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Cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of glioblastoma specimens yielded cells with CAF morphology and single-cell transcriptomic profiles based on their lack of copy number variations (CNVs) and elevated individual cell CAF probability scores derived from the expression of 9 CAF markers and absence of 5 markers from non-CAF stromal cells sharing features with CAFs. Cells without CNVs and with high CAF probability scores were identified in single-cell RNA-Seq of 12 patient glioblastomas. Pseudotime reconstruction revealed that immature CAFs evolved into subtypes, with mature CAFs expressing actin alpha 2, smooth muscle (ACTA2). Spatial transcriptomics from 16 patient glioblastomas confirmed CAF proximity to mesenchymal glioblastoma stem cells (GSCs), endothelial cells, and M2 macrophages. CAFs were chemotactically attracted to GSCs, and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF and TGF-ß as mediators of GSC effects on CAFs and osteopontin and HGF as mediators of CAF-induced GSC enrichment. CAFs induced M2 macrophage polarization by producing the extra domain A (EDA) fibronectin variant that binds macrophage TLR4. Supplementing GSC-derived xenografts with CAFs enhanced in vivo tumor growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target. [ABSTRACT FROM AUTHOR]

Introduction: Patients requiring postoperative therapeutic anticoagulation may have increased risk of bleeding complications, infection, and poor wound healing. The purpose of this study was to perform a systematic review and meta-analysis assessing bleeding complication rates among orthopaedic surgery patients receiving perioperative therapeutic anticoagulation., Methods: A systematic review and meta-analysis was performed in concordance with the Preferred Reporting Items for Systematic Review and Meta Analysis 2020 guidelines. PubMed was queried for articles related to therapeutic anticoagulation in orthopaedic surgery and complications using keywords and medical subject headings. Inclusion/exclusion criteria were any study reporting bleeding complications after orthopaedic surgery among patients on perioperative therapeutic anticoagulation with a minimum 1-year follow-up. Studies were reviewed for heterogeneity and risk of bias. Pooled analysis was done to determine postoperative complication rates among patients on therapeutic anticoagulation., Results: Thirty-seven studies with 3,990 patients were included. Studies were grouped by their surgical subspecialty with 16 from arthroplasty, one foot and ankle, two spine, one sports, 13 trauma, and four upper extremity. Among patients on therapeutic anticoagulation, the pooled rate and 95% confidence intervals of bleeding complications was 8% (5 to 11%) overall, 10% (5 to 15%) in arthroplasty, 6% (3 to 11%) in trauma, and 5% (1 to 30%) in upper extremity. The overall rates (95% CI) of venous thromboembolism (VTE) were 2% (2 to 4%), infection 5% (3 to 10%), and revision surgery 4% (3 to 6%). Upper extremity VTE rates were 0% (0 to 15%), infection 4% (3 to 6%), and revision surgery 4% (3 to 6%). Trauma VTE rates were 4% (2 to 5%), infection 2% (1 to 6%), and revision surgery 3% (2 to 4%). Arthroplasty VTE rates were 2% (1 to 5%), infection 9% (4 to 18%), and revision surgery 4% (2 to 7%)., Conclusions: Therapeutic postoperative anticoagulation may increase the risk of bleeding complications when compared with the general population. Incidence of VTE was similar when compared with historical data., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)

Background: Prior studies have demonstrated that industry payments affect physician prescribing patterns, but their effect on orthopaedic surgical costs is unknown. This study examines the relationship between industry payments and the total costs of primary total joint arthroplasty, as well as operating room cost, length of stay, 30-day mortality, and 30-day readmission., Methods: Open Payments data were matched across a 20% sample of Medicare-insured patients undergoing primary elective total hip arthroplasty (THA) (n = 130,872) performed by 7,539 surgeons or primary elective total knee arthroplasty (TKA) (n = 230,856) performed by 8,977 surgeons from 2013 to 2015. Patient, hospital, and surgeon-specific factors were gathered. Total and operating room costs, length of stay, mortality, and readmissions were recorded. Multivariable linear and logistic regression models were used to identify the risk-adjusted relationships between industry payments and the primary and secondary outcomes., Results: In this study, 96.7% of THA surgeons and 97.4% of TKA surgeons received industry payments. After multivariable risk adjustment, for each $1,000 increase in industry payments, the total costs of THA increased by $0.50 (0.003% of total costs) and the operating room costs of THA increased by $0.20 (0.003% of total costs). Industry payments were not associated with TKA cost. Industry payments were not associated with 30-day mortality after either THA or TKA. Higher industry payments were independently associated with a marginal decrease in the length of stay for patients undergoing THA (0.0045 days per $1,000) or TKA (0.0035 days per $1,000) and a <0.1% increase in the odds of 30-day readmission after THA for every $1,000 in industry payments. The median total THA costs were $300 higher (p < 0.001), whereas the median TKA costs were $150 lower (p < 0.001), for surgeons receiving the highest 5% of industry payments. These surgical procedures were more often performed in large urban areas, in hospitals with a higher number of beds, with a higher wage index, and by more experienced surgeons and were associated with a 0.4 to 1-day shorter length of stay (p < 0.001)., Conclusions: Although most arthroplasty surgeons received industry payments, a minority of surgeons received the majority of payments. Overall, arthroplasty costs and outcomes were not meaningfully impacted by industry relationships., Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H779 )., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

Purpose: While the effects of tranexamic acid (TXA) use on transfusion rates after acetabular fracture surgery are unclear, previous evidence suggests that holding deep vein thrombosis (DVT) chemoprophylaxis may improve TXA efficacy. This study examines whether holding DVT chemoprophylaxis in patients receiving TXA affects intraoperative and postoperative transfusion rates in acetabular fracture surgery., Methods: We reviewed electronic medical records (EMR) of 305 patients who underwent open reduction and internal fixation of acetabular fractures (AO/OTA 62) and stratified patients per the following perioperative treatment: (1) no intraoperative TXA (noTXA), (2) intraoperative TXA and no preoperative DVT prophylaxis (opTXA/noDVTP), or (3) intraoperative TXA and preoperative DVT prophylaxis (opTXA/opDVTP). The primary outcomes were need for intraoperative or postoperative transfusion. Risk factors for each primary outcome were assessed using multivariable regression., Results: Intraoperative or postoperative transfusion rates did not significantly differ between opTXA/opDVTP and opTXA/noDVTP groups (46.2% vs. 36%, p = 0.463; 15.4% vs. 28%, p = 0.181). Median units transfused did not differ between groups (2 ± 1 vs. 2 ± 1, p = 0.515; 2 ± 1 vs. 2 ± 0, p = 0.099). There was no association between preoperative DVT chemoprophylaxis and TXA with intraoperative or postoperative transfusions. EBL, preoperative hematocrit, and IV fluids were associated with intraoperative transfusions; age and Charlson Comorbidity Index (CCI) were associated with postoperative transfusions., Conclusion: Our findings suggest holding DVT prophylaxis did not alter the effect of TXA on blood loss or need for transfusion., (© 2023. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Introduction: Certain patient and operative factors limit accurate estimation of acetabular component positioning during total hip arthroplasty (THA). This study aimed to determine whether an intraoperative external alignment guide decreases variance in acetabular component positioning., Materials and Methods: Adult patients who underwent primary THA from 2014-2018 were reviewed. Exclusion criteria were navigation, robot-assisted surgery, and inflammatory, post-traumatic, or avascular arthritis. One surgeon used an external guide while the second surgeon resected osteophytes and utilized available anatomical landmarks for positioning. Anteversion and inclination, variance, "safe zone" positioning, operative time, and hip instability were assessed. Multivariable regression models were used to examine effects on primary and secondary outcomes., Results: 409 patients were included, of which 182 underwent component placement with landmarks only. Patients undergoing component placement with landmarks only were younger (p=0.002) and more often smokers (p=0.016). After multivariable risk adjustment, use of the external alignment guide was independently associated with 2.7° higher anteversion (CI: 1.6° to 3.8°) and smaller anteversion variance (-0.3, CI: -0.6 to 0.1) compared to landmarks only. It was independently associated with 3.2° higher inclination (CI: 2.0° to 4.4°), but there was no difference in inclination variance (-0.1, CI: -0.3 to 0.2). The external alignment guide was independently associated with a 14-minute shorter operative time (CI: 9.6 to 18.7) and smaller operative time variance (-0.9, CI: -1.2 to 0.6)., Discussion: Use of anatomical landmarks alone was associated with increased likelihood of safe zone positioning but lower precision and longer operative time. While this study was limited by lack of randomization and its retrospective nature, an acetabular positioner may be preferable to palpable or visible anatomy alone for acetabular component placement.

New anabolic medications (abaloparatide and romosozumab) were recently approved for osteoporosis, and data suggest that prescribing antiresorptive medications after a course of anabolic medications offers better outcomes. This study aimed to characterize prescription trends, demographics, geographical distributions, out-of-pocket costs, and treatment sequences for anabolic and antiresorptive osteoporosis medications. Using a commercial claims database (Clinformatics Data Mart), adult patients with osteoporosis from 2003 to 2021 were retrospectively reviewed and stratified based on osteoporosis medication class. Patient demographics and socioeconomic variables, provider types, and out-of-pocket costs were collected. Multivariable regression analyses were used to identify independent predictors of receiving osteoporosis treatment. A total of 2,988,826 patients with osteoporosis were identified; 616,635 (20.6%) received treatment. Patients who were female, Hispanic or Asian, in the Western US, had higher net worth, or had greater comorbidity burden were more likely to receive osteoporosis medications. Among patients who received medication, 31,112 (5.0%) received anabolic medication; these were more likely to be younger, White patients with higher education level, net worth, and greater comorbidity burden. Providers who prescribed the most anabolic medications were rheumatologists (18.5%), endocrinologists (16.8%), and general internists (15.3%). Osteoporosis medication prescriptions increased fourfold from 2003 to 2020, whereas anabolic medication prescriptions did not increase at this rate. Median out-of-pocket costs were $17 higher for anabolic than antiresorptive medications, though costs for anabolic medications decreased significantly from 2003 to 2020 (compound annual growth rate: -0.6%). A total of 8388 (1.4%) patients tried two or more osteoporosis medications, and 0.6% followed the optimal treatment sequence. Prescription of anabolic osteoporosis medications has not kept pace with overall osteoporosis treatment, and there are socioeconomic disparities in anabolic medication prescription, potentially driven by higher median out-of-pocket costs. Although prescribing antiresorptive medications after a course of anabolic medications offers better outcomes, this treatment sequence occurred in only 0.6% of the study cohort. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Background Context: Bone morphogenic protein (BMP) promotes bony fusion but increases costs. Recent trends in BMP use among Medicare patients have not been well-characterized., Purpose: To assess utilization trends, complication, payments, and costs associated with BMP use in spinal fusion in a Medicare-insured population., Study Design/setting: Retrospective cohort study., Patient Sample: Total of 316,070 patients who underwent spinal fusion in a 20% sample of Medicare-insured patients, 2006 to 2015., Outcome Measures: Utilization trends across time and geography, complications, payments, and costs., Methods: Patients were stratified by fusion type and diagnosis. Multivariable logistic and linear regression were used to adjust for the effect of baseline characteristics on complications and total payments or cost, respectively., Results: BMP was used in 60,249 cases (19.1%). BMP utilization rates decreased from 23.1% in 2006 to 12.0% in 2015, most significantly in anterior cervical (7.5%-3.1%), posterior cervical (17.0%-8.3%), and posterior lumbar fusions (31.5%-15.8%). There are significant state- and region-level geographic differences in BMP utilization. Across all years, states with the highest BMP use were Indiana (28.5%), Colorado (26.6%), and Nevada (25.7%). States with the lowest BMP use were Maine (2.3%), Vermont (8.2%), and Mississippi (10.4%). After multivariate risk adjustment, BMP use was associated with decreased overall complications in thoracic (odds ratios [OR] [95% confidence intervals [CI]): 0.89 [0.81-0.99]) and anterior lumbar fusions (OR [95% CI]: 0.89 [0.84-0.95]), as well as increased reoperation rates in anterior cervical (OR [95% CI]: 1.11 [1.04-1.19]), posterior cervical (OR (95% CI): 1.14 (1.04-1.25)), thoracic (OR (95% CI): 1.32 (1.23-1.41)), and posterior lumbar fusions (OR (95% CI): 1.11 (1.06-1.16)). BMP use was also associated with greater total costs, independent of fusion type, after multivariate risk adjustment (p<.0001). Payments, however, were comparable between groups in anterior and posterior cervical fusion with or without BMP. BMP use was associated with greater total payments in thoracic, anterior lumbar, and posterior lumbar fusions. Notably, the difference in payments was smaller than the associated cost increase in all fusion types., Conclusions: BMP use has declined across all fusion types over the last decade, after a peak in 2007. While BMP is associated with greater costs, reimbursement does not increase proportionally with BMP cost., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Musculoskeletal (MSK) education is underemphasized in medical school curricula, which can lead to decreased confidence in treating MSK conditions and suboptimal performance on orthopaedic surgery elective rotations or subinternships. Given the low amount of formalized education in MSK medicine, students aiming to learn about orthopaedic surgery must gain much of their foundational knowledge from other resources. However, there are currently no centralized introductory educational resources to fill this need. We provide a framework for navigating the different types of resources available for trainees and highlight the unaddressed needs in this area., (Copyright © 2022 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Objective: Neurosurgery is consistently one of the most competitive specialties for resident applicants. The emphasis on research in neurosurgery has led to an increasing number of publications by applicants seeking a successful residency match. The authors sought to produce a comprehensive analysis of research produced by neurosurgical applicants and to establish baseline data of neurosurgery applicant research productivity given the increased emphasis on research output for successful residency match., Methods: A retrospective review of publication volume for all neurosurgery interns in 2009, 2011, 2014, 2016, and 2018 was performed using PubMed and Google Scholar. Missing data rates were 11% (2009), 9% (2011), and < 5% (all others). The National Resident Matching Program report "Charting Outcomes in the Match" (ChOM) was interrogated for total research products (i.e., abstracts, presentations, and publications). The publication rates of interns at top 40 programs, students from top 20 medical schools, MD/PhD applicants, and applicants based on location of residency program and medical school were compared statistically against all others., Results: Total publications per neurosurgery intern (mean ± SD) based on PubMed and Google Scholar were 5.5 ± 0.6 in 2018 (1.7 ± 0.3, 2009; 2.1 ± 0.3, 2011; 2.6 ± 0.4, 2014; 3.8 ± 0.4, 2016), compared to 18.3 research products based on ChOM. In 2018, the mean numbers of publications were as follows: neurosurgery-specific publications per intern, 4.3 ± 0.6; first/last author publications, 2.1 ± 0.3; neurosurgical first/last author publications, 1.6 ± 0.2; basic science publications, 1.5 ± 0.2; and clinical research publications, 4.0 ± 0.5. Mean publication numbers among interns at top 40 programs were significantly higher than those of all other programs in every category (p < 0.001). Except for mean number of basic science publications (p = 0.1), the mean number of publications was higher for interns who attended a top 20 medical school than for those who did not (p < 0.05). Applicants with PhD degrees produced statistically more research in all categories (p < 0.05) except neurosurgery-specific (p = 0.07) and clinical research (p = 0.3). While there was no statistical difference in publication volume based on the geographical location of the residency program, students from medical schools in the Western US produced more research than all other regions (p < 0.01). Finally, research productivity did not correlate with likelihood of medical students staying at their home institution for residency., Conclusions: The authors found that the temporal trend toward increased total research products over time in neurosurgery applicants was driven mostly by increased nonindexed research (abstracts, presentations, chapters) rather than by increased peer-reviewed publications. While we also identified applicant-specific factors (MD/PhDs and applicants from the Western US) and an outcome (matching at research-focused institutions) associated with increased applicant publications, further work will be needed to determine the emphasis that programs and applicants will need to place on these publications.

Objective: Glioblastoma (GBM) carries a high economic burden for patients and caregivers, much of which is associated with initial surgery. The authors investigated the impact of insurance status on the inpatient hospital costs of surgery for patients with GBM., Methods: The authors conducted a retrospective review of patients with GBM (2010-2015) undergoing their first resection at the University of California, San Francisco, and corresponding inpatient hospital costs., Results: Of 227 patients with GBM (median age 62 years, 37.9% females), 31 (13.7%) had Medicaid, 94 (41.4%) had Medicare, and 102 (44.9%) had private insurance. Medicaid patients had 30% higher overall hospital costs for surgery compared to non-Medicaid patients ($50,285 vs $38,779, p = 0.01). Medicaid patients had higher intensive care unit (ICU; p < 0.01), operating room (p < 0.03), imaging (p < 0.001), room and board (p < 0001), and pharmacy (p < 0.02) costs versus non-Medicaid patients. Medicaid patients had significantly longer overall and ICU lengths of stay (6.9 and 2.6 days) versus Medicare (4.0 and 1.5 days) and privately insured patients (3.9 and 1.8 days, p < 0.01). Medicaid patients had similar comorbidity rates to Medicare patients (67.8% vs 68.1%), and both groups had higher comorbidity rates than privately insured patients (37.3%, p < 0.0001). Only 67.7% of Medicaid patients had primary care providers (PCPs) versus 91.5% of Medicare and 86.3% of privately insured patients (p = 0.009) at the time of presentation. Tumor diameter at diagnosis was largest for Medicaid (4.7 cm) versus Medicare (4.1 cm) and privately insured patients (4.2 cm, p = 0.03). Preoperative (70 vs 90, p = 0.02) and postoperative (80 vs 90, p = 0.03) Karnofsky Performance Scale (KPS) scores were lowest for Medicaid versus non-Medicaid patients, while in subgroup analysis, postoperative KPS score was lowest for Medicaid patients (80, vs 90 for Medicare and 90 for private insurance; p = 0.03). Medicaid patients had significantly shorter median overall survival (10.7 months vs 12.8 months for Medicare and 15.8 months for private insurance; p = 0.02). Quality-adjusted life year (QALY) scores were 0.66 and 1.05 for Medicaid and non-Medicaid patients, respectively (p = 0.036). The incremental cost per QALY was $29,963 lower for the non-Medicaid cohort., Conclusions: Patients with GBMs and Medicaid have higher surgical costs, longer lengths of stay, poorer survival, and lower QALY scores. This study indicates that these patients lack PCPs, have more comorbidities, and present later in the disease course with larger tumors; these factors may drive the poorer postoperative function and greater consumption of hospital resources that were identified. Given limited resources and rising healthcare costs, factors such as access to PCPs, equitable adjuvant therapy, and early screening/diagnosis of disease need to be improved in order to improve prognosis and reduce hospital costs for patients with GBM.