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OBJECTIVE The aim of this study was to compare the rate of achievement of the minimal clinically important difference (MCID) in patient-reported outcomes (PROs) and satisfaction between cervical spondylotic myelopathy (CSM) patients with and without class III obesity who underwent surgery. METHODS The authors analyzed patients from the 14 highest-enrolling sites in the prospective Quality Outcomes Database CSM cohort. Patients were dichotomized based on whether or not they were obese (class III, BMI ≥ 35 kg/m 2 ). PROs including visual analog scale (VAS) neck and arm pain, Neck Disability Index (NDI), modified Japanese Orthopaedic Association (mJOA), EQ-5D, and North American Spine Society patient satisfaction scores were collected at baseline and 24 months after cervical spine surgery. RESULTS Of the 1141 patients with CSM who underwent surgery, 230 (20.2%) were obese and 911 (79.8%) were not. The 24-month follow-up rate was 87.4% for PROs. Patients who were obese were younger (58.1 ± 12.1 years vs 61.2 ± 11.6 years, p = 0.001), more frequently female (57.4% vs 44.9%, p = 0.001), and African American (22.6% vs 13.4%, p = 0.002) and had a lower education level (high school or less: 49.1% vs 40.8%, p = 0.002) and a higher American Society of Anesthesiologists grade (2.7 ± 0.5 vs 2.5 ± 0.6, p < 0.001). Clinically at baseline, the obese group had worse neck pain (VAS score: 5.7 ± 3.2 vs 5.1 ± 3.3), arm pain (VAS score: 5.4 ± 3.5 vs 4.8 ± 3.5), disability (NDI score: 42.7 ± 20.4 vs 37.4 ± 20.7), quality of life (EQ-5D score: 0.54 ± 0.22 vs 0.56 ± 0.22), and function (mJOA score: 11.6 ± 2.8 vs 12.2 ± 2.8) (all p < 0.05). At the 24-month follow-up, however, there was no difference in the change in PROs between the two groups. Even after accounting for relevant covariates, no significant difference in achievement of MCID and satisfaction was observed between the two groups at 24 months. CONCLUSIONS Despite the class III obese group having worse baseline clinical presentations, the two cohorts achieved similar rates of satisfaction and MCID in PROs. Class III obesity should not preclude and/or delay surgical management for patients who would otherwise benefit from surgery for CSM.

Background The term ‘precision medicine’ encompasses strategies to optimize diagnosis and outcome prediction and to tailor treatment for individual patients, in consideration of their unique characteristics. The greater availability of multifaceted datasets and strategies to model such data have made precision medicine increasingly possible in recent years. Precision medicine is especially needed in the migraine field since the response to migraine treatments is not universal amongst all individuals with migraine. Objective To provide a narrative review describing contributions to achieving precision medicine for migraine treatment. Methods A search of PubMed for English language articles of human participants published from 2005 to January 2024 was conducted to identify articles that reported research contributing to precision medicine for migraine treatment. The published literature was categorized and summarized according to the type of data that were included: clinical phenotypes, genomics, proteomics, physiologic measures, and brain imaging. Results Published studies have investigated characteristics associated with acute and preventive treatment responses, such as nonsteroidal anti-inflammatory drugs, triptans, onabotulinumtoxinA, and anti-calcitonin gene-related peptide monoclonal antibodies, in patients with episodic or chronic migraine. There is evidence that clinical, genetic, epigenetic, proteomic, physiologic, and brain imaging features might associate with migraine treatment outcomes, although inconsistencies for such findings clearly exist. Conclusions The published literature suggests that there are clinical and biological features which associate with, and might be useful for predicting, migraine treatment responses. To achieve precision medicine for migraine treatment, further research is needed that validates and expands on existing findings and tests the accuracy and value of migraine treatment prediction models in clinical settings.

Abstract Mounting evidence indicates the involvement of peripheral immunity in the regulation of brain function, influencing aspects such as neuronal development, emotion, and cognitive abilities. Previous studies from our laboratory have revealed that neonatal hepatitis B vaccination can downregulate hippocampal neurogenesis, synaptic plasticity and spatial learning memory. In the current post-epidemic era characterized by universal vaccination, understanding the impact of acquired immunity on neuronal function and neuropsychiatric disorders, along with exploring potential underlying mechanisms, becomes imperative. We employed hepatitis B vaccine-induced CD3 positive T cells in immunodeficient mice to investigate the key mechanisms through which T cell subsets modulate hippocampal neurogenesis and anxiety-like behaviours. Our data revealed that mice receiving hepatitis B vaccine-induced T cells exhibited heightened anxiety and decreased hippocampal cell proliferation compared to those receiving phosphate-buffered saline-T cells or wild-type mice. Importantly, these changes were predominantly mediated by infiltrated CD8+ T cells into the brain, rather than CD4+ T cells. Transcriptome profiling of CD8+ T cells unveiled that C-X-C motif chemokine receptor 6 positive (CXCR6+) CD8+ T cells were recruited into the brain through microglial and astrocyte-derived C-X-C motif chemokine ligand 16 (CXCL16). This recruitment process impaired neurogenesis and induced anxiety-like behaviour via tumour necrosis factor-α-dependent mechanisms. Our findings highlight the role of glial cell derived CXCL16 in mediating the recruitment of CXCR6+CD8+ T cell subsets into the brain. This mechanism represents a potential avenue for modulating hippocampal neurogenesis and emotion-related behaviours after hepatitis B vaccination.

OBJECTIVE Depression and anxiety are associated with poor outcomes following spine surgery. However, the influence of these conditions on achieving a minimal clinically important difference (MCID) following lumbar spine surgery, as well as the potential compounding effects of comorbid depression and anxiety, is not well understood. This study explores the impact of comorbid depression and anxiety on long-term clinical outcomes following surgical treatment for degenerative lumbar spondylolisthesis. METHODS This study was a retrospective analysis of the multicenter, prospectively collected Quality Outcomes Database (QOD). Patients with surgically treated grade 1 lumbar spondylolisthesis from 12 centers were included. Preoperative baseline characteristics and comorbidities were recorded, including self-reported depression and/or anxiety. Pre- and postoperative patient-reported outcomes (PROs) were recorded: the numeric rating scale (NRS) score for back pain (NRS-BP), NRS score for leg pain (NRS-LP), Oswestry Disability Index (ODI), and EQ-5D. Patients were grouped into 3 cohorts: no self-reported depression or anxiety (non-SRD/A), self-reported depression or anxiety (SRD/A), or presence of both comorbidities (SRD+A). Changes in PROs over time, satisfaction rates, and rates of MCID were compared. A multivariable regression analysis was performed to establish independent associations. RESULTS Of the 608 patients, there were 452 (74.3%) with non-SRD/A, 81 (13.3%) with SRD/A, and 75 (12.3%) with SRD+A. Overall, 91.8% and 80.4% of patients had ≥ 24 and ≥ 60 months of follow-up, respectively. Baseline PROs were universally inferior for the SRD+A cohort. However, at 60-month follow-up, changes in all PROs were greatest for the SRD+A cohort, resulting in nonsignificant differences in absolute NRS-BP, NRS-LP, ODI, and EQ-5D across the 3 groups. MCID was achieved for the SRD+A cohort at similar rates to the non-SRD/A cohort. All groups achieved > 80% satisfaction rates with surgery without significant differences across the cohorts (p = 0.79). On multivariable regression, comorbid depression and anxiety were associated with worse baseline PROs, but they had no impact on 60-month PROs or 60-month achievement of MCIDs. CONCLUSIONS Despite lower baseline PROs, patients with comorbid depression and anxiety achieved comparable rates of MCID and satisfaction after surgery for lumbar spondylolisthesis to those without either condition. This quality-of-life benefit was durable at 5-year follow-up. These data suggest that patients with self-reported comorbid depression and anxiety should not be excluded from consideration of surgical intervention and often substantially benefit from surgery.

OBJECTIVE Myelopathy in the cervical spine can present with diverse symptoms, many of which can be debilitating for patients. Patients with radiculopathy symptoms demonstrate added complexity because of the overlapping symptoms and treatment considerations. The authors sought to assess outcomes in patients with myelopathy presenting with or without concurrent radiculopathy. METHODS The Quality Outcomes Database, a prospectively collected multi-institutional database, was used to analyze demographic, clinical, and surgical variables of patients presenting with myelopathy or myeloradiculopathy as a result of degenerative pathology. Outcome measures included arm (VAS-arm) and neck (VAS-neck) visual analog scale (VAS) scores, modified Japanese Orthopaedic Association (mJOA) scale score, EuroQol VAS (EQ-VAS) score, and Neck Disability Index (NDI) at 3, 12, and 24 months compared with baseline. RESULTS A total of 1015 patients were included in the study: 289 patients with myelopathy alone (M0), 239 with myeloradiculopathy but no arm pain (MRAP−), and 487 patients with myeloradiculopathy and arm pain (MRAP+). M0 patients were older than the myeloradiculopathy cohorts combined (M0 64.2 vs MRAP− + MRAP+ 59.5 years, p < 0.001), whereas MRAP+ patients had higher BMI and a greater incidence of current smoking compared with the other cohorts. There were more anterior approaches used in in MRAP+ patients and more posterior approaches used in M0 patients. In severely myelopathic patients (mJOA scale score ≤ 10), posterior approaches were used more often for M0 (p < 0.0001) and MRAP+ (p < 0.0001) patients. Patients with myelopathy and myeloradiculopathy both exhibited significant improvement at 1 and 2 years across all outcome domains. The amount of improvement did not vary based on surgical approach. In comparing cohort outcomes, postoperative outcome differences were associated with patient-reported scores at baseline. CONCLUSIONS Patients with myelopathy and those with myeloradiculopathy demonstrated significant and similar improvement in arm and neck pain scores, myelopathy, disability, and quality of life at 3 months that was sustained at 1- and 2-year follow-up intervals. More radicular symptoms and arm pain increased the likelihood of a surgeon choosing an anterior approach, whereas more severe myelopathy increased the likelihood of approaching posteriorly. Surgical approach itself was not an independent predictor of outcome.

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease provide strategies for the prevention, diagnosis, and treatment of venous thromboembolism (VTE) in adult patients with cancer. VTE is a common and life-threatening condition in patients with cancer, and its management often requires multidisciplinary efforts. The NCCN panel is comprised of specialists spanning various fields, including cardiology, hematology, medical oncology, internal medicine, interventional radiology, and pharmacology. The content featured in this issue specifically addresses the evaluation and recommended treatment options outlined in the NCCN Guidelines for the diverse subtypes of cancer-associated VTE.

OBJECTIVE Lumbar decompression and/or fusion surgery is a common operation for symptomatic lumbar spondylolisthesis refractory to conservative management. Multiyear follow-up of patient outcomes can be difficult to obtain but allows for identification of preoperative patient characteristics associated with durable pain relief, improved functional outcome, and higher patient satisfaction. METHODS A query of the Quality Outcomes Database (QOD) low-grade spondylolisthesis module for patients who underwent surgery for grade 1 lumbar spondylolisthesis (from July 2014 to June 2016 at the 12 highest-enrolling sites) was used to identify patient satisfaction, as measured with the North American Spine Society (NASS) questionnaire, which uses a scale of 1–4. Patients were considered satisfied if they had a score ≤ 2. Multivariable logistic regression was performed to identify baseline demographic and clinical predictors of long-term satisfaction 5 years after surgery. RESULTS Of 573 eligible patients from a cohort of 608, patient satisfaction data were available for 81.2%. Satisfaction (NASS score of 1 or 2) was reported by 389 patients (83.7%) at 5-year follow-up. Satisfied patients were predominantly White and ambulation independent and had lower baseline BMI, lower back pain levels, lower Oswestry Disability Index (ODI) scores, and greater EQ-5D index scores at baseline when compared to the unsatisfied group. No significant differences in reoperation rates between groups were reported at 5 years. On multivariate analysis, patients who were independently ambulating at baseline had greater odds of long-term satisfaction (OR 1.12, p = 0.04). Patients who had higher 5-year ODI scores (OR 0.99, p < 0.01) and were uninsured (OR 0.43, p = 0.01) were less likely to report long-term satisfaction. CONCLUSIONS Lumbar surgery for the treatment of grade 1 spondylolisthesis can provide lasting pain relief with high patient satisfaction. Baseline independent ambulation is associated with a higher long-term satisfaction rate after surgery. Higher ODI scores at 5-year follow-up and uninsured status are associated with lower postoperative long-term satisfaction.

Abstract Extracellular vesicles (EVs) are key mediators of cell–cell communication and are involved in transferring specific biomolecular cargo to recipient cells to regulate their physiological functions. A major challenge in the understanding of EV function in vivo is the difficulty ascertaining the origin of the EV particles. The recent development of the “Snorkel-tag,” which includes EV-membrane-targeted CD81 fused to a series of extra-vesicular protein tags, can be used to mark EVs originating from a specific source for subsequent isolation and characterization. We developed an in vivo mouse model, termed “CAGS-Snorkel,” which expresses the Snorkel-tag under the control of the Cre-lox system, and crossed this mouse with either Prx1-Cre (mesenchymal progenitors) or Ocn-Cre (osteoblasts/osteocytes) and isolated Snorkel-tagged EVs from the mouse bone marrow plasma using a magnetic bead affinity column. miRNA-sequencing was performed on the isolated EVs, and although similar profiles were observed, a few key miRNAs involved in bone metabolism (miR-106b-5p, miRs-19b-3p, and miRs-219a-5p) were enriched in the Ocn-derived relative to the Prx1-derived EV subpopulations. To characterize the effects of these small EVs on a bone cell target, cultured mouse bone marrow stromal cells were treated with Prx1 or Ocn EVs, and mRNA-sequencing was performed. Pathways involved in ossification, bone development, and extracellular matrix interactions were regulated by both EV subpopulations, whereas a few pathways including advanced glycation end-products signaling were uniquely regulated in the Ocn EV subpopulation, underlying important biological effects of specific EV subpopulations within the bone marrow microenvironment. These data demonstrate that EV isolation in vivo using the CAGS-Snorkel mouse model is a useful tool in characterizing the cargo and understanding the biology of tissue-specific EVs. Moreover, while bone mesenchymal cell populations share a common EV secretory profile, we uncover key differences based on the stage of osteoblastic differentiation that may have important biological consequences.

OBJECTIVE Posterior lumbar interbody fusion (PLIF) and/or transforaminal lumbar interbody fusion (TLIF), referred to as "PLIF/TLIF," is a commonly performed operation for lumbar spondylolisthesis. Its long-term cost-effectiveness has not been well described. The aim of this study was to determine the 5-year cost-effectiveness of PLIF/TLIF for grade 1 degenerative lumbar spondylolisthesis using prospective data collected from the multicenter Quality Outcomes Database (QOD). METHODS Patients enrolled in the prospective, multicenter QOD grade 1 lumbar spondylolisthesis module were included if they underwent single-stage PLIF/TLIF. EQ-5D scores at baseline, 3 months, 12 months, 24 months, 36 months, and 60 months were used to calculate gains in quality-adjusted life years (QALYs) associated with surgery relative to preoperative baseline. Healthcare-related costs associated with the index surgery and related reoperations were calculated using Medicare reimbursement–based cost estimates and validated using price transparency diagnosis-related group (DRG) charges and Medicare charge-to-cost ratios (CCRs). Cost per QALY gained over 60 months postoperatively was assessed. RESULTS Across 12 surgical centers, 385 patients were identified. The mean patient age was 60.2 (95% CI 59.1–61.3) years, and 38% of patients were male. The reoperation rate was 5.7%. DRG 460 cost estimates were stable between our Medicare reimbursement–based models and the CCR-based model, validating the focus on Medicare reimbursement. Across the entire cohort, the mean QALY gain at 60 months postoperatively was 1.07 (95% CI 0.97–1.18), and the mean cost of PLIF/TLIF was $31,634. PLIF/TLIF was associated with a mean 60-month cost per QALY gained of $29,511. Among patients who did not undergo reoperation (n = 363), the mean 60-month QALY gain was 1.10 (95% CI 0.99–1.20), and cost per QALY gained was $27,591. Among those who underwent reoperation (n = 22), the mean 60-month QALY gain was 0.68 (95% CI 0.21–1.15), and the cost per QALY gained was $80,580. CONCLUSIONS PLIF/TLIF for degenerative grade 1 lumbar spondylolisthesis was associated with a mean 60-month cost per QALY gained of $29,511 with Medicare fees. This is far below the well-established societal willingness-to-pay threshold of $100,000, suggesting long-term cost-effectiveness. PLIF/TLIF remains cost-effective for patients who undergo reoperation.