Michael S. Schallmo

Sulfated glycopeptide nanostructures for multipotent protein activation

Biological systems have evolved to utilize numerous proteins with capacity to bind polysaccharides for the purpose of optimizing their function. A well-known subset of these proteins with binding domains for the highly diverse sulfated polysaccharides are important growth factors involved in biological development and tissue repair. We report here on supramolecular sulfated glycopeptide nanostructures, which display a trisulfated monosaccharide on their surfaces and bind five critical proteins with very different polysaccharide binding domains. Binding does not disrupt the filamentous shape of the nanostructures or their internal β-sheet backbone, but must involve accessible adaptive configurations to interact with such different proteins. The glycopeptide nanostructures amplified signaling of bone morphogenetic protein 2 significantly more than the natural sulfated polysaccharide heparin, and promoted regeneration of bone in the spine with a protein dose that is 100-fold lower than expected. These super-bioactive nanostructures may enable many therapies in the horizon involving proteins.

Sport and Sex-Specific Reporting Trends in the Epidemiology of Concussions Sustained by High School Athletes

Background: Approximately 300,000 U.S. adolescents sustain concussions annually while participating in organized athletics. This study aimed to track sex and sport-specific trends among high school sports-related concussions over time, to identify whether a particular sport predisposes athletes to a higher risk, and to assess whether traumatic brain injury law enactments have been successful in improving recognition. Methods: Injury data for academic years 2005 to 2014 were collected from annual reports generated by High School RIO (Reporting Information Online). The relative proportions of total estimated concussions to total estimated injuries were compared using an injury proportion ratio. The concussion rate was defined as the number of concussions per 10,000 athlete exposures (1 athlete participating in 1 practice or competition), with rates compared using a rate ratio. To evaluate the impact of legislation on sports-related concussions in this population, trends in concussion rates and proportions were analyzed before enactment (academic years 2005-2009) and after enactment (academic years 2010-2014). Results: Between 2005-2006 and 2014-2015, a significant increase (p < 0.0001) in the overall number of concussions for all sports combined, the overall concussion rate (rate ratio, 2.30 [95% confidence interval, 2.04 to 2.59]), and the overall proportion of concussions (injury proportion ratio, 2.68 [95% confidence interval, 2.66 to 2.70]) was seen. Based on the injury proportion ratio, during the 2014-2015 academic year, concussions were more common in girls’ soccer than in any other sport (p < 0.0001). Conclusions: Because of potentially devastating consequences, concussion prevention and recognition measures continue to be emphasized in high school contact sports. The data in our study suggest that significant increases in the overall rate and proportion of reported concussions during the past decade could have been affected by traumatic brain injury legislation. To our knowledge, this is the first study to show that girls’ soccer players may have an even greater risk of sustaining a concussion than all other sports. Clinical Relevance: Sports-related concussions in adolescent athletes can have devastating consequences, and we now know that female athletes, especially girls’ soccer players, may be at an even greater risk for sustaining this injury than all other athletes. Knowledge of the trends identified by this study may help lead to policy and prevention measures that can accommodate each sport effectively and potentially halt these trends.

Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation

While inhibition of bone healing and increased rates of pseudarthrosis are known adverse outcomes associated with cigarette smoking, the underlying mechanisms by which this occurs are not well understood. Recent work has implicated the Aryl Hydrocarbon Receptor (Ahr) as one mediator of the anti-osteogenic effects of cigarette smoke (CS), which contains numerous toxic ligands for the Ahr. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity Ahr ligand frequently used to evaluate Ahr pathway activation. The purpose of this study was to elucidate the downstream mechanisms of dioxin action on bone regeneration and investigate Ahr antagonism as a potential therapeutic approach to mitigate the effects of dioxin on bone. Markers of osteogenic activity and differentiation were assessed in primary rat bone marrow stromal cells (BMSC) after exposure to dioxin, Ahr antagonists, or antagonist + dioxin. Four Ahr antagonists were evaluated: α-Naphthoflavone (ANF), resveratrol (Res), 3,3′-Diindolylmethane (DIM), and luteolin (Lut). Our results demonstrate that dioxin inhibited ALP activity, migratory capacity, and matrix mineralization, whereas co-treatment with each of the antagonists mitigated these effects. Dioxin also inhibited BMSC chemotaxis, while co-treatment with several antagonists partially rescued this effect. RNA and protein expression studies found that dioxin down-regulated numerous pro-osteogenic targets, whereas co-treatment with Ahr antagonists prevented these dioxin-induced expression changes to varying degrees. Our results suggest that dioxin adversely affects bone regeneration in a myriad of ways, many of which appear to be mediated by the Ahr. Our work suggests that the Ahr should be investigated as a therapeutic target to combat the adverse effects of CS on bone healing.

Factors Associated with Financial Relationships between Spine Surgeons and Industry

Study Design. A retrospective review of Centers for Medicare and Medicaid Services Database. Objective. Utilizing Open Payments data, we aimed to determine the prevalence of industry payments to orthopedic and neurospine surgeons, report the magnitude of those relationships, and help outline the surgeon demographic factors associated with industry relationships. Summary of Background Data. Previous Open Payments data revealed that orthopedic surgeons receive the highest value of industry payments. No study has investigated the financial relationship between spine surgeons and industry using the most recent release of Open Payments data. Methods. A database of 5898 spine surgeons in the United States was derived from the Open Payments website. Demographic data were collected, including the type of residency training, years of experience, practice setting, type of medical degree, place of training, gender, and region of practice. Multivariate generalized linear mixed models were utilized to determine the relationship between demographics and industry payments. Results. A total of 5898 spine surgeons met inclusion criteria. About 91.6% of surgeons reported at least one financial relationship with industry. The median total value of payments was

Do Demographic Factors of Spine Surgeons Affect the Rate at Which Spinal Fusion Is Performed on Patients

994.07. Surgeons receiving over

Effects of Conflicts of Interest on Practice Patterns and Complication Rates in Spine Surgery

1,000,000 from industry during the reporting period represented 6.6% of the database and accounted for 83.5% of the total value exchanged. Orthopedic training (P < 0.001), academic practice setting (P < 0.0001), male gender (P < 0.0001), and West or South region of practice (P < 0.0001) were associated with industry payments. Linear regression analysis revealed a strong inverse relationship between years of experience and number of payments from industry (r = -0.967, P < 0.0001). Conclusion. Financial relationships between spine surgeons and industry are highly prevalent. Surgeon demographics have a significant association with industry-surgeon financial relationships. Our reported value of payments did not include ownership or research payments and thus likely underestimates the magnitude of these financial relationships. Level of Evidence: 3

A cross-sport comparison of performance-based outcomes of professional athletes following primary microfracture of the knee

Study Design. Retrospective study. Objective. The purpose of this study was to evaluate associations between spine surgeon demographics and the rate at which elective spine fusion is performed. Summary of Background Data. Rapidly increasing rates of elective spinal fusion in the United States have given rise to important questions about what factors may drive spine surgeon decision making. Methods. Publicly available spine surgeon practice pattern data from Centers for Medicare and Medicaid Services were reviewed retrospectively. Fusion rate was defined as the number of fusion procedures performed on Medicare beneficiaries by a surgeon per total number of unique Medicare beneficiaries seen. Inclusion criteria were neurological or orthopedic spine surgeons who performed 11 or more separate spine fusion procedures on Medicare patients between 2011 and 2013 as defined by this database. Demographic information was collected from public record. The increased probability of a surgeon performing spine fusion was assessed using a relative risk (RR) and corresponding 95% confidence interval (CI). Results. A total of 3979 spine surgeons who practice in the United States and performed spine fusion on 171,676 Medicare patients from 2011 to 2013 met the inclusion criteria. The average rate of spine fusion for surgeons in this database was 7.5%. Surgeons with higher fusion rates practiced in an academic versus private setting (RR = 1.44, 95% CI [1.35–1.53]; P < 0.0001), were more likely neurological versus orthopedic surgeons (RR = 1.10, 95% CI [1.05–1.15]; P < 0.0001), and practiced in the West versus Midwest, South, and Northeast region of the United States (RR = 1.20, 95% CI [1.14–1.27]; P < 0.0001). Number of years in practice was significantly associated negatively with fusion rate (P < 0.0001). Conclusion. Significant variation in the rate of spine fusion based on practice type, training, region, and experience suggests poor consensus on indications for this procedure. Knowledge of these relationships may help identify underlying reasons for variations in surgical care and improve surgical outcomes. Level of Evidence: 3

Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells

Study Design. Retrospective cohort study. Objective. We sought to determine whether financial relationships with industry had any impact on operative and/or complication rates of spine surgeons performing fusion surgeries. Summary of Background Data. Recent actions from Congress and the Institute of Medicine have highlighted the importance of conflicts of interest among physicians. Orthopedic surgeons and neurosurgeons have been identified as receiving the highest amount of industry payments among all specialties. No study has yet investigated the potential effects of disclosed industry payments with quality and choices of patient care. Methods. A comprehensive database of spine surgeons in the United States with compiled data of industry payments, operative fusion rates, and complication rates was created. Practice pattern data were derived from a publicly available Medicare-based database generated from selected CPT codes from 2011 to 2012. Complication rate data from 2009 to 2013 were extracted from the ProPublica-Surgeon-Scorecard database, which utilizes postoperative inhospital mortality and 30-day-readmission for designated conditions as complications of surgery. Data regarding industry payments from 2013 to 2014 were derived from the Open Payments website. Surgeons performing <10 fusions, those without complication data, and those whose identity could not be verified through public records were excluded. Pearson correlation coefficients and multivariate regression analyses were used to determine the relationship between industry payments, operative fusion rate, and/or complication rate. Results. A total of 2110 surgeons met the inclusion criteria for our database. The average operative fusion rate was 8.8% (SD 4.8%), whereas the average complication rate for lumbar and cervical fusion was 4.1% and 1.9%, respectively. Pearson correlation analysis revealed a statistically significant but negligible relationship between disclosed payments/transactions and both operative fusion and complication rates. Conclusion. Our findings do not support a strong correlation between the payments a surgeon receives from industry and their decisions to perform spine fusion or associated complication rates. Large variability in the rate of fusions performed suggests a poor consensus for indications for spine fusion surgery. Level of Evidence: 3

Arthroscopic Treatment of Hip Chondral Defect With Microfracture and Platelet-Rich Plasma–Infused Micronized Cartilage Allograft Augmentation

BACKGROUND The purpose of this study was to compare performance-based outcomes among professional athletes in four major North American sports following microfracture to treat symptomatic chondral defects of the knee. METHODS Major League Baseball (MLB), National Basketball Association (NBA), National Football League (NFL), and National Hockey League (NHL) athletes who underwent primary unilateral microfracture of the knee were identified through a previously reported protocol based on public sources. Successful return-to-play was defined as returning for at least one professional regular season game after surgery. Regular season player statistics and sport-specific performance scores were compiled for each player. Each player served as his own control, with the season prior to surgery defined as baseline. Comparisons across sports were enabled by adjusting for expected season and career length differences between sports and by calculating percent changes in performance. RESULTS One hundred thirty one professional athletes who underwent microfracture were included. One hundred three athletes (78.6%) successfully returned to play. The ratio of games started-to-games played before surgery was found to be a significant positive independent predictor of returning (p = 0.002). Compared with their preoperative season, basketball and baseball players demonstrated significantly decreased performance one season after surgery (-14.8%, p = 0.029 and -12.9%, p = 0.002, respectively) that was recoverable to baseline by postoperative seasons 2-3 for baseball players but not for basketball players (-9.7%, p = 0.024). CONCLUSION Knee microfracture surgery is associated with a high rate of return to the professional level. However, the impact of this procedure on postoperative performance varied significantly depending on sport.

Return-to-Play and Performance Outcomes of Professional Athletes in North America After Hip Arthroscopy From 1999 to 2016:

The inhibition of bone healing in humans is a well-established effect associated with cigarette smoking, but the underlying mechanisms are still unclear. Recent work using animal cell lines have implicated the aryl hydrocarbon receptor (AhR) as a mediator of the anti-osteogenic effects of cigarette smoke, but the complexity of cigarette smoke mixtures makes understanding the mechanisms of action a major challenge. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity AhR ligand that is frequently used to investigate biological processes impacted by AhR activation. Since there are dozens of AhR ligands present in cigarette smoke, we utilized dioxin as a prototype ligand to activate the receptor and explore its effects on pro-osteogenic biomarkers and other factors critical to osteogenesis using a human osteoblast-like cell line. We also explored the capacity for AhR antagonists to protect against dioxin action in this context. We found dioxin to inhibit osteogenic differentiation, whereas co-treatment with various AhR antagonists protected against dioxin action. Dioxin also negatively impacted cell adhesion with a corresponding reduction in the expression of integrin and cadherin proteins, which are known to be involved in this process. Similarly, the dioxin-mediated inhibition of cell migration correlated with reduced expression of the chemokine receptor CXCR4 and its ligand, CXCL12, and co-treatment with antagonists restored migratory capacity. Our results suggest that AhR activation may play a role in the bone regenerative response in humans exposed to AhR activators, such as those present in cigarette smoke. Given the similarity of our results using a human cell line to previous work done in murine cells, animal models may yield data relevant to the human setting. In addition, the AhR may represent a potential therapeutic target for orthopedic patients who smoke cigarettes, or those who are exposed to secondhand smoke or other environmental sources of aryl hydrocarbons.