Citations

Significance Statement Although corticosteroids are an effective first-line therapy for minimal change disease, relapse, steroid dependence, and intolerance are common in this podocytopathy of unknown etiology. The efficacy of B cell–targeted therapies in some patients suggests an autoantibody-mediated etiology. This study describes the novel discovery in both adults and children with minimal change disease of autoantibodies targeting nephrin, a critical component of the podocyte slit diaphragm that ensures integrity of the glomerular filtration barrier. This observation aligns with the established proteinuric effect of antinephrin antibodies demonstrated in animal models. These findings identify an important autoimmune mechanism in a subset of patients with minimal change disease and provide a framework for the application and development of precision medicine strategies in this condition. Background Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B cell–targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease. Methods We evaluated sera from patients with minimal change disease, enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions, for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence. Results In two independent patient cohorts, we identified circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response in a subset of patients with minimal change disease. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end stage kidney disease; she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies. Conclusions Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as a framework for instigation of precision therapeutics for these patients.

ObjectiveMiddle‐aged subjects with meniscal tear treated with arthroscopic partial meniscectomy (APM) experience greater progression of damage to joint structures on imaging than subjects treated nonoperatively. It is unclear whether these changes are clinically relevant. The goal of this study was to assess whether worsening in magnetic resonance imaging (MRI)–assessed tissue damage over 18 months leads to subsequent worsening in knee pain over the subsequent 3.5 years.MethodsWe used data from the Meniscal Tear in Osteoarthritis Research (MeTeOR) trial of APM versus physical therapy for subjects ages ≥45 years with knee pain, cartilage damage, and meniscal tear. We assessed whether change in cartilage surface area damage score (and other structural measures) from baseline to 18 months, assessed on MRI with the MRI Osteoarthritis Knee Score (MOAKS) system, was associated with change in Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score (range 0–100; 100 = worst) from 18 to 60 months.ResultsThe primary analysis included 168 subjects with complete MRI data at baseline and 18 months and KOOS data at 18 and 60 months. We did not observe clinically important associations between change in cartilage surface area score between baseline and 18 months and change in pain scores from 18 to 60 months. Pain scores in the worst tertile for cartilage surface area damage score progression worsened by 0.45 points more than in the best tertile (95% confidence interval –4.45, 5.35). Similarly, we did not observe clinically important associations between changes in bone marrow lesions, osteophytes, or synovitis and subsequent pain.ConclusionWe did not observe clinically important associations between early changes in cartilage damage and other structural measures and worsening in pain over the subsequent 3.5 years. Further follow‐up is required to assess this association over a longer follow‐up period.

Abstract The purpose of this study is to compare the image quality of an integrating proton radiography (PR) system, composed of a monolithic scintillator and two digital cameras, using integral lateral-dose and integral depth-dose image reconstruction techniques. Monte Carlo simulations were used to obtain the energy deposition in a 3D monolithic scintillator detector (30 × 30 × 30 cm 3 poly vinyl toluene organic scintillator) to create radiographs of various phantoms—a slanted aluminum cube for spatial resolution analysis and a Las Vegas phantom for contrast analysis. The light emission of the scintillator was corrected using Birks scintillation model. We compared two integrating PR methods and the expected results from an idealized proton tracking radiography system. Four different image reconstruction methods were utilized in this study: integral scintillation light projected from the beams-eye view, depth-dose based reconstruction methods both with and without optimization, and single particle tracking PR was used for reference data. Results showed that heterogeneity artifact due to medium-interface mismatch was identified from the Las Vegas phantom simulated in air. Spatial resolution was found to be highest for single-event reconstruction. Contrast levels, ranked from best to worst, were found to correspond to particle tracking, optimized depth-dose, depth-dose, and projection-based image reconstructions. The image quality of a monolithic scintillator integrating PR system was sufficient to warrant further exploration. These results show promise for potential clinical use as radiographic techniques for visualizing internal patient anatomy during proton radiotherapy.

Secretory carcinoma (SC) was first recognized as a distinct salivary malignancy in 2010. In the nine years since its recognition, there have been multiple reports of SC of the major and minor salivary glands, as well one case of tongue base involvement. Here we present the first reported case of bilateral SC. The first tumor, diagnosed before the recognition of SC, was classified as mucoepidermoid carcinoma. After the contralateral parotid tumor was diagnosed as SC in 2016, the two histologies were compared, and the mucoepidermoid carcinoma was reclassified as SC. In this report, we describe our patient’s clinical course and review the SC literature, with a focus on pathologic diagnosis and clinical prognosis.