Faculty Bibliography

Chromosomal rearrangements on the short arm of Chromosome 8 cause 8p syndrome, a rare developmental disorder characterized by neurodevelopmental delays, epilepsy, and cardiac abnormalities. Although significant progress has been made in managing the symptoms of 8p syndrome and other conditions caused by large-scale chromosomal aneuploidies, no therapeutic approach has yet been demonstrated to target the underlying disease-causing chromosome. Here, we establish a two-step approach to eliminate the abnormal copy of Chromosome 8 and restore euploidy in cells derived from an individual with a complex rearrangement of Chromosome 8p. Transcriptomic analysis revealed 361 differentially expressed genes between the proband and the euploid revertant, highlighting genes both within and outside the 8p region that may contribute to 8p syndrome pathology. Furthermore, we demonstrate that the proband exhibits a significant defect in neural differentiation that could be partially rescued by treatment with small-molecule inhibitors of cell death. Our work demonstrates the feasibility of using chromosome engineering to correct complex aneuploidies in vitro and establishes a platform to further dissect the pathophysiology of 8p syndrome and other conditions caused by chromosomal rearrangements.

PURPOSE OF REVIEW/OBJECTIVE:This review discusses the current state of the evidence related to the relationship between the cerebellum and epilepsy, highlighting evidence on neurostimulation of the cerebellum for treatment of epilepsy, and placing current knowledge into historical context. RECENT FINDINGS/RESULTS:The cerebellum plays an important role in certain epilepsy types, both as a key part of epileptic networks and an area that can give rise to seizures. Cerebellar stimulation as a potential treatment for drug-resistant epilepsy is a recurring, albeit niche, topic of interest. Over decades of intermittent, often highly limited investigations into this area of research, there are still more questions than answers. However, more recent preclinical insights point the way towards leveraging modern surgical techniques and technology in investigating cerebellar stimulation as a potential viable treatment approach to select types of epilepsy. SUMMARY/CONCLUSIONS:Cerebellar stimulation holds promise for improving seizure control in people with specific types of drug-resistant epilepsy. Future studies should leverage new preclinical data, along with modern technology, neurosurgical techniques, and clinical trial design, to help determine the optimal stimulation parameters, optimal stimulation targets, and optimal patient-selection for this promising area of investigation.

BACKGROUND/UNASSIGNED:Lateral ankle sprains are the most common lower extremity injury in athletes, most often involving the anterior talofibular ligament (ATFL). Although ATFL repair outcomes are well studied, optimal management for patients with generalized ligamentous laxity (GLL) remains less understood. PURPOSE/UNASSIGNED:To (1) evaluate the radiographic findings, clinical measures, and complications in patients with GLL undergoing modified Broström-Gould repair and to (2) assess the role of suture augmentation in optimizing outcomes. STUDY DESIGN/UNASSIGNED:Systematic review; Level of evidence, 4. METHODS/UNASSIGNED:During July 2025, the PubMed, EMBASE, and Cochrane library databases were systematically searched to identify studies examining outcomes and complications in GLL patients who underwent modified Broström-Gould repair. RESULTS/UNASSIGNED:= .03). When suture augmentation was performed, no significant difference in complication rates existed between cohorts. CONCLUSION/UNASSIGNED:Patients with GLL experienced significantly higher rates of complication and failure following modified Broström-Gould repair compared with patients without ligamentous laxity. Suture augmentation may lower complication rates in GLL patients, but its effect on failure rates remains undetermined, as no studies directly compared augmented and nonaugmented GLL patients. Importantly, both GLL patients and patients without ligamentous laxity experienced clinical improvements from the modified Broström-Gould repair. While GLL increases the risk of mechanical complications, it should not be considered a contraindication to undergoing the modified Broström-Gould procedure. However, suture augmentation may be beneficial for GLL patients to reduce the risk of complications after undergoing ATFL repair. REGISTRATION/UNASSIGNED:CRD420251182303 (PROSPERO identifier).

INTRODUCTION/BACKGROUND:This community-led research study protocol emphasises placing black youth impacted by the legal system, their families and their communities at the forefront of substance use treatment development research and decision-making. The study, the Cultural Adaptation of a Substance Use Treatment (CAST) Project, challenges traditional top-down approaches to treatment creation, advocating for a grassroots model that centres community knowledge, values and active participation. METHODS AND ANALYSIS/METHODS:The CAST project is a US-based mixed-methods study with an exploratory design that examines the impact of racial discrimination on substance use in black youth impacted by the legal system. The study participants are black youth impacted by the legal system (N=15), parents of black youth impacted by the legal system (N=10) and community members who serve black youth (N=10) (total N=35 study participants). Study participants from each group (youth, parents and community members) will participate in three separate focus groups, respectively, to provide feedback on the culturally responsive content needed to best support black youth impacted by the legal system around substance use and mental health. The eight-step Assess, Decision, Adaptation, Production, Topical Expert, Integration, Training, Testing framework will be used as a guide to inform adaptations to the Motivational Enhancement Therapy and Cognitive Behavioural Therapy (MET/CBT12) for black youth impacted by the legal system. Once the cultural adaptation process has been completed, the study will conclude with an open feasibility and accessibility trial of the culturally adapted MET/CBT12 manual. The primary outcomes of this study are the feasibility and acceptability of the culturally adapted manual, measured by treatment attendance and participant feedback. Secondary outcomes include reductions in substance use and discrimination distress, and improvements in mental health symptoms. ETHICS AND DISSEMINATION/BACKGROUND:This study was approved by the Institutional Review Board (IRB) at the University of California, San Francisco (IRB Protocol Number: 23-40126). All study procedures will be conducted in accordance with the ethical standards outlined by the institutional review board. The results from this study will be shared through peer-reviewed publications, academic conferences, community forums and policy briefs to support broader implementation of culturally adapted adolescent substance use interventions that address discrimination-related stress and substance use among black individuals impacted by the legal system. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT06003725.

AIM/UNASSIGNED:Inadequate adherence to colorectal cancer screening reduces individual and population level health benefits. Blood-based tests offer a new modality that may help patients overcome barriers, but there are concerns about the impact of patients switching from existing guideline-recommended screening modalities. This study estimates the population health outcomes and cost-effectiveness of offering blood-based testing using a validated individual-level simulation model based on patient preference evidence from randomized controlled trials. MATERIALS AND METHODS/UNASSIGNED:In this study, a validated discrete-event simulation model was used to evaluate the performance of different combinations of colorectal cancer screening strategy preferences per 10,000 screened individuals beginning at age 45. Preferences for screening options were informed by randomized controlled trials of patients with and without the option of blood-based testing. Adherence to initial patient preferences over a simulated lifetime was modeled as: (1) assumed 100% adherence and (2) longitudinal using a calibrated model. Simulated outcomes included clinical outcomes and cost-effectiveness from a healthcare sector perspective. A strategy was deemed cost-effective at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year gained. RESULTS/UNASSIGNED:The introduction of blood-based testing to an unscreened population with evidence from randomized controlled trials is projected to increase colorectal cancer deaths averted by 35% to 116% and from 68% to 247% relative to no screening, for stated preference and revealed preference scenarios, respectively. These outcomes are cost-effective, with incremental cost-effectiveness ratios ranging from $63,994 to $85,497 and from $30,464 to $54,764 across stated preference and revealed preference scenarios, respectively. LIMITATIONS/UNASSIGNED:Given limited data, natural history and real-world longitudinal adherence to screening are based on evidence-informed assumptions. CONCLUSIONS/UNASSIGNED:Using a simulation model to extrapolate data from two recent trials, we demonstrate that the introduction of blood-based tests has the potential to lead to cost-effective increases in the number of CRC deaths averted among the unscreened population.

INTRODUCTION/BACKGROUND:Plasma phosphorylated tau 217 (p-tau217) is a leading blood-based biomarker of Alzheimer's disease. Its performance in underrepresented racial/ethnic groups remains insufficiently characterized. METHODS:We analyzed 2798 participants from the Health and Aging Brain Study-Health Disparities, including non-Hispanic White, non-Hispanic Black, and Hispanic adults. Multivariable logistic regression and receiver operating characteristic analyses assessed associations and discriminative accuracy between plasma p-tau217 and clinical cognitive impairment with racial/ethnic-specific thresholds. RESULTS:Across all groups, p-tau217 levels were higher in cognitively impaired than unimpaired participants. Elevated p-tau217 was associated with greater odds of cognitive impairment in all racial and ethnic groups. Discriminative accuracy was modest but significant (area under the curve 0.65-0.72), with highest performance in non-Hispanic Black and lowest in Hispanic participants. DISCUSSION/CONCLUSIONS:Plasma p-tau217 is robustly associated with cognitive impairment across diverse populations with varying thresholds, highlighting the need for population-specific calibration to support equitable biomarker implementation.

CONTEXT/BACKGROUND:More health systems are establishing outpatient palliative care (PC) programs, increasing demand for ambulatory PC clinicians. However, existing outpatient training during hospice and palliative medicine (HPM) fellowship remains limited and suboptimal. Little is known about the outpatient-specific knowledge and skills PC trainees should acquire for competent outpatient practice. OBJECTIVES/OBJECTIVE:To identify and prioritize outpatient-focused educational topics for HPM fellows and clinicians new to ambulatory practice. METHODS:A cross-sectional survey of United States (U.S.) outpatient PC clinicians (physicians, advanced practice practitioners [APPs]). Using a list of 51 educational topics, respondents selected a maximum of 20 topics they would prioritize as essential to prepare learners for outpatient practice. RESULTS:Of 247 clinicians, 136 (55%) responded, including 115 physicians and 21 APPs from all U.S. regions. Seven of 51 topics were prioritized by more than two-thirds of respondents (n = 92-119, 68%-86%). Four focused on outpatient application of core PC skills (pain management [n = 113, 83%], nonpain symptom management [n = 117, 86%], depression/anxiety [n = 107, 79%], goals of care [n = 92, 68%]). The remaining three covered discrete topics related to pain and opioid management, including best practices for caring for patients with comorbid pain and substance use disorder (n = 104, 76%). CONCLUSION/CONCLUSIONS:This national survey identified foundational outpatient-focused educational topics for HPM learners and suggests that outpatient curricula prioritize deliberate education on the unique application of core PC skills in outpatient settings. This prioritized list provides education leaders a roadmap to enhance existing curricula and informs the development of outpatient educational resources that can be shared across institutions.

PURPOSE/OBJECTIVE:To describe the first successful whole eye transplantation (WET) in a human, performed with concurrent partial face transplantation, and to characterize postoperative outcomes. DESIGN/METHODS:Case report. PARTICIPANT/METHODS:A 46-year-old male with severe facial and ocular deficits following high-voltage electrical injury, including left eye enucleation and extensive soft tissue and aesthetic deformities. METHODS:Comprehensive preoperative evaluation, precise microsurgical techniques including vascular anastomosis and optic nerve coaptation, and serial postoperative assessments with optical coherence tomography (OCT), fluorescein angiography (FA), electroretinography (ERG), and visual evoked potentials (VEP). MAIN OUTCOME MEASURES/METHODS:Sustained globe viability, vascular perfusion, retinal structural integrity, and electrophysiological function. RESULTS:The transplanted globe demonstrated robust vascular perfusion and structural preservation over 12 months. Outer retinal function was maintained, as indicated by ERG, despite retinal nerve fiber layer loss and optic nerve transection. VEP confirmed absence of visual perception. The procedure achieved substantial aesthetic restoration. CONCLUSIONS:This study establishes the feasibility of WET in humans, with sustained globe viability and preserved outer retinal function. These findings serve as a critical step toward future exploration of ocular transplantation.

BACKGROUND:Motivational text messages can encourage increased physical activity. This study aimed to validate motivational text messages among older adults and care partners and to assess differences in perceived motivational value between the two groups. METHODS:We designed nine motivational text messages to capture nine distinct physical activity scenarios. For this cross-sectional observational study, we enrolled 14 content experts, 310 older adults, and 305 care partners. Content experts assessed the relevance, while the older adults and care partners assessed the perceived motivational value of each text message on a 5-point Likert scale. We computed the item content validity index and assessed differences in perceived motivational value among older adults and care partners using quantile regression while adjusting for sociodemographic and health characteristics. RESULTS:The item content validity index ranged from 0.86 to 1.00. The median (interquartile range) perceived motivational value for each text message was 4.0 (3.0-5.0), and there were no statistically significant differences in reported motivational values between older adults and care partners. CONCLUSION/CONCLUSIONS:We present nine content-validated text messages with high motivational value for older adults and care partners that can be integrated into technology-based intervention studies and may improve physical activity behavior in both groups.