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Item The Interval Between Preoperative Radiation and Surgery Is Not Associated with Overall Survival for Soft-tissue Sarcomas: An Analysis of the National Cancer Database(Wolters Kluwer, 2021) Collier, Christopher D.; Kim, Chang-Yeon; Liu, Raymond W.; Getty, Patrick J.; Orthopaedic Surgery, School of MedicineBackground: Most cancer centers prefer preoperative radiation therapy (preRT) over postoperative therapy to treat soft-tissue sarcoma (STS) to limit long-term fibrosis, joint stiffness, and edema. Surgery is often delayed after preRT to allow for tissue recovery and to reduce wound complications. However, the association between the time interval between preRT and surgery and survival is unknown. Questions/purposes: (1) What factors are associated with the preRT-surgery interval in patients with STS? (2) Is the preRT-surgery interval associated with overall survival? Methods: The National Cancer Database, a nationwide registry that includes 70% of all new cancers in the United States with 90% follow-up, was reviewed to identify 6378 patients who underwent preRT and surgical resection for a localized extremity or pelvic STS from 2004 to 2014. Patients were excluded if they had lymphatic or metastatic disease at diagnosis (23%; n = 1438), underwent neoadjuvant chemotherapy (24%; 1531), were missing vital status (8%; 487), had chemosensitive histologies (9%; 603), underwent radiation other than external beam (1%; 92), were missing preRT-surgery interval (1%; 45), or had a preRT-surgery interval greater than 120 days (< 1%; 6). A total of 2176 patients were included for analysis, with a mean preRT-surgery interval of 35 ± 16 days. A multiple linear regression model was generated to assess demographic, clinicopathologic, and treatment characteristics associated with the preRT-surgery interval. A Kaplan-Meier survival analysis was then conducted, stratified by the preRT-surgery interval, to assess survival over 10 years. Finally, a multivariate Cox regression analysis model was constructed to further evaluate the association between the preRT-surgery interval and overall survival, adjusted for demographic, clinicopathologic, and treatment characteristics. Results: A longer preRT-surgery interval was associated with higher age (β = 0.002 per year [95% CI 0.0 to 0.004]; p = 0.026), tumor location in the pelvis (compared with the lower extremity; β = 0.15 [95% CI 0.082 to 0.22]; p < 0.001), and malignant peripheral nerve sheath tumor subtype (compared with undifferentiated pleomorphic sarcoma; β = 0.17 [95% CI 0.044 to 0.29]; p = 0.008). A shorter preRT-surgery interval was associated with higher facility volume (β = -0.002 per case [95% CI -0.003 to -0.002]; p = 0.026) and higher tumor stage (compared with Stage I; β = -0.066 [95% CI -0.13 to -0.006]; p = 0.03 for Stage II; β = -0.12 [95% CI -0.17 to -0.065]; p < 0.001 for Stage III). The 5-year overall survival rates were similar across all preRT-surgery interval groups: less than 3 weeks (66% [95% CI 60 to 72]), 3 to 4 weeks (65% [95% CI 60 to 71]), 4 to 5 weeks (65% [95% CI 60 to 71]), 5 to 6 weeks (66% [95% CI 60 to 72]), 6 to 7 weeks (63% [95% CI 54 to 72]), 7 to 9 weeks (66% [95% CI 58 to 74]), and more than 9 weeks (59% [95% CI 48 to 69]). Over 10 years, no difference in overall survival was observed when stratified by the preRT-surgery interval (p = 0.74). After controlling for potentially confounding variables, including age, sex, Charlson/Deyo comorbidity score, histology, tumor size, stage and surgery type, the preRT-surgery interval was not associated with survival (hazard ratio = 1 per day [95% CI 1 to 1]; p = 0.88). Conclusion: With the numbers available, this study demonstrates that a delay in surgery up to 120 days after radiation is not associated with poorer survival. Therefore, clinicians may be able to delay surgery to minimize the risks of wound complications and modifiable comorbidities without affecting overall survival.Level of Evidence Level III, therapeutic study.Item Bone Fragility in High Fat Diet-induced Obesity is Partially Independent of Type 2 Diabetes in Mice(Springer, 2024) Uppuganti, Sasidhar; Creecy, Amy; Fernandes, Daniel; Garrett, Kate; Donovan, Kara; Ahmed, Rafay; Voziyan, Paul; Rendina‑Ruedy, Elizabeth; Nyman, Jeffry S.; Orthopaedic Surgery, School of MedicineObesity and type 2 diabetes (T2D) are risk factors for fragility fractures. It is unknown whether this elevated risk is due to a diet favoring obesity or the diabetes that often occurs with obesity. Therefore, we hypothesized that the fracture resistance of bone is lower in mice fed with a high fat diet (45% kcal; HFD) than in mice that fed on a similar, control diet (10% kcal; LFD), regardless of whether the mice developed overt T2D. Sixteen-week-old, male NON/ShiLtJ mice (resistant to T2D) and age-matched, male NONcNZO10/LtJ (prone to T2D) received a control LFD or HFD for 21 weeks. HFD increased the bodyweight to a greater extent in the ShiLtJ mice compared to the NZO10 mice, while blood glucose levels were significantly higher in NZO10 than in ShiLtJ mice. As such, the glycated hemoglobin A1c (HbA1c) levels exceeded 10% in NZO10 mice, but it remained below 6% in ShiLtJ mice. Diet did not affect HbA1c. HFD lowered trabecular number and bone volume fraction of the distal femur metaphysis (micro-computed tomography or μCT) in both strains. For the femur mid-diaphysis, HFD significantly reduced the yield moment (mechanical testing by three-point bending) in both strains but did not affect cross-sectional bone area, cortical thickness, nor cortical tissue mineral density (μCT). Furthermore, the effect of diet on yield moment was independent of the structural resistance of the femur mid-diaphysis suggesting a negative effect of HFD on characteristics of the bone matrix. However, neither Raman spectroscopy nor assays of advanced glycation end-products identified how HFD affected the matrix. HFD also lowered the resistance of cortical bone to crack growth in only the diabetic NZO10 mice (fracture toughness testing of other femur), while HFD reduced the ultimate force of the L6 vertebra in both strains (compression testing). In conclusion, the HFD-related decrease in bone strength can occur in mice resistant and prone to diabetes indicating that a diet high in fat deleteriously affects bone without necessarily causing hyperglycemia.Item Combined Thermoneutral Housing and Raloxifene Treatment Improves Trabecular Bone Microarchitecture and Strength in Growing Female Mice(Springer, 2023) Jacobson, Andrea; Tastad, Carli A.; Creecy, Amy; Wallace, Joseph M.; Orthopaedic Surgery, School of MedicineThermoneutral housing and Raloxifene (RAL) treatment both have potential for improving mechanical and architectural properties of bone. Housing mice within a 30 to 32 °C range improves bone quality by reducing the consequences of cold stress, such as shivering and metabolic energy consumption (Chevalier et al. in Cell Metab 32(4):575-590.e7, 2020; Martin et al. in Endocr Connect 8(11):1455-1467, 2019; Hankenson et al. in Comp Med 68(6):425-438, 2018). Previous work suggests that Raloxifene can enhance bone strength and geometry (Ettinger et al. in Jama 282(7):637-645, 1999; Powell et al. in Bone Rep 12:100246, 2020). An earlier study in our lab utilized long bones to examine the effect of thermoneutral housing and Raloxifene treatment in mice, but no significant interactive effects were found. The lack of an impact is hypothesized to be connected to the short 6-week duration of the study and the type of bone analyzed. This study will examine the same question within the axial skeleton, which has a higher proportion of trabecular bone. After 6 weeks of treatment with RAL, vertebrae from female C57BL/6 J mice underwent microcomputed tomography (μCT), architectural analysis, and compression testing. Most of the tested geometric properties (bone volume/tissue volume percent, trabecular thickness, trabecular number, trabecular spacing) improved with both the housing and RAL treatment. The effect sizes suggested an additive effect when treating mice housed under thermoneutral conditions. While ultimate force was enhanced with the treatment and housing, force normalized by bone volume fraction was not significantly different between groups. For longer pre-clinical trials, it may be important to consider the impacts of temperature on mice to improve the accuracy of these models.Item Acute Bone Loss and Infrapatellar Fat Pad Fibrosis in the Knee After an In Vivo ACL Injury in Adolescent Mice(Sage, 2023) Ahn, Taeyong; Loflin, Benjamin E.; Nguyen, Nicholas B.; Miller, Ciena K.; Colglazier, Kaitlyn A.; Wojtys, Edward M.; Schlecht, Stephen H.; Orthopaedic Surgery, School of MedicineBackground: Young patients are 6 times more likely than adults to have a primary anterior cruciate ligament (ACL) graft failure. Biological factors (ie, tunnel osteolysis) may account for up to a third of these failures. Previous evaluations of patient ACL explants indicated significant bone loss within the entheseal regions. However, it remains unknown if the degree of bone loss within the ACL insertion regions, wherein ACL grafts are fixated, exceeds that of the femoral and tibial condylar bone. Hypothesis: Bone loss in the mineralized matrices of the femoral and tibial ACL entheses is distinct from that clinically reported across the whole knee after injury. Study design: Controlled laboratory study. Methods: We developed a clinically relevant in vivo mouse ACL injury model to cross-sectionally track the morphological and physiological postinjury changes within the ACL, femoral and tibial entheses, synovial joint space, and load-bearing epiphyseal cortical and trabecular bone components of the knee joint. Right ACLs of 10-week-old C57BL/6J female mice (N = 75) were injured in vivo with the contralateral ACLs serving as controls. Mice were euthanized at 1, 3, 7, 14, or 28 days after injury (n = 12/cohort). Downstream analyses included volumetric cortical and trabecular bone analyses and histopathologic assessments of the knee joint after injury. Gait analyses across all time points were also performed (n = 15 mice). Results: The majority of the ACL injuries in mice were partial tears. The femoral and tibial cortical bone volumes were 39% and 32% lower, respectively, at 28 days after injury than those of the uninjured contralateral knees (P < .01). Trabecular bone measures demonstrated little difference between injured and control knees after injury. Across all bone measures, bone loss was similar between the injured knee condyles and ACL entheses. There was also significant inflammatory activity within the knee after injury. By 7 days after injury, synovitis and fibrosis were sigificantly elevated in the injured knee compared with the controls (P < .01), which corresponded with significantly higher osteoclast activity in bone at this time point compared with the controls. This inflammatory response signficantly persisted throughout the duration of the study (P < .01). The hindlimb gait after injury deviated from normal, but mice habitually loaded their injured knee throughout the study. Conclusion: Bone loss was acute and persisted for 4 weeks after injury in mice. However, the authors' hypothesis was not confirmed, as bone quality was not significantly lower in the entheses compared with the condylar bone regions after injury. With relatively normal hindlimb loading but a significant physiological response after injury, bone loss in this model may be driven by inflammation. Clinical relevance: There is persistent bone resorption and fibrotic tissue development after injury that is not resolved. Inflammatory and catabolic activity may have a significant role in the postinjury decline of bone quality in the knee.Item Two-stage corrective operation for the treatment of pes cavovarus in patients with spina bifida(Baishideng, 2024-07-18) Padgett, Anthony Mack; Kothari, Ezan; Conklin, Michael J.; Orthopaedic Surgery, School of MedicineBackground: Pes cavovarus has an estimated incidence of 8%-17% in patients with spina bifida (SB). The majority of the current literature on surgical treatment of cavovarus feet in children and adolescents includes a variety of diagnoses. There are currently no case series describing a treatment algorithm for deformity correction in this specific patient population. The authors of this study present the results of a retrospective case series performed to assess the radiographic outcomes of two-stage corrective surgery in patients with SB. Aim: To assess the radiographic outcomes of a staged operation consisting of radical plantar release followed by osteotomy for pes cavovarus in patients with SB. Methods: Retrospective chart review was performed on patients with SB with a diagnosis of pes cavovarus at a freestanding children's hospital who underwent surgical correction of the deformity. Patients were excluded for lack of two-stage corrective operation, nonambulatory status, lack of at least six months follow-up, and age > 18 years at the time of surgery. This resulted in a cohort of 19 patients. Radiographic analysis was performed on 11 feet that had a complete series of preoperative and postoperative weightbearing X-rays. Preoperative and postoperative radiographic outcome measurements were compared using a two-sample t-test. Results: Significant changes between the preoperative and postoperative measurements were seen in Meary's angle, the anteroposterior talo-first metatarsal (AP TMT1) angle, and the talonavicular coverage. Mean values of Meary's angle were 17.9 ± 13.1 preoperatively and 4.7 ± 10.3 postoperatively (P = 0.016). Mean AP TMT1 angle was 20.6 ± 15.1 preoperatively and 9.3 ± 5.5 postoperatively (P = 0.011). Mean talonavicular coverage values were -10.3 ± 9.6 preoperatively and -3.8 ± 10.1 postoperatively (P = 0.025). Conclusion: The two-stage corrective procedure demonstrated efficacy in correcting cavovarus deformity in patients with SB. Providers should strongly consider employing the staged surgical algorithm presented in this manuscript for management of these patients.Item Assault-related anoxia and neck injuries in US emergency departments(BMJ, 2024-05-20) Khurana, Bharti; Prakash, Jaya; Lewis-Oconnor, Annie; Green, William M.; Rexrode, Katherine; Loder, Randall T.; Orthopaedic Surgery, School of MedicineBackground: Early identification of non-fatal strangulation in the context of intimate partner violence (IPV) is crucial due to its severe physical and psychological consequences for the individual experiencing it. This study investigates the under-reported and underestimated burden of IPV-related non-fatal strangulation by analysing assault-related injuries leading to anoxia and neck injuries. Methods: An IRB-exempt, retrospective review of prospectively collected data were performed using the National Electronic Injury Surveillance System All Injury Programme data from 2005 to 2019 for all assaults resulting in anoxia and neck injuries. The type and mechanism of assault injuries resulting in anoxia (excluding drowning, poisoning and aspiration), anatomical location of assault-related neck injuries and neck injury diagnosis by morphology, were analysed using statistical methods accounting for the weighted stratified nature of the data. Results: Out of a total of 24 493 518 assault-related injuries, 11.6% (N=2 842 862) resulted from IPV (defined as perpetrators being spouses/partners). Among 22 764 cases of assault-related anoxia, IPV accounted for 40.4%. Inhalation and suffocation were the dominant mechanisms (60.8%) of anoxia, with IPV contributing to 41.9% of such cases. Neck injuries represented only 3.0% of all assault-related injuries, with IPV accounting for 21% of all neck injuries and 31.9% of neck contusions. Conclusions: The study reveals a significant burden of IPV-related anoxia and neck injuries, highlighting the importance of recognising IPV-related strangulation. Comprehensive screening for IPV should be conducted in patients with unexplained neck injuries, and all IPV patients should be screened for strangulation events.Item Megakaryocyte Secreted Factors Regulate Bone Marrow Niche Cells During Skeletal Homeostasis, Aging, and Disease(Springer, 2023) Karnik, Sonali J.; Nazzal, Murad K.; Kacena, Melissa A.; Bruzzaniti, Angela; Orthopaedic Surgery, School of MedicineThe bone marrow microenvironment contains a diverse array of cell types under extensive regulatory control and provides for a novel and complex mechanism for bone regulation. Megakaryocytes (MKs) are one such cell type that potentially acts as a master regulator of the bone marrow microenvironment due to its effects on hematopoiesis, osteoblastogenesis, and osteoclastogenesis. While several of these processes are induced/inhibited through MK secreted factors, others are primarily regulated by direct cell-cell contact. Notably, the regulatory effects that MKs exert on these different cell populations has been found to change with aging and disease states. Overall, MKs are a critical component of the bone marrow that should be considered when examining regulation of the skeletal microenvironment. An increased understanding of the role of MKs in these physiological processes may provide insight into novel therapies that can be used to target specific pathways important in hematopoietic and skeletal disorders.Item An Adolescent Murine In Vivo Anterior Cruciate Ligament Overuse Injury Model(Sage, 2023) Loflin, Benjamin E.; Ahn, Taeyong; Colglazier, Kaitlyn A.; Banaszak Holl, Mark M.; Ashton-Miller, James A.; Wojtys, Edward M.; Schlecht, Stephen H.; Orthopaedic Surgery, School of MedicineBackground: Overuse ligament and tendon injuries are prevalent among recreational and competitive adolescent athletes. In vitro studies of the ligament and tendon suggest that mechanical overuse musculoskeletal injuries begin with collagen triple-helix unraveling, leading to collagen laxity and matrix damage. However, there are little in vivo data concerning this mechanism or the physiomechanical response to collagen disruption, particularly regarding the anterior cruciate ligament (ACL). Purpose: To develop and validate a novel in vivo animal model for investigating the physiomechanical response to ACL collagen matrix damage accumulation and propagation in the ACL midsubstance, fibrocartilaginous entheses, and subchondral bone. Study design: Controlled laboratory study. Methods: C57BL/6J adolescent inbred mice underwent 3 moderate to strenuous ACL fatigue loading sessions with a 72-hour recovery between sessions. Before each session, randomly selected subsets of mice (n = 12) were euthanized for quantifying collagen matrix damage (percent collagen unraveling) and ACL mechanics (strength and stiffness). This enabled the quasi-longitudinal assessment of collagen matrix damage accrual and whole tissue mechanical property changes across fatigue sessions. Additionally, all cyclic loading data were quantified to evaluate changes in knee mechanics (stiffness and hysteresis) across fatigue sessions. Results: Moderate to strenuous fatigue loading across 3 sessions led to a 24% weaker (P = .07) and 35% less stiff (P < .01) ACL compared with nonloaded controls. The unraveled collagen densities within the fatigued ACL and entheseal matrices after the second and third sessions were 38% (P < .01) and 15% (P = .02) higher compared with the nonloaded controls. Conclusion: This study confirmed the hypothesis that in vivo ACL collagen matrix damage increases with tissue fatigue sessions, adversely impacting ACL mechanical properties. Moreover, the in vivo ACL findings were consistent with in vitro overloading research in humans. Clinical relevance: The outcomes from this study support the use of this model for investigating ACL overuse injuries.Item Effect of the NFL’s Super Bowl on emergency department visits for assault-related injuries(Springer, 2024) Khurana, Bharti; Prakash, Jaya; Chopra, Rohan R.; Loder, Randall T.; Orthopaedic Surgery, School of MedicinePurpose: Through its associations with mass gatherings, alcohol consumption, emotional cues, and gambling, the Super Bowl (SB) has been implicated in increased rates of interpersonal violence and assaults. This study endeavors to investigate the relationship between assault-related injuries, especially intimate partner violence (IPV) and SB. Method: A retrospective review of prospectively collected data from the National Electronic Injury Surveillance System (NEISS) spanning 2005 to 2017 was conducted. Assault-related injuries were examined in relation to (1) the 4-day Super Bowl weekend (Friday-Monday), (2) Super Bowl Sunday, and (3) the Super Bowl week (Friday-Thursday) for all years, following the loss of the projected winning team (underdog victories), and losses despite a significant point spread favoring one team (upset losses). National estimates of injuries and associated variables were derived using the SUDAAN software. Results: While there were no significant differences in the overall number of assaults or assault types during the SB weekend (5.6% vs 5.5%; p = 0.31), relative decreases were observed for altercations (21.1% vs 24.8%; p < 0.01), sexual assault (3.4% vs 4.0%; p < 0.01), and IPV (8.3% vs 12.5%; p < 0.01) on the Friday preceding SB, and robbery incidents on SB Sunday (2.1% vs 3.5%; p = 0.01). No changes in the incidence of assault-related injuries were found based on the favored or underdog status of the teams, including upset losses. Conclusion: Contrary to expectations, SB was not associated with increased assault-related injuries. This study underscores the need for year-round structural changes in addressing violence rather than relying solely on heightened awareness during specific events.Item Correction: Foley et al. Emerging Technologies within Spine Surgery. Life 2023, 13, 2028(MDPI, 2024-05-27) Foley, David; Hardacker, Pierce; McCarthy, Michael; Orthopaedic Surgery, School of MedicineIn the original publication [1], there was a mistake in Figure 1 as published. The plumb line drawn for the calculation of the cervical sagittal vertical axis should originate from the center of the C2 body. In the original figure, the line incorrectly begins at the anterior body. The corrected Figure 1 appears below. The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated.