Publications by Year: 2026

Heart failure care has advanced, yet outcomes remain inconsistent and clinical deterioration is still recognized too late. Traditional artificial intelligence has evolved from rule-based, predictive, to generative and generally operates at the population level. Thus, it cannot keep pace with the rapidly shifting physiologic states that define heart failure. Digital twin technology offers a decisive shift: a continuously calibrated, mechanistically grounded computational replica of an individual patient that integrates multimodal physiologic, imaging, clinical, molecular, and behavioral data. Anchored in physics-informed models and paired with advanced artificial intelligence layers, the digital twin functions as a real-time simulator rather than a static predictor. It enables 4 transformative applications: early physiologic instability forecasting, virtual comparator control arms for pragmatic trials, mechanism-anchored phenotyping, and system-level resource optimization. If built with rigor, equity, and transparent validation, digital twins can transition heart failure care from reactive management to anticipatory, individualized, and mechanistically informed decision-making, bringing long-sought precision to this complex syndrome. Yet, this staged translation will require responsible, evidence-based implementation and precise recognition of limitations.

PURPOSE: Nutrition education remains limited in medical training, prompting recent national policy proposals for reform. Our intention was to assess the feasibility of implementing a condensed online nutrition course within the curriculum at Harvard Medical School and explore its influence on students' understanding of nutrition in clinical practice.

METHODS: A condensed online clinical nutrition course developed by the nonprofit Gaples Institute was integrated into the Health Sciences & Technology track curriculum at Harvard Medical School. Four module knowledge assessments and written reflections ("Aha! Moments") were required. Qualitative analysis of reflections used thematic analysis to identify recurring patterns of meaning.

RESULTS: All students (n = 56) successfully completed the course, meeting the ≥ 80% passing threshold on each module assessment and submitting all reflections. Qualitative analysis identified three key themes: 1) deeper understanding of the impact of dietary factors on patient care and the social determinants of this relationship, including dispelling misinformation and appreciating the scale of dietary impacts; 2) greater sense of agency to integrate nutrition counseling into clinical practice; and 3) increased motivation to adopt healthier personal dietary habits. Over 75% of students completed the course in under 3 hours.

CONCLUSIONS: These findings highlight the feasibility of enhancing nutrition education in medical school despite curricular time constraints. The results describe a practical model that can inform efforts to advance nutrition training in medical education and help prepare physicians to address the burden of diet-related disease.

INTRODUCTION: Aerobic exercise and cold exposure modulate lipid mediator production, which may optimize physiological resilience. The Yukon Arctic Ultra (YAU), a 692-km self-provisioned multiday endurance event, offers a unique opportunity to examine lipidomic adaptations to nutrients and environmental and physical stress. This study aimed to identify lipid mediators responsive in YAU athletes compared to control participants.

METHODS: Nine athletes and six controls were recruited from the 2017 and 2019 YAU events. Targeted liquid chromatography-tandem mass spectrometry/mass spectrometry-based signaling lipidomic analysis was conducted on serum samples collected from participants at pre-event, during the event, and post-event time points.

RESULTS: Athletes and controls did not differ significantly in age, body mass index (BMI), fat mass index (FMI), or fat-free mass index. During the event, athletes exhibited significant reductions in BMI, fat mass, and FMI, whereas no changes were observed in controls. Athletes showed higher baseline levels of anti-inflammatory oxylipins, including resolvin D2 and lipoxin A4 (LXA4), and lower levels of the pro-inflammatory leukotriene E4 compared to controls. Linoleic acid- and α-linolenic acid-derived oxylipins were also elevated in athletes. Notably, these anti-inflammatory lipids remained elevated throughout the event. Certain hydroxy-eicosapentaenoic acids demonstrated a declining trend during the event in athletes.

DISCUSSION: YAU athletes exhibit a distinct lipidomic signature marked by persistently elevated anti-inflammatory oxylipins, likely reflecting a complex interplay between adipose tissue and skeletal muscle. Overall, the oxylipin shifts point to anti-inflammatory and thermogenic adaptations that support physiological resilience during physical, nutrient, and environmental stress in austere circumstances.

BACKGROUND: CD19-directed chimeric antigen receptor T-cell therapy (CD19-CAR) has yielded encouraging efficacy in CNS lymphomas (CNSL), but most patients ultimately experience progressive disease (PD). Risk factors, progression patterns as well as optimal salvage therapies remain unclear.

METHODS: Clinical and radiological characteristics of CD19-CAR failure were therefore retrospectively defined in CNSL treated at Massachusetts General Hospital from 2018 to 2024. PD patterns were defined as local or distant. CNS-progression-free survival from CD19-CAR infusion (CNS-PFS1) and first subsequent progression (CNS-PFS2) were analyzed.

RESULTS: CD19-CAR achieved a 60% overall response rate (45% complete (CR), 15% partial response) in 60 recurrent CNSL. Median CNS-PFS1 was 4 months with radiographic PD in 36 patients (local 23.3%; local and distant 16.7%; distant 20%). PD patterns were associated with prior CD19-CAR response: Distant relapse typically occurred after CR whereas local PD followed CD19-CAR refractory disease. Peripherally contrast enhancing CNSL (pCE) at CD19-CAR infusion correlated with refractory disease. Leptomeningeal involvement (LMD) was associated with recurrence after CR. On multivariable Cox regression, pCE (Hazard ratio [HR]: 2.75; 95%-Confidence interval [CI]: 1.08-6.68, p = 0.03) and LMD (HR: 2.72; CI: 1.20-6.25, p = 0.02) were independently associated with shorter CNS-PFS1. At progression, peripheral CD19+-B-cell aplasia suggested CD19-CAR persistence in 93% of patients. Median CNS-PFS2 after CD19-CAR failure was one month. Salvage immune checkpoint inhibition, and lenalidomide with rituximab/tafasitamab yielded prolonged responses.

CONCLUSIONS: This study identifies novel radiological risk factors for CD19-CAR failure in CNSL, namely pCE and LMD. Outcome in this setting is unfavorable and encouraging salvage treatments warrant prospective evaluation.

BACKGROUND: Genioplasty and chin-augmentation are well-established procedures aimed at enhancing lower facial aesthetics. Traditionally, aesthetic outcomes have been assessed subjectively through expert opinions and patient-reported measures. The integration of artificial intelligence (AI) offers an objective approach to evaluating surgical results. This study utilizes the ICA Aesthetic Navigation AI Research Metrics Model (ICAAN® ARMM) to analyze postoperative changes in facial attractiveness, youthfulness, and skin quality following genioplasty.

METHODS: Pre- and postoperative full-frontal images of 50 patients undergoing osseous genioplasty were analyzed using the ICAAN® ARMM. Therefore, an array of three aesthetic scores, the Facial Aesthetic Index (FAI), Facial Youthfulness Index (FYI), and Skin Quality Index (SQI), were measured before and after surgery, with subgroup analyses by age, sex, and ethnicity. Minimally clinically important differences (MCIDs) were estimated.

RESULTS: All three aesthetic scores demonstrated improvement postoperatively, with FAI showing the greatest increase (82 (73-89) to 85 (75-92); p = 0.296), without showing statistical significance. Older patients (≥ 35 years) exhibited greater improvements in FAI scores compared to younger individuals (4 (1-10) vs. 1 (- 3-5); p = 0.028). Sex-related trends were observed, while lacking statistical significance. Ethnic subgroup analysis revealed no differences in score changes, suggesting cross-cultural applicability. Observed improvements did not exceed estimated MCIDs.

CONCLUSION: AI-assisted aesthetic analysis offers a novel, contemporary, and objective method for assessing genioplasty outcomes. While our study suggests general aesthetic improvements following surgery, further research incorporating larger data collections and subjective patient-reported measures is necessary. AI tools hold promise as a complementary tool in aesthetic medicine, supporting both clinicians and patients in surgical decision-making.

LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

SOS/VOD is a life-threatening complication of hematopoietic stem cell transplantation, especially in children, with incidences reaching up to 15-20%. Despite efforts, SOS/VOD remains unpredictable with significant morbidity and mortality. High-risk criteria are clearly defined, and the pediatric EBMT diagnostic criteria have improved sensitivity, reducing treatment delays and enhancing outcomes. A meta-analysis combining retrospective and prospective studies found a risk ratio of 0.30 for SOS/VOD with defibrotide (DF) prophylaxis. Additionally, two prospective trials were conducted: the pediatric prevention trial (NCT00272948) and the Harmony Trial (NCT02851407), involving adults and children, with primary outcomes of incidence and SOS/VOD-free survival, respectively. The trials produced conflicting results regarding the effectiveness of prophylactic DF. Despite significant limitations of the Harmony trial, a direct healthcare professional communication (DHPC) from the European Medicines Agency (EMA) advised against prophylactic DF. This recommendation has serious consequences for children, especially infants, who are among the most vulnerable groups receiving HSCT. Therefore, a panel of experts issued guidelines for children at high risk for SOS/VOD, in which DF prophylaxis is considered justified. These guidelines include a weighted scoring system based on all relevant high-risk criteria to predict SOS/VOD, supporting decisions regarding the use of prophylactic DF in children.

Gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to oncometabolite (R)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for IDH1-mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H is uniquely autopalmitoylated at C269, which is not observed in wild-type IDH1. This modification responds to fatty acids and regulates R132H enzymatic activity by enhancing substrate and cofactor binding, as well as dimerization. Loss of C269 palmitoylation reverses IDH1-R132H-induced metabolic reprogramming and hypermethylation phenotypes and impairs cell transformation. Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1R132H mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers.