Faculty Bibliography

BACKGROUND:Abdominal wall reconstruction (AWR) carries significant postoperative morbidity, including surgical site infection, wound dehiscence, and readmission. Frailty and sarcopenia have emerged as critical predictors of surgical outcomes; however, their role in AWR is not well defined. We aimed to evaluate the independent and combined predictive value of frailty and sarcopenia proxies on morbidity and mortality after AWR. METHODS:A retrospective analysis using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was conducted from 2015 to 2020. Frailty was assessed using the Modified Frailty Index (mFI-5), and sarcopenia proxies were defined by ≥ 1 validated proxy markers (BMI < 20, > 10% weight loss/malnutrition, hypoalbuminemia, hematocrit < 30%). Propensity score matching (PSM) was performed to create balanced cohorts, and conditional logistic regression on matched pairs was used to evaluate associations between frailty, sarcopenia proxies, and postoperative outcomes. Primary outcomes were 30-day morbidity and mortality. RESULTS:15,466 adult patients undergoing elective AWR were included. Frailty and sarcopenia proxies were present in 19.4% and 11.3% of patients, respectively. After propensity score matching, frailty was associated with increased odds of overall morbidity (OR 1.16, 95% CI 1.01-1.32; p = 0.035), major complications (OR 1.27, 95% CI 1.07-1.52; p = 0.008), and discharge to a non-home facility (OR 1.40, 95% CI 1.09-1.80; p = 0.008). Sarcopenia proxies demonstrated similar associations. The combined frailty and sarcopenia-proxy phenotype (dual-impairment) conferred the highest odds of morbidity, major complications, and discharge to a non-home facility. Thirty-day mortality and operative time did not differ significantly between groups after matching. CONCLUSION/CONCLUSIONS:Frailty and sarcopenia proxies are prevalent among patients undergoing elective AWR and are independently associated with increased postoperative morbidity, with their coexistence (dual-impairment) conferring the greatest risk. Incorporating these factors into risk calculators may improve patient selection, nutritional optimization, and prehabilitation strategies in complex hernia repair.

Platelets are central to hemostasis and thrombosis. Excessive platelet activation contributes to arterial thrombotic events, including myocardial infarction, ischemic stroke, and complications of peripheral artery disease, whereas excessive platelet inhibition increases bleeding risk. Antiplatelet therapy remains a cornerstone of secondary prevention in atherosclerotic and thrombotic cardiovascular diseases, yet current treatment paradigms do not fully account for biological heterogeneity in platelet function, including differences related to sex, age, hormonal status, and disease context. This state-of-the-art review examines current antiplatelet strategies, fundamental mechanisms of signal transduction, clinical indications, and limitations of preclinical and clinical studies, with a focus on sex-specific considerations and opportunities for personalized antiplatelet therapy. Aspirin and P2Y₁₂ receptor antagonists are widely used for secondary prevention. However, women have been underrepresented in many pivotal clinical trials, limiting the precision of sex-specific estimates of efficacy and bleeding risk. In parallel, commonly used preclinical models often fail to recapitulate the physiological conditions in which platelets interact with the vasculature, leukocytes, and soluble factors. Emerging therapeutic approaches seek to refine platelet inhibition by targeting pathways that reduce thrombotic risk while preserving hemostasis. Advancing antiplatelet therapy will require integration of mechanistic platelet biology with diverse clinical trial populations, standardized platelet phenotyping, and disease-specific approaches that account for how platelet function is altered across health and vascular disease.

BACKGROUND:As a 6-month waiting period is required to receive exception points to prioritize patients with hepatocellular carcinoma (HCC) for liver transplantation, prompt addition to the waitlist is critical in access to LT. METHODS:Using Epic Cosmos data on patients with HCC referred for LT 1/2018-10/2024, we used modified Poisson regression to calculate rates of waitlisting. Center-level and individual (socioeconomic, geographic, and insurance) factors were measured among those who progressed. RESULTS:Among 11,422 HCC patients referred for LT at 70 centers, with median age 63 [IQR: 58, 68], 71.5% initiated evaluation and, of those who began evaluation, 57.6% were waitlisted for LT. Of those referred, patients who were older (age 70+ vs. 51-60; RR 0.77, 95% CI: 0.65-0.90, p < 0.001), on Medicaid (0.83, 95% CI: 0.71-0.97, p = 0.02), never-married (0.82, 95% CI: 0.73-0.91, p < 0.001), or low SES (Q4: 0.87, 95% CI: 0.77-0.97, p = 0.002) had lower rates of waitlisting. Among waitlisted patients, median time from referral was 3.3 months [IQR: 2.0, 5.3]. Despite adjustment for patient level covariates, there was high center-level variation in rate of waitlisting within 12 months; 13% of centers listed patients at a rate ≥ 20% below the national median. CONCLUSION/CONCLUSIONS:Only a fraction of referred patients with HCC are waitlisted for LT. High variation in access to waitlisting based on non-clinical factors suggests barriers to waitlisting that must be addressed. Centers should focus on interventions to reduce barriers to waitlisting in patients with HCC.

BACKGROUND:Transcranial photobiomodulation (t-PBM) with near-infrared light stimulates mitochondria and may have antidepressant effects. We evaluated dose-dependent effects of t-PBM on the hemodynamic blood-oxygenation-level-dependent (BOLD) power in major depressive disorder (MDD). METHODS:. t-PBM (808 nm) was delivered to the prefrontal cortex, bilaterally. fMRI was recorded at 3T before, during, and after t-PBM. We used mixed-effects linear regression to evaluate changes in BOLD power during stimulation, compared to sham. The analysis was repeated for the middle frontal gyrus (MFG), the prefrontal areas irradiated by t-PBM, and the entire brain cortex. RESULTS:We found similar results in the MFG, the prefrontal cortex directly irradiated, and the entire brain cortex: medium dose t-PBM was associated with a statistically significant increase in BOLD power, whereas low dose t-PBM was associated with a significant decrease in BOLD. There were no significant changes in BOLD power with the high (pulsed) t-PBM dose or with sham. Single administrations of any t-PBM dose did not result in significant changes in depression severity (versus sham). All 3 t-PBM doses were well tolerated. CONCLUSION/CONCLUSIONS:The acute effect of t-PBM on the hemodynamic BOLD power is robust, dose-dependent, bidirectional, and extends beyond the areas directly illuminated. These findings may provide a reference for future dose selection and clinical efficacy studies. CLINICALTRIALS/RESULTS:GOV: NCT04366258.

IMPORTANCE/UNASSIGNED:Hispanic and non-Hispanic Black (hereafter, Black) children with acute myeloid leukemia (AML) have historically experienced worse survival outcomes compared with non-Hispanic White (hereafter, White) children. Understanding specific intermediate pathways underlying these outcome disparities is a critical step to directing interventional efforts and resources. OBJECTIVE/UNASSIGNED:To compare survival outcomes by race and ethnicity in a large contemporary cohort of pediatric patients with AML and to examine presentation acuity, frontline organ toxic effects, and relapse as potential mediators of any observed outcome disparities. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This retrospective cohort study was analyzed from April 2025 to January 2026 and included 13 US children's hospitals across 10 states participating in the Real-World Epidemiology of Acute Leukemia-AML cohort. Participants included children treated for de novo AML from January 2011 through May 2024. EXPOSURE/UNASSIGNED:Race and ethnicity (Black, Hispanic, and White). MAIN OUTCOMES AND MEASURES/UNASSIGNED:The main outcome was overall survival (OS), defined as the time from AML diagnosis until death from any cause. RESULTS/UNASSIGNED:The study cohort included 773 children (median [IQR] age, 9 [2-14] years; 402 males [52.0%]), of whom 125 (16.2%) were Black, 237 (30.7%) were Hispanic, and 411 (53.2%) were White (median [IQR] follow-up, 51.2 [25.7-86.9] months), treated for de novo AML. Among the patients, Black (5-year OS, 61.1% [95% CI, 52.6%-71.0%]; adjusted hazard ratio [AHR], 1.55 [95% CI, 1.26-1.91]) and Hispanic (5-year OS, 65.4% [95% CI, 58.9%-72.5%]; AHR, 1.32 [95% CI, 1.03-1.68]) children had worse OS compared with White children (5-year OS, 70.0% [95% CI, 65.2%-75.1%]). Compared with White patients, Black patients had increased risk of higher cardiovascular (adjusted risk ratio [ARR], 2.09 [95% CI, 1.23-3.56]), respiratory (ARR, 1.36 [95% CI, 1.05-1.77]), and renal (ARR, 3.08 [95% CI, 1.02-9.32]) acuity at presentation. There were no statistically significant increases in severe frontline organ toxic effects or relapse rates by race and ethnicity. Cardiovascular acuity (AHR, 1.83 [95% CI, 1.51-2.22]) and respiratory acuity (AHR, 1.43 [95% CI, 1.15-1.77]) at presentation were independently associated with all-cause mortality. Cardiovascular acuity (proportion mediated, 14%) and respiratory acuity (proportion mediated, 8%) at presentation partially mediated the total absolute survival difference between Black and White children. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study of pediatric patients with AML, differential cardiovascular and respiratory acuity at presentation were partial mediators of outcome disparities for Black children with AML. Other intermediates along the care continuum should be identified to account for the remainder of the observed outcomes and to prioritize focus areas for interventional efforts to mitigate the survival differences.

Cryo-electron tomography (cryo-ET) has emerged as a transformative technique for visualizing the native ultrastructure of eukaryotic parasites, from proteins to cellular architecture. Recent technical advances in sample preparation, data collection, and computational analysis have enabled unprecedented insights into structural cell biology of medically important pathogens including Toxoplasma gondii, Plasmodium falciparum, Trypanosoma brucei and Trypanosoma cruzi, Cryptosporidium parvum, and Microsporidia. This review highlights the range of resolutions and cellular structures accessible by cryo-ET, and the kinds of biological insights that may be obtained, using eukaryotic parasites as case studies. Lower-resolution data (20-30 Å) provide structural information on organelles, whole-cells, and cell-cell interactions, while at the higher-resolution end, near-atomic structures can be resolved in situ using subtomogram averaging, typically for large, abundant particles such as ribosomes. Combined with orthogonal techniques, cryo-ET is a powerful tool for studying the structural cell biology of parasites.

PURPOSE/UNASSIGNED:The high mortality associated with metastatic colorectal cancer (mCRC) illuminates an unmet need for innovative therapeutic modalities. Radiopharmaceutical therapy (RPT) offers a potent, molecular-scale approach for managing and treating cancers with distant micrometastases. However, its clinical use in mCRC remains an unrealized opportunity. We have therefore identified the transmembrane glycoprotein mucin 13 (MUC13) as a promising antigen for developing a targeted RPT and have undertaken preclinical evaluation of its potential by utilizing a monoclonal antibody tool representative of a future class of translatable therapeutics. EXPERIMENTAL DESIGN/UNASSIGNED:The immunoreactivity and transcriptome of patients with colorectal cancer (n = 72 primary, 100 liver metastases) were characterized using annotated clinical datasets. Preclinical assessment of MUC13 as an RPT target for mCRC was then performed in mice using a monoclonal MUC13-targeted antibody C14 labeled with either zirconium-89 for positron emission tomography (PET) measurement of mCRC-associated MUC13 density or terbium-161 for targeted RPT. RESULTS/UNASSIGNED:Strong MUC13 immunoreactivity was observed in ∼70% of mCRC and was inversely correlated with overall survival (P < 0.01). MUC13 levels were visualized by PET and agreed with immunohistochemically determined antigen presence. Furthermore, MUC13-targeted RPT exhibited in vivo proof-of-concept efficacy and enhanced survival in preclinical colorectal cancer models. Resulting imaging, therapeutic, and pathologic analyses elucidated relationships between target density, therapeutic outcome, and a potential genetic signature. CONCLUSIONS/UNASSIGNED:MUC13-targeted RPT response was not only associated with radiopharmaceutical accumulation but also seemed to be balanced by DNA damage repair gene expression, suggesting a potential sensitivity signature that could complement a future clinical theranostic approach in MUC13-positive mCRC.

OBJECTIVES/OBJECTIVE:Propofol is used sparingly in pediatrics owing to the risk of propofol-related infusion syndrome (PRIS). The objective of this study is to evaluate the safety of propofol in pediatrics and describe its effectiveness at facilitating extubation and decreasing concomitant sedation. METHODS:This retrospective, descriptive study evaluated critically ill children who received continuous propofol infusions for at least 12 consecutive hours while admitted to pediatric, congenital cardiac, or neonatal intensive care units. The primary outcome was PRIS incidence. Secondary outcomes included change from baseline in laboratory parameters, discontinuation due to adverse effects, change in sedative requirements following sedation washout, and successful extubation. RESULTS:From January 1, 2019, to November 1, 2023, a total of 100 children received 120 courses of propofol infusions. The median infusion rate was 106 mcg/kg/min (IQR, 68-149) and 27.5% of courses exceeded 48 hours in duration. No PRIS events were identified. Patients experienced a moderate, non-duration-dependent increase in triglycerides, with no impact on aspartate aminotransferase (AST)/alanine aminotransferase (ALT) concentrations; 11.7% of infusions were discontinued for adverse effects. No children self-extubated while on propofol when used for peri-extubation (N = 49). Opioid and benzodiazepine requirements were decreased by 17% and 26% from baseline, respectively, during a 24-hour period following sedation washout (N = 26). CONCLUSIONS:Propofol was tolerated by most patients at doses commonly exceeding guideline-recommended maximum rate and duration. Propofol was safely used to facilitate extubation and decreased baseline sedative exposure when used for sedation washout in a complex critically ill pediatric population.