Novel bisphosphonate-based cathepsin K-triggered compound targets the enthesis without impairing soft tissue-to-bone healing.

Background: Osteoadsorptive fluorogenic sentinel 3 (OFS-3) is a recently described compound that contains a bone-targeting bisphosphonate (BP) and cathepsin K (Ctsk)-triggered fluorescence signal. A prior study in a murine Achilles repair model demonstrated its effectiveness at targeting the site of tendon-to-bone repair, but the intrinsic effect of this novel bisphosphonate chaperone on tendon-to-bone healing has not been previously explored. We hypothesized that application of this bisphosphonate-fluorophore cargo conjugate would not affect the biomechanical properties or histologic appearance of tendon-bone repairs. Materials and Methods: Right hindlimb Achilles tendon-to-bone repair was performed on 12-week old male mice. Animals were divided into 2 groups of 18 each: 1) Achilles repair with OFS-3 applied directly to the repair site prior to closure, and 2) Achilles repair with saline applied prior to closure. Repaired hindlimbs from 12 animals per group were harvested at 6 weeks for biomechanical analysis with a custom 3D-printed jig. At 4 and 6 weeks, repaired hindlimbs from the remaining animals were assessed histologically using H&E, immunohistochemistry (IHC) staining for the presence of Ctsk, and second harmonic generation (SHG) imaging to evaluate collagen fibers. Results: At 6 weeks, there was no significant difference in failure load, stiffness, toughness, or displacement to failure between repaired hindlimbs that received OFS-3 versus saline. There was no difference in tissue healing on H&E or Ctsk staining on immunohistochemistry between animals that received OFS-3 versus saline. Finally, second harmonic generation imaging demonstrated no difference in collagen fiber parameters between the two groups. Conclusion: OFS-3 did not significantly affect the biomechanical properties or histologic appearance of murine Achilles tendon-to-bone repairs. This study demonstrates that OFS-3 can target the site of tendon-to-bone repair without causing intrinsic negative effects on healing. Further development of this drug delivery platform to target growth factors to the site of tendon-bone repair is warranted.

MELD score predicts short-term outcomes after surgical management of proximal humerus fractures: a matched analysis.

Objective: We aimed to evaluate the difference in 30-day outcomes after surgical management of proximal humerus fractures (PHFs) between patients with and without chronic liver disease as defined by a MELD score greater than 10. Design: This was a retrospective database review. Setting: All centers participating in the American College of Surgeons National Surgical Quality Improvement Program database were included. Patients/Participants: Patients with proximal humerus fractures who (1) underwent ORIF, HA, or SA and (2) had calculable MELD scores were included. Intervention: Open reduction and internal fixation, hemiarthroplasty, or shoulder arthroplasty was used for treatment. Main outcome measurements: Thirty-day complications, mortality, readmission, and reoperation rates were measured. Results: Of the total 1732 PHF patients identified, 300 had a MELD score higher than 10. After propensity matching by significant covariates, MELD score higher than 10 was found to be significantly associated with higher rates of 30-day mortality, 30-day readmission, transfusion within 72 hours, and systemic complications. Among patients with a MELD score higher than 10, treatment with SA or HA instead of ORIF was associated with a higher rate of transfusion and longer operative time. There were no significant differences between treatment cohorts regarding mortality, reoperation, readmission, or complications. Conclusions: A MELD score higher than 10 is associated with higher risk of surgical complications, transfusion, and death in patients undergoing surgery for proximal humerus fractures. Among patients with a MELD score higher than 10, ORIF was associated with a lower transfusion rate and shorter operative time than arthroplasty or hemiarthroplasty. Level of Evidence: Prognostic Level III.

Changes in the incidence of stress reactions and fractures among intercollegiate athletes after the COVID-19 pandemic.

PURPOSE: The purpose of this study was to characterize the impact of detraining due to the COVID-19 pandemic on incidence of bony injuries and stress fractures in collegiate athletes. METHODS: A comprehensive collegiate athletic conference injury database was queried for all in-season, sport-related bony injuries (defined as all stress reactions and fractures) that occurred across all sports from January 2016 to June 2021. The bony injury rate per 1000 athlete exposure hours (AEH) was calculated and compared between the immediate post-hiatus season and historic rates from pre-hiatus seasons (2016-2019). Injury characteristics were also compared between the pre- and post-hiatus time periods. RESULTS: A total of 868 bony injuries across 23 sports were identified. The sports with highest overall baseline bony injury rates in historic seasons were women's cross country (0.57 injuries per 1000 AEH) and men's cross country (0.32). Compared to historic pre-hiatus rates, female cross-country runners demonstrated a significantly lower bony injury incidence rate in the post-hiatus season (0.24 vs. 0.57, p = 0.016) while male swimming athletes demonstrated a statistically significant increase in bony injury rate (0.09 vs. 0.01, p = 0.015). The proportion of bony injuries attributed to repetitive trauma increased; while, the proportion of injuries attributed to running decreased between the pre- and post-hiatus seasons. CONCLUSION: Across all sports, there was no consistent trend toward increased rates of bony injury in the immediate post-hiatus season. However, female cross-country runners demonstrated lower rates of bony injury in the post-hiatus season while male swimmers demonstrated higher rates. Furthermore, bony injuries in the post-hiatus season were more likely to be the result of repetitive trauma and less likely to be from running. LEVEL OF EVIDENCE: Level III, retrospective, cross sectional study.

Short-Term Outcomes and Long-Term Implant Survival After Inpatient Surgical Management of Geriatric Proximal Humerus Fractures.

Introduction: The most common surgical options for geriatric proximal humerus fractures are open reduction and internal fixation (ORIF), hemiarthroplasty (HA), and reverse total shoulder arthroplasty. We used a longitudinal inpatient discharge database to determine the cumulative incidence of conversion to arthroplasty after ORIF of geriatric proximal humerus fractures. The rates of short-term complications and all-cause reoperation were also compared. Patients and Methods: All patients 65 or older who sustained a proximal humerus fracture and underwent either ORIF, HA, or shoulder arthroplasty (SA) as an inpatient from 2000 through 2017 were identified. Survival analysis was performed with ORIF conversion to arthroplasty and all-cause reoperation as the endpoints of interest. Rates of 30-day readmission and short-term complications were compared. Trends in procedure choice and outcomes over the study period were analyzed. Results: A total of 27 102 geriatric patients that underwent inpatient surgical management of proximal humerus fractures were identified. Among geriatric patients undergoing ORIF, the cumulative incidence of conversion to arthroplasty within 10 years was 8.2%. The 10-year cumulative incidence of all-cause reoperation was 12.1% for ORIF patients and less than 4% for both HA and SA patients. Female sex was associated with increased risk of ORIF conversion and younger age was associated with higher all-cause reoperation. ORIF was associated with higher 30-day readmission and short-term complication rates. Over the study period, the proportion of patients treated with ORIF or SA increased while the proportion of patients treated with HA decreased. Short-term complication rates were similar between arthroplasty and ORIF patients in the later cohort (2015-2017). Conclusion: The 10-year cumulative incidence of conversion to arthroplasty for geriatric patients undergoing proximal humerus ORIF as an inpatient was found to be 8.2%. All-cause reoperations, short-term complications, and 30-day readmissions were all significantly lower among patients undergoing arthroplasty, but the difference in complication rate between arthroplasty and ORIF was attenuated in more recent years. Younger age was a risk factor for reoperation and female sex was associated with increased risk of requiring conversion to arthroplasty after ORIF.

Impact of the COVID-19 Pandemic Hiatus From Sports Activities on Injuries Observed Among Division I NCAA Athletes.

Background: The coronavirus disease 2019 (COVID-19) pandemic significantly disrupted athletic activities, including those in the Pacific 12 (Pac-12) Conference of the National Collegiate Athletic Association. It is currently unknown how the disruption in training and competition impacted athletes' risk of injury upon resumption of activities. Purpose: To describe and compare the rate, timing, mechanism, and severity of injuries among collegiate athletes across multiple sports in the Pac-12 Conference before and after the COVID-19 pandemic-associated hiatus of intercollegiate athletic activities. Study Design: Descriptive epidemiology study. Methods: Descriptive and injury data among intercollegiate athletes from both the season before the hiatus and the season after the hiatus were acquired from the Pac-12 Health Analytics Program database. Injury elements (timing of injury onset, injury severity, mechanism, recurrence, outcome, need for procedural intervention, and event segment during which the injury took place) were compared by time using the chi-square test and a multivariate logistic regression model. Subgroup analyses were performed on knee and shoulder injuries among athletes participating in sports with traditionally high rates of knee and shoulder injuries. Results: A total of 12,319 sports-related injuries across 23 sports were identified, with 7869 pre-hiatus injuries and 4450 post-hiatus injuries. There was no difference in the overall incidence of injury between the pre-hiatus and post-hiatus seasons. However, the proportion of noncontact injuries was higher in the post-hiatus season for football, baseball, and softball players, and the proportion of nonacute injuries in the post-hiatus season was higher among football, basketball, and rowing athletes. Finally, the overall proportion of injuries sustained by football players in the final 25% of competition or practice was higher in the post-hiatus season. Conclusion: Athletes competing in the post-hiatus season were observed to have higher rates of noncontact injuries and injuries sustained in the final 25% of competition. This study demonstrates that the COVID-19 pandemic has had varied effects on athletes from different sports, suggesting that many factors must be considered when designing return-to-sports programs for athletes after an extended absence from organized training.

Biologically-coupled bisphosphonate chaperones effectively deliver molecules to the site of soft tissue-bone healing.

Tendon injuries are common and often treated surgically, however, current tendon repair healing results in poorly organized fibrotic tissue. While certain growth factors have been reported to improve both the strength and organization of the repaired enthesis, their clinical applicability is severely limited due to a lack of appropriate delivery strategies. In this study, we evaluated a recently developed fluorescent probe, Osteoadsorptive Fluorogenic Sentinel-3 that is composed of a bone-targeting bisphosphonate (BP) moiety linked to fluorochrome and quencher molecules joined via a cathepsin K-sensitive peptide sequence. Using a murine Achilles tendon-to-bone repair model, BP-based and/or Ctsk-coupled imaging probes were applied either locally or systemically. Fluorescence imaging was used to quantify the resultant signal in vivo. After tendon-bone repair, animals that received either local or systemic administration of imaging probes demonstrated significantly higher fluorescence signal at the repair site compared to the sham surgery group at all time points (p < 0.001), with signal peaking at 7-10 days after surgery. Our findings demonstrate the feasibility of using a novel BP-based targeting and Ctsk-activated delivery of molecules to the site of tendon-to-bone repair and creates a foundation for further development of this platform as an effective strategy to deliver bioactive molecules to sites of musculoskeletal injury.

In Vitro Cellular Strain Models of Tendon Biology and Tenogenic Differentiation.

Research has shown that the surrounding biomechanical environment plays a significant role in the development, differentiation, repair, and degradation of tendon, but the interactions between tendon cells and the forces they experience are complex. In vitro mechanical stimulation models attempt to understand the effects of mechanical load on tendon and connective tissue progenitor cells. This article reviews multiple mechanical stimulation models used to study tendon mechanobiology and provides an overview of the current progress in modelling the complex native biomechanical environment of tendon. Though great strides have been made in advancing the understanding of the role of mechanical stimulation in tendon development, damage, and repair, there exists no ideal in vitro model. Further comparative studies and careful consideration of loading parameters, cell populations, and biochemical additives may further offer new insight into an ideal model for the support of tendon regeneration studies.

Revision total knee arthroplasty outcomes in solid organ transplant Patients, a matched cohort study of aseptic and infected revisions.

BACKGROUND: Previous studies have demonstrated that solid organ transplant (SOT) patients undergoing primary total knee arthroplasty (TKA) are at an increased risk of postoperative complications. The purpose of this study is to utilize a large, national database to investigate revision TKA (rTKA) outcomes in SOT patients. METHODS: This was a retrospective review utilizing the Nationwide Readmissions Database (NRD) and ICD-9 codes to identify patients who underwent rTKA from 2010-2014 with a history of at least one SOT. Propensity-score-matching (PSM) was used to compare rTKA outcomes in SOT patients compared to matched patients without SOT. RESULTS: A total of 303,867 rTKAs, with 464 of those being performed in SOT patients, were included in the study. Of these, 71,903 and 182 were performed for PJI in non-SOT and SOT patients, respectively. rTKA was performed most frequently in kidney transplant patients (53.0%) followed by liver transplant patients (34.3%). For non-PJI patients, SOT patients had a higher 90-day readmission rate than matched non-SOT rTKA patients (23.2% vs 12.6%, p = 0.006). However, there were no differences in 90-day readmission rates for specific rTKA complications, subsequent revision rTKA, or mortality. Among patients undergoing rTKA for PJI, there was no difference in overall 90-day readmission rate, readmission for specific rTKA complications, subsequent revision rTKA, or mortality. CONCLUSIONS: While the increased medical comorbidities associated with SOT place patients at increased risk for complications following rTKA, it appears that SOT alone does not do so when patients are matched based on overall medical comorbidity.

Communication between oocytes and somatic cells regulates volatile pheromone production in Caenorhabditis elegans.

Males of the androdioecious species Caenorhabditis elegans are more likely to attempt to mate with and successfully inseminate C. elegans hermaphrodites that do not concurrently harbor sperm. Although a small number of genes have been implicated in this effect, the mechanism by which it arises remains unknown. In the context of the battle of the sexes, it is also unknown whether this effect is to the benefit of the male, the hermaphrodite, or both. We report that successful contact between mature sperm and oocyte in the C. elegans gonad at the start of fertilization causes the oocyte to release a signal that is transmitted to somatic cells in its mother, with the ultimate effect of reducing her attractiveness to males. Changes in hermaphrodite attractiveness are tied to the production of a volatile pheromone, the first such pheromone described in C. elegans.