Affinity-matured DLL4 ligands as broad-spectrum modulators of Notch signaling.

The Notch pathway regulates cell fate decisions and is an emerging target for regenerative and cancer therapies. Recombinant Notch ligands are attractive candidates for modulating Notch signaling; however, their intrinsically low receptor-binding affinity restricts their utility in biomedical applications. To overcome this limitation, we evolved variants of the ligand Delta-like 4 with enhanced affinity and cross-reactivity. A consensus variant with maximized binding affinity, DeltaMAX, binds human and murine Notch receptors with 500- to 1,000-fold increased affinity compared with wild-type human Delta-like 4. DeltaMAX also potently activates Notch in plate-bound, bead-bound and cellular formats. When administered as a soluble decoy, DeltaMAX inhibits Notch in reporter and neuronal differentiation assays, highlighting its dual utility as an agonist or antagonist. Finally, we demonstrate that DeltaMAX stimulates increased proliferation and expression of effector mediators in T cells. Taken together, our data define DeltaMAX as a versatile tool for broad-spectrum activation or inhibition of Notch signaling.

The impact of osteoporosis on adult deformity surgery outcomes in Medicare patients.

OBJECTIVE: To identify the impact of osteoporosis (OS) on postoperative outcomes in Medicare patients undergoing ASD surgery. BACKGROUND: Patients with OP and advanced age experience higher than average rates of ASD. However, poor bone density could undermine the durability of a deformity correction. METHODS: We queried the MarketScan Medicare Supplemental database to identify patients Medicare patients who underwent ASD surgery from 2007 to 2016. RESULTS: A total of 2564 patients met the inclusion criteria of this study, of whom n = 971 (61.0%) were diagnosed with osteoporosis. Patients with OP had a similar 90-day postoperative complication rates (OP: 54.6% vs. non-OP: 49.2%, p = 0.0076, not significant after multivariate regression correction). This was primarily driven by posthemorrhagic anemia (37.6% in OP, vs. 33.1% in non-OP). Rates of revision surgery were similar at 90 days (non-OP 15.0%, OP 16.8%), but by 2 years, OP patients had a significantly higher reoperation rate (30.4% vs. 22.9%, p < 0.0001). In multivariate regression analysis, OP increased odds for revision surgery at 1 year (OR 1.4) and 2 years (OR 1.5) following surgery (all p < 0.05). OP was also an independent predictor of readmission at all time points (90 days, OR 1.3, p < 0.005). CONCLUSION: Medicare patients with OP had elevated rates of complications, reoperations, and outpatient costs after undergoing primary ASD surgery.

Predictors of 2-year reoperation in Medicare patients undergoing primary thoracolumbar deformity surgery.

OBJECTIVE: This was a retrospective cohort study in which the authors used a nationally representative administrative database. Their goal was to identify the risk factors for reoperation in Medicare patients undergoing primary thoracolumbar adult spinal deformity (ASD) surgery. Previous literature reports estimate that 20% of patients undergoing thoracolumbar ASD correction undergo revision surgery within 2 years. Most published data discuss risk factors for revision surgery in the general population, but these have not been explored specifically in the Medicare population. METHODS: Using the MarketScan Medicare Supplemental database, the authors identified patients who were diagnosed with a spinal deformity and underwent ASD surgery between 2007 and 2015. The interactions of patient demographics, surgical factors, and medical factors with revision surgery were investigated during the 2 years following primary ASD surgery. The authors excluded patients without Medicare insurance and those with any prior history of trauma or tumor. RESULTS: Included in the data set were 2564 patients enrolled in Medicare who underwent ASD surgery between 2007 and 2015. The mean age at diagnosis with spinal deformity was 71.5 years. A majority of patients (68.5%) were female. Within 2 years of follow-up, 661 (25.8%) patients underwent reoperation. Preoperative osteoporosis (OR 1.58, p < 0.0001), congestive heart failure (OR 1.35, p = 0.0161), and paraplegia (OR 2.41, p < 0.0001) independently increased odds of revision surgery. The use of intraoperative bone morphogenetic protein was protective against reoperation (OR 0.71, p = 0.0371). Among 90-day postoperative complications, a wound complication was the strongest predictor of undergoing repeat surgery (OR 2.85, p = 0.0061). The development of a pulmonary embolism also increased the odds of repeat surgery (OR 1.84, p = 0.0435). CONCLUSIONS: Approximately one-quarter of Medicare patients with ASD who underwent surgery required an additional spinal surgery within 2 years. Baseline comorbidities such as osteoporosis, congestive heart failure, and paraplegia, as well as short-term complications such as pulmonary embolism and wound complications significantly increased the odds of repeat surgery.