Negative allosteric modulation of CB1 cannabinoid receptor signalling decreases intravenous morphine self-administration and relapse in mice.

The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators. We hypothesized that negative allosteric modulation of CB1R signalling would reduce the reinforcing properties of morphine and decrease behaviours associated with opioid misuse. By employing intravenous self-administration in mice, we studied the effects of GAT358, a functionally-biased CB1R negative allosteric modulator (NAM), on morphine intake, relapse-like behaviour and motivation to work for morphine infusions. GAT358 reduced morphine infusion intake during the maintenance phase of morphine self-administration under a fixed ratio 1 schedule of reinforcement. GAT358 also decreased morphine-seeking behaviour after forced abstinence. Moreover, GAT358 dose dependently decreased the motivation to obtain morphine infusions under a progressive ratio schedule of reinforcement. Strikingly, GAT358 did not affect the motivation to work for food rewards in an identical progressive ratio task, suggesting that the effect of GAT358 in decreasing opioid self-administration was reward specific. Furthermore, GAT58 did not produce motor ataxia in the rotarod test. Our results suggest that CB1R NAMs reduced the reinforcing properties of morphine and could represent a viable therapeutic route to safely decrease misuse of opioids.

Frameless Stereotactic Biopsy of Brainstem Tumors Using the Stealth Autoguide: A Technical Note.

BACKGROUND AND OBJECTIVES: In the molecular era of neuro-oncology, it is increasingly necessary to obtain tissue for next-generation sequencing and methylome profile for prognosis and targeted oncological management. Brainstem tumors can be technically challenging to biopsy in the pediatric population. Frame-based and frameless techniques have previously been described and proven to be safe and efficacious in children. Recent cranial robotic guidance platforms have augmented the fluency of frameless stereotactic approaches, but the technical nuances of these procedures in children are not often discussed. We present a technical workflow for frameless stereotactic biopsy of brainstem tumors in children using the Medtronic Stealth Autoguide cranial robotic guidance platform and examine safety and efficacy of this surgical approach. METHODS: A minimally invasive, frameless, transcerebellar approach is described, including operative steps and workflow. We assessed operative times, diagnostic accuracy and yield, and complication rates. RESULTS: Five patients underwent biopsy with the technique described. The youngest patient in our series was of 2 years. The intended target was achieved on postoperative imaging in all cases, and diagnostic tissue was obtained in all 5 patients. One patient had a clinically insignificant hemorrhage. CONCLUSION: Frameless stereotactic biopsy of the brainstem can be performed safely, efficiently, and accurately using the Medtronic Stealth Autoguide robotic platform in children as young as 2 years.

Match rate of neurosurgery residents in the United States at their home institution: A comparative analysis of Pre COVID-19, During COVID-19 and Post COVID-19 pandemic.

OBJECTIVE: Limitations to medical student clinical rotation opportunities brought on by the pandemic has the potential to exacerbate differences in access to clinical experience between medical schools, and thus impact the distribution of graduates matching into neurosurgical programs nationwide. The utilization of virtual interviews that started after the pandemic are likely here to stay. In this study we seek to evaluate match rates for American (AMGs) and international medical graduates (IMGs) across the 6 most recent academic years, examining specifically the rate of home-institution matching before, during, and after the COVID-19 pandemic. METHODS: All neurological surgery residents for the years 2018-2024 were included in this analysis, with basic information about each resident being collected using publicly available online resources. For any remaining programs where information was not publicly available, program directors were contacted. Statistical analysis was performed using SPSS version 26.0 with a level of significance p<0.05. RESULTS: Of the total of 1271 AMGs, 1005 (79.1 %) matched away from their home institution. When dividing the 6 academic years into 3 subgroups (pre, intra, and post COVID-19), there was no significant variation between the rates of home institution matching (pre=21.0 %, during=20.4 %, post=21.3 %, p=0.740). Similar results were found while assessing IMGs (pre=28.6 %, during=30.8 %, post=32.3 %, p=0.777). Our analysis found no variation in match rates when isolating for gender across the 6 years studied either for AMGs or IMGs. However, overall institute-specific variations were found where some programs showed increased likelihood of home program match (p<0.001). CONCLUSION: Preliminary data analysis suggests that contrary to the broader trends seen in other specialties, neurosurgery applicants do not exhibit a significant shift towards matching in closer proximity to their home institutions post COVID-19 pandemic and during the virtual interviews era.

Investigating Thoracic Vertebral Fractures in Residential Environments.

INTRODUCTION: Thoracic vertebral fractures within homes are pivotal public health concerns due to their associated morbidity and significant healthcare expenditures. This study aims to dissect the intricate epidemiology of these injuries, integrating comprehensive risk factors beyond conventional demographics and location analyses. METHODS: Utilizing a decade of data (2013-2022) from the National Electronic Injury Surveillance System, this study examines thoracic vertebral fractures across age and gender in household settings. Inclusion criteria targeted specific thoracic spine-related terms, analyzing fractures by location (e.g., kitchen, stairs) and associated products. Data processing employed R programming, with statistical analysis focusing on descriptive statistics and multivariate logistic regression, to identify fracture patterns and assess gender differences in fracture risks through Adjusted Odds Ratios (AORs). RESULTS: Analysis of 46,371 thoracic vertebral fractures identified stairs as the primary site (26.81%), with subsequent frequent locations being bedrooms (18.52%), living rooms (17.88%), and kitchens (16.29%). Gender-specific risk analysis revealed females had a higher likelihood of fractures on stairs (AOR = 1.24, 95% CI: 1.16-1.37, P < 0.001) and in bedrooms (AOR = 1.13, 95% CI: 1.09-1.54, P < 0.001). The most affected age group was 51-60, showcasing the multifaceted nature of risk factors beyond mere location. DISCUSSION: This study transcends prior insights by detailing the influence of various factors, including socioeconomic status and lifestyle, on fracture risk. It emphasizes the complexity of household fractures, highlighting gender and age as pivotal but not exclusive risk determinants. CONCLUSIONS: By offering a comprehensive analysis that incorporates a wide array of risk factors, this study advances the understanding of thoracic vertebral fractures in residential environments. It underscores the necessity for targeted preventive measures that are cognizant of the multifactorial nature of these injuries, paving the way for improved safety interventions and public health policies.

Preoperative aspirin and anticoagulants do not affect partial nephrectomy bleeding.

INTRODUCTION: Studies have reached mixed conclusions on the role of antiplatelet and anticoagulant agents on postoperative complications of partial nephrectomies. This study examines whether preoperative anticoagulation use affected the risk of hemorrhagic complications after partial nephrectomy. MATERIALS AND METHODS: This is a retrospective chart review of all partial nephrectomies performed between 2017 and 2022 at a single institution. For each operation, preoperative data was gathered on whether the patient was on anticoagulation, the type and dose of anticoagulation, and how many days the anticoagulation was held preoperatively. Bivariate analyses for continuous measures were performed using Student's t-tests when there were two comparison groups and ANOVA models when there were more than two comparison groups and Chi-Square tests were used for categorical variables, with Fisher's Exact being used when expected cell counts were small. RESULTS: In this study, warfarin was held for an average of 5.43 days, clopidogrel was held for an average of 6.60 days, aspirin was held for an average of 7.65 days, and direct oral anticoagulants (DOACs) were held for an average of 4.00 days. There was no significant difference in hemoglobin (Hb) change, rate of intraoperative transfusion, postoperative transfusion, bleeding complication, pseudoaneurysm rate, or additional bleeding processes between patients on prior anticoagulation therapy and those not on therapy. There was no significant difference in intraoperative or postoperative outcomes based on history of aspirin use and continuation of aspirin through the surgery. While estimated blood loss appeared statistically significant initially, this difference was accounted for by the covariates of comorbidities, RENAL score, surgical approach, and type of renorrhaphy. Overall, there was no difference in complication rate based solely on aspirin use or continuation of aspirin through surgery. CONCLUSIONS: No difference in complication rate of partial nephrectomy was determined to be solely due to prior use of anticoagulation or aspirin use alone with appropriate cessation of anticoagulation preoperatively. Overall, patients on anticoagulation are not at a higher risk of intraoperative or postoperative bleeding complications when undergoing partial nephrectomy.

A Sodium Oxychlorosene-Based Infection Prevention Protocol Safely Decreases Postoperative Wound Infections in Adult Spinal Deformity Surgery.

INTRODUCTION: This study sought to determine the efficacy of a complex multi-institutional sodium oxychlorosene-based infection protocol for decreasing the rate of surgical site infection after instrumented spinal surgery for adult spinal deformity (ASD). Infection prevention protocols have not been previously studied in ASD patients. METHODS: A retrospective analysis was performed of patients who underwent posterior instrumented spinal fusion of the thoracic or lumbar spine for deformity correction between January 1, 2011, and May 31, 2019. The efficacy of a multi-modal infection prevention protocol was examined. The infection prevention bundle consisted of methicillin-resistant Staphylococcus aureus testing, chlorhexidine gluconate bathing preoperatively, sodium oxychlorosene rinse, vancomycin powder placement, and surgical drain placement at the time of surgery. RESULTS: About 254 patients fit the inclusion criteria. Among these patients, nine (3.5%) experienced post-surgical deep-wound infection. Demographics and surgical characteristics amongst infected and non-infected cohorts were similar, although diabetes trended towards being more prevalent in patients who developed a postoperative wound infection (p=0.07). Among 222 patients (87.4%) who achieved a minimum of two years of follow-ups, 184 patients (82.9%) experienced successful fusion, comparing favorably with pseudarthrosis rates in the ASD literature. Rates of pseudarthrosis and proximal junction kyphosis were similar amongst infected and non-infected patients. CONCLUSION: An intraoperative comprehensive sodium oxychlorosene-based infection prevention protocol helped to provide a low rate of infection after major deformity correction without negatively impacting other postoperative procedure-related metrics.

Negative allosteric modulation of CB1 cannabinoid receptor signaling decreases intravenous morphine self-administration and relapse in mice.

The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators. We hypothesized that pharmacological inhibition of CB1R signaling through negative allosteric modulation (NAM) would reduce the reinforcing properties of morphine and decrease opioid addictive behaviors. By employing i.v. self-administration in mice, we studied the effects of the CB1-biased NAM GAT358 on morphine intake, relapse-like behavior, and motivation to work for morphine infusions. Our data revealed that GAT358 reduced morphine infusion intake during the maintenance phase of morphine self-administration under fixed ratio 1 schedule of reinforcement. GAT358 decreased morphine-seeking behavior after forced abstinence. Moreover, GAT358 dose-dependently decreased the motivation to obtain morphine infusions in a progressive ratio schedule of reinforcement. Strikingly, GAT358 did not affect the motivation to work for food rewards in an identical progressive ratio task, suggesting that the effect of GAT358 in decreasing opioid self-administration is reward specific. Furthermore, GAT58 did not produce motor ataxia in the rota-rod test. Our results suggest that CB1R NAMs reduced the reinforcing properties of morphine and could represent a viable therapeutic route to safely decrease opioid-addicted behaviors.