Faculty Bibliography

OBJECTIVE/UNASSIGNED:Surgical education guided by Halsted's, "see one, do one, teach one," model leans heavily on an apprenticeship structure since formalization of surgical education in the 1890s. While the sentiment holds true, surgical education must adapt with evolution of medicine, work hour restrictions, exponential increase in knowledge, and technological advances. DESIGN/UNASSIGNED:A longitudinal course grounded in adult learning theories was curated to cultivate knowledge in surgery residents on imaging-based liver anatomy and operative approaches, techniques, and decision making. PARTICIPANTS/UNASSIGNED:Junior surgical residents (PGY2-3) in dedicated research time at the Surgical Oncology and Immunotherapy Clinical Research Fellowship Programs of the NIH. RESULTS/UNASSIGNED:Nineteen participants demonstrated significant improvement in all metrics assessed. Overall pre-course knowledge scores (52.1%, 95%CI [48.2%, 56%]) significantly increased in post-course evaluations (87.7%, 95%CI [85.1%, 90%], p<0.0001), maintaining significance in individual course score comparisons. Confidence improved across all disciplines from 2.49 to 2.99 points (5-point Likert scale) (p<0.0001). Significance was maintained in subgroup analysis of individual skills (anatomic delineation (2.93 to 3.51), technical approach (2.39 to 2.83), and decision-making (2.17 to 2.65), (p<0.0001)). Participants reported positive feedback regarding content and course structure which guided real-time course augmentation. CONCLUSION/UNASSIGNED:This course represents a feasible educational model highlighting potential of a theory-based curriculum to enhance surgical education. Emphasizing adult learning theories can support deeper learning and advance critical thinking in trainees.

BACKGROUND:Care coordination between primary care providers and nephrologists is crucial for preemptive kidney transplantation (KT), which confers health advantages over KT after dialysis. Residence in areas with limited primary care (Medically Underserved Areas [MUAs]/Health Professional Shortage Areas [HPSAs]) and nephrology access may differentially affect preemptive listing/KT. OBJECTIVE:To quantify access to preemptive KT by residence in limited primary care/nephrology access areas. DESIGN/METHODS:Retrospective cohort study from the US national registry. PARTICIPANTS/METHODS:A total of 353,636 adult KT candidates (age ≥ 18) listed between 2005-2020. EXPOSURES/METHODS:ZIP-code level MUA and HPSA information (HRSA), and distance to nearest nephrologist (CMS; urbanicity-specific thresholds for "far" from nephrologists: suburban, > 5.8 km; urban, > 2.3 km; small town, > 19.4 km; rural, > 25.2 km). MAIN MEASURES/METHODS:Poisson regression with robust variance estimator quantified adjusted prevalence ratios (aPRs) of preemptive listing, and cause-specific hazards models quantified adjusted hazard ratios (aHRs) of preemptive KT by MUAs/HPSAs/distance to nephrologists. Interaction terms quantified differences in the aforementioned associations by race and ethnicity/neighborhood urbanicity/socioeconomic determinants. KEY RESULTS/RESULTS: < 0.05). Lastly, there were no associations between distance to nephrologists and preemptive listing/KT. CONCLUSIONS:Limited primary care access may impede KT access. Greater investment in primary care within MUAs/HPSAs, addressing geographic/linguistic barriers, and improved nephrology care coordination may increase transplant equity. CLINICAL TRIAL NUMBER/BACKGROUND:Not applicable.

The molecular mechanisms behind Dengue virus-dependent host pathogenesis, especially genome instability, remain largely unclear. This RNA virus causes a debilitating disease during active infection and presents future risks of postdengue syndromes, leukemia, and DNA damage in the blood cells of infected patients, with the underlying mechanisms unknown. In this study, we show that DENV-4 infection induces significant DNA damage and suppresses the transcription of genes involved in DNA repair and select mutagenic translesion synthesis (TLS) polymerases, indicating that DENV-4-dependent pathobiology leaves durable biological "scars" that incrementally increase chronic disease risk, including carcinogenesis and postdengue syndromes.

OBJECTIVE:The quality of discharge processes impacts adverse outcomes post hospitalization for children with medical complexity (CMC). Perspectives of caregivers at risk for communication challenges (eg, non-English speakers, those with limited health literacy, immigrants) on understandability and feasibility of discharge instructions for CMC are understudied. Our objective was to explore their perspectives on barriers and facilitators to comprehension and implementation of discharge instructions for CMC. PATIENTS AND METHODS/METHODS:In this qualitative, descriptive study, we used maximum variation sampling to enroll caregivers of CMC (N = 40) discharged from acute or intensive care units of 2 urban hospitals. English- and Spanish-speaking caregivers of CMC (Pediatric Medical Complexity Algorithm) aged 18 years or older and discharged on 1 or more daily medications were eligible. We conducted semistructured interviews, audio-recorded and transcribed interviews, and performed content analysis. Two team members applied codes from a codebook (developed based on prior literature and preliminary analyses) and identified emerging themes. RESULTS:Equal numbers of participants spoke English and Spanish (n = 20 per language) and were recruited from each hospital (n = 20 per hospital). Half (47.5%) had low health literacy; 85% were of non-US birth. Themes emerged across 4 categories: (1) clinician and medication access; (2) patient- and family-centered approaches to discharge planning and education; (3) caregiver prior experience; and (4) resources and support systems. CONCLUSIONS:Caregivers identified barriers and facilitators affecting discharge plan comprehension and implementation. Optimizing postdischarge care for CMC is complex and requires family-centered, language-concordant, and health literacy-informed processes. Future interventions should focus on systems-level changes that enhance access and account for caregiver perspectives.

In the phase 3 randomized controlled trial (RCT; NCT03355209) of fenfluramine in Lennox-Gastaut syndrome (LGS), patients in fenfluramine treatment groups (0.2 mg/kg/day, 0.7 mg/kg/day) experienced greater reduction from baseline in frequency of seizures associated with a fall versus placebo, which was sustained in the open-label extension (OLE) study (NCT03355209). In this post hoc analysis, trajectories of fenfluramine effectiveness and safety, along with dose changes over time, are described for patients with LGS randomized to placebo in RCT who switched to fenfluramine in OLE (PBO-FFA) and those who received fenfluramine in both RCT/OLE (FFA-FFA). Among patients who completed 12 months in OLE (N = 151), numerical improvements in effectiveness outcomes were seen in the PBO-FFA group (n = 59) after initiating fenfluramine and were similar to those in the FFA-FFA group (n = 92). Regression to the mean was not observed in the PBO-FFA group, suggesting that changes were due to fenfluramine. Incidence of the most commonly reported treatment-emergent adverse events increased in the PBO-FFA group after fenfluramine initiation but decreased in the FFA-FFA group in OLE. These data demonstrate rapid improvement in seizure frequency and global functioning in both groups with continued clinical improvement as the mean fenfluramine dose was increased. These results confirm that sustained fenfluramine treatment is effective and tolerable. PLAIN LANGUAGE SUMMARY: This study assessed the change over time in the number of seizures, overall improvement, and side effects in patients with LGS receiving placebo (no active medicine) or fenfluramine in a 14-week study; all patients later received fenfluramine in the extension study. Overall, the number of seizures (associated with a fall) decreased once patients initially receiving placebo changed to fenfluramine (optimal effect around Month 4 while receiving a higher dose), but as expected, common side effects were reported more frequently once patients began fenfluramine treatment. Patients, parents, and doctors should be aware of this time course to allow fenfluramine enough time to work.

Study DesignConsensus-based classification development utilizing a modified Delphi process.ObjectivesTo develop a practical, standardized classification system to quantify surgical invasiveness in minimally invasive degenerative lumbar spine procedures.MethodsAn international panel of 45 spine surgeons from the AO Spine Knowledge Forum - Degenerative participated in a three-stage, modified Delphi consensus process. First, candidate determinants of invasiveness were identified through evaluation of existing indices and literature review, then refined through iterative expert rounds. The scale was applied to standardized case scenarios, with internal review by the AO Spine Knowledge Forum - Degenerative and external review by the AO Spine MISS Task Force. Finally, a consensus survey reached ≥75% agreement on all final factors for inclusion in the grading scale.ResultsThe final classification system included nine factors: operative time, number of approaches, blood loss, instrumentation, muscle dissection/access, anesthesia, number of levels, fusion technique, and revision status. Consensus was achieved on all components of the scale following iterative refinement. Each factor was scored from 0 (least invasive) to 2 (most invasive), generating a cumulative invasiveness score. Application of the scale across representative procedures demonstrated a spectrum ranging from least invasive (endoscopic 1-level discectomy) to most invasive (thoracic-to-pelvis fixation). Procedures were stratified into minimally invasive, less invasive, and more invasive categories.ConclusionsMISS-INC (L) is a proposed, consensus-based classification that quantifies surgical invasiveness among minimally invasive lumbar spine procedures. It offers a user-friendly framework for communication, research, and patient counseling, with further validation against clinical outcomes representing an important next step.

INTRODUCTION/BACKGROUND:Craniopharyngioma is histologically benign yet locally aggressive, with frequent recurrence. Long-term multicenter outcomes after stereotactic radiosurgery (SRS) remain incompletely defined. METHODS:We performed a retrospective multi-institutional cohort study through the International Radiosurgery Research Foundation including 296 patients from 13 centers. Median age at first SRS was 33.6 years. Median tumor volume was 1.32 cm³ and median margin dose was 12.0 Gy. The primary endpoint was local control (LC); secondary endpoints were progression-free survival (PFS) and overall survival (OS). Kaplan-Meier methods estimated outcomes, and Cox proportional hazards models evaluated predictors of LC. RESULTS:Actuarial 1-, 5-, and 10-year LC was 93.5%, 76.2%, and 70.1%. Actuarial 1-, 5-, and 10-year OS was 98.2%, 93.6%, and 85.2%, and PFS was 92.4%, 73.6%, and 64.8%. Mixed solid-cystic phenotype had worse LC than non-mixed tumors (log-rank p = 0.025); non-mixed phenotype remained independently associated with improved LC (HR 0.53, p = 0.026). Visual fields improved in 10%, were unchanged in 86%, and deteriorated in 4%; visual acuity improved in 6%, was unchanged in 91%, and worsened in 3%. Ten-year freedom from endocrine deterioration was 96.7%. Diabetes insipidus improved in 6.3%, worsened in 0.5% and other pituitary dysfunction was noted in 2.6%, CONCLUSION: In this international multi-institutional experience, SRS achieved durable long-term control with favorable survival and low incidence of visual and endocrinologic dysfunction. Mixed phenotype was an important determinant of LC. CLINICAL TRIAL NUMBER/BACKGROUND:Not applicable.

UNLABELLED:Diffuse large B-cell lymphomas (DLBCL) are genetically and phenotypically heterogeneous, making diagnosis and treatment challenging. Current models suggest DLBCLs derive from follicular B cells engaged in adaptive immune responses. By studying cooccurring truncating mutations in SPEN and NOTCH2 in the BN2-DLBCL subtype, our data suggest a previously unrecognized extrafollicular trajectory. Using animal models and human specimens, we find that this cooperative mutational axis supports expansion of putative clonal precursors with features of marginal zone, memory, and a distinct, autoimmune B cell-like state. This trajectory is associated with sex-biased outcomes: Female patients and mice exhibit reduced survival compared with males in our cohorts. Further analysis links this disparity to enhanced X-chromosome-linked expression and functionality of Toll-like receptor signaling. We show that IRAK inhibition represents a potential sex-specific therapeutic strategy in preclinical models. These findings support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy. SIGNIFICANCE/UNASSIGNED:The findings in this article support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy.

Withania somnifera (L.) Dunal, commonly known as ashwagandha, has been widely used in Ayurvedic medicine for its adaptogenic properties and therapeutic potential and has been investigated for its benefits related to sleep and stress management by Western medicine. However, concerns regarding its teratogenic and abortifacient effects have emerged following reports from the World Health Organization (WHO) and regulatory bodies. This systematic and ethnobotanical review critically evaluates these claims by assessing ashwagandha's toxicokinetics, toxicodynamics, and available safety data. A comprehensive literature review following PRISMA guidelines was conducted to identify studies on its reproductive toxicity, molecular interactions, and traditional usage. Historical ethnobotanical reports suggest potential abortifacient effects, but citation distortion and lack of primary source validation raise concerns regarding the validity of such claims. Toxicological studies in animal models demonstrate high tolerability, with no significant reproductive toxicity observed at doses relevant to human consumption. Human clinical studies also show no adverse effects on thyroid function, hormonal balance, or reproductive health. Altogether, evidence supporting significant teratogenic or abortifacient activity remains inconclusive. This review highlights the need for standardized, high-quality research addressing fertility and developmental outcomes in controlled conditions. Given the widespread use of ashwagandha as a dietary supplement ingredient and traditional medicine, a balanced and evidence-based approach is required to assess its safety, ensuring that regulatory actions are informed by robust scientific data rather than historical speculation.

BACKGROUND/UNASSIGNED:The American Heart Association Predicting Risk of Cardiovascular Disease EVENT (PREVENT) equations were developed from observational research cohorts and electronic health record data and provide sex-specific risk estimates for cardiovascular disease (CVD), atherosclerotic CVD (ASCVD), and heart failure (HF). External validation in large contemporary samples across multiple health systems in the United States is needed. METHODS/UNASSIGNED:We assembled a national electronic health record-based cohort of US adults with individual-level patient data pooled from a collective of 30 health systems (Truveta) to externally validate the outcome-specific 10-year PREVENT equations (PREVENT-CVD, PREVENT-ASCVD, and PREVENT-HF). We included patients aged 30 to 79 years without a history of prior CVD and with an ambulatory encounter in the electronic health record between 2013 and 2018. The outcomes were defined as total CVD (composite of ASCVD and HF), ASCVD, and HF through December 2024 using diagnosis codes. Model performance of the outcome-specific PREVENT base equations was assessed with the Harrell C statistic and calibration slope, stratified by sex. RESULTS/UNASSIGNED:Of the 680 864 adults included, the mean (SD) age was 55 (13) years, and 56% were female. Over a mean (SD) follow-up of 6.8 (2.3) years, there were 29 535 incident CVD events, 19 280 incident ASCVD events, and 16 824 incident HF events. The median (interquartile range) 10-year predicted risk of PREVENT-CVD among women was 3.6% (1.3%-8.8%), and among men was 5.8% (2.5%-11.7%). The C statistic (95% CI) was 0.788 (0.786-0.790), and the calibration slope (95% CI) was 0.98 (0.95-1.01) for PREVENT-CVD. PREVENT-ASCVD and PREVENT-HF demonstrated similar C statistics (0.774 [0.771-0.777] and 0.824 [0.820-0.828]) and calibration slopes (1.07 [1.04-1.10] and 1.01 [0.97-1.04]) for prediction of the 10-year risk of ASCVD and HF, respectively. CONCLUSIONS/UNASSIGNED:The PREVENT equations accurately and precisely estimate the 10-year risk of CVD, ASCVD, and HF in a large sample of US adults. These findings support the generalizability of the PREVENT equations to inform guideline-recommended risk assessment and preventive efforts.