 2-dose recommendation are warranted

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10−7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.