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Background: The Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS) is a validated patient-reported outcome measure that evaluates subjective cosmetic and functional complaints. The goa...

Although tumor-propagating cells can be derived from glioblastomas (GBM) of the proneural and mesenchymal subtypes, a glioma stem-like cell (GSC) of the classic subtype has not been identified. It is unclear whether mesenchymal GSCs (mGSC) and/or proneural GSCs (pGSC) alone are sufficient to generate the heterogeneity observed in GBM. We performed single-cell/single-nucleus RNA sequencing of 28 gliomas, and single-cell ATAC sequencing for 8 cases. We found that GBM GSCs reside on a single axis of variation, ranging from proneural to mesenchymal. In silico lineage tracing using both transcriptomics and genetics supports mGSCs as the progenitors of pGSCs. Dual inhibition of pGSC-enriched and mGSC-enriched growth and survival pathways provides a more complete treatment than combinations targeting one GSC phenotype alone. This study sheds light on a long-standing debate regarding lineage relationships among GSCs and presents a paradigm by which personalized combination therapies can be derived from single-cell RNA signatures, to overcome intratumor heterogeneity.Significance:Tumor-propagating cells can be derived from mesenchymal and proneural glioblastomas. However, a stem cell of the classic subtype has yet to be demonstrated. We show that classic-subtype gliomas are comprised of proneural and mesenchymal cells. This study sheds light on a long-standing debate regarding lineage relationships between glioma cell types.See related commentary by Fine, p. 1650.This article is highlighted in the In This Issue feature, p. 1631

Table S1: Clinical and molecular characteristics of the glioma cases profiled by scRNA-seq.

Supplementary Figures

Supplementary Table S2 has primer sequences used to analyze expression of genes known to be expressed by GBM stem cells.

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy.Significance:Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes.

Supplementary Figures S1-S23 show some extra data including immunohistochemical stains and bar graphs that could not fit in the main text.

Supplementary Methods describes details about methods including animal work, microarray analysis, neurosphere assays, and hyaluronic acid assays that could not fit in the main methods.

BACKGROUND: Irrigation and debridement (I&D) of open finger and hand fractures can be performed in the emergency department as opposed to the operating room (OR), though reports of postoperative infection rates vary greatly. The authors hypothesized that I&D of open finger and hand fractures in the OR would decrease over time. They also describe rates of postoperative infection, reoperation, readmission, and costs. METHODS: A large nationwide administrative claims dataset was retrospectively reviewed to identify patients who underwent I&D after open finger and hand fractures from 2007 to 2016. The incidence of I&D procedures performed outside the OR was reported and trends over the study period were assessed. RESULTS: The proportion of open finger and hand fractures that underwent I&D outside the OR did not change significantly over time. Rates of postoperative surgical site infection, readmission, and reoperation were higher in the OR cohort at 90 days after the index stay. The OR cohort had greater total costs and out-of-pocket costs for the index stay. At 90 days, the OR cohort had greater total cost, but out-of-pocket costs were similar. CONCLUSIONS: Site of service for treatment of open finger and hand fractures has not significantly changed from 2007 to 2016. Given that total costs are significantly greater among patients undergoing I&D in the OR, prospective trials are needed to assess the safety of treating open finger and hand fractures outside of the OR to optimize management of these injuries. LEVEL OF EVIDENCE: III

OBJECTIVES: High energy long bone fractures with critical bone loss are at risk for nonunion without strategic intervention. We hypothesize that a synthetic membrane implanted at a single stage improves bone healing in a preclinical nonunion model. METHODS: Using standard laboratory techniques, microspheres encapsulating bone morphogenic protein-2 (BMP2) or platelet derived growth factor (PDGF) were designed and coupled to a type 1 collagen sheet. Critical femoral defects were created in rats and stabilized by locked retrograde intramedullary nailing. The negative control group had an empty defect. The induced membrane group (positive control) had a polymethylmethacrylate spacer inserted into the defect for four weeks and replaced with a bare polycaprolactone/beta-tricalcium phosphate (PCL/β-TCP) scaffold at a second stage. For the experimental groups, a bioactive synthetic membrane embedded with BMP2, PDGF or both enveloped a PCL/β-TCP scaffold was implanted in a single stage. Serial radiographs were taken at 1, 4, 8, and 12 weeks postoperatively from the definitive procedure and evaluated by two blinded observers using a previously described scoring system to judge union as primary outcome. RESULTS: All experimental groups demonstrated better union than the negative control (p=0.01). The groups with BMP2 incorporated into the membrane demonstrated higher average union Mehta scores than the other groups (p=0.01). The induced membrane group performed similarly to the PDGF group. Complete union was only demonstrated in groups with BMP2-eluting membranes. CONCLUSIONS: A synthetic membrane comprised of type 1 collagen embedded with controlled release BMP2 improved union of critical bone defects in a preclinical nonunion model.

BACKGROUND: The orthopaedic surgery residency program website represents a recruitment tool that can be used to demonstrate a program’s commitment to diversity and inclusion to prospective applicants. The authors assessed how orthopaedic surgery residency programs demonstrated diversity and inclusion on their program websites and whether this varied based on National Institutes of Health (NIH) funding, top-40 medical school affiliation, university affiliation, program size, or geographic region. METHODS: The authors evaluated 187 orthopaedic surgery residency program websites for the presence of 12 elements that represented program commitment to diversity and inclusion values, based on prior work and ACGME recommendations. Mann-Whitney U and Kruskal-Wallis tests were used to assess whether NIH funding and other program characteristics were associated with commitment to diversity and inclusion on affiliated residency websites. RESULTS: Orthopaedic surgery residency websites included a mean of 4.9 ± 2.1 diversity and inclusion elements, with 21% (40/187) featuring a majority (7+) of elements. Top 40 NIH funded programs (5.4 ± 2.0) did not have significantly higher website diversity scores when compared with nontop-40 programs (4.8 ± 2.1) (P = 0.250). University-based or affiliated programs (5.2 ± 2.0) had higher diversity scores when compared with community-based programs (3.6 ± 2.2) (P = 0.003). CONCLUSIONS: Most orthopaedic surgery residency websites contained fewer than half of the diversity and inclusion elements studied, suggesting opportunities for further commitment to diversity and inclusion. Inclusion of diversity initiatives on program websites may attract more diverse applicants and help address gender and racial or ethnic disparities in orthopaedic surgery. LEVEL OF EVIDENCE: Level V

To determine postoperative complications and quality outcomes of single-stage and multistage surgical management for lumbar degenerative disease (LDD).This retrospective cohort study using a national administrative database identified patients who underwent surgery for LDD between 2007 and 2016. Patients were stratified based on whether their surgeon chose to perform single-stage or multistage LDD surgery, and these cohorts were mutually exclusive. Propensity score matching was used to mitigate intergroup differences between single-stage and multistage patients. Patients who underwent ≥3 levels of surgical correction, who were18 years old, or who had any prior history of trauma or tumor were excluded from the study. Baseline comorbidities, postoperative complication rates, and reoperation rates were determined.Primary surgery for LDD was performed in 47,190 patients; 9438 (20%) of these patients underwent multistage surgery. After propensity score matching, baseline covariates of the 2 cohorts were similar. The complication rate was 6.1% in the single-stage cohort and 11.0% in the multistage cohort. Rates of posthemorrhagic anemia, infection, wound complication, deep vein thrombosis, and hematoma all were higher in the multistage cohort. Length of stay, revisions, and readmissions were also significantly higher in the multistage cohort. Through 2 years of follow-up, multistage surgery was associated with higher payments throughout the 2-year follow-up period ($57,036 vs. $39,318, P0.05).Single-stage surgery for LDD demonstrated improved outcomes and lower health care utilization. Spine surgeons should carefully consider single-stage surgery when treating patients with LDD requiring3 levels of correction.

OBJECTIVE Publications are key for advancement within academia. Although women are underrepresented in academic neurosurgery, the rates of women entering residency, achieving board certification, and publishing papers are increasing. The goal of this study was to assess the current status of women in academic neurosurgery publications. Specifically, this study sought to 1) survey female authorship rates in the Journal of Neurosurgery (JNS [not including JNS: Spine or JNS: Pediatrics]) and Neurosurgery from 2010 to 2019; 2) analyze whether double-blind peer review (started in Neurosurgery in 2011) altered female authorship rates relative to single-blind review (JNS); and 3) evaluate how female authorship rates compared with the number of women entering neurosurgery residency and obtaining neurosurgery board certification. METHODS Genders of the first and last authors for JNS and Neurosurgery articles from 2010 to 2019 were obtained. Data were also gathered on the number and percentage of women entering neurosurgery residency and women obtaining American Board of Neurological Surgeons (ABNS) certification between 2010 and 2019. RESULTS Women accounted for 13.4% (n = 570) of first authors and 6.8% (n = 240) of last authors in JNS and Neurosurgery publications. No difference in rates of women publishing existed between the two journals (first authors: 13.0% JNS vs 13.9% Neurosurgery, p = 0.29; last authors: 7.3% JNS vs 6.0% Neurosurgery, p = 0.25). No difference existed between women first or last authors in Neurosurgery before and after initiation of double-blind review (p = 0.066). Significant concordance existed between the gender of first and last authors: in publications with a woman last author, the odds of the first author being a woman was increased by twofold (OR 2.14 [95% CI 1.43–3.13], p = 0.0001). Women represented a lower proportion of authors of invited papers (8.6% of first authors and 3.1% of last authors were women) compared with noninvited papers (14.1% of first authors and 7.4% of last authors were women) (first authors: OR 0.576 [95% CI 0.410–0.794], p = 0.0004; last authors: OR 0.407 [95% CI 0.198–0.751], p = 0.001). The proportion of women US last authors (7.4%) mirrors the percentage of board-certified women neurosurgeons (5.4% in 2010 and 6.8% in 2019), while the percentage of women US first authors (14.3%) is less than that for women entering neurosurgical residency (11.2% in 2009 and 23.6% in 2018). CONCLUSIONS This is the first report of female authorship in the neurosurgical literature. The authors found that single- versus double-blind peer review did not impact female authorship rates at two top neurosurgical journals.

Acetabular fracture open reduction and internal fixation (ORIF) is generally associated with high intraoperative blood loss. Hypotensive anesthesia has been shown to decrease blood loss and intraoperative transfusion in total joint arthroplasty and posterior spinal fusion. In this study, we assessed the effect of reduction in intraoperative mean arterial pressures (MAPs) during acetabular fracture surgery on intraoperative blood loss and need for transfusion.Three hundred and one patients with acetabular fractures who underwent ORIF at an academic Level 1 trauma center were retrospectively reviewed. Patients were separated based on mean intraoperative MAPs (60 mmHg, 60-70 mmHg,70 mmHg). Thirteen patients had mean intraoperative MAP60 mmHg, 95 had MAP 60-70 mmHg, and 193 had MAP70 mmHg. Rates of intraoperative and postoperative allogeneic blood transfusion were compared.Mean intraoperative MAPs were significantly different between groups (p0.0001). Time from injury to surgery, estimated blood loss, operative time and intraoperative IV fluids were comparable. The proportion of patients who received blood transfusion and mean units transfused intraoperatively and postoperatively were similar between groups. Mean differences in preoperative and postoperative hemoglobin and hematocrit were also similar. There was no difference in hospital length of stay or perioperative complications between the groups. Multivariate logistic regression analysis demonstrated that body mass index30 (p0.05) and anterior surgical approach (p0.01) were independently associated with intraoperative transfusion and an anterior surgical approach (p0.001) was independently associated with postoperative transfusion.Decreased intraoperative MAP during acetabular fracture surgery does not reduce blood loss or need for transfusion. On the other hand, no increased end-organ ischemia was seen with hypotensive anesthesia.Therapeutic Level III.

BACKGROUND: Single position (SP) lateral transpsoas lumbar interbody fusion (LLIF) with posterior pedicle screw fixation (PPSF) reduces operative time compared to dual positioning. However, the learning curve has not yet been described. The purpose of this study was to define the learning curve SP LLIF with PPSF. METHODS: This retrospective case series included the first 161 consecutive patients who underwent SP LLIF and PPSF with the senior author. Primary analysis of operative time versus case number included single level cases without adjacent level procedures. Secondary analyses included 1−3 level cases without adjacent level procedures. Operative time for 2 and 3 level procedures was normalized to single-level cases. The learning curve was assessed with linear regression, which was found to fit the data better than logarithmic regression as judged by R(2) values and data visualization. Perioperative outcomes as a function of case number were analyzed by least squares linear regression and Mann Whitney U-tests. RESULTS: For single level surgeries without adjacent procedures (n=87), operative time decreased by a total of 28.7 (95% CI, 9.6, 47.9) minutes over the series (P

Retrospective cohort study.To assess outcomes and mortality in elderly patients following unstable spine fractures depending on treatment modality.Operative management of unstable spine fractures in the elderly remains controversial due to increased risk of perioperative complications. Mortality rates after operative versus nonoperative treatment of these injuries have not been well-characterized.Patients aged above 65 with unstable spine fractures without neurologic injury from 2015 to 2021 were identified from the Clinformatics ® Data Mart (CDM) Database. Demographics, complications, and mortality were collected. Multivariable logistic regression was used to adjust for the effect of baseline characteristics on mortality following unstable fracture diagnosis.Of the 3688 patients included, 1330 (36.1%) underwent operative management and 2358 (63.9%) nonoperative. At baseline, nonoperative patients were older, female, had higher Elixhauser comorbidity scores, and were more likely to have a cervical fracture. Operative patients had a longer length of stay in the hospital compared with nonoperative patients (9.7 vs. 7.7 days; P0.001). Although patients in the operative group had higher rates of readmission at 30, 60, 90, and 120 days after diagnosis ( P0.01), they had lower mortality rates up to five years after injury. After adjusting for covariates, nonoperative patients had a 60% greater risk of mortality compared with operative patients (hazard ratio: 1.60, 95% confidence interval: 1.40-1.78, P0.001). After propensity score matching, operative patients age 65 to 85 had greater survivorship compared with their nonoperative counterparts.Elderly patients with an unstable spine fracture who undergo surgery experience lower mortality rates up to five years postdiagnosis compared with patients who received nonoperative management, despite higher hospital readmission rates and an overall perioperative complication rate of 37.3%. Operating on elderly patients with unstable spine fractures may outweigh the risks and should be considered as a viable treatment option in appropriately selected patients.

Tranexamic acid (TXA) reduces need for transfusion in total joint arthroplasty, though findings in acetabular surgery are conflicting. We compared outcomes after acetabular fracture surgery with or without perioperative intravenous (IV) TXA administration. We performed a retrospective review of 305 patients with acetabular fractures that underwent open reduction and internal fixation (ORIF). Eighty-nine patients received TXA, and 216 did not. The primary outcome was rates of intraoperative and postoperative allogeneic blood transfusion. Baseline demographics and characteristics were similar. Time from injury to surgery and estimated blood loss were comparable. Operative time (p

Achieving durable mechanical stability in geriatric intertrochanteric proximal femur fractures remains a challenge. Concomitant poor bone quality, unstable fracture patterns, and suboptimal reduction are additional risk factors for early mechanical failure. Cement augmentation of the proximal locking screw or blade is one proposed method to augment implant anchorage. The purpose of this review is to describe the biomechanical and clinical evidence for cement augmentation of geriatric intertrochanteric fractures, and to elaborate indications for cement augmentation. The PubMed database was searched for English language studies up to January 2021. Studies that assessed effect of calcium phosphate or methylmethacrylate cement augmentation during open reduction and internal fixation of intertrochanteric fractures were included. Studies with sample size

Objective In patients with new primary intradural spinal tumors, the best screening strategy for additional central nervous system (CNS) lesions is unclear. The goal of this study was to document the rate of additional CNS tumors in these patients. Methods Adults with primary intradural spinal tumors were retrospectively reviewed. Imaging strategy at diagnosis was classified as focused spine (cervical, thoracic, or lumbar), total spine, or complete neuraxis (brain and total spine). Tumor pathology, genetic syndromes, and presence of additional CNS lesions at diagnosis or follow-up were collected. Results The study comprised 319 patients with mean age of 51 years and mean follow-up of 41 months. In 151 patients with focused spine imaging, 3 (2.0%) were found to have new lesions with 2 (1.4%) requiring treatment. In 35 patients with total spine imaging, there were no additional lesions. In 133 patients with complete neuraxis imaging, 4 (3.0%) were found to have new lesions with 2 (1.5%) requiring treatment. There was no difference in the identification of new lesions (P = 0.542) or new lesions requiring treatment (P = 0.772) across imaging strategies. Among patients without genetic syndromes, rates of new lesions requiring treatment were 1.4% for focused spine, 0% for total spine, and 2.2% for complete neuraxis (P = 0.683). There were no cases of delayed identification causing risk to life or neurological function. Complete neuraxis imaging carried an increased charge of $4420 per patient. Conclusions Among patients without an underlying genetic syndrome, the likelihood of identifying additional CNS lesions requiring treatment is low. In appropriate cases, focused spine imaging may be a more cost-effective strategy.

The American Association for the Surgery of Trauma (AAST) recently developed a classification system to standardize outcomes analyses for several emergency general surgery conditions. To highlight this system's full potential, we conducted a study integrating prospective AAST grade assignment within the electronic medical record.Our institution integrated AAST grade assignment into our clinical workflow in July 2018. Patients with acute diverticulitis were prospectively assigned AAST grades and modified Hinchey classes at the time of surgical consultation. Support vector machine-a machine learning algorithm attuned for small sample sizes-was used to compare the associations between the two classification systems and decision to operate and incidence of complications.67 patients were included (median age of 62 y, 40% male) for analysis. The decision for operative management, hospital length of stay, intensive care unit admission, and intensive care unit length of stay were associated with both increasing AAST grade and increasing modified Hinchey class (all P 0.001). AAST grade additionally showed a correlation with complication severity (P = 0.02). Compared with modified Hinchey class, AAST grade better predicted decision to operate (88.2% versus 82.4%).This study showed the feasibility of electronic medical record integration to support the full potential of AAST classification system's utility as a clinical decision-making tool. Prospectively assigned AAST grade may be an accurate and pragmatic method to find associations with outcomes, yet validation requires further study.

STUDY DESIGN Retrospective cohort studying using a national, administrative database. OBJECTIVE The aim of this study was to determine the postoperative complications and quality outcomes of patients with and without obesity undergoing surgical management for lumbar degenerative disease (LDD). SUMMARY OF BACKGROUND DATA Obesity is a global epidemic that negatively impacts health outcomes. Characterizing the effect of obesity on LDD surgery is important given the growing elderly obese population. METHODS This study identified patients with who underwent surgery for LDD between 2007 and 2016. Patients were stratified based on whether the patient had a concurrent diagnosis of obesity at time of surgery. Propensity score matching (PSM) was then utilized to mitigate intergroup differences between patients with and without obesity. Patients who underwent three or more levels surgical correction, were under the age of 18 years, or those with any previous history of trauma or tumor were excluded from this study. Baseline comorbidities, postoperative complication rates, and reoperation rates were determined. RESULTS A total of 67,215 patients underwent primary lumbar degenerative surgery, of which 22,405 (33%) were obese. After propensity score matching, baseline covariates of the two cohorts were similar. The complication rate was 8.3% in the nonobese cohort and 10.4% in the obese cohort (P

Excessive fracture site collapse and shortening in intertrochanteric femur fractures alter hip biomechanics and patient outcomes. The purpose of the study was to compare extent of collapse in cephalomedullary nails with blades or lag screws. We hypothesized that there would be no difference in collapse between helical blades and lag screws. Retrospective cohort study. Single U.S. Level I Trauma Center. 171 consecutive patients treated with cephalomedullary nails with either lag screw or blade for AO/OTA 31A1-3 proximal femur fractures and minimum 3-month follow-up. Lag screw or helical blade in a cephalomedullary nail. The primary outcome was fracture site collapse at 3 months. There was a significantly higher proportion of reverse-oblique and transverse intertrochanteric femur fractures (31-A3) in the lag screw group (15/42 vs 25/129). A3 patterns were associated with more collapse. There was significantly less collapse in the blade group (median 4.7 mm, inter-quartile range 2.5–7.8 mm) than the screw group (median 8.4 mmm, inter-quartile range 3.7–11.2 mm, p 0.006). Median collapse was no different between blades and screws when comparing stable and unstable patterns. However, blades were independently associated with 2.5 mm less collapse (95%CI − 4.2, − 0.72 mm, p 0.006) and lower likelihood of excessive collapse (> 10 mm at 3 months, OR 0.3, 95% CI 0.13–0.74, p 0.007), regardless of fracture pattern. Helical blades are independently associated with significantly less collapse than lag screws in intertrochanteric proximal femur fractures, after adjusting for unstable fracture patterns. In fracture patterns at risk for collapse, surgeons can consider use of a helical blade due to its favorable sliding properties compared to screws.

Background Although prior studies have identified a low risk of venous thromboembolism (VTE) in rhinoplasty, these studies are limited by small samples and associated risk factors remain unknown. Objectives The aim of this study was to discern the incidence of VTE following rhinoplasty in a large patient population through analysis of a nationwide insurance claims database. Methods This study involved a population-based retrospective analysis of insurance claims made by patients who underwent rhinoplasty between 2007 and 2016. Established risk factors for VTE, demographic data, procedural details, and absolute incidence of VTE were collected. Results We identified a total of 55,287 patients who underwent rhinoplasty from 2007 to 2016. Mean age [standard error of the mean] was 38.74 [0.06] years (range, 18-74 years), and 54% were female. The overall incidence of VTE was 111, of which 70 were DVT and 41 were PE. From multivariate regression analysis, previous VTE (odds ratio [OR], 52.8; 95% confidence interval [CI], 35.2-78.6; P Conclusions We demonstrate a low overall incidence of VTE in rhinoplasty patients. Previous VTE, PICC/central line, advancing age, IBD, and intraoperative rib graft harvest were most strongly associated with VTE in this population cohort. Level of Evidence: 4

The primary aim of this study was to compare clinical outcomes in patients with associated both column (ABC) acetabular fractures with fracture of the posterior wall (PW), in which the PW underwent reduction and fragment-specific fixation versus those that were treated with column fixation alone. Secondary aims were to assess PW fracture incidence and morphology, as well as to compare radiographic outcomes including fracture healing and interval displacement of the PW in those that did and did not undergo fragment-specific fixation of the PW. This was a retrospective series of ABC acetabular fractures treated at a single Level I trauma center. Separate fractures of the PW were identified, and associated features were assessed. Associated both column fractures that underwent reduction and fragment-specific fixation of the PW where then compared to ABC fractures with PW involvement that underwent column reconstruction alone. Radiographic and clinical outcomes were compared. Fractures of the PW occurred in 55.7% of ABC fractures and were associated with central displacement of the femoral head. The majority of PW fractures were large and involved the acetabular roof. All PW fractures healed without displacement by 3 months, regardless of whether or not reduction and stabilization was performed. Mid-term outcomes at 1-year were similar regardless of whether or not the PW was reduced and stabilized, with regards to Tonnis grade, Merle d'Aubigne-Postel score, and conversion to total hip arthroplasty. Reduction and fragment-specific fixation of the PW component of ABC acetabular fractures did not improve outcomes in this small comparative study. Posterior wall fractures associated with ABC patterns are frequently large-sized fragments that involve the acetabular roof and are rendered stable after reconstruction of the columns.

This study examined the complications and outcomes of geriatric acetabular fractures treated with open reduction internal fixation (ORIF) and total hip arthroplasty (THA) performed via combined ilioinguinal or anterior intrapelvic (AIP) approach to acetabulum and anterior approach to the hip. Eight patients with a fracture of the acetabulum were treated at a Level I trauma center between 2010 and 2019 with combined ORIF/THA using an ilioinguinal or AIP approach for the acetabulum and a separate anterior approach to the hip. Wound dehiscence, peri-incisional skin necrosis, surgical site infection, dislocation, fracture union, acetabular component stability, and heterotopic ossification (HO) were utilized as outcome measures. Merle d'Aubigne–Postel scores were collected for the six patients that had one-year minimum follow-up. The mean patient age was 77 years. Four patients had anterior wall fractures, two had associated both column fractures, and two had anterior column–posterior hemitransverse fractures. All fractures healed with stable fixation of the acetabular component by 6 months. There were no instances of skin necrosis, dislocation, infection, or re-operation. One patient had a superficial wound dehiscence that resolved with local wound care. One patient developed radiographic HO but was clinically asymptomatic. The mean Merle d'Aubigne–Postel score was 15.8 (range = 14–16). Our small series of geriatric patients with fracture of the acetabulum treated with combined ORIF/THA, via the ilioinguinal or AIP approach with a separate anterior approach to the hip, demonstrates satisfactory outcomes with low complications after one-year of follow-up. Further research of these challenging injuries with more patients is warranted in order to determine the subset of fracture types best treated with this method and THA survivorship.

Increasing costs put the value of spine surgery under scrutiny. In health economics, cost-effectiveness analyses (CEA) are used to compare the value of competing procedures. However, inconsistent methodology prevents standardization and implementation of recommendations. The goal of this study is to perform a systematic review of all U.S. CEAs in spine surgery reported to date, highlight their strengths and weaknesses, and define metrics essential for high-quality CEAs.We followed AMSTAR systematic review methods, identifying all U.S. spine surgery CEAs reported to March 2019 with a structured, reproducible search of PubMed, Embase, and the Tufts CEA Registry.We identified 40 CEA studies. Twelve (30%) used outcome data from a randomized controlled trial. To calculate costs, 22 (55%) used allowed charges but costing methods were often unclear or imprecise. Studies applying discounting had mean follow-up of 5.92 years compared with 3.00 years for studies without. Eleven of 15 (73%) cervical studies compared cervical disc arthroplasty with anterior cervical discectomy and fusion, finding cervical disc arthroplasty to be cost-effective ($100,000/quality-adjusted life year) for 1-level and 2-level procedures. Eleven of 25 lumbar studies (44%) compared operative with nonoperative interventions for intervertebral disc herniation, lumbar stenosis, and lumbar spondylolisthesis. Lumbar studies comparing surgical with nonoperative intervention found surgery at least cost-effective for intervertebral disc herniation and lumbar stenosis, but cost-effective only for lumbar spondylolisthesis at 4 years follow-up. Most studies (70%) lacked appropriate sensitivity analyses.Costing methodology remains obscure and inconsistent and incremental cost-effectiveness ratio results incomparable. The language of costing methodology must be standardized and sensitivity analyses of outcome and cost inputs mandatory for publication.

Intra-articular screw cut-out is a potential complication of intertrochanteric femur fracture fixation with a cephalomedullary nail. Cement augmentation of fixation in the proximal segment offers the prospect of increased stability and fewer complications, but clinical experience with non-resorbable cement is limited. To determine the handling properties and efficacy of this new technique, we performed a retrospective propensity-matched cohort of forty-four geriatric intertrochanteric femur fractures treated with a cephalomedullary nail with (n = 11) or without (n = 33) augmentation with non-resorbable cement injected into the proximal segment. In the patients treated with cement augmentation, at minimum 3-month follow-up, there were no instances of intra-articular cut-out, and no increase in re-operation compared to conventional fixation. Cement augmentation appears to be safe and effective in geriatric intertrochanteric femur fractures to mitigate risk of cut-out.

This study examined osteotomy union and heterotopic ossification (HO) after performing digastric trochanteric osteotomies during open reduction and internal fixation (ORIF) of acetabular and combined femoral head fractures. Femoral head osteonecrosis and trochanteric screw removal were secondarily assessed. Twenty-six patients treated at a Level I trauma center, from years 2003 to 2019, who received a digastric trochanteric osteotomy during acetabular and combined femoral head fracture ORIF through a posterior surgical approach were retrospectively identified. Osteotomies were fixed with two 3.5 mm cortical lag screws. Rates of osteotomy union, HO, femoral head osteonecrosis, and trochanteric screw removal were determined. All osteotomies went onto union without displacement or failure of fixation. Only three (12%) patients developed severe HO (modified-Brooker class III–IV). There were no instances of femoral head osteonecrosis and only one (7%) patient required trochanteric screw removal. The digastric trochanteric osteotomy heals reliably with low rates of severe HO, femoral head osteonecrosis, and screw removal for soft-tissue irritation. A review of the literature is presented and found comparable findings.

The optimal management of valgus-impacted femoral neck fractures remains controversial. Internal fixation is associated with significant rates of re-operation, while historical non-operative management strategies consisting of prolonged bed rest also resulted in patient morbidity. Our hypothesis was that screw fixation would have comparable failure rates to non-operative treatment and immediate mobilization for valgus-impacted femoral neck fractures. Retrospective cohort at a single academic Level I trauma center of patients with valgus-impacted femoral neck fractures (AO/OTA 31-B1) treated with percutaneous screw fixation (n = 97) or non-operatively (n = 28). Operative treatment consisted of percutaneous screw fixation. Non-operative treatment consisted of early mobilization. The primary outcome was a salvage operation. Patient demographics were assessed between groups. More non-operatively treated patients were permitted unrestricted weight-bearing (WBAT; p = 0.002). There was no increase in complication rates or mortality, and return to previous ambulatory status was comparable between operatively and non-operatively treated patients. 35.7% (10/28) of non-operatively treated patients underwent a subsequent operation, compared to 15.5% (15/97) of patients with screw fixation (p = 0.03). Only WBAT was independently associated with treatment failure (OR 3.1, 95%CI 1.2–8.3, p =0.02). WBAT was predictive of treatment failure only in the non-operatively treated group (64.3%, 9/14 WBAT vs 8.3%, 1/12 partial, p =0.005). After controlling for weight-bearing restrictions, we found no difference in failure rates between non-operative treatment and screw fixation. Non-operative treatment with partial weight-bearing had low failure rates, comparable complication and mortality rates, and equivalent functional outcomes to operative treatment and is reasonable if a patient would like to avoid surgery and accepts the risk of subsequent arthroplasty. Overall, there were relatively high failure rates in all groups.

The increasing competitiveness of the neurosurgical residency match has made it progressively difficult for foreign medical graduates (FMGs) to match in neurosurgery. We compared FMG to U.S. medical graduate (USMG) match rates in neurosurgery and identified factors associated with match outcomes for FMGs in neurosurgery.Retrospective review of American Association of Neurological Surgeons membership data and Association of American Medical Colleges Charting the Outcomes match reports (2007-2017).Across 1857 neurosurgical residents (USMG: 91.1%, FMG: 8.9%), average FMG match rates were 24% (range, 15%-35%) versus 83% (range, 75%-94%; P0.001) for USMG. FMGs were more male (89.5% vs. 82.0%, P = 0.016), older (33.9 vs. 31.8 years, P = 0.008), and more likely to take research year(s) before matching (95.8% vs. 78.5%, P0.001). FMGs had greater publications (5 vs. 2, P0.001) and H-indices (3 vs. 1, P0.001). The number of matched USMGs increased by 3.3 annually, whereas that of matched FMGs remained unchanged (β = 0.07). Compared with USMGs, FMGs were less likely to match to National Institutes of Health (NIH) Top 40 (32.7% vs. 47.5%, P0.001) and Doximity Top 20 (20.0% vs. 29.0%, P = 0.014) programs. FMGs with prior U.S. neurosurgery program affiliation were more likely to match at NIH and Doximity Top 20 programs (P0.05). For NIH programs, FMGs were older (35.3 vs. 32.0, P = 0.011), had higher H-indices (5 vs. 2, P0.001), publications (7 vs. 2, P0.001), and were more likely to take research year(s) (94.4% vs. 76.0%, P = 0.002) than USMGs. FMGs had similar patterns for matching into Doximity Top 20 programs.Although FMGs have lower match rates into U.S. neurosurgery residencies than USMGs, several demographic, professional, and academic factors could increase the chances of successful FMG neurosurgical match.

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. Significance: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes.

INTRODUCTION: Though long-term functional outcomes of olecranon fracture plate fixation are favorable, postoperative implant irritation commonly leads to elective removal. We hypothesized that mini-fragment plates will decrease implant removal compared to precontoured plates. METHODS: Patients with isolated olecranon fracture (AO/OTA 2U1–B1) treated with plate fixation were retrospectively reviewed. Patients were stratified into groups based on whether they underwent open reduction and internal fixation with a (1) surgeon contoured mini-fragment or (2) precontoured olecranon-specific plate. Rates of symptomatic implants and implant removal were compared. RESULTS: 98 and 32 patients were treated with precontoured and mini-fragment plates, respectively. Baseline demographics and comorbidities were similar. Mean follow-up was 20.6 months. There were no differences in rates of postoperative complication (22/98, 22.4% vs. 5/32, 15.6%; p = 0.41) or reoperation (37/98, 37.8% vs. 8/32, 25%; p = 0.19). Symptomatic implants were common in the precontoured cohort (44/98, 44.9% vs. 7/32, 21.9%; p

Study Design Retrospective cohort study. Objective To investigate the effect of preoperative epidural steroid injection (ESI) on quality outcomes and costs in patients undergoing surgery for cervical degenerative disease. Methods We queried the MarketScan database, a national administrative claims dataset, to identify patients who underwent cervical degenerative surgery from 2007 to 2016. Patients under 18 and patients with history of tumor or trauma were excluded. Patients were stratified by ESI use at 3, 6, 12, 18, and 24 or more months preoperative. Propensity score matched controls for these groups were obtained. Baseline demographics, postoperative complications, reoperations, readmissions, and costs were compared via univariate and multivariate analysis. Results 97 117 patients underwent cervical degenerative surgery, of which 29 963 (30.7%) had ESI use at any time preoperatively. Overall, 90-day complication rate was not significantly different between groups. The ESI cohorts had shorter length of stay, but higher 90-day readmission and reoperation rates. ESI use was associated with higher total payments through the 2-year follow-up period. Among patients who received preoperative ESI, male sex, history of cancer, obesity, PVD, rheumatoid arthritis, nonsmokers, cervical myelopathy, BMP use, anterior approach, 90-day complication, 90-day reoperation, and 90-day readmission were independently associated with increased 90-day total cost. Conclusion ESI can offer pain relief in some patients refractory to other conservative management techniques, but those who eventually undergo surgery have greater healthcare resource utilization. Certain characteristics can predispose patients who receive preoperative ESI to incur higher healthcare costs.

Background: Thumb carpometacarpal (CMC) osteoarthritis (OA) is a common condition. The contribution of surrounding ligaments and tendons to the stability of the CMC joint is likely altered in OA. The flexor carpi radialis (FCR) tendon runs in the trapezial FCR groove and is often noted to be frayed during CMC arthroplasty. We hypothesized that decreased integrity of the FCR tendon is related to FCR groove morphology and is associated with increased severity of CMC OA. Methods: We examined 3-dimensional surface models based on computed tomography (CT) scans of explanted trapezia from patients who underwent thumb CMC arthroplasty. Fraying of the FCR tendon was rated intraoperatively. Measurements were taken of the FCR groove to evaluate its morphology. Preoperative thumb CMC radiographs for each patient were scored using the modified Eaton classification system and the Thumb Osteoarthritis Index. Differences in the tendon groups were examined, and multivariable linear regression models were used to test the association between tendon group and FCR groove measurement. Results: There were 136 patients who were categorized into 4 tendon groups: intact, minor fraying, fraying, and ruptured. There were no differences between the tendon groups on any measures. Conclusions: Our findings do not demonstrate a significant influence of FCR groove morphology on FCR tendon fraying in CMC arthroplasty patients. We also did not find a significant association between the FCR tendon state and degree of radiographic CMC OA. Further studies should investigate the in vivo FCR tendon to evaluate its tearing and inflammation in relation to basilar thumb pain.

STUDY DESIGN This was a retrospective comparative study. OBJECTIVE The objective of this study was to assess the effect of increased age on perioperative and postoperative complication rates, reoperation rates, and patient-reported pain and disability scores after lateral lumbar interbody fusion (LLIF). SUMMARY OF BACKGROUND DATA LLIF was developed to minimize soft tissue trauma and reduce the risk of vascular injury; however, there is little evidence regarding the effect of advanced age on outcomes of LLIF. METHODS Patients who underwent LLIF from 2009 to 2019 at one institution with a minimum 6-month follow-up were retrospectively reviewed. Patients less than 18 years old with musculoskeletal tumor or trauma were excluded. The primary outcome was the preoperative to postoperative change in the Numeric Pain Rating Scale (NPRS) for back pain. Operative time, estimated blood loss, length of stay, perioperative and 90-day complications, unplanned readmissions, reoperations, and change in Oswestry Disability Index were also evaluated. Relationships with age were assessed both with age as a continuous variable and segmenting by age below 70 versus 70+. RESULTS In total, 279 patients were included. The median age was 65±13 years and 159 (57%) were female. Age was not related to improvements in back NPRS and Oswestry Disability Index. Operative time, estimated blood loss, length of stay, perioperative and 90-day complications, unplanned readmissions, reoperations, and radiographic fusion rate also were not related to age. After multivariable risk adjustment, increasing age was associated with greater improvements in back NPRS. The decrease in back NPRS was 0.68 (95% confidence interval: 0.14, 1.22; P=0.014) points greater for every 10-year increase in age. Age was not associated with rates of complication, readmission, or reoperation. CONCLUSIONS LLIF is a safe and effective procedure in the elderly population. Advanced age is associated with larger improvements in preoperative back pain. Surgeons should consider the benefits of LLIF and other minimally invasive techniques when evaluating elderly candidates for lumbar fusion. LEVEL OF EVIDENCE Level III.

Metastases cause 90% of human cancer deaths. The metastatic cascade involves local invasion, intravasation, extravasation, metastatic site colonization, and proliferation. Although individual mediators of these processes have been investigated, interactions between these mediators remain less well defined. We previously identified a complex between receptor tyrosine kinase c-Met and β1 integrin in metastases. Using cell culture and in vivo assays, we found that c-Met/β1 complex induction promoted intravasation and vessel wall adhesion in triple-negative breast cancer cells, but did not increase extravasation. These effects may have been driven by the ability of the c-Met/β1 complex to increase mesenchymal and stem cell characteristics. Multiplex transcriptomic analysis revealed upregulated Wnt and hedgehog pathways after c-Met/β1 complex induction. A β1 integrin point mutation that prevented binding to c-Met reduced intravasation. OS2966, a therapeutic antibody disrupting c-Met/β1 binding, decreased breast cancer cell invasion and mesenchymal gene expression. Bone-seeking breast cancer cells exhibited higher levels of c-Met/β1 complex than parental controls and preferentially adhered to tissue-specific matrix. Patient bone metastases demonstrated higher c-Met/β1 complex than brain metastases. Thus, the c-Met/β1 complex drove intravasation of triple-negative breast cancer cells and preferential affinity for bone-specific matrix. Pharmacological targeting of the complex may have prevented metastases, particularly osseous metastases.

Despite their identification in some cancers, pro-tumoral cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of primary glioblastoma cultures yielded cells with CAF morphology, CAF transcriptomic profile, and mesenchymal lineage in single-cell RNA-seq. Glioblastoma CAFs were attracted to glioblastoma stem cells (GSCs) and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF-β and TGF-β as mediators of GSC effects on CAFs, and osteopontin and hepatocyte growth factor as mediators of CAF-induced GSC enrichment. Glioblastoma CAFs also induced M2 macrophage polarization by producing the EDA fibronectin variant. Glioblastoma CAFs were enriched in the subventricular zone which houses neural stem cells that produce GSCs. Including CAFs in GSC-derived xenografts induced in vivo growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.