Preoperative Mobile Health Data Improve Predictions of Recovery From Lumbar Spine Surgery.

BACKGROUND AND OBJECTIVES: Neurosurgeons and hospitals devote tremendous resources to improving recovery from lumbar spine surgery. Current efforts to predict surgical recovery rely on one-time patient report and health record information. However, longitudinal mobile health (mHealth) assessments integrating symptom dynamics from ecological momentary assessment (EMA) and wearable biometric data may capture important influences on recovery. Our objective was to evaluate whether a preoperative mHealth assessment integrating EMA with Fitbit monitoring improved predictions of spine surgery recovery. METHODS: Patients age 21-85 years undergoing lumbar surgery for degenerative disease between 2021 and 2023 were recruited. For up to 3 weeks preoperatively, participants completed EMAs up to 5 times daily asking about momentary pain, disability, depression, and catastrophizing. At the same time, they were passively monitored using Fitbit trackers. Study outcomes were good/excellent recovery on the Quality of Recovery-15 (QOR-15) and a clinically important change in Patient-Reported Outcomes Measurement Information System Pain Interference 1 month postoperatively. After feature engineering, several machine learning prediction models were tested. Prediction performance was measured using the c-statistic. RESULTS: A total of 133 participants were included, with a median (IQR) age of 62 (53, 68) years, and 56% were female. The median (IQR) number of preoperative EMAs completed was 78 (61, 95), and the median (IQR) number of days with usable Fitbit data was 17 (12, 21). 63 patients (48%) achieved a clinically meaningful improvement in Patient-Reported Outcomes Measurement Information System pain interference. Compared with traditional evaluations alone, mHealth evaluations led to a 34% improvement in predictions for pain interference (c = 0.82 vs c = 0.61). 49 patients (40%) had a good or excellent recovery based on the QOR-15. Including preoperative mHealth data led to a 30% improvement in predictions of QOR-15 (c = 0.70 vs c = 0.54). CONCLUSION: Multimodal mHealth evaluations improve predictions of lumbar surgery outcomes. These methods may be useful for informing patient selection and perioperative recovery strategies.

Advances in Anterolateral Approaches to the Lumbar Spine: A Focus on Technological Developments.

A historical overview of the evolution of anterolateral approaches to the lumber spine and associated patient outcomes is presented. In addition, the modern incorporation of new technologies is discussed, including interbody cages, intraoperative image guidance, robotics, augmented reality, and machine learning, which have significantly improved the spine surgery safety and efficacy profile. Current challenges and future directions are also covered, emphasizing the need for further research and development, particularly in robotic assistance and machine learning algorithms.

Spatial Computing for preoperative planning and postoperative evaluation of single-position lateral approaches in spinal revision surgery.

Spatial computing (SC) in a surgical context offers reconstructed interactive four-dimensional models of radiological imaging. Preoperative and postoperative assessment with SC can offer more insight into personalized surgical approaches. Spine surgery has benefitted from the use of perioperative SC assessment. Herein, we describe the use of SC to perform a perioperative assessment of a revision spinal deformity surgery. A 79-year-old wheelchair-bound male presented to the neurosurgery clinic with a history of chronic lumbar pain associated with bilateral lower extremity weakness. His surgical history is significant for an L2-L5 lumbar decompression with posterior fixation 1 year prior. On examination, there were signs of thoracic myelopathy. Imaging revealed his previous instrumentation, pseudoarthrosis, and cord compression. We perform a two-staged operation to address the thoracic spinal cord compression and myelopathy, pseudoarthrosis, and malalignment with a lack of global spinal harmony. His imaging is driven by a spatial computing and SC environment and offers support for the diagnosis of his L2-3 and L4-5 pseudoarthrosis on the reconstructed SC-based computed tomography scan. SC enabled the assessment of the configuration of the psoas muscle and course of critical neurovascular structures in addition to graft sizing, trajectory and approach, evaluation of the configuration and durability of the anterior longitudinal ligament, and the overlying abdominal viscera. SC increases the familiarity of the patient's specific anatomy and enhances perioperative assessment. As such, SC can be used to preoperatively plan for spinal revision surgery.

Mapping the geographic migration of United States neurosurgeons across training and current practice regions: associations with academic productivity.

OBJECTIVE: Characterizing changes in the geographic distribution of neurosurgeons in the United States (US) may inform efforts to provide a more equitable distribution of neurosurgical care. Herein, the authors performed a comprehensive analysis of the geographic movement and distribution of the neurosurgical workforce. METHODS: A list containing all board-certified neurosurgeons practicing in the US in 2019 was obtained from the American Association of Neurological Surgeons membership database. Chi-square analysis and a post hoc comparison with Bonferroni correction were performed to assess differences in demographics and geographic movement throughout neurosurgeon careers. Three multinomial logistic regression models were performed to further evaluate relationships among training location, current practice location, neurosurgeon characteristics, and academic productivity. RESULTS: The study cohort included 4075 (3830 male, 245 female) neurosurgeons practicing in the US. Seven hundred eighty-one neurosurgeons practice in the Northeast, 810 in the Midwest, 1562 in the South, 906 in the West, and 16 in a US territory. States with the lowest density of neurosurgeons included Vermont and Rhode Island in the Northeast; Arkansas, Hawaii, and Wyoming in the West; North Dakota in the Midwest; and Delaware in the South. Overall, the effect size, as measured by Cramér's V statistic, between training stage and training region is relatively modest at 0.27 (1.0 is complete dependence); this finding was reflected in the similarly modest pseudo R2 values of the multinomial logit models, which ranged from 0.197 to 0.246. Multinomial logistic regression with L1 regularization revealed significant associations between current practice region and residency region, medical school region, age, academic status, sex, or race (p < 0.05). On subanalysis of the academic neurosurgeons, the region of residency training correlated with an advanced degree type in the overall neurosurgeon cohort, with more neurosurgeons than expected holding Doctor of Medicine and Doctor of Philosophy degrees in the West (p = 0.021). CONCLUSIONS: Female neurosurgeons were less likely to practice in the South, and neurosurgeons in the South and West had reduced odds of holding academic rather than private positions. The Northeast was the most likely region to contain neurosurgeons who had completed their training in the same locality, particularly among academic neurosurgeons who did their residency in the Northeast.

Magnetic resonance imaging-guided stereotactic laser ablation therapy for the treatment of pediatric epilepsy: a retrospective multiinstitutional study.

OBJECTIVE: The authors of this study evaluated the safety and efficacy of stereotactic laser ablation (SLA) for the treatment of drug-resistant epilepsy (DRE) in children. METHODS: Seventeen North American centers were enrolled in the study. Data for pediatric patients with DRE who had been treated with SLA between 2008 and 2018 were retrospectively reviewed. RESULTS: A total of 225 patients, mean age 12.8 ± 5.8 years, were identified. Target-of-interest (TOI) locations included extratemporal (44.4%), temporal neocortical (8.4%), mesiotemporal (23.1%), hypothalamic (14.2%), and callosal (9.8%). Visualase and NeuroBlate SLA systems were used in 199 and 26 cases, respectively. Procedure goals included ablation (149 cases), disconnection (63), or both (13). The mean follow-up was 27 ± 20.4 months. Improvement in targeted seizure type (TST) was seen in 179 (84.0%) patients. Engel classification was reported for 167 (74.2%) patients; excluding the palliative cases, 74 (49.7%), 35 (23.5%), 10 (6.7%), and 30 (20.1%) patients had Engel class I, II, III, and IV outcomes, respectively. For patients with a follow-up ≥ 12 months, 25 (51.0%), 18 (36.7%), 3 (6.1%), and 3 (6.1%) had Engel class I, II, III, and IV outcomes, respectively. Patients with a history of pre-SLA surgery related to the TOI, a pathology of malformation of cortical development, and 2+ trajectories per TOI were more likely to experience no improvement in seizure frequency and/or to have an unfavorable outcome. A greater number of smaller thermal lesions was associated with greater improvement in TST. Thirty (13.3%) patients experienced 51 short-term complications including malpositioned catheter (3 cases), intracranial hemorrhage (2), transient neurological deficit (19), permanent neurological deficit (3), symptomatic perilesional edema (6), hydrocephalus (1), CSF leakage (1), wound infection (2), unplanned ICU stay (5), and unplanned 30-day readmission (9). The relative incidence of complications was higher in the hypothalamic target location. Target volume, number of laser trajectories, number or size of thermal lesions, or use of perioperative steroids did not have a significant effect on short-term complications. CONCLUSIONS: SLA appears to be an effective and well-tolerated treatment option for children with DRE. Large-volume prospective studies are needed to better understand the indications for treatment and demonstrate the long-term efficacy of SLA in this population.

Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma.

The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown disrupted the SOX2 gene network and inhibited both self-renewal capacity as well as in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, via its C-terminal PRYSPRY domain, but independent of its RING domain, stabilizes SOX2 protein by directly inhibiting the interaction of SOX2 with WWP2, which we identify as a bona fide SOX2 E3 ligase in GSCs. Our work identifies E3 ligase competition as a critical mechanism of SOX2 regulation, with functional consequences for GSC identity and maintenance.

Magnetic resonance-guided stereotactic laser ablation therapy for the treatment of pediatric brain tumors: a multiinstitutional retrospective study.

OBJECTIVE: This study aimed to assess the safety and efficacy of MR-guided stereotactic laser ablation (SLA) therapy in the treatment of pediatric brain tumors. METHODS: Data from 17 North American centers were retrospectively reviewed. Clinical, technical, and radiographic data for pediatric patients treated with SLA for a diagnosis of brain tumor from 2008 to 2016 were collected and analyzed. RESULTS: A total of 86 patients (mean age 12.2 ± 4.5 years) with 76 low-grade (I or II) and 10 high-grade (III or IV) tumors were included. Tumor location included lobar (38.4%), deep (45.3%), and cerebellar (16.3%) compartments. The mean follow-up time was 24 months (median 18 months, range 3-72 months). At the last follow-up, the volume of SLA-treated tumors had decreased in 80.6% of patients with follow-up data. Patients with high-grade tumors were more likely to have an unchanged or larger tumor size after SLA treatment than those with low-grade tumors (OR 7.49, p = 0.0364). Subsequent surgery and adjuvant treatment were not required after SLA treatment in 90.4% and 86.7% of patients, respectively. Patients with high-grade tumors were more likely to receive subsequent surgery (OR 2.25, p = 0.4957) and adjuvant treatment (OR 3.77, p = 0.1711) after SLA therapy, without reaching significance. A total of 29 acute complications in 23 patients were reported and included malpositioned catheters (n = 3), intracranial hemorrhages (n = 2), transient neurological deficits (n = 11), permanent neurological deficits (n = 5), symptomatic perilesional edema (n = 2), hydrocephalus (n = 4), and death (n = 2). On long-term follow-up, 3 patients were reported to have worsened neuropsychological test results. Pre-SLA tumor volume, tumor location, number of laser trajectories, and number of lesions created did not result in a significantly increased risk of complications; however, the odds of complications increased by 14% (OR 1.14, p = 0.0159) with every 1-cm3 increase in the volume of the lesion created. CONCLUSIONS: SLA is an effective, minimally invasive treatment option for pediatric brain tumors, although it is not without risks. Limiting the volume of the generated thermal lesion may help decrease the incidence of complications.

Staged Laser Interstitial Thermal Therapy (LITT) Treatments to Left Insular Low-Grade Glioma.

BACKGROUND AND IMPORTANCE: Low-grade insular gliomas remain challenging tumors for aggressive resection because of the numerous functional and vascular structures surrounding them. Because of the potential morbidities associated with open surgical resection, less invasive techniques may confer a more optimal balance between cytoreduction and surgical complications. For this reason, we evaluated the use of laser interstitial thermal therapy (LITT) for resection of a dominant hemisphere oligodendroglioma World Health Organization (WHO) grade II in a 68-yr-old patient by use of multiple staged surgeries for its resection. CLINICAL PRESENTATION: Patient KK was a 68-yr-old female who was found to have a large, left-sided insular mass that was shown to be an oligodendroglioma WHO grade II, positive for codeletion 1p/19q and IDH1 mutant on biopsy. Over the course of 3 mo, KK underwent 2 stages of LITT, targeting different areas of the 5-cm tumor. The 60-d magnetic resonance imaging (MRI) demonstrated a reduction in size of the tumor from 5.2 × 3.3 × 2.4 cm to 3.6 × 1.9 × 1.4 cm. She returned for a second stage targeting the anterior portion of the tumor. KK did well postoperatively and went on to postsurgical chemoradiation. At the 2-yr follow-up, the lesion showed near resolution on MRI. CONCLUSION: This case report demonstrates successful use of LITT for staged surgeries to treat a left hemisphere-dominant insular lesion. This establishes the use of LITT as a viable, minimally invasive option to treat tumors that are difficult to access or pose concerns for increased morbidity through an open surgery.

Amyloid-beta and Alzheimer's disease: the role of neprilysin-2 in amyloid-beta clearance.

Accumulation of the amyloid-beta (Aß) peptide is a central factor in Alzheimer's disease (AD) pathogenesis as supported by continuing evidence. This review concisely summarizes this evidence supporting a critical role for Aß in AD before discussing the clearance of this peptide. Mechanisms of clearance of Aß are critical for preventing pathological elevations in Aß concentration. Direct degradation of Aß by endopeptidases has emerged as one important pathway for clearance. Of particular interest are endopeptidases that are sensitive to the neprilysin (NEP) inhibitors thiorphan and phosphoramidon (i.e., are "NEP-like") as these inhibitors induce a dramatic increase in Aß levels in rodents. This review will focus on neprilysin-2 (NEP2), a NEP-like endopeptidase which cooperates with NEP to control Aß levels in the brain. The evidence for the involvement of NEP2 in AD is discussed as well as the therapeutic relevance with regards to gene therapy and the development of molecular markers for the disease.

Altered NEP2 expression and activity in mild cognitive impairment and Alzheimer's disease.

Neprilysin-2 (NEP2), a close homolog of neprilysin (NEP), degrades amyloid-ß (Aß) and serves an important role in clearing Aß in vivo. We measured NEP2 and NEP mRNA levels from non-impaired (NI), mild cognitive impaired (MCI), and clinical Alzheimer's disease (AD) subjects in the mid-temporal gyrus, mid-frontal gyrus, caudate, and cerebellum. NEP2 activity levels were also determined. Our results indicate that NEP2 and NEP mRNA expression is altered in MCI subjects relative to NI subjects in AD-susceptible regions. NEP2 enzymatic activity was lowered in association with MCI and AD and was positively associated with cognitive function, independent of diagnostic category. Our finding that NEP2 expression and activity are altered in MCI is significant as these changes may potentially serve as preclinical markers for AD and reduced NEP2 activity may be associated with the development of AD.

Neprilysin-2 is an important ß-amyloid degrading enzyme.

Proteases that degrade the amyloid-ß peptide (Aß) are important in protecting against Alzheimer's disease (AD), and understanding these proteases is critical to understanding AD pathology. Endopeptidases sensitive to inhibition by thiorphan and phosphoramidon are especially important, because these inhibitors induce dramatic Aß accumulation (∼30- to 50-fold) and pathological deposition in rodents. The Aß-degrading enzyme neprilysin (NEP) is the best known target of these inhibitors. However, genetic ablation of NEP results in only modest increases (∼1.5- to 2-fold) in Aß, indicating that other thiorphan/phosphoramidon-sensitive endopeptidases are at work. Of particular interest is the NEP homolog neprilysin 2 (NEP2), which is thiorphan/phosphoramidon-sensitive and degrades Aß. We investigated the role of NEP2 in Aß degradation in vivo through the use of gene knockout and transgenic mice. Mice deficient for the NEP2 gene showed significant elevations in total Aß species in the hippocampus and brainstem/diencephalon (∼1.5-fold). Increases in Aß accumulation were more dramatic in NEP2 knockout mice crossbred with APP transgenic mice. In NEP/NEP2 double-knockout mice, Aß levels were marginally increased (∼1.5- to 2-fold), compared with NEP(-/-)/NEP2(+/+) controls. Treatment of these double-knockout mice with phosphoramidon resulted in elevations of Aß, suggesting that yet other NEP-like Aß-degrading endopeptidases are contributing to Aß catabolism.

Intranasal phosphoramidon increases beta-amyloid levels in wild-type and NEP/NEP2-deficient mice.

Intranasal administration is emerging as a reliable and non-invasive method to bypass the blood-brain barrier and deliver drugs to the brain. This approach has been primarily used to explore therapeutic avenues for neurological diseases. However, intranasal administration could also be used to create animal models of brain disease. Beta-amyloid peptide (Aß) accumulation is a key feature of Alzheimer's disease (AD), and the most common models of AD are transgenic mice expressing mutant human genes linked to familial AD. An alternative model of amyloidosis utilizes intracerebroventricular infusion of thiorphan or phosphoramidon to block the activity of key Aß degrading enzymes (NEP, NEP2) resulting in accumulation of Aß. Here, we demonstrate that intranasal administration of phosphoramidon produces significantly elevated cerebral Aß levels in wild-type mice. Furthermore, intranasal phosphoramidon administration in double knockout mice lacking NEP and NEP2 also showed increased levels of Aß(40). These data show that intranasal delivery of drugs can be used to model AD and suggest that other phosphoramidon-sensitive peptidases are degrading Aß in NEP/NEP2-deficient mice.

Senescence in the worker honey bee Apis Mellifera.

Honey bees are social insects that exhibit striking caste-specific differences in longevity. Queen honey bees live on average 1-2 years, whereas workers live 2-6 weeks in the summer and about 20 weeks in the winter. It is not clear whether queen-worker differences in longevity are due to intrinsic physiological differences in the rate of senescence, to differential exposure to extrinsic factors such as predation and adverse environmental conditions, or both. To determine if the relatively short lifespan of worker bees involves senescence, we measured age-specific resistance to three different physiological stressors (starvation, thermal, and oxidative stress) while eliminating age-related differences in foraging activity and minimizing age-related differences in energy expenditure. Despite these manipulations, older worker bees were still significantly less resistant to all three stressors than were younger bees. These results indicate that the regulation of worker bee lifespan involves senescence, in addition to extrinsic factors.