The synovium is a mesenchymal tissue composed mainly of fibroblasts with a lining and sublining that surrounds the joints. In rheumatoid arthritis (RA), the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive and destroys the joint 1 , 2 . Recently, we and others found that a subset of fibroblasts located in the sublining undergoes major expansion in RA and is linked to disease activity 3 , 4 , 5 . However, the molecular mechanism by which these fibroblasts differentiate and expand in RA remains unknown. Here, we identified a critical role for NOTCH3 signaling in the differentiation of perivascular and sublining CD90( THY1 )+ fibroblasts. Using single cell RNA-sequencing and synovial tissue organoids, we found that NOTCH3 signaling drives both transcriptional and spatial gradients in fibroblasts emanating from vascular endothelial cells outward. In active RA, NOTCH3 and NOTCH target genes are markedly upregulated in synovial fibroblasts. Importantly, genetic deletion of Notch3 or monoclonal antibody-blockade of NOTCH3 signaling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit positional identity regulated by endothelium-derived Notch signaling and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.

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The SARS-CoV-2 (COVID-19) pandemic has had a global influence on health care. The authors examined the early effect of hospital- and state-mandated restrictions on an orthopedic surgery department and hypothesized that the volume of ambulatory clinic encounters, office and surgical procedures, and cases would dramatically decrease. A retrospective review was performed of all encounters in an orthopedic surgery department at a level I academic trauma center during a 4-week period, from March 16, 2020, to April 12, 2020. The results were compared with two control 4-week periods, February 17, 2020, to March 15, 2020, and March 16, 2019, to April 12, 2019. Weekly volume and work relative value units (RVUs) of clinic encounters, office and surgical procedures, and cases were assessed. The type of ambulatory visit also was recorded. Comparisons of mean weekly volume and RVUs between the study and control periods were performed with Student's t test. Surgical cases were categorized into fracture or dislocation, acute soft tissue or nerve injury, infection, oncology, and elective or nonurgent. After implementation of hospital- and state-mandated restrictions on elective health care, the volume of ambulatory orthopedic surgery clinic encounters decreased by 74% to 77%, the volume of clinic procedures decreased by 95%, and the volume of surgical cases decreased by 88%. The percentage of clinic visits performed via telemedicine increased from 0.3% to 81.2%. Elective surgical cases ceased, and the volume of nonelective surgical cases decreased by 51%. During the first 4 weeks after COVID-19–related restrictions were imposed, an immediate and dramatic effect was observed. Compared with the control periods, significant reductions were seen in the volume of ambulatory encounters, office-based procedures, and surgical cases. In addition, the volume of nonelective surgical cases decreased by 51%. [ Orthopedics . 2020;43(4):228–232.]

Amyloidosis is a disorder of misfolded proteins in human tissues, which can result in morbid cardiac and neurological disease. Historically, the utility of tissue biopsy during orthopaedic procedures to detect amyloidosis has been limited because no disease-modifying therapies were available; however, new drug therapies have recently emerged for the treatment of amyloidosis. Although these novel pharmaceuticals show promise for slowing disease progression, they are primarily effective in the early stages of amyloidosis, underscoring the importance of early diagnosis. Common orthopaedic manifestations of amyloidosis include carpal tunnel syndrome, trigger finger, spontaneous distal biceps tendon rupture, rotator cuff disease, and lumbar spinal stenosis. Carpal tunnel syndrome is frequently the earliest manifestation of amyloidosis, on average preceding a formal diagnosis of amyloidosis by over four years. By recognizing the constellation of musculoskeletal symptoms in the patient with amyloidosis, orthopaedic surgeons can play an active role in patient referral, early detection of systemic disease, and prompt initiation of disease-modifying treatment. There may be a role for selective biopsy for amyloid deposition in at-risk patients during routine orthopaedic procedures.