Publications by authors named "Timothy Witham"

222 Publications

Augmented Reality in Spine Surgery: A Narrative Review.

HSS J 2021 Oct 14;17(3):351-358. Epub 2021 Jul 14.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Augmented reality (AR) navigation refers to novel technologies that superimpose images, such as radiographs and navigation pathways, onto a view of the operative field. The development of AR navigation has focused on improving the safety and efficacy of neurosurgical and orthopedic procedures. In this review, the authors focus on 3 types of AR technology used in spine surgery: AR surgical navigation, microscope-mediated heads-up display, and AR head-mounted displays. Microscope AR and head-mounted displays offer the advantage of reducing attention shift and line-of-sight interruptions inherent in traditional navigation systems. With the U.S. Food and Drug Administration's recent clearance of the XVision AR system (Augmedics, Arlington Heights, IL), the adoption and refinement of AR technology by spine surgeons will only accelerate.
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http://dx.doi.org/10.1177/15563316211028595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436352PMC
October 2021

Intraoperative cone-beam and slot-beam CT: 3D image quality and dose with a slot collimator on the O-arm imaging system.

Med Phys 2021 Sep 14. Epub 2021 Sep 14.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.

Purpose: To characterize the 3D imaging performance and radiation dose for a prototype slot-beam configuration on an intraoperative O-arm™ Surgical Imaging System (Medtronic Inc., Littleton MA) and identify potential improvements in soft-tissue image quality for surgical interventions.

Methods: A slot collimator was integrated with the O-arm system for slot-beam axial CT. The collimator can be automatically actuated to provide 1.2° slot-beam longitudinal collimation. Cone-beam and slot-beam configurations were investigated with and without an antiscatter grid (12:1 grid ratio, 60 lines/cm). Dose, scatter, image noise, and soft-tissue contrast resolution were evaluated in quantitative phantoms for head and body configurations over a range of exposure levels (beam energy and mAs), with reconstruction performed via filtered-backprojection. Qualitative imaging performance across various anatomical sites and imaging tasks was assessed with anthropomorphic head, abdomen, and pelvis phantoms.

Results: The dose for a slot-beam scan varied from 0.02-0.06 mGy/mAs for head protocols to 0.01-0.03 mGy/mAs for body protocols, yielding dose reduction by ∼1/5 to 1/3 compared to cone-beam, owing to beam collimation and reduced x-ray scatter. The slot-beam provided a ∼6-7× reduction in scatter-to-primary ratio (SPR) compared to the cone-beam, yielding SPR ∼20%-80% for head and body without the grid and ∼7%-30% with the grid. Compared to cone-beam scans at equivalent dose, slot-beam images exhibited a ∼2.5× increase in soft-tissue CNR for both grid and gridless configurations. For slot-beam scans, a further ∼10-30% improvement in CNR was achieved when the grid was removed. Slot-beam imaging could benefit certain interventional scenarios in which improved visualization of soft tissues is required within a fairly narrow longitudinal region of interest (7 mm in ) - e.g., checking the completeness of tumor resection, preservation of adjacent anatomy, or detection of complications (e.g., hemorrhage). While preserving existing capabilities for fluoroscopy and cone-beam CT, slot-beam scanning could enhance the utility of intraoperative imaging and provide a useful mode for safety and validation checks in image-guided surgery.

Conclusions: The 3D imaging performance and dose of a prototype slot-beam CT configuration on the O-arm system was investigated. Substantial improvements in soft-tissue image quality and reduction in radiation dose are evident with the slot-beam configuration due to reduced x-ray scatter. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/mp.15221DOI Listing
September 2021

Timing of referral to peripheral nerve specialists in patients with postoperative C5 palsy.

J Clin Neurosci 2021 Oct 23;92:169-174. Epub 2021 Aug 23.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurosurgery, Zucker School of Medicine at Hofstra, Long Island Jewish Medical Center and North Shore University Hospital, Northwell Health, Manhasset, NY 11030, USA. Electronic address:

The objective of this study was to examine the association between electrophysiology data post-C5-palsy and referral to peripheral nerve surgeons (PNS) using a 15-year cohort of patients who underwent posterior cervical decompression. Endpoints included the associations of postoperative treatments employed with functional recovery and abnormal electrophysiology data. Of 77 included patients (median 64 yr; 68% male), 48% completely recovered. The most common treatments were physical therapy (90%), occupational therapy (34%), oral corticosteroids (18%), and PNS referral (17%). Baseline weakness did not associate with PNS referral or postoperative treatment strategy. None of the treatments predicted recovery, though patients with no [versus complete] recovery were more likely to be recommended for nerve transfers (22.2 vs 0%; p = 0.03). Abnormal electromyography data associated with PNS referral (p < 0.01), nerve transfer recommendation (p < 0.01), occupational therapy referral, and oral corticosteroid therapy. Abnormal findings on EMG obtained between 6-weeks and 6-months post-injury were the most strongly associated with peripheral nerve surgeon referral (p = 0.02) and nerve transfer recommendation (p < 0.01). These data suggest strategies for postoperative C5 palsy management are highly heterogeneous. None of the treatments employed significantly predicted the extent of functional recovery. However, patients with abnormal electrophysiology results were most likely to receive multimodal treatment, suggesting these results may significantly alter medical management of patients with postoperative C5 palsy. Early (6-week to 6-month) electrophysiology data may help to ensure that patients likely to benefit from nerve transfer procedures are referred to a PNS within the 9-12-month time frame associated with the best recovery of function.
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http://dx.doi.org/10.1016/j.jocn.2021.08.007DOI Listing
October 2021

Surgical Decompression for Cervical Spondylotic Myelopathy in Patients with Associated Hypertension: A Single-Center Retrospective Cohort and Systematic Review of the Literature.

World Neurosurg 2021 Aug 13. Epub 2021 Aug 13.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objective: To explore the relationship between spinal cord compression and hypertension through analysis of blood pressure (BP) variations in a cervical spondylotic myelopathy (CSM) cohort after surgical decompression, along with a review of the literature.

Methods: A single-institution retrospective review of patients with CSM who underwent cervical decompression between 2016 and 2017 was conducted. Baseline clinical and imaging characteristics, preoperative and postoperative BP readings, heart rate, functional status, and pain scores were collected. In addition, a PRISMA guidelines-based systematic review was performed.

Results: We identified 264 patients with CSM treated surgically; 149 (56.4%) of these had hypertension. The degree of spinal canal compromise and spinal cord compression, preoperative neurologic examination, and the presence of T2-signal hyperintensity on magnetic resonance imaging were associated with hypertension. Overall mean arterial pressure (MAP) decreased significantly at 1 and 12 months after surgery. Patients without T2-signal hyperintensity on imaging showed a MAP reduction at 12 months postoperatively, whereas those with T2-signal hyperintensity showed a transient MAP reduction at 1 month postoperatively before returning to preoperative values. At 12 months after surgery, 24 of 97 patients (24.7%) with initially uncontrolled hypertension had controlled BP values with significant reduction of MAP, systolic BP, and diastolic BP. Including the present study, 5 articles were eligible for systematic review, with all reporting a BP decrease in patients with CSM after decompression.

Conclusions: Analysis of our retrospective cohort and a systematic review suggest that cervical surgical decompression reduces BP in some patients with CSM. However, this improvement is less apparent in patients with preoperative spinal cord T2-signal hyperintensity.
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http://dx.doi.org/10.1016/j.wneu.2021.08.038DOI Listing
August 2021

Does the Specialty of the Surgeon Performing Elective Anterior/Lateral Lumbar Interbody Fusion for Degenerative Spine Disease Correlate with Early Perioperative Outcomes?

World Neurosurg 2021 Aug 12. Epub 2021 Aug 12.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address:

Background: Comparative effectiveness research has a vital role in health reform and policies. Specialty training is one of these provider-side variables, and surgeons performing the same procedure who were trained in different specialties may have different outcomes. The objective of this study was to investigate the impact of spine surgeon specialty (neurosurgery vs. orthopedic surgery) on early perioperative outcome measures of elective anterior/lateral lumbar interbody fusion (ALIF/LLIF) for degenerative disc diseases.

Methods: In a retrospective, 1:1 propensity score-matched cohort study, 9070 patients were reviewed from the American College of Surgeons National Surgical Quality Improvement Program database. Propensity score matching and subgroup analysis were used.

Results: In both groups (single-level and multilevel ALIF/LLIF), patients operated on by neurosurgeons had longer operative time (188 minutes vs. 172 minutes/239 minutes vs. 221 minutes); shorter total hospital stay (71 hours vs. 90 hours/89 hours vs. 96 hours); and lower rates of return to the operating room (2.1% vs. 4.1%/2.4% vs. 4.2%), nonhome discharge (8.7% vs. 11.1%/10.1% vs. 14.9%), discharge after postoperative day 3 (22.0% vs. 30.0%/38.0% vs. 43.9%), and perioperative blood transfusion (2.1% vs. 5.1%/5.0% vs. 9.9%) (P < 0.05). In multilevel ALIF/LLIF, patients operated on by neurosurgeons had lower readmission rates (3.9% vs. 6.9%) (P < 0.05). Other outcome measures and mortality rates were similar between the single-level and multilevel ALIF/LLIF cohorts regardless of surgeon specialty.

Conclusions: Our analysis found significant differences in early perioperative outcomes of patients undergoing ALIF/LLIF by neurosurgeons and orthopedic surgeons. These differences have significant clinical and cost implications for patients, physicians, program directors, payers, and health systems.
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http://dx.doi.org/10.1016/j.wneu.2021.08.010DOI Listing
August 2021

Perceptions of the Virtual Neurosurgery Application Cycle During the Coronavirus Disease 2019 (COVID-19) Pandemic: A Program Director Survey.

World Neurosurg 2021 Aug 4. Epub 2021 Aug 4.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address:

Objective: The novel coronavirus disease 2019 (COVID-19) pandemic has led to a shift to virtual residency interviews for the 2020-2021 neurosurgery match, with unknown implications for stakeholders. This study seeks to analyze the perceptions of residency program directors (PDs) and associate program directors (APDs) regarding the current virtual format used for residency selection and interviews.

Methods: An anonymous, 30-question survey was constructed and sent to 115 neurosurgery PDs and 26 APDs to assess respondent demographics, factors used to review applicants, perceptions of applicants and applicant engagement, perceptions of standardized letters and interview questions, the effect of the virtual interview format on various stakeholders, and the future outlook for the virtual residency interview format.

Results: A total of 38 PDs and APDs completed this survey, constituting a response rate of 27.0%. Survey respondents received significantly more Electronic Residency Application Service applications in the 2020-2021 cycle compared with the 2019-2020 cycle (P = 0.0029). Subinternship performance by home-rotators, (26.3%), letters of recommendation (23.7%), and Step 1 score (18.4%) were ranked as the most important factors for evaluating candidates during the current virtual application cycle.

Conclusions: Our study highlights that applicants applied to a greater number of residency programs compared with years prior, that the criteria used by PDs/APDs to evaluate applicants remained largely consistent compared to previous years, and that the virtual residency interview format may disproportionately disadvantage Doctor of Osteopathic medicine and international medical graduate applicants. Further exploring attitudes toward signaling mechanisms and standardized letters may serve to inform changes to future neurosurgery match cycles.
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http://dx.doi.org/10.1016/j.wneu.2021.07.078DOI Listing
August 2021

Impact of international research fellows in neurosurgery: results from a single academic center.

J Neurosurg 2021 Jul 23:1-11. Epub 2021 Jul 23.

Objective: International research fellows have been historically involved in academic neurosurgery in the United States (US). To date, the contribution of international research fellows has been underreported. Herein, the authors aimed to quantify the academic output of international research fellows in the Department of Neurosurgery at The Johns Hopkins University School of Medicine.

Methods: Research fellows with Doctor of Medicine (MD), Doctor of Philosophy (PhD), or MD/PhD degrees from a non-US institution who worked in the Hopkins Department of Neurosurgery for at least 6 months over the past decade (2010-2020) were included in this study. Publications produced during fellowship, number of citations, and journal impact factors (IFs) were analyzed using ANOVA. A survey was sent to collect information on personal background, demographics, and academic activities.

Results: Sixty-four international research fellows were included, with 42 (65.6%) having MD degrees, 17 (26.6%) having PhD degrees, and 5 (7.8%) having MD/PhD degrees. During an average 27.9 months of fellowship, 460 publications were produced in 136 unique journals, with 8628 citations and a cumulative journal IF of 1665.73. There was no significant difference in total number of publications, first-author publications, and total citations per person among the different degree holders. Persons holding MD/PhDs had a higher number of citations per publication per person (p = 0.027), whereas those with MDs had higher total IFs per person (p = 0.048). Among the 43 (67.2%) survey responders, 34 (79.1%) had nonimmigrant visas at the start of the fellowship, 16 (37.2%) were self-paid or funded by their country of origin, and 35 (81.4%) had mentored at least one US medical student, nonmedical graduate student, or undergraduate student.

Conclusions: International research fellows at the authors' institution have contributed significantly to academic neurosurgery. Although they have faced major challenges like maintaining nonimmigrant visas, negotiating cultural/language differences, and managing self-sustainability, their scientific productivity has been substantial. Additionally, the majority of fellows have provided reciprocal mentorship to US students.
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http://dx.doi.org/10.3171/2021.1.JNS203824DOI Listing
July 2021

Interrater and Intrarater Reliability of the Vertebral Bone Quality Score.

World Neurosurg 2021 Jul 9. Epub 2021 Jul 9.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neurosurgery, Zucker School of Medicine at Hofstra, Long Island Jewish Medical Center and North Shore University Hospital, Northwell Health, Manhasset, New York, USA. Electronic address:

Background: Vertebral bone quality had a significant impact on postoperative outcomes in spinal fusion surgery. New magnetic resonance imaging-based measures, such as the Vertebral Bone Quality (VBQ) score, may allow for bone quality assessment without the radiation associated with conventional testing. In the present study, we sought to assess the intrarater and interrater reliability of VBQ scores calculated by medical professionals and trainees.

Methods: Thirteen reviewers of various specialties and levels of training were recruited and asked to calculate VBQ scores for 30 patients at 2 time points separated by 2 months. Scored volumes were acquired from patients treated for both degenerative and oncologic indications. Intrarater and interrater agreement, quantified by intraclass correlation coefficient (ICC), was assessed using 2-way random effects modeling. Square-weight Cohen κ and Kendall Tau-b were used to determine whether raters assigned similar scores during both evaluations.

Results: All raters showed moderate to excellent reliability for VBQ score (ICC 0.667-0.957; κ0.648-0.921) and excellent reliability for all constituent components used to calculate VBQ score (ICC all ≥0.97). Interrater reliability was also found to be good for VBQ score on both the first (ICC = 0.818) and second (ICC = 0.800) rounds of assessment; scores for the constituent component all had ICC values ≥0.97 for the constituent components.

Conclusions: The VBQ score appears to have both good intrarater and interrater reliability. In addition, there appeared to be no correlation between score reliability and level of training. External validation and further investigations of its ability to accurately model bone biomechanical properties are necessary.
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http://dx.doi.org/10.1016/j.wneu.2021.07.020DOI Listing
July 2021

Captopril inhibits Matrix Metalloproteinase-2 and extends survival as a temozolomide adjuvant in an intracranial gliosarcoma model.

Clin Neurol Neurosurg 2021 08 22;207:106771. Epub 2021 Jun 22.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Captopril is a well-characterized, FDA-approved drug that has demonstrated promise as a repurposed oncology therapeutic. Captopril's known anti-cancer effects include inhibition of Matrix Metalloproteinase-2 (MMP-2), an endopeptidase which selectively breaks down the extracellular matrix to promote cell migration. MMP-2 is a known therapeutic target in gliomas, tumors with significant clinical need. Using an aggressive gliosarcoma model, we assessed captopril's effects on MMP-2 expression in vitro and in vivo as well as its efficacy as an adjuvant in combination therapy regimens in vivo.

Methods: Following captopril treatment, MMP-2 protein expression and migratory capabilities of 9 L gliosarcoma cells were assessed in vitro via western blots and scratch wound assays, respectively. Rats were intracranially implanted with 9 L gliosarcoma tumors, and survival was assessed in the following groups: control; captopril (30 mg/kg/day); temozolomide (TMZ) (50 mg/kg/day), and captopril+TMZ. In vivo experiments were accompanied by immunohistochemistry for MMP-2 from brain tissue.

Results: In vitro, captopril decreased MMP-2 protein expression and reduced migratory capacity in 9 L gliosarcoma cells. In a gliosarcoma animal model, captopril decreased MMP-2 protein expression and extended survival as a TMZ adjuvant relative to untreated controls, captopril monotherapy, and TMZ monotherapy groups (27.5 versus 14 (p < 0.001), 16 (p < 0.001), and 23 (p = 0.018) days, respectively).

Conclusions: Captopril decreases gliosarcoma cell migration, which may be mediated by reduction in MMP-2 protein expression. Captopril provided a survival advantage as a TMZ adjuvant in a rat intracranial gliosarcoma model. Captopril may represent a promising potential adjuvant to TMZ therapy in gliosarcoma as a modulator of the MMP-2 pathway.
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http://dx.doi.org/10.1016/j.clineuro.2021.106771DOI Listing
August 2021

Predictors of an academic career among fellowship-trained spinal neurosurgeons.

J Neurosurg Spine 2021 Jun 11:1-8. Epub 2021 Jun 11.

1Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: Although fellowship training is becoming increasingly common in neurosurgery, it is unclear which factors predict an academic career trajectory among spinal neurosurgeons. In this study, the authors sought to identify predictors associated with academic career placement among fellowship-trained neurological spinal surgeons.

Methods: Demographic data and bibliometric information on neurosurgeons who completed a residency program accredited by the Accreditation Council for Graduate Medical Education between 1983 and 2019 were gathered, and those who completed a spine fellowship were identified. Employment was denoted as academic if the hospital where a neurosurgeon worked was affiliated with a neurosurgical residency program; all other positions were denoted as nonacademic. A logistic regression model was used for multivariate statistical analysis.

Results: A total of 376 fellowship-trained spinal neurosurgeons were identified, of whom 140 (37.2%) held academic positions. The top 5 programs that graduated the most fellows in the cohort were Cleveland Clinic, The Johns Hopkins Hospital, University of Miami, Barrow Neurological Institute, and Northwestern University. On multivariate analysis, increased protected research time during residency (OR 1.03, p = 0.044), a higher h-index during residency (OR 1.12, p < 0.001), completing more than one clinical fellowship (OR 2.16, p = 0.024), and attending any of the top 5 programs that graduated the most fellows (OR 2.01, p = 0.0069) were independently associated with an academic career trajectory.

Conclusions: Increased protected research time during residency, a higher h-index during residency, completing more than one clinical fellowship, and attending one of the 5 programs graduating the most fellowship-trained neurosurgical spinal surgeons independently predicted an academic career. These results may be useful in identifying and advising trainees interested in academic spine neurosurgery.
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http://dx.doi.org/10.3171/2020.12.SPINE201771DOI Listing
June 2021

Predictors of Academic Neurosurgical Career Trajectory among International Medical Graduates Training Within the United States.

Neurosurgery 2021 Aug;89(3):478-485

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Within the literature, there has been limited research tracking the career trajectories of international medical graduates (IMGs) following residency training.

Objective: To compare the characteristics of IMG and US medical school graduate (USMG) neurosurgeons holding academic positions in the United States and also analyze factors that influence IMG career trajectories following US-based residency training.

Methods: We collected data on 243 IMGs and 2506 USMGs who graduated from Accreditation Council for Graduate Medical Education (ACGME)-accredited neurosurgery residency programs. We assessed for significant differences between cohorts, and a logistic regression model was used for the outcome of academic career trajectory.

Results: Among the 2749 neurosurgeons in our study, IMGs were more likely to pursue academic neurosurgery careers relative to USMGs (59.7% vs 51.1%; P = .011) and were also more likely to complete a research fellowship before beginning residency (odds ratio [OR] = 9.19; P < .0001). Among current US academic neurosurgeons, USMGs had significantly higher pre-residency h-indices relative to IMGs (1.23 vs 1.01; P < .0001) with no significant differences between cohorts when comparing h-indices during (USMG = 5.02, IMG = 4.80; P = .67) or after (USMG = 14.05, IMG = 13.90; P = .72) residency. Completion of a post-residency clinical fellowship was the only factor independently associated with an academic career trajectory among IMGs (OR = 1.73, P = .046).

Conclusion: Our study suggests that while IMGs begin their US residency training with different research backgrounds and achievements relative to USMG counterparts, they attain similar levels of academic productivity following residency. Furthermore, IMGs are more likely to pursue academic careers relative to USMGs. Our work may be useful for better understanding IMG career trajectories following US-based neurosurgery residency training.
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http://dx.doi.org/10.1093/neuros/nyab194DOI Listing
August 2021

Comparing the efficacy of adipose-derived and bone marrow-derived cells in a rat model of posterolateral lumbar fusion.

J Orthop Res 2021 Jun 3. Epub 2021 Jun 3.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Although bone marrow-derived mesenchymal stem cells (BMCs) have been widely used in spinal fusion procedures, adipose-derived stem cells (ASCs) offer a number of advantages as an alternative clinical cell source. This study directly compares the efficacy of ASCs and BMCs from the same donor animals to achieve successful fusion when combined with a clinical-grade bone graft substitute in a rat lumbar fusion model. ASCs and BMCs were isolated from the same Lewis donor rats and grown to passage 2 (P2). Single-level bilateral posterolateral intertransverse process lumbar fusion surgery was performed on syngeneic rats divided into three experimental groups: clinical-grade bone graft substitute alone (CBGS); CBGS+ rat ASCs (rASC); and, CBGS+ rat BMCs (rBMC). Eight weeks postoperatively, fusion was evaluated via micro-CT, manual palpation and histology. In vitro analysis of the osteogenic capacity of rBMCs and rASCs was also performed. Results indicated that the average fusion volume in the rASC group was the largest and was significantly larger than the CBGS group. Although the rASC group displayed the highest fusion rates via micro-CT and manual palpation, this difference was not statistically significant. Cell-seeded grafts showed more histological bone formation than cell-free grafts. P2 rASCs and rBMCs displayed similar in vitro osteogenic differentiation capacities. Overall, this study showed that, when combined with a clinical-grade bone graft substitute in a rat model, rASCs cells yielded the largest fusion masses and comparable fusion results to rBMCs. These results add to growing evidence that ASCs provide an attractive alternative to BMCs for spinal fusion procedures.
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http://dx.doi.org/10.1002/jor.25111DOI Listing
June 2021

Effects of Single-Dose Versus Hypofractionated Focused Radiation on Vertebral Body Structure and Biomechanical Integrity: Development of a Rabbit Radiation-Induced Vertebral Compression Fracture Model.

Int J Radiat Oncol Biol Phys 2021 10 11;111(2):528-538. Epub 2021 May 11.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Purpose: Vertebral compression fracture is a common complication of spinal stereotactic body radiation therapy. Development of an in vivo model is crucial to fully understand how focal radiation treatment affects vertebral integrity and biology at various dose fractionation regimens. We present a clinically relevant animal model to analyze the effects of localized, high-dose radiation on vertebral microstructure and mechanical integrity. Using this model, we test the hypothesis that fractionation of radiation dosing can reduce focused radiation therapy's harmful effects on the spine.

Methods And Materials: The L5 vertebra of New Zealand white rabbits was treated with either a 24-Gy single dose of focused radiation or 3 fractionated 8-Gy doses over 3 consecutive days via the Small Animal Radiation Research Platform. Nonirradiated rabbits were used as controls. Rabbits were euthanized 6 months after irradiation, and their lumbar vertebrae were harvested for radiologic, histologic, and biomechanical testing.

Results: Localized single-dose radiation led to decreased vertebral bone volume and trabecular number and a subsequent increase in trabecular spacing and thickness at L5. Hypofractionation of the radiation dose similarly led to reduced trabecular number and increased trabecular spacing and thickness, yet it preserved normalized bone volume. Single-dose irradiated vertebrae displayed lower fracture loads and stiffness compared with those receiving hypofractionated irradiation and with controls. The hypofractionated and control groups exhibited similar fracture load and stiffness. For all vertebral samples, bone volume, trabecular number, and trabecular spacing were correlated with fracture loads and Young's modulus (P < .05). Hypocellularity was observed in the bone marrow of both irradiated groups, but osteogenic features were conserved in only the hypofractionated group.

Conclusions: Single-dose focal irradiation showed greater detrimental effects than hypofractionation on the microarchitectural, cellular, and biomechanical characteristics of irradiated vertebral bodies. Correlation between radiologic measurements and biomechanical properties supported the reliability of this animal model of radiation-induced vertebral compression fracture, a finding that can be applied to future studies of preventative measures.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.050DOI Listing
October 2021

Aortic injury in spine surgery……What a spine surgeon needs to know.

Neurosurg Rev 2021 Apr 14. Epub 2021 Apr 14.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Aortic injury is a rare, yet underreported and underestimated complication of spine surgery. Anatomical relation between the aorta and the spine changes under physiological (positional) as well as pathological (deformity) conditions, which puts the aorta at risk of injury during spine surgery. Clinical presentation of aortic injury ranges from asymptomatic perforation of the aorta to acute fatal bleeding. Although several diagnostic methods have been reported, CT-angiography remains an important diagnostic study. Several advancements in the open and the endovascular surgical management have been reported to be successfully used in the management of aortic injury following spine surgery. Management approach of malpositioned screws abutting the aorta is still controversial. Anatomical knowledge and understanding of the previously reported mechanisms of aortic injury are important to be integrated in the preoperative planning process. If the complication occurs, time-to- recognition and to-appropriate-management are important factors for predicting mortality. If unrecognized and untreated in the acutely injured patients, mortality can approach 100%.
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http://dx.doi.org/10.1007/s10143-021-01527-zDOI Listing
April 2021

Influence of Sex on Early Outcomes of Elective Lumbar Fusions: An Updated Propensity-Matched and Subgroup Analysis.

World Neurosurg 2021 06 17;150:e388-e399. Epub 2021 Mar 17.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address:

Objective: Existing data have demonstrated significant differences in morbidity and mortality measures between men and women undergoing various spinal surgeries. However, studies of lumbar fusion surgery have been limited. Thus, we investigated the effects of patient sex on 30-day perioperative outcomes after elective lumbar fusion spine surgery.

Methods: Patients who had undergone lumbar fusion from 2015 to 2018 were reviewed from the American College of Surgeons National Surgical Quality Improvement Program database. Propensity score matching was used to determine whether the patient's sex had influenced the 30-day perioperative complications.

Results: A total of 44,526 cases had met the inclusion criteria and were reviewed. Of the 44,526 patients, 13,715 had undergone posterior lumbar fusion, 21,993 had undergone posterior/transforaminal lumbar interbody fusion, and 8818 had undergone anterior/lateral lumbar interbody fusion. The women were more likely to be older, functionally dependent, and taking steroids for chronic conditions and to have a higher body mass index and lower preoperative hematocrit level. The men were more likely to be white, to smoke, and to have diabetes mellitus, hypertension, and bleeding disorders. In all cohorts, except for a higher incidence of urinary tract infection in the female patients and myocardial infarction in the male patients, no significant differences were found in morbidity and mortality between the sexes.

Conclusions: Several differences in demographics and baseline health status were found between men and women undergoing lumbar fusion. When attempting to control for comorbid conditions using propensity score matching, we found that sex was an independent predictor of urinary tract infection in women and myocardial infarction in men across major morbidity and mortality categories in patients undergoing lumbar fusion surgery.
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http://dx.doi.org/10.1016/j.wneu.2021.03.025DOI Listing
June 2021

Augmented reality-mediated stereotactic navigation for execution of en bloc lumbar spondylectomy osteotomies.

J Neurosurg Spine 2021 Mar 5:1-6. Epub 2021 Mar 5.

2Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

En bloc spinal tumor resections are technically demanding procedures with high morbidity because of the conventionally large exposure area and aggressive resection goals. Stereotactic surgical navigation presents an opportunity to perform the smallest possible resection plan while still achieving an en bloc resection. Augmented reality (AR)-mediated spine surgery (ARMSS) via a mounted display with an integrated tracking camera is a novel FDA-approved technology for intraoperative "heads up" neuronavigation, with the proposed advantages of increased precision, workflow efficiency, and cost-effectiveness. As surgical experience and capability with this technology grow, the potential for more technically demanding surgical applications arises. Here, the authors describe the use of ARMSS for guidance in a unique osteotomy execution to achieve an en bloc wide marginal resection of an L1 chordoma through a posterior-only approach while avoiding a tumor capsule breach. A technique is described to simultaneously visualize the navigational guidance provided by the contralateral surgeon's tracked pointer and the progress of the BoneScalpel aligned in parallel with the tracked instrument, providing maximum precision and safety. The procedure was completed by reconstruction performed with a quad-rod and cabled fibular strut allograft construct, and the patient did well postoperatively. Finally, the authors review the technical aspects of the approach, as well as the applications and limitations of this new technology.
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http://dx.doi.org/10.3171/2020.9.SPINE201219DOI Listing
March 2021

Dataset of the first report of pharmacogenomics profiling in an outpatient spine setting.

Data Brief 2021 Apr 3;35:106832. Epub 2021 Feb 3.

Department of Neurosurgery, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Meyer 7-113, Baltimore, MD 21287, USA.

Here we describe the dataset of the first report of pharmacogenomics profiling in an outpatient spine setting with the primary aims to catalog: 1) the genes, alleles, and associated rs Numbers (accession numbers for specific single-nucleotide polymorphisms) analysed and 2) the genotypes and corresponding phenotypes of the genes involved in metabolizing 37 commonly used analgesic medications. The present description applies to analgesic medication-metabolizing enzymes and may be especially valuable to investigators who are exploring strategies to optimize pharmacologic pain management (e.g., by tailoring analgesic regimens to the genetically identified sensitivities of the patient). Buccal swabs were used to acquire tissue samples of 30 adult patients who presented to an outpatient spine clinic with the chief concern of axial neck and/or back pain. Array-based assays were then used to detect the alleles of genes involved in the metabolism of pain medications, including all common (wild type) and most rare variant alleles with known clinical significance. Both CYP450 isozymes - including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 - and the phase II enzyme UDP-glucuronosyltransferase-2B7 (UGT2B7) were examined. Genotypes/phenotypes were then used to evaluate each patient's relative ability to metabolize 37 commonly used analgesic medications. These medications included both non-opioid analgesics (i.e., aspirin, diclofenac, nabumetone, indomethacin, meloxicam, piroxicam, tenoxicam, lornoxicam, celecoxib, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, naproxen, and mefenamic acid) and opioid analgesics (i.e., morphine, codeine, dihydrocodeine, ethylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, alfentanil, fentanyl, sufentanil, meperidine, ketobemidone, dextropropoxyphene, levacetylmethadol, loperamide, methadone, buprenorphine, dextromethorphan, tramadol, tapentadol, and tilidine). The genes, alleles, and associated rs Numbers that were analysed are provided. Also provided are: 1) the genotypes and corresponding phenotypes of the genes involved in metabolizing 37 commonly used analgesic medications and 2) the mechanisms of metabolism of the analgesic medications by primary and ancillary pathways. In supplemental spreadsheets, the raw and analysed pharmacogenomics data for all 30 patients evaluated in the primary research article are additionally provided. Collectively, the presented data offer significant reuse potential in future investigations of pharmacogenomics for pain management.
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http://dx.doi.org/10.1016/j.dib.2021.106832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893444PMC
April 2021

Low-Intensity Pulsed Ultrasound as a Potential Adjuvant Therapy to Promote Spinal Fusion: Systematic Review and Meta-analysis of the Available Data.

J Ultrasound Med 2021 Oct 8;40(10):2005-2017. Epub 2020 Dec 8.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Despite extensive research, nonunion continues to affect a nontrivial proportion of patients undergoing spinal fusion. Recently, preclinical studies have suggested that low-intensity pulsed ultrasound (LIPUS) may increase rates of spinal fusion. In this study, we summarized the available in vivo literature evaluating the effect of LIPUS on spinal fusion and performed a meta-analysis of the available data to estimate the degree to which LIPUS may mediate higher fusion rates. Across 13 preclinical studies, LIPUS was associated with a 9-fold increase in the odds of successful spinal fusion. Future studies are necessary to establish the benefit of LIPUS on spinal fusion in clinical populations.
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http://dx.doi.org/10.1002/jum.15587DOI Listing
October 2021

Clinical Accuracy, Technical Precision, and Workflow of the First in Human Use of an Augmented-Reality Head-Mounted Display Stereotactic Navigation System for Spine Surgery.

Oper Neurosurg (Hagerstown) 2021 02;20(3):300-309

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Augmented reality mediated spine surgery is a novel technology for spine navigation. Benchmark cadaveric data have demonstrated high accuracy and precision leading to recent regulatory approval. Absence of respiratory motion in cadaveric studies may positively bias precision and accuracy results and analogous investigations are prudent in live clinical scenarios.

Objective: To report a technical note, accuracy, precision analysis of the first in-human deployment of this technology.

Methods: A 78-yr-old female underwent an L4-S1 decompression, pedicle screw, and rod fixation for degenerative spine disease. Six pedicle screws were inserted via AR-HMD (xvision; Augmedics, Chicago, Illinois) navigation. Intraoperative computed tomography was used for navigation registration as well as implant accuracy and precision assessment. Clinical accuracy was graded per the Gertzbein-Robbins (GS) scale by an independent neuroradiologist. Technical precision was analyzed by comparing 3-dimensional (3D) (x, y, z) virtual implant vs real implant position coordinates and reported as linear (mm) and angular (°) deviation. Present data were compared to benchmark cadaveric data.

Results: Clinical accuracy (per the GS grading scale) was 100%. Technical precision analysis yielded a mean linear deviation of 2.07 mm (95% CI: 1.62-2.52 mm) and angular deviation of 2.41° (95% CI: 1.57-3.25°). In comparison to prior cadaveric data (99.1%, 2.03 ± 0.99 mm, 1.41 ± 0.61°; GS accuracy 3D linear and angular deviation, respectively), the present results were not significantly different (P > .05).

Conclusion: The first in human deployment of the single Food and Drug Administration approved AR-HMD stereotactic spine navigation platform demonstrated clinical accuracy and technical precision of inserted hardware comparable to previously acquired cadaveric studies.
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http://dx.doi.org/10.1093/ons/opaa398DOI Listing
February 2021

Posterior Vertebral Column Subtraction Osteotomy for Recurrent Tethered Cord Syndrome: A Multicenter, Retrospective Analysis.

Neurosurgery 2021 02;88(3):637-647

Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona.

Background: Few have explored the safety and efficacy of posterior vertebral column subtraction osteotomy (PVCSO) to treat tethered cord syndrome (TCS).

Objective: To evaluate surgical outcomes after PVCSO in adults with TCS caused by lipomyelomeningocele, who had undergone a previous detethering procedure(s) that ultimately failed.

Methods: This is a multicenter, retrospective analysis of a prospectively collected cohort. Patients were prospectively enrolled and treated with PVCSO at 2 institutions between January 1, 2011 and December 31, 2018. Inclusion criteria were age ≥18 yr, TCS caused by lipomyelomeningocele, previous detethering surgery, and recurrent symptom progression of less than 2-yr duration. All patients undergoing surgery with a 1-yr minimum follow-up were evaluated.

Results: A total of 20 patients (mean age: 36 yr; sex: 15F/5M) met inclusion criteria and were evaluated. At follow-up (mean: 23.3 ± 7.4 mo), symptomatic improvement/resolution was seen in 93% of patients with leg pain, 84% in back pain, 80% in sensory abnormalities, 80% in motor deficits, 55% in bowel incontinence, and 50% in urinary incontinence. Oswestry Disability Index improved from a preoperative mean of 57.7 to 36.6 at last follow-up (P < .01). Mean spinal column height reduction was 23.4 ± 2.7 mm. Four complications occurred: intraoperative durotomy (no reoperation), wound infection, instrumentation failure requiring revision, and new sensory abnormality.

Conclusion: This is the largest study to date assessing the safety and efficacy of PVCSO in adults with TCS caused by lipomyelomeningocele and prior failed detethering. We found PVCSO to be an excellent extradural approach that may afford definitive treatment in this particularly challenging population.
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http://dx.doi.org/10.1093/neuros/nyaa491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884146PMC
February 2021

Experience with an Enhanced Recovery After Spine Surgery protocol at an academic community hospital.

J Neurosurg Spine 2020 Dec 25:1-8. Epub 2020 Dec 25.

Departments of1Neurosurgery.

Objective: Enhanced Recovery After Surgery (ERAS) protocols have rapidly gained popularity in multiple surgical specialties and are recognized for their potential to improve patient outcomes and decrease hospitalization costs. However, they have only recently been applied to spinal surgery. The goal in the present work was to describe the development, implementation, and impact of an Enhanced Recovery After Spine Surgery (ERASS) protocol for patients undergoing elective spine procedures at an academic community hospital.

Methods: A multidisciplinary team, drawing on prior publications and spine surgery best practices, collaborated to develop an ERASS protocol. Patients undergoing elective cervical or lumbar procedures were prospectively enrolled at a single tertiary care center; interventions were standardized across the cohort for pre-, intra-, and postoperative care using standardized order sets in the electronic medical record. Protocol efficacy was evaluated by comparing enrolled patients to a historic cohort of age- and procedure-matched controls. The primary study outcomes were quantity of opiate use in morphine milligram equivalents (MMEs) on postoperative day (POD) 1 and length of stay. Secondary outcomes included frequency and duration of indwelling urinary catheter use, discharge disposition, 30-day readmission and reoperation rates, and complication rates. Multivariable linear regression was used to determine whether ERASS protocol use was independently predictive of opiate use on POD 1.

Results: In total, 97 patients were included in the study cohort and were compared with a historic cohort of 146 patients. The patients in the ERASS group had lower POD 1 opiate use than the control group (26 ± 33 vs 42 ± 40 MMEs, p < 0.001), driven largely by differences in opiate-naive patients (16 ± 21 vs 38 ± 36 MMEs, p < 0.001). Additionally, patients in the ERASS group had shorter hospitalizations than patients in the control group (51 ± 30 vs 62 ± 49 hours, p = 0.047). On multivariable regression, implementation of the ERASS protocol was independently predictive of lower POD 1 opiate consumption (β = -7.32, p < 0.001). There were no significant differences in any of the secondary outcomes.

Conclusions: The authors found that the development and implementation of a comprehensive ERASS protocol led to a modest reduction in postoperative opiate consumption and hospital length of stay in patients undergoing elective cervical or lumbar procedures. As suggested by these results and those of other groups, the implementation of ERASS protocols may reduce care costs and improve patient outcomes after spine surgery.
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http://dx.doi.org/10.3171/2020.7.SPINE20358DOI Listing
December 2020

Radiographic and clinical outcomes of silicate-substituted calcium phosphate (SiCaP) bone grafts in spinal fusion: Systematic review and meta-analysis.

J Clin Neurosci 2020 Nov 23;81:353-366. Epub 2020 Oct 23.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Pseudarthrosis continues to affect a nontrivial proportion of spine fusion patients. Given its ties to poorer patient outcomes and high reoperation rates, there remains great interest in interventions aimed at reducing the rates of nonunion. Recently, silicate-substituted calcium phosphate (SiCaP) bone grafts have been suggested to improve fusion rates, yet there exists no systematic review of the body of evidence for SiCaP grafts. Here, we present the first such review along with a meta-analysis of the effect of SiCaP bone grafts on fusion rates. Using the PubMed, Embase, and Web of Science databases, we queried the English-language literature for all studies examining the effect of SiCaPs on spinal fusion. Primary endpoints were: 1) radiographic fusion rate at last follow-up and 2) postoperative improvements in Visual Analog Scale (VAS) pain scores and Oswestry Disability Index (ODI) at last follow-up. Meta-analyses were performed for each endpoint using random effects. Ten articles (694 patients treated with SiCaP bone grafts) were included. Among SiCaP-treated patients, 93% achieved radiographic fusion (range: 79-100%), with comparable rates across subgroups. Meta-analysis of the three randomized controlled trials demonstrated no difference in fusion rates between SiCaP-treated patients and patients receiving grafts with recombinant human bone morphogenetic protein-2 (rhBMP-2) (OR: 1.11; p = 0.83). Patients treated with SiCaP bone grafts experienced significant improvements in VAS back pain (-3.3 points), VAS leg pain (-4.8 points), and ODI (-31.6 points) by last follow-up (p < 0.001 for each). Additional high-quality research is needed to evaluate the relative cost-effectiveness of SiCaP bone grafts in spinal fusion.
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http://dx.doi.org/10.1016/j.jocn.2020.09.073DOI Listing
November 2020

An Online Calculator for Predicting Academic Career Trajectory in Neurosurgery in the United States.

World Neurosurg 2021 01 5;145:e155-e162. Epub 2020 Oct 5.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address:

Objective: Determining factors that predict a career in academic neurosurgery can help to improve neurosurgical training and faculty mentoring efforts. Although many academic career predictors have been established in the literature, no method has yet been developed to allow for individualized predictions of an academic career trajectory. The objective of the present study was to develop a Web-based calculator for predicting the probability of a career in academic neurosurgery.

Methods: The present study used data from neurosurgeons listed in the American Association of Neurological Surgeons database. A logistic regression model was used to predict probability of an academic career, and bootstrapping with 2000 samples was used to calculate an optimism-corrected C-statistic. P < 0.05 was considered statistically significant.

Results: A total of 1818 neurosurgeons were included in our analysis. Most surgeons were male (89.7%) and employed in nonacademic positions (60.2%). Factors independently associated with an academic career were female sex, attending a residency program affiliated with a top 10 U.S. News medical school, attaining a Doctor of Philosophy (PhD) degree, attaining a Master of Science (MS) degree, higher h-index during residency, more months of protected research time during residency, and completing a clinical fellowship. Our final model had an optimism-corrected C-statistic of 0.74. This model was incorporated into a Web-based calculator (https://neurooncsurgery.shinyapps.io/academic_calculator/).

Conclusions: The present study consolidates previous research investigating neurosurgery career predictors into a simple, open-access tool. Our work may serve to better clarify the many factors influencing trainees' likelihood of pursuing a career in academic neurosurgery.
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http://dx.doi.org/10.1016/j.wneu.2020.09.161DOI Listing
January 2021

Comparison of Freshly Isolated Adipose Tissue-derived Stromal Vascular Fraction and Bone Marrow Cells in a Posterolateral Lumbar Spinal Fusion Model.

Spine (Phila Pa 1976) 2021 May;46(10):631-637

Johns Hopkins University School of Medicine, Department of Neurosurgery, Baltimore, MD.

Study Design: Rat posterolateral lumbar fusion model.

Objective: The aim of this study was to compare the efficacy of freshly isolated adipose tissue-derived stromal vascular fraction (A-SVF) and bone marrow cells (BMCs) cells in achieving spinal fusion in a rat model.

Summary Of Background Data: Adipose tissue-derived stromal cells (ASCs) offer advantages as a clinical cell source compared to bone marrow-derived stromal cells (BMSCs), including larger available tissue volumes and reduced donor site morbidity. While pre-clinical studies have shown that ex vivo expanded ASCs can be successfully used in spinal fusion, the use of A-SVF cells better allows for clinical translation.

Methods: A-SVF cells were isolated from the inguinal fat pads, whereas BMCs were isolated from the long bones of syngeneic 6- to 8-week-old Lewis rats and combined with Vitoss (Stryker) bone graft substitute for subsequent transplantation. Posterolateral spinal fusion surgery at L4-L5 was performed on 36 female Lewis rats divided into three experimental groups: Vitoss bone graft substitute only (VO group); Vitoss + 2.5 × 106 A-SVF cells/side; and, Vitoss + 2.5 × 106 BMCs/side. Fusion was assessed 8 weeks post-surgery via manual palpation, micro-computed tomography (μCT) imaging, and histology.

Results: μCT imaging analyses revealed that fusion volumes and μCT fusion scores in the A-SVF group were significantly higher than in the VO group; however, they were not significantly different between the A-SVF group and the BMC group. The average manual palpation score was highest in the A-SVF group compared with the BMC and VO groups. Fusion masses arising from cell-seeded implants yielded better bone quality than nonseeded bone graft substitute.

Conclusion: In a rat model, A-SVF cells yielded a comparable fusion mass volume and radiographic rate of fusion to BMCs when combined with a clinical-grade bone graft substitute. These results suggest the feasibility of using freshly isolated A-SVF cells in spinal fusion procedures.Level of Evidence: N/A.
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http://dx.doi.org/10.1097/BRS.0000000000003709DOI Listing
May 2021

Comparing the efficacy of syngeneic iliac and femoral allografts with iliac crest autograft in a rat model of lumbar spinal fusion.

J Orthop Surg Res 2020 Sep 15;15(1):410. Epub 2020 Sep 15.

Department of Neurosurgery, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA.

Background: Despite widespread use of femoral-sourced allografts in clinical spinal fusion procedures and the increasing interest in using femoral reamer-irrigator-aspirator (RIA) autograft in clinical bone grafting, few studies have examined the efficacy of femoral grafts compared to iliac crest grafts in spinal fusion. The objective of this study was to directly compare the use of autologous iliac crest with syngeneic femoral and iliac allograft bone in the rat model of lumbar spinal fusion.

Methods: Single-level bilateral posterolateral intertransverse process lumbar spinal fusion surgery was performed on Lewis rats divided into three experimental groups: iliac crest autograft, syngeneic iliac crest allograft, and syngeneic femoral allograft bone. Eight weeks postoperatively, fusion was evaluated via microCT analysis, manual palpation, and histology. In vitro analysis of the colony-forming and osteogenic capacity of bone marrow cells derived from rat femurs and hips was also performed to determine whether there was a correlation with the fusion efficacy of these graft sources.

Results: Although no differences were observed between groups in CT fusion mass volumes, iliac allografts displayed an increased number of radiographically fused fusion masses and a higher rate of bilateral fusion via manual palpation. Histologically, hip-derived grafts showed better integration with host bone than femur derived ones, likely associated with the higher concentration of osteogenic progenitor cells observed in hip-derived bone marrow.

Conclusions: This study demonstrates the feasibility of using syngeneic allograft bone in place of autograft bone within inbred rat fusion models and highlights the need for further study of femoral-derived grafts in fusion.
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http://dx.doi.org/10.1186/s13018-020-01936-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490887PMC
September 2020

First Report of Pharmacogenomic Profiling in an Outpatient Spine Setting: Preliminary Results from a Pilot Study.

World Neurosurg 2021 01 8;145:e21-e31. Epub 2020 Sep 8.

Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. Electronic address:

Objective: Pharmacogenomics may help personalize medicine and improve therapeutic selection. This is the first study investigating how pharmacogenomic testing may inform analgesic selection in patients with spine disease. We profile pharmacogenetic differences in pain medication-metabolizing enzymes across patients presenting at an outpatient spine clinic and provide preliminary evidence that genetic polymorphisms may help explain interpatient differences in preoperative pain refractory to conservative management.

Methods: Adults presenting to our outpatient spine clinic with chief symptoms of neck and/or back pain were prospectively enrolled over 9 months. Patients completed the Wong-Baker FACES and numeric pain rating scales for their chief pain symptom and provided detailed medication histories and cheek swab samples for genomic analysis.

Results: Thirty adults were included (mean age, 60.6 ± 15.3 years). The chief concern was neck pain in 23%, back pain in 67%, and combined neck/back pain in 10%. At enrollment, patient analgesic regimens comprised 3 ± 1 unique medications, including 1 ± 1 opioids. After genomic analysis, 14/30 patients (47%) were identified as suboptimal metabolizers of ≥1 medications in their analgesic regimen. Of these patients, 93% were suboptimal metabolizers of their prescribed opioid analgesic. Nonetheless, pain scores were similar between optimal and suboptimal metabolizer groups.

Conclusions: This pilot study shows that a large proportion of the spine outpatient population may use pain medications for which they are suboptimal metabolizers. Further studies should assess whether these pharmacogenomic differences indicate differences in odds of receiving therapeutic benefit from surgery or if they can be used to generate more effective postoperative analgesic regimens.
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http://dx.doi.org/10.1016/j.wneu.2020.09.007DOI Listing
January 2021

Oxysterols as promising small molecules for bone tissue engineering: Systematic review.

World J Orthop 2020 Jul 18;11(7):328-344. Epub 2020 Jul 18.

Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.

Background: Bone tissue engineering is an area of continued interest within orthopaedic surgery, as it promises to create implantable bone substitute materials that obviate the need for autologous bone graft. Recently, oxysterols - oxygenated derivatives of cholesterol - have been proposed as a novel class of osteoinductive small molecules for bone tissue engineering. Here, we present the first systematic review of the evidence describing the potential therapeutic utility of oxysterols for bone tissue engineering.

Aim: To systematically review the available literature examining the effect of oxysterols on bone formation.

Methods: We conducted a systematic review of the literature following PRISMA guidelines. Using the PubMed/MEDLINE, Embase, and Web of Science databases, we queried all publications in the English-language literature investigating the effect of oxysterols on bone formation. Articles were screened for eligibility using PICOS criteria and assessed for potential bias using an expanded version of the SYRCLE Risk of Bias assessment tool. All full-text articles examining the effect of oxysterols on bone formation were included. Extracted data included: Animal species, surgical/defect model, description of therapeutic and control treatments, and method for assessing bone growth. Primary outcome was fusion rate for spinal fusion models and percent bone regeneration for critical-sized defect models. Data were tabulated and described by both surgical/defect model and oxysterol employed. Additionally, data from all included studies were aggregated to posit the mechanism by which oxysterols may mediate bone formation.

Results: Our search identified 267 unique articles, of which 27 underwent full-text review. Thirteen studies (all preclinical) met our inclusion/exclusion criteria. Of the 13 included studies, 5 employed spinal fusion models, 2 employed critical-sized alveolar defect models, and 6 employed critical-sized calvarial defect models. Based upon SYRCLE criteria, the included studies were found to possess an overall "unclear risk of bias"; 54% of studies reported treatment randomization and 38% reported blinding at any level. Overall, seven unique oxysterols were evaluated: 20()-hydroxycholesterol, 22()-hydroxycholesterol, 22()-hydroxycholesterol, Oxy4/Oxy34, Oxy18, Oxy21/Oxy133, and Oxy49. All had statistically significant osteoinductive properties, with Oxy4/Oxy34, Oxy21/Oxy133, and Oxy49 showing a dose-dependent effect in some cases. In the eight studies that directly compared oxysterols to rhBMP-2-treated animals, similar rates of bone growth occurred in the two groups. Biochemical investigation of these effects suggests that they may be primarily mediated by direct activation of Smoothened in the Hedgehog signaling pathway.

Conclusion: Present preclinical evidence suggests oxysterols significantly augment bone formation. However, clinical trials are necessary to determine which have the greatest therapeutic potential for orthopaedic surgery patients.
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http://dx.doi.org/10.5312/wjo.v11.i7.328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453739PMC
July 2020

Assessing underlying bone quality in spine surgery patients: a narrative review of dual-energy X-ray absorptiometry (DXA) and alternatives.

Spine J 2021 02 2;21(2):321-331. Epub 2020 Sep 2.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

Poor bone quality and low bone mineral density (BMD) have been previously tied to higher rates of postoperative mechanical complications in patients undergoing spinal fusion. These include higher rates of proximal junctional kyphosis, screw pullout, pseudoarthrosis, and interbody subsidence. For these reasons, accurate preoperative assessment of a patient's underlying bone quality is paramount for all elective procedures. Dual-energy X-ray absorptiometry (DXA) is currently considered to be the gold standard for assessing BMD. However, a growing body of research has suggested that in vivo assessments of BMD using DXA are inaccurate and have, at best, moderate correlations to postoperative mechanical complications. Consequently, there have been investigations into using alternative methods for assessing in vivo bone quality, including using computed tomography (CT) and magnetic resonance imaging (MRI) volumes that are commonly obtained as part of surgical evaluation. Here we review the data regarding the accuracy of DXA for the evaluation of spine bone quality and describe the alternative imaging modalities currently under investigation.
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http://dx.doi.org/10.1016/j.spinee.2020.08.020DOI Listing
February 2021

Introduction. Lumbar spinal osteoporosis.

Neurosurg Focus 2020 08;49(2):E1

4Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.3171/2020.5.FOCUS20412DOI Listing
August 2020
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