BMP Antagonists - A Possible Cause for Spinal Non-Fusion?

INTRODUCTION:Spinal fusion is a procedure where the intervertebral disc (IVD) is removed and two adjacent vertebrae are forced to fuse by compression. This procedure is the most commonly applied procedure to achieve spinal stability and relief of back pain. However, non-successful fusion leads to pseudo-athrosis and ongoing pain. There is increasing evidence that supraphysiological doses of BMP2 and burst-release of this cytokine did not generate satisfying results in clinical studies. Current hypothesis was raised that IVD cells and/or tissue seem to inhibit the action of BMP2. In this overview we summarize the current evidence that BMPs might be inhibited by the secretome of human IVD cells, i.e., nucleus pulposus cells (NPC), annulus fibrosus cells (AFC) and cartilaginous endplate (CEPC) cells. METHODS:We stimulated low-passage (2-3) human bonemarrow-derived mesenchymal stromal cells (MSCs) and femoral hip-derived osteoblasts (OBs) and co-cultured these with allogeneic IVD cells obtained from spinal surgery. We then stimulated MSCs and the OBs in monolayer and osteogenic medium, whereas IVD cells were kept in 3D alginate bead culture and separated by high density pore culture inserts (0.4 µm pore size). We quantified relative gene expression at bone-relevant genes, alkaline phosphatase (ALP) activity and Alizarin red (ALZR) staining after 21 days. Furthermore, to test the effect of a previously investigated BMP2 analog to block the inhibitors, cells were further stimulated with 100 ng/mL BMP2 and/or L51P. RESULTS:We found significant inhibitory effects of IVD cells onto MSCs undergoing differentiation in presence of NPC, AFC and CEPC as shown in reduced osteogenic gene expression, ALZR staining and ALP activity (N = 11 donors paired on each side). In the case of allogeneic human OBs only a trend towards inhibition could be demonstrated (N = 7 donors on each side). The addition of L51P to the coculture recovered ossification. On the side of the IVD cells BMP2 and/or L51P had a strong chondrogenic effect. DISCUSSION & CONCLUSIONS:Our data suggested evidence for inhibition for MSCs. However, OBs did not show the same inhibitory effects but showed a trend in presence of IVD’s secretome. This warrants for animal models where the donor variance can be better controlled. ACKNOWLEDGEMENTS:This work was supported by a start-up grant from the Center for Applied Biotechnology and Molecular Medicine (CABMM). Further funds were received from the Swiss Society of Orthopaedics (SGOT), the clinical trials unit (CTU) of Bern University Hospital, and by a Eurospine Task Force Research grant #2019_22

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)