An overview of the safety and efficacy of LX-9211 in treating neuropathic pain conditions.

INTRODUCTION: LX-9211 is a drug designed to treat neuropathic pain conditions. It functions by inhibiting the adaptor-associated kinase 1 (AAK1) enzyme which promotes clathrin-dependent endocytosis. Preclinical studies have shown that LX-9211 does produce a reduction in nociceptive related behaviors and produces no major adverse effects in rats. Thus, LX-9211 has advanced to clinical trials to assess its safety and efficacy in humans. So far, phase 1 and phase 2 clinical trials involving patients with postherpetic neuralgia and diabetic peripheral neuropathic pain have been conducted with phase 3 trials planned in the future. AREAS COVERED: This paper highlights preclinical studies involving LX-9211 in rodents. Additionally, phase 1 clinical trials examining the safety of LX-9211 in healthy subjects as well as phase 2 studies looking at the safety and efficacy of LX-9211 compared to placebo in patients with diabetic peripheral neuropathic pain and postherpetic neuralgia are also discussed. EXPERT OPINION: In phase 1 and phase 2 clinical trials conducted so far, LX-9211 has been shown to produce few adverse effects as well as cause a significantly greater reduction in pain compared to placebo. However, more clinical studies are needed to further assess its effects in humans to ensure its safety.

Organizing a Regional In-Person Medical Student Symposium in Neuroscience and Neurosurgery Research: A How-To Guide.

BACKGROUND: Medical students are increasingly seeking out research opportunities to build their skills and network with future colleagues. Medical student-led conferences are an excellent endeavor to achieve this goal. METHODS: The American Association of Neurological Surgeons student chapter at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell designed an in-person medical student research symposium alongside the Northwell Health Department of Neurosurgery. Postconference feedback forms were sent out digitally to student attendees to evaluate event planning and execution and responses were given on a scale of 1-5 (5 being the highest score). RESULTS: In December 2023, the Northeast Medical Student Research Symposium was held with over 80 participants and 52 medical student presenters. Keynote speakers delivered lectures geared toward students interested in neurosurgery and neuroscience research, followed by an interactive poster board session and resident/attending networking dinner. After the conference, students affirmed that they learned more about neuroscience research after the event (mean: 4.3), were more inclined to attend other neuroscience research events in the future (mean: 4.7), and would attend this event if held next year (mean: 4.8). The poster sessions (mean: 4.75) and keynote lectures (mean: 5) were the highest rated events, while the resident/attending networking dinner (mean: 3.6) was a potential area for improvement. CONCLUSIONS: Regional in-person conferences are an excellent way to foster interest in neurosurgery and neuroscience research, network with like-minded peers, and prepare students for presentations at national meetings.

Direct (D)-Wave Monitoring Enhancement With Subdural Electrode Placement: A Case Series.

PURPOSE: Direct-wave (D-wave) neuromonitoring is a direct measure of corticospinal tract integrity that detects potential injury during spinal cord surgery. Epidural placement of electrodes used for D-wave measurements can result in high electrical impedances resulting in substantial signal noise that can compromise signal interpretation. Subdural electrode placement may offer a solution. METHODS: Medical records for consecutive patients with epidural and subdural D-wave monitoring were reviewed. Demographic and clinical information including preoperative and postoperative motor strength were recorded. Neuromonitoring charts were reviewed to characterize impedances and signal amplitudes of D-waves recorded epidurally (before durotomy) and subdurally (following durotomy). Nonparametric statistics were used to compare epidural and subdural D-waves. RESULTS: Ten patients (50% women, median age 50.5 years) were analyzed, of which five patients (50%) were functionally independent (modified McCormick grade ≤ II) preoperatively. D-waves were successfully acquired by subdural electrodes in eight cases and by epidural electrodes in three cases. Subdural electrode placement was associated with lower impedance values ( P = 0.011) and a higher baseline D-wave amplitude ( P = 0.007) relative to epidural placement. No association was observed between D-wave obtainability and functional status, and no adverse events relating to subdural electrode placement were encountered. CONCLUSIONS: Subdural electrode placement allows successful D-wave acquisition with accurate monitoring, clearer waveforms, and a more optimal signal-to-noise ratio relative to epidural placement. For spinal surgeries where access to the subdural compartment is technically safe and feasible, surgeons should consider subdural placement when monitoring D-waves to optimize clinical interpretation.

Influence of Preoperative Motor Score and Patient Comorbidities on Transcranial Motor-Evoked Potential Acquisition in Intracranial Surgery: A Retrospective Cohort Study.

BACKGROUND AND OBJECTIVES: Intraoperative neurophysiological monitoring plays a pivotal role in modern neurosurgery, aiding in real-time assessment of eloquent neural structures to mitigate iatrogenic neural injury. This study represents the largest retrospective series to date in monitoring corticospinal tract integrity during intracranial surgery with transcranial motor-evoked potentials (TCMEPs), focusing on the influence of demographic factors, comorbidities, and preoperative motor deficits on the reliability of intraoperative neurophysiological monitoring. While the impact of patient-specific factors affecting TCMEP monitoring in spine surgery is well-documented, similar insights for intracranial surgery are lacking. METHODS: A total of 420 craniotomy patients were retrospectively analyzed from electronic medical records from December 2017 to February 2023, excluding patients without preoperative Medical Research Council scores or medical histories. Using intrinsic hand muscles as a robust data set, 840 hand TCMEPs acquired during intracranial surgery were assessed. Demographic and clinical factors, including preoperative motor scores, were analyzed to identify associations with TCMEP acquisition and amplitude. Nonparametric statistics and multivariate regression analysis were employed. RESULTS: TCMEPs were successfully acquired in 734 (87.7%) patient hands, even in the presence of preoperative motor deficits in 13.9% of total patient hands. Preoperative motor scores did not predict the ability to acquire baseline TCMEPs (P = .6). Notably, older age (P < .001) and hypertension (P = .01) were independent predictors of lower TCMEP acquisition rates. Preoperative motor scores significantly influenced TCMEP amplitudes, with higher scores correlating with higher amplitudes (1771 [SD = 1550] eve vs 882 [SD = 856] µV, P < .0001). Older age (P < .001) and chronic kidney disease (P = .04) were also associated with reduced TCMEP amplitudes. CONCLUSION: Our investigation into TCMEPs during intracranial surgery demonstrated a notably high acquisition rate in hand muscles, irrespective of preoperative motor deficits. Preoperative motor scores reliably correlated with TCMEP amplitudes in a linear fashion while advanced age and renal disease emerged as independent predictors of lower TCMEP amplitudes.

Comparing U.S. and Canadian treatment patterns on venous thromboembolism outcomes in the GARFIELD-VTE registry.

BACKGROUND: Economically developed countries continue to find that venous thromboembolism (VTE) is a major cause of morbidity and mortality. OBJECTIVE: To compare baseline risk profiles and patient workflow patterns between the United States (U.S.) and Canadian management of VTE patients from 2014 to 2017. METHODS: The Global Anticoagulant Registry in the FIELD (GARFIELD-VTE) is a prospective, observational study of 10,679 patients with objectively confirmed VTE, followed for 3 years. In total 1101 patients enrolled in the U.S. and Canada were included in this analysis. RESULTS: Median age and body mass index were comparable between the U.S. (60.5; 30.2) and Canadian (59.7; 29) patients. A higher percentage of U.S. patients were black (n = 128, 24.1 %; n = 22, 3.9 %) and had a higher VTE-associated risk profile, including immobilization, hospitalization, and recent surgery. U.S. patients had a higher combined DVT and PE primary diagnoses (20.3 %) and were more likely to be treated in hospitals (77.2 %) than Canadians (13.3 %; 48.1 %). Direct oral anticoagulant therapy (DOAC) was nearly two-fold more frequent in Canadian patients (n = 218, 39.2 %) at the end of 3 years in comparison to the U.S. (n = 118, 23.0 %). Adjusted for sex, recent bleed event, heart failure, chronic immobilization, family history of VTE, history of cancer and prior VTE, and renal insufficiency, the risk of all-cause mortality was 51.9 % higher in patients from the U.S. compared to those in Canada after 3 years. Patients from the U.S. also had a higher likelihood of hospitalization, major bleeding, and recurrent VTE after controlling for prior history and comorbid conditions. CONCLUSION: Higher rates of adverse VTE-associated outcomes in the U.S. may be attributed to different baseline risk profiles, facility care, and distribution of specialists and their subsequent treatment strategies. TYPE OF RESEARCH: Global, multicentre, non-interventional, prospective registry titled Global Anticoagulant Registry in the FIELD - Venous Thromboembolism (GARFIELD-VTE). KEY FINDINGS: 531 U.S. and 557 Canadians patients included in study. DOAC use more frequent in Canadian patients after 3 years than U.S. (39.2 % vs. 23.0 %, respectively). Adjusted for sex, recent bleed event, heart failure, chronic immobilization, family history of VTE, history of cancer and prior VTE, and renal insufficiency, all-cause mortality risk remained higher in U.S. patients vs. Canadian patients after 3 years. U.S. patients had higher likelihood of hospitalization, major bleeding, and recurrent VTE. TAKE-HOME MESSAGE: Higher rates of adverse VTE-associated outcomes in the U.S. may be attributed to different baseline risk profiles, facility care, and composition of specialists and their subsequent treatment strategies. TABLE OF CONTENTS SUMMARY: Global, multicentre, non-interventional, prospective registry titled Global Anticoagulant Registry in the FIELD - Venous Thromboembolism (GARFIELD-VTE). Higher rates of adverse VTE-associated outcomes were observed in U.S. patients vs Canadian patients, which may be attributed to different baseline risk profiles, facility care, and distribution of specialists and their subsequent treatment strategies.

Overview of Median Arcuate Ligament Syndrome: A Narrative Review.

Median arcuate ligament syndrome (MALS) is a rare disorder caused primarily by compression of the celiac trunk by the median arcuate ligament (MAL). This disorder typically results in patients presenting with bloating, weight loss, nausea, vomiting, and abdominal pain. The MALS diagnosis is one of exclusion, as the disorder has no specific diagnostic criteria. Imaging modalities are often utilized to assist in making the diagnosis, such as ultrasound, computed tomography angiography (CTA), and magnetic resonance angiography (MRA). These imaging modalities typically reveal a stenosed celiac artery with post-stenotic dilation in patients. This disorder is usually treated by dividing the MAL, thus relieving the compression of the celiac artery. The surgery may be done through either an open approach or a minimally invasive approach, which can be either laparoscopic or robot-assisted. Most patients respond well to this treatment, though certain factors that predict a poorer response to treatment include elderly age, a history of alcohol abuse, and psychiatric illness.

Exploring the Intersection of Artificial Intelligence and Neurosurgery: Let us be Cautious With ChatGPT.

BACKGROUND AND OBJECTIVES: ChatGPT is a novel natural language processing artificial intelligence (AI) module where users enter any question or command and receive a single text response within seconds. As AI becomes more accessible, patients may begin to use it as a resource for medical information and advice. This is the first study to assess the neurosurgical information that is provided by ChatGPT. METHODS: ChatGPT was accessed in January 2023, and prompts were created requesting treatment information for 40 common neurosurgical conditions. Quantitative characteristics were collected, and four independent reviewers evaluated the responses using the DISCERN tool. Prompts were compared against the American Association of Neurological Surgeons (AANS) "For Patients" webpages. RESULTS: ChatGPT returned text organized in paragraph and bullet-point lists. ChatGPT responses were shorter (mean 270.1 ± 41.9 words; AANS webpage 1634.5 ± 891.3 words) but more difficult to read (mean Flesch-Kincaid score 32.4 ± 6.7; AANS webpage 37.1 ± 7.0). ChatGPT output was found to be of "fair" quality (mean DISCERN score 44.2 ± 4.1) and significantly inferior to the "good" overall quality of the AANS patient website (57.7 ± 4.4). ChatGPT was poor in providing references/resources and describing treatment risks. ChatGPT provided 177 references, of which 68.9% were inaccurate and 33.9% were completely falsified. CONCLUSION: ChatGPT is an adaptive resource for neurosurgical information but has shortcomings that limit the quality of its responses, including poor readability, lack of references, and failure to fully describe treatment options. Hence, patients and providers should remain wary of the provided content. As ChatGPT or other AI search algorithms continue to improve, they may become a reliable alternative for medical information.

Early Follow-Up after Arteriovenous Fistula Creation is Associated with Improved Access-Related Outcomes.

BACKGROUND: Up to 60% of arteriovenous fistulas (AVF) require intervention to assist maturation, which prolongs the time until it can be used for hemodialysis (HD). Current guidelines recommend early postoperative AVF examination to detect and address immaturity to decrease time to maturation. This study evaluates how the timing of postoperative follow-up to assess AVF maturity affects patients' outcomes. METHODS: All patients who underwent AVF creation between 2017 and 2021 in an academic medical center were retrospectively reviewed, excluding patients lost to follow-up or not on HD. Outcomes were compared between patients that had delayed follow-up to assess AVF maturity, >8 weeks post surgery, versus early follow-up, <8 weeks post-surgery. AVF evaluation for maturity consisted of physical examination and duplex ultrasound. Primary endpoints were time to first cannulation (interval from AVF creation to first successful cannulation) and time to catheter-free dialysis (interval from AVF creation to central venous catheter removal). RESULTS: A total of 400 patients were identified: 111 in the delayed follow-up group and 289 in the early follow-up group. The median time to follow-up was 78 days (interquartile range [IQR], 66-125) in the delayed follow-up group versus 39 days (IQR, 36-47) in the early follow-up group, (P < 0.0001). The maturation rate was 87% in the delayed follow-up group versus 81% in the early follow-up group, (P = 0.1) and both groups had similar rates of interventions to assist maturation (66% vs. 57%, P = 0.2). The early follow-up group had a significantly shorter median time to first cannulation (50 vs. 88 days; P < 0.0001) and shorter time to catheter-free HD (75 vs. 118 days; P <0.0001). At 4 months after AVF creation, the incidence of first cannulation was 74% in the early follow-up group versus 63% in the delayed follow-up group (P = 0.001). Similarly, the incidence of catheter-free dialysis was 65% in the early follow-up group versus 50% in the delayed follow-up group at 4 months postoperatively, (P = 0.036). CONCLUSIONS: Early postoperative follow-up for evaluation of fistula maturation is associated with reduced time to first successful cannulation of AVF for HD and reduced time to catheter-free dialysis.

Calcium imaging and analysis of the jugular-nodose ganglia enables identification of distinct vagal sensory neuron subsets.

Objective.Sensory nerves of the peripheral nervous system (PNS) transmit afferent signals from the body to the brain. These peripheral nerves are composed of distinct subsets of fibers and associated cell bodies, which reside in peripheral ganglia distributed throughout the viscera and along the spinal cord. The vagus nerve (cranial nerve X) is a complex polymodal nerve that transmits a wide array of sensory information, including signals related to mechanical, chemical, and noxious stimuli. To understand how stimuli applied to the vagus nerve are encoded by vagal sensory neurons in the jugular-nodose ganglia, we developed a framework for micro-endoscopic calcium imaging and analysis.Approach.We developed novel methods forin vivoimaging of the intact jugular-nodose ganglion using a miniature microscope (Miniscope) in transgenic mice with the genetically-encoded calcium indicator GCaMP6f. We adapted the Python-based analysis package Calcium Imaging Analysis (CaImAn) to process the resulting one-photon fluorescence data into calcium transients for subsequent analysis. Random forest classification was then used to identify specific types of neuronal responders.Results.We demonstrate that recordings from the jugular-nodose ganglia can be accomplished through careful surgical dissection and ganglia stabilization. Using a customized acquisition and analysis pipeline, we show that subsets of vagal sensory neurons respond to different chemical stimuli applied to the vagus nerve. Successful classification of the responses with a random forest model indicates that certain calcium transient features, such as amplitude and duration, are important for encoding these stimuli by sensory neurons.Significance.This experimental approach presents a new framework for investigating how individual vagal sensory neurons encode various stimuli on the vagus nerve. Our surgical and analytical approach can be applied to other PNS ganglia in rodents and other small animal species to elucidate previously unexplored roles for peripheral neurons in a diverse set of physiological functions.

Transient Receptor Potential Ankyrin-1-expressing vagus nerve fibers mediate IL-1ß induced hypothermia and reflex anti-inflammatory responses.

BACKGROUND: Inflammation, the physiological response to infection and injury, is coordinated by the immune and nervous systems. Interleukin-1ß (IL-1ß) and other cytokines produced during inflammatory responses activate sensory neurons (nociceptors) to mediate the onset of pain, sickness behavior, and metabolic responses. Although nociceptors expressing Transient Receptor Potential Ankyrin-1 (TRPA1) can initiate inflammation, comparatively little is known about the role of TRPA1 nociceptors in the physiological responses to specific cytokines. METHODS: To monitor body temperature in conscious and unrestrained mice, telemetry probes were implanted into peritoneal cavity of mice. Using transgenic and tissue specific knockouts and chemogenetic techniques, we recorded temperature responses to the potent pro-inflammatory cytokine IL-1ß. Using calcium imaging, whole cell patch clamping and whole nerve recordings, we investigated the role of TRPA1 during IL-1ß-mediated neuronal activation. Mouse models of acute endotoxemia and sepsis were used to elucidate how specific activation, with optogenetics and chemogenetics, or ablation of TRPA1 neurons can affect the outcomes of inflammatory insults. All statistical tests were performed with GraphPad Prism 9 software and for all analyses, P ≤ 0.05 was considered statistically significant. RESULTS: Here, we describe a previously unrecognized mechanism by which IL-1ß activates afferent vagus nerve fibers to trigger hypothermia, a response which is abolished by selective silencing of neuronal TRPA1. Afferent vagus nerve TRPA1 signaling also inhibits endotoxin-stimulated cytokine storm and significantly reduces the lethality of bacterial sepsis. CONCLUSION: Thus, IL-1ß activates TRPA1 vagus nerve signaling in the afferent arm of a reflex anti-inflammatory response which inhibits cytokine release, induces hypothermia, and reduces the mortality of infection. This discovery establishes that TRPA1, an ion channel known previously as a pro-inflammatory detector of cold, pain, itch, and a wide variety of noxious molecules, also plays a specific anti-inflammatory role via activating reflex anti-inflammatory activity.

Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation.

Transient receptor potential (TRP) channels are a superfamily of non-selective cation channels that act as polymodal sensors in many tissues throughout mammalian organisms. In the context of ion channels, they are unique for their broad diversity of activation mechanisms and their cation selectivity. TRP channels are involved in a diverse range of physiological processes including chemical sensing, nociception, and mediating cytokine release. They also play an important role in the regulation of inflammation through sensory function and the release of neuropeptides. In this review, we discuss the functional contribution of a subset of TRP channels (TRPV1, TRPV4, TRPM3, TRPM8, and TRPA1) that are involved in the body's immune responses, particularly in relation to inflammation. We focus on these five TRP channels because, in addition to being expressed in many somatic cell types, these channels are also expressed on peripheral ganglia and nerves that innervate visceral organs and tissues throughout the body. Activation of these neural TRP channels enables crosstalk between neurons, immune cells, and epithelial cells to regulate a wide range of inflammatory actions. TRP channels act either through direct effects on cation levels or through indirect modulation of intracellular pathways to trigger pro- or anti-inflammatory mechanisms, depending on the inflammatory disease context. The expression of TRP channels on both neural and immune cells has made them an attractive drug target in diseases involving inflammation. Future work in this domain will likely yield important new pathways and therapies for the treatment of a broad range of disorders including colitis, dermatitis, sepsis, asthma, and pain.

Integrated solid-state NMR and molecular dynamics modeling determines membrane insertion of human ß-defensin analog.

Human ß-defensins (hBD) play central roles in antimicrobial activities against various microorganisms and in immune-regulation. These peptides perturb phospholipid membranes for function, but it is not well understood how defensins approach, insert and finally disrupt membranes on the molecular level. Here we show that hBD-3 analogs interact with lipid bilayers through a conserved surface that is formed by two adjacent loops in the solution structure. By integrating a collection of 13C, 1H and 31P solid-state NMR methods with long-term molecular dynamic simulations, we reveal that membrane-binding rigidifies the peptide, enhances structural polymorphism, and promotes ß-strand conformation. The peptide colocalizes with negatively charged lipids, confines the headgroup motion, and deforms membrane into smaller, ellipsoidal vesicles. This study designates the residue-specific, membrane-bound topology of hBD-3 analogs, serves as the basis for further elucidating the function-relevant structure and dynamics of other defensins, and facilitates the development of defensin-mimetic antibiotics, antifungals, and anti-inflammatories.

Molecular architecture of fungal cell walls revealed by solid-state NMR.

The high mortality of invasive fungal infections, and the limited number and inefficacy of antifungals necessitate the development of new agents with novel mechanisms and targets. The fungal cell wall is a promising target as it contains polysaccharides absent in humans, however, its molecular structure remains elusive. Here we report the architecture of the cell walls in the pathogenic fungus Aspergillus fumigatus. Solid-state NMR spectroscopy, assisted by dynamic nuclear polarization and glycosyl linkage analysis, reveals that chitin and α-1,3-glucan build a hydrophobic scaffold that is surrounded by a hydrated matrix of diversely linked ß-glucans and capped by a dynamic layer of glycoproteins and α-1,3-glucan. The two-domain distribution of α-1,3-glucans signifies the dual functions of this molecule: contributing to cell wall rigidity and fungal virulence. This study provides a high-resolution model of fungal cell walls and serves as the basis for assessing drug response to promote the development of wall-targeted antifungals.