Faculty Bibliography

BACKGROUND/UNASSIGNED:Mal de débarquement syndrome (MdDS) is a chronic vestibular disorder of non-spinning vertigo, with various somatic, cognitive, and affective symptoms. The manifestation of MdDS is often only subjective, and different symptoms are variably emphasized when patients appraise the severity of their illness. The etiology of MdDS remains unclear but may lie in improperly sustained neuroplasticity in the velocity storage mechanism of the central vestibular system. Two broad approaches targeting velocity storage-one focusing on correcting velocity storage's maladapted behavior and the other on attenuating its contribution to higher-order processing-have yielded varying degrees of treatment success. METHODS/UNASSIGNED:We conducted a secondary analysis of data from our recent study contrasting the outcomes of the above two approaches. We examined the variations in individual emphases of separate symptoms by correlating the subjective ratings of overall MdDS severity with those of specific symptoms across time points for each subject. We also explored the possibility that variations in symptom presentation influence the responsiveness to the two approaches of treatment. RESULTS/UNASSIGNED:Many symptoms correlated with the overall severity rating, but even those that showed strong correlation among many subjects, such as dizziness, fatigue, and brain fog, were endorsed variably across subjects. A moderate unfavorable dependence on visual sensitivity was found for the responsiveness to the velocity storage attenuation treatment, which distinguished the two treatment approaches. CONCLUSION/UNASSIGNED:Results provide a glimpse into the complexity of MdDS manifestations. Individual variations in what contributes to their perceived overall symptom severity may aid the choice of treatment approach.

BACKGROUND/UNASSIGNED:Vascularized composite allotransplantation (VCA) restores form and function in patients with severe disfigurement, yet acute rejection remains common within the first year. In solid organ transplantation, rituximab, a B cell-depleting agent, has been shown to reduce rejection in highly sensitized recipients, and donor-specific antibodies (DSAs) are established biomarkers of rejection. The impact of rituximab and DSAs in VCA remains unclear. This study examined rejection-free survival following rituximab induction and the relationship between positive DSA levels and rejection in VCA recipients. METHODS/UNASSIGNED:This retrospective review analyzed 4 patients who underwent facial transplantation between 2015 and 2023 at our institution. All patients received rituximab and antithymocyte globulin as part of their induction immunosuppression. Rejection-free survival was the primary outcome, with DSA levels assessed at baseline and throughout follow-up. A generalized linear mixed-effects model was used to evaluate the relationship between DSA positivity and rejection. RESULTS/UNASSIGNED:= 0.693). Some patients were DSA-negative during clinical rejection, and some were DSA-positive without signs of rejection. CONCLUSIONS/UNASSIGNED:This is the first study to evaluate rituximab-based induction in a cohort of VCA recipients, demonstrating median rejection-free survival exceeding one and a half years. Although some patients were DSA-positive during rejection episodes, no significant correlation was observed, challenging the predictive value of DSAs as seen in solid organ transplantation and highlighting the need to explore alternative biomarkers for rejection in VCA.

BACKGROUND:Gastroparesis is a chronic disorder characterized by delayed gastric emptying without mechanical obstruction, significantly impacting patient quality of life. Management of refractory gastroparesis remains challenging, with both gastric electrical stimulation (GES) and prokinetic medications used as treatment options. This systematic review synthesizes the available evidence on GES clinical outcomes, the role of continued prokinetic therapy after GES, and indirect comparative data relevant to symptom management in adult patients with refractory gastroparesis. METHODS:A comprehensive systematic review was conducted following PRISMA guidelines. Multiple databases were searched for studies published between 2000 and 2011 focusing on GES for gastroparesis. This window was selected to capture the period from initial FDA Humanitarian Device Exemption approval of the Enterra system (2000) through publication of cohorts with mature, multi-year follow-up (up to 10 years), maximizing the durability evidence available for analysis. Inclusion criteria required adult patients with refractory gastroparesis, GES as primary intervention, symptom-related outcomes, and minimum 6-week follow-up. Eight studies met eligibility criteria with follow-up periods ranging from 6 weeks to 10 years. Quality assessment utilized the Newcastle-Ottawa Scale for cohort studies and Cochrane risk-of-bias tools for controlled trials. RESULTS:Gastric electrical stimulation (GES) demonstrated significant symptom improvement in patients with treatment-resistant gastroparesis. Controlled studies showed vomiting frequency reduction of 57% at 6 weeks, improving to 67.8% after one year (p < 0.001). Long-term data revealed ≥ 50% reduction in Total Symptom Scores in 58% of diabetic gastroparesis patients, 53% of post-surgical cases, and 48% of idiopathic gastroparesis patients (p < 0.05) (Fig. 3; Table 2). Combination therapy (GES plus prokinetics) yielded significantly better symptom scores (1.35) compared to GES alone (2.20, p = 0.02). Device-related infection requiring removal occurred in approximately 7% of cases. No direct head-to-head comparisons between GES and prokinetic medications alone were identified. CONCLUSION/CONCLUSIONS:GES provides substantial symptom relief for treatment-resistant gastroparesis, particularly in diabetic gastroparesis. Combination therapy with GES plus prokinetics appears superior to GES monotherapy. However, the absence of direct comparative studies limits definitive conclusions regarding relative effectiveness versus prokinetic medications alone. Future randomized controlled trials are needed to establish optimal treatment protocols and patient selection criteria along with the role of other surgical approaches. Planned next steps include direct comparisons of GES with pyloric-directed interventions - namely gastric per-oral endoscopic myotomy (G-POEM) and surgical pyloroplasty - to clarify the optimal positioning of GES within the contemporary treatment algorithm for refractory gastroparesis.

BACKGROUND/UNASSIGNED:Advancements in surgical techniques and immunosuppressive therapies have transformed care for patients through vascularized composite allotransplantation (VCA). However, lifelong systemic immunosuppression (SI) carries significant risks, specifically during acute rejection (AR), which typically requires increasing SI dosages. Mitigating such risks may be achieved through topical tacrolimus (TT). Although TT shows promise for VCA in preclinical studies, robust clinical data are lacking. This systematic review aims to evaluate the clinical use of TT in VCA. METHODS/UNASSIGNED:A systematic review was performed in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines using Cochrane, PubMed, Scopus, and Web of Science. Studies included patients who underwent VCA and received TT treatment. Study details, patient demographics, VCA characteristics, Banff grade, induction and SI maintenance protocols, complications, AR episodes, and treatment plans following these episodes were collected. RESULTS/UNASSIGNED:The search yielded 271 articles; 11 met inclusion criteria, encompassing 15 VCA recipients (mean age 39.9 y). Thirty-two AR episodes were reported; 22 (68.8%) involved TT. TT was mostly used in Banff grade I-II AR episodes. Resolution occurred in 65.5% of TT-treated episodes, though this finding was not statistically significant. TT was frequently used with steroids and adjunct therapies. CONCLUSIONS/UNASSIGNED:This systematic review highlights the potential role that TT may play in mitigating the need for increased doses of SI during AR episodes. As clinical data continue to grow, further research is essential to establish the potential benefits and efficacy of TT use in VCA.

Squamous cell carcinomas (SCCs) are common epithelial malignancies frequently associated with EZH2 upregulation, which correlates with aggressive growth and poor prognosis. EZH2 functions as the catalytic subunit of Polycomb repressive complex 2 (PRC2), which deposits the repressive H3K27me3 histone mark, yet PRC2 function in SCC pathogenesis remains unresolved. Here, we uncover a paradox: although EZH2 is elevated, the PRC2-catalyzed H3K27me3 is profoundly reduced in human SCC and complementary murine models. Mechanistically, we identify that oncogenic Ras signaling causes degradation of the PRC2 subunit EED, destabilizing PRC2 and depleting H3K27me3. Loss of EED reprograms keratinocytes into an aggressive tumor-specific cell state and induces paracrine factors that remodel the tumor microenvironment, driving metastasis. Remarkably, reintroducing EED suppresses tumor growth via restoring PRC2 integrity and H3K27me3 levels, revealing the reversibility of this epigenetic collapse. These findings link oncogenic signaling to epigenetic reprogramming and uncover PRC2 reconstitution as a potential therapeutic option in epithelial cancers.

BACKGROUND/UNASSIGNED:Librarians providing feedback on Evidence-Based Medicine (EBM) assignments face time constraints. This case report describes implementing a semi-automated rubric - defined here as a tool that automatically calculates scores from grader-selected ratings while narrative feedback is still written by the instructor - to reduce grading time for an EBM capstone assignment for first-year medical students. CASE PRESENTATION/UNASSIGNED:Two cohorts of approximately 100 students completed the same EBM assignment. The 2023 cohort received manual feedback, while the 2024 cohort received feedback using the semi-automated rubric. Grading time was logged for both cohorts. The rubric, adapted from a template, automatically calculates scores based on selected criteria, streamlining the feedback process. CONCLUSIONS/UNASSIGNED:The semi-automated rubric reduced grading time by 30%, from an average of seven minutes per assignment to five minutes. This simple, adaptable intervention can help reduce educator workload, improve feedback timeliness, and enhance assessment consistency. While limited by its single-grader and single institution design, this case report offers practical insights for educators seeking to improve feedback efficiency in EBM and other disciplines.

PURPOSE/OBJECTIVE:To assess whether adding fluoropyrimidine sensitized radiotherapy (CXRT) to adjuvant chemotherapy improves overall survival (OS) after curative intent resection of the pancreatic head. METHODS:This was a multicenter, randomized phase III, two step trial. Step 1: gemcitabine versus gemcitabine + erlotinib (previously reported). Step 2: random assignment to sixth chemotherapy cycle ± CXRT after five cycles of step 1 chemotherapy without progression. Outcomes of step 2 random assignment are reported here. Assuming 17 months median OS (chemotherapy alone), the sample size was 354 patients (hazard ratio [HR], 0.76, 80% power, one-sided α = .05, 316 OS events). OS/disease-free survival (DFS) were estimated by Kaplan-Meier and arms compared using the log-rank test. RESULTS:= .014) in node-negative patients. CONCLUSION/CONCLUSIONS:Overall, the addition of adjuvant CXRT to adjuvant gemcitabine did not statistically significantly improve OS, DFS, or increase grade 4/5 toxicity. For node-negative patients, CXRT improved OS and DFS. These results, if confirmed in studies with current or future systemic therapies, would support the use of adjuvant/neoadjuvant CXRT for node-negative patients.

The Substance P/neurokinin-1 receptor (SP/NK1R) pathway plays a significant role in several cancers, including pancreatic, breast, glioblastoma, and lung malignancies. This review highlights its involvement in metastasis, angiogenesis, proliferation, resistance, and apoptosis. Aprepitant, an NK1R antagonist and approved antiemetic, shows promising anticancer and protective effects, supporting its use in combination therapies. NK1R-targeted strategies may enhance treatment efficacy while reducing chemotherapy- and radiotherapy-induced toxicities.

Healthcare workers (HCWs) in emergency departments face significant mental health risk due to chronic stressors and repeated trauma, yet symptom underreporting and bias in self-reports hinder accurate assessments. Expressive flexibility, the ability to dynamically modulate and recover from stressor-related changes in emotional arousal as reflected in observable behavior, has been linked to resilience. This NIH-funded study (R01HL156134) utilized digital phenotyping and computer vision to analyze dynamic facial expressivity during video-recorded interviews about work-related stressful situations with 240 HCWs (278 assessments). Participants additionally completed validated questionnaires to assess burnout, PTSD, depression, anxiety, and resilience. Latent profile analysis revealed two clinical phenotypes: At-risk (57.6%) and Resilient/Adaptive (42.4%). Machine learning models demonstrated high classification performance (accuracy = 0.83 ± 0.06, F1-score = 0.87 ± 0.05). Our findings indicate that digital biomarkers of temporal facial dynamics may serve as objective behavioral proxies of expressive flexibility, potentially capturing dynamics consistent with underlying stress-regulatory processes. These findings highlight their potential to improve identification of resilience-related phenotypes and support well-being and mental health in HCWs.