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.

After bone injury, developmental processes such as endochondral and intramembranous ossification are recapitulated as the skeleton regenerates. In contrast to development, skeletal healing involves inflammation. During the early stages of healing a variety of inflammatory cells infiltrate the injured site, debride the wound, and stimulate the repair process. Little is known about the inflammatory process during bone repair. In this work, we examined the effect of a pro-inflammatory cytokine, Interleukin-1 beta (IL-1b), on osteoblast and stem cell differentiation and on intramembranous and endochondral ossification, because IL-1b exerts effects on skeletal homeostasis and is upregulated in response to fracture. We determined that IL-1b stimulated proliferation of osteoblasts and production of mineralized bone matrix, but suppressed proliferation and inhibited differentiation of bone marrow derived MSCs. We next performed loss-and gain-offunction experiments to determine if altering IL-1b signaling affects fracture healing. We did not detect any differences in callus, cartilage, and bone matrix production during healing of nonstabilized or stabilized fractures in mice that lacked the IL-1b receptor compared to wildtype animals. We observed subtle alterations in the healing process after administering IL-1b during the early phases of repair. At day 10 after injury, the ratio of cartilage to callus was increased, and by day 14, the proportion of cartilage to total callus and to bone was reduced. These changes could reflect a slight acceleration of endochondral ossification, or direct effects on cartilage and bone formation.

ImportanceDelirium is a common, serious, and potentially preventable problem for older adults, associated with adverse outcomes. Coupled with its preventable nature, these adverse sequelae make delirium a significant public health concern; understanding its economic costs is important for policy makers and health care leaders to prioritize care.ObjectiveTo evaluate current 1-year health care costs attributable to postoperative delirium in older patients undergoing elective surgery.Design, Setting, and ParticipantsThis prospective cohort study included 497 patients from the Successful Aging after Elective Surgery (SAGES) study, an ongoing cohort study of older adults undergoing major elective surgery. Patients were enrolled from June 18, 2010, to August 8, 2013. Eligible patients were 70 years or older, English-speaking, able to communicate verbally, and scheduled to undergo major surgery at 1 of 2 Harvard-affiliated hospitals with an anticipated length of stay of at least 3 days. Eligible surgical procedures included total hip or knee replacement; lumbar, cervical, or sacral laminectomy; lower extremity arterial bypass surgery; open abdominal aortic aneurysm repair; and open or laparoscopic colectomy. Data were analyzed from October 15, 2019, to September 15, 2020.ExposuresMajor elective surgery and hospitalization.Main Outcomes and MeasuresCumulative and period-specific costs (index hospitalization, 30-day, 90-day, and 1-year follow-up) were examined using Medicare claims and extensive clinical data. Total inflation-adjusted health care costs were determined using data from Medicare administrative claims files for the 2010 to 2014 period. Delirium was rated using the Confusion Assessment Method. We also examined whether increasing delirium severity was associated with higher cumulative and period-specific costs. Delirium severity was measured with the Confusion Assessment Method–Severity long form. Regression models were used to determine costs associated with delirium after adjusting for patient demographic and clinical characteristics.ResultsOf the 566 patients who were eligible for the study, a total of 497 patients (mean [SD] age, 76.8 [5.1] years; 281 women [57%]; 461 White participants [93%]) were enrolled after exclusion criteria were applied. During the index hospitalization, 122 patients (25%) developed postoperative delirium, whereas 375 (75%) did not. Patients with delirium had significantly higher unadjusted health care costs than patients without delirium (mean [SD] cost, $146 358 [$140 469] vs $94 609 [$80 648]). After adjusting for relevant confounders, the cumulative health care costs attributable to delirium were $44 291 (95% CI, $34 554-$56 673) per patient per year, with the majority of costs coming from the first 90 days: index hospitalization ($20 327), subsequent rehospitalizations ($27 797), and postacute rehabilitation stays ($2803). Health care costs increased directly and significantly with level of delirium severity (none-mild, $83 534; moderate, $99 756; severe, $140 008), suggesting an exposure-response relationship. The adjusted mean cumulative costs attributable to severe delirium were $56 474 (95% CI, $40 927-$77 440) per patient per year. Extrapolating nationally, the health care costs attributable to postoperative delirium were estimated at $32.9 billion (95% CI, $25.7 billion-$42.2 billion) per year.Conclusions and RelevanceThese findings suggest that the economic outcomes of delirium and severe delirium after elective surgery are substantial, rivaling costs associated with cardiovascular disease and diabetes. These results highlight the need for policy imperatives to address delirium as a large-scale public health issue.