Faculty Bibliography

INTRODUCTION/UNASSIGNED:Downbeat nystagmus (DBN) is classically attributed to cerebellar pathology. Far less often, DBN arises from brainstem disease, with midbrain etiologies being exceptionally rare and poorly characterized. In particular, DBN with the dorsal midbrain syndrome has been sporadically reported and its mechanism is unclear. METHODS/RESULTS/UNASSIGNED:We analyzed non-human primate and human literature on vertical gaze and brainstem-related DBN in the context of three patients with DBN and dorsal midbrain syndrome. Upgaze paresis was universal, skew deviation present in two, and parkinsonism developed in two after shunt-related complications. We reviewed the literature using strict criteria requiring DBN in central gaze and at least two definitive features of the dorsal midbrain syndrome, identifying two additional patients. DISCUSSION/UNASSIGNED:In five patients with DBN and dorsal midbrain syndrome, aqueductal stenosis or compression with upgaze paresis were unifying features. Potential mechanisms for DBN include involvement of the interstitial nucleus of Cajal, disruption of descending midbrain projections to paramedian tracts, or unstable cerebellar outflow, but clinical and experimental evidence makes these explanations less compelling. Converging evidence from our series, prior reports, and non-human primate studies suggests bilateral posterior commissural dysfunction related to aqueductal pathology as the most plausible mechanism for DBN with the dorsal midbrain syndrome.

Protease-activated receptor 2 (PAR₂) is a central regulator of intestinal barrier function, inflammation, and pain. Upregulated intestinal proteolysis and PAR₂ signaling are implicated in inflammatory bowel diseases (IBDs) and irritable bowel syndrome (IBS), conditions often associated with gut microbiome alterations. To identify potential bacterial regulators of PAR₂ activity, we developed a functional assay for PAR₂ processing to screen a library of diverse gut microbes. We identify multiple bacteria that secrete proteases capable of cleaving host PAR₂. Using chemoproteomic profiling with a covalent irreversible inhibitor, we uncovered a previously uncharacterized Bacteroides fragilis serine protease 1 (Bfp1) and show that it cleaves and activates PAR₂ in multicellular and murine models. PAR₂ cleavage by Bfp1 disrupts the intestinal barrier, sensitizes nociceptors, and triggers colonic inflammation and abdominal pain. Collectively, our findings uncover Bfp1-mediated PAR₂ processing as an axis of host-commensal interaction in the gut that has the potential to be targeted for therapeutic intervention in IBD or IBS.

OBJECTIVES/UNASSIGNED:Hyperbaric Oxygen (HBO₂) Therapy has been associated with some risks and adverse events. Previous studies examining otologic complications from HBO₂ therapy vary in their reported incidence of adverse events. This study aims to systematically review the otologic complications associated with HBO₂ therapy and investigate contributing risk and protective factors. REVIEW METHOD/UNASSIGNED:A systematic review was conducted to identify studies reporting otologic adverse effects due to HBO₂ therapy. Utilizing PRISMA 2020 guidelines, titles and abstracts were screened before conducting a full-text analysis. Studies reporting the incidence of otologic complications and studies reporting risk or protective factors for otologic complications were included. RESULTS/UNASSIGNED:A search for articles on HBO₂ therapy otologic complications yielded 2,027 articles, of which 183 were relevant to the research question. Ultimately, 54 studies met the inclusion criteria. Fifteen percent of the 18,284 patients treated with HBO₂ therapy experienced adverse events. Of the middle ear barotrauma (MEB) that occurred, 42.8% was mild, and 6.4% was severe. The major risk factors were increasing age, female sex, head and neck pathology, sensory neuropathy, and pre-treatment difficulty equalizing ear pressure. The main protective factor was experience with effective equalization techniques. CONCLUSIONS/UNASSIGNED:15% of patients experienced otologic complications due to HBO₂ therapy. Older age, female sex, and a history of head and neck or neurological conditions may increase the risk for MEB. Increased monitoring of higher-risk patients during initial treatment sessions and proper equalization techniques may help prevent MEB during HBO₂ therapy. This is the most comprehensive systematic review on the topic to date.

BACKGROUND/UNASSIGNED:) and intensity modulation), patient perception of their voice remains unexamined despite its clinical importance. This study aimed to characterize the relationship between patient-reported vocal tremor severity and acoustic voice outcomes at baseline and after botulinum toxin injections. METHOD/UNASSIGNED: RESULTS/UNASSIGNED: DISCUSSION/UNASSIGNED:Participants reporting more severe vocal tremor demonstrated more aberrant acoustic voice outcomes. After botulinum toxin injection, substantial heterogeneity was observed in acoustic voice measures which varied based on patient perception of change. These preliminary, exploratory findings provide a foundation for future investigations to define meaningful change in this population.

BACKGROUND:for HNC as a digital patient-reported symptom monitoring system that enables early symptom detection and real-time interventions at the point of care. With this study protocol, we aim to test the effectiveness of the ePVA in improving HNC outcomes in real-world settings and to identify implementation strategies optimizing its effectiveness. METHODS:We will conduct a longitudinal mixed-methods hybrid type I study at four National Cancer Institute-designated Comprehensive Cancer Centers serving diverse populations in rural and urban settings (New York University, the University of Kansas Cancer Center, Fox Chase Cancer Center, and Baylor College of Medicine) guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Patient eligibility criteria include having histologically diagnosed HNC and undergoing radiation therapy with or without chemotherapy for curative intent. We will also interview clinicians caring for patients with HNC at the participating institutions regarding facilitators and barriers to implementing the ePVA. The accrual goal is 270 patients. Aim 1 is to determine the effect of the ePVA on HNC symptoms in a two-arm (usual care vs. ePVA + usual care) trial. The study's primary outcomes are patients' self-reported social function, senses of taste and smell, and swallowing, measured by the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-H&N35. For Aim 2, we will interview patients (n = 40) as well as clinicians (n = 30) caring for patients with HNC at the participating institutions regarding facilitators and barriers to implementing the ePVA. In Aim 3, we will integrate Aims 1 and 2 data to identify strategies that optimize the use of the ePVA. DISCUSSION/CONCLUSIONS:The overarching goal of this research is to advance cancer care by identifying implementation standards for effective, widespread use of the ePVA that apply to all patient-reported outcomes in cancer care. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT06030011. Registered on 8 September 2023.

Rapid and precise activation of the laryngeal musculature, particularly the thyroarytenoid (TA), is required for the production of rat ultrasonic vocalizations (USVs). Although the role of the TA in USV production has been established through denervation and excised larynx studies, how TA muscle dysfunction affects USV acoustics remains unknown. This study examined how iatrogenic, transmuscular vocal fold injury influences USV production by comparing acoustic parameters between rats receiving bilateral transmuscular vocal fold injury (including the TA muscle) versus sham surgery. Twenty adult male rats were randomly assigned to injury or sham groups and assessed at 30 or 60 days post-surgery. USVs were recorded at each timepoint (pre- and post-surgery) and analyzed for changes in principal frequency, frequency complexity (standard deviation and sinuosity), power (intensity of the USV), tonality, and duration. Injury significantly decreased USV frequency complexity and reduced the likelihood of producing frequency-modulated vocalizations in both post-surgical time groups. These findings demonstrate that while TA muscle integrity is crucial for frequency modulation, it is not necessary for basic USV production, offering new insights into the biomechanical role of the TA muscle in rat vocalization and laying the groundwork for investigating therapeutic interventions targeting laryngeal muscle function.

Analgesia by non-steroidal anti-inflammatory drugs (NSAIDs) is ascribed to inhibition of prostaglandin (PG) biosynthesis and ensuing inflammation. However, NSAIDs have life-threatening side effects, and inhibition of inflammation delays pain resolution. Decoupling the mechanisms underlying PG-evoked pain vs. protective inflammation would facilitate pain treatment. Herein, we reveal that selective silencing of the PGE₂ receptor 2 (EP2) in Schwann cells via adeno-associated viral vectors abrogates the indomethacin-sensitive component of pain-like responses in mice elicited by inflammatory stimuli without affecting inflammation. In human Schwann cells and in mice, EP2 activation and optogenetic stimulation of adenylyl cyclase evokes a plasma membrane-compartmentalized cyclic adenosine monophosphate (cAMP) signal that, via A-kinase anchor protein-associated protein kinase A, sustains inflammatory pain-like responses, but does not delay their resolution. Thus, an unforeseen and druggable EP2 receptor in Schwann cells, via specific cAMP nanodomains, encodes PGE₂-mediated persistent inflammatory pain but not PG-dependent protective inflammation.

OBJECTIVE:Mentorship and training relationships shape the careers and influence of neurosurgeons. Network analysis can reveal structural characteristics and key individuals who support network connectivity and drive the field's development. This endeavor analyzed the U.S.-based neurosurgical training network derived from NeurosurGen.com. METHODS:A network graph was constructed representing neurosurgical training relationships, including chairperson-trainee, program director-trainee, and coresident connections. Graph- and node-level metrics, with a focus on centrality measures, were calculated for a trainer-trainee subgraph. RESULTS:The network consisted of 8840 neurosurgeons represented as nodes, and 382,143 relationships represented as edges. It evolved from an early small-world structure to a hierarchical and decentralized structure dominated by local clusters. Demographic shifts over time reflected increasing diversity and inclusion, with greater representation of female, Hispanic, Asian, and Black trainees across 285 training programs. Nodes were preferentially connected via residency, and the connectivity among underrepresented populations improved in concert with increased representation. Harvey W. Cushing was the quintessential neurosurgeon-influencer in the United States, ranking highly across most centrality measures over time. CONCLUSIONS:The neurosurgical training network is sparse but interconnected, typical of large real-world professional networks. While many small groups of neurosurgeons are closely tied within their immediate training hierarchy and peer group, in modern neurosurgery, each surgeon is only connected to a small fraction of the total network. Highly central individuals have played critical roles in linking disparate groups and shaping network structure. Increasing diversity in recent decades indicates progress toward inclusivity, although overall representation remains low.