Faculty Bibliography

Up to half of individuals with depression do not respond to first-line treatments, possibly due to a lack of treatment interventions informed by neurobiology. A novel therapeutic approach for depression has recently emerged from translational work targeting aberrant activity of ventral tegmental area (VTA) dopamine neurons via modulation of the KCNQ voltage-gated potassium channels. In this study, individuals with major depressive disorder (MDD) with elevated anhedonia were randomized to five weeks of the KCNQ channel opener, ezogabine (up to 900 mg/day) or placebo. Participants completed functional MRI during a monetary anticipation task and resting-state at baseline and at end-of-treatment. The clinical results were reported previously. Here, we examined VTA activity during monetary anticipation and resting-state functional connectivity between the VTA and the ventromedial prefrontal cortex (mesocortical pathway) and ventral striatum (mesolimbic pathway) at baseline and end-of-treatment. Results indicated a significant drug-by-time interaction in VTA activation during anticipation (F_(1,34) = 4.36, p = 0.044), where VTA activation was reduced from pre-to-post ezogabine, compared to placebo. Mesocortical functional connectivity was also higher in depressed participants at baseline compared to a healthy control group (t₍₅₆₎ = 2.68, p = 0.01) and associated with VTA hyper-activity during task-based functional MRI at baseline (R = 0.352, p = 0.033). Mesocortical connectivity was also reduced from pre-to-post ezogabine, compared to placebo (significant drug-by-time interaction, F_(1,33) = 4.317, p = 0.046). Together this translational work is consistent with preclinical findings highlighting VTA hyper-activity in depression, and suggesting a mechanism of action for KCNQ channel openers in normalizing this hyper-activity in individuals with both depression and anhedonia.

Brain excitability is dysfunctional in epilepsy and overlapping neuropsychiatric conditions including autism spectrum disorder (ASD). Epilepsy and ASD are often attributed to malfunctioning coordination between synaptic excitation and inhibition. Dravet syndrome (DS) is a severe form of epilepsy arising from haploinsufficiency of the SCN1A gene that encodes the voltage-gated sodium channel Nav1.1. A DS mouse model (Scn1a^+/-) recapitulated essential features of DS and revealed that sodium current density was profoundly reduced in GABAergic inhibitory interneurons while pyramidal cells were spared, suggesting that DS is an "interneuronopathy." Further studies from the Catterall group and others have expanded this picture: DS symptoms, which include recurrent seizures, ataxia, cognitive impairment, ASD, and premature death, could be assigned in part to brain region-specific effects; the Nav1.1 mutations cause dysfunction in some subtypes of interneurons, not others, and are temporally restricted; DS-causing sodium channel mutations were found throughout SCN1A as well as in SCN1B, encoding the β1 subunit. Interest in therapeutic approaches was sparked by preclinical studies of cannabidiol (CBD) that led to the 2018 US Food and Drug Administration approval for treatment of seizures in patients with DS. Independent evidence showed that CBD antagonized GPR55, a G protein-coupled receptor activated by the lipid signaling molecule lysophosphatidylinositol (LPI). We summarized evidence from our group and others that CBD has a dual mechanism of action, targeting both ion channels and GPR55. CBD quells an epileptogenic vicious cycle: seizures strengthen LPI-GPR55 signaling while LPI-GPR55 signaling elevates the synaptic excitatory-inhibitory ratio, thereby promoting further seizures. SIGNIFICANCE STATEMENT: Modern medicine relies on ion channels and G protein-coupled receptors (GPCRs) as key targets. In studies of Dravet syndrome, a devastating genetic disorder with features of epilepsy and autism, William Catterall connected NaV1.1 mutations to deficient excitability of inhibitory neurons. He and his colleagues explored preclinical interventions using cannabidiol (CBD) and clobazam, opening the way to a current understanding of CBD's therapeutic mechanism. CBD affects both ion channels and GPR55, a GPCR activated by lysophosphatidylinositol, an activity-dependent lipid messenger, readjusting the synaptic excitatory-inhibitory ratio.

INTRODUCTION/UNASSIGNED:Medical students' accounts of gender bias in their patient care learning experiences remain limited. This study examines students' responses to gender bias and their consideration for how to prepare for gender bias in their futures. METHODS/UNASSIGNED:We analyzed reflective writings of third-year clinical students. Within a phenomenology framework, conventional content analysis was used to inductively analyze all essays, using HyperResearch software. We coded in teams and reconciled disagreements, then combined codes in categories to identify themes. RESULTS/UNASSIGNED:Sixty-seven students (39 females; 28 males) wrote about gender bias in patient encounters. We identified five themes: bias, context, students' responses to patients' bias, patient-centered approach, and preparation for future encounters. Observations of bias addressed gender and structural bias, sexism, and racism. Students reflected on how context framed their experiences. Students aimed for patient-centered care, while simultaneously feeling ambivalence regarding patients' expressed bias. Students described their need to prepare for future experiences of gender bias and their plans to use specific strategies to cope with this bias. DISCUSSION/UNASSIGNED:Our study offers the voices of medical students regarding gender bias in their clinical learning, presenting an important perspective, given an often-hierarchical system of medical education. This examination, which includes recommendations for curricula and policies, informs education leaders of the need to incorporate preparation for dealing with gender bias and to help students personally as they face challenging encounters with patients and medical teams. Enlightened by critical theories, these findings should also motivate resident and faculty development and promote critical inquiry for institutional changes.

Achilles tendon pathologies are prevalent, impacting ~6% of the general population and up to 50% of elite endurance runners over their lifetimes. These conditions substantially affect quality of life and work productivity, leading to substantial societal costs. Achilles tendinopathy (AT) is a condition marked by localized pain and functional impairment related to mechanical loading. AT can considerably impair participation and potentially also performance in sports and daily activities. The aetiology of AT is multifactorial and repetitive overloading of the tendon is often observed as the inciting factor by health professionals. However, AT can also be associated with adverse effects of certain medication, ageing and various comorbidities. Characteristic tendon changes include proteoglycan accumulation, fluid accumulation with swelling and hypervascularization. Tissue disorganization advances as pathological changes in matrix structure are driven by altered cellular function and makeup, often accompanied by persistent inflammation. Treatment strategies include various interventions, although these can be protracted and challenging for both patients and health-care providers, often with high failure rates. Current research focuses on understanding the pathological processes at the cellular and molecular levels to distinguish between disease categories and to investigate the role of inflammation, metabolic maladaptation and mechanical stress. Emerging therapeutic approaches need to be developed to address these underlying mechanisms. These approaches focus on optimizing rehabilitation protocols and advancing the development of adjunct therapies, such as advanced therapy medicinal products, alongside the integration of precision medicine to improve treatment outcomes.

Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), are at increased risk of atherosclerosis, including peripheral arterial disease (PAD). Critical limb ischemia (CLI) may complicate PAD and is associated with significant mortality and morbidity. Despite the increased risk of thrombosis with MPN, outcomes of CLI in MPN patients are unclear. We conducted an analysis utilizing the 2017-2020 National Readmission Database (NRD) of patients hospitalized for CLI with and without MPN. Patients with MPN were propensity score matched (PSM) with patients without MPN. Primary outcome was composite outcome of major adverse cardiovascular and limb events (MACLE). Logistic regression was utilized to estimate risk of MACLE in patients with MPN vs. without MPN. Inverse-probability treatment weighted (IPTW) analysis was performed to evaluate the effect of revascularization on MACLE in patients with MPN. A total of 102,598 patients were included, 931 (0.9%) had MPN. After PSM, MPN was associated with increased risk of MACLE (47.3% vs. 39.1%; OR 1.40, 95% CI 1.21-1.62). After IPTW, revascularization was associated with decreased risk of MACLE among patients with MPN (45.0% vs. 50.7%; OR 0.80, 95% CI 0.66-0.96). Among patients admitted with CLI, MPN was associated with increased risk of MACLE especially ET and MF phenotypes. Revascularization was associated with decreased risk of MACLE among patients with MPN. Further investigation is needed in order to improve outcomes in patients with MPN and CLI.

Facial trauma presents a significant healthcare challenge in low- and middle-income countries (LMICs) due to limited access to specialized surgical care. This case report describes the management of a complex forehead degloving injury in a 20-year-old woman in Somalia, highlighting the role of remote surgical mentorship in resource-limited settings. The patient sustained a right forehead degloving injury in a motor vehicle collision, exposing a 3 × 5 cm segment of the frontal bone. Initial debridement resulted in a large soft-tissue defect, and the local surgical team faced challenges in selecting an optimal reconstructive approach due to limited experience and resources. The patient's aesthetic concerns further complicated decision-making. Through the Surgeons in Humanitarian Alliance for Reconstruction, Research, and Education program, the team sought virtual expert consultation via a secure WhatsApp platform. Based on expert recommendations, conservative management with daily Vaseline dressings was initiated to promote granulation tissue formation. Over 6 weeks, complete bone coverage was achieved, followed by full-thickness skin grafting, resulting in a satisfactory aesthetic outcome. This case demonstrates the value of global surgical networks in guiding complex reconstructions in LMICs, allowing local teams to deliver high-quality care despite resource constraints. Although short-term results were successful, long-term follow-up is necessary to assess functional and aesthetic durability. The success of this case underscores the importance of international collaborations in improving surgical education, patient outcomes, and sustainability of reconstructive techniques in LMICs.

Low-dose oral minoxidil (LDOM) has emerged as a widely used off-label treatment for different types of alopecia, showing a favorable safety profile and effectiveness. Despite its growing use, it is essential to understand the possible associated adverse events (AEs) and their appropriate management to optimize this therapy. The aim of this article was to comprehensively review the AEs of LDOM treatment, describing their frequency, risk factors, affected anatomical sites, and management strategies. A search in the PubMed and EMBASE databases was performed for studies published before 31 December 2024, reporting the treatment of any type of hair loss with oral minoxidil. The most frequent AE is hypertrichosis, occurring in approximately 15% of patients, with a higher incidence in women and patients with higher doses. Fluid retention affects 1.3-10% of patients, particularly women, and typically occurs within 1-3 months of treatment. Other cardiovascular AEs, such as tachycardia or dizziness, occur in fewer than 5% of cases and are usually mild and transient. Severe AEs, including pericardial effusion, are extremely rare and often linked to compounding errors comprising an excessive dose. Management strategies include dose reduction, pharmacological interventions like diuretics for edema, and lifestyle measures such as sodium restriction. In most cases, AEs resolve without the need for treatment discontinuation. The favorable safety profile of LDOM makes it a valuable therapeutic option for alopecia, though careful patient selection, dose titration, and monitoring are essential to minimize risks.